Current progress in perioperative chemotherapy for biliary tract cancer

Abstract Biliary tract cancer (BTCs) is a heterogeneous malignancy divided into cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Due to little or no symptoms, most patients with BTCs are diagnosed with unresectable or metastatic disease. Only 20%–30% of all BTCs are suitable for potentially resectable diseases. Although radical resection with a negative surgical margin is the only potentially curative method for BTCs, most patients develop postoperative recurrence, which is associated with poor prognosis. Therefore, perioperative treatment is necessary to improve survival. There are very few randomized phase III clinical trials of perioperative chemotherapy due to the relative rarity of BTCs. Adjuvant chemotherapy with S‐1 for patients with resected BTC significantly increased overall survival compared with upfront surgery in a recent ASCOT trial. In East Asia, S‐1 is currently considered the standard adjuvant chemotherapy, while capecitabine may still be used in other areas. Since then, our phase III trial (KHBO1401), gemcitabine and cisplatin plus S‐1 (GCS) has become the standard chemotherapy for advanced BTCs. GCS not only improved overall survival but demonstrated a high response rate. The efficacy of GCS as a preoperative neoadjuvant chemotherapy for resectable BTCs has been investigated in a randomized phase III trial (JCOG1920) in Japan. In this review, we summarize the current and ongoing clinical trials focusing on adjuvant and neoadjuvant chemotherapy for BTCs.

GEM, and S-1, oral fluoropyrimidine prodrug, therapy (GS), and GC and S-1 therapy (GCS) are also considered first-line standard chemotherapy options, and are commonly used in Japan following previous phase III studies. [17][18][19] Despite advances in chemotherapy, there are no standard second-line treatment options for BTCs. [20][21][22] Therefore, the median overall survival (OS) remains dismal at ~1 y. [16][17][18] Surgical resection is the only curative treatment available for BTCs. Recent advances in surgical techniques, such as concomitant vascular resection and perioperative management, have increased resectability and improved patient outcomes. [23][24][25][26][27] Positive surgical margins, lymph node metastasis, and venous invasion are prognostic factors for predicting OS and disease-free survival (DFS). [28][29][30] Despite curative resections, most patients develop postoperative recurrences, and the prognosis remains unsatisfactory, with a 5-y survival rate of <50%. [31][32][33][34][35] To improve long-term outcomes after surgery, perioperative chemotherapy has been investigated, although surgical resection alone remains the first-line therapy for patients with resectable BTC. In this review, we summarize the current and ongoing clinical trials that focused on perioperative chemotherapy for BTCs. A literature search was carried out using the PubMed database. The following terms were used in combination: "biliary tract cancer" and ("adjuvant therapy" or "neoadjuvant therapy") and "clinical trial." Original articles published in English were included.
Relevant articles or clinical trials identified through manual searching of reference lists were also included.

| ADJ U VANT CHEMOTHER APY
Surgical resection is the only curative treatment option for BTCs, but the recurrence rate is high. Hence, effective adjuvant therapy needs to be developed to improve a poor prognosis. Due to the relative rarity of BTCs, evidence for adjuvant chemotherapy is based on a few phase II clinical trials and retrospective analyses. 36-39 Between 1986 and 1992, the first randomized controlled trial was conducted to evaluate adjuvant chemotherapy with mitomycin C and fluorouracil (MF group) vs surgery alone (control group) in patients with pancreatic carcinoma (n = 158), bile duct carcinoma (n = 118), gallbladder carcinoma (n = 112), or ampullary cancer (n = 48). 40 No statistically significant difference was observed in the 5-y OS and 5-y DFS rates between patients with pancreatic carcinoma, bile duct carcinoma, or ampullary cancer. Although the 5-y OS rate of the MF group (26.0% vs 14.4%, P = 0.0367) and the 5-y DFS rate (20.3% vs 11.6%, P = 0.0210) in gallbladder carcinoma improved, no significant improvement was demonstrated in the intent-to-treat analysis. Over the last decade, several adjuvant chemotherapy regimens have been investigated in randomized phase III trials (Table 1).

| The ESPAC-3 trial
This phase III study compared surgery alone with 5-FU plus folinic acid or gemcitabine monotherapy in 428 patients with periampullary region cancer (mainly ampullary carcinoma [n = 297] and extrahepatic cholangiocarcinoma [n = 96]). 41 The primary outcome was OS in the treatment group compared with that in the surgery alone group. was demonstrated in the intent-to-treat (ITT) analysis, and the data were underpowered and, thus, significance could not be concluded.

| The BILCAP trial
This phase III trial in the UK compared surgery alone with capecitabine in patients with resected cholangiocarcinoma and gallbladder cancer. 45 The primary endpoint was OS. In an ITT analysis of 447

| NEOADJ U VANT CHEMOTHER APY
Adjuvant chemotherapy has been previously investigated to improve prognosis after surgery. However, some patients cannot complete adjuvant chemotherapy after surgical resection due to postoperative complications or poor tolerance. In the BILCAP study, only 55% of patients completed the eight planned cycles of adjuvant treatment. 45 In contrast, neoadjuvant chemotherapy offers some advan-

AUTH O R CO NTR I B UTI O N S
Tatsuya Ioka wrote the initial draft of the article. Yoshitaro Shindo, Makoto Ueno and Hiroaki Nagano contributed to review references and assisted in the presentation of the article. All authors revised and contributed to the interpretation of the findings, and accepted the final article.

ACK N OWLED G M ENTS
We thank Editage (www.edita ge.com) for English language editing.

FU N D I N G I N FO R M ATI O N
No funding was received for this study. Hiroaki Nagano https://orcid.org/0000-0002-7074-3315