Poor Evidence to Standardize Adjuvant Treatment for Patients With Biliary Tract Cancer
Authors: Giovanni M. Bariani, Maria Ignez Braghiroli, Rachel P. Riechelmann
Journal: Journal of Clinical Oncology (2012)

or both) compared with surgery alone for the entire group of biliary tract cancers (odds ratio [OR], 0.74; P .06). A sensitivity analysis demonstrated significant benefit in survival in patients with nodepositive and R1 disease (OR, 0.49; P .004; and OR, 0.36; P .002, respectively). With these results, the authors concluded that adjuvant therapy is the standard of care for high-risk patients and recommend againstano-treatmentarminfuturerandomizedtrialsinthissetting. We respectfully disagree with their conclusions. Selection bias, stagemigration,andheterogeneoustreatmentsarelikelytohaveconfoundedtheauthors’findings.Westronglybelievethatadjuvanttherapy for biliary tract cancer is not yet a standard and that the authors were hasty when they condemned a no-treatment arm as the control group in forthcoming trials. Basically, the quality of studies included in their meta-analysis was poor. Of the 20 studies included, there was only one randomized trialthatfoundanimproved5-yearsurvivalratewithadjuvantchemotherapyforpatientswithgallbladdercancer,butnotinthesubgroup of patients with cholangiocarcinomas. 2 The great majority of data were pooled from uncontrolled retrospective studies, in which mixed groups of patients with various tumor types (some studies included pancreatic and ampullary cancers) were treated with different adjuvant therapies. These factors combine to result in several intrinsic biases.First,becauseoftheretrospectivenatureofthestudiesincluded in this meta-analysis, selection bias could explain the better outcomes reported for adjuvant therapy. The authors discuss that patients with high-risk features could have been more likely to receive adjuvant therapy, which makes their results even more striking. We argue the opposite: similar to the case with other cancer types, patients with better performance status and/or younger age could have been more likely to receive adjuvant treatment in comparison with elderly patients, those with many comorbid illnesses, those who experienced serious postoperative complications, and/or patients who had poor clinical conditions. 3,4 Such confounders may have led to an overestimation of the adjuvant treatment and misinterpretation of the data. Second, the variability of diagnostic/staging tests used across the time spancoveredbythemeta-analysismayhaveledtostagemigrationasa result of instrumental bias. It is quite possible that patients who were stagedashavinglocalizeddiseaseinoldstudiesactuallyhadmetastatic disease; imbalances in the number of patients with metastatic disease between the adjuvant and control groups could have compromised the results. Third, the meta-analysis is based on literature-extracted data instead of individual patient information, which may produce different efficacy estimations and levels of evidence. 5 Fourth, many studies included do not report on resection margins. When margins are compromised, postoperative treatment is acceptable with the aim ofimprovinglocalcontrol,butthiscannotbeconsideredanadjuvant intervention per the definition of adjuvant. It simply involves early treatment of advanced disease. Other drawbacks such as unpublished negativetrials,shortfollow-up,andvariable,unscheduledtimepoints for recurrence evaluation across studies may have also generated biased interpretation with respect to the adjuvant treatment. The authors highlight some of these limitations in their discussion session. Nevertheless, they still endorse the use of adjuvant therapy for patients with node-positive disease and R1 resection. Although we agree that this could be an acceptable strategy, we advise against a definitive recommendation—particularly in the subset of node-positive tumors. High-risk status does not mean that a patient will benefit from adjuvant treatment. In fact, adjuvant treatments have been reportedly ineffective in certain tumor types that harbor high risk for recurrence such as rectal cancer and ampullary adenocarcinoma. 6,7