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.

Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial.

BACKGROUND: Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. METHODS: We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731. FINDINGS: We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths. INTERPRETATION: Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. FUNDING: Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Very Long-Term Complete Remission Can Be Achieved in Men With High-Risk Localized Prostate Cancer and a Very High PSA Value: An Analysis of the GETUG 12 Phase 3 Trial.

INTRODUCTION: Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established. PATIENTS AND METHODS: Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions. RESULTS: The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events. CONCLUSIONS: Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

Impact of suboptimal tandem implantation on local control and complications in intracavitary brachytherapy for cervix cancer.

PURPOSE: Correct tandem implantation for cervix cancer intracavitary brachytherapy may be challenging. We investigated whether suboptimal implantation can be related to patient and disease characteristics and may result in subsequent underutilization of brachytherapy in cervical cancer. METHODS AND MATERIALS: Consecutive cervix cancer patients referred for intracavitary brachytherapy after external beam radiation therapy performed in several general hospitals from 2013 to 2017 were included. RESULTS: In 172 patients having 301 procedures, 95 implantations were suboptimal (15% inadequate tandem insertions, 10% subserosal insertion, and 6% uterine perforation on postimplant CT scan). Risk factors were age, myometrium invasion, and uterine retroversion. Median followup was 21 months. Three-year local control and survival rates were 72% and 85%, respectively. Forty-seven patients (27%) failed to receive brachytherapy. Failure to perform brachytherapy was associated with poorer local control (OR = 0.34 [0.17-0.67], p = 0.001). By contrast, suboptimal implantation did not increase local failure or toxicity rates in patients undergoing brachytherapy. No peritoneal carcinomatosis occurred after uterine perforation in our cohort. CONCLUSIONS: Suboptimal implantation was frequent. In the absence of image guidance during implantation, conversion to other treatment modalities (including external beam radiation therapy) due to insertion difficulties resulted in worse local control. With optimization, however, suboptimal brachytherapy implantation did not result in suboptimal dose coverage or poorer local control. Failure to perform a brachytherapy boost correlates with increased local failure risk in patients with cervix cancer, whereas tandem malposition does not. Real-time intraoperative ultrasound guidance may be useful to reduce uterine perforation rates and thus increase brachytherapy use.

Pairwise comparison of 18F-FDG and 18F-FCH PET/CT in prostate cancer patients with rising PSA and known or suspected second malignancy.

OBJECTIVE: This study aimed to evaluate the usefulness of combining fluorine-18 choline (F-FCH) and fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in patients with rising prostate-specific antigen and known or suspected second malignancy. MATERIALS AND METHODS: F-FCH and F-FDG PET/CT were performed 15±9 days apart on the same PET/CT system and acquisition and reconstruction parameters. A mean standardized uptake value (SUVmean) was computed for every lesion that could be discriminated with both tracers. PET results were confirmed by histology (eight patients) and clinical and imaging follow-up (mean±SD: 15±9 months). RESULTS: Of 77 consecutive patients who underwent F-FCH PET/CT scans for suspected prostate cancer recurrence, 10 (13%) were suspected to have a second malignancy because of F-FCH PET pattern inconsistency with that of prostate cancer (n=6), because of a history of a second malignancy with similar metastatic patterns (n=2) or inconsistency between disease burden and prostate-specific antigen value (n=2). Seventy lesions were studied, with a final diagnosis of prostate cancer, other cancers and benign disease in 55, nine and six lesions, respectively. F-FCH SUVmean and F-FCH/F-FDG SUVmean ratios were significantly different between prostate cancer, nonprostate cancer and benign disease (P<0.0001 and P=0.04, respectively). Receiving operating characteristic analysis showed that the F-FCH/F-FDG ratios were not better than F-FCH SUVmean in discriminating prostate cancer from nonprostate cancer and benign diseases (sensitivity, specificity and area under the curve were 69%, 80%, 0.71 and 84%, 80% and 0.89, respectively). CONCLUSION: We found that F-FCH/F-FDG SUVmean ratios cannot differentiate prostate cancer recurrences from other cancer types when both diagnoses are suspected. Doubtful lesions should be biopsied.

Outcome According to Elective Pelvic Radiation Therapy in Patients With High-Risk Localized Prostate Cancer: A Secondary Analysis of the GETUG 12 Phase 3 Randomized Trial.

PURPOSE: The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial. METHODS AND MATERIALS: Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS). RESULTS: A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio [HR]: 2.52 [95% confidence interval [CI]: 1.78-3.54], P<.0001), Gleason score 8 or higher (HR: 1.41 [95% CI: 1.03-1.93], P=.033) and PSA higher than 20 ng/mL (HR: 1.41 [95% CI: 1.02-1.96], P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 [95% CI: 0.48-0.9], P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 [95% CI: 0.78-1.55], P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 [95% CI: 0.59-1.31], P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity. CONCLUSIONS: This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients.

A phase III trial of docetaxel-estramustine in high-risk localised prostate cancer: a planned analysis of response, toxicity and quality of life in the GETUG 12 trial.

AIM: To assess docetaxel-estramustine in patients with localised high-risk prostate cancer. PATIENTS AND METHODS: After staging pelvic lymph node dissection, patients with high-risk prostate cancer randomly received androgen deprivation therapy (ADT) (3 years)+DE (4 cycles of docetaxel 70 mg/m(2)/3 weeks+estramustine 10mg/kg/dd1-5) or ADT alone. Local therapy was administered at 3 months. RESULTS: Four hundred and thirteen patients were accrued: T3-T4 (67%), Gleason score ~8 (42%), PSA >20 ng/mL (59%), pN+ (29%). In the chemotherapy arm, 94% of patients received the planned four cycles of docetaxel. Local treatment consisted of radiotherapy in 358 patients (87%) (median dose 74 Gy in both arms). ADT was given for 36 months in both arms. A PSA response (PSA ~0.2 ng/mL after 3 months of treatment) was obtained in 34% and 15% in the ADT+DE arm and in the ADT arm, respectively (p<0.0001). Febrile neutropenia occurred in only 2%. Moderate to severe hot flashes occurred less often in the ADT+DE arm (2% versus 22%; p<0.001). There was no toxicity-related death, no secondary leukaemia, and no excess second cancers. Chemotherapy had a negative impact on quality of life (global health status, p = 0.01; fatigue, p = 0.003; role functioning, p = 0.003; social functioning, p = 0.006) at 3 months but this effect disappeared at 1 year. CONCLUSION: Docetaxel-estramustine can be combined safely with standard therapy in high-risk prostate cancer, with a promising PSA response rate and no negative impact on quality of life after 1 year. Long-term follow-up is required to assess the impact on relapse and survival.

Randomized phase III trial (GORTEC 98-03) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent.

PURPOSE: This randomized phase III trial investigated the potential benefit of concurrent re-irradiation, fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary head and neck squamous cell carcinoma (HNSCC) in previously irradiated area. PATIENTS AND METHODS: Patients with recurrent HNSCC or a second primary not amenable to curative-intent treatment were randomized to the R-RT arm (concurrent re-irradiation, fluorouracil and hydroxyurea) or to the Ch-T arm (methotrexate). The primary endpoint was overall survival (OS). Due to a very slow accrual, the trial was closed after inclusion of 57 patients. RESULTS: Fifty-seven patients were included. All patients died in the two arms with a maximal follow-up of 5years. Although four complete responses were achieved in R-RT arm, (none in Ch-T arm) re-irradiation did not improve OS compared with methotrexate (23% versus 22% at 1year, NS). Sixteen patients experienced clinical grade ⩾3 late toxicities (>6months), 11 in R-RT arm and five in Ch-T arm. CONCLUSIONS: Premature discontinuation of the trial did not allow us to draw firm conclusions. However, there was no suggestion that concurrent re-irradiation, fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC.

Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01.

PURPOSE: To assess the benefit and toxicity and quality-of-life (QOL) outcomes of pelvic nodes irradiation in nonmetastatic prostate carcinoma patients. PATIENTS AND METHODS: Between December 1998 and June 2004, 444 patients with T1b-T3, N0 pNx, M0 prostate carcinoma were randomly assigned to either pelvic and prostate radiotherapy or prostate radiotherapy only. Patients were stratified according to the prognostic factor of lymph node involvement (LNI). Short-term 6-month neoadjuvant and concomitant hormonal therapy was allowed only for patients in the high-risk group. The pelvic dose was 46 Gy. The total dose recommended to the prostate was changed during the course of the study from 66 Gy to 70 Gy. Criteria for progression-free survival (PFS) included biologic prostate-specific antigen recurrences or a local or metastatic evolution. Acute and late toxicities were recorded according to the Radiation Therapy Oncology Group and Late Effects in Normal Tissues Subjective, Objective, Management, and Analytic scales, respectively. The QOL outcome was recorded with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, the International Prostatic Symptom Score, and the Sexual Function Index scales. RESULTS: With a 42.1-month median follow-up time, the 5-year PFS and overall survival were similar in the two treatment arms for the whole series and for each stratified group. On multivariate analysis, low LNI risk and hormonal therapy were statistically associated with increased PFS. However, subgroup analyses based on these factors did not show any benefit for pelvic irradiation. There were no significant differences in acute and late digestive toxicities and in QOL outcomes. CONCLUSION: Pelvic node irradiation was well tolerated but did not improve PFS.

Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial.

PURPOSE: With the aim to increase the dose intensity of radiation therapy (RT), and subsequently the locoregional control rate, a very accelerated RT regimen was compared with conventional RT in a series of patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Between 1994 and 1998, 268 patients with T3 or T4, N0 to N3 HNSCC (staged by 1997 International Union Against Cancer criteria) that was not eligible for surgery were randomly assigned to receive either conventional RT, delivering 70 Gy in 7 weeks to the primary tumor and 35 fractions of 2 Gy over 49 days, or to receive very accelerated RT, delivering 62 to 64 Gy in 31 to 32 fractions of 2 Gy over 22 to 23 days (2 Gy/fraction bid). RESULTS: The most common tumor site was the oropharynx and most of the patients (70%) had T4 and N1 to N3 tumors in 72% of patients. The main patient and tumor characteristics were well-balanced between the two arms. The median total doses were 63 Gy (accelerated) and 70 Gy (conventional), with a median overall time of 22 days and 48 days, respectively. Acute mucositis was markedly increased in the accelerated-RT arm (P < .001). The locoregional control rate was improved by 24% at 6 years with accelerated RT. In contrast, disease-free survival and overall survival were not significantly different between the two arms. There was no difference in late effects between the two arms. CONCLUSION: The very accelerated RT regimen was feasible and provided a major benefit in locoregional control but had a modest effect on survival.