Has adherence to treatment guidelines for mid/low rectal cancer affected the management of patients? A monocentric study of 604 consecutive patients.

INTRODUCTION: In 2006 under the supervision of the French health authorities (HAS), recommendations for clinical practice (RCP) in the management of rectal cancers were first published. The primary objective of this study was to assess the impact of these guidelines on multidisciplinary management in terms of therapeutic strategies based on disease staging and quality indicators for surgical excision. Secondarily, we assessed the impact of the RCPs on postoperative and oncological outcomes. METHODS: All consecutive patients having undergone curative surgical excision for middle and low (subperitoneal) rectal cancer from 1995 to 2017 in the university hospital of Caen were included in accordance with the relevant French guidelines. They were divided into two groups: before (Gr1) and after (Gr2) 2006. For each group, a chart review was conducted on demographic variables, preoperative rectal tumor features, disease severity variables and quality of surgery variables. Postoperative and oncological outcomes were likewise assessed and compared between the two groups. RESULTS: Six hundred and four patients were included (Gr1, n=266; Gr2, n=338). Compliance with French guidelines significantly improved (i) use of magnetic resonance imaging (P<0.0001) and CT-scan (P<0.0001)]; (ii) organization of multidisciplinary tumor boards (P<0.0001) leading to suitable neo-adjuvant treatment plan classification (P<0.0001). Consequently, compliance improved widespread total mesorectal excision (P<0.0001), sphincter-sparing surgery (P=0,0005), and completeness of curative resection in the specimen (P<0.0001). Although postoperative 90-day mortality was similar, overall postoperative morbidity significantly increased in Gr2 (P<0.0001). Overall (P=0.0005) and disease-free survival (P=0.0016) of patients in Gr2 were significantly prolonged and correlated with a significant reduction in local and distant recurrences. CONCLUSION: Compliance with the relevant French guidelines improved the quality of multidisciplinary management of patients undergoing curative surgery for subperitoneal rectal cancer. However, further progress is still needed to render accession to the recommendations more comprehensive.

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.

Is pathological complete response after a trimodality therapy, a predictive factor of long-term survival in locally-advanced esophageal cancer? Results of a retrospective monocentric study.

OBJECTIVE: To evaluate long-term (5- and 10-year) survival and recurrence rates on the basis of the pathological complete response (pCR) in the specimens of patients with esophageal carcinoma, treated with trimodality therapy. METHODS: Between 1993 and 2014, all consecutives patients with esophageal locally-advanced non-metastatic squamous cell carcinoma (SCC) or adenocarcinoma (ADC) who received trimodality therapy were reviewed. According to histopathological analysis, patients were divided in two groups with pCR and with pathological residual tumor (pRT). The primary endpoint was overall survival (OS). The secondary endpoints included the disease-free survival (DFS), the recurrence rate, and the predictive factors of overall survival and recurrence. RESULTS: One hundred and three patients were included: 49 patients with pCR and 54 patients with pRT. The median OS was significantly longer in pCR group than in pRT group (132±22.3 vs. 25.5±4 months), with both 5- and 10-years OS rates of 75.2% vs. 29.1%, and 51.1% vs. 13.6%, respectively (P<0.001). Also, pRT, major postoperative complications (Dindo-Clavien grade>IIIb) and recurrence were the 3 independent predictive factors for worse OS. CONCLUSIONS: Patients with locally-advanced oesophageal carcinoma, who responded to trimodality therapy with a pCR, could be achieved a 10-year survival rate of 51%.

Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer.

BACKGROUND: A recent prospective randomised trial did not reveal significant differences in median progression-free survival between two chemoradiotherapy (CRT) regimens for inoperable non-metastatic oesophageal cancer patients. This secondary analysis aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, dysphagia, fatigue and pain and to evaluate whether baseline HRQOL domains can predict overall survival. PATIENTS AND METHODS: A total of 267 patients were randomly assigned to receive with 50 Gy of radiotherapy in 25 fractions six cycles of FOLFOX or four cycles of fluorouracil and cisplatin on day 1. HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18). RESULTS: Both groups showed high baseline compliance. Subsequently, compliance reduced to 41% at the 6-month follow-up. Baseline HRQOL scores showed no statistical differences between treatment arms. During treatment, both groups exhibited lower physical and social functioning and increased fatigue and dyspnoea, although dysphagia moderately improved in the fluorouracil-cisplatin arm only (p = 0.047). During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens. Linear mixed model exhibited a treatment-by-time interaction effect for dysphagia (p = 0.017) with a greater decrease in dysphagia in the fluorouracil-cisplatin group. Time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. However, time until definitive deterioration was significantly longer for the fluorouracil and cisplatin arm compared with FOLFOX for appetite loss (p = 0.002), QLQ-OES-18 pain (p = 0.008), trouble swallowing saliva (p = 0.011) and trouble talking (p = 0.020). CONCLUSION: Analyses of HRQOL scores revealed no statistically significant differences between patients with inoperable non-metastatic oesophageal cancer treated by FOLFOX versus those treated with a fluorouracil-cisplatin regimen as part of definitive CRT.

Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial.

BACKGROUND: This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy. METHODS: In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Phase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%). CONCLUSION: The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).

Clinical value of circulating endothelial cell levels in metastatic colorectal cancer patients treated with first-line chemotherapy and bevacizumab.

BACKGROUND: We investigated whether circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: In a substudy of the randomized phase II FNCLCC ACCORD 13/0503 trial, CECs (CD45- CD31+ CD146+ 7-amino-actinomycin- cells) were enumerated in 99 patients by four-color flow cytometry at baseline and after one cycle of treatment. We correlated CEC levels with objective response rate (ORR), 6-month progression-free survival (PFS) rate (primary end point of the trial), PFS, and overall survival (OS). Multivariate analyses of potential prognostic factors, including CEC counts and Köhne score, were carried out. RESULTS: By multivariate analysis, high baseline CEC levels were the only independent prognostic factor for 6-month PFS rate (P < 0.01) and were independently associated with worse PFS (P = 0.02). High CEC levels after one cycle were the only independent prognostic factor for ORR (P = 0.03). High CEC levels at both time points independently predicted worse ORR (P = 0.025), 6-month PFS rate (P = 0.007), and PFS (P = 0.02). Köhne score was the only variable associated with OS. CONCLUSION: CEC levels at baseline and after one treatment cycle may independently predict ORR and PFS in mCRC patients starting first-line bevacizumab and chemotherapy.

Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy.

The predictive value of KRAS mutation in metastatic colorectal cancer (MCRC) patients treated with cetuximab plus chemotherapy has recently been suggested. In our study, 59 patients with a chemotherapy-refractory MCRC treated with cetuximab plus chemotherapy were included and clinical response was evaluated according to response evaluation criteria in solid tumours (RECIST). Tumours were screened for KRAS mutations using first direct sequencing, then two sensitive methods based on SNaPshot and PCR-ligase chain reaction (LCR) assays. Clinical response was evaluated according to gene mutations using the Fisher exact test. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. A KRAS mutation was detected in 22 out of 59 tumours and, in six cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. Remarkably, no KRAS mutation was found in the 12 patients with clinical response. KRAS mutation was associated with disease progression (P=0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, P=0.015). Our study confirms that KRAS mutation is highly predictive of a non-response to cetuximab plus chemotherapy in MCRC and highlights the need to use sensitive molecular methods, such as SNaPshot or PCR-LCR assays, to ensure an efficient mutation detection.

Induction cisplatin-irinotecan followed by concurrent cisplatin-irinotecan and radiotherapy without surgery in oesophageal cancer: multicenter phase II FFCD trial.

A recent phase I study showed that weekly cisplatin, irinotecan and concurrent radiotherapy can be administered with moderate toxicity in patients with oesophageal cancer. Patients with no prior treatment and oesophageal cancer stage I to III, performance status <3, caloric intake >1,500 kcal day(-1) were included. Chemotherapy, with cisplatin 30 mg m(-2) and irinotecan 60 mg m(-2), was administered at days 1, 8, 22, 29, and concurrently with radiotherapy at days 43, 50, 64 and 71. Radiotherapy was delivered with 50 or 50.4 Gy in 25 fractions/5 weeks. Forty-three patients were included, 10 stage I, 19 stage II and 14 stage III. Mean age was 59.2 years (range 44-79). A total of 30 out of 43 (69.8%) patients underwent all planned treatment. During induction chemotherapy, 14 severe toxicities of grade 3 or 4 in 10 patients (23.3%) were reported with 57.1% due to haematoxicity. During chemoradiotherapy, 31 severe toxicities of grade 3 or 4 with 64.5% due to haematotoxicity were reported in 18 patients. One toxic death occurred (diarrhoea grade 4). The complete clinical response rate was 58.1% (95% CI: 43.4-72.8%). Overall survival rate at 1 and 2 years was 62.8%, (95% CI, 58.3-77.3%) and 27.9% (95% CI, 13.4-41.3%), respectively. In conclusion, cisplatin-irinotecan-radiotherapy is an active and well-tolerated regimen feasible in out-patients.

Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature.

OBJECTIVE: Liver adenomatosis (LA) is a rare disease originally defined by Flejou et al in 1985 from a series of 13 cases. In 1998, 38 cases were available for analysis, including eight personal cases. The aim of this study was to review and reappraise the characteristics of this rare liver disease and to discuss diagnosis and therapeutic options. BACKGROUND: LA was defined as the presence of >10 adenomas in an otherwise normal parenchyma. Neither female predominance nor a relation with estrogen/progesterone intake has been noted. Natural progression is poorly known. METHODS: The clinical presentation, evolution, histologic characteristics, and therapeutic options and results were analyzed based on a personal series of eight new cases and an updated review of the literature. RESULTS: From a diagnostic standpoint, two forms of liver adenomatosis with different presentations and evolution can be defined: a massive form and a multifocal form. The role of estrogen and progesterone is reevaluated. The risks of hemorrhage and malignant transformation are of major concern. In the authors' series, liver transplantation was indicated in two young women with the massive, aggressive form, and good results were obtained. CONCLUSION: Liver adenomatosis is a rare disease, more common in women, where outcome and evolution vary and are exacerbated by estrogen intake. Most often, conservative surgery is indicated. Liver transplantation is indicated only in highly symptomatic and aggressive forms of the disease.