Michael J. Zeléfsky

Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, 8-10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3+4=7 and 4+3=7 are often considered the same prognostic group.To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data.Between 2005 and 2014, 20,845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions.Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores.In the surgery cohort, we found large differences in recurrence rates between both Gleason 3+4 versus 4+3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3+4, 4+3, 8, and 9-10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five-grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death.The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.

Three-dimensional conformal radiation therapy (3D-CRT) is a technique designed to deliver prescribed radiation doses to localized tumors with high precision, while effectively excluding the surrounding normal tissues. It facilitates tumor dose escalation which should overcome the relative resistance of tumor clonogens to conventional radiation dose levels. The present study was undertaken to test this hypothesis in patients with clinically localized prostate cancer.A total of 743 patients with clinically localized prostate cancer were treated with 3D-CRT. As part of a phase I study, the tumor target dose was increased from 64.8 to 81 Gy in increments of 5.4 Gy. Tumor response was evaluated by post-treatment decrease of serum prostate-specific antigen (PSA) to levels of < or = 1.0 ng/ml and by sextant prostate biopsies performed > or = 2.5 years after completion of 3D-CRT. PSA relapse-free survival was used to evaluate long-term outcome. The median follow-up was 3 years (range: 1-7.6 years).Induction of an initial clinical response was dose-dependent, with 90% of patients receiving 75.6 or 81.0 Gy achieving a PSA nadir < or = 1.0 ng compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy, respectively (p < 0.001). The 5-year actuarial PSA relapse-free survival for patients with favorable prognostic indicators (stage T1-2, pretreatment PSA < or = 10.0 ng/ml and Gleason score < or = 6) was 85%, compared to 65% for those with intermediate prognosis (one of the prognostic indicators with a higher value) and 35% for the group with unfavorable prognosis (two or more indicators with higher values) (p < 0.001). PSA relapse-free survival was significantly improved in patients with intermediate and unfavorable prognosis receiving > or = 75.6 Gy (p < 0.05). A positive biopsy at > or = 2.5 years after 3D-CRT was observed in only 1/15 (7%) of patients receiving 81.0 Gy, compared with 12/25 (48%) after 75.6 Gy, 19/42 (45%) after 70.2 Gy, and 13/23 (57%) after 64.8 Gy (p < 0.05).The data provide evidence for a significant effect of dose escalation on the response of human prostate cancer to irradiation and defines new standards for curative radiotherapy in this disease.

An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence.Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients.The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69.Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.

To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT).Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6-60 months).Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of >/= late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of >/= late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively.These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 Sep 2001HIGH DOSE RADIATION DELIVERED BY INTENSITY MODULATED CONFORMAL RADIOTHERAPY IMPROVES THE OUTCOME OF LOCALIZED PROSTATE CANCERis corrected byOUTCOME OF LOCALIZED PROSTATE CANCER MICHAEL J. ZELEFSKY, ZVI FUKS, MARGIE HUNT, HENRY J. LEE, DANNA LOMBARDI, CLIFTON C. LING, VICTOR E. REUTER, E.S. VENKATRAMAN, and STEVEN A. LEIBEL MICHAEL J. ZELEFSKYMICHAEL J. ZELEFSKY , ZVI FUKSZVI FUKS , MARGIE HUNTMARGIE HUNT , HENRY J. LEEHENRY J. LEE , DANNA LOMBARDIDANNA LOMBARDI , CLIFTON C. LINGCLIFTON C. LING , VICTOR E. REUTERVICTOR E. REUTER , E.S. VENKATRAMANE.S. VENKATRAMAN , and STEVEN A. LEIBELSTEVEN A. LEIBEL View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)65855-7AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We present the long-term outcome and tolerance of 3-dimensional (D) conformal and intensity modulated radiation therapy for localized prostate cancer. Materials and Methods: Between October 1988 and December 1998, 1,100 patients with clinical stages T1c-T3 prostate cancer were treated with 3-D conformal or intensity modulated radiation therapy. Patients were categorized into prognostic risk groups based on pretreatment prostate specific antigen (PSA), Gleason score and clinical stage. Sextant biopsies were performed 2.5 years or greater after treatment to assess local control. PSA relapse was defined according to the consensus guidelines of the American Society for Therapeutic Radiation Oncology. Late toxicity was classified according to the Radiation Therapy Oncology Group morbidity grading scale. Median followup was 60 months. Results: At 5 years the PSA relapse-free survival rate in patients at favorable, intermediate and unfavorable risk was 85% (95% confidence interval [CI] ± 4), 58% (95% CI ± 6) and 38% (95% CI ± 6), respectively (p <0.001). Radiation dose was the most powerful variable impacting PSA relapse-free survival in each prognostic risk group. The 5-year actuarial PSA relapse-free survival rate for patients at favorable risk who received 64.8 to 70.2 Gy. was 77% (95% CI ± 8) compared to 90% (95% CI ± 8) for those treated with 75.6 to 86.4 Gy. (p = 0.05). The corresponding rates were 50% (95% CI ± 8) versus 70% (95% CI ± 6) in intermediate risk cases (p = 0.001), and 21% (95% CI ± 8) versus 47% (95% CI ± 6) in unfavorable risk cases (p = 0.002). Only 4 of 41 patients (10%) who received 81 Gy. had a positive biopsy 2.5 years or greater after treatment compared with 27 of 119 (23%) after 75.6, 23 of 68 (34%) after 70.2 and 13 of 24 (54%) after 64.8 Gy. The incidence of toxicity after 3-D conformal radiation therapy was dose dependent. The 5-year actuarial rate of grade 2 rectal toxicity in patients who received 75.6 Gy. or greater was 14% (95% CI ± 2) compared with 5% (95% CI ± 2) in those treated at lower dose levels (p <0.001). Treatment with intensity modulated radiation therapy significantly decreased the incidence of late grade 2 rectal toxicity since the 3-year actuarial incidence in 189 cases managed by 81 Gy. was 2% (95% CI ± 2) compared with 14% (95% CI ± 2) in 61 managed by the same dose of 3-D conformal radiation therapy (p = 0.005). The 5-year actuarial rate of grade 2 urinary toxicity in patients who received 75.6 Gy. or greater 3-D conformal radiation therapy was 13% compared with 4% in those treated up to lower doses (p <0.001). Intensity modulated radiation therapy did not affect the incidence of urinary toxicity. Conclusions: Sophisticated conformal radiotherapy techniques with high dose 3-D conformal and intensity modulated radiation therapy improve the biochemical outcome in patients with favorable, intermediate and unfavorable risk prostate cancer. Intensity modulated radiation therapy is associated with minimal rectal and bladder toxicity, and, hence, represents the treatment delivery approach with the most favorable risk-to-benefit ratio. References 1 : Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA1999; 281: 1598. Google Scholar 2 : The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. 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Google Scholar From the Departments of Radiation Oncology, Medical Physics, Pathology and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York© 2001 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited ByMahal B, O'Leary M and Nguyen P (2018) Hydrogel Spacing for Radiotherapy of Prostate Cancer: A Review of the LiteratureUrology Practice, VOL. 1, NO. 2, (79-85), Online publication date: 1-Jul-2014.Stone N, Stone M, Rosenstein B, Unger P and Stock R (2018) Influence of Pretreatment and Treatment Factors on Intermediate to Long-Term Outcome After Prostate BrachytherapyJournal of Urology, VOL. 185, NO. 2, (495-500), Online publication date: 1-Feb-2011.Kapoor D, Zimberg S, Ohrin L, Underwood W and Olsson C (2018) Utilization Trends in Prostate Cancer TherapyJournal of Urology, VOL. 186, NO. 3, (860-864), Online publication date: 1-Sep-2011.Stone N, Stock R, White I and Unger P (2018) Patterns of Local Failure Following Prostate BrachytherapyJournal of Urology, VOL. 177, NO. 5, (1759-1764), Online publication date: 1-May-2007.Zelefsky M, Chan H, Hunt M, Yamada Y, Shippy A and Amols H (2018) Long-Term Outcome of High Dose Intensity Modulated Radiation Therapy for Patients With Clinically Localized Prostate CancerJournal of Urology, VOL. 176, NO. 4, (1415-1419), Online publication date: 1-Oct-2006.TOUMA N, IZAWA J and CHIN J (2018) CURRENT STATUS OF LOCAL SALVAGE THERAPIES FOLLOWING RADIATION FAILURE FOR PROSTATE CANCERJournal of Urology, VOL. 173, NO. 2, (373-379), Online publication date: 1-Feb-2005.ZIETMAN A, CHUNG C, COEN J and SHIPLEY W (2018) 10-Year Outcome for Men With Localized Prostate Cancer Treated With External Radiation Therapy:: Results of a Cohort StudyJournal of Urology, VOL. 171, NO. 1, (210-214), Online publication date: 1-Jan-2004.POLLACK A, HANLON A, HORWITZ E, FEIGENBERG S, UZZO R and HANKS G (2018) Prostate Cancer Radiotherapy Dose Response: An Update of the Fox Chase ExperienceJournal of Urology, VOL. 171, NO. 3, (1132-1136), Online publication date: 1-Mar-2004.KOH H, KATTAN M, SCARDINO P, SUYAMA K, MARU N, SLAWIN K, WHEELER T and OHORI M (2018) A Nomogram to Predict Seminal Vesicle Invasion by the Extent and Location of Cancer in Systematic Biopsy ResultsJournal of Urology, VOL. 170, NO. 4 Part 1, (1203-1208), Online publication date: 1-Oct-2003.ZELEFSKY M, MARION C, FUKS Z and LEIBEL S (2018) Improved Biochemical Disease-Free Survival of Men Younger Than 60 Years With Prostate Cancer Treated With High Dose Conformal External Beam RadiotherapyJournal of Urology, VOL. 170, NO. 5, (1828-1832), Online publication date: 1-Nov-2003.Related articlesJournal of UrologyNov 9, 2018, 11:31:10 AMOUTCOME OF LOCALIZED PROSTATE CANCER Volume 166Issue 3September 2001Page: 876-881 Advertisement Copyright & Permissions© 2001 by American Urological Association, Inc.Keywordsradiation dosageprostatic neoplasmsradiotherapy, conformalriskprostateMetricsAuthor Information MICHAEL J. ZELEFSKY More articles by this author ZVI FUKS More articles by this author MARGIE HUNT More articles by this author HENRY J. LEE More articles by this author DANNA LOMBARDI More articles by this author CLIFTON C. LING More articles by this author VICTOR E. REUTER More articles by this author E.S. VENKATRAMAN More articles by this author STEVEN A. LEIBEL More articles by this author Expand All Advertisement PDF DownloadLoading ...

To report the incidence and predictors of treatment-related toxicity at 10 years after three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for localized prostate cancer.Between 1988 and 2000, 1571 patients with stages T1-T3 prostate cancer were treated with 3D-CRT/IMRT with doses ranging from 66 to 81 Gy. The median follow-up was 10 years. Posttreatment toxicities were all graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events.The actuarial likelihood at 10 years for the development of Grade>or=2 GI toxicities was 9%. The use of IMRT significantly reduced the risk of gastrointestinal (GI) toxicities compared with patients treated with conventional 3D-CRT (13% to 5%; p<0.001). Among patients who experienced acute symptoms the 10-year incidence of late toxicity was 42%, compared with 9% for those who did not experience acute symptoms (p<0.0001). The 10-year incidence of late Grade>or=2 genitourinary (GU) toxicity was 15%. Patients treated with 81 Gy (IMRT) had a 20% incidence of GU symptoms at 10 years, compared with a 12% for patient treated to lower doses (p=0.01). Among patients who had developed acute symptoms during treatment, the incidence of late toxicity at 10 years was 35%, compared with 12% (p<0.001). The incidence of Grade 3 GI and GU toxicities was 1% and 3%, respectively.Serious late toxicity was unusual despite the delivery of high radiation dose levels in these patients. Higher doses were associated with increased GI and GU Grade 2 toxicities, but the risk of proctitis was significantly reduced with IMRT. Acute symptoms were a precursor of late toxicities in these patients.

To compare acute and late toxicities of high-dose radiation for prostate cancer delivered by either conventional three-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT).Between September 1992 and February 1998, 61 patients with clinical stage T1c- T3 prostate cancer were treated with 3D-CRT and 171 with IMRT to a prescribed dose of 81 Gy. To quantitatively evaluate the differences between conventional 3D-CRT and IMRT, 20 randomly selected patients were planned concomitantly by both techniques and the resulting treatment plans were compared. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group toxicity scale.Compared with conventional 3D-CRT, IMRT improved the coverage of the clinical target volume (CTV) by the prescription dose and reduced the volumes of the rectal and bladder walls carried to high dose levels (P<0.01), indicating improved conformality with IMRT. Acute and late urinary toxicities were not significantly different for the two methods. However, the combined rates of acute grade 1 and 2 rectal toxicities and the risk of late grade 2 rectal bleeding were significantly lower in the IMRT patients. The 2-year actuarial risk of grade 2 bleeding was 2% for IMRT and 10% for conventional 3D-CRT (P<0.001).The data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.

Most advice currently available with regard to fluoroscopic skin reactions is based on a table published in 1994. Many caveats in that report were not included in later reproductions, and subsequent research has yielded additional insights. This review is a consensus report of current scientific data. Expected skin reactions for an average patient are presented in tabular form as a function of peak skin dose and time after irradiation. The text and table indicate the variability of reactions in different patients. Images of injuries to skin and underlying tissues in patients and animals are provided and are categorized according to the National Cancer Institute skin toxicity scale, offering a basis for describing cutaneous radiation reactions in interventional fluoroscopy and quantifying their clinical severity. For a single procedure performed in most individuals, noticeable skin changes are observed approximately 1 month after a peak skin dose exceeding several grays. The degree of injury to skin and subcutaneous tissue increases with dose. Specialized wound care may be needed when irradiation exceeds 10 Gy. Residual effects from radiation therapy and from previous procedures influence the response of skin and subcutaneous tissues to subsequent procedures. Skin irradiated to a dose higher than 3-5 Gy often looks normal but reacts abnormally when irradiation is repeated. If the same area of skin is likely to be exposed to levels higher than a few grays, the effects of previous irradiation should be included when estimating the expected tissue reaction from the additional procedure.

To report tumor control and toxicity for patients treated with image-guided intensity-modulated radiotherapy (RT) for spinal metastases with high-dose single-fraction RT.A total of 103 consecutive spinal metastases in 93 patients without high-grade epidural spinal cord compression were treated with image-guided intensity-modulated RT to doses of 18-24 Gy (median, 24 Gy) in a single fraction between 2003 and 2006. The spinal cord dose was limited to a 14-Gy maximal dose. The patients were prospectively examined every 3-4 months with clinical assessment and cross-sectional imaging.The overall actuarial local control rate was 90% (local failure developed in 7 patients) at a median follow-up of 15 months (range, 2-45 months). The median time to local failure was 9 months (range, 2-15 months) from the time of treatment. Of the 93 patients, 37 died. The median overall survival was 15 months. In all cases, death was from progression of systemic disease and not local failure. The histologic type was not a statistically significant predictor of survival or local control. The radiation dose was a significant predictor of local control (p = 0.03). All patients without local failure also reported durable symptom palliation. Acute toxicity was mild (Grade 1-2). No case of radiculopathy or myelopathy has developed.High-dose, single-fraction image-guided intensity-modulated RT is a noninvasive intervention that appears to be safe and very effective palliation for patients with spinal metastases, with minimal negative effects on quality of life and a high probability of tumor control.

To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and identify predictors of improved disease-free survival.Eleven institutions combined data on 2,693 patients treated with permanent interstitial BT monotherapy for T1-T2 prostate cancer. Of these patients, 1,831 (68%) were treated with I-125 (median dose, 144 Gy) and 862 (32%) were treated with Pd-103 (median dose, 130 Gy). Criteria for inclusion were: available pre-BT PSA, BT > or =5 years before data submission, BT between 1988-1998, and no androgen deprivation before failure. The median follow-up was 63 months.Among patients where the I-125 dose to 90% of the prostate (D90) was > or =130 Gy, the 8-year PSA relapse-free survival (PRFS) was 93% compared with 76% for those with lower D90 dose levels (p < 0.001). A multivariable analysis identified tumor stage (p = 0.002), Gleason score (p < 0.001), pretreatment PSA level (p < 0.001), treatment year (p = 0.001), and the isotope used (p = 0.004) as pretreatment and treatment variables associated with PRFS. When restricted to patients with available postimplantation dosimetric information, D90 emerged as a significant predictor of biochemical outcome (p = 0.01), and isotope was not significant. The 8-year PRFS was 92%, 86%, 79%, and 67%, respectively, for patients with PSA nadir values of 0-0.49, 0.5-0.99, 1.0-1.99, and >2.0 ng/mL (p < 0.001). Among patients free of biochemical relapse at 8 years, the median nadir level was 0.1 ng/mL, and 90% of these patients achieved a nadir PSA level <0.6 ng/mL.Outcome after permanent BT for prostatic cancer relates to tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < or =0.5 ng/mL was particularly associated with durable long-term PSA disease-free survival. The only controllable factor to impact on long-term outcome was the D90 which is a reflection of implant quality.

To compare toxicity profiles and biochemical tumor control outcomes between patients treated with high-dose image-guided radiotherapy (IGRT) and high-dose intensity-modulated radiotherapy (IMRT) for clinically localized prostate cancer.Between 2008 and 2009, 186 patients with prostate cancer were treated with IGRT to a dose of 86.4 Gy with daily correction of the target position based on kilovoltage imaging of implanted prostatic fiducial markers. This group of patients was retrospectively compared with a similar cohort of 190 patients who were treated between 2006 and 2007 with IMRT to the same prescription dose without, however, implanted fiducial markers in place (non-IGRT). The median follow-up time was 2.8 years (range, 2-6 years).A significant reduction in late urinary toxicity was observed for IGRT patients compared with the non-IGRT patients. The 3-year likelihood of grade 2 and higher urinary toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (p = 0.02). Multivariate analysis identifying predictors for grade 2 or higher late urinary toxicity demonstrated that, in addition to the baseline Internatinoal Prostate Symptom Score, IGRT was associated with significantly less late urinary toxicity compared with non-IGRT. The incidence of grade 2 and higher rectal toxicity was low for both treatment groups (1.0% and 1.6%, respectively; p = 0.81). No differences in prostate-specific antigen relapse-free survival outcomes were observed for low- and intermediate-risk patients when treated with IGRT and non-IGRT. For high-risk patients, a significant improvement was observed at 3 years for patients treated with IGRT compared with non-IGRT.IGRT is associated with an improvement in biochemical tumor control among high-risk patients and a lower rate of late urinary toxicity compared with high-dose IMRT. These data suggest that, for definitive radiotherapy, the placement of fiducial markers and daily tracking of target positioning may represent the preferred mode of external-beam radiotherapy delivery for the treatment of prostate cancer.

No AccessJournal of UrologyAdult urology1 Oct 2006Long-Term Outcome of High Dose Intensity Modulated Radiation Therapy for Patients With Clinically Localized Prostate Cancer Michael J. Zelefsky, Heather Chan, Margie Hunt, Yoshiya Yamada, Alison M. Shippy, and Howard Amols Michael J. ZelefskyMichael J. Zelefsky Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author , Heather ChanHeather Chan Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author , Margie HuntMargie Hunt Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author , Yoshiya YamadaYoshiya Yamada Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Financial interest and/or other relationship with Varian Medical. More articles by this author , Alison M. ShippyAlison M. Shippy Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author , and Howard AmolsHoward Amols Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2006.06.002AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We report on the long-term results and late toxicity outcomes of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. Materials and Methods: Between 1996 and 2000 a total of 561 patients with clinically localized prostate cancer were treated with intensity modulated radiation therapy. All patients were treated to a dose of 81 Gy prescribed to the planning target volume. Prostate specific antigen relapse was defined according to the American Society for Therapeutic Radiology and Oncology consensus and Houston definitions (absolute nadir plus 2 ng/ml dated at the call). Median followup was 7 years (range 5 to 9). Results: The 8-year actuarial PSA relapse-free survival rates for patients in favorable, intermediate and unfavorable risk groups according to the American Society for Therapeutic Radiology and Oncology definition were 85%, 76% and 72%, respectively (p <0.025). The 8-year actuarial prostate specific antigen relapse-free survival rates for patients in favorable, intermediate and unfavorable risk groups according to the Houston definition were 89%, 78% and 67%, respectively (p = 0.0004). The 8-year actuarial likelihood of grade 2 rectal bleeding was 1.6%. Three patients (0.1%) experienced grade 3 rectal toxicity requiring either 1 or more transfusions or a laser cauterization procedure. No grade 4 rectal complications have been observed. The 8-year likelihood of late grade 2 and 3 (urethral strictures) urinary toxicities were 9% and 3%, respectively. Among patients who were potent before intensity modulated radiation therapy, erectile dysfunction developed in 49%. The cause specific survival outcomes for favorable, intermediate and unfavorable risk cases were 100%, 96% and 84%, respectively. Conclusions: These long-term results confirm our previous observations regarding the safety of high dose intensity modulated radiation therapy for clinically localized prostate cancer. Despite the application of high radiation doses, the incidence of rectal bleeding at 8 years was less than 2%. Despite the increased conformality of the dose distribution associated with intensity modulated radiation therapy, excellent long-term tumor control outcomes were achieved. References 1 : Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys2002; 53: 1097. Google Scholar 2 : Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate. JAMA2005; 294: 1233. Google Scholar 3 : High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol2001; 166: 876. Link, Google Scholar 4 : Intensity modulated radiotherapy as primary treatment for prostate cancer: acute toxicity in 114 patients. Int J Radiat Oncol Biol Phys2004; 60: 777. Google Scholar 5 : Dose escalation for localized prostate cancer: substantial benefit observed with 3D conformal therapy. 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Google Scholar 11 : Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys2000; 48: 635. Google Scholar 12 : Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys2001; 49: 685. Google Scholar 13 : Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radioth Oncol2000; 55: 241. Google Scholar 14 : Planning, delivery, and quality assurance of intensity-modulated radiotherapy using dynamic multileaf collimator: a strategy for large-scale implementation for the treatment of carcinoma of the prostate. Int J Radiat Oncol Biol Phys1997; 39: 863. Google Scholar 15 : Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys1997; 37: 1035. 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Google Scholar © 2006 by American Urological AssociationFiguresReferencesRelatedDetailsCited byTurchan W, Cutright D, Wu T, Leng J, Dignam J, Eggener S and Liauw S (2022) Hematuria following Post-Prostatectomy Radiotherapy: Incidence Increases with Long-Term FollowupJournal of Urology, VOL. 207, NO. 6, (1236-1245), Online publication date: 1-Jun-2022.Zelefsky M, Goldman D, Reuter V, Kollmeier M, McBride S, Zhang Z, Varghese M, Pei X and Fuks Z (2019) Long-Term Implications of a Positive Posttreatment Biopsy in Patients Treated with External Beam Radiotherapy for Clinically Localized Prostate CancerJournal of Urology, VOL. 201, NO. 6, (1127-1133), Online publication date: 1-Jun-2019.Griebling T (2016) Re: Clinical Outcomes of Helical Tomotherapy for Super-Elderly Patients with Localized and Locally Advanced Prostate Cancer: Comparison with Patients under 80 Years of AgeJournal of Urology, VOL. 196, NO. 1, (107-107), Online publication date: 1-Jul-2016.Zumsteg Z, Spratt D, Romesser P, Pei X, Zhang Z, Kollmeier M, McBride S, Yamada Y and Zelefsky M (2015) Anatomical Patterns of Recurrence Following Biochemical Relapse in the Dose Escalation Era of External Beam Radiotherapy for Prostate CancerJournal of Urology, VOL. 194, NO. 6, (1624-1630), Online publication date: 1-Dec-2015.Khanna A, Hu J, Gu X, Nguyen P, Lipsitz S and Palapattu G (2012) Certificate of Need Programs, Intensity Modulated Radiation Therapy Use and the Cost of Prostate Cancer CareJournal of Urology, VOL. 189, NO. 1, (75-79), Online publication date: 1-Jan-2013.Elliott S, Adejoro O, Konety B, Jarosek S, Dusenbery K and Virnig B (2012) Intensity Modulated Radiation Therapy Replaces 3-Dimensional Conformal Radiotherapy as Prostate Cancer TreatmentJournal of Urology, VOL. 187, NO. 4, (1253-1258), Online publication date: 1-Apr-2012.Kapoor D, Zimberg S, Ohrin L, Underwood W and Olsson C (2011) Utilization Trends in Prostate Cancer TherapyJournal of Urology, VOL. 186, NO. 3, (860-864), Online publication date: 1-Sep-2011. Volume 176Issue 4October 2006Page: 1415-1419 Advertisement Copyright & Permissions© 2006 by American Urological AssociationKeywordsprostatic neoplasmsintensity-modulatedradiotherapytoxicityMetricsAuthor Information Michael J. Zelefsky Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author Heather Chan Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author Margie Hunt Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author Yoshiya Yamada Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Financial interest and/or other relationship with Varian Medical. More articles by this author Alison M. Shippy Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author Howard Amols Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York Nothing to disclose. More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining. Significance: We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer. Cancer Discov; 3(11); 1245–53. ©2013 AACR. See related commentary by Bartek et al., p. 1222 This article is highlighted in the In This Issue feature, p. 1207

What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long‐term follow‐up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non‐uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long‐term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000–2010. Over 18 000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow‐up of 5 years; stratification into low‐, intermediate‐ and high‐risk groups; clinical and pathological staging; accepted standard definitions for prostate‐specific antigen failure; minimum patient number of 100 in each risk group (50 for high‐risk group). A statistical analysis (standard deviational ellipse) of the study outcomes suggested that, in terms of biochemical‐free progression, brachytherapy provides superior outcome in patients with low‐risk disease. For intermediate‐risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high‐risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone or EBRT. It is anticipated that the study will assist physicians and patients in selecting treatment for men with newly diagnosed prostate cancer.

Purpose To provide updated American Brachytherapy Society (ABS) guidelines for transrectal ultrasound-guided transperineal interstitial permanent prostate brachytherapy (PPB). Methods and Materials The ABS formed a committee of brachytherapists and researchers experienced in the clinical practice of PPB to formulate updated guidelines for this technique. Sources of input for these guidelines included prior published guidelines, clinical trials, published literature, and experience of the committee. The recommendations of the committee were reviewed and approved by the Board of Directors of the ABS. Results Patients with high probability of organ-confined disease or limited extraprostatic extension are considered appropriate candidates for PPB monotherapy. Low-risk patients may be treated with PPB alone without the need for supplemental external beam radiotherapy. High-risk patients should receive supplemental external beam radiotherapy if PPB is used. Intermediate-risk patients should be considered on an individual case basis. Intermediate-risk patients with favorable features may appropriately be treated with PPB monotherapy but results from confirmatory clinical trials are pending. Computed tomography–based postimplant dosimetry performed within 60 days of the implant is considered essential for maintenance of a satisfactory quality assurance program. Postimplant computed tomography–magnetic resonance image fusion is viewed as useful, but not mandatory. Conclusions Updated guidelines for patient selection, workup, treatment, postimplant dosimetry, and followup are provided. These recommendations are intended to be advisory in nature with the ultimate responsibility for the care of the patients resting with the treating physicians.

We previously demonstrated that intensity-modulated radiation therapy (IMRT) significantly improves radiation dose distribution over three-dimensional planning for nasopharynx cancer and reported positive early clinical results. We now evaluate whether IMRT has resulted in improved outcomes for a larger cohort of patients with longer follow-up.Since 1998, all 74 patients with newly diagnosed, nonmetastatic nasopharynx cancer were treated with IMRT using accelerated fractionation to 70 Gy; 59 received a hyperfractionated concomitant boost, and more recently 15 received once-daily treatment with dose painting. With the exception of Stage I disease (n = 5) and patient preference (n = 1), 69 patients received concurrent and adjuvant platinum-based chemotherapy similar to that in the Intergroup 0099 trial.median age 45; 32% Asian; 72% male; 65% World Health Organization III; 6% Stage I, 16% Stage II, 30% Stage III, 47% Stage IV. Median follow-up is 35 months. The 3-year actuarial rate of local control is 91%, and regional control is 93%; freedom from distant metastases, progression-free survival, and overall survival at 3 years are 78%, 67%, and 83%, respectively. There was 100% local control for Stage T1/T2 disease, compared to 83% for T3/T4 disease (p = 0.01). Six patients failed at the primary site, with median time to local tumor progression 16 months; 5 were exclusively within the 70 Gy volume, and 1 was both within and outside the target volume. There is a trend for improved local control with IMRT when compared to local control of 79% for 35 patients treated before 1998 with three-dimensional planning and chemotherapy (p = 0.11). Six months posttherapy, 21%, 13%, 15%, and 0% of patients with follow-up audiograms (n = 24 patients) had Grade 1, 2, 3, and 4 sensorineural hearing loss, respectively. For patients with >1 year follow-up (n = 59), rates of long-term xerostomia were as follows: 26% none, 42% Grade 1, 32% Grade 2, and zero Grade 3.The pattern of primary site failure within the target volume suggests locally advanced T stage disease may require a higher biologic dose to gross tumor. Rates of severe (Grade 3-4) ototoxicity and xerostomia are low with IMRT as a result of normal-tissue protection. Distant metastases are now the dominant form of failure, emphasizing the need for improved systemic therapy.

Abstract Answer questions and earn CME/CNE Prostate cancer survivors approach 2.8 million in number and represent 1 in 5 of all cancer survivors in the United States. While guidelines exist for timely treatment and surveillance for recurrent disease, there is limited availability of guidelines that facilitate the provision of posttreatment clinical follow‐up care to address the myriad of long‐term and late effects that survivors may face. Based on recommendations set forth by a National Cancer Survivorship Resource Center expert panel, the American Cancer Society developed clinical follow‐up care guidelines to facilitate the provision of posttreatment care by primary care clinicians. These guidelines were developed using a combined approach of evidence synthesis and expert consensus. Existing guidelines for health promotion, surveillance, and screening for second primary cancers were referenced when available. To promote comprehensive follow‐up care and optimal health and quality of life for the posttreatment survivor, the guidelines address health promotion, surveillance for prostate cancer recurrence, screening for second primary cancers, long‐term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and nononcology specialists. A key challenge to the development of these guidelines was the limited availability of published evidence for management of prostate cancer survivors after treatment. Much of the evidence relies on studies with small sample sizes and retrospective analyses of facility‐specific and population databases. CA Cancer J Clin 2014;64:225–249. © 2014 American Cancer Society .

The management of intermediate-risk prostate cancer (PCa) is controversial, in part due to the heterogeneous nature of patients falling within this classification. We propose a new risk stratification system for intermediate-risk PCa to aid in prognosis and therapeutic decision making. Between 1992 and 2007, 1024 patients with National Comprehensive Cancer Network intermediate-risk PCa and complete biopsy information were treated with definitive external-beam radiation therapy (EBRT) utilizing doses ≥81 Gy. Unfavorable intermediate-risk (UIR) PCa was defined as any intermediate-risk patient with a primary Gleason pattern of 4, percentage of positive biopsy cores (PPBC) ≥50%, or multiple intermediate-risk factors (IRFs; cT2b–c, prostate-specific antigen [PSA] 10–20, or Gleason score 7). All patients received EBRT with ≥81 Gy with or without neoadjuvant and concurrent androgen-deprivation therapy (ADT). Univariate and multivariate analyses were performed using a Cox proportional hazards model for PSA recurrence-free survival (PSA-RFS) and distant metastasis (DM). PCa-specific mortality (PCSM) was analyzed using a competing-risk method. Median follow-up was 71 mo. Primary Gleason pattern 4 (hazard ratio [HR]: 3.26; p < 0.0001), PPBC ≥50% (HR: 2.72; p = 0.0007), and multiple IRFs (HR: 2.20; p = 0.008) all were significant predictors of increased DM in multivariate analyses. Primary Gleason pattern 4 (HR: 5.23; p < 0.0001) and PPBC ≥50% (HR: 4.08; p = 0.002) but not multiple IRFs (HR: 1.74; p = 0.21) independently predicted for increased PCSM. Patients with UIR disease had inferior PSA-RFS (HR: 2.37; p < 0.0001), DM (HR: 4.34; p = 0.0003), and PCSM (HR: 7.39; p = 0.007) compared with those with favorable intermediate-risk disease, despite being more likely to receive neoadjuvant ADT. Short follow-up and retrospective study design are the primary limitations. Intermediate-risk PCa is a heterogeneous collection of diseases that can be separated into favorable and unfavorable subsets. These groups likely will benefit from divergent therapeutic paradigms.

To define the indications for elective neck treatment, the cases of 474 previously untreated patients were reviewed who had locally confined major salivary gland cancers treated between 1939 and 1982, Clinically positive nodes were present in 14% (67 of 474). Overall, clinically occult, pathologically positive nodes occurred in 12% (47 of 407). By univariate analysis, several factors appeared to predict the risk of occult metastases; however, multivariate analysis revealed that only size and grade were significant risk factors. Tumors 4 cm or more in size had a 20% (32 of 164) risk of occult metastases compared with a 4% (nine of 220) risk for smaller tumors [P < 0.00001). High-grade tumors (regardless of histologic type) had a 49% (29 of 59) risk of occult metastases compared with a 7% (15 of 221) risk for intermediate-grade or low-grade tumors [P < 0.00001). In view of the low frequency of occult metastases in the entire group, routine elective treatment of the neck is not recommended. High-grade tumors and larger tumors have a high rate of occult neck metastases, and treatment should be considered in this group.

Based on contemporary epidemiological and pathological characteristics of prostate cancer we explain the rationale for and concerns about focal therapy for low risk prostate cancer, review potential methods of delivery and propose study design parameters.Articles regarding the epidemiology, diagnosis, imaging, treatment and pathology of localized prostate cancer were reviewed with a particular emphasis on technologies applicable for focal therapy, defined as targeted ablation of a limited area of the prostate expected to contain the dominant or only focus of cancer. A consensus summary was constructed by a multidisciplinary international task force of prostate cancer experts, forming the basis of the current review.In regions with a high prevalence of prostate specific antigen screening the over detection and subsequent overtreatment of prostate cancer is common. The incidence of unifocal cancers in radical prostatectomy specimens is 13% to 38%. In many others there is an index lesion with secondary foci containing pathological features similar to those found incidentally at autopsy. Because biopsy strategies and imaging techniques can provide more precise tumor localization and characterization, there is growing interest in focal therapy targeting unifocal or biologically unifocal tumors. The major arguments against focal therapy are multifocality, limited accuracy of staging, the unpredictable aggressiveness of secondary foci and the lack of established technology for focal ablation. Emerging technologies with the potential for focal therapy include high intensity focused ultrasound, cryotherapy, radio frequency ablation and photodynamic therapy.Early detection of prostate cancer has led to concerns that while many cancers now diagnosed pose too little a threat for radical therapy, many men are reluctant to accept watchful waiting or active surveillance. Several emerging technologies seem capable of focal destruction of prostate tissue with minimal morbidity. We encourage the investigation of focal therapy in select men with low risk prostate cancer in prospective clinical trials that carefully document safety, functional outcomes and cancer control.

Purpose To report prostate-specific antigen (PSA) relapse-free survival and distant metastases–free survival (DMFS) outcomes for patients with clinically localized prostate cancer treated with high-dose conformal radiotherapy. Methods and Materials Between 1988 and 2004, a total of 2,047 patients with clinically localized prostate cancer were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Prescribed dose levels ranged from 66–86.4 Gy. Median follow-up was 6.6 years (range, 3–18 years). Results Although no differences were noted among low-risk patients for the various dose groups, significant improvements were observed with higher doses for patients with intermediate- and high-risk features. In patients with intermediate-risk features, multivariate analysis showed that radiation dose was an important predictor for improved PSA relapse-free survival (p < 0.0001) and improved DMFS (p = 0.04). In patients with high-risk features, multivariate analysis showed that the following variables predict for improved PSA relapse-free survival: dose (p < 0.0001); age (p = 0.0005), and neoadjuvant-concurrent androgen deprivation therapy (ADT; p = 0.01). In this risk group, only higher radiation dose was an important predictor for improved DMFS (p = 0.04). Conclusions High radiation dose levels were associated with improved biochemical tumor control and decreased risk of distant metastases. For high-risk patients, despite the delivery of high radiation dose levels, the use of ADT conferred an additional benefit for improved tumor control outcomes. We observed a benefit for ADT in high-risk patients who received higher doses. To report prostate-specific antigen (PSA) relapse-free survival and distant metastases–free survival (DMFS) outcomes for patients with clinically localized prostate cancer treated with high-dose conformal radiotherapy. Between 1988 and 2004, a total of 2,047 patients with clinically localized prostate cancer were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Prescribed dose levels ranged from 66–86.4 Gy. Median follow-up was 6.6 years (range, 3–18 years). Although no differences were noted among low-risk patients for the various dose groups, significant improvements were observed with higher doses for patients with intermediate- and high-risk features. In patients with intermediate-risk features, multivariate analysis showed that radiation dose was an important predictor for improved PSA relapse-free survival (p < 0.0001) and improved DMFS (p = 0.04). In patients with high-risk features, multivariate analysis showed that the following variables predict for improved PSA relapse-free survival: dose (p < 0.0001); age (p = 0.0005), and neoadjuvant-concurrent androgen deprivation therapy (ADT; p = 0.01). In this risk group, only higher radiation dose was an important predictor for improved DMFS (p = 0.04). High radiation dose levels were associated with improved biochemical tumor control and decreased risk of distant metastases. For high-risk patients, despite the delivery of high radiation dose levels, the use of ADT conferred an additional benefit for improved tumor control outcomes. We observed a benefit for ADT in high-risk patients who received higher doses.

Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. Cetuximab has activity in squamous cell carcinoma and enhances both chemotherapy and radiotherapy. We conducted a pilot phase II study of a new combined-modality paradigm of targeted therapy (cetuximab) with chemoradiotherapy.Eligible patients had stage III or IV, M0, squamous cell head and neck cancer. Treatment included concomitant boost radiotherapy (1.8 Gy/d weeks 1 to 6; boost: 1.6 Gy 4 to 6 hours later weeks 5 to 6; 70 Gy total to gross disease), cisplatin (100 mg/m2 intravenously weeks 1 and 4), and cetuximab (400 mg/m2 intravenously week 1, followed by 250 mg/m2 weeks 2 to 10).Twenty-two patients were enrolled (median age, 57 years; range, 41 to 72 years; median Karnofsky status, 90%; range, 70% to 90%; oropharynx primary tumor, 59% of patients; T4, 36%; N2/3, 77%; stage IV disease, 86%). One patient did not receive study treatment because of an ineligible diagnosis. The severity of expected, acute toxicities was typical of concurrent cisplatin and radiotherapy alone. Grade 3 or 4 cetuximab-related toxicities included acne-like rash (10%) and hypersensitivity (5%). However, the study was closed for significant adverse events, including two deaths (one pneumonia and one unknown cause), one myocardial infarction, one bacteremia, and one atrial fibrillation. With a median follow-up of 52 months, the 3-year overall survival rate is 76%, the 3-year progression-free survival rate is 56%, and the 3-year locoregional control rate is 71%.This regimen is not currently recommended outside of the clinical trial setting. Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.

We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center.Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (> or = 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate-specific antigen level, biopsy Gleason score, and year of treatment.The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P < .001). Results were similar for prostate cancer-specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression).Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer-specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy.

To determine whether prostate cancer local recurrence after radiation therapy (RT) occurs at the site of primary tumor by retrospectively comparing the tumor location on pre-RT and post-RT magnetic resonance imaging (MRI) and using step-section pathology after salvage radical prostatectomy (SRP) as the reference standard.Nine patients with localized prostate cancer were treated with intensity modulated RT (69-86.4 Gy), and had pre-RT and post-RT prostate MRI, biopsy-proven local recurrence, and SRP. The location and volume of lesions on pre-RT and post-RT MRI were correlated with step-section pathology findings. Tumor foci >0.2 cm(3) and/or resulting in extraprostatic disease on pathology were considered clinically significant.All nine significant tumor foci (one in each patient; volume range, 0.22-8.63 cm(3)) were detected both on pre-RT and post-RT MRI and displayed strikingly similar appearances on pre-RT and post-RT MRI and step-section pathology. Two clinically insignificant tumor foci (</=0.06 cm(3)) were not detected on imaging. The ratios between tumor volumes on pathology and on post-RT MRI ranged from 0.52 to 2.80.Our study provides a direct visual confirmation that clinically significant post-RT local recurrence occurs at the site of primary tumor. Our results are in agreement with reported clinical and pathologic results and support the current practice of boosting the radiation dose within the primary tumor using imaging guidance. They also suggest that monitoring of primary tumor with pre-RT and post-RT MRI could lead to early detection of local recurrence amenable to salvage treatment.

To report toxicity and preliminary biochemical outcomes with high-dose intensity-modulated radiation therapy (IMRT) to a dose of 86.4 Gy for localized prostate cancer.Between August 1997 and March 2004, 478 patients were treated with 86.4 Gy using a 5- to 7-field IMRT technique. To adhere to normal tissue constraints, the mean D95 and V100 for the planning target volume were 83 Gy and 87%, respectively. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse was calculated. The median follow-up was 53 months.Thirty-seven patients (8%) experienced acute Grade 2 gastrointestinal (GI) toxicity. There was no acute Grade 3 or 4 GI toxicity. One hundred and five patients (22%) experienced acute Grade 2 genitourinary (GU) toxicity and three patients (0.6%) had Grade 3 GU toxicity. There was no acute Grade 4 GU toxicity. Sixteen patients (3%) developed late Grade 2 GI toxicity and two patients (<1%) developed late Grade 3 GI toxicity. Sixty patients (13%) had late Grade 2 GU toxicity and 12 (<3%) experienced late Grade 3 GU toxicity. The 5-year actuarial PSA relapse-free survival according to the nadir plus 2 ng/mL definition was 98%, 85% and 70% for the low, intermediate, and high risk NCCN prognostic groups.This report represents the largest data set of patients treated to ultra-high radiation dose levels of 86.4 Gy using IMRT for localized prostate cancer. Our findings indicate that this treatment is well tolerated and the early excellent biochemical control rates are encouraging.

Abstract Purpose: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined. Experimental Design: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models. Results: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score ≥7) tumors (85% versus 57%; P = 0.0002) compared with non–BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer–specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers. Conclusions: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer. Clin Cancer Res; 16(7); 2115–21. ©2010 AACR.

To report long-term survival and toxicity outcomes with the use of high-dose intensity modulated radiation therapy (IMRT) to 86.4 Gy for patients with localized prostate cancer.Between August 1997 and December 2008, 1002 patients were treated to a dose of 86.4 Gy using a 5-7 field IMRT technique. Patients were stratified by prognostic risk group based on National Comprehensive Cancer Network risk classification criteria. A total of 587 patients (59%) were treated with neoadjuvant and concurrent androgen deprivation therapy. The median follow-up for the entire cohort was 5.5 years (range, 1-14 years).For low-, intermediate-, and high-risk groups, 7-year biochemical relapse-free survival outcomes were 98.8%, 85.6%, and 67.9%, respectively (P<.001), and distant metastasis-free survival rates were 99.4%, 94.1%, and 82.0% (P<.001), respectively. On multivariate analysis, T stage (P<.001), Gleason score (P<.001), and >50% of initial biopsy positive core (P=.001) were predictive for distant mestastases. No prostate cancer-related deaths were observed in the low-risk group. The 7-year prostate cancer-specific mortality (PCSM) rates, using competing risk analysis for intermediate- and high-risk groups, were 3.3% and 8.1%, respectively (P=.008). On multivariate analysis, Gleason score (P=.004), percentage of biopsy core positivity (P=.003), and T-stage (P=.033) were predictive for PCSM. Actuarial 7-year grade 2 or higher late gastrointestinal and genitourinary toxicities were 4.4% and 21.1%, respectively. Late grade 3 gastrointestinal and genitourinary toxicity was experienced by 7 patients (0.7%) and 22 patients (2.2%), respectively. Of the 427 men with full potency at baseline, 317 men (74%) retained sexual function at time of last follow-up.This study represents the largest cohort of patients treated with high-dose radiation to 86.4 Gy, using IMRT for localized prostate cancer, with the longest follow-up to date. Our findings indicate that this treatment results in excellent clinical outcomes with acceptable toxicity.

Purpose To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Patients and Methods Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18–24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20–30 Gy. The median follow-up was 12 months (range, 1–48). Results The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a high single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). Conclusion High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking. To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18–24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20–30 Gy. The median follow-up was 12 months (range, 1–48). The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a high single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.

Depending on the pathologic tumour stage, up to 60% of prostate cancer patients who undergo radical prostatectomy will develop biochemical relapse and require further local treatment.We reviewed the results of early salvage radiation therapy (RT), defined as prostate-specific antigen (PSA) values prior to RT ≤ 0.5 ng/ml in the setting of lymph node-negative disease.Ten retrospective studies, including one multicentre analysis, were used for this analysis. Among them, we received previously unpublished patient characteristics and updated outcome data from five retrospective single-centre trials to perform a subgroup analysis for early salvage RT.Patients treated with early salvage RT have a significantly improved biochemical recurrence-free survival (BRFS) rate compared with those receiving salvage RT initiated after PSA values are >0.5 ng/ml. Similarly, within the cohort of patients with pre-RT PSA values <0.5 ng/ml, improved BRFS rates were noted among those with lower rather higher pre-RT PSA levels. It is possible that higher RT dose levels and the use of adjunctive androgen-deprivation therapy improve biochemical control outcomes in the salvage setting.Based on a literature review, improved 5-yr BRFS rates are observed for patients who receive early salvage RT compared with patients treated with salvage RT with a pre-RT PSA value >0.5 ng/ml. Whether the routine application of early salvage RT in patients with initially undetectable PSA levels will be associated with demonstrable clinical benefit awaits the results of ongoing prospective trials.

OBJECTIVE An analysis of factors contributing to durable radiographic control of spinal metastases was undertaken, drawing from a large single-institution database in an attempt to elucidate indications and dose requirements for successful treatment. METHODS All patients treated at a single institution with stereotactic radiosurgery (SRS) of the spine as first-line therapy were assessed for local progression of the treated site, defined as radiographic enlargement of the treated tumor and/or biopsy-proven evidence of active tumor cells. All patients were followed with CT, PET, or MR imaging every 3–6 months until death. Treatment decisions were made by a multidisciplinary team of radiation oncologists, neurosurgeons, and neuroradiologists. Target volumes were defined according to the international consensus guidelines and were reviewed in a multidisciplinary conference. Image-guided techniques and intensity modulation were used for every case. The tumor's histological type, gross tumor volume (GTV), dose that covers 95% of the GTV (GTV D95), percentage of GTV covered by 95% of the prescribed dose (GTV V95), planning target volume (PTV), dose that covers 95% of the PTV (PTV D95), and percentage of PTV covered by 95% of the prescribed dose (PTV V95) were analyzed for significance in relation to local control, based on time to local progression. RESULTS A total of 811 lesions were treated in 657 patients between 2003 and 2015 at a single institution. The mean follow-up and overall survival for the entire cohort was 26.9 months (range 2–141 months). A total of 28 lesions progressed and the mean time to failure was 26 months (range 9.7–57 months). The median prescribed dose was 2400 cGy (range 1600–2600 cGy). Both GTV D95 and PTV D95 were highly significantly associated with local failure in univariate analysis, but GTV and PTV and histological type did not reach statistical significance. The median GTV D95 for the cohort equal to or above the GTV D95 1830 cGy cut point (high dose) was 2356 cGy, and it was 1709 cGy for the cohort of patients who received less than 1830 cGy (low dose). In terms of PTV D95, the median dose for those equal to or above the cut point of 1740 cGy (high dose) was 2233 cGy, versus 1644 cGy for those lesions below the PTV D95 cut point of 1740 cGy (low dose). CONCLUSIONS High-dose single-session SRS provides durable long-term control, regardless of the histological findings or tumor size. In this analysis, the only significant factors predictive of local control were related to the actual dose of radiation given. Although the target volumes were well treated with the intended dose, those lesions irradiated to higher doses (median GTV D95 2356 cGy, minimum 1830 cGy) had a significantly higher probability of durable local control than those treated with lower doses (median PTV D95 2232 cGy, minimum of 1740 cGy) (p &lt; 0.001). Patients in the high-dose cohort had a 2% cumulative rate of local failure. Histological findings were not associated with local failure, suggesting that radioresistant histological types benefit in particular from radiosurgery. For patients with a favorable prognosis, a higher dose of SRS is important for long-term outcomes.

The management of biochemical failure (BF) following external beam radiotherapy (EBRT) for prostate cancer is controversial, due to both the heterogeneous disease course following a BF and a lack of clinical trials in this setting. We sought to characterize the natural history and predictors of outcome for patients experiencing BF in a large cohort of men with localized prostate cancer undergoing definitive dose-escalated EBRT. This retrospective analysis included 2694 patients with localized prostate cancer treated with EBRT at a large academic center. Of these, 609 experienced BF, defined as prostate-specific antigen (PSA) nadir + 2 ng/ml. The median follow-up was 83 mo for all patients and 122 mo for BF patients. All patients received EBRT at doses of 75.6–86.4 Gy. The primary objective of this study was to determine predictors of distant progression at the time of BF. Cox proportional hazards models were used in univariate and multivariate analyses of distant metastases (DM), and a competing risks method was used to analyze prostate cancer–specific mortality (PCSM). From the date of BF, the median times to DM and PCSM mortality were 5.4 yr and 10.5 yr, respectively. Shorter posttreatment PSA doubling time, a higher initial clinical tumor stage, a higher pretreatment Gleason score, and a shorter interval from the end of radiotherapy to BF were independent predictors for clinical progression following BF. Patients with two of these risk factors had a significantly higher incidence of DM and PCSM following BF than those with zero or one risk factor. The main limitations of this study are its retrospective nature and heterogeneous salvage interventions. Clinical and pathologic factors can help identify patients at high risk of clinical progression following BF. In this report, we look at predictors of outcome for patients with prostate cancer recurrence, as determined by prostate-specific antigen (PSA) levels, following radiation treatment. We found that the approximate median times to distant metastasis and death from prostate cancer for patients in this situation were 5 yr and 10 yr, respectively. Furthermore, we found that patients with a rapid increase in PSA levels following treatment, a short time to PSA recurrence, invasion of extraprostatic organs, or a high Gleason score had worse outcomes.

Late rectal bleeding is a potentially dose limiting complication of three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. The frequency of late rectal bleeding has been shown to increase as the prescription dose rises above 70 Gy. The purpose of this study is to identify features of the cumulative dose-volume histogram (DVH) for the rectal wall that correlate with late rectal bleeding after 3D-CRT for prostate cancer.Follow-up information on rectal bleeding is available for 261 and 315 patients treated using 3D-CRT at Memorial Sloan-Kettering Cancer Center for Stage T1c-T3 prostate cancer with minimum target doses of 70.2 and 75.6 Gy, respectively. All patients in this study were treated with a coplanar 6-field technique (2 lateral and 4 oblique fields). Patients were classified as having rectal bleeding if they bled (> or = Grade 2) before 30 months, and nonbleeding (< or = Grade 1) if they were without bleeding at 30 months, using the RTOG morbidity scale. Rectal bleeding was observed in 13 and 38 of the patients treated at 70.2 and 75.6 Gy, respectively. Treatment plans were analyzed for 39 nonbleeding and 13 bleeding patients receiving 70.2 Gy, and 83 nonbleeding and 36 bleeding patients receiving 75.6 Gy. Dose-volume histograms (DVHs) for the anatomic rectal wall were calculated. Average DVHs of the bleeding and nonbleeding patients were generated, and a permutation test was used to assess the significance of differences between them, for each dose group. The confounding effect of total rectal wall volume (V(RW)) was removed by calculating the average differences in DVHs between all combinations of bleeding and nonbleeding patients with similar V(RW)s. Finally, multivariate analysis using logistic regression was performed to test the significance of the DVH variables in the presence of anatomic, geometric, and medical variables previously found to correlate with rectal bleeding in a companion analysis of the same patients.The area under the average percent volume DVH for the rectal wall of patients with bleeding was significantly higher than those of patients without bleeding in both dose groups (p = 0.02, 70.2 Gy; p < 0.0001, 75.6 Gy). However, small V(RW)s were associated with rectal bleeding (p = 0.06, 70.2 Gy; p < 0.01, 75.6 Gy), resulting in an increase in average percent volumes exposed to all doses for patients with rectal bleeding. For patients with similar V(RW)s, rectal bleeding was significantly correlated with the volumes exposed to 46 Gy in both dose groups (p = 0.02, 70.2 Gy; p = 0.005, 75.6 Gy, tolerance in V(RW): 5 ccs). For the 75.6 Gy dose group, the percent volume receiving 77 Gy was significantly correlated with rectal bleeding (p < 0.005). Bivariate analysis using logistic regression, including V(RW) together with a single DVH variable, showed good agreement with the above analysis. Multivariate analysis revealed a borderline significant correlation of the percent volume receiving 71 Gy in the 70.2 Gy dose group. It also showed that the DVH variables were highly correlated with geometric and dosimetric variables previously found to correlate with rectal bleeding in multivariate analysis.Significant volume effects were found in the probability of late rectal bleeding for patients undergoing 3D-CRT for prostate cancer with prescription doses of 70.2 and 75.6 Gy. The percent volumes exposed to 71 and 77 Gy in the 70.2 and 75.6 Gy dose groups respectively were significantly correlated with rectal bleeding. The independent correlation of small V(RW) with rectal bleeding may indicate the existence of a functional reserve for the rectum. The independent association with larger percent volumes exposed to intermediate doses ( approximately 46 Gy) seen in both dose groups may indicate that a large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.

BACKGROUND The current study was undertaken to evaluate the incidence and predictors of late toxicity in patients with localized prostate carcinoma treated with high dose three-dimensional conformal radiotherapy (3D-CRT). METHODS A total of 743 patients with prostate carcinoma classified as T1c–T3 were treated with 3D-CRT that targeted the prostate and seminal vesicles. A minimum tumor dose of 64.8 gray (Gy) was given to 96 patients (13%), 70.2 Gy to 266 patients (365), 75.6 Gy to 320 patients (43%), and 81.0 Gy to 61 patients (8%). The median follow-up time was 42 months (range, 18–109 months). Late toxicity was graded according to the Radiation Therapy Oncology Group morbidity scoring scale. RESULTS Late gastrointestinal (GI) and urinary (GU) toxicities were absent or minimal (Grade 0 or 1) in 90% of patients. The 5-year actuarial likelihood of the development of Grade 2 and 3 late GI toxicities was 11% and 0.75%, respectively. A multivariate analysis identified doses ≥75.6 Gy (P < 0.001), history of diabetes mellitus (P = 0.01), and the presence of acute GI symptoms during treatment (P = 0.02) as independent predictors of Grade ≥2 late GI toxicity. The 5-year actuarial likelihood of the development of Grade 2 and 3 late GU toxicities was 10% and 3%, respectively. Doses ≥75.6 Gy (P = 0.008) and acute GU symptoms (P < 0.001) were independent predictors of Grade ≥2 late GU toxicity. Among 544 patients who were potent before treatment (73% of all patients), 211 (39%) became impotent after 3D-CRT. The 5-year actuarial risk of potency loss was 60%. Doses ≥75.6 Gy (P < 0.001) and the use of neoadjuvant androgen deprivation (P = 0.01) were independent predictors of posttreatment erectile dysfunction. CONCLUSIONS The incidence of severe late complications after high dose 3D-CRT was minimal. Radiation doses ≥75.6 Gy and the presence of acute treatment-related symptoms during 3D-CRT correlated with a higher incidence of Grade ≥2 late GI and GU toxicities. In addition to higher doses, the use of androgen deprivation therapy increased the likelihood of permanent impotence in these patients. Intensity-modulated radiotherapy, which makes it possible to enhance the conformality of the dose distribution, has recently been implemented in an attempt to reduce the incidence of moderate grade toxicities in patients receiving high dose 3D-CRT. Cancer 1999;85:2460–8. © 1999 American Cancer Society.

PURPOSE: To compare the prostate-specific antigen (PSA) relapse-free survival outcome and incidence of late toxicity for patients with early-stage prostate cancer treated at a single institution with either three-dimensional conformal radiotherapy (3D-CRT) or transperineal permanent implantation (TPI) with iodine-125 seeds. MATERIALS AND METHODS: Patients with favorable-risk prostate cancer, defined as a pretreatment PSA of less than or equal to 10.0 ng/mL, Gleason score of 6 or lower, and stage less than or equal to T2b, were selected for this analysis. Between 1989 and 1996, 137 such patients were treated with 3D-CRT and 145 with TPI. The median ages of the 3D-CRT and TPI groups were 68 years and 64 years, respectively. The median dose of 3D-CRT was 70.2 Gy, and the median implant dose was 150 Gy. Prostate-specific antigen relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was graded according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up times for the 3D-CRT and TPI groups were 36 and 24 months, respectively. RESULTS: Eleven patients (8%) in the 3D-CRT group and 12 patients (8%) in the TPI group developed a biochemical relapse. The 5-year PSA relapse-free survival rates for the 3D-CRT and the TPI groups were 88% and 82%, respectively (P = .09). Protracted grade 2 urinary symptoms were more prevalent among patients treated with TPI compared with 3D-CRT. Grade 2 urinary toxicity, which was manifest after the implant and persisted for more than 1 year after this procedure, was observed in 45 patients (31%) in the TPI group. In these 45 patients, the median duration of grade 2 urinary symptoms was 23 months (range, 12 to 70 months). On the other hand, acute grade 2 urinary symptoms resolved within 4 to 6 weeks after completion of 3D-CRT, and the 5-year actuarial likelihood of late grade 2 urinary toxicity for the 3D-CRT group was only 8%. The 5-year actuarial likelihood of developing a urethral stricture (grade 3 urinary toxicity) for the 3D-CRT and TPI groups was 2% and 12%, respectively (P &lt; .0002). Of 45 patients who developed grade 2 or higher urinary toxicity after TPI, the likelihood of resolution or significant improvement of these symptoms at 36 months from onset was 59%. The 5-year likelihood of grade 2 late rectal toxicity for the 3D-CRT and TPI patients was similar (6% and 11%, respectively; P = .97). No patient in either group developed grade 3 or higher late rectal toxicity. The 5-year likelihood of posttreatment erectile dysfunction among patients who were initially potent before therapy was 43% for the 3D-CRT group and 53% for the TPI group (P = .52). CONCLUSION: Both 3D-CRT and TPI are associated with an excellent PSA outcome for patients with early-stage prostate cancer. Urinary toxicities are more prevalent for the TPI group and subsequently resolve or improve in most patients. In addition to evaluating long-term follow-up, future comparisons will require detailed quality-of-life assessments to further determine the impact of these toxicities on the overall well-being and quality of life of the individual patient.

Several studies have defined risk groups for predicting the outcome after external-beam radiotherapy of localized prostate cancer. However, most models formed patient risk groups, and none of these models considers radiation dose as a predictor variable. The purpose of this study was to develop a nomogram to improve the accuracy of predicting outcome after three-dimensional conformal radiotherapy.This study was a retrospective, nonrandomized analysis of patients treated at the Memorial Sloan-Kettering Cancer Center between 1988 and 1998. Clinical parameters of the 1,042 patients included stage, biopsy Gleason score, pretreatment serum prostate-specific antigen (PSA) level, whether neoadjuvant androgen deprivation therapy was administered, and the radiation dose delivered. Biochemical (PSA) treatment failure was scored when three consecutive rises of serum PSA occurred. A nomogram, which predicts the probability of remaining free from biochemical recurrence for 5 years, was validated internally on this data set using a bootstrapping method and externally using a cohort of patients treated at the Cleveland Clinic, Cleveland, OH.When predicting outcomes for patients in the validation data set from the Cleveland Clinic, the nomogram had a Somers' D rank correlation between predicted and observed failure times of 0.52. Predictions from this nomogram were more accurate (P<.0001) than the best of seven published risk stratification systems, which achieved a Somers' D coefficient of 0.47.The development process illustrated here produced a nomogram that seems to predict more accurately than other available systems and may be useful for treatment selection by both physicians and patients.

The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis.Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy-13 patients, 75. 6 Gy-36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy-39 patients, 75.6 Gy-83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables.A dose response for >/= Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with >/= Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p < 0.02), and 2) smaller anatomically defined rectal wall volume (p < 0.05). After 75.6 Gy, the following factors were significant: 1) smaller anatomically defined rectal wall volume (p < 0.01), 2) higher rectal D(max) (p < 0.01), 3) enclosure of rectal contour by Iso50 (p < 0.01), 4) patient age (p = 0.02), and 5) history of diabetes mellitus (p = 0.04). In addition to these five factors, acute rectal toxicity was also significantly correlated (p = 0.05) with late rectal bleeding when patients from both dose groups were combined in multivariate analysis.A multivariate logistic regression model is presented which describes the probability of developing late rectal bleeding after conformal irradiation of prostate cancer. Late rectal bleeding correlated with factors which may indicate that a greater fractional volume of rectal wall was exposed to high dose, such as smaller rectal wall volume, inclusion of the rectum within the 50% isodose on the isocenter slice, and higher rectal D(max).

To implement intensity-modulated radiation therapy (IMRT) for primary nasopharynx cancer and to compare this technique with conventional treatment methods.Between May 1998 and June 2000, 23 patients with primary nasopharynx cancer were treated with IMRT delivered with dynamic multileaf collimation. Treatments were designed using an inverse planning algorithm, which accepts dose and dose-volume constraints for targets and normal structures. The IMRT plan was compared with a traditional plan consisting of phased lateral fields and a three-dimensional (3D) plan consisting of a combination of lateral fields and a 3D conformal plan.Mean planning target volume (PTV) dose increased from 67.9 Gy with the traditional plan, to 74.6 Gy and 77.3 Gy with the 3D and IMRT plans, respectively. PTV coverage improved in the parapharyngeal region, the skull base, and the medial aspects of the nodal volumes using IMRT and doses to all normal structures decreased compared to the other treatment approaches. Average maximum cord dose decreased from 49 Gy with the traditional plan, to 44 Gy with the 3D plan and 34.5 Gy with IMRT. With the IMRT plan, the volume of mandible and temporal lobes receiving more than 60 Gy decreased by 10-15% compared to the traditional and 3D plans. The mean parotid gland dose decreased with IMRT, although it was not low enough to preserve salivary function.Lower normal tissue doses and improved target coverage, primarily in the retropharynx, skull base, and nodal regions, were achieved using IMRT. IMRT could potentially improve locoregional control and toxicity at current dose levels or facilitate dose escalation to further enhance locoregional control.

To improve the local control of patients with adenocarcinoma of the prostate we have implemented intensity modulated radiation therapy (IMRT) to deliver a prescribed dose of 81 Gy. This method is based on inverse planning and the use of dynamic multileaf collimators (DMLC). Because IMRT is a new modality, a major emphasis was on the quality assurance of each component of the process and on patient safety. In this article we describe in detail our procedures and quality assurance program.Using an inverse algorithm, we have developed a treatment plan consisting five intensity-modulated (IM) photon fields that are delivered with DMLC. In the planning stage, the planner specifies the number of beams and their directions, and the desired doses for the target, the normal organs and the "overlap" regions. Then, the inverse algorithm designs intensity profiles that best meet the specified criteria. A second algorithm determines the leaf motion that would produce the designed intensity pattern and produces a DMLC file as input to the MLC control computer. Our quality assurance program for the planning and treatment delivery process includes the following components: 1) verification of the DMLC field boundary on localization port film, 2) verification that the leaf motion of the DMLC file produces the planned dose distribution (with an independent calculation), 3) comparison of dose distribution produced by DMLC in a flat phantom with that calculated by the treatment planning computer for the same experimental condition, 4) comparison of the planned leaf motions with that implemented for the treatment (as recorded on the MLC log files), 5) confirmation of the initial and final positions of the MLC for each field by a record-and-verify system, and 6) in vivo dose measurements.Using a five-field IMRT plan we have customized dose distribution to conform to and deliver 81 Gy to the PTV. In addition, in the overlap regions between the PTV and the rectum, and between the PTV and the bladder, the dose is kept within the tolerance of the respective organs. Our QA checks show acceptable agreement between the planned and the implemented leaf motions. Correspondingly, film and TLD dosimetry indicates that doses delivered agrees with the planned dose to within 2%. As of September 15, 1996, we have treated eight patients to 81 Gy with IMRT.For complex planning problems where the surrounding normal tissues place severe constraints on the prescription dose, IMRT provides a powerful and efficient solution. Given a comprehensive and rigorous quality-assurance program, the intensity-modulated fields can be efficaciously and accurately delivered using DMLC. IMRT treatment is now ready for routine implementation on a large scale in our clinic.

To report the long-term outcome for patients with Stage T1-T2 adenocarcinoma of the prostate definitively irradiated in the prostate-specific antigen (PSA) era.Nine institutions combined data on 4839 patients with Stage T1b, T1c, and T2 adenocarcinoma of the prostate who had a pretreatment PSA level and had received >or=60 Gy as definitive external beam radiotherapy. No patient had hormonal therapy before treatment failure. The median follow-up was 6.3 years. The end point for outcome analysis was PSA disease-free survival at 5 and 8 years after therapy using the American Society for Therapeutic Radiology and Oncology (ASTRO) failure definition.The PSA disease-free survival rate for the entire group of patients was 59% at 5 years and 53% at 8 years after treatment. For patients who had received >or=70 Gy, these percentages were 61% and 55%. Of the 4839 patients, 1582 had failure by the PSA criteria, 416 had local failure, and 329 had distant failure. The greatest risk of failure was at 1.5-3.5 years after treatment. The failure rate was 3.5-4.5% annually after 5 years, except in patients with Gleason score 8-10 tumors for whom it was 6%. In multivariate analysis for biochemical failure, pretreatment PSA, Gleason score, radiation dose, tumor stage, and treatment year were all significant prognostic factors. The length of follow-up and the effect of backdating as required by the ASTRO failure definition also significantly affected the outcome results. Dose effects were most significant in the intermediate-risk group and to a lesser degree in the high-risk group. No dose effect was seen at 70 or 72 Gy in the low-risk group.As follow-up lengthens and outcome data accumulate in the PSA era, we continue to evaluate the efficacy and durability of radiotherapy as definitive therapy for early-stage prostate cancer. Similar studies with higher doses and more contemporary techniques will be necessary to explore more fully the potential of this therapeutic modality.

To report the 5-year prostate-specific antigen (PSA) relapse-free survival outcome and incidence of long-term morbidity for patients with localized prostate cancer treated with CT-planned permanent I-125 prostate implantation using a transperineal technique (TPI).Between 1989-1996, 248 patients with clinically localized prostate cancer were treated with TPI. The median age was 65 years (range: 45-80 years). The clinical stage was T1c in 143 patients (58%), Stage T2a in 102 (41%), and T2b in 3 (1%). Thirty patients (12%) had Gleason scores <6, 158 patients (64%) had Gleason scores of 6, and 60 (24%) had scores >or =7. The median pretreatment PSA was 7 ng/mL (range: 1-58 ng/mL). The median prescribed implant dose was 150 Gy. Patients were characterized as having favorable risk disease if their pretreatment PSA level was < or =10.0 ng/mL and Gleason score < or = 6; those with one and two adverse prognostic features (PSA > 10 ng/mL and Gleason score >6) were classified as having intermediate and unfavorable risk disease, respectively. PSA relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was scored according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up was 48 months (range: 12-126 months).Thirty-eight patients (15%) developed a PSA relapse, and the overall 5-year PSA relapse-free survival (PRFS) rate was 71%. The 5-year PRFS rates for favorable-risk (n = 146), intermediate-risk (n = 85), and unfavorable-risk (n = 17) patients were 88%, 77%, and 38%, respectively (p < 0.0001). The 5-year PRFS rates among patients treated with a 2-month course of neoadjuvant androgen deprivation (NAAD) prior to TPI compared to patients treated with TPI only were 100% and 77%, respectively (p = 0.03). Multivariate analysis identified pretreatment PSA > 10 ng/mL and Gleason score >6 as independent predictors for biochemical relapse after TPI. The 5-year actuarial likelihood of late Grade 2 urinary toxicity was 41%. The 5-year likelihood of urethral stricture development was 10%, and the median time to stricture development was 18 months. One patient (0. 4%) in the early phase of this clinical experience developed a Grade 4 urethral complication. The actuarial incidence of late Grade 2 rectal bleeding was 9%. One patient (0.4%) developed a Grade 4 rectal complication.Especially for favorable risk disease, the 5-year biochemical outcome with this approach was excellent and appears to be comparable to other therapeutic interventions. Grade 2 urinary symptoms were common in these patients but gradually resolved in most. Improved treatment planning approaches that further constrain the urethral dose without compromising the target volume dose will likely decrease the incidence of Grade 2 and 3 urinary symptoms after TPI.

To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center.From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n = 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT).With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p < 0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p < 0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT.Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted.

Purpose: To determine the extent and predictors for prostatic motion in a large number of patients evaluated with multiple CT scans during radiotherapy, and evaluate the implications of these data on the design of appropriate treatment margins for patients receiving high-dose three-dimensional conformal radiotherapy. Materials and methods: Fifty patients underwent four serial computerized tomography (CT) scans, consisting of an initial planning scan and subsequent scans at the beginning, middle, and end of the treatment course. Each scan was performed with the patient in the prone treatment position within an immobilization device used during therapy. Contours of the prostate and seminal vesicles were drawn on the axial CT slices of each scan, and the scans were matched by alignment of the pelvic bones with a chamfer matching algorithm. Using the contour information, distributions of the displacement of the organ center of mass and organ border from the planning position were determined separately for the prostate and seminal vesicles in each of the three principle directions: anterior–posterior (AP), superior–inferior (SI) and left–right (LR). Each distribution was fitted to a normal (Gaussian) distribution to determine confidence limits in the center of mass and border displacements and thereby evaluate for the optimal margins needed to contain target motion. Results: The most common directions of displacement of the prostate center of mass (COM) were in the AP and SI directions and were significantly larger than any LR movement. The mean prostate COM displacement (±1 standard deviation, SD) for the entire population was −1.2±2.9 mm, −0.5±3.3 mm and −0.6±0.8 mm in the, AP and SI and LR directions respectively (negative values indicate posterior, inferior or left displacement). The mean (±1 SD) seminal vesicle COM displacement for the entire population was −1.4±4.9 mm, 1.3±5.5 mm and −0.8±3.1 mm in the AP and SI and LR directions, respectively. The data indicate a tendency for the population towards posterior displacements of the prostate from the planning position and both posterior and superior displacements of the seminal vesicles. AP movement of both the prostate and seminal vesicles were correlated with changes in rectal volume (P=0.0014 and <0.0001, respectively) more than with changes in bladder volume (P=0.030 for seminal vesicles and 0.19 for prostate). A logistic regression analysis identified the combination of rectal volume > 60 cm3 and bladder volumes > 40 cm3 as the only predictor of large (> 3 mm) systematic deviations for the prostate and seminal vesicles (P=0.05) defined for each patient as the difference between organ position in the planning scan and mean position as calculated from the three subsequent scans. Conclusions: Prostatic displacement during a course of radiotherapy is more pronounced among patients with initial planning scans with large rectal and bladder volumes. Such patients may require more generous margins around the CTV to assure its enclosure within the prescription dose region. Identification and correction of patients with large systematic errors will minimize the extent of the margin required and decrease the volume of normal tissue exposed to higher radiation doses.

To perform a retrospective analysis of patients with paranasal sinus (PNS) cancer treated with postoperative radiotherapy (RT) at Memorial Sloan-Kettering Cancer Center.Between January 1987 and July 2005, 85 patients with PNS and nasal cavity cancer underwent postoperative RT. Most patients had squamous cell carcinoma (49%; n = 42), T4 tumors (52%; n = 36), and the maxillary sinus (53%; n = 45) as the primary disease site. The median radiation dose was 63 Gy. Of the 85 patients, 76 underwent CT simulation and 53 were treated with either three-dimensional conformal RT (27%; n = 23) or intensity-modulated RT (35%; n = 30). Acute and late toxicities were scored according to the Radiation Therapy Oncology Group radiation morbidity scoring criteria.With a median follow-up for surviving patients of 60 months, the 5-year estimates of local progression-free, regional progression-free, distant metastasis-free, disease-free, and overall survival rates were 62%, 87%, 82%, 55%, and 67%, respectively. On multivariate analysis, squamous cell histology and cribriform plate involvement predicted for an increased likelihood of local recurrence, and squamous cell histologic features predicted for worse overall survival. None of the patients who underwent CT simulation and were treated with modern techniques developed a Grade 3-4 late complication of the eye.Complete surgical resection followed by adjuvant RT is an effective and safe approach in the treatment of PNS cancer. Emerging tools, such as three-dimensional conformal treatment and, in particular, intensity-modulated RT for PNS tumors, may minimize the occurrence of late complications associated with conventional RT techniques. Local recurrence remains a significant problem.

This study was conducted to evaluate quality of life in patients treated with primary radiotherapy (RT) for cancer of the base of tongue.From 1981 to 1990, 36 patients with primary squamous cell cancer of the base of tongue were managed with primary radiotherapy. Ages ranged from 35 to 71 years (median, 58 years), T Stage was: T1, n = 11; T2, n = 14; T3, n = 10; T4, n = 1. Thirty-one patients (86%) had palpable cervical lymph node metastases at initial examination (N1, n = 16; N2, n = 11; N3, n = 4). Patients received external beam RT to their primary site and necks, followed by a brachytherapy boost to the tongue. Those with neck nodes also had a neck dissection. The median follow-up is 5 years (minimum, 3 years). Actuarial 5-year local control was 85%; regional control was 96%; distant metastases-free survival was 87.5%; and overall survival, 85%. Twenty-nine of the 30 long-term survivors completed (1) Memorial Symptom Assessment Scale (MSAS), (2) Functional Assessment of Cancer Therapy (FACT), (3) Performance Status Scale for Head and Neck Cancer (PSS), and (4) a sociodemographic and economic questionnaire. At the time of cancer diagnosis, 62% were employed full-time, and 21% were employed part-time; 83% were earning > $20,000/year, and 59% were earning > $60,000/year.At follow-up, annual incomes were similar to those at initial examination. Of those who had been working full-time, 72% were still in full-time work, and of those who had been working part-time, 83% were still in part-time work. Average PSS scores were 90 for eating in public, 96 for understandability of speech, and 68 for normalcy of diet. On the MSAS, the following symptoms had prevalence: > 30% xerostomia, difficulty swallowing, decreased energy, pain, worrying, insomnia, cough, drowsy, change in taste, and irritability. Scores on the FACT exceeded published values collected for a mixed cancer population.The overwhelming majority of patients achieved excellent functional status and quality of life and could maintain their prediagnosis earning potential and employment status after primary radiation for advanced base of tongue cancer.

PURPOSE This report is a patterns-of-failure analysis of resected renal cell carcinoma (RCC) performed to determine the relative incidences of local failure (LF) and distant failure, to identify the pathologic features predicting for each using a multivariate analysis, and to assess the relative impact of each form of failure on overall survival (OS). In this way, the potential value of and selection of patients for adjuvant local and/or systemic therapy can be better evaluated. MATERIALS AND METHODS The records of 172 patients with unilateral, nonmetastatic RCC who were treated with definitive surgery between 1978 and 1988, and who had a minimum follow-up duration of 1 year, were identified through the Memorial Sloan-Kettering tumor registry. Distribution by stage included T1, 10 patients; T2, 102; T3a, 32; T3b, 27; and T4, one. The incidences of positive lymph nodes (LNs) and positive margins were 5.8% and 6.4%, respectively. RESULTS LF developed in only six patients, yielding a 7-year actuarial incidence of 5%. In this subset, four patients developed distant metastases (DM), three occurring concurrently with or before LF. DM developed in 30 patients, yielding a 7-year actuarial incidence of 26%. Among the variables that had an impact on the development of DM according to univariate log-rank tests, only positive LNs (P = .026) and renal vein extension (P = .001) remained as significant independent prognosticators. The overall 7-year actuarial survival rate was 80%. Eleven patients died of RCC during follow-up, nine of whom (82%) died of metastatic disease. CONCLUSION LF is rare following surgical management of RCC, and shows no clear causal relationship with the development of DM. Patients die of DM, and not LF. These data do not support the role of adjuvant radiation therapy in this disease. Patients with LN involvement or renal vein extension have a significantly increased risk for developing DM, and are therefore appropriate candidates for trials investigating systemic therapy.

To determine the etiology of treatment-induced erectile dysfunction among patients who underwent surgery or radiotherapy for prostatic cancer.Ninety-eight patients were evaluated for erectile dysfunction after definitive therapy for prostate cancer with Duplex ultrasonography before and after intracorporal prostaglandin injection. Patients were classified as having arteriogenic, cavernosal, mixed (arteriogenic/cavernosal), or neurogenic impotence based upon the results of the Duplex studies.Among patients who underwent radical prostatectomy (RP), 31 (52%) had cavernosal dysfunction, 19 (32%) had arteriogenic dysfunction, 3 (5%) were classified as mixed, and 7 (12%) as neurogenic dysfunction. Among patients treated with radiotherapy (RT), 24 (63%) had arteriogenic dysfunction, 12 (32%) had cavernosal dysfunction, 1 (2.5%) were classified as mixed, and 1 (2.5%) as neurogenic dysfunction. A multivariate analysis identified prior RT as the only predictor of an arteriogenic etiology (p < 0.001) and prior RP as the only predictor of a cavernosal etiology (p < 0.04) for erectile dysfunction among these patients. In the RP and RT groups, the median erectile responses were 70 and 65%, respectively. Arterial peak flows < 25 cc/min predicted for a suboptimal erectile response with intracavernosal prostaglandin injections. Among 47 patients with arterial peak flows < 25 cc/min, 21 (55%) had erectile responses of < 70%, while for 51 patients with arterial peak flows > or = 25 cc/min, 31 (39%) had erectile responses of < 70% (p < 0.039).While the etiology of erectile dysfunction after definitive therapy for prostatic cancer is likely a multifactorial phenomenon, these data suggest that the predominant etiology among patients who undergo RT is arteriogenic and among patients who undergo RP is veno-occlussive/cavernosal pathology. This information may have implications for the design of more effective therapies to address erectile dysfunction in this patient population.

The preplanned technique used for permanent prostate brachytherapy has limitations that may be overcome by intraoperative planning. The goal of the American Brachytherapy Society (ABS) project was to assess the current intraoperative planning process and explore the potential for improvement in intraoperative treatment planning (ITP).Members of the ABS with expertise in ITP performed a literature review, reviewed their clinical experience with ITP, and explored the potential for improving the technique.The ABS proposes the following terminology in regard to prostate planning process: *Preplanning--Creation of a plan a few days or weeks before the implant procedure. *Intraoperative planning--Treatment planning in the operating room (OR): the patient and transrectal ultrasound probe are not moved between the volume study and the seed insertion procedure. * Intraoperative preplanning--Creation of a plan in the OR just before the implant procedure, with immediate execution of the plan. *Interactive planning--Stepwise refinement of the treatment plan using computerized dose calculations derived from image-based needle position feedback. *Dynamic dose calculation--Constant updating of dose distribution calculations using continuous deposited seed position feedback. Both intraoperative preplanning and interactive planning are currently feasible and commercially available and may help to overcome many of the limitations of the preplanning technique. Dosimetric feedback based on imaged needle positions can be used to modify the ITP. However, the dynamic changes in prostate size and shape and in seed position that occur during the implant are not yet quantifiable with current technology, and ITP does not obviate the need for postimplant dosimetric analysis. The major current limitation of ITP is the inability to localize the seeds in relation to the prostate. Dynamic dose calculation can become a reality once these issues are solved. Future advances can be expected in methods of enhancing seed identification, in imaging techniques, and in the development of better source delivery systems. Additionally, ITP should be correlated with outcome studies, using dosimetric, toxicity, and efficacy endpoints.ITP addresses many of the limitations of current permanent prostate brachytherapy and has some advantages over the preplanned technique. Further technologic advancement will be needed to achieve dynamic real-time calculation of dose distribution from implanted sources, with constant updating to allow modification of subsequent seed placement and consistent, ideal dose distribution within the target volume.

Abstract BACKGROUND. The authors investigated long‐term tumor control and toxicity outcomes after high‐dose, intensity‐modulated radiation therapy (IMRT) in patients who had clinically localized prostate cancer. METHODS. Between April 1996 and January 1998, 170 patients received 81 gray (Gy) using a 5‐field IMRT technique. Patients were classified according to the National Comprehensive Cancer Network‐defined risk groups. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse, distant metastases, and cause‐specific survival outcomes were calculated. The median follow‐up was 99 months. RESULTS. The 10‐year actuarial prostate‐specific antigen relapse‐free survival rates were 81% for the low‐risk group, 78% for the intermediate‐risk group, and 62% for the high‐risk group; the 10‐year distant metastases–free rates were 100%, 94%, and 90%, respectively; and the 10‐year cause‐specific mortality rates were 0%, 3%, and 14%, respectively. The 10‐year likelihood of developing grade 2 and 3 late genitourinary toxicity was 11% and 5%, respectively; and the 10‐year likelihood of developing grade 2 and 3 late gastrointestinal toxicity was 2% and 1%, respectively. No grade 4 toxicities were observed. CONCLUSIONS. To the authors' knowledge, this report represents the longest followed cohort of patients who received high‐dose radiation levels of 81 Gy using IMRT for localized prostate cancer. The findings indicated that high‐dose IMRT is well tolerated and is associated with excellent long‐term tumor‐control outcomes in patients with localized prostate cancer Cancer 2011. © 2010 American Cancer Society.

Local failure is a major obstacle to the cure of locally advanced non small-cell lung cancer. Three-dimensional conformal radiation therapy (3-DCRT) selects optimal treatment parameters to increase dose to tumor and reduce normal tissue dose, potentially representing an enhancement of the therapeutic ratio of radiation therapy for lung cancer. We performed this analysis of 45 non-small cell lung cancer patients treated with 3-DCRT alone, to evaluate the ability of computer derived lung dose volume histograms to predict serious pulmonary toxicity, to assess the feasibility of this approach, and to examine the resulting survival.There were 28 males (62%) and 17 females (38%). The median age was 65 (range: 38-82). Tumor stage was Stage I/II in 13%, IIIa in 42%, and IIIb in 44%. The histology was squamous in 44%, adenocarcinoma in 36%, and other non-small cell histologies in the others. Only 47% of patients. had combined favorable prognostic factors (i.e. KPS < or = 80, and < or = 5% wt. loss). The median dose of radiation to gross disease was 70.2 Gy (range: 52.2-72 Gy) delivered in fractions of 1.8 Gy, 5 days per week.Seven patients did not complete 3-DCRT due to disease progression outside the port. Follow-up data are mature: the median follow up of the 6 survivors is 43.5 months (35-59). Thoracic progression occurred in 46%. Median survival (all 45 patients.) is 15.7 months and survival is 32% at 2 years and 12% at 59 months. Pulmonary toxicity > or = grade 3 occurred in 9% of patients. Dose volume histograms were available in 31 patients and showed a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or higher pulmonary toxicity occurred in 38% (3/8) of patients with > 30% of lung volume receiving > or = 25 Gy, versus 4% (1/23) of patients with < or = 30% lung receiving > or = 25 Gy (P = 0.04). Grade 3 or higher pulmonary toxicity occurred in 29% (4/14) of patients with a predicted pulmonary normal tissue complication probability of 12% or higher versus 0% (0/17) in patients with a predicted probability of less than 12% (P = 0.03).Despite adverse prognostic criteria median survival is encouraging and may be higher than some combined modality approaches. Dose volume histogram parameters may be useful to determine the maximum dose for individual patients and thereby permit avoidance of toxicity.

Purpose To develop an optimization method using volumetric modulated arc therapy (VMAT) and evaluate VMAT plans relative to the standard intensity-modulated radiotherapy (IMRT) approach in prostate cancer. Methods and Materials A single gantry rotation was modeled using 177 equispaced beams. Multileaf collimator apertures and dose rates were optimized with respect to gantry angle subject to dose-volume–based objectives. Our VMAT implementation used conjugate gradient descent to optimize dose rate, and stochastic sampling to find optimal multileaf collimator leaf positions. A treatment planning study of 11 prostate cancer patients with a prescription dose of 86.4 Gy was performed to compare VMAT with a standard five-field IMRT approach. Plan evaluation statistics included the percentage of planning target volume (PTV) receiving 95% of prescribed dose (V95), dose to 95% of PTV (D95), mean PTV dose, tumor control probability, and dosimetric endpoints of normal organs, whereas monitor unit (MU) and delivery time were used to assess delivery efficiency. Results Patient-averaged PTV V95, D95, mean dose, and tumor control probability in VMAT plans were 96%, 82.6 Gy, 88.5 Gy, and 0.920, respectively, vs. 97%, 84.0 Gy, 88.9 Gy, and 0.929 in IMRT plans. All critical structure dose requirements were met. The VMAT plans presented better rectal wall sparing, with a reduction of 1.5% in normal tissue complication probability. An advantage of VMAT plans was that the average number of MUs (290 MU) was less than for IMRT plans (642 MU). Conclusion The VMAT technique can reduce beam on time by up to 55% while maintaining dosimetric quality comparable to that of the standard IMRT approach. To develop an optimization method using volumetric modulated arc therapy (VMAT) and evaluate VMAT plans relative to the standard intensity-modulated radiotherapy (IMRT) approach in prostate cancer. A single gantry rotation was modeled using 177 equispaced beams. Multileaf collimator apertures and dose rates were optimized with respect to gantry angle subject to dose-volume–based objectives. Our VMAT implementation used conjugate gradient descent to optimize dose rate, and stochastic sampling to find optimal multileaf collimator leaf positions. A treatment planning study of 11 prostate cancer patients with a prescription dose of 86.4 Gy was performed to compare VMAT with a standard five-field IMRT approach. Plan evaluation statistics included the percentage of planning target volume (PTV) receiving 95% of prescribed dose (V95), dose to 95% of PTV (D95), mean PTV dose, tumor control probability, and dosimetric endpoints of normal organs, whereas monitor unit (MU) and delivery time were used to assess delivery efficiency. Patient-averaged PTV V95, D95, mean dose, and tumor control probability in VMAT plans were 96%, 82.6 Gy, 88.5 Gy, and 0.920, respectively, vs. 97%, 84.0 Gy, 88.9 Gy, and 0.929 in IMRT plans. All critical structure dose requirements were met. The VMAT plans presented better rectal wall sparing, with a reduction of 1.5% in normal tissue complication probability. An advantage of VMAT plans was that the average number of MUs (290 MU) was less than for IMRT plans (642 MU). The VMAT technique can reduce beam on time by up to 55% while maintaining dosimetric quality comparable to that of the standard IMRT approach.

To identify predictors of biochemical outcome following radiotherapy in patients with a rising prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer.One hundred fifteen patients with a rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy (3D-CRT) alone or with neoadjuvant androgen deprivation. Tumor-related and treatment-related factors were evaluated to identify predictors of subsequent PSA failure.The median follow-up time after 3D-CRT was 42 months. The 4-year actuarial PSA relapse-free survival, distant metastasis-free survival, and overall survival rates were 46%, 83%, and 95%, respectively. Multivariate analysis, which was limited to 70 patients receiving radiation without androgen deprivation therapy, showed that negative/close margins (P =.03), absence of extracapsular extension (P <.01), and presence of seminal vesicle invasion (P <.01) were independent predictors of PSA relapse after radiotherapy. Neoadjuvant androgen deprivation did not improve the 4-year PSA relapse-free survival in patients with positive margins, extracapsular extension, and no seminal vesicle invasion (P =.24). However, neoadjuvant androgen deprivation did improve PSA relapse-free survival when one or more of these variables were absent (P =.03).Salvage 3D-CRT can provide biochemical control in selected patients with a rising PSA after radical prostatectomy. Among patients with positive margins and no poor prognostic features, 77% achieved PSA control after salvage 3D-CRT. Salvage neoadjuvant androgen deprivation therapy may improve short-term biochemical control, but it requires further study.

To assess the merit of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after external beam radiotherapy for prostate cancer by testing alternative prostate-specific antigen (PSA) failure definitions against the "gold standard" of clinical failure and to study the effect of backdating the time of failure.Nine participating institutions agreed to submit follow-up results for all patients with clinically localized prostatic cancer (Stage T1b, T1c, T2, N0M0) treated between 1986 and 1995 by external beam radiotherapy only, to doses of >or=60 Gy, with no androgen deprivation before treatment. A total of 4839 men met the study criteria, with a median follow-up time of 6.3 years. The prediction of clinical failure by 102 definitions of biochemical failure was assessed using various quantitative measures.Four definitions were superior as measured by the sensitivity, specificity, positive and negative predictive values, and hazard of clinical failure after biochemical failure: two rises of at least 0.5 ng/mL backdated, PSA level at or greater than the absolute nadir plus 2 ng/mL at the call date, and PSA level at or greater than the current nadir plus 2 or 3 ng/mL at the call date. The absolute nadir was the lowest measured PSA level during all of follow-up, and the current nadir was the lowest PSA measured previous to a particular PSA measurement during follow-up. With the possible exception of patients in the low-risk group, the likelihood of ultimate clinical failure decreased as the time of biochemical failure increased. Failure definitions based on PSA levels >0.2 or 0.5 ng/mL were inferior to other definitions. Backdating the failure time introduced bias into the estimate of freedom from biochemical failure, which was increasingly overestimated at shorter median follow-up times. This bias can be circumvented either by using a failure definition based on the call date or by backdating the censoring times of patients with one or two rises who could potentially have failure at a future (unobserved) time. A short follow-up time as such does not result in bias unless the failures are backdated; in the absence of backdating, it is the precision of failure-free survival that is increasingly compromised as the follow-up time is reduced.The ASTRO failure definition ended the confusion resulting from different failure definitions that had been in use, and it did so accurately enough that it is probably not necessary to recalculate previously published results. Nevertheless, for the current pooled analysis of outcome in 4839 men with a 6.3-year median follow-up, other definitions of biochemical failure were superior as assessed by various quantitative measures of concordance of biochemical and ultimate clinical failure. An additional disadvantage of the ASTRO definition is the bias introduced by backdating failures, as well as the necessarily retrospective nature of its application. Some "current" definitions, but not those based on the PSA level rising above a fixed threshold, have significantly higher sensitivity and specificity, do not lead to biased estimations of biochemical disease-free survival, and are directly applicable during patient counseling. These are all issues that would play a role in replacing the ASTRO consensus definition.

This study describes and quantitates the motion, i.e., variation in position, of the prostate within the pelvis and its effect on target and normal organ dose.The motion of the planning target volume (PTV) borders and center of mass was studied in 13 patients with carcinoma of the prostate through the use of superimposed serial computerized tomography (CT) scans. Changes in bladder and rectal volumes were measured and their relationship to displacements of the PTV position were noted. The effects of this motion on target and normal organ doses were measured.A variability in the position of the PTV is seen over time, which is related to changes in bladder and rectal volumes. The one standard deviation displacements of the PTV center of mass with respect to the planning scan center of mass position were 0.12, 0.40, and 0.31 cm in the lateral, anterior-posterior, and superior-inferior directions, respectively. Movement was significantly larger in the superior part of the PTV above the base of the bladder than in the inferior part. Movement of the borders of the PTV outward from the patient axis; hence, toward the edges of the treatment field, was also examined. Outward displacements of the anterior target border below the base of the bladder were less than 0.3 cm in 90% of the cases, and 1.4 cm above the bladder base. For the posterior wall these displacements were less than 0.7 cm and 1.1 cm, respectively, whereas the lateral border displacements were less than 0.3 cm throughout (90% confidence limits). These displacements would cause a median of 6% of the PTV to receive less than 95% of the planned dose for any given treatment day in these patients; the effect on rectal and bladder wall doses was greater and true doses may not be measurable through the use of only one treatment planning CT scan.The prostate is not a static organ, but rather has some limited motion in the pelvis secondary to bladder and rectal volume changes. This motion has been quantified for a group of patients, and may provide a guide to further studies on the placement of field borders.

To determine the significance of prostate-specific antigen (PSA) nadir (nPSA) and the time to nPSA (T(nPSA)) in predicting biochemical or clinical disease-free survival (PSA-DFS) and distant metastasis-free survival (DMFS) in patients treated with definitive external beam radiotherapy (RT) for clinical Stage T1b-T2 prostate cancer.Nine participating institutions submitted data on 4839 patients treated between 1986 and 1995 for Stage T1b-T2cN0-NxM0 prostate cancer. All patients were treated definitively with RT alone to doses > or =60 Gy, without neoadjuvant or planned adjuvant androgen suppression. A total of 4833 patients with a median follow-up of 6.3 years met the criteria for analysis. Two endpoints were considered: (1) PSA-DFS, defined as freedom from PSA failure (American Society for Therapeutic Radiology and Oncology definition), initiation of androgen suppression after completion of RT, or documented local or distant failure; and (2) DMFS, defined as freedom from clinically apparent distant failure. In patients with failure, nPSA was defined as the lowest PSA measurement before any failure. In patients without failure, nPSA was the lowest PSA measurement during the entire follow-up period. T(nPSA) was calculated from the completion of RT to the nPSA date.A greater nPSA level and shorter T(nPSA) were associated with decreased PSA-DFS and DMFS in all patients and in all risk categories (low [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level < or =10 ng/mL], intermediate [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level >10 but < or =20 ng/mL, or Stage T2b or T2c, Gleason score < or =6, and PSA level < or =20 ng/mL, or Gleason score 7 and PSA level < or =20 ng/mL], and high [Gleason score 8-10 or PSA level >20 ng/mL]), regardless of RT dose. The 8-year PSA-DFS and DMFS rate for patients with nPSA <0.5 ng/mL was 75% and 97%; nPSA > or =0.5 but <1.0 ng/mL, 52% and 96%; nPSA > or =1.0 but <2.0 ng/mL, 40% and 91%; and nPSA > or =2.0 ng/mL, 17% and 73%, respectively. The 8-year PSA-DFS and DMFS rate for patients with T(nPSA) <6 months was 27% and 66%; T(nPSA) > or =6 but <12 months, 31% and 85%; T(nPSA) > or =12 but <24 months, 42% and 94%; and T(nPSA) > or =24 months, 75% and 99%, respectively. A shorter T(nPSA) was associated with decreased PSA-DFS and DMFS, regardless of the nPSA. Both nPSA and T(nPSA) were significant predictors of PSA-DFS and DMFS in multivariate models incorporating clinical stage, Gleason score, initial PSA level, and RT dose. The significance of nPSA and T(nPSA) was supported by landmark analysis, as well as by analysis of nPSA and T(nPSA) as time-dependent covariates. A dose > or =70 Gy was associated with a lower nPSA level and longer T(nPSA) in all risk categories, and a greater dose was significantly associated with greater PSA-DFS and DMFS in multivariate analysis. Regression analysis confirmed that higher clinical stage, Gleason score, and initial PSA were associated with a greater nPSA level.The results of this large, multi-institutional analysis of 4833 patients have provided important evidence that nPSA and T(nPSA) after definitive external beam RT are not only predictive of a predominantly PSA endpoint (PSA-DFS), but are also predictive of distant metastasis in all clinical risk categories. Greater RT doses were associated with lower nPSA, longer T(nPSA), and improved PSA-DFS and DMFS.

We report local control outcomes, as assessed by posttreatment biopsies in patients who underwent 3-dimensional conformal radiotherapy for clinically localized prostate cancer. In addition, we report the influence of local tumor control on long-term distant metastases and cause specific survival outcomes.Posttreatment prostate biopsies were performed in 339 patients who underwent 3-dimensional conformal radiotherapy for clinically localized prostate cancer. The histological outcome of prostate biopsy was classified as positive-prostatic adenocarcinoma without typical radiation induced changes or negative-no evidence of carcinoma or severe treatment effect. Median followup in this group of 339 patients was 10 years after the completion of treatment and 6.25 years after posttreatment biopsy.Overall biopsy outcomes in these patients were positive in 32%, severe treatment effect in 21% and negative in 47%. A higher radiation dose in the intermediate and high risk subgroups was associated with a lower incidence of positive biopsy. Of patients at intermediate risk who received a dose of 75.6 or greater 24% had a positive biopsy compared to 42% who received 70.2 Gy or less (p = 0.03). In the high risk group positive treatment biopsies were noted in 51% of patients who received 70.2 Gy or less, 33% of those who received 75.6 Gy and 15% of those who received 81 Gy or greater (70.2 or less vs 75.6 Gy p = 0.07 and 75.6 vs 81 Gy or greater p = 0.05). Short course neoadjuvant androgen deprivation therapy before 3-dimensional conformal radiotherapy had a significant impact on the posttreatment biopsy outcome. Of patients who did not receive androgen deprivation therapy 42% had a positive biopsy compared to 16% who received androgen deprivation therapy (p <0.0001). Patients with negative and severe treatment effect biopsies had similar 10-year prostate specific antigen relapse-free survival outcomes that were markedly different from outcomes in those with positive treatment biopsies. Multivariate analysis indicated that the strongest predictor of biochemical failure was posttreatment biopsy status (positive vs severe treatment effect or negative p <0.001), followed by pretreatment prostate specific antigen (p = 0.05) and clinical T stage (p = 0.09). Similarly multivariate analysis revealed that a positive posttreatment biopsy was one of the strongest predictors of distant metastasis and prostate cancer death in this cohort of patients.As assessed by posttreatment prostate biopsies, local control is improved with higher radiation doses. Long-term biochemical outcomes in patients with posttreatment biopsies demonstrating severe treatment effect changes were not different than those in patients with negative biopsies. We also noted that local tumor control was associated with a decrease in distant metastases and prostate cancer mortality, further highlighting the importance of achieving optimal tumor control in patients with clinically localized disease.

Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients. Identify predictors of biochemical tumor control and distant metastases–free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT. This retrospective analysis comprised 2551 patients with clinical stages T1–T3 PCa. Median follow-up was 8 yr, extending >20 yr. Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo. A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed. Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels <70.2 Gy and 70.2–79.2 Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse–free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes. Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.

To determine the extent of reduction of volume of normal tissue structures exposed to high doses of radiation therapy (RT) after administration of neoadjuvant hormonal therapy (NHT) in patients with bulky, geometrically unfavorable prostatic cancers.Twenty-two patients with bulky prostatic cancers were treated with a 3 month course of neoadjuvant leuprolide acetate and eulexin prior to three-dimensional (3-D) conformal radiotherapy. Patients were included if 3-D treatment planning revealed that either > 30% of the rectal wall would receive 95% of the prescription dose (D95) (n = 13); > or = 50% of the bladder wall would receive D95 (n = 10); or that any volume of small bowel would receive > or = 65% of the prescription dose (n = 16). All patients underwent simulation and conformal treatment planning before and after NHT. Pre and posthormone cumulative dose volume histogram (DVH) calculations for all normal tissue structures were analyzed and compared for each patient.The median percentage of target volume reduction after NHT was 25% (range: 3-52%). Ten of 13 patients (78%) whose prehormone rectal DVH demonstrated > 30% of the rectal wall receiving D95 responded to NHT with a median 25% (range: 16-48%) reduction of rectal volume receiving the D95. A median reduction of 50% (range: 6-64%) of the bladder volume receiving D95 was observed in nine of ten patients (90%), while 13 of 16 (81%) showed a reduction of small bowel volume to a median percentage of 88% (range: 67-100%) of the prehormonal values.Neoadjuvant hormonal therapy is an effective method for decreasing the size of bulky prostatic tumors as well as for optimizing the geometry of the target volume in relation to the adjacent normal tissue structures prior to radiation therapy. Such an approach allows for reduction of the volume of normal tissues exposed to high doses in the majority of treated patients. Currently, studies are underway to determine whether NHT will lead to a decreased likelihood of long-term complications associated with radiotherapy of bulky, geometrically unfavorable prostatic tumors, and permit the safe delivery of escalated dose levels using conformal treatment techniques.

To update the Memorial Sloan-Kettering Cancer Center's experience with intensity-modulated radiotherapy (IMRT) in the treatment of oropharyngeal cancer (OPC).Between September 1998 and April 2009, 442 patients with histologically confirmed OPC underwent IMRT at our center. There were 379 men and 63 women with a median age of 57 years (range, 27-91). The disease was Stage I in 2%, Stage II in 4%, Stage III in 21%, and Stage IV in 73% of patients. The primary tumor subsite was tonsil in 50%, base of tongue in 46%, pharyngeal wall in 3%, and soft palate in 2%. The median prescription dose to the planning target volume of the gross tumor was 70 Gy for definitive (n = 412) cases and 66 Gy for postoperative cases (n = 30). A total 404 patients (91%) received chemotherapy, including 389 (88%) who received concurrent chemotherapy, the majority of which was platinum-based.Median follow-up among surviving patients was 36.8 months (range, 3-135). The 3-year cumulative incidence of local failure, regional failure, and distant metastasis was 5.4%, 5.6%, and 12.5%, respectively. The 3-year OS rate was 84.9%. The incidence of late dysphagia and late xerostomia ≥Grade 2 was 11% and 29%, respectively.Our results confirm the feasibility of IMRT in achieving excellent locoregional control and low rates of xerostomia. According to our knowledge, this study is the largest report of patients treated with IMRT for OPC.

The acute morbidity of doses of 64.8-75.6 Gy and preliminary observations of late complications and tumor response using 3-dimensional conformal radiation therapy in carcinoma of the prostate are assessed.123 patients (Stage A2-12, B1-17, B2-43, C-51) were irradiated to the prostate and seminal vesicles using a 3-dimensional conformal radiation therapy technique. The median follow-up time was 15.2 months. The minimum tumor dose was 64.8-66.6 Gy in 49 patients, 70.2 Gy in 46, and 75.6 Gy in 28. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading system.This technique of 3-dimensional conformal radiation therapy was well-tolerated with minimal acute morbidity. Only 32% of patients had grade 2 or 3 acute morbidity requiring short-term medication for relief of urinary symptoms or diarrhea. Only one patient (0.8%) has so far developed a severe (grade 4) late complication. Serum prostate specific antigen concentrations normalized in 67% of patients (64/96) within 1-14 months (median 4.5 months) after treatment and were progressively decreasing at last measurement in an additional 22% (21/96). Abnormal rising prostate specific antigen levels were observed in 15 patients, 11 of whom have already developed other evidence of relapsing disease.Acute toxicity for the doses tested with this 3-dimensional conformal radiation therapy technique is reduced compared to traditional treatment techniques, and the initial tumor response as assessed by prostate specific antigen measurement is highly encouraging with prostate specific antigen levels returning to normal in the majority of patients. Based on these results, a further increase of the dose to 81 Gy has been implemented in accordance with the schema of an ongoing Phase I dose-escalation study.

In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC).To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC.Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States.Use of metformin in localized prostate cancer.Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer-specific mortality (PCSM), overall survival (OS), and development of CRPC.With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24-3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78-7.62]; p<0.001), and PCSM (HR: 5.15 [1.53-17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83-119.89]; p=0.01). The retrospective study design was the primary limitation of the study.To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.

To compare the quality of life and functional outcome in patients with squamous cell cancer of the base of tongue treated with primary radiation vs. primary surgery.At our institution, patients with base of tongue cancer are primarily treated either by radiation or surgery depending upon the philosophy of their primary physician. Primary radiation consists of 45-54 Gy external beam radiation followed by an 192Ir implant delivering an additional 20-30 Gy over 2-3 days. A neck dissection is done at the same time as the implant for those with involved nodes. Primary surgery consists of resection of the base of tongue lesion, neck dissection and postoperative radiation therapy. Because both groups have similar local control in our experience (80-90%), we used a subjective performance status scale for head and neck cancer patients to assess the quality of life in these patients (0-100, 0 = worst function, 100 = normal function). This scale measures ability to eat in public, understandability of speech, and normalcy of diet. There were 30 radiation patients (21: T1-T2; nine: T3-T4) and ten surgery patients (five: T1-T2; five: T3-T4) available for long-term quality of life assessment.Patients treated with radiation had consistently better performance status scores and quality of life according to our study. This was true for those with early (T1-2) as well as more advanced (T3-4) disease. For eating in public, T1-2 patients had scores of 85 vs. 75 (p = .31) and T3-4 patients had scores of 82 vs. 35 (p < .0001) for radiation vs. surgery, respectively. For understandability of speech, T1-2 patients had scores of 92 vs. 65 (p = .0021), and T3-4 patients had scores of 95 vs. 35 (p < .0001) for radiation vs. surgery, respectively. For normalcy of diet, T1-2 patients had scores of 74 vs. 50 (p = .047), and T3-4 patients had scores of 78 vs. 32 (p = .0012) for radiation vs. surgery, respectively. In addition, we compared scores for early vs. advanced disease treated by the same modality. For radiation, there was no difference in all three functional categories for T1-2 vs. T3-4 (p = .84), showing that quality of life scores remain high for all stages. For surgery, functional status deteriorated significantly when comparing T1-2 vs. T3-4 (p = .0014), consistent with the fact that larger tumors require more extensive operations.Radiation therapy provides a better performance status than surgery for base of tongue cancer. This is true for both early and advanced disease. Because radiation also provides similar local control and survival, our data suggests that radiation may be the preferred strategy. Functional scores remain high for all T stages treated with radiation, but deteriorate with more advanced T stages for patients treated with surgery. Similar studies using objective criteria are needed to further compare these treatments.

Purpose: The aim of this study was to compare toxicity/efficacy of conventional radiotherapy using delayed accelerated concomitant boost radiotherapy (CBRT) vs. intensity-modulated radiotherapy (IMRT) in the setting of concurrent chemotherapy (CT) for locally advanced oropharyngeal carcinoma.Methods and Materials: Between September 1998 and June 2004, a total of 293 consecutive patients were treated at our institution for cancer of the oropharynx. Of these, 112 had Stage III/IV disease and squamous cell histology. In all, 41 were treated with IMRT/CT and 71 were treated with CBRT/CT, both to a median dose of 70 Gy. Most common CT was a planned two cycles given every 3 to 4 weeks of cisplatin, 100 mg/m2 i.v., but an additional cycle was given to IMRT patients when possible. Both groups were well-matched for all prognostic factors.Results: Median follow-up was 46 months (range, 3–93 months) for the CBRT patients and 31 months (range, 20–64 months) for the IMRT group. Three-year actuarial local-progression–free, regional-progression-free, locoregional progression-free, distant-metastases–free, disease-free, and overall survival rates were 85% vs. 95% (p = 0.17), 95% vs. 94% (p = 0.90), 82% vs. 92% (p = 0.18), 85% vs. 86% (p = 0.78), 76% vs. 82% (p = 0.57), and 81% vs. 91% (p = 0.10) for CBRT and IMRT patients, respectively. Three patients died of treatment-related toxicity in the CBRT group vs. none undergoing IMRT. At 2 years, 4% IMRT patients vs. 21% CBRT patients were dependent on percutaneous endoscopic gastrostomy (p = 0.02). Among those who had ≥20 months follow-up, there was a significant difference in Grade ≥2 xerostomia as defined by the criteria of the Radiation Therapy and Oncology Group, 67% vs. 12% (p = 0.02), in the CBRT vs. IMRT arm.Conclusion: In the setting of CT for locally advanced oropharyngeal carcinoma, IMRT results in lower toxicity and similar treatment outcomes when compared with CBRT. Purpose: The aim of this study was to compare toxicity/efficacy of conventional radiotherapy using delayed accelerated concomitant boost radiotherapy (CBRT) vs. intensity-modulated radiotherapy (IMRT) in the setting of concurrent chemotherapy (CT) for locally advanced oropharyngeal carcinoma. Methods and Materials: Between September 1998 and June 2004, a total of 293 consecutive patients were treated at our institution for cancer of the oropharynx. Of these, 112 had Stage III/IV disease and squamous cell histology. In all, 41 were treated with IMRT/CT and 71 were treated with CBRT/CT, both to a median dose of 70 Gy. Most common CT was a planned two cycles given every 3 to 4 weeks of cisplatin, 100 mg/m2 i.v., but an additional cycle was given to IMRT patients when possible. Both groups were well-matched for all prognostic factors. Results: Median follow-up was 46 months (range, 3–93 months) for the CBRT patients and 31 months (range, 20–64 months) for the IMRT group. Three-year actuarial local-progression–free, regional-progression-free, locoregional progression-free, distant-metastases–free, disease-free, and overall survival rates were 85% vs. 95% (p = 0.17), 95% vs. 94% (p = 0.90), 82% vs. 92% (p = 0.18), 85% vs. 86% (p = 0.78), 76% vs. 82% (p = 0.57), and 81% vs. 91% (p = 0.10) for CBRT and IMRT patients, respectively. Three patients died of treatment-related toxicity in the CBRT group vs. none undergoing IMRT. At 2 years, 4% IMRT patients vs. 21% CBRT patients were dependent on percutaneous endoscopic gastrostomy (p = 0.02). Among those who had ≥20 months follow-up, there was a significant difference in Grade ≥2 xerostomia as defined by the criteria of the Radiation Therapy and Oncology Group, 67% vs. 12% (p = 0.02), in the CBRT vs. IMRT arm. Conclusion: In the setting of CT for locally advanced oropharyngeal carcinoma, IMRT results in lower toxicity and similar treatment outcomes when compared with CBRT. 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Kim H.M. et al.Conformal and intensity modulated irradiation of head and neck cancer: the potential for improved target irradiation, salivary gland function, and quality of life.Acta Oto-Rhino-Laryngol Belgica. 1999; 53: 271-275PubMed Google Scholar, 16Chui C.S. Chan M.F. Yorke E. et al.Delivery of intensity-modulated radiation therapy with a conventional multileaf collimator: comparison of dynamic and segmental methods.Med Phys. 2001; 28: 2441-2449Crossref PubMed Scopus (77) Google Scholar). Studies have shown the advantage of IMRT in head-and-neck cancer with respect to salivary preservation, and a recent randomized trial has confirmed these findings (17Eisbruch A. Kim H.M. Terrell J.E. et al.Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.Int J Radiat Oncol Biol Phys. 2001; 50: 695-704Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 18Chao K.S. Majhail N. Huang C.J. et al.Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques.Radiother Oncol. 2001; 61: 275-280Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 19Kam M.K. Leung S.F. Zee B. et al.Impact of Intenstiy-modulated radiotherapy (IMRT) on salivary gland function in early-stage nasopharyngeal carcinoma (NPC) patients.Proc Am Soc Clin Oncol. 2005; 23 ([Abstract]): 500sGoogle Scholar). Furthermore, several centers have shown that IMRT reduces xerostomia without compromising tumor control (17Eisbruch A. Kim H.M. Terrell J.E. et al.Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.Int J Radiat Oncol Biol Phys. 2001; 50: 695-704Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 18Chao K.S. Majhail N. Huang C.J. et al.Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques.Radiother Oncol. 2001; 61: 275-280Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar). Given considerations of toxicity as well as tumor geometry and anatomy, we now routinely use IMRT with concurrent CT to treat oropharyngeal carcinoma. The purpose of this article is to compare retrospectively the toxicity and efficacy of IMRT with conventional 2D RT using delayed accelerated concomitant boost (CBRT) in the setting of concurrent platinum-based CT for patients with locally advanced oropharyngeal carcinoma. To our knowledge, this is the first direct comparison of these two different treatment approaches in this disease site.Methods and materialsPatient evaluationFrom September 1998 to June 2004, a total of 293 consecutive patients with oropharyngeal cancer underwent RT at Memorial Sloan-Kettering Cancer Center. To maximize homogeneity between the two groups, 181 were excluded from this analysis: non-SCC, early Stage, Stage IVC, prior RT with or without CT, synchronous primary, performance status <60 resulting in palliative treatment, patients with upfront surgery, IMRT as boost, and those who received chemoradiotherapy + cetuximab.This analysis included 112 patients who underwent RT concurrent with platinum-based CT. Of these, 71 were treated with conventional 2D RT using CBRT and 41 underwent IMRT. Pretreatment evaluations were history and physical, indirect, and/or direct fiberoptic endoscopic examination, CBC, chemistries, urinalysis, creatinine clearance, ECG, audiogram, CXR, computed tomography (CAT), and/or magnetic resonance imaging (MRI) of head/neck, and dental evaluation. Positron emission tomography (PET) was performed whenever possible. CAT scan of the chest/abdomen, bone scan was obtained when indicated. Disease was staged per the 1997 American Joint Committee on Cancer classification. All had histologic confirmation of SCC.Radiation treatmentPatients were immobilized with a thermoplastic head-and-neck mask encompassing the shoulders to ensure reproducibility of RT. CAT simulation was performed in some treated with CBRT and in all IMRT patients. Patients were planned using the MSKCC treatment planning system with 6-MV photons (20Chui C.S. Spirou S.V. Inverse planning algorithms for external beam radiation therapy.Med Dosim. 2001; 26: 189-197Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Electrons were used when indicated. No patients had brachytherapy.Of the patients, 71 underwent CBRT to a dose of 70 to 72 Gy. Large RT portals using parallel-opposed fields encompassing the primary, draining sites, and bilateral necks were treated to 54 Gy/1.8 Gy per fraction for 6 weeks. During the last 2 to 2.5 weeks, smaller portals either using parallel-opposed fields or simple 3D boost to all gross disease were treated to 16 Gy/1.6 Gy or 18 Gy/1.5 Gy per fraction (11Fu K.K. Pajak T.F. Trotti A. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.Int J Radiat Oncol Biol Phys. 2000; 48: 7-16Abstract Full Text Full Text PDF PubMed Scopus (1116) Google Scholar, 21Harrison L.B. Pfister D.G. Fass D.E. et al.Concomitant chemotherapy-radiation therapy followed by hyperfractionated radiation therapy for advanced unresectable head and neck cancer.Intl J Radiat Oncol Biol Phys. 1991; 21: 703-708Abstract Full Text PDF PubMed Scopus (49) Google Scholar). These boost fields were treated 6 h apart from the larger RT fields. All patients received a low anterior neck field (LAN) matched to upper neck RT fields.A total of 41 patients underwent IMRT. Of these, 32 had dose-painting (DP) IMRT (a.k.a., simultaneous integrated boost), which is our current practice (Fig. 1), whereas 9 underwent concomitant boost IMRT. Details of these IMRT techniques as used at our institution have been previously published (22de Arruda F.F. Puri D.R. Zhung J. et al.Intensity-modulated radiation therapy (IMRT) for advanced oropharyngeal carcinoma: the MSKCC experience.Int J Radiat Oncol Biol Phys. 2006; 64: 363-373Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar). All but 1 received IMRT to the primary/upper neck above vocal cords, whereas the low neck/supraclavicular fossae received a LAN field using conventional RT. One patient was treated with extended-field IMRT from skull base to low neck. It is our preference to only treat patients with extended-field IMRT when there is gross primary disease or involved nodes in the low neck. Of those who underwent concomitant boost IMRT, the large field and boost field treatments were 6 h apart. These fields were planned using IMRT. For patients who received DP IMRT, different doses were given to various target volumes once per day (qd) as described below. Among patients treated before 2003, there were 7 IMRT vs. 61 CBRT patients. Since 2003, more patients underwent IMRT (n = 34) vs. CBRT (n = 10). It is presently our routine to use IMRT to treat patients who present with oropharyngeal carcinoma.Target volumesGross tumor volume (GTV) was defined as tumor shown by imaging and physical examination. Imaging tools used to delineate GTV were CAT, MRI, and/or PET. When indicated, MRI fusion with treatment planning CAT scan was done. The clinical tumor volume (CTV) was defined as the GTV plus microscopic spread and regional lymph nodes (levels II to IV, retropharyngeal). Levels I/V were included in the CTV in patients with clinically positive nodes or at high risk for involvement. To account for setup error/organ motion, planning target volumes (PTVs) were added to the GTV/CTV with margin ranging from 3 mm to 1 cm. Normal structures, including parotid glands and cochlea, were outlined.Dose specificationsThe median prescribed dose was 70 Gy (range, 66–70 Gy) to the PTVGTV; 59.4 Gy (range, 59.4–60 Gy) to the PTV of high-risk subclinical disease. A third dose of 54 Gy was prescribed to the PTV of low-risk subclinical disease. The median dose per fraction was 2.12 Gy (range, 2.12–2.2 Gy) to PTVGTV; 1.8 Gy (range, 1.8–2.0 Gy) to the PTVhigh risk; and 1.64 Gy (range, 1.64–1.8 Gy) to PTVlow risk. When possible, mean parotid dose of ≤26 Gy was achieved. Because of the frequent presence of gross level II nodes, submandibular glands were not routinely spared. In our earlier experience, contouring of the oral cavity was not routinely done and as a result, Grade 3 mucositis was commonly observed. Subsequently, we delineated the oral cavity with the goal of achieving a mean dose of ≤35 Gy.ChemotherapyIt is our routine practice to give concurrent CT with radiation therapy for patients with Stage III/IV oropharyngeal cancer. The most commonly used chemotherapeutic regimen was high dose CDDP, 100 mg/m2 i.v., over 2 days for both the IMRT as well as the CBRT group. However, in some patients, because of their preexisting medical conditions and/or preference, carboplatin (60–70 mg/m2 daily i.v.) and 5-fluorouracil (600 mg/m2 daily CI) [CFU] for 4 days were given. In the CBRT group, patients were scheduled to undergo two cycles of CT during Weeks 1, 4 of RT. For the IMRT group, two to three cycles of concurrent CT was given every 3 to 4 weeks.Follow-upAll patients were evaluated weekly during treatment and subsequently followed for 1 to 3 months for first 2 years; every 4 to 6 months thereafter by 3 independent physicians: head/neck surgeon, medical oncologist, and radiation oncologist. A baseline CAT/MRI and PET scans were performed between 2 and 4 months post-treatment. Acute/late toxicities were graded per the Radiation Therapy and Oncology Group (RTOG) and U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute and Common Toxicity Criteria Adverse Event (CTVAE) version 3.0.Statistical methodsDescriptive statistics were calculated for the patient/disease characteristics, treatment features and toxicities. The 3-year actuarial local-progression–free (LPF), regional-progression–free, locoregional progression–free, distant metastases–free, disease-free survival (DFS), and overall survival probabilities were estimated using the Kaplan-Meier product–limit method. Durations were calculated from diagnosis. Freedom from local progression was defined as absence of primary tumor on physical and radiographic examinations. Differences in actuarial outcomes between the two groups were calculated using the Chi-square test. Fisher’s Exact test was used to detect any patient/tumor differences. Persistent neck disease was defined as presence of pathologically viable tumor cells at posttreatment planned neck dissection.ResultsPatient characteristicsTable 1 lists the demographic and disease characteristics of the 112 patients. The groups were well balanced for all prognostic factors, with no statistically significant differences.Table 1Patient and disease characteristicsCharacteristicCBRT (n = 71)IMRT (n = 41)Fisher’s ExactNo.%No.%Age, years Median5655NS Range33–8028–78Sex Male59833688NS Female1217512Ethnicity White64803995NS African American6925 Asian1100Karnofsky Performance Status ≥9056793483NS 70–901521717Histology Poorly differentiated30431741NS Moderate differentiated29411537NS Well differentiated1125NS Unknown1115717Tumor stage T1–T237522561NS T3–T434481639Nodal stage N069410NS N11521615 N245632970 N357251997 AJCC stage III1320615NS IVA52733380 IVB5725Site Base of tongue43612151NS Tonsil24341844 Others4525Abbreviations: AJCC = American Joint Committee on Cancer; CBRT = concomitant boost radiotherapy; NS = not significant; IMRT = intensity-modulated radiotherapy. Open table in a new tab Treatment outcomeThe median follow-up for surviving patients was 43 months (range, 11–93 months). The median follow-up for all CBRT patients was 46 months (range, 3–93 months) and was 31 months (range, 20–64 months) for the IMRT group. There were 12 local failures in CBRT vs. 2 in IMRT group, resulting in 3-year actuarial LPF rates of 85% vs. 95%, respectively (p = 0.17) (Fig. 2). The 3-year RPF rates were not different between the 2 groups, 95% vs. 94% (p = 0.90) (Fig. 3). The 3-year LRPF rates were 82% vs. 92% (p = 0.18) (Fig. 4). Most common sites of distant failure were bone, lung, and liver. Freedom from distant metastases at 3 years was 85% vs. 86% (p = 0.78) for CBRT and IMRT, respectively (Fig. 5). There was no difference between the 2 groups with respect to DFS, at 76% vs. 82% (p = 0.57) (Fig. 6). The 3-year OS was 81% vs. 91% (p = 0.10) (Fig. 7) for the CBRT and IMRT, respectively. Table 2 indicates causes of death. Five patients in the CBRT group died of local recurrence at 7, 8, 10, 24, and 42 months post-treatment, respectively, vs. none in the IMRT group.Fig. 2Kaplan-Meier estimate of local progression–free probabilities. CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy.View Large Image Figure ViewerDownload (PPT)Fig. 3Kaplan-Meier estimate of regional progression–free probabilities. CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy.View Large Image Figure ViewerDownload (PPT)Fig. 4Kaplan-Meier estimate of locoregional progression–free probabilities. CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy.View Large Image Figure ViewerDownload (PPT)Fig. 5Kaplan-Meier estimate of distant metastases–free probabilities. CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy.View Large Image Figure ViewerDownload (PPT)Fig. 6Kaplan-Meier estimate of disease-free survival probabilities. CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy.View Large Image Figure ViewerDownload (PPT)Fig. 7Kaplan-Meier estimate of overall survival probabilities. CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy.View Large Image Figure ViewerDownload (PPT)Table 2Cause of death and patterns of failure according to treatment groupCategoryCBRT n = 71IMRT n = 41No. of patients%No. of patients%Alive at last follow-up5577.54097.5Dead1622.512.5Cause of deathOropharyngeal carcinoma1115.512.5Radiation and chemotherapy toxicity3400 Secondary tumor11.500 Unknown11.500Pattern of failure Local121725 Regional3425 Distant metastases1217512.5Abbreviations: CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy. Open table in a new tab Neck dissections were performed when there was radiographic and/or clinical suspicion of persistent disease after treatment (Table 3). In the the CBRT group 20 patients underwent neck dissection and 4 had pathologic residual disease. Median time to neck dissection was 2.1 months (range, 1.2–3.5 months). One patient who initially had T2N2b SCC of the tonsil had suspicious disease involving the neck on follow-up. He subsequently underwent neck dissection at 21 months post-RT and had 16 nodes removed, all negative. Among those treated with IMRT, 1 of 11 patients who underwent neck dissection had residual disease. Median time to neck dissection was 2.9 months (range, 1.7–4.2 months). One patient with T4N3 disease underwent neck dissection at 11.1 months post-RT when he had persistent base-of-tongue disease and had 48 nodes removed, all negative.Table 3Neck node management in study patientsNeck stageNo. of patientsNeck dissectionPathologic CRNeck recurrenceN010000N121430N2A13430N2b3713120N2C24650N37430 Open table in a new tab Treatment details and patient complianceOverall, both groups were compliant to full-dose RT. In the CBRT group, 2 patients died of treatment toxicity (renal failure and aspiration pneumonia). The third patient discontinued the concomitant boost portion of RT secondary to toxicity. In contrast, all patients in the IMRT group completed their planned dose. Although treating physicians avoided RT treatment breaks and no breaks were built into either RT regimen, 12 CBRT patients and 4 IMRT patients required treatment breaks of >3 days because of acute toxicity. The 3 patients who required a break in the IMRT group underwent concomitant boost IMRT, but there was no statistical difference in toxicity between those treated with DP vs. concomitant boost IMRT.Overall CT compliance was excellent (Table 4). In the CBRT group, 97% received both cycles of CT. Among those who received CDDP (n = 50), 44 (88%) had a full dose for both cycles. Three CDDP patients switched to alternative drugs (CFU in 2 patients and 5FU alone in 1) because of ototoxicity. Two did not receive the second cycle because of toxicity (renal failure/cardiac toxicity). One patient required dose reduction because of renal toxicity. Of 15 patients, 14 completed full-dose CFU; 1 had to be switched to CDDP because of mucositis. Three patients received carboplatin as a single agent.Table 4Treatment details and compliance in study patientsParameterCBRT (n = 71)IMRT (n = 41)Radiation therapyMedian RT dose, Gy (range)70 (70–72)70 (66–70)Median delay to start RT after diagnoses, months (range)1.30 (0.1–2.5)1.05 (0.4–3.6)Median RT overall treatment time, weeks (range)6 (5.6–9)6.4 (5.6–8.3)RT breaks >3 days, no. (%)12 (17)4 (10)RT not completed, no. (%)3 (4)0ChemotherapyPatients receiving 2 or more concomitant cycles, no. (%)69 (97)41 (100)Patients able to receive 3 concomitant cycles, no. (%)05 (12)Patients receiving cisplatin, no. (%)50 (71)27 (66)Patients receiving CFU, no. (%)15 (25)14 (34)Patients receiving carboplatin alone, no. (%)3 (4)0Abbreviations: CFU = carboplatin + 5-fluorouracil; RT = radiotherapy; CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy. Open table in a new tab For the IMRT group, 100% of the patients completed at least two cycles of CT. No patient in the CBRT group received more than two cycles of CT, whereas 5 patients (12%) in the IMRT group completed an additional (third) cycle (p < 0.05). Of 27 patients, 23 (85%) received full dose for both cycles of CDDP. One patient needed reduced CDDP dose at cycle 2. Three patients, initially treated with CDDP, were switched to CFU because of ototoxicity. These patients subsequently received full-dose CFU. Of 14 patients, 11 underwent full-dose CFU. Three could not receive the full 5FU dose because of mucositis (Table 4).Acute ToxicityTable 5 presents information on acute toxicity. The only Grade 4 toxicity experienced in either group was hematologic.Table 5Acute Grade 3 toxicity in study patientsParameterScaleCBRT, No (%) (n = 71)IMRT, No (%) (n = 41)G3G4G3G4SkinRTOG/EORTC14 (20)4 (10)MucositisRTOG/EORTC51 (72)27 (66)BloodNCI/CTC21 (30)⁎Five patients in the CBRT group and 3 patients in the IMRT group experienced Grade 4 hematologic toxicity.11 (27)⁎Five patients in the CBRT group and 3 patients in the IMRT group experienced Grade 4 hematologic toxicity.Nausea/vomitingNCI/CTC7 (10)7 (17)Abbreviations: CBRT = concomitant boost radiotherapy; IMRT = intensity-modulated radiotherapy. Five patients in the CBRT group and 3 patients in the IMRT group experienced Grade 4 hematologic toxicity. Open table in a new tab Percutaneous endoscopic gastrostomyUntil recently it was not our institution’s policy to have prophylactic percutaneous endoscopic gastrostomy (PEG) placement. Therefore, more patients in the IMRT group underwent upfront PEG compared with those in the CBRT group. In general, CBRT patients without upfront PEG placement required more hydration and monitoring during and even after completion of treatment. Of 27 patients in the CBRT, 12 ultimately went on to have a PEG placed whereas 15 were able to receive the treatment without PEG. Of these 15 patients who did not receive intratreatment PEG placement, 8 were hospitalized because of toxicity (aspiration pneumonia/mucositis/pharyngitis). In the IMRT gr

Purpose: To investigate the correlations between observed clinical morbidity and dosimetric parameters for whole pelvic radiotherapy (WPRT) for prostate cancer using either three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). Methods and Materials: Between December 1996 and January 2002, 27 patients with prostate adenocarcinoma were treated with conformal WPRT as part of their definitive treatment. WPRT was delivered with 3D-CRT in 14 patients and with IMRT in 13 patients. For each of the patients treated with IMRT, optimized conventional two-dimensional (2D) and 3D-CRT plans were retrospectively generated for the whole pelvic phase of the treatment. Dose–volume histograms for the bowel, bladder, and rectum were compared for the three techniques. Acute toxicities were evaluated for all 27 patients, and late toxicities were evaluated for 25 patients with sufficient follow-up. Toxicities were scored according to the Radiation Therapy Oncology Group morbidity grading scales. Median follow-up was 30 months. Results: Three-dimensional-CRT resulted in a 40% relative reduction (p < 0.001) in the volume of bowel receiving 45 Gy compared with 2D, and IMRT provided a further 60% reduction relative to 3D-CRT (p < 0.001). Compared with either 2D or 3D-CRT, IMRT reduced the volume of rectum receiving 45 Gy by 90% (p < 0.001). Overall, 9 patients (33%) experienced acute Grade 2 gastrointestinal (GI) toxicity, and only 1 of these patients was treated with IMRT. Antidiarrhea medication was required for 6 patients (22%). However, 5 of these 6 patients also received chemotherapy, and none were treated with IMRT. No Grade 3 or higher acute or late GI toxicities were observed. No cases of late radiation enteritis were observed. Acute and late genitourinary toxicity did not appear significantly increased by the addition of conformal WPRT. Conclusions: Compared to conventional 2D planning, conformal planning for WPRT resulted in significant reductions in the doses delivered to the bowel, rectum, and bladder. IMRT was superior to 3D-CRT in limiting the volume of bowel and rectum within high-dose regions. These dosimetric findings correlated with low rates of acute and late GI morbidity. Purpose: To investigate the correlations between observed clinical morbidity and dosimetric parameters for whole pelvic radiotherapy (WPRT) for prostate cancer using either three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). Methods and Materials: Between December 1996 and January 2002, 27 patients with prostate adenocarcinoma were treated with conformal WPRT as part of their definitive treatment. WPRT was delivered with 3D-CRT in 14 patients and with IMRT in 13 patients. For each of the patients treated with IMRT, optimized conventional two-dimensional (2D) and 3D-CRT plans were retrospectively generated for the whole pelvic phase of the treatment. Dose–volume histograms for the bowel, bladder, and rectum were compared for the three techniques. Acute toxicities were evaluated for all 27 patients, and late toxicities were evaluated for 25 patients with sufficient follow-up. Toxicities were scored according to the Radiation Therapy Oncology Group morbidity grading scales. Median follow-up was 30 months. Results: Three-dimensional-CRT resulted in a 40% relative reduction (p < 0.001) in the volume of bowel receiving 45 Gy compared with 2D, and IMRT provided a further 60% reduction relative to 3D-CRT (p < 0.001). Compared with either 2D or 3D-CRT, IMRT reduced the volume of rectum receiving 45 Gy by 90% (p < 0.001). Overall, 9 patients (33%) experienced acute Grade 2 gastrointestinal (GI) toxicity, and only 1 of these patients was treated with IMRT. Antidiarrhea medication was required for 6 patients (22%). However, 5 of these 6 patients also received chemotherapy, and none were treated with IMRT. No Grade 3 or higher acute or late GI toxicities were observed. No cases of late radiation enteritis were observed. Acute and late genitourinary toxicity did not appear significantly increased by the addition of conformal WPRT. Conclusions: Compared to conventional 2D planning, conformal planning for WPRT resulted in significant reductions in the doses delivered to the bowel, rectum, and bladder. IMRT was superior to 3D-CRT in limiting the volume of bowel and rectum within high-dose regions. These dosimetric findings correlated with low rates of acute and late GI morbidity.

The 2 primary therapeutic interventions for localized prostate cancer are delivered by different types of physicians, urologists, and radiation oncologists. We evaluated how visits to specialists and primary care physicians (PCPs) by men with localized prostate cancer are related to treatment choice.Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified 85 088 men with clinically localized prostate cancer diagnosed at age 65 years or older, between 1994 and 2002. Men were categorized by primary treatment received within 9 months of diagnosis: radical prostatectomy (n = 18 201 [21%]), radiotherapy (n = 35 925 [42%]), androgen deprivation (n = 14 021 [17%]), or expectant management (n = 16 941 [20%]). Visits to specialists and PCPs were analyzed by patient characteristics and primary therapies received and were identified using Medicare claims and the American Medical Association Physician Masterfile.Overall, 42 309 men (50%) were seen exclusively by urologists, 37 540 (44%) by urologists and radiation oncologists, 2329 (3%) by urologists and medical oncologists, and 2910 (3%) by all 3 specialists. There was a strong association between the type of specialist seen and primary therapy received. Visits to PCPs were infrequent between diagnosis and receipt of therapy (22% of patients visited any PCP and 17% visited an established PCP) and were not associated with a greater likelihood of specialist visits. Irrespective of age, comorbidity status, or specialist visits, men seen by PCPs were more likely to be treated expectantly.Specialist visits relate strongly to prostate cancer treatment choices. In light of these findings, prior evidence that specialists prefer the modality they themselves deliver and the lack of conclusive comparative studies demonstrating superiority of one modality over another, it is essential to ensure that men have access to balanced information before choosing a particular therapy for prostate cancer.

Since its introduction into clinical use in the mid-1990s, intensity-modulated radiation therapy (IMRT) has emerged as the most effective and widely used form of external-beam radiotherapy for localized prostate cancer. Multiple studies have confirmed the importance of delivering sufficiently high doses to the prostate to achieve cure. The dosimetric superiority of IMRT over conventional techniques to produce conformal dose distributions that allow for organ sparing has been shown. A growing number of reports have confirmed that IMRT is the safest way to deliver high doses of external-beam irradiation to the prostate and the regional lymph nodes. Advances in imaging and onboard verification systems continue to advance the capabilities of IMRT and have potential implications with regards to further dose escalation and hypofractionated regimens. The clinical data in support of IMRT and the associated technical aspects of IMRT treatment planning and implementation are highlighted in this review.

Purpose To investigate the biochemical control rates and survival for Gleason score 7–10 prostate cancer patients undergoing permanent prostate brachytherapy as a function of the biologic effective dose (BED). Methods and Materials Six centers provided data on 5,889 permanent prostate brachytherapy patients, of whom 1,078 had Gleason score 7 (n = 845) or Gleason score 8–10 (n = 233) prostate cancer and postimplant dosimetry results available. The median prostate-specific antigen level was 7.5 ng/mL (range, 0.4–300). The median follow-up for censored patients was 46 months (range, 5–130). Short-term hormonal therapy (median duration, 3.9 months) was used in 666 patients (61.8%) and supplemental external beam radiotherapy (EBRT) in 620 (57.5%). The patients were stratified into three BED groups: <200 Gy (n = 645), 200–220 Gy (n = 199), and >220 Gy (n = 234). Biochemical freedom from failure (bFFF) was determined using the Phoenix definition. Results The 5-year bFFF rate was 80%. The bFFF rate stratified by the three BED groups was 76.4%, 83.5%, and 88.3% (p < 0.001), respectively. Cox regression analysis revealed Gleason score, prostate-specific antigen level, use of hormonal therapy, EBRT, and BED were associated with bFFF (p < 0.001). Freedom from metastasis improved from 92% to 99% with the greatest doses. The overall survival rate at 5 years for the three BED groups for Gleason score 8–10 cancer was 86.6%, 89.4%, and 94.6%, respectively (p = 0.048). Conclusion These data suggest that permanent prostate brachytherapy combined with EBRT and hormonal therapy yields excellent bFFF and survival results in Gleason score 7–10 patients when the delivered BEDs are >220 Gy. These doses can be achieved by a combination of 45-Gy EBRT with a minimal dose received by 90% of the target volume of 120 Gy of 103Pd or 130 Gy of 125I. To investigate the biochemical control rates and survival for Gleason score 7–10 prostate cancer patients undergoing permanent prostate brachytherapy as a function of the biologic effective dose (BED). Six centers provided data on 5,889 permanent prostate brachytherapy patients, of whom 1,078 had Gleason score 7 (n = 845) or Gleason score 8–10 (n = 233) prostate cancer and postimplant dosimetry results available. The median prostate-specific antigen level was 7.5 ng/mL (range, 0.4–300). The median follow-up for censored patients was 46 months (range, 5–130). Short-term hormonal therapy (median duration, 3.9 months) was used in 666 patients (61.8%) and supplemental external beam radiotherapy (EBRT) in 620 (57.5%). The patients were stratified into three BED groups: <200 Gy (n = 645), 200–220 Gy (n = 199), and >220 Gy (n = 234). Biochemical freedom from failure (bFFF) was determined using the Phoenix definition. The 5-year bFFF rate was 80%. The bFFF rate stratified by the three BED groups was 76.4%, 83.5%, and 88.3% (p < 0.001), respectively. Cox regression analysis revealed Gleason score, prostate-specific antigen level, use of hormonal therapy, EBRT, and BED were associated with bFFF (p < 0.001). Freedom from metastasis improved from 92% to 99% with the greatest doses. The overall survival rate at 5 years for the three BED groups for Gleason score 8–10 cancer was 86.6%, 89.4%, and 94.6%, respectively (p = 0.048). These data suggest that permanent prostate brachytherapy combined with EBRT and hormonal therapy yields excellent bFFF and survival results in Gleason score 7–10 patients when the delivered BEDs are >220 Gy. These doses can be achieved by a combination of 45-Gy EBRT with a minimal dose received by 90% of the target volume of 120 Gy of 103Pd or 130 Gy of 125I.

To compare concurrent cisplatin (CDDP) and radiation (RT) with cetuximab (C225) and RT for locally advanced head-and-neck cancer (LAHNC).This study retrospectively compared 174 consecutive, newly diagnosed LAHNC patients definitively treated from March 1, 2006, to April 1, 2008, with single-agent CDDP/RT (n = 125) or C225/RT (n = 49). We excluded patients who received additional concurrent, induction, or adjuvant systemic therapy; weekly cisplatin; prior head-and-neck radiotherapy; or primary surgical resection. Outcomes were analyzed by the Kaplan-Meier method, Cox model, and competing-risks analysis tools.The C225/RT patients were older and had decreased creatinine clearance. At a median follow-up of 22.5 months for living patients, the 2-year locoregional failure rate was 5.7% for CDDP/RT and 39.9% for C225/RT (p < 0.0001). The 2-year failure-free survival (FFS) and overall survival (OS) rates were 87.4% vs. 44.5% (p < 0.0001) and 92.8% vs. 66.6% (p = 0.0003), respectively, in favor of CDDP/RT. When the Cox proportional hazards model was used for multivariate analysis, treatment with CDDP/RT predicted for improved locoregional control (p < 0.0001), FFS (p < 0.0001), and OS (p = 0.01). Late Grade 3 or 4 toxicity or feeding tube dependence 9 months after completion of RT was observed in 21% of patients in the CDDP/RT cohort and 24% in the C225/RT cohort (p = 0.66).In this study of LAHNC patients, CDDP/RT achieved better locoregional control, FFS, and OS than C225/RT. Although the results were upheld on multivariate analysis, they must be interpreted cautiously because of the retrospective nature of the study and significant differences in patient selection. There was no statistically significant difference in late Grade 3 or 4 effects or feeding tube dependence.

To report the 5-year tumor control and toxicity outcomes for patients with localized prostate treated with I-125 permanent implantation using an intraoperative real-time conformal planning technique.Between January 1998 and June 2002, 367 patients with prostate cancer were treated with I-125 permanent interstitial implantation using a transrectal ultrasound-guided approach. Real-time intraoperative treatment planning which incorporated inverse planning optimization was used. The median follow-up time was 63 months.The median V100 and D90 were 96% and 173 Gy, respectively. In 96% of cases a D90 of >140 Gy was achieved. The median urethral and rectal doses were 100% and 33% of the prescription doses, respectively. The 5-year PSA relapse-free survival outcomes for favorable and intermediate risk patients according to the ASTRO definition were 96% and 89%, respectively. In these patients no dosimetric parameter was identified which influenced the biochemical outcome. Of 38% who developed acute Grade 2 urinary symptoms, 63% had resolution of their symptoms within a median time of 6 months. The incidence of late rectal and urinary Grade 3 or higher toxicities were 1% and 4%, respectively. Seven percent (n = 27) developed late rectal bleeding (Grade 2) and 19% experienced late Grade 2 urinary symptoms.Real-time intraoperative planning consistently achieved optimal coverage of the prostate with the prescription dose with concomitant low doses delivered to the urethra and rectum. Biochemical control outcomes were excellent at 5 years and late toxicity was unusual. These data demonstrate that real-time planning methods can consistently and reliably deliver the intended dose distribution to achieve an optimal therapeutic ratio between the target and normal tissue structures.

<h3>Purpose</h3> External beam radiotherapy (EBRT) plays a controversial role in the management of nonanaplastic thyroid cancer. We reviewed our institution's outcomes in patients treated with EBRT for advanced or recurrent nonanaplastic thyroid cancer. <h3>Methods and Materials</h3> Between April 1989 and April 2006, 76 patients with nonanaplastic thyroid cancer were treated with EBRT. The median follow-up for the surviving patients was 35.3 months (range, 4.2–178.4). The lesions were primarily advanced and included Stage T2 in 5 (7%), T3 in 5 (7%), and T4 in 64 (84%) patients. Stage N1 disease was present in 60 patients (79%). Distant metastases before EBRT were identified in 27 patients (36%). The median total EBRT dose delivered was 6,300 cGy. The histologic features examined included medullary in 12 patients (16%) and nonmedullary in 64 (84%). Of the 76 patients, 71 (93%) had undergone surgery before RT, and radioactive iodine treatment was used in 56 patients (74%). <h3>Results</h3> The 2- and 4-year overall locoregional control rate for all histologic types was 86% and 72%, respectively, and the 2- and 4-year overall survival rate for all patients was 74% and 55%, respectively. No significant differences were found in locoregional control, overall survival, or distant metastases-free survival for patients with complete resection, microscopic residual disease, or gross residual disease. Grade 3 acute mucositis and dysphagia occurred in 14 (18%) and 24 (32%) patients, respectively. Late adverse toxicity was notable for percutaneous endoscopic gastrostomy tube use in 4 patients (5%). <h3>Conclusion</h3> The results of our study have shown that EBRT is effective for locoregional control of selected locally advanced or recurrent nonanaplastic thyroid malignancies, with acceptable acute toxicity.

High-risk prostate cancer (PCa) is a potentially lethal disease. It is clinically important to identify patients with high-risk PCa early on because they stand to benefit the most from curative therapy. Because of recent advances in PCa management, a multimodal approach may be advantageous. Define high-risk PCa, and identify the best diagnostic and treatment patterns for patients with clinically localized and locally advanced disease. A critical analysis of published results following monomodal and/or multimodal therapy for high-risk PCa patients was also performed. A review of the literature was performed using the Medline, Embase, Scopus, and Web of Science databases as well as the Cochrane Database of Systematic Reviews. High-risk PCa accounts for ≤15% of all new diagnoses. Compared with patients with low- and intermediate-risk PCa, patients with high-risk PCa are at increased risk of treatment failure. Unfortunately, no contemporary randomized controlled trials comparing different treatment modalities exist. Evaluation of the results published to date shows that no single treatment can be universally recommended. Most often, a multimodal approach is warranted to optimize patient outcomes. A significant minority of patients continue to present with high-risk PCa, which remains lethal in some cases. Outcomes following treatment of men with high-risk tumors have not substantially improved over time. However, not all high-risk patients are at the same risk of PCa progression and death. At present, a multimodal approach seems the best way to achieve acceptable outcomes for high-risk PCa patients.

To determine the potential association between genitourinary (GU) toxicity and planning dose-volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients.A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose-volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analyses were done by the Kaplan-Meier method and Cox proportional hazard models, respectively.Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19).The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the bladder trigone seems to be associated with a reduction in late GU toxicity.

Purpose Osteoradionecrosis (ORN) is a known complication of radiation therapy to the head and neck. However, the incidence of this complication with intensity-modulated radiation therapy (IMRT) and dental sequelae with this technique have not been fully elucidated. Methods and Materials From December 2000 to July 2007, 168 patients from our institution have been previously reported for IMRT of the oral cavity, nasopharynx, larynx/hypopharynx, sinus, and oropharynx. All patients underwent pretreatment dental evaluation, including panoramic radiographs, an aggressive fluoride regimen, and a mouthguard when indicated. The median maximum mandibular dose was 6,798 cGy, and the median mean mandibular dose was 3,845 cGy. Patient visits were retrospectively reviewed for the incidence of ORN, and dental records were reviewed for the development of dental events. Univariate analysis was then used to assess the effect of mandibular and parotid gland dosimetric parameters on dental endpoints. Results With a median clinic follow-up of 37.4 months (range, 0.8–89.6 months), 2 patients, both with oral cavity primaries, experienced ORN. Neither patient had preradiation dental extractions. The maximum mandibular dose and mean mandibular dose of the 2 patients were 7,183 and 6,828 cGy and 5812 and 5335 cGy, respectively. In all, 17% of the patients (n = 29) experienced a dental event. A mean parotid dose of >26 Gy was predictive of a subsequent dental caries, whereas a maximum mandibular dose >70 Gy and a mean mandibular dose >40 Gy were correlated with dental extractions after IMRT. Conclusions ORN is rare after head-and-neck IMRT, but is more common with oral cavity primaries. Our results suggest different mechanisms for radiation-induced caries versus extractions. Osteoradionecrosis (ORN) is a known complication of radiation therapy to the head and neck. However, the incidence of this complication with intensity-modulated radiation therapy (IMRT) and dental sequelae with this technique have not been fully elucidated. From December 2000 to July 2007, 168 patients from our institution have been previously reported for IMRT of the oral cavity, nasopharynx, larynx/hypopharynx, sinus, and oropharynx. All patients underwent pretreatment dental evaluation, including panoramic radiographs, an aggressive fluoride regimen, and a mouthguard when indicated. The median maximum mandibular dose was 6,798 cGy, and the median mean mandibular dose was 3,845 cGy. Patient visits were retrospectively reviewed for the incidence of ORN, and dental records were reviewed for the development of dental events. Univariate analysis was then used to assess the effect of mandibular and parotid gland dosimetric parameters on dental endpoints. With a median clinic follow-up of 37.4 months (range, 0.8–89.6 months), 2 patients, both with oral cavity primaries, experienced ORN. Neither patient had preradiation dental extractions. The maximum mandibular dose and mean mandibular dose of the 2 patients were 7,183 and 6,828 cGy and 5812 and 5335 cGy, respectively. In all, 17% of the patients (n = 29) experienced a dental event. A mean parotid dose of >26 Gy was predictive of a subsequent dental caries, whereas a maximum mandibular dose >70 Gy and a mean mandibular dose >40 Gy were correlated with dental extractions after IMRT. ORN is rare after head-and-neck IMRT, but is more common with oral cavity primaries. Our results suggest different mechanisms for radiation-induced caries versus extractions.

With salvage radiation therapy (SRT) in the postprostatectomy setting, the need to deliver sufficient radiation doses to achieve a high probability of tumor control is balanced with the risk of increased toxicity. Intensity-modulated radiation therapy (IMRT) in the postprostatectomy salvage setting is gaining interest as a treatment strategy. Compare acute and late toxicities in patients treated with IMRT and three-dimensional conformal radiation therapy (3D-CRT) in the postprostatectomy salvage setting. A total of 285 patients who were treated at our institution between 1988 and 2007 with SRT after radical prostatectomy for biochemical recurrence were identified. All medical records were reviewed and toxicity recorded. Median follow-up was 60 mo. All patients were treated with SRT with either 3D-CRT (n = 109) or IMRT (n = 176). A total of 205 patients (72%) were treated with doses ≥70 Gy. Late gastrointestinal (GI) and genitourinary (GU) toxicities were recorded using the Common Terminology Criteria for Adverse Events v. 3.0 definition. The 5-yr actuarial rates of late grade ≥2 GI and GU toxicity were 5.2% and 17.0%, respectively. IMRT was independently associated with a reduction in grade ≥2 GI toxicity compared with 3D-CRT (5-yr IMRT, 1.9%; 5-yr 3D-CRT, 10.2%; p = 0.02). IMRT was not associated with a reduction in risk of grade ≥2 GU toxicity (5-yr IMRT, 16.8%; 5-yr 3D-CRT, 15.8%; p = 0.86), urinary incontinence (5-yr IMRT, 13.6%; 5-yr 3D-CRT, 7.9%; p = 0.25), or grade 3 erectile dysfunction (5-yr IMRT, 26%; 5-yr 3D-CRT, 30%; p = 0.82). Of patients who developed late grade ≥2 GI or GU toxicity, 38% and 44%, respectively, experienced resolution of their symptoms prior to the last follow-up. Our experience with high-dose IMRT in the postprostatectomy salvage setting demonstrates that the treatment can be delivered safely with an associated reduction in late GI toxicity.

PurposeWe report the toxicity and biochemical tumor control outcome of a prospective Phase II study using high-dose-rate brachytherapy (HDR) alone as a salvage therapy for recurrent disease after external beam radiotherapy (EBRT).MethodsForty-two patients with biopsy-proven recurrence were enrolled on a Phase II study of salvage HDR monotherapy using iridium-192. Median pretreatment EBRT dose was 8100 cGy (6840–8640 cGy) and the median time from completion of EBRT to salvage HDR was 73 months. The protocol prescription dose of 3200 cGy was delivered in four fractions over 30 hours in a single insertion. Median followup after salvage HDR was 36 months (6–67 months).ResultsThe actuarial prostate-specific antigen biochemical relapse-free survival and distant metastases-free survival rates at 5 years were 68.5% and 81.5%, respectively. Cause-specific survival was 90.3%. Late genitourinary Grade 1and 2 toxicities were found in 38% and 48%, respectively, and one patient developed Grade 3 urinary incontinence. Late Grade 1 and 2 gastrointestinal toxicity was noted in 17% and 8% of patients, respectively. Three patients (7%) developed Grade 2 late urinary toxicity (urethral stricture), which were corrected with urethral dilatation, and one patient developed Grade 3 urinary incontinence. No Grade 4 toxicities were observed.ConclusionsGenitourinary toxicity was the most commonly encountered toxicity observed after salvage HDR but severe toxicities were uncommon. Salvage HDR is an effective and well-tolerated modality for locally recurrent prostate cancer and should be considered even for patients who have previously been treated with ultra-high dose levels of EBRT.

Purpose We report on a retrospective comparison of biochemical outcomes using an ultra-high dose of conventionally fractionated intensity-modulated radiation therapy (IMRT) vs. a lower dose of IMRT combined with high-dose-rate (HDR) brachytherapy to increase the biologically effective dose of IMRT. Methods Patients received IMRT of 86.4 Gy (n=470) or HDR brachytherapy (21 Gy in three fractions) followed by IMRT of 50.4 Gy (n=160). Prostate-specific antigen (PSA) relapse was defined as PSA nadir+2. Median followup was 53 months for IMRT alone and 47 months for HDR. Results The 5-year actuarial PSA relapse-free survival (PRFS) for HDR plus IMRT vs. ultra-high-dose IMRT were 100% vs. 98%, 98% vs. 84%, and 93% vs. 71%, for National Comprehensive Cancer Network low- (p=0.71), intermediate- (p<0.001), and high-risk (p=0.23) groups, respectively. Treatment (p=0.0006), T stage (p<0.0001), Gleason score (p<0.0001), pretreatment PSA (p=0.0037), risk group (p<0.0001), and lack of androgen-deprivation therapy (p=0.0005) were significantly associated with improved PRFS on univariate analysis. HDR plus IMRT vs. ultra-high-dose IMRT (p=0.0012, hazard ratio [HR]=0.184); age (p=0.0222, HR=0.965); and risk group (p<0.0001, HR=2.683) were associated with improved PRFS on multivariate analysis. Conclusion Dose escalation of IMRT by adding HDR brachytherapy provided improved PRFS in the treatment of prostate cancer compared with ultra-high-dose IMRT, independent of risk group on multivariate analysis, with the most significant benefit for intermediate-risk patients.

To compare diagnostic accuracy of T2-weighted magnetic resonance (MR) imaging with that of multiparametric (MP) MR imaging combining T2-weighted imaging with diffusion-weighted (DW) MR imaging, dynamic contrast material-enhanced (DCE) MR imaging, or both in the detection of locally recurrent prostate cancer (PCa) after radiation therapy (RT).This retrospective HIPAA-compliant study was approved by the institutional review board; informed consent was waived. Fifty-three men (median age, 70 years) suspected of having post-RT recurrence of PCa underwent MP MR imaging, including DW and DCE sequences, within 6 months after biopsy. Two readers independently evaluated the likelihood of PCa with a five-point scale for T2-weighted imaging alone, T2-weighted imaging with DW imaging, T2-weighted imaging with DCE imaging, and T2-weighted imaging with DW and DCE imaging, with at least a 4-week interval between evaluations. Areas under the receiver operating characteristic curve (AUC) were calculated. Interreader agreement was assessed, and quantitative parameters (apparent diffusion coefficient [ADC], volume transfer constant [K(trans)], and rate constant [k(ep)]) were assessed at sextant- and patient-based levels with generalized estimating equations and the Wilcoxon rank sum test, respectively.At biopsy, recurrence was present in 35 (66%) of 53 patients. In detection of recurrent PCa, T2-weighted imaging with DW imaging yielded higher AUCs (reader 1, 0.79-0.86; reader 2, 0.75-0.81) than T2-weighted imaging alone (reader 1, 0.63-0.67; reader 2, 0.46-0.49 [P ≤ .014 for all]). DCE sequences did not contribute significant incremental value to T2-weighted imaging with DW imaging (reader 1, P > .99; reader 2, P = .35). Interreader agreement was higher for combinations of MP MR imaging than for T2-weighted imaging alone (κ = 0.34-0.63 vs κ = 0.17-0.20). Medians of quantitative parameters differed significantly (P < .0001 to P = .0233) between benign tissue and PCa (ADC, 1.64 × 10(-3) mm(2)/sec vs 1.13 × 10(-3) mm(2)/sec; K(trans), 0.16 min(-1) vs 0.33 min(-1); k(ep), 0.36 min(-1) vs 0.62 min(-1)).MP MR imaging has greater accuracy in the detection of recurrent PCa after RT than T2-weighted imaging alone, with no additional benefit if DCE is added to T2-weighted imaging and DW imaging.

To evaluate a commercial synthetic CT (syn-CT) software for use in prostate radiotherapy. Twenty-five prostate patients underwent CT and MR simulation scans in treatment position on a 3T MR scanner. A commercially available MR protocol was used that included a T2w turbo spin-echo sequence for soft-tissue contrast and a dual echo 3D mDIXON fast field echo (FFE) sequence for generating syn-CT. A dual-echo 3D FFE B 0 map was used for patient-induced susceptibility distortion analysis and a new 3D balanced-FFE sequence was evaluated for identification of implanted gold fiducial markers and subsequent image-guidance during radiotherapy delivery. Tissues were classified as air, adipose, water, trabecular/spongy bone and compact/cortical bone and assigned bulk HU values. The accuracy of syn-CT for treatment planning was analyzed by transferring the structures and plan from planning CT to syn-CT and recalculating the dose. Accuracy of localization at the treatment machine was evaluated by comparing registration of kV radiographs to either digitally reconstructed radiographs (DRRs) generated from syn-CT or traditional DRRs generated from the planning CT. Similarly, accuracy of setup using CBCT and syn-CT was compared to that using the planning CT. Finally, a MR-only simulation workflow was established and end-to-end testing was completed on five patients undergoing MR-only simulation. Dosimetric comparison between the original CT and syn-CT plans was within 0.5% on average for all structures. The de-novo optimized plans on the syn-CT met institutional clinical objectives for target and normal structures. Patient-induced susceptibility distortion based on B 0 maps was within 1 mm and 0.5 mm in the body and prostate respectively. DRR and CBCT localization based on MR-localized fiducials showed a standard deviation of <1 mm. End-to-end testing and MR simulation workflow was successfully validated. MRI derived synthetic CT can be successfully used for a MR-only planning and treatment for prostate radiotherapy.

To report tumor local control after treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) to extracranial metastatic sites.A total of 126 metastases in 103 patients were treated with SD-IGRT to prescription doses of 18-24 Gy (median, 24 Gy) between 2004 and 2007.The overall actuarial local relapse-free survival (LRFS) rate was 64% at a median follow-up of 18 months (range, 2-45 months). The median time to failure was 9.6 months (range, 1-23 months). On univariate analysis, LRFS was significantly correlated with prescription dose (p = 0.029). Stratification by dose into high (23 to 24 Gy), intermediate (21 to 22 Gy), and low (18 to 20 Gy) dose levels revealed highly significant differences in LRFS between high (82%) and low doses (25%) (p < 0.0001). Overall, histology had no significant effect on LRFS (p = 0.16). Renal cell histology displayed a profound dose-response effect, with 80% LRFS at the high dose level (23 to 24 Gy) vs. 37% with low doses (≤22 Gy) (p = 0.04). However, for patients who received the high dose level, histology was not a statistically significant predictor of LRFS (p = 0.90). Target organ (bone vs. lymph node vs. soft tissues) (p = 0.5) and planning target volume size (p = 0.55) were not found to be associated with long-term LRFS probability. Multivariate Cox regression analysis confirmed prescription dose to be a significant predictor of LRFS (p = 0.003).High-dose SD-IGRT is a noninvasive procedure resulting in high probability of local tumor control. Single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and target organ, provided sufficiently high doses (> 22 Gy) of radiation are delivered.

To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer.A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5 Gy in 5 fractions, and doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60 cm3. Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5 years, respectively.The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were 16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P = .013).SBRT doses ranging from 32.5 to 40 Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses.

We provide a comprehensive analysis of anatomical patterns of recurrence following external beam radiotherapy in patients with localized prostate cancer.This retrospective analysis included 2,694 patients with localized prostate cancer who received definitive, dose escalated external beam radiotherapy from 1991 to 2008. First recurrence sites were defined as initial sites of clinically detected recurrence and any subsequent clinically detected recurrence within 3 months. Anatomical recurrence patterns were classified as local (prostate/seminal vesicles only), lymphotropic (lymph nodes only) and osteotropic (bones only) in patients with disease confined only to these respective sites for at least 2 years from the initial clinically detected recurrence.Prostate was the most common first recurrence site in the low, intermediate and high risk groups with an 8-year cumulative incidence of 3.5%, 9.8% and 14.6%, respectively. The 8-year risk of isolated pelvic lymph node relapse as the first recurrence site was 0%, 1.0% and 3.3%, respectively. In the 474 patients with clinically detected recurrence the most common first recurrence site was local in 55.3%, bone in 33.5%, pelvic lymph nodes in 21.3% and abdominal lymph nodes in 9.1%. Patients showed unique relapse distributions, including a pattern that was local in 41.6%, lymphotropic in 9.7%, osteotropic in 20.3% and multiorgan/visceral in 28.5%. Anatomical recurrence pattern was the strongest predictor of prostate cancer specific mortality on multivariate analysis of patients with clinically detected recurrence.The most common first recurrence site after dose escalated external beam radiotherapy for prostate cancer is in the prostate and seminal vesicles in all risk groups. In contrast, patients treated without elective pelvic lymph node irradiation are at relatively low risk for isolated pelvic lymph node relapse. Recurrence patterns revealed a tropism for specific anatomical distributions with divergent prognoses, suggesting underlying biological differences among tumors.

To describe the details and experience of implementing a MR-only workflow in the clinic for simulation and planning of prostate cancer patients.Forty-eight prostate cancer patients from June 2016 - Dec 2016 receiving external beam radiotherapy were scheduled to undergo MR-only simulation. MR images were acquired for contouring (T2w axial, coronal, sagittal), synthetic-CT generation (3D FFE-based) and fiducial identification (3D bFFE-based). The total acquisition time was 25 min. Syn-CT was generated at the console using commercial software called MRCAT. As part of acceptance testing of the MRCAT package, external laser positioning system QA (< 2 mm) and geometric fidelity QA (< 2 mm within 50 cm LR and 30 cm AP) were performed and baseline values were set. Our current combined CT + MR simulation process was modified to accommodate a MRCAT-based MR-only simulation workflow. An automated step-by-step process using a MIM™ workflow was created for contouring on the MR images. Patient setup for treatment was achieved by matching the MRCAT DRRs with the orthogonal KV radiographs based on either fiducial ROIs or bones. 3-D CBCTs were acquired and compared with the MR/syn-CT to assess the rectum and bladder filling compared to simulation conditions.Forty-two patients successfully underwent MR-only simulation and met all of our institutional dosimetric objectives that were developed based on a CT + MR-based workflow. The remaining six patients either had a hip prosthesis or their large body size fell outside of the geometric fidelity QA criteria and thus they were not candidates for MR-only simulation. A total time saving of ~15 min was achieved with MR-based simulation as compared to CT + MR-based simulation. An automated and organized MIM workflow made contouring on MR much easier, quicker and more accurate compared with combined CT + MR images because the temporal variations in normal structure was minimal. 2D and 3D treatment setup localization based on bones/fiducials using a MRCAT reference image was successfully achieved for all cases.MR-only simulation and planning with equivalent or superior target delineation, planning and treatment setup localization accuracy is feasible in a clinical setting. Future work will focus on implementing a robust 3D isotropic acquisition for contouring.

Magnetic resonance (MR) only radiation therapy for prostate treatment provides superior contrast for defining targets and organs-at-risk (OARs). This study aims to develop a deep learning model to leverage this advantage to automate the contouring process.Six structures (bladder, rectum, urethra, penile bulb, rectal spacer, prostate and seminal vesicles) were contoured and reviewed by a radiation oncologist on axial T2-weighted MR image sets from 50 patients, which constituted expert delineations. The data was split into a 40/10 training and validation set to train a two-dimensional fully convolutional neural network, DeepLabV3+, using transfer learning. The T2-weighted image sets were pre-processed to 2D false color images to leverage pre-trained (from natural images) convolutional layers' weights. Independent testing was performed on an additional 50 patient's MR scans. Performance comparison was done against a U-Net deep learning method. Algorithms were evaluated using volumetric Dice similarity coefficient (VDSC) and surface Dice similarity coefficient (SDSC).When comparing VDSC, DeepLabV3+ significantly outperformed U-Net for all structures except urethra (P < 0.001). Average VDSC was 0.93 ± 0.04 (bladder), 0.83 ± 0.06 (prostate and seminal vesicles [CTV]), 0.74 ± 0.13 (penile bulb), 0.82 ± 0.05 (rectum), 0.69 ± 0.10 (urethra), and 0.81 ± 0.1 (rectal spacer). Average SDSC was 0.92 ± 0.1 (bladder), 0.85 ± 0.11 (prostate and seminal vesicles [CTV]), 0.80 ± 0.22 (penile bulb), 0.87 ± 0.07 (rectum), 0.85 ± 0.25 (urethra), and 0.83 ± 0.26 (rectal spacer).A deep learning-based model produced contours that show promise to streamline an MR-only planning workflow in treating prostate cancer.

This prospective phase 3 randomized trial was designed to test whether ultra high single-dose radiation therapy (24 Gy SDRT) improves local control of oligometastatic lesions compared to a standard hypofractionated stereotactic body radiation therapy regimen (3 × 9 Gy SBRT). The secondary endpoint was to assess the associated toxicity and the impact of ablation on clinical patterns of metastatic progression.Between November 2010 and September 2015, 117 patients with 154 oligometastatic lesions (≤5/patient) were randomized in a 1:1 ratio to receive 24 Gy SDRT or 3 × 9 Gy SBRT. Local control within the irradiated field and the state of metastatic spread were assessed by periodic whole-body positron emission tomography/computed tomography and/or magnetic resonance imaging. Median follow-up was 52 months.A total of 59 patients with 77 lesions were randomized to 24 Gy SDRT and 58 patients with 77 lesions to 3 × 9 Gy SBRT. The cumulative incidence of local recurrence for SDRT-treated lesions was 2.7% (95% confidence interval [CI], 0%-6.5%) and 5.8% (95% CI, 0.2%-11.5%) at years 2 and 3, respectively, compared with 9.1% (95% CI, 2.6%-15.6%) and 22% (95% CI, 11.9%-32.1%) for SBRT-treated lesions (P = .0048). The 2- and 3-year cumulative incidences of distant metastatic progression in the SDRT patients were 5.3% (95% CI, 0%-11.1%), compared with 10.7% (95% CI, 2.5%-18.8%) and 22.5% (95% CI, 11.1%-33.9%), respectively, for the SBRT patients (P = .010). No differences in toxicity were observed.The study confirms SDRT as a superior ablative treatment, indicating that effective ablation of oligometastatic lesions is associated with significant mitigation of distant metastatic progression.

Artificial intelligence advances have stimulated a new generation of autosegmentation, however clinical evaluations of these algorithms are lacking. This study assesses the clinical utility of deep learning-based autosegmentation for MR-based prostate radiotherapy planning.Data was collected prospectively for patients undergoing prostate-only radiation at our institution from June to December 2019. Geometric indices (volumetric Dice-Sørensen Coefficient, VDSC; surface Dice-Sørensen Coefficient, SDSC; added path length, APL) compared automated to final contours. Physicians reported contouring time and rated autocontours on 3-point protocol deviation scales. Descriptive statistics and univariable analyses evaluated relationships between the aforementioned metrics.Among 173 patients, 85% received SBRT. The CTV was available for 167 (97%) with median VDSC, SDSC, and APL for CTV (prostate and SV) 0.89 (IQR 0.83-0.95), 0.91 (IQR 0.75-0.96), and 1801 mm (IQR 1140-2703), respectively. Physicians completed surveys for 43/55 patients (RR 78%). 33% of autocontours (14/43) required major "clinically significant" edits. Physicians spent a median of 28 min contouring (IQR 20-30), representing a 12-minute (30%) time savings compared to historic controls (median 40, IQR 25-68, n = 21, p < 0.01). Geometric indices correlated weakly with contouring time, and had no relationship with quality scores.Deep learning-based autosegmentation was implemented successfully and improved efficiency. Major "clinically significant" edits are uncommon and do not correlate with geometric indices. APL was supported as a clinically meaningful quantitative metric. Efforts are needed to educate and generate consensus among physicians, and develop mechanisms to flag cases for quality assurance.

Using an magnetic resonance linear accelerator (MR-Linac) may improve the precision of visible tumor boosting with ultra-hypofractionation by accounting for daily positional changes in the target and organs at risk (OAR).Fifteen patients with prostate cancer and an MR-detected dominant lesion were treated on the MR-Linac with stereotactic body radiation (SBRT) to 40 Gy in 5 fractions, boosting the gross tumor volume (GTV) to 45 Gy with daily adaptive planning. Imaging was acquired again after initial planning (verification scan), and immediately after treatment (post-treatment scan). Prior to beam-on, additional adjustments were made on the verification scan. Contours were retrospectively adjusted on verification and post-treatment scans, and the daily plan recalculated on these scans to estimate the true dose delivered.The median prostate D95% for plan 1, 2 and 3 was 40.3 Gy, 40.5 Gy and 40.3 Gy and DIL D95% was 45.7 Gy, 45.2 Gy and 44.6 Gy, respectively. Bladder filling was associated with reduced GTV coverage (p = 0.03, plan 1 vs 2) and prostate coverage (p = 0.03, plan 2 vs 3). The D0.035 cc constraint was exceeded on verification and post-treatment plans in 24 % and 33 % of fractions for the urethra, 31 % and 45 % for the bladder, and 35 % and 25 % for the rectum, respectively.MR-Linac guided, daily adaptive SBRT with focal boosting of the GTV yields acceptable planned and delivered dosimetry. Adaptive planning with a MR-Linac may reliably deliver the prescribed dose to the intended tumor target.

To determine the spatial distribution of setup errors for patients treated with six-field, three-dimensional (3D) conformal radiation therapy for prostate cancer.Port films for 50 patients were analyzed retrospectively. The port films were digitized and compared, using image registration software, to simulator films (representing the ideal treatment position). Patient positioning uncertainty for a given setup was determined using port films from three projections, two obliques, and one lateral. A total of 1239 port films and 300 simulator films were analyzed for the study. Patient position was analyzed for out-of-plane rotations and time trends over the course of treatment.The distribution of systematic setup errors for the 50 patients, defined as the mean patient displacement for the treatment course, had a mean and standard deviation (SD) of (-0.1 +/- 1.9) mm, (0.4 +/- 1.4) mm, and (-0.3 +/- 1.3) mm in the mediolateral (ML), superior-inferior (SI) and anterior-posterior (AP) directions, and (-0.1 +/- 0.2) for rotational errors. The distribution of random setup errors about the mean approximated a normal distribution and the standard deviations for the population of patients in the ML, SI, and AP directions, were 2.0 mm, 1.7 mm, and 1.9 mm, respectively. The distribution of out-of-plane rotations had 1 SD of 0.9 degrees and 0.6 degrees about the SI and AP axes. Ten of the 50 patients demonstrated a statistically significant time trend in their setup position resulting in shifts ranging from 2 to 7 mm.The setup verification protocol appears to minimize systematic setup errors to a level that approaches the sensitivity of the image registration technique. The random day to day fluctuations, represented by the average values of the standard deviations, are minor in comparison to the currently used margins, which further emphasizes the effectiveness of this protocol in conjunction with the use of the immobilization device.

There are several nomograms for the patient considering radiation therapy for clinically localized prostate cancer. Because of the questionable clinical implications of prostate-specific antigen (PSA) recurrence, its use as an end point has been criticized in several of these nomograms. The goal of this study was to create and to externally validate a nomogram for predicting the probability that a patient will develop metastasis within 5 years after three-dimensional conformal radiation therapy (CRT).We conducted a retrospective, nonrandomized analysis of 1,677 patients treated with three-dimensional CRT at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1988 to 2000. Clinical parameters examined were pretreatment PSA level, clinical stage, and biopsy Gleason sum. Patients were followed until their deaths, and the time at which they developed metastasis was noted. A nomogram for predicting the 5-year probability of developing metastasis was constructed from the MSKCC cohort and validated using the Cleveland Clinic series of 1,626 patients.After three-dimensional CRT, 159 patients developed metastasis. At 5 years, 11% of patients experienced metastasis by cumulative incidence analysis (95% CI, 9% to 13%). A nomogram constructed from the data gathered from these men showed an excellent ability to discriminate among patients in an external validation data set, as shown by a concordance index of 0.81.A nomogram with reasonable accuracy and discrimination has been constructed and validated using an external data set to predict the probability that a patient will experience metastasis within 5 years after three-dimensional CRT.

No AccessJournal of UrologyClinical Urology: Original Article1 Jul 1997Long-Term Results of Retropubic Permanent125 Iodine Implantation of the Prostate for Clinically Localized Prostatic Cancer Michael J. Zelefsky and Jr. WhitmoreWillet F. Michael J. ZelefskyMichael J. Zelefsky More articles by this author and Jr. WhitmoreJr. Whitmore (Whitmore) Deceased. More articles by this author View All Author Informationhttps://doi.org/10.1097/00005392-199707000-00005AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: The historical series of retropubic prostate radioactive source implantation from the Memorial Sloan-Kettering Cancer Center has served as the framework for the current transperineal implant approaches used in the treatment of localized prostatic cancer. We report the final assessment of the 15-year outcome. Materials and Methods: Between March 1970 and December 1987, 1,078 patients with biopsy proved adenocarcinoma of the prostate were treated at our cancer center with permanent implantation of125 iodine via a retropubic approach. In addition, all patients underwent bilateral pelvic lymphadenectomy before implantation. The clinical stages of disease were B1 in 234 patients (22%), B2 in 472 (44%), B3 in 145 (14%) and C in 227 (20%). Of the patients 733 (68%) had pathologically negative lymph nodes, whereas 345 (32%) had positive lymph nodes at lymph node dissection. Median followup was 11 years. Results: Multivariate analysis identified nodal involvement, high grade disease, clinical stage B3/C and implant doses less than 140 Gy. as independent predictors of local relapse. Independent predictors of distant metastases included nodal involvement, stage B3/C disease and poorly differentiated histological status. The local recurrence-free survival rates for patients with negative nodes at 5, 10 and 15 years were 69, 44 and 24%, respectively. The distant metastases-free survival rates at 5, 10 and 15 years for patients with negative lymph nodes were 59, 36 and 21%, respectively. Conclusions: (125) Iodine implantation of the prostate via the retropubic approach was associated with a greater than expected incidence of local relapse at 15 years. Technical limitations of the retropubic technique resulting in suboptimal distribution of the isotope within the prostate are believed to be the explanation for the inferior local control outcome. Although long-term results are not yet available, the 5-year results of the computer optimized transperineal prostate implantation suggest that improved implant techniques will translate into a greater likelihood of tumor control. References 1 : Radiumbehandlung eines prostatasarkoms.. Wein. Klin. Woschr.1910; 23: 1715. Google Scholar 2 : Long-term results after combined radioactive gold seed implantation and external beam radiotherapy for localized prostatic cancer. In: A Multidiscplinary Analysis of Controversies in the Management of Prostate Cancer. Edited by . New York: Plenum Press1988: 109. Google Scholar 3 : The rationale and results of ablative surgery for prostatic cancer.. Cancer1963; 16: 1119. Google Scholar 4 : Retropubic implantation of iodine 125 in the treatment of prostatic cancer. J. Urol.1972; 108: 918. Link, Google Scholar 5 : Spacing nomograph for interstitial implants of 125I seeds.. Med. Phys.1976; 3: 48. Google Scholar 6 : Nonparametric estimations from incomplete observations.. J. Amer. Stat. Ass.1958; 53: 457. Google Scholar 7 : The analysis of multiple classifications with unequal number in the different classes.. J. Amer. Stat. Ass.1934; 29: 51. Google Scholar 8 : Regression models and life tables.. J. Roy. Stat. Soc. B.1972; 34: 187. 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Clin. Oncol.1996; 14: 449. Google Scholar 28 : Permanent implants using Au-198, Pd-103 and I-125: radiobiological considerations based on the linear quadratic model.. Int. J. Rad. Oncol. Biol. Phys.1992; 23: 81. Google Scholar 29 : Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone.. Int. J. Rad. Oncol. Biol. Phys.1995; 32: 3. Google Scholar 30 : Relative reliability of five serially measured markers for prognosis of progression in prostate cancer.. J. Natl. Cancer Inst.1986; 76: 179. Google Scholar 31 : Prostate specific antigen after irradiation for prostatic carcinoma.. J. Urol.1990; 144: 1172. Abstract, Google Scholar 32 : Clinical adenocarcinoma of the prostate in patients under 50 years of age.. J. Urol.1965; 93: 618. Abstract, Google Scholar 33 : Prostatic adenocarcinoma occurring in men under 50 years of age.. J. Surg. Oncol.1972; 4: 207. Google Scholar 34 : Prostate adenocarcinoma in men younger than 50 years. A retrospective review of 151 patients. Cancer1994; 74: 1768. Google Scholar 35 : The prognosis of prostatic cancer in the younger man.. Brit. J. Urol.1983; 55: 315. Google Scholar 36 : Age and survival in prostatic carcinoma.. Brit. J. Urol.1983; 55: 529. Google Scholar 37 : Prostate cancer in men less than 45 years old: influence of stage, grade and therapy.. J. Urol.1987; 137: 888. Abstract, Google Scholar From the Departments of Radiation Oncology and Surgery (Urology Service), Memorial Sloan-Kettering Cancer Center, New York, New York.© 1997 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byThompson I, Thrasher J, Aus G, Burnett A, Canby-Hagino E, Cookson M, D’Amico A, Dmochowski R, Eton D, Forman J, Goldenberg S, Hernandez J, Higano C, Kraus S, Moul J and Tangen C (2018) Guideline for the Management of Clinically Localized Prostate Cancer: 2007 UpdateJournal of Urology, VOL. 177, NO. 6, (2106-2131), Online publication date: 1-Jun-2007.STONE N, STOCK R and UNGER P (2018) INTERMEDIATE TERM BIOCHEMICAL-FREE PROGRESSION AND LOCAL CONTROL FOLLOWING 125IODINE BRACHYTHERAPY FOR PROSTATE CANCERJournal of Urology, VOL. 173, NO. 3, (803-807), Online publication date: 1-Mar-2005.Walsh P (2018) RE: RADICAL PROSTATECTOMY FOR LOCALIZED PROSTATE CANCER PROVIDES DURABLE CANCER CONTROL WITH EXCELLENT QUALITY OF LIFE: A STRUCTURED DEBATEJournal of Urology, VOL. 165, NO. 1, (193-193), Online publication date: 1-Jan-2001.CRITZ F, WILLIAMS W, LEVINSON A, BENTON J, HOLLADAY C and SCHNELL F (2018) SIMULTANEOUS IRRADIATION FOR PROSTATE CANCER: INTERMEDIATE RESULTS WITH MODERN TECHNIQUESJournal of Urology, VOL. 164, NO. 3 Part 1, (738-743), Online publication date: 1-Sep-2000.WAGNER T, YOUNG D and BAHNSON R (2018) CHARGE AND LENGTH OF HOSPITAL STAY ANALYSIS OF RADICAL RETROPUBIC PROSTATECTOMY AND TRANSPERINEAL PROSTATE BRACHYTHERAPYJournal of Urology, VOL. 161, NO. 4, (1216-1218), Online publication date: 1-Apr-1999. (2018) EDITORIAL COMMENTJournal of Urology, VOL. 161, NO. 4, (1203-1204), Online publication date: 1-Apr-1999. Volume 158Issue 1July 1997Page: 23-30 Advertisement Copyright & Permissions© 1997 by American Urological Association, Inc.MetricsAuthor Information Michael J. Zelefsky More articles by this author Jr. Whitmore (Whitmore) Deceased. More articles by this author Expand All Advertisement PDF downloadLoading ...

To evaluate retrospectively the accuracy of endorectal magnetic resonance (MR) imaging for the depiction of tumor, extracapsular extension (ECE), and seminal vesicle invasion (SVI) before salvage prostatectomy in patients with locally recurrent prostate cancer after radiation therapy, by using pathologic analysis as the reference standard.The Institutional Review Board granted exempt status for this HIPAA-compliant study, with a waiver of informed consent. Forty-five consecutive patients (age range, 43-76 years) were identified who underwent salvage radical prostatectomy for prostate cancer at Memorial Sloan-Kettering Cancer Center between December 1, 1998, and October 31, 2004, and who underwent endorectal MR imaging prior to surgery. Tumor localization and determination of local stage with MR imaging were performed independently by two radiologists. Interpretations were compared to pathologic findings from surgical specimens. Interrater variability was estimated with the kappa statistic. Areas under the receiver operating characteristic curve (AUCs) were used to assess the accuracy of endorectal MR imaging in tumor detection and determination of ECE and SVI.Findings of histologic examination showed that tumor was present in all patients. For tumor detection, the AUC value for reader 1 was 0.75 (95% confidence interval [CI]: 0.67, 0.84), whereas the AUC value for reader 2 was 0.61 (95% CI: 0.52, 0.71). The AUC values for prediction of ECE were 0.87 (95% CI: 0.80, 0.94) for reader 1 and 0.76 (95% CI: 0.67, 0.85) for reader 2. The AUC values for prediction of SVI were 0.76 (95% CI: 0.62, 0.90) for reader 1 and 0.70 (95% CI: 0.56, 0.85) for reader 2. For all variables, the kappa statistics used to assess interrater agreement between readers were fair (0.45, 0.52, and 0.47 for tumor location, ECE, and SVI, respectively).Endorectal MR imaging following radiation therapy can help identify tumor sites and depict ECE and SVI with reasonable accuracy in patients with recurrent prostate cancer.

The specific aim of 3-dimensional conformal radiation therapy is to improve the target dose distribution while concomitantly reducing normal tissue dose. Such an approach should permit dose escalation until the limits of acceptable normal tissue toxicity are reached. To evaluate the feasibility of tumor dose escalation for nine patients with lung cancer, we determined the dose distribution to the target and normal tissues with 3-dimensional conformal radiation therapy and conventional planning.Plans were compared to assess adequacy of dose delivery to target volumes, dose-volume histograms for normal tissue, and normal tissue complication probabilities (NTCP) for nine patients with lung tumors.The mean percentage of gross disease which received < or = 70.2 Gy with 3-dimensional conformal radiation therapy (3DCRT) was 40% of the mean percentage of gross disease which received < or = 70.2 Gy with conventional treatment planning (CTP). The mean NTCP for lung parenchyma with 3DCRT was 36% of the mean NTCP with CTP. The mean esophageal NTCP with 3DCRT was 88% of the mean NTCP with CTP.This preliminary analysis suggests that three dimensional conformal radiation therapy may provide superior delivery of high dose radiation with reduced risk to normal tissue, suggesting that this approach may have the potential to improve the therapeutic ratio of high dose radiation therapy for lung cancer.

Adjuvant radiotherapy (RT) has been shown to improve local control in patients with soft tissue sarcoma of the extremities (STS). The specific impact of adjuvant radiation on patients with positive margins, however, has not been clearly defined. The purpose of this study was to determine if adjuvant RT improves local control in patients with high-grade STS who had positive margins of resection.Between 8/82 and 2/97, 110 adult patients with primary high-grade STS of an extremity underwent limb sparing surgery and were found to have a histologically positive microscopic surgical margin. Ninety-one (83%) received RT and 19 (17%) had no RT. The two groups were balanced with regard to size, site, location, and tumor depth. Adjuvant RT was delivered with brachytherapy (BRT) alone in 34 patients, external beam radiotherapy (EBRT) alone in 33 patients, or BRT+EBRT in 24 patients. The BRT dose was 45 Gy when used alone and 15-20 Gy when used as a boost. The EBRT dose was 60-70 Gy when used alone and 45-50 Gy when given with BRT. The median follow-up time was 41 months (range, 3-186 months).The overall 5 year local control rate was 71%. This rate was significantly higher in the RT group compared to the no RT group (74% vs. 56%, respectively) (p = 0.01). On univariate analysis, lower extremity site and proximal location were also found to be predictors of improved local control (p = 0.03 and 0.03, respectively). However, only proximal location and the use of RT retained their significance as predictors of improved local control on multivariate analysis (p = 0.003 and 0.01, respectively). The overall 5-year distant relapse-free survival, disease-free survival, and overall survival rates were 54%, 44%, and 53%, respectively. No statistical differences were found in these survival rates between RT and no RT groups.Based on this study, adjuvant radiotherapy seems to improve local control in patients with high-grade STS of the extremity with positive margins. However, local recurrence still occurs in a substantial proportion of patients, mandating further need for improvement.

Purpose: Recent studies have demonstrated that magnetic-resonance spectroscopic imaging (MRSI) of the prostate may effectively distinguish between regions of cancer and normal prostatic epithelium. This diagnostic imaging tool takes advantage of the increased choline plus creatine versus citrate ratio found in malignant compared to normal prostate tissue. The purpose of this study is to describe a novel brachytherapy treatment-planning optimization module using an integer programming technique that will utilize biologic-based optimization. A method is described that registers MRSI to intraoperative-obtained ultrasound images and incorporates this information into a treatment-planning system to achieve dose escalation to intraprostatic tumor deposits. Methods: MRSI was obtained for a patient with Gleason 7 clinically localized prostate cancer. The ratios of choline plus creatine to citrate for the prostate were analyzed, and regions of high risk for malignant cells were identified. The ratios representing peaks on the MR spectrum were calculated on a spatial grid covering the prostate tissue. A procedure for mapping points of interest from the MRSI to the ultrasound images is described. An integer-programming technique is described as an optimization module to determine optimal seed distribution for permanent interstitial implantation. MRSI data are incorporated into the treatment-planning system to test the feasibility of dose escalation to positive voxels with relative sparing of surrounding normal tissues. The resultant tumor control probability (TCP) is estimated and compared to TCP for standard brachytherapy-planned implantation. Results: The proposed brachytherapy treatment-planning system is able to achieve a minimum dose of 120% of the 144 Gy prescription to the MRS positive voxels using 125I seeds. The preset dose bounds of 100–150% to the prostate and 100–120% to the urethra were maintained. When compared to a standard plan without MRS-guided optimization, the estimated TCP for the MRS-optimized plan is superior. The enhanced TCP was more pronounced for smaller volumes of intraprostatic tumor deposits compared to estimated TCP values for larger lesions. Conclusions: Using this brachytherapy-optimization system, we could demonstrate the feasibility of MRS-optimized dose distributions for 125I permanent prostate implants. Based on probability estimates of anticipated improved TCP, this approach may have an impact on the ability to safely escalate dose and potentially improve outcome for patients with organ-confined but aggressive prostatic cancers. The magnitude of the TCP enhancement, and therefore the risks of ignoring the MR data, appear to be more substantial when the tumor is well localized; however, the gain achievable in TCP may depend quite considerably on the MRS tumor-detection efficiency.

No AccessJournal of UrologyAdult Urology: Oncology: Prostate/Testis/Penis/Urethra1 Mar 2005DEFINITIONS OF BIOCHEMICAL FAILURE THAT BEST PREDICT CLINICAL FAILURE IN PATIENTS WITH PROSTATE CANCER TREATED WITH EXTERNAL BEAM RADIATION ALONE: A MULTI-INSTITUTIONAL POOLED ANALYSIS ERIC M. HORWITZ, HOWARD D. THAMES, DEBORAH A. KUBAN, LARRY B. LEVY, PATRICK A. KUPELIAN, ALVARO A. MARTINEZ, JEFFREY M. MICHALSKI, THOMAS M. PISANSKY, HOWARD M. SANDLER, WILLIAM U. SHIPLEY, MICHAEL J. ZELEFSKY, GERALD E. HANKS, and ANTHONY L. ZIETMAN ERIC M. HORWITZERIC M. HORWITZ More articles by this author , HOWARD D. THAMESHOWARD D. THAMES More articles by this author , DEBORAH A. KUBANDEBORAH A. KUBAN More articles by this author , LARRY B. LEVYLARRY B. LEVY More articles by this author , PATRICK A. KUPELIANPATRICK A. KUPELIAN More articles by this author , ALVARO A. MARTINEZALVARO A. MARTINEZ More articles by this author , JEFFREY M. MICHALSKIJEFFREY M. MICHALSKI More articles by this author , THOMAS M. PISANSKYTHOMAS M. PISANSKY More articles by this author , HOWARD M. SANDLERHOWARD M. SANDLER More articles by this author , WILLIAM U. SHIPLEYWILLIAM U. SHIPLEY More articles by this author , MICHAEL J. ZELEFSKYMICHAEL J. ZELEFSKY More articles by this author , GERALD E. HANKSGERALD E. HANKS More articles by this author , and ANTHONY L. ZIETMANANTHONY L. ZIETMAN More articles by this author View All Author Informationhttps://doi.org/10.1097/01.ju.0000152556.53602.64AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Pooled data on 4,839 patients with T1-2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions have previously provided long-term biochemical failure (BF) and clinical outcomes using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. In this report we determined the sensitivity and specificity of several BF definitions using distant failure (DF) alone or clinical failure (CF), defined as local failure (LF) and/or DF. Materials and Methods: The pooled cohort was treated between 1986 and 1995 with external beam RT (60 Gy or greater) without pre-RT androgen suppression or planned post-RT adjuvant androgen suppression. Median followup was 6.3 years. The sensitivity and specificity of 102 definitions of BF relative to DF and LF were assessed. Results: The BF definitions with higher sensitivity and specificity than the ASTRO definition for DF only and CF are reported. The sensitivity and specificity of the ASTRO definition to predict DF alone was 55% and 68%, respectively. Three definitions had higher sensitivity and specificity, namely prostate specific antigen (PSA) greater than current nadir (lowest PSA prior to current measurement) plus 3 ng/ml (sensitivity 76% and specificity 72%), dated at the call (failure date as the date when the criterion was met), PSA greater than absolute nadir plus 2 ng/ml (sensitivity 72% and specificity 70%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 69% and specificity 73%). The sensitivity and specificity of the ASTRO definition to predict CF was 60% and 72%, respectively. Three definitions had higher sensitivity and specificity, namely PSA greater than current nadir plus 3 ng/ml (sensitivity 66% and specificity 77%), dated at the call, PSA greater than absolute nadir plus 2 ng/ml (sensitivity 64% and specificity 74%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 67% and specificity 78%). Conclusions: Using what is to our knowledge the largest data set of patients with prostate cancer treated with RT alone we correlated multiple definitions of BF with the strict clinical end points of DF alone and CF (DF or local failure). Defining BF as PSA greater than absolute nadir plus 2 ng/ml, dated at the call, PSA greater than current nadir plus 3 ng/ml, dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated, had higher sensitivity and specificity for DF alone or CF compared with the ASTRO definition. This information should contribute to the discussion regarding suggested modifications to the ASTRO definition of biochemical failure. References 1 : Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control. Int J Radiat Oncol Biol Phys1996; 36: 565. Google Scholar 2 Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys1997; 37: 1035. Google Scholar 3 : The correlation between the ASTRO consensus panel definition of biochemical failure and clinical outcome for patients with prostate cancer treated with external beam irradiation. American Society of Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys1998; 41: 267. Google Scholar 4 : Changes in biochemical disease-free survival rates as a result of adoption of the consensus conference definition in patients with clinically localized prostate cancer treated with external-beam radiotherapy. Int J Radiat Oncol Biol Phys1998; 41: 511. Google Scholar 5 : A standard definition of disease freedom is needed for prostate cancer: undetectable prostate specific antigen compared with the American Society of Therapeutic Radiology and Oncology consensus definition. J Urol2002; 167: 1310. 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Anderson Cancer Center, Houston, Texas, Department of Radiation Oncology, Cleveland Clinic Foundation (PAK), Cleveland, Ohio, and William Beaumont Hospital (AAM), Royal Oak and University of Michigan (HMS), Ann Arbor, Michigan, Department of Radiation Oncology, Mallinckrodt Institute of Radiology (JMM), St. Louis, Missouri, Division of Radiation Oncology, Mayo Clinic College of Medicine (TMP), Rochester, Minnesota, Department of Radiation Oncology, Massachusetts General Hospital (WUS, ALZ), Boston, Massachusetts, and Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center (MJZ), New York, New York© 2005 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byTaneja S (2018) Re: Surrogate End Points for All-Cause Mortality in Men with Localized Unfavorable-Risk Prostate Cancer Treated with Radiation Therapy vs Radiation Therapy plus Androgen Deprivation Therapy: A Secondary Analysis of a Randomized Clinical TrialJournal of Urology, VOL. 199, NO. 1, (28-28), Online publication date: 1-Jan-2018.Pastuszak A, Khanna A, Badhiwala N, Morgentaler A, Hult M, Conners W, Sarosdy M, Yang C, Carrion R, Lipshultz L and Khera M (2018) Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate CancerJournal of Urology, VOL. 194, NO. 5, (1271-1276), Online publication date: 1-Nov-2015.Greene K, Albertsen P, Babaian R, Carter H, Gann P, Han M, Kuban D, Sartor A, Stanford J, Zietman A and Carroll P (2018) Prostate Specific Antigen Best Practice Statement: 2009 UpdateJournal of Urology, VOL. 189, NO. 1S, (S2-S11), Online publication date: 1-Jan-2013.Greene K, Albertsen P, Babaian R, Carter H, Gann P, Han M, Kuban D, Sartor A, Stanford J, Zietman A and Carroll P (2018) Prostate Specific Antigen Best Practice Statement: 2009 UpdateJournal of Urology, VOL. 182, NO. 5, (2232-2241), Online publication date: 1-Nov-2009.Cookson M, Aus G, Burnett A, Canby-Hagino E, D’Amico A, Dmochowski R, Eton D, Forman J, Goldenberg S, Hernandez J, Higano C, Kraus S, Moul J, Tangen C, Thrasher J and Thompson I (2018) Variation in the Definition of Biochemical Recurrence in Patients Treated for Localized Prostate Cancer: The American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel Report and Recommendations for a Standard in the Reporting of Surgical OutcomesJournal of Urology, VOL. 177, NO. 2, (540-545), Online publication date: 1-Feb-2007.Freedland S and Moul J (2018) Prostate Specific Antigen Recurrence After Definitive TherapyJournal of Urology, VOL. 177, NO. 6, (1985-1991), Online publication date: 1-Jun-2007.Thompson I, Thrasher J, Aus G, Burnett A, Canby-Hagino E, Cookson M, D’Amico A, Dmochowski R, Eton D, Forman J, Goldenberg S, Hernandez J, Higano C, Kraus S, Moul J and Tangen C (2018) Guideline for the Management of Clinically Localized Prostate Cancer: 2007 UpdateJournal of Urology, VOL. 177, NO. 6, (2106-2131), Online publication date: 1-Jun-2007.Nurani R, Wallner K, Merrick G, Virgin J, Orio P and True L (2018) Optimized Prostate Brachytherapy Minimizes the Prognostic Impact of Percent of Biopsy Cores Involved With AdenocarcinomaJournal of Urology, VOL. 178, NO. 5, (1968-1973), Online publication date: 1-Nov-2007.Walsh P (2018) Failure Definition-Dependent Differences in Outcome Following Radiation for Localized Prostate Cancer: Can One Size Fit All?Journal of Urology, VOL. 174, NO. 3, (928-929), Online publication date: 1-Sep-2005. Volume 173Issue 3March 2005Page: 797-802 Advertisement Copyright & Permissions© 2005 by American Urological Association, Inc.Keywordsprostateprostatic neoplasmsprostate-specific antigenMetricsAuthor Information ERIC M. HORWITZ More articles by this author HOWARD D. THAMES More articles by this author DEBORAH A. KUBAN More articles by this author LARRY B. LEVY More articles by this author PATRICK A. KUPELIAN More articles by this author ALVARO A. MARTINEZ More articles by this author JEFFREY M. MICHALSKI More articles by this author THOMAS M. PISANSKY More articles by this author HOWARD M. SANDLER More articles by this author WILLIAM U. SHIPLEY More articles by this author MICHAEL J. ZELEFSKY More articles by this author GERALD E. HANKS More articles by this author ANTHONY L. ZIETMAN More articles by this author Expand All Advertisement PDF downloadLoading ...

To summarize the urinary, rectal, and sexual symptoms occurring during the first 12 months following 125I prostatic implantation.Thirty-one patients with Stage T1 or T2 prostatic carcinoma were evaluated for morbidity following computed tomography-guided transperineal 125I implants from 1988 to 1991. The median total activity used was 47 mCi (range 35-73 mCi). Toxicity was evaluated using a modification of the Radiation Therapy Oncology Group grading system.Nocturia was the most common treatment-related symptom, reported by 80% of patients within 2 months after implantation, and persisted at 12 months in 45% of the patients. Mild dysuria developed in 48% of patients within 2 months of implantation; two patients needed analgesics for their dysuria. Terazosin hydrochloride (2-10 mg qd) provided subjective improvement of urinary symptoms in seven of eight patients in whom it was tried. Rectal urgency, soft stools, and increased frequency of bowel movements was reported by 25% of the patients within 1-2 months after implantation. The incidence of asymptomatic rectal bleeding or ulceration occurring at any time after implantation was 47%, but resolved in all patients with expectant treatment. Self-limited ulceration of the rectal mucosal occurred in 16%, but only one patient developed a prostato-rectal fistula, managed with an ileal conduit. Five of the 18 potent patients experienced discomfort on erection or ejaculation, beginning within several weeks of their implant. The discomfort resolved within 6 months in three of the patients, but persisted for 18 and 24 months in the other two.125I implantation, as performed in this series, is generally associated with only mild-moderate genitourinary and rectal symptoms that may persist 6 months or more after implantation. Prostatic carcinoma, Brachytherapy, Morbidity.

<h2>Abstract</h2><h3>Objectives</h3> To determine the impact of neoadjuvant hormonal therapy (NHT) prior to conformal radiotherapy on the reduction of volume of normal tissue structures exposed to high doses of radiation therapy and to evaluate the overall late toxicity and response to treatment among patients treated with this approach. <h3>Methods</h3> Among 214 patients treated with neoadjuvant leuprolide acetate and flutamide for 3 months prior to three-dimensional conformal radiotherapy (3D-CRT), 45 patients were prospectively evaluated with detailed dose-volume histogram (DVH) analyses to determine the extent of improvement of the geometry of the target volume after NHT. All patients underwent simulation and conformal treatment planning before and after NHT, and the pre- and posthormone DVH calculations for all normal tissue structures were compared for each patient. In addition, toxicity and response to therapy were evaluated in the 214 patients treated with this combined approach. <h3>Results</h3> In the 45 patients evaluated, the median reduction of the rectal and bladder volumes receiving 95% of the prescription dose (D₉₅) were 18% and 46%, respectively, while 91% showed a reduction of small bowel volume in a range of 27% to 100% of the prehormonal values. Among the entire group of 214 patients treated with NHT and 3D-CRT, no grade 3 or 4 toxicity was observed with a median follow-up of 15 months after 3D-CRT. The 3-year actuarial grade 2 late gastrointestinal and genitourinary toxicity rates were 6% and 18%, respectively. <h3>Conclusions</h3> Neoadjuvant hormonal therapy effectively reduces the volume of normal tissue exposed to high radiation doses in the majority of treated patients and decreases the potential morbidity of therapy.

Management of locally recurrent colorectal adenocarcinoma represents a significant challenge. Many of these tumors adhere to or invade into vital pelvic structures rendering surgery or external beam radiotherapy (EBRT) as palliative treatment. Therefore, a treatment approach was developed to evaluate the role of high-dose-rate intraoperative brachytherapy (HDR-IORT) and surgery as a component of therapy in the management of locally recurrent colorectal cancer. This is an update of our preliminary report with longer follow-up and larger patient numbers.Between January 1992 and September 1998, 74 patients with locally recurrent rectal cancer were treated with surgery and HDR-IORT. Additional EBRT was given to 29 patients, and 33 patients received 5-fluorouracil based chemotherapy. All patients underwent complete gross resection, and 21 of 74 had positive microscopic margin. The dose of HDR-IORT ranged from 10 to 18 Gy.With a median follow-up of 22 months, the 5-year local control, distant metastasis disease-free, disease-free, and overall survival rates were 39%, 39%, 23%, and 23%, respectively. The only predictor of improved local control was a negative margin of resection with a 5-year local control rate of 43%, compared to 26% in those with positive margin (p = 0.02). For overall survival, a negative microscopic margin (p = 0.04) and the use of IORT + EBRT (p = 0.04) were significant predictors of improved survival. The incidence of peripheral neuropathy was 16%.The results with HDR-IORT in this group of patients are encouraging. Further improvements in local and distant control are still needed.

The presence of a positive or close margin after resection of a squamous cancer of the head and neck is associated with a significant risk of local recurrence. To determine the efficacy of postoperative radiation therapy for patients with advanced oral cavity and oropharyngeal cancers with inadequate margins of resection, the present retrospective analysis was undertaken.One hundred and two patients were treated with surgery and postoperative radiation therapy for advanced squamous cell carcinomas of the oral cavity and oropharynx. The anatomic subsites treated include oral tongue (n = 29), floor of mouth (n = 22), base of tongue (n = 31) and tonsillar fossa (n = 20). Twenty-five patients (25%) had positive margins, 41 patients (40%) had close margins (< or = 0.5 cm from the surgical margin) and 36 (35%) had negative margins. The median radiation dose was 6000 cGy.With a median follow-up of 7 years, the actuarial control rate for patients with positive, close and negative margins was 79%, 71%, and 79%, respectively. When postoperative doses of > or = 60 Gy were delivered to patients with positive/close margins (excluding patients with oral tongue lesions), the 7-year actuarial control was 92%. In similar patients receiving < 60 Gy, the actuarial control was 44% (p = 0.0007). Compared to other anatomic subsites, inferior control rates were obtained with oral tongue lesions. For this subsite, the control rates for positive, close, and negative margins were 50%, 62% and 69% respectively.We conclude that excellent local control can be achieved with postoperative radiation therapy, despite the presence of inadequate margins of resection, when doses of > or = 60 Gy are used. Future strategies must be directed at further improving these results in patients with oral tongue lesions.

<h2>Abstract</h2> Objectives. To determine the efficacy of sildenafil for patients with erectile dysfunction after radiotherapy for localized prostate cancer. Methods. Fifty patients with erectile dysfunction after radiotherapy were treated with sildenafil. Their median age was 68 years (range 54 to 78). All were treated with a three-dimensional conformal external beam radiotherapy approach, and the median dose prescribed to the planning target volume was 75.6 Gy. Patients were initially given 50 mg of sildenafil and instructed to use the medication on at least three occasions. They were then contacted to ascertain the efficacy of and tolerance to the medication. Results. Significant improvement in the firmness of the erection after sildenafil was reported in 37 patients (74%), 2 (4%) had partial improvement, and 11 (22%) had no response. Significant improvement in the durability of the erection was reported in 33 patients (66%), 3 (6%) had partial improvement, and 14 (28%) reported no improvement. Patients with partial or moderate erectile function before using sildenafil were more likely to benefit from the medication compared with those with absent function. Among 29 patients with erections classified as partial after radiotherapy, 26 (90%) had a significant response to the medication. In contrast, only 11 (52%) of 21 with erections classified as flaccid after radiotherapy had a significant response to the medication (<i>P = 0.007).</i> Conclusions. Sildenafil improved erectile function in greater than two thirds of patients with postradiotherapy impotence. Patients with less severe dysfunction are most likely to benefit from this intervention.

Three-dimensional conformal radiotherapy (3D-CRT) has been associated with a reduction in acute and late toxicity among patients treated for localized prostatic cancer. The purpose of this study is to assess the acute and late toxicity of 3D-CRT delivered to patients in the postprostatectomy setting and to analyze which factors predict for durable biochemical control in this group of patients.Between 1988 and 1994, 42 patients were treated after prostatectomy with three-dimensional conformal radiotherapy. The median time from prostatectomy to radiotherapy was 11 months. Indications for treatment included a rising serum PSA level in 28 patients (65%) and positive surgical margins without a rising PSA level in 14 (35%). Twenty-five patients (60%) had pathologic stage T3 disease, and 32 (74%) had tumor at or close to the surgical margins. The median dose was 64.8 Gy, and the median follow-up time was 2 years.3D-CRT in the postprostatectomy setting was well tolerated. Three patients (7%) experienced Grade II acute genitourinary toxicity and nine patients (21%) experienced Grade II acute gastrointestinal toxicity during treatment. No patient experienced Grade III or higher acute morbidity. The 2-year actuarial risk for Grade II late genitourinary and gastrointestinal late complications were 5 and 9%, respectively. In patients with existing incontinence, the incidence of worsening stress incontinence 6 months after treatment was 17%, which resolved within 12 months to its preradiotherapy level in four of six cases (66%). The overall 2-year postirradiation PSA relapse-free survival rate was 53%. The 2-year PSA relapse-free survival was 66% for patients with undetectable PSA levels in the immediate postoperative period compared to 26% for those with detectable levels of PSA after surgery (p < 0.006). Furthermore, for patients with preradiotherapy PSA levels of < or = 1.0 ng/ml, the 2-year PSA relapse-free survival was 74% compared to 17% of those with preradiotherapy PSA levels of > 1.0 ng/ml (p < 0.002). The resection margin status, presence of seminal vesicle involvement, Gleason score, and the preprostatectomy PSA level did not impact on PSA relapse-free survival. A Cox proportional hazards regression analysis demonstrated that a preradiotherapy PSA value of > 1 ng/ml (p < 0.002) was the most important covariate predicting for a rising PSA after radiotherapy.After prostatectomy, three-dimensional conformal radiotherapy is associated with minimal treatment-related morbidity. Patients with postprostatectomy, preradiotherapy PSA levels < or = 1.0 ng/ml, and those patients who had undetectable PSA levels in the immediate postoperative period are more likely to benefit from local adjuvant therapy.

We describe a method of incorporating organ motion into three-dimensional (3D) conformal treatment plans, which predicts the effect of organ motion on the calculated dose to both the clinical target volume (CTV) and nontarget organs.The method is based on measurements of organ motion by means of multiple computed tomography (CT) scans from a group of "reference" patients, in which the data consist of previously drawn contours of the target and nontarget organs. A computer program records the differences in contour position and shape that occur between scans in the reference data, and according to those differences adjusts the contours and dose calculation points of a "study" patient currently being planned, thus simulating organ motion. Dose-volume histograms (DVHs) are accumulated, and the process is repeated over the set of reference patient scans, resulting in a set of treatment plans that are ranked according to a dose-based endpoint. Two plans are selected corresponding to specified lower and upper confidence limits in the endpoint, and the DVHs from these plans are displayed for comparison with the DVHs from the nominal plan in the absence of motion.As an example of the method's use, it is applied to a 6-field conformal treatment plan for prostate cancer. Confidence limit DVHs of the CTV and rectal wall (in which the plans were ranked by probabilities for tumor control and normal tissue complication, respectively) are presented and compared to those from the nominal plan.The method provides a means of estimating the uncertainty in dose delivered by a treatment plan when organ motion is present. It is generally applicable to any treatment site for which data in the form of multiple CT scans are available, and can be extended to include other treatment uncertainties such as variation in patient positioning.