Survival and response outcomes in patients with recurrent/metastatic head and neck cancer treated with opioids and statins: an exploratory pilot study
Brief Report

Survival and response outcomes in patients with recurrent/metastatic head and neck cancer treated with opioids and statins: an exploratory pilot study

Elihu Igbinadolor1, Tyler J. Kristoff2,3, Dong M. Shin2,3, Conor E. Steuer2,3, Nabil F. Saba2,3, Nicole C. Schmitt2,4 ORCID logo

1Emory University School of Medicine, Emory University, Atlanta, GA, USA; 2Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA; 3Winship Cancer Institute, Emory University, Atlanta, GA, USA; 4Department of Otolaryngology-Head and Neck Surgery, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA

Correspondence to: Nicole C. Schmitt, MD. Director for Translational Research, Head and Neck Program, Professor of Otolaryngology-Head and Neck Surgery, Department of Otolaryngology-Head and Neck Surgery, Winship Cancer Institute, School of Medicine, Emory University, 550 Peachtree Street NE, 11th Floor Otolaryngology, Atlanta, GA 30308, USA; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA. Email: Nicole.cherie.schmitt@emory.edu.

Abstract: Anti-PD-1 immune checkpoint blockade (ICB) is a common first-line treatment for patients with recurrent/metastatic head and neck cancer (HNC), but many patients fail to respond. There is a growing interest in the impact of concomitant medications on responses to ICB, with studies in other tumor types showing poor responses in patients taking opioid pain medications and modest improvements in response to ICB in patients taking statins for hyperlipidemia. Our previous preclinical and retrospective clinical data suggest that use of specific statin drugs is associated with increased responses to ICB in HNC, and emerging studies suggest that opioids may have the opposite effect. In this retrospective cohort study, pharmacy records were searched for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) treated at our institution with pembrolizumab or nivolumab from 2015 to 2022. We recorded whether patients were taking opioid pain medications upon initiation of ICB or later during ICB therapy. Response to ICB was determined by reviewing routine surveillance imaging. A total of 158 patients met inclusion criteria; 102 were taking opioids, and 44 were taking statins. There was no difference in objective response rate (ORR) based on opioid use at the start of immunotherapy (P=0.74). There was also no significant difference in progression-free survival (PFS; P=0.14), though patients not taking opioids had superior overall survival (OS; median OS 20.67 versus 13.5 months in opioid users, P=0.002). Interestingly, use of both drugs together was associated with improved ORR [odds ratio (OR) =2.8], and use of opioids without statins was associated with worse ORR (OR =0.34), though these results did not reach statistical significance (P=0.06). Patients taking both statins and opioids had superior PFS versus patients taking either drug class alone (P=0.02). Our data suggest a complex relationship between statins and opioids in HNSCC patients treated with ICB. Larger, prospective clinical studies are needed to verify these results, and preclinical studies are needed to determine how opioids and statins impact T-cell function and other aspects of the tumor microenvironment.

Keywords: Opioids; statins; immunotherapy; immune checkpoint blockade (ICB); head and neck cancer (HNC)

Submitted Sep 15, 2025. Accepted for publication Nov 28, 2025. Published online Jan 22, 2026.

doi: 10.21037/tcr-2025-2041

Introduction

Anti programmed cell death 1 (PD-1) immune checkpoint blockade (ICB) has become a common first line therapy for head and neck cancer (HNC) because of the growing literature on their efficacy (1), particularly when local control options such as salvage surgery and re-irradiation are not feasible or have failed, but only 18% of patients typically respond in the recurrent/metastatic setting (2). There is an unmet clinical need for predictors of response to ICB, and a growing interest in the impact of concomitant medications on responses to ICB. Our previous preclinical and retrospective clinical data suggest that use of specific statin drugs is associated with increased responses to ICB in HNC (3,4), and the literature at large supports this finding (5-8). Interactions of opioids with the immune system have also been described, but a conclusive positive or negative effect on the immune system remains unclear and may even be specific to each opioid (9). Because of the painful nature of HNC, many patients undergoing therapy are also prescribed opioids for pain control. Although some preclinical and clinical studies suggest that opioids may dampen the efficacy of ICB in HNC (10), the effects of opioids have not been extensively studied in this patient population.

We hypothesized that opioid use in patients treated with ICB would be associated with lower response and survival, and that statin drugs might in part mitigate these differences. We performed a retrospective, single-institution, observational study of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) treated with ICB, to see what impact opioid use had on ICB response. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2041/rc).

Methods

Study approval

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board (IRB) of Emory University (No. #00004222). Written informed consent was waived by the IRB.

Patient characteristics and records search

Patients at Winship Cancer Institute who received at least 3 doses of pembrolizumab or nivolumab between January 2015 and December 2022 were selected for the study. Patients were identified via pharmacy records, as previously described (4). Patients were excluded if they received less than three doses, had insufficient data recorded, or also received other anticancer agents on a clinical trial (11). We recorded clinicopathologic characteristics including stage and p16 status, programmed cell death ligand 1 (PD-L1) status (combined positive score), body mass index, and concurrent use of chemotherapy, radiation, and other treatments. We also recorded whether patients were taking opioid pain medications upon initiation of ICB or later during ICB therapy. Response was determined via retrospective review of clinical notes and imaging reports and was defined as a partial or complete response during the first six months of therapy. Progression-free survival (PFS) was defined as the time from initiation of immunotherapy to disease progression or death from any cause, and overall survival (OS) was defined as the time from initiation of immunotherapy to death from any cause.

Statistical analyses

Chi-squared test was used to compare response according to opioid use, and log rank test was used to compare survival outcomes. Results were further stratified by statin usage, as our previous retrospective clinical data showed that statins independently increased responses to ICB in HNC (4). A P value of <0.05 was considered statistically significant for all analyses. All analyses were conducted using GraphPad Prism software.

Results

A total of 350 records were reviewed, and 158 patients met inclusion criteria (treatment with at least 3 doses of ICB); 102 patients were receiving opioids, and 44 were receiving statins. Median follow-up was 11.8 months. Our prior data showed that statins are independently associated with response to ICB, with no significant effect of statins alone on survival (4). Patient demographics and disease characteristics according to opioid use are listed in Table 1. Although groups according to opioid use were similar according to most variables, opioid users were more likely to be of Black race and have worse performance status.

Table 1

Baseline patient characteristics according to opioid use

Covariate Total (n=158), n (%) Opioid use at start of immunotherapy, n (%) P value†
No (n=72, 45.6%) Yes (n=86, 54.4%)
Gender 0.34
   Female 37 (23.4) 14 (19.4) 23 (26.7)
   Male 121 (76.6) 58 (80.6) 63 (73.3)
Race 0.01
   White 104 (65.8) 56 (77.7) 48 (55.8)
   Black 32 (20.2) 9 (12.5) 23 (26.7)
   Other 22 (13.9) 7 (9.7) 15 (17.4)
Drug prescribed 0.53
   Pembrolizumab 120 (75.9) 53 (73.6) 67 (77.9)
   Nivolumab 38 (24.1) 19 (26.4) 19 (22.1)
ECOG baseline <0.001
   0–1 116 (80.0) 64 (92.8) 52 (68.4)
   2–3 29 (20.0) 5 (7.2) 24 (31.6)
irAEs 0.01
   No 102 (64.6) 54 (75.0) 48 (55.8)
   Yes 56 (35.4) 18 (25.0) 38 (44.2)
Objective response 0.54
   No 129 (81.6) 57 (79.2) 72 (83.7)
   Yes 29 (18.4) 15 (20.8) 14 (16.3)

†, the P value is calculated by either parametric (Chi-squared) or non-parametric (Fisher’s exact) test, where appropriate. ECOG, Eastern Cooperative Oncology Group; irAEs, immune-related adverse events.

We began our data analysis by stratifying our sample according to opioid use versus no opioid use. Opioid use had no effect on objective response rate (P=0.74) or PFS (P=0.14). Patients not taking opioids had superior OS (median OS 20.67 versus 13.5 months in opioid users, P=0.002).

We then further stratified opioid users by statin use, seeking to control for the known benefit of statins on ICB response (5-8).Use of both classes of drugs was associated with improved ORR [odds ratio (OR) =2.8], and use of opioids without statins was associated with worse ORR (OR =0.34), but these results did not reach statistical significance (P=0.06); a post-hoc power analysis indicated less than 50% power to detect differences of this magnitude with alpha of 0.05 (Figure 1). Patients taking both statins and opioids had superior PFS versus patients taking opioids alone [hazard ratio (HR) =1.88 with 95% confidence interval (CI) of 1.114 to 3.172, P=0.02] (Figure 2). OS had a similar trend as PFS in these groups, that also did not quite reach significance (HR =1.618 with 95% CI of 0.937 to 2.794, P=0.08), with a post-hoc power analysis indicating 79.5% power to detect a difference in 5-year survival of this magnitude with alpha of 0.05 (Figure 3). It is notable that patients taking opioids without statins were significantly more likely to have a lower performance status (P=0.003, Table S1).

Figure 1 Rate of objective response by imaging, according to opioid and statin use. OR, odds ratio.
Figure 2 PFS according to opioid and statin use. PFS was significantly higher in patients taking both statins and opioids versus opioids alone; all other comparisons were not statistically significant by log-rank test. PFS, progression-free survival.
Figure 3 Overall survival according to opioid and statin use. All comparisons were not statistically significant by log-rank test. OS, overall survival.

Discussion

Statins have recently been associated with responses to ICB in HNC and other solid tumors, whereas opioids have shown the opposite association. Use of opioids had no effect on ORR, nor PFS in our overall dataset. Opioid use did predict a decreased OS. This result is likely confounded by the significantly lower performance status of the opioid users (Table 1) in addition to other confounding factors. Lower Eastern Cooperative Oncology Group (ECOG) performance status suggests increased disease burden and/or comorbid conditions.

The use of opioids and statins together was associated with increased PFS (P=0.02). The use of opioids and statins also showed trends toward improved ORR and OS that did not reach statistical significance (P=0.08 and P=0.06, respectively). Opioid use without statin use trended toward worse ORR, again not quite statistically significant at P=0.06, suggesting that statins may somehow negate the negative impact of opioids. However, our study did not have sufficient statistical power to show these associations definitively or to run a multivariable analysis to explore other confounding variables.

Statins have been shown to independently improve response to ICB (4-6) and have been associated with improved outcomes in HNC (12-16). Our data suggests this benefit from statins may be most prominent in opioids users. Uncovering the mechanisms behind this modulation first requires knowledge on the mechanisms by which statins interact with ICB, which we are just beginning to understand. The literature describes several of these mechanisms, including improvement of the tumor microenvironment by increasing CD8+ T cells, favorable macrophage polarization, and other mechanisms (3,7,8,17-20); attenuating cholesterol’s inhibition of TCR signaling (21); and inhibition of mTOR signaling (22,23).

Some studies suggest the activation of mu opioid receptors on immune cells downregulate their activity in vitro, in animal studies, and in patients (24,25). Other studies looking at κ receptors have seen that their activation increases T-cell proliferation in vivo (26), but not in vitro (27). There is research suggesting low doses of opioids can stimulate natural killer cells (28), while high doses inhibit them (29). Some studies have suggested decreased efficacy of anti-PD-1 ICB with concomitant opioid use, including another single-institution cohort of HNC patients (10,30). The overall impact of opioids on cancer outcomes is also unclear. Many studies show a negative impact of opiates on cancer outcomes but cannot match control to opioid groups, leaving the door open to the same confounder as seen in the present study: increased disease burden requiring increased pain medication (25,31). For now, we can only speculate about the possible mechanisms driving the complex interactions among statins, opioids, and ICB.

Our findings suggest that opioids might positively modulate the effects of statins on ICB, or vice versa. These findings are somewhat counterintuitive and warrant further pre-clinical and clinical studies to elucidate the complex interaction between opioids and statins in the setting of ICB therapy. Clinically, our findings, if validated in larger studies, could be used to guide pain management decision making in the setting of HNC. If a patient is on ICB and statin therapy, they may not exhibit deleterious effects from pain management with opioids.

Strengths of our study include long-term follow-up and a novel comparison of outcomes stratified by both opioids and statins. The main limitations of our study are its retrospective nature and small sample size, which likely limited our ability to find statistical significance when stratifying the data by opioid and statin use simultaneously. Our sample size also provided insufficient statistical power to run a multivariate analysis incorporating statins, opioids, and other independent variables. Further, we did not thoroughly compare groups according to other important variables including nutritional status (32,33), other concomitant medications, and comorbid conditions, which can influence the need for both statins and opioids. The study was also not sufficiently powered to compare individual doses or drugs (for statins or opioids). Lastly, combined positive score (CPS) score PD-L1 staining had not yet been established when many of these patients were seen, limiting our ability to include CPS as an additional variable. Future studies may need to incorporate patients from multiple institutions over several years to reach adequate sample size to draw more decisive conclusions on the interaction between opioids, statins, and ICB in HNC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2041/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2041/prf

Funding: This study was supported by Winship Cancer Institute and the Department of Otolaryngology at Emory University School of Medicine. This work was supported in part by the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH) under award number K24DC022077, and NIH/National Cancer Institute under award number P30CA138292. The content is solely the responsibility of the authors.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2041/coif). N.C.S. reports research funding from Taiho Oncology and National Institutes of Health; consulting for Johnson & Johnson, GeoVax, Aspargo Labs, Inc., and Regeneron; paid DSMB membership for Aspargo Labs, Inc.; and one provisional patent unrelated to this work. N.F.S. reports funding from the National Institutes of Health, and grants from Exelixis and Bristol Myers Squibb; and consulting or advisory roles for Astra Zeneca, Eisai Medical, Exelixis, Merck, Merck EMD Serono, Pfizer, Kura, Vaccinex, CUE, BionTech, GSK, TOSK, Seagen, Flamingo, Infinity , Inovio, Aveo, Medscape, Onclive, Uptodate, BMS, J&J, Johnson Cornerstone, Celldex, Surface Oncology, Urogen, Summit, Guidepoints, Astex, Imugene, Faron Pharmaceutical, Coherus, Adagene, Fulgent, Reddy Laboratories, Springer, Nanobiotix, and Taiho. C.E.S. reports honoraria from Merck; consulting or advising for Abbvie, ARMO BioSciences, AstraZeneca, Bayer, BerGenBio, Caris Life Sciences, Daiichi Sankyo/Lilly, Lilly, Mirati Therapeutics, Novocure, Sanofi/Regeneron, and Takeda; and research funding from Daiichi Sankyo, Infinity Pharmaceuticals, Seagen, and Vaccinex. D.M.S. reports research funding from Loxo/Bayer and Sensei Biotherapeutics. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board (IRB) of Emory University (No. #00004222). Written informed consent was waived by the IRB.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Igbinadolor E, Kristoff TJ, Shin DM, Steuer CE, Saba NF, Schmitt NC. Survival and response outcomes in patients with recurrent/metastatic head and neck cancer treated with opioids and statins: an exploratory pilot study. Transl Cancer Res 2026;15(1):63. doi: 10.21037/tcr-2025-2041

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