Adjuvant treatment in resected biliary cancers: fluoropyrimidines on the spotlight

We read with great interest the article published by Nakachi et al., a randomized phase III trial that evaluated adjuvant treatment with S-1 for 24 weeks or observation in resected biliary tract cancers (BTC) (1). This trial is very important considering that other chemotherapy regimens including gemcitabine and gemcitabine plus oxaliplatin were evaluated in randomized trials in the same scenario with negative results (2,3).

BTCs are a group of malignancies that arises from the bile ducts or gallbladder. Although rare, more than half of the cases can be diagnosed in advanced stages and the overall prognosis is poor (1). Patients submitted to surgery can be treated with adjuvant chemotherapy, however the data of trials are contradictory (2-7). Also, it is very common surgical specimens with locally advanced disease with positive lymph nodes and not complete resections in the trials (1-8). Two trials were positive with oral fluoropyrimidines in the adjuvant setting. In this editorial we will address and compare both trials.

The ASCOT study was a randomized phase III trial conducted in 38 Japanese hospitals and included patients with cholangiocarcinoma, gallbladder, and ampullary cancers that underwent resection (1). Patients were randomized to the observation group or to receive S-1, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles (1). The study was conducted between 2013 and 2018, and a total of 440 patients were randomized between the two arms, with a data cutoff date of June 23, 2021 (1). The trial met its primary endpoint, with improvements in 3-year overall survival (OS) of 77.1% [95% confidence interval (CI): 70.9–82.1%] in the S-1 group, compared with 67.6% (95% CI: 61.0–73.3%) in the observation group [hazard ratio (HR) 0.69, 95% CI: 0.51–0.94; one-sided P=0.008]. Furthermore, improvements in relapse-free survival (RFS) were also observed; 3-year RFS was 62.4% (95% CI: 55.6–68.4%) in the S-1 group compared to 50.9% (95% CI: 44.1–57.2%) in the observation group (HR 0.80, 95% CI: 0.61–1.04; two-sided P=0.088) (1). The toxicity associated with S-1 was manageable, including biliary tract infection (7%) and decreased neutrophil count (14%), which are more common grades 3–4 adverse events (AEs) (1).

Before this trial, adjuvant treatment for resected BTC had been investigated multiple times (4). A meta-analysis, including twenty studies with more than 6 thousand patients evaluated, concluded that adjuvant systemic treatments in resected BTC could improve OS, particularly in node-positive and margin-positive cases (4). However, when all the studies were evaluated, including two registry studies, the meta-analysis was negative (4).

More recently, the BILCAP trial was the first to show some improvements in OS with adjuvant chemotherapy in resected BTC (5). The trial was conducted in the United Kingdom; a total of 44 centers participated in the recruitment. It was a controlled, randomized trial. The study randomized resected BTC (cholangiocarcinoma or gallbladder) patients to receive oral capecitabine twice daily on days 1–14 of a 21-day cycle, for eight cycles, or observation. A total of 447 patients were included between 2006 and 2014, with the data cutoff date of March 6, 2017 (5). The study did not meet its primary endpoint, with a median OS by intention-to-treat (ITT) of 51.1 months (95% CI: 34.6–59.1) in the capecitabine group compared to 36.4 months (29.7–44.5) in the observation group (HR 0.81, 95% CI: 0.63–1.04; P=0.097) (5). However, after a sensitivity analysis adjusting for nodal status, sex, and disease grade, the study was positive for improving median OS (HR 0.71, 95% CI: 0.55–0.92; P=0.010). Furthermore, the ITT median RFS was longer with capecitabine than with observation, at 24.4 months (95% CI: 18.6–35.9) versus 17.5 months (12.0–23.8), particularly in the first 2 years (HR 0.75, 95% CI: 0.58–0.98; P=0.033) (5).

There are some points that these two randomized controlled trials have in common and some points that are misaligned. First, both evaluated single-agent oral fluoropyrimidines in adjuvant treatment for resected BTC. Second, both studies included a fair number of patients—around 400 patients in both trials. Third, all disease stages were also represented in both trials, I to IV. And finally, around half of the patients in both trials had positive nodes. However, some differences stood out. First, the Eastern Cooperative Oncology Group (ECOG) performance status of patients in the BILCAP trial is worse, with higher ECOG 1 and 2 (55% versus 12%) than in the ASCOT trial. Second, R1 resections in the investigative arm were higher in the BILCAP trial as well (38% versus 14%) (1,5). Third, no ampullary carcinomas were included in the BILCAP trial. Another important difference is related to the population; it is well known that Asian patients respond and tolerate fluoropyrimidines better than Caucasian patients, probably influencing the higher proportion of treatment completion (72%) of 207 among the safety population in the ASCOT trial, compared with 58% of 210 for the capecitabine group in the BILCAP trial (1,5). And finally, while BILCAP is a controlled trial, ASCOT is an open-label trial (Table 1). All those points could have influenced the final results, with higher RFS and OS with S-1 therapy in the ASCOT trial when compared to capecitabine, in the BILCAP trial (1,5). It is important to note that compliance of protocols in both studies were high, in the BILCAP trial, in the capecitabine arm, only 14 patients withdrew from trial treatment, 9 withdrew consent to be followed up and 13 were excluded for other causes for per-protocol analysis, in the observation arm, a total of 10 patients were excluded. In the ASCOT trial, in the S1 arm, 6 patients were ineligible, in the observation arm, 5 patients, but all patients were evaluated on the efficacy analysis (1,5). No crossover was reported.

An updated OS from the BILCAP trial was also published after a median follow-up time of 106 months (6). In this report, in the ITT analysis, median OS was 49.6 months (95% CI: 35.1–59.1) in the capecitabine group compared with 36.1 months (95% CI: 29.7–44.2) in the observation group (HR 0.84; 95% CI: 0.67–1.06) (6). Although the BILCAP trial was submitted to modifications of the statistical plan and the OS was only positive after the sensitivity analysis adjusted for clinical factors, capecitabine is still considered a standard adjuvant option for this group of patients by many guidelines (6). Intensifying the adjuvant treatment with more active regimens in the metastatic setting, including gemcitabine and cisplatin, is under investigation in the ACTICCA-01 trial (7). However, it is important to note that this regimen was not superior to capecitabine in the STAMP phase II randomized trial, presented recently, in patients with distal cholangiocarcinoma and positive lymph nodes (8). Those results confirmed that oral fluoropyrimidines are still the control arm to beat (8).

S-1 and capecitabine are easy to administer and convenient (oral), and both are easily manageable in terms of dose reductions due to toxicities (1,5). Furthermore, both drugs are safe and have low-grade 3–4 AEs (1,5). Additionally, they are affordable (9). Finally, fluoropyrimidines as adjuvant treatment are interesting in terms of systemic treatment options, considering that cross-resistance to potential first-line therapies with platinum-gemcitabine combinations is less likely to occur.

In conclusion, both S-1 and capecitabine should be considered standard options for adjuvant therapies in resected BTC. New horizons in the field would evaluate targeted treatments in the adjuvant setting based on molecular findings, and recruiting trials are ongoing (NCT05565794).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1007/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1007/coif). The authors have no conflicts of interest to declare.

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References

1. Nakachi K, Ikeda M, Konishi M, et al. Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet 2023;401:195-203. [Crossref] [PubMed]
2. Ebata T, Hirano S, Konishi M, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg 2018;105:192-202. [Crossref] [PubMed]
3. Edeline J, Benabdelghani M, Bertaut A, et al. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol 2019;37:658-67. [Crossref] [PubMed]
4. Horgan AM, Amir E, Walter T, et al. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 2012;30:1934-40. [Crossref] [PubMed]
5. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019;20:663-73. [Crossref] [PubMed]
6. Bridgewater J, Fletcher P, Palmer DH, et al. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol 2022;40:2048-57. [Crossref] [PubMed]
7. Stein A, Arnold D, Bridgewater J, et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial. BMC Cancer 2015;15:564. [Crossref] [PubMed]
8. Jeong H, Kim KP, Jeong JH, et al. Adjuvant gemcitabine plus cisplatin versus capecitabine in node-positive extrahepatic cholangiocarcinoma: the STAMP randomized trial. Hepatology 2023;77:1540-9. [Crossref] [PubMed]
9. Malka D, Edeline J. Adjuvant capecitabine in biliary tract cancer: a standard option? Lancet Oncol 2019;20:606-8. [Crossref] [PubMed]