Phase I study of neoadjuvant S‐1 plus cisplatin with concurrent radiation for biliary tract cancer (Tokyo Study Group for Biliary Cancer: TOSBIC02)

Abstract Aim Neoadjuvant chemoradiotherapy may improve survival in patients with advanced cholangiocarcinoma. This Phase I study aimed to determine the recommended dose of neoadjuvant chemoradiotherapy and decide whether to move to a Phase II study. Methods Patients diagnosed with resectable stage II–IVa cholangiocarcinoma were administered cisplatin (40 [level 0], 50 [level 1 as starting dose], or 60 [level 2] mg/m2), 80 mg/m2 of S‐1, and 50.4 Gy of external beam radiation. The recommended dose was defined as a dose one‐step lower than the maximum‐tolerated dose, which was defined when dose‐limiting toxicity was observed in three or more of the six patients. Results Twelve patients were eligible from November 2012 to May 2016. Ten patients had perihilar cholangiocarcinoma and two patients had distal cholangiocarcinoma. Dose‐limiting toxicity was observed in one of the first six patients at level 1 and two of the next six patients at level 2; thus, the maximum‐tolerated dose was not determined even at level 2 and the recommended dose was determined as level 2. Four patients had partial response, four patients had stable disease, and two patients had progression of disease because of liver metastases. Finally, nine patients underwent radical surgery and seven cases achieved R0 resection. However, five cases suffered biliary leakage and one suffered intrahospital death due to rupture of the hepatic artery. Conclusion We determined the recommended dose of neoadjuvant chemoradiotherapy for resectable cholangiocarcinoma. However, we terminated the trial due to a high incidence of morbidity and unexpected mortality.


| INTRODUC TI ON
Biliary tract cancer (BTC) is known as one of the most lethal malignant diseases in the world and its incidence has been increasing. 1,2 Although surgical resection plays a key role in the curative treatment for this disease, prognosis is poor due to frequent postoperative recurrence. 3 Therefore, a multimodal treatment approach is warranted. Although previous studies have reported the effectiveness of adjuvant chemotherapy after consecutive resection for BTC, [4][5][6] it remains unclear whether neoadjuvant chemotherapy and chemoradiotherapy are more effective than surgery alone, and they have not been recommended by any clinical guidelines. 7,8 In cases where radical surgery is highly invasive, such as esophageal or pancreatic cancer, neoadjuvant chemotherapy may be more effective than adjuvant chemotherapy. 9,10 Radical surgery for BTC is also highly invasive; thus, we examined the efficacy of preoperative therapy for BTC. Moreover, a complete R0 resection of BTC has been recognized as a better prognostic factor, 11 with previous studies reporting that neoadjuvant chemoradiotherapy (NACRT) achieved a high R0 resection rate. [12][13][14][15] Therefore, a possibility exists that neoadjuvant therapy may be effective for BTC. However, previous studies on preoperative therapy for resectable BTC were mainly retrospective studies, and there has been no consensus on neoadjuvant therapy for BTC.
S-1 is a well-known oral cancer treatment consisting of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate. In fact, a Phase II trial evaluating unresectable and recurrent BTC indicated that S-1 had a 35% response rate. 16 Moreover, chemotherapy utilizing S-1 plus cisplatin has the potential to suppress the proliferation of BTC. 17 It is also known that the anticancer effects of radiation are enhanced by exposure to gimeracil combined with S-1. 18 Therefore, we hypothesized that neoadjuvant chemoradiotherapy using S-1 and cisplatin would improve the prognosis. First, we conducted a prospective Phase I study to explore the maximum tolerated dose (MTD) and recommended dose (RD) of NACRT using S-1 and cisplatin combined with concurrent radiation for the treatment of advanced resectable BTC.

| Treatment schedule
The treatment schedule is summarized in Figure 1

| Determination of dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD)
The recommended dose, which was the primary outcome of this study, was determined according to the following protocol. DLT was determined over the course of 14 d after chemoradiotherapy, and was defined as one or more of the following events: At least three patients were enrolled at each dose level. If DLT was not observed, the dose was escalated to the next level. If DLT was observed in one or two patients, three additional patients were needed at that dose level. If only one or two of the six patients experienced DLT, the dose was escalated to the next level. There was no dose escalation in individual patients. MTD was defined as the dose that produced DLT in all three initial patients or in three or more of the six patients. RD was defined as a one-step lower dose of the MTD. If MTD was reached at level 1, the dose was de-escalated to level 0. If MTD was undetermined at level 2, RD was determined as level 2.

| Evaluation of response by NACRT
We radiologically and pathologically evaluated the efficacy of NACRT as secondary outcomes. The tumor was evaluated using the RECIST criteria v.1.1 20 through an abdominal CT and/or MRI performed within 28 d after treatment. We clinically diagnosed the extent of the tumor based on the enhancement and thickness of the bile duct walls. For cases without evident measurable lesions, such as intrahepatic masses or swollen lymph nodes, the diameters of the enhanced and thickened bile ducts were measured and compared before and after chemoradiotherapy.
For cases who underwent radical surgery, the pathological grade of the chemoradiation treatment effects were diagnosed according to the grading system of -Evans criteria, which was established for pancreatic cancer. 21

| Surgery after treatment
After chemoradiation, portal venous embolization (PVE) was performed in patients who required an increase in remnant liver volume for major liver resection. Surgery was performed more than 3 weeks after PVE. Patients who did not need PVE underwent surgery within 4 weeks after chemoradiation therapy. We also examined the morbidity and mortality rates after surgery as secondary outcomes. Posthepatectomy liver failure (PHLF) was diagnosed based on the International Study Group of Liver Surgery criteria. 22 F I G U R E 1 Treatment schedule. Cisplatin was intravenously administered over 2 h on d 1 and 29. The starting dose of cisplatin was 50 mg/ m 2 (defined as level 1). The second dose (level 2) was 60 mg/m 2 , and the de-escalated dose (level 0) was 40 mg/m 2 . S-1 was administered orally every d on d 1-14 and d 29-42, and the total dose was based on the patient's body surface area as follows: <1.25 m 2 , 80 mg; 1.25-1.5 m 2 , 100 mg; >1.5 m 2 , 120 mg. Radiation was delivered to the tumor and nodal regions as a total dose of 50.4 Gy (28 fractions to 1.8 Gy)

| Patient characteristics
Between October 2012 and May 2016, 13 patients were enrolled in this study and 12 were eligible. Patients' characteristics are summarized in Table 1. The median age was 69 (range, 53-74) y. Ten patients had perihilar cholangiocarcinoma and two had distal cholangiocarcinoma. Eleven patients required biliary drainage before the start of treatment.

| Confirmation of MTD and RD
A summary of the dose level in this study is shown in Table 2 Therefore, an additional three patients were enrolled at level 2. One of the additional patients who had DLT (Grade 4 leukocytopenia lasting more than 3 d) was observed. In total, two out of the six patients suffered DLT at level 2. Based on these results, MTD was not determined even at level 2; therefore, RD was defined as level 2 dosage according to our protocol.

| Adverse events
Adverse events that occurred at each level are shown in Table 3.
Hematological events, including leukocytopenia and thrombocytopenia, were more frequent than nonhematological events. Grade 3 or 4 toxicities were observed in three cases at each level. Cholangitis occurred in 3 of the 12 cases.

| Evaluation of efficacy and perioperative course of each patient
The outcomes after NACRT are summarized in Table 4. Four patients had partial response (PR), four patients had stable disease (SD), and two patients had progression of disease (PD) because of liver metastases. Two patients were not evaluated because of artifacts from the drainage tube and changing of hospital before evaluation.
Finally, nine patients underwent radical surgery and seven cases reached R0 resection. In the pathological response, resected cases were evaluated in the Evans grade, which is recognized as the standardized diagnostic criteria for evaluating the pathological therapeutic effect of chemoradiotherapy for pancreatic carcinoma. One case was diagnosed as grade III and two were grade IIb, while the other six cases were grade IIa or lower.

| Perioperative and prognostic outcomes
Perioperative and prognostic outcomes are shown in Table 5. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

TA B L E 3 Summary of adverse events
In terms of long-term prognosis, the three patients who did not undergo radical surgery died within 1 y. Among the nine patients who underwent curative surgery, two of them had a 3-y survival without recurrence, all of which had pathological effects of III or IIb and a certain degree of tumor shrinkage. The pre-NACRT and post-NACRT CT and pathological findings of a representative case (case #2) are shown in Figure 2. A dynamic CT study revealed enhanced hilar biliary tract and intrahepatic cholangial dilation. It involved the right hepatic artery and portal vein (Figure 2A). The regional lymph node was also swollen. Preoperative evaluation by CT revealed that the enhanced tumor had shrunk ( Figure 2B). In the pathological analysis, almost all of the tumor cells were markedly swollen and vacuolated, with a deeply eosinophilic cytoplasm, which were irreversibly degenerated and classified into nonviable cells ( Figure 2C,D).  our study concluded that the RD of cisplatin was 60 mg/m 2 , which is equal to that of gastric cancer. Thus, our results suggest that preoperative patients with BTC tolerated this relatively strong regimen.

TA B L E 5 Clinical courses of each case
Although this study mainly aimed to determine the RD based on the safety of NACRT itself, however, in order to determine whether we should continue to a Phase II study, we had to examine whether the postoperative course was feasible. In our study, three patients did not undergo surgery although they had been diagnosed as resectable before NACRT. While it is possible that they may have an early relapse after surgery even if they underwent surgery alone, it is also considered that NACRT may have led to missed surgical opportunities. As a result, we achieved R0 resection in 7 out of the 12 patients. In considering that 11 of the 12 cases were clinical stage III or IV and we performed vessel reconstruction for seven cases, hepato-pancreatoduodenectomy for two cases, and left trisectionectomy for seven cases, our R0 resection rate of about 60% was relatively agreeable. In terms of long-term outcomes, our study showed that cases who achieved both a pathologically effective findings and R0 resection had a preferable prognosis although they had high locally advanced BTC. This study was only a Phase I study, but our results implied that there was some potential for the effectiveness of NACRT.
However, in considering perioperative complications associated with chemoradiotherapy, five out of nine cases who underwent curative surgery had postoperative bile leakage from hepaticojejunostomy. In general, bile leakage from hepaticojejunostomy occurs in 4-15% of patients. 28,29 At our institute, the incidence of bile leakage for perihilar cholangiocarcinoma without preoperative treatment between January 2013 and August 2020 was 19% (unpublished data). Compared with those, the incidence from this study seemed higher. One prospective study on NACRT for gallbladder carcinoma also reported a 43% incidence of biliary leakage. 30 It has been reported that wound healing worsens due to impaired blood flow caused by radiotherapy. 31 In fact, anastomotic leakage is reported to increase after anterior resection for rectal cancer following neoadjuvant chemoradiotherapy, and the routine use of a diverting ileostomy has become a standard procedure. 32 Although there is a lack of evidence for bile duct reconstruction, it is considered that a high dose of radiation can contribute to an increased in- to become highly inflamed. 33,34

ACK N OWLED G M ENTS
We thank to Hiroshi Yagi, Kentaro Matsubara, Go Oshima, Shutaro Hori, and Yuki Masuda, who are our colleagues at the Department of Surgery, Keio University School of Medicine for their contributions to this trial and checking our article.

FU N D I N G I N FO R M ATI O N
There is no funding to be disclosed.

CO N FLI C T O F I NTER E S T S TATEM ENT
Author Other authors have no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets used in this study are available from the corresponding author on reasonable request.

E TH I C S S TATEM ENT
Approval of the