Afatinib maintenance therapy following post-operative radiochemotherapy in head and neck squamous cell carcinoma: Results from the phase III randomised double-blind placebo-controlled study BIB2992ORL (GORTEC 2010-02).

OBJECTIVE: We investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT). METHODS: This French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%). RESULTS: Among the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48-0.72) in the afatinib group and 64% (95% CI 0.51-0.74) in the placebo group (HR 1.12, 95% CI 0.70-1.80). CONCLUSION: Maintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials. CLINICALTRIALS: gov identifier NCT01427478.

Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial.

BACKGROUND: How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. METHODS: This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 µg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475. FINDINGS: Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75-84] vs 62% [57-67]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred. INTERPRETATION: Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population. FUNDING: French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.

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

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.

Defining preoperative treatment strategies in t3 rectal cancer.

Preoperative treatments for patients with T3 rectal cancer have significantly improved local recurrence rates, while survival outcomes have not changed significantly relative to those achieved with surgery alone. The prognosis of patients with T3 tumors, however, is heterogeneous; therapy should be carefully selected based on characteristics of the tumor and other prognostic indices to provide an optimal outcome for each patient. This paper summarizes key findings from several large trials that have examined use of preoperative radiotherapy and chemoradiotherapy for rectal cancer, how these results can be applied to selection of the best therapy for an individual patient, as well as prognostic/predictive factors that have been identified and clinical tools for measuring them.

Intensity-modulated radiation therapy in head and neck cancer: prescribed dose, clinical challenges and results.

PURPOSE: To analyse clinical and dosimetric characteristics with regard to clinical constraints in head and neck cancer patients treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Between August 2001 and July 2005, 75 patients with non-metastatic head and neck cancers were treated with IMRT with curative intent. Dose-volume histograms (DVH) drawn up from inverse dosimetry were analysed and compared to the prescription according to the clinical presentation of the disease. RESULTS: For bilateral irradiation, the mean doses delivered to the contralateral and ipsilateral parotid glands were, respectively, 28.1 and 26.3Gy. Dose constraints to the submandibular glands were only respected for the contralateral gland during unilateral irradiation. For tumors located in paranasal sinuses, the maximal dose to the contralateral and ipsilateral optic nerves remained significantly lower than the constraint doses while the constraints for the anterior part of the eyes could not be respected. CONCLUSIONS: Significant differences were observed concerning respect of the constraints applied to the parotid or to the submandibular glands for medial tumors. The respect of constraints for the organs at risk critically depends on the location and size of the primary tumor and on the definition of the CTV. The clinical impact has to be further evaluated.

Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group.

The appropriate application of 3-D conformal radiotherapy, intensity modulated radiotherapy or image guided radiotherapy for patients undergoing post-operative radiotherapy for prostate cancer requires a standardisation of the target volume definition and delineation as well as standardisation of the clinical quality assurance procedures. Recommendations for this are presented on behalf of the European Organisation for Research and Treatment of Cancer (EORTC) Radiation Oncology Group and in addition to the already published guidelines for radiotherapy as the primary treatment.

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

Combining cisplatin and mitomycin with radiotherapy in anal carcinoma.

PURPOSE: The European Organization for Research and Treatment of Cancer (EORTC) phase II study No. 22953 demonstrated the feasibility of reducing the overall treatment time of chemoradiation, delivering mitomycin C twice rather than once and fluorouracil during the whole treatment. We tested the feasibility of chemoradiation in anal carcinoma with mitomycin and cisplatin in a phase II study. METHODS: Twenty-one patients with locally advanced anal carcinoma (15 women, 6 men) were treated. The first sequence of radiotherapy consisted of 36 Gy over four weeks. After a gap interval of 16 days, a second sequence of radiotherapy was given, delivering 23.4 Gy over 2.5 weeks. Mitomycin C was delivered at 10 mg/m(2) day 1 of each sequence and cisplatin was delivered at 25 mg/m(2)/week of each sequence. RESULTS: The compliance rates for the first sequence with radiation, mitomycinm, and cispaltin (dose and timing) were 100 percent. The median duration gap was 16 days (14-30 days). The compliance rates for the second sequence with radiation, mitomycin, and cisplatin (dose and timing) were 100, 76.2, and 85.7 percent, respectively. Grade > or = 2 acute toxicities of 62, 29, 25, and 5 percent were observed for skin, diarrhea, hematologic, and renal toxicities, respectively. Nineteen patients were in complete response (90.5 percent). CONCLUSIONS: Combining radiation with mitomycin and cisplatin in patients with locally advanced anal cancer is feasible. The results are promising. The EORTC is currently comparing this combination with mitomycin and 5-fluorouracil in a large phase II-III trial.

Tumor volume as outcome determinant in patients treated with chemoradiation for locally advanced esophageal cancer.

OBJECTIVE: The currently used tumor-node metastasis (TNM) staging method is generally not applicable to patients with unresectable esophageal carcinomas. There is a need for both an efficient, easy-to-perform clinical classification and for identification of pretherapeutic prognostic factors that would be useful for oncologists, one of which is tumor volume. METHODS: Records of 148 patients, admitted to hospital during the period January 1993 to December 2001, were evaluated retrospectively. Median age was 65.7 years (range, 35.5-85.5 years). Most patients had SCC (84.5%). Using the computed tomography (CT) scan classification, tumors were recorded as follows: 1 T1, 42 T2, 93 T3, 6 T4, 2 Nx, 72 N0, 74 N1. Tumor volume from the CT scans was determined as the sum of 2 opposed truncated cones. Median tumor volume was 57.5 cm3 (range, 0.6-288 cm3). RESULTS: Median follow-up was 15.1 month (range, 0.3-82.8 months). Survival rates at 1, 2, and 3 years were 42.5%, 21.6%, and 8%, respectively. Prognostic factors identified by univariate analysis were: dysphagia grade > or =2, other histology than squamous cell, tumor location below the carina, age <65 years and tumor volume > or =100 cm3. Prognostic factors identified with multivariate analysis were: dysphagia grade > or =2 (P = 0.013), weight loss > or =10% (P = 0.047), tumor location below the carina (P = 0.002), and tumor volume > or =100 cm3 (P = 0.041). CONCLUSIONS: For patients that the TNM staging system is not applicable, tumor volume is a new powerful determinant of survival. Further clinical trials need to be carried out to validate this prospectively.

Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study.

PURPOSE: To retrospectively analyze a series of mucosal melanoma of the upper aerodigestive tract to determine the prognostic factors and contribute to understanding the role of radiotherapy in the therapeutic strategy. METHODS AND MATERIALS: Seventy-four patients were analyzed. The most frequent locations were nasal and oral, in 31 patients (41.9%) and 12 patients (16.2%), respectively. Sixty-three patients (85.1%) were in Stage I, 5 (6.8%) in Stage II, and 6 (8.1%) in Stage III. Treatment consisted of surgery in 17 patients (23.0%), surgery and radiotherapy in 42 (56.8%), radiotherapy in 11 (14.9%), and chemo-immunotherapy in 4 (5.4%). Median follow-up was 20 months. RESULTS: Local control at 3 years was 57% after surgery alone and 71% after surgery and radiotherapy. Overall and disease-free survival rates, respectively, were 41% and 31% at 3 years and 14% and 22% at 10 years. After univariate analysis, female gender, melanosis, tumor size