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1 ANGEWANDTE KREBSFORSCHUNG INSTITUTION FÜR TRANSLATIONALE FORSCHUNG WIEN (ACR ITR VIENNA) ZVR-Zahl P U B L I K A T I O N E N 2014 Im Berichtsjahr wurden acht Originalarbeiten, zwei davon online, in peer-reviewed Journalen (PUBL#1-8) sowie drei Übersichtsartikel, davon zwei online (PUBL#16,18,19) sowie ein Editorial (PUBL#17) veröffentlicht. Sechs Abstracts/Symposiumsbeiträge (PUBL#9-14) wurden bei Symposien/Kongressen eingereicht und in den jeweiligen Abstractbänden bzw. online publiziert. Darüber hinaus wurden zwei Fortbildungsbeiträge (PUBL#20,21) verfasst. Überdies wurde an der Erstellung einer Zusammenfassung der aktualisierten EAU-Richtlinien zum Muskel-invasiven und metastasierten Harnblasenkarzinom mitgewirkt (PUBL#15). Drei Originalarbeiten bzw. ein Buchbeitrag befanden sich in Druck. Pharmakokinetische Evaluierungsmethode In dieser im Berichtsjahr in Druck befindlichen Originalarbeit wurde eine einfache Methode für den Vergleich von enzymatischer Aktivierung von Capecitabin bei verschiedenen Mono- und Kombinationschemotherapien vorgestellt. Untersuchung zu Biomarkern Klinischer Biomarker PUBL#11) Die im Berichtsjahr als Abstract veröffentlichte prospektive Studie untersuchte, ob Serumspiegel des Follikelstimulierenden Hormons (FSH) als Surrogatparameter für die Erfassung der Effektivität einer adjuvanten Hormontherapie bei prämenopausalen Patientinnen mit Hormonrezeptor-positivem Mammakarzinom herangezogen werden können. Die Analyse lässt vermuten, dass FSH-Serumspiegel, erhoben bei Patientinnen unter Therapie, verlässliche Surrogatmarker für die Wirksamkeit adjuvanter endokriner Therapie sind. Abstract: Background: Endocrine therapy is an effective, targeted therapy in patients with hormone receptor positive breast cancer (BC). However, in the adjuvant setting no indicator exists visualizing its effectiveness during therapy. In this analysis, we test whether FSH serum levels during therapy might be a surrogate parameter for the effectiveness of adjuvant endocrine therapy. Methods: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6mgq4wSC) in combination with anastrozole or tamoxifen ± zoledronic acid (ZOL, (4mgIVq6mo) in premenopausal women with endocrine-responsive BC. Prospective collected data on FSH serum levels were used for the analyses. Disease-free survival (DFS), distant metastasis free survival (DMFS) and overall survival (OS) were calculated by Kaplan-Meier method, results were compared by using the log-rank test and Cox proportional hazard modelling. Results: Analyses are based on 503 patients with FSH levels at baseline, 562 patients with FSH levels during therapy and 641 patients with FSH levels during follow up. Mean FSH levels were significantly lower during therapy, when compared to baseline and follow up, respectively (4.87mIU/ml vs mIU/ml vs mIU/ml, p<0.001). Patients treated with anastrozole had significantly higher FSH levels during therapy compared to patients treated with tamoxifen (7.05mIU/ml vs. 2.45mIU/ml, p<0.001). Patients with FSH levels above the mean during therapy (4.87mIU/ml) had a worse outcome compared to patients with FSH levels below 4.87mIU/ml (DFS HR 1.347, p=0.18; DMFS HR 1.939, p=0.035; OS HR 2.208, p=0.096). This could be confirmed with borderline significance in the subgroup of patients treated with ZOL (DFS HR 1.886, p=0.075; DMFS HR 2.537, p=0.077; OS HR 1.306, p=0.726). BMI had no impact on FSH serum levels in any group during therapy. Conclusions: This study suggests that FSH serum levels during therapy might be a good surrogate parameter for the effectiveness of adjuvant endocrine therapy. Klinische Studien Klinische Phase I-Studien PUBL#4,14) Die im Berichtsjahr sowohl als Originalarbeit als auch als Abstract veröffentlichte Phase I-Studie hatte die Testung der Kombination von Chemo-Radiotherapie bei Patienten mit lokal fortgeschrittenem Übergangszellkarzinom der Harnblase, die entweder inoperabel oder für eine Operation ungeeignet waren, zum Inhalt. Im Rahmen dieser klinischen Studie wurden die maximal tolerable Dosis (MTD) und die Dosis-limitierenden Toxizitäten (DLTs), vor allem aber Spättoxizitäten, von Gemcitabin in Kombination mit Strahlentherapie bei Patienten, die weder für operative noch für Cisplatin-Therapie geeignet waren, erfasst. Die Ergebnisse zeigten, dass Gemcitabin in Kombination mit Strahlentherapie in diesem Patientenkollektiv gut verträglich ist. Die empfohlene Dosis für Gemcitabin in nachfolgenden Studien ist 40mg/m², zweimal pro Woche mit gleichzeitiger Bestrahlung. Abstract: Background: We conducted a phase I trial of gemcitabine (gem) with concurrent radiotherapy in patients with muscle-invasive bladder cancer (BC) ineligible for surgery or cisplatin or refusing organ loss. Patients and Methods: Patients with urothelial cancer, ct2- T4, cn0-1, M0, ineligible for surgery due to local tumor extension, PS, age or co-morbidities or who refused surgery were included. After maximal transurethral resection, the treatment schedule included: twice-weekly i.v. infusion of gem [dose levels (DL) 1-6: 20, 27, 30, 33, 50 and 40 mg/m(2), respectively] for 30 min and concurrent radiotherapy (RT) to the bladder with 55.5 Gy. The primary end point was to determine the maximum-tolerated dose (MTD) and the dose recommended (RD) for further studies of this gem schedule. The secondary end point was late toxicity. The MTD was defined by dose-limiting toxicity (DLT) in 2 or more of 6 patients, discontinuation of RT and/or

2 2 gem for >1 week in 2 or more of 6 patients due to grade (G) 3/4 acute and/or late toxicity in more than 2 of 18 patients. Results: Thirty-five of 44 patients were assessable for toxicity and thus the primary end point. DLTs occurred in two of five patients at dose level 5: one G3 alanine aminotransferase elevation and one G3 fatigue. The MTD, therefore, was 50 mg/m(2) gem twice weekly. At DL 6 with 40 mg/m(2), the RD was established: only one of six patients developed G3 fatigue and diarrhea. Late toxicity was rare and of low grade (only G1-2). The 2-year locoregional failure rate was 32% (9/28); 10 of 28 patients (38%) were alive with an intact bladder and no evidence of recurrent disease, 9 patients developed distant metastases and 6 died of their disease. Conclusions: Gemcitabine in combination with RT is well tolerated in BC patients ineligible for surgery and/or cisplatin. The RD of gemcitabine for subsequent trials is 40 mg/m(2) twice weekly with concurrent radiation. PUBL#12,13) Die im Berichtsjahr in Form von Abstracts publizierte Phase Ib-Studie hatte die Evaluierung einer Triple- Kombinationstherapie, bestehend aus Capecitabin, Erlotinib und Bevacizumab, bei Patienten mit unresezierbarem und/oder metastasiertem Pankreaskarzinom zum Inhalt. Die maximal tolerable Dosis (MTD), Sicherheit und die Dosierung für nachfolgende Phase II-Studien wurden ermittelt, und pharmakokinetische Parameter sowie das prognostische Potenzial zirkulierender Tumorzellen (CTCs) erfasst. Die Studie ergab, dass diese Triple-Kombination gut verträglich war und auch klinische Aktivität zeigte. Die empfohlene Dosierung für nachfolgende Phase II-Studien lag für Capecitabin bei 800mg/m² bid, für Erlotinib bei 150mg po/tag und für Bevacizumab bei 10mg/kg alle 2 Wochen. Die Evaluierung pharmakokinetischer Parameter ergab keine Interaktionen zwischen Capecitabin und Erlotinib; der Nachweis von CTCs vor Therapiebeginn war von prognostischer Bedeutung. Abstract: Background: UMPC represents an unmet therapeutic need. Maximum tolerated dose (MTD), PK, safety, and doses recommended for phase II (RPIID) of CEB were determined, and the prognostic potential of CTCs was assessed (EudraCT ). Methods: A 3+3 design was used with stepwise dose escalation (DE) starting with C until reaching MTD followed by DE of E and B of one step each. C, E, and metabolites were measured with HPLC. CTCs were determined by anti-epcam immunomagnetic enrichment technology. Results: 30 out of 35 pts (15 f, 15 m) aged yrs, with ECOG status 0 (77%) or 1 (23%) and unresectable (N=1)/metastatic disease (N=29) were evaluable for MTD. C (mg/m² bid) was started with 500 (dose level (DL) 1; N=7), escalated to 650 (DL2; N=6), 800 (DL3; N=8), and reached MTD with 900 (DL4; N=8). At DL5 (N=3), C 800 was combined with E escalated from 100 to 150mg po d. At DL6 (N=3), C and E dosages were kept, B was escalated from 5 to 10mg/kg q 2wks. Whereas DLTs in form of diarrhea (N=2), erythema, herpes, rectal bleeding, and hand-foot syndrome (N=1 each) were found during DE of C in DL1 (1 pt), DL2 (1 pt), DL3 (1 pt), and DL4 (3 pts), no further DLT was observed with the DE of E and B. Overall, 264 cycles were applied. Extensive PK could not verify modulation of E by C. Due to the different modes of activation and metabolization of C and E, a PK interaction seems not to be probable. High inter-individual variability of PKs was detected. The most severe G3/4 toxicities per pt were: hand-foot syndrome (16.7%), diarrhea, hyperbilirubinemia, rash/acne (10% each), myocardial infarction, paronychia, cheilitis, anemia (3.3% each). 2 pts (7%) reached PR, 17 pts (61%) had stable disease. PFS was median 3.6 mos ( ), OS was median 6.8 mos ( ). No CTC (CTC-) was detected in 13 pts, 1-4 CTCs (CTC+) in 11 pts. PFS in CTC- was median 9.6 mos (95%CI 5.2, 13.9), in CTC+ median 2.8 mos (95%CI 1.36, 4.2); this difference revealed a trend (p=0.079; Breslow). Conclusions: RPIID is C 800mg/m² bid, E 150mg po d and B 10mg/kg q2 wks. CEB can be applied safely and has demonstrated clinical activity. Weiters wurden im Berichtsjahr die Ergebnisse einer Phase I-Dosiseskalationsstudie mit dem Aurora Kinase B-Inhibitor BI bei Patienten mit fortgeschrittenen soliden Tumoren in Form einer Originalarbeit zur Publikation angenommen und online publiziert (PUBL#8). Klinische Phase II-Studien PUBL#2) Eine im Berichtsjahr als Originalarbeit publizierte, multizentrische randomisierte Phase II-Studie widmete sich der Testung von Pemetrexed im Vergleich zu Pemetrexed in Kombination mit Erlotinib als Zweitlinientherapie bei Patienten mit lokal fortgeschrittenem oder metastasiertem, nicht-squamösem, nicht-kleinzelligem Bronchuskarzinom. Als primärer Endpunkt wurde das Progressions-freie Überleben (PFS) erfasst; sekundäre Endpunkte waren Gesamtüberleben (OS), Zeit bis zum Therapieversagen (TTTF), Ansprechen und Toxizität. Als Ergebnis wies die Kombination von Pemetrexed und Erlotinib im Vergleich zu alleiniger Gabe von Pemetrexed eine signifikante Verbesserung von PFS, OS und TTTF unter gleichzeitigem Anstieg der Grad 3/4 Toxizitäten auf. Abstract: Introduction: Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed+erlotinib in patients with advanced non-squamous NSCLC. Methods: NSCLC stage III-IV patients who failed one prior platinum-based chemotherapy regimen, 1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status 2 were eligible. Patients received pemetrexed 500 mg/m(2) with vitamin B12 and folic acid q3w alone or combined with erlotinib 150 mg daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity. Results: Of 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed+erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed+erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = ). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus (8.18, 16.66) for pemetrexed+erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed+erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = ). One patient died in pemetrexed+erlotinib arm due to febrile neutropenia. Grades 3/4 drugrelated toxicities (in 5% of patients) in pemetrexed/pemetrexed+erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). Conclusions: Pemetrexed+erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone. PUBL#6) Die finalen Ergebnisse dieser multizentrischen, nicht-randomisierten Phase II-Studie zur Evaluierung von Dovitinib, einem oralen Inhibitor von angiogenen Faktoren, darunter Fibroblasten-Wachstumsfaktor-Rezeptor 3 (FGFR3), bei intensiv vorbehandelten Patienten mit fortgeschrittenem Urothelkarzinom wurden im Berichtsjahr als Originalarbeit veröffentlicht. Patienten wurden in dieser Studie entsprechend dem Mutationsstatus des FGFR3 in zwei Gruppen stratifiziert: Patienten mit Tumoren mit FGFR3 Genmutation (mut) und Tumoren ohne FGFR3 Genmutation (non-mut). Aus der Analyse der erhobenen Daten wurde geschlossen, dass Dovitinib als Einzelsubstanz lediglich mäßige Aktivität, ungeachtet des FGFR3 Mutationsstatus, in diesem Patientenkollektiv aufwies. Abstract: Background: Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib -a broad-targeted inhibitor of tyrosine kinases, including FGFR3- were evaluated in

3 3 patients with previously treated advanced UC with and without FGFR3 mutations. Methods: Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2- days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Results: Most of the patients were men (75%) and over half of the patients were aged 65 years (61%). All patients had received 1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], ) and FGFR3(WT) (3.2%; 95% CI, ) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Conclusion: Although generally well tolerated, dovitinib has very limited singleagent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. Eine im Berichtsjahr in Druck befindliche Arbeit hatte eine Phase II-Studie mit Lapatinib plus pegyliertem liposomalem Doxorubicin bei Patientinnen mit lokal fortgeschrittenem oder metastasiertem HER-2 positivem Mammakarzinom, die unter Trastuzumab progredient wurden, zum Inhalt. Klinische Phase III-Studie PUBL#9) Im Berichtsjahr wurden die Ergebnisse einer prospektiven, sequentiellen Phase III-Studie bei Patienten mit metastasiertem Nierenzellkarzinom in Form eines Abstracts präsentiert. Systemisch unvorbehandelte, für Zytokin-Therapie ungeeignete Patienten wurden entweder in den Sorafenib/Sunitinib-Arm oder in den Sunitinib/Sorafenib-Arm randomisiert. Als primärer Endpunkt wurde das Progressions-freie Überleben (T-PFS), erfasst vom Beginn der Randomisierung bis zum Ereignis (Progression, Unverträglichkeit) unter second-line Therapie, festgelegt. Die Analyse der Studie zeigte, dass kein signifikanter Unterschied zwischen den beiden sequentiellen Behandlungen hinsichtlich T-PFS, Gesamtüberleben, Disease control rate und PFS unter first-line Therapie bestand. Die Toxizitätsprofile unterschieden sich; Toxizitäten waren generell weniger zahlreich unter der second-line Therapie, die von mehr Patienten des Sorafenib/Sunitinib-Armes erreicht wurde. Abstract: Background: The sequential use of SO and SU has been investigated retrospectively in patients with mrcc. We report here results from the first randomized study to prospectively compare SO/SU versus SU/SO. Methods: Pts with mrcc unsuitable for cytokines without prior systemic therapy, ECOG PS 0/1, MSKCC score low or intermediate, and 1 measurable lesion were randomized to receive open-label SO/SU (arm A) or SU/SO (arm B) in standard dosage. Primary endpoint: total PFS (T-PFS) from randomization to event during 2 nd line therapy. Therapy continued until progression or intolerability. The study was powered to detect a 47% increase in T-PFS with SO/SU compared to SU/SO using log-rank testing and Cox proportional hazard regression model. (NCT ). Results: A total of 365 pts were enrolled: 182 arm A, 183 arm B. The two arms were well balanced: median age (A/B): 64/65 yrs; prior nephrectomy: 74/65%; MSKCC intermediate: 59/51%, low: 39/45%; clear cell histology: 90/84%. At time of final T-PFS analysis 220 events had occurred (A, n=117 [64%]; B, n=103 [56%]). There was no statistically significant difference in T-PFS across arms: HR 1.01, p=0.54, arm A and arm B, respectively. Likewise, there was no statistically significant difference in OS: HR 0.997, p=0.49, nor in the first PFS across arms: HR 1.19, p=0.92. Fewer pts crossed over to receive SO in arm B (n=76) than to receive SU in arm A (n=103). Overall DCR was 72/67%. There was a marked difference in AEs leading to permanent discontinuation between the two groups (18.6/29.5%). Most frequent (>20%) side effects under 1 st -line treatment SO vs SU were alopecia (29/4%), diarrhea (43/29%), dysgeusia (8/21%), fatigue (21/34%), HFSR (37/20%), hypertension (24/24%), nausea (18/24%) and rash (22/3%). AEs were generally lower during 2 nd -line therapy. Conclusions: There was no significant difference in T-PFS, OS, DCR and 1 st -line PFS between the two sequential treatments. Both drugs provided overall benefit regardless of sequence. Side effect profiles differ, but were generally less frequent during 2 nd -line therapy. More patients reached 2 nd -line in the SO/SU arm. Kasuistischer Bericht über eine Langzeitremission unter dualer Therapie mit monoklonalen Antikörpern beim primären Mammakarzinom PUBL#1) Eine weitere im Berichtsjahr verfasste Arbeit beinhaltet eine Untersuchung zur Langzeitremission einer Patientin mit HER-2/neu positivem primärem Mammakarzinom unter Therapie mit zwei monoklonalen Antikörpern, die an unterschiedlichen Zielstrukturen ansetzen. Als Ergebnis zeigte sich, dass kombinierte Gabe von Trastuzumab und Bevacizumab klinisch effektiv, sicher und nicht-toxisch ist und überdies als Langzeitgabe eingesetzt werden kann. Abstract: Background: The attempt to act on several signaling pathways involved in tumor development simultaneously appears to be more attractive than attacking a single target structure alone. Vascular endothelial growth factor (VEGF) over-expression is frequently observed in human epidermal growth factor receptor 2 (Her2/neu) positive patients with breast cancer and over-expression of the protooncogene Her2/neu is associated with an up-regulation of VEGF. Case Report: The case of a Her2/neu positive patient with breast cancer who refused cytotoxic chemotherapy with its potential side effects as well as mastectomy is presented. Our patient has been receiving the combined double administration of bevacizumab and trastuzumab for more than 4 years. Conclusions: This case report shows that (a) the combined double administration of bevacizumab and trastuzumab be clinically effective; (b) The combination of bevacizumab and trastuzumab is safe and non-toxic; (c) Bevacizumab and trastuzumab can be used as a long-term application. Epidemiologische Untersuchungen Die langjährige Kollaboration mit den Channing Laboratories, Brigham and Women s Hospital and Harvard Medical School, namentlich mit Frau PD DDr. Eva Schernhammer, einem ACR-ITR VIEnna Mitglied, führte im Berichtsjahr zu drei Veröffentlichungen in peer-reviewed Journalen, eine davon online. Eine Arbeit befand sich im Druck. PUBL#3) Inhalt dieser epidemiologischen Arbeit war, im Rahmen einer randomisierten, Placebo-kontrollierten Studie den Effekt von Melatonin-Supplementierung auf Schlafgewohnheiten, Stimmung und Hitzewallungen bei 95 postmenopausalen Frauen nach Brustkrebs zu erfassen. Die Ergebnisse dieser Studie zeigten, dass Melatonin mit einer Verbesserung an subjektiver Schlafqualität ohne jeglichen signifikanten Nebeneffekt verknüpft war. Keine signifikanten Unterschiede konnten im Vergleich zur Placebo-Gruppe hinsichtlich Stimmung oder Hitzewallungen gefunden werden. Abstract: The purpose is to examine the effects of melatonin supplementation on sleep, mood, and hot flashes in postmenopausal breast cancer survivors. In a randomized, double-blind, placebo-controlled study, 95 postmenopausal women with a prior history of stage 0-III breast cancer, who had completed active cancer treatment (including hormonal therapy) were randomly assigned 1:1 to either 3 mg oral melatonin (n = 48) or placebo daily (n = 47) for 4 months. Sleep, mood, and hot flashes were assessed at baseline and 4 months via selfadministered questionnaire using the Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiologic Studies-Depression (CES-D), and the North Central Cancer Treatment Group (NCCTG) hot flash diary, respectively. Eighty-six women (91 %) completed the study and

4 4 provided pre- and post-questionnaires. At baseline, 52 % of participants reported poor sleep in the month prior to enrollment. Compared to subjects on placebo, subjects randomized to melatonin experienced significantly greater improvements in subjective sleep quality as measured by the PSQI, including domains on sleep quality, daytime dysfunction and total score. For example, the mean change in PSQI score was -0.1 in the placebo group compared to -1.9 in the melatonin group (p < 0.001). There were no significant differences in measures of depression or hot flashes. Sleep disturbances are common among breast cancer survivors, even after completion of active cancer treatment. This is the first randomized placebo-controlled study among breast cancer survivors to demonstrate that melatonin was associated with an improvement in subjective sleep quality, without any significant adverse effects. PUBL#5) Eine weitere im Berichtsjahr veröffentlichte Untersuchung war der Evaluierung des möglichen Zusammenhanges zwischen Konsum von Alkohol, einem Methylgruppen-Antagonisten, und dem Kolorektalkrebsrisiko an Hand von Daten von 993 Fällen mit kolorektalen Tumoren mit bekanntem DNA-Methylierungsstatus aus zwei prospektiven Kohorten-Studien, der Nurses Health Study (NHS) und der Health Professional Follow-up Study, gewidmet. Hoher Alkoholkonsum könnte das Kolorektalkrebsrisiko durch Hypomethylierung an der unterschiedlich methylierten Region-0 (DMRO) des Insulin-like growth factor 2 (IGF2), welche mit schlechterer Prognose verknüpft ist, erhöhen. Das Ergebnis dieser Analyse zeigte, dass der Zusammenhang zwischen größerem Alkoholkonsum und dem Risiko, an Kolorektalkrebs zu erkranken, bedingt durch den Tumor IGF2 DMRO Methylierungsstatus variiert und dass er stärker bei Tumoren mit IGF2 DMRO Hypomethylierung ausgeprägt war. IGF2 DMRO Hypomethylierung ist möglicherweise ein Mechanismus, durch welchen Alkoholkonsum das Kolorektalkrebsrisiko beeinflusst und daher das Risiko für potenziell aggressivere Tumoren aufgrund der schlechteren Prognose durch Alkohol zusätzlich erhöht. Dieser Zusammenhang kann, möglicherweise durch epigenetische Faktoren bedingt, unterschiedlich ausfallen. Abstract: Background: Although a higher consumption of alcohol, which is a methyl-group antagonist, was previously associated with colorectal cancer risk, mechanisms remain poorly understood. Objective: We hypothesized that excess alcohol consumption might increase risk of colorectal carcinoma with hypomethylation of insulin-like growth factor 2 (IGF2) differentially methylated region-0 (DMR0), which was previously associated with a worse prognosis. Design: With the use of a molecular pathologic epidemiology database in 2 prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association between alcohol intake and incident colorectal cancer according to the tumor methylation level of IGF2 DMR0. Duplication-method Cox proportional cause-specific hazards regression for competing risk data were used to compute HRs and 95% CIs. In addition, we investigated intakes of vitamin B-6, vitamin B-12, methionine, and folate as exposures. Results: During 3,206,985 person-years of follow-up, we identified 993 rectal and colon cancer cases with an available tumor DNA methylation status. Compared with no alcohol consumption, the consumption of 15 g alcohol/d was associated with elevated risk of colorectal cancer with lower levels of IGF2 DMR0 methylation [within the first and second quartiles: HRs of 1.55 (95% CI: 1.08, 2.24) and 2.11 (95% CI: 1.44, 3.07), respectively]. By contrast, alcohol consumption was not associated with cancer with higher levels of IGF2 DMR0 methylation. The association between alcohol and cancer risk differed significantly by IGF2 DMR0 methylation level (P-heterogeneity = 0.006). The association of vitamin B-6, vitamin B-12, and folate intakes with cancer risk did not significantly differ according to IGF2 DMR0 methylation level (P-heterogeneity > 0.2). Conclusions: Higher alcohol consumption was associated with risk of colorectal cancer with IGF2 DMR0 hypomethylation but not risk of cancer with high-level IGF2 DMR0 methylation. The association between alcohol intake and colorectal cancer risk may differ by tumor epigenetic features. Eine im Berichtsjahr online publizierte epidemiologische Untersuchung widmete sich dem möglichen Zusammenhang zwischen Nachtschichtarbeit in unterschiedlichen Alterskategorien in Bezug auf das Risiko, chronisch zu erkranken, und zwar an Krebs oder kardiovaskulär (PUBL#7). Auch eine weitere im Berichtsjahr in Druck befindliche Arbeit befasste sich mit den Zusammenhängen zwischen rotierender Nachtschichtarbeit und verschiedenen chronischen Erkrankungen, darunter Krebs. Übersichtsartikel / Richtlinie-Empfehlung / Editorial PUBL#16) Ein im Berichtsjahr veröffentlichter systematischer Übersichtsartikel befasst sich mit der Auswirkung des Ausmaßes von Lymphadenektomie auf das Ergebnis bei Patienten mit Harnblasenkarzinom, bei denen eine radikale Zystektomie durchgeführt wurde. Abstract: Context: Controversy exists regarding the therapeutic value of lymphadenectomy (LND) in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). Objective: To systematically review the relevant literature assessing the impact of LND on oncologic and perioperative outcomes in patients undergoing RC for MIBC. Evidence acquisition: Medline, Medline In- Process, Embase, the Cochrane Central Register of Controlled Trials, and the Latin American and Caribbean Center on Health Sciences Information (LILACS) were searched up to December Comparative studies reporting on no LND, limited LND (L-LND), standard LND (S-LND), extended LND (E-LND), superextended LND (SE-LND), and oncologic and perioperative outcomes were included. Risk-of-bias and confounding assessments were performed. Evidence synthesis: Twenty-three studies reporting on 19,793 patients were included. All but one study were retrospective. Planned meta-analyses were not possible because of study heterogeneity; therefore, data were synthesized narratively. There were high risks of bias and confounding across most studies as well as extreme heterogeneity in the definition of the anatomic boundaries of LND templates. All seven studies comparing LND with no LND favored LND in terms of better oncologic outcomes. Seven of 14 studies comparing (super)extended LND with L-LND or S-LND reported a beneficial outcome for (super)extended LND in at least a subset of patients. No difference in outcome was reported in two studies comparing E-LND and S-LND. The comparative harms of different extents of LND remain unclear. Conclusions: Although the quality of the data was poor, the available evidence indicates that any kind of LND is advantageous over no LND. Similarly, E-LND appears to be superior to lesser degrees of dissection, while SE-LND offered no additional benefits. It is hoped that data from ongoing randomized clinical trials will clarify remaining uncertainties. Patient summary: The current literature suggests that removal of lymph nodes in bladder cancer surgery is beneficial and might result in better outcomes in terms of prolonging survival; however, the quality of the available studies is poor, and high-quality studies are needed. PUBL#15) Eine im Berichtsjahr publizierte Richtlinie aktualisierte jene der European Association of Urology über die Diagnostik und Therapie für das Muskel-invasive und metastasierte Harnblasenkarzinom unter Berücksichtigung der neuesten Entwicklungen. Abstract: Context: The European Association of Urology (EAU) guidelines panel on Muscle-invasive and Metastatic bladder cancer (BCa) updates its guidelines yearly. This updated summary provides a synthesis of the 2013 guidelines document, with emphasis on the latest developments. Objective: To provide graded recommendations on the diagnosis and treatment of patients with muscle-invasive BCa (MIBC), linked to a level of evidence. Evidence acquisition: For each section of the guidelines, comprehensive literature searches covering the past 10 yr in several databases were conducted, scanned, reviewed, and discussed both within the panel and with external experts. The final results are reflected in the recommendations provided. Evidence synthesis: Smoking and work-related carcinogens