Treatment sequences and prognostic/predictive factors in metastatic pancreatic ductal adenocarcinoma: univariate and multivariate analyses of a real-world study in Europe.

BACKGROUND: Real-world data on treatment patterns/outcomes for metastatic pancreatic cancer (mPAC) are limited. This study aims to assess real-world treatment patterns, survival outcomes, and prognostic/predictive factors in patients with mPAC. METHODS: Retrospective, observational, chart-review involving medical oncologists and gastroenterologists from five European countries. Physicians reported information on disease and patient characteristics, diagnosis, and treatment for patients diagnosed with mPAC from January-October 2016. Outcomes included median progression-free survival (mPFS), median overall survival (mOS), and the impact of baseline performance status on survival. Univariate/multivariate regression analyses were undertaken to identify prognostic/predictive factors. RESULTS: Three hundred four physicians and 3432 patients were included. First-line therapies included modified (m)FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%). Frequent second-line therapies were gemcitabine monotherapy (25.0%), fluorouracil (5-FU) + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). Most frequent first- to second-line treatment sequences were gemcitabine + nab-paclitaxel followed by fluoropyrimidine combinations. Longest unadjusted estimated mOS was observed with (m)FOLFIRINOX followed by gemcitabine-based combinations (19.1 months). Multivariate analysis identified significant prognostic/predictive factors for OS and PFS including performance status and carbohydrate antigen 19-9 (CA 19-9) levels. CONCLUSIONS: Treatment and treatment sequences were generally in accordance with guidelines at the time of the study. Identification of prognostic/predictive factors for survival may help inform the individualised management of mPAC patients in the future.

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.

BACKGROUND: This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). METHODS: Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m2 followed by oxaliplatin 130 mg/m2 (maximum 8 cycles) and then S-1 [20 mg/m2 (cohort 1) or 25 mg/m2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer. RESULTS: DLT was reported for two of the five patients in cohort 2, defining 20 mg/m2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. CONCLUSIONS: The promising activity of EOS (S-1 dose level, 25 mg/m2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer.

The management of metastatic breast cancer becomes increasingly intricate, requiring new drugs and combinations. We present here the results of a phase I study evaluating the maximal tolerated dose of vinorelbine combined with capecitabine as first-line chemotherapy. Vinorelbine was administered intravenously on days 1 and 15, and capecitabine was given orally twice daily from day 1 to 14 (three cycles every 21 days). Three out of six patients receiving vinorelbine at 25mg/m2/day and capecitabine at 2000 mg/m2/day presented with a dose-limiting toxicity, consisting of protracted grade 3 neutropenia, hand-foot syndrome and/or liver test disturbances. Despite of a dose reduction in vinorelbine (20mg/m2/day), one patient among four developed a dose-limiting febrile neutropenia. This regimen cannot be recommended as first-line treatment of metastatic breast cancer. These findings are not in agreement with previous publications of this schedule, or with promising results using both drugs orally.

A randomized multicenter study of optimal circadian time of vinorelbine combined with chronomodulated 5-fluorouracil in pretreated metastatic breast cancer patients: EORTC trial 05971.

Studies in animals synchronized with an alternation of 12 h of light and 12 h of darkness have showed that hematological and systemic toxicities could be reduced if vinorelbine were administered 19 or 23 hours after light onset (HALO), corresponding to 17:00 and 21:00 h in diurnally active humans. This trial aimed to define the least toxic time of vinorelbine administration in metastatic breast cancer patients. Initially, the study treatment consisted of three courses of vinorelbine of 30 mg/m(2)/d on D1 and D6 and chronomodulated 5-fluorouracil of 850 mg/m(2) from D2 to D5 every 21 days. Ninety metastatic breast cancer patients were randomized to receive vinorelbine at one of the eight possible dosing times. Further to the recommendations of the Independent Data Monitoring Committee, the vinorelbine dose was reduced to 25 mg/m(2)/d midway through the study. The primary objective of the study was detection of the least toxic time based on the incidence of grade 3-4 (G3-4) neutropenia. To show a significant result, the 90% confidence interval width of the least toxic time had to be<6 h. The least toxic time detection based on the incidence of other toxicities was also analyzed. The time of least drug toxic was estimated using a logistic regression model assuming that the logit transformation of the toxicity rate follows a sinusoidal distribution over 24 h. The bootstrap technique was used to obtain the 90% confidence interval. The least toxic time of G3-4 neutropenia was observed at 21:00 h with a non-significant 90% CI. Secondary endpoint analyses indicated the least toxic time could differ when based on other toxicity parameters (e.g., a significant least toxic time of 17:00 h was observed for G3-4 leucopenia), in agreement with animal data. The least toxic time of 10:30 h was estimated for any G3-4 gastrointestinal toxicity. This results of this study do not allow us to recommend an optimal time for vinorelbine administration. It has highlighted, however, the inherent methodological difficulties in the conduct of such a trial in the human setting. It indicates that future optimal time-finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity. The randomized optimal time-finding design may be used to identify the best time of chemotherapy administration.