Management of non-metastatic anal cancer in the elderly: ancillary study of the French multicenter prospective cohort FFCD-ANABASE.

BACKGROUND: Standard care for non-metastatic squamous cell carcinoma of the anus (SCCA) is chemoradiotherapy, data about elderly patients are scarce. METHODS: All consecutive patients treated for non-metastatic SCCA from the French multicenter FFCD-ANABASE cohort were included. Two groups were defined according to age: elderly (≥75 years) and non-elderly (<75). RESULTS: Of 1015 patients, 202 (19.9%) were included in the elderly group; median follow-up was 35.5 months. Among the elderly, there were more women (p = 0.015); frailer patients (p < 0.001), fewer smokers (p < 0.001) and fewer HIV-infected (p < 0.001) than in the non-elderly group. Concomitant chemotherapy and inguinal irradiation were less frequent (p < 0.001 and p = 0.04). In the elderly group; 3-year overall survival (OS), recurrence-free survival (RFS) and colostomy-free survival (CFS) were 82.9%, 72.4% and 78.0%, respectively; complete response rate at 4-6 months was 70.3%. There were no differences between groups for all outcomes and toxicity. In multivariate analyses for the elderly, PS ≥ 2 and locally-advanced tumors were significantly associated with poor OS (HR = 3.4 and HR = 2.80), RFS (HR = 2.4 and HR = 3.1) and CFS (HR = 3.8 and HR = 3.0); and treatment interruption with poor RFS (HR = 1.9). CONCLUSION: In the FFCD-ANABASE cohort, age did not influence tumor and tolerance outcomes of non-metastatic SCCA. Optimal curative treatment should be offered to elderly patients.

Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design.

BACKGROUND: Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care. METHODS: We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436. FINDINGS: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone. INTERPRETATION: Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients. FUNDING: Janssen-Cilag, Ipsen, Sanofi, and the French Government.

Association of Radiochemotherapy to Immunotherapy in unresectable locally advanced Oesophageal carciNoma-randomized phase 2 trial ARION UCGI 33/PRODIGE 67: the study protocol.

BACKGROUND: In case of locally advanced and/or non-metastatic unresectable esophageal cancer, definitive chemoradiotherapy (CRT) delivering 50 Gy in 25 daily fractions in combination with platinum-based regimen remains the standard of care resulting in a 2-year disease-free survival of 25% which deserves to be associated with new systemic strategies. In recent years, several immune checkpoint inhibitors (anti-PD1/anti-PD-L1, anti-Program-Death 1/anti-Program-Death ligand 1) have been approved for the treatment of various solid malignancies including metastatic esophageal cancer. As such, we hypothesized that the addition of an anti-PD-L1 to CRT would provide clinical benefit for patients with locally advanced oesophageal cancer. To assess the efficacy of the anti-PD-L1 durvalumab in combination with CRT and then as maintenance therapy we designed the randomized phase II ARION (Association of Radiochemotherapy with Immunotherapy in unresectable Oesophageal carciNoma- UCGI 33/PRODIGE 67). METHODS: ARION is a multicenter, open-label, randomized, comparative phase II trial. Patients are randomly assigned in a 1:1 ratio in each arm with a stratification according to tumor stage, histology and centre. Experimental arm relies on CRT with 50 Gy in 25 daily fractions in combination with FOLFOX regimen administrated during and after radiotherapy every two weeks for a total of 6 cycles and durvalumab starting with CRT for a total of 12 infusions. Standard arm is CRT alone. Use of Intensity Modulated radiotherapy is mandatory. The primary endpoint is to increase progression-free survival at 12 months from 50 to 68% (HR = 0.55) (power 90%; one-sided alpha-risk, 10%). Progression will be defined with central external review of imaging. ANCILLARY STUDIES ARE PLANNED: PD-L1 Combined Positivity Score on carcinoma cells and stromal immune cells of diagnostic biopsy specimen will be correlated to disease free survival. The study of gut microbiota will aim to determine if baseline intestinal bacteria correlates with tumor response. Proteomic analysis on blood samples will compare long-term responder after CRT with durvalumab to non-responder to identify biomarkers. CONCLUSION: Results of the present study will be of great importance to evaluate the impact of immunotherapy in combination with CRT and decipher immune response in this unmet need clinical situation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT: 03777813.Trial registration date: 5th December 2018.

Short course radiotherapy versus radiochemotherapy for locally advanced rectal cancers in the elderly (UNICANCER PRODIGE 42/GERICO 12 study): Quality of life and comprehensive geriatric assessment.

BACKGROUND: The results of the PRODIGE 42/GERICO 12 study showed that short course radiotherapy had a better tolerance profile than radiochemotherapy, with comparable oncological results. We have included Quality of Life analyses and oncogeriatric evaluations in this study. PATIENTS AND METHODS: In all, 101 patients ≥75 years of age with resectable T3-T4 rectal adenocarcinoma less than 12 cm from the anal margin received short course radiotherapy (5X5 Gy in one week) or radiochemotherapy (50 Gy, 2 y/f and capecitabine 800 mg/m2, 5 days/week) with delayed surgery (7 weeks ± 1) in both groups. The Quality of Life analyses (EORTC QLQ C-30 et ELD14) were conducted upon inclusion, pre-operatively, at 3, 6 and 12 months post-op, together with the oncogeriatric evaluations, including an evaluation of the IADL and ADL scores, walking speed, GDS15, MMSE, MNA. RESULTS: We did not highlight any statistical difference for the global EORTC QLQ-C30 score; several factors are statistically in favor of the short course radiotherapy group at 3 months post-op (cognitive functions, fatigue, appetite). In the case of the ELD14 score, the disease burden is perceived as more negative at 3, 6 and 12 months postop in the radiochemotherapy group. The IADL score deteriorated in 44.8 % of the radiochemotherapy group and 14.8 % of the radiotherapy group (p = 0.032); similarly, the GDS15 depression score was better preserved in the short course radiotherapy group (p = 0.05). An analysis of the other scores: ADL, walking speed, MNA, MMSE did not highlight any statistical difference. CONCLUSION: Short course radiotherapy achieves better results in terms of Quality of Life and preservation of autonomy in patients aged ≥75 treated for locally advanced rectal cancer.

Comparison of short course radiotherapy with chemoradiotherapy for locally advanced rectal cancers in the elderly: A multicentre, randomised, non-blinded, phase 3 trial.

BACKGROUND: There is no specific guideline for the treatment of locally advanced rectal cancers in the elderly. Here we compared R0 resection rate and degradation of autonomy based on the instrumental activities of daily living score between neoadjuvant, short course radiotherapy and chemoradiotherapy in this specific population. PATIENTS AND METHODS: Patients ≥75 years with resectable T3-T4 rectal adenocarcinoma within 12 cm of the anal verge or T2 of the very low rectum were randomised between short course radiotherapy (5 × 5 Gy in one week) and chemoradiotherapy (50 Gy, 2 Gy/f, 5 weeks with capecitabine: 800 mg/m2 twice daily, 5 days per week), with delayed surgery 7 ± 1 weeks for the two arms. RESULTS: One hundred and three eligible patients were enrolled between January 2016 and December 2019 when the trial was closed due to poor accrual. The R0 resection rate (first co-primary objective) was 84.3%; confidence interval 95% [73.26-94.18] in the short course group and 88%; confidence interval 95% [77.77-96.60] in the chemoradiotherapy group (non-inferiority p = 0.28). The deterioration of the instrumental activities of daily living score was not different during the pre-operative phase, it was significantly more deteriorated in the chemoradiotherapy group at 3 months post-operative (44.8% versus 14.8%; p = 0.032) but was not different at 12 months post-operative (second co-primary objective). During pre-operative phase, 9.8% of patients in short course group and 22% of patients in chemoradiotherapy group presented a serious adverse event, but we observed no difference during the post-operative phase between the two groups. CONCLUSION: Although the main objectives of the study were not achieved, the short course radiotherapy followed by delayed surgery could represent a preferred treatment option in patients ≥75 years with locally advanced rectal cancer; a new study must be performed to confirm the improvement in overall and specific survival results.

Panitumumab in combination with chemoradiotherapy for the treatment of locally-advanced anal canal carcinoma: Results of the FFCD 0904 phase II trial.

BACKGROUND AND PURPOSE: Standard treatment of squamous cell carcinoma of the anus (SCCA)is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study (EudraCT: 2011-005436-26) assessed the tolerance and complete response (CR) rate at 8 weeks of panitumumab (Pmab) combined with MMC-5FU-based CRT. METHODS: Patients with locally advanced tumors without metastases (T2 > 3 cm, T3-T4, or N + whatever T stage) were treated with IMRT up to 65 Gy and concomitant CT according to the doses defined by a previous phase I study (MMC: 10 mg/m2; 5FU: 400 mg/m2; Pmab: 3 mg/kg). The expected CR rate was 80%. RESULTS: Forty-five patients (male: 9, female: 36; median age: 60.1 [41.5-81]) were enrolled in 15 French centers. The most common related grade 3-4 toxicities observed were digestive (51.1%), hematologic (lymphopenia: 73.4%; neutropenia: 11.1%), radiation dermatitis (13.3%), and asthenia (11.1%) with RT interruption in 14 patients. One patient died because of mesenteric ischemia during the CRT, possibly related to treatment. In ITT analysis, the CR rate at 8 weeks after CRT was 66.7% [90%CI: 53.4-78.2]. Median follow-up was 43.6 months [IC 95%: 38.61-47.01]. Overall survival, recurrence-free and colostomy-free survival at 3 years were 80% [95%CI: 65.1-89], 62.2% [IC95%: 46.5-74.6] and 68.8 % [IC95%: 53.1-80.2] respectively. CONCLUSION: Panitumumab in combination with CRT for locally advanced SCCA failed to meet the expected CR rate and exhibited a poor tolerance. Furthermore, late RFS, CFS, and OS did not suggest any outcome improvement to justify further clinical trials. CLINICALTRIALS: gov identifier: NCT01581840.

Treatment, outcome, and prognostic factors in non-metastatic anal cancer: The French nationwide cohort study FFCD-ANABASE.

INTRODUCTION: International guidelines regarding the treatment of squamous cell carcinoma of the anus (SCCA) recommend intensity-modulated radiotherapy (IMRT) combined with mitomycin-based chemotherapy (CT). The French FFCD-ANABASE cohort aimed at evaluating clinical practices, treatment, and outcomes of SCCA patients. METHODS: This prospective multicentric observational cohort included all non-metastatic SCCA patients treated in 60 French centers from January 2015 to April 2020. Patients and treatment characteristics, colostomy-free survival (CFS), disease-free survival (DFS), overall survival (OS), and prognostic factors were analyzed. RESULTS: Among 1015 patients (male: 24.4 %; female: 75.6 %; median age: 65 years), 43.3 %presented with early-stage(T1-2, N0) and 56.7 % with locally advanced stage (T3-4 or N + ) tumors. IMRT was used for 815 patients (80.3 %) and a concurrent CT was administered in 781 patients, consisting of mitomycin-based CT for 80 %. The median follow-up was 35.5 months. DFS, CFS, and OS at 3 years were 84.3 %, 85.6 %, and 91.7 % respectively in the early-stage group compared to 64.4 %, 66.9 %, and 78.2 % in the locally-advanced group (p < 0.001). In multivariate analyses, male gender, locally-advanced stage, and ECOG PS ≥ 1 were associated with poorer DFS, CFS, and OS. IMRT was significantly associated with a better CFS in the whole cohort and almost reached significance in the locally-advanced group. CONCLUSION: Treatment of SCCA patients showed good respect for current guidelines. Significant differences in outcomes advocate for personalized strategies by either de-escalation for early-stage tumors or treatment intensification for locally-advanced tumors.

Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol.

Background: As in other solid tumors, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis than patients with extensive metastatic disease. Stereotactic body radiotherapy (SBRT) is now considered an option in this population.Programmed death-1 (PD-1) and its ligands (PD-L1) are targeted by immune checkpoint inhibitors. Preclinical studies have shown that the tumor immune microenvironment changes when combining radiotherapy with immunotherapy, especially with hypofractionated radiotherapy.The oligometastatic setting appears to be the most relevant clinical situation for evaluating the immune response generated by radiotherapy and immune checkpoint inhibitors in patients with an intact immune system.We hypothesize that durvalumab will enhance the immune response following SBRT targeting oligometastatic lesions. Our purpose is to demonstrate, via a randomized 2:1 phase II trial, that SBRT (3 fractions) with durvalumab in oligometastatic hormone-sensitive prostate cancer patients would improve progression-free survival in patients with prostate cancer with up to 5 metastases compared to patients who exclusively received SBRT. Methods: This is a multicentric randomized phase II study in French academic hospitals. Patients with prostate cancer and up to 5 metastases (lymph node and/or bone) were randomized into a 2:1 ratio between Arm A (experimental group), corresponding to durvalumab and SBRT to the metastases, and Arm B (control group), corresponding to SBRT alone to the metastases. The study aims to accrue a total of 96 patients within 3 years. The primary endpoint is two-year progression-free survival and secondary endpoints include androgen deprivation therapy-free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response. Discussion: The expected benefit for the patients in the experimental arm is longer life expectancy with acceptable toxicity. We also expect our study to provide data for better understanding the synergy between immunotherapy and radiotherapy in oligometastatic prostate cancer.

What is the optimal treatment for T1N0 anal squamous cell carcinoma? Analysis of current practices in the prospective French FFCD ANABASE cohort.

INTRODUCTION: for localized T1N0 squamous cell carcinoma of the anus (SCCA) standard radiotherapy (RT) may result in overtreatment and alternative strategies are debated. METHODS: T1N0M0 SCCA treated between 2015 and 2020 by local excision (LE) or RT were analyzed from the French prospective FFCD ANABASE cohort. Treatment strategies, recurrence-free and colostomy-free survivals (RFS, CFS) and prognostic factors were reported. RESULTS: among 1135 SCCA patients, 99 T1N0M0 were treated by LE(n = 17,17.2%), or RT (n = 82,82.8%) including RT alone (n = 65,79.2%) or chemo-RT (n = 17, 20.7%). Median follow-up was 27.2 months [0.03-54.44]. Median tumor size were 11.4 mm [0.9-20] and 15.3 mm [2-20] in the LE and RT groups respectively. Mean RT tumor dose was 59.4 Gy [18-69.4 Gy]. One patient in LE group and 9 in RT group had a pelvic recurrence, either local (60%), nodal (10%) or both (30%). RFS and CFS at 24 months were 92.2%[95%CI,83.4-96.4] and 94.6%[95%CI,86.1-98.0], at 36 months 88.1%[95%CI,77.1-94.2] and 88.5%[95%CI,77.0-94.5], in LE and RT group respectively, without any significative difference (HR = 0.57;[95%CI,0.07-4.45];p = 0.60). By univariate analysis, male gender was the only prognostic factor(HR = 5.57;95%CI, 1.76-17.63; p = 0.004). CONCLUSION: this cohort confirms the heterogeneity of T1N0M0 SCCA management, questioning the place of RT alone, reduced dose or RT volume, and the safety of LE.

MRI-Based Radiomics Input for Prediction of 2-Year Disease Recurrence in Anal Squamous Cell Carcinoma.

PURPOSE: Chemo-radiotherapy (CRT) is the standard treatment for non-metastatic anal squamous cell carcinomas (ASCC). Despite excellent results for T1-2 stages, relapses still occur in around 35% of locally advanced tumors. Recent strategies focus on treatment intensification, but could benefit from a better patient selection. Our goal was to assess the prognostic value of pre-therapeutic MRI radiomics on 2-year disease control (DC). METHODS: We retrospectively selected patients with non-metastatic ASCC treated at the CHU Bordeaux and in the French FFCD0904 multicentric trial. Radiomic features were extracted from T2-weighted pre-therapeutic MRI delineated sequences. After random division between training and testing sets on a 2:1 ratio, univariate and multivariate analysis were performed on the training cohort to select optimal features. The correlation with 2-year DC was assessed using logistic regression models, with AUC and accuracy as performance gauges, and the prediction of disease-free survival using Cox regression and Kaplan-Meier analysis. RESULTS: A total of 82 patients were randomized in the training (n = 54) and testing sets (n = 28). At 2 years, 24 patients (29%) presented relapse. In the training set, two clinical (tumor size and CRT length) and two radiomic features (FirstOrder_Entropy and GLCM_JointEnergy) were associated with disease control in univariate analysis and included in the model. The clinical model was outperformed by the mixed (clinical and radiomic) model in both the training (AUC 0.758 versus 0.825, accuracy of 75.9% versus 87%) and testing (AUC 0.714 versus 0.898, accuracy of 78.6% versus 85.7%) sets, which led to distinctive high and low risk of disease relapse groups (HR 8.60, p = 0.005). CONCLUSION: A mixed model with two clinical and two radiomic features was predictive of 2-year disease control after CRT and could contribute to identify high risk patients amenable to treatment intensification with view of personalized medicine.

Anal canal cancer: management of inguinal nodes and benefit of prophylactic inguinal irradiation (CORS-03 Study).

PURPOSE: To evaluate the benefit of prophylactic inguinal irradiation (PII) in anal canal squamous cell carcinoma (ASCC). METHODS AND MATERIALS: This retrospective study analyzed the outcome of 208 patients presenting with ASCC treated between 2000 and 2004 in four cancer centers of the south of France. RESULTS: The population study included 35 T1, 86 T2, 59 T3, 20 T4, and 8 T stage unknown patients. Twenty-seven patients presented with macroscopic inguinal node involvement. Of the 181 patients with uninvolved nodes at presentation, 75 received a PII to a total dose of 45-50 Gy (PII group) and 106 did not receive PII (no PII group). Compared with the no PII group, patients in the PII group were younger (60% vs. 41% of patients age <68 years, p = 0.01) and had larger tumor (T3-4 = 46% vs. 27% p = 0.01). The other characteristics were well balanced between the two groups. Median follow-up was 61 months. Fourteen patients in the no PII group vs. 1 patient in the PII group developed inguinal recurrence. The 5-year cumulative rate of inguinal recurrence (CRIR) was 2% and 16% in PII and no PII group respectively (p = 0.006). In the no PII group, the 5-year CRIR was 12% and 30% for T1-T2 and T3-T4 respectively (p = 0.02). Overall survival, disease-specific survival, and disease-free survival were similar between the two groups. In the PII group, no Grade >2 toxicity of the lower extremity was observed. CONCLUSION: PII with a dose of 45 Gy is safe and highly efficient to prevent inguinal recurrence and should be recommended for all T3-4 tumors. For early-stage tumors, PII should also be discussed, because the 5-year inguinal recurrence risk remains substantial when omitting PII (about 10%).

High-dose split-course radiation therapy for anal cancer: outcome analysis regarding the boost strategy (CORS-03 study).

PURPOSE: To retrospectively assess the clinical outcome in anal cancer patients treated with split-course radiation therapy and boosted through external-beam radiation therapy (EBRT) or brachytherapy (BCT). METHODS AND MATERIALS: From January 2000 to December 2004, a selected group (162 patients) with invasive nonmetastatic anal squamous cell carcinoma was studied. Tumor staging reported was T1 = 31 patients (19%), T2 = 77 patients (48%), T3 = 42 patients (26%), and T4= 12 patients (7%). Lymph node status was N0-1 (86%) and N2-3 (14%). Patients underwent a first course of EBRT: mean dose 45.1 Gy (range, 39.5-50) followed by a boost: mean dose 17.9 Gy (range, 8-25) using EBRT (76 patients, 47%) or BCT (86 patients, 53%). All characteristics of patients and tumors were well balanced between the BCT and EBRT groups. RESULTS: The mean overall treatment time (OTT) was 82 days (range, 45-143) and 67 days (range, 37-128) for the EBRT and BCT groups, respectively (p < 0.001). The median follow-up was 62 months (range, 2-108). The 5-year cumulative rate of local recurrence (CRLR) was 21%. In the univariate analysis, the prognostic factors for CRLR were as follows: T stage (T1-2 = 15% vs. T3-4 = 36%, p = 0.03), boost technique (BCT = 12% vs. EBRT = 33%, p = 0.002) and OTT (OTT <80 days = 14%, OTT ≥80 days = 34%, p = 0.005). In the multivariate analysis, BCT boost was the unique prognostic factor (hazard ratio = 0.62 (0.41-0.92). In the subgroup of patients with OTT <80 days, the 5-year CRLR was significantly increased with the BCT boost (BC = 9% vs. EBRT = 28%, p = 0.03). In the case of OTT ≥80 days, the 5-year CRLR was not affected by the boost technique (BCT = 29% vs. EBRT = 38%, p = 0.21). CONCLUSION: In anal cancer, when OTT is <80 days, BCT boost is superior to EBRT boost for CRLR. These results suggest investigating the benefit of BCT boost in prospective trials.