Although concurrent chemotherapy and radiation is considered standard care, treatment of locally advanced NSCLC continues to be challenging, leading researchers to search for patients who may benefit from the addition of cyclooxygenase 2 inhibitors.
A phase II randomized study failed to demonstrate the value of adding celecoxib (Celebrex) to concurrent chemoradiation (CCCRT) for patients with unresectable, inoperable, locally advanced non-small cell lung cancer (NSCLC), according to a report published in JAMA Network Open.
Though the treatment was well tolerated and reduced the risk of symptomatic radiation pneumonitis by 44%, the difference was statistically insignificant.
In this cohort of 96 patients with histologically and cytologically confirmed unresectable stage III NSCLC, 51 participants were randomized to CCRT alone and 45 were randomized to CCRT with celecoxib at 400 mg per day. The median overall survival (OS) time was 32.8 months (95% CI, 17.0-48.5) months in the group that received CCRT with celecoxib and 35.5 months (95% CI, 25.8-45.2) in the group that only received CCRT (P = .88).
Patients who received the cyclooxygenase 2 (COX-2) inhibitor celecoxib in combination with CCRT tolerated the treatment well. The incidence of symptomatic radiation pneumonitis was 6.6% (95% CI, 1.4%-18.0%) in the group that received CCRT with celecoxib and 11.8% (95% CI, 4.4%-23.9%) in the group that received CCRT alone (P = .49).
“In the era of molecular targeted therapy, the optimal selection of patients who may benefit from a combined strategy of COX-2 suppression and CCRT appears to be critical,” the authors wrote. “However emerging evidence indicated that it seems inappropriate to use this method for patient selection, which is possibly because of tumor heterogeneity as well as potential subjectivity of immunohistochemistry evaluation.”
In patients who had the high-risk genotype, celecoxib plus CCRT was not associated with higher progression-free survival (hazard ratio [HR], .36; 95% CI, 0.13-1.04; P = .05) or OS (HR, .50; 95% CI, .15-1.72; P =.26) compared with CCRT by itself.
In a predefined analysis, researchers found that the COX-2-1195dupA genotype could be associated with benefit from the combination of celecoxib and CCRT. This genotype was identified in 30.2% of the assessable blood samples. “We previously identified that the genetic polymorphisms in the COX-2 gene were associated with outcomes in patients with local advanced NSCLC treated with chemoradiotherapy or radiotherapy alone,” the authors wrote. “This concept is now confirmed for the first time in a prospective trial.”
The authors indicated that this could potentially explain the negative results presented in the entire group, because the positive effect among patients with the high-risk genotype might have been obscured by the negative effects on those with the low-risk genotype. Furthermore, it was the rationale of the researchers that a more intensive treatment, such as a combination of chemotherapy and COX-2 inhibition, could increase the survival in patients with the unfavorable COX-2-1195dupA genotype.
These results may be noteworthy in designing further clinical trials of COX-2 inhibitors.
Approximately 30% of patients with NSCLC have locally advanced disease, according to the authors. Although concurrent chemotherapy and radiation is considered standard care, treatment of locally advanced NSCLC remains challenging, with a survival rate of less than 20% at 5 years.
Bi N, Liang J, Zhou Z, et al. Effect of Concurrent Chemoradiation With Celecoxib vs Concurrent Chemoradiation Alone on Survival Among Patients With Non-Small Cell Lung Cancer With and Without Cyclooxygenase 2 Genetic Variants. JAMA Network Open. doi:10.1001/jamanetworkopen/2019.18070.