Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. METHODS: We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. FINDINGS: Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). INTERPRETATION: Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. FUNDING: Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Combination of Abiraterone Acetate, Prostate Bed Radiotherapy, and Luteinizing Hormone-releasing Hormone Agonists in Biochemically Relapsing Patients After Prostatectomy (CARLHA): A Phase 2 Clinical Trial.

BACKGROUND: The relevance of next-generation hormone therapies and circulating tumor cells (CTCs) are not elucidated in biochemical recurrence after prostatectomy. OBJECTIVE: To evaluate the combination of abiraterone acetate plus prednisone (AAP), prostate bed radiotherapy (PBRT), and goserelin in biochemically relapsing men after prostatectomy, and to investigate the utility of CTCs. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm multicenter phase 2 trial, 46 biochemically relapsing men were enrolled between December 2012 and January 2019. The median follow-up was 47 mo. INTERVENTION: All patients received AAP 1000 mg daily (but 750 mg during PBRT), salvage PBRT, and goserelin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 3-yr biochemical recurrence-free survival (bRFS) when prostate-specific antigen (PSA) levels were ≥0.2 ng/ml. The secondary outcomes included alternative bRFS (alt-bRFS) when PSA levels were ≥0.5 ng/ml and safety assessment. CTC count was assessed. RESULTS AND LIMITATIONS: The 3-yr bRFS and alt-bRFS were 81.5% (95% confidence interval or CI [66.4-90.3%]) and 95.6% (95% CI [83.5-98.9%]), respectively. The most common acute radiotherapy-related adverse effect (AE; all grades was pollakiuria (41.3%). The most common late AE (all grades) was urinary incontinence (15.2%). Grade 3-4 acute or late radiotherapy-related AEs were scarce. Most frequent AEs nonrelated to radiotherapy were hot flashes (76%), hypertension (63%), and hepatic cytolysis (50%, of which 20% were of grades 3-4). Of the patients, 11% had a CTC count of ≥5, which was correlated with poorer bRFS (p = 0.042) and alt-bRFS (p = 0.008). The association between CTC count and higher rates of relapse was independent of the baseline PSA level and PSA doubling time (p = 0.42 and p = 0.09, respectively). This study was nonrandomized with a limited number of patients, and few clinical events were reported. CONCLUSIONS: Adding AAP to salvage radiation therapy and goserelin resulted in high bRFS and alt-bRFS. AEs remained manageable, although a close liver surveillance is advised. CTC count appears as a promising biomarker for prognosis and predicting response to treatment. PATIENT SUMMARY: Our study was a phase 2 clinical trial that exhibited the efficacy and tolerance of a novel androgen-receptor targeting agent (abiraterone acetate plus prednisone) in patients with prostate cancer who experienced rising prostate-specific antigen after radical prostatectomy, in combination with prostate bed radiotherapy. The results also indicated the feasibility and potential value of circulating tumor cell detection, which constitutes a possible advance in managing prostate cancers.

Prospective results for 5-year survival and toxicity of moderately hypofractionated radiotherapy with simultaneous integrated boost (SIB) in (very) high-risk prostate cancer.

Purpose: High-risk (HR) prostate cancer patients usually receive high-dose radiotherapy (RT) using a two-phase sequential technique, but data on a simultaneous integrated boost (SIB) technique are lacking. We prospectively evaluated the long-term results of urinary (GU) and digestive (GI) toxicity and survival data for high-dose RT using a SIB technique in HR and very high-risk (VHR) prostate cancer. Methods: Patients were treated using an SIB technique in 34 fractions, at a dose of 54.4 Gy to the pelvis and seminal vesicles and 74.8 Gy to the prostate, combined with 36 months of androgen-depriving therapy in a prospective multicenter study. Acute and late GU and GI toxicity data were collected. Overall survival (OS), biochemical-relapse-free survival (bRFS), loco-regional-relapse-free survival (LRRFS), metastasis-free-survival (MFS) and disease-free-survival (DFS) were assessed. Results: We recruited 114 patients. After a median follow-up of 62 months, very few patients experienced acute (M0-M3) (G3-4 GU = 3.7 %; G3-4 GI = 0.9 %) or late (M6-M60) severe toxicity (G3-4 GU = 5.6 %; G3-4 GI = 2.8 %). The occurrence of acute G2 + GU or GI toxicity was significantly related to the consequential late G2 + toxicity (p < 0.01 for both GU and GI). Medians of OS, bRFS, LRRFS, MFS and DFS were not reached. At 60 months, OS, bRFS, LRRFS, MFS and DFS were 88.2 % [82.1; 94.7], 86.0 % [79.4 %;93.2 %], 95.8 % [91.8 %;99.9 %], 87.2 % [80.9 %;94.0 %] and 84.1 % [77.2 %;91.6 %] respectively. Conclusion: SIB RT at a dose of 54.4 Gy to the pelvis and 74.8 Gy to the prostate is feasible, leading to satisfying tumor control and reasonable toxicity in HR and VHR prostate cancer.

Cost and Toxicity Comparisons of Two IMRT Techniques for Prostate Cancer: A Micro-Costing Study and Weighted Propensity Score Analysis Based on a Prospective Study.

BACKGROUND: Intensity modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT) has become the standard treatment for patients with high-risk prostate cancer. Two techniques of rotational IMRT are commonly used in this indication: Volumetric Modulated Arc Therapy (VMAT) and helical tomotherapy (HT). To the best of our knowledge, no study has compared their related costs and clinical effectiveness and/or toxicity in prostate cancer. We aimed to assess differences in costs and toxicity between VMAT and HT in patients with high-risk prostate cancer with pelvic irradiation. MATERIAL AND METHODS: We used data from the "RCMI pelvis" prospective multicenter study (NCT01325961) including 155 patients. We used a micro-costing methodology to identify cost differences between VMAT and HT. To assess the effects of the two techniques on total actual costs per patient and on toxicity we used stabilized inverse probability of treatment weighting. RESULTS: The mean total cost for HT, €2019 3,069 (95% CI, 2,885-3,285) was significantly higher than the mean cost for VMAT €2019 2,544 (95% CI, 2,443-2,651) (p <.0001). The mean ± SD labor and accelerator cost for HT was €2880 (± 583) and €1978 (± 475) for VMAT, with 81 and 76% for accelerator, respectively. Acute GI and GU toxicity were more frequent in VMAT than in HT (p = .021 and p = .042, respectively). Late toxicity no longer differed between the two groups up to 24 months after completion of treatment. CONCLUSION: Use of VMAT was associated with lower costs for IMRT planning and treatment than HT. Similar stabilized long-term toxicity was reported in both groups after higher acute GI and GU toxicity in VMAT. The estimates provided can benefit future modeling work like cost-effectiveness analysis.

Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.

BACKGROUND: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. METHODS: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. FINDINGS: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. INTERPRETATION: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.

Outcome According to Elective Pelvic Radiation Therapy in Patients With High-Risk Localized Prostate Cancer: A Secondary Analysis of the GETUG 12 Phase 3 Randomized Trial.

PURPOSE: The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial. METHODS AND MATERIALS: Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS). RESULTS: A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio [HR]: 2.52 [95% confidence interval [CI]: 1.78-3.54], P<.0001), Gleason score 8 or higher (HR: 1.41 [95% CI: 1.03-1.93], P=.033) and PSA higher than 20 ng/mL (HR: 1.41 [95% CI: 1.02-1.96], P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 [95% CI: 0.48-0.9], P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 [95% CI: 0.78-1.55], P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 [95% CI: 0.59-1.31], P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity. CONCLUSIONS: This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients.