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The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI.

ABSTRACT: Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases.This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled.If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention.The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014-002665-30.

SUBMITTER: Al-Batran SE

PROVIDER: S-EPMC5745860 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI.

Al-Batran Salah-Eddin SE Goetze Thorsten O TO Mueller Daniel W DW Vogel Arndt A Winkler Michael M Lorenzen Sylvie S Novotny Alexander A Pauligk Claudia C Homann Nils N Jungbluth Thomas T Reissfelder Christoph C Caca Karel K Retter Steffen S Horndasch Eva E Gumpp Julia J Bolling Claus C Fuchs Karl-Hermann KH Blau Wolfgang W Padberg Winfried W Pohl Michael M Wunsch Andreas A Michl Patrick P Mannes Frank F Schwarzbach Matthias M Schmalenberg Harald H Hohaus Michael M Scholz Christian C Benckert Christoph C Knorrenschild Jorge Riera JR Kanngießer Veit V Zander Thomas T Alakus Hakan H Hofheinz Ralf-Dieter RD Roedel Claus C Shah Manish A MA Sasako Mitsuru M Lorenz Dietmar D Izbicki Jakob J Bechstein Wolf O WO Lang Hauke H Moenig Stefan P SP

BMC cancer 20171228 1

<h4>Background</h4>Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases.<h4>Methods</h4>This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients ...[more]

PMID: 29282088

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Project description:ImportanceSurgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction.ObjectiveTo evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection.Design, setting, and participantsThe AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013.InterventionsPatients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT.Main outcomes and measuresThe primary end point was overall survival.ResultsIn total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients.Conclusions and relevancePatients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials.Trial registrationclinicaltrials.gov identifier: NCT00849615.

Project description:ImportanceTotal neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established.ObjectiveTo report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer.Design, setting, and participantsThis secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020.InterventionsPatients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups.Main outcomes and measuresThe end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score.ResultsOf the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45, P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%, P = .67) and distant metastases (18% vs 16%, P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels.Conclusions and relevanceThis secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority.Trial registrationClinicalTrials.gov identifier: NCT02363374.

Project description:BackgroundImprovement in treatment for patients with recurrent ovarian cancer is needed. Standard therapy in patients with platinum-sensitive recurrent ovarian cancer consists of platinum-based chemotherapy. Median overall survival is reported between 18 and 35 months. Currently, the role of surgery in recurrent ovarian cancer is not clear. In selective patients a survival benefit up to 62 months is reported for patients undergoing complete secondary cytoreductive surgery. Whether cytoreductive surgery in recurrent platinum-sensitive ovarian cancer is beneficial remains questionable due to the lack of level I-II evidence.Methods/designMulticentre randomized controlled trial, including all nine gynecologic oncologic centres in the Netherlands and their affiliated hospitals. Eligible patients are women, with first recurrence of FIGO stage Ic-IV platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, who meet the inclusion criteria. Participants are randomized between the standard treatment consisting of at least six cycles of intravenous platinum based chemotherapy and the experimental treatment which consists of secondary cytoreductive surgery followed by at least six cycles of intravenous platinum based chemotherapy. Primary outcome measure is progression free survival. In total 230 patients will be randomized. Data will be analysed according to intention to treat.DiscussionWhere the role of cytoreductive surgery is widely accepted in the initial treatment of ovarian cancer, its value in recurrent platinum-sensitive epithelial ovarian cancer has not been established so far. A better understanding of the benefits and patients selection criteria for secondary cytoreductive surgery has to be obtained. Therefore the 4th ovarian cancer consensus conference in 2010 stated that randomized controlled phase 3 trials evaluating the role of surgery in platinum-sensitive recurrent epithelial ovarian cancer are urgently needed. We present a recently started multicentre randomized controlled trial that will investigate the role of secondary cytoreductive surgery followed by chemotherapy will improve progression free survival in selected patients with first recurrence of platinum-sensitive epithelial ovarian cancer.

Project description:PurposePlatinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established.DesignMATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints.ResultsFrom 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P = 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P = 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%).ConclusionsS-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

Project description:BackgroundCurrently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20-40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC's are conflicting.MethodsThis is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator's choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019.DiscussionThe current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and - if possible - postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines.Trial registrationClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017-004444-38 from 02.11.2017.

Project description:Importance:Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.. Objective:In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Design, Setting, and Participants:The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010. Interventions:Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy. Main Outcomes and Measures:The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model. Results:Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002). Conclusions and Relevance:This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer. Trial Registration:ClinicalTrials.gov Identifier: NCT00349076.

Project description:BackgroundEfforts to improve the outcome of liver surgery by combining curative resection with chemotherapy have failed to demonstrate definite overall survival benefit. This may partly be due to the fact that these studies often involve strict inclusion criteria. Consequently, patients with a high risk profile as characterized by Fong's Clinical Risk Score (CRS) are often underrepresented in these studies. Conceptually, this group of patients might benefit the most from chemotherapy. The present study evaluates the impact of neo-adjuvant chemotherapy in high-risk patients with primary resectable colorectal liver metastases, without extrahepatic disease. Our hypothesis is that adding neo-adjuvant chemotherapy to surgery will provide an improvement in overall survival (OS) in patients with a high-risk profile.Methods/designCHARISMA is a multicenter, randomized, phase III clinical trial. Patients will be randomized to either surgery alone (standard treatment, arm A) or to 6 cycles of neo-adjuvant oxaliplatin-based chemotherapy, followed by surgery (arm B). Patients must be ≥ 18 years of age with liver metastases of histologically confirmed primary colorectal carcinoma. Patients with extrahepatic metastases are excluded. Liver metastases must be deemed primarily resectable. Only patients with a CRS of 3-5 are eligible. The primary study endpoint is OS. Secondary endpoints are progression free survival (PFS), quality of life, morbidity of resection, treatment response on neo-adjuvant chemotherapy, and whether CEA levels can predict treatment response.DiscussionCHARISMA is a multicenter, randomized, phase III clinical trial that will provide an answer to the question if adding neo-adjuvant chemotherapy to surgery will improve OS in a well-defined high-risk patient group with colorectal liver metastases.Trial registrationThe CHARISMA is registered at European Union Clinical Trials Register (EudraCT), number: 2013-004952-39 , and in the "Netherlands national Trial Register (NTR), number: 4893.

Dataset Information

The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI.

Publications

The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI.

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