Abstract
Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity.
Highlights
From 1975–2014 in the US, 5-year relative survival for invasive ovarian cancer has increased from33.6% to 46.8% [1]
Cyclooxygenase (COX) inhibitors have been largely studied for cancer chemoprevention [26,27,28,29], but new evidence suggests that women who used non-steroidal anti-inflammatory drugs (NSAIDs) after an ovarian cancer diagnosis had improved disease-specific survival compared with never-users [30,31]
In one breast center (n = 172 patients), ketorolac/diclofenac was a strong predictor of recurrence-free survival (multivariate adjusted HR = 0.2, 95%CI = 0.07–0.4) with recurrences reported in 6.9% of NSAID users at 60 months relative to 29.6% of non-users (p-value < 0.001)
Summary
From 1975–2014 in the US, 5-year relative survival for invasive ovarian cancer has increased from. Annual age-adjusted death rates have dropped from 9.84/100,000 to 6.74/100,000 paralleling a drop in incidence in the same time period [1], but this mortality drop is modest relative to the 5-year survival increase. Ovarian cancer remains the leading cause of death from gynecologic malignancy, primarily due to the emergence of drug resistant disease following front-line surgery and systemic chemotherapy [3,4,5,6,7,8]. The mainstays of ovarian cancer treatment include a defined combination of surgery and chemotherapy. The peri-operative period has received greater attention as a unique and largely overlooked opportunity for intervention in cancer treatment. Retrospective studies provide support for greater attention on the peri-operative window, randomized-control clinical trials are needed to resolve the potential of peri-operative strategies to improve cancer patient outcomes. We discuss supporting evidence of the benefits of peri-operative ketorolac administration in cancer patients and underlying mechanisms that may account for these observations in ovarian cancer
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