Exploring Factors Associated With Long-Term Opioid Therapy in Cancer Survivors: An Integrative Review.

ObjectiveTo investigate the relationship between treatment modality and chronic opioid use in a large cohort of patients with head and neck cancer.Study DesignRetrospective cohort study.SettingSing...

Implications of Treatment Modality on Chronic Opioid Use Following Treatment for Head and Neck Cancer

The demographics of head and neck cancer (HNC) survivors are changing, contributing to a growing number of survivors and a greater length of survivorship. Curative treatment involves intense multimodal therapy, which contributes to both short-term toxicities and long-term treatment-related effects. Delivering high-quality, relevant cancer survivorship care is a growing national priority. Various survivorship models and tools, such as survivorship care plans, have been utilized in an attempt to enhance care and optimize outcomes. However, an essential, yet understudied, component of high-quality survivorship care is the identification and management of late and long-term treatment-related effects. In this article, we will describe the current advancements in survivorship care as well as the research related to late and long-term treatment effects. While there is a growing body of literature that describes the prevalence of treatment-related effects and their impact on quality of life, more work is needed. Research that investigates the interplay of these complex treatment effects, the biological mechanisms that contribute to their variability, and interventions designed to mitigate them are desperately needed. While de-intensification offers the potential to alleviate these effects for future survivors, we need clinically meaningful assessment tools and therapies to provide the survivors we evaluate and treat daily. Targeted patient-reported outcomes and objective measures validated through clinical research are needed to help us systematically identify and treat late and long-term effects. In order to tailor and optimize the care we provide to our HNC survivors, we will need to leverage these tools as well as the expertise of all members of our multidisciplinary survivorship teams.

Late and Long-Term Treatment-Related Effects and Survivorship for Head and Neck Cancer Patients

Background Survivors of head and neck cancer (HNC) have increased risk of opioid misuse. Methods Using Surveillance, Epidemiology and End-Results-Medicare data, we matched adults ≥66 years diagnosed with HNC 2008-2015 with cancer-free controls. We computed odds ratios (OR) for receipt of chronic opioid therapy (COT, claims for ≥90 consecutive days) for HNC survivors compared to controls each year after matching through 2016. Results The cohort of HNC survivors declined from 5107 in the first year after diagnosis to 604 in the sixth year after diagnosis. For 5 years, rates of COT among HNC survivors exceeded that of controls. Differences between survivors and controls declined each year (ORs: year 1, 4.36; year 2, 2.60; year 3, 2.18; year 4, 1.85; and year 5, 1.35; all P-values Conclusions Among older HNC survivors, cancer-associated opioid use in the first years after diagnosis suggests that the benefit of opioids must balance the risk of opioid misuse.

Trends in chronic opioid therapy among survivors of head and neck cancer.

Background The use of opioids in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is associated with shorter survival and not dependent on the expression of the mu-opioid receptor (MOR). The role of opioid use and MOR expression in stage I-III PDAC has not been investigated. Methods We conducted retrospective study in patients with stage I-III PDAC. MOR expression and OPRM1 gene expression in tumour tissue and non-tumour tissue was measured. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Secondary endpoints included perineural invasion, intraoperative sufentanil consumption, and length of stay. We performed a subgroup group analysis to evaluate the interaction between levels of MOR expression, amount of opioids use (high versus low) and its association with survival. Results A total of 236 patients were enrolled in this study.There were no significantly difference in OS rates in patients with high versus low levels of MOR (1-year OS: 65.2% versus 70.6%, P=0.064; 3-year: 31.4% versus 35.8%, P=0.071; 5-year: 19.4% versus. 16.2%, P=0.153, respectively) in the tumours. The DFS rates between the groups were no significantly difference. Of note, a high expression of MOR combined with high opioid consumption was associated with poor prognosis in stage I-III PDAC patients. Tumor expressing high levels of MOR show higher rates of perineural invasion. Conclusion MOR is not an independent predictor of poor survival in stage I-III PDAC but associated with perineural invasion. Patients requiring high amounts of opioids intraoperatively show worse outcome if they are expressing high levels of MOR.

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Association of Mu-Opioid Receptor(MOR) Expression and Opioids Requirement With Survival in Patients With Stage I-III Pancreatic Ductal Adenocarcinoma.

Background Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use. Methods After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use. Results A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery. Conclusions Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use.

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma.

The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and metastasis in lung cancer cell lines. The effect of MNTX on other cell lines such as head and neck squamous cell carcinoma (HNSCC) has not been investigated. We measured the expression and activity of the receptor in different HNSCC cell lines. Then, we evaluated the impact of modulating the expression MOR and the effect of MNTX on the proliferation, clonogenic activity, invasion, and migration of two HNSCC (FaDu and MDA686Tu) cell lines expressing MOR and one cell line (UMSCC47) not expressing the receptor. We also evaluated the impact of MNTX on tumor growth and metastasis formation in vivo. Activation of the receptor with [d-Ala2,N-Me-Phe4, Gly5-ol] (DAMGO) caused a significant reduction in cyclic adenosine monophosphate levels in FaDu cells. Knockdown of MOR inhibited in vitro aggressive cell behaviors on FaDu and MDA686Tu cells and correlated with a reduction in markers of epithelial-mesenchymal transition. In vitro studies showed that MNTX strongly inhibited the proliferation, clonogenic activity, invasion, and migration of FaDu and MDA686Tu cells but has no effect on UMSCC47 cells. In vivo experiments demonstrated that MNTX suppresses tumor growth in HNSCC cell tumor-bearing mice. Our studies indicate that MOR could be considered as a therapeutic target to treat HNSCC.

Miguel Patino

Papers

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma.

Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu-opioid receptor.