Biliary Tract Cancers: Finding Better Ways to Lump and Split

In the article that accompanies this editorial, Ben-Josef et al present the results of the intergroup study SWOG 0809 (S0809), which reported on the clinical efficacy and toxicity of treatment with gemcitabine plus capecitabine followed by chemoradiotherapy in 79 patients post resection of extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA). Expert central review of surgical procedures, pathology findings, and radiation established diagnostic and stage accuracy as well as quality. The regimen showed feasibility: 86% of patients completed treatment as planned, with acceptable toxicity. In the study population, the 2-year overall survival was 65%, with disease-free survival of 52%, local relapse rate of 11%, and distant relapse rate of 42% (including combined local and distant relapses). These outcomes were similar in EHCC versus GBCA, and in R0 versus R1 subanalyses. The authors rightfully conclude that the regimen is feasible, tolerable, and effective when absolute outcomes are examined in the context of the available published historical controls. Those not well versed in hepatobiliary cancer clinical research may question the value of a single-arm trial in a heterogeneous population without a clearly established null hypothesis, a design that cannot discriminate the relative impact of any of its component parts and that is susceptible to confounding by prognostic covariates. Although these factors clearly limit the conclusions that may be drawn from S0809, they do not diminish its importance. To place this trial into context, it is the first multicenter clinical trial of adjuvant chemotherapy plus chemoradiotherapy in biliary tract cancers, and it was conducted in the Cooperative Group setting with rigorous surgical, pathology, and radiation quality control. A recent meta-analysis of more than 6,700 patients from 20 studies reported an association between adjuvant chemotherapy or chemoradiotherapy and improved overall survival compared with radiation alone or observation, with the greatest benefits in R1 or node-positive tumors. This important meta-analysis, referenced in clinical practice guidelines to inform adjuvant therapy decisions, was composed predominantly of retrospective, institutional studies; does not define the outcomes of individual treatment regimens; and is confounded by the inherent bias of retrospective data. Underscoring the paucity of prospective clinical research in biliary tract cancers, it was not until the ABC-02 trial of gemcitabine plus cisplatin in 2010 that any randomized clinical trial had proven a survival benefit from chemotherapy in advanced biliary tract cancers. The landmark ABC-02 trial was conducted in an unselected population treated with conventional cytotoxics—in a booming era of molecular medicine—and represented a major therapeutic advance. Its single-arm design notwithstanding, S0809 likewise establishes a timely and essential adjuvant benchmark for future hepatobiliary cancer research. A key strength of S0809 is its restriction to the EHCC and GBCA subsets of biliary tract cancer, proving that prospective, anatomically selected trials are possible in this heterogeneous family of cancers. A longstanding challenge to clinical trial design in biliary tract cancers has been whether to lump or split eligibility on the basis of anatomic site of tumor origin. Proponents of lumping cite the challenges of trial accrual in a rare cancer and the difficulty of discerning actual site of origin in some cases, whereas those in favor of splitting raise concerns about confounding by lead time bias, heterogeneous rates of complications of biliary obstruction, and the long-perceived differences in patterns of recurrence and prognosis by anatomic site. Lending new support to splitting, however, is emerging evidence suggesting differences in tumor biology by anatomic subset. Genomic analyses of resection specimens show varying rates of driver genomic mutations in genes, including KRAS, IDH1/2, and FGFR2, and differences in gene expression associated with intrahepatic versus extrahepatic location of the primary tumor. It stands to reason that these biologic subsets may affect prognosis and likelihood of response to different systemic therapies, but how can we integrate this emerging understanding of the biology of biliary tract cancers into the existing clinical subdivisions of biliary tract cancers? Despite the rising incidence of intrahepatic cholangiocarcinomas in particular, this cancer remains rare, and the prospect of both anatomic and genomic selection for ever-narrower subsets of patients simply does not allow for clinical testing of each subset individually. More than ever, robust preclinical models are essential to guide our clinical research questions and designs in this rare, heterogeneous, and grim cancer in which most patients have only one or two chances at systemic treatment. As an added difficulty, not only is the mutational spectrum of biliary tract cancers distinct for each organ site, but there is also substantial genetic heterogeneity within GBCA, EHCC, and intrahepatic cholangiocarcinoma individually. Unlike colon and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 24 AUGUST 2