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BACKGROUND Treatment options for patients with metastatic pancreatic cancer depend on various factors, including performance status, tumor burden and patient preferences. Metastatic pancreatic cancer is incurable and many systemic treatment options have been investigated over the past decades. This analysis of patterns of practice was performed to identify decision criteria and their impact on the choice of first-line management of metastatic pancreatic cancer. MATERIALS AND METHODS Members of the Swiss Group for Clinical Cancer Research (SAKK) Gastrointestinal Cancer Group were contacted and agreed to participate in this analysis. Decision trees for the first line treatment of metastatic pancreatic cancer from 9 centers in Switzerland were collected and analyzed based on the objective consensus methodology to identify consensus and discrepancies in clinical decision-making. RESULTS The final treatment algorithms included 3 decision criteria (comorbidities, performance status and age) and 5 treatment options: FOLFIRINOX, FOLFOX, gemcitabine + nab-paclitaxel, gemcitabine mono and best supportive care. CONCLUSION We identified multiple decision criteria relevant to all participating centers. We found consensus for the treatment of young (age below 65) patients with good performance status with FOLFIRINOX. For patients with increasing age and reducing performance status there was a decreasing trend to use gemcitabine + nab-paclitaxel. Gemcitabine monotherapy was typically offered to patients in the presence of comorbidities. For patients with ECOG 3-4, most of the experts recommended BSC.

Background KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. Methods Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. Results Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3–75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). Conclusions Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov : NCT00869570 .

Summary Background There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. Methods We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3–6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. Findings Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4–9·4) with pembrolizumab and 6·9 months (5·9–8·0) with standard of care (hazard ratio 0·80, 0·65–0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). Interpretation The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co.

Introduction While the anti-VEGF antibody bevacizumab was studied repeatedly as part of low-intensity regimens in less fit elderly patients with metastatic colorectal cancer (mCRC), anti-EGFR antibodies as upfront treatment modality have been scarcely investigated. Material and Methods In SAKK 41/10, the benefit of cetuximab, either alone or in combination with capecitabine, was evaluated in vulnerable elderly patients with RAS/BRAF-wild-type mCRC. Results and Discussion The trial was stopped prematurely due to slow accrual after the inclusion of 24 patients (11 in the monotherapy arm, 13 in the combination arm). Median patient age was 80 years (range 71–89), median CIRS-G score 7 (range 2–13), and median IADL score 7 (range 3–8). At week 12, 6 of 11 patients (55%) were progression-free in the cetuximab monotherapy arm and 9 of 13 patients (69%) in the combination arm. Response rate was 9% in the monotherapy arm and 38% combination arm. The 6 patients with right-sided primary tumors were not responsive to cetuximab. NGS revealed additional mutations affecting the RAS/RAF/MAP kinase pathway in 5 patients; 4 of these patients showed early disease progression. Cetuximab was generally well tolerated and a trend toward an improvement of symptom-related QoL was observed. In the combination arm, a higher incidence of toxicities and treatment stoppings was observed. In conclusion, trial recruitment – requiring both geriatric as well as molecular eligibility criteria – proved more difficult than expected. Bearing in mind the very small sample size, upfront cetuximab treatment appeared tolerable and showed promising activity in left-sided tumors in both treatment arms.

Dieser Artikel bietet eine Ubersicht uber die neuen medikamentosen Behandlungsmoglichkeiten.

BACKGROUND We tested whether a switch maintenance treatment with orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel. METHODS Men with mCRPC and non-progressive disease after a cumulative dose of ?300mg/m2 docetaxel for first line treatment were randomized 1:1 to receive orteronel 300mg twice daily or placebo. The primary endpoint was event-free survival (EFS) defined as the time from randomization to death or the combination of at least two of radiographic, clinical, or PSA progression. Ninety-six patients per arm were planned to demonstrate an improvement of median EFS from 4 months on placebo to 6.7 months on orteronel (hazard ratio (HR) 0.6; type I error 5% and power 90%). RESULTS Forty-seven patients (23 orteronel, 24 placebo) were randomized before premature closure of the trial because of discontinuation of clinical development of orteronel. Median EFS was 8.5 months with orteronel and 2.9 months with placebo (P¼0.001; HR 0.32; 95%CI 0.15–0.65). Median radiographic progression-free survival (rPFS) was 8.5 and 2.8 months (P¼0.02; HR 0.42; 95%CI 0.20–0.91) in the orteronel and placebo arm, respectively. PSA decline ?50% was seen in 57% on orteronel and 4% on placebo. Toxicity was mainly mild, one patient on orteronel developed transient grade 3 adrenal insufficiency and one grade 4 pneumonitis. CONCLUSIONS Orteronel significantly prolongs EFS in men with mCRPC who achieve disease stabilization with docetaxel. The concept of switch maintenance therapy in mCRPC warrants further research.

Background There is evidence linking metformin to improved prostate cancer–related outcomes. Patients and Methods Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial between November 2013 and September 2016. Metformin was added to abiraterone continuously at 1000 mg twice daily in uninterrupted 4-week cycles. The primary end point was the absence of disease progression at 12 weeks (PFS12). The Fleming single-stage design was applied. With a 5% significance level and 80% power, 25 patients were required to test PFS12 ≤ 15% (H0) compared to ≥ 35% (H1). Secondary end points included toxicity and safety issues. The study was registered at ClinicalTrials.gov ( NCT01677897 ). Results The primary end point PFS12 was 12% (3 of 25 patients) (95% confidence interval, 3-31). Most patients had PSA progression, almost half had radiographic progression, but only 1 patient had symptomatic progression. Eleven (44%) of 25 patients had grade 1 and 2 patients each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhea, loss of appetite). One patient discontinued treatment at week 5 because of intolerable grade 3 diarrhea. Conclusion The addition of metformin to abiraterone for patients with metastatic castration-resistant prostate cancer and PSA progression while receiving abiraterone therapy does not affect further progression and has no meaningful clinical benefit. A higher-than-expected gastrointestinal toxicity attributed to metformin was observed.

Background Second line endocrine therapy has limited antitumour activity. Fulvestrant inhibits and downregulates the oestrogen receptor. The mitogen-activated protein kinase (MAPK) pathway is one of the major cascades involved in resistance to endocrine therapy. We assessed the efficacy and safety of fulvestrant with selumetinib, a MEK 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI). Patients and methods This randomised phase II trial included postmenopausal patients with endocrine-sensitive breast cancer. They were ramdomised to fulvestrant combined with selumetinib or placebo. The primary endpoint was disease control rate (DCR) in the experimental arm. ClinicalTrials.gov Indentifier: NCT01160718. Results Following the planned interim efficacy analysis, recruitment was interrupted after the inclusion of 46 patients (23 in each arm), because the selumetinib–fulvestrant arm did not reach the pre-specified DCR. DCR was 23% (95% confidence interval (CI) 8–45%) in the selumetinib arm and 50% (95% CI 27–75%) in the placebo arm. Median progression-free survival was 3.7 months (95% CI 1.9–5.8) in the selumetinib arm and 5.6 months (95% CI 3.4–13.6) in the placebo arm. Median time to treatment failure was 5.1 (95% CI 2.3–6.7) and 5.6 (95% CI 3.4–10.2) months, respectively. The most frequent treatment-related adverse events observed in the selumetinib–fulvestrant arm were skin disorders, fatigue, nausea/vomiting, oedema, diarrhoea, mouth disorders and muscle disorders. Conclusions The addition of selumetinib to fulvestrant did not show improving patients’ outcome and was poorly tolerated at the recommended monotherapy dose. Selumetinib may have deteriorated the efficacy of the endocrine therapy in some patients.

Background: Bevacizumab combined with chemotherapy has been shown to improve response rate and progression free survival in metastatic breast cancer. The aim of the health economic analysis (HEA) of this study was to demonstrate that the combination regimen of bevacizumab with cyclophosphamide and capecitabine (metronomic chemotherapy) compared to bevacizumab and paclitaxel treatment decreases overall treatment costs in patients with breast cancer without suffering any losses in effectiveness. Methods: In this multicenter, randomized phase III trial, we compared bevacizumab (10 mg/kg i.v. q 2 weeks) with either paclitaxel (90 mg/m2) i.v. on days 1, 8, and 15 of a 4 week cycle (arm A) or daily oral capecitabine (3x500 mg) and cyclophosphamide (50 mg, arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. Primary endpoint of the health economic analysis was the total incurred treatment costs until patients stopped trial treatment (time to trial treatment stop (TTS)). TTS was defined as treatment stop due to progressive disease, symptom deterioration, unacceptable adverse events, patient refusal, death or other reasons for withdrawal. The HEA adopted a health system perspective including all substantial direct medical costs incurred in the treatment of the patient. Health-related quality of life was measured by means of the EQ-5D utility instrument. Statistical differences between costs in the treatment arms were tested by the Wilcoxon rank-sum test. A global multivariable linear model, with a gamma distribution and a logarithmic cost transformation was used to analyze the costs for the two arms controlled for age. Results: Between September 2010 and December 2012, 147 patients were included at 22 centers in Switzerland, 73 (intention to treat (ITT) n=71) in arm A and 74 (ITT n=68) in arm B. The clinical study results will be presented at ASCO 2014. In January 2014, 66 patients in arm A and 63 in arm B of the ITT patients had reached TTS and were analyzed. Mean TTS was 7.3 month in arm A (95%CI 6.3–8.2, median 5.9; quality adjusted mean 5.9, median 5.1) versus 8.5 month (95%CI 6.7–10.2, median 6.8; quality adjusted mean 6.5, median 5.0) in arm B. Total incurred mean costs per patient were CHF 69’474 in arm A (95%CI 60’624–78’324, median CHF 61’815; mean cost per month CHF 10’044) versus CHF 80’324 in arm B (95%CI 62’975–97’672, median CHF 61’751; mean cost per month CHF 10’229). There were no significant differences in costs between the treatment arms and age had no significant effect on the results. Conclusion: Metronomic chemotherapy plus bevacizumab compared to bevacizumab and paclitaxel treatment showed no substantial reductions in treatment costs. In view of the clinical results the HEA does not favor the metronomic approach. An incremental cost-utility analysis is planned. Citation Format: Klazien W Matter-Walstra, Martin Bigler, Matthias Schwenkglenks, Daniela Bertschi, Jörg Brechbühl, Ursula Hasler-Strub, Roger von Moos, Andreas Müller, Ralph Winterhalder, Christoph Rochlitz. Health economic evaluation of: Bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced breast cancer: A multicenter, randomized phase III trial - SAKK 24/0 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-10-06.

There is evidence linking metformin to improved prostate cancer (PCa)-related outcomes.To evaluate treatment with metformin in patients with castration-resistant PCa (CRPC) and the effect of the treatment on progression-free survival (PFS) and PSA doubling time (PSA DT).Forty-four men with progressive metastatic CRPC from 10 Swiss centers were included in this single-arm phase 2 trial between December 2010 and December 2011.Patients received metformin 1000 mg twice daily until disease progression.The primary end point was the absence of disease progression at 12 wk. Simon two-stage optimal design was applied. With a 5% significance level and 90% power, 44 patients were required to test PFS at 12 wk ≤ 15% (H0) compared with ≥ 35% (H1).Thirty-six percent of patients were progression-free at 12 wk, 9.1% were progression-free at 24 wk, and in two patients a confirmed ≥ 50% prostate-specific antigen (PSA) decline was demonstrated. In 23 patients (52.3%) we observed a prolongation of PSA DT after starting metformin. The homeostatic model assessment index fell by 26% from baseline to 12 wk, indicating an improvement in insulin sensitivity. There was a significant change in insulin-like growth factor-1 and insulin-like growth factor binding protein 3 from baseline to 12 wk. Sample size and lack of a control arm are the limitations of this trial; analyses are therefore exploratory.Treatment with metformin is safe in nondiabetic patients, and it yields objective PSA responses and may induce disease stabilization. The activity of metformin in PCa, along with its low cost, favorable toxicity profile, and positive effect on metabolic parameters, suggests that further investigation of metformin as therapy for patients with PCa is of interest.In this trial we assessed the use of the diabetes mellitus drug metformin in patients with advanced prostate cancer. We found disease stabilization and prolongation of prostate-specific antigen doubling time in some patients as well as effects on metabolic parameters.This study is registered with ClinicalTrials.gov with the identifier NCT01243385.The study was presented at ESMO 2012 (abstract 1460).

139 Background: DN given q4w has shown superiority in delaying skeletal related events over q4w zoledronic acid (ZA). Recently it has been demonstrated that ZA q12w is non-inferior to ZA q4w. The objective of REDUSE is to show non-inferiority for DN q12w versus q4w in terms of SSE. Here we present an interim analysis for the secondary endpoint HC. Methods: Patients (pts) with castration resistant prostate cancer (planned N=690) were randomized 1:1 to DN q4w (Arm A) vs q12w (Arm B) after a 16 week induction phase with application q4w. All pts received vitamin D (ViD) 400 U and calcium (Ca) 500 mg daily. Measurement of corrected serum-Ca was mandatory before each DN injection. This interim analysis was performed after 3.5 years of accrual. Men who received ≥ 1 dose of DN were considered evaluable. Results: 383 pts were evaluable. HC occurred in 28.7% during the first 16 weeks (DN q4w for all pts) and 30.2% afterwards. After the induction phase HC occurred in 40.2% in Arm A and in 20.3% in Arm B. Grade 3 (2.1%) and 4 (1.1%) HC were rare, most frequently occurring in the first 16 weeks. After 1 year of treatment, the incidence of HC was lower in both arms (A: 30.8%, B: 18.7%). A clinically relevant difference for HC was noted between the two arms after the induction phase (table). Conclusions: In our trial nearly 30% of all men treated with DN experienced HC in the q4w induction phase despite mandatory supplementation of calcium and ViD and measurement of Ca. This rate was considerably higher than reported in the registration trials of DN (13%). After induction treatment the incidence of HC is considerably lower in the q12w arm compared to q4w. This suggests that DN given q12w has a more favorable long time toxicity profile (HC) compared to DN q4w. Change in HC grade after week 16 (week 1 – 12: DN q4w Arm A+B), thereafter q4w in Arm A and q12w in Arm B. Clinical trial information: NCT02051218. [Table: see text]

Background: Mitogen-activated protein kinase (MAPK) pathway is one of the major signaling cascades responsible for resistance to endocrine therapy by promoting estrogen-independent tumor growth. Sel is a potent selective MEK1 and MEK2 inhibitor active in melanoma, ovarian, colorectal and non-small cell lung cancers. Fulvestrant (Fulv) is a pure antagonist and downregulator of nuclear and membranous/cytoplasmic estrogen receptor (ER). The combination of a MEK inhibitor with Fulv may improve the efficacy of endocrine therapy by reversing and/or delaying the development of resistance. Material and methods: Postmenopausal patients with advanced stage endocrine-sensitive (ER and/or progesterone receptors ≥10%) breast cancer progressing after aromatase inhibitor were randomized to intramuscular Fulv 500 mg (day 1, 15, 29 then every 28±2 days) combined with either oral Sel 75 mg bid or placebo bid. The primary endpoint was disease control (DC = CR + PR + stable disease ≥ 24 weeks). Sample size was calculated according to Simon's optimal two-stage design. A DC rate of ≤30% in the experimental arm was considered as not interesting and ≥50% as promising. Using a 5% significance level and 80% power, 46 patients were needed, 15 in the first stage and 31 in the second stage. In the control arm a total of 43 patients was needed to estimate the DC rate with a confidence interval width of ≤30%. An interim efficacy analysis was planned according to Herndon's modification of Simon's optimal two-stage design. Results: Forty-six patients were included (23 per arm). Seventy percent of the patients in the experimental arm had measurable disease and 57% had visceral metastases. Patients had received AI in the metastatic (61%) or adjuvant (39%) setting (65% had also prior tamoxifen). Five of 23 patients (22%) reached DC in the experimental arm. DC rate being inferior to the statistical hypothesis the study was terminated following the planned interim efficacy analysis. Most frequently reported adverse events (AEs) were rash and other skin disorders, fatigue, diarrhea, hypertension, edema, nausea/vomiting, anorexia, musculoskeletal symptoms, dry mouth and paresthesia. AEs were mainly grade 1 and 2 (NCI-CTCAE v4.0), but they often precluded treatment continuation. Most of the first patients exposed to Sel 75 mg bid stopped treatment before disease progression. Seven of the 23 patients (30%) were exposed to Sel for only 1 cycle or less. After an amendment facilitating early dose-reduction, patients decreasing to 75 mg qd had much better tolerance and improved treatment duration with Sel. Four out of the 5 patients reaching DC had Sel dose reduction. Conclusion: The combination of Sel with fulvestrant did not reach the prespecified disease control rate. The toxicity of Sel 75 mg bid led to frequent treatment interruptions/dose reductions and poor exposure to the drug. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-19.

New multimodality treatment approaches for prostate cancer require multidisciplinary management of patients. We aimed to assess the current practices of multidisciplinarity and their possible implications in treatment management in Switzerland.In a survey, urologists and medical oncologists in Switzerland were asked to include at least 25 or 15 consecutive patients with the diagnosis of prostate cancer, respectively. Information about treatment patterns and multidisciplinary parameters of these patients was collected retrospectively.Thirty-seven urologists and 20 oncologists from the French- and German-speaking parts of Switzerland representing 7 out of 11 non-university tertiary centres and 20/10 % of all office-based urologists/oncologists in Switzerland collected data on 1,184 patients. Sixty-five percent of the office-based (16/24 urologists; 6/10 oncologists) and 95 % of the hospital-based (10/11 urologists; 8/8 oncologists) physicians participate in multidisciplinary tumour boards (MTBs). However, only 1.5 % of patients with a new diagnosis of prostate cancer (13 of 883) are discussed at a MTB. Overall, second opinions at diagnosis are requested in 23 % of patients, mainly from radiation oncologists (8.4 %) or fellow urologists (7.4 %). Second opinions are more often requested by urologists who participate at MTBs and in case of advanced stage.Participation at MTBs is high among Swiss urologists and oncologists in private practice and at non-university tertiary centers. In spite of that only a small minority of patietns with prostate cancer are presented at MTBs.

BACKGROUND We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Background Investigate the usefulness of echocardiography and acoustic cardiography to monitor patients exposed to anthracycline chemotherapy. Hypothesis Serial echocardiographies to monitor systolic function may not be neccessary in all patients undergoing anthracycline chemotherapy. Methods In a prospective study, consecutive patients undergoing anthracycline-containing chemotherapy were evaluated with echocardiography and acoustic cardiography at baseline, after completion of chemotherapy, and after a median follow-up of 3.8 years. Systolic dysfunction was defined as a left ventricular ejection fraction ≤50%. Results A total of 187 patients (83% female) with a mean age of 55 ± 14 years underwent chemotherapy for breast cancer (73%), malignant lymphoma (23%), and sarcoma (4%). None of the patients had systolic dysfunction at baseline. Patients were treated with doxorubicin 276 ± 74 mg/m2 or epirubicin 317 ± 55 mg/m2. After chemotherapy, 170 (91%) had normal systolic function, 8 (4%) developed systolic dysfunction, and 9 (5%) had died. Of those 8 patients with systolic dysfunction, 4 (50%) improved to normal systolic function, 1 (13%) remained unchanged, and 3 (37%) died. Patients with normal systolic function after chemotherapy had a mortality rate of 3.5%, and 1.8% developed late systolic dysfunction. Acoustic cardiography-derived percent electromechanical activation time >12.4% had a sensitivity of 88% and a specificity of 84% to identify patients with systolic dysfunction (area under the receiver operating characteristic curve 0.87). Conclusions Patients with systolic dysfunction early after anthracycline treatment had worse outcome. Acoustic cardiography was able to identify these patients with a high sensitivity and specificity. Based on the findings of this study, we propose a simple algorithm to monitor patients undergoing anthracycline-containing chemotherapy. The authors have no funding, financial relationships, or conflicts of interest to disclose.

We tested whether a switch maintenance treatment with orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration-resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel.Men with mCRPC and non-progressive disease after a cumulative dose of ≥300 mg/mForty-seven patients (23 orteronel, 24 placebo) were randomized before premature closure of the trial because of discontinuation of clinical development of orteronel. Median EFS was 8.5 months with orteronel and 2.9 months with placebo (P = 0.001; HR 0.32; 95%CI 0.15-0.65). Median radiographic progression-free survival (rPFS) was 8.5 and 2.8 months (P = 0.02; HR 0.42; 95%CI 0.20-0.91) in the orteronel and placebo arm, respectively. PSA decline ≥50% was seen in 57% on orteronel and 4% on placebo. Toxicity was mainly mild, one patient on orteronel developed transient grade 3 adrenal insufficiency and one grade 4 pneumonitis.Orteronel significantly prolongs EFS in men with mCRPC who achieve disease stabilization with docetaxel. The concept of switch maintenance therapy in mCRPC warrants further research. Prostate 76:1519-1527, 2016. © 2016 Wiley Periodicals, Inc.

Background Enzalutamide is a second-generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors. High activity has been proven in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and in chemotherapy-naive patients with mCRPC. However, its activity in patients previously treated with other novel agents (for example, abiraterone and/or cabazitaxel), remains controversial. Patients and Methods The aim of this retrospective analysis of the Swiss Enzalutamide Named Patient Program was to evaluate clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel and other lines of therapy considering different treatment sequences. We report on 44 patients treated with enzalutamide. Results The median survival time from diagnosis of CPRC was 41.1 months (95% confidence interval [CI], 32.3-49.8 months). Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh-line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. The median duration of enzalutamide treatment was 3.0 months (range, 1-21 months). Median progression-free survival was 3.0 months (95% CI, 2.4-3.7 months). The estimated median overall survival was 6.3 months (95% CI, 4.6-8.1 months). Sixteen patients (36.4%) had a prostate-specific antigen decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. In multivariate analysis, the absence of previous therapy with abiraterone and a prostate-specific antigen response of ≥ 50% on enzalutamide therapy were significantly associated with overall survival on enzalutamide treatment. Conclusions Our results show that enzalutamide has modest activity in extensively pretreated patients. However, there is a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone.

Mit der zunehmenden Anwendung von Bildgebungen sind Arzte vermehrt mit Inzidentalomen konfrontiert. Eine seltene Untergruppe mit schlechter Prognose sind Nebennierenrindenkarzinome. Der Artikel fasst das komplexe Krankheitsbild zusammen. Der Fokus liegt dabei auf der Erorterung der interdisziplinaren Therapiemoglichkeiten.

Avec l’utilisation croissante d’examens d’imagerie, les medecins sont de plus en plus confrontes a des incidentalomes. Les carcinomes corticosurrenaliens en representent un sous-groupe rare au pronostic mediocre. Cet article s’est fixe comme objectif de fournir un apercu de leur tableau clinique, assez complexe, avec le focus centre sur les options therapeutiques interdisciplinaires.

TPS3621Background: Exercise has become a main focus of basic and clinical research worldwide during the current pandemic of physical inactivity. A clear link between inactivity and cancer incidence...

This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13-36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer.

BACKGROUND: This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC). METHODS: The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival. RESULTS: Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P = 0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P = 0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P = 0.07). OCT1 and MATE1 were not associated with PFS. CONCLUSIONS: The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.

In this trial, stopping bevacizumab after completion of induction chemotherapy was associated with a shorter time to progression, but no statistically significant difference in overall survival compared with the bevacizumab continuation strategy. Non-inferiority could not be demonstrated. Treatment costs are substantially higher for continuous bevacizumab treatment. Background Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. Patients and methods In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4–6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. Results The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1–5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8–3.8) months for no continuation; HR 0.74 (95% CI 0.58–0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63–1.1;P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30 000 USD per patient. Conclusions Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4–6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. Clinical trial registration ClinicalTrials.gov, number NCT00544700.

Background: There is current evidence that non-melanoma skin cancers can be successfully treated with cetuximab. Objective: To evaluate the use and efficacy of cetuximab (with or without radiotherapy) in a series of previously treated patients with metastatic squamous cell cancer of the skin (SCCS) in Switzerland. Methods: We performed a retrospective analysis of six patients from four centers. Endpoints were disease control rates (DCRs) at 4-8 weeks, 12-14 weeks and 20-36 weeks of treatment. Treatment-related toxicity was evaluated additionally. Results: A median of 14 cycles of cetuximab were applied. DCR was 67% at 4-8 weeks, 50% at 12-14 weeks and 33% at 20-36 weeks. In 4-8 weeks responders, mean relapse-free time was 12 ± 6.2 months and mean overall survival was 25 ± 16.2 months. Grade I-III acne-like rash developed around week 3 of treatment in 83%. Conclusions: Cetuximab treatment in patients with metastatic SCCS achieved an overall DCR of 67% at 4-8 weeks of treatment. This study underlines the current evidence that SCCS can be successfully treated with cetuximab.

Background: Antiangiogenic therapy is routinely used in a variety of cancer entities. Hypertension is the most common side effect of all currently available antiangiogenic treatments. Patients and Methods: In this prospective observational clinical trial, we investigated risk factors for blood pressure elevation in patients exposed to an antiangiogenic agent and explored the correlation between hypertension and the duration of antiangiogenic treatment. Results: In 169 patients, pre-existing antihypertensive medication was the most prominent risk factor associated with increased blood pressure during therapy. Between visits 1 and 3, the median systolic blood pressure increased by 10.85 mmHg in patients with pre-existing hypertension receiving antihypertensive medication while it increased by only 2.69 mmHg in patients without hypertension. The median increase in diastolic pressure was 7.28 versus 0.11 mmHg in patients with versus without pre-existing hypertension. Increases in blood pressure occurred early (within 6 weeks of starting therapy). In spite of this significant increase in the blood pressure, no major bleeding events or other related complications were observed during antiangiogenic therapy. Conclusions: Pre-existing hypertension and treatment with antihypertensive medication correlated with a more pronounced increase in blood pressure. Thus, intensified antihypertensive therapy might be warranted early during bevacizumab therapy in patients already receiving antihypertensive treatment.

Le carcinome gastrique est une entite clinique inhomogene. Les stades tumoraux localises beneficient d’un traitement multimodal qui augmente les chances de guerison. Au stade avance une chimiotherapie ameliore la survie. Le status HER2 doit etre precise de routine.

Background Elevated concentrations of doxorubicin are found in eccrine sweat glands of the palms and soles. We therefore evaluated an antiperspirant as preventive treatment for palmar–plantar erythrodysesthesia (hand–foot syndrome) in patients with metastatic breast cancer treated with pegylated liposomal doxorubicin. Patients and methods An antiperspirant containing aluminum chlorohydrate or placebo cream was applied to the left or right hand and foot in a double-blinded manner (intra-patient randomization). The primary endpoint was the rate of grade 2 or 3 palmar–plantar erythrodysesthesia. A secondary endpoint was the patient-reported symptom burden (tingling, numbness, pain, or skin problems). Using McNemar's matched pairs design, 53 patients were needed to detect a 20% difference between the treatment and placebo sides with a significance level of 5% and power of 90%. Results Grade 2 or 3 PPE occurred in 30 (58%) of 52 evaluable patients; in six patients adverse effects occurred on the placebo side but not on the treatment side, whereas one patient developed palmar–plantar erythrodysesthesia on the treatment side only ( P = 0.07). Four patients developed grade 2 or 3 palmar–plantar erythrodysesthesia on their foot on the placebo side but not on the treatment side ( P = 0.05). In the cohort with grade 2 or 3 palmar–plantar erythrodysesthesia there was a trend towards fewer dermatologic symptomatologies with the active treatment ( P = 0.05), and no difference for other adverse events. Conclusion Using topical aluminum chlorohydrate as an antiperspirant appears to reduce the incidence of grade 2 or 3 palmar–plantar erythrodysesthesia following pegylated liposomal doxorubicin chemotherapy for metastatic breast cancer.

Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine tumor of the skin in elderly patients with higher mortality compared with melanoma. No evidence-based standardized chemotherapy exists for metastasized patients.We report the case of an 87-year-old patient with the history of resection of a large MCC of the parietal scalp planned for radiotherapy and staged with FDG PET/CT showing disseminated distant metastases. Ga-DOTATATE PET/CT revealed more extensive tumor load compared with FDG, and due to the intensive expression of somatostatin receptors the patient qualified for Y DOTATOC therapy.

Background The phosphatase and tensin homolog ( PTEN ) tumor suppressor gene is deregulated in many advanced prostate cancers, leading to activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway and thus increased cell survival. Objective To evaluate everolimus, an inhibitor of mTOR, in patients with metastatic castration-resistant prostate cancer (mCRPC), and to explore potentially predictive serum biomarkers by proteomics, the significance of PTEN status in tumor tissue, and the impact of everolimus on immune cell subpopulations and function. Design, setting, and participants A total of 37 chemotherapy-naive patients with mCRPC and progressive disease were recruited to this single-arm phase 2 trial (ClinicalTrials.gov identifier NCT00976755). Intervention Everolimus was administered continuously at a dose of 10mg daily. Outcome measurements and statistical analysis The primary end point was progression-free survival (PFS) at 12 wk defined as the absence of prostate-specific antigen (PSA), radiographic progression, or clinical progression. Groups were compared using Wilcoxon rank-sum tests or Fisher exact tests for continuous and discrete variables, respectively. Time-to-event end points were analyzed using the Kaplan-Meier method and univariate Cox regression. Results and limitations A total of 13 patients (35%; 95% confidence interval, 20–53) met the primary end point. Confirmed PSA response ≥50% was seen in two (5%), and four further patients (11%) had a PSA decline ≥30%. Higher serum levels of carboxypeptidase M and apolipoprotein B were predictive for reaching the primary end point. Deletion of PTEN was associated with longer PFS and response. Treatment was associated with a dose-dependent decrease of CD3, CD4, and CD8 T lymphocytes and CD8 proliferation and an increase in regulatory T cells. Small sample size was the major limitation of the study. Conclusions Everolimus activity in unselected patients with mCRPC is moderate, but PTEN deletion could be predictive for response. Several serum glycoproteins were able to predict PFS at 12 wk. Prospective validation of these potential biomarkers is warranted. Trial registration This study is registered with ClinicalTrials.gov with the identifier NCT00976755. Results of this study were presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology (June 3–7, 2011; Chicago, IL, USA) and the annual meeting of the German, Austrian, and Swiss Societies for Oncology and Hematology (September 30–October 4, 2011; Basel, Switzerland).

Purpose: The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer. Experimental Design: Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m2 every 3 weeks or 35 mg/m2 on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m2 on day 1 and then 250 mg/m2 weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted. Results: Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%–52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3–15.4). Seven patients (20%) had a confirmed ≥50% and 11 patients (31%) a confirmed ≥30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN. Conclusions: EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further. Clin Cancer Res; 18(21); 6049–57. ©2012 AACR.

Background: Hemangioblastomas represent rare benign tumors of the central nervous system. In the case of metastatic spread and limited surgical options, systemic treatment may be considered. However there is no standard of care beyond surgery. Case Report: We report the cases of 2 patients with progressive multilocular hemangioblastomas, who showed clinical benefit and radiological stabilization of tumor growth after treatment with bevacizumab, an antibody against the vascular endothelial growth factor. Conclusion: Our case reports suggest activity of bevacizumab in hemangioblastomas after failure of standard therapeutic options.

Background: Gemcitabine remains the mainstay of palliative treatment of advanced pancreatic carcinoma (APC). Adding capecitabine or a platinum derivative each significantly prolonged survival in recent meta-analyses. The purpose of this study was to determine dose, safety and preliminary efficacy of a first-line regimen combining all three classes of active cytotoxic drugs in APC. Patients and methods: Chemotherapy-naive patients with locally advanced or metastatic, histologically proven adenocarcinoma of the pancreas were treated with a 21-day regimen of gemcitabine [1000 mg/m2 day (d) 1, d8], escalating doses of oxaliplatin (80-130 mg/m2 d1) and capecitabine (650-800 mg/m2 b.i.d. d1-d14). The recommended dose (RD), determined in the phase I part of the study by interpatient dose escalation in cohorts of three to six patients, was further studied in a two-stage phase II part with the primary end point of response rate by RECIST criteria. Results: Forty-five patients were treated with a total of 203 treatment cycles. Thrombocytopenia and diarrhea were the toxic effects limiting the dose to an RD of gemcitabine 1000 mg/m2 d1, d8; oxaliplatin 130 mg/m2 d1 and capecitabine 650 mg/m2 b.i.d. d1-14. Central independent radiological review showed partial remissions in 41% [95% confidence interval (CI) 26% to 56%] of patients and disease stabilization in 37% (95% CI 22% to 52%) of patients. Conclusion: This triple combination is feasible and, by far, met the predefined efficacy criteria warranting further investigations

Objectives: While oral anticancer treatment has increased the convenience for patients with no risk of venous access complications compared to intravenous drug administration, a high level of compliance cannot always be assumed. The aim of the present report was to evaluate real-life drug adherence in a prospective cohort analysis of patients with gastrointestinal or breast cancer treated with capecitabine-based chemotherapy. Methods: Twenty-nine Swiss oncologists recruited patients receiving capecitabine, either as monotherapy or in combination with other chemotherapeutic agents, in a prospective fashion. Patients recorded both their capecitabine intake and any adverse effects each day in patient diaries. Results: A total of 177 patients were included, 143 (81%) with gastrointestinal tumours and 34 (19%) with breast cancer. Overall, 161 patients (91%) were considered as fully compliant, while 16 patients (9%) reported some kind of compliance error. Reasons for non-compliance included forgetting to take treatment (n = 9), side effects (n = 4) and misunderstanding instructions (n = 3). Self-reported compliance was not influenced by age or Eastern Cooperative Oncology Group performance status, but there was a trend towards better compliance with capecitabine therapy if fewer adverse effects occurred (p = 0.07, simple logistic regression). Conclusions: Self-reported compliance with capecitabine-based therapy in clinical practice is high and seems to be adversely affected by side effects.

Adrenal metastases are a common finding in metastatic lung and breast cancer. Often there are no clinical symptoms suggesting them. In this paper, we present a case of a 66-year-old man with metastatic lung cancer suffering from severe hyperkaliemia due to hypoaldosteronism as a result of bilateral adrenal metastasis.

762 Background: We conducted a randomized phase II multicenter trial evaluate the anti-epidermal growth factor receptor (EGFR) panitumumab (P) in combination with CRT with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS LARC. Methods: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT either with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Secondary end-points were pathological response, R0-resection, sphincter preservation, downstaging, time to local relapse, time to distant failure and disease-free survival (DFS). Results: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT either with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Secondary end-points were pathological response, R0-resection, sphincter preservation, downstaging, time to local relapse, time to distant failure and disease-free survival (DFS). Conclusions: An addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. Up to date no local recurrence occurred and DFS compared favorably to other trials. Clinical trial information: NCT00814619.

In a phase II study, we assessed the toxicity and efficacy of daily low-dose cisplatin (6 mg/m2) and weekly vinorelbine (15 mg/m2) with concurrent thoracic irradiation (60 Gy) for locally advanced non-metastasized non-small-cell lung cancer. The overall response rate was 65%, complete response 12% and the median overall survival was 64 weeks.

518 Background: Bevacizumab combined with chemotherapy has been shown to improve response rate and PFS in metastatic breast cancer. The aim of our study was to demonstrate decreased toxicity of met...