Pierre Richaud

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.

Organization of the genes necessary for hydrogenase expression in Rhodobacter capsulatus. Sequence analysis and identification of two hyp regulatory mutants

A 25kbp DNA fragment from the chromosome of Rhodobacter capsulatus B10 carrying hydrogenase (hup) determinants was completely sequenced. Coding regions corresponding to 20 open reading frames were identified. The R. capsulatus hydrogenase‐specific gene (hup and hyp) products bear significant structural identity to hydrogenase gene products from Escherichia coli (13), from Rhizobium liguminosarum (16), from Azotobacter vinelandii (10) and from Alcaligenes eutrophus (11). The sequential arrangement of the R. capsulatus genes is: hupR2‐hupU‐hypF‐hupS‐hupL‐hupM‐hupD‐hupF‐hupG‐hupH‐huoJ‐hupK‐hypA‐hypB‐hupR1‐hypC‐hypD‐hypE‐ORF19‐ORF20, all contiguous and transcribed from the same DNA strand. The last two potential genes do not encode products that are related to identified hydrogenase‐specific gene products in other species. The sequence of the 12 R. capsulatus genes underlined above is presented. The mutation site in two of the Hup− mutants used in this study, RS13 and RCC12, was identified in the hypF gene (deletion of one G) and in the hypD qene (deletion of 54 bp), respectively. The hypF gene product shares 45% identity with the product of hydA from E. coli and the product of hypF from R. leguminosarum. Those products present at their N‐terminus a Cys arrangement typical of zinc‐finger proteins. The G deletion in the C‐terminal region of hypF in the RS13 mutant

A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED MULTICENTER STUDY OF MESALAZINE FOR THE PREVENTION OF ACUTE RADIATION ENTERITIS

BACKGROUND AND PURPOSE Symptoms of acute radiation enteritis (ARE), dominated by diarrhea, occur in more than 70% of patients receiving pelvic irradiation. Eicosanoids and free radicals release have been implicated in the pathogenesis. Mesalazine (5-ASA) is a potent inhibitor of their synthesis in the mucosa and could therefore be of some interest in preventing ARE. PATIENTS AND METHODS The study was performed in six radiotherapy units in France who agreed on standardized irradiation procedures. One hundred and fifty-three patients planned for external beam radiotherapy to the pelvis > or = 45 Gy for prostate (n = 97) or uterus (n = 54) cancer were randomized on a double blind basis to receive prophylactic 5-ASA (4 g/day Pentasa) or placebo. Patients with concomitant chemotherapy were excluded. Prostate and uterus cancers were chosen since these centropelvic tumors require a similar radiotherapy protocol during the first step of treatment and involve a comparable volume of small intestine. The symptoms of ARE and their severity were assessed every week during irradiation, and 1 and 3 months after its end. All patients followed a low fiber and low lactose diet. End points were diarrhea, use of antidiarrheal agents, abdominal pain, and body weight. Effficacy was evaluated using intention to treat. RESULTS (means +/- SD) Groups did not differ for age (mean 64 +/- 9 years), sex, tumor site, or irradiation procedure. During irradiation, diarrhea occurred in 69% and 66% of the 5-ASA and placebo groups, respectively (chi2, P = 0.22). Curves of survival without diarrhea did not differ between groups (logrank P = 0.09). Severity of diarrhea did not differ between groups except at d15 where it was significantly more severe in the 5-ASA group (ANOVA P = 0.006). Duration of diarrhea did not differ (22 +/- 15 days in both groups, P = 0.88). Abdominal pain was less frequently reported in the 5-ASA group at d28 (34% vs. 51%, P = 0.048). Use of antidiarrheal agents and body weight did not differ between groups. CONCLUSION Mesalazine 4 g/day did not decrease the symptoms of ARE.

Recurrences of rectal cancers: Results of a multimodal approach with intraoperative radiation therapy

PURPOSE Prognosis of recurrent rectal cancer remains poor, mainly because of the difficulties of achieving a satisfactory local control. Intraoperative radiation therapy (IORT) allows for the delivery of a complementary single dose to the tumor residues or to the tumor bed and could be useful jn a multimodal treatment. In an attempt to evaluate this interest, a retrospective analysis of patients treated with IORT in six French hospitals has been performed. METHODS AND MATERIALS Data have been collected in 73 patients (41 men), with a mean age of 62 years, treated with IORT. Initial rectal tumors were large (mean diameter: 45 mm), partially or totally fixed to the contiguous structures in 39%, and with nodal involvement in 50% of the cases. Initial surgery had been a sphincter-sparing surgery in 67%; external radiation therapy had been delivered in 52%, and a chemotherapy had been given in 10% of the patients. Recurrences were isolated (without metastases) in 86%, and were posterior or posterolateral in 55% of the cases. Surgery allowed for a complete macroscopical resection in 57%, a partial resection with gross residual disease in 29%, and no resection in 14% of the recurrences. Intraoperative radiation therapy was delivered in a dose of 10 to 25 Gy (mean 18.5) through localizators of a mean diameter of 75 mm (60 to 110). External radiation therapy, either preoperative or postoperatively was given to 30 patients without prior radiation therapy. Ten patients received additional chemotherapy with 5-fluorouracil. RESULTS Four postoperative deaths occurred. Postoperative morbidity occurred in 16 patients and some complications were probably related to the IORT procedure. Four long-term complications were observed. Overall actuarial survival occurred in 72.4% of the patients at 1 year, in 44.6% at 2 years, and in 30.6% at 3 years. Twenty-one local failures have been observed. Actuarial local control occurred in 71.3% of the patients at 1 year, 47.7% at 2 years, and 31.3% at 3 years. CONCLUSION Intraoperative radiation therapy is a complementary treatment for recurrences of rectal cancer. It provides encouraging results, particularly in some selected situations, when patients have not previously been treated with external radiation therapy. Further studies of multimodal treatments are necessary.

Intraoperative radiation therapy in recurrent carcinoma of the uterine cervix: Report of the French intraoperative group on 70 patients

PURPOSE To evaluate the feasibility and oncologic results of intraoperative radiation therapy (IORT) for recurrent uterine cervical carcinoma in a cohort of patients treated in seven French institutions. METHODS AND MATERIALS From 1985 to 1993, 70 patients with pelvic recurrences underwent IORT with/ without external radiation therapy (ERT) and chemotherapy (CT). Treatment modalities for recurrence were IORT alone (40 out of 70), IORT + ERT (30 out of 70), additional chemotherapy (20 out of 70). Gross complete resection (CR) was performed in 30 out of 70 cases, partial resection (PR) in 37 out of 70, and unspecified surgery in 3 out of 70. Sixty-five patients had electron beam IORT and 5, 100 KV photon IORT. Mean IORT cone size, electron beam energy, and dose (calculated at the 90% isodose line) were, respectively, 75 mm (40 to 90), 12 MeV (6 to 20), and 18 Gy (10 to 25) after CR and 80 mm (45 to 100), 15 MeV (7 to 24), and 19 Gy (10 to 30) after PR. RESULTS Mean follow-up after IORT was 15 months (2 to 69). One, 2- and 3-year overall survival rates were 47, 17, and 8%, respectively; median survival was 11 months and local control, 21%. Median survival and local control rates increased after CR (13 months, 27%) vs. PR (10 months, 17%) and when initial treatment consisted of surgery (S) alone (15 months, 25%) vs. radiation therapy (RT +/- S) (10 months, 16%). However, these differences were not statistically significant. No death-related toxicity was observed. Grade 2 or 3 toxicity was observed in 19 out of 70 patients (27%), including 9 not directly IORT-related complications (13%) (three digestive tract fistulas, one rectal stricture, three urinary fistulas, two infections) and 10 directly IORT-related complications (14%) (five neuropathies, four ureteral obstructions, and one rectal stricture). CONCLUSION This retrospective study demonstrates the feasibility of IORT. The usefulness of IORT still needs to be evaluated in primary treatment of advanced stages of cervical carcinoma.

Intra-operative radiotherapy of rectal cancer: Results of the French multi-institutional randomized study

PURPOSE To assess efficacy and tolerance of intra-operative radiation therapy (IORT) in patients suffering from locally advanced rectal cancer, treated with preoperative radiotherapy followed by surgical resection. METHODS AND MATERIALS In this French, multicenter, comparative, phase III study, 142 patients with locally advanced rectal cancer (T3 or T4 or N+, and M0), treated with a 4-week preoperative radiotherapy (40 grays) were randomly assigned to either surgical resection alone ( CONTROL GROUP n=69) or combined to 18-gray intra-operative radiation therapy (IORT group: n=73) between 1993 and 2001. RESULTS The 5-year cumulative incidence of local control was 91.8% with IORT and 92.8% with surgery alone (p=0.6018); the mean duration without local relapse (Kaplan-Meier method) was 107 versus 126 months, respectively. No statistically significant difference was demonstrated for overall survival (p=0.2578) disease-free survival (p=0.7808) and probability of metastatic relapse (p=0.6037) with 5-year cumulative incidences of 69.8% versus 74.8%, 63.7% versus 63.1%, and 26.1% versus 30.2%, respectively. 48 patients of the IORT group and 53 patients of the control group were alive with a median follow-up of 60.1 and 61.2 months, respectively. Post-operative complications were observed in the IORT group in 21 patients (29.6%) and in the control group in 13 patients (19.1%) (p=0.15), with an acceptable tolerance profile. CONCLUSIONS Although this randomized study did not demonstrate any significant improvement in local control and disease-free survival in rectal cancer patients treated with preoperative radiation therapy receiving IORT or not, it confirmed the technical feasibility and the necessity for evaluating IORT for rectal carcinoma in further clinical studies.

ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer (EORTC)☆

BACKGROUND Since there is increasing evidence that both acute (perfusion-limited) and chronic (diffusion-limited) hypoxia, and tumor repopulation may prejudice the outcome of radiotherapy, the combination of carbogen (95% oxygen-5% carbon dioxide) and nicotinamide with accelerated radiotherapy (ARCON) should reduce the impact of these factors of radioresistance. AIM This clinical study was aimed at determining the feasibility, as well as the qualitative and quantitative toxic effects of a therapeutic approach based on ARCON, and assessing the tumor response rates that can be achieved with this regime in patients with locally advanced tumors of the head and neck. METHODS A phase I/II study conducted between 1993 and 1996 by the Co-operative Group of Radiotherapy of the EORTC included three consecutive steps: accelerated fractionation (AF) combined with carbogen (11 analyzable patients), AF combined with the daily administration of nicotinamide (n=10), and AF with both carbogen and nicotinamide (n=17). Radiotherapy was based on an accelerated regime (72 Gy in 5.5 weeks). Nicotinamide was delivered 90 min before the first irradiation session, at a daily dose of 6 g. Carbogen breathing started 5 min before irradiation and lasted throughout the entire radiotherapy sessions. RESULTS No significant difference in loco-regional toxicity was found among the three study steps, when carbogen and nicotinamide, either alone or in combination, were combined with AF. The feasibility of the ARCON protocol, as proposed in the present EORTC study, appears to be significantly impaired when nicotinamide is added, at a daily dose of 6 g, to AF and carbogen, in an unselected group of patients. More than 20% of patients experienced grade 2 or 3 emesis. It also demonstrates, in unselected groups of patients, no significant difference in tumor response and local control when carbogen and nicotinamide, either alone or in combination, are added to accelerated radiotherapy. The percentages of objective response at 2 months were 81, 70 and 87%, respectively. CONCLUSION Future ARCON trials should target selected head and neck tumor localizations and stages, and a lower nicotinamide dose is needed to reduce severe upper gastro-intestinal toxicity.

ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC

BACKGROUND Non small cell lung cancers (NSCLC) are rapidly proliferating tumours, which are characterized by the presence of extensive hypoxic components, especially in patients with advanced loco-regional disease. Previous studies suggest a deleterious impact of acute (perfusion-limited) hypoxia on the outcome of radiotherapy for these tumours. AIM This pilot study was aimed at determining the feasibility and tumour response rates that can be achieved with an ARCON regime in patients with locally advanced, staged IIIA or B, NSCLC tumours. METHODS The phase I/II study included three steps: accelerated fractionation (AF) combined with carbogen (ten analysable patients), AF together with the daily administration of nicotinamide (n = 11 ) and AF with both carbon and nicotinamide (n = 14). Radiotherapy was based on a large daily dose per fraction (2.75 Gy up to 55 Gy in 4 weeks). Nicotinamide was administered at a dose of 6 g per patient per treatment day and carbogen was inhaled for 5 min before and during radiotherapy. RESULTS The incidence of grade 3 + acute toxicity during the irradiation did not exceed 10%, neither in the lung parenchyma nor in the mediastinum. No significant difference was found in loco-regional, radio-induced toxicity among the three study steps. Although a similar fraction of patients showed grade 2 or 3 emesis in all the steps, of the 25 patients entered in the two Nicotinamide containing steps 10 (40%) developed grade 2 or greater reactions which significantly detracted from their quality of life. There was no significant difference in tumour clearance rate among the three steps. The percentage of objective responses at 2 months was 60, 54 and 57% in steps 1, 2 and 3, respectively. CONCLUSION The feasibility of this ARCON protocol, using 2.75 Gy doses per fraction over 4 weeks, is good as regards radiotherapy-related side effects but it appears necessary in future to reduce the dose of Nicotinamide to reduce the incidence of nausea and vomiting. There was no significant difference in time to progression among the three study steps.

Retroperitoneal soft tissue sarcomas: A pilot study of intraoperative radiation therapy

This pilot study was conducted to evaluate the feasibility and tolerance of a multimodal therapy of retroperitoneal soft tissue sarcoma (STS), including intraoperative radiation therapy (IORT). Nineteen patients (14 primarily treated patients and 5 treated for a recurrent tumor) were included. Surgery included a complete resection (14), a partial resection (2), and no resection (2). The median IORT dose was 17 Gy. Thirteen patients also received an external radiation therapy (ERT). Nine patients received chemotherapy. There was no postoperative mortality. Immediate postoperative complications occurred in four patients (21%). Delayed complications occurred in six patients, including one lethal iliac artery disruption. With a median follow‐up of 17 months, the 2‐year disease‐free survival rate was 60%, and the 2‐year actuarial local control rate was 76%. A multimodality approach of treatment, including IORT and ERT and eventually chemotherapy, appears feasible in patients with retroperitoneal STS. However, the treatment‐related morbidity appeared relatively high in this study.

Ethmoidal cancers : a retrospective study of 22 cases

From April 1978 to June 1990, 22 patients with ethmoidal cancer were treated at Fondation Bergonié by a combination of surgery and radiation therapy. The mean age was 59.6 years (range 34-79 years) and the sex ratio is 2.7 (16 males/6 females). Histologic types were: adenocarcinoma, 13 cases; squamous carcinoma, 4 cases; undifferentiated carcinoma, 3 cases and esthesioneuroblastoma, 2 cases. Exposure to wood dust was encountered in 11 patients, especially in cases of adenocarcinoma: 10/13 (77%). Staging according to the classification of the University of Florida was: Stage I, 10 patients; Stage II, 5 patients and Stage III, 7 patients. Resection was considered as complete in 16 cases and only one orbital exenteration was performed. The postoperative radiation therapy delivered a mean given dose of 55.7 Gy (range 50-70 Gy) expressed to the hot spot using a technique adapted to tumor location and extension. Complete remission was achieved in 20 cases. Median follow-up is 28 months. The 5-year overall and disease-free survival are 44% and 38%, respectively. Analysis of recurrences according to staging gives: 5/10 Stage I, 2/5 Stage II and 5/7 Stage III. Recurrence is pejorative since death occurs in all cases within an average of 6 months following salvage treatment, except for three patients still alive within less than 6 months and in second remission. Prognosis of ethmoidal cancer depends on staging and local control.