Emerging Systemic Therapies in Advanced Unresectable Biliary Tract Cancer: Review and Canadian Perspective^†

Round 1

Reviewer 1 Report

I read this article with great interest, and I think it could be a good contribution to science. The authors discuss the emerging therapies under investigation. By the way the authors should revise the article according to my comments and then the article could be accepted.     They should expand discussions on the role of surgery. I think that one of the most important steps in the cure of this cancer is the likelihood of resection after neoadjuvant treatment.
Curative treatment of perihilar tumors requires major hepatectomy responsible for high morbidity and mortality. Could the authors explain the role of the neoadjuvant treatment in Canada?
Any place for downstaging with radioembolization or chemotherapy? (https://doi.org/10.1245/s10434-020-08486-7)
  Is there any validated treatment after surgery? I know that this is an oncological report but they should consider that the patient must be seen in his totality; from the nutritional aspect to the oncological aspect.  Undernutrition is a factor that can impact prognosis and also treatments such as surgery. Undernourished patients face more complications if they have surgery.

 

Author Response

Thank you for reviewing our manuscript and for providing thoughtful comments. We have outlined how we have addressed your comments below.

 

• Comment 1: Expand discussions on the role of surgery and the role of neoadjuvant treatment in Canada.
  • Given that the intention of the manuscript, as stated in the title, was to review the emerging systemic therapies for advanced, unresectable BTC, we feel that a detailed review of the role of surgery and neoadjuvant treatment is out of scope and that a separate review would be most appropriate to cover this important topic. We have however included a few sentences in the introduction to acknowledge the role of surgery, adjuvant therapy, and neoadjuvant therapy followed by liver transplantation. See lines 52-62:

“For patients with resectable tumours, curative intent therapy with surgery followed by adjuvant chemotherapy is the standard of care, resulting in a median overall survival (OS) of over 4 years [7]. Radiotherapy may also be used as neoadjuvant or adjuvant therapy in conjunction with surgical resection, although the optimal methods for delivery of radiotherapy are unclear [8]. Nevertheless, only 20% of BTCs may be eligible for potentially curative resection [9]. Neoadjuvant chemoradiation followed by liver transplantation is an option for unresectable cholangiocarcinoma without metastases, with a single center study from the Mayo Clinic demonstrating a 4-year survival rate of 51% with this method [10]. However, eligibility criteria to receive this therapy are strict. A similar chemoradiotherapy protocol used at Toronto General Hospital and Princess Margaret Cancer Centre showed a high rate of dropout and disease progression [11].”

• Comment 2: Any place for downstaging with chemoembolization or chemotherapy? (https://doi.org/10.1245/s10434-020-08486-7)
  • The role for downstaging with a combination of local (selective internal radiation therapy) and systemic chemotherapy is unclear, with only retrospective, observational studies published to date (like the study highlighted in your comments). As stated in the response to comment 1, we feel further discussion on surgery and/or radiotherapy warrants a separate review and would dilute the focus of the current manuscript. We have however briefly mentioned the importance of downstaging in the original manuscript and have additionally included a sentence describe the findings from the retrospective study by Riby et al (line 314-320: “A large, durable response can downstage patients, as was reported in 20% of patients in the phase II trial of albumin-bound paclitaxel plus gemcitabine-cisplatin [14]. This may allow them to receive potentially curative surgery. In addition, retrospective studies have observed similar survival outcomes after surgery in patients with initially unresectable localized intrahepatic cholangiocarcinoma that were down-staged following chemotherapy compared with initially resectable patients [63, 64].” and Line 396-399 “To better understand how new therapies might provide value to patients, clinical trials and real-world studies should aim to capture outcomes such as biliary stenting, hospitalizations, and down-staging, and explore whether these correlate with patient quality of life.”

 

• Comment 3: Is there any validated treatments after surgery?
  • As mentioned earlier, we have now included a brief sentence in the introduction stating that adjuvant chemotherapy following surgery is standard of care for resectable patients (lines 52-54). For reasons already discussed, we have not elaborated further on this.
    
    
• Comment 4: Impact of undernutrition on surgical outcomes.
  • While this is of interest, as stated above we feel this is out of scope with the intended focus of the manuscript and have therefore not included it.

Reviewer 2 Report

The paper is well written and offers to the readers an interesting recap about latest therapies in treatment of biliary cancer. However it could be better to describe also controindications of these therapies and real life complications after treatments than describe the difficult application in Canadian scenario that could be not so interesting for scientists from other worldwide countries.

 

Author Response

Thank you for reviewing our manuscript and for providing thoughtful comments. We have outlined how we have addressed your comments below.

 

• Comment 1: It could be better to describe contraindications of therapies and real-life complications after treatments rather than describe the difficult application of treatments in Canada which may not be of interest to scientists in other countries.
  • Since Current Oncology has historically been a Canadian journal, the authors felt it would be fitting to focus on the Canadian perspective, particularly as significant barriers exist in accessing therapies for BTC in Canada which has a direct impact on patient and physicians. Although this may not be relevant to all readers, we feel that stating “Review and Canadian Perspective” in the title alerts readers that the content will be presented from a Canadian Lens. We also feel that real-life complications after treatment are less applicable in the advanced stage when systemic therapies are used. As stated in lines 360-363, many patients are treated with gemcitabine-cisplatin beyond 8 cycles. We have now included the potential for neuropathy as a dose-limiting toxicity to cisplatin (“However, anecdotally, many Canadian oncologists will give gemcitabine-cisplatin until progression or dose-limiting toxicity (such as neuropathy related to cisplatin), or treatment is continued with gemcitabine monotherapy after cycle 8.”) The real-life complications of chemotherapy in the neoadjuvant setting followed by surgery may be of greater interest to readers; however, discussion of surgery is out of scope for this manuscript which focuses on systemic therapies in patients with advanced, unresectable disease. We have included a general statement surrounding contraindications to chemotherapy on line 73-75: “In addition, patients who are elderly or have poor performance status are unable to tolerate chemotherapy, with their treatment limited to supportive care including decompression of the biliary tree through biliary stenting and ablation techniques [13].”

Reviewer 3 Report

Tam et al. briefly described Biliary Tract Cancer (BTC) in this review. Then, the authors about various treatment strategies for BTC, including Chemotherapy, Immunotherapy, and marker-driven therapies for BTCs driven by genomic alterations. Finally, the authors discussed the Canadian perspective regarding access to these treatments and recommendations for assessing treatment options for BTC in Canada.

 

Given how rare yet aggressive these malignancies are, scientific reports discussing BTC are of paramount importance. This review will be of interest to the readers of the journal. It is well written, and the flow is logical. I have the following minor recommendations before considering this review for publication:

 

1- It will be essential to discuss the latest updates on Radiotherapy treatment options for BTC.

 

2- A figure summarizing treatment options reviewed for BTC is highly beneficial for this review. 

 

3- Briefly discussing the results of the molecular and Single-cell analyses of Biliary Tract Cancer TMEs (e.g., Farshidfar et al., 2017, Okawa et al., 2021 and Shi et al., 2022) will add an edge to this review over other BTC reviews, as their findings could have implications over therapeutic strategies.

Author Response

Thank you for reviewing our manuscript and for providing thoughtful comments. We have outlined how we have addressed your comments below.

 

• Comment 1: It will be essential to discuss the latest updates on Radiotherapy treatment options for BTC.
• Given that the intention of the manuscript, as stated in the title, was to review the emerging systemic therapies for advanced, unresectable BTC, we feel that a detailed review of the role of radiotherapy in BTC management is out of scope for this review and is deserving of a review of its own. We have however acknowledged that radiotherapy does play a role in the neoadjuvant and adjuvant setting in lines 54-56 and 57-62 of the introduction:

“Radiotherapy may also be used as neoadjuvant or adjuvant therapy in conjunction with surgical resection, although the optimal methods for delivery of radiotherapy are un-clear [8].”
“Neoadjuvant chemoradiation followed by liver transplantation is an option for unresectable cholangiocarcinoma without metastases, with a single center study from the Mayo Clinic demonstrating a 4-year survival rate of 51% with this method [10]. However, eligibility criteria to receive this therapy are strict. A similar chemoradiotherapy protocol used at Toronto General Hospital and Princess Margaret Cancer Centre showed a high rate of dropout and disease progression [11].”

• Comment 2: A figure summarizing treatment options reviewed for BTC is highly beneficial for this review.
  • Figure 1 has been added on page 3 which summarizes current and emerging treatments by class and provides their approval and access status in Canada
    
    
• Comment 3: Briefly discussing the results of the molecular and Single-cell analyses of Biliary Tract Cancer TMEs (e.g., Farshidfar et al., 2017, Okawa et al., 2021 and Shi et al., 2022) will add an edge to this review over other BTC reviews, as their findings could have implications over therapeutic strategies.
  • A small paragraph at the end of section 2.3 (Biomarker-driven therapies) has been included which describe the potential impact of the studies mentioned above and emphasize the role of precision medicine in the management of BTC. See lines 235-248:
    “Increasingly sophisticated genomic analyses in BTC are expected to reveal insights on additional biomarkers of treatment response and new therapeutic targets. For example, a multi-omics analysis in iCCA tumour samples identified an IDH mutant-enriched subtype that correlated with hypermethylation and decreased expression of ARID1A, suggesting that inhibition of chromatin modifiers such as EZH2 may be effective in this subtype [53]. Other studies have reported a high frequency of other actionable biomarkers in BTC including PTEN, CDKN2A, and KRAS which warrant further investigation in clinical trials [54, 55]. Outside of MSI, biomarkers that can predict response to immune checkpoint inhibitors have been unsuccessful thus far, likely due to the heter-ogeneity of immune cells in the tumour microenvironment of BTC. Single-cell RNA sequencing techniques can characterize complex immune cell populations in the tumour microenvironment and have shown promise in identifying biomarkers for immunotherapy response [56]. Together this emphasizes the continued role precision medicine will play in improving treatment response in BTC.”