{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:06:14Z","timestamp":1772168774829,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/f1000research.123250.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000}},{"DOI":"10.12688\/f1000research.123250.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000}}],"reference-count":27,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007288","name":"Mahasarakham University","doi-asserted-by":"publisher","award":["64\/04\/01"],"award-info":[{"award-number":["64\/04\/01"]}],"id":[{"id":"10.13039\/501100007288","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Background Cholangiocarcinoma (CCA) incidence in Northeastern Thailand is very high and a major cause of mortality. CCA patients typically have a poor prognosis and short-term survival rate due to late-stage diagnosis. Thailand is the first Southeast Asian country to approve medicinal cannabis treatment, especially for palliative care with advanced cancer patients. Methods A retrospective cohort study compared survival among 491 newly diagnosed advanced CCA patients between September 2019 and June 2021. Of these, 404 received standard palliative pain management (ST), and 87 received medicinal cannabis treatment (CT). Patients were enrolled from four tertiary hospitals and two secondary hospitals in five provinces of Northeast Thailand. Cumulative survival was calculated by the Kaplan-Meier method, and independent prognostic factors were analyzed using Cox regression. Results For ST patients, follow-up time was 790 person-months, with a mortality rate of 48.35\/100 person-months. For CT patients, follow-up time was 476 person-months, with a mortality rate of 10.9\/100 person-months. The median survival time after registration at a palliative clinic was 0.83 months (95% CI: 0.71\u20130.95) for ST and 5.66 months (95% CI: 1.94\u20139.38) for CT. Multivariate analysis showed CT was significantly associated with prolonged survival (HRadj = 0.28; 95% CI: 0.20\u20130.37; p &lt; 0.001). Conclusions The medical cannabis increased overall survival rates among CCA patients. In this retrospective cohort, Medicinal cannabis treatment was associated with more prolonged survival among advanced CCA patients in Northeastern Thailand. While this association remained significant after multivariable adjustment, unmeasured or residual confounding factors may have influenced the observed outcomes. Although the association remained significant after adjustment, unmeasured or residual confounders may have influenced outcomes. Further prospective studies are warranted to confirm these findings and explore potential mechanisms.<\/ns3:p>","DOI":"10.12688\/f1000research.123250.3","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T15:15:07Z","timestamp":1759504507000},"page":"1212","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Survival rate of patients with combined hepatocellular cholangiocarcinoma receiving medical cannabis treatment: A retrospective, cohort comparative 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Furthermore, the study did not control or include other confounding factors that could affect the survival outcome.<\/i> \n<b>Response:<\/b> We appreciate this important observation. The Abstract conclusion has been revised to avoid implying causality. The new conclusion now reads: \u201cIn this retrospective cohort, medicinal cannabis use was associated with longer overall survival among advanced CCA patients; however, causality cannot be inferred due to the retrospective design and residual confounding.\u201d This rewording aligns with the study design and acknowledges the potential impact of unmeasured confounding factors. \n<i>(Page 1, Lines 36\u201339)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Introduction (1)<\/b> \n<i>Clarify the population of this study (receiving palliative or curative treatment) and describe more information about these treatments specific to this population before mentioning medical cannabis. Include survival rates and treatments for CCA in Thailand.<\/i> \n<b>Response:<\/b> We have clarified that all patients in this study were diagnosed with advanced disease and were registered at palliative care or cannabis clinics. No patients received curative-intent treatment. We have expanded the description of standard palliative care and systemic treatment options available in Thailand, including expected survival times, supported by local and international references. \n<i>(Page 2, Lines 70\u201376, 78\u201379)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Introduction (2)<\/b> \n<i>Mention the rationale (literature reviewed) of the covariates and medical cannabis treatment used in this study from previous studies.<\/i> \n<b>Response:<\/b> We have added a paragraph explaining the rationale for each covariate (age, sex, type of cancer treatment, time from diagnosis to registration) based on prior survival studies. We also strengthened the rationale for examining medicinal cannabis by summarizing evidence from Thai and global literature on its palliative benefits and possible anti-cancer effects. \n<i>(Page 2, Lines 70\u201379)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Statistical Analysis (1)<\/b> \n<i>Compare baseline characteristics to address possible selection bias.<\/i> \n<b>Response:<\/b> We have compared baseline characteristics between treatment groups in the new Table 1 and discussed differences that may indicate potential selection bias. \n<i>(Page 4, Table 1)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Statistical Analysis (2)<\/b> \n<i>Mention the assumption for the log-rank test.<\/i> \n<b>Response:<\/b> We have explicitly stated the assumptions for the log-rank test (proportional hazards, non-informative censoring) in the Statistical Analysis section. \n<i>(Methods: Statistical Analysis)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Statistical Analysis (3)<\/b> \n<i>Use Kaplan\u2013Meier graph to compare survival outcomes between treatments by covariates (e.g., age, cancer treatments).<\/i> \n<b>Response:<\/b> We have added stratified Kaplan\u2013Meier survival curves by age group (&lt;65 vs \u226565) and prior cancer treatment (yes\/no) in the supplementary material. Figure 1 presents the overall survival curves for the two treatment groups. \n<i>(Figure 1; Supplementary Figures)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Statistical Analysis (4)<\/b> \n<i>Mention the assumption of Cox regression and steps of analysis (univariable and multivariable).<\/i> \n<b>Response:<\/b> We have described the proportional hazards assumption checks (Schoenfeld residuals, log-minus-log plots) and outlined the two-step analysis process: univariable screening (p&lt;0.20) followed by multivariable Cox regression adjusting for selected covariates. \n<i>(Methods: Statistical Analysis)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Results (1)<\/b> \n<i>Separate tables: Table 1 for baseline characteristics, separate from tables presenting study objectives.<\/i> \n<b>Response:<\/b> We have reorganized the results into separate tables:  \n<b>Table 1:<\/b> Baseline characteristics by treatment group \n<b>Table 2:<\/b> Survival outcomes (median survival, person-time, log-rank test) \n<b>Table 3:<\/b> Cox regression results (crude and adjusted HRs) \n<i>(Pages 4\u20136, Tables 1\u20133)<\/i>   \n<b>Reviewer\u2019s Comment \u2013 Results (2)<\/b> \n<i>Present survival outcomes in another table along with Kaplan\u2013Meier graph by covariates.<\/i> \n<b>Response:<\/b> Survival outcomes are now presented in Table 2 and illustrated in Kaplan\u2013Meier curves (Figure 1). Stratified curves by age and prior cancer treatment are included in the supplementary material. \n<b>Reviewer\u2019s Comment \u2013 Results (3)<\/b> \n<i>Present Cox proportional hazard results in a table with crude and adjusted HR, interpret HR&lt;1.<\/i> \n<b>Response:<\/b> Table 3 presents both crude and adjusted HRs, with interpretation provided in the Results section. We explain that HR&lt;1 indicates a reduced hazard of death, reflecting longer survival in that group. \n<i>(Page 6, Table 3)<\/i> \n<b>Reviewer\u2019s Comment \u2013 Discussion<\/b> \n<i>Discuss all covariates and the mechanism of medical cannabis treatment.<\/i> \n<b>Response:<\/b> We have discussed each covariate\u2019s association with survival outcomes, supported by relevant literature. Additionally, we expanded the discussion on potential mechanisms of medicinal cannabis, including symptom relief (pain, nausea, appetite, sleep) and preclinical evidence for anti-tumor activity (apoptosis induction, angiogenesis inhibition, tumor proliferation suppression). \n<i>(Pages 6\u20137, Discussion)<\/i>","URL":"https:\/\/f1000research.com\/articles\/11-1212\/v3#referee-comment-14359","order":3,"name":"referee-comment-14359","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.186703.r420117, Nuttapong Ngamphaiboon, Mahidol University, Bangkok, 14 Oct 2025, version 3, indexed","URL":"https:\/\/f1000research.com\/articles\/11-1212\/v3#referee-response-420117","order":4,"name":"referee-response-420117","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.180104.r400722, Dima Malkawi, University of Colorado, Denver, Colorado, 12 Aug 2025, version 2, 1 approved, 1 approved with reservations, 3 not approved","URL":"https:\/\/f1000research.com\/articles\/11-1212\/v2#referee-response-400722","order":5,"name":"referee-response-400722","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This research was financially supported by Faculty of Medicine, Mahasarakham University with the reference no. 64\/04\/01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}