Cholangiocarcinoma (CCA) is a rare liver tumor worldwide (incidence <6 cases per 100,000), but, is highly prevalent in parts of Thailand. ¹ The Northeastern (Isaan) region of Thailand has > 85 cases per 100,000, especially in Khon Kaen Province with 118.5 cases per 100,000 populations. Which is 100 times higher than the global rate. ² Typically, CCAs are asymptomatic in the early stages, and are consequently not diagnosed until late stage when the cancer has already metastasized, severely limiting effective therapeutic options and becoming a major cause of mortality. ³ For these patients, palliative treatments such as chemotherapy or supportive care are standard, and median survival ranges from 4 to 6 months ^{4 , 5} ; 5 and the 6-month survival is only 35%. ⁵ The major surgical treatments are surgical resection and/or liver transplantation, whereas chemotherapies are virtually palliative given the typical late-stage diagnosis and marked chemo-resistance of this cancer. ⁶

Health-related quality of life (HRQoL) is a multidimensional concept encompassing physical, emotional, and social well-being, and is a key outcome in cancer care. ⁷ Among advanced cholangiocarcinoma (CCA) patients, pain and sleep disturbances are particularly common and have been strongly associated with impaired HRQoL. ^{8 – 10} Persistent pain not only limits physical functioning but also disrupts sleep, contributing to fatigue, anxiety, and emotional distress. ^{11 , 12} This symptom burden creates a cycle that further reduces overall quality of life, especially in palliative care settings. Effective management of pain and sleep-related symptoms is therefore critical in improving HRQoL for these patients.

Medical cannabis has been used in palliative care to alleviate pain, relieve nausea and stimulate appetite, ¹³ and has been shown to attain good symptom control and reduce the number of palliative care drugs used. ¹⁴ A recent oncology study on the short-term outcomes of medical cannabis showed significant improvement in multiple symptoms between baseline and one-month follow-up, including reductions in pain intensity, affective and sensory pain, improved sleep quality and duration and reduced cancer distress, and both physical and psychological symptom burden. ¹⁵ However, no studies have yet compared the quality of life of patients with advanced CCA treated with, either, a standard palliative-care treatment protocol, or, with medical cannabis.

Thailand was the first country in Southeast Asia to approve cannabis for medical treatment. ¹⁶ Currently, in Thailand, there are two palliative care treatment protocols allowed for cancer patients; standard treatment regime, and medical cannabis treatment. As there is no comparative Thai research yet on HRQoL from the perspective of patients, this study was designed to compare the perceived quality of life outcomes between the two treatment protocol options.

Initially, 52 patients chose a standard treatment (ST), and 63 patients chose medical cannabis treatment (CT), all with Palliative Performance Scores (PPS) > 50. However, by the four-month follow-up point, there were only 72 patients remaining (21 dropped out at the 2 ^nd month, and a further 12 at 4 months), leaving 30 patients in the ST group and 42 in the CT group, respectively. In total, 30 patients were in the ST group (15 males and 15 females) and 42 patients in the CT group (27 males and 15 females). Their mean ages were 66.03 (S.D. = 11.46) and 65.80 years (S. D. = 10.55), respectively. Most patients were single/widowed (66.64%/59.52%) and worked in agriculture (50.0%/52.38%). Mean PPS scores were 79.33 (S.D. = 5.83) and 80.23 (S.D. = 12.78), respectively. Table 1 displays fuller demographic characteristics of the 72 CCA patients.

Comparison of variables in EORTC QLQ-C30, QLQ-QLQ-BIL21 at the pre-treatment, 2 ^nd and 4 ^th month treatment ( Table 2).

This study aimed primarily to compare health-related quality of life (HRQoL) between patients with advanced cholangiocarcinoma receiving standard palliative care (ST) versus those receiving medicinal cannabis treatment (CT). This is the first multi-center study in Thailand to explore this comparison in a real-world clinical setting. Although the two groups had similar HRQoL scores at baseline, the CT group consistently reported better global health status, functional outcomes, and lower symptom burden at the 2- and 4-month follow-ups.

To our knowledge, this is the first multi-center study comparing the effects of standard palliative care versus medicinal cannabis treatment on QoL on patients with advanced CCA. The two groups had little difference at baseline but at 2- and 4-month follow-ups the CT group consistently self-reported higher global health status and functional behaviors, and lower illness/symptom-related scores than the standard palliative-care group.

The CT regimen for our CCA patients was associated with meaningful improvements in health-related QoL consistent with previous improvements seen in pain reduction, quality of life, social life, and activity levels with other chronic pain patients. ²⁸ From the second month of treatment our CT patients rated improvements in fatigue levels, insomnia, appetite loss, constipation, eating tiredness and weight loss. There was also a significant improvement in dyspnea at the fourth month, maybe due to cannabis’ beneficial effect on appetite, sleep and rest. ²⁹ Other cannabis studies have shown more than 10% weight gain, ³⁰ and cancer patients feeling refreshed, less fatigued and having reduced side-effects such as nausea, vomiting, and loss of appetite from treatment. ³¹ Cannabinoids can also stimulate a therapeutic response via immune response enhancement. ³² This is relevant due to current standard chemotherapy treatments which increase inflammation in all body systems with consequent intellectual impairments including attention, memory, decision making, risk management, fatigue, lack of motivation and peripheral nerve inflammation. ³³ Cannabis or its derivatives have been widely used by patients with advanced cancer to help with cancer symptoms and treat side effects, ³² and patients affirm its use for pain, anxiety, depression, and significantly prefer it over antianxiety medications. ³⁴ It is also reported as useful for nausea, sleep, appetite stimulation, ³⁴ and even at one-month follow-up, most parameters have been shown to improve significantly from baseline, including pain intensity, affective and sensory pain, sleep quality and duration, cancer distress, and both physical and psychological symptom burden. ¹⁵

We found no inter-group differences in pain ratings between the second- and fourth-month follow-ups. Pain is one of most common symptoms associated with cancer, ¹⁰ and is one of the symptoms patients fear most. ¹¹ Unrelieved pain denies patients comfort and greatly affects their activities, motivation, social interactions, and overall quality of life. ¹² Pain management goals are, therefore, is to reduce pain to a level that allows for an acceptable quality of life, and both CT and ST treatments appeared to do this satisfactorily. The benefit of pain relief must be balanced against the risk of adverse side-effects and overdose. Opioid analgesics are essential for the adequate treatment of moderate and severe cancer pain, however, despite good opioid control of baseline pain, some patients do have short-term, short-lived, intense pain episodes. A recent study on cannabis palliative care in oncology patients, had similar findings, suggesting that medical cannabis reduced chronic or neuropathic pain in advanced cancer patients ¹¹ with significant improvements in other assessed parameters, including reduced pain intensity, improved sleep, and a decrease in pharmaceutical analgesics consumption. ³³

There was no inter-group difference in anxiety ratings between the second- and fourth- month follow-ups for our patient groups. Anxiety is common in cancer patients and greatly influences survival rate, adherence to treatment, and quality of life. Advanced stage cancer patients, and those with metastasis, are more likely to have higher levels of anxiety than those with no sign of metastasis. ³⁵ Some research on cannabis use in surviving cancer patients has found it alleviated 41.6% of anxiety symptoms, ³⁶ however, research on cannabis use for anxiety and depression is currently limited, and there are many confounding factors. In addition, depression and anxiety are both normal and common responses to a cancer diagnosis, and therefore diagnosing clinical levels of anxiety and studying treatments to address these levels in the context of cancer is difficult. ³⁷

In addition to quality-of-life outcome differences between ST and CT, research also shows a range of potential patient CT palliative-care access issues. Most patients need oncologist or primary care physician consultations. Thus, the primary care physician needs to be qualified and have good knowledge and a positive attitude towards the use of cannabis treatment among these patients. In an Australian study, most doctors felt their own knowledge was inadequate and only 28.8% felt comfortable discussing medicinal cannabis with patients. GPs generally rated their medical cannabis knowledge as poor and shared care arrangements with a specialist, though supported medical cannabis use in chronic cancer pain and palliative care. ³⁸ Four themes were found to underpin reluctance to authorize medical cannabis in Canada; presumed lack of evidence, indications for therapeutic use, discomfort with therapeutic use and practitioner’s openness to emerging evidence. ³⁹ Importantly, patients deciding to use cannabis to alleviate cancer symptoms, desired the approval from their medical team. While some patients found their physicians were willing to prescribe cannabis, or, refer them to a medical cannabis expert, some found their physicians were unwilling to discuss a cannabis option for managing their cancer symptoms ⁴⁰ and, were not ready, or, did not want to answer patients’ questions about medical cannabis. ⁴¹ Some clinicians feel hampered by a lack of clinically relevant information about cannabis use, efficacy, side-effects and have difficulty discussing the medicinal benefits of cannabis in a clinical settings. ⁴² Another study found only 30% of oncologists felt sufficiently informed to make recommendations regarding medical cannabis treatment. ²⁹

Most patients with advanced cancer experience symptoms throughout the disease trajectory, often with greater intensity as death approaches. If poorly managed, such symptoms can have a considerable impact on patients’ ability to function, their quality of life and ability to comply with anticancer treatments and use of health care resources. ¹² Medical cannabis is another option to relieve symptoms caused by the cancer itself, direct or indirect consequences of the cancer, early or late adverse effects of treatment, and/or comorbid conditions cancer treatment, especially late stage cancer. Medical cannabis has been shown to relieve symptoms caused by cancer, to reduce chronic or neuropathic pain in advanced cancer patients ⁴³ and to improve patients’ quality of life outcomes. Past medical cannabis treatment research evidence has been inconsistent and generally limited by poor quality, with large variations in cannabis-based products limiting the ability to make direct comparisons, ⁴⁴ as well as studies lacking statistical power and with small subject sizes, and recommendations against the use of medical cannabis as a first or second line option for palliative cancer pain or when other treatments have failed. ⁴⁵ Our study, found beneficial outcomes in a range of quality of life and symptom measures for cannabis treatment over standard palliative care protocols, using standardized medical cannabis products and treatment protocols.

This study has several limitations. One is the number of patients who dropped out before study completion likely due to rapid disease progression. Most patients were elderly and suffered from advanced CCA. Newly diagnosed CCA patients typically have a poor prognosis and short-term survival due to late-stage diagnosis. Registration for the standard palliative care clinic and/or cannabis clinic in each hospital also differs across physicians. Decision-making across patients, families, at different stages of disease, organ metastasis, and for methods of treatment also varies.

To the best of our knowledge, this is the first study to compare quality of life of CCA patients who received ST or CT and were monitored before treatment commencement and at 2 ^nd and 4 ^th month follow-ups and, across 8 hospitals, and 5 provinces. Medical cannabis products and usage was standardized under the Thai Food and Drug Administration regulations. The side effects, safety, benefits and harms of this cannabis have been reviewed and certified for patient treatment, by trained and Thai registered prescribers of medical cannabis.