Hartmut Link

Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer.In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927.Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2-67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1-63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85-1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8-10·8) in the cetuximab group and 10·3 months (9·8-11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88-1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0-36·6) in the cetuximab group compared with 25·0 months (22·7-27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62-0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]).Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer.Merck KGaA.

All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

Summary Background A randomised trial comparing filgrastim-mobilised peripheral blood progenitor cell (PBPC) transplants with autologous bone marrow transplantation (ABMT) for haematopoietic stem cell support has not been done. We compared the effects of filgrastim-mobilised PBPC or autologous bone marrow reinfused to lymphoma patients after high-dose chemotherapy in a prospective randomised multicentre trial. Methods The trial was done at six centres in three European countries. After high-dose chemotherapy (carmustine, etoposide, cytarabine, and melphalan [BEAM protocol]) 58 patients with advanced Hodgkin's disease or high-grade non-Hodgkin lymphoma received either filgrastim-mobilised PBPC (n=27) or bone marrow (n=31) for haemopoietic reconstitution. Findings The median number of days with platelet transfusions after grafting was 6 in the PBPC transplantation group and 10 in the ABMT group (estimate of treatment difference 5 days, 95% Cl 3-7 days). Time to platelet recovery above 20×109/L was 16 days in the PBPC transplantation group and 23 days in the ABMT group (p=0·02). Time to neutrophil recovery above 0·5×109/L was also reduced in the PBPC transplantation group (11 vs 14 days, p=0·005). Patients randomised to PBPC transplantation needed fewer red blood cell transfusions (two vs three, p=0·002) and spent less time in hospital (17 vs 23 days, p=0·002). Early post-transplant morbidity and mortality as well as overall survival (median follow-up 311 days) were similar in both groups. There was no notable toxicity ascribed to filgrastim administration or the leucapheresis procedures. Interpretation In patients with lymphoma treated with high-dose chemotherapy, reinfusing filgrastim-mobilised PBPC instead of autologous bone marrow significantly reduced the number of platelet transfusions, the time to platelet and neutrophil recovery, and led to earlier discharge from hospital.

Abstract We designed a multicenter randomized trial comparing chemotherapy with daunorubicin-Ara C (chemotherapy group) and all transretinoic acid (ATRA) combined to the same chemotherapy (ATRA group) in newly diagnosed APL patients aged 65 years or less. The major endpoint of the study was event-free survival (EFS) (“events” being defined as failure to achieve complete remission [CR], occurrence of relapse, or death in CR). Early termination of the trial was decided after the first interim analysis, as EFS was significantly higher in the ATRA group. At the time, 101 patients had been randomized (54 in the ATRA group and 47 in the chemotherapy group). In the ATRA group, 49 (91%) patients achieved CR, 5 (9%) had early death, and 0 had resistant leukemia, compared with 38 (81%), 4 (8%), and 5 (10%) patients, respectively, in the chemotherapy group. The difference in CR rate between the two groups was not significant. The duration of coagulopathy was significantly reduced in the ATRA group, compared with the chemotherapy group. In the ATRA group, six patients relapsed after 7 to 15.5 months. In the chemotherapy group, 12 patients relapsed after 1 to 16 months, and 2 died in CR. Kaplan-Meier EFS was estimated at 79% +/- 7% and 50% +/- 9% at 12 months, respectively, in the ATRA and the chemotherapy group (P = .001). Kaplan-Meier estimate of relapse was 19% +/- 8% and 40% +/- 12% at 12 months (P = .005). In conclusion, ATRA followed by chemotherapy increases EFS in newly diagnosed APL. These results strongly suggest that ATRA should be incorporated in the front line therapy of newly diagnosed APL.

Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine.This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993.Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4).Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.Roche Pharma AG (Grenzach-Wyhlen, Germany).

Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks. We do not recommend the use of higher than standard initial doses of erythropoietic proteins with the aim of producing higher haematological responses, due to the limited body of evidence available. There is Level I evidence that, within reasonable limits of body weight, fixed doses of erythropoietic proteins can be used to treat patients with chemotherapy-induced anaemia. This analysis confirms that there are no baseline predictive factors of response to erythropoietic proteins that can be routinely used in clinical practice if functional iron deficiency or vitamin deficiency is ruled out; a low serum erythropoietin (EPO) level (only in haematological malignancies) appears to be the only predictive factor to be verified in Level I studies. Further studies are needed to investigate the value of hepcidin, c-reactive protein, and other measures as predictive factors. In these updated guidelines, we explored a new question of whether oral or intravenous iron supplementation increases the response rate to erythropoietic proteins. We found no evidence of increased response with the addition of oral iron supplementation, but there is Level II evidence of improved response to erythropoietic proteins with the addition of intravenous iron. However, the doses and schedules for intravenous iron supplementation are not yet well defined, and further studies in this area are warranted. The two major goals of erythropoietic protein therapy are prevention or elimination of transfusions and improvement of QoL. The total body of evidence shows that red blood cell (RBC) transfusion requirements are reduced following treatment with erythropoietic proteins. This analysis also confirms that QoL is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease following erythropoietic protein therapy, with more robust evidence now available that QoL was improved in studies investigating early intervention in cases of chemotherapy- or radiotherapy-induced anaemia. There is only indirect evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase. None of the studies addressed the question in a prospective, randomised fashion, and so the Taskforce does not recommend dose escalation as a general approach in all patients who are not responding. There is still insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. Our analysis of survival endpoints in studies involving patients receiving radio(chemo)therapy found that most studies were inconclusive, with no clear link between the use of erythropoietic proteins and survival. Likewise, we found no clear link between erythropoietic therapy and other endpoints such as local tumour control, time to progression, and progression-free survival. There is no evidence that pure red cell aplasia occurs in cancer patients following treatment with erythropoietic proteins, and the fear of this condition developing should not lead to erythropoietic proteins being withheld in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Additional trials are warranted, especially to define the optimal doses and schedules of intravenous iron supplementation during erythropoietic therapy. While our review did not address cost benefit evaluations in detail, the consensus is that studies taking into account all real determinants of cost and benefit need to be performed prospectively.

Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger.This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18-60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0-2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1:1) to receive two cycles of induction therapy with daunorubicin (60 mg/m(2) on days 3-5) plus cytarabine (100 mg/m(2) on days 1-7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m(2) twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10-19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40).Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35·5-38·1), median event-free survival was 9 months (95% CI 4-15) in the placebo group versus 21 months (9-32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13-32) in the placebo group versus 40% (29-51) in the sorafenib group (hazard ratio [HR] 0·64, 95% CI; 0·45-0·91; p=0·013). The most common grade 3-4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1·54, 95% CI 1·04-2·28), diarrhoea (RR 7·89, 2·94-25·2), bleeding (RR 3·75, 1·5-10·0), cardiac events (RR 3·46, 1·15-11·8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4·06, 1·25-15·7).In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease.Bayer HealthCare.

Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10 9 /L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P &lt; .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

Inhalt 1. Informationen zu dieser Leitlinie 462 1.1. Herausgeber 462 1.1.1. Federführende Fachgesellschaft 462 1.1.2. Kontakt 462 1.1.3. Verfügbare Dokumente zur Leitlinie 462 1.2. Besonderer Hinweis 462 1.3. Autoren dieser Leitlinie 462 1.4. Ziele des Leitlinienprogramms Onkologie 462 2. Einführung 463 2.1. Geltungsbereich und Zweck 463 2.1.1. Zielsetzung und Fragestellung 463 2.1.2. Adressaten 464 2.1.3. Verbreitung u. Implementierung d. Leitlinien 464 2.1.4. Finanzierung der Leitlinie und Darlegung möglicher Interessenskonflikte 464 2.1.5. Gültigkeitsdauer u. Aktualisierungsverfahren 465 2.2. Grundlagen der Methodik 465 2.2.1. Schema der Evidenzgraduierung nach Oxford 465 2.3. Verwendete Abkürzungen 466 3. Konsentierte und abgestimmte Empfehlungen 466 3.1. Risikofaktoren 466 3.1.1. Helicobacter pylori 466 3.1.2. Weitere Risikofaktoren 467 3.2. Risikogruppen 468 3.2.1. Familiäres Risiko 468 3.2.2. Hereditäres nonpolypöses kolorektales Karzinom (HNPCC) 469 3.3. Screening und Prävention 470 3.3.1. Screening 470 3.3.2. Prävention 471 3.4. Primärdiagnostik 472 3.4.1. Endoskopische Untersuchung 472 3.4.2. Staging 472 3.4.3. Histologie 472 3.5. Staging 473 3.5.1. Ultraschalldiagnostik 473 3.5.2. Röntgendiagnostik 474 3.5.3. Laparoskopie 475 3.5.4. Laborchemische Parameter 476 3.6. Histopathologie 476 3.7. Endoskopische Therapie 477 3.7.1. Resektion 477 3.7.2. Rezidiv 479 3.7.3. Komplikationen 479 3.7.4. Nachsorge 479 3.8. Chirurgische Therapie 479 3.8.1. Resektion 479 3.8.2. Rezidiv 483 3.8.3. Definitive Radiochemotherapie 483 3.9. Multimodale Therapie 483 3.9.1. Perioperative Chemotherapie 483 3.9.2. Präoperative Radiochemotherapie 488 3.9.3. Präoperative Antikörper-Therapie 488 3.9.4. Restaging nach neoadjuvanter Therapie 488 3.9.5. Postoperative Therapie 489 3.9.6. Adjuvante Therapiekonzepte 491 3.10. Tumorgerichtete palliative Therapie 493 3.10.1. Medikamentöse Tumortherapie 493 3.10.2. Vorgehen bei Tumoren ohne HER-2-Überexpression 494 3.10.3. Vorgehen bei HER-2-überexprimierenden/-amplifizierenden Tumoren 498 3.10.4. Zweit-Chemotherapie 498 3.11. Weitere palliative Situationen u. deren Therapie 499 3.11.1. Palliative Therapieoptionen 499 3.11.2. Therapie der Tumorblutung 500 3.11.3. Palliative operative Therapie 500 3.11.4. Chemotherapie-refraktärer maligner Aszites 500 3.12. Supportive Maßnahmen 501 3.12.1. Fatigue-Syndrom 501 3.12.2. Zusammenfassung weiterer Maßnahmen 501 3.13. Ernährung 505 3.13.1. Allgemeine Entscheidungshilfen 505 3.13.2. Präoperative Ernährungstherapie 506 3.13.3. Postoperative Ernährungstherapie 507 3.13.4. Ernährung unter Chemotherapie oder Strahlentherapie 507 3.13.5. Ernährung in der Sterbephase 509 3.14. Nachsorge und Rehabilitation 509 3.14.1. Lebensqualität 509 3.14.2. Substitutionen nach Gastrektomie 509 3.14.3. Rehabilitationsmaßnahmen 509 3.14.4. Bestimmung von Tumormarkern 510 3.15. Psychoonkologie 510 3.15.1. Patientennahes Informationsmanagement 510 3.15.2. Lebensqualität 510 3.15.3. Psychoonkologische Betreuung 511 3.16. Komplementäre Therapie 512 3.16.1. Abgestimmte Empfehlungen 512 3.16.2. Weitere Hinweise der Arbeitsgruppe zur komplementären Therapie 514 4. Qualitätsindikatoren 515 Literatur 517

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Anaemia and iron deficiency (ID) are frequent complications in patients with solid tumours or haematological malignancies, particularly in patients treated with chemotherapeutic agents [1.Ludwig H. Van Belle S. Barrett-Lee P. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients.Eur J Cancer. 2004; 40: 2293-2306http://dx.doi.org/10.1016/j.ejca.2004.06.019Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar, 2.Ludwig H. Muldur E. Endler G. Hubl W. Prevalence of iron deficiency across different tumors and its association with poor performance status, disease status and anemia.Ann Oncol. 2013; 24: 1886-1892http://dx.doi.org/10.1093/annonc/mdt118Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 3.Delarue R. Tilly H. 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Cleeland C.S. et al.Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy.Cancer. 2002; 95: 888-895http://dx.doi.org/10.1002/cncr.10763Crossref PubMed Scopus (366) Google Scholar, 7.Demetri G.D. Anaemia and its functional consequences in cancer patients: current challenges in management and prospects for improving therapy.Br J Cancer. 2001; 84: 31-37Crossref PubMed Google Scholar]. Consequences of anaemia may include impaired response to cancer treatment and reduced overall survival (OS), even though a causal direct relationship has not yet been established [8.Caro J.J. Salas M. Ward A. Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review.Cancer. 2001; 91: 2214-2221Crossref PubMed Scopus (718) Google Scholar, 9.Hudis C.A. Van Belle S. Chang J. Muenstedt K. rHuEPO and treatment outcomes: the clinical experience.Oncologist. 2004; 9: 55-69Crossref PubMed Scopus (0) Google Scholar]. These new ESMO Clinical Practice Guidelines provide tools to evaluate anaemia, also in patients with myelodysplastic syndromes (MDS), and include recommendations on how to safely manage chemotherapy-induced anaemia (CIA) with erythropoiesis-stimulating agents (ESAs), iron preparations for intravenous (i.v.) or oral administration, red blood cell (RBC) transfusions and combinations of these treatments [10.Aapro M. Österborg A. Gascón P. et al.Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of intravenous iron.Ann Oncol. 2012; 23: 1954-1962Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 11.National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology; Cancer and Chemotherapy-Induced Anemia – v.1.2018, 2017; http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf (18 October 2017, date last accessed).Google Scholar, 12.Aapro M. Chernov V.M. Gladkov O.A. et al.Practical recommendations for the treatment of anemia in cancer patients.Malignant Tumors. 2016; 4: 368-377Google Scholar, 13.Rizzo J.D. Brouwers M. Hurley P. et al.American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer.Blood. 2010; 116: 4045-4059http://dx.doi.org/10.1182/blood-2010-08-300541Crossref PubMed Scopus (168) Google Scholar]. The major aims of anaemia management are the reduction or resolution of anaemia symptoms, particularly fatigue, and an improved QoL with the minimum invasive treatment that corrects the underlying causes and proves to be safe. Underlying causes of anaemia, mainly impaired erythropoietic activity and disturbed iron homeostasis, can be consequences of increased release of inflammatory cytokines due to the underlying cancer and/or toxicity of cancer therapy. Furthermore, vitamin B12 and folate deficiency are relatively rare causes of anaemia in cancer patients. Notably, also more than half of patients with MDS are characterised by a haemoglobin (Hb) level < 10 g/dL, resulting in reduced functional capacities and health-related QoL, and > 80% of these patients require RBC transfusions [14.Santini V. Clinical use of erythropoietic stimulating agents in myelodysplastic syndromes.Oncologist. 2011; 16: 35-42Crossref PubMed Google Scholar, 15.Malcovati L. Hellström-Lindberg E. Bowen D. et al.Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet.Blood. 2013; 122: 2943-2964Crossref PubMed Scopus (404) Google Scholar, 16.Efficace F. Gaidano G. Breccia M. et al.Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes.Br J Haematol. 2015; 168: 361-370http://dx.doi.org/10.1111/bjh.13138Crossref PubMed Scopus (35) Google Scholar, 17.de Swart L. Smith A. Johnston T.W. et al.Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry.Br J Haematol. 2015; 170: 372-383http://dx.doi.org/10.1111/bjh.13450Crossref PubMed Google Scholar]. However, ESAs were not approved by the European Medicines Agency (EMA) for use in MDS patients despite being used effectively in MDS for at least 20 years; their activity has been demonstrated in numerous clinical trials, with published evidence existing for more than 2500 ESA-treated MDS patients [14.Santini V. Clinical use of erythropoietic stimulating agents in myelodysplastic syndromes.Oncologist. 2011; 16: 35-42Crossref PubMed Google Scholar]. Randomised clinical trials are ongoing. Since the publication of the European Society of Medical Oncology (ESMO) anaemia Clinical Practice Guidelines in 2010 [18.Schrijvers D. De Samblanx H. Roila F. Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use.Ann Oncol. 2010; 21: v244-v247Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar] and the last review of the European Organisation for Research and Treatment of Cancer (EORTC) anaemia treatment guidelines in 2006 [19.Bokemeyer C. Aapro M. Courdi A. et al.EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update.Eur J Cancer. 2007; 43: 258-270http://dx.doi.org/10.1016/j.ejca.2006.10.014Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar] (last update in 2007 [20.Aapro M.S. Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents.Oncologist. 2008; 13: 33-36Crossref PubMed Scopus (156) Google Scholar]), clinical experience with ESAs and iron preparations and the understanding of iron homeostasis have markedly increased [10.Aapro M. Österborg A. Gascón P. et al.Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of intravenous iron.Ann Oncol. 2012; 23: 1954-1962Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 21.Aapro M. Jelkmann W. Constantinescu S.N. Leyland-Jones B. Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer.Br J Cancer. 2012; 106: 1249-1258Crossref PubMed Scopus (83) Google Scholar]. Furthermore, specific safety aspects of the different treatment options have been addressed by several analyses and reviews in recent years, although data on the use of blood transfusions in cancer patients are sparse. Therefore, new ESMO guidelines for the diagnosis and treatment of anaemia and ID in cancer patients were deemed necessary. In addition, these guidelines include aspects related to anaemia management in patients with MDS and update the most recent ESMO and European LeukemiaNet (ELN) treatment guidelines for MDS [15.Malcovati L. Hellström-Lindberg E. Bowen D. et al.Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet.Blood. 2013; 122: 2943-2964Crossref PubMed Scopus (404) Google Scholar, 22.Fenaux P. Haase D. Sanz G.F. et al.Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii57-iii69Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. Questions addressed by these guidelines and respective recommendations including levels of evidence and grades of recommendations [23.Dykewicz C.A. Summary of the guidelines for preventing opportunistic infections among haematopoietic stem cell transplant recipients.Clin Infect Dis. 2001; 33: 139-144http://dx.doi.org/10.1086/321805Crossref PubMed Scopus (0) Google Scholar] are summarised in Table 1 for the management of anaemia and ID in patients with solid tumours or haematological malignancies and in Table 2 for the management of MDS. These recommendations are further illustrated in treatment algorithms (Figures 1 and 2). Discussions of specific aspects underlying the recommendations and related to the different treatment options are summarised in this article.Table 1Managing anaemia and ID in patients with solid tumours or haematological malignanciesWhen should ESA treatment be considered?Treatment of anaemia with an ESA should be considered in patients under ChT after correction of ID and other underlying causes other than the cancer or its treatment [I, A].Which patients should receive ESA therapy?ESA therapy is recommended in patients with symptomatic anaemia who receive ChT [I, A] or combined RT-ChT [II, B] and present with an Hb level < 10 g/dL, as well as patients with asymptomatic anaemia who receive ChT and present with an Hb level < 8 g/dL.Should patients who do not receive ChT treatment be treated with an ESA?ESA treatment is not recommended in patients who are not on ChT [I, A].What is the Hb target range for treatment with an ESA?The Hb target is a stable level of ∼ 12 g/dL without RBC transfusions [I, A].At what doses should ESAs be given?Dosing should follow the approved labels of the individual products; the currently recommended dosage is approximately 450 IU/week/kg body weight for epoetins alpha, beta and zeta; 6.75 µg/kg body weight every 3 weeks or 2.25 µg/kg body weight weekly for darbepoetin alpha; and 20 000 IU once weekly for epoetin theta [I, A].Should ESA doses be increased or ESA preparations changed in patients not responding within 4–8 weeks?Except for patients receiving epoetin theta (given at an intentionally low starting dose), ESA dose escalations and changes from one ESA to another in patients not responding within 4–8 weeks are not recommended. Patients who do not show evidence of at least an initial Hb response at this time should stop ESA therapy. The epoetin theta dose may be doubled after 4 weeks if Hb has not increased by at least 1 g/dL, unless functional ID is detected (see next recommendation) [I, A].Which patients should receive iron therapy?Patients receiving ongoing ChT who present with anaemia (Hb ≤ 11 g/dL or Hb decrease ≥ 2 g/dL from a baseline level ≤ 12 g/dL) and absolute ID (serum ferritin < 100 ng/mL) should receive iron treatment with an i.v. iron preparation to correct ID. If ESA treatment is considered, iron treatment should be given before the initiation of and/or during ESA therapy in the case of functional ID (TSAT < 20% and serum ferritin > 100 ng/mL) [I, A].Should patients receive i.v. iron therapy without an ESA?i.v. iron without additional anaemia therapy may be considered in individual patients with functional ID (TSAT < 20% and serum ferritin > 100 ng/mL) [III, C].Should patients who are not on ChT receive iron therapy?Iron treatment should be limited to patients on ChT. In patients receiving cardiotoxic ChT, i.v. iron should either be given before or after (not on the same day) administration of ChT or at the end of a treatment cycle [III, C].At what doses should i.v. iron be given?Patients with confirmed functional ID should receive a dose of 1000 mg iron given as single dose or multiple doses according to the label of available i.v. iron formulations. Patients with confirmed absolute ID should receive i.v. iron doses according to the approved labels of available products until correction of ID [I, A].Which patients should be considered for RBC transfusions?In patients with Hb < 7–8 g/dL and/or severe anaemia-related symptoms (even at higher Hb levels) and the need for immediate Hb and symptom improvement, the administration of RBC transfusions without delay is justified [II, B].ChT, chemotherapy; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; RBC, red blood cell; RT, radiotherapy; TSAT, transferrin saturation. Open table in a new tab Table 2Managing anaemia in patients with MDSWhen should ESA treatment be considered?aESAs are not all EMA-approved for use in patients with MDS. Epoetin alpha is indicated by the EMA for the treatment of symptomatic anaemia (haemoglobin concentration of ≤ 10 g/dL) in adults with low or intermediate-1 risk primary MDS who have low serum EPO (<200 IU/mL).Treatment of anaemia with an ESA should be considered in MDS patients with symptomatic anaemia, Hb < 10 g/dL, low to intermediate-1 risk (IPSS) or very low to intermediate risk (IPSS-R), less than two RBC transfusions per month and/or serum EPO < 500 IU/L [I, A].At what doses should ESAs be given?ESAs should be given as fixed-dose, weekly, subcutaneous treatment at an initial dose in the range of 30 000–80 000 IU recombinant human EPO (epoetin theta starting dose is 20 000 IU) or up to 300 µg darbepoetin alpha [I, A].How should MDS patients who are not responding to ESA treatment be treated?In patients not responding to ESA treatment after 8–12 weeks, G-CSF should be added at ∼ 300 µg/week, given in 2–3 doses. RBC transfusions or investigational medicinal products should be considered as second-line treatment in patients without a 5q deletion, and lenalidomide in patients who acquired a 5q deletion [I, A].How should transfusion-dependent, anaemic MDS patients be treated?Patients who require 2 or more RBC transfusions per month should be considered for treatment with an investigational agent or supportive care with RBC transfusions if they have no 5q deletion, or for lenalidomide if they have a 5q deletion [I, A].EMA, European Medicines Agency; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, haemoglobin; IPSS, International Prognostic Scoring System; IPSS-R, revised International Prognostic Scoring System; MDS, myelodysplastic syndrome; RBC, red blood cell.a ESAs are not all EMA-approved for use in patients with MDS. Epoetin alpha is indicated by the EMA for the treatment of symptomatic anaemia (haemoglobin concentration of ≤ 10 g/dL) in adults with low or intermediate-1 risk primary MDS who have low serum EPO (<200 IU/mL). Open table in a new tab Figure 2Management of anaemia in patients with very low to intermediate-risk MDS. aESA-treated patients who are iron deficient and transfusion independent may be considered for i.v. iron treatment. EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, haemoglobin; IPSS, International Prognostic Scoring System; IPSS-R, revised International Prognostic Scoring System; i.v., intravenous; MDS, myelodysplastic syndrome; RBC, red blood cell; SF, serum ferritin; TSAT, transferrin saturation. Adapted from [22.Fenaux P. Haase D. Sanz G.F. et al.Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii57-iii69Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) ChT, chemotherapy; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; RBC, red blood cell; RT, radiotherapy; TSAT, transferrin saturation. EMA, European Medicines Agency; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, haemoglobin; IPSS, International Prognostic Scoring System; IPSS-R, revised International Prognostic Scoring System; MDS, myelodysplastic syndrome; RBC, red blood cell. ESAs have been shown to increase Hb levels and to reduce the need for RBC transfusions in cancer patients receiving chemotherapy [24.Gabrilove J.L. Cleeland C.S. Livingston R.B. et al.Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing.J Clin Oncol. 2001; 19: 2875-2882http://dx.doi.org/10.1200/JCO.2001.19.11.2875Crossref PubMed Google Scholar, 25.Hedenus M. Adriansson M. San Miguel J. et al.Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study.Br J Haematol. 2003; 122: 394-403http://dx.doi.org/10.1046/j.1365-2141.2003.04448.xCrossref PubMed Scopus (287) Google Scholar, 26.Littlewood T.J. Bajetta E. Nortier J.W. et al.Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial.J Clin Oncol. 2001; 19: 2865-2874http://dx.doi.org/10.1200/JCO.2001.19.11.2865Crossref PubMed Scopus (918) Google Scholar, 27.Vansteenkiste J. Pirker R. Massuti B. et al.Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy.J Natl Cancer Inst. 2002; 94: 1211-1220http://dx.doi.org/10.1093/jnci/94.16.1211Crossref PubMed Google Scholar] and are approved for the treatment of CIA since 1993 [28.Aapro M. An update on twenty years of anemia management with erythropoiesis-stimulating agents in nephrology and oncology/hematology.Oncologist. 2009; 14: 1-5Crossref PubMed Scopus (14) Google Scholar]. Furthermore, a meta-analysis of 23 studies that reported QoL results and included 5584 patients showed a statistically significant difference between patients treated with ESAs and controls when combining QoL parameters and fatigue-related symptoms well as anaemia-related symptoms [29.Tonia T. Mettler A. Robert N. et al.Erythropoietin or darbepoetin for patients with cancer.Cochrane Database Syst Rev. 2012; 12: CD003407.PubMed Google Scholar] (Table 3). However, the authors considered this finding to be not clinically important. Conversely, experience with patients responding to therapy and a recently published meta-analysis of 37 randomised, controlled trials with 10 581 patients suggest a small but clinically important improvement in anaemia-related symptoms [30.Bohlius J. Tonia T. Nüesch E. et al.Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data.Br J Cancer. 2014; 111: 33-45Crossref PubMed Scopus (37) Google Scholar].Table 3Benefit-risk profiles of treatments for anaemia and ID in cancer patientsBenefitsRisks or limitationsESAs•Reduction of RBC transfusions•Improvement in anaemia-related symptoms•Increase in thrombotic events•PRCA in rare casesaDocumented only in non-cancer chronic kidney disease patients.•Increased mortality in patients receiving no cancer therapy or only RT•Only effective in 60% of patients•Induction of functional ID and decreasing response over timei.v. ironbOral iron to be considered only for patients with both absolute ID (ferritin < 100 ng/mL) and non-inflammatory conditions (CRP < 5 mg/L).•Correction of ID anaemia•Reduction of RBC transfusions•Increase response to ESAs•Long-term safety in oncology not yet fully establishedRBC transfusions•Immediate increase of Hb and haematocrit levels in 100%•Rapid improvement in anaemia-related symptoms•Increase in thrombotic events•Transfusion reactions and circulatory overload•Transmission of known/unknown pathogens•Possibly decreased survival in certain types of cancer treated by surgery•Increased risk of infections due to immunosuppressionCRP, C-reactive protein; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; PRCA, pure red cell aplasia; RBC, red blood cell; RT, radiotherapy.a Documented only in non-cancer chronic kidney disease patients.b Oral iron to be considered only for patients with both absolute ID (ferritin < 100 ng/mL) and non-inflammatory conditions (CRP < 5 mg/L). Open table in a new tab CRP, C-reactive protein; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; PRCA, pure red cell aplasia; RBC, red blood cell; RT, radiotherapy. Since early dose finding studies with epoetin beta did not show a difference in Hb response to 5000 and 10 000 IU/day (corresponding to 500 and 1000 IU/kg/week in a 70 kg individual) [31.Cazzola M. Messinger D. Battistel V. et al.Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin’s lymphoma: dose finding and identification of predictors of response.Blood. 1995; 86: 4446-4453Crossref PubMed Google Scholar], and since there is not a single study on dose escalations showing a benefit, dose escalations in patients who do not respond within 4–8 weeks are not recommended (except for epoetin theta’s low starting dose to be doubled after 4 weeks if Hb response is < 1 g/dL). Instead, ESA treatment should be stopped at this time point if there is no emerging sign of Hb response. There is no evidence of differing efficacy among ESAs (Table 4) and no recommendation can be made to change from one product to another in the case of an insufficient response. Because of possible safety issues, we continue to recommend that products should not be used interchangeably without adequate traceability and without notifying the treating physician [V, C].Table 4Approved ESAs and i.v. iron compounds and their approved dosing in patients with solid tumours and haematological malignanciesaEpoetin alpha is EMA-approved for low or intermediate-1 risk MDS (see text).,bBoth originator products and biosimilars approved by the EMA have been shown to have similar safety and therapeutic equivalence in clinical practice.ESAsEpoetin alpha450 IU/kg subcutaneously once weekly or 150 IU/kg subcutaneously 3 times per weekEpoetin beta30 000 IU subcutaneously (i.e. ∼ 450 IU/kg body weight in a 70 kg patient) given once weekly or divided over 3–7 times per weekEpoetin theta20 000 IU subcutaneously independent of body weight given once weekly, dose may be doubled after 4 weeks if Hb has not increased by at least 1 g/dLEpoetin zeta450 IU/kg subcutaneously once weekly, or 150 IU/kg subcutaneously 3 times per weekDarbepoetin alpha500 μg (6.75 μg/kg body weight) subcutaneously given once every 3 weeks or 2.25 μg/kg body weight subcutaneously once weeklyi.v. ironcFollow the label indications in your country.Ferric gluconateMaximum infusion dose: 125 mg ironMinimum infusion time: 60 minIron sucroseMaximum infusion dose: 200–500 mg ironMinimum infusion time: 30–210 minIron dextrandLow molecular weight iron dextran.Maximum infusion dose: depends on exact iron dextran type; refer to label.Minimum infusion time: 240–360 minIron isomaltosideMaximum infusion dose: 20 mg/kg body weight (up to 1000 mg ironeThe authors suggest a dose up to 1000 mg, while drug labels might allow more.)Minimum infusion time: 15 minfIf dose is up to 1000 mg; if dose exceeds 1000 mg iron, more than 30 min is recommended, as per label.Ferric carboxymaltoseMaximum infusion dose: 20 mg/kg body weight (up to 1000 mg iron per week)Minimum infusion time: 15 minEMA, European Medicines Agency; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; i.v., intravenous; MDS, myelodysplastic syndrome.a Epoetin alpha is EMA-approved for low or intermediate-1 risk MDS (see text).b Both originator products and biosimilars approved by the EMA have been shown to have similar safety and therapeutic equivalence in clinical practice.c Follow the label indications in your country.d Low molecular weight iron dextran.e The authors suggest a dose up to 1000 mg, while drug labels might allow more.f If dose is up to 1000 mg; if dose exceeds 1000 mg iron, more than 30 min is recommended, as per label. Open table in a new tab EMA, European Medicines Agency; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; i.v., intravenous; MDS, myelodysplastic syndrome. In the late 2000s, the safety of ESAs was discussed when meta-analyses suggested that ESA treatment may affect mortality in cancer patients [32.Bennett C.L. Silver S.M. Djulbegovic B. et al.Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.JAMA. 2008; 299: 914-924http://dx.doi.org/10.1001/jama.299.8.914Crossref PubMed Scopus (603) Google Scholar, 33.Bohlius J. Schmidlin K. Brillant C. et al.Erythropoietin or darbepoetin for patients with cancer–meta-analysis based on individual patient data.Cochrane Database Syst Rev. 2009; 3: CD007303PubMed Google Scholar], particularly if target Hb levels exceeded 12 g/dL [34.Henke M. Laszig R. Rübe C. et al.Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.Lancet. 2003; 362: 1255-1260Abstract Full Text Full Text PDF PubMed Scopus (1123) Google Scholar, 35.Hoff C.M. Hansen H.S. Overgaard M. et al.The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy—results from the randomized DAHANCA 5 study.Radiother Oncol. 2011; 98: 28-33Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 36.Leyland-Jones B. Semiglazov V. Pawlicki M. et al.Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study.J Clin Oncol. 2005; 23: 5960-5972http://dx.doi.org/10.1200/JCO.2005.06.150Crossref PubMed Scopus (581) Google Scholar, 37.Smith Jr, R.E. Aapro M.S. Ludwig H. et al.Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study.J Clin Oncol. 2008; 26: 1040-1050http://dx.doi.org/10.1200/JCO.2007.14.2885Crossref PubMed Scopus (179) Google Scholar, 38.Wright J.R. Ung Y.C. Julian J.A. et al.Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia.J Clin Oncol. 2007; 25: 1027-1032http://dx.doi.org/10.1200/JCO.2006.07.1514Crossref PubMed Scopus (355) Google Scholar]. Consequently, the recommended Hb target range for ESA treatment is 10–12 g/dL, and an Hb rise of > 2 g/dL over a 4-week period should be avoided. In 2014, a study in anaemic patients with metastatic breast cancer suggested that addition of erythropoietin (EPO) to standard of care with a target Hb > 12 g/dL did not meet the non-inferiority criteria for progression-free survival (PFS) versus standard of care alone [39.Leyland-Jones B. Bondarenko I. Nemsadze G. et al.A randomized, open-label, multicenter, phase III study of epoetin alfa (EPO) plus standard supportive care versus standard supportive care in anemic patients with metastatic breast cancer (MBC) receiving standard chemotherapy.J Clin Oncol. 2016; 34: 1197-1207http://dx.doi.org/10.1200/JCO.2015.63.5649Crossref PubMed Scopus (0) Google Scholar]. However, the late separation of the PFS and OS curves can hardly be explained by a few weeks of EPO exposure. Notably, the most recent Cochrane review included subgroup analyses and showed statistically significant on-study mortality in patients with baseline Hb > 12 g/dL but not for Hb categories Hb < 10 g/dL and Hb = 10–12 g/dL that correspond to the currently approved cut-off for initiation and the target Hb range of ESA therapy [29.Tonia T. Mettler A. Robert N. et al.Erythropoietin or darbepoetin for patients with cancer.Cochrane Database Syst Rev. 2012; 12: CD003407.PubMed Google Scholar]. When excluding one study with a target Hb range above the labelled guidance (BEST, target Hb = 12–14 g/dL [36.Leyland-Jones B. Semiglazov V. Pawlicki M. et al.Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study.J Clin Oncol. 2005; 23: 5960-5972http://dx.doi.org/10.1200/JCO.2005.06.150Crossref PubMed Scopus (581) Google Scholar]), the effect lost statistical significance [od

Abstract In 105 consecutive patients with de novo acute myeloid leukemia (French-American-British M3 excluded), we compared prospectively the risk of bleeding complications, the number of platelet and red blood cell transfusions administered, and the costs of transfusions using two different prophylactic platelet transfusion protocols. Two hundred sixteen cycles of induction or consolidation chemotherapy and 3,843 days of thrombocytopenia less than 25 × 109/L were evaluated. At the start of the study, each of the 17 participating centers decided whether they would use a 10 × 109/L prophylactic platelet transfusion trigger (group A/8 centers) or a 20 × 109/L trigger (group B/9 centers). Bleeding complications (World Health Organization grade 2-4) during treatment cycles were comparable in the two groups: 20 of 110 (18%) in group A and 18 of 106 (17%) in group B (P = .8). Serious bleeding events (grade 3-4) were generally not related to the patient's platelet count but were the consequence of local lesions and plasma coagulation factor deficiencies due to sepsis. Eighty-six percent of the serious bleeding episodes occurred during induction chemotherapy. No patient died of a bleeding complication. There were no significant differences in the number of red blood cell transfusions administered between the two groups, but there were significant differences in the number of platelet transfusions administered per treatment cycle: pooled random donor platelet concentrates averaged 15.4 versus 25.4 (P &lt; .01) and apheresis platelets averaged 3.0 versus 4.8 (P &lt; .05) for group A versus group B, respectively. This resulted in the cost of platelet therapy being one third lower in group A compared with group B without any associated increase in bleeding risk.

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996–2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see Table 4). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration ⩽105 g/L, but none compared the effect of different baseline Hb levels on the response to treatment. Similarly, several studies defined the target Hb concentration as 120–130 g/L following treatment with erythropoietic proteins, but none specifically addressed the correlation between target Hb level and clinical benefit in a randomised fashion. Level I evidence shows that red blood cell (RBC) transfusion requirements are significantly reduced with erythropoietic protein therapy in patients with chemotherapy-induced anaemia or when used to prevent cancer anaemia (approximately 20% reduction compared with controls). We found indirect Level I and III evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase (absolute increases in response rate ranged from 8% to 18%). However, none of these studies examined the effect on response rates of a longer treatment period at the lower dose, or performed a randomised comparison of a dose increase versus an unchanged dose. There is Level I evidence to show that quality-of-life (QOL) is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease, particularly in patients achieving a Hb response to erythropoietic protein therapy. There are insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week (TIW) is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. There is Level III evidence that initial doses of erythropoietic proteins considered to be higher than current standard practice produce higher haematological responses in patients with chemotherapy-induced anaemia or anaemia of chronic disease. Level I evidence demonstrates that several baseline patient parameters (e.g., low endogenous erythropoietin [EPO] concentration, age <60 years, Hb concentration ⩾90 g/L) impact upon the response to erythropoietic proteins when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. Evidence indicates that endogenous EPO concentration impacts on response in patients with lymphoproliferative malignancies, but is not a valid parameter in patients with solid tumours. There is Level I evidence that fixed doses of erythropoietic proteins can be used at the start of therapy to treat patients with chemotherapy-induced anaemia, but maintenance doses should be titrated individually. There is no evidence that pure red cell aplasia (PRCA) occurs following treatment with erythropoietic proteins in patients with chemotherapy-induced anaemia or when used prophylactically in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Level I evidence supports the effectiveness of erythropoietic proteins to prevent anaemia in non-anaemic cancer patients receiving chemotherapy or radiotherapy or in those undergoing cancer surgery. However, these are non-licensed indications and we do not currently recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients who have normal Hb values at the start of treatment. Additional trials are warranted, especially on the issues of iron replacement and cost-effectiveness of erythropoietic protein therapy, as well as on tumour response/progression and survival.

Data on 49 allogeneic bone marrow transplant (BMT) recipients who developed interstitial pneumonia due to cytomegalovirus (CMV) were collected retrospectively. All patients were treated with ganciclovir and high doses of intravenous immune globulin, although types of immune globulins and schedules of treatment varied. Seventeen (35%) of 49 patients responded to treatment. Thirty days after the diagnosis of interstitial pneumonia, the survival rate among patients was 31%. CMV was detected in 81% of patients on whom autopsies were performed. The survival rate among patients who received total body irradiation (TBI) was significantly lower (11 [27%] of 41) than that among patients who did not receive TBI (six [75%] of eight; odds ratio = 12.3; P = .009). No other factor, including age, grade of graft-versus-host disease, types and dose of immune globulin used, or dose of ganciclovir, was correlated to survival. These results show that although survival of allogeneic BMT recipients with CMV interstitial pneumonia has improved, more than one-half of the patients still died of pneumonia. Thus, both prophylaxis for and treatment of CMV infection must be improved.

Anemia is frequently experienced by cancer patients receiving chemotherapy and can negatively impact the patient's prognosis. Blood transfusions, iron supplementation (in absolute or functionally iron-deficient anemias), and erythropoiesis-stimulating agents (ESAs) are among the treatment options for anemia. Treatment options for anemia management should be selected based on the best benefit-to-risk ratio for each individual patient. In September 2007, the working party of the European Organization for Research and Treatment of Cancer (EORTC) updated their guidelines on the use of ESAs, which are summarized in this paper. ESAs reduce the number of transfusions required and significantly improve quality of life in patients with chemotherapy-induced anemia. A sustained hemoglobin level of about 12 g/dl should be the target for treatment with ESAs. ESAs should be used according to the EORTC guidelines and within label with carefully considered exceptions.

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.

BackgroundThe study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P).Patients and methodsPatients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m2 i.v. on days 1, 15 and 22); FA (200 mg/m2 i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m2 i.v. bolus, then 22-h, 600 mg/m2 infusion) or CAPIRI: irinotecan (250 mg/m2 i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m2 b.i.d. on days 1–15 and 22–36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 × 200 mg b.i.d.).ResultsThe trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months).ConclusionDue to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 11, Issue s6 p. 1-116 GuidelinesFree Access Malignant Melanoma S3-Guideline “Diagnosis, Therapy and Follow-up of Melanoma” Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorshipSearch for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorshipSearch for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln, Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisc-Onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorshipSearch for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorshipSearch for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln, Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisc-Onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author First published: 09 September 2013 https://doi.org/10.1111/ddg.12113_supplCitations: 85 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume11, Issues6Special Issue: Malignes Melanom S3‐Leitlinie “Diagnostik, Therapie und Nachsorge des Melanoms”/Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”. The German Society of Dermatology and Wiley have published this supplement without financial support.August 2013Pages 1-116 RelatedInformation

Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence-based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship.

The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses.Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms.With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups.Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients.NCT 00567554, www.clinicaltrials.gov.

Iron deficiency and iron deficiency-associated anemia are common complications in cancer patients. Most iron deficient cancer patients present with functional iron deficiency (FID), a status with adequate storage iron, but insufficient iron supply for erythroblasts and other iron dependent tissues. FID is the consequence of the cancer-associated cytokine release, while in absolute iron deficiency iron stores are depleted resulting in similar but often more severe symptoms of insufficient iron supply. Here we present a short review on the epidemiology, pathophysiology, diagnosis, clinical symptoms, and treatment of iron deficiency in cancer patients. Special emphasis is given to intravenous iron supplementation and on the benefits and limitations of different formulations. Based on these considerations and recommendations from current international guidelines we developed recommendations for clinical practice and classified the level of evidence and grade of recommendation according to the principles of evidence-based medicine.

LeitlinieDieses

Abstract Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib ( n = 134) or placebo ( n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.

High-dose chemotherapy (HDC) with peripheral-blood progenitor cell (PBPC) and autologous bone marrow (ABM) transplant (T) has documented survival benefits for relapsed Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Treatment costs associated with HDC and its supportive care have restricted its use both on and off clinical trial. In a prospective randomized clinical trial, filgrastim-mobilized PBPCT resulted in faster recovery of bone marrow function, with less hospitalization and supportive care than ABMT. This study was undertaken to analyze the costs of the two strategies using prospectively collected data from a randomized clinical trial that compared filgrastim-mobilized PBPCT versus ABMT.Clinical results and resource utilization from a randomized clinical trial that compared filgrastim-mobilized PBPCT versus ABMT following carmustine, etoposide, cytarabine, and melphalan (BEAM) HDC for HD and NHL are presented. The trial was performed in six centers in Germany, the United Kingdom, and Belgium. Resource utilization data were used to project costs and Massay Cancer Center (MCC) in the United States incurred the cost of treating the cohort. Costs were projected to the United States, because the economic implications to United States centers are significant, costs of care vary markedly among countries but resource utilization on this trial did not, and a randomized trial is unlikely to be performed in the United States.Fifty-eight patients with relapsed HD or NHL underwent HDC with BEAM. The PBPCT and ABMT groups had similar short-term survival after BEAM. PBPCT patients had a shorter hospitalization (median, 17 v 23 days; P = .002), neutrophil recovery (11 v 14 days; P = .005), platelet recovery to > or = 20 x 10(9)/L (16 v 23 days; P = .02), and days of platelet transfusions (6 v 10; P < .001). Estimated costs were $8,531 for ABM harvest and $5,760 for PBPC collection, including filgrastim mobilization. The total estimated average cost was $59,314 for each ABMT patient versus $45,792 for each PBPCT patient. Cost savings of $13,521 (23%) were due to shorter hospitalizations with less supportive care.PBPCT is as safe and more effective than ABMT for HD and NHL in the short term. PBPCT represents a significant cost savings due to lower autograft collection costs, shorter hospital stays, and less supportive care. The savings exceed the costs for filgrastim mobilization and PBPC collection. Actual savings will vary depending on local practice patterns, charges, and costs.

Pluripotent stem cells of hematopoiesis and lymphopoiesis are among the CD34+ cells in blood or bone marrow. After granulocyte-colony stimulating factor (G-CSF) treatment, 1% to 2% of the mononuclear cells in blood are CD34+ cells, which can be procured by leukapheresis. We investigated the potential of CD34+ blood cells for reconstituting hematopoiesis and lymphopoiesis after allogeneic transplantation. HLA- identical sibling donors of 10 patients with hematologic malignancies were treated with G-CSF (filgrastim), 5 microgram/kg subcutaneously twice daily for 5 to 7 days. CD34+ cells were selected from the apheresis concentrates by immunoadsorption, concomitantly the number of T cells was reduced 100- to 1,000-fold. After transplantation, five patients received cyclosporine A for graft-versus-host disease (GvHD) prophylaxis (group I); five patients additionally received methotrexate (group II). G-CSF and erythropoietin were given to all patients. Mean numbers of 7.45 x 10(6) CD34+ and 1.2 x 10(6) CD3+ cells per kilogram were transplanted. In group I, the median times of neutrophil recovery to 100, 500, and 1,000 per mm3 were 10, 10, and 11 days, respectively. Group II patients reached these neutrophil levels after 10, 14, and 15 days, respectively. Platelet transfusions were administered for a median of 18 days in group I and 30 days in group II, and red blood cells for 9 and 12 days, respectively. Between day 30 and 60, lymphocytes reached levels of 353 +/- 269 cells per mm3. The median grades of acute GvHD were III in group I and I in group II. Two patients in group I died from acute GvHD. Two leukemic relapses occurred in group II. Complete and stable donor hematopoiesis was shown in all patients with a median follow up of 370 (45 to 481) days. Allogeneic blood CD34+ cells can successfully reconstitute hematopoiesis and lymphopoiesis. Reduction of T cells by CD34+ blood cell enrichment and cyclosporine A alone might not be sufficient for prophylaxis of severe acute GvHD.

Different empirical approaches to antimicrobial treatment of lung infiltrates in patients with neutropenia were studied within a prospective, randomized multicenter trial.Patients with neutropenia with hematologic malignancies and fever of 38.5 degrees C or higher associated with newly diagnosed lung infiltrates were randomized for an initial therapy with acylaminopenicillin plus aminoglycoside (Group A), third-generation cephalosporin plus aminoglycoside (Group B), or the double beta-lactam combination (Group C), each in combination with rifampin. Nonresponders were given empirical amphotericin B plus 5-fluorocytosine beginning on day 4, day 5, or day 6 under study.Of 295 patients entered, 91.2% were evaluable. Complete response was obtained in 61.3% with no significant difference between treatment groups. The addition of rifampin did not improve treatment results. Only 27.1% of patients achieved a complete response by antibiotic therapy without additional antifungal therapy. Fungi dominated in cases of microbiologically documented infections and were associated with a poorer outcome compared with bacterial pneumonias. The trend of leukocyte counts under study had a highly significant effect on the outcome of infection.Lung infiltrates in febrile patients with neutropenia represent a high risk of treatment failure. Persistent neutropenia has a significantly adverse effect on the outcome of infection. Incorporation of systemic antifungal agents into first-line therapy, particularly in selected high-risk subgroups, might improve future treatment results. The quality of diagnostic techniques to establish the etiology of pulmonary infiltrates needs to be improved.

Summary. Twenty‐seven patients with Philadelphia chromosome positive chronic myelogenous leukaemia in the chronic phase were treated with low doses of recombinant interferon (IFN) alpha‐2b. Ten patients entered a complete and six a partial haematologic remission with a median duration of 5·8 and 9·1 months respectively. Five minor cytogenetic responses were observed. These results are inferior compared to other studies with higher interferon‐doses. Fever was an acute side effect after injection of IFN, limb pains and fatigue occurred protractedly. Haematologic side effects, nonspecific EEG changes, weight loss, and development of pulmonary infiltrates were observed in later periods of the treatment. Eight patients developed neutralizing anti‐IFN antibodies after 4·2–20·4 months (median 12·8 months). Anti‐IFN antibodies were associated with relapse or refractoriness to IFN treatment: five out of nine patients with rising WBC after initial fall had antibodies, while four did not. Two out of four patients with primary non‐response had IFN‐antibodies. These results may indicate a serious problem in the long‐term treatment of CML with recombinant interferon.

This trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer.Patients were randomly assigned to receive carboplatin area under the curve 5 mg x min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1-3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity.Of 226 patients, 216 were eligible. Median PFS was 6.0 months [95% confidence interval (CI) 5.0-7.0] in the IP arm and 6.0 months (95% CI 5.2-6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4-11.6) and 9.0 months (95% CI 7.6-10.4) in the IP and EP arm (P = 0.06), respectively. Hazard ratios for disease progression and OS were 1.29 (95% CI 0.96-1.73, P = 0.095) and 1.34 (95% CI 0.97-1.85, P = 0.072), respectively. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm.This trial failed to show superiority of irinotecan over etoposide in combination with carboplatin.

Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Method The process of updating the S3 guideline published in 2012 was based on the adaptation of identified source guidelines. They were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and with the results of a systematic search of literature databases followed by the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point and used them to develop suggestions for recommendations and statements, which were then modified and graded in a structured consensus process procedure. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of primary, recurrent and metastatic breast cancer. Loco-regional therapies are de-escalated in the current guideline. In addition to reducing the safety margins for surgical procedures, the guideline also recommends reducing the radicality of axillary surgery. The choice and extent of systemic therapy depends on the respective tumor biology. New substances are becoming available, particularly to treat metastatic breast cancer.Ziele Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren. Methode Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-Fragen (PICO: Patients/Interventions/Control/Outcome), systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen – und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden. Empfehlungen Teil 2 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Therapie des primären, rezidivierten und metastasierten Mammakarzinoms: Die lokoregionären Therapien erfahren in der aktuellen Leitlinie eine Deeskalation. Neben einer Verringerung des Sicherheitsabstandes bei den operativen Verfahren gibt die Leitlinie auch Empfehlungen zu einer reduzierten Radikalität bei axillären Interventionen. Die Systemtherapie richtet sich nach den tumorbiologischen Eigenschaften, neue Substanzen stehen insbesondere beim metastatierten Mammakarzinom zur Verfügung.

Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on granulocyte colony-stimulating factors (G-CSF) for prevention of FN, but guidance is unclear regarding use of short- vs long-acting G-CSF (e.g., filgrastim vs pegfilgrastim/lipegfilgrastim, respectively). An international panel of experts convened to develop guidance on appropriate use of pegfilgrastim for prevention of chemotherapy-induced FN.Guidance recommendations were developed following a literature review, survey, evaluation of current practice, and an expert meeting. Consensus was established using an anonymous Delphi-based approach.Guidance recommendations for prevention of treatment-associated FN were as follows: for treatment with curative intent, maintenance of dose intensity using G-CSF to prevent dose delays/reduction should be standard of care; for treatment-associated FN risk ≥ 20%, short-acting G-CSF/pegfilgrastim should be given from cycle 1 onwards; and for treatment-associated FN risk < 20%, short-acting G-CSF/pegfilgrastim should be given if factors suggest overall risk (including treatment-related and patient-related risk factors) is ≥ 20%. It was agreed that pegfilgrastim and 11 days' filgrastim have similar efficacy and safety and that pegfilgrastim is preferred to < 11 days' filgrastim (and may be preferred to ≥ 11 days' filgrastim based on adherence and convenience); pegfilgrastim is not appropriate in weekly chemotherapy; in split-dose chemotherapy, pegfilgrastim is recommended 24 h after last chemotherapy dose; and during palliative chemotherapy, patient adherence and convenience may favor pegfilgrastim.In this era of targeted therapies, additional trials with G-CSF are still required. These recommendations should be used with existing guidelines to optimize pegfilgrastim use in clinical practice.

Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Methods The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure. Recommendations Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.Ziele Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren. Methoden Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden. Empfehlungen Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Früherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestätigt und bildet damit die Grundlage der Früherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei höherem Rückfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle für die körperliche Untersuchung, Ultraschall und Mammografie, während weiterführende Gerätediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.

The risk of infection after allogeneic stem cell transplantation is determined by the underlying disease, the intensity of previous treatments and complications that may have occurred during that time, but above all, the risk of infection is determined by the selected transplantation modality (e.g. HLA-match between the stem cell donor and recipient, T cell depletion of the graft, and others). In comparison with patients treated with high-dose chemotherapy and autologous stem cell transplantation, patients undergoing allogeneic stem cell transplantation are at a much higher risk of infection even after hematopoietic reconstitution, due to the delayed recovery of T and B cell functions. The rate at which immune function recovers after hematopoietic reconstitution greatly influences the incidence and type of post-transplant infectious complications. Infection-associated mortality, for example, is significantly higher following engraftment than during the short neutropenic period that immediately follows transplantation.

Acute promyelocytic leukaemia (APL) is characterized by the translocation t(15;17)(q22;q21). Usually t(15;17) is the sole cytogenetic abnormality, but some patients show other chromosome aberrations in addition to t(15;17). The influence of additional chromosome aberrations on the clinical outcome of patients with t(15;17) is unclear. We have analysed 50 cases of APL carrying the translocation t(15;17). Additional chromosome aberrations were observed in 17/47 patients (36%) studied at initial diagnosis and in all three patients studied at relapse. In nine cases (18%) an additional chromosome 8 and in six cases (12%) an isochromosome of the long arm of the derivative chromosome 17 was observed. Various structural rearrangements in addition to t(15;17) were detected in nine patients (18%). Clinical follow‐up data were available for 44 patients studied at diagnosis. A complete remission (CR) was achieved in 34 patients (77%). 10 patients (23%) died within 1 month after diagnosis due to infection or bleeding, eight (24%) relapsed within 10–18 months after initial diagnosis. 28 patients are alive 2–93 months after diagnosis (25 in first CR, two in second and one in third CR) (median follow‐up 18.5 months). Bone marrow transplantation was performed in six patients (three in first CR, two in second CR, one in third CR), all are alive and in CR. An influence of secondary chromosome anomalies on prognosis was not observed. However, if a higher rate of long‐term remission can be reached, specific secondary chromosome aberrations might turn out to be of prognostic value.

Abstract Infections during granulocytopenia are major complications of autologous bone marrow transplantation (ABMT). Since recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) has proved to accelerate bone marrow recovery after cytostatic chemotherapy, we studied its effects on hematopoietic regeneration and on infectious complications after total body irradiation (TBI) and high-dose chemotherapy followed by ABMT. Eighty-one patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) or with non- Hodgkin's lymphoma (NHL) in CR or partial remission were randomized in a double-blind, placebo-controlled trial. They received either rhuGM- CSF 250 micrograms/m2 (Escherichia coli-derived) daily by continuous infusion after ABMT, or placebo. Treatment was continued until the neutrophil counts reached greater than 500/microL for 1 week. The maximum treatment duration was 30 days. Thirty-nine patients in the rhuGM-CSF group and 40 patients in the placebo group were evaluable. The median time needed to reach a neutrophil count of 500/microL was 15 days with rhuGM-CSF and 28 days with placebo (P = .0001). Bacterial infections occurred in 14 (35.9%) of the patients with rhuGM-CSF and in 25 (62.5%) of the patients given the placebo (P = .024). Nine of the 14 bacterial infections in the rhuGM-CSF group and 20 of the 25 infections in the placebo group were diagnosed within the first 10 days after ABMT. Capillary leakage and a reversible fluid retention were seen in five of the rhuGM-CSF-treated patients. Patients treated with rhuGM-CSF had lower serum protein and albumin levels than patients in the placebo group. There was no statistically relevant difference in overall survival between the two groups (P = .47). Relapse occurred in 14 (34%) patients with rhuGM-CSF and in 18 (45%) patients with placebo. We conclude that continuous infusion of rhuGM-CSF after ABMT accelerates the regeneration of granulocytes and reduces the number of bacterial infections.

Platinum/taxane combinations are widely used in patients with carcinoma of unknown primary (CUP), yielding response rates of 30% and median overall survival of 9–11 months in selected patients. Yet these combinations have not been subject to a randomised trial to overcome selection bias, a major problem in CUP. We randomised 92 patients to either paclitaxel/carboplatin (arm A) or the non-platinum non-taxane regimen gemcitabine/vinorelbine (arm B). The primary endpoint was rate of practicability as defined: application of ⩾2 cycles of therapy (1) with a maximal delay of 1 week (2) and survival of ⩾8 months (3). Practicability was shown in 52.4% (95% CI 36–68%) in arm A and in 42.2% (95% CI 28–58%) in arm B, respectively. The median overall survival, 1-year survival -rate and response rate of patients treated in arm A was 11.0 months, 38, and 23.8%, arm B 7.0 months, 29, and 20%. In conclusion, the paclitaxel/carboplatin regimen showed clinically meaningful activity in this randomised trial (Clinical trial registration number 219, ‘Deutsches KrebsStudienRegister’, German Cancer Society.)

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 11, Issue 6 p. 563-602 Guidelines S3-Guideline “Diagnosis, therapy and follow-up of melanoma” – short version Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorship,Search for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorship,Search for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln – Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorship,Search for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorship,Search for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln – Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author First published: 30 May 2013 https://doi.org/10.1111/ddg.12044Citations: 21 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20–80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×109/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0–13)​. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3–34) and 19 months (range 7–110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1–135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia, (c) presentation in chronic or blast phase, (d) rapid responses and long-term remission on low-dose imatinib, and (e) possible adverse prognostic impact of a complex karyotype.

Abstract Recombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels &gt; or = 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to &gt; 42) with placebo (P &lt; .003). The mean (+/- SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P = .075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and hemorrhage significantly increased the number of transfusions. However, after day 20, rHuEPO significantly reduced the number of erythrocyte transfusions in these patient groups, as well as reducing incompatibility in the major ABO-blood group. For the whole study period, rHuEPO reduced the transfusion requirements in GVHD III and IV from 18.4 +/- 8.6 to 8.5 +/- 6.8 U (P = .05). After autologous BMT, there was no difference in the time to independence from erythrocyte transfusions and in the regeneration of reticulocytes. Marrow purging strongly increased the requirement for transfusions as well as the time to transfusion independence.

The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA).Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone.Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33-45] versus 55% (95% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513).The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.

For the treatment of patients with cancer to be successful and well-tolerated, the complications and side effects of the disease and its treatment must be treated and limited as far as possible. Summarized recommendations based on the constantly increasing evidence in the area of supportive care must be defined, standardized, and communicated.We systematically reviewed the literature on the topics of anemia, neutropenia, nausea/vomiting, diarrhea, oral mucositis, skin toxicity, and peripheral neurotoxicity induced by cancer treatment, as well as osseous complications, extravasation, and side effects of radiotherapy. Recommendations were approved in a moderated, formalized consensus procedure.In patients suffering from chemotherapy-induced anemia, the administration of agents that stimulate erythropoiesis can be considered. This can potentially improve these patients' quality of life and lessen the frequency of blood transfusions, but it can also lead to thromboembolic complications and arterial hypertension. If only a single individual risk factor is present in a patient whose risk of febrile neutropenia is estimated at 10-20%, there is no obligatory indication for the administration of granulocyte-colony stimulating factor. Antiemetic treatment before carboplatin is given can consist of a neurokinin-1 receptor antagonist along with a setron and dexamethasone. Duloxetine is recommended for the treatment of neuropathic pain. Sensorimotor training is effective in the treatment of chemotherapy-induced peripheral neuropathy and can already be given at the same time as the chemotherapy. Women with bony metastases of breast cancer who have been taking zoledronate at four-week intervals for a year should take it at 12-week intervals from then onward in order to lessen the likelihood of osseus complications. There is no evidence for any effective prophylactic treatment of chemotherapy-induced diarrhea.Supportive measures are an integral component of all oncological treatments. More research is needed to determine how side effects can be lessened and prevented.

A case of acute myelogenous leukemia (AML) with double minutes (dmin) and X chromosome loss is presented. Using comparative genomic hybridization (CGH), a region of high-level DNA amplification was detected at 8q24, the locus of the c-MYC proto-oncogene. Fluorescence in situ hybridization (FISH) with a DNA probe specific for the human c-MYC gene confirmed the extrachromosomal amplification of this proto-oncogene in the dmin of the leukemic cells. During the course of the disease, three relapses occurred; two complete remissions could be achieved by treatment with various chemotherapy regimens. The patient's survival time of 25 months was considerably longer than in most reported cases of AML with extrachromosomal c-MYC amplification. Therefore, the present case challenges the view that the occurrence of dmin in AML is generally an indication of poor prognosis.

Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear.Seven hundred and eighty-three newly diagnosed AML patients treated in the German SHG-AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission-rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers.With a median follow-up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox-regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients </= 60 years.Immunophenotyping is not only helpful for diagnosis but is of independent significance for prognosis, and may be useful for risk stratification in AML patients.

Summary We have previously reported an altered surface marker expression and chemotaxis of G‐CSF‐induced neutrophils from patients with severe congenital neutropenia. However, effects of G‐CSF and influence of the underlying disease on neutrophils could not be discerned. In this study we have evaluated the effects of G‐CSF on neutrophil phenotype and function in patients under chemotherapy and in healthy test subjects. We found a significantly enhanced expression of FcγRI, CD14 and CD54 and a decrease in the level of FcγRIII during G‐CSF treatment. In addition, motility of G‐CSF‐induced neutrophils was significantly decreased. The effects were seen in patients under cytotoxic chemotherapy and in healthy test subjects. Surface marker alterations and neutrophil motility were affected by G‐CSF administration in a dose‐dependent manner. Kinetic studies on neutrophils from healthy test subjects demonstrated that all effects could be seen after a single administration of 300 μg G‐CSF and began to appear within 4 h. Release of partially immature neutrophils from the bone marrow and indirect activation of these cells by G‐CSF are discussed as possible reasons for the findings presented. They demonstrate that G‐CSF has profound effects on neutrophil phenotype and function in vivo which might have clinical implications.

BACKGROUND This Phase I/II study investigates increasingly high doses of ifosfamide combined with full dose doxorubicin chemotherapy supported with peripheral blood stem cells (PBSC) and granulocyte-colony stimulating factor (G-CSF) in patients with metastatic soft tissue sarcoma (STS). METHODS Patients with histologically proven metastatic or advanced adult STS without prior treatment received doxorubicin, 75 mg/m2, on Day 1 followed by 4-day continuous infusion of ifosfamide at 5 consecutive dose levels starting with 8 g/m2 and escalating to 16 g/m2 in increments of 2 g/m2. Three patients per dose level and a maximum of 5 treatment cycles per level at 3-week intervals were planned. Each cycle was followed by G-CSF and retransfusion of PBSC. PBSC separation was performed prior to chemotherapy by steady state mobilization with G-CSF. RESULTS Eighteen patients (median age, 45 years, range, 25-57 years) were included, with 4, 3, 4, 4, and 3 patients assigned to Levels 1-5, respectively. Metastatic sites included the lungs in 12 patients (67%), lymph nodes in 8 patients (44%), and the liver in 5 patients (28%). Nine patients (50%) achieved objective responses with 4 complete responses (22%) and 5 partial responses (28%). Lung metastases and a histology of synovial sarcoma or malignant fibrous histiocytoma were favorable features for response to therapy. The median survival for all patients was 13+ months (range, 3-19+ months). Hematotoxicity was manageable and treatment could be administered at a median interval of 24 days. One case of World Health Organization Grade 3 neurotoxicity occurred. Nephrotoxicity was dose-limiting, with 1 patient in Level 4 (WHO Grade 2) and 2 patients in Level 5 (WHO Grade 3). CONCLUSIONS Multiple cycles of dose-intensive therapy with doxorubicin and high dose ifosfamide can be administered safely with PBSC support. Nephrotoxicity is dose-limiting for ifosfamide at total doses of 16 g/m2. Multiple cycles of high dose chemotherapy at short treatment intervals using ifosfamide at a dose of 14 g/m2 should be investigated further in a neoadjuvant setting in patients with STS. Cancer 1997; 80:1221-7. © 1997 American Cancer Society.

A group of proliferative diseases of the epidermal Langerhans' cells are commonly referred to as Langerhans' cell histiocytosis (LCH). A small number of the patients with this disease face an unfavorable disease course despite chemotherapy and radiation therapy. in LCH patients with a poor prognosis, allogeneic bone marrow transplantation (BMT) could be the appropriate treatment with proven antiproliferative effects and may be able to repopulate the recipient with stem cell-derived Langerhans' cells from the donor or correct the presumed underlying immunodeficiency. An LCH was diagnosed in a 15-year-old boy with multiple osteolytic lesions, anemia, and diabetes insipidus centralis. Repeated flare-ups of the disease had necessitated several courses of conventional chemotherapy including cyclophosphamide (CY), prednisolone (P), 6-mercaptopurine (6-MP), vincristine (VCR), and additional local irradiation without stable remission. Three years after first being diagnosed with LCH the patient underwent high-dose chemotherapy-radiation therapy followed by allogeneic BMT from his human lymphocyte antigen (HLA)-identical brother. Currently, he is alive and well and has been disease-free for more than 41 months after BMT.

In secondary immunodeficiency, immunoglobulin replacement therapy (IgRT) is recommended by guidelines (GL) for patients with IgG level < 4 g/l and more than 3 infections or a severe infection. IgRT may be appropriate if IgG level < 4 g/l and/or 1-3 less severe infections (≤ grade 2).This was a retrospective sample analysis representative for practices and hospitals in Germany. The treatments and infection data were collected from patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). GL adherence (GLAD) was analyzed.Data from 1086 patients (CLL 490, MM 596) were collected from 86 centers. Of all patients, 34.8% developed IgG deficiency during therapy (CLL 35.5%; MM 34.2%). IgRT was given in 23.5% of CLL and 14.4% of MM patients. GLAD in hypogammaglobulinemia and indication to IgRT was 23.3% of 86 CLL and 22.1% of 77 MM patients. Without GLAD, the hazard ratio (HR) for any infection was 4.49 (95% CI 3.72-5.42; p < 0.001) and for severe infections (grade ≥ 3) 10.64 (95% CI 7.54-15.00; p < 0.001). Significant independent risk factors for infections were a higher Charlson Comorbidity Index, IgG deficiency, and 3rd + line treatment, as well as therapy with BTK inhibitors or chemotherapy in CLL. Multivariable analysis showed a significantly lower risk of severe infections after start of IgRT with a HR of 0.47 (95% CI 0.28-0.77; p = 0.003).Guideline adherence correlated with fewer and less severe infections but was low in patients with indication to IgRT. Risk factors for infection can be identified. Risk of severe infections was significantly lower in patients with IgRT.

Sixty-six adult patients were treated for relapsing or refractory acute lymphocytic leukemia (ALL). The induction treatment consisted in a (1) first phase with vindesine 3 mg/m2 intravenously (IV) on days 1, 8, and 15; daunorubicin 45 mg/m2 IV on days 1, 8, and 15; erwinia-asparaginase 10,000 U/m2 IV on days 7, 8, 14, and 15; and prednisone 60 mg/m2 orally on days 1 to 21 and a (2) second phase with cytarabine 3000 mg/m2 as a 3-hour infusion two times a day on days 1 to 4 (in patients greater than 50 years of age we used 1000 mg/m2), and etoposide 100 mg/m2 IV on days 1 to 5. Side effects of induction Phase I were predominantly hematologic with subsequent infections. In Phase II, some patients additionally had gastrointestinal, cutaneous, ocular, and hepatic toxicity. Five patients died during Phase I and another died during Phase II. Five of these patients had T-cell ALL. Thirty-four (64%) of 54 patients in their first relapse had a complete remission (CR) with a median disease-free survival (DFS) of 2.9 months. The median overall survival (OAS) was 6.6 months. Seven of 12 patients with primary refractory disease, a second relapse, or relapse after bone marrow transplantation (BMT) had a CR. The CR rate and survival after first relapse was significantly better in patients with a preceding CR of more than 18 months compared with those with a shorter preceding remission. The leukocyte count was a second significant but not independent risk factor. There was a negative correlation between the leukocyte count and the duration of the preceding CR. The duration of the preceding CR was the major prognostic factor for survival in multivariate analysis. Twenty-two patients received BMT. None of nine patients with autologous BMT is alive and disease-free; 5 of 13 who underwent allogeneic BMT are. It was concluded that this treatment efficiently induced remission with tolerable toxicity. The remission duration should be improved by optimized consolidation treatment.

In the last two decades, extensive research failed to significantly improve the outcome of patients with sepsis. In part, this drawback is based on a gap in our knowledge about molecular mechanisms understanding the pathogenesis of sepsis. During sepsis, T cells are usually depleted. Recent studies in mice and human cells suggested a role of the peroxisome proliferator-activated receptor gamma (PPARgamma) in provoking apoptosis in activated T lymphocytes. Therefore, we studied whether expression/activation of PPARgamma might contribute to T cell death during sepsis. We observed PPARgamma up-regulation in T cells of septic patients. In contrast to controls, PPARgamma expressing cells from septic patients responded with apoptosis when exposed to PPARgamma agonists. Cell demise was attenuated by SR-202, a synthetic PPARgamma antagonist, and specificity was further verified by excluding a proapoptotic response to a PPARalpha agonist. We propose that up-regulation of PPARgamma sensitizes T cells of septic patients to undergo apoptosis. PPARgamma activation in T cells requires an exogenous PPARgamma agonist, which we identified in sera of septic patients. Septic sera were used to study reporter gene expression containing a PPAR-responsive element. We conclude that PPARgamma plays a significant role in T cell apoptosis, contributing to lymphocyte loss in sepsis. Thus, inhibition of PPARgamma may turn out to be beneficial for patients suffering from lymphopenia during sepsis.

Summary The role of allogeneic stem cell transplantation ( HSCT ) as compared to chemotherapy in acute myeloid leukaemia ( AML ) patients with abnormalities of chromosome 17p [abnl(17p)] has not yet been defined. Therefore, we analysed 3530 AML patients treated in three randomized, prospective, controlled clinical trials and compared post‐remission therapies using a multivariate C ox regression analysis to determine whether allogeneic HSCT is superior than chemotherapy in overcoming the detrimental impact of patients with abnl(17p) AML . One hundred and forty‐three patients (4%) were identified with abnl(17p) AML . All patients had received intensive induction chemotherapy. Forty‐seven patients with a median age of 54 years (18–69 years) proceeded to allogeneic HSCT in first or second remission. The 3‐year overall survival ( OS ) rate for the entire cohort of patients was 4% [95% confidence interval ( CI ), 1–7%]. OS and event‐free survival at 3 years, calculated from the day of HSCT , was 11% (95% CI , 2–20%) and 6% (95% CI , 0–13%), respectively. Multivariate C ox regression analysis showed no benefit of allogeneic HSCT compared to chemotherapy (Hazard Ratio 0·97, 95% CI 0·56–1·67, P = 0·9). In conclusion, allogeneic HSCT does not improve survival in patients with abnl(17p) AML as compared to other adverse cytogenetic risk abnormalities.

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874

Abstract Background: The addition of sorafenib to standard induction and consolidation therapy in newly diagnosed patients (pts) ≤60 years (yrs) with acute myeloid leukemia (AML) led to significant prolongation of event-free survival (EFS) and relapse-free survival (RFS) in the randomized placebo-controlled SORAML trial (NCT00893373). After a median follow-up of 3 yrs, a benefit for sorafenib treated pts was observed also in overall survival (OS), but this difference was not significant. Here, we present updated survival data and information on relapse treatment and outcome. Methods: In the SORAML trial, 267 newly diagnosed untreated fit AML pts up to 60 yrs of age and irrespective of FLT3 mutation status received two cycles of induction chemotherapy with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Allogeneic stem cell transplantation (SCT) was scheduled for all intermediate-risk pts in first complete remission (CR) with a sibling donor and for all high-risk pts with a matched related or unrelated donor. At study inclusion, pts were randomized to receive either sorafenib (2x400 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Study medication was given on days 10-19 of DA I+II, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months (mos) after the end of consolidation. The primary endpoint of the trial was EFS. The results after follow-up of 3 yrs were presented at ASH 2014 (Röllig et al., Blood 2014; 124: 6) and fully published (Röllig et al., Lancet Oncol 2015; 16: 1691-9). Here, we present the results after prolonged follow-up. For this analysis, information on remission and survival status, mode and outcome of relapse treatment including SCT were collected for all randomized pts and analyzed by standard statistical methods. Results: Of 267 treated pts, 134 were randomized in the sorafenib arm and 133 in the placebo arm with a resulting CR rate of 60% and 59%, respectively. After a median observation time of 78 mos, the primary study endpoint EFS in the placebo vs sorafenib arm was 9 mos vs 26 mos (HR 0.68, p=0.01) in univariate Kaplan Meier analysis. The beneficial effect of sorafenib on EFS was confirmed in multivariate Cox regression analysis with a HR of 0.61 (p=0.005). Median RFS in the placebo vs sorafenib arms was 22 vs 63 mos, corresponding to a HR of 0.64 (p=0.033). Exploratory analyses were performed in the 70 relapsing pts (40 after placebo vs 30 after sorafenib treatment). Among relapsing pts, 82% vs 73% achieved a second CR. In these two groups, 88% and 87% of pts received a SCT as part of salvage treatment. A lower proportion of pts in the placebo arm received a second SCT as salvage treatment (5% vs 13%). In the context of salvage SCT, the proportion of haploident donors in the placebo and sorafenib group was 3% vs 15% and the incidence of Grade 3/4 GVDH was 17% vs 0%. SCT-related non-relapse mortality (NRM) was similar in both groups, but the cumulative incidence of second relapse (CIR) was higher in the sorafenib group (35% vs 54% after 48 mos). Therefore, median OS from relapse in the placebo vs sorafenib groups were 27 mos vs 10 mos, corresponding to a HR of 1.68 (p=0.098). The projected median OS from randomization is 83 mos in the placebo arm and was not reached for the sorafenib arm, corresponding to a 5-year OS of 52% vs 61% (HR 0.81, p=0.263). Conclusion: Mature follow-up data confirms the antileukemic efficacy of sorafenib in younger AML pts with and without FLT3 mutation. The addition of sorafenib to standard chemotherapy resulted in a significantly longer EFS and clinically relevant 36% risk reduction for relapse or death. Five pts need to be treated (NNT) to prevent one relapse or death at 3 years and six pts at 5 yrs. Exploratory analyses in relapsing pts show that survival after relapse is shorter after sorafenib which might be due to i) a higher rate of second SCTs and a higher incidence of haploidentical SCT despite the lower frequency of severe GVHD, most likely by chance and not explainable by systematic reasons and ii) a lower response to salvage treatment after sorafenib therapy. Despite these observations, primary sorafenib treatment led to an OS benefit with a 19% risk reduction for death which was not statistically significant since this phase II trial was not adequately powered to detect OS differences. Figure Figure. Disclosures Rollig: Bayer: Research Funding; Janssen: Research Funding. Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis: Acceleron: Consultancy; Celgene: Consultancy. Mackensen: AMGEN: Research Funding. Hänel: Roche: Honoraria; Novartis: Honoraria. Thiede: Roche: Consultancy; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Agendix: Employment. Schetelig: Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg (‘high-dose’) imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Although a T-cell response in human cytomegalovirus (HCMV)-immune individuals exists against the most abundantly expressed protein pp65 of the virus matrix, less is known about the determinants that evoke this response. The aim of the study was to identify regions within HCMV pp65 (ppUL83) that contain sequences for the cellular immune response by the use of three recombinant overlapping β-galactosidase pp65 fusion proteins (C74, C35, and C47), covering the C-terminal 265 amino acids of the entire pp65 sequence. Two T-cell epitope determinants were recognized by human lymphocytes of healthy, HCMV-seropositive, human leukocyte antigen (HLA)-typed individuals. One T-cell determinant (amino acids [aa] 303–388) was localized in the mid-region of the entire pp65 sequence and a second T-cell determinant (aa 477–561) within the C-terminal region. By fine mapping with synthetic hexadecamer peptides three T-cell epitopes were identified within these two regions: P10-I (aa 361–376) in the mid-region, P3-II (aa) 485–499), and P6-II (aa 509–524) in the C-terminal region. Inhibition studies with monoclonal antibodies to HLA class I or class II revealed a class I restricted response to peptides P10-I or P6-II, respectively. P10-I responders shared the HLA-DR11 allele and P6-II responders the -DR3 allele. Therefore, these T-cell epitopes of HCMV pp65 might be presented in association with particular HLA class II alleles. J. Med. Virol. 52:68–76, 1997. © 1997 Wiley-Liss, Inc.

In febrile neutropenic patients with high-grade hematologic malignancies, empirical antimicrobial intervention is mandatory. Large randomized clinical trials have elucidated the benefit of broad-spectrum beta lactam antibiotics used as single drugs or in combination with aminoglycosides in order to provide activity against gram-negative aerobes as well as against streptococci and Staphylococcus aureus. As a result, infection-related mortality was reduced to less than 10% also in patients undergoing intensified remission induction or consolidation therapy for acute leukemias. Distinct subgroups of patients have been identified who need an empirical modification of antimicrobial treatment, i.e., patients with catheter-related infections, patients with pulmonary infiltrates, and patients with unexplained fever not responding to first-line antibiotics. In two consecutive, prospectively randomized trials conducted by the Paul Ehrlich Society it was demonstrated that empirical antifungal therapy is beneficial for second-line treatment in patients with persistent unexplained fever and should be part of the first-line approach in patients with lung infiltrates. The empirical addition of glycopeptides, however, should be restricted to patients with catheter-related infections due to coagulase-negative staphylococci.

The goal of this study concerned the pretherapeutic identification of high-risk acute myeloid leukemia (AML) patients by data pattern analysis from flow cytometric immunophenotype, cytogenetic, and clinical data.Sixty-seven parameters of AML patients at diagnosis were classified for predictive information by algorithmic data sieving using iteratively self optimizing triple matrix data pattern analysis (http://www.biochem.mpg.de/valet/classif1.html).Pretherapeutic predictive values for nonsurvival within five years and two years were 100.0% and 83.2%, respectively, compared to 13.9% and 47.4% for the prediction of survival at five years and two years, respectively. At diagnosis, five-year nonsurvivors showed increased patient age and higher concentration of cells in the analyzed specimen, as well as increased levels of % CD2, CD4, CD13, CD36, and CD45 positive AML blasts. Two-year nonsurvivors were characterized by a data pattern of increased patient age and levels of % CD4, CD7, CD11b, CD24, CD45, TH126, and HLA-DR positive AML blasts and decreased levels of % CD1, CD65, CD95, and TC25 positive AML blasts. Cytogenetic abnormalities were not selected for the optimized discriminatory data patterns.The comparatively accurate pretherapeutic identification of high-risk AML patients may prove useful for the development of individualized therapy protocols in stratified clinical patients groups.

Current guidelines (GL) recommend neutropenia prophylaxis with G-CSF after chemotherapy (CTX) for patients with high (≥ 20%), or, if additional risk factors are present, intermediate (≥ 10–20%) risk of febrile neutropenia. The first sample survey in 2012 (NP1) showed lack of GL adherence. The aim of this second sample survey was to evaluate if GL adherence and implementation have improved. The sample size represented 1.0% of the incidences of lung and 1.1% of breast cancer in Germany in 2010. Data of patients with a febrile neutropenia (FN) risk ≥ 10% who had received at least 2 cycles of chemotherapy between October 2014 and September 2015 was surveyed retrospectively. Data from 573 lung cancer (LC) and 801 breast cancer (BC) patients was collected from 109 hospitals and 83 oncology practices with 222 physicians participating. Compared with the NP1 survey, GL adherence increased in LC and FN high-risk (HR) chemotherapy from 15.4 to 47.8% (p < 0.001), and in FN intermediate-risk (IR) chemotherapy from 38.8 to 44.3% (p = 0.003). In BC and FN-HR chemotherapy, GL adherence was unchanged: 85.6% vs. 85.1% (p = 0.73) but increased in FN-IR from 49.3 to 57.8% (p < 0.001). In all IR CTX cycles, there are also no significant differences in GL adherence between the first (51.3%) and subsequent cycles (51.1%; p = 0.948). In LC patients treated in certified or comprehensive cancer centers, the GL adherence in FN-HR chemotherapy was 53.0% vs. 44.9% in other centers (p = 0.295); in FN-IR chemotherapy, it was 45.1% vs. 43.8% (p = 0.750). In BC with FN-HR chemotherapy, GL adherence in certified or comprehensive centers was 85.4% vs. 84.7% in other institutions (p = 0.869); in FN-IR chemotherapy, it was 60.2% vs. 55.0% (p = 0.139). GL adherence in FN-HR chemotherapy and in FN-IR chemotherapy differed between pulmonologists and hematologist-oncologists (FN-HR: 25.0% vs. 43.6%, p < 0.001; 38.1% vs. 48.6%, p < 0.001). Comparing gynecologists with hematologist-oncologists, GL adherence in FN-HR chemotherapy was 86.2% vs. 82.5%. In FN-IR chemotherapy, GL adherence by gynecologists and hematologist-oncologists was 58.6% and 55.6%, respectively (p = 0.288; p = 0.424). Classification and regression tree analysis split pulmonologists and other specialists, with the latter adhering more to GL (p < 0.001). Hematologist-oncologists and gynecologists with more than 2 years of professional training in medical cancer therapy adhered more closely to GL than others (68.7% vs. 46.2%, p < 0.001). Pulmonologists attending ≥ 2 national congresses annually adhered more to guidelines than other pulmonologists (44.8% vs. 24.3%, p < 0.001). Adherence to G-CSF GL in Germany has increased but is still insufficient. Certified and comprehensive cancer centers show a higher rate of GL implementation. In GL adherence, there is still a disparity between cancer types and between oncology treatment specialists.

Abstract Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE‐3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE‐3 evaluated first‐line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS ‐WT tumors (ie, wild‐type in KRAS and NRAS exons 2‐4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and &lt;5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio ( P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13‐2.38; P = .0098) and progression‐free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18‐2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.

Abstract Purpose Clinical practice guidelines recommend the use of all approved granulocyte colony-stimulating factors (G-CSFs), including filgrastim and pegfilgrastim, as primary febrile neutropenia (FN) prophylaxis in patients receiving high- or intermediate-risk regimens (in those with additional patient risk factors). Previous studies have examined G-CSF cost-effectiveness by cancer type in patients with a high baseline risk of FN. This study evaluated patients with breast cancer (BC), non-small cell lung cancer (NSCLC), or non-Hodgkin’s lymphoma (NHL) receiving therapy who were at intermediate risk for FN and compared primary prophylaxis (PP) and secondary prophylaxis (SP) using biosimilar filgrastim or biosimilar pegfilgrastim in Austria, France, and Germany. Methods A Markov cycle tree-based model was constructed to evaluate PP versus SP in patients with BC, NSCLC, or NHL receiving therapy over a lifetime horizon. Cost-effectiveness was evaluated over a range of willingness-to-pay (WTP) thresholds for incremental cost per quality-adjusted life year (QALY) gained. Sensitivity analyses evaluated uncertainty. Results Results demonstrated that using biosimilar filgrastim as PP compared to SP resulted in incremental cost-effectiveness ratios (ICERs) well below the most commonly accepted WTP threshold of €30,000. Across all three countries, PP in NSCLC had the lowest cost per QALY, and in France, PP was both cheaper and more effective than SP. Similar results were found using biosimilar pegfilgrastim, with ICERs generally higher than those for filgrastim. Conclusions Biosimilar filgrastim and pegfilgrastim as primary prophylaxis are cost-effective approaches to avoid FN events in patients with BC, NSCLC, or NHL at intermediate risk for FN in Austria, France, and Germany.

Anemia in cancer should be diagnosed and treated according to guideline recommendations. The implementation of ESMO and German guidelines and their effect on anemia correction was analyzed.This retrospective epidemiological study, representative for Germany, analyzed data on anemia management of cancer patients with anemia ≥ grade 2. The Guideline Adherence Score (GLAD) for diagnosis (GLAD-D) and therapy (GLAD-T) was defined as follows: 2 points for complete, 1 point for partial, 0 point for no adherence.Data were analyzed for 1046 patients. Hb levels at diagnosis of anemia were 8-10 g/dL in 899 (85.9%) patients, 7-8 g/dL in 92 (8.7%), and < 7 g/dL (5.0%) in 52. Transferrin saturation was determined in 19% of patients. Four hundred fifty-six patients received RBC (43.6%), 198 (18.9%) iron replacement, 106 (10.1%) ESA, and 60 (5.7%) vitamin B12 replacement. 60.6% of patients receiving iron replacement were treated intravenously and 39.4% were treated orally. Two hundred eighty-eight (36.6%) of 785 patients receiving transfusions had no guideline-directed indication. GLAD-D was 2 in 310 patients (29.6%), 1 in 168 (16.1%), and 0 in 568 (54.3%). GLAD-T was 2 in 270 patients (25.8%), 1 in 320 patients (30.6%), and 0 in 456 patients (43.6%). Higher GLAD-D significantly correlated with higher GLAD-T (τB = 0.176, p < 0.001). GLAD-T 2 was significantly associated with greater Hb increase than GLAD-T 0/1 (p < 0.001) at 28 days (10.2 vs. 9.7 g/dL) and at 2 months (10.4 vs. 9.9 g/dL).Anemia assessment is inadequate, transfusion rates too high, and iron and ESA therapy too infrequent.ClinicalTrials.gov, NCT05190263, date: 2022-01-13.

13 Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .

A consensus meeting held under the auspices of the European School of Oncology concluded that the use of granulocyte growth factors is definitely indicated, or acceptable given existing evidence, in the following circumstances: to alleviate congenital neutropenia; in the mobilisation of peripheral blood progenitor cells for autotransfusion; to encourage engraftment following bone marrow transplantation and in cases of failed engraftment; to support continuation of ganciclovir anti-CMV therapy in certain patients with AIDS, where the switch to foscarnet is contraindicated or where toxicity to foscarnet develops. It was also agreed that there is an overwhelming need for carefully controlled clinical trials in a wide range of indications in which growth factor use may improve outcome. In the majority of tumours, the possible benefit of dose optimisation and intensification, and therefore the role of growth factors in support of such measures has still to be defined. Extramedullary toxicities may in these instances become dose limiting.

Abstract Sepsis accounts for the majority of fatal casualties in critically ill patients, because extensive research failed to significantly improve appropriate therapy strategies. Thus, understanding molecular mechanisms initiating the septic phenotype is important. Symptoms of septic disease are often associated with monocyte/macrophage desensitization. In this study, we provide evidence that a desensitized cellular phenotype is characterized by an attenuated oxidative burst. Inhibition of the oxidative burst and depletion of protein kinase Cα (PKCα) were correlated in septic patients. To prove that PKCα down-regulation indeed attenuated the oxidative burst, we set up a cell culture model to mimic desensitized monocytes/macrophages. We show that LPS/IFN-γ-treatment of RAW264.7 and U937 cells lowered PKCα expression and went on to confirm these data in primary human monocyte-derived macrophages. To establish a role of PKCα in cellular desensitization, we overexpressed PKCα in RAW264.7 and U937 cells and tested for phorbolester-elicited superoxide formation following LPS/IFN-γ-pretreatment. Inhibition of the oxidative burst, i.e., cellular desensitization, was clearly reversed in cells overexpressing PKCα, pointing to PKCα as the major transmitter in eliciting the oxidative burst in monocytes/macrophages. However, PKCα inactivation by transfecting a catalytically inactive PKCα mutant attenuated superoxide formation. We suggest that depletion of PKCα in monocytes from septic patients contributes to cellular desensitization, giving rise to clinical symptoms of sepsis.

We disagree with the Leading Edge published in the in the February issue of The Lancet Oncology, which calls for the use of erythropoietin–stimulating agents (ESAs) in the management of chemotherapy-induced anaemia to be halted. 1 The Lancet OncologyErythropoietin analogues: an unnecessary class of drugs. Lancet Oncol. 2008; 9: 81 Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar In addition to being used in patients with renal anaemia and other indications, ESAs are currently approved in Europe for the treatment of symptomatic anaemia in adult patients with non-myeloid malignancies who are receiving chemotherapy. Although the safety of ESAs is being debated, there are no prospective randomised trials that have adequately tested blood transfusions as an alternative approach to managing anaemia or that have assessed the risks of transfusion in terms of safety and cost. 2 Nowrousian M Dunst J Vaupel P Erythropoietin-stimulating agents: favorable safety profile when used as indicated. Strahlenther Onkol. 2008; 184: 121-136 Crossref PubMed Scopus (28) Google Scholar Updated guidelines on the use of ESAs, published by the European Organisation for Research and Treatment of Cancer (EORTC) working party in September, 2007, 3 Bokemeyer C Aapro MS Courdi A et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer. 2007; 43: 258-270 Summary Full Text Full Text PDF PubMed Scopus (360) Google Scholar , 4 EORTC guidelines on the use of erythropoietin. http://www.cancerworld.org/CancerWorld/eventDetail.aspx?id_sito=1&id_stato=1&id=1795 Google Scholar agree with the quality-of-life data contained in the summaries of product characteristics of drugs that have been reviewed by the European Medicines Agency and with the findings of meta-analyses, including the one prepared for the UK National Institute of Health and Clinical Excellence appraisal, that suggest a positive effect in favour of an improved health-related quality of life (HRQoL) for patients on ESAs. 5 Wilson J Yao G Rafferty J et al. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment. Health Technol Assess. 2007; 11: 1-202 Crossref PubMed Scopus (67) Google Scholar , 6 Seidenfeld J Piper M Bohlius J et al. Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. http://effectivehealthcare.ahrq.gov/repFiles/EPO%20Final.pdf Google Scholar For example, one of these studies noted the following: HRQoL data were analysed by use of vote counting and qualitative assessment and a positive effect was noted in favour of an improved HRQoL for patients on erythropoietin, 6 Seidenfeld J Piper M Bohlius J et al. Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. http://effectivehealthcare.ahrq.gov/repFiles/EPO%20Final.pdf Google Scholar although no published evidence from a quantitative meta-analysis exists because of methodological issues.

4014 Background: 5-FU based CRT is regarded standard perioperative treatment in LARC. Here we report safety data of a non-inferiority phase III trial investigating (neo-)adjuvant CRT with Cape in comparison with 5-FU. Methods: Patients (pts) aged ≥18 years with LARC UICC stages II or III were recruited in this two-arm, two-strata randomized phase-III trial (arm A: Cape, arm B: 5-FU; stratum [S] I: adjuvant, S II: neoadjuvant). Regimens: Arm A: CRT: 50.4 Gy + Cape 1,650 mg/m 2 days 1–38 plus five cycles of Cape 2,500 mg/m 2 d 1–14, rep. d 22 (S I: 2 x Cape, CRT, 3 x Cape; S II: CRT, TME surgery followed by Cape x 5). Arm B: CRT: 50.4 Gy + 5-FU 225 mg/m 2 c.i. daily [S I] or 5-FU 1,000 mg/m 2 c.i. d 1–5 and 29–33 [S II] plus 4 cycles of bolus 5-FU 500mg/m 2 d 1–5, rep. d 29 (S I: 2 x 5-FU, CRT, 2 x 5-FU; S II: CRT, TME surgery followed by 5-FU x 4). Primary endpoint was survival, secondary endpoints comprised safety and disease-free survival. Results: Of 401 randomized pts a total of 392 are evaluable (Arm A n=197, arm B n=195; S I n=231, S II n=161). Both arms were well balanced with respect to age, sex, WHO status, T- and N- stages. Regarding duration of treatment, 78% (Cape) and 80% (5-FU) completed all scheduled treatment cycles in S I, and 46% (Cape) and 40% (5-FU) in neoadjuvant stratum S II. In S II a total of 38% (Cape) and 43% (5-FU) did not continue chemotherapy after tumour resection. Concerning early efficacy endpoints in S II, pts treated with Cape (evaluable thus far n=121) exhibited a higher rate of T-downstaging (defined as ypT0–2; 52 vs 39%; p=0.16) and N0 (71 vs 56%; p=0.09). Regarding overall safety (NCI-CTC), pts receiving Cape experienced significantly less leukopenia (25 vs 35%; p=0.04), but more hand-foot syndrome (31 vs. 2%; p&lt;0.001). Stomatitis/mucositis, diarrhea, nausea/vomiting, and radiodermatitis were not significantly different between both arms. Conclusions: Given the observed safety profile and the trend in improved downstaging in neoadjuvant stratum, Cape exhibits a potential to replace 5-FU as perioperative treatment of LARC. Efficacy results on the primary endpoint are expected for 2010. [Table: see text]

Abstract Abstract 6 Background Simultaneous ATRA and chemotherapy (CHT) is the current gold standard for newly diagnosed APL resulting in ∼80% cure rates, while arsenic trioxide (ATO) is the treatment of choice for relapsed patients. ATO in variable combinations including ± ATRA ± CHT has also been tested as front-line therapy yielding encouraging results in several pilot studies as well as in two phase III studies conducted in China and the US. So far, no randomised studies have compared front-line CHT-free ATO+ATRA combination against the standard ATRA+CHT approach. Patients and Methods The phase III, randomised, prospective APL0406 trial was started in October 2007 by the Italian GIMEMA group and joined in November 2008 by the German SAL and AMLSG multicenter groups. Eligible patients were adults aged 18-&lt;71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10×109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally reported by the MD Anderson group (Estey et al. Blood 2006, arm A), or the Italian AIDA2000 risk-adapted protocol for non high-risk disease (arm B). Patients in arm A received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in arm B received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based plus ATRA consolidation and low dose CHT and ATRA for maintenance as reported (Lo-Coco et al., Blood 2011). The primary study objective was EFS at 2 years. The study was designed to show that the rate of patients alive event-free at two years in the experimental treatment arm is at least 80%. Secondary objectives included OS, DFS, CIR rates, molecular response and toxicity profile. Results From October 2007 to September 2010, the required sample size of 162 enrolled patients was completed. Median age was 45.3 years (18.7–70.2 years) and median WBC 1.50 × 109/L. As to the Sanz's risk score, 61.8% and 38.2% of patients were in the intermediate- and low-risk categories, respectively. The two treatment arms were well balanced for main baseline characteristics including age, sex, median WBC and Sanz's score. Eight patients were not evaluable for induction due to ineligibility or protocol violation. Of 154 patients evaluable for response to induction, CR was achieved in 150 (97.4%): 75/75 (100%) in arm A vs 75/79 (95%) in arm B (P=0.12). After a median follow-up of 31 months (range 0.07–50.4) the 2 year EFS (primary objective) was 97% (C.I.95%: 93.1–100) and 86.7% (C.I.95%: 80.3–93.6) in arms A and B respectively (P=0.03). There were 1 death in CR and 2 relapses in arm A, and 7 deaths (4 in induction, 3 in CR) and 4 relapses in arm B. As to secondary objectives, OS, DFS, and CIR rates were 98.7% vs. 91.1% (P=0.03), 97% vs. 91.6% (P=0.19) and 1.6% vs. 4.3% (P=0.41) in arm A and B, respectively. Fever episodes, prolonged (&gt;15 d) grade ≥ 3 neutropenia and thrombocytopenia were significantly more frequent in patients in arm B as compared to those in arm A (P &lt;.001 for all comparisons). Other side effects including differentiation syndrome and increase of liver enzymes were recorded with similar frequency in the two study arms. Two patients in arm A had QTc prolongation requiring ATO discontinuation with final withdrawal in one case. PCR analysis of PML/RARA (sensitivity 10−4) was centrally performed in Rome (F. Lo-Coco) and Dresden (C. Thiede) and showed molecular CR in 141/142 (99%) of evaluable patients after completion of 3rd consolidation. One patient in arm B who tested PCR-positive at this time point was considered resistant and taken off protocol as per study design. Conclusions For patients with newly diagnosed non-high-risk APL, as compared to the standard AIDA regimen, the front-line CHT-free ATO+ATRA combination is at least not inferior for 2 year EFS. Disclosures: Lo-Coco: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Cephalon: Speakers Bureau. Off Label Use: Arsenic Trioxide (ATO) is currently approved for therapy of relapsed APL in the US and Europe. In this study the role of ATO in front-line therapy of APL is explored. Fiedler:Pfizer Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Breccia:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Platzbecker:GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy.

To assess adherence to the current European Society for Medical Oncology (ESMO) clinical practice guideline on bone health in cancer patients and the German guidelines for lung, breast, and prostate cancer among German oncologists in hospitals and office-based physicians and to identify predictors of guideline compliance to assess the needs for dedicated training. This was a retrospective sample analysis representing hospitals and office-based physicians in Germany in 2016. Records from lung, breast, and prostate cancer patients who had received a diagnosis of bone metastasis between April 1, 2015, and March 31, 2016, were included. Oncologists at participating centers answered a self-assessment survey on aspects related to their professional life, including guideline adherence and years of clinical experience in medical oncology. Guideline adherence rates were assessed from patient records. Treatment variables and survey data were used to identify predictors of guideline compliance in a Classification and Regression Tree (CART) analysis. Disregarding recommendations for supplementation of calcium and vitamin D, guideline adherence among physicians treating lung, breast, or prostate cancer patients was 62%, 92%, and 83%, respectively. Compliance was 15%, 42%, and 40% if recommendations for dietary supplements were taken into account. Identified predictors of guideline compliance included treatment setting, medical specialty, years of professional experience, and frequency of quality circle attendance. Compliance with the ESMO and the German guidelines in cancer patients varies between medical specialties. In particular, patients with lung cancer and bone metastases often do not receive the recommended osteoprotective treatment and required supplementation. Discrepancies between guideline recommendations and common practice should be addressed with dedicated training.

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbacks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.

&lt;b&gt;&lt;i&gt;Background: &lt;/i&gt;&lt;/b&gt;The aim was to re-evaluate the current prevalence and management of cancer-associated anaemia as defined by the World Health Organisation (WHO) and related risk factors. &lt;b&gt;&lt;i&gt;Patients and Methods: &lt;/i&gt;&lt;/b&gt;This was a prospective, 2-day web-based cross-sectional survey in cancer patients with non-myeloid malignancies in German outpatient clinics. &lt;b&gt;&lt;i&gt;Results: &lt;/i&gt;&lt;/b&gt;89 centres collected data from 3,867 patients, of whom 74% received active cancer therapy. The median age was 65 years (range 19-99 years) and almost two-thirds were women; 68% of the patients had solid tumours (breast 34%, colorectal 17%, lung 8%), with 56% of them being metastatic; 73% had a WHO performance score of ≤ 1. The mean haemoglobin level was 12.0 ± 1.7 g/dl (± standard deviation; range 4.3-17.8 g/dl); the prevalence of levels below 12.0 g/dl was 49%. Two-thirds of these patients were not treated for anaemia; one-third received erythropoiesis-stimulating agents (12.6%), iron therapy (8.1%), transfusions (7.5%) or combinations thereof (8.0%) during the 4 weeks before evaluation. Chemotherapy, female sex, age and poor performance status were identified as significant anaemia-associated factors. &lt;b&gt;&lt;i&gt;Conclusions: &lt;/i&gt;&lt;/b&gt;The prevalence of untreated anaemia and the decreased performance status of cancer patients in Germany have hardly changed since the European Cancer Anaemia Survey (ECAS) in 2001. The treatment practice may not only be driven by guidelines and does not yet reflect new concepts of anaemia management.

The fluorescence in situ hybridization (FISH) technique for detection of the 9;22 translocation was compared with the "gold standard" of conventional cytogenetics. For this purpose, both methods were applied to 81 bone marrow aspirates and/or peripheral blood specimens comprising 50 CML cases and controls from 31 patients without CML. Independently, core biopsies of these 81 patients were investigated by three histopathologists. Conventional karyotype analysis from unstimulated bone marrow cells was successful in 71/81 cases and demonstrated the Ph-chromosome in 42/46 CML patients. With FISH, results were obtained in all 81 cases investigated, confirming fusion of the ber and abl genes in all cytogenetically Ph-positive patients. Among the five Ph-chromosome-negative specimens bcr/abl fusions were detected in only one patient. The percentage of cells found to be Ph-positive by both methods was correlated, but in individual cases considerable differences in the numbers of Ph-positive cells were observed. Different results may be due to selection of cells after in vitro cultivation predominantly. FISH proved to be a very reliable technique for specimens that do not contain dividing cells. With FISH, large numbers of cells can easily be scored which is an advantage compared to conventional cytogenetics. Therefore, this method is particularly suitable for those whose therapy is being monitored or a relapse is suspected. However, the FISH results should be evaluated critically with respect to the practical limit of sensitivity since non-specific fusion signals can also be observed in a small percentage of cells in non-CML cases. It is suggested that each laboratory define its own threshold of bcr/abl fusion signals for diagnosing Ph-positive CML by FISH.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 11, Issue s6 p. 1-126 LeitlinienFree Access Malignes Melanom S3-Leitlinie “Diagnostik, Therapie und Nachsorge des Melanoms” Annette Pflugfelder, Annette Pflugfelder Universitäts-Hautklinik Tübingen geteilte ErstautorenschaftSearch for more papers by this authorCorinna Kochs, Corinna Kochs Klinik für Dermatologie, Universitätsklinik Essen geteilte ErstautorenschaftSearch for more papers by this authorAndreas Blum, Andreas Blum Dermatologische Praxis, KonstanzSearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorChristina Czeschik, Christina Czeschik Klinik für Dermatologie, Universitätsklinik EssenSearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik LüdenscheidtSearch for more papers by this authorEdgar Dippel, Edgar Dippel Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorThomas Eigentler, Thomas Eigentler Universitäts-Hautklinik TübingenSearch for more papers by this authorPetra Feyer, Petra Feyer Klinik für Strahlentherapie und Radioonkologie, Vivantes Klinikum Neukölln – BerlinSearch for more papers by this authorMarkus Follmann, Markus Follmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorBernhard Frerich, Bernhard Frerich Klinik und Poliklinik für Mund- Kiefer- und Plastische Gesichtschirurgie, Universitätsmedizin RostockSearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorJan Gärtner, Jan Gärtner Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorJessica Hassel, Jessica Hassel Universitäts-Hautklinik HeidelbergSearch for more papers by this authorAxel Hauschild, Axel Hauschild Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Sektion Spezielle Chirurgische Onkologie & Thoraxchirurgie, UniversitätsMedizin MannheimSearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe-Universität, Frankfurt am MainSearch for more papers by this authorMartin Kaatz, Martin Kaatz Klinik für Hautkrankheiten und Allergologie, Wald-Klinikum GeraSearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, HamburgSearch for more papers by this authorOliver Kölbl, Oliver Kölbl Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum RegensburgSearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Klinik für Strahlentherapie und Radioonkologie, Universitätsklinik LeipzigSearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorPeter Kurschat, Peter Kurschat Klinik u. Poliklinik für Dermatologie und Venerologie, Universitätsklinikum KölnSearch for more papers by this authorUlrike Leiter, Ulrike Leiter Universitäts-Hautklinik TübingenSearch for more papers by this authorHartmut Link, Hartmut Link Medizinische Klinik, Westpfalz-Klinikum KaiserslauternSearch for more papers by this authorCarmen Loquai, Carmen Loquai Universitäts-Hautklinik MainzSearch for more papers by this authorChristoph Löser, Christoph Löser Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Medizinische Klinik 5 – Hämatologie/Onkologie, Universitätsklinikum ErlangenSearch for more papers by this authorFriedegund Meier, Friedegund Meier Universitäts-Hautklinik TübingenSearch for more papers by this authorPeter Mohr, Peter Mohr Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Universitäts-Hautklinik Tübingen Praxisklinik Tübingen – Haut und VenenSearch for more papers by this authorDorothee Nashan, Dorothee Nashan Hautklinik, Klinikum DortmundSearch for more papers by this authorSven Reske, Sven Reske Klinik für Nuklearmedizin, Universitätsklinikum UlmSearch for more papers by this authorChristian Rose, Christian Rose LübeckSearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. GeorgSearch for more papers by this authorImke Satzger, Imke Satzger Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Psychosoziale Onkologie, Fachklinik-HornheideSearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorLothar Swoboda, Lothar Swoboda Deutsche Gesellschaft für Thoraxchirurgie, HamburgSearch for more papers by this authorUwe Trefzer, Uwe Trefzer Klinik für Dermatologie Venerologie und Allergologie, Charité – Universitätsmedizin BerlinSearch for more papers by this authorRaymond Voltz, Raymond Voltz Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorDirk Vordermark, Dirk Vordermark Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Halle (Saale)Search for more papers by this authorMichael Weichenthal, Michael Weichenthal Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorAndreas Werner, Andreas Werner Tumorzentrum Rheinland-Pfalze. V., MainzSearch for more papers by this authorSimone Wesselmann, Simone Wesselmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Klinik für Dermatologie, Fachklinik Bad BentheimSearch for more papers by this authorWolfgang Wick, Wolfgang Wick Abteilung für Neuroonkologie, Universitätsklinik HeidelbergSearch for more papers by this authorClaus Garbe, Claus Garbe Universitäts-Hautklinik Tübingen geteilte LetztautorenschaftSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Klinik für Dermatologie, Universitätsklinik Essen geteilte LetztautorenschaftSearch for more papers by this author Annette Pflugfelder, Annette Pflugfelder Universitäts-Hautklinik Tübingen geteilte ErstautorenschaftSearch for more papers by this authorCorinna Kochs, Corinna Kochs Klinik für Dermatologie, Universitätsklinik Essen geteilte ErstautorenschaftSearch for more papers by this authorAndreas Blum, Andreas Blum Dermatologische Praxis, KonstanzSearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorChristina Czeschik, Christina Czeschik Klinik für Dermatologie, Universitätsklinik EssenSearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik LüdenscheidtSearch for more papers by this authorEdgar Dippel, Edgar Dippel Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorThomas Eigentler, Thomas Eigentler Universitäts-Hautklinik TübingenSearch for more papers by this authorPetra Feyer, Petra Feyer Klinik für Strahlentherapie und Radioonkologie, Vivantes Klinikum Neukölln – BerlinSearch for more papers by this authorMarkus Follmann, Markus Follmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorBernhard Frerich, Bernhard Frerich Klinik und Poliklinik für Mund- Kiefer- und Plastische Gesichtschirurgie, Universitätsmedizin RostockSearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorJan Gärtner, Jan Gärtner Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorJessica Hassel, Jessica Hassel Universitäts-Hautklinik HeidelbergSearch for more papers by this authorAxel Hauschild, Axel Hauschild Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Sektion Spezielle Chirurgische Onkologie & Thoraxchirurgie, UniversitätsMedizin MannheimSearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe-Universität, Frankfurt am MainSearch for more papers by this authorMartin Kaatz, Martin Kaatz Klinik für Hautkrankheiten und Allergologie, Wald-Klinikum GeraSearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, HamburgSearch for more papers by this authorOliver Kölbl, Oliver Kölbl Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum RegensburgSearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Klinik für Strahlentherapie und Radioonkologie, Universitätsklinik LeipzigSearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorPeter Kurschat, Peter Kurschat Klinik u. Poliklinik für Dermatologie und Venerologie, Universitätsklinikum KölnSearch for more papers by this authorUlrike Leiter, Ulrike Leiter Universitäts-Hautklinik TübingenSearch for more papers by this authorHartmut Link, Hartmut Link Medizinische Klinik, Westpfalz-Klinikum KaiserslauternSearch for more papers by this authorCarmen Loquai, Carmen Loquai Universitäts-Hautklinik MainzSearch for more papers by this authorChristoph Löser, Christoph Löser Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Medizinische Klinik 5 – Hämatologie/Onkologie, Universitätsklinikum ErlangenSearch for more papers by this authorFriedegund Meier, Friedegund Meier Universitäts-Hautklinik TübingenSearch for more papers by this authorPeter Mohr, Peter Mohr Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Universitäts-Hautklinik Tübingen Praxisklinik Tübingen – Haut und VenenSearch for more papers by this authorDorothee Nashan, Dorothee Nashan Hautklinik, Klinikum DortmundSearch for more papers by this authorSven Reske, Sven Reske Klinik für Nuklearmedizin, Universitätsklinikum UlmSearch for more papers by this authorChristian Rose, Christian Rose LübeckSearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. GeorgSearch for more papers by this authorImke Satzger, Imke Satzger Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Psychosoziale Onkologie, Fachklinik-HornheideSearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorLothar Swoboda, Lothar Swoboda Deutsche Gesellschaft für Thoraxchirurgie, HamburgSearch for more papers by this authorUwe Trefzer, Uwe Trefzer Klinik für Dermatologie Venerologie und Allergologie, Charité – Universitätsmedizin BerlinSearch for more papers by this authorRaymond Voltz, Raymond Voltz Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorDirk Vordermark, Dirk Vordermark Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Halle (Saale)Search for more papers by this authorMichael Weichenthal, Michael Weichenthal Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorAndreas Werner, Andreas Werner Tumorzentrum Rheinland-Pfalze. V., MainzSearch for more papers by this authorSimone Wesselmann, Simone Wesselmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Klinik für Dermatologie, Fachklinik Bad BentheimSearch for more papers by this authorWolfgang Wick, Wolfgang Wick Abteilung für Neuroonkologie, Universitätsklinik HeidelbergSearch for more papers by this authorClaus Garbe, Claus Garbe Universitäts-Hautklinik Tübingen geteilte LetztautorenschaftSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Klinik für Dermatologie, Universitätsklinik Essen geteilte LetztautorenschaftSearch for more papers by this author First published: 09 September 2013 https://doi.org/10.1111/ddg.12113Citations: 51 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume11, Issues6Special Issue: Malignes Melanom S3‐Leitlinie “Diagnostik, Therapie und Nachsorge des Melanoms”/Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”. The German Society of Dermatology and Wiley have published this supplement without financial support.August 2013Pages 1-126 RelatedInformation

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 11, Issue 6 p. 563-594 Leitlinien S3-Leitlinie ,,Diagnostik, Therapie und Nachsorge des Melanoms” – Kurzfassung Annette Pflugfelder, Annette Pflugfelder Universitäts-Hautklinik Tübingen geteilte Erstautorenschaft,Search for more papers by this authorCorinna Kochs, Corinna Kochs Klinik für Dermatologie, Universitätsklinik Essen geteilte Erstautorenschaft,Search for more papers by this authorAndreas Blum, Andreas Blum Dermatologische Praxis, KonstanzSearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorChristina Czeschik, Christina Czeschik Klinik für Dermatologie, Universitätsklinik EssenSearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik LüdenscheidtSearch for more papers by this authorEdgar Dippel, Edgar Dippel Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorThomas Eigentler, Thomas Eigentler Universitäts-Hautklinik TübingenSearch for more papers by this authorPetra Feyer, Petra Feyer Klinik für Strahlentherapie und Radioonkologie, Vivantes Klinikum Neukölln – BerlinSearch for more papers by this authorMarkus Follmann, Markus Follmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorBernhard Frerich, Bernhard Frerich Klinik und Poliklinik für Mund- Kiefer- und Plastische Gesichtschirurgie, Universitätsmedizin RostockSearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorJan Gärtner, Jan Gärtner Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorJessica Hassel, Jessica Hassel Universitäts-Hautklinik HeidelbergSearch for more papers by this authorAxel Hauschild, Axel Hauschild Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Sektion Spezielle Chirurgische Onkologie & Thoraxchirurgie, UniversitätsMedizin MannheimSearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe-Universität, Frankfurt am MainSearch for more papers by this authorMartin Kaatz, Martin Kaatz Klinik für Hautkrankheiten und Allergologie, Wald-Klinikum GeraSearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, HamburgSearch for more papers by this authorOliver Kölbl, Oliver Kölbl Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum RegensburgSearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Klinik für Strahlentherapie und Radioonkologie, Universitätsklinik LeipzigSearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorPeter Kurschat, Peter Kurschat Klinik u. Poliklinik für Dermatologie und Venerologie, Universitätsklinikum KölnSearch for more papers by this authorUlrike Leiter, Ulrike Leiter Universitäts-Hautklinik TübingenSearch for more papers by this authorHartmut Link, Hartmut Link Medizinische Klinik, Westpfalz-Klinikum KaiserslauternSearch for more papers by this authorCarmen Loquai, Carmen Loquai Universitäts-Hautklinik MainzSearch for more papers by this authorChristoph Löser, Christoph Löser Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Medizinische Klinik 5 – Hämatologie/Onkologie, Universitätsklinikum ErlangenSearch for more papers by this authorFriedegund Meier, Friedegund Meier Universitäts-Hautklinik TübingenSearch for more papers by this authorPeter Mohr, Peter Mohr Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Universitäts-Hautklinik Tübingen Praxisklinik Tübingen – Haut und VenenSearch for more papers by this authorDorothee Nashan, Dorothee Nashan Hautklinik, Klinikum DortmundSearch for more papers by this authorSven Reske, Sven Reske Klinik für Nuklearmedizin, Universitätsklinikum UlmSearch for more papers by this authorChristian Rose, Christian Rose LübeckSearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. GeorgSearch for more papers by this authorImke Satzger, Imke Satzger Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Psychosoziale Onkologie, Fachklinik-HornheideSearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorLothar Swoboda, Lothar Swoboda Deutsche Gesellschaft für Thoraxchirurgie, HamburgSearch for more papers by this authorUwe Trefzer, Uwe Trefzer Klinik für Dermatologie Venerologie und Allergologie, Charité – Universitätsmedizin BerlinSearch for more papers by this authorRaymond Voltz, Raymond Voltz Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorDirk Vordermark, Dirk Vordermark Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Halle (Saale)Search for more papers by this authorMichael Weichenthal, Michael Weichenthal Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorAndreas Werner, Andreas Werner Tumorzentrum Rheinland-Pfalz e. V., MainzSearch for more papers by this authorSimone Wesselmann, Simone Wesselmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Klinik für Dermatologie, Fachklinik Bad BentheimSearch for more papers by this authorWolfgang Wick, Wolfgang Wick Abteilung für Neuroonkologie, Universitätsklinik HeidelbergSearch for more papers by this authorClaus Garbe, Claus Garbe Universitäts-Hautklinik Tübingen geteilte LetztautorenschaftSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Klinik für Dermatologie, Universitätsklinik Essen geteilte LetztautorenschaftSearch for more papers by this author Annette Pflugfelder, Annette Pflugfelder Universitäts-Hautklinik Tübingen geteilte Erstautorenschaft,Search for more papers by this authorCorinna Kochs, Corinna Kochs Klinik für Dermatologie, Universitätsklinik Essen geteilte Erstautorenschaft,Search for more papers by this authorAndreas Blum, Andreas Blum Dermatologische Praxis, KonstanzSearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorChristina Czeschik, Christina Czeschik Klinik für Dermatologie, Universitätsklinik EssenSearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik LüdenscheidtSearch for more papers by this authorEdgar Dippel, Edgar Dippel Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorThomas Eigentler, Thomas Eigentler Universitäts-Hautklinik TübingenSearch for more papers by this authorPetra Feyer, Petra Feyer Klinik für Strahlentherapie und Radioonkologie, Vivantes Klinikum Neukölln – BerlinSearch for more papers by this authorMarkus Follmann, Markus Follmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorBernhard Frerich, Bernhard Frerich Klinik und Poliklinik für Mund- Kiefer- und Plastische Gesichtschirurgie, Universitätsmedizin RostockSearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorJan Gärtner, Jan Gärtner Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorJessica Hassel, Jessica Hassel Universitäts-Hautklinik HeidelbergSearch for more papers by this authorAxel Hauschild, Axel Hauschild Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Sektion Spezielle Chirurgische Onkologie & Thoraxchirurgie, UniversitätsMedizin MannheimSearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe-Universität, Frankfurt am MainSearch for more papers by this authorMartin Kaatz, Martin Kaatz Klinik für Hautkrankheiten und Allergologie, Wald-Klinikum GeraSearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, HamburgSearch for more papers by this authorOliver Kölbl, Oliver Kölbl Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum RegensburgSearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Klinik für Strahlentherapie und Radioonkologie, Universitätsklinik LeipzigSearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik HornheideSearch for more papers by this authorPeter Kurschat, Peter Kurschat Klinik u. Poliklinik für Dermatologie und Venerologie, Universitätsklinikum KölnSearch for more papers by this authorUlrike Leiter, Ulrike Leiter Universitäts-Hautklinik TübingenSearch for more papers by this authorHartmut Link, Hartmut Link Medizinische Klinik, Westpfalz-Klinikum KaiserslauternSearch for more papers by this authorCarmen Loquai, Carmen Loquai Universitäts-Hautklinik MainzSearch for more papers by this authorChristoph Löser, Christoph Löser Hautklinik, Hauttumorzentrum, Klinikum LudwigshafenSearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Medizinische Klinik 5 – Hämatologie/Onkologie, Universitätsklinikum ErlangenSearch for more papers by this authorFriedegund Meier, Friedegund Meier Universitäts-Hautklinik TübingenSearch for more papers by this authorPeter Mohr, Peter Mohr Arbeitsgemeinschaft Dermatologische Prävention (ADP) e.V., BuxtehudeSearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Universitäts-Hautklinik Tübingen Praxisklinik Tübingen – Haut und VenenSearch for more papers by this authorDorothee Nashan, Dorothee Nashan Hautklinik, Klinikum DortmundSearch for more papers by this authorSven Reske, Sven Reske Klinik für Nuklearmedizin, Universitätsklinikum UlmSearch for more papers by this authorChristian Rose, Christian Rose LübeckSearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. GeorgSearch for more papers by this authorImke Satzger, Imke Satzger Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule HannoverSearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer Abteilung Radiologie, Deutsches Krebsforschungszentrum HeidelbergSearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Psychosoziale Onkologie, Fachklinik-HornheideSearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Klinik für Hautkrankheiten, Universitätsklinikum MünsterSearch for more papers by this authorLothar Swoboda, Lothar Swoboda Deutsche Gesellschaft für Thoraxchirurgie, HamburgSearch for more papers by this authorUwe Trefzer, Uwe Trefzer Klinik für Dermatologie Venerologie und Allergologie, Charité – Universitätsmedizin BerlinSearch for more papers by this authorRaymond Voltz, Raymond Voltz Klinik und Poliklinik für Palliativmedizin, Universitätsklinikum KölnSearch for more papers by this authorDirk Vordermark, Dirk Vordermark Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Halle (Saale)Search for more papers by this authorMichael Weichenthal, Michael Weichenthal Klinik für Dermatologie, Venerologie, Allergologie, Universitätsklinikum Schleswig-Holstein, Campus KielSearch for more papers by this authorAndreas Werner, Andreas Werner Tumorzentrum Rheinland-Pfalz e. V., MainzSearch for more papers by this authorSimone Wesselmann, Simone Wesselmann Deutsche Krebsgesellschaft BerlinSearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Klinik für Dermatologie, Fachklinik Bad BentheimSearch for more papers by this authorWolfgang Wick, Wolfgang Wick Abteilung für Neuroonkologie, Universitätsklinik HeidelbergSearch for more papers by this authorClaus Garbe, Claus Garbe Universitäts-Hautklinik Tübingen geteilte LetztautorenschaftSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Klinik für Dermatologie, Universitätsklinik Essen geteilte LetztautorenschaftSearch for more papers by this author First published: 30 May 2013 https://doi.org/10.1111/ddg.12044_supplCitations: 14 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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In metastatic colorectal cancer (mCRC), liver‐limited disease (LLD) is associated with a higher chance of metastectomy leading to long‐term survival. However, limited data describes the prognostic and predictive relevance of initially unresectable LLD with regard to targeted first‐line therapy. The present analysis investigated the relevance of initially unresectable LLD in mCRC patients treated with targeted therapy against either the epidermal growth factor receptor (EGFR) or vascular epithelial growth factor (VEGF). The analysis was performed based on FIRE‐3, a randomized phase III trial comparing first‐line chemotherapy with FOLFIRI plus either cetuximab (anti‐EGFR) or bevacizumab (anti‐VEGF) in RAS wild‐type (WT) mCRC. Of 400 patients, 133 (33.3%) had LLD and 267 (66.8%) had non‐LLD. Median overall survival (OS) was significantly longer in LLD compared to non‐LLD patients (36.0 vs . 25.4 months; hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.51–0.87; p = 0.002). In a multivariate analysis also including secondary hepatic resection as time‐dependent variable, LLD status was independently prognostic for OS (HR = 0.67; 95% CI: 0.50–0.91; p = 0.01). As assessed by interaction tests, treatment benefit from FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab was independent of LLD status with regard to objective response rate (ORR), early tumour shrinkage ≥20% (ETS), depth of response (DpR) and OS (all p &gt; 0.05). In conclusion, LLD could be identified as a prognostic factor in RAS‐WT mCRC, which was independent of hepatic resection in patients treated with targeted therapy. LLD had no predictive relevance since benefit from FOLFIRI plus cetuximab over bevacizumab was independent of LLD status.

Recombinant granulocyte colony-stimulating factors (rG-CSFs), such as filgrastim, are administered to prevent complications in patients receiving chemotherapy. In Europe, a biosimilar to filgrastim, tevagrastim/ratiograstim/biograstim, was approved in 2008. In the USA, the same product was approved as tbo-filgrastim under a 351(a) biologic license application in 2012 with the brand name Granix®. Postmarket surveillance remains a priority for monitoring the safety of biologics and biosimilars to identify rare and immunogenicity-related events. We report the global and US pharmacovigilance data for tevagrastim/ratiograstim/biograstim and tbo-filgrastim, respectively.Cumulative exposure and adverse event data from initial approval in Europe to December 31, 2016, were collected globally from spontaneous reports submitted by healthcare professionals and consumers, scientific literature, competent authorities, and solicited case reports from non-interventional studies. A separate search was conducted on the global data set to identify reports originating from the USA and Puerto Rico to describe the US experience.Overall, the global safety profile of tevagrastim/ratiograstim/biograstim in the postmarket, real-world setting was comparable to clinical trial experience. Postmarket safety experience of tbo-filgrastim in the USA was consistent with global data. The most common SAEs were febrile neutropenia and decreased white blood cell count. The most common non-serious event was bone pain. There was no evidence of immunogenicity.This pharmacovigilance analysis indicates that postmarket experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim is consistent with clinical trials. Adverse reactions associated with the originator rG-CSF (capillary leak syndrome and glomerulonephritis) have not been observed with tevagrastim/ratiograstim/biograstim or tbo-filgrastim during the postmarket period.

High-dose chemotherapy with autologous transplantation of in vivo purged PBSC is a new and interesting therapeutic option for CML patients not eligible for allogeneic transplantation. We investigated the feasibility and toxicity of this approach in 57 patients with Ph-positive CML. For mobilization of Ph-negative PBSC, patients were treated either with ‘5 + 2/7 + 3’-type chemotherapy or with ‘mini-ICE/ICE’ chemotherapy followed by administration of G-CSF. Fourteen patients were in early chronic phase, 30 patients in late chronic phase and 13 patients in accelerated phase (AP) or blast crisis (BC). Cytogenetic responses in the PBSC harvests were dependent on both disease stage and type of chemotherapy: in late chronic phase and AP/BC, a complete or major cytogenetic response could be obtained in nine out of 13 patients treated with ‘mini-ICE/ICE’ but only in three out of 23 patients treated with ‘5 + 2/7 + 3’ chemotherapy. However, in early chronic phase a Ph-negative autograft could be obtained in three out of eight patients upon mobilization with ‘5 + 2’ chemotherapy. Thirty-one patients underwent PBSC transplantation and all of them successfully engrafted. Post-transplant cytogenetic analysis was available on 21 cases, of whom seven achieved a complete or major cytogenetic response, with two minor cytogenetic remissions. One patient (1/57) in blast crisis died during mobilization therapy (1.8%). Transplantation related mortality was 0%. This study demonstrates that mobilization of Ph-negative PBSC after myelosuppressive chemotherapy is feasible in CML patients and is associated with acceptable toxicity. Autologous transplantation of in vivo purged PBSC is a safe procedure with rapid and complete hematopietic recovery.

Summary Salvage therapy followed by high‐dose therapy ( HDT ) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R‐Dexa BEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT . Patients aged 18–65 years, Eastern Cooperative Oncology Group performance score 0–2, with relapsed/refractory B‐cell non‐Hodgkin lymphoma ( NHL ) were eligible. R‐Dexa‐ BEAM was given for two cycles followed by stem cell mobilization and HDT . Primary endpoint of the trial was progression‐free‐survival ( PFS ). One hundred and three patients were included: aggressive NHL ( aNHL ): diffuse large B‐cell lymphoma 55, mantle cell lymphoma 7, follicular lymphoma (FL ) grade 3: 5, indolent Lymphoma ( iNHL ): FL grade 1–2: 29, marginal zone lymphoma 6, Immunocytoma 1. The overall response rate after salvage therapy was 62% for aNHL and 78% for iNHL patients. 66% of patients with aNHL and 86% with iNHL underwent HDT . Treatment‐related mortality for HDT was 1·3%. For aNHL patients, the median PFS was 0·83 years with 44% alive at the median follow‐up of 7·3 years. Corresponding figures for iNHL were: median PFS 3·7 years and 72% alive after 8 years. The combination of rituximab with Dexa BEAM followed by HDT resulted in high response rates and sustained remissions in responders. R‐Dexa BEAM followed by HDT can be considered a valid salvage option for NHL .

The aim of this prospective cohort study was to assess current antianemic treatment of cancer patients in German routine practice, including diagnostics, treatments, and quality of life (QoL). 88 study sites recruited 1018 patients at the start of antianemic treatment with hemoglobin (Hb) levels <11 g/dL (females) or <12 g/dL (males). Patients were followed up for 12 weeks. 63% of the patients had inoperable solid tumors, 22% operable solid tumors, and 15% hematological malignancies. Over 85% received chemotherapy. Median age was 67 years; 48% were male. Red blood cell transfusions (RBCTx) were given to 59% of all patients and to 55% of the patients with Hb ≥8 g/dL on day 1 of the observation period (day 1 treatment). Erythropoiesis-stimulating agents (ESAs) were the second most frequently applied day 1 treatment (20%), followed by intravenous (IV) iron (15%) and ESA + IV iron (6%). Only about a third of patients were tested for blood serum iron parameters at the start of treatment. Overall, more than half of the patients had long-term responses to antianemic therapy. Our data suggest that in routine practice diagnostics for treatable causes of anemia are underused. A high proportion of cancer patients receive RBCTx. It should be discussed whether thorough diagnostics and earlier intervention could decrease the need for RBCTx. This trial is registered with NCT01795690.

Abstract Background Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. Patient and methods One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. Results Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was − 0.3 days (95% confidence interval, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC &lt; 0.1 × 10 9 /L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 10 9 /L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. Conclusions This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. Trial registration number ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23

The most common cause of anemia is iron deficiency, followed by anemia of chronic disease, which is due to an inflammatory reaction in chronic diseases such as heart failure, renal failure, rheumatoid diseases and cancer. Also from the therapeutic point of view, it is useful to divide iron deficiency anemia into two forms: absolute and functional iron deficiency. Absolute iron deficiency is characterized by low iron stores and low total iron. In functional iron deficiency, a sufficient amount of storage iron is present, but it cannot be mobilized. Therapy of iron deficient anemia should always eliminate the underlying cause. The goal of therapy is sustained normalization of hemoglobin concentration and total body iron. Therapy for absolute iron deficiency focuses on improving iron stores, eliminating chronic blood losses, and optimizing iron absorption via an iron-rich diet and iron supplementation. In the case of functional iron deficiency with inflammation present, IV iron supplementation is recommended in certain situations in addition to treatment of the underlying disease, especially in patients with cancer.

This Phase I/II study investigates increasingly high doses of ifosfamide combined with full dose doxorubicin chemotherapy supported with peripheral blood stem cells (PBSC) and granulocyte-colony stimulating factor (G-CSF) in patients with metastatic soft tissue sarcoma (STS).Patients with histologically proven metastatic or advanced adult STS without prior treatment received doxorubicin, 75 mg/m2, on Day 1 followed by 4-day continuous infusion of ifosfamide at 5 consecutive dose levels starting with 8 g/m2 and escalating to 16 g/m2 in increments of 2 g/m2. Three patients per dose level and a maximum of 5 treatment cycles per level at 3-week intervals were planned. Each cycle was followed by G-CSF and retransfusion of PBSC. PBSC separation was performed prior to chemotherapy by steady state mobilization with G-CSF.Eighteen patients (median age, 45 years, range, 25-57 years) were included, with 4, 3, 4, 4, and 3 patients assigned to Levels 1-5, respectively. Metastatic sites included the lungs in 12 patients (67%), lymph nodes in 8 patients (44%), and the liver in 5 patients (28%). Nine patients (50%) achieved objective responses with 4 complete responses (22%) and 5 partial responses (28%). Lung metastases and a histology of synovial sarcoma or malignant fibrous histiocytoma were favorable features for response to therapy. The median survival for all patients was 13+ months (range, 3-19+ months). Hematotoxicity was manageable and treatment could be administered at a median interval of 24 days. One case of World Health Organization Grade 3 neurotoxicity occurred. Nephrotoxicity was dose-limiting, with 1 patient in Level 4 (WHO Grade 2) and 2 patients in Level 5 (WHO Grade 3).Multiple cycles of dose-intensive therapy with doxorubicin and high dose ifosfamide can be administered safely with PBSC support. Nephrotoxicity is dose-limiting for ifosfamide at total doses of 16 g/m2. Multiple cycles of high dose chemotherapy at short treatment intervals using ifosfamide at a dose of 14 g/m2 should be investigated further in a neoadjuvant setting in patients with STS.

A total of 229 patients with chronic myeloid leukaemia (CML) in chronic phase were randomized between 1986 and 1990 to receive or not receive additional splenic irradiation as part of their conditioning prior to bone marrow transplantation (BMT). Both groups, 115 patients with and 114 patients without splenic irradiation, were very similar regarding distribution of age, sex, donor/recipient sex combination, conditioning, graft‐versus‐host disease (GvHD) prevention method and blood counts at diagnosis or prior to transplant. 135 patients (59%) are alive as of October 1995 with a minimum follow‐up of 5 years. 52 patients have relapsed (23%), 26 patients in the irradiated, 26 patients in the non‐irradiated group (n.s.) with a relapse incidence at 6 years of 28%. The main risk factor for relapse was T‐cell depletion as the method for GvHD prevention, and an elevated basophil count in the peripheral blood prior to transplant. Relapse incidence between patients with or without splenic irradiation was no different in patients at high risk for relapse, e.g. patients transplanted with T‐cell‐ depleted marrows ( P = n.s.) and in patients with low risk for relapse, e.g. patients transplanted with non‐T‐cell‐depleted transplants and basophil counts &lt;3% prior to transplant ( P = n.s.). However, relapse incidence differed significantly in patients with non‐T‐cell‐depleted transplants and high basophil counts (&gt; 3% basophils in peripheral blood). In this patient group, relapse incidence was 11% at 6 years with splenic irradiation but 32% in the non‐irradiated group ( P = 0.05). Transplant‐related mortality was similar whether patients received splenic irradiation or not. This study suggests an advantage in splenic irradiation prior to transplantation for CML in this subgroup of patients and illustrates the need for tailored therapy.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study