First-Line Chemotherapy for Metastatic Esophageal Squamous Cell Carcinoma: Clinico-Biological Predictors of Disease Control.

OBJECTIVE: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy. METHODS: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients. RESULTS: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC. CONCLUSION: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.

Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial.

BACKGROUND: Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial. METHODS/DESIGN: PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio. DISCUSSION: This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors. TRIAL REGISTRATION: NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

Single-port or Classic Laparoscopy Compared With Laparotomy to Assess the Peritoneal Cancer Index in Primary Advanced Epithelial Ovarian Cancer.

A thorough laparoscopic assessment of the abdominopelvic cavity is a crucial step in the workup of primary advanced epithelial ovarian cancer to decide whether up-front cytoreductive surgery or neoadjuvant chemotherapy is the best option for adequate management. The purpose of our study was to compare single-port laparoscopy (SPL), classic laparoscopy (CL), and laparotomy using the peritoneal cancer index (PCI). Patients treated for Fédération Internationale de Gynécologie et d'Obstétrique stage 3 or 4 epithelial ovarian cancer were included in our study when they underwent a PCI evaluation by laparoscopy followed by laparotomy for cytoreduction. According to the technique used for the "noninvasive" procedure (SPL vs CL), 2 groups were compared retrospectively. The individual records of all patients were reviewed and analyzed. From 2011 to 2014, 21 patients were assessed for PCI by SPL plus laparotomy versus 21 by CL plus laparotomy. The clinicopathological features were similar in both groups (not significant [NS]), except for performance status >0, which was more frequent in the SPL group (39% vs 6%, p = .04). Quotation of PCI was possible for all patients. Nonbrowsing areas marked 3 procedures in the SPL group and 2 procedures in the CL group (NS). The mean PCI score and the score of each region assessed by SPL and CL were comparable with the evaluation by laparotomy (NS). Completeness of cytoreduction was achieved in 78% of cases in both groups (NS). SPL and widely mini-invasive procedures seem to be effective tools compared with laparotomy to adequately assess the resectability of a peritoneal carcinomatosis using the PCI.

Managing Endometrial Cancer: The Role of Pelvic Lymphadenectomy and Secondary Surgery.

PURPOSE: In November 2010, the French National Cancer Institute published new guidelines for managing endometrial cancer. Pelvic lymphadenectomy is not indicated for preoperative low-intermediate risk type 1 endometrial cancer, and high-risk patients should undergo secondary surgery with para-aortic lymphadenectomy. This study evaluated these new guidelines with regard to overall survival (OS), relapse-free survival (RFS), and morbidity for patients with low-intermediate risk disease. METHODS: We evaluated all type 1 endometrial cancer patients with low-intermediate risk of recurrence who were treated from 1 January 1997 through 31 December 2012. All patients were classified according to the 2009 International Federation of Gynecology and Obstetrics staging criteria and the European Society for Medical Oncology. RESULTS: Overall, 230 patients were included (159 before and 71 after the new guidelines were issued). Pelvic lymphadenectomies were performed before and after the new guidelines in 77.4 and 28.6 % of patients, respectively (p < 0.001). After 2010, eight patients also underwent secondary surgery, which consisted of a para-aortic lymphadenectomy for lymphovascular space invasion (LVSI). This second surgery changed the adjuvant treatment for one patient. OS and RFS were similar between both groups, and no difference in morbidity was observed between the groups. LVSI was an independent factor for OS [hazard ratio (HR) 7.2, 95 % CI 3.1-17; p < 0.001] and RFS (HR 3.7, 95 % CI 1.6-8.5; p < 0.003). CONCLUSIONS: Fewer pelvic lymphadenectomies in low-intermediate risk patients did not affect OS, RFS, or morbidity, including patients with secondary surgery. We must gather additional data with a longer follow-up period to not only confirm our results but to also fully investigate the paradoxical absence of decreased morbidity that our study has shown.

Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial.

BACKGROUND: Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial. METHODS/DESIGN: We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not > 3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; ß = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients. DISCUSSION: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) February 2012).

Minimally invasive surgical management of early-stage cervical cancer: an analysis of the risk factors of surgical complications and of oncologic outcomes.

OBJECTIVES: The objective of this study was to evaluate the morbidity and the oncologic outcomes of laparoscopic radical hysterectomy in treating early-stage cervical cancer. METHODS: We included all patients with early-stage cervical cancer (IA, IB1, IIA1, and IIB), as assessed by the Federation International of Gynecology and Obstetrics staging criteria, undergoing laparoscopic radical hysterectomy from January 1999 to December 2013 in our center. Morbidity was classified according to the Clavien and Dindo classification. RESULTS: A total of 170 patients were included in which 7 patients were in stage IA2, 150 in IB1, 2 in IIA, and 7 in IIB. The mean operation time was 256 minutes (67-495 minutes). Fourteen severe perioperative complications (8.2%) occurred, in which 5 patients (2.9%) required conversion to an open procedure: 3 bowel injuries, 3 hemorrhages, 2 ureteral injuries, 3 bladder injuries, 2 severe adhesions, and 1 intolerance to the Trendelenburg position. Fourteen patients (8.2%) presented with 1 severe postoperative complication (grade III or more). Two factors appeared as independent risk factors for perioperative and/or postoperative complications: the tumor size (odds ratio, 1.128; 95% confidence interval, 1.054-1.207) and operative time (odds ratio, 1.0116; 95% confidence interval, 1.003-1.020). In a median follow-up of 47.7 months, the 5-year overall survival was 94.1% (range, 88.1%-97.3%), and the 5-year disease-free survival was 88.8% (range, 81.0%-92.6%). CONCLUSIONS: The laparoscopic approach was favorable for both perioperative and postoperative morbidity. With the advantage of minimal invasiveness, laparoscopic treatment by experienced surgeons is an alternative for early-stage cervical cancer with correct long-term survival outcomes. Mini-invasive surgery could be the standard in early-stage cervical cancer.

Safety of adjuvant intensity-modulated postoperative radiation therapy in endometrial cancer: Clinical data and dosimetric parameters according to the International Commission on Radiation Units (ICRU) 83 report.

AIM: To report a single-institution experience using postoperative pelvic Intensity Modulation Radiation Therapy (IMRT) using tomotherapy accelerators (TA) in postoperative endometrial cancer (EC) regarding ICRU 83 recommendations. BACKGROUND: IMRT in gynecological malignancies provides excellent dosimetric data, lower rates of adverse events and clinical data similar to historical series. MATERIAL AND METHODS: Seventy-six patients with EC were postoperatively treated with adjuvant IMRT using TA. The IMRT dose was 45 Gy for patients without positive lymph nodes and Type I histology and 50.4 Gy for patients with positive lymph nodes and/or type II histology. RESULTS: With a median follow-up of 29 months, the 12- and 24-month Overall Survival (OS) and Disease-Free Survival (DFS) were 96%, 93%, 87%, and 74%, respectively. Age of less than 60 years was associated with better OS (HR: 8.9; CI: 1.1-68) and DFS (HR: 3.5; CI: 1.2-10.2). Patients with Type II and Type I Grade III histology had a worse OS (HR: 3.3; CI: 1.1-11). Five women (6.6%) presented in-field local vaginal recurrence, 2 (2.6%) presented non-in-field vaginal recurrence, 4 (5.2%) presented pelvic node and distant recurrence and 11 (14.4%) presented only distant metastases. One patient stopped radiation treatment due to Grade III acute diarrhea. No Grade III late toxicity was observed. Planning Target Volume (PTV) coverage showed mean D2, D50, D95, and D98 of 51.64-46.23 Gy, 49.49-44.97 Gy, 48.62-43.96 Gy, and 48.47-43.58 Gy for patients who received 45 and 50.4 Gy, respectively. CONCLUSIONS: IMRT with TA in postoperative EC shows excellent conformity and homogeneity of PTV dose. Without Grade III late toxicity, data from this cohort demonstrated the utility of IMRT.

Clinical complete responders to definite chemoradiation or radiation therapy for oesophageal cancer: predictors of outcome.

BACKGROUND: To identify predictors of long-term outcome for patients with clinical complete response (cCR) after definite chemoradiotherapy (CRT) or radiation therapy (RT) for oesophageal cancer (EC). METHODS: In this retrospective study, we reviewed the files of all patients from our institution that underwent definitive RCT or RT for EC, from January 1998 to December 2003. Among 402 consecutive patients with EC, 110 cCR responses were observed, i.e. without evidence of tumour on morphological examination of the biopsy specimens, 8 to 10 weeks after radiation. Baseline patient and tumour characteristics were as follows: male = 98/110, median age = 60, squamous histology = 103/110, tumour site (upper/middle/lower third) = 41/50/19, weight loss none/<10%/≥10% = 36/45/29, dysphagia grade 1/2/≥3 = 30/14/66. Patients were staged according to endosonography and/or computed tomography. There were 9 stage I, 31 stage IIA, 15 stage IIB, 41 stage III, 6 stage IV. Post treatment nutritional characteristics were as follows: weight loss during treatment none/<10% ≥ 10% = 35/38/37, remaining dysphagia grade 1/2/≥3 = 54/24/32. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method. RESULTS: During follow up (median: 6 [0.4-9.8] years), 16 patients had salvage surgery. Median OS was 2.5 years, and 5-year OS was 33.5%. Histological type, stage, age, gender, and treatment characteristics had no significant impact on outcome. The risk of death was increased two-fold for patients with grade ≥ 3 dysphagia after treatment (HR = 1.9 [1.2-3.1], p = 0.007). Weight loss ≥10% during treatment also negatively affected outcome (HR = 1.8 [1.0-3.2], p = 0.040). CONCLUSION: One EC patient among 3 with cCR after definite CRT/RT is still alive at 5 years. Variables related to reduced OS were: remaining significant dysphagia after treatment and weight loss ≥10% during treatment.

A Multicenter Phase 2 Study of Ultrahypofractionated Stereotactic Boost After External Beam Radiotherapy in Intermediate-risk Prostate Carcinoma: A Very Long-term Analysis of the CKNO-PRO Trial.

Background: Genitourinary (GU) or gastrointestinal (GI) complications and tumor relapse can occur in the long term after radiotherapy for prostate cancer. Objective: To assess the late tolerance and relapse-free survival (RFS) in patients undergoing hypofractionated stereotactic boost therapy after external beam radiotherapy (EBRT) for intermediate-risk prostate cancer. Design setting and participants: Seventy-six patients with intermediate-risk prostate carcinoma between August 2010 and April 2013 were included. The first course delivered a dose of 46 Gy by conventional fractionation; the second course was a boost of 18 Gy (3 × 6 Gy) within 10 d. Outcome measurements and statistical analysis: GU and GI toxicities were evaluated as the primary outcomes. The secondary outcomes were overall survival and RFS. The cumulative incidence of toxicity was calculated using a competing-risk approach. Overall survival and RFS were estimated using the Kaplan-Meier method. Results and limitations: The median follow-up period was 88 mo (range, 81-99 mo). Sixty (79%) patients were treated with the CyberKnife and 16 (21%) using a linear accelerator. The cumulative incidences of GU and GI grade ≥2 toxicities at 120 mo were 1.4% (95% confidence interval [CI]: 0.1-6.6%) and 11.0% (95% CI: 5.1-19.4%), respectively. The overall survival and RFS rates at 8 yr were 89.1% (95% CI: 77-95%) and 76.9% (95% CI: 63.1-86.1), respectively. Conclusions: A very long follow-up showed low GU and GI toxicities after a hypofractionated stereotactic boost after EBRT for intermediate-risk prostate cancer. Dose escalation of the boost delivered by hypofractionated radiation therapy appears safe for use in future trials. Patient summary: We found low toxicity and good survival rates after a short and high-precision boost after external beam radiotherapy for intermediate-risk prostate cancer, with a long-term follow-up of 88 mo. This long-term treatment is safe and should be considered in future trials.

Prophylactic Radical Fimbriectomy with Delayed Oophorectomy in Women with a High Risk of Developing an Ovarian Carcinoma: Results of a Prospective National Pilot Study.

Risk-reducing salpingo-oophorectomy is the gold standard for the prophylaxis of ovarian cancer in high-risk women. Due to significant adverse effects, 20-30% of women delay or refuse early oophorectomy. This prospective pilot study (NCT01608074) aimed to assess the efficacy of radical fimbriectomy followed by a delayed oophorectomy in preventing ovarian and pelvic invasive cancer (the primary endpoint) and to evaluate the safety of both procedures. The key eligibility criteria were pre-menopausal women ≥35 years with a high risk of ovarian cancer who refused a risk-reducing salpingo-oophorectomy. All the surgical specimens were subjected to the SEE-FIM protocol. From January 2012 to October 2014, 121 patients underwent RF, with 51 in an ambulatory setting. Occult neoplasia was found in two cases, with one tubal high-grade serous ovarian carcinoma. Two patients experienced grade 1 intraoperative complications. No early or delayed grade ≥3 post-operative complications occurred. After 7.3 years of median follow-up, no cases of pelvic invasive cancer have been noted. Three of the fifty-two patients developed de novo breast cancer. One BRCA1-mutated woman delivered twins safely. Twenty-five patients underwent menopause, including fifteen who had received chemotherapy for breast cancer, and twenty-three underwent menopause before the delayed oophorectomy, while two did not undergo a delayed oophorectomy at all. Overall, 46 women underwent a delayed oophorectomy. No abnormalities were found in any delayed oophorectomy specimens. Radical fimbriectomy followed by delayed oophorectomy appears to be a safe and well-tolerated risk-reducing approach, which avoids early menopause for patients with a high risk of breast and ovarian cancer.

Correlation between toxicity and dosimetric parameters for adjuvant intensity modulated radiation therapy of breast cancer: a prospective study.

ORCID: 0000-0001-6019-7309. In the treatment of breast cancer, intensity-modulated radiation therapy (IMRT) reportedly reduces the high-dose irradiation of at-risk organs and decreases the frequency of adverse events (AEs). Comparisons with conventional radiotherapy have shown that IMRT is associated with lower frequencies of acute and late-onset AEs. Here, we extended a prospective, observational, single-center study of the safety of IMRT to a second investigating center. Patients scheduled for adjuvant IMRT after partial or total mastectomy were given a dose of 50 Gy (25 fractions of 2 Gy over 5 weeks), with a simultaneous integrated boost in patients having undergone conservative surgery. 300 patients were included in the study, and 288 were analyzed. The median follow-up period was 2.1 years. The 2-year disease-free survival rate [95% CI] was 93.4% [89.2-96.0%]. Most AEs were mild. The most common AEs were skin-related-mainly radiodermatitis [in 266 patients (92.4%)] and hyperpigmentation (in 178 (61.8%)). 35% and 6% of the patients presented with grade 2 acute skin and esophageal toxicity, respectively. Only 4 patients presented with a grade 3 event (radiodermatitis). Smoking (odds ratio) [95% CI] = 2.10 [1.14-3.87]; p = 0.017), no prior chemotherapy (0.52 [0.27-0.98]; p = 0.044), and D98% for subclavicular skin (1.030 [1.001-1.061]; p = 0.045) were associated with grade ≥ 2 acute AEs. In a univariate analysis, the mean dose, (p < 0.0001), D2% (p < 0.0001), D50% (p = 0.037), D95% (p = 0.0005), D98% (p = 0.0007), V30Gy (p < 0.0001), and V45Gy (p = 0.0001) were significantly associated with grade ≥ 1 acute esophageal AEs. In a multivariate analysis, D95% for the skin (p < 0.001), D98% for the subclavicular skin and low D95% for the internal mammary lymph nodes were associated with grade ≥ 1 medium-term AEs. The safety profile of adjuvant IMRT after partial or total mastectomy is influenced by dosimetric parameters. TRIAL REGISTRATION: ClinicalTrials.gov NCT02281149.

A Multicenter Phase 2 study of Hypofractionated Stereostatic Boost in Intermediate Risk Prostate Carcinoma: A 5-Year Analysis of the CKNO-PRO Trial.

PURPOSE: The aim of this analysis was to assess the 5-year tolerance and survival in patients undergoing hypofractionated stereotactic boost after external beam radiation therapy (EBRT) for intermediate-risk prostate cancer. METHODS AND MATERIALS: Between August 2010 and April 2013, 76 patients with intermediate-risk prostate carcinoma were included in the study. A first course delivered 46 Gy using conventional fractionation. The second course delivered a boost of 18 Gy (3 × 6 Gy) within 10 days using stereotactic body radiation therapy (SBRT). Gastrointestinal and genitourinary toxicities were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0. Secondary outcome measures were overall, biochemical relapse-free, and relapse-free survival; prostate-specific antigen kinetics; and patient functional status (urinary and sexual) according to the International Index of Erectile Function and International Prostate Symptom Score questionnaires. RESULTS: Sixty patients (79%) were treated by CyberKnife and 16 (21%) by linear accelerator. Median follow-up was 62 months (range, 29-69). The cumulative incidence of genitourinary and gastrointestinal grade ≥2 toxicities at month 60 after the end of radiation therapy was 1.4% (95% confidence interval [CI], 0.1%-6.6%) and 9.3% (95% CI, 4.1%-17.1%), respectively. Biochemical relapse-free and relapse-free survival rates at 5 years were 87.4% (95% CI, 77.1%-93.2%) and 86.2% (95% CI, 75.8-92.3), respectively. The mean (standard deviation) prostate-specific antigen variation within 3 months and 5 years post-radiation therapy was -1.20 ng/mL/mo (0.79) and -1.30 ng/mL/y (1.05), respectively. There was no significant difference between the International Prostate Symptom quality of life score between inclusion and month 60. For the International Index of Erectile Function, there was a significant difference between inclusion and month 60 (P = .005), with a higher proportion of severe/noninterpretable disorders at 60 months. CONCLUSIONS: The results of the trial demonstrate that the EBRT and SBRT combination is well tolerated and yields good efficacy results. These data provide a good basis for comparing EBRT and brachytherapy boost to EBRT and SBRT boost in future prospective studies.

[Evaluation of drug interactions in patients treated for a lung or digestive cancer]. / Évaluation des interactions médicamenteuses chez des patients traités pour un cancer pulmonaire ou digestif.

INTRODUCTION: Cancer patients are particularly at risk for drug interactions. However, in oncology, this risk has not been studied in depth in France. The main objective of this study was to describe the proportion of drug interactions in patients with lung or digestive cancer. METHODS: The drug prescriptions of 93 patients were analyzed from may 27th, 2019 to July 07th, 2019 using two software programs (Thériaque™ and DDI Predictor™) in oncology patients hospitalized in our comprehensive cancer center. RESULTS: Of the 88 patients included in the study, 544 drug interactions were identified, in 66 patients (75.0%, 95% CI: 64.6-83.6). For 20/88 patients (22.7% CI: 14.5-32.9) a non-recommended combination or a theoretical contraindication was reported. Etoposide was the anticancer molecule most involved in combinations that are contraindicated or not recommended. No combinations defined as not recommended or contraindicated were observed in any of the 49 patients treated with chemotherapy during their hospitalization. The most common toxicities were alertness and metabolic disorders, including hyperkalemia. The use of three or more drugs was a risk factor for drug interactions (83 vs. 23%, P<0.001). CONCLUSION: Drug interactions remain a major concern in cancer hospitalized patients. It is important to continue and strengthen the collaboration between physicians and pharmacists in order to better prevent their occurrence.

Stereotactic irradiation of non-small cell lung cancer brain metastases: evaluation of local and cerebral control in a large series.

Stereotactic radiotherapy (SRT) of brain metastases (BM) results are often reported in the heterogeneous primitive population. Here, we report our experience in consecutively treated patients who underwent SRT alone for BM from non-small cell lung cancer (NSCLC). This retrospective analysis included consecutive patients with no history of cerebral treatment who underwent Cyberknife™ SRT for BM from NSCLC in our institution from 2007 to 2016. One hundred patients were included in the study, with a median follow-up of 33 months (20-64). Mean age was 63 years (SD ± 10); 88% had Karnofsky Performance Status (KPS) > 70; 67% had unique BM; 18 patients received single-fraction SRT (20-25 Gy), and 82 received hypo-fractionated SRT (HSRT) (24-36 Gy in 3-5 fractions). We reported a complication rate of 17% (2% of G3-4). Median survival was 10.1 months [95% confidence interval (CI) 7.8-13.9]. At 1 year, local and cerebral control rates were respectively 78.7% (95% CI 70-86.5%) and 43% (95% CI 33.5-53%). Thirty patients underwent salvage treatment (whole brain radiation therapy, n = 13; SRT, n = 14; surgery, n = 3). Cyberknife™-based SRT is an effective treatment associated with high local control rate with low morbidity for patients with NSCLC's BM. Close follow-up is necessary to perform salvage treatment.

Prospective Study of Intensity-Modulated Radiation Therapy for Locally Advanced Breast Cancer.

The objective of this study was to evaluate the acute and medium-term toxicities, the quality of life, and aesthetic results of patients with breast cancer (BC) treated with tomotherapy. This was a prospective study, including patients with BC treated by tomotherapy. Radiation therapy delivered 50 Gy in 25 fractions to the breast or chest wall and to lymph node areas, with a simultaneous integrated boost at a dose of 60 Gy at the tumor bed in cases of breast conservative surgery. We included 288 patients, 168 and 120 treated with breast-conserving surgery and mastectomy respectively. Two hundred sixty patients (90.3%) received lymph node irradiation. Median follow-up was 25 months (6-48). Acute dermatitis was observed in 278 patients (96.5%), mostly grade 1 (59.7%). The aesthetic aspect of the breast at one year was reported as "good" or "excellent" in 84.6% of patients. The patients' quality of life improved over time, especially those treated with chemotherapy. The two-year overall survival and disease-free survival were 97.8% (95% confidence interval (CI): 94.1-99.2%), and 93.4% (95% CI: 89.2-96.0%) respectively. Tomotherapy for locally advanced BC has acceptable toxicity, supporting its use in this indication; however, longer follow-up is needed to assess long-term outcomes.

GETUG-AFU 31: a phase I/II multicentre study evaluating the safety and efficacy of salvage stereotactic radiation in patients with intraprostatic tumour recurrence after external radiation therapy-study protocol.

INTRODUCTION: Prostate cancer is the third most important cancer in terms of mortality in men. No standard local treatment exists for patients with an intraprostatic recurrence after radiotherapy. Stereotatic body radiotherapy (SBRT) could be a curative treatment for local recurrence. The phase I/II primary objective is the selection of the recommended dose for salvage-SBRT and to estimate the efficacy. METHODS AND ANALYSIS: We plan to perform a multicentre prospective phase I/II study including at least 47 patients. Eligible patients are patients with biochemical recurrence occurring at least 2 years after external radiotherapy for prostatic adenocarcinoma by the Phoenix definition (prostate-specific antigen (PSA) nadir +2 ng/mL) and histologically proven intraprostatic recurrence only (stage T1-T2 on relapse, PSA level ≤10 ng/mL, PSA doubling time >10 months, absence of pelvic or metastatic recurrence proven by choline or PSMA positron emission tomography scan, and pelvic and prostatic assessment by multiparametric MRI). The phase I primary objective is the selection of the recommended dose for salvage-SBRT (5×6, 6×6 or 5×5 Gy) based on dose-limiting toxicity (DLT). The dose of salvage-SBRT will be selected using a time-to-event continual reassessment method based on DLT defined as grade ≥3 gastrointestinal or urinary toxicity or any other grade 4 adverse event. The phase II primary outcome is to estimate the efficacy of the salvage-SBRT in terms of biochemical relapse-free survival rate (Phoenix definition: increase in serum total PSA ≥2 ng/mL above the nadir). Phase II secondary outcomes are acute and late toxicities, quality of life, clinical progression-free survival defined as the time interval between the date of registration and the date of clinical progression or death irrespective of the cause. ETHICS AND DISSEMINATION: The study has received ethical approval from the Ethics committee 'Ile-de-France III'. Academic dissemination will occur through publication and conference presentations. TRIAL REGISTRATION NUMBER: NCT03438552.

Intensity-modulated radiation therapy with simultaneous integrated boost for locally advanced breast cancer: a prospective study on toxicity and quality of life.

Radiotherapy after breast conserving surgery and mastectomy with node positive disease has been shown to reduce risk of recurrence and mortality in the treatment of breast cancer. Intensity-modulated radiation therapy (IMRT) after conservative surgery offers several advantages over conventional RT including improved acute and late toxicity and quality of life (QoL). We undertook this study to prospectively evaluate acute (≤90 days after last dose of radiotherapy) and long-term (>90 days) cutaneous, esophageal, and fibrosis toxicity and QoL in breast cancer patients treated by adjuvant IMRT after breast surgery. We included patients with complex volumes for which 3D RT does not allow a good coverage of target volumes and sparing organs at risk. We report here an interim analysis with a median follow-up of 13.1 months (range, 6.5-25.9 months). Most of the acute toxicity was cutaneous (95.9%) and oesophageal (59.6%), and mostly grade 1 and 2. Medium-term cutaneous toxicity rate was 25.6%, and mostly grade 1. Medium-term esophageal toxicity was rare (1.8%). In this series acute oesophageal toxicity was found to be associated with dosimetric factors. QoL was well preserved throughout the study, and aesthetic outcomes were good. Based on these data, tomotherapy may be a favorable alternative to other techniques in patients needing a complex irradiation of the breast and lymph node volumes.

Diffusion weighted MRI as an early predictor of tumor response to hypofractionated stereotactic boost for prostate cancer.

We evaluated the feasibility of using the kinetic of diffusion-weighted MRI (DWI) and the normalized apparent coefficient diffusion (ADC) map value as an early biomarker in patients treated by external beam radiotherapy (EBRT). Twelve patients were included within the frame of a multicenter phase II trial and treated for intermediate risk prostate cancer (PCa). Multiparametric MRI was performed before treatment (M0) and every 6 months until M24. Association between nADC and PSA or PSA kinetic was evaluated using the test of nullity of the Spearman correlation coefficient. The median rates of PSA at the time of diagnosis, two years and four years after EBRT were 9.29 ng/ml (range from 5.26 to 17.67), 0.68 ng/ml (0.07-2.7), 0.47 ng/ml (0.09-1.39), respectively. Median nADC increased from 1.14 × 10-3 mm2/s to 1.59 × 10-3 mm2/s between M0 and M24. Only one patient presented a decrease of nADC (1.35 × 10-3 mm2/s and 1.11 × 10-3 mm2/s at M0 and M12 respectively). The increase in nADC at M6 was correlated with PSA decrease at M18, M24 and M30 (p < 0.05). The increase in nADc at M12 was correlated with PSA decrease at M36 (p = 0.019). Early nADC variation were correlated with late PSA decrease for patients with PCa treated by EBRT.

Hypofractionated stereotactic boost in intermediate risk prostate carcinoma: Preliminary results of a multicenter phase II trial (CKNO-PRO).

PURPOSE: Dose escalation may improve curability in intermediate-risk prostate carcinoma. A multicenter national program was developed to assess toxicity and tumor response with hypofractionated stereotactic boost after conventional radiotherapy in intermediate-risk prostate cancer. METHODS AND MATERIAL: Between August 2010 and April 2013, 76 patients with intermediated-risk prostate carcinoma were included in the study. A first course delivered 46 Gy by IMRT (68.4% of patients) or 3D conformal radiotherapy (31.6% of patients). The second course delivered a boost of 18 Gy (3x6Gy) within 10 days. Gastrointestinal (GI) and genitourinary (GU) toxicities were evaluated as defined by NCI-CTCAE (v4.0). Secondary outcome measures were local control, overall and metastasis-free survival, PSA kinetics, and patient functional status (urinary and sexual) according to the IIEF5 and IPSS questionnaires. RESULTS: The overall treatment time was 45 days (median, range 40-55). Median follow-up was 26.4 months (range, 13.6-29.9 months). Seventy-seven per cent (n = 58) of patients presented a Gleason score of 7. At 24 months, biological-free survival was 98.7% (95% CI, 92.8-99.9%) and median PSA 0.46 ng/mL (range, 0.06-6.20 ng/mL). Grade ≥2 acute GI and GU toxicities were 13.2% and 23.7%, respectively. Grade ≥2 late GI and GU toxicities were observed in 6.6% and 2.6% of patients, respectively. No grade 4 toxicity was observed. CONCLUSIONS: Hypofractionated stereotactic boost is effective and safely delivered for intermediate-risk prostate carcinoma after conventional radiation. Mild-term relapse-free survival and tolerance results are promising, and further follow-up is warranted to confirm the results at long term. TRIAL REGISTRATION: ClinicalTrials.gov NCT01596816.

Identification of single nucleotide polymorphisms of the PI3K-AKT-mTOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.

INTRODUCTION: The PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms (SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancer patients. METHODS: The GENEOM study (NCT00959556) included blood sample collection from breast cancer patients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). RESULTS: Of 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p < 0.00085). Multivariate analysis showed associations between AKT1-rs3803304, AKT2-rs3730050, PDK1-rs11686903 and PI3KR1-rs706716 and CNS metastasis . CONCLUSION: PI3KR1-rs706716 may be associated with CNS metastasis in metastatic breast cancer patients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype.