NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: something for nothing in breast cancer? M Retsky 1,5 , R Rogers 1 , R Demicheli 2 , W Hrushesky 3 , I Gukas 4 , JS Vaidya 5 , M Baum 5 , P Forget 6 , M DeKock 6 , K Pachmann 7 1 Harvard School of Public Health, 2 Istituto Nazionale Tumori, 3 Oncology Analytics, Inc., 4 James Paget University Hospital, 5 University College London , 6 Universite catholique de Louvain, 7 Friedrich Schiller University, Jena , jj, Methods, Materials and Results Abstract Background Discussion • Our findings suggest that most relapses occurring within 1- 4 years may be induced by the effects of breast cancer surgery. • A possible mechanism is transient systemic inflammation which, in the presence of circulating cancer cells and cells released as a result of surgery, produce what has been called inflammatory oncotaxis. • We have found that peri-operative anti-inflammatory agents appear to abrogate the early hazard of recurrence and we estimate that such intervention could reduce breast cancer mortality by 25% to 50%. • High priority should be given to test this hypothesis in a randomized trial as it is implementable regardless of state of socio-economic development because expensive drugs, modern imaging facilities and advanced pathology services are not particularly relevant to implementing this simple change. • Also as noted by Wallace et al (15), the racial disparity in breast cancer outcome is due primarily to deaths within the first few years after diagnosis providing an additional motivation to test at the earliest opportunity what we report here. We acknowledge the support of Komen Foundation Grant: 100484 Methods and Materials: In June 2010, Forget et al (2) reported data from a retrospective disease free survival study of 327 consecutive patients comparing various perioperative analgesics and anesthetics (sufentanil, clonidine, ketorolac, and ketamine) 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. Patients who received anti-inflammatory drugs were compared with those who had not and their hazard of recurrence was analysed and compared. Results: Perioperative administration of the NSAID ketorolac, a common surgical anti- inflammatory analgesic, was associated with significantly superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse peak is all but absent in the ketorolac data (fig. 4); specifically, the reduction is approximately 4 – 6 fold. The few events in the ketorolac group show a small bump in the first 10 months and then slowly rising until the 4 th year when follow-up of this series ends. Simulations of the two early relapse modes are shown in fig. 3. Using these data, we have been able to help explain a wide variety of previously unpredictable breast cancer observations with this hypothesis. These include the high effectiveness of adjuvant chemotherapy predominantly seen in premenopausal node positive women and why mammographic screening is more effective for women age 50-59 than for women age 40-49. Background: To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients treated by mastectomy we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastes and then on to growing deposits. To explain the early relapses, 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 that appeared to be surgery-induced angiogenesis of dormant avascular micrometastases. This hypothesis could explain a wide variety of breast cancer observations. 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 and Discussion: 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 events are all but absent. 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. Possible mechanism: The transient systemic inflammation accompanying surgery could be part of the metastatic tumor seeding process and could have been effectively blocked by peri- operative anti-inflammatory agents. Even with the insight of simulations, it is sometimes impossible to determine with certainty what happened to each of the various relapse modes in a particular report. However in this case it appears that perisurgical ketorolac may dramatically reduce the initiation of surgery-induced angiogenesis as well as single cell proliferation after surgery. If this observation holds up to further scrutiny, it could mean that the simple use of this safe and effective anti-inflammatory agent at the time of surgery might eliminate most early relapses. Balkwill et al writes that if genetic damage is the “match that lights the fire” of cancer, then inflammation is the “fuel that feeds the flames” and that inflammation affects both the survival and proliferation of already initiated cancer cells (3). Since Virchow first proposed in 1863 that tumors could originate from sites of chronic inflammation, it has been well established that chronic inflammation both contributes to cancer progression and predisposes tissue to various types of primary and metastatic cancer (4). Based on Pascual et al data from a colon cancer study, transient inflammation can also be both local and systemic (5). They measured the proinflammatory cytokine interleukin-6 (IL-6) in serum prior to surgery and in peritoneal fluid during surgery to establish baseline IL-6, and again at 4, 12, 24 and 48 hours and at 4 days after surgery to determine a temporal trend. They found levels of IL-6 in serum at approximately 1/300 of the concentrations seen in peritoneal fluid. Judging by their data it would seem that levels in serum would gradually return to baseline in a week or so. While not breast cancer surgery we can assume that systemically and transiently something similar occurs in surgery to remove breast cancer. The inflammatory response is initiated by tissue damage and is intensified by mast cells, which release histamine, which then markedly increases the permeability of adjacent capillaries. The severity, timing, and local character of any particular inflammatory response depend on the cause, location and site of the area affected, and host’s condition (6). Inflammatory oncotaxis, a term used to describe tumor growth at a site of inflammation, is occasionally seen in persons with known or occult cancer and who have local trauma (7,8). Martins-Green et al studied an avian system in which a virus is the carcinogenic agent (9). When newly hatched chicks are given injections of Rous sarcoma virus, a tumor develops only at the site of injection unless a wound is made a distance away from the primary tumor where a tumor develops at the site of wounding. They found that when inflammation was inhibited, tumors were also inhibited; when inflammation could not be stopped, tumors developed as before. It is well established that many cancer patients have circulating cancer cells (10,11). Data from Pachmann show a surge in circulating epidermal cells after primary breast cancer surgery, but intriguingly, that surge occurs 3-7 days after surgery (12). Such a delayed increase in what may be circulating cancer cells after breast cancer surgery was also reported by Daskalakis et al (13). Blood flow in capillaries is only 0.03cm/sec which would make leaky capillary venules a very efficient way for circulating cancer cells to enter tissue, thereby reducing their concentration in circulation. Perhaps the transient systemic inflammation accompanying surgery and subsequent inflammatory oncotaxis is part of the metastatic tumor seeding process. It may be that what we previously called dormant single cells induced into metastatic growth were at least in some cases residing not at the site of eventual relapse. Rather, circulating cancer cells in an inflammatory environment extravasate, resulting months later in a metastatic tumor. Circulating cancer cells are a reality. Surgical induction of inflammation is universal. Capillary leakage is enhanced by inflammation. It is thereby logical to expect that an effective peri- surgical anti-inflammatory strategy may affect surgery-induced and possibly angiogenesis-mediated cancer spread. Figure 5 shows a schematic description of what we suspect to be the mechanisms governing metastatic relapse from early breast cancer. There are only a few relapses in the ketorolac data shown in fig. 4 that appear to be surgery-induced angiogenesis events. This may be attributed to the reduced usage of opioids for pain management with ketorolac and its antiangiogenic properties (14). Also seen in fig. 4 is what appears to be the leading edge of the late broad peak. If so, this would be the first such sighting. Are the missing early relapses never to happen or are they merely postponed to become late relapses? Whatever their source, cancer cells in circulation probably have half life of a few days or less. Unless injected into more hospitable surroundings such as tissue, these cells will likely harmlessly die off. These data and our analysis suggest that at least for some patients the early relapses apparently avoided in the Forget et al data do not show up later. While there is much worthwhile interest in personalized cancer treatment, that may not be the only way to solve the early relapse problem. References 1. Retsky, M.; Demicheli, R.; Hrushesky, W.; Baum, M.; Gukas, I. Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An Inconvenient Truth? Cancers 2010, 2, 305-337. http://www.mdpi.com/2072-6694/2/2/305/ 2. Forget P, Vandenhende J, Berliere M, Machiels JP, Nussbaum B, Legrand C, De Kock M Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. Anesth Analg. 2010 Jun 1;110(6):1630-5. 3. Balkwill F, Mantovani A, Inflammation and cancer: back to Virchow? Lancet, 0099-5355, Feb 17, 2001; 357: 9255 4. Keibel A, Singh V, Sharma MC. Inflammation, microenvironment, and the immune system in cancer progression. Curr Pharm Des. 2009;15(17):1949-55. Review. 5. Pascual M, Alonso S, Parés D, Courtier R, et al. Randomized clinical trial comparing inflammatory and angiogenic response after open versus laparoscopic curative resection for colonic cancer. Br J Surg. 2011 Jan;98(1):50-9. 6. Demaria S, Pikarsky E, Karin M, et al. Cancer and inflammation: promise for biologic therapy. J Immunother. 2010 May;33(4):335-51. 7. El Saghir NS, Elhajj II, Geara FB, et al. Trauma-associated growth of suspected dormant micrometastasis. BMC Cancer 2005; 5:94. 8. Walter ND, Rice PL, Redente EF, Kauvar EF, Lemond L, Aly T, Wanebo K, Chan ED. Wound healing after trauma may predispose to lung cancer metastasis: review of potential mechanisms. Am J Respir Cell Mol Biol. 2011 May;44(5):591-6. 9. Martins-Green M, Boudreau N, Bissell MJ. Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res. 1994 Aug 15;54(16):4334-41. 10. Krebs MG, Hou JM, Ward TH, Blackhall FH, Dive C. Circulating tumour cells: their utility in cancer management and predicting outcomes. Ther Adv Med Oncol. 2010 Nov;2(6):351-65. 11. Zhe X, Cher ML, Bonfil RD. Circulating tumor cells: finding the needle in the haystack. Am J Can Res 2011;1(6):740-51. 12. Pachmann K. Tumor Cell Seeding During Surgery—Possible Contribution to Metastasis Formations. Cancers 2011, 3, 2540-2553. 13. Daskalakis M, Mavroudis D, Sanidas E, et al . Assessment of the effect of surgery on the kinetics of circulating tumour cells in patients with operable breast cancer based on cytokeratin-19 mRNA detection. Eur J Surg Oncol. 2011 May;37(5):404-10. 14. Pakneshan P, Birsner AE, Adini I, Becker CM, D'Amato RJ. Differential suppression of vascular permeability and corneal angiogenesis by nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci. 2008 Sep;49(9):3909-13. 15. Wallace TA, Martin DN, Ambs S. Interactions among genes, tumor biology and the environment in cancer health disparities: examining the evidence on a national and global scale. Carcinogenesis. 2011 Aug;32(8):1107-21. *M. Retsky has a patent pending for treatment of early stage cancer. No other conflicts of interest reported. This presentation is the intellectual property of the author/presenter. Contact Michael.Retsky@gmail.com for permission to reprint and or distribute. We acknowledge the support of Komen Foundation Grant: 100484 0 0.01 0.02 0.03 0.04 0.05 0.06 0 12 24 36 48 60 72 84 96 108 120 Hazard Months Post-mastectomy recurrence hazard for postmenopausal patients in Milan database Patients at risk 316 283 260 223 150 Keto group 175 162 155 140 99 No-Keto group 141 121 105 83 51 0 0.01 0.02 0.03 0.04 0.05 0.06 0 12 24 36 48 60 72 84 96 108 120 Hazard Months Post-mastectomy recurrence hazard for premenopausal patients in Milan database Our analysis of the Milan National Cancer Institute found an unexpected bimodal pattern of relapse hazard among 1173 early stage breast cancer patients treated by mastectomy (1). Figure 1 shows Milan data for premenopausal patients and fig. 2 shows postmenopausal patients in relapse hazard format. Similar patterns have 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. Under closer examination, the first peak consists of two distinct groups centered at 10 months and 30 months. This pattern was not explainable by accepted theories. We proposed that the broad second peak relapses result from steady stochastic progressions from single dormant malignant cells to avascular micro-metastases and then on to growing deposits. To explain the first peak, we postulated that events such as induction of angiogenesis at the time of surgery provoked sudden exits from dormant phases to active growth and then to detection, which appeared to explain the particularly sharp early relapse mode within 10 months most predominant among premenopausal patients with positive nodes. The remainder of the relapses within the first 40 months we suggested to be surgery- induced growth of previously dormant single malignant cells. . Simulation of early peaks at 10 months and 30 months Analysis of Forget et al (2010) data as hazard plots Methods, Materials and Results Summary and Conclusions San Antonio Breast Cancer Symposium Dec 6-10, 2011 Primary breast cancer CTCs Primary surgery Transient systemic inflammation (1 week) Cells released during surgery Cells in circulation before, during and after surgery Direct or indirect action on avascular micrometastases and single tumor cells Relapses at 9 – 18 months post surgery Points of blockage with perioperative NSAID ketorolac and reduced opioids Long lasting CTCs or cancer cells imbedded in reservoirs or organs leading to late relapses Cancer stem cells in marrow or other reservoir Proposed explanation of why perioperative NSAID ketorolac prevents early relapses