J. Taieb

Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial

PURPOSE Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, we conducted a phase III study comparing GemOx with Gem alone in advanced pancreatic cancer. PATIENTS AND METHODS Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced v metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion). RESULTS Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% v 17.3%, respectively; P = .04), progression-free survival (5.8 v 3.7 months, respectively; P = .04), and clinical benefit (38.2% v 26.9%, respectively; P = .03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P = .13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx v 3.2% for Gem), vomiting (8.9% for GemOx v 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx v 0% for Gem). CONCLUSION These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.

Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study

BACKGROUND Small-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce. PATIENTS AND METHODS All patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study. RESULTS Ninety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX. CONCLUSIONS This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.

Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer?

Purpose of review The recent advances in the use of targeted therapy in pancreatic cancer are based on the knowledge of genetic alterations that occur during pancreatic carcinogenesis. We describe the repository of frequent alterations targeting tumour suppressor genes and oncogenes. We focus our attention on the epidermal growth factor receptor signalling pathway, which can be activated through different alterations and seems to play a central role in the cell transformation. Multiple targeted drugs have been developed against different partners of this network trying to improve the treatment of pancreatic cancer patients. Recent findings Tarceva has obtained approval in the USA and Europe for metastatic pancreatic cancer with a modest increase of median survival and a 6% increase in 1-year survival rates, suggesting that only a small fraction of patients truly benefit from it. The comparison with lung and colon cancer suggests that Kras mutations could be a predictive marker of resistance. Other promising drugs targeting different partners of the epidermal growth factor receptor signalling pathway could play a synergistic role with Tarceva as inhibitors of mTOR, mitogen-activated protein kinase kinase 1, and nuclear factor-κB or can directly turn down Ras. Summary The biology of the epidermal growth factor receptor, mitogen-activated protein kinase, PI3K/mTOR network suggests that a combination of drugs targeting simultaneously different partners should improve survival.

Cost-effectiveness modeling of colorectal cancer: Computed tomography colonography vs colonoscopy or fecal occult blood tests

OBJECTIVES To assess the cost-effectiveness of three colorectal-cancer (CRC) screening strategies in France: fecal-occult-blood tests (FOBT), computed-tomography-colonography (CTC) and optical-colonoscopy (OC). METHODS Ten-year simulation modeling was used to assess a virtual asymptomatic, average-risk population 50-74 years old. Negative OC was repeated 10 years later, and OC positive for advanced or non-advanced adenoma 3 or 5 years later, respectively. FOBT was repeated biennially. Negative CTC was repeated 5 years later. Positive CTC and FOBT led to triennial OC. Total cost and CRC rate after 10 years for each screening strategy and 0-100% adherence rates with 10% increments were computed. Transition probabilities were programmed using distribution ranges to account for uncertainty parameters. Direct medical costs were estimated using the French national health insurance prices. Probabilistic sensitivity analyses used 5000 Monte Carlo simulations generating model outcomes and standard deviations. RESULTS For a given adherence rate, CTC screening was always the most effective but not the most cost-effective. FOBT was the least effective but most cost-effective strategy. OC was of intermediate efficacy and the least cost-effective strategy. Without screening, treatment of 123 CRC per 10,000 individuals would cost €3,444,000. For 60% adherence, the respective costs of preventing and treating, respectively 49 and 74 FOBT-detected, 73 and 50 CTC-detected and 63 and 60 OC-detected CRC would be €2,810,000, €6,450,000 and €9,340,000. CONCLUSION Simulation modeling helped to identify what would be the most effective (CTC) and cost-effective screening (FOBT) strategy in the setting of mass CRC screening in France.

RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study

Background RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration Clinicaltrials.gov, NCT02502656.

3 Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.

Colon Cancer Mutation: Prognosis/Prediction–Letter

We read with great interest the recent study by Gavin and colleagues ([1][1]), who evaluated the prognostic and predictive value of DNA mismatch repair (MMR) status for oxaliplatin-containing adjuvant chemotherapy in patients with stage II and III colon cancer from National Surgical Adjuvant Breast

Sequential FOLFIRI.3 + Gemcitabine Improves Health-Related Quality of Life Deterioration-Free Survival of Patients with Metastatic Pancreatic Adenocarcinoma: A Randomized Phase II Trial

Background A randomized multicenter phase II trial was conducted to assess the sequential treatment strategy using FOLFIRI.3 and gemcitabine alternately (Arm 2) compared to gemcitabine alone (Arm 1) in patients with metastatic non pre-treated pancreatic adenocarcinoma. The primary endpoint was the progression-free survival (PFS) rate at 6 months. It concludes that the sequential treatment strategy appears to be feasible and effective with a PFS rate of 43.5% in Arm 2 at 6 months (26.1% in Arm 1). This paper reports the results of the longitudinal analysis of the health-related quality of life (HRQoL) as a secondary endpoint of this study. Methods HRQoL was evaluated using the EORTC QLQ-C30 at baseline and every two months until the end of the study or death. HRQoL deterioration-free survival (QFS) was defined as the time from randomization to a first significant deterioration as compared to the baseline score with no further significant improvement, or death. A propensity score was estimated comparing characteristics of partial and complete responders. Analyses were repeated with inverse probability weighting method using the propensity score. Multivariate Cox regression analyses were performed to identify independent factors influencing QFS. Results 98 patients were included between 2007 and 2011. Adjusting on the propensity score, patients of Arm 2 presented a longer QFS of Global Health Status (Hazard Ratio: 0.52 [0.31-0.85]), emotional functioning (0.35 [0.21–0.59]) and pain (0.50 [0.31 – 0.81]) than those of Arm 1. Conclusion Patients of Arm 2 presented a better HRQoL with a longer QFS than those of Arm 1. Moreover, the propensity score method allows to take into account the missing data depending on patients’ characteristics. Trial registration information Eudract N° 2006-005703-34. (Name of the Trial: FIRGEM).

Chimiothérapie intra-artérielle hépatique, chimioembolisation et radioembolisation : un apport important pour le traitement des métastases hépatiques des cancers colorectaux

RésuméLes traitements locaux des métastases hépatiques (MH) des adénocarcinomes colorectaux (CCR) prennent une place de plus en plus importante dans les stratégies thérapeutiques des patients ayant des MH non résécables limitées ou prédominantes au foie. La chimiothérapie intraartérielle hépatique (CIAH) a démontré très tôt son efficacité. Sa combinaison avec des polychimiothérapies systémiques a permis de doubler les taux de réponse et d’augmenter les taux de résection secondaires et la survie des patients. L’efficacité des chimioembolisations (CE) et des radioembolisations (RE) a surtout été établie à partir d’études de phase II ou de phase III les ayant évaluées à des stades très avancés, où la survie sans progression et la survie globale étaient augmentées. La place de ces traitements à des stades plus précoces est en cours d’évaluation, et devrait permettre d’optimiser la prise en charge des patients avec MH. Ces traitements locaux doivent être aujourd’hui utilisés en combinaison avec des traitements systémiques efficaces et/ou des résections, et le choix des meilleures stratégies et protocoles doit être fait en RCP spécialisées.AbstractLocal treatment of liver metastases (LM) of colorectal adenocarcinomas (CRC) has an emerging role in strategies of treatment for patients with limited or predominant unresectable LM. Hepatic intra-arterial chemotherapy (HIAC) demonstrated efficacy. Its combination with systemic chemotherapy allowed to double the response rate, and increased the rate of secondary resection and survival of patients. The effectiveness of chemoembolization (CE) and radio-embolization (RE) was primarily established from Phase II or Phase III evaluation of patients in very advanced stages, and progression-free survival and overall survival were increased. The role of these treatments at earlier stages is being evaluated and is expected to optimize the care of patients with LM. These local treatments must now be used in combination with effective systemic therapies, and/or resection, and the choice of the best strategies and protocols must be done in specialized team with collaboration of expert radiologist, nuclear medicine and oncologist.

Chemosensitivity in ovarian metastases from gastric cancer: A case series

The development of ovarian metastases from gastric cancer indicates a turning point of the disease progression and is usually associated with poor prognosis. Efficacy of modern chemotherapy protocols in ovarian metastases from gastric cancer is unknown. In this case series, we have evaluated the chemosensitivity of ovarian metastases from gastric cancer in eight consecutive patients treated in our institution between January 2000 and April 2012. Median age at gastric cancer diagnosis was 48.3 years and ovarian metastases were mainly metachronous (88%). Patients were treated with FOLFOX or FOLFIRI protocols in first-line and with EOX protocol in second-line chemotherapy. These protocols of chemotherapy used in first- and second-line treatment were able to control the disease in 33.3% for ovarian metastases compared to 66.7% for extraovarian metastases. Mean overall survival (OS) from ovarian metastases diagnosis was 14.2 months. The four patients treated by bilateral oophorectomy had a longer mean OS (16 months) than the four patients who did not experienced surgery (12.3 months). In conclusion, this case series suggests that ovarian metastases from gastric cancer are less sensitive than extraovarian metastases to modern protocol of chemotherapy. To confirm these observations, a large retrospective study is ongoing.