Christophe Hennequin

Comparison of Two Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Rectal Cancer: Results of the Phase III Trial ACCORD 12/0405-Prodige 2

PURPOSE Neoadjuvant chemoradiotherapy is considered a standard approach for T3-4 M0 rectal cancer. In this situation, we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy plus capecitabine and oxaliplatin. PATIENTS AND METHODS We randomly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m(2) twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m(2) twice daily 5 days per week and oxaliplatin 50 mg/m(2) once weekly (Capox 50). The primary end point was complete sterilization of the operative specimen (ypCR). RESULTS Five hundred ninety-eight patients were randomly assigned to receive Cap 45 (n = 299) or Capox 50 (n = 299). More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group (25 v 1%; P < .001). Surgery was performed in 98% of patients in both groups. There were no differences between groups in the rate of conservative surgery (75%) or postoperative deaths at 60 days (0.3%). The ypCR rate was 13.9% with Cap 45 and 19.2% with Capox 50 (P = .09). When ypCR was combined with yp few residual cells, the rate was respectively 28.9% with Cap 45 and 39.4% with Capox 50 (P = .008). The rate of positive circumferential rectal margins (between 0 and 2 mm) was 19.3% with Cap 45 and 9.9% with Capox 50 (P = .02). CONCLUSION The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation. Cap 50 merits investigation for T3-4 rectal cancers.

Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in ∼10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patients performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

Clinical Outcome of the ACCORD 12/0405 PRODIGE 2 Randomized Trial in Rectal Cancer

PURPOSE The ACCORD 12 trial investigated the value of two different preoperative chemoradiotherapy (CT-RT) regimens in T3-4 Nx M0 resectable rectal cancer. Clinical results are reported after follow-up of 3 years. PATIENTS AND METHODS Between November 2005 and July 2008, a total of 598 patients were randomly assigned to preoperative CT-RT with CAP45 (45-Gy RT for 5 weeks with concurrent capecitabine) or CAPOX50 (50-Gy RT for 5 weeks with concurrent capecitabine and oxaliplatin). Total mesorectal excision was planned 6 weeks after CT-RT. The primary end point was sterilization of the operative specimen, which was achieved in 13.9% versus 19.2% of patients, respectively (P = .09). Clinical results were analyzed for all randomly assigned patients according to the intention-to-treat principle. RESULTS At 3 years, there was no significant difference between CAP45 and CAPOX50 (cumulative incidence of local recurrence, 6.1% v 4.4%; overall survival, 87.6% v 88.3%; disease-free survival, 67.9% v 72.7%). Grade 3 to 4 toxicity was reported in four patients in the CAP45 group and in two patients in the CAPOX50 group. Bowel continence, erectile dysfunction, and social life disturbance were not different between groups. In multivariate analysis, the sterilization rate (Dworak score) of the operative specimen was the main significant prognostic factor (hazard ratio, 0.32; 95% CI, 0.21 to 0.50). CONCLUSION At 3 years, no significant difference in clinical outcome was achieved with the intensified CAPOX regimen. When compared with other recent randomized trials, these results indicate that concurrent administration of oxaliplatin and RT is not recommended.

Chemoradiotherapy in the Management of Locally Advanced Pancreatic Carcinoma: A Qualitative Systematic Review

PURPOSE Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At time of diagnosis, 30% of patients present with a locally advanced unresectable but nonmetastatic pancreatic carcinoma (LAPC). The French program Standards, Options, and Recommendations was promoted to conduct a qualitative systematic review to evaluate the role of radiotherapy in patients with LAPC. METHODS A search to identify eligible studies was undertaken using the MEDLINE database. All phase III randomized trials and systematic reviews evaluating the role of radiotherapy in LAPC were included, together with some noncontrolled studies if no phase III trials were retrieved. The quality and clinical relevance of the studies were evaluated using validated checklists, which allowed associating each result with a level of evidence. RESULTS Twenty-one studies were included, as follows: two meta-analyses, 13 randomized trials, and six nonrandomized trials. Chemoradiotherapy increases overall survival when compared with best supportive care (level of evidence C) or with exclusive radiotherapy (level B1), but is more toxic (level B1). Chemoradiotherapy is not superior to chemotherapy in terms of survival (level B1) and increases toxicity (level A). Recent data favor limited irradiation to the tumor volume (level C). Fluorouracil is still the reference chemotherapy in association with radiotherapy (level B1). Induction chemotherapy before chemoradiotherapy improves survival (level C). CONCLUSION No standard treatment exists, but there are two options for treatment of LAPC; these are gemcitabine-based chemotherapy and chemoradiotherapy. Induction chemotherapy followed by a chemoradiotherapy is a promising strategy for selection of patients without early metastatic/progressing disease.

Induction Chemotherapy and Dose Intensification of the Radiation Boost in Locally Advanced Anal Canal Carcinoma: Final Analysis of the Randomized UNICANCER ACCORD 03 Trial

PURPOSE Concomitant radiochemotherapy (RCT) is the standard for locally advanced anal canal carcinoma (LAACC). Questions regarding the role of induction chemotherapy (ICT) and a higher radiation dose in LAACC are pending. Our trial was designed to determine whether dose escalation of the radiation boost or two cycles of ICT before concomitant RCT lead to an improvement in colostomy-free survival (CFS). PATIENTS AND METHODS Patients with tumors ≥ 40 mm, or < 40 mm and N1-3M0 were randomly assigned to one of four treatment arms: (A) two ICT cycles (fluorouracil 800 mg/m(2)/d intravenous [IV] infusion, days 1 through 4 and 29 to 32; and cisplatin 80 mg/m(2) IV, on days 1 and 29), RCT (45 Gy in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), and standard-dose boost (SD; 15 Gy); (B) two ICT cycles, RCT, and high-dose boost (HD; 20-25 Gy); (C): RCT and SD boost (reference arm); and (D) RCT and HD boost. RESULTS Two hundred eighty-three of 307 patients achieved full treatment. With a median follow-up period of 50 months, the 5-year CFS rates were 69.6%, 82.4%, 77.1%, and 72.7% in arms A, B, C, and D, respectively. Considering the 2 × 2 factorial analysis, the 5-year CFS was 76.5% versus 75.0% (P = .37) in groups A and B versus C and D, respectively (ICT effect), and 73.7% versus 77.8% in groups A and C versus B and D, respectively (RT-dose effect; P = .067). CONCLUSION Using CFS as our main end point, we did not find an advantage for either ICT or HD radiation boost in LAACC. Nevertheless, the results of the most treatment-intense arm B should prompt the design of further intensification studies.

Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature

For several years, azole antifungal drugs have been a treatment option for potentially life-threatening Candida infections. However, azole resistance can occur through various mechanisms such as alterations in ERG11, encoding lanosterol 14alpha-demethylase (CYP51). In this study, we investigated the antifungal susceptibility to fluconazole, itraconazole, and voriconazole of 73 clinical isolates of Candida albicans. Screening for amino acid substitutions in Erg11 was performed on each of the 73 isolates. Twenty isolates displayed a marked decrease in azole susceptibility. Amino acid substitutions were detected in more than two-thirds of the strains. In all, 23 distinct substitutions were identified. Four have not been described previously, among which N136Y and Y447H are suspected to be involved in azole resistance. We suggest that the high genetic polymorphism of ERG11 must be considered in the rationale design of new azole compounds targeting lanosterol 14alpha-demethylase. A review of all Erg11 amino acid polymorphisms described to date is given.

Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy

PURPOSE To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy. METHODS AND PATIENTS This multicenter phase 3 study enrolled patients with positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index ≥70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes. RESULTS T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 [only for medial/central] or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival. CONCLUSIONS In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.

Cancer de la prostate

Mutations “ciblables” dans les cancers de la prostate métastatiques Fruit de la collaboration entre de grandes institutions américaines et européennes, un groupe de chercheurs international (1) a analysé, par séquençage systémique de l’exome entier et du transcriptome, les échantillons de 150 patients atteints d’un cancer de la prostate résistant à la castration métastatique (CPRCm). Près de 90 % des hommes testés présentaient au moins 1 mutation permettant de prédire une réponse ou une résistance à des thérapies connues. Des mutations au niveau du récepteur des androgènes (RA) ont été notées chez près du tiers des patients (63 %). Les autres anomalies génomiques retrouvées le plus fréquemment concernaient les gènes de fusion ETS, TP53 et PTEN (40 à 60 % des cas) avec, par rapport aux cancers de la prostate primaires, un enrichissement des altérations du RA et de TP53. De nouvelles altérations ont été identifiées : PI3K3CA/B, R-spondin , BRAF/RAF1, APC, β-caténine, ZBTB16/PLZF. Mais la découverte sans doute la plus importante est le fait, encore une fois par rapport aux tumeurs primaires, que de nombreux patients (23 %) présentaient des mutations des gènes de la réparation de l’ADN, comme BRCA2, BRCA1 et ATM, ouvrant des perspectives thérapeutiques particulières. Ces patients pourraient répondre à des inhibiteurs de PARP, comme l’olaparib (2) .

Effect of 18F-FDG PET/CT Imaging in Patients With Clinical Stage II and III Breast Cancer

PURPOSE To investigate the potential effect of using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the initial assessment of patients with clinical Stage II or III breast cancer. METHODS AND MATERIALS During 14 consecutive months, 39 patients (40 tumors) who presented with Stage II or III breast cancer on the basis of a routine extension assessment were prospectively included in this study. PET/CT was performed in addition to the initial assessment. RESULTS In 3 cases, PET/CT showed extra-axillary lymph node involvement that had not been demonstrated with conventional techniques. Two of these patients had hypermetabolic lymph nodes in the subpectoral and infraclavicular regions, and the third had a hypermetabolic internal mammary node. PET/CT showed distant uptake in 4 women. Of these 4 women, 1 had pleural involvement and 3 had bone metastasis. Overall, of the 39 women, the PET/CT results modified the initial stage in 7 (18%). The modified staging altered the treatment plan for 5 patients (13%). It led to radiotherapy in 4 patients (bone metastasis, pleural lesion, subpectoral lymph nodes, and internal mammary nodes) and excision of, and radiotherapy to, the infraclavicular lymph nodes in 1 patient. CONCLUSIONS PET/CT can provide information on extra-axillary lymph node involvement and can uncover occult distant metastases in a significant percentage of patients. Therefore, initial PET/CT could enable better treatment planning for patients with Stage II and III breast cancer.

anal Carcinomas in Hiv-positive Patients: High-dose Chemoradiotherapy Is Feasible in the Era of Highly Active Antiretroviral Therapy

BACKGROUNDAnal carcinoma, a common disease in HIV-positive patients, is usually treated with chemoradiotherapy. Generally tolerance was poor before the availability of highly active antiretroviral therapies. We report our experience of treating anal carcinoma in the era of new antiviral drugs.PATIENTS AND METHODSBetween 1997 and 2001, nine men on highly active antiretroviral therapies with good immune status before chemoradiotherapy received concomitant chemoradiotherapy consisting of 5-fluorouracil and cisplatinum, and high-dose radiotherapy (60–70 Gy) for anal carcinoma. Six cancers were Stage I, two were Stage II, and one was Stage III. CD4+ cell counts were <200/ml for four patients, between 200/ml and 500/ml for four, and >500/ml for one.RESULTSAll patients received the planned dose of radiation (≥60 Gy). The chemotherapy dose was reduced 25 percent in six patients. Overall treatment time was 58 days. Grade 3 hematologic or skin toxicity occurred in four patients. No association was observed between high-grade toxicity and CD4+ cell count. None of the patients developed opportunistic infections during follow-up. Eight patients were disease-free after a median follow-up of 33 months. Among them, four had no or minor anal function impairment at the last follow-up visit. One patient with T4N2 disease relapsed locally one year after treatment and underwent salvage abdominoperineal excision.CONCLUSIONHigh-dose chemoradiotherapy for anal carcinomas is feasible with low toxicity in HIV-positive patients treated with highly active antiretroviral therapies. Local control is similar to that obtained for HIV-negative patients.