Non-steroidal anti-inflammatory drugs (NSAIDs) appear to shorten overall and progression-free survival in people being treated for metastatic renal cell carcinoma (mRCC), a pooled retrospective analysis found.
Among 4,736 patients receiving targeted therapy for mRCC in phase II and III clinical trials, overall survival (OS) and progression-free survival (PFS) were significantly less in those who used non-aspirin NSAIDs compared with those who did not use NSAIDs (OS hazard ratio [HR] 1.47, P< 0.0001; PFS HR 1.29, P< 0.0001), researchers reported in Kidney Cancer.
Median OS among users of non-aspirin NSAIDs such as ibuprofen compared with those who did not use NSAIDs was 11.6 versus 21.1 months, while median PFS was 4.6 versus 7.4 months, respectively, according to the study by Rana R. McKay, MD, of the University of California San Diego Moores Cancer Center, and colleagues.
Overall survival was significantly shorter in users of non-aspirin NSAIDs compared with non-users of NSAIDs in untreated or previously treated patients, and across groups irrespective of the type of targeted therapy received, either vascular endothelial growth factor (74%), mammalian target of rapamycin (14%), or interferon alpha (12%), the team reported.
“The clinical trials database utilized in our analysis is a powerful tool to investigate clinically relevant questions,” McKay said in a news release. “In the era of drug repurposing, evaluating the impact of agents that have the potential to demonstrate anti-cancer activity in patients is clinically meaningful.
“Our study, which is the largest to date investigating the impact of NSAIDs on mRCC, demonstrates that the use of non-aspirin NSAIDs reduced overall or progression-free survival time for patients with metastatic disease, compared with patients who do not use NSAIDs.”
This contrasts, however, with the results of prior studies suggesting that NSAIDs have anti-tumorigenic activity in several cancers, particularly in colorectal cancer, McKay et al noted. These effects are thought to be due to inhibition of cyclooxygenase (COX)-2, which suppresses prostaglandin synthesis and ultimately decreases inflammation, as well as additional COX-independent mechanisms.
Aspirin, unique among NSAIDs in irreversibly inhibiting COX-1 and COX-2, did not confer a survival advantage or have an apparent anti-cancer effect for mRCC patients; survival rates for patients who used aspirin only or aspirin and non-aspirin NSAIDs did not differ from the survival rates of the non-NSAID users.
In RCC, COX-2 expression is present in most tumors, and is associated with worse stage, grade, and microvessel density and poorer survival, the researchers explained. However, non-aspirin NSAIDs, unlike aspirin, have also been implicated as a risk factor for RCC development.
“Other studies have shown mixed results with regards to the impact of NSAIDs,” McKay told MedPage Today via email. “Underlying cancer histology and disease pathogenesis may be an important factor here. No study has previously evaluated the effect in renal cancer. Patients with RCC may be particularly susceptible to the negative impact of NSAIDs, especially on renal function.”
Dose reductions (31.3%) and treatment discontinuations (14.3%) due to adverse events were similar across the cohorts.
At study entry, most patients (69%) were younger than 65 and male (71%), with good performance status (98%); 70% had undergone removal of one or both kidneys, and 67% had not had drug treatment prior to the study.
The four groups of patients — users of aspirin only (10%), non-aspirin NSAIDs (13%), aspirin and non-aspirin NSAIDs (1%), and no NSAIDs (76%) — were not balanced in terms of baseline and disease characteristics, the researchers noted.
Other limitations, the team added, included the small number of patients using both aspirin and non-aspirin NSAIDs (n = 61), and the fact that the database was not designed to capture the duration, dosage, or constituents of the drugs used.
“While thought-provoking, these results should be interpreted cautiously as hypothesis-generating rather than definitive, and highlight the need for studies investigating the mechanisms of action underlying our observation,” the group wrote.
“The key message is for practitioners to be conscious of the risk and benefit of concurrent medications that their cancer patients are taking,” McKay added.
Regarding the divergence from other data suggesting NSAIDs’ anti-tumorigenic benefits, David Topolsky, MD, of Cancer Treatment Centers of America in Philadelphia, who was not involved with the study, echoed McKay et al’s suggestion that in RCC, the dose of NSAID to achieve the anti-inflammatory/analgesic effect may be less than that needed to achieve an anti-tumor effect and/or that the negative effect on renal function diminishes the effectiveness of the targeted therapy.
Topolsky told MedPage Today that further study is needed, and that “for now, I would not make a major change in the way I treat RCC with supportive drugs, but I would be more cautious about the use of non-aspirin NSAIDs for analgesia. If I believe that there is a need for a non-opioid analgesic or nonsteroidal anti-inflammatory, I would first consider aspirin before a NSAID.”
The study was supported by Pfizer; the Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Program of Research Excellence; and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute.
McKay reported institutional research funding from Pfizer and Bayer. Other co-authors reported financial relationships with Pfizer, Novartis, GlaxoSmithKline, Genentech, Merck, Bayer, and Onyx. One co-author is a Pfizer employee, and another is a former employee.