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Background CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. Patients and methods This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. Results 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). Conclusion CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. Clinical trial information German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Die qualitatsgesicherte, pratherapeutische Bildgebung des lokal fortgeschrittenen Rektumkarzinoms mittels Magnetresonanztomographie ermoglicht eine optimale Planung der perioperativen Therapie dieses Tumors. Im vorliegenden Beitrag werden Qualitatskriterien der Magnetresonanztomographie sowie deren potenzielle therapeutische Implikation sowie laufende Studien der Deutschen Rektumkarzinom-Studiengruppe von einem multidisziplinaren Autorenteam dargestellt.

This article deals with the treatment of metastatic colorectal cancer (stage IV). The treatment goals and approaches are determined by the resectability status of the metastases: resectable liver and lung metastases are primarily resected and perioperative chemotherapy appears to be dispensable. In potentially resectable metastases, a conversion therapy is attempted to enable a potentially curative resection. In the case of nonresectability the treatment goal is palliative. Induction and maintenance therapy as well as drug holidays are suggested in an attempt to achieve extended survival while maintaining the quality of life, beginning with the best possible individual treatment. For some patients with stage IV, molecular targeted therapies are available. The study situation and approval status are dealt with in detail. With improved molecular characterization of tumors the treatment can be further individualized.

The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial.We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3-4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (60, 60-70, and ≥70 years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis.A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P 0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50 months, in patients aged60 years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P = 0.013) and systemic recurrences (P = 0.023), DFS (P = 0.011), and even overall survival (OS; P = 0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40-70 years compared with elderly patients treated with oxaliplatin.The addition of oxaliplatin significantly improved DFS and OS in younger patients aged60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit.NCT00349076.

Background Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab. Patients and methods Patients receiving first-line cetuximab + FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade ≥ 2 skin rash (NCI CTCAE version 4.02) during 8 weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade ≥ 2 skin rash. Results A total of 126 patients were analyzed. The incidence of skin rash grade ≥ 2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms. Conclusion The primary end point of decreasing grade ≥ 2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.

Purpose. To compare rigid rectoscopy with three different MRI measurement techniques for rectal cancer height determination, all starting at the anal verge, in order to evaluate whether MRI measurements starting from the anal verge could be an alternative to rigid rectoscopy. Moreover, potential cut-off values for MRI in categorizing tumor height measurements were evaluated. Methods. In this retrospective study, 106 patients (75 men, 31 female, mean age 64±11.59 years) with primary rectal cancer underwent rigid rectoscopy as well as MR imaging. Three different measurements (MRI1–3) in T2w sagittal scans were used to evaluate the exact distance from the anal verge (AV) to the distal ending of the tumor (MRI1: two unbowed lines, AV to the upper ending of the anal canal and upper ending of the anal canal to the lower border of the tumor; MRI2: one straight line from the AV to the lower boarder of the tumor; MRI3: a curved line beginning at the AV and following the course of the rectum wall ending at the lower border of the tumor). Furthermore, agreement between the gold standard rigid rectoscopy (UICC classification: low part, 0-6 cm; mid part, 6-12 cm; and high part, >12 cm) and each MRI measuring technique was analyzed. Results. Only a fair correlation in terms of individual measures between rectoscopy and all 3 MRI measurement techniques was shown. The proposed new cut-off values utilizing ROC analysis for the three different MRI beginning at the anal verge were low 0-7.7 cm, mid 7.7-13.3 cm, and high>13.3 cm (MRI1); low 0-7.4 cm, mid 7.4-11.2 cm, and high>11.2 cm (MRI2); and low 0-7.1 cm, mid 7.1-13.7 cm, and high>13.7 cm (MRI3). For MRI1 and MRI3, the agreement to the gold standard was substantial (r=0.66, r=0.67, respectively). Conclusion. This study illustrates that MRI1 and MRI3 measures can be interchangeably used as a valid method to determine tumor height compared to the gold standard rigid rectoscopy.

Background Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. Patients and methods Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1–4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. Results The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06–2.98; P = 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79–1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. Conclusion EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. Trial registration ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

Valid HER2 testing is essential for optimal therapy of patients with HER2 positive gastric cancer and the correct use of first-line treatment. While each breast cancer is routinely being tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is often only done upon request by the therapist. An interdisciplinary German expert group took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this manuscript reflect the consensus of all participants and correspond to their opinions and long-term experience.

Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this article reflect the consensus of all participants and correspond to their opinions and long-term experience.

Background Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P

Background The anti-angiogenic fusion protein AFL targets VEGF-A, VEGF-B and PlGF. It is approved in combination with FOLFIRI for treatment of mCRC that is resistant to or has progressed after oxaliplatin-containing therapy. Methods QoLiTrap is an ongoing non-interventional study conducted in the DACH region to evaluate Quality of Life in 1500 mCRC patients treated with AFL+FOLFIRI using the EORTC-QLQ C30 questionnaire at baseline and before every cycle. Results For this interim analysis (cut-off: 02 Jan 2019) 839 patients (mean age: 64.7 ± 9.8 years; 64.4% male, 50.9% with documented RAS mutation, ECOG 0-1: 86.0%) who completed the baseline and at least 2 post-baseline EORTC-QLQ C30 questionnaires were evaluated. AFL was administered for a median of 7 cycles to RAS-wild-type (wt) (range: 1-61) and RAS-mutated (mut) (range 1-44) patients. Of those 772 patients with a previous therapy, 56.7 % received bevacizumab (BEV), 15.3% anti-EGFR antibodies (cetuximab and/or panitumumab) and 14.6 % both agents. 42.1% of RAS-wt and 56.7% of RAS-mut patients received AFL in second line setting. Median global health score at baseline was 58.3 and decreased moderately (mean change -3.4%, p Conclusions The current interim analysis suggests that FOLFIRI + AFL administered in routine conditions after either BEV or anti-EGFR is an active second-line therapy. Both RAS-wt and RAS-mut patients benefited from this combination. No clinically relevant decrease in global health status was observed during study treatment. Supported by Sanofi-Aventis Deutschland GmbH. Clinical trial identification AIO-LQ-0113. Editorial acknowledgement Sandra Baumgart (Alcedis GmbH Giesen, Germany), funded by Sanofi-Aventis Deutschland GmbH. Legal entity responsible for the study Sanofi-Aventis Deutschland GmbH. Funding Sanofi-Aventis Deutschland GmbH. Disclosure R. von Moos: Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Sanofi Aventis; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Vifor; Travel / Accommodation / Expenses: Pfizer. F. Scholten: Honoraria (self), Travel / Accommodation / Expenses: Pharmamar; Travel / Accommodation / Expenses: Eli-Lilly; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Sanofi-Aventis. H. Derigs: Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Roche. R.D. Hofheinz: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Sanofi; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Research grant / Funding (self): Medac; Honoraria (self): Boehringer; Honoraria (self): Celgene; Honoraria (self): Saladax; Honoraria (self): AstraZeneca; Speaker Bureau / Expert testimony: Deutsche Krebshilfe. All other authors have declared no conflicts of interest.

BACKGROUND Docetaxel is a widely used cytotoxic agent. This study evaluates the impact of docetaxel toxicities on patient's health-related quality of life (QoL). PATIENTS AND METHODS We conducted a multicenter, prospective, non-interventional trial, in which the QoL was assessed using the EORTC QLQ-C30 questionnaires at baseline and every 4 weeks up to 40 weeks in patients receiving a docetaxel-based chemotherapy for metastatic disease. Treatment-related adverse events were correlated with the corresponding QoL scores. Uni- and multivariate analyses were applied. RESULTS From January 2008 to June 2011, a total of 2659 patients were included. The majority of patients (48.1%) had prostate cancer, followed by breast (17.1%) and non-small-cell-lung cancer (15.8%). Patients received a median of 5 docetaxel cycles with the median dose of 75 mg/m(2). The presence of grade 3/4 diarrhea showed the strongest effect on global health status/QoL average scores (50.91 versus 33.06), followed by vomiting (50.91 versus 35.17), dyspnea (50.94 versus 35.81), mucositis/stomatitis (50.88 versus 36.41), nausea (50.91 versus 36.68), infection (50.90 versus 37.14), fatigue (50.90 versus 43.82) and anemia (50.91 versus 41.03), P < 0.05 for all comparisons. Grade 3/4 leukopenia/neutropenia, alopecia, constipation, neurotoxicity and nail disorders had no significant impact on the global health status/QoL or other items. CONCLUSION In this large non-interventional trial, docetaxel-associated grade 3 or 4 toxicities were shown to have a strong detrimental effect on patient's QoL. Notably, diarrhea and vomiting had the strongest negative impact on QoL measures. This has to be kept in mind while making therapeutic decisions and providing optimized supportive treatment measures. CLINICAL TRIALS NUMBER This study was registered at Deutsches Krebsstudienregister (DKSR, primary registry in the WHO Registry Network) with the ID 527.

Die perioperative Radiochemotherapie (RChT) beim lokal fortgeschrittenen Rektumkarzinom (LARC) ist seit den 1990er Jahren als Standard in Deutschen Leitlinien verankert. Die neoadjuvante 5-Fluorouracil- (5-FU-) basierte RChT hat hierbei die adjuvante RChT vor etwa 10 Jahren abgelost. Ziel des vorliegenden Beitrags ist es, die Studiendaten zum Ersatz von 5-FU durch orale Fluoropyrimidine, zum Stellenwert der adjuvanten Chemotherapie, zum Einsatz von Oxaliplatin sowie monoklonalen Antikorpern darzustellen und kritisch zu wurdigen. In zwei Studien wurde gezeigt, dass Capecitabin intravenosem 5-FU nicht unterlegen ist. In sechs grosen randomisierten Studien zur perioperativen Therapie wurde Oxaliplatin untersucht. Zwei der Studien erreichten ihren primaren Endpunkt, eine Verbesserung des krankheitsfreien Uberlebens (DFS) zu zeigen: In der koreanischen ADORE-Studie fuhrte die Hinzunahme von Oxaliplatin bei Hochrisikopatienten postoperativ zu einer Verbesserung des DFS, in der Deutschen CAO/ARO/AIO-04-Studie wurde Oxaliplatin pra- und postoperativ zum Standard addiert und fuhrte zu einem besseren DFS. Vier Studien zeigten keinen Benefit. Monoklonale Antikorper sind in Phase-III-Studien beim LARC bislang nicht untersucht und daher auserhalb von klinischen Studien nicht einzusetzen. Capecitabin kann 5-FU in der perioperativen Therapie des LARC ersetzen. Die Daten zum Einsatz von Oxaliplatin sind insgesamt nicht kongruent. Der alleinige Einsatz wahrend der neoadjuvanten RChT ist keine gute Strategie, wahrend die Daten der CAO/ARO/AIO-04 darauf hinweisen, dass der pra- und postoperative Einsatz von Oxaliplatin eine neue mogliche Therapieoption darstellt, die bei der Therapieentscheidung mit erwogen werden kann. Der Einsatz von Oxaliplatin bei Hochrisikopatienten in der postoperativen Situation sollte nach Daten der ADORE Studie bedacht werden.

Purpose. The addition of cetuximab to radiochemotherapy (RCT) failed to improve complete response rates in locally advanced rectal cancer (LARC). We report the long-term results in patients treated within two sequential clinical trials.Methods. Patients receiving neoadjuvant RCT using capecitabine and irinotecan (CapIri) within a phase I/II trial or CapIri + cetuximab within a phase II trial were evaluated for analysis of disease-free survival (DFS) and overall survival (OS). KRAS exon 2 mutational status had been analyzed in patients receiving cetuximab.Results. 37 patients from the CapIri trial and 49 patients from the CapIri-cetuximab treatment group were evaluable. Median follow-up time was 75.2 months. The 5-year DFS rate was 82% (CapIri) and 79% (CapIri-cetuximab)(P=0.62). The median OS was 127.4 months. 5-year OS was 73% for both groups (CapIri and CapIri-cetuximab)(P=0.61). No significant difference in DFS(P=0.86)or OS(P=0.39)was noticed between patients receiving CapIri and those receiving CapIri-cetuximab with KRAS wild-type tumors.Conclusions. As the addition of cetuximab did not improve neither DFS nor OS it should not play a role in the perioperative treatment of patients with LARC, not even of patients with (K)RAS WT tumors.

WOS: 000411827200016, PubMed ID: 28961832, Background: This randomized study was designed to investigate the superiority of gemcitabine (gem) plus nimotuzumab (nimo), an anti-epidermal growth factor receptor monoclonal antibody, compared with gem plus placebo as first-line therapy in patients with advanced pancreatic cancer. Patients and methods: Patients with previously untreated, unresectable, locally advanced or metastatic pancreatic cancer were randomly assigned to receive gem: 1000 mg/m(2), 30-min i.v. once weekly (d1, 8, 15; q29) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or gem plus placebo, until progression or unacceptable toxicity. The primary end point was overall survival (OS), secondary end points included time to progression, overall response rate, safety and quality of life. Results: A total of 192 patients were randomized, with 186 of them being assessable for efficacy and safety (average age 63.6 years). One-year OS/progression-free survival (PFS) was 34%/22% for gem plus nimo compared with 19%/10% for gem plus placebo (HR = 0.69; P = 0.03/HR = 0.68; P = 0.02). Median OS/PFS was 8.6/5.1 months for gem plus nimo versus 6.0/3.4 mo in the gem plus placebo group (HR = 0.69; P = 0.0341/HR = 0.68; P = 0.0163), with very few grade 3/4 toxicities. KRAS wildtype patients experienced a significantly better OS than those with KRAS mutations (11.6 versus 5.6 months, P = 0.03). Conclusion: This randomized study showed that nimo in combination with gem is safe and well tolerated. The 1-year OS and PFS rates for the entire population were significantly improved. Especially, those patients with KRAS wildtype seem to benefit. The study was registered as protocol ID OSAG101-PCS07, NCT00561990 and EudraCT 2007-000338-38., Oncoscience AG, Schenefeld, Germany, This multi-institutional, randomized phase IIb trial was sponsored by Oncoscience AG, Wedel (recently Schenefeld), Germany. There is no grant number applicable.

Aims While the influence on survival is only seen in patients with complete regression after neoadjuvant treatment in locally advanced rectal cancer the impairment of the continence capacity weighs even more for patients with little oncological benefit. Methods Patients treated with intensified preoperative radiochemotherapy patients treated only by TME surgery were asked five years after treatment to complete the Wexner and SF-12 quality of life questionnaire. Results 25 after neoadjuvant treatment had a median Wexner score of 14 [3–20] after 63 [42–78] months. Histopathological stage or grade of regression did not influence the Wexner score ( p = 0.76, resp. p = 0.9). 12% describe themselves as being permanently continent; 40% are stool incontinent “always” or “most of the time”. 68% are always wearing pads. 29 patients after TME only showed a median Wexner score of 5 [range 0–17] after 66 months [26–133]. SF-12 showed significantly lower values in physical ( p = 0.02) as well as mental summary scales ( p = 0.015) in patients after RCTX while patients after radical surgery showed no difference to the norm population. Conclusion This study shows that continence is significantly worse five years after neoadjuvant treatment. Moreover, patients after neoadjuvant treatment and surgery have impaired quality of life compared to norm population. These results may contribute to the discussion of only applying neoadjuvant chemoradiation selectively in patients with advanced rectal cancer.

Background The majority of patients (pts) with gastroesophageal cancer present with inoperable or metastatic disease and there is a strong need for efficient and tolerable first-line (1L) treatment. Oxaliplatin-based regimens like FOLFOX have become one standard of care. However, median survival is still below 12 months. Results from trials using nivolumab plus ipilimumab treatment of subjects with advanced/metastatic GC and GEJ cancers demonstrated clinical activity, in pts whose tumors did or did not express PD-L1; in addition, nivolumab alone and in combination with ipilimumab demonstrated clinical benefits in various other tumor types. Based on this clinical experience, the AIO-STO-0417 trial (Moonlight) has been designed to evaluate the combination of chemotherapy with two checkpoint inhibitors in first-line therapy of pts with gastroesophageal adenocarcinoma. Trial design This is a prospective, multicenter, randomized, investigator-initiated phase II trial. Pts with Her2-negative, inoperable, advanced or metastatic gastric or esophagogastric junction cancer will be randomized 1:1 to 1L treatment with FOLFOX (Oxaliplatin 85 mg/m²; Leucovorin 400 mg/m²; 5FU 400 mg/m² on d1 of each treatment cycle and 5FU 2400 mg/m² continuous infusion over 44 hrs) every 2 weeks plus Nivolumab 240 mg every 2 weeks and Ipilimumab 1mg/kg every 6 weeks (Arm A) or FOLFOX alone (Arm B). Primary endpoint of the trial is progression-free survival based on the ITT population. Main secondary endpoints are overall survival, objective response rate, Safety and Quality of life (EORTC QLQ-C30). 118 pts (59 per arm) will be enrolled to provide 80% power for detecting an average HR of 0.68 using the log rank test at a one-sided type I error of 10%. At the date of submission (May 2019), 45 of planned 118 pts are randomized. Clinical trial identification NCT03647969. Legal entity responsible for the study IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest. Funding Bristol-Myers Squibb. Disclosure S. Lorenzen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy: Servier; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene. T.O. Goetze: Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Shire; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Speaker Bureau / Expert testimony: MCI Group; Research grant / Funding (self), Research grant / Funding (institution): German Research Foundation. E. Goekkurt: Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Serono; Travel / Accommodation / Expenses: Servier. T.J. Ettrich: Advisory / Consultancy: Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Merck Serono; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (self): Baxalta. N. Homann: Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Merck. P.C. Thuss-Patience: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Nordic Bioscience; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Research grant / Funding (self): Novartis; Travel / Accommodation / Expenses: Teva; Travel / Accommodation / Expenses: Astellas Korea. H. Schmalenberg: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Research grant / Funding (self): Archigen. R.D. Hofheinz: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. S. Al-Batran: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution): Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Nordic Bioscience; Advisory / Consultancy: Merck Sharp and Dohme; Leadership role, Shareholder / Stockholder / Stock options: IKF Klinische Krebsforschung GmbH; Speaker Bureau / Expert testimony: AIO gGmbH; Speaker Bureau / Expert testimony: Forum fur Medizinische Fortbildung; Speaker Bureau / Expert testimony: MCI group; Speaker Bureau / Expert testimony: promedicis; Research grant / Funding (self), Research grant / Funding (institution): Medac; Research grant / Funding (self), Research grant / Funding (institution): Hospira; Research grant / Funding (self), Research grant / Funding (institution): Sanofi; Research grant / Funding (self), Research grant / Funding (institution): German Cancer Aid; Research grant / Funding (self), Research grant / Funding (institution): German Research Foundation; Research grant / Funding (self), Research grant / Funding (institution): Federal Ministry of Education and Research of Germany; Research grant / Funding (self), Research grant / Funding (institution): Vifor Pharma. All other authors have declared no conflicts of interest.

Background: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. Methods: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m−2 twice daily on days 1–14; oxaliplatin 100/130 mg m−2 on day 1; bevacizumab 7.5 mg kg−1 on day 1; imatinib 300 mg day−1 on days 1–21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). Results: Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. Conclusion: The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis.Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression.Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58).Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

Background This prospective multicentre phase II trial assessed the feasibility and efficacy of perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in patients with gastro-oesophageal adenocarcinoma. Methods Patients with curatively resectable adenocarcinoma of the stomach, the gastro-oesophageal junction or the lower third of the oesophagus were enrolled. Patients received docetaxel 75 mg/m2 plus cisplatin 60 mg/m2 (day 1), followed by oral capecitabine 1875 mg/m2 divided into two doses (days 1–14) every 3 weeks. There were three cycles preoperatively and three cycles postoperatively. The primary end point was the R0 resection rate. Results Fifty-one patients were recruited and assessed for feasibility and efficacy. 94.1% of patients received all three planned cycles preoperatively, and 52.9% received three cycles postoperatively. The R0 resection rate was 90.2%. 13.7% of patients showed complete pathological remission (pCR). Toxicity was acceptably tolerable. Without prophylactic granulocyte colony-stimulating factor administration, neutropenic fever developed in 21.5% of patients preoperatively (grade 3 or 4) and in 11.1% of patients postoperatively. Conclusions DCX is a safe and feasible perioperative regimen in the treatment of gastro-oesophageal adenocarcinoma with a high percentage of cycles delivered pre- and postoperatively, compared with standard practice. The high efficacy in terms of R0 resection rate and pCR is very promising.

Background: Hand–foot–skin reaction (HFSR) is an adverse event frequently observed during treatment with capecitabine (cape). In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials. Methods: Patients of the Arbeitsgemeinschaft für Internistische Onkologie (AIO) KRK-0104 and the Mannheim rectal cancer trial were evaluated. HFSR was graded according to NCI-CTC criteria in both trials. Time to first occurrence of HFSR was described per cycle and HFSR developing during cycles 1 and 2 was defined as ‘early HFSR'. Baseline characteristics between the patient groups with or without HFSR were compared using Mann–Whitney-U, Fisher's exact or χ2-test, as appropriate. Haematological and non-haematological toxicities observed in both groups were compared using Fisher's exact test. Progression-free (PFS) or disease-free (DFS) as well as overall survival (OS) data from both trials were pooled and the HFSR group was compared with the non-HFSR using Kaplan–Meier analysis. Results: A total of 374 patients were included, of whom 29.3% developed any HFSR. Of these, 51% had early HFSR. Baseline characteristics were comparable between both HFSR groups concerning age, gender, ECOG performance status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFSR. The percentage of all-grade (and grade 3–4) haematological toxicities did not differ between both the groups. By contrast, patients exhibiting HFSR had a significantly higher rate of all-grade (but not grade 3–4) diarrhoea, stomatitis/mucositis and fatigue (P