Prognostic Impact of Prostate-Specific Antigen at 6 Months After Radiotherapy in Localized Prostate Cancer: An Individual Patient Data Analysis of Randomized Trials.

PURPOSE: We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT). PATIENTS AND METHODS: Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment. RESULTS: Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT - MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT - MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL. CONCLUSION: PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.

Long-term Outcomes and Patterns of Relapse Following High-dose Elective Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Nodes in Prostate Cancer: OLIGOPELVIS (GETUG-P07).

Androgen deprivation therapy (ADT) is a mainstay of treatment for metastatic prostate cancer, while additional salvage radiotherapy may offer prolonged remission for patients with regional node relapses. We report 5-yr outcomes from OLIGOPELVIS (GETUG-P07), an open-label phase 2 trial assessing long-term outcomes and patterns of relapse after 6-mo ADT and elective nodal radiotherapy (ENRT) in men with pelvic nodal oligorecurrence (<6 lesions) of prostate cancer. Progression was defined as two consecutive prostate-specific antigen (PSA) levels above the level at inclusion and/or clinical progression according to Response Evaluation Criteria in Solid Tumors v1.1 and/or death from any cause. Sixty-seven patients were recruited. Median follow-up was 6.1 yr (95% confidence interval 5.9-6.3). Rates of grade 2+ toxicities among patients without progression at 3, 4, and 5 yr were 15%, 9%, and 4% for genitourinary toxicities, and 2%, 3%, and 4% for gastrointestinal toxicities, respectively. The 5-yr progression-free, biochemical relapse-free, and ADT-free survival rates were 39%, 31%, and 64%, respectively. In total, 45 patients experienced progression, which was PSA-only progression in seven cases. Among the other 38 patients, local clinical progression occurred in 18%, progression to N1 stage in 29%, to M1a stage in 50%, to M1b stage in 32%, and to M1c stage in 11%. Finally, combined ENRT and ADT appeared to prolong tumor control with limited toxicity. At 5 yr, one-third of the patients had not experienced biochemical relapse. The major site of relapse was the para-aortic lymph nodes. PATIENT SUMMARY: We evaluated long-term results for high-dose radiotherapy in patients with recurrence of prostate cancer in pelvic lymph nodes. We found that this treatment provided prolonged tumor control without significant toxicity. One-third of the patients were still in complete remission after 5 years.

A comparison of two modalities of stereotactic body radiation therapy for peripheral early-stage non-small cell lung cancer: results of a prospective French study.

OBJECTIVES: This prospective, observational, non-randomized multicentric study was conducted to compare efficiency and toxicity using different modalities of stereotactic body radiation therapy (SBRT) in early-stage peripheral non-small cell lung cancer (NSCLC). METHODS: From 9 April to 11 December, 106 patients were treated according to the local equipment availability for peripheral NSCLC with SBRT: 68 by linear accelerator equipped for SBRT and 38 by Cyberknife®. Multivariate analysis and propensity score analysis using Inverse Probability Treatment Weighting (IPTW) were undertaken in an effort to adjust for potential bias due to non-randomization. RESULTS: 2-year local control rates were 97.0% (95% CI: [90.6%; 99.4%]) with SBRT by Linac vs 100% (95% CI: ([100%; 100%]) with Cyberknife® (p = 0.2839). 2-year PFS and 2-year OS rates were 52.7% (95% CI [39.9%;64.0%]) versus 54.1% (95% CI [36.8; 68.6%]) (p = 0.8582) and 65.1% (95% CI: [51.9%; 75.5%] versus 83.9% (95% CI: [67.5%; 92.4%] (p = 0.0831) using Linac and Cyberknife® respectively. Multivariate regression analysis indicates no significant effect of SBRT treatment type on PFS or OS. Local relapse could not be modeled due to the small number of events (n = 2). Acute and late toxicity rates were not significantly different. After IPTW adjustment, results were unchanged. CONCLUSIONS: No difference in efficiency or toxicity was shown after SBRT of peripheral NSCLC treatment using Linac or Cyberknife®. ADVANCES IN KNOWLEDGE: This is the first large prospective non-randomized study focusing on peripheral localized NSCLC comparing SBRT using an appropriately equipped linac with Cyberknife®. No significant difference in efficiency or toxicity was shown in this situation.

Early Toxicity of a Phase 2 Trial of Combined Salvage Radiation Therapy and Hormone Therapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS GETUG P07).

PURPOSE: Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiation therapy as considered in the BLINDED trial is an attractive option, but there are concerns about its toxicity. This article describes early toxicity with the technique. METHODS AND MATERIALS: BLINDED was a prospective multicenter phase 2 trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron emission tomography-positive pelvic lymph nodes, combined with 6-month androgen blockade. The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathologic pelvic lymph nodes. Early toxicity was defined as toxicity until 1 year after radiation therapy. Patients quality of life was assessed using the European Organisation for Research and Treatment of Cancer questionnaires (QLQ-C30 and QLQ-PR25). RESULTS: Seventy-four patients were recruited in 15 French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included 67 patients. Half had received prior prostatic irradiation. Median age was 67.7 ± 6.5 years. Grade 2 acute urinary toxicity was observed in 9 of 67 patients (13.4%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10 of 67 patients (14.9%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. The European Organisation for Research and Treatment of Cancer questionnaire scores at 1 year did not worsen significantly. CONCLUSIONS: The acute and 1-year toxicity of the BLINDED protocol was satisfactory, even in patients with a history of prostatic irradiation.

Cyberknife® stereotactic radiation therapy for stage I lung cancer and pulmonary metastases: evaluation of local control at 24 months.

BACKGROUND: CyberKnife® stereotactic radiotherapy allows for minimally invasive treatment with satisfactory results in patients with inoperable primary or metastatic lung cancer. The objective of this study was to identify factors influencing the probability of local control. METHODS: Ninety-five patients (100 lung tumors) treated between January and December 2013 at our department by SBRT (stereotactic body radiation therapy) using CyberKnife® were included in the study. There were 71 stage T1 or T2 primary tumors and 29 secondary tumors. The tracking methods were as follow: fiducial markers with Synchrony® in 50 cases (gold seeds in 35, coils in 15 cases), spine with 4D-CT and Xsight® Spine in 43 cases, and direct viewing by Xsight® Lung in 7 cases. The methods were allocated according to the characteristics of each target. RESULTS: With a median follow-up of 24 months, the probability of local control at 24 months was 88%. The probability of local control differed according to the size of the target (92% for tumors ≤35 mm and 54% for tumors >35 mm: P=0.013) and according to the distance of the fiducial markers in relation to the target (95% when <50 mm and 69% when ≥50 mm: P=0.011). CONCLUSIONS: The best results were obtained with small lesions. With Synchrony®, the distance of the target relative to the fiducial markers should be less than 50 mm. Gold seeds are recommended, although coils may be used instead of gold seeds. The number of fiducial markers did not have a significant impact on the probability of local control. With an appropriate tracking method, stereotactic radiotherapy is an efficient treatment for stage I lung cancer and lung oligometastases.

Daily Versus Weekly Prostate Cancer Image Guided Radiation Therapy: Phase 3 Multicenter Randomized Trial.

PURPOSE: The optimal frequency of prostate cancer image guided radiation therapy (IGRT) has not yet been clearly identified. This study sought to compare the safety and efficacy of daily versus weekly IGRT. MATERIALS AND METHODS: This phase 3 randomized trial recruited patients with N0 localized prostate cancer. The total IGRT doses in the prostate ranged from 70 Gy to 80 Gy, sparing the lymph nodes. Patients were randomly assigned (1:1) to 2 prostate IGRT frequency groups: daily and weekly (ie, on days 1, 2, and 3 and then weekly). The primary outcome was 5-year recurrence-free survival. Secondary outcomes included overall survival and toxicity. Post hoc analyses included biochemical progression-free interval, clinical progression-free interval, and other cancer-free interval. RESULTS: Between June 2007 and November 2012, 470 men from 21 centers were randomized into the 2 groups. Median follow-up was 4.1 years. There was no statistically significant difference in recurrence-free survival between the groups (hazard ratio [HR] = 0.81; P = .330). Overall survival was worse in the daily group than in the weekly group (HR = 2.12 [95% confidence interval (CI), 1.03-4.37]; P = .042). Acute rectal bleeding (grade ≥1) was significantly lower in the daily group (6%) (n = 14) than in the weekly group (11%) (n = 26) (P = .014). Late rectal toxicity (grade ≥1) was significantly lower in the daily group (HR = 0.71 [95% CI, 0.53-0.96]; P = .027). Biochemical progression-free interval (HR = 0.45 [95% CI, 0.25 - 0.80]; P = .007) and clinical progression-free interval (HR = 0.50 [95% CI, 0.24-1.02]; P = .057) were better in the daily group, whereas other cancer-free interval was worse in the daily group (HR = 2.21 [95% CI, 1.10-4.44]; P = .026). CONCLUSIONS: Compared with weekly control, daily IGRT control in prostate cancer significantly improves biochemical progression-free and clinical progression-free interval, and rectal toxicity.

Independent component analysis for rectal bleeding prediction following prostate cancer radiotherapy.

BACKGROUND AND PURPOSE: To evaluate the benefit of independent component analysis (ICA)-based models for predicting rectal bleeding (RB) following prostate cancer radiotherapy. MATERIALS AND METHODS: A total of 593 irradiated prostate cancer patients were prospectively analyzed for Grade ≥2 RB. ICA was used to extract two informative subspaces (presenting RB or not) from the rectal DVHs, enabling a set of new pICA parameters to be estimated. These DVH-based parameters, along with others from the principal component analysis (PCA) and functional PCA, were compared to "standard" features (patient/treatment characteristics and DVH bins) using the Cox proportional hazards model for RB prediction. The whole cohort was divided into: (i) training (N = 339) for ICA-based subspace identification and Cox regression model identification and (ii) validation (N = 254) for RB prediction capability evaluation using the C-index and the area under the receiving operating curve (AUC), by comparing predicted and observed toxicity probabilities. RESULTS: In the training cohort, multivariate Cox analysis retained pICA and PC as significant parameters of RB with 0.65 C-index. For the validation cohort, the C-index increased from 0.64 when pICA was not included in the Cox model to 0.78 when including pICA parameters. When pICA was not included, the AUC for 3-, 5-, and 8-year RB prediction were 0.68, 0.66, and 0.64, respectively. When included, the AUC increased to 0.83, 0.80, and 0.78, respectively. CONCLUSION: Among the many various extracted or calculated features, ICA parameters improved RB prediction following prostate cancer radiotherapy.

Intensity-modulated radiation therapy from 70Gy to 80Gy in prostate cancer: six- year outcomes and predictors of late toxicity.

OBJECTIVE: To report grade ≥2 overall late rectal and urinary toxicities in patients (pts) with prostate cancer treated by intensity-modulated radiotherapy (IMRT) at 3 dose-levels. Identify predictors of radiation toxicity and report biochemical progression free survival (bPFS). METHODS: A total of 277 pts were treated with 70Gy (10.8%), 74Gy (63.9%) and 80 Gy (25.3%) using IMRT without pelvic irradiation were analyzed. Short or long-course androgen deprivation therapy (ADT) was allowed in 46.1% of pts. The toxicity was described using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 scale. Cox regression models addressed demographics, disease and dosimetry characteristics as potential predictors of late grade ≥2 toxicity after adjusting for other modifying factors. RESULTS: The median follow-up was 77 months (range 15; 150). There was no grade ≥4 toxicity. The 5-year cumulative rate of grade ≥2 late rectal and urinary toxicities was 6.3% (95% CI = 3.8%; 10.3%) and 25.3% (95% CI = 19.8%; 31.8%) respectively. In multivariate analysis, only the dose (80Gy vs 74 and 70Gy) was found to increase the risk of rectal toxicity (HR = 2.96 [1.07; 8.20]). For pts receiving 74 Gy, International Prostate Symptom Score (IPSS) at baseline ≥8 (HR = 2.40 [1.08; 5.35]) and dose ≥73Gy delivered in more than 2% of bladder (D2%) were found to be predictors of bladder toxicity (HR = 3.29 [1.36; 7.98]). The 5-year biochemical relapse free survival was 81.0% [74.5%; 86.0%] in the entire population, 97.5% [83.5%; 99.6%] in the low risk group, 84.9% [76.7%; 90.3%] in the intermediate risk group and 66.4% [51.8%; 77.4%] in the high-risk group. D'Amico low (HR = 0.09 [0.01; 0.69]) and intermediate risk groups (HR = 0.50 [0.28; 0.88]) as well as PSA nadir ≥0.2 ng/ml (HR = 1.79 [1.01; 3.21]) were predictive of biochemical relapse. CONCLUSIONS: The rate of late rectal toxicity increased with higher doses, while Dmax ≥74Gy, D2% ≥ 73Gy for bladder wall and baseline IPSS ≥8 increased late urinary toxicity.

Nomogram to predict rectal toxicity following prostate cancer radiotherapy.

BACKGROUND: To identify predictors of acute and late rectal toxicity following prostate cancer radiotherapy (RT), while integrating the potential impact of RT technique, dose escalation, and moderate hypofractionation, thus enabling us to generate a nomogram for individual prediction. METHODS: In total, 972 patients underwent RT for localized prostate cancer, to a total dose of 70 Gy or 80 Gy, using two different fractionations (2 Gy or 2.5 Gy/day), by means of several RT techniques (3D conformal RT [3DCRT], intensity-modulated RT [IMRT], or image-guided RT [IGRT]). Multivariate analyses were performed to identify predictors of acute and late rectal toxicity. A nomogram was generated based on the logistic regression model used to predict the 3-year rectal toxicity risk, with its accuracy assessed by dividing the cohort into training and validation subgroups. RESULTS: Mean follow-up for the entire cohort was 62 months, ranging from 6 to 235. The rate of acute Grade ≥2 rectal toxicity was 22.2%, decreasing when combining IMRT and IGRT, compared to 3DCRT (RR = 0.4, 95%CI: 0.3-0.6, p<0.01). The 5-year Grade ≥2 risks for rectal bleeding, urgency/tenesmus, diarrhea, and fecal incontinence were 9.9%, 4.5%, 2.8%, and 0.4%, respectively. The 3-year Grade ≥2 risk for overall rectal toxicity increased with total dose (p<0.01, RR = 1.1, 95%CI: 1.0-1.1) and dose per fraction (2Gy vs. 2.5Gy) (p = 0.03, RR = 3.3, 95%CI: 1.1-10.0), and decreased when combining IMRT and IGRT (RR = 0.50, 95% CI: 0.3-0.8, p<0.01). Based on these three parameters, a nomogram was generated. CONCLUSIONS: Dose escalation and moderate hypofractionation increase late rectal toxicity. IMRT combined with IGRT markedly decreases acute and late rectal toxicity. Performing combined IMRT and IGRT can thus be envisaged for dose escalation and moderate hypofractionation. Our nomogram predicts the 3-year rectal toxicity risk by integrating total dose, fraction dose, and RT technique.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).

See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-ß = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

Is There a Role for Pelvic Irradiation in Localized Prostate Adenocarcinoma? Update of the Long-Term Survival Results of the GETUG-01 Randomized Study.

PURPOSE: To report the long-term results of the French Genitourinary Study Group (GETUG)-01 study in terms of event-free survival (EFS) and overall survival (OS) and assess the potential interaction between hormonotherapy and pelvic nodes irradiation. PATIENTS AND METHODS: Between December 1998 and June 2004, 446 patients with T1b-T3, N0pNx, M0 prostate carcinoma were randomly assigned to either pelvic nodes and prostate or prostate-only radiation therapy. Patients were stratified into 2 groups: "low risk" (T1-T2 and Gleason score 6 and prostate-specific antigen <3× the upper normal limit of the laboratory) (92 patients) versus "high risk" (T3 or Gleason score >6 or prostate-specific antigen >3× the upper normal limit of the laboratory). Short-term 6-month neoadjuvant and concomitant hormonal therapy was allowed only for high-risk patients. Radiation therapy was delivered with a 3-dimensional conformal technique, using a 4-field technique for the pelvic volume (46 Gy). The total dose recommended to the prostate moved from 66 Gy to 70 Gy during the course of the study. Criteria for EFS included biologic prostate-specific antigen recurrences and/or a local or metastatic progression. RESULTS: With a median follow-up of 11.4 years, the 10-year OS and EFS were similar in the 2 treatment arms. A higher but nonsignificant EFS was observed in the low-risk subgroup in favor of pelvic nodes radiation therapy (77.2% vs 62.5%; P=.18). A post hoc subgroup analysis showed a significant benefit of pelvic irradiation when the risk of lymph node involvement was <15% (Roach formula). This benefit seemed to be limited to patients who did not receive hormonal therapy. CONCLUSION: Pelvic nodes irradiation did not statistically improve EFS or OS in the whole population but may be beneficial in selected low- and intermediate-risk prostate cancer patients treated with exclusive radiation therapy.

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.

Random forests to predict rectal toxicity following prostate cancer radiation therapy.

PURPOSE: To propose a random forest normal tissue complication probability (RF-NTCP) model to predict late rectal toxicity following prostate cancer radiation therapy, and to compare its performance to that of classic NTCP models. METHODS AND MATERIALS: Clinical data and dose-volume histograms (DVH) were collected from 261 patients who received 3-dimensional conformal radiation therapy for prostate cancer with at least 5 years of follow-up. The series was split 1000 times into training and validation cohorts. A RF was trained to predict the risk of 5-year overall rectal toxicity and bleeding. Parameters of the Lyman-Kutcher-Burman (LKB) model were identified and a logistic regression model was fit. The performance of all the models was assessed by computing the area under the receiving operating characteristic curve (AUC). RESULTS: The 5-year grade ≥2 overall rectal toxicity and grade ≥1 and grade ≥2 rectal bleeding rates were 16%, 25%, and 10%, respectively. Predictive capabilities were obtained using the RF-NTCP model for all 3 toxicity endpoints, including both the training and validation cohorts. The age and use of anticoagulants were found to be predictors of rectal bleeding. The AUC for RF-NTCP ranged from 0.66 to 0.76, depending on the toxicity endpoint. The AUC values for the LKB-NTCP were statistically significantly inferior, ranging from 0.62 to 0.69. CONCLUSIONS: The RF-NTCP model may be a useful new tool in predicting late rectal toxicity, including variables other than DVH, and thus appears as a strong competitor to classic NTCP models.

Nomograms to predict late urinary toxicity after prostate cancer radiotherapy.

OBJECTIVE: To analyze late urinary toxicity after prostate cancer radiotherapy (RT): symptom description and identification of patient characteristics or treatment parameters allowing for the generation of nomograms. METHODS: Nine hundred and sixty-five patients underwent RT in seventeen French centers for localized prostate cancer. Median total dose was 70 Gy (range, 65-80 Gy), using different fractionations (2 or 2.5 Gy/day) and techniques. Late urinary toxicity and the corresponding symptoms (urinary frequency, incontinence, dysuria/decreased stream, and hematuria) were prospectively assessed in half of the patients using the LENT-SOMA classification. Univariate and multivariate Cox regression models addressed patient or treatment-related predictors of late urinary toxicity (≥grade 2). Nomograms were built up, and their performance was assessed. RESULTS: The median follow-up was 61 months. The 5-year (≥grade 2) global urinary toxicity, urinary frequency, hematuria, dysuria, and urinary incontinence rates were 15, 10, 5, 3 and 1 %, respectively. The 5-year (≥grade 3) urinary toxicity rate was 3 %. The following parameters significantly increased the 5-year risk of global urinary toxicity (≥grade 2): anticoagulant treatment (RR = 2.35), total dose (RR = 1.09), and age (RR = 1.06). Urinary frequency was increased by the total dose (RR = 1.07) and diabetes (RR = 4). Hematuria was increased by anticoagulant treatment (RR = 2.9). Dysuria was increased by the total dose (RR = 1.1). Corresponding nomograms and their calibration plots were generated. Nomogram performance should be validated with external data. CONCLUSIONS: The first nomograms to predict late urinary toxicity but also specific urinary symptoms after prostate RT were generated, contributing to prostate cancer treatment decision.

Cost of prostate image-guided radiation therapy: results of a randomized trial.

PURPOSE: This cost analysis aimed to quantify the cost of IGRT in relation to IGRT frequency and modality with Cone Beam Computed Tomography (CBCT) or orthogonal electronic portal imaging with fiducial markers (EPI-FM). MATERIAL AND METHODS: Patients undergoing IGRT for localized prostate cancer were randomized into two prostate control frequencies (daily or weekly). Costs were calculated based on the micro-costing results according to hospitals' perspectives (in Euros, 2009) and the time horizon was radiation therapy. RESULTS: A total of 208 patients were enrolled in seven French cancer centers. A total of 6865 fractions were individually analyzed. The mean total treatment fraction duration was 21.0 min for daily CBCT and 18.3 min for daily EPI-FM. Increasing the control frequency from weekly to daily increased the mean treatment fraction duration by 7.3 min (+53%) for CBCT and 1.7 min (+10%) for EPI-FM (p ≤ 0.01). The mean additional cost per patient of daily controls compared with weekly controls was €679 and €187 for CBCT and EPI-FM, respectively (p<0.0001). CONCLUSIONS: The incremental costs due to different prostate IGRT strategies are relatively moderate, suggesting that daily IGRT combined with intensity-modulated RT (IMRT) could be administered in cases of high-dose radiation delivery to the prostate.

Respiratory gating techniques for optimization of lung cancer radiotherapy.

PURPOSE: The primary objective of the STIC 2003 project was to compare the clinical and economic aspects of respiratory-gated conformal radiotherapy (RGRT), an innovative technique proposed to limit the impact of respiratory movements during irradiation, versus conventional conformal radiotherapy, the reference radiation therapy for lung cancer. METHODS AND MATERIALS: A comparative, nonrandomized, multicenter, and prospective cost toxicity analysis was performed in the context of this project between April 2004 and June 2008 in 20 French centers. Only the results of the clinical study are presented here, as the results of the economic assessment have been published previously. RESULTS: The final results based on 401 evaluable patients confirm the feasibility and good reproducibility of the various RGRT systems. The results of this study demonstrated a marked reduction of dosimetric parameters predictive of pulmonary, cardiac and esophageal toxicity as a result of the various respiratory gating techniques. These dosimetric benefits were mainly observed with deep inspiration breath-hold (DIBH) techniques (ABC and SDX systems), which markedly increased the total lung volume compared with the inspiration-synchronized system based on tidal volume (Real-time Position Management). These theoretical dosimetric benefits were correlated clinically with a significant reduction of pulmonary acute toxicity, and the pulmonary, cardiac, and esophageal late toxicities, especially with DIBH techniques. Pulmonary function parameters, although more heterogeneous, especially DLCO, showed a tendency to reduction of pulmonary toxicity in the RGRT group. CONCLUSIONS: RGRT seems to be essential to reduce toxicities, especially the pulmonary, cardiac, and esophageal late toxicities with the DIBH methods.

Quality of life assessment after concurrent chemoradiation for invasive bladder cancer: results of a multicenter prospective study (GETUG 97-015).

PURPOSE: To evaluate bladder preservation and functional quality after concurrent chemoradiotherapy for muscle-invasive cancer in 53 patients included in a Phase II trial. PATIENT AND METHODS: Pelvic irradiation delivered 45 Gy, followed by an 18-Gy boost. Concurrent chemotherapy with cisplatin and 5-fluorouracil by continuous infusion was performed at Weeks 1, 4, and 7 during radiotherapy. Patients initially suitable for surgery were evaluated with macroscopically complete transurethral resection after 45 Gy, followed by radical cystectomy in case of incomplete response. The European Organization for Research and Treatment of Cancer quality of life questionnaire QLQ-C30, specific items on bladder function, and the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic (LENT-SOMA) symptoms scale were used to evaluate quality of life before treatment and 6, 12, 24, and 36 months after treatment. RESULTS: Median age was 68 years for 51 evaluable patients. Thirty-two percent of patients had T2a tumors, 46% T2b, 16% T3, and 6% T4. A visibly complete transurethral resection was possible in 66%. Median follow-up was 8 years. Bladder was preserved in 67% (95% confidence interval, 52-79%) of patients. Overall survival was 36% (95% confidence interval, 23-49%) at 8 years for all patients, and 45% (28-61%) for the 36 patients suitable for surgery. Satisfactory bladder function, according to LENT-SOMA, was reported for 100% of patients with preserved bladder and locally controlled disease 6-36 months after the beginning of treatment. Satisfactory bladder function was reported for 35% of patients before treatment and for 43%, 57%, and 29%, respectively, at 6, 18, and 36 months. CONCLUSIONS: Concurrent chemoradiation therapy allowed bladder preservation with tumor control for 67% patients at 8 years. Quality of life and quality of bladder function were satisfactory for 67% of patients.

70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial.

PURPOSE: To perform a randomized trial comparing 70 and 80 Gy radiotherapy for prostate cancer. PATIENTS AND METHODS: A total of 306 patients with localized prostate cancer were randomized. No androgen deprivation was allowed. The primary endpoint was biochemical relapse according to the modified 1997-American Society for Therapeutic Radiology and Oncology and Phoenix definitions. Toxicity was graded using the Radiation Therapy Oncology Group 1991 criteria and the late effects on normal tissues-subjective, objective, management, analytic scales (LENT-SOMA) scales. The patients' quality of life was scored using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item cancer-specific and 25-item prostate-specific modules. RESULTS: The median follow-up was 61 months. According to the 1997-American Society for Therapeutic Radiology and Oncology definition, the 5-year biochemical relapse rate was 39% and 28% in the 70- and 80-Gy arms, respectively (p = .036). Using the Phoenix definition, the 5-year biochemical relapse rate was 32% and 23.5%, respectively (p = .09). The subgroup analysis showed a better biochemical outcome for the higher dose group with an initial prostate-specific antigen level >15 ng/mL. At the last follow-up date, 26 patients had died, 10 of their disease and none of toxicity, with no differences between the two arms. According to the Radiation Therapy Oncology Group scale, the Grade 2 or greater rectal toxicity rate was 14% and 19.5% for the 70- and 80-Gy arms (p = .22), respectively. The Grade 2 or greater urinary toxicity was 10% at 70 Gy and 17.5% at 80 Gy (p = .046). Similar results were observed using the LENT-SOMA scale. Bladder toxicity was more frequent at 80 Gy than at 70 Gy (p = .039). The quality-of-life questionnaire results before and 5 years after treatment were available for 103 patients with no differences found between the 70- and 80-Gy arms. CONCLUSION: High-dose radiotherapy provided a better 5-year biochemical outcome with slightly greater toxicity.

Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial.

Locally advanced non-small cell lung cancers share a risk of both local and systemic recurrence and justifies a therapeutic strategy combining focal and systemic treatment. In resectable stage IIIA-N2 tumors, peri-operative chemotherapy significantly increases survival rates. Chemoradiotherapy, which is the standard treatment of non-resectable locally advanced tumors, may have a role as an induction treatment to reduce locoregional recurrence rates. In the present phase II trial, we aimed at comparing standard induction chemotherapy (arm A: cisplatin and gemcitabine) with 2 different regimens of induction chemoradiotherapy (total dose: 46 Gy) including third-generation cytotoxic agents (arm B: cisplatin and vinorelbine; arm C: carboplatin and paclitaxel) in patients with resectable stage IIIA-N2 NSCLC, using feasibility of the whole strategy, including surgery, as a primary endpoint. A total of 46 patients were included. Response rate was significantly higher after induction chemoradiotherapy vs. chemotherapy (87% vs. 57%, p=0.049). A total of 44 patients underwent operation. The feasibility rate of the proposed therapeutic strategy was 89% for the whole cohort, 93% in arm A (induction chemotherapy with cisplatin and gemcitabine), 88% in arm B (induction chemoradiotherapy with cisplatin and vinorelbine), and 87% in arm C (induction chemoradiotherapy with carboplatin and paclitaxel) (p=0.857). Overall median, 1-year, and 3-year survival were 30 months, 87%, and 43%, respectively. Induction chemoradiotherapy with modern treatment regimens is highly feasible and may show promises in the current and future developments of multimodal therapeutic strategies in locally advanced NSCLC.

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.