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Purpose: A joint modeling approach is recommended for analysis of longitudinal health-related quality of life (HRQoL) data in the presence of potentially informative dropouts. However, the linear mixed model modeling the longitudinal HRQoL outcome in a joint model often assumes a linear trajectory over time, an oversimplification that can lead to incorrect results. Our aim was to demonstrate that a more flexible model gives more reliable and complete results without complicating their interpretation., Methods: Five dimensions of HRQoL in patients with esophageal cancer from the randomized clinical trial PRODIGE 5/ACCORD 17 were analyzed. Joint models assuming linear or spline-based HRQoL trajectories were applied and compared in terms of interpretation of results, graphical representation, and goodness of fit., Results: Spline-based models allowed arm-by-time interaction effects to be highlighted and led to a more precise and consistent representation of the HRQoL over time; this was supported by the martingale residuals and the Akaike information criterion., Conclusion: Linear relationships between continuous outcomes (such as HRQoL scores) and time are usually the default choice. However, the functional form turns out to be important by affecting both the validity of the model and the statistical significance., Trial Registration: This study is registered with ClinicalTrials.gov, number NCT00861094., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Health-related quality of life (HRQoL) has become a major endpoint to assess the clinical benefit of new therapeutic strategies in oncology clinical trials. Typically, HRQoL outcomes are analyzed using linear mixed models (LMMs). However, longitudinal analysis of HRQoL in the presence of missing data remains complex and unstandardized. Our objective was to compare the modeling alternatives that account for informative dropout., Methods: We investigated three alternative methods-the selection model (SM), pattern-mixture model (PMM), and shared-parameters model (SPM)-in relation to the LMM. We first compared them on the basis of methodological arguments highlighting their advantages and drawbacks. Then, we applied them to data from a randomized clinical trial that included 267 patients with advanced esophageal cancer for the analysis of four HRQoL dimensions evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire., Results: We highlighted differences in terms of outputs, interpretation, and underlying modeling assumptions; this methodological comparison could guide the choice of method according to the context. In the application, none of the four models detected a significant difference between the two treatment arms. The estimated effect of time on HRQoL varied according to the method: for all analyzed dimensions, the PMM estimated an effect that contrasted with those estimated by the SM and SPM; the LMM estimated effects were confirmed by the SM (on two of four HRQoL dimensions) and SPM (on three of four HRQoL dimensions)., Conclusions: The PMM, SM, or SPM should be used to confirm or invalidate the results of LMM analysis when informative dropout is suspected. Of these three alternative methods, the SPM appears to be the most interesting from both theoretical and practical viewpoints., Trial Registration: This study is registered with ClinicalTrials.gov , number NCT00861094 .

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 (HR CT-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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Two randomised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma, chemoradiation alone leads to the same overall survival (OS) as chemoradiation followed by surgery. One of these trials, FFCD 9102, randomised only fit, compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery. In the present analysis, the outcome in the patients not eligible for randomisation was calculated to determine if attempt of surgery should be recommended., Methods: Eligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer. After initial chemoradiation, patients with no clinical response, or with contraindication to follow any attributed treatment, were not randomised. OS was studied first in the whole population of not randomised patients, and then specifically in clinical non-responders. The impact of surgery on OS was studied in these two populations., Findings: Of the 451 registered patients in the trial, 192 were not randomised. Among them, 111 were clinical non-responders. Median OS was significantly shorter for non-randomised patients (11.5 months) than for randomised patients (18.9 months; p=0.0024). However, for the 112 non-randomised patients who underwent surgery, median OS was not different from that in randomised patients: 17.3 versus 18.9 months (p=0.58). Concerning clinical non-responders, median OS was longer for those who underwent surgery compared to non-operated patients: 17.0 versus 5.5 months (hazard ratio (HR)=0.39 [0.25-0.61]; p<0.0001), and again was not different from that in responding, randomised patients (p=0.40)., Interpretation: In patients with locally advanced thoracic oesophageal cancer, overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation. Surgery should therefore be considered in those patients who are still operable., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer., Methods: We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I-IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0-2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), bolus fluorouracil 400 mg/m(2), and infusional fluorouracil 1600 mg/m(2) (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m(2) per day for 4 days and cisplatin 75 mg/m(2) on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094., Findings: 134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9-36·4). Median progression-free survival was 9·7 months (95% CI 8·1-14·5) in the FOLFOX group and 9·4 months (8·1-10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70-1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil-cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin-fluorouracil group, p<0·0001), sensory neuropathy (24 [18%] vs one [1%], p<0·0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0·002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0·007), mucositis (35 [27%] vs 41 [32%], p=0·011), and alopecia (two [2%] vs 12 [9%], p=0·005) were more common in the fluorouracil and cisplatin group., Interpretation: Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery., Funding: UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: After curative resection, the prognosis of gastroesophageal adenocarcinoma is poor. This phase III trial was designed to evaluate the benefit in overall survival (OS) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma., Patients and Methods: Overall, 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111). Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m(2)) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m(2)/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. The primary end point was OS., Results: Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%; hazard ratio [HR] for death: 0.69; 95% CI, 0.50 to 0.95; P = .02); and a better disease-free survival (5-year rate: 34% v 19%; HR, 0.65; 95% CI, 0.48 to 0.89; P = .003). In the multivariable analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = .01) and stomach tumor localization (P < .01). Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%; P = .04). Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia) but postoperative morbidity was similar in the two groups., Conclusion: In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS.

Background: Concurrent chemoradiotherapy is a valuable treatment option for localised oesophageal cancer (EC), but improvement is still needed. A randomised phase II trial was initiated to assess the feasibility and efficacy in terms of the endoscopic complete response rate (ECRR) of radiotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) or cisplatin/fluorouracil., Methods: Patients with unresectable EC (any T, any N, M0 or M1a), or medically unfit for surgery, were randomly assigned to receive either six cycles (three concomitant and three post-radiotherapy) of FOLFOX4 (arm A) or four cycles (two concomitant and two post-radiotherapy) of cisplatin/fluorouracil (arm B) along with radiotherapy 50 Gy in both arms. Responses were reviewed by independent experts., Results: A total of 97 patients were randomised (arm A/B, 53/44) and 95 were assessable. The majority had squamous cell carcinoma (82%; arm A/B, 42/38). Chemoradiotherapy was completed in 74 and 66%. The ECRR was 45 and 29% in arms A and B, respectively. Median times to progression were 15.2 and 9.2 months and the median overall survival was 22.7 and 15.1 months in arms A and B, respectively., Conclusion: Chemoradiotherapy with FOLFOX4, a well-tolerated and convenient combination with promising efficacy, is now being tested in a phase III trial.

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.

Background: No multivariate study has assessed the independent prognostic role of endoscopic ultrasonography (EUS) in esophageal cancer, even when considering computed tomography (CT)., Objective: To evaluate the prognostic value of EUS in esophageal cancer before exclusive or preoperative radiochemotherapy., Methods: From 1993 to 1999, the FFCD 9102 study enrolled 444 patients who had cancer of the thoracic esophagus, stages T3-4, N0-1 and M0 on CT. The patients received two sessions of chemotherapy in addition to radiotherapy. The 259 patients with objective response and no contraindications for further treatment were randomized to undergo surgery or to continue with radiochemotherapy. EUS was performed in 174 patients enrolled in the trial (mean age: 59 years). Tumor characteristics and lymph node status were prospectively recorded. A Cox statistical model was used to identify any predictive prognostic factors among the clinical, EUS and CT data., Results: In the multivariate analysis, three factors were associated with a poor prognosis: inability to ingest solid food (OR: 1.98; P=0.0008); more than three neoplastic subdiaphragmatic lymph nodes (LN) on EUS (OR: 2.41; P<0.0045) and age>65 (OR: 1.53; P<0.056). Their prognostic value persisted after adjustment for type of treatment given. Two- and five- year survival rates were 21.5 and 10.5%, respectively, in the presence of three neoplastic subdiaphragmatic LN, and 43 and 30%, respectively, in all other cases., Conclusion: Degree of dysphagia, age and presence of neoplastic subdiaphragmatic LN on EUS were independently predictive of the prognosis for locally advanced esophageal cancer. EUS results should be taken into account in future trials.

Aim: To combine and test the EORTC questionnaires for assessing quality of life (HRQL) for oesophageal (QLQ-OES18) and stomach cancer (QLQ-STO22), into a single questionnaire for tumours of the oesophagus, oesophago-gastric junction or stomach., Methods: The QLQ-OES18, QLQ-STO22 and seven modified items were administered to 300 patients with oesophageal (n=148), junctional (n=66), or gastric cancer (n=86). Semi-structured interviews assessed item and scale preference and multi-trait scaling analyses confirmed the scale structure of the new module (QLQ-OG25). This was further tested for validity., Results: The QLQ-OG25 has six scales, dysphagia, eating restrictions, reflux, odynophagia, pain and anxiety. Scales have good reliability (alpha range 0.67-0.87) and they distinguish between tumour sites and disease stage. Scales do not correlate highly with scores from the core questionnaire, thus indicating that the module was addressing separate HRQL aspects., Conclusion: The QLQ-OG25 is recommended to supplement the EORTC QLQ-C30 when assessing HRQL in patients with oesophageal, junctional or gastric cancer.

Purpose: Uncontrolled studies suggest that chemoradiation has similar efficacy as surgery for esophageal cancer. Therefore, a randomized trial was carried out to compare, in responders only, chemoradiation alone with chemoradiation followed by surgery in patients with locally advanced tumors., Patients and Methods: Eligible patients had operable T3N0-1M0 thoracic esophageal cancer. Patients received two cycles of fluorouracil (FU) and cisplatin (days 1 to 5 and 22 to 26) and either conventional (46 Gy in 4.5 weeks) or split-course (15 Gy, days 1 to 5 and 22 to 26) concomitant radiotherapy. Patients with response and no contraindication to either treatment were randomly assigned to surgery (arm A) or continuation of chemoradiation (arm B; three cycles of FU/cisplatin and either conventional [20 Gy] or split-course [15 Gy] radiotherapy). Chemoradiation was considered equivalent to surgery if the difference in 2-year survival rate was less than 10%., Results: Of 444 eligible patients, 259 were randomly assigned; 230 patients (88.8%) had epidermoid cancer, and 29 (11.2%) had glandular carcinoma. Two-year survival rate was 34% in arm A versus 40% in arm B (hazard ratio for arm B v arm A = 0.90; adjusted P = .44). Median survival time was 17.7 months in arm A compared with 19.3 months in arm B. Two-year local control rate was 66.4% in arm A compared with 57.0% in arm B, and stents were less required in the surgery arm (5% in arm A v 32% in arm B; P < .001). The 3-month mortality rate was 9.3% in arm A compared with 0.8% in arm B (P = .002). Cumulative hospital stay was 68 days in arm A compared with 52 days in arm B (P = .02)., Conclusion: Our data suggest that, in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation.

Background: The aim of the study was to compare the longitudinal quality of life (QoL) between chemoradiation with or without surgery in patients with locally advanced squamous resectable esophageal cancer included in a randomized multicenter phase III trial (FFCD 9102)., Materials and Methods: All patients with locally advanced resectable (T3-4 N0-1 M0) epidermoid or glandular esophageal cancer (n = 451) received induction chemoradiation. Responders (n = 259) were randomized between surgery (arm A) and continuation of chemoradiation (arm B). The Spitzer QoL Index was scored (0-10) at inclusion and at each follow-up, every 3 months during 2 years. QoL at baseline and longitudinal changes were respectively compared with univariate ANOVA and mixed-model analysis of variance for repeated measurements. The time interval between the follow-up was assessed and the same analyses were performed among survivors with 2 years of follow-up., Results: The squamous histology was predominant in both arms. The mean QoL score decreased between baseline and the first follow-up and between the first and the second follow-ups. QoL scores at the first follow-up were comparatively worse in arm A than in arm B (7.52 versus 8.45, P < 0.01), whereas the longitudinal QoL study showed no difference between treatments (adjusted P = 0.26). Furthermore, the longitudinal QoL was not different (adjusted P = 0.23) among survivors with 2 years of follow-up., Conclusions: Among patients responding to induction chemoradiation, surgery and continuation of chemoradiation had the same impact on QoL in patients with locally advanced, resectable esophageal cancer although a significantly greater decrease in the Spitzer Index was observed in the postoperative period.

An accurate assessment of health-related quality of life (QoL) in patients with oesophageal or gastric cancer (OGC) is essential to inform clinical decisions by providing insights into patients' experiences of the impact of the disease and its treatments on physical, social and emotional health. Robust QoL questionnaires have been developed and validated in the past decade to measure the QoL of OGC patients. Baseline QoL variables are also prognostic for survival in patients with oesophageal cancer or metastatic gastric cancer. This article reviews the impact of surgery and reconstructive techniques, as well as of adjuvant and palliative treatments on the QoL of patients with OGC., (Copyright 2006 S. Karger AG, Basel.)

Quality of life (QOL) assessment requires clinically relevant questionnaires that yield accurate data. This study defined measurement properties and the clinical validity of the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire module to assess QOL in oesophageal cancer. The oesophageal module the QLQ-OES24 and core questionnaire, the Quality of Life-Core 30 questionnaire (QLQ-C30) was administered patients undergoing treatment with curative (n=267) or palliative intent (n=224) and second assessments performed 3 months or 3 weeks later respectively. Psychometric tests examined scales and measurement properties of the module. Questionnaires were well accepted, compliance rates were high and less than 2% of items had missing data. Multi-trait scaling analyses and face validity refined the module to four scales and six single items (QLQ-OES18). Selective scales distinguished between clinically distinct groups of patients and demonstrated treatment-induced changes over time. The EORTC QLQ-OES18 demonstrates good psychometric and clinical validity. It is recommended for use with the core questionnaire, the QLQ-C30, to assess QOL in patients with oesophageal cancer.

Background: Vinorelbine and cisplatin are active against squamous cell oesophageal carcinoma. The purpose of this phase II study was to evaluate the efficacy and safety of vinorelbine plus cisplatin in previously untreated patients with metastatic squamous cell oesophageal carcinoma and to estimate the progression-free survival, overall survival and quality of life (QoL) of the patient population., Patients and Methods: Seventy-one eligible patients were entered into a study of vinorelbine 25 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1, every 3 weeks. Degree of dysphagia relief was monitored and QoL was measured using the EORTC QLQ-C30., Results: All eligible patients were assessed for response and 24 achieved a confirmed partial response (33.8%; 95% confidence interval 23-46); the median duration of response was 6.8 months, progression-free survival was 3.6 months and median survival of the whole group was 6.8 months. Toxicity was mainly related to neutropenia (grade 3/4 in 41% of patients). At cycle 2, 43% of the patients reported at least a moderate improvement in global health status/QoL and 25% experienced a large improvement., Conclusions: Vinorelbine plus cisplatin represents a well-tolerated active palliative regimen for patients with advanced squamous cell carcinoma of the oesophagus. This combination may offer a better therapeutic index than cisplatin-5-fluorouracil.

Objectives: Concomitant radiochemotherapy improves survival from inoperable esophageal cancer compared to radiotherapy alone. Several regimens of radiotherapy (standard or concentrated split course radiotherapy) are used, however the optimum protocol remains to be determined. The aim of this study was to analyze the efficacy and tolerance of concentrated concomitant split course radiochemotherapy. Prognostic factors as well as those positively influencing complete response were also studied., Methods: This multicentric phase II trial looked at patients with histologically proven, inoperable, squamous cell esophageal carcinoma without metastases or invasion of the tracheobronchial mucosa. Treatment included 3 cycles of chemotherapy by 5-FU continuous infusion (800 mg/m2.d D1-D5, D22-D26, D43-D47), cisplatin (70 mg/m2 D2, D23, D44) and radiotherapy 15 Gy/5d (D1-D5, D22-26, D43-D47). Efficacy was analyzed by endoscopy, biopsy and computerized axial tomography during the 12th week of treatment., Results: The trial included 122 patients from 21 centers (110 M and 12F, mean age 63.1 +/- 8.6 years, range 40-78). In accordance with the TNM-UICC classification (1978), 8 patients were classified stage I (T1 N0), 13 stage II (T2 N0), 100 stage III (T3 and/or N1) and stage was unknown in 1 patient. Median follow-up was 63 months. Treatment was complete in half of the patients. 5 premature deaths (4.1%) were recorded over the treatment period, one of which was directly linked to the toxicity of the treatment. 16% of patients showed at least one severe side-effect. 117 patients received all 3 cycles of the treatment, 88 of them without delay, and all were evaluated. 58 (47.5% of the patients included) showed a complete response with a negative biopsy, 36 (29.5%) showed a partial response, 13 (10.7%) were stable and 10 (8.2%) showed progressive disease. The median duration of complete responses was 11.5 months. Symptomatically, dysphagia improved in 80% of the cases, performance status in 40%, and weight gain was observed in 30% of the patients with weight loss. At evaluation, oral feeding was impossible in 4 patients only and possible in 113 patients; however, endoscopic treatment of the dysphagia remained necessary in 28 patients. Median survival in the 122 patients included was 13.0 +/- 1.6 months and survival rates were 52.9, 29.8 and 12.1% at 1, 2 and 5 years, respectively. Three pretherapeutic prognostic factors influenced survival in a multivariate analysis: initial severe dysphagia (risk of premature death increased 3-fold in the first year), circumferential extension and the differentiated nature of the tumor (risk of death doubled regardless of the time delay). Factors influencing a complete clinical response were an early tumor stage, a poorly differenciated tumor in patients older than 65, and no circumferential extension. The risk of recurrence was 54.8% at 1 year in the 58 patients with complete remission. Complete circumferential extension and a well or moderately differentiated tumour influenced recurrence., Conclusion: This trial confirms the efficacy and good tolerance of concentrated split course radiochemotherapy in patients with inoperable esophageal cancer with a 5-year survival rate of 12%. This reinforces the need for a comparative trial (split course irradiation vs standard irradiation) such as the one currently being conducted in France.

Introduction: Despite improvements in surgical techniques and perioperative mortality, only slight improvements in the 5-year survival of patients with esophageal cancer have been observed in the last 20 years. Many patients with apparently localized cancer will have recurrences or metastatic disease despite surgery with curative resection. Consequently, multimodal therapies, including chemotherapy and radiotherapy, were introduced. This review outlines and critically analyzes current non-surgical treatments, including palliative care., Current Knowledge and Key Points: Esophageal cancers appear to be chemosensitive but the median duration of response is short and toxicity consistent, especially in metastatic disease. Consequently, palliative chemotherapy should be offered preferably within a clinical trial. Chemotherapy as the only adjuvant treatment cannot be recommended outside clinical trials. Radiotherapy alone as a curative treatment has been proven to be inferior to chemoradiotherapy in inoperable tumors. Some data support the use of preoperative chemoradiotherapy, but randomized trials are conflicting. A pathological complete response has been identified as a favorable prognostic factor for survival. Self-expanding esophageal metal stents are a simple and effective palliative treatment of malignant dysphagia and can be considered as the reference treatment in patients with obstruction of the lower esophagus or with fistula., Future Prospects and Projects: Taxanes should be evaluated in randomized studies using chemotherapy or chemo-radiotherapy. Progress in radiotherapy, such as accelerated fractionation, greater radiation dose, and the addition of brachytherapy, will increase locoregional control and probably survival. The role of secondary surgery in patients responding to chemoradiotherapy still needs to be answered.

Objectives: The aim of this study was to analyze the efficacy and tolerance of preoperative radiochemotherapy in esophageal squamous cell carcinoma. Patterns of recurrence and prognostic factors were also studied., Patients and Methods: This multicentric phase II trial included patients deemed operable. Preoperative treatment associated 5-FU 800 mg/m2/d by continuous infusion, cisplatin 20 mg/m2/d and radiotherapy 3 Gy/d D 1-5 and D 22-26. Resection was planned 50 to 60 days after the beginning of therapy., Results: Seventeen centers accrued 96 patients, mean age 55.4 years. According to UICC 1978 classification: stage I 13%, stage II 53% and stage III 30%. Mean follow-up was 73 months. Pre-operative treatment was delivered at full dose in half of the patients. Ten percent of the patients did not receive the second cycle. Toxicity reached grade 3 in 23% and grade 4 in 7% of the patients. Two preoperative deaths occurred. Curative resection was performed in 82% of the patients. Operative mortality was 9%. tumors were sterilized on the operative specimen in 20% of the patients and microscopic remnants were observed in 13%. Preoperative clinical work-up overestimated histologic response in 10% of the cases underestimated it in 29%. After 2 years, a recurrence was observed in 56% of the patients: loco-regional in 30%, metastases in 19% and both in 7%. Median survival was 17 months and survival rates were 58% at 1 year and 25% at 5 years. Four prognostic factors influenced survival in multivariate analysis (Cox model): hematological toxicity grade 3 or 4, no complete response, circumferential extension > 2/3 and nodes visible on CT-scan. Factors positively influencing complete response were in multivariate analysis: a fungating tumor, weight loss < 8% and a full dose preoperative treatment., Conclusion: In this study, preoperative treatment associating 5-FU-cisplatin and radiotherapy allowed a high resectability rate, with one third of patients achieving complete or nearly complete histologic response. A randomized study is warranted to know whether this combined treatment is better than surgery alone.

Patients with measurable or evaluable locally advanced or metastatic squamous cell carcinoma of the oesophagus were treated with cisplatin (CDDP), 100 mg/m2, combined with 5-fluorouracil (5-FU) at a dose of 1000 mg/m2 as a continuous infusion from days 1-5 (Arm A) or with CDDP alone (Arm B). Cycles were repeated every 3 weeks. 92 patients were randomised centrally, 88 were eligible. The response rate was 35% (95% CI (confidence interval), 20-54%) in Arm A and 19% (95% CI, 8-35%) in Arm B. One complete response was observed in each arm. The median duration of survival was 33 weeks and 28 weeks for Arm A and Arm B, respectively. Haematological and non-haematological toxicities were more frequent and more severe in Arm A. The most prominent toxicities were grade 4 aplasia and septicaemia (2), meningeal haemorrhage (1), cerebrovascular accident (3) and ischaemia of the lower limbs (1) all occurring in Arm A. Overall, seven treatment-related deaths (16%) were observed in Arm A, none in Arm B. The severe side-effects induced by the combination suggest that, currently, no standard chemotherapy can be recommended for patients with advanced squamous cell oesophageal cancer.

Purpose: To evaluate the response rate and toxic effects of vinorelbine (VNB) administered as a single agent in metastatic squamous cell esophageal carcinoma., Patients and Methods: Forty-six eligible patients with measurable lesions were included and were stratified according to previous chemotherapy. Thirty patients without prior chemotherapy and 16 pretreated with cisplatin-based chemotherapy were assessable for toxicity and response. VNB was administered weekly as a 25-mg/m2 short intravenous (i.v.) infusion., Results: Six of 30 patients (20%) without prior chemotherapy achieved a partial response (PR) (95% confidence interval [CI], 8% to 39%). The median duration of response was 21 weeks (range, 17 to 28). One of 16 patients (6%) with prior chemotherapy had a complete response (CR) of 31 weeks' duration (95% CI, 0% to 30%). The overall response rate (World Health Organization [WHO] criteria) was 15% (CR, 2%; PR 13%; 95% CI, 6% to 29%). The median dose-intensity (DI) was 20 mg/m2/wk. VNB was well tolerated and zero instances of WHO grade 4 nonhematologic toxicity occurred. At least one episode of grade 3 or 4 granulocytopenia was seen in 59% of patients. A grade 2 or 3 infection occurred in 16% of patients, but no toxic deaths occurred. Other side effects were rare, and peripheral neurotoxicity has been minor (26% grade 1)., Conclusion: These data indicate that VNB is an active agent in metastatic esophageal squamous cell carcinoma. Given its excellent tolerance profile and low toxicity, further evaluation of VNB in combination therapy is warranted.

The data of the literature demonstrate the poor global results of surgical treatment of the principal gastrointestinal cancers: oesophagus, stomach, bile ducts, liver, exocrine pancreas, colon and rectum. Surgery which was thought to be curative all too frequently proves to be simply a palliative procedure. The risk of failure is so high that a strategy should now be systematically adopted, combining surgery, radiotherapy, chemotherapy and symptomatic treatments. The rigor of this multidisciplinary approach is based on comparative studies confirming the prospective series and measuring the quality and duration of survival. Some protocols provide considerable improvement, for example preoperative radiotherapy of cancers of the rectum, or propose an interesting alternative such as the combination of radiotherapy and chemotherapy in cancer of the oesophagus. The participation of surgeons in multicentre prospective studies should validate and improve current oncological practice while also evaluating the contribution of a new method such as laparoscopic surgery. This commitment includes a definition of therapeutic objectives, definition of the reference treatment, selection of the criteria of the quality of the procedures involved in this treatment and objective assessment of the results.