Survival rate of patients with combined hepatocellular cholangiocarcinoma receiving medical cannabis treatment: A retrospective, cohort comparative study [version 1; peer review: awaiting peer review]

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 comparative study of survival rates among 491 newly diagnosed advanced CCA patients was carried out between September 1, 2019, and June 30, 2021. A total of 404 patients were in the standard palliative care pain management treatment group (ST), and 87 were in the medicinal cannabis treatment group (CT). Patients with CCA were recruited from four tertiary hospitals and two secondary hospitals in five provinces of Northeast Thailand. The cumulative survival rates were calculated by the Kaplan-Meier method, and independent Conclusions: The medical cannabis increased overall survival rates among CCA patients. This article is included in the Oncology gateway. knowledge, no studies on the survival rate of patients treated with medicinal cannabis from the patients ’ perspective have been carried out to date. The present study aims to compare survival rates in palliative cHCC-CC patients who were treated with standard treatment (ST) or cannabis treatment (CT) palliative care protocols.


Introduction
Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare, but severely aggressive primary liver cancer manifesting characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The incidence rate is approximately 0.59 per 1,000,000 populations worldwide 1 but it is highly prevalent in Thailand. 2 The highest reported CC incidence internationally is in northeastern Thailand, 118.5 per 100,000, in Khon Kaen Province, which is over 100 times higher than the global rate. 3 CC is generally asymptomatic in early stages and is 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 CC 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 cHCC-CC, 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 CC patients receiving surgery (an average of 29.38 months), best supportive treatment was 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 patients with cancer appears to be well-tolerated, effective and a safe pain-relief option with significant improvement in quality of life shown after 6 months of treatment. 10 In patients with cancer, cannabinoids have mainly been used as part of palliative care to alleviate pain, relieve nausea and stimulate appetite. 11 Thailand legalized medical cannabis in February 2019, becoming the first country in Southeast Asia to regulate medical treatment. 12 Currently, there are two treatment options for palliative cancer patients in Thailand; the standard current treatment and the new cannabis treatment. However, to the best of our knowledge, no studies on the survival rate of patients treated with medicinal cannabis from the patients' perspective have been carried out to date. The present study aims to compare survival rates in palliative cHCC-CC patients who were treated with standard treatment (ST) or cannabis treatment (CT) palliative care protocols.

Ethical approval
This study was reviewed and approved by the Mahasarakham University Human Research Ethics Committee (Reference No. 204/2563; approved on July 24, 2020), and Roi-Et Regional Hospital (Reference RE064/2563; approved on August 26, 2020), Buriram Regional Hospital Ethics Committee for Human Research, based on the Declaration of Helsinki and the ICH Good Clinical Practice Guidelines (Reference No. GCP0066/2563; approved on February 4, 2020). Because of its retrospective manner, informed consent was waived by the Roi-Et Regional Hospital and Buriram Regional Hospital. Data were collected from August 30, 2020, to June 30, 2021, which collected event data on 491 cases from September 1, 2019, to June 30, 2021.

Study design
A retrospective cohort study was conducted with 491 cHCC-CC patients (404 received ST and 87 received CT), who were diagnosed at least by ultrasonography and treated by supportive treatment at a palliative care and/or cannabis care clinic between September 1, 2019, and June 30, 2021. Data were extracted from the four tertiary hospitals, and two secondary hospitals serving five provinces of northeastern Thailand (Roi-Et Regional Hospital, Buriram Regional Hospital, Surin Provincial Hospital, Sawang Dandin Crown Prince Hospital, Panna Nikhom Hospital and Pana Hospital).

Data collection
The independent variables were age at registration (palliative clinic and/or cannabis clinic), sex, cancer treatment and period of diagnosis to registration. The dependent variable was the survival time of patients with cHCC-CC. In order to calculate survival time, the starting point was identified as the date of registration, and the follow-up period ended when a patient passed away or on completion of the study. Censored data were used for those still alive at the end of the study (June 30, 2021) or lost to follow-up. Death status on the cause of treatment was confirmed by linkage with the death certificates from the national statistics database and by a telephone call to the patient or public health officer in community health centers.

Statistical methods
Statistical analysis was performed with Stata (RRID:SCR_012763) version 15 (free alternative, Rstudio). Descriptive statistics were used to present baseline characteristics and clinical subject data. Frequency and percentages were constructed to describe categorical data and expressed as the means deviation (in SD) or medians with ranges to describe continuous data. The Kaplan-Meier method was used for observing survival duration with 95% confidence intervals (95% CI). Then between-group comparisons were evaluated using a log-rank test. The test for associations between the diverse covariates and survival rate was performed using the Cox proportional hazard regression model. The results were submitted as hazard ratios (HR) with 95% CI for HR. A p-value less than 0.05 is typically considered to be statistically significant. ). There were factors found that affected the survival of patients receiving palliative care for liver and bile duct cancer. The most significant treatment factor found was between those patients who received standard therapy and those who received medical cannabis. Those on standard therapy were 3.57% more at risk of death than those on cannabis.

Discussion
The impact of two types of treatment that affect the survival of cHCC-CC 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 findings for after supportive treatment 7 where survival time was only 4.3 months post-diagnosis. Patients diagnosed at an advanced stage were twice as likely to pass away (HR: 1.8, 95% CI: 1.1-2.9). 13 By contrast, patients with advanced cancer using cannabis showed a significantly decreased overall survival compared to non-users. 14 In the univariate analysis, cancer treatment and period of diagnosis with advanced cHCC-CC to registration were associated with survival rate. It was found that the ST registered patients survived less than three months after being diagnosed with advanced-stage cHCC-CC. The reason for this might be that some patients had been consulting and were being cared for by an oncologist or other doctor rather than those patients who were registered for and receiving supportive treatment at a Palliative Clinic. Furthermore, most patients had been treated with a combination of surgery and chemotherapy, before being admitted to a Palliative Clinic. Although the registered patients at the Cannabis Clinic were >70 years old, they had no cancer treatment, only supportive treatment at the Cannabis Clinic. At the community hospitals where CT/MRI/biopsy/US have shown advanced organ metastases others who received treatment at a Cannabis clinic without waiting for a consultation with an oncologist were able to receive chemotherapy along with cannabis. This study has several limitations. A number of patients in the CT group dropped out before completion of the study. As a consequence, most patients suffering from advanced cancers and receiving heavy oncological treatments were older adults.