Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. METHODS: We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. FINDINGS: Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). INTERPRETATION: Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. FUNDING: Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Treatment algorithm and prognostic factors for patients with stage I-III carcinoma of the anal canal: a 20-year multicenter study.

Despite a growing incidence in developed countries and a recent improved understanding of its pathogenesis, anal cancer management has not evolved over the past decades and drug combination used as first-line regimen still largely depends on clinician preferences. Aiming at paving the way for precision medicine, a large cohort of 372 HIV-negative patients diagnosed over a 20-year time period with locally advanced anal carcinoma was collected and carefully characterized at the clinical, demographic, histopathologic, immunologic, and virologic levels. Both the prognostic relevance of each clinicopathological parameter and the efficacy of different concurrent chemoradiation strategies were determined. Overall, the incidence of anal cancer peaked during the sixth decade (mean: 63.4) and females outnumbered males (ratio: 2.51). After completion of treatment, 95 (25.5%) patients experienced progression of persistent disease or local/distant recurrence and 102 (27.4%) died during the follow-up period (median: 53.8 months). Importantly, uni-multivariate analyses indicated that both negative HPV/p16ink4a status and aberrant p53 expression were far better predictors for reduced progression-free survival than traditional risk factors such as tumor size and nodal status. As for overall survival, the significant influences of age at diagnosis, p16ink4a status, cTNM classification as well as both CD3+ and CD4+ T-cell infiltrations within tumor microenvironment were highlighted. Cisplatin-based chemoradiotherapy was superior to both radiotherapy alone and other concurrent chemoradiation therapies in the treatment of HPV-positive tumors. Regarding their HPV-uninfected counterparts, frequent relapses were observed, whatever the treatment regimen administered. Taken together, our findings reveal that current anal cancer management and treatment have reached their limits. A dualistic classification according to HPV/p53 status should be considered with implications for therapy personalization and optimization.

Chemoradiation in elderly esophageal cancer patients: rationale and design of a phase I/II multicenter study (OSAGE).

BACKGROUND: The management of elderly patients with cancer is a therapeutic challenge and a public health problem. Definitive chemoradiotherapy (CRT) is an accepted standard treatment for patients with locally advanced esophageal cancer who cannot undergo surgery. However, there are few reports regarding tolerance to CRT in elderly patients. We previously reported results for CRT in patients aged ≥75 years. Following this first phase II trial, we propose to conduct a phase I/II study to evaluate the combination of carboplatin and paclitaxel, with concurrent RT in unresectable esophageal cancer patients aged 75 years or older. METHODS/DESIGN: This prospective multicenter phase I/II study will include esophageal cancer in patients aged 75 years or older. Study procedures will consist to determinate the tolerated dose of chemotherapy (Carboplatin, paclitaxel) and of radiotherapy (41.4-45 and 50.4 Gy) in the phase I. Efficacy will be assessed using a co-primary endpoint encompassing health related quality of life and the progression-free survival in the phase II with the dose recommended of CRT in the phase I. This geriatric evaluation was defined by the French geriatric oncology group (GERICO). DISCUSSION: This trial has been designed to assess the tolerated dose of CRT in selected patient aged 75 years or older. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02735057 . Registered on 18 March 2016.

Cross-cultural adaptation and validation of the French version of the Expanded Prostate cancer Index Composite questionnaire for health-related quality of life in prostate cancer patients.

BACKGROUND: Health-related quality of life (HRQoL) has been positioned as one of the major endpoints in oncology. Thus, there is a need to validate cancer-site specific survey instruments. This study aimed to perform a transcultural adaptation of the 50-item Expanded Prostate cancer Index Composite (EPIC) questionnaire for HRQoL in prostate cancer patients and to validate the psychometric properties of the French-language version. METHODS: The EPIC questionnaire measures urinary, bowel, sexual and hormonal domains. The first step, corresponding to transcultural adaptation of the original English version of the EPIC was performed according to the back translation technique. The second step, comprising the validation of the psychometric properties of the EPIC questionnaire, was performed in patients under treatment for localized prostate cancer (treatment group) and in patients cured of prostate cancer (cured group). The EORTC QLQ-C30 and QLQ-PR25 prostate cancer module were also completed by patients to assess criterion validity. Two assessments were performed, i.e., before and at the end of treatment for the Treatment group, to assess sensitivity to change; and at 2 weeks' interval in the Cured group to assess test-retest reliability. Psychometric properties were explored according to classical test theory. RESULTS: The first step showed overall good acceptability and understanding of the questionnaire. In the second step, 215 patients were included from January 2012 to June 2014: 125 in the Treatment group, and 90 in the Cured group. All domains exhibited good internal consistency, except the bowel domain (Cronbach's α = 0.61). No floor effect was observed. Test-retest reliability assessed in the cured group was acceptable, expect for bowel function (intraclass coefficient = 0.68). Criterion validity was good for each domain and subscale. Construct validity was not demonstrated for the hormonal and bowel domains. Sensitivity to change was exhibited for 5/8 subscales and 2/4 summary scores for patients who experienced toxicities during treatment. CONCLUSIONS: The French EPIC questionnaire seems to have adequate psychometric properties, comparable to those exhibited by the original English-language version, except for the construct validity, which was not available in original version.

Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. METHODS: We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. FINDINGS: We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0.97, 95% CI 0.81-1.17; p=0.775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0.91, 95% CI 0.77-1.07; p=0.230) or distant recurrences (0.94, 0.78-1.14; p=0.523) compared with observation. However, in subgroup analyses, patients with a tumour 10-15 cm from the anal verge had improved disease-free survival (0.59, 0.40-0.85; p=0.005, p(interaction)=0.107) and fewer distant recurrences (0.61, 0.40-0.94; p=0.025, p(interaction)=0.126) when treated with adjuvant chemotherapy compared with patients undergoing observation. INTERPRETATION: Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10-15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted. FUNDING: None.

Impact of neoadjuvant chemoradiation on lymph node status in esophageal cancer: post hoc analysis of a randomized controlled trial.

OBJECTIVE: The study objectives were to analyze the impact of the number of lymph nodes (LNs) reported as resected (NLNr) and the number of LNs invaded (NLNi) on the prognosis of esophageal cancer (EC) after neoadjuvant chemoradiotherapy. BACKGROUND: Pathological LN status is a major disease prognostic factor and marker of surgical quality. The impact of neoadjuvant chemoradiation (nCRT) on LN status remains poorly studied in EC. METHODS: Post hoc analysis from a phase III randomized controlled trial comparing nCRT and surgery (group nCRT) to surgery alone (group S) in stage I and II EC (NCT00047112). Only patients who underwent surgical resection were considered (n = 170). RESULTS: nCRT resulted in tumoral downstaging (pT0, 40.7% vs 1.1%, P < 0.001), LN downstaging (pN0, 69.1% vs 47.2%, P = 0.016), and reduction in the median NLNr [16.0 (range, 0-47.0) vs 22.0 (range, 3.0-58.0), P = 0.001] and NLNi [0 (range, 0-25) vs 1.0 (range, 0-25), P = 0.001]. A good histological response (TRG1/2) in the resected esophageal specimen correlated with reduced median NLNi [0 (range, 0-10) vs 1.0 (range, 0-4), P = 0.007]. After adjustment by treatment, NLNi [hazards ratio (HR) (1-3 vs 0) 3.5, 95% confidence interval (CI): 2.3-5.5, and HR (>3 vs 0) 3.5, 95% CI: 2.0-6.2, P < 0.001] correlated with prognosis, whereas NLNr [HR (<15 vs ≥15) 0.95, 95% CI: 0.6-1.4, P = 0.807 and HR (<23 vs ≥23) 1.4, 95% CI: 0.9-2.0, P = 0.131] did not. In Poisson regression analysis, nCRT was an independent predictive variable for reduced NLNr [exp(coefficient) 0.80, 95% CI: 0.66-0.96, P = 0.018]. CONCLUSIONS: nCRT is not only responsible for disease downstaging but also predicts fewer LNs being identified after surgical resection for EC. This has implications for the current quality criteria for surgical resection.

Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.

BACKGROUND: EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. METHODS: We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m(2) per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m(2) per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. FINDINGS: 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8-13·1), 10-year overall survival was 49·4% (95% CI 44·6-54·1) for the preoperative radiotherapy group and 50·7% (45·9-55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83-1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0-56·4) for the adjuvant chemotherapy group and 48·4% (43·6-53·0) for the surveillance group (HR 0·91, 95% CI 0·77-1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5-48·8) for the preoperative radiotherapy group and 46·4% (41·7-50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79-1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2-51·6) for the adjuvant chemotherapy group and 43·7% (39·1-48·2) for the surveillance group (HR 0·91, 95% CI 0·77-1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1-27·6) with radiotherapy alone, 11·8% (7·8-15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1-18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7-15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). INTERPRETATION: Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. FUNDING: EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.

A longitudinal analysis of patient satisfaction with care and quality of life in ambulatory oncology based on the OUT-PATSAT35 questionnaire.

BACKGROUND: In the oncology setting, there has been increasing interest in evaluating treatment outcomes in terms of quality of life and patient satisfaction. The aim of our study was to investigate the determinants of patient satisfaction, especially the relationship between quality of life and satisfaction with care and their changes over time, in curative treatment of cancer outpatients. METHODS: Patients undergoing ambulatory chemotherapy or radiotherapy in two centers in France were invited to complete the OUT-PATSAT35, at the beginning of treatment, at the end of treatment, and three months after treatment. This questionnaire evaluates patients' perception of doctors and nurses, as well as other aspects of care organization and services. Additionally, for each patient, socio-demographic and clinical characteristics, and self-reported quality of life data (EORTC QLQ-C30) were collected. RESULTS: Of the 691 patients initially included, 561 answered the assessment at all three time points. By cross-sectional analysis, at the end of the treatment, patients who experienced a deterioration of their global health reported less satisfaction on most scales (p ≤ 0.001). Three months after treatment, the same patients had lower satisfaction scores only in the evaluation of doctors (p ≤ 0.002). Furthermore, longitudinal analysis showed a significant relationship between a deterioration in global health and a decrease in satisfaction with their doctor and, conversely, between an improvement in global health and an increase in satisfaction on the overall satisfaction scale. Global health at baseline was largely and significantly associated with all satisfaction scores measured at the following assessment time points (p < 0.0001). Younger age (<55 years), radiotherapy (versus chemotherapy) and head and neck cancer (versus other localizations) were clinical factors significantly associated with less satisfaction on most scales evaluating doctors. CONCLUSIONS: Pre-treatment self-evaluated global health was found to be the major determinant of patient satisfaction with care. The subsequent deterioration of global health, during and after treatment, emphasized the decrease in satisfaction scores, mainly in the evaluation of doctors. Early initiatives aimed at improving the delivery of care in patients with poor health status should lead to improved perception of the quality of care received.

Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911).

BACKGROUND: We report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate, to confirm whether previously reported progression-free survival was sustained. METHODS: This randomised, phase 3, controlled trial recruited patients aged 75 years or younger with untreated cT0-3 prostate cancer (WHO performance status 0 or 1) from 37 institutions across Europe. Eligible patients were randomly assigned centrally (1:1) to postoperative irradiation (60 Gy of conventional irradiation to the surgical bed for 6 weeks) or to a wait-and-see policy until biochemical progression (increase in prostate-specific antigen >0·2 µg/L confirmed twice at least 2 weeks apart). We analysed the primary endpoint, biochemical progression-free survival, by intention to treat (two-sided test for difference at α=0.05, adjusted for one interim analysis) and did exploratory analyses of heterogeneity of effect. This trial is registered with ClinicalTrials.gov, number NCT00002511. FINDINGS: 1005 patients were randomly assigned to a wait-and-see policy (n=503) or postoperative irradiation (n=502) and were followed up for a median of 10·6 years (range 2 months to 16·6 years). Postoperative irradiation significantly improved biochemical progression-free survival compared with the wait-and-see policy (198 [39·4%] of 502 patients in postoperative irradiation group vs 311 [61·8%] of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0·49 [95% CI 0·41-0·59]; p<0·0001). Late adverse effects (any type of any grade) were more frequent in the postoperative irradiation group than in the wait-and-see group (10 year cumulative incidence 70·8% [66·6-75·0] vs 59·7% [55·3-64·1]; p=0.001). INTERPRETATION: Results at median follow-up of 10·6 years show that conventional postoperative irradiation significantly improves biochemical progression-free survival and local control compared with a wait-and-see policy, supporting results at 5 year follow-up; however, improvements in clinical progression-free survival were not maintained. Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older. FUNDING: Ligue Nationale contre le Cancer (Comité de l'Isère, Grenoble, France) and the European Organisation for Research and Treatment of Cancer (EORTC) Charitable Trust.

Determinants of patient satisfaction in ambulatory oncology: a cross sectional study based on the OUT-PATSAT35 questionnaire.

BACKGROUND: The aim of this study was to identify factors associated with satisfaction with care in cancer patients undergoing ambulatory treatment. We investigated associations between patients' baseline clinical and socio-demographic characteristics, as well as self-reported quality of life, and satisfaction with care. METHODS: Patients undergoing ambulatory chemotherapy or radiotherapy in 2 centres in France were invited, at the beginning of their treatment, to complete the OUT-PATSAT35, a 35 item and 13 scale questionnaire evaluating perception of doctors, nurses and aspects of care organisation. Additionally, for each patient, socio-demographic variables, clinical characteristics and self-reported quality of life using the EORTC QLQ-C30 questionnaire were recorded. RESULTS: Among 692 patients included between January 2005 and December 2006, only 6 were non-responders. By multivariate analysis, poor perceived global health strongly predicted dissatisfaction with care (p < 0.0001). Patients treated by radiotherapy (vs patients treated by chemotherapy) reported lower levels of satisfaction with doctors' technical and interpersonal skills, information provided by caregivers, and waiting times. Patients with primary head and neck cancer (vs other localisations), and those living alone were less satisfied with information provided by doctors, and younger patients (< 55 years) were less satisfied with doctors' availability. CONCLUSIONS: A number of clinical of socio-demographic factors were significantly associated with different scales of the satisfaction questionnaire. However, the main determinant was the patient's global health status, underlining the importance of measuring and adjusting for self-perceived health status when evaluating satisfaction. Further analyses are currently ongoing to determine the responsiveness of the OUT-PATSAT35 questionnaire to changes over time.

Chemotherapy with preoperative radiotherapy in rectal cancer.

BACKGROUND: Preoperative radiotherapy is recommended for selected patients with rectal cancer. We evaluated the addition of chemotherapy to preoperative radiotherapy and the use of postoperative chemotherapy in the treatment of rectal cancer. METHODS: We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy, preoperative chemoradiotherapy, preoperative radiotherapy and postoperative chemotherapy, or preoperative chemoradiotherapy and postoperative chemotherapy. Radiotherapy consisted of 45 Gy delivered over a period of 5 weeks. One course of chemotherapy consisted of 350 mg of fluorouracil per square meter of body-surface area per day and 20 mg of leucovorin per square meter per day, both given for 5 days. Two courses were combined with preoperative radiotherapy in the group receiving preoperative chemoradiotherapy and the group receiving preoperative chemoradiotherapy and postoperative chemotherapy; four courses were planned postoperatively in the group receiving preoperative radiotherapy and postoperative chemotherapy and the group receiving preoperative chemoradiotherapy and postoperative chemotherapy. The primary end point was overall survival. RESULTS: We enrolled 1011 patients in the trial. There was no significant difference in overall survival between the groups that received chemotherapy preoperatively (P=0.84) and those that received it postoperatively (P=0.12). The combined 5-year overall survival rate for all four groups was 65.2%. The 5-year cumulative incidence rates for local recurrences were 8.7%, 9.6%, and 7.6% in the groups that received chemotherapy preoperatively, postoperatively, or both, respectively, and 17.1% in the group that did not receive chemotherapy (P=0.002). The rate of adherence to preoperative chemotherapy was 82.0%, and to postoperative chemotherapy was 42.9%. CONCLUSIONS: In patients with rectal cancer who receive preoperative radiotherapy, adding fluorouracil-based chemotherapy preoperatively or postoperatively has no significant effect on survival. Chemotherapy, regardless of whether it is administered before or after surgery, confers a significant benefit with respect to local control. (ClinicalTrials.gov number, NCT00002523 [ClinicalTrials.gov].).

Feasibility of chemoradiotherapy for oesophageal cancer in elderly patients aged >or=75 years: a prospective, single-arm phase II study.

BACKGROUND: The number of elderly patients with oesophageal cancer is expected to increase with the aging of the population and the rapidly increasing incidence of adenocarcinoma. Surgical resection is standard treatment for patients with localized disease considered fit for operation. However, elderly patients with oesophageal cancer are rarely referred for surgery. The aim of this prospective, single-arm, phase II study was to evaluate the feasibility and efficacy (tumour response) of chemoradiotherapy in the treatment of elderly patients with localized oesophageal cancer. Secondary endpoints were progression-free survival (PFS) and quality of life (QOL). METHODS: The main study inclusion criteria were: patients aged >or=75 years; oesophageal cancer disease stage II-III; Charlson co-morbidity index score

Cancer of the anal region.

Anal canal accounts for 2% of all cancer and its incidence increases with age with a predominance in woman. About 80% of all primary anal canal cancers are squamous; adenocarcinoma arising from the glands or glandular ducts shows a behaviour that is similar to that of the adenocarcinoma of the rectum. Risk factors includes sexually transmitted infection with Human Papillomavirus, cigarette smoking, immunosuppression, and sexual practices. The standard treatment for anal canal is chemo - radiation with a combination of fluoropyrimidines and mitomycin or cisplatin. Salvage surgery may be necessary for residual disease after radiotherapy or chemoradiation, for locoregional relapse and/or for sequelae. In the metastatic setting a multidisciplinary approach is preferred and includes medical treatment, surgery, and RT, if appropriate. Discussing these possible options in the initial stage is of most importance to ensure the best quality of life (QoL) for patients.

Pooled Analysis of external-beam RADiotherapy parameters in phase II and phase III trials in radiochemotherapy in Anal Cancer (PARADAC).

PURPOSE: Concomitant external-beam radiochemotherapy (5-fluorouracil-mitomycin C) has become the standard of care in anal cancer since the '90s. A pooled analysis of individual patient data from 7 major trials was performed quantifying the effect of radiation therapy (RT)-related parameters on the outcome of patients with anal cancer. MATERIALS AND METHODS: Pooling databases from combined modality trials, the impact of RT parameters (total dose, gap duration, OTT: overall treatment time) on outcome including locoregional failure (LRF), 5-year progression free survival (PFS) and toxicities were investigated. Individual patient data were received for 10/13 identified published studies conducted from 1987 to 2008 (n = 3031). A Cox regression model was used (landmark = 3 months after RT for first follow-up). RESULTS: After data inspection indicating severe heterogeneity between trials, only 1343 patients from 7/10 studies received were analysed (the most recent ones, since 1994; median follow-up = 4.1 years). A higher overall 5-year LRF rate [22.8% (95% confidence interval [CI] 22.3-27.3%)] significantly correlated with longer OTT (p = 0.03), larger tumour size (p < 0.001) and male gender (p = 0.045). Although significant differences were not observed, subset analyses for LRF (dose range: 50.4-59 Gy) seemed to favour lower doses (p = 0.412), and when comparing a 2-week gap versus 3 (dose: 59.4 Gy), results suggested 3 weeks might be detrimental (p = 0.245). For a 2-week gap versus none (dose range: 55-59.4 Gy), no difference was observed (p = 0.89). Five-year PFS was 65.7% (95% CI: 62.8-68.5%). Higher PFS rates were observed in women (p < 0.001), smaller tumour sizes (p < 0.001) and shorter OTT (p = 0.025). Five-year overall survival [76.7% (95% CI: 73.9%-79.3%)] correlated positively with female gender (p < 0.001), small tumour size (p = 0.027) and short OTT (p = 0.026). Descriptive toxicity data are presented. CONCLUSION: For patients receiving concurrent external-beam doublet chemoradiation, a longer OTT seems detrimental to outcome. Further trials involving modern techniques may better define optimal OTT and total dose.

Recent advances in the treatment of localized rectal cancer.

Randomized clinical trials have recently established preoperative chemoradiotherapy as the new standard treatment for patients with localized cT3-T4 or N+ rectal cancer. Although its inclusion in the modern multidisciplinary management of patients with rectal cancer makes total eradication of pelvic failure a near reality, it does not yet translate into improved survival. As a result, clinical research should be primarily directed against the micrometastatic process, focusing on integrating innovative strategies, such as upfront chemotherapy before chemoradiation, in subgroups of patients recognized to be at high risk.

[Radiation-induced enteropathy]. / Entéropathie radique.

Small and large bowels are dose-limiting structures for acute and late toxicity of abdominopelvic radiotherapy. Minor or moderate toxicities are underestimated. Major toxicities may occur years from treatment. Current optimal radiotherapy planning may predict precisely toxicities and new technologies for treatment delivery may prevent and/or reduce the frequency and severity of radiation enteropathy.

Quality of surgery in T3-4 rectal cancer: involvement of circumferential resection margin not influenced by preoperative treatment. Results from EORTC trial 22921.

PURPOSE: The present analyses aimed to determine risk factors for rectal cancer patients associated with circumferential resection margin (CRM) and number of examined lymph nodes (LN) and to correlate these parameters of surgical quality with local recurrence (LR), disease-free and overall survival (DFS and OS). MATERIALS AND METHODS: Data of 884 eligible patients, who underwent a resection and had no metastases at time of surgery, were analysed. RESULTS: Age, period of treatment, distance and pT-stage were associated with surgical quality. CRM involvement, but not the number of examined LN, was associated with a higher risk of an LR, reduced DFS and OS. An abdomino-perineal resection (APR) was a risk factor for adverse outcome. CONCLUSION: Surgical quality is an important predictor of outcome, also for patients treated with conventional RT or chemoradiotherapy (CRT). Preoperative CRT results in downstaging and downsizing of the tumour, but not in less CRM involvement.

Does concurrent radiochemotherapy affect cosmetic results in the adjuvant setting after breast-conserving surgery? Results of the ARCOSEIN multicenter, Phase III study: patients' and doctors' views.

PURPOSE: To evaluate the cosmetic results of sequential vs. concurrent adjuvant chemotherapy with radiotherapy after breast-conserving surgery for breast cancer, and to compare ratings by patients and physicians. METHODS AND MATERIALS: From 1996 to 2000, 716 patients with Stage I-II breast cancers were included in a multicenter, Phase III trial (the ARCOSEIN study) comparing, after breast-conserving surgery with axillary dissection, sequential treatment with chemotherapy first followed by radiotherapy vs. chemotherapy administered concurrently with radiotherapy. Cosmetic results with regard to both the overall aspect of the breast and specific changes (color, scar) were evaluated in a total of 214 patients (107 in each arm) by means of questionnaires to both the patient and a physician whose rating was blinded to treatment allocation. RESULTS: Patients' overall satisfaction with cosmesis was not statistically different between the two arms, with approximately 92% with at least satisfactory results (p = 0.72), although differences between the treated and untreated breasts were greater after the concurrent regimen (29% vs. 14% with more than moderate differences; p = 0.0015). Physician assessment of overall cosmesis was less favorable, with lower rates of at least satisfactory results in the concurrent arm (60% vs. 85%; p = 0.001). Consequently, the concordance for overall satisfaction with cosmesis between patients and doctors was only fair (kappa = 0.62). CONCLUSION: After breast-conserving surgery, the concurrent use of chemotherapy with radiotherapy is significantly associated with greater differences between the breasts. These differences do not translate into patients' lessened satisfaction with cosmesis.

Preoperative radiotherapy in elderly patients with rectal cancer.

PURPOSE: We performed a retrospective analysis in order to evaluate the compliance with preoperative radiotherapy in patients aged>or=70 with locally advanced resectable rectal cancer, and to evaluate the influence of comorbidities on treatment tolerance and oncological results. METHODS: From March 1984 to December 2000, 95 patients with T3-T4 N0 M0 rectal cancer received a preoperative radiotherapy in 2 radiotherapy departments. Nineteen patients received concomitant chemotherapy. RESULTS: All patients completed the radiation schedule. Six patients suffered grade 3 acute WHO toxicity. Surgical resection was performed in 87 patients. There were 3 post-operative deaths. Analysis of peri-operative complications showed thromboembolism (4.9%), ileus (9.8%) and diarrhoea (6.1%). After a median follow-up of 29 months, the 3- and 5-year overall survival rates were 65% and 49% respectively. In univariate analysis, a tumour located in the mid part of the rectum, a radiation dose less than 40 Gy, the absence of chemotherapy were significantly associated with a poor prognosis. There was a trend to a better survival for patients with a Charlson score of 0 (P=0.0584). In multivariate analysis, only initial WHO performance status was significant. CONCLUSIONS: Compliance with preoperative radiotherapy is good in elderly patients. Toxicity rates are similar to those described in randomised trials in which only younger patients were included. Initial WHO performance status