Association of COX-inhibitors with cancer patients' survival under chemotherapy and radiotherapy regimens: a real-world data retrospective cohort analysis

Abstract

Introduction: We conducted an extensive, sex-oriented real-world data analysis to explore the impact and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs) on cancer treatment outcomes. This is particularly relevant given the role of the COX-2/PGE2 pathway in tumor cell resistance to chemotherapy and radiotherapy.

Methods: The study applied a retrospective cohort design utilizing the TriNetX research database consisting of patients receiving cancer treatment in 2008-2022. The treated cohorts included patients who were prescribed with coxibs, aspirin or ibuprofen, while individuals in the control cohort did not receive these medicines during their cancer treatment. A 1:1 propensity score matching technique was used to balance the baseline characteristics in the treated and control cohorts. Then, Cox proportional hazards regression and logistic regression were applied to assess the mortality and morbidity risks among patient cohorts in a 5-year follow-up period.

Results: Use of coxibs (HR, 0.825; 95% CI 0.792-0.859 in females and HR, 0.884; 95% CI 0.848-0.921 in males) and ibuprofen (HR, 0.924; 95% CI 0.903-0.945 in females and HR, 0.940; 95% CI 0.917-0.963 in males) were associated with improved survival. Female cancer patients receiving aspirin presented increased mortality (HR, 1.078; 95% CI 1.060-1.097), while male cancer patients also had improved survival when receiving aspirin (HR, 0.966; 95% CI 0.951-0.980). Cancer subtype specific analysis suggests coxibs and ibuprofen correlated with survival, though ibuprofen and aspirin increased emergency department visits' risk. Secondary analyses, despite limited by small cohort sizes, suggest that COX inhibition post-cancer diagnosis may benefit patients with specific cancer subtypes.

Discussion: Selective COX-2 inhibition significantly reduced mortality and emergency department visit rates. Further clinical trials are needed to determine the optimal conditions for indication of coxibs as anti-inflammatory adjuvants in cancer treatment.

Keywords: COX-inhibitors; cancer survival; chemotherapy; multiarm; multistage; non-steroidal anti-inflammatory drugs; platform; radiotherapy.

Figure 1

Study flow diagram. The control cohort was formed by patients that had one of the cancers investigated and were treated with chemotherapy and/or radiotherapy without exposure to any of the NSAIDs assed (Coxibs, Aspirin, or Ibuprofen). This control cohort was then compared to NSAIDs exposed cohorts, which were only exposed to either Coxibs, Aspirin, or Ibuprofen during their oncologic treatment with chemotherapy and/or radiotherapy. Cancer-specific analyses using the same eligibility criteria and setup were performed to address the impact of these drugs on specific cancer types. The secondary analysis applied the same method to investigate the post-cancer diagnosis impact of COX-inhibitor drugs.

Figure 2

Overall survival of cancer patients that receive COX-inhibitors under chemotherapy and/or radiotherapy. (A) Kaplan-Meier curves of female patients and (B) male patients that used Coxibs under chemotherapy and/or radiotherapy. The 5-year overall survival rate was, respectively for females and males, 71.53% and 53.93% in the Coxibs group and 67.60% and 50.50% in the control group. (C) Kaplan-Meier curves of female patients and (D) male patients that used Aspirin under chemotherapy and/or radiotherapy. The 5-year overall survival rate was, respectively for females and males, 59.17% and 50.16% in the Aspirin group and 61.25% and 49.06% in the control group. (E) Kaplan-Meier curves of female patients and (F) male patients that used Ibuprofen under chemotherapy and/or radiotherapy. The 5-year overall survival rate was, respectively for females and males, 71.05% and 60.35% in the Ibuprofen group and 69.69% and 58.02% in the control group.

Figure 3

Association of COX-inhibitors with mortality in patients with specific types of cancer. Forest plots demonstrate the hazard ratios (HRs) and 95% confidence intervals (CI) associated with the use of Coxibs, Aspirin and Ibuprofen on mortality of different cancer types in female and male patients. Number of patients included in each cancer type cohort are indicated in the plots.

Figure 4

Association of Coxibs plus chemotherapy and/or radiotherapy with medication-related toxic events in cancer patients. Forest plots demonstrate the Odds ratios (ORs) and 95% confidence intervals (CI) of Coxibs association with toxic events incidence on female and male cancer patients, including emergency department visits, gastrointestinal ulcers, liver toxicity, cardiovascular and cerebrovascular events, kidney damage and hypertensive events. Number of patients included in each cancer type cohort are indicated in the plots. DR, Death Risk; ED, Emergency Department visits; GU, Gastrointestinal Ulcers; LT, Liver Toxicity; CE, Cardiovascular and cerebrovascular Events; KD, Kidney Damage; HE, Hypertensive Events.