A Population-Based Survey to Assess Cannabis on Quality of Life among Colorectal Cancer Survivors

Background: As more states legalize cannabis for medical and recreational use, people increasingly use cannabis to treat medical conditions and associated symptoms. The prevalence and utility of cannabis for cancer-related symptoms may be claried by examining cannabis use among patients with a common cancer diagnosis. We aimed to determine the prevalence of cannabis use among colorectal cancer (CRC) survivors and its associations with quality of life (QoL) and cancer-related symptomatology. Methods: A cross-sectional survey of patient-reported QoL outcomes and behaviors, including cannabis use, was conducted within the Patient Outcomes To Advance Learning network’s (PORTAL) CRC Cohort. The cohort included a population-based sample of healthcare system members ≥ 18 years old diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2016. We assessed the association between cannabis use and QoL using the European Organization for Research and Treatment of Cancer QLQ-C30 summary score. Results: Of the 1,784 respondents, 293 (16.4%) reported cannabis use following CRC diagnosis. Current tobacco smokers were more likely to use cannabis compared to former or never tobacco smokers (adjusted odds ratio [aOR] 2.71, 95% CI 1.56 to 4.70). Greater alcohol use (> 4 drinks per month versus ≤ 4 drinks per month) was associated with cannabis use (aOR 2.17, 95% CI 1.65 to 2.85). There was an association between cannabis use and cancer stage at diagnosis, with stage 3 or 4 CRC patients more likely to use cannabis than stage 1 or 2 CRC patients (aOR 1.68, 95% CI 1.25 to 2.25). After adjusting for demographics, medical comorbidities, stage and site of CRC diagnosis, and prescription opioid use, people who used cannabis had signicantly lower QoL than people who did not use cannabis (difference of -6.14, 95% CI -8.07 to -4.20). Conclusion: Among CRC survivors, cannabis use was common, associated with more advanced stages of disease, associated with tobacco and alcohol use, and not associated with better QoL. Clinicians about cannabis use and provide evidence-based recommendations for cancer-related

4.70). Greater alcohol use (> 4 drinks per month versus ≤ 4 drinks per month) was associated with cannabis use (aOR 2.17, 95% CI 1.65 to 2.85). There was an association between cannabis use and cancer stage at diagnosis, with stage 3 or 4 CRC patients more likely to use cannabis than stage 1 or 2 CRC patients (aOR 1.68, 95% CI 1.25 to 2.25). After adjusting for demographics, medical comorbidities, stage and site of CRC diagnosis, and prescription opioid use, people who used cannabis had signi cantly lower QoL than people who did not use cannabis (difference of -6.14, 95% CI -8.07 to -4.20). Conclusion: Among CRC survivors, cannabis use was common, associated with more advanced stages of disease, associated with tobacco and alcohol use, and not associated with better QoL.
Clinicians should inquire about cannabis use among their patients and provide evidence-based recommendations for cancer-related symptoms.

Background
In 2016, there were an estimated 1.4 million people living with colorectal cancer (CRC). 1 Patients report physical and emotional complications associated with cancer treatment including nausea, vomiting, pain, depression, anxiety, and fatigue. 2,3 As more states legalize cannabis for medical and recreational use, people increasingly use cannabis to treat medical conditions and associated symptomatology. Evidence supports the use of cannabis to treat chemotherapy-related nausea and vomiting, though its effectiveness relative to traditional pharmacologic agents is unclear. 4 The role of cannabis to treat pain, 5 reduce cancer-related anorexia, 6 and improve quality of life among patients living with cancer remains inconclusive. 6,7 With legalization of cannabis for medical and recreational use, the number of people using cannabis-containing products is likely to continue to increase. As with any other addictive substance, include alcohol or tobacco, it is important that clinicians inquire about their patients' use of cannabis and to provide evidence-based recommendations to prevent or reduce adverse health effects related to cannabis use. The prevalence and utility of cannabis use for cancer-related symptoms may be Page 3/11 clari ed by examining cannabis use among patients with a common cancer diagnosis. Using a standardized and comprehensive patient-centered outcome measurement set for patients with CRC, we assessed the use of cannabis on physical and emotional health measures and quality of life (QoL) outcomes among CRC survivors. 8 We hypothesized that cannabis use would not be associated with better patient-reported functional measures nor better QoL measures.

Methods
This study was conducted within the Patient Outcomes To Advance Learning (PORTAL) network's CRC Cohort, a retrospective cohort of healthcare system members ≥ 18 years old and diagnosed with adenocarcinoma of the colon or rectum from January 1, 2010 through December 31, 2016. 9 Within the PORTAL CRC cohort, four healthcare systems in Minnesota, Colorado, California and Oregon conducted an online survey during July 2018 to October 2018 to assess patient reported QoL and behavioral factors, including cannabis use. We excluded patients with CRC who died or left the health system prior to June 2018, those without an available email address, and those with in situ CRC, prior cancer, or previous colectomy. The study was approved by the Kaiser Permanente Colorado Institutional Review Board.
Patients were invited via email to complete a survey that included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) to assess patient-reported measures of functional and symptom-related outcomes and other survey domains. 10 Demographic and medical data were extracted from health records.

Statistical Analyses
We used logistic regression to estimate unadjusted and adjusted odds ratios (aORs) and 95% con dence intervals (CIs) to compare the odds of cannabis use after CRC diagnosis to patient demographics, health behaviors, comorbidity burden, 11 and tumor characteristics.
For QoL measures, we calculated functional and symptom scales ranging from 0 to 100. 10 Functional scales included: physical, social, role, emotional, and cognitive domains. For functional scales, a higher score represented a higher or healthier level of functioning. Symptom scales included: fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea. For symptoms scales, a higher score indicated a higher level of symptomatology or worse symptoms. We calculated a QLQ-C30 summary score where higher scores indicated better functioning and fewer symptoms. 12 We used linear regression models to estimate unadjusted and adjusted mean differences and 95% con dence intervals (CI) for each score comparing people with CRC who used cannabis to people with CRC who did not use cannabis. Table 2 lists the covariates in the adjusted model. We conducted sensitivity analyses, strati ed by time from CRC diagnosis to survey completion (≤ 2 years vs. > 2 years).

Power calculation
Using PASS 15 Power Analysis and Sample Size Software (2017) (NCSS, LLC. Kaysville, Utah), we calculated that given our sample size and α = 0.05, our study had 80% power to detect a mean difference in overall QoL score of 3 or greater.
Cannabis use was more common among younger survivors, tobacco smokers, and those with greater alcohol use (Table 1). Cannabis use was more likely in patients diagnosed with stage 3 or 4 CRC than stage 1 or 2 CRC (adjusted odds ratio [aOR] 1.68, 95% CI 1.25 to 2.25).
After adjusting for demographics, comorbidities, stage and site of cancer diagnosis, and prescription opioid use, the mean summary QoL score was 6.14 points lower (95% CI -8.07 to -4.20) in people who used cannabis compared to people who did not use cannabis. People who used cannabis reported lower functioning roles (all statistically signi cant) and higher symptom scores (all statistically signi cant except for diarrhea) compared to people who did not use cannabis ( Table 2).
In a sensitivity analysis of recency of CRC diagnosis (> 2 years; ≤ 2 years), there were no statistically signi cant differences in the results by recency of CRC diagnosis. However, all estimates within ≤ 2 years of diagnoses were more extreme than estimates within > 2 years of diagnosis, indicating worse functioning and symptom severity for the cannabis use group (data not shown).

Discussion
We surveyed over 1,700 CRC survivors and found cannabis use was not associated with improved QoL or cancer-related function or symptoms compared to CRC survivors without cannabis use. Previous studies report con icting evidence regarding the use of cannabis to improve QoL among oncology patients. 6,7 Our results suggest that, although use is common among patients with CRC, they do not have improved QoL compared to non-users, even after adjusting for baseline factors. Our ndings may have differed because we limited our sample to CRC patients, potential confounding by indication (whereby more symptomatic patients were users), and because the tool used to measure outcomes in this study was developed to assess patient-centered outcomes among CRC patients. 8 Despite the observation that cannabis use was associated with lower QoL, functional status, and symptomatology, approximately 16% of patients in this study reported cannabis use, with the majority of recent users reporting medically-indicated use. As states increasingly legalize cannabis, more patients will likely use cannabis to treat cancer-related symptoms. Current evidence suggests that clinicians may lack the knowledge to properly advise patients about cannabis use, including in the context of co-use with alcohol and tobacco. In a survey of 400 oncology providers practicing across the United States, 70% reported insu cient knowledge to make clinical recommendations about cannabis use in people living with cancer. 13 A survey of 494 health care providers in Washington state found that 64.4% had limited knowledge of cannabis-containing products or where to get them. 14 Conversely, a survey of adult patients with a cancer diagnosis from a state with legalized cannabis found that 75% of respondents would like to have received education about cannabis use from their medical team, but only 15% received information. 15 Our results demonstrated that patients who used cannabis generally reported feeling worse than patients who did not use cannabis. Whether patients who used cannabis discussed their cannabis use with their medical team is unknown.
Our study has several strengths, including a well-de ned population of CRC survivors and the use of validated, CRC speci c QoL measures. 10,12 Our study limitations should also be acknowledged. The cross-sectional design does not allow us to directly evaluate effectiveness or to examine cannabis use prior to CRC diagnosis. Most of the patients surveyed would have completed treatment several years prior to receiving the survey. Interestingly, results from our sensitivity analysis found lower QoL scores among people who used cannabis and completed the survey within 2 years of their CRC diagnosis. This nding suggests increased symptomatology related to recency of diagnosis, though these results were not statistically signi cant. Patients with more severe symptoms and reduced function may be more likely to use cannabis, resulting in confounding by indication. While states are increasingly legalizing medical and recreational cannabis, it remains a United States Drug Enforcement Administration (DEA) schedule I substance. For this reason, patients may be reluctant to report cannabis use on the survey, leading to misclassi cation and attenuation of our results. Finally, the effect of cannabis on cancer-related symptoms may correlate with the potency of the tetrahydrocannabinol (THC), its ratio of THC to cannabidiol (CBD) in the cannabis product, the frequency of use (daily, weekly, monthly) and route of use (edibles, smoked). In our study, there was a wide range of frequency of cannabis use and data on THC potency or ratio was not collected in the survey thus was unavailable.

Conclusion
Cannabis use was associated with lower QoL and functional status among CRC survivors. Despite inconclusive evidence to support cannabis use to manage cancer-related symptomatology, patients will likely continue to use cannabis. Health care providers should inquire about cannabis use among their patients with cancer. They should provide their patients with current evidence-based recommendations for cancer-related symptoms and explore their patient's goals for cannabis use. In this way, clinician may better understand how to best help their patients improve their functional status, reduce their symptom burden, and maximize their patient's quality of life. Authors' Contributions: SC, AH, and HF were responsible for study conception, hypothesis generation, and manuscript writing and editing. JP conducted the data analysis. DC, CM, and PP contributed to manuscript writing and editing. All authors read and approved the manuscript.