Stéphane Cattan

Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301)

Purpose Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted. Methods Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0–2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%). Results 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0–1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018). Conclusion This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy.

Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: A large multicenter AGEO study

BACKGROUND & AIMS The current standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib. This drug is effective but generally does not induce tumor shrinkage and other treatment options are still needed. METHODS This retrospective multicenter study included all consecutive patients with advanced HCC treated with gemcitabine and oxaliplatin (GEMOX) between 2001 and 2010. Survival curves were drawn with the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were used to evaluate prognostic factors. RESULTS Two hundred four consecutive patients were treated with GEMOX (median age, 60 years; men, 86%; underlying cirrhosis, 76%). Grade 3-4 toxicity was observed in 44% of the patients (thrombocytopenia 24%, neutropenia 18%, diarrhea 14%, neurotoxicity 12%) leading to treatment discontinuation in 16% of the cases. The overall response and disease control rates were 22% (95% CI, 16-27) and 66% (95% CI, 59-72), respectively. No clinical or biological factors were associated with the treatment response, and 8.5% of the patients were subsequently eligible for curative-intent therapies after downstaging. Median PFS, TTP, and OS were 4.5 (95% CI, 4-6), 8 (95% CI, 6-11), and 11 months (95% CI, 9-14), respectively. In multivariate analysis, gender (p=0.03), underlying cirrhosis (p=0.01), CLIP score (p=0.03), and response to GEMOX (p<0.0001) were independently associated with OS. CONCLUSIONS This large study confirms that GEMOX is effective with manageable toxicity in patients with advanced HCC. Tumor responses permitted potentially curative treatment that was not initially feasible in a significant proportion of patients.

Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a phase III multicentre, randomised, double blind placebo-controlled study.

BACKGROUND A previous study reported a significant survival benefit for octreotide compared with no treatment in patients with advanced hepatocellular carcinoma (HCC). This was investigated further in this multicentre study. PATIENTS AND METHODS Two hundred and seventy two patients with HCC who were ineligible for curative treatments or had relapsed following potentially curative therapies were randomised to receive long-acting octreotide, 30 mg as an intramuscular injection once every 4 weeks for up to 2 years, or placebo. RESULTS At the time of the final analysis, median overall survival (OS) was 6.53 months (95% confidence interval [CI], 4.8-8.3) for octreotide versus 7.03 months (95% CI, 5.43-8.53) for placebo (p=0.34). Progression-free survival (p=0.26) also did not differ significantly between the two treatment groups. No objective responses were achieved in the octreotide group but 33% of patients achieved disease stabilisation for a mean time of 5.5 months (95% CI, 1.1-9.9). The median time until definitive global health score deterioration (according to QLQ-C30) was 2.3 months (95% CI, 1.4-3.7) in the octreotide and 4 months (95% CI, 2.2-5.7) in the placebo group (p=0.09). There were four objective responses in the placebo group. Octreotide was well tolerated; seven patients reported severe adverse events possibly related to octreotide and there were no cases of haematoma or cholecystitis. CONCLUSIONS In patients with advanced HCC, octreotide has a favourable safety profile but does not improve OS and could have a negative impact on quality of life.

Hepatocellular carcinoma screening in patients with compensated hepatitis C virus (HCV)‐related cirrhosis aware of their HCV status improves survival: A modeling approach

Because of the ongoing debate on the benefit of ultrasound (US) screening for hepatocellular carcinoma (HCC), we assessed the impact of screening on hepatitis C virus (HCV)‐related compensated cirrhosis patients aware of their HCV status. A Markov model simulated progression from HCC diagnosis to death in 700 patients with HCV‐related compensated cirrhosis aware of their HCV status to estimate life expectancy (LE) and cumulative death at 5 years. Five scenarios were compared: S1, no screening; S2, screening by currently existing practices (57% access and effectiveness leading to the diagnosis of 42% at Barcelona Clinic Liver Cancer stage [BCLC‐0/A]); S3, S2 with increased access (97%); S4, S2 with an efficacy of screening close to that achieved in a randomized controlled trial leading to the diagnosis of 87% of patients at stage BCLC‐0/A; S5, S3+S4. The analysis was corrected for lead‐time bias. Currently existing practices of HCC screening increased LE by 11 months and reduced HCC mortality at 5 years by 6% compared to no screening (P = 0.0013). Compared to current screening practices, we found that: 1) increasing the rate of access to screening would increase LE by 7 months and reduce HCC mortality at 5 years by 5% (P = 0.045); 2) optimal screening would increase LE by 14 months and reduce HCC mortality at 5 years by 9% (P = 0.0002); 3) the combination of an increased rate of access and optimal effectiveness of HCC screening would increase LE by 31 months and decrease HCC mortality at 5 years by 20% (P < 0.0001). Conclusion: The present study shows that US screening for HCC in patients with compensated HCV‐related cirrhosis aware of their HCV status improves survival and emphasizes the crucial role of screening effectiveness. (Hepatology 2014;59:1471‐1481)

Phase II Trial of Docetaxel Therapy in Patients with Advanced Hepatocellular Carcinoma

Objectives: We assessed the safety and efficacy of docetaxel, a microtubule inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Methods: HCC patients that were not suitable for local therapy, but who possessed measurable disease, good performance status and adequate organ function were eligible. Docetaxel was administered every 3 weeks at a dose of 100 mg/m2 (or 75 mg/m2 if transaminase levels were between 1.5 and 3.5 times the upper normal limit). Efficacy was assessed radiologically every three cycles of chemotherapy. Results: Fifteen patients were enrolled: 11 males and 4 females; their median age was 64 years (range, 42–72 years). Nine patients had underlying cirrhosis. Four patients had been surgically treated before relapse (liver resection in 3 cases and transplantation in 1), 3 had been treated with arterial chemoembolization and 1 with arterial chemotherapy (doxorubicin). A total of 57 cycles of docetaxel were delivered (median 3, range 1–6). Significant toxicity was observed: mostly grade 3–4 neutropenia and fatigue (6 and 4 patients, respectively). Treatment had to be stopped because of toxicity in 6 patients, all having underlying cirrhosis. An important partial response was obtained in 1 patient, a result that enabled liver transplantation; this patient is still alive after 34 months. Five patients had transient stable disease. Conclusion: When used in this schedule, docetaxel does not appear to be safe and effective enough in patients with advanced HCC and cirrhosis.

Experience of Gemcitabine plus Oxaliplatin Chemotherapy in Patients with Advanced Biliary Tract Carcinoma

Backgrounds: The combination gemcitabine-oxaliplatin (GEMOX) is frequently used in patients with advanced biliary tract carcinoma (BTC). However, this is only based on phase II studies performed in selected patients.We assessed the efficacy and safety of the GEMOX regimen in non-selected patients with advanced BTC. Methods: All consecutive patients with advanced BTC received the GEMOX regimen in a setting outside a study: gemcitabine 1,000 mg/m2 on day 1, and oxaliplatin 100 mg/m2 on day 2, treatment repeated every 2 weeks until progression or unacceptable toxicity. Results: Forty-four patients were enrolled. Efficacy: 1 complete and 6 partial responses (objective response rate = 16.3%), 18 tumour stabilizations (41.9%, disease control rate = 58.1%), median progression-free survival was 5.0 months and median overall survival was 11.0 months. Toxicity: grade 3 neuropathy in 4 patients, grade 3 asthenia in 5 patients. Conclusion: The GEMOX combination was well tolerated, with a modest activity in non-selected patients with advanced BTC. This regimen should be compared to the new standard gemcitabine-cisplatin combination.

Prédisposition héréditaire aux cancers digestifs, mammaires, gynécologiques et gonadiques : état des lieux du syndrome de Peutz-Jeghers

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease due to mutations in the tumor suppressor gene STK11. PJS is characterized by periorificial hyperpigmented macules (lentiginosis) and hamartomatous polyposis. Polyps can be located anywhere in the gastrointestinal tract, but are preferably observed in the small bowel (70-90%), the colon (50%) and the stomach (25%). They tend to be cancerous in a particular sequence hamartoma-dysplasia-cancer. The diagnosis is often made in the first or second decade following the appearance of lentigines or upon the occurrence of complications due to polyps (obstruction, intussusception, occult bleeding responsible for anemia). Furthermore PJS is associated with a significant increase in cancer risk (relative risk of 89% over the life according to the most recent series). Digestive cancers are the more frequent with cumulative incidences of 55% for gastro-intestinal cancer (39% for colorectal cancer, 13% for small bowel cancer and between 11 and 36% for pancreatic cancer, respectively). There is also an increased risk of non digestive cancers. In particular the risk of breast cancer is similar to that of patients carrying deleterious BRCA1 or BRCA2 mutations (cumulative incidence of 45%). Gynecological and gonadal tumors are frequent as well and can be more (adenoma malignum) or less aggressive (ovarian sex cord tumors with annular tubules and testicular tumors with calcified Sertoli cells). Finally the frequency of lung cancer is moderately increased. Recommendations for screening and management based on retrospective series in the literature have led to various strategies. The aim of this paper is to summarize the clinical and molecular diagnostic criteria of PJS as well as recommendations on screening strategies, management and monitoring.

CA-125, but not galectin-3, complements CA 19-9 for discriminating ductal adenocarcinoma versus non-malignant pancreatic diseases

BACKGROUND/OBJECTIVES CA 19-9 is the gold standard biomarker of pancreatic adenocarcinoma despite several weaknesses in particular a high rate of false positives or negatives. CA-125 corresponding to MUC16 and galectin-3, a lectin able to interact with mucin-associated carbohydrates, are tumor-associated proteins. We investigated whether combined measurement of CA 19-9, galectin-3 and CA-125 may help to better discriminate pancreatic adenocarcinoma versus non-malignant pancreatic diseases. METHODS We evaluated by immunohistochemistry the expression of MUC4, MUC16 (CA-125) and galectin-3 in 31 pancreatic adenocarcinomas. We measured CA 19-9, CA-125 and Gal-3 in the serum from patients with pancreatic benign diseases (n = 58) or adenocarcinoma (n = 44). Clinical performance of the 3 biomarkers for cancer diagnosis and prognosis was analyzed. RESULTS By immunohistochemistry, MUC16 and Gal-3 were expressed in 74% and 84% of adenocarcinomas versus 0% and 3.2% in peri-tumoral regions, respectively. At the serum level, CA 19-9 and CA125 were significantly higher in patients with pancreatic adenocarcinoma whereas Gal-3 levels did not differ. The performance of CA 19-9 for cancer detection was higher than those of CA-125 or Gal-3 by ROC analysis. However, CA-125 offers the highest specificity for malignancy (81%) because of an absence of false positives among type 2 diabetic patients. Cancer deaths assessed 6 or 12 months after diagnosis varied according to the initial CA-125 level (p < 0.006). CONCLUSION Gal-3 is not an interesting biomarker for pancreatic adenocarcinoma detection. CA 19-9 alone exhibits the best performance but measuring CA-125 provides complementary information in terms of diagnosis and prognosis.

In which context is physician empathy associated with cancer patient quality of life

OBJECTIVE In cancer settings, physician empathy is not always linked to a better patient emotional quality of life quality of life (eQoL). We tested two possible moderators of the inconsistent link: type of consultation (bad news versus follow-up) and patient emotional skills (emoSkills, i.e., the way patients process emotional information). METHODS In a cross-sectional design, 296 thoracic and digestive tract cancer patients completed validated questionnaires to assess their physician empathy, their emoSkills and eQoL. Moderated multiple regressions were performed. RESULTS In follow-up consultations, physician empathy was associated with a better eQoL in patients with low or average emotional skills. Those with high emotional skills did not benefit from physician empathy. Their eQoL was nonetheless very good. In bad news consultations, the pattern was reversed: only patients with average or high emotional skills benefited from physician empathy. Those with low emotional skills were not sensitive to it and presented a poor eQoL. CONCLUSION Medical empathy is important in all consultations. However, in bad news consultations, patients with low emoSkills are at risk of psychological distress even with an empathetic doctor. PRACTICE IMPLICATIONS Accordingly, physicians should be trained to detect patients with low emoSkills in order to refer them to supportive care.

Prédisposition héréditaire aux cancers digestifs, mammaires, gynécologiques et gonadiques : état des lieux du syndrome de Peutz-JeghersHereditary predisposition to cancers of the digestive tract, breast, gynecological and gonadal: Focus on the Peutz-Jeghers

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease due to mutations in the tumor suppressor gene STK11. PJS is characterized by periorificial hyperpigmented macules (lentiginosis) and hamartomatous polyposis. Polyps can be located anywhere in the gastrointestinal tract, but are preferably observed in the small bowel (70-90%), the colon (50%) and the stomach (25%). They tend to be cancerous in a particular sequence hamartoma-dysplasia-cancer. The diagnosis is often made in the first or second decade following the appearance of lentigines or upon the occurrence of complications due to polyps (obstruction, intussusception, occult bleeding responsible for anemia). Furthermore PJS is associated with a significant increase in cancer risk (relative risk of 89% over the life according to the most recent series). Digestive cancers are the more frequent with cumulative incidences of 55% for gastro-intestinal cancer (39% for colorectal cancer, 13% for small bowel cancer and between 11 and 36% for pancreatic cancer, respectively). There is also an increased risk of non digestive cancers. In particular the risk of breast cancer is similar to that of patients carrying deleterious BRCA1 or BRCA2 mutations (cumulative incidence of 45%). Gynecological and gonadal tumors are frequent as well and can be more (adenoma malignum) or less aggressive (ovarian sex cord tumors with annular tubules and testicular tumors with calcified Sertoli cells). Finally the frequency of lung cancer is moderately increased. Recommendations for screening and management based on retrospective series in the literature have led to various strategies. The aim of this paper is to summarize the clinical and molecular diagnostic criteria of PJS as well as recommendations on screening strategies, management and monitoring.