P2-01-06: NSAID Analgesic Ketorolac Used Perioperatively May Suppress Early Breast Cancer Relapse: Something for Nothing in Breast Cancer?
Authors: Retsky MW , Rogers RA , Demicheli R , Hrushesky WJM , Gukas ID , Vaidya JS , Baum M , Forget P , De Kock M 
Published: June 2012

Background: Over a decade ago, we were confronted with data that showed an unexpected bimodal pattern of hazard of relapse among early stage breast cancer patients treated by mastectomy without any adjuvant systemic treatment. This pattern has now been identified in 20 independent databases from US, Europe and Asia. There is an early peak of relapses at 18 months, a nadir at 50 months and a broad second peak extending from 60 months to over 15 years. Fifty to eighty percent of relapses, the proportion increasing with primary tumor size, reside within the first peak. This pattern was not explainable by accepted theories. We proposed based on computer simulations that the broad second peak relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. To explain the first peak, we had to postulate that something happened at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. There was a particularly sharp early relapse mode within 10 months for premenopausal patients with positive nodes that appeared to be surgery-induced angiogenesis of dormant avascular micrometastases. We have been able to explain a wide variety of breast cancer observations with this hypothesis. These include high effectiveness of adjuvant chemotherapy only for premenopausal node positive women and why early detection works better for women age 50–59 than for women age 40–49.

Methods and Materials: Forget et al reported data from a retrospective study of 327 consecutive patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Follow-up is average 27.3 months with range 13–44 months. Results: NSAID ketorolac, a common analgesic used in surgery, produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse peak is all but absent. These results are superior to any adjuvant therapy we have examined. Discussion: If this observation holds up to further scrutiny, it could mean that the simple use of this safe and effective anti-inflammatory agent at surgery might eliminate early relapses. Concerning a possible mechanism, since ketorolac is the only anti-inflammatory agent among the analgesics studied, our attention is drawn to inflammation. Might this imply that transient systemic inflammation accompanying surgery is part of the metastatic tumor seeding process? Inflammation can be a very rapidly occurring effect since bump and redness following a mosquito bite occur within seconds. It is well established that many cancer patients have circulating cancer cells. Data show a surge in circulating epidermal cells after primary breast cancer surgery but that intriguingly occurs days later. Blood speed in capillaries is 0.03cm/sec which would make leaky capillary venules a very efficient way for circulating cancer cells to enter tissue. From our simulations the few relapses in the ketorolac data look like the leading edge of the late broad peak — viewable for the first time.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-06.