No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection.

We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL.

Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% (P < .001).

There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.

Biliary tract cancers (BTCs) are malignant neoplasms that arise from the biliary tract, including intrahepatic cholangiocarcinomas (ICCs), extrahepatic (perihilar or distal) cholangiocarcinomas (ECCs), and gallbladder carcinomas (GBCs).1,2 The incidence of some of these neoplasms currently is rising partly as a result of better disease recognition and an increase in risk factors for underlying liver disease, such as nonalcoholic steatohepatitis.3

The prognosis of BTC remains dismal because most patients are diagnosed with inoperable disease, and even after curative-intent surgical resection, the 5-year overall survival (OS) rate is only approximately 20%.4 Main adverse prognostic factors are R1 resection and lymph node involvement. When we designed our study, data that supported adjuvant therapy were scarce and consisted mostly retrospective studies and a negative clinical trial that tested fluorouracil and mitomycin after curative and noncurative resection in patients with BTCs and pancreatic cancers.5 A previous meta-analysis of mostly retrospective data suggested a potential benefit of adjuvant chemotherapy4; however, because of the low level of evidence, no specific adjuvant treatment was recommended in this setting by the majority of international guidelines.

In the advanced setting, gemcitabine combined with cisplatin was reported to improve OS compared with gemcitabine alone in the ABC-02 phase III trial (ClinicalTrials.gov identifier: NCT00262769) and in the BT-22 randomized phase II trial (ClinicalTrials.gov identifier: NCT00380588).6-8 Gemcitabine and oxaliplatin chemotherapy (GEMOX) was shown to be active and tolerable in advanced BTC in phase II trials9 and was superior to best supportive care and fluorouracil and folinic acid combination in a single-center phase III trial limited to GBC.10 GEMOX has been selected as the control arm or as the chemotherapy backbone of several randomized trials in patients with unresectable disease,11-14 with a median OS achieved comparable to that in the ABC-02 trial.7 We thus aimed to assess whether adjuvant GEMOX given after resection of BTC with curative intent could improve outcomes compared with surveillance alone.

Study Design and Patients

PRODIGE 12-ACCORD 18 (UNICANCER GI Group) was a multicenter, open-label, randomized phase III trial conducted in 33 centers in France within the PRODIGE French Group of Digestive Oncology (FFCD), UNICANCER GI Group (UCGI), Multidisciplinary Cooperative Group in Oncology (GERCOR) intergroup. Patients deemed eligible were age 18 years or older and had undergone a curative-intent, macroscopically complete (R0 or R1) resection of a localized BTC (ICC, ECC, or GBC; ampullary carcinomas excluded) less than 3 months before randomization. A contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis with no evidence of disease was required within 30 days before randomization. At enrollment, patients had to have recovered from surgery with a European Cooperative Oncology Group performance status less than or equal to 2 and adequate hematologic (hemoglobin > 10 g/dL, neutrophil count > 1.5 GL, platelets > 75 GL), renal (creatinine clearance > 40 mL/min according to the Cockroft-Gault equation), and liver (prothrombin time ratio > 60%, aminotransferases ≤ five times the upper limit of normal, alkaline phosphatases ≤ 2.5 times the upper limit of normal, and conjugated bilirubin ≤ 35 μmol/L) functions.

The trial was approved by an ethics committee and was conducted in accordance with Good Clinical Practice Guidelines and the Declaration of Helsinki. All patients provided written informed consent before participating in the trial.

Patients deemed eligible were randomly assigned (1:1) to either adjuvant GEMOX or surveillance only. Randomization with minimization was stratified by primary site (ICC v ECC v GBC), extent of resection (R0 v R1), lymph node involvement (N+ v N0 v Nx), and center. Patients had to start treatment within 7 days of their random assignment.

Procedure

Patients allocated to adjuvant chemotherapy (arm A) were given gemcitabine (1,000 mg/m2 intravenously) over 100 minutes (fixed-dose infusion rate, 10 mg/m2/min) on day 1 and oxaliplatin (85 mg/m2 intravenously) over 2 hours on day 2 every 2 weeks for 12 cycles. In the event of toxicity, the treatment dose could be adapted as described in the protocol. Patients were assessed for toxicity before each treatment cycle.

Follow-up consultations were planned in both arms at baseline, every 3 months from randomization for 2 years, and then every 6 months for the next 3 years. During the surveillance visits, clinical examination; chest, abdomen, and pelvis CT scans; and blood tests (including liver and renal function tests, carcinoembryonic antigen, and cancer antigen 19-9) were performed. Health-related quality of life (HRQOL) was evaluated by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 version 3.0, which was completed at every visit for 5 years.

Outcomes

The primary end points were relapse-free survival (RFS) and time to definitive deterioration (TDD) of HRQOL in the intention-to-treat population. RFS was considered as the primary endpoint for statistical power calculation, and TDD of HRQOL was considered as an additional primary endpoint, tested in a separate analysis. RFS was defined as the time between randomization and disease recurrence as evaluated by the investigators, new primary BTC, or death, whichever occurred first. TDD of HRQOL was defined as the time between randomization and worsening of global, physical functioning, or fatigue Quality of Life Questionnaire-C30 scores of at least 5 points, with no subsequent improvement of at least 5 points. Patients with no events were censored at the date of last news.

Secondary end points were OS, toxicity, and exploratory translational end points (including study of potential, predictive, and prognostic factors). OS was defined as the time between randomization and death (as a result of any cause). Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0), except for neurotoxicity, which was assessed using Levi’s scale.15

Statistical Analysis

The trial was designed to detect a difference in median RFS from 18 months in the surveillance arm to 30 months in the GEMOX arm, which corresponds to a hazard ratio (HR) of 0.60. With a two-sided α of 5% and a statistical power of 80%, 126 RFS events were required, and 180 patients had to be enrolled in 5 years, with a minimum follow-up of 2 years for the last patient included. With an envisioned 5% loss to follow-up, 190 patients were planned to be included in the trial. The statistical power to show a difference in global HRQOL of at least 5 points with 180 patients included was 80%.

The data cutoff date was June 30, 2017. Completeness of the trial was evaluated as proposed by Clark et al.16 The analyses of the primary end points were planned on the intention-to-treat population that comprised all patients who were randomly assigned. RFS was estimated using the Kaplan-Meier method and compared with the log-rank and stratified log-rank tests (according to the stratification factors) for univariable analyses. Multivariable analysis included variables associated with RFS in the univariable analysis with P < .20, except for the treatment arm and stratification factors, which were forced into the model. OS was analyzed using the same methodology as RFS. Toxicity was assessed in all patients in the GEMOX arm who received at least one dose of study treatment and all patients in the surveillance arm.

Exploratory subgroup analyses were planned according to stratification parameters. An exploratory per-protocol analysis was planned on the subpopulation of patients without deviation in inclusion or exclusion criteria and for the GEMOX arm, those who received at least 50% of the chemotherapy dose during the first six cycles. A two-sided significance level of P < .05 was used throughout the analyses.

Population

Between July 2009 and February 2014, 196 patients were included. Two patients randomly assigned to the GEMOX arm withdrew consent, which left 95 patients in the GEMOX arm and 99 in the surveillance arm for the intention-to-treat analysis (Fig 1). Demographic, pathologic, and biologic characteristics of the patients are listed in Table 1. The most frequent primary location was ICC (44%) lymph node involvement (36%) and R1 resection (13%), and these characteristics were balanced between the study arms.

Table

TABLE 1. Patient Baseline Characteristics

Survival

After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), there were 126 RFS events: 59 in the GEMOX arm (55 disease progressions and four deaths) and 67 in the surveillance arm (61 disease progressions and six deaths). Completeness of the trial was 74%.

The RFS was not different between arms, with a median of 30.4 months (95% CI, 15.4 to 43.0 months) in the GEMOX arm versus 18.5 months (95% CI, 12.6 to 38.2 months; log-rank P = .47) in the surveillance arm (HR, 0.88; 95% CI, 0.62 to 1.25; P = .48; Fig 2A). RFS rates were 66% versus 64% at 12 months, 53% versus 46% at 24 months, 47% versus 43% at 36 months, and 36% versus 33% at 48 months in the GEMOX versus surveillance arms, respectively. The per-protocol analysis was consistent with no benefit for GEMOX (HR, 0.86; 95% CI, 0.59 to 1.27; P = .45). Moreover, a similar proportion of patients experienced metastatic recurrence: 41 (75%) of the 55 patients in the GEMOX arm versus 43 (71%) in the surveillance arm. At recurrence, the most frequently used chemotherapy regimens were gemcitabine-based regimens in the surveillance arm and fluoropyrimidine-based regimens in the GEMOX arm (Appendix Table A1, online only).

At the time of analysis, 82 patients had died (41 in the GEMOX arm and 41 in the surveillance arm). The OS was not different between arms, with a median of 75.8 months (95% CI, 34.4 months to not estimable) in the GEMOX arm versus 50.8 months (95% CI, 38.0 months to not estimable; log-rank P = .74) in the surveillance arm (HR, 1.08; 95% CI, 0.70 to 1.66; P = .74; Fig 2B). OS rates were 86% versus 94% at 12 months, 69% versus 76% at 24 months, 60% versus 65% at 36 months, and 51% versus 52% at 48 months in the GEMOX versus surveillance arms, respectively. Of note, postrelapse survival tended to be worse in the GEMOX arm than in the surveillance arm (median, 8.0 v 15.2 months, respectively; HR, 1.55; 95% CI, 0.98 to 2.47; P = .06; Appendix Fig A1, online only).

The planned subgroup analyses, which corresponded to stratification factors, did not suggest any subgroup with a benefit with adjuvant GEMOX (Fig 3). In contrast, there was a significantly worse RFS and OS in the subgroup of patients with GBC in the GEMOX arm versus the surveillance arm (P = .034 for RFS and P = .017 for OS, n = 17 in the GEMOX arm and n = 21 in the surveillance arm).

Univariable analysis of RFS showed that R1 resection, N+ or Nx status, portal vein thrombosis, cancer antigen 19-9 greater than or equal to 37, and microvascular invasion were associated with worse RFS (Table 2). In multivariable analysis, all these factors except portal vein thrombosis were independently associated with worse RFS. Treatment arm and tumor site were not associated with worse RFS either in univariable or in multivariable analysis.

Table

TABLE 2. Univariable and Multivariable Cox Proportional Hazards Regression Model of Relapse-Free Survival in the Intention-to-Treat Population

HRQOL

The number of patients who completed the HRQOL questionnaires were 80 and 81 at baseline, 66 and 78 at 3 months, 59 and 64 at 6 months, 43 and 54 at 9 months, and 42 and 47 at 12 months in the GEMOX and surveillance arms, respectively. There was no difference in TDD of global HRQOL (log-rank P = .39; Appendix Fig A2A, online only). There was also no significant difference in TDD of physical functioning (P = .15) and fatigue (P = .07) score, despite a trend for an earlier decrease in the GEMOX arm (Appendix Figs A2B and A2C).

Safety

In the GEMOX arm, a median of 12 cycles (range, 1 to 12 cycles) and a mean of 9.7 cycles (standard deviation, 3.6 cycles) were administered. Oxaliplatin was given for a median of 10 cycles and a mean of 8.5 cycles. Four patients did not receive chemotherapy because of worsening condition between randomization and the beginning of chemotherapy. Adverse events that occurred during the first 6 months of the trial are listed in Table 3. As expected, treatment with GEMOX was associated with an increased incidence of hematologic, neurologic, and liver toxicities (cytolysis and cholestasis without increase of bilirubin). Only one patient had febrile neutropenia in the GEMOX arm. The worse adverse events were grade 3 in 56 patients (62%) versus 18 (18%) in the GEMOX arm and grade 4 in 10 patients (11%) versus 3 (3%) in the surveillance arm (P < .001 for grade 3 v 4 toxicity). During the initial 6 months of the study (treatment period for the GEMOX arm), four deaths were recorded in the GEMOX arm (three as a result of tumor progression, one as a result of a road accident) versus two deaths in the surveillance arm (both as a result of tumor progression). At 12 months, sensory neuropathy was noted as grade 1 in nine patients (10%), grade 2 in five patients (6%), and grade 3 in four patients (4%) in the GEMOX arm.

Table

TABLE 3. Main Adverse Events That Occurred in the First 6 Months of the Trial

This study failed to show any benefit for GEMOX compared with surveillance in the adjuvant setting of BTC. This trial was the first large phase III trial to our knowledge to be reported in this context and demonstrated that collaborative efforts could lead to appropriate randomized trials, even in rare tumors. The median RFS observed in this study was comparable with that used for the statistical hypothesis (18.5 and 30.4 months observed v 18 and 30 months planned), and the planned HR of 0.6 was ambitious, which may suggest that the trial was underpowered. However, the observed HR of 0.88 suggests a low chance of clinically significant benefit, and the median RFS was achieved at a plateau with the largest separation between the curves, meaning that the median was less representative of the true difference than the HR. Moreover, we did not observe a trend toward an OS benefit, with an HR greater than 1. The median OS of 50.8 and 75.8 months again is not representative because of a plateau in the curves at the median, whereas the OS rates were higher in the surveillance arm than in the GEMOX arm during most of follow-up. This discrepancy between an RFS trend and no OS benefit may be partly due to the chemotherapy given after relapse, which differed between arms. Patients in the surveillance arm may have benefited more from chemotherapy given at relapse than patients pretreated with GEMOX. This finding is supported by the trend toward lower postrelapse survival in the GEMOX arm. However, other unknown factors might also explain the lack of benefit in OS of GEMOX.

These results were not driven by suboptimal delivery of chemotherapy, with a median of 12 cycles received and a median of 10 cycles of oxaliplatin, which mirrors that achieved in the adjuvant setting of colorectal cancer.17 Moreover, the toxicity with GEMOX was as expected. In addition, the treatment had no significant detrimental effect on TDD of global HRQOL. The reference first-line regimen in the advanced setting is currently gemcitabine-cisplatin combination. However, when the study was designed, GEMOX combination was also frequently considered as being a valuable regimen for advanced disease on the basis of phase II studies. A single-center randomized study that used a modified GEMOX combination suggested an efficacy similar to gemcitabine-cisplatin combination for treating advanced GBCs.18

Our results contrast with those recently reported in the phase III Capecitabine or Observation After Surgery in Treating Patients With Biliary Tract Cancer (BILCAP) trial (ClinicalTrials.gov identifier: NCT00363584) that compared adjuvant capecitabine with surveillance in patients with a resected BTC.19 In the BILCAP trial, capecitabine improved OS compared with surveillance in per-protocol and adjusted analyses according to some baseline characteristics, despite initial, only borderline significance of the intention-to-treat analysis. Differences in study designs may explain the different results of the two trials: BILCAP had OS as a primary end point; included more patients than PRODIGE 12 with thus a higher statistical power; and had more patients with ECC (35% v 28%), R1 (38% v 13%), and N+ (47% v 38%). We also can hypothesize that most of the patients in BILCAP more frequently received the gemcitabine-platinum combination after relapse than in our trial (albeit these data have not been presented yet), thus diluting the effect of adjuvant chemotherapy to a lesser extent than what was seen in PRODIGE 12. The BILCAP study reported a statistically significantly improved HR of 0.76 for RFS, which fell inside the 95% CI of the HR we detected for the GEMOX arm in PRODIGE 12. Recently, the results of the Bile Duct Cancer Adjuvant Trial (BCAT) also were reported.20 This phase III trial performed in Japan randomly assigned 225 patients with resected ECC between adjuvant gemcitabine and surveillance. The proportion of patients with N+ (38%) and R1 (12%) was similar to ours. The study failed to show any benefit in OS or RFS, which confirms the lack of efficacy of gemcitabine in the adjuvant setting. The ACTICCA-1 trial (ClinicalTrials.gov identifier: NCT02170090) currently is enrolling patients with resected BTC to test adjuvant gemcitabine-cisplatin combination.

In PRODIGE 12, patients with BTC with various primary sites were included for a practical reason—the need to include a large number of patients with rare tumors in large-scale phase III trials. Previous data on advanced BTC are conflicting with regard to differential efficacy of chemotherapy related to tumor location. Some studies with the GEMOX regimen have suggested no differential effect, but a previous study with GEMOX suggested lower efficacy in GBC than in other locations.8,9 Our exploratory subgroup analysis shows significantly shorter RFS and OS in patients with GBC, but the small number of patients in these subgroups might suggest a chance finding. However, the biology of the tumor according to primary site significantly differs,21 and this might influence the effect of chemotherapy. We tried to address this issue by stratifying according to primary site. Future trials should address the question of treatment according to the biology (eg, IDH and KRAS mutations, fibroblast growth factor receptor alterations), and indeed, BTC might be an adequate setting to test the personalized oncology paradigm.21 In the MOSCATO-01 (ClinicalTrials.gov identifier: NCT01566019) screening program, BTCs were the tumors with the highest probability for matching therapies.22

HRQOL was included in the study as a primary end point. This was motivated by the fact that RFS is not a validated surrogate of OS in BTC. We added HRQOL to ensure that any benefit in RFS will translate into clinical benefit for patients. The primary analysis showed no detrimental effect in terms of TTD of global HRQOL score. However, and as expected, some HRQOL parameters worsened during the treatment period in the GEMOX arm but improved after the end of treatment. Additional analysis of HRQOL will be presented elsewhere.

In conclusion, the PRODIGE 12 trial results did not provide evidence for superiority of GEMOX adjuvant chemotherapy compared with surveillance in patients with a resected BTC.

© 2019 by American Society of Clinical Oncology

Presented at the ASCO 2017 Gastrointestinal Cancers Symposium, San Francisco, CA, January 19-21, 2017, and European Society for Medical Oncology 2017 Congress, Madrid, Spain, September 8-12, 2017.

Supported by Programme Hospitalier de Recherche Clinique (PHRC 2009) and Ligue Nationale Contre le Cancer.

Clinical trial information: EudraCT 2008-004560-39.

Conception and design: Julien Edeline, Karim Boudjema, Laetitia Fartoux, Jean-François Seitz, Eveline Boucher, Christophe Louvet, David Malka, Jean-Marc Phelip

Administrative support: Eveline Boucher, Trevor Stanbury, David Malka, Jean-Marc Phelip

Provision of study material or patients: Julien Edeline, Jérôme Watelet, Pascal Hammel, Jean-Paul Joly, Karim Boudjema, Karine Bouhier-Leporrier, Jean-Louis Jouve, Véronique Guerin-Meyer, Jean-Emmanuel Kurtz, Jean-François Seitz, David Tougeron, Christelle de la Fouchardière, Catherine Lombard-Bohas, Eveline Boucher, David Malka, Jean-Marc Phelip

Collection and assembly of data: Julien Edeline, Meher Benabdelghani, Jérôme Watelet, Pascal Hammel, Jean-Paul Joly, Karim Boudjema, Laetitia Fartoux, Karine Bouhier-Leporrier, Jean-Louis Jouve, Roger Faroux, Véronique Guerin-Meyer, Isabelle Baumgaertner, David Tougeron, Christelle de la Fouchardière, Catherine Lombard-Bohas, Eveline Boucher, Trevor Stanbury, David Malka, Jean-Marc Phelip

Data analysis and interpretation: Julien Edeline, Aurélie Bertaut, Karim Boudjema, Laetitia Fartoux, Jean-Louis Jouve, Jean-Emmanuel Kurtz, Eric Assénat, David Tougeron, Christelle de la Fouchardière, Catherine Lombard-Bohas, Eveline Boucher, Trevor Stanbury, David Malka, Jean-Marc Phelip

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Julien Edeline

Consulting or Advisory Role: BTG Pharmaceuticals, Bristol-Myers Squibb, AstraZeneca, Bayer AG, Ipsen

Research Funding: Bristol-Myers Squibb (Inst)

Travel, Accommodations, Expenses: Amgen, Bristol-Myers Squibb

Meher Benabdelghani

Consulting or Advisory Role: Amgen, Sanofi, Merck Serono, Bayer AG, Ipsen, Novartis, Pfizer

Travel, Accommodations, Expenses: Roche, Amgen, Novartis, Pfizer, Ipsen, Bayer AG, Sandoz, Sanofi

Pascal Hammel

Honoraria: Celgene

Consulting or Advisory Role: Celgene, Shire, VECT-HORUS, Amgen, Halozyme, Erytech Pharma (Inst)

Speakers’ Bureau: Celgene, Shire

Travel, Accommodations, Expenses: Merck Serono, Ipsen, Halozyme, Shire, Eli Lilly

Karim Boudjema

Consulting or Advisory Role: Sanofi

Travel, Accommodations, Expenses: Astellas Pharma

Karine Bouhier-Leporrier

Honoraria: Ipsen, Novartis, Amgen

Roger Faroux

Research Funding: Merck Serono (Inst)

Travel, Accommodations, Expenses: Merck Serono, Amgen, Celgene

Jean-Emmanuel Kurtz

Consulting or Advisory Role: TESARO, AstraZeneca, Clovis Oncology

Travel, Accommodations, Expenses: Roche, PharmaMar, TESARO

Eric Assénat

Honoraria: Bayer AG, Ipsen, Novartis, Amgen, Sanofi, Aventis

Consulting or Advisory Role: Bayer AG, Ipsen

Travel, Accommodations, Expenses: Bayer AG, Pfizer, Ipsen

Jean-François Seitz

Honoraria: Eli Lilly, Merck Serono, Sanofi, Amgen

Consulting or Advisory Role: Servier

Travel, Accommodations, Expenses: Ipsen

David Tougeron

Honoraria: Amgen, Roche, Novartis, Sanofi, Bristol-Myers Squibb, Merck Serono, MSD

Consulting or Advisory Role: Amgen, Sanofi, Merck Serono, Bristol-Myers Squibb, MSD

Travel, Accommodations, Expenses: Sanofi, Amgen, Bristol-Myers Squibb

Christelle de la Fouchardière

Consulting or Advisory Role: Eli Lilly, Roche, Bayer AG, Shire, Amgen, Bristol-Myers Squibb, Servier

Research Funding: Roche

Travel, Accommodations, Expenses: Roche, Celgene, Amgen, Bristol-Myers Squibb

Catherine Lombard-Bohas

Consulting or Advisory Role: Ipsen, Novartis, Pfizer

Christophe Louvet

Consulting or Advisory Role: Halozyme

Travel, Accommodations, Expenses: Roche

David Malka

Honoraria: Roche, Amgen, Bayer AG, Merck Serono, Servier, Sanofi

Consulting or Advisory Role: Roche, Sanofi, Merck Serono, MSD, Servier, Bayer AG, Incyte, Amgen

Travel, Accommodations, Expenses: Roche, Bayer AG, Sanofi, Merck Serono, Amgen

Jean-Marc Phelip

Honoraria: Merck Serono, Roche, Sanofi, Amgen, Eli Lilly, Servier, Bayer AG

Consulting or Advisory Role: Roche, Merck Serono, Amgen, Servier, Bayer AG, Sanofi

Research Funding: Roche, Merck Serono

Travel, Accommodations, Expenses: Roche, Merck Serono, Bayer AG, Servier, Sanofi, Amgen

No other potential conflicts of interest were reported.

Table

TABLE A1. Chemotherapy Regimens Administered at Disease Recurrence

ACKNOWLEDGEMENT

We salute the memories of Franck Bonnetain, PhD, former methodologist of the PRODIGE 12 study, and Christophe Mariette, MD, PhD, who participated in the writing committee of the protocol to provide his surgical expertise, both of whom died during the conduct of the study.

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ARTICLE CITATION

DOI: 10.1200/JCO.18.00050 Journal of Clinical Oncology 37, no. 8 (March 10, 2019) 658-667.

Published online February 01, 2019.

PMID: 30707660

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