Adjuvant therapies for biliary tract cancers

Biliary tract cancers (BTC) represent a heterogenous group, including gallbladder cancer, intrahepatic, perihilar, and distal cholangiocarcinoma (see Figure 1). Although these tumors all represent malignant transformation of epithelium with biliary differentiation, they have proven to be incredibly diverse from a genetic standpoint. Improved selection, operative techniques, and perioperative care have benefitted patients with these tumors; however, recurrence rates remain high and survival poor.¹ Chemotherapeutic options for these patients have been limited and reserved most often for metastatic or recurrent disease. The Advanced Biliary Cancer [also known as the ABC]-02 trial compared gemcitabine to the combination of gemcitabine and cisplatin in patients with recurrent or metastatic BTCs demonstrating an improved survival in the gemcitabine-cisplatin group (11.7 months versus 8.1 months, p<0.001).² The relative rarity of these diseases, extensive resections, as well as the heterogenous nature of BTCs remain hurdles to optimal therapy in the adjuvant setting; however, three important trials were recently completed and reported: SWOG (also known as the Southwest Oncology Group) S0809,³ PRODIGE 12–ACCORD 18 trial (Gemcitabine Hydrochloride and Oxaliplatin or Observation in Treating Patients with Biliary Tract Cancer that Has Been Removed by Surgery),⁴ and BILCAP (also known as Capecitabine or Observation after Surgery in Treating Patients with Biliary Tract Cancer)⁵ (see Table 1).

Figure 1. Biliary tract cancers

Table 1. Biliary Tract Cancer Trials

SWOG S0809 (NCT00789958)

The SWOG S0809 was a single-arm, phase II trial of adjuvant chemotherapy and chemo-radiotherapy in patients after resection of gallbladder cancer or extrahepatic cholangiocarcinoma (perihilar and distal). Patients received gemcitabine and capecitabine followed by capecitabine and radiotherapy. Therapy was relatively well tolerated with 86 percent of patients completing therapy. The two-year survival rate was 65 percent (95 percent CI 53–74 percent) with a median overall survival of 35 months.⁶ Most notably, patients with R1 disease had a similar overall survival (OS) rate as the patients with R0 disease following surgery (34 months versus 35 months), suggesting efficacy of the treatment. Consistent with the expected disease biology, the patients with gallbladder cancer had a higher rate of distant relapse (52 percent) compared with either the distal cholangiocarcinoma (42 percent) or perihilar cholangiocarcinoma (23 percent) groups. The lack of a control arm limits the impact of the findings, but the tolerability of the therapy and overall favorable survival results compared with historic cohorts supports further consideration of this regimen in gallbladder cancer and EHCC.

PRODIGE 12–ACCORD 18

The PRODIGE 12–ACCORD 18 trial (NCT01313377) was a phase III randomized, multicenter trial evaluating adjuvant gemcitabine and oxaliplatin (GemOx) versus observation alone in resected BTCs (including all types). The study randomized 196 patients at 33 French centers over a five-year period and sought to evaluate recurrence-free survival (RFS) and quality of life (QOL). Unfortunately, the trial results were negative, with no difference in RFS between study arms.⁷ The QOL was not different between the two arms, indicating that treatment was tolerated; however, only 33 percent of patients in the GemOx arm received all six cycles of planned treatment. Subgroup analysis by tumor type did not demonstrate any favorable trends.

BILCAP – (NCT00363584)

The BILCAP trial was a phase III randomized, multicenter trial that evaluated adjuvant capecitabine (eight cycles) versus observation alone in patients with resected BTCs (including all types). This trial accrued over an eight-year period at 44 sites in the U.K. This study randomized 447 patients, and its primary endpoint was OS. In the intention to treat analysis, the median OS was 51 months for the capecitabine group as compared with 36 months for control (HR 0.80, 95 percent CI 0.63, 1.04; p = 0.097); however, in the per-protocol analysis median, OS was 53 months in the capecitabine group as compared with 36 months in the control arm (HR 0.75, 95 percent CI 0.58, 0.97; p = 0.028).⁸ Based on these findings, the investigators recommend adjuvant capecitabine as the standard of care in resected BTCs.

Implications for the future

Based on the recently reported trials of adjuvant therapy in resected BTCs, adjuvant capecitabine should now be considered for all patients. Patients with gallbladder cancer or EHCC with a positive resection margin may benefit from considering the addition of chemoradiation; however, further investigation is warranted. Given the heterogenous nature of these disease processes and the relatively poor outcomes, even in anatomically resectable diseases, a neoadjuvant strategy may be the optimal approach to further understand the tumor biology and chemoresponsiveness of BTCs. It is likely that most patients with BTCs have micrometastatic disease at presentation and neoadjuvant therapy may allow selection of patients most likely to benefit from surgical intervention and allow for evaluation of efficacy of specific therapy regimens either through objective response (tumor marker levels, morphologic changes) and/or metabolic response.

References

1. Sasaki K, Margoinis GA, Andreatos N, et al. Preoperative risk score and prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma. J Am Coll Surg. December 21, 2017 [Epub ahead of print].
2. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281.
3. Southwest Oncology Group. S0809: Capecitabine, gemcitabine, and RT in patients with cholangiocarcinoma of the gallbladder or bile duct (NCT00789958). Available at: https://clinicaltrials.gov/ct2/show/NCT00789958. Accessed  February 20, 2018.
4. UNICANCER. Gemcitabine hydrochloride and oxaliplatin or observation in treating patients with biliary tract cancer that has been removed by surgery (NCT01313377). Available at: https://clinicaltrials.gov/ct2/show/NCT01313377. Accessed February 24, 2018.
5. University Hospital Southampton NHS Trust. Capecitabine or observation after surgery in treating patients with biliary tract cancer (ISRCTN72785446). Available at: https://clinicaltrials.gov/ct2/show/NCT00363584. Accessed February 20, 2018.
6. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33(24):2617-2622.
7. Edeline J, Bonnetain F, Phelip JM, et al. Gemox versus surveillance following surgery of localized biliary tract cancer: Results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial [abstract]. J Clin Oncol. 2017;35(4 Suppl):225.
8. Primrose JN, Fox R, Palmer DH, et al. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study [abstract]. J Clin Oncol. 2017;35(15 Suppl):4006.