The effect of opioids on the efficacy of immunotherapy in recurrent/ metastatic squamous cell carcinoma of the head and neck

Objectives: Head and neck squamous cell carcinoma (HNSCC) causes severe pain and opioids, the mainstay of pain management, may have immunomodulatory effects. We evaluated the effect of opioids on immunotherapy efficacy in recurrent/metastatic (R/M) HNSCC patients.Materials and Methods: In a retrospective study of 66 R/M HNSCC patients from 2015 to 2020, opioid dosage, calculated as mean morphine milligram equivalent per day, was assessed on the day of anti-PD-1 monoclonal antibody (mAb) treatment and most recent prior visit. Intratumoral T cells were evaluated by single cell RNAseq and immunohistochemistry prior to treatment. Univariable and multivariable Cox proportional hazards and logistic regression models were used to estimate the association between opioid usage, progression-free survival (PFS), overall survival (OS), disease control rate.Results: Patients were 79% male, 35% oropharynx, 35% oral cavity, 40% locoregional recurrence, and 56% platinum failure. Higher opioid dosage by continuous variable was significantly associated with lower PFS (p = 0.016) and OS (p < 0.001). In multivariable analysis, including platinum failure status and PD-L1, higher opioids were associated with lower OS. Opioid usage by categorical variable was associated with significantly lower intratumoral CD8+ T cells. Opioid receptor, OPRM1, expression was identified in intratumoral and circulating T cells.Conclusions: In our study cohort of anti-PD-1 mAb treatment in R/M HNSCC patients, higher opioids were associated with significantly lower PFS and OS and lower CD8+ T cells in the tumor microenvironment. To our knowledge, this is the first analysis in R/M HNSCC patients and further research into the clinical and biologic effect of opioids is warranted.