Survival Rate of Cholangiocarcinoma, Hepatocellular Patients Received Cannabis Treatment

Introduction: 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 rst Southeast Asian country to approve medicinal cannabis treatment, especially for palliative care with advanced cancer patients.. Patients and methods: A retrospectively cohort comparative study of , survival rates among 491 newly diagnosed advanced CCA patients was carried out between September 2019 and 30 July, 2021; (404 patients in a standard palliative care pain management treatment group (ST), and 87 in a medicinal cannabis treatment group (CT). CCA Patients were recruited from 4 tertiary hospitals and 2 secondary hospitals in ve provinces of Northeast Thailand. The cumulative survival rates were calculated by the Kaplan-Meier method, and independent prognostic factors were investigated using Cox regression.


Introduction
Combined hepatocellular-cholangiocarcinoma (cHCC/CCA) represents a rare but highly aggressive primary liver cancer featuring disease characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The global incidence rates is around 0.59 per 1,000,000 people (1) but it is highly prevalent in Thailand. (2)The highest reported CCA incidence internationally is in Northeastem Thailand, 118.5 per 100,000, in Khon Kaen Province, which is over 100 times higher than the global rate .
(3) CCAs are generally asymptomatic in early stages and are usually diagnosed late, when the disease has already metastasized. Late-stage diagnosis limits the effective therapeutic options, and has an aggressive disease course (4) and very poor prognosis (5) resulting in lower survival rates.
Previous studies have shown the median post-diagnosis survival of CCA patients to be about 9 months (95% CI 7-11), with 1-, 3-, and 5-year survival rates at 43.4%, 21.5%, and 17.1%, respectively. (1). Mean overall survival rate at 1-, 3-, and 5-year was 66.6, 41.5, and 32.7% for patients with transitional HCC-CC (Gentile et al. 2020), with median survival time from diagnosis 4.3 months (95% CI: 3.3-5.1) (6), and after supportive treatment was 4 months (7). Survival time was increased among CCA patients receiving surgery an average of 29.38 months, best supportive treatment 5.12 months and 13.38 months for chemotherapy patients. (8) At present, medical cannabis products are in use in many countries (9) Cannabis as a palliative treatment for cancer patients appears to be well-tolerated, effective and a safe pain-relief option with signi cant improvement in quality of life shown after 6 months treatment (10

Study design
A retrospective cohort study was conducted with 491 patients ( 404 received standard treatment (ST) and 87 received cannabis treatment (CT) who were diagnosed (at least by ultrasonography and treated by supportive treatment at a palliative care and/ or cannabis care clinic between 1 September 2019 and 31 December, 2020. Data was extracted from the 4 tertiary hospitals, and 2 secondary hospitals serving ve provinces of Northeastem Thailand (Roi-Et Regional Hospital, Burirum Regional Hospital, Surin Provincial Hospital , Sawang Dandin Crown Prince Hospital, Panna Nikhom Hospital and Pana Hospital). The patients were followed up until death or the end of the study (30 June, 2021) The independent variables were age at registration (Palliative clinic and/or Cannabis clinic),gender, cancer treatment and period of diagnosis to registration. The dependent variable was the post-diagnosis survival time of patients with CCA,HCC. In order to calculate the survival time, the starting point was identi ed as the date of registration, and the follow up period ended when a patient died or on completion of the study. Censored data were used for those still alive at the end of the study, or, lost to follow-up. The follow-up status of each patient was checked from medical records and by linkage with the death registry of the national statistics database.

Ethical approved
This study was reviewed and approved by the Maha-Sarakham University Human Research Ethics Committee (Reference NO.204/2563), and Roi-Et Regional Hospital (Reference RE064/2563), Burirum Regional Hospital Ethics Committee for Human Research, based on the Declaration of Helsinki and the ICH Good Clinical Practice Guidelines (Reference No. GCP0066/2563).

Statistical methods
Descriptive statistics were used to present baseline characteristics and clinical subject data. Frequency and percentages were used to describe categorical data and means with standard deviations or medians with ranges were used to describe continuous data. The observed survival rate was calculated by the Kaplan-Meier method for median survival time with 95% con dence intervals (CIs). The log-rank test were used for comparisons between groups. The Cox proportional hazard regression model was used to assess associations between the various covariates and survival rate. The results were presented as hazard ratios (HR) with 95% con dence intervals (95%CI). The level of statistical signi cance was set as a p-value less than 0.05. Table 1 shows the study participants' characteristics. There were 491 patients (296 males and

Discussion
In the present study, we reported the impact of two types of treatment that affect the survival of CCA,HCC patients who either had supportive treatment at palliative clinic,, or, a cannabis clinic. CT was the most effective treatment, with an overall survival time of 5.66 months, while overall survival time was 0.83 months for ST. Meanwhile, The overall survival times are consistent with other ndings for after supportive treatment (12) where survival time was only 4.3 months post-diagnosis. Patients diagnosed at an advanced stage were twice as likely to die (HR: 1.8, 95%CI: 1.1-2.9), (13) In contrast Advanced cancer patients using cannabis showed a signi cantly decreased overall survival (OS) compared to nonusers. The median OS for cannabis use was 6.4 months (95% CI,3.2-9.7) and 28.5 months (95% CI, 15.6-NA) for non-users (14) In the univariate analysis, cancer treatment and period of diagnosis with advanced CCA,HCC to registration were associated with survival rate. It was found that the ST registered patients survived less than 3 months after being diagnosed with advanced-stage CCA,HCC., maybe because patients who will have to be consulted by a oncologist and other doctors who is the main physician in taking care of patients before The patients were registered and received supportive treatment at Palliative clinic, along with most of the patients undergoing a combination of surgery, chemotherapy, and a combination of treatments before being admitted to Palliative clinic, while the registered patients at Cannabis clinic were > 70 years, no cancer treatment and supportive treatment at Cannabis clinic, especially at community hospitals where CT / MRI / biopsy / US has been shown to have advanced organ metastases. another will receive treatment at Cannabis clinic without waiting for a consult from the oncologist and found that patients were able to receive chemotherapy along with cannabis This study has several limitations. One is the number of patients who dropped out before study completion Level of disease progression may explain this for a number of patients. Most patients suffered from advanced cancers and received heavy oncological treatments and were elderly. Patients with CCA have poor prognosis and short-term survival at the time of diagnosis. Registration, and decision-making at the standard and / or cannabis clinic in each hospital differs across physicians, patients, families, stages of disease, organ metastasis, methods of treatment, and severity of symptoms.
To the best of our knowledge, this is the rst study that has compared survival rate and quality of life of CCA,HCC patients who received either ST, or, CT. across tertiary and secondary hospitals and across 5 Patient's data were available in medical records room of the Roi-Et Regional Hospital, Burirum Regional Hospital, Surin Provincial Hospital , Sawang Dandin Crown Prince Hospital, Panna Nikhom Hospital and Pana Hospital. The datasets generated and/or analysed during the current study are not publicly available due to they are les in medical records room in our hospital, but are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
This study was reviewed and approved by the Maha-Sarakham University Human Research Ethics Committee (Reference NO.204/2563), Because of its retrospective manner, informed consent was waived by the Roi-Et Regional Hospital (Reference RE064/2563), Burirum Regional Hospital).

Figure 1
Comparison of overall survival period of advanced diagnosis to register :< 3 months, 3-6 months,6-9 months,> 9 months between standard treatment vs cannabis treatment Comparison of overall survival period of age < 60 y , 60-69 y, >70 y between Standard treatment vs Cannabis treatment Figure 4