Continuation versus discontinuation of first-line chemotherapy in patients with metastatic squamous cell oesophageal cancer: A randomised phase II trial (E-DIS).

PURPOSE: The role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC). PATIENTS AND METHODS: E-DIS is a discontinuation trial, aimed at estimating efficacy, quality of life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival. RESULTS: Sixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval [CI]: 37-62%) and 48% (85% CI: 35-60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer [EORTC] core quality of life questionnaire) was 6.6 months (95% CI: 3.3-12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9-6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82-2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18. CONCLUSION: CT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.

Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

Evaluation in usual practice of the bevacizumab-FOLFIRI combination for the first-line treatment of patients with unresectable metastatic colorectal cancer treated in 2006: focus on resected patients and oncogeriatrics: AVASTIN OUEST cohort of the Observatory of Cancer of the Brittany and Pays de la Loire Areas (Observatoire dédié au Cancer Bretagne / Pays de la Loire).

BACKGROUND: In 2006, bevacizumab, a targeted therapy agent was combined with FOLFIRI for the firstline treatment of patients with unresectable metastatic colorectal cancer. METHODS/RESULTS: A study on a homogenous series of 111 patients from the Brittany and Pays de la Loire areas who received bevacizumab-FOLFIRI as first-line treatment in 2006 showed the following results: 51 responses, 29 stabilisations, 21 progressions and 10 cases of toxicity prior to assessment. Median overall survival (OS) was 25.1 months and median progression-free survival was 10.2 months. Surgery secondary to treatment tripled median OS which reached 59.2 months in resected patients versus 18.8 months in unresected patients. Comparison of patients aged more or less than 70 years showed no differences in terms of benefits or risks. CONCLUSION: Bevacizumab-FOLFIRI could be administered as part of a routine care protocol to elderly patients previously evaluated by a geriatric assessment and validated by a multidisciplinary staff.

En 2006, bevacizumab-FOLFIRI représente la thérapie ciblée administrable dès la première ligne chez les patients porteurs d'un cancer colorectal métastatique non opérable. Une série homogène de 111 patients colligés en région Bretagne et Pays de la Loire ayant reçu du bevacizumab- FOLFIRI en première ligne en 2006 révèle les résultats suivants: 51 réponses, 29 stabilités, 21 progressions et 10 toxicités avant évaluation. La médiane de survie globale (OS) est de 25,1 mois et la médiane de survie sans progression (PFS) de 10,2 mois. Dans le cas d'une chirurgie secondaire, l'OS médian triple de 18,8 mois chez les patients non réséqués versus 59,2 mois ceux réséqués. En comparant les sujets âgés de plus et de moins de 70 ans, aucune différence n'a été mise en évidence en termes de bénéfice ou de risque. Bevacizumab-FOLFIRI pourrait être administré en pratique courante chez les personnes âgées sous couvert d'une évaluation gériatrique et d'une approche multidisciplinaire.

High preoperative serum vascular endothelial growth factor levels predict poor clinical outcome after curative resection of gastric cancer.

BACKGROUND: Tumour vascular endothelial growth factor (VEGF) and tumour urokinase-type plasminogen activator (uPA) are prognostic factors in gastric cancer but surgical specimens are required for testing. The prognostic value of preoperative serum VEGF (s-VEGF) and serum uPA (s-uPA) levels was evaluated in patients undergoing potentially curative (R0) gastric cancer resection. METHODS: Concentrations of s-VEGF and s-uPA were measured 97 patients with gastric cancer and 20 controls. Angiogenesis was measured in vitro based on human endothelial cell tube formation. RESULTS: Levels of s-VEGF were higher in patients with gastric cancer than controls (median 288 versus 189 pg/ml respectively; P = 0.002). They were associated with pathological tumour node metastasis (pTNM) stage, pT, pN, lymph node ratio and perineural invasion, and correlated with platelet counts. In multivariable analysis, s-VEGF over 320 pg/ml was the only preoperative predictor of both recurrence and disease-specific survival. Serum from patients with raised s-VEGF levels enhanced angiogenesis in vitro significantly more than serum from those with a s-VEGF level of 320 pg/ml or less. CONCLUSION: High preoperative s-VEGF level is an independent prognostic factor for recurrence and survival after R0 resection of gastric cancer. This may provide a useful guide to decision making regarding neoadjuvant and adjuvant therapies.

Use of positron emission tomography in surgery follow-up of esophageal cancer.

INTRODUCTION: Although the prognosis of patients with esophageal cancer has been improved by extended dissection, the incidence of recurrence still remains high. In esophageal cancer, positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) already demonstrated to be useful for initial staging and monitoring response to therapy. This prospective study compared the ability of FDG-PET and conventional imaging to detect early recurrence of esophageal cancer after initial surgery in asymptomatic patients. MATERIALS AND METHODS: Between October 2003 and September 2006, 41 patients with esophageal cancer were included in a prospective study after initial radical esophagectomy. FDG-PET, thoracoabdominal computed tomography (CT), abdominal ultrasonography, and endoscopy were performed every 6 months after initial treatment. RESULTS AND DISCUSSION: Twenty-three patients had recurrent disease (56%), mostly within the first 6 months after surgery (70%). Despite two false-positive scans due to postoperative changes, FDG-PET was more accurate than CT (91% vs. 81%, p = 0.02) for the detection of recurrence with a sensitivity of 100% (vs. 65%), a specificity of 85% (vs. 91%), and a negative predictive value of 100% on a patient-by-patient-based analysis. For the detection of locoregional recurrence, FDG-PET was more accurate than CT (96.2% vs. 88.9%). FDG-PET was also more accurate than CT for the detection of distant metastases (92.5% vs. 84.9%), especially when involving either bones (100%) or liver (98.1%). A lower sensitivity of FDG-PET (57%) for the early detection of small lung metastases did not affect patient management (accuracy = 92.5%). CONCLUSION: FDG-PET appears to be very useful for the systematic follow-up of asymptomatic patients after esophagectomy with an initial scan performed 6 months after surgery.

Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer.

This dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended doses (RDs) of 5-fluorouracil (5FU), folinic acid and oxaliplatin (FOLFOX) with concomitant radiotherapy in inoperable/metastatic oesophageal squamous cell carcinoma or adenocarcinoma. Patients received three courses of LV5FU2 regimen (folinic acid 200 mg m(-2), bolus 5FU 300-400 mg/m(2), continuous infusion 5FU 400-600 mg m(-2) on days 1 and 2) and escalating doses of oxaliplatin 50 to 100 mg m(-2) on day 1 (FOLFOX). This regimen was repeated every 2 weeks, concomitant to a 50-gray radiotherapy per 5 weeks. Three more cycles were delivered after completion of radiation therapy. Three to six patients were allocated to each of the five dose levels until MTD was reached. Thirty-three patients were enroled and 21 had metastatic disease. Maximum tolerated dose was oxaliplatin 100 mg m(-2), and continuous infusion 5FU was 600 mg m(-2) day(-) (level 5). The most common toxicities were neutropenia, dysphagia and oesophagitis. The RDs were those of FOLFOX-4 regimen (oxaliplatin 85 mg m(-2) and full doses of LV5FU2). The overall response was 48.5%, including 12% complete response. Response rate on primary tumour was 62.9%. This FOLFOX-4 regimen was reasonably well tolerated and effective in inoperable/metastatic oesophageal carcinoma and warrants additional investigation.

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer.

Squamous cell carcinoma of the oesophagus (SCCO) is still a pathology of bad prognosis. Specific therapies are now developed against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, c-kit receptor (CD117), vascular endothelial growth factor (VEGF) and p53 protein. This study was aimed at assessing their expression in a large series of SCCO, as well as their potential therapeutic interest in this pathology. Immunohistochemical expression of these factors was assessed retrospectively in 107 cases of SCCO with primary surgery, as well as their relationships to recurrence, metastasis and overall survival on a long-term follow-up. Human epidermal growth factor receptor 2 and CD117 were expressed in less than 3% of the cases. Epidermal growth factor receptor and p53 were overexpressed in 68.2 and 66.4% of the cases, and VEGF in 38.3%. Epidermal growth factor receptor overexpression was significantly related to vascular invasion (P=0.023). Its diffuse positivity was significantly related in multivariate analysis to higher local recurrence (P=0.006) and lower overall survival (P=0.003), in a subgroup of patients of poor outcome who had received postoperative adjuvant treatment. These results highlight the great potential prognostic and therapeutic interest of evaluating EGFR diffuse positivity in locally advanced SCCO.

[Results of surgical resection of squamous cells carcinoma of the oesophagus with or without preoperative radiochemotherapy: comparative and retrospective study]. / Résultats de la radiochimiothérapie préopératoire dans les cancers épidermoïdes de l'oesophage: étude rétrospective et comparative.

AIM OF THE STUDY: The aim of the study was to assess preoperative radio-chemotherapy for squamous cell carcinoma of the esophagus. MATERIAL AND METHODS: This study was a retrospective comparison between radio-chemotherapy followed by surgical resection (RCPO) and surgery alone. The RCPO group included patients with tumor located in the middle or lower third of the esophagus, staged T2 or T3 tumors without distant metastases by pretherapeutic assessment. These patients were matched with patients who underwent immediate surgery, who constituted the surgical group (CHIR). Both groups were matched for gender, age, tumor localization (middle or lower third), T stage, and surgical procedure. Each group included 77 men and 9 women, 50 tumors of the middle third and 36 of the lower third of the oesophagus, and 19 tumors T2 and 67 T3 ones. RESULTS: Morbidity of both groups was not significantly different. The mortality was 4% in the group CHIR and 12% in the group RCPO (P =0.07). The rate of radical resection (R0) was significantly higher in the RCPO group (74% vs. 51%; P =0.001). The overall 5-year survival rate was 38% after R0 surgery and 11% after R1 or R2 surgery (P <0.0001). After R0 surgery, the 5-year survival rate was 47% in the CHIR group and 32% in the RCPO group (P =0.06). CONCLUSION: Preoperative radiochemotherapy increases the rate of radical surgical resection without significant increase in postoperative morbidity and mortality.

p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer.

This study was undertaken to determine the value of tumour microvessel density (MVD) and the expression of p53 and vascular endothelial growth factor (VEGF) as prognostic markers in patients with gastric cancer operated on for cure. In all, 156 patients with curatively resected gastric cancer constituted the basis of this blinded retrospective evaluation. Patients were treated with either surgery alone (n=53) or surgery plus adjuvant chemotherapy (n=103). Tumour MVD, p53 expression, and VEGF expression were assayed using immunohistochemical techniques. After a mean follow-up of 43 months, 64 (41%) patients had died and 55 (35%) patients developed tumour recurrence. Positive correlations between MVD and both p53 (P=0.005) and VEGF (P=0.005) expression were observed. Both MVD >/=100 (P=0.05) and positive VEGF expression (P<0.02) were associated with shorter disease-free survival, and positive VEGF expression (P=0.01) was also associated with shorter overall survival. Multivariate analysis confirmed that, in addition to the pathological tumour stage, lymph node ratio, the extent of lymphadenectomy and perineural invasion, p53 expression, and VEGF expression were independently associated with both disease-free survival (P<0.0005 and 0.02, respectively) and overall survival (P<0.02 and 0.01, respectively). Finally, patients whose tumours did not show p53 expression had a survival benefit compared to those expressing p53 when treated with adjuvant chemotherapy (P=0.01). This investigation demonstrates that p53 expression and VEGF expression are independent prognostic factors for both disease-free survival and overall survival in patients with curatively resected gastric cancer, and that p53 status may also influence response to chemotherapy.

[Gastroduodenal metastases: an unusual manifestation of lung cancer. Study of two cases and review ot the literature]. / Métastases gastroduodénales: un mode de révélation exceptionnel du cancer du poumon. Etude de deux cas et revue de la littérature.

INTRODUCTION: Diagnosis of gastroduodenal metastases is rare. Primary tumors are essentially melanomas and breast cancer, and exceptionally lung cancer. EXEGESIS: We report two patients who have a diagnosis of gastroduodenal metastases as initial manifestation of lung cancer. In one case, the patient died 3 weeks after the diagnosis. In the other case, chemotherapy was performed and complete response was obtained for the gastric metastasis. After a few months, node recurrence was diagnosed and the patient died 8 months after the diagnosis. CONCLUSION: We review the endoscopic and non-endoscopic literature and discuss the different histological types and therapeutic strategies concerning these unusual manifestations of lung cancer.

[Pyoderma gangrenosum and breast cancer: a new case]. / Pyoderma gangrenosum et cancer du sein: un nouveau cas.

We report here a new case of pyoderma gangrenosum (PG) associated with a breast cancer in a 39-year-old woman. We only found in literature three other reports of this rare entity which seems usually to be associated with monoclonal gammopathy, gastro-intestinal diseases such as Crohn's disease, chronic ulcerative colitis, leukemias or rheumatologic diseases. A commun hapten between of tumor and skin may explain the origin of this inflammatory lesion. In our case, PG could be a paraneoplastic syndrome.

Radiotherapy in head and neck cancer in the elderly: a challenge.

Elderly patients represent the most rapidly growing subgroup of the patient population in France and in the majority of industrialized countries. The effect of age in terms of the prognosis and response to treatment remains unclear. The management strategy (curative versus palliative) for head and neck cancer in the elderly has given vent to divergent opinions and controversies in several respects (the type and quality of treatment, quality of life and economic consequences). This review only focuses on the radiotherapy schedule and head and neck cancers. We compare aged patients with head and neck cancer to younger patients in terms of clinical features, tumor biology, type of treatment, side effects and response. We conclude that if the patient is in a good general condition following a complete evaluation of the cancer, physicians should propose curative treatment with radiotherapy because retrospective trials demonstrate that response in older patients when treated aggressively is comparable to that of younger patients. However, specific trials concerning aged patients with head and neck cancer, quality of life and radiotherapy are warranted.

[Split-course concomitant radiochemotherapy plus surgery vs. surgery alone in squamous cell carcinoma of the esophagus. A non-randomized retrospective study of 184 patients]. / Radiochimiothérapie concomitante en split-course plus chirurgie contre chirurgie seule pour les carcinomes épidermoïdes de l'oesophage. Etude rétrospective non randomisée de 184 patients.

From April 1989 to October 1995, 184 patients with squamous cell carcinomas of the esophagus were treated either with surgery alone (112 patients) or with preoperative concomitant radiochemotherapy (72 patients) (2 courses of 18.5 Gy in 5 fractions, days 1-5 with continuous infusion 5-fluorouracil (5-FU) days 1-5 and cisplatinum day 2, separated by a 2-week interval) followed by surgery, and by 4 more courses of chemotherapy alone for good responders. Twenty-seven of these last 72 patients showed histological complete response at surgery (37.5%). There was no statistically significant difference in overall survival between the 2 groups although there were much more T1 patients (small tumors < or = 5 cm in the previous TNM classifications) and less T3 patients (evidence of spread beyond the esophagus) in the surgery alone group, and nevertheless, median survival was better in the combined treatment group (33.6 months versus 21.8 months). However, considering tumor size, there was a statistically significant difference in median survival in favor of the combined treatment group for all T2 patients (> 5 cm without evidence of spread beyond the esophagus in the previous TNM classification) (48.6 months versus 13.8 months), both for T2N0 and T2N1 patients, but also for T1N1 patients (< or = 5 cm with nodal involvement). For the few T3 patients (evidence of spread beyond the esophagus in the previous TNM classification), there was no statistically significant difference between the 2 groups, but the survival curves seemed to show some advantage in favor of the combined treatment group for T3N1 patients. The sex of the patients and the third of the esophagus involved by the tumor did not seem to be of any influence on survival. On the other hand, patients 70-year-old and older showed a poorer survival than other patients. Finally, significantly less patients died with loco-regional recurrences in the preoperatory radiochemotherapy group (32% versus 48%) than in the group treated by surgery alone.

p53 protein accumulation in oesophageal squamous cell carcinomas and precancerous lesions.

AIMS: To investigate the immunohistochemical expression of p53 protein in oesophageal squamous cell carcinomas and in dysplastic areas of the oesophageal mucosa surrounding the tumours. METHODS: Biopsy samples were obtained from 20 patients with an oesophageal squamous cell carcinoma. Blocks of the tumours and of the surrounding mucosa were immunostained with the monoclonal antibody DO-7. RESULTS: Fourteen of the 20 carcinomas were positive for p53 (70%). The frequency of p53 overexpression increased with the differentiation of the tumour. Nine out of 13 dysplastic specimens were positive for p53 (69%): eight cases with severe dysplasia and one case with moderate dysplasia. No p53 immunostaining was detected in normal oesophageal epithelium. All p53 positive dysplastic specimens were taken from the mucosa adjacent to tumours that were also immunostained. In moderate dysplastic mucosa the p53 positive cells were located in the proliferative basal zone, whereas in severe dysplasia the immunostained cells increased in number and spread to upper cell layers of the epithelium. CONCLUSION: This study supports the hypothesis that TP53 gene is frequently involved in the development of oesophageal squamous cell carcinoma and that p53 protein accumulation is an early event in human oesophageal carcinogenesis.