French Phase III Trial Reveals Adjuvant GEMOX No Better Than Surveillance in Localized Biliary Tract Cancer

French Phase III Trial Reveals Adjuvant GEMOX No Better Than Surveillance in Localized Biliary Tract Cancer

Dr. Julien Edeline
Dr. Milind M. Javle
Despite an impressive attempt to demonstrate that adjuvant chemotherapy prolongs relapse-free survival (RFS) in patients with localized biliary tract cancer following resection, the findings of the prospective phase III PRODIGE 12–ACCORD 18 (UNICANCER GI) trial came up short. Median RFS turned out to be no different statistically for GEMOX versus surveillance (Abstract 225).

Although adjuvant GEMOX was feasible, “clearly, further research through international collaboration is required to improve outcomes of these patients,” said lead study investigator Julien Edeline, MD, of the Oncology Medical Eugene Marquis Comprehensive Cancer Center, in France.

Failure of PRODIGE 12–ACCORD 18 represents a disappointment given the long line of challenges in establishing the potential benefit of adjuvant chemotherapy in localized biliary tract cancer. Relapse rates are high following disease resection, which offers the only potential for cure. Adjuvant strategies hold promise for keeping local disease in check and prolonging long-term survival, but the rarity of the cancer and the fact that, according to discussant Milind M. Javle, MD, of The University of Texas MD Anderson Cancer Center, only 20% of patients have resectable disease at presentation pose hurdles to conducting a large randomized trial. The best the field has come by are institutional case series, registry studies, and meta-analyses that hint at benefits with adjuvant treatment, which is commonly used in up to 70% of centers worldwide.1

The PRODIGE 12–ACCORD 18 trial endeavored to provide clear Level I evidence supporting the value of adjuvant chemotherapy following resection of localized biliary tract cancer. GEMOX was selected as the investigational regimen of choice given signals of activity and prolonged survival with gemcitabine/platinum combinations in the palliative setting.

Between 2009 and 2014, 193 patients with R0 or R1 resection of localized biliary tract cancer (i.e., intrahepatic, perihilar, extrahepatic cholangiocarcinoma, or gallbladder cancer) underwent random assignment to 12 cycles of GEMOX or surveillance within 3 months of surgery. The majority of these individuals had node-negative disease (63%), and R0 resection was achieved in most (87%).

Based on a median follow-up of 44.3 months, median RFS—a co-primary endpoint—reached 30.4 months with GEMOX as compared with 22.0 months with surveillance (HR 0.83, 95% CI [0.58, 1.19]; p = 0.31), failing to meet statistical significance. RFS rates at 4 years—39.3% and 33.2%, respectively—perhaps better reflect the similarities between the GEMOX and surveillance arms.

Analysis of predefined subgroups also did not uncover any subpopulations that might benefit from adjuvant GEMOX with respect to primary site of disease, nodal status, or extent of resection.

“As RFS is not validated as a surrogate of overall survival in biliary tract cancer, we decided to add a quality-of-life co-primary endpoint to ensure that any improvement in RFS will translate into clinical benefit for patients,” Dr. Edeline said.

Quality-of-life measures also reflected similar outcomes between arms. No differences in global health–related quality-of-life scores emerged between the GEMOX and surveillance groups at either 12 months (71.4% vs. 77.0%, respectively) or 24 months (75.9% vs. 78.8%, respectively).

As expected, grade 3-5 toxicities occurred more often with GEMOX as compared with surveillance at 73.5% versus 30.3%, respectively, but were manageable. The chief adverse events observed more frequently with GEMOX included grade 3/4 peripheral neuropathy (21.3% vs. 1.1%), neutropenia (18.1% vs. 0%), increases in gamma-glutamyl transferase (37.2% vs. 17.1%), and increases in alkaline phosphatase (10.7% vs. 3.0%).

Dr. Javle put a fine point on the PRODIGE 12–ACCORD 18 outcomes by stating, “There is no role for routine adjuvant [therapy] in resected biliary cancer. Patients at high risk for recurrence should be offered clinical trials.”

This may change in the near future depending on the results of the ongoing BILCAP trial in the United Kingdom. Given the larger number of patients enrolled in this study (360 patients), it should be better powered to clarify whether adjuvant therapy with capecitabine can augment disease-free survival when compared with surveillance following curative surgery for biliary tract cancer.

Although the PRODIGE 12–ACCORD 18 trial was negative, Dr. Javle recognized the difficulty of conducting the study and congratulated Dr. Edeline and colleagues for their pioneering work. Both PRODIGE 12–ACCORD 18, started in 2009, and BILCAP, started in 2006, have been burdened by slow patient accrual that has hindered therapeutic progress in biliary tract cancer.

“Although this disease is more common in other parts of the world, there is no representation in these trials from high-incidence countries such as Thailand, India, and Chile,” which is a circumstance that needs to be rectified, Dr. Javle said.

–Kara Nyberg, PhD