Cancers of the biliary tract are a heterogeneous and diverse group that includes cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Associated with significant morbidity and mortality, biliary tract cancers are highly aggressive malignancies that often evade early detection. While surgical resection may be curative, postoperative recurrences are well documented. Systemic chemotherapy has been widely adopted as a primary treatment in advanced cases involving metastatic disease, as well as for adjuvant therapy in refractory cases that recur after surgery.
Recently, a review published in the Journal of Clinical Medicine by researchers from Tokyo, Japan discussed the latest evidence for chemotherapy in biliary tract cancer. Despite only 20 years of dedicated research into the efficacy of chemotherapy for the treatment of malignancies of the biliary tract, an increasing number of clinical studies have confirmed its utility in treating the disease at multiple stages, according to the review. Furthermore, a chemotherapy treatment algorithm was proposed for advanced biliary tract cancer based on the available literature.
A First-Line Treatment for Advanced Cancers
Research into the efficacy of chemotherapy for the treatment of biliary tract cancer began around 2000, according to the authors. Prior to that, protocols were derived from research on chemotherapeutic regimens for pancreatic cancer. Pooled analyses of clinical trials conducted around this time concluded that combination treatment with gemcitabine and a platinum compound, such as cisplatin, represented the provisional standard of chemotherapy for biliary tract cancer when compared to monotherapy.
An early clinical trial from the United Kingdom (ABC-02) demonstrated that treatment with gemcitabine and cisplatin led to a median overall survival of 11.7 months compared to 8.1 months in patients only treated with cisplatin (hazard ratio [HR]=0.64, P <.001), while median progression-free survival in the combination group was 8.0 months vs 5.0 months in the monotherapy group (P <.001).
Since then, several studies have sought to identify treatment regimens superior to combination therapy with gemcitabine and platinum compounds. An oral fluoropyrimidine derivative known as S-1 has shown promise when added to combination therapy with gemcitabine and cisplatin. In 2018, Japanese researchers randomized 246 patients to receive either triple therapy with gemcitabine + cisplatin + S-1 or combination therapy with gemcitabine + cisplatin alone. The study found that overall survival increased to 13.5 months in the triple therapy group compared to 12.6 months in the combination therapy group (HR=0.791, P =.046). As such, triple therapy with gemcitabine + cisplatin + S-1 has also become an accepted regimen in many countries.
Other Regimens Less Clear
The review notes that research comparing second-line chemotherapeutic agents is limited, with few prospective trials comparing specific regimens. Selection criteria for appropriate candidates for second-line treatment is also not well established, with some studies suggesting that patients with low cancer antigen 19-9 (CA19-9) levels and previous surgery on their primary tumor may benefit the most from second-line chemotherapy.
The randomized trial ABC-06, conducted in the United Kingdom, compared FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) with supportive care only. Treatment with FOLFOX led to improved survival at 6 months and 12 months (51% vs 36%), as well as improved median overall survival (6.2 vs 5.3 months, HR=0.69, 95% CI, 0.50-0.97). As such, FOLFOX is often utilized as a second-line chemotherapeutic treatment option.
In addition to cytotoxic regimens, immune checkpoint inhibitors such as pembrolizumab have shown promise in patients with particular gene alterations implicated in biliary tract tumorigenesis, including isocitrate dehydrogenase (IDH) 1, IDH2, fibroblast growth factor receptor (FGFR) 1, and human epidermal growth factor receptor (HER) 2.
A seminar on biliary tract cancer recently published in The Lancet also highlighted the importance of gene-specific therapies, concluding that “the identification of distinct patient subgroups, harboring unique molecular alterations with corresponding targeted therapies (such as [IDH1] mutations and [FGFR2] fusions in intrahepatic cholangiocarcinoma, among others) is changing the treatment paradigm.”
While surgical resection of primary biliary tract cancer can be curative when performed early, postoperative recurrence can occur, often heralding a poor prognosis. Adjuvant chemotherapy regimens for recurrent disease are controversial, with varying practice patterns globally. In BILCAP, a British phase 3 study, adjuvant capecitabine was compared with surgery alone. A per-protocol analysis of the data demonstrated significant improvements in survival, according to the review.
As such, capecitabine as a monotherapy is often considered the standard treatment for recurrent biliary tract cancer in Western countries. The study authors note that surgery alone is the current standard of care in Japan, citing the need for continued prospective research on adjuvant treatment protocols.
The Search for Effective Treatment Continues
Biliary tract cancer is a devastating disease with considerable mortality. Effective treatments remain elusive, and the development of new therapies is urgently needed. In addition to traditional cytotoxic chemotherapeutic regimens, molecular targeted agents and immune checkpoint inhibitors are also an area of continued research.
Like many other cancers, immunotherapy and molecular targeted drugs such as FGFR inhibitors are expected to improve outcomes compared to currently available therapies, with several clinical trials currently underway. As the review authors note, “If the effectiveness of molecular-targeted drugs and immunotherapy based on the characteristics of cancer is shown at first-line setting, it is thought that the trend of investigating genetic alterations from the time of diagnosis will accelerate in the future.”
The study authors conclude their review by stating that “while evidence relating to chemotherapy for biliary tract cancer had been limited, numerous clinical studies have been conducted in the last decade and evidence is steadily accumulating.” They added, “Many large-scale clinical studies are still underway, some of which may lead to improved treatment outcomes going forward.”
Sasaki T, Takeda T, Okamoto T, Ozaka M, Sasahira N. Chemotherapy for biliary tract cancer in 2021. J Clin Med. 2021;10(14):3108. doi:10.3390/jcm10143108
Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397(10272):428-444. doi:10.1016/S0140-6736(21)00153-7