Phase III randomized, double-blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).

The RADPAC trial evaluated paclitaxel with everolimus in patients with advanced gastroesophageal cancer (GEC) who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Patients were randomly assigned to receive paclitaxel (80 mg/m2 ) on day 1, 8 and 15 plus everolimus (10 mg daily, arm B) d1-d28 or placebo (arm A), repeated every 28 days. Primary end point was overall survival (OS). Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01248403. Between October 2011 and September 2015, 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (arm A, 150, arm B, 150). In the intention to treat population, there was no significant difference in progression-free survival (PFS; everolimus, 2.2 vs placebo, 2.07 months, HR 0.88, P = .3) or OS (everolimus, 6.1 vs placebo, 5.0 months, HR 0.93, P = .54). For patients with prior taxane use, everolimus improved PFS (everolimus, 2.7 vs placebo 1.8 months, HR 0.69, P = .03) and OS (everolimus, 5.8 vs placebo 3.9 months, HR 0.73, P = .07). Combination of paclitaxel and everolimus was associated with significantly more grade 3-5 mucositis (13.3% vs 0.7%; P < .001). The addition of everolimus to paclitaxel did not improve outcomes in pretreated metastatic gastric/gastroesophageal junction (GEJ) cancer. Activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit.

Baseline and On-Treatment Markers Determining Prognosis of First-Line Chemotherapy in Combination with Bevacizumab in Patients with Metastatic Colorectal Cancer.

BACKGROUND: In metastatic colorectal cancer, no upfront or on-treatment markers are available to determine the prognosis or efficacy for chemotherapy in combination with bevacizumab. PATIENTS AND METHODS: The current analysis was performed to evaluate the prognostic value of disease and patient characteristics (age, number of metastatic sites, stage of primary tumor, performance status, carcinoembryonic antigen (CEA)) and on-treatment changes of CEA (response after 8-12 weeks of treatment and specific patterns of CEA kinetics) in patients from an observational cohort study of chemotherapy with bevacizumab. RESULTS: Baseline factors were available from 1,438 patients. Patients with baseline CEA levels > 20 ng/ml, more than 1 metastatic site, and age > 75 years showed significantly lower progression-free (PFS) and overall survival in multivariate analysis. A CEA response of > 30% during treatment was associated with increased PFS. In addition, the pattern of CEA kinetics predicts survival and response to treatment. CONCLUSION: In summary, baseline CEA, number of metastatic sites, and age are strong independent prognostic factors for survival. By monitoring CEA, clear patterns with distinct prognostic value can be determined. CEA kinetics and/or response after 8-12 weeks might be a useful and simple tool to stratify the post-induction treatment approach based on individual prognosis in the future.

Bevacizumab plus chemotherapy as first-line treatment for patients with metastatic colorectal cancer: results from a large German community-based observational cohort study.

BACKGROUND: After approval of bevacizumab in Germany in 2005 for the treatment of unresectable advanced or refractory colorectal cancer (CRC), this observational cohort study was initiated to assess the efficacy and safety of bevacizumab with various chemotherapy regimen in patients with metastatic CRC (mCRC). MATERIAL AND METHODS: To facilitate enrolment of a typical mCRC population, eligibility criteria were minimised. Choice of chemotherapy regimen was at the physicians' discretion, but influenced by current registration status. Predefined endpoints were treatment characteristics, response rate, progression-free survival (PFS), overall survival (OS) and adverse events assessed as potentially related to bevacizumab treatment. Patients were followed for up to four years. RESULTS: In total 1777 eligible patients were enrolled at 261 sites from January 2005 to June 2008. Median age: 64 years (range 19-100); male 62%; ECOG performance status 0-1/≥ 2 89%/11%. Chemotherapy choice was fluoropyrimidine (FU) 12%, FU/oxaliplatin 18%, FU/irinotecan 64%, no chemotherapy concurrent to bevacizumab 2% and other 4%. Best investigator-assessed response rate was 60% (complete response 10%, partial response 51%). Median PFS was 10.2 months and median OS was 24.8 months. CONCLUSIONS: The efficacy and safety profile of bevacizumab in this population of mCRC patients with different chemotherapy regimens is consistent with that observed in other patient registries/non-randomised trials and also corresponds well with data from similar treatment arms of phase III trials.

Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial.

PURPOSE: To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy. PATIENTS AND METHODS: A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status. RESULTS: Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001). CONCLUSION: Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.

Molecular cytogenetic monitoring from CD34+ peripheral blood cells in myelodysplastic syndromes: first results from a prospective multicenter German diagnostic study.

The gold standard of cytogenetic analysis in myelodysplastic syndromes (MDS) is conventional chromosome banding (CCB) analysis of bone marrow (BM) metaphases. Most aberrations can also be detected by fluorescence-in situ-hybridization (FISH). For this prospective multicenter German diagnostic study (www.clinicaltrials.gov: #NCT01355913) 360 patients, as yet, were followed up to 3 years by sequential FISH analyses of immunomagnetically enriched CD34+ peripheral blood (PB) cells using comprehensive FISH probe panels, resulting in a total number of 19,516 FISH analyses. We demonstrate that CD34+ PB FISH correlates significantly with CCB analysis and represents a feasible method for a reliable non-invasive cytogenetic monitoring from PB.

Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.

BACKGROUND: Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy. METHODS: In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy. RESULTS: After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively. INTERPRETATION: Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.