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Effectiveness of omega-3 fatty acid administration on completion rate of adjuvant chemotherapy for biliary tract cancer: study protocol for a single-centre, open-label, single-arm, historically controlled study

Introduction Multimodal treatment prolongs the survival of patients with biliary tract cancer (BTC). However, the chemotherapy choices for this disease are few, and completing each chemotherapy session is important. Adjuvant chemotherapy has been attempted for BTC, but has only had a 75% completion rate. Body weight loss and cholangitis are reasons for the interruption of chemotherapy. Previous reports suggested that nutritional intervention with omega-3 fatty acids maintained body weight and improved the completion rate for chemotherapy. Moreover, omega-3 fatty acids have an anti-inflammatory effect. Therefore, we theorised that omega-3 fatty acids would improve the completion rate of adjuvant chemotherapy in patients with BTC. The aim of this study is thus to evaluate the effectiveness of omega-3 fatty acids for patients planning adjuvant chemotherapy for BTC. Method and analysis This study is a single-centre, open-label, single-arm, historically controlled study with a planned enrolment of 55 participants. Protocol treatment consists of four courses of S-1 adjuvant chemotherapy and an oral omega-3 fatty acid pharmaceutic adjuvant (LOTRIGA 2 g (Takeda Pharmaceutical Co.)), which includes 2 g of omega-3 fatty acids from day 1 until day 168 of the treatment period. The primary endpoint is the completion rate of four total courses of S-1. Secondary endpoints are postoperative cholangitis, time to recurrence or distant metastasis, changes in nutritional index, changes in the lymphocyte blast transformation test induced by phytohaemagglutinin, and concanavalin A and diamine oxidase serum activity during adjuvant chemotherapy. All adverse events will be evaluated. Ethics and dissemination This protocol was approved by the Institutional Review Board of Kobe University Hospital. The findings from this study will be presented at national and international conferences and published in peer-reviewed journals. Trial registration number UMIN000031247.


GENERAL COMMENTS
In this protocol, Ueno et al seek to evaluate how omega-3 fatty acid supplementation may impact the completion rate of adjuvant chemotherapy for biliary tract cancers. The authors predict that omega-3 FA should improve completion rate of adjuvant S1 therapy to 90% (from a historical rate of 76%). The trial will be single-centered, single-armed, and will rely on historical control. I expect that it will be a low-risk study.
I have a few questions/comments for the authors: 1. As the rate of failure to complete adjuvant S-1 attributed to adverse events was 12%, and adverse events are the main area that they predict will be impacted by omega-3, should they not expect the improvement of completion of adjuvant S-1 to be 12%? 2. Since their primary endpoint is rate of completion of adjuvant S-1 therapy, I don't understand, nor fully agree with, the authors' decision with regards to inclusion criteria. Why not just include any and all patients with biliary tract cancer for whom adjuvant S-1 is recommended based on multidisciplinary review and patient choice? 3. Along the same line, I find their explanation for which stage of which cancer type should be included arbitrary and lacking in solid data. For instance, stating that patients with stage I perihilar cholangioCA or stage IA distal CBD cancer get "few benefits from adjuvant therapy", when they acknowledge that "the target for adjuvant chemotherapy for biliary tract cancer is still controversial", may not be supported by data. 4. The authors should point out that their trial may not be generalizable to other chemotherapy regimens. 5. There are several syntax and grammatically errors throughout the manuscript the authors should correct.

Replies to Reviewer #1：
Thank you for your kind and useful comments for improving our manuscript. In response to your advice, we have revised the manuscript as follows： Reviewer #1: The English requires reviewing. Otherwise protocol is of adequate quality and the objectives and study design are clear.
All the text has been checked and corrected by a native English speaker.

Replies to Reviewer #2：
In this protocol, Ueno et al seek to evaluate how omega-3 fatty acid supplementation may impact the completion rate of adjuvant chemotherapy for biliary tract cancers. The authors predict that omega-3 FA should improve completion rate of adjuvant S1 therapy to 90% (from a historical rate of 76%). The trial will be single-centered, single-armed, and will rely on historical control. I expect that it will be a low-risk study.
Thank you for your constructive comments for improving our manuscript. In response to your concerns, we have extensively revised the manuscript as follows: 1. As the rate of failure to complete adjuvant S-1 attributed to adverse events was 12%, and adverse events are the main area that they predict will be impacted by omega-3, should they not expect the improvement of completion of adjuvant S-1 to be 12%?
Thank you for your comment. We estimated the recurrence rate as 10%, a little less than that of the previous report. That is because we thought that improving the completion rate with omega-3 may reduce early recurrence. We cannot immediately change the sample size, but we have mentioned the power when the improvement in completion is 12% in the sample size section.
2. Since their primary endpoint is rate of completion of adjuvant S-1 therapy, I don't understand, nor fully agree with, the authors' decision with regards to inclusion criteria. Why not just include any and all patients with biliary tract cancer for whom adjuvant S-1 is recommended based on multidisciplinary review and patient choice?
Ishihara et al. 15 reported that the 5-year survival rate in Stage Ⅰ of biliary tract cancer from 2008 to 2013 in Japan was 91% for gallbladder cancer and 92% for ampullary region cancer. Although somewhat low, 74% for perihilar bile duct cancer and 78% for distal bile duct cancer, cancer deaths for these are not common. Potential reasons for the low ratios include perioperative death and late complications such as cholangitis. Therefore, since we had thought that these patients get few benefits from adjuvant chemotherapy, in principle, adjuvant chemotherapy was not performed for Stage Ⅰ.
In comparison, the 5-year survival rate of intrahepatic cholangiocarcinoma in patients with the tumor, less than 2 cm in diameter, that corresponds to Stage I is 36.3% in Japan's National Primary Liver Cancer Follow-up Survey (the 18th), which was worse than the same stage for other biliary tract cancers. Adjuvant chemotherapy seems to be beneficial for patients with Stage I intrahepatic cholangiocarcinoma.
Based on these data, we have corrected the inclusion criteria for adjuvant chemotherapy in biliary tract cancer in Table 1 and added to the discussion. Furthermore, reference No.15 has been cited.
3. Along the same line, I find their explanation for which stage of which cancer type should be included arbitrary and lacking in solid data. For instance, stating that patients with stage I perihilar cholangioCA or stage IA distal CBD cancer get "few benefits from adjuvant therapy", when they acknowledge that "the target for adjuvant chemotherapy for biliary tract cancer is still controversial", may not be supported by data.
Thank you for your suggestion. The current problems with adjuvant chemotherapy for biliary tract cancer include the small number of cases and the lack of data with evidence at the highest level due to the biological specificity of each biliary tract cancer. Therefore, the indication criteria for adjuvant chemotherapy are controversial.
The clinical trial, Japan Clinical Oncology Group (JCOG) 1202 14 is currently in progress (registration has been completed and is currently being analyzed). The 1202 trial only includes stage 1 intrahepatic cholangiocarcinoma and other biliary tract cancers targeted at stage 2 or higher according to the above data that we previously described in session 2. So that, in this study the indication criteria for adjuvant chemotherapy were according to JCOG 1202.