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The real impact of bevacizumab maintenance as single agent in metastatic colorectal cancer (mCRC) remains unclear. SAKK-41/06 and PRODIGE-9 failed to demonstrate the non-inferiority and superiority of bevacizumab versus no maintenance, respectively, while AIO-KRK-0207 showed the non-inferiority of maintenance bevacizumab versus bevacizumab and fluoropyrimidines for time to strategy failure.Bibliography electronic databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials) were searched for English published clinical trials prospectively randomizing mCRC patients to receive bevacizumab maintenance or not after first-line chemotherapy plus bevacizumab. Individual patients' data (IPD) were provided by investigators for all included trials. Primary end-points were progression-free survival (PFS) and overall survival (OS), both from the start of induction and maintenance. Univariate and multivariate analyses for PFS and OS were performed.Three phase III studies - PRODIGE-9, AIO-KRK-0207 and SAKK-41/06 - were included. Considering the different timing of randomization, IPD of patients not progressed during induction and starting maintenance phase entered the analysis. 909 patients were included, 457 (50%) received bevacizumab maintenance. Median PFS from induction start was 9.6 and 8.9 months in bevacizumab group versus no maintenance group, respectively (HR 0.78; 95%CI: 0.68-0.89; p 0.0001). Subgroups analysis for PFS showed a significant interaction according for RAS status (p = 0.048), with a maintenance benefit limited to RAS wild-type patients. No difference in terms of OS was observed.Despite the statistically significant PFS improvement for bevacizumab maintenance, the absolute benefit appears limited. Subgroup analysis shows a differential effect of bevacizumab maintenance in favor of RAS wild-type patients. Considering these results, maintenance therapy with fluoropyrimidine with or without bevacizumab remains the first option. Single agent bevacizumab maintenance can be considered in selected cases, such as cumulative toxicity or patient's refusal, in particular for RAS wild-type patients.

BACKGROUND & AIMS: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis.METHODS: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated.RESULTS: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p 0.05, p = 0.08 respectively).CONCLUSIONS: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors.LAY SUMMARY: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time.

BACKGROUND Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction. METHODS This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naive, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response. RESULTS Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached. CONCLUSIONS Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54. © 2018 American Cancer Society.

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 .

Dark chocolate is claimed to have effects on gastrointestinal function and to improve well-being. This randomised controlled study tested the hypothesis that cocoa slows gastric emptying and intestinal transit. Functional brain imaging identified central effects of cocoa on cortical activity. Healthy volunteers (HV) ingested 100 g dark (72 % cocoa) or white (0 % cocoa) chocolate for 5 d, in randomised order. Participants recorded abdominal symptoms and stool consistency by the Bristol Stool Score (BSS). Gastric emptying (GE) and intestinal and colonic transit time were assessed by scintigraphy and marker studies, respectively. Combined positron emission tomography–computed tomography (PET–CT) imaging assessed regional brain activity. A total of sixteen HV (seven females and nine males) completed the studies (mean age 34 (21–58) years, BMI 22·8 (18·5–26·0) kg/m2). Dark chocolate had no effect on upper gastrointestinal function (GE half-time 82 (75–120) v. 83 (60–120) min; P=0·937); however, stool consistency was increased (BSS 3 (3–5) v. 4 (4–6); P=0·011) and there was a trend to slower colonic transit (17 (13–26) v. 21 (15–47) h; P=0·075). PET–CT imaging showed increased [18F]fluorodeoxyglucose (FDG) in the visual cortex, with increased FDG uptake also in somatosensory, motor and pre-frontal cortices (P

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.

Background Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. Patients and methods Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. Results From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. Conclusions Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. ClinicalTrials.gov number NCT01197885.

Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n = 82) or ipilimumab and additional LPT (n = 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P = 0.0028). Adverse immune-related events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31–1.01, P = 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation. Cancer Immunol Res; 4(9); 744–54. ©2016 AACR.

Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations. We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines. A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma. Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.

Background Inclusion of all patients (pts) with advanced biliary tract cancer (aBTC), irrespective of anatomic location, with assessment of overall survival (OS) in prospective trials, is debated. Additionally, outcome is typically described as estimated OS, but CS offers more relevant information once pts have survived for some time; this study assessed the impact of anatomic site of BTC origin and CS. Methods Pts enrolled into 15 prospective first-line aBTC clinical trials were included. OS was analysed using Cox proportional hazard regression; CS and 95% confidence intervals (CIs) were calculated. Results Overall, 1333 pts were included (Jan 97-Dec 13) with a median (med) age of 63 yrs (range 23-85); 46% male; 84% ECOG PS 0/1; 25% locally advanced (LA) stage, 72% metastatic (met), and 3% not reported (NR). Anatomic site of origin was gallbladder (GBC): 385 (29%), cholangiocarcinoma not specified (CCA-NS): 363 (27%), extrahepatic (EHC): 247 (19%), intrahepatic (IHC): 209 (16%), ampulla: 53 (4%) and 76 (6%) NR. Treatment was mono-chemotherapy: 310 (23%), cis/gem combination: 482 (36%), other combination: 520 (39%) and NR: 21 (2%). Med OS: 10.2 mths (95% CI 9.6-10.9). All sites, adjusted for treatment, had decreased risk of death vs GBC: EHC (p .05, p=.08 respectively). Conclusions Pts with GBC have worse OS compared to other anatomic BTC sites. Inclusion of other BTC subtypes, at least, in prospective aBTC clinical trials is justified. Conditional probabilities allow adjusted prognosis prediction for survivors with aBTC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

3550 Background: Although CAIRO3 and AIO KRK 0207 trials demonstrated the benefit of BV + fluoropyrimidine as a M regimen after induction CT + BV, the role of BV alone is not clear. Indeed, SAKK 41/06 and PRODIGE 9 trials failed to demonstrate the superiority of BV alone vs no M, while AIO KRK 0207 showed the non-inferiority of BV alone vs combo M. Thus, in order to evaluate the magnitude of the eventual benefit of M with BV alone vs no M, an IPD meta-analysis was performed. Methods: Trials whereas mCRC pts were prospectively randomized to receive BV M or not were considered eligible. Primary end-points were PFS and OS, both from the start of induction and M. Univariate and multivariate analyses for PFS and OS were performed, with the following variables: baseline ECOG PS; age ( > vs ≤ 65 years); RAS and BRAF status; LDH and CEA baseline level; RR (PR or CR vs SD) during induction; induction CT (oxa- vs iri-based); resected primary tumor; primary tumor side; synchronous vs metachronous; adjuvant treatment; number (N) of metastatic sites; liver-only disease. Results: IPD of 1,064 pts enrolled in the PRODIGE 9, AIO KRK 0207 and SAKK 41/06 trials were collected. Considering the different timing of randomization in PRODIGE 9 (at the start of induction) vs AIO KRK 0207 and SAKK 41/06 (at the start of M), IPD of pts not progressed during induction and starting M phase entered the analysis. 909 pts were included, 457 (50%) received BV M. Median PFS from induction start was 9.6 and 8.9 months in BV group vs no M group, respectively (HR 0.78; 95%CI: 0.68-0.89; p < 0.0001). At the multivariate PFS analysis, BV M, resected primary tumor, N of metastatic sites and liver-only disease were significant. No difference in terms of OS between the 2 groups was observed. Conclusions: This is the first IPD meta-analysis investigating the role of BV alone M vs no M after first-line induction CT+BV in mCRC pts. Despite the significant PFS improvement in favor of BV M, the absolute benefit appears limited, and without a clear clinical relevance. On these bases, a predictive nomogram to identify pts most likely to benefit from BV M is under evaluation and will be presented during the Congress.

We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico-biliary cancer.We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m(2) day 1, 8 and oral capecitabine 650 mg/m(2) b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) ≤15 μmol/L] and 3 cohorts with increasing TB (16-39, 40-80,80 μmol/L). Three patients with a creatinine clearance60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography-tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis.Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose-limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10(-3)) and capecitabine (p = 10(-5)), and low intracellular gemcitabine triphosphate concentrations (p = 10(-3)).Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine's activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia.

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.

Introduction Clinical practice guidelines regarding follow-up in patients after curative resection of colorectal cancer (CRC) vary widely. Current follow-up recommendations do not include additional postoperative imaging before starting adjuvant treatment in any patients. We evaluated the potential benefit of our institutional approach, recommending 18fluor-deoxy-glucose (FDG)-positron emission tomography (PET)-computed tomography (CT) imaging in CRC stage III patients with ≥4 locoregional lymph node metastases (pN2). Patients and Methods Our study included all patients from a single center with complete resection of a pT1-4, pN2, cM0 CRC. All patients were considered free of distant metastases on the basis of preoperative CT imaging of the chest, abdomen, and pelvis. The main objective of the present study was to assess the proportion of patients with changes of therapeutic management (defined as any other treatment than the preplanned adjuvant chemotherapy) because of the results of additional postoperative FDG-PET-CT imaging. Results Fifty patients (22 female/28 male) were included; the median age was 64 years (range, 37-78 years). Previously undiagnosed metastatic disease resulting in a change of the therapeutic management was detected using postoperative FDG-PET-CT imaging in 7 patients (14.0%; 95% confidence interval, 5.8%-26.7%). The number needed to screen to detect new or previously occult metastases was 7 (7 of 50). Conclusion To our knowledge, this is the first study to evaluate the role of an additional postoperative FDG-PET-CT scan before adjuvant treatment in patients with completely resected CRC with ≥4 lymph node metastases (pT1-4, pN2) and without distant metastases on preoperative CT imaging (cM0). Postoperative FDG-PET-CT imaging represents a valuable tool for the detection of new macrometastases in the subgroup of pN2 cM0 CRC patients. The low number needed to screen for consequent therapeutic changes is clinically relevant and should be further evaluated.

Introduction.Inflammatory myofibroblastic tumors (IMT) of the spleen are rare neoplasms and only little is known about the origin and behavior of these tumors. Here we report the case of a 37-year-old woman with an atypical spindle cell neoplasm showing features strongly suggesting an IMT of the spleen with hepatic metastasis.Methods.A 37-year-old patient had been complaining about pain in the left upper abdomen for the last two months. A CT scan revealed a tumor mass in her spleen and liver. After complete staging, a splenectomy and atypical liver resection of segments VII and VIII were performed. Literature was screened for similar cases and existing further literature.Results.A R0 resection was achieved. Histological analysis showed a multinodular infiltration of the spleen by an atypical mesenchymal neoplasia. Immunohistochemically there was an expression of histiocytic markers (CD4, CD68) as well as smooth muscle cell markers (SMA, H-Caldesmon) in the tumor cells. A diagnosis of an atypical spindle cell neoplasm showing features most suggestive of an IMT was rendered.Conclusion.Synchronous hepatic metastasis of an IMT of the spleen is a rarity. Therefore no experience in the treatment of these tumors exists. Fibroblastic reticular cell tumor is a differential diagnosis, but differentiation of these two entities is difficult.

Summary BACKGROUND: Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome. Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance. Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome. OBJECTIVE: The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015. DESIGN: Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1, PMS2, MSH2 and MSH6, independent of clinical criteria. In the case of loss of MLH1, the somatic BRAF mutation V600E was assessed with molecular testing and/ or immunohistochemistry. Clinical follow-up of potential Lynch syndrome carriers (patients with tumours showing loss of MLH1 expression with absence of BRAFV600E, loss of PMS2, MSH2 or MSH6) was evaluated. RESULTS: Of all patients (n = 486), loss of MMR protein expression was found in 73 (15.0%) tumours. Twenty-eight (6.0%) were classified as potential Lynch syndrome carriers. Of the genetically tested potential Lynch syndrome carriers (10 out of 28 patients), 40% were first diagnosed with Lynch syndrome. CONCLUSIONS: Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related. Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and, in MMR deficient cases, include clear recommendations for genetic counselling for all potential Lynch syndrome patients.

This update includes articles on upper GI-cancers published in 2011 and in early 2012, which we consider particularly interesting for medical oncologists. In addition, abstracts from the 2011 ASCO meeting are also considered We reviewed the important literature in the field of GI-oncology and selected articles, which addressed key topics related to the treatment of esophageal and gastric cancer, and of cancers of the pancreas, the ampulla of Vater and the biliary tract, respectively. As the format of a short review is limited, we have focused on articles which are considered relevant for routine care.

The approval of sorafenib as the first effective drug for the treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. Likewise, the combination of cisplatin and gemcitabine was adopted as a first-line standard chemotherapy option for the treatment of advanced biliary tract cancers based on the results from a large randomized study (ABC-02). This review will briefly summarize the rationale, status and future perspectives of innovative targeted approaches for the treatment of hepatocellular and biliary tract carcinomas. Data from ongoing trials will likely result in a further refinement of treatment recommendations over the course of the next few years.

Objectives: Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and RET (REarranged during Transfection) signaling. The primary objective of this open-label phase I trial was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of vandetanib in combination with gemcitabine in patients with unresectable, locally advanced or metastatic pancreatic adenocarcinoma (PAC). Methods: Patients received vandetanib (100 or 300 mg/day) plus gemcitabine (1,000 mg/m2 i.v. on days 1, 8 and 15 per 28-day cycle) until disease progression, unacceptable toxicity or withdrawal of patient consent. The MTD was determined by the assessment of dose-limiting toxicity (DLT) during the first 28 days of treatment. Results: Fifteen patients were treated. No DLTs occurred in the first cohort of vandetanib 100 mg (n = 3) and recruitment continued at the 300-mg dose level. At the 300-mg dose, 3 out of 12 patients (including 2 in the expansion cohort) experienced DLTs (aphasia, elevated liver enzymes and neutropenia; all of them grade 3), thus exceeding the MTD. No objective responses were observed, with stable disease being the best response in 78% of evaluable patients. Conclusions: Vandetanib 100 mg/day is the RD in combination with gemcitabine in the treatment of patients with advanced PAC.

Purpose To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m2 twice daily on days 1 through 14 plus Gem 1,000 mg/m2 in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2 in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for ≥ 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight. Results Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05). Conclusion There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.

Purpose To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer. Patients and Methods Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption ≥ 10 mg of morphine equivalents per day, and average pain intensity score of ≥ 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m2 twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m2 as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles. Results Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively. Conclusion Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.

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.

The BIG 1-98 trial is a large, randomized, independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer. We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients, which compares monotherapy with letrozole versus tamoxifen. This pre-planned core analysis allowed the use of patient data from the monotherapy arms of letrozole and tamoxifen and from the sequential arms prior to the drug switch point. Patients randomized to letrozole had a 19% improved disease-free survival (hazard ratio [HR] = 0.81; P = 0.003), due especially to reduced distant metastases (HR = 0.73; P = 0.001). A 14% risk reduction of fatal events in favor of letrozole was also observed (P = NS). The results from the monotherapy arms alone confirmed the findings from the primary core analysis. Based on the results from this trial, the aromatase inhibitor letrozole (Femara®) is currently recommended as a part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer and has recently been approved in the early adjuvant setting in both Europe and the United States. A subsequent analysis after additional follow-up will address the question of monotherapy versus sequential therapy.

Purpose This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2 by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Karnofsky performance score (KPS), presence of pain, and disease extent. Results A total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms. Conclusion GemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.

Treatment guidelines are useful tools that enable physicians to integrate the latest clinical research into their practices. The large volume of rapidly evolving clinical data in breast cancer has been summarised and incorporated into treatment recommendations by well-known and reliable institutions, including the National Comprehensive Cancer Network, the American Society for Clinical Oncology, the European Society for Medical Oncology and the St. Gallen International Consensus Panel. Adjuvant therapy is a key component of breast cancer treatment, and many of the current consensus guidelines now recognise the important role of the aromatase inhibitors as an alternative to or in sequence after tamoxifen, hitherto the standard adjuvant treatment of choice for receptor-positive women. Data from ongoing trials such as the Breast International Group 1-98 trial and those still in the accrual phase will be forthcoming and will likely result in a further refinement of treatment recommendations over the course of the next few years. Despite the availability of such guidelines, however, there is evidence that adherence to and implementation of treatment recommendations is less than optimal. Further research is needed to determine more effective means of disseminating those clinical recommendations that can have a significant impact on treatment strategies and ultimately improve outcomes in breast cancer.

BACKGROUND: Patients with advanced, incurable cancer receiving anticancer treatment often experience multidimensional symptoms. We hypothesize that real-time monitoring of both symptoms and clinical syndromes will improve symptom management by oncologists and patient outcomes. PATIENTS AND METHODS: In this prospective multicenter cluster-randomized phase-III trial, patients with incurable, symptomatic, solid tumors, who received new outpatient chemotherapy with palliative intention, were eligible. Immediately before the weekly oncologists' visit, patients completed the palm-based E-MOSAIC assessment (Edmonton-Symptom-Assessment-Scale, ≤3 additional symptoms, estimated nutritional intake, body weight change, Karnofsky Performance Status, medications for pain, fatigue, nutrition). A cumulative, longitudinal monitoring sheet (LoMoS) was printed immediately. Eligible experienced oncologists were defined as one cluster each and randomized to receive the immediate print-out LoMoS (intervention) or not (control). Primary analysis limited to patients having uninterrupted (>4/6 visits with same oncologist) patient-oncologist sequences was a mixed model for the difference in patients global quality of life (G-QoL; items 29/30 of EORTC-QlQ-c30) between baseline (BL) and week 6. Intention-to-treat (ITT) analysis included all eligible patients. RESULTS: In 8 centers, 82 oncologists treated 264 patients (median 66 years; overall survival intervention 6.3, control 5.4 months) with various tumors. The between-arm difference in G-QoL of 102 uninterrupted patients (intervention: 55; control: 47) was 6.8 (P = 0.11) in favor of the intervention; in a sensitivity analysis (oncologists treating ≥2 patients; 50, 39), it was 9.0 (P = 0.07). ITT analysis revealed improvement in symptoms (difference last study visit-BL: intervention -5.4 versus control 2.1, P = 0.003) and favored the intervention for communication and coping. More patients with high symptom load received immediate symptom management (chart review, nurse-patient interview) by oncologists getting the LoMoS. CONCLUSION: Monitoring of patient symptoms, clinical syndromes and their management clearly reduced patients' symptoms, but not QoL. Our results encourage the implementation of real-time monitoring in the routine workflow of oncologist with a computer solution.

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.

To determine the efficacy, impact on quality-of-life (QoL) and tolerability of two different irinotecan administration schedules in combination with capecitabine as first-line treatment of metastatic colorectal cancer.We carried out a randomized phase II trial to select one of the following treatment regimens for further investigation: weekly irinotecan at a dose of 70 mg/m(2) days 1, 8, 15, 22, 29 (arm A) or 3-weekly irinotecan at a dose of 300/240 mg/m(2) day 1 and days 22 (arm B) in combination with capecitabine 1000 mg/m(2) twice daily days 1-14 and days 22-35 every 6 weeks.Seventy-five patients with good performance status entered the trial. The two arms were well balanced for relevant patient and disease characteristics. The most frequent toxic effects were grade 3/4 diarrhea (arm A: 34%, B: 19%), grade 3/4 neutropenia (A: 5%, B: 19%) and grade 2/3 alopecia (A: 26%, B: 65%). Other grade 3/4 toxic effects were rare (5%). Response rates were 34% [95% confidence interval (CI) 20% to 51%] in arm A and 35% (95% CI: 20% to 53%) in arm B. Median time to progression was 6.9 (4.6-10.1) and 9.2 (7.9-11.5) months and median overall survival was 17.4 (12.6-23.0+) and 24.7 (16.3-26.4+) months. Patients with an objective tumor response reported better physical well-being (P0.01), mood (P0.05), functional performance (P0.05) and less effort to cope (P0.05) compared with the non-responders and stable disease patients.The primary end point of this study was the objective response rate and based on the statistical design of the trial, the 3-weekly irinotecan schedule was selected over weekly irinotecan administration. The 3-weekly irinotecan schedule also seemed advantageous in terms of grade 3/4 diarrhea, time to progression, overall survival and patient convenience, but the study was not designed to detect differences in these parameters. In addition, tumor response was shown to have a beneficial effect on QoL indicators.

Background Obesity is a risk factor for developing pancreatic cancer. We investigated the impact of obesity on survival in patients diagnosed with locally advanced or metastatic pancreatic cancer. Methods In a multicentre, retrospective study, we included all patients with advanced or metastatic pancreatic cancer treated at four Swiss hospitals between 1994 and 2004. We categorized patients into four body mass index (BMI) groups (

The goals of this study were the assessment (1) of all costs of terminal care of patients with osteolytic bone disease and pain and (2) of the economic consequences of the pamidronate treatment as observed in a prospective clinical trial on the effectiveness of pamidronate. A total of 70 patients were recruited, who were all suffering from advanced tumour diseases (60% breast cancer, 21% multiple myeloma, and 19% other tumours). In a single-institution study the patients were randomly assigned to receive, in a double-blinded setting, pamidronate 60 mg i.v. or 90 mg i.v. every 3 weeks for a maximum of six cycles. Perception of pain intensity was recorded by self-assessment, using a linear analogue scale. Follow-up lasted 6 months after treatment. All elements of direct costs of in-patient and out-patient care were recorded in cooperation with the hospital administration and the health insurance companies [Krankenkassen]. Average monthly direct costs amounted to ECU 1,290 (+/-410) and 1,050 (+/- 430) during the treatment phase and follow-up, respectively. Average in-patient costs were about three times the out-patient costs. Significantly higher costs (by a factor of 2) were observed for terminal care in hospital (last 3 months before death) than for continued care (of patients surviving the study period). The treatment with pamidronate reduced pain significantly but did not add noticeably to the costs. The study showed that it is practicable and quite efficient to combine a pharmaco-economic evaluation with a clinical trial, although it may be difficult (depending on the setting and availability of information) to assess true costs, i.e. total resource usage.

The aim of this double-blind, randomized study was to compare the effects of two pamidronate dosages, given as repeated infusions in patients with advanced malignant osteolytic bone disease and bone pain. Seventy patients were randomly assigned to receive pamidronate 60 mg or 90 mg i.v. every 3 weeks for a maximum of six cycles. Pain parameters, analgesic consumption and performance status were assessed at baseline and throughout the study. Furthermore, total-body bone mineral density was measured using dual- energy X-ray absorptiometry at baseline, after three and after six infusions. Sixty percent (95% CI 41–77%) of the patients in the 60 mg group and 63% (95% CI 44–79%) of the patients in the 90-mg group had a sustained reduction of pain intensity and were classified as pain responders. Median duration of pain response was 15 versus 12 weeks in the 60-mg and 90-mg groups, respectively (P=0.32). After two infusions, significant changes in pain intensity, pain frequency, general well-being and WHO pain score were observed (P

Seventy cancer patients with malignant osteolytic bone disease received pamidronate every three weeks for a maximum of six cycles. Bone resorption parameters, urinary calcium excretion, and pain parameters were assessed at baseline and throughout the study. At baseline, 80–95 % of patients showed elevated urinary pyridinoline, deoxypyridinoline, Osteomark® NTx and serum ICTP® levels, whereas only 35 % of patients had elevated urinary CrossLaps® excretion rates. During bisphosphonate therapy, significant decreases in Osteomark® NTx, CrossLaps® and calcium excretion were observed, which were not related to the clinical outcome. The baseline levels of bone resorption markers were used to predict the probability of non-progressive bone disease or reduction in pain intensity during bisphosphonate therapy. Significant predictors of non-progressive bone disease were urinary pyridinoline and serum ICTP levels; significant predictors of reduction in pain intensity were urinary free deoxypyridinoline and serum ICTP levels. Our data indicate that serum ICTP levels predict significantly the response to bisphosphonate therapy in patients with advanced malignant osteolytic bone disease. CrossLaps did not predict the clinical outcome, but decreased significantly during bisphosphonate therapy. Our data demonstrate that the different bone resorption markers are reflecting different aspects of bone metabolism, and therefore differ in their diagnostic and prognostic properties.

Plasma endothelin-1 (ET-1) and cortisol were measured around the clock at hourly intervals on 7 clinically healthy, diurnally active, nocturnally resting subjects 22-27 years of age. The circadian rhythm in cortisol is demonstrated for each subject (por = 0.020) as well as on a group basis (p = 0.002), peaking in the morning. By contrast, the circadian variation of ET-1 is statistically significant in only one of the subjects, and it is not detected for the group as a whole (p0.20). Instead, ET-1 is characterized by an about 8-h component (p0.001) that is not found for cortisol.

Context Oncologists perform a range of pharmacological and nonpharmacological interventions to manage the symptoms of outpatients with advanced cancer. Objectives The aim of this study was to develop and test a symptom management performance checklist (SyMPeC) to review medical charts. Methods First, the content of the checklist was determined by consensus of an interprofessional team. The SyMPeC was tested using the data set of the SAKK 96/06 E-MOSAIC (Electronical Monitoring of Symptoms and Syndromes Associated with Cancer) trial, which included six consecutive visits from 247 patients. In a test data set (half of the data) of medical charts, two people extracted and quantified the definitions of the parameters (content validity). To assess the inter-rater reliability, three independent researchers used the SyMPeC on a random sample (10% of the test data set), and Fleiss's kappa was calculated. To test external validity, the interventions retrieved by the SyMPeC chart review were compared with nurse-led assessment of patient-perceived oncologists' palliative interventions. Results Five categories of symptoms were included: pain, fatigue, anorexia/nausea, dyspnea, and depression/anxiety. Interventions were categorized as symptom specific or symptom unspecific. In the test data set of 123 patients, 402 unspecific and 299 symptom-specific pharmacological interventions were detected. Nonpharmacological interventions ( n = 242) were mostly symptom unspecific. Fleiss's kappa for symptom and intervention detections was K = 0.7 and K = 0.86, respectively. In 1003 of 1167 visits (86%), there was a match between SyMPeC and nurse-led assessment. Seventy-nine percent (195 of 247) of patients had no or one mismatch. Conclusion Chart review by SyMPeC seems reliable to detect symptom management interventions by oncologists in outpatient clinics. Nonpharmacological interventions were less symptom specific. A template for documentation is needed for standardization.

Purpose This study investigated satisfaction with treatment decision (SWTD), decision-making preferences (DMP), and main treatment goals, as well as evaluated factors that predict SWTD, in patients receiving palliative cancer treatment at a Swiss oncology network. Patients and methods Patients receiving a new line of palliative treatment completed a questionnaire 4–6 weeks after the treatment decision. Patient questionnaires were used to collect data on sociodemographics, SWTD (primary outcome measure), main treatment goal, DMP, health locus of control (HLoC), and several quality of life (QoL) domains. Predictors of SWTD (6 = worst; 30 = best) were evaluated by uni- and multivariate regression models. Results Of 480 participating patients in eight hospitals and two private practices, 445 completed all questions regarding the primary outcome measure. Forty-five percent of patients preferred shared, while 44 % preferred doctor-directed, decision-making. Median duration of consultation was 30 (range: 10–200) minutes. Overall, 73 % of patients reported high SWTD (≥24 points). In the univariate analyses, global and physical QoL, performance status, treatment goal, HLoC, prognosis, and duration of consultation were significant predictors of SWTD. In the multivariate analysis, the only significant predictor of SWTD was duration of consultation (p = 0.01). Most patients indicated hope for improvement (46 %), followed by hope for longer life (26 %) and better quality of life (23 %), as their main treatment goal. Conclusion Our results indicate that high SWTD can be achieved in most patients with a 30-min consultation. Determining the patient’s main treatment goal and DMP adds important information that should be considered before discussing a new line of palliative treatment.

Background Bevacizumab (BEV)-containing therapies are costly. We performed a health economic analysis of a randomized phase 3 study (SAKK 41/06) that compared BEV continuation as a single agent (BEV) with treatment holidays (no BEV) after completing 4 to 6 cycles of first-line chemotherapy plus BEV in metastatic colorectal cancer patients. Patients and Methods Costs for first-line chemotherapy with BEV, BEV continuation therapy, hospitalizations (length of stay), control visits, diagnostic tests, and second-line and later rounds of chemotherapy were collected. Mean costs per patient per treatment arm and an incremental cost-effectiveness ratio were calculated. Probabilistic sensitivity analysis was performed to account for uncertainty in the input parameters. Results The total incurred mean costs per patient were 126,631 Swiss francs (CHF) [95% confidence interval (CI), 116,521-136,740] for BEV versus CHF100,146 (95% CI, 92,811-107,481) for no BEV. The incremental cost effectiveness ratio was CHF108,991 per life-year gained (LYG; 95% CI from probabilistic sensitivity analysis, 62,890-248,515). Compared to a willingness-to-pay threshold of CHF100,000/LYG, there was 42% probability that BEV continuation was cost effective, which decreased to 20% at a threshold of CHF75,000/LYG. Economic equality was reached in only 0.07% of cases. Conclusion The clinical conclusion that BEV continuation as a single agent after completion of first-line chemotherapy is of low therapeutic value is supported by this health economic analysis. Costs increase without significant clinical benefit in this setting.

Background In patients with advanced, incurable cancer, anticancer treatment may be used to alleviate cancer-related symptoms, but monitoring of them in daily practice is rarely done. We aim to test the effectiveness of a real-time symptom and syndrome assessment using the E-MO S AIC software installed in handheld computer generating a longitudinal monitoring sheet (LoMoS) provided to the oncologists in a phase III setting. Methods In this prospective multicentre cluster randomized phase-III trial patients with any incurable solid tumor and having defined cancer related symptoms, who receive new outpatient chemotherapy in palliative intention (expected tumor-size response rate ≤20%) are eligible. Immediately before the weekly visit to oncologists, all patients complete with nurse assistance the E-MO S AIC Assessment: Edmonton Symptom Assessment Scale, ≤3 additional symptoms, estimated nutritional intake, body weight, Karnofsky and medications for pain and cachexia. Experienced oncologists will be randomized to receive the LoMoS or not. To minimize contamination, LoMoS are removed from the medical charts after visits. Primary endpoint is the difference in global quality of life (items 29 & 30 of EORTC-QlQ-C30) between baseline and last study visit at week 6, with a 10 point between-arm difference considered to be clinically relevant. 20 clusters (=oncologists) per treatment arm with 4–8 patients each are aimed for to achieve a significance level of 5% and a power of 80% in a mixed model approach. Selected co- variables are included in the model for adjustment. Secondary endpoints include patient-perceived patient-physician communication symptom burden over time, and oncologists’ symptom management performance (predefined thresholds of symptoms compared to oncologists’ pharmacological, diagnostic or counselling actions [structured chart review]). Discussion This trial will contribute to the research question, whether structured, longitudinal monitoring of patients’ multidimensional symptoms, indicators for symptom management, and clinical benefit outcomes can influence patients’ quality of life and symptom distress, in a setting of routine oncology practice. Trial registration Current Controlled Trials NCT00477919

A sequential treatment design was chosen in this trial to ensure complete resistance to single-agent non-steroidal aromatase inhibitor (AI) and trastuzumab both given as monotherapy before receiving the combination of a non-steroidal AI and trastuzumab. Key eligibility criteria included postmenopausal patients with advanced, measurable, human epidermal growth factor receptor-2 (HER-2)-positive disease (assessed by FISH, ratio (≥2)), hormone receptor (HR)-positive disease, and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in the adjuvant or in the advanced setting. Patients received standard dose trastuzumab monotherapy in step 1 and upon disease progression continued trastuzumab in combination with letrozole in step 2. The primary endpoint was clinical benefit rate (CBR) in step 2. Totally, 13 patients were enrolled. In step 1, six patients (46%) achieved CBR. Median time to progression (TTP) was 161 days (95% confidence interval (CI): 82-281). In step 2, CBR was observed in eight out of the 11 evaluable patients (73%), including one patient with partial response. Median TTP for all the 11 patients was 188 days (95% CI: 77-not reached). Results of this proof-of-concept trial suggest that complete resistance to both AI and trastuzumab can be overcome in a proportion of patients by combined treatment of AI and trastuzumab, as all patients served as their own control. Our results appear promising for a new treatment strategy that offers a chemotherapy-free option for at least a subset of patients with HR-positive, HER-2-positive breast cancer over a clinically relevant time period.

There is no standard treatment for patients with locally advanced esophageal carcinoma without systemic metastasis in whom surgery is no longer considered a reasonable option.Patients with cervical esophageal tumors, locally very advanced stage (T4 and/or M1a) or locally advanced (T3 and/or N+) with comorbidities were included.2 cycles of induction chemotherapy (cisplatin and docetaxel, both 75 mg/m(2) 3-weekly) followed by chemoradiation therapy (CRT) comprising a total radiation dose of 59.4 Gy together with docetaxel 15 mg/m(2) and cisplatin 25 mg/m(2) (5 weekly doses). Primary endpoint: Histologically proven freedom from local failure 6 months after CRT completion.21 patients were included: 12 had locally very advanced tumors, 3 had cervical esophagus tumors, and 6 were medically unfit for surgery. 18 patients completed therapy per protocol. Grade 3/4 toxicities during CRT were thrombopenia (10%) and dysphagia (15%). 1 patient died due to herpes simplex infection. The primary endpoint was achieved by 4 patients, 6 were alive after median follow-up of 34 months, and median survival was 16 months. Most patients experienced lasting improvement of dysphagia following induction chemotherapy.This regimen is feasible, showed clinically meaningful, long-lasting improvements in quality of life and resulted in long-term survival in 29% of the patients.

Background. Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). Patients and Methods. Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). Results. Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%–47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. Conclusion. Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Objectives: The purpose of this investigation was firstly to assess the overall frequency of subjectively experienced symptoms self-reported by patients receiving endocrine therapy and secondly to compare these symptoms with side effects assessed by clinicians in pivotal trials. Methods: Unselected patients with early and advanced breast cancer receiving endocrine therapy were approached consecutively during a routine outpatient visit. They received a questionnaire called Checklist for Patients with Endocrine Therapy (C-PET), a validated self-assessment tool to determine prespecified symptoms associated with endocrine therapy. Data on toxicity were also obtained from previously published trials. Results: 405 patients were approached and 373 agreed to participate in this study. Some symptoms were significantly more often recorded by the women in the adjuvant setting completing the C-PET than by physicians’ reports in pivotal trials: hot flushes/sweats (C-PET 70%, ATAC 40% and BIG1-98 38%), low energy (C-PET 45%, ATAC 15% and BIG1-98 9%), fluid retention (C-PET 22% and BIG1-98 7%) and vaginal dryness (C-PET 30% and BIG1-98 3%). Similar differences were observed in the metastatic and adjuvant setting. Conclusions: A simple tool like the C-PET questionnaire is able to reflect the treatment burden of endocrine therapies and may be helpful to improve communication between patients and care providers. Some symptoms were significantly more often reported by the women in the C-PET than by physicians in pivotal trials.

GOALS OF WORK: In patients with locally advanced esophageal cancer, only those responding to the treatment ultimately benefit from preoperative chemoradiation. We investigated whether changes in subjective dysphagia or eating restrictions after two cycles of induction chemotherapy can predict histopathological tumor response observed after chemoradiation. In addition, we examined general long-term quality of life (QoL) and, in particular, eating restrictions after esophagectomy. MATERIALS AND METHODS: Patients with resectable, locally advanced squamous cell- or adenocarcinoma of the esophagus were treated with two cycles of chemotherapy followed by chemoradiation and surgery. They were asked to complete the EORTC oesophageal-specific QoL module (EORTC QLQ-OES24), and linear analogue self-assessment QoL indicators, before and during neoadjuvant therapy and quarterly until 1 year postoperatively. A median change of at least eight points was considered as clinically meaningful. MAIN RESULTS: Clinically meaningful improvements in the median scores for dysphagia and eating restrictions were found during induction chemotherapy. These improvements were not associated with a histopathological response observed after chemoradiation, but enhanced treatment compliance. Postoperatively, dysphagia scores remained low at 1 year, while eating restrictions persisted more frequently in patients with extended transthoracic resection compared to those with limited transhiatal resection. CONCLUSIONS: The improvement of dysphagia and eating restrictions after induction chemotherapy did not predict tumor response observed after chemoradiation. One year after esophagectomy, dysphagia was a minor problem, and global QoL was rather good. Eating restrictions persisted depending on the surgical technique used.

“No, you know, that can’t be right. I just can’t accept it.” Patients and family members can express astonishing repression, known in psychology as denial. A young university graduate in his 40s sits in a wheelchair in front of us. He was still working until a few weeks ago. Now he has come to the hospital with his brother and his parents —but not with his girlfriend—to hear his definitive diagnosis: metastatic renal cell cancer. There is no doubt. He wants to know exactly how long he is going to live. The doctors among us tell him that he has “many months,” maybe as long as 2 years. He interrupts the doctors’ explanation in a loud voice: “No, you know, that can’t be right. I just can’t accept it. That’s not true.” His mother, of slight build yet formidable, a strictly devout woman, repeats: “That simply can’t be right. That can’t happen to my son, God won’t allow that. Let’s go!” She gets up. Her son, the patient, asks her to sit down again. Although we are familiar with such situations, we are struck by the vehemence of their reaction. Their sheer desperation is so total that we are speechless.

Background Positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG–PET) is an accurate imaging modality for the staging of breast cancer. The aim of this study was to determine the potential therapeutic impact of pre- and postoperative FDG–PET in patients with clinically intermediate or high-risk breast cancer. Patients and methods One hundred and fourteen patients with newly diagnosed breast cancer were examined before (73) or after (41) surgery. Patient data were translated into three scoring sheets corresponding to information available before positron emission tomography (PET), after PET and after further diagnostic tests. Three medical oncologists independently reviewed the retrospectively acquired patient data and prospectively made decisions on the theoretically planed treatment for each time point, according to the recommendations of St Gallen Consensus Guidelines 2005. Results FDG–PET changed the planed treatment in 32% of 114 patients. In 20% of cases, therapeutic intention (curative versus palliative) was modified. Radiation treatment planning was changed in 27%, surgical planning in 9%, chemotherapy in 11% and intended therapy with bisphosphonates in 13% of all patients. Conclusion Based on current treatment guidelines, FDG–PET, as a staging procedure in patients with newly diagnosed clinically intermediate or high-risk breast cancer examined pre- and postoperatively, may have a substantial therapeutic impact on treatment planning.

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.

The third-generation aromatase inhibitor letrozole offers a promising approach to treating hormone-sensitive breast cancer for postmenopausal women, through potent and specific inhibition of estrogen synthesis. In neoadjuvant and first-line treatment, letrozole demonstrated superior efficacy compared with tamoxifen in randomized Phase III trials. Initial results of Breast InterGroup 1-98, a large ongoing randomized trial investigating primary adjuvant endocrine treatment with either letrozole or tamoxifen, have recently been presented. Patients treated with letrozole demonstrated a 19% improvement in disease-free survival and a significant reduced risk of distant recurrences, holding out the prospect of a survival advantage over tamoxifen treatment with further maturation of the trial. For patients who have already completed 5 years of tamoxifen, extended endocrine therapy with letrozole is a new therapeutic option based on the results of the MA-17 trial. The optimal use of aromatase inhibitors remains an open question, at least until results from randomized trials (BIG 1-98, TEAM) investigating the sequential use of an aromatase inhibitor and tamoxifen in comparison with continuous monotherapy become available.

Aim: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients (pts) with gastrointestinal stromal tumor (GIST), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of bcr-abl, kit and src-family kinases, and imatinib resistant cells, providing the rationale of this trial. Evaluation of GIST treated with TKIs is routinely done by computed tomography (CT). 18F-fluorodeoxyglucose positron-emission-tomography (FDG-PET) measures tumor metabolic activity for early response assessment and outcome prediction. Aim of this study is to evaluate the efficacy of dasatinib in TKI-naive patients with GIST. Methods: This two-stage phase II trial investigated dasatinib in pts with TKI-naive GIST. Dasatinib starting dose was 2x70mg/day in pts with histologically proven, FDG-PET positive GIST. Response evaluation was done by serial CT and FDG-PET using EORTC PET response criteria (Young et al. 1999). Elective surgery was allowed after 6 months of trial treatment. Primary endpoint was response (CR+PR) by FDG-PET after one month of dasatinib. In case of progression the treatment was changed to imatinib. Results: 47 of 52 planned pts had been enrolled from December 2007 to November 2011, when the trial was terminated due to slow accrual. 42 pts were eligible. Median age was 61 years, 24 pts were male, 18 female. Performance status was 0 in 29 and 1 in 13 patients. Median follow-up (mFU) was 47.7 months. Pts went off trial for elective surgery (n=8), after 26 cycles as per protocol (n=5), progression (n=14), toxicity (n=7), other (n=5) and three patients died (two off-drug, one on-drug). Toxicity was most often gastrointestinal or pulmonary, G4 was observed in 5% of pts, and G3 in 48% of pts. Dose was interrupted or reduced in 25% of cycles. The primary endpoint, FDG-PET response rate (CR+PR) at 4 weeks was 74% (14 CR, 17 PR, 6 SD, 3 PD, 2 not evaluable). Median progression-free survival (mPFS) is 13.6 months and median overall survival (mOS) has not been reached yet. Conclusions: Dasatinib shows high metabolic response rates in TKI-naive pts with FDG-PET positive GIST. Toxicity was manageable at the dose studied. Median PFS was 13.6 months and 74% alive at 4 years (95% CI: 60-91%). Disclosure: P. Rutkowski: PR has served as a member of Advisory Board and received honoraria from Novartis, BMS. All other authors have declared no conflicts of interest.

Aim: Sorafenib (S), a multitargeted tyrosine kinase inhibitor, has become standard of care for first-line systemic treatment of advanced HCC. Everolimus (E) is a potent inhibitor of the mTOR. In preclinical HCC-models, S + E has additive effects compared to S. The objective of the health economic analysis (HEA) alongside the SAKK77/08 trial was to investigate the incremental cost utility ratio (ICER) of the treatment with S + E. Methods: Patients (pts) with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomly assigned to receive daily S 800 mg (n = 46) or S 800 mg + E 5 mg (n = 60) until progression or unacceptable toxicity. The primary endpoint of the HEA was the ICER for Swiss pts (n = 60). The HEA adopted a health system perspective including all substantial direct medical costs incurred in the treatment of the pts. Health-related quality of life was measured by means of the EQ-5D utility instrument. A generalized linear model (glm) was used to analyze utilities and the costs (using a gamma distribution and a logarithmic cost transformation) for the two arms, controlling for gender and age. Results: In January 2014 (time point of data extraction) 2 pts in the S (n = 26) and 8 pts in the S + E (n = 34) arm were still alive. The clinical study results will be presented at ASCO 2014. Mean observation time for the HEA was 1.0 years in arm S (95%CI 0.7–1.3) versus 1.1 years (95%CI 0.8–1.4) in arm S + E. Utilities were slightly but not significantly higher in the S + E arm (glm). Total incurred mean costs per patient were CHF 48′396 in arm S (95%CI 35'857–60'934; overall cost per year (cpy) CHF 48'564) versus CHF 56'425 (95%CI 43'745–69'104; cpy CHF 52'669) in arm S + E. The costs for S accounted for 42%, S + E for 56% of the total costs in the respective arms. In the glm, total costs were not significantly different between treatment arms and age and sex had no significant effect on the results. The ICER was CHF 58'160/QALY. Conclusions: Addition of a reduced dose of everolimus to full doses of sorafenib is slightly more costly in Swiss patients. In view of the clinical results the HEA does not favor the S + E strategy. Disclosure: All authors have declared no conflicts of interest.

3531 Background: K-ras mutation is found in up to 40% of LARC. Sor is a multitarget tyrosine kinase inhibitor including raf and VEGFR and has demonstrated radiosensitizing effects. Sor might improv...