Bernard Dubray

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.

Simultaneous positron emission tomography (PET) assessment of metabolism with 18F-fluoro-2-deoxy-d-glucose (FDG), proliferation with 18F-fluoro-thymidine (FLT), and hypoxia with 18fluoro-misonidazole (F-miso) before and during radiotherapy in patients with non-small-cell lung cancer (NSCLC): A pilot study

OBJECTIVES To investigate the changes in tumour proliferation (using FLT), metabolism (using FDG), and hypoxia (using F-miso) during curative (chemo-) radiotherapy (RT) in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty PET scans were performed in five patients (4 males, 1 female) that had histological proof of NSCLC and were candidates for curative-intent RT. Three PET-CT (Biograph S16, Siemens) scans were performed before (t(0)) and during (around dose 46 Gy, t(46)) RT with minimal intervals of 48 h between each PET-CT scan. The tracers used were (18)fluoro-2deoxyglucose (FDG) for metabolism, (18)fluorothymidine (FLT) for proliferation, and (18)F-misonidasole (F-miso) for hypoxia. The 3 image sets obtained at each time point were co-registered (rigid: n=9, elastic: n=1, Leonardo, TrueD, Siemens) using FDG PET-CT as reference. VOIs were delineated (40% SUV(max) values were used as a threshold) for tumours and lymph nodes on FDG PET-CT, and they were automatically pasted on FLT and F-miso PET-CT images. ANOVA and correlation analyses were used for comparison of SUV(max) values. RESULTS Four tumours and twelve nodes were identified on initial FDG PET-CT images. FLT SUV(max) values were significantly lower (p<0.0006) at t(46) in both tumours and nodes. The decrease in FDG SUV(max) values had a trend towards significance (p=0.048). F-Miso SUV(max) values were significantly higher in tumours than in nodes (p=0.02) and did not change during radiotherapy (p=0.39). A significant correlation was observed between FLT and FDG uptake (r=0.56, p<10(-4)) when all data were pooled together, and they remained similar when the before and during RT data were analysed separately. FDG and F-miso uptakes were significantly correlated (r=0.59, p=0.0004) when all data were analysed together. The best fit was obtained after adjusting for lesion type (tumour vs. node). This correlation was observed for the SUV(max) measured during RT (r=0.70, p=0.008) but not for the pre-RT data (r=0.19, p=0.35). The weak correlation between FLT and F-miso uptakes only became significant (r=0.66, p=0.002) when the analysis was restricted to the data acquired during RT. CONCLUSION Three different PET acquisitions can be performed quasi-simultaneously (4-7 days) before and during radiotherapy in patients with NSCLC. Our results at 46 Gy suggest that a fast decrease in the proliferation of both tumours and nodes exists during radiotherapy with differences in metabolism (borderline significant decrease) and hypoxia (stable).

Radiation-induced lung damage after thoracic irradiation for Hodgkin's disease: the role of fractionation

PURPOSE to estimate the alpha/beta ratio for damage to human lung after thoracic irradiation for Hodgkins disease. PATIENTS AND METHODS The criterion for lung injury was the presence of radiological changes in the vicinity of the mediastinum as assessed on regular follow-up chest X-ray examinations. Patients with supradiaphragmatic stage I-II Hodgkins disease received mantle field irradiation as part of their treatment between 1964 and 1981 (E.O.R.T.C. protocols H1, H2, and H5). The total mediastinal doses fixed by the protocols were 35-40 Gy. The fractional doses were left to the decision of the physicians in charge: the most frequent regimens were 5 x 1.8, 5 x 2.0, 4 x 2.5 and 3 x 3.3 Gy per week. The data were fit to the linear-quadratic (L.Q.) model using time-to-injury as endpoint. RESULTS 1048 (97%) of 1082 patients were evaluable. The mean follow-up duration was 8 years. One hundred and ninety-five cases of radiologically-visible lung damage were observed after a median interval of 6 months (range: 0-101). The 3-year actuarial probability of lung damage was 19% (95% confidence limits: 17, 21). Multivariate analysis (Cox model, stratified by protocol) showed an increased risk of damage with dose per fraction (relative risk, R.R. = 2.22 per Gy (1.75, 2.82)), the presence of systemic symptoms (R.R. = 1.53 (1.09, 2.15)), and total mediastinal dose (R.R. = 1.06 per Gy (1.01, 1.12)). Age, sex, histological type, number of involved nodal sites and radiotherapy duration did not significantly modify the risk of lung damage. The L.Q. model parameters were: alpha = 0.031 Gy-1 (0.003, 0.059), beta = 0.010 Gy-2 (0.007, 0.013), alpha/beta = 3.07 Gy (-0.23, 8.46). CONCLUSION this low alpha/beta ratio is consistent with late effects values from animals and humans, and illustrates the influence of large fraction sizes on the occurrence of late pulmonary complications.

Evaluation of a Rigid Registration Method of Lung Perfusion SPECT and Thoracic CT

OBJECTIVE The objective of our study was to evaluate a rigid registration method in lung perfusion SPECT using thoracic CT as a standard. MATERIALS AND METHODS The reproducibility of markers selection and the robustness of the method were assessed on a torso phantom. The accuracy of registration regarding the number and location of markers and the breathing state during CT was evaluated on eight patients using 10 external markers placed around the thorax before SPECT and CT acquisitions. The accuracy of registration was assessed using the mean errors (ME) between 10 markers after registration. RESULTS Registration using external markers on a phantom was accurate (ME, < 3 mm) when rotation was less than 40 degrees (p = 0.02). The accuracy of registration improved markedly from four to six markers for phantom (5.5-3.6 mm) and patients (11.2-9.5 mm) and then remained constant up to 10 markers. The ME was less when using markers that well encompassed the thorax for phantom and patients (p = 0.02 and p = 0.05, respectively). The use of four anatomic markers was not accurate (ME, 20 mm). CONCLUSION The registration method is reproducible and accurate, and six external markers were required to get an ME of less than 10 mm in patients.

Post-irradiation hyperamylasemia as a biological dosimeter

Serum alpha-amylase was measured before and 24 h after either total body (31 patients) or localized irradiation including the salivary glands (40 patients) or the pancreatic area (22 patients). A significant increase in amylasemia was observed for doses to the parotid glands larger than 0.5 Gy. A sigmoid function of dose was fitted to the data and predicted a maximum amylasemia level for doses larger than 4 Gy and smaller than 10 Gy. The raw data from other published series were adequately described by the same model. However, the confidence limits of the parameters remained wide, because of a considerable interindividual variability. Post-irradiation hyperamylasemia appears to provide a good criterion for triage of accidentally irradiated patients: 24 h after a dose larger than 2 Gy to the parotid glands, 91% of the patients had an amylasemia level higher than 2.5-fold the upper normal value (sensitivity). Conversely, 96% had their serum amylasemia lower than 2.5-fold the upper normal value when dose was smaller than 2 Gy (specificity). However, a retrospective estimation of the absorbed dose (dosimetry) is not likely to be very precise because of the large interindividual variability.

Time factors in breast carcinoma: influence of delay between external irradiation and brachytherapy

From 1971 to 1983, 398 (33 T1, 309 T2, 56 T3) biopsy-proven breast adenocarcinomas were treated conservatively at Hôpital Henri Mondor by an initial course of external irradiation (45 Gy, 25 fractions, 5 weeks) followed by interstitial iridium-192 implant for a further 37 Gy to the tumor. The mean interval between external irradiation and brachytherapy was 5.9 weeks (S.D. 1.7, range 1-18). Seventy-seven local failures were observed at 10-148 months (median 34.5). The actuarial probabilities (S.E.) of local control at 5 and 10 years were 0.86 (0.02) and 0.74 (0.03), respectively. The follow-up for patients free of local recurrence was 4-205 months (median 95). Multivariate analysis showed an increasing probability of local failure with longer interval between external irradiation and brachytherapy (Relative Risk [R.R.] 1.23 [95% confidence limits: 1.07, 1.41] per week, p = 0.005), and a lower risk of failure in case of complete tumor regression after external irradiation (R.R. 0.47 [0.25, 0.90], p = 0.022), and higher brachytherapy dose rate (R.R. 0.13 [0.02, 1.02] per Gy/h, p = 0.053). No influence of tumor size and total dose (possibly because only limited variations in total dose were observed), or histological grading (not performed in 140 [35%] patients) was found. Because of the lack of dose-control relationship, quantification of the effects of delay between external irradiation and brachytherapy (in terms of compensatory dose) and of dose rate (Incomplete Repair Model) was not possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Areas of High 18F-FDG Uptake on Preradiotherapy PET/CT Identify Preferential Sites of Local Relapse After Chemoradiotherapy for Non–Small Cell Lung Cancer

The high rates of failure in the radiotherapy target volume suggest that patients with stage II or III non–small cell lung cancer (NSCLC) should receive an increased total dose of radiotherapy. Areas of high 18F-FDG uptake on preradiotherapy 18F-FDG PET/CT have been reported to identify intratumor subvolumes at high risk of relapse after radiotherapy. We wanted to confirm these observations on a cohort of patients included in 3 sequential prospective studies. Our aim was to assess an appropriate threshold (percentage of maximum standardized uptake value [SUVmax]) to delineate subvolumes on staging 18F-FDG PET/CT scans assuming that a smaller target volume would facilitate isotoxic radiotherapy dose escalation. Methods: Thirty-nine patients with inoperable stage II or III NSCLC, treated with chemoradiation or with radiotherapy alone, were extracted from 3 prospective studies (ClinicalTrials.gov identifiers NCT01261585, NCT01261598, and RECF0645). All patients underwent 18F-FDG PET/CT at initial staging, before radiotherapy, during radiotherapy, and during systematic follow-up in a single institution. All 18F-FDG PET/CT acquisitions were coregistered on the initial scan. Various subvolumes in the initial acquisition (30%, 40%, 50%, 60%, 70%, 80%, and 90% SUVmax thresholds) and in the 3 subsequent acquisitions (40% and 90% SUVmax thresholds) were pasted on the initial scan and compared. Results: Seventeen patients had a local relapse. The SUVmax measured during radiotherapy was significantly higher in locally relapsed tumors than in locally controlled tumors (mean, 6.8 vs. 4.6; P = 0.02). The subvolumes delineated on initial PET/CT scans with 70%–90% SUVmax thresholds were in good agreement with the recurrent volume at a 40% SUVmax threshold (common volume/baseline volume, 0.60–0.80). The subvolumes delineated on initial PET/CT scans with 30%–60% SUVmax thresholds were in good to excellent agreement with the core volume of the relapse (90% SUVmax threshold) (common volume/recurrent volume and overlap fraction indices, 0.60–0.93). The agreement was moderate (>0.51) when a 70% SUVmax threshold was used to delineate on initial PET/CT scans. Conclusion: High 18F-FDG uptake areas on pretreatment PET/CT scans identify tumor subvolumes at greater risk of relapse in patients with NSCLC treated by concomitant chemoradiation. We propose a 70% SUVmax threshold to delineate areas of high 18F-FDG uptake on initial PET/CT scans as the target volumes for potential radiotherapy dose escalation.

The clinical significance of ratios of radiobiological parameters

PURPOSE Interindividual heterogeneity of the radiobiological characteristics of malignant and normal tissues hampers the derivation of radiobiological parameters from clinical data. Focusing on the ratio Dprolif, i.e., the dose to compensate 1 day of treatment interruption, this article investigates the hypothesis that ratios of parameters might be less sensitive to interpatient heterogeneity and may constitute a more reliable description of the radiobiological properties of tissues than the parameters themselves. METHODS AND MATERIALS Analytic calculations were performed in an idealized example in which the only source of heterogeneity was the number of clonogenic cells. Computer simulations were used to assess the effects of heterogeneity in radiosensitivity and in proliferative capacity. Treatment outcome was simulated in pseudopatients with increasing dose-time correlation. RESULTS Interindividual heterogeneity in clonogenic cell number, radiosensitivity, or proliferative ability results in a marked underestimation of the response parameters describing these processes. In contrast, the estimates of the ratio Dprolif were more stable. The coefficients of variation increased with increasing heterogeneity. However, this only became unacceptable when heterogeneity in radiosensitivity was marked, or when total dose and treatment time were closely correlated. CONCLUSION Parameter ratios may provide more robust radiobiological information than single parameters estimated from clinical data except when interindividual heterogeneity is very large or when the treatment modalities are too highly correlated. As usual, caution is advised in the presence of patient selection, a correlation between treatment prescription and expected outcome, or limited ranges of dose-time treatment patterns.

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.

Interobserver Agreement of Qualitative Analysis and Tumor Delineation of 18F-Fluoromisonidazole and 3′-Deoxy-3′-18F-Fluorothymidine PET Images in Lung Cancer

As the preparation phase of a multicenter clinical trial using 18F-fluoro-2-deoxy-d-glucose (18F-FDG), 18F-fluoromisonidazole (18F-FMISO), and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) in non–small cell lung cancer (NSCLC) patients, we investigated whether 18 nuclear medicine centers would score tracer uptake intensity similarly and define hypoxic and proliferative volumes for 1 patient and we compared different segmentation methods. Methods: Ten 18F-FDG, ten 18F-FMISO, and ten 18F-FLT PET/CT examinations were performed before and during curative-intent radiotherapy in 5 patients with NSCLC. The gold standards for uptake intensity and volume delineation were defined by experts. The between-center agreement (18 nuclear medicine departments connected with a dedicated network, SFMN-net [French Society of Nuclear Medicine]) in the scoring of uptake intensity (5-level scale, then divided into 2 levels: 0, normal; 1, abnormal) was quantified by κ-coefficients (κ). The volumes defined by different physicians were compared by overlap and κ. The uptake areas were delineated with 22 different methods of segmentation, based on fixed or adaptive thresholds of standardized uptake value (SUV). Results: For uptake intensity, the κ values between centers were, respectively, 0.59 for 18F-FDG, 0.43 for 18F-FMISO, and 0.44 for 18F-FLT using the 5-level scale; the values were 0.81 for 18F-FDG and 0.77 for both 18F-FMISO and 18F-FLT using the 2-level scale. The mean overlap and mean κ between observers were 0.13 and 0.19, respectively, for 18F-FMISO and 0.2 and 0.3, respectively, for 18F-FLT. The segmentation methods yielded significantly different volumes for 18F-FMISO and 18F-FLT (P < 0.001). In comparison with physicians, the best method found was 1.5 × maximum SUV (SUVmax) of the aorta for 18F-FMISO and 1.3 × SUVmax of the muscle for 18F-FLT. The methods using the SUV of 1.4 and the method using 1.5 × the SUVmax of the aorta could be used for 18F-FMISO and 18F-FLT. Moreover, for 18F-FLT, 2 other methods (adaptive threshold based on 1.5 or 1.6 × muscle SUVmax) could be used. Conclusion: The reproducibility of the visual analyses of 18F-FMISO and 18F-FLT PET/CT images was demonstrated using a 2-level scale across 18 centers, but the interobserver agreement was low for the 18F-FMISO and 18F-FLT volume measurements. Our data support the use of a fixed threshold (1.4) or an adaptive threshold using the aorta background to delineate the volume of increased 18F-FMISO or 18F-FLT uptake. With respect to the low tumor-on-background ratio of these tracers, we suggest the use of a fixed threshold (1.4).