Drs. Yee and colleagues have done an excellent job of surveying the treatment of gallbladder cancer and cholangiocarcinomas. These relatively uncommon tumors are among the more difficult encountered by surgical, medical, and radiation oncologists, as evidenced by the lack of new therapies or change in prognosis over the past several decades.
Progress in surgical intervention has been hampered by advanced disease stage at presentation and lack of effective adjuvant therapy. Where results appear more favorable, denominators tend to be small, selected, and uncontrolled. Adjuvant chemotherapy and radiotherapy trials generally cannot be anticipated because of the small and geographically dispersed population sample from which eligible candidates could be selected. Moreover, the generally poor response rates to chemotherapy in patients with disseminated disease provide little enthusiasm for choosing an agent to be studied over the number of years it would require to complete such trials.
How, then, do we attempt to make progress against this dismal backdrop? Clearly, understanding the etiology of biliary tract cancers in order to implement screening and detection of earlier disease would accomplish the most in terms of enhancing cure and survival. Discovery of molecular etiologic clues may also provide targets for future therapies that are more specific and, therefore, potentially more effective in the treatment of these disease entities.
Elucidating Molecular Pathogenesis
Microarray technology is in its infancy for the detection of genetic abnormalities associated with specific tumor types. The goal is not only to define the genetic pathway of disease development by comparing tumor and normal tissue profiles in large numbers of samples, but also to define the timing and specific mutations or deletions involved in tumorigenesis with the hope of providing discrete targets for therapeutic intervention.
Recent examples of this analytic approach have been seen with colorectal and hepatocellular cancers.[2,3] Uncommon tumors for which there is little empiric, effective therapy would seem ideal for examination in this fashion. Indeed, currently available targeted therapies have been developed in cancers of lower incidence (eg, acute promyelocytic leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors) and in subsets of cancers with particular molecular-biological markers (eg, c-erbB2 in HER2/neu-positive breast cancer).
Signal Transduction Targets