Individual Participant Data Network Meta-Analysis of Neoadjuvant Chemotherapy or Chemoradiotherapy in Esophageal or Gastroesophageal Junction Carcinoma.

PURPOSE: The optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups. PATIENTS AND METHODS: All, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158). RESULTS: IPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P < .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09), P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (P = .003, .012, respectively). CONCLUSION: Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.

Statistical Shape Model to Generate a Planning Library for Cervical Adaptive Radiotherapy.

External beam radiotherapy is extensively used to treat cervical carcinomas. A single planning CT scan enables the calculation of the dose distribution. The treatment is delivered over five weeks. Large per-treatment anatomical variations may hamper the dose delivery, with the potential of an organ-at-risk (OAR) overdose and a tumor underdose. To anticipate these deformations, a recent approach proposed three planning CTs with variable bladder volumes, which had the limitation of not covering all per-treatment anatomical variations. An original patient-specific population-based library has been proposed. It consisted of generating two representative anatomies, in addition to the standard planning CT anatomy. First, the cervix and bladder meshes of a population of 20 patients (314 images) were registered to an anatomical template, using a deformable mesh registration. An iterative point-matching algorithm was developed based on local shape context (histogram of polar or cylindrical coordinates and geodesic distance to the base) and on a topology constraint filter. Second, a standard principal component analysis (PCA) model of the cervix and bladder was generated to extract the dominant deformation modes. Finally, specific deformations were obtained using posterior PCA models, with a constraint representing the top of the uterus deformation. For a new patient, the cervix-uterus and bladder were registered to the template, and the patient's modeled planning library was built according to the model deformations. This method was applied following a leave-one-patient-out cross-validation. The performances of the modeled library were compared to those of the three-CT-based library, showing an improvement in both target coverage and OAR sparing.

CBCT-guided evolutive library for cervical adaptive IMRT.

PURPOSE: In the context of adaptive radiation therapy (ART) for locally advanced cervical carcinoma (LACC), this study proposed an original cone-beam computed tomography (CBCT)-guided "Evolutive library" and evaluated it against four other known radiotherapy (RT) strategies. MATERIAL AND METHODS: For 20 patients who underwent intensity-modulated radiation therapy (IMRT) for LACC, three planning CTs [with empty (EB), intermediate (IB), and full (FB) bladder volumes], a CT scan at 20 Gy and bi-weekly CBCTs for 5 weeks were performed. Five RT strategies were simulated for each patient: "Standard RT" was based on one IB planning CT; "internal target volume (ITV)-based RT" was an ITV built from the three planning CTs; "RT with one mid-treatment replanning (MidTtReplan)" corresponded to the standard RT with a replanning at 20 Gy; "Pretreatment library ART" using a planning library based on the three planning CTs; and the "Evolutive library ART", which was the "Pretreatment library ART" strategy enriched by including some CBCT anatomies into the library when the daily clinical target volume (CTV) shape differed from the ones in the library. Two planning target volume (PTV) margins of 7 and 10 mm were evaluated. All the strategies were geometrically compared in terms of the percentage of coverage by the PTV, for the CTV and the organs at risk (OAR) delineated on the CBCT. Inadequate coverage of the CTV and OARs by the PTV was also assessed using deformable image registration. The cumulated dose distributions of each strategy were likewise estimated and compared for one patient. RESULTS: The "Evolutive library ART" strategy involved a number of added CBCTs: 0 for 55%; 1 for 30%; 2 for 5%; and 3 for 10% of patients. Compared with the other four, this strategy provided the highest CTV geometric coverage by the PTV, with a mean (min-max) coverage of 98.5% (96.4-100) for 10 mm margins and 96.2% (93.0-99.7) for 7 mm margins (P < 0.05). Moreover, this strategy significantly decreased the geometric coverage of the bowel. CTV undercoverage by PTV occurred in the anterior and superior uterine regions for all strategies. The dosimetric analysis at 7 mm similarly demonstrated that the "Evolutive library ART" increased the V42.75Gy of the CTV by 27%, 20%, 13%, and 28% compared with "Standard RT", "ITV-based RT", "MidTtReplan", and "Pretreatment library ART", respectively. The dose to the bowel was also decreased by the "Evolutive library ART" compared with that by the other strategies. CONCLUSION: The "Evolutive library ART" is a personalized ART strategy that comprises a pretreatment planning library of three CT scans, enriched for half of the patients by one to three per-treatment CBCTs. This original strategy increased both the CTV coverage and bowel sparing compared with all the other tested strategies and enables us to consider a PTV margin reduction.

Pre- and per-treatment 18F-FDG PET/CT parameters to predict recurrence and survival in cervical cancer.

PURPOSE: To describe the evolution and to assess the predictive value of metabolic parameters with different SUV threshold segmentations calculated from two 18F-FDG-PET/CT, one prior to and the other one during concomitant chemoradiation therapy (CCRT), for locally-advanced cervical cancer (LACC). MATERIAL AND METHODS: 53 patients treated for LACC by CCRT underwent FDG-PET/CT before treatment (PET1) and another one at 40Gy (PET2). The PET analyzed parameters were: maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). MTVs were automatically segmented using various percentage SUVmax thresholds (30-70%) and fixed SUV thresholds (all voxels with SUV >1-20). The parameters' predictive capabilities for disease-free (DFS) and overall survival (OS) were assessed using the Harrell's C-index (c) and Cox regression model. RESULTS: Depending on the SUVmax threshold, the relative decreases in MTV and TLG from PET1 to PET2 were, on average, 65% (range: 63-70%) and 85% (range: 83-86%), respectively. The strongest predictive threshold segmentations were 55% SUVmax in PET1 and 32% in PET2. Significant predictors of DFS in multivariate analysis (c=0.82) were MTV1 (55% SUVmax) in PET1 and TLG2 (32% SUVmax) in PET2. MTV1 (55%) was the most significant OS predictor. CONCLUSIONS: MTV and TLG calculated with a threshold of 55% SUVmax and 32% SUVmax from pre- and per-treatment PET scans respectively, can be used to predict patient outcome after CCRT for LACC.

Impact of post operative intensity modulated radiotherapy on acute gastro-intestinal toxicity for patients with endometrial cancer: results of the phase II RTCMIENDOMETRE French multicentre trial.

PURPOSE/OBJECTIVE: Whole "conventional" pelvic irradiation (up to 45-50Gy) following hysterectomy is associated with a high rate of adverse gastro-intestinal (GI) adverse events, of which around 60% correspond to acute grade 2 toxicity. The phase II RTCMIENDOMETRE trial was designed to test the hypothesis that IMRT could reduce the incidence of grade 2 or more acute GI toxicity to less than 30% in patients irradiated post-operatively for an endometrial cancer. MATERIALS/METHODS: Patients with post-operative stage Ib G3, Ic or II endometrial carcinomas with no history of chronic inflammatory bowel disease were eligible. Guidelines for volume delineation and dose prescription were detailed in the protocol. The investigators were advised to use a web-based atlas developed for the RTOG 0418 study. The dose of the vaginal and nodal PTV was 45Gy in 25 fractions. To assess the ability of the participating centres to comply with the protocol guidelines, they were requested to complete a dummy run procedure before inclusion of their 1st patient. GI and genito-urinary (GU) toxicity were graded according to the CTCAE V 3.0 classification and were prospectively recorded every week during irradiation, as well as at time of brachytherapy insertions and during the follow-up visit at week 15 (W15). Special attention was given to note any changes to the grade of adverse events between W5 and W15. RESULTS: From May 2008 to April 2010, 49 patients from 6 centres were recruited for the trial. One patient could not be treated, one patient died of vascular stroke at W3 without toxicity, and 1 patient refused to be followed-up after treatment. Thus, 46 cases were available for analysis at W15. The distribution by stage was as follows: Ib 16.3%, Ic 64.2%, II 20.4%. Thirty six patients (75%) received an additional vaginal vault boost of 6-10Gy delivered by HDR brachytherapy in 1 or 2 fractions. Among the 47 patients who completed IMRT, 27% (95% CI 14.5-39.7%) developed at least 1 GI grade 2 adverse event (diarrhoea in 92% of cases), which mainly occurred at W4 and W5. No event corresponding to grade 3 or above was recorded. At W15, the number of patients complaining about GI events was low: 5 patients complained about persistent grade 1 diarrhoea, and 4 patients complained about haemorrhoids. Nineteen percent (95% CI 8.9-32.6%) of patients experienced grade 2 cystitis or urinary frequency which had disappeared by W15. CONCLUSION: In accordance with our hypothesis, post-operative IMRT resulted in a low rate (less than 30%) of acute GI grade 2 toxicity, in patients with endometrial carcinomas. At W15, no patient demonstrated a grade 2 adverse event, and the prevalence of remaining grade 1 events was less than 20%.

Salivary gland-sparing other than parotid-sparing in definitive head-and-neck intensity-modulated radiotherapy does not seem to jeopardize local control.

BACKGROUND: The objective was to analyze locoregional (LR) failure patterns in patients with head-and-neck cancer (HNC) treated using intensity-modulated radiotherapy (IMRT) with whole salivary gland-sparing: parotid (PG), submandibular (SMG), and accessory salivary glands represented by the oral cavity (OC). METHODS: Seventy consecutive patients with Stage I-II (23%) or III/IV (77%) HNC treated by definitive IMRT were included. For all LR failure patients, the FDG-PET and CT scans documenting recurrence were rigidly registered to the initial treatment planning CT. Failure volumes (Vf) were delineated based on clinical, radiological, and histological data. The percentage of Vf covered by 95% of the prescription isodose (Vf-V95) was analyzed. Failures were classified as "in-field" if Vf-V95 ≥ 95%, "marginal" if 20% < Vf-V95 < 95%, and "out-of-field" if Vf-V95 ≤20%. Correlation between Vf-V95 and mean doses (Dmean) in the PG, SMG, and OC was assessed using Spearman's rank-order correlation test. The salivary gland dose impact on the LR recurrence risk was assessed by Cox analysis. RESULTS: The median follow-up was 20 months (6-35). Contralateral and ipsilateral PGs were spared in 98% and 54% of patients, respectively, and contralateral and ipsilateral SMG in 26% and 7%, respectively. The OC was spared to a dose ≤40 Gy in 26 patients (37%). The 2-year LR control rate was 76.5%. One recurrence was "marginal", and 12 were "in-field". No recurrence was observed in vicinity of spared structures. Vf-V95 was not significantly correlated with Dmean in PG, SMG, and OC. The LR recurrence risk was not increased by lower Dmean in the salivary glands, but by T (p = 0.04) and N stages (p = 0.03). CONCLUSION: Over 92% of LR failures occurred "in-field" within the high dose region when using IMRT with a whole salivary gland-sparing strategy. Sparing SMG and OC in addition to PG thus appears a safe strategy.

High-dose-rate brachytherapy for non-small-cell lung carcinoma: a retrospective study of 226 patients.

PURPOSE: To evaluate the efficacy and toxicity of high-dose-rate (HDR) brachytherapy in patients with inoperable endobronchial carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the records (April 1991-May 2004) of patients with non-small-cell carcinoma, with no extrabronchial spread on computed tomography scans, who underwent HDR brachytherapy because of contraindications to surgery and external beam radiation therapy. Kaplan-Meier survival curves were compared by the log-rank test. Prognostic factors were analyzed by multivariate analysis. RESULTS: 226 patients (223 men, 3 women, mean age: 62.2 years (range, 40-84)) were included. Of those, 217 (97%) had squamous cell carcinoma (Tis/T1/T2/Tx: 60/153/9/4). Dose was prescribed at 1 cm from the radius (24-35 Gy in 4-6 fractions). Mean follow-up was 30.4 months (range, 9-116). Complete endoscopic response rate was 93.6% at 3 months. One hundred twenty-eight patients (56%) died of intercurrent disease (n = 45), local failure (n = 36), metastasis (n = 10), local failure and metastasis (n = 11), complications (n = 13), and other causes (n = 12). The 2-year and 5-year survival rates were, respectively, 57% and 29% (overall) (median, 28.6 months), 81% and 56% (cancer-specific), and 68% and 50% (local disease-free). Acute toxicity included pneumothorax (1.5%) and mucosal inflammation (10%). Late complications were hemoptysis (6.6% with 5% of fatalities), bronchitis (19.5%), and necrosis (3.5%). In multivariate analysis, a distal tumor location and the use of two catheters were associated with improved local disease-free survival (p = 0.003 and p = 0.007, respectively) and a distal tumor location with improved overall survival (p = 0.0001). CONCLUSIONS: This large retrospective study confirms that HDR brachytherapy is an efficient and safe treatment in patients with inoperable endobronchial carcinoma.