STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer

International audienceBackground: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. Methods/Design: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.Discussion: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. Trial registration: STRATEGIC-1 is registered a

Budd-Chiari Syndrome: Long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt

<p>Abstract</p> <p>Background</p> <p>Budd-Chiari syndrome (BCS) generally implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. Treatment depends on the underlying cause, the anatomic location, the extent of the thrombotic process and the functional capacity of the liver. It can be divided into medical treatment including anticoagulation and thrombolysis, radiological procedures such as angioplasty and transjugular intrahepatic porto-systemic shunt (TIPS) and surgical interventions including orthotopic liver transplantation (OLT). Controlled trials or reports on larger cohorts are limited due to rare disease frequency. The aim of this study was to report our single centre long term results of patients with BCS receiving one of three treatment options i.e. medication only, TIPS or OLT on an individually based decision of our local expert group.</p> <p>Methods</p> <p>20 patients with acute, subacute or chronic BCS were treated between 1988 and 2008. Clinical records were analysed with respect to underlying disease, therapeutic interventions, complications and overall outcome.</p> <p>Results</p> <p>16 women and 4 men with a mean age of 34 ± 12 years (range: 14-60 years) at time of diagnosis were included. Myeloproliferative disorders or a plasmatic coagulopathy were identified as underlying disease in 13 patients, in the other patients the cause of BCS remained unclear. 12 patients presented with an acute BCS, 8 with a subacute or chronic disease. 13 patients underwent TIPS, 4 patients OLT as initial therapy, 2 patients required only symptomatic therapy, and one patient died from liver failure before any specific treatment could be initiated. Eleven of 13 TIPS patients required 2.5 ± 2.4 revisions (range: 0-8). One patient died from his underlying hematologic disease. The residual 12 patients still have stable liver function not requiring OLT. All 4 patients who underwent OLT as initial treatment, required re-OLT due to thrombembolic complications of the graft. Survival in the TIPS group was 92.3% and in the OLT group 75% during a median follow-up of 4 and 11.5 years, respectively.</p> <p>Conclusion</p> <p>Our results confirm the role of TIPS in the management of patients with acute, subacute and chronic BCS. The limited number of patients with OLT does not allow to draw a meaningful conclusion. However, the underlying disease may generate major complications, a reason why OLT should be limited to patients who cannot be managed by TIPS.</p

Could baseline health-related quality of life (QoL) predict overall survival in metastatic colorectal cancer? The results of the GERCOR OPTIMOX 1 study

International audienceBackground: Health-related quality of life (QoL) has prognostic value in many cancers. A recent study found that the performance of prognostic systems for metastatic colorectal cancer (mCRC) were improvable. We evaluated the independent prognostic value of QoL for overall survival (OS) and its ability to improve two prognostic systems'performance (Köhne and GERCOR models) for patients with mCRC. Methods: The EQ-5D questionnaire was self-completed before randomization in the OPTIMOX1, a phase III trial comparing two strategies of FOLFOX chemotherapy which included 620 previously untreated mCRC patients recruited from January 2000 to June 2002 from 56 institutions in five countries. The improvement in models' performance (after addition of QoL) was studied with Harrell's C-index and the net reclassification improvement. Results: Of the 620 patients, 249 (40%) completed QoL datasets. The Köhne model could be improved by LDH, mobility and pain/discomfort; the C-index rose from 0.54 to 0.67. The associated NRI for 12-month death was 0.23 [0.05; 0.46]. Mobility and pain/discomfort could be added to the GERCOR model: the C-index varied from 0.63 to 0.68. The NRI for 12 months death was 0.35 [0.12; 0.44]. Conclusions: Mobility and pain dimensions of EQ5D are independent prognostic factors and could be useful for staging and treatment assignment of mCRC patients. Presented at the 2011 ASCO Annual Meeting (#3632)

CAPRA: Safety, efficacy, and translational biomarkers of weekly everolimus, carboplatin, and paclitaxel as induction therapy for locally advanced head and neck squamous cell carcinoma (HNSCC).

6036 Background: ThePI3K/mTOR pathway is activated in &gt;50% of HNSCC with preclinical synergism between everolimus and carboplatin/paclitaxel. Methods: Patients (pts) with untreated locally advanced HNSCC with ECOG PS&lt;2 received 9 consecutive weekly (w) cycles (cy) of CAPRA combining everolimus (30 mg/w at dose-level 1 then 50 mg/w at dose-level 2) with carboplatin (AUC2) and paclitaxel (60 mg/m2) followed by chemoradiotherapy. Endpoints were safety (CTCv3.0), antitumor activity (RECIST1.1), pharmacodynamic biomarkers on tumor biopsy. Results: A total of 50 pts with stage IV HNSCC (41 males, 9 females, median age 61) were enrolled. Among 7 patients included in the phase I, no dose-limiting toxicity was reported and the recommended dose (RD) of everolimus was 50 mg/w. Safety evaluation in 46 pts treated at RD for 325 cy and a mean number cy/pt of 7.1 (95%CI: 6.3-7.8) showed grade (Gr) 1-2 adverse events consisting of asthenia (50%), nausea/vomiting (28%), alopecia (26%), mucositis (24%), and constipation (20%). Hematological toxicities (Gr1-2/3-4) were neutropenia (35%/39%), anemia (61%/17%), and thrombocytopenia (54%/13%). Everolimus-related Gr3 toxicities were rashes (1pt), pruritus (1pt), dyspnea (1pt), hyperglycemia (2pts), and Gr1-2 hypercholesterolemia (23pts). There was no toxic death. Among 38 pts evaluable for antitumor activity, one pt experienced a complete response (2.6%), 29 pts a partial response (76.3%), and 8 pts a stable disease (21%) for an overall response rate of 79% (no progression reported). Interestingly, 20 major responses (&gt;50% reduction tumor volume) were observed in large necrotic primary tumors/N3 involvement. Efficacy was not correlated to KRAS/BRAF/PI3KCA/EGFR mutations. Significant decreases of Ki67/p-S6K activities were observed in post CAPRA biopsies compared to baseline. Conclusions: Weekly everolimus with carboplatin/paclitaxel as induction regimen was well tolerated with 11% grade 3 and no grade 4/5 toxicity. Translational data showed direct effects of everolimus in tumors. CAPRA yields high rate of objective responses in patients with locally advanced HNSCC. Clinical trial information: NCT01333085. </jats:p

Sunitinib as second-line treatment in patients with advanced intrahepatic cholangiocarcinoma (SUN-CK phase II trial): Safety, efficacy, and updated translational results.

343 Background: There is no validated option beyond gemcitabine plus platinum standard first-line combination for advanced cholangiocarcinoma (CK). Second-line 5FU-based chemotherapy yields a median progression-free survival (PFS) and overall survival (OS) of 3 and 6-7 months, respectively. Intrahepatic CK subtypes overexpress VEGF, providing a rationale for testing sunitinib as second-line treatment in patients (pts) with advanced intrahepatic CK. Methods: A multicenter phase 2 study was designed for pts with locally advanced or metastatic intrahepatic CK after failure of first-line gemcitabine-based chemotherapy. Sunitinib was given at the dose of 37.5 mg/day continuously until disease progression or limiting toxicity. Pts were required to be ECOG PS 0-1 and with adequate liver function (alkaline phosphatase and transaminases &lt; 5ULN, bilirubin &lt;1.5ULN). Main objective was to exceed a median OS of 6.3 months. Secondary endpoints were PFS, response (RECIST 1.1 &amp; Choi criteria), safety, pharmacokinetics (PK) and biomarker analysis (VEGFA, VEGFC, sKIT, HGF, SDF1, and osteopontin). Results: 53 pts were enrolled, with 34 pts evaluable for intermediate safety and efficacy analysis. Median age was 62 years (range 36–80), with 19 females/15 males. ECOG PS was 0/1 in 23/11 pts. Sixteen pts had prior surgical resection and 8 pts received adjuvant chemotherapy. Five pts (15%) had partial responses and 24 stable diseases (71%) by RECIST (disease control rate 85%). Ten pts had disease control &gt; 6 months (range 6-14 months). With a median follow-up of 15.4 months, median OS was 9.6 months [95%CI: 5.8-13.1]. Median PFS was 5.2 months. Frequent adverse events were grade (Gr) 1-2 asthenia (80% of pts), mucositis (80%), diarrhea (60%), and hand-foot syndrome (43%). Gr 3/4 asymptomatic hematological toxicity occurred in 25% of pts (neutropenia n=8, thrombocytopenia n=7), Gr 3 hypertension was observed in 7 pts, and Gr 3 asthenia in 4 pts. Updated PK and biomarker analysis will be presented at the meeting. Conclusions: Second line sunitinib is well tolerated and shows promising activity with a 9.6-month OS in pts with advanced intrahepatic CK. Clinical trial information: NCT01718327. </jats:p

BIOSHARE multicenter neoadjuvant phase 2 study: Results of pre-operative sorafenib in patients with resectable hepatocellular carcinoma (HCC)—From GERCOR IRC.

252 Background: This open-label, multicenter, phase II study aimed at investigating the activity of sorafenib including radiological, pathological and biological changes in tumor from patients with resectable HCC. Methods: Preoperative administration of sorafenib 400 mg bid for 4 weeks was followed by surgery. Primary endpoints were antitumor activity and histological changes on paired tumor samples and plasma biomarkers between baseline and post sorafenib. Secondary endpoints were safety, R0 surgery and post-surgical complications. Results: Among 30 patients enrolled, 28 were evaluable for safety. Neoadjuvant sorafenib was not feasible in 3 patients (early limiting toxicities). Twenty-five patients (21 men; median age: 61.5 years) were evaluable for the primary endpoints. Baseline median tumor size was 37 mm and 21 patients (84%) had a single lesion. Median duration and dosing of sorafenib were 28 days and 793 mg/day respectively. Overall, the safety profile of preoperative sorafenib was good. According to RECIST criteria, all patients showed stable disease. Among 19 patients evaluated according to mRECIST and Choi criteria, objective responses were observed for 6 (32%) and 10 (53%) patients respectively. All evaluable patients went on liver resection and no unexpected complication occurred. R0 tumor resection was achieved in 22 patients (88%). Surgical specimen showed macrovascular and microvascular invasion in 12% and 48%, respectively. Intratumor necrosis was observed in 17 (68%) surgical specimen with necrosis ≥ 50% in 24 % of cases. Blood biomarkers analysis showed a trend toward increased angiogenesis biomarkers (VEGF-A, VEGF-C and PlGF) after sorafenib treatment. Biomarkers from pre- and post-treatment tissue will be presented during the meeting. Conclusions: Neoadjuvant sorafenib displays a favorable toxicity profile and yields significant activity in patients with resectable HCC. BIOSHARE trial also allows exploration of drug effects on tumor biology. Clinical trial information: NCT01182272. </jats:p

Multivariate prospective pharmacogenetic analysis in patients with resectable metastatic colorectal cancer (mCRC) receiving FOLFOX chemotherapy.

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FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in patients with initially resectable metastatic colorectal cancer: A GERCOR randomized phase III study (MIROX).

3506 Background: Perioperative FOLFOX4 is the standard chemotherapy (CT) in patients with resectable metastases from colorectal cancer (CRC) (Nordlinger et al, Lancet 2008). To increase curability and reduce the risk of severe neuropathy, we evaluated the sequential administration of a dose-dense oxaliplatin-based regimen followed by an irinotecan-based regimen. Methods: Patients with CRC and initially resectable or resected metastases were randomized between arm A (control): FOLFOX4 (12 cycles; oxaliplatin 85 mg/m²) or arm B (investigational): FOLFOX7 (6 cycles; oxaliplatin 130 mg/m²) followed by FOLFIRI (6 cycles; irinotecan 180 mg/m²). CT was either perioperative or postoperative. Stratification criteria were: perioperative vs. postoperative CT, surgery alone vs. radiofrequency ablation +/- surgery, Blumgart’s prognostic score (0-1 vs. 2-3 vs. 4-5). Only one metastatic site was allowed, but the number of metastases per organ was not limited. The primary endpoint was disease-free survival (DFS). Results: From May 2004 to June 2010, 284 patients were randomized (142 in each arm). Baseline patient characteristics were similar in both arms. Liver was the main metastatic site. There was only one metastasis in 70 (49.3%) patients in arm A and 69 (48.6%) patients in arm B. CT was administered perioperatively in 168 (59.1%) patients, and postoperatively in 116 (40.9%) patients. In case of perioperative CT, R0-R1 resection was achieved in 58/85 (68.2%) patients in arm A and 67/83 (80.7%) patients in arm B. Grade 3 neuropathy occurred in 34 (23.9%) and 28 (20.0%) patients in arm A and B, respectively. Grade 3/4 thrombocytopenia and gastrointestinal toxicities (nausea, vomiting, diarrhea) were more frequent in arm B. Median follow-up was 50.4 months [95% CI: 45.6-54.4]. Median DFS were 22.4 months [95% CI: 17.9-36.2] in arm A and 23.0 months [95% CI: 19.7-35.6] in arm B (HR=0.97 [95% CI: 0.72-1.31]; p=.856). Conclusions: FOLFOX7 followed by FOLFIRI is not superior to the standard FOLFOX4 chemotherapy in patients with resectable metastatic colorectal cancer. </jats:p