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NSAID analgesic ketorolac used perioperatively may suppress early
breast cancer relapse: something for nothing in breast cancer?
M Retsky1,5, R Rogers1, R Demicheli2, W Hrushesky3, I Gukas4, JS Vaidya5, M Baum5, P Forget6, M DeKock6, K Pachmann7
1Harvard School of Public Health, 2Istituto Nazionale Tumori, 3 Oncology Analytics, Inc., 4James Paget University Hospital, 5University College London , 6Universite catholique de Louvain, 7Friedrich Schiller University, Jena
San Antonio Breast Cancer Symposium Dec 6-10, 2011 Based on Pascual et al data from a colon cancer study, transient inflammation can Summary and Conclusions
Abstract
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 • Our findings suggest that most relapses occurring within 1- 4 years may be induced establish baseline IL-6, and again at 4, 12, 24 and 48 hours and at 4 days after by the effects of breast cancer surgery.
Background: To explain a bimodal pattern of hazard of relapse among early stage breast
Methods and Materials: In June 2010, Forget et al (2) reported data from a retrospective
surgery to determine a temporal trend. They found levels of IL-6 in serum at • A possible mechanism is transient systemic inflammation which, in the presence of cancer patients treated by mastectomy we proposed that late relapses result from steady disease free survival study of 327 consecutive patients comparing various perioperative approximately 1/300 of the concentrations seen in peritoneal fluid. Judging by their circulating cancer cells and cells released as a result of surgery, produce what has stochastic progressions from single dormant malignant cells to avascular micrometastes and analgesics and anesthetics (sufentanil, clonidine, ketorolac, and ketamine) in one Belgian data it would seem that levels in serum would gradually return to baseline in a week then on to growing deposits. To explain the early relapses, we had to postulate that something hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant happened at about the time of surgery to provoke sudden exits from dormant phases to active or so. While not breast cancer surgery we can assume that systemically and • We have found that peri-operative anti-inflammatory agents appear to abrogate the therapy. Follow-up is average 27.3 months with range 13-44 months. Patients who received growth and then to detection. There was a particularly sharp early relapse mode within 10 transiently something similar occurs in surgery to remove breast cancer.
early hazard of recurrence and we estimate that such intervention could reduce breast anti-inflammatory drugs were compared with those who had not and their hazard of months that appeared to be surgery-induced angiogenesis of dormant avascular The inflammatory response is initiated by tissue damage and is intensified by mast micrometastases. This hypothesis could explain a wide variety of breast cancer observations.
recurrence was analysed and compared.
cells, which release histamine, which then markedly increases the permeability of • High priority should be given to test this hypothesis in a randomized trial as it is Results: Perioperative administration of the NSAID ketorolac, a common surgical anti-
Methods and Materials: Forget et al reported data from a retrospective study of 327
adjacent capillaries. The severity, timing, and local character of any particular implementable regardless of state of socio-economic development because inflammatory analgesic, was associated with significantly superior disease-free survival in the consecutive patients comparing various perioperative analgesics and anesthetics in one Belgian inflammatory response depend on the cause, location and site of the area affected, expensive drugs, modern imaging facilities and advanced pathology services are not hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant first 5 years after surgery. The expected prominent early relapse peak is all but absent in the and host’s condition (6). Inflammatory oncotaxis, a term used to describe tumor particularly relevant to implementing this simple change. therapy. Follow-up is average 27.3 months with range 13-44 months. ketorolac data (fig. 4); specifically, the reduction is approximately 4 – 6 fold. The few events growth at a site of inflammation, is occasionally seen in persons with known or • Also as noted by Wallace et al (15), the racial disparity in breast cancer outcome is Results and Discussion: NSAID ketorolac, a common analgesic used in surgery, produced far
in the ketorolac group show a small bump in the first 10 months and then slowly rising until occult cancer and who have local trauma (7,8). Martins-Green et al studied an avian due primarily to deaths within the first few years after diagnosis providing an additional superior disease-free survival in the first 5 years after surgery. The expected prominent early the 4th year when follow-up of this series ends. system in which a virus is the carcinogenic agent (9). When newly hatched chicks motivation to test at the earliest opportunity what we report here. relapse events are all but absent. If this observation holds up to further scrutiny, it could mean Simulations of the two early relapse modes are shown in fig. 3. Using these data, we have are given injections of Rous sarcoma virus, a tumor develops only at the site of that the simple use of this safe and effective anti-inflammatory agent at surgery might eliminate Proposed explanation of why perioperative NSAID ketorolac prevents early relapses been able to help explain a wide variety of previously unpredictable breast cancer injection unless a wound is made a distance away from the primary tumor where a observations with this hypothesis. These include the high effectiveness of adjuvant Possible mechanism: The transient systemic inflammation accompanying surgery could be part
tumor develops at the site of wounding. They found that when inflammation was chemotherapy predominantly seen in premenopausal node positive women and why of the metastatic tumor seeding process and could have been effectively blocked by peri- inhibited, tumors were also inhibited; when inflammation could not be stopped, mammographic screening is more effective for women age 50-59 than for women age 40-49.
It is well established that many cancer patients have circulating cancer cells (10,11). Background
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). Our analysis of the Milan National Cancer Institute found an unexpected bimodal pattern of Such a delayed increase in what may be circulating cancer cells after breast cancer relapse hazard among 1173 early stage breast cancer patients treated by mastectomy (1). surgery was also reported by Daskalakis et al (13). Blood flow in capillaries is only Figure 1 shows Milan data for premenopausal patients and fig. 2 shows postmenopausal 0.03cm/sec which would make leaky capillary venules a very efficient way for Cells in circulation before, during and after surgery circulating cancer cells to enter tissue, thereby reducing their concentration in Post-mastectomy recurrence hazard for
Post-mastectomy recurrence hazard
postmenopausal patients in Milan
for premenopausal patients in Milan
database
Perhaps the transient systemic inflammation accompanying surgery and database
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 References
Patients at risk
relapse. Rather, circulating cancer cells in an inflammatory environment 1. Retsky, M.; Demicheli, R.; Hrushesky, W.; Baum, M.; Gukas, I. Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An extravasate, resulting months later in a metastatic tumor. Circulating cancer cells 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 are a reality. Surgical induction of inflammation is universal. Capillary leakage is 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 Discussion
enhanced by inflammation. It is thereby logical to expect that an effective peri- 4. Keibel A, Singh V, Sharma MC. Inflammation, microenvironment, and the immune system in cancer progression. Curr Pharm Des. surgical anti-inflammatory strategy may affect surgery-induced and possibly angiogenesis-mediated cancer spread. Figure 5 shows a schematic description of 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. what we suspect to be the mechanisms governing metastatic relapse from early 6. Demaria S, Pikarsky E, Karin M, et al. Cancer and inflammation: promise for biologic therapy. J Immunother. 2010 May;33(4):335-51. Similar patterns have now been identified in 20 independent databases from US, Europe and Even with the insight of simulations, it is sometimes impossible to determine with certainty breast cancer. There are only a few relapses in the ketorolac data shown in fig. 4 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 Asia. There is an early peak of relapses at 18 months, a nadir at 50 months and a broad what happened to each of the various relapse modes in a particular report. However in this that appear to be surgery-induced angiogenesis events. This may be attributed to cancer metastasis: review of potential mechanisms. Am J Respir Cell Mol Biol. 2011 May;44(5):591-6. second peak extending from 60 months to over 15 years. Fifty to eighty percent of relapses, case it appears that perisurgical ketorolac may dramatically reduce the initiation of the reduced usage of opioids for pain management with ketorolac and its 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.
the proportion increasing with primary tumor size, reside within the first peak. Under closer surgery-induced angiogenesis as well as single cell proliferation after surgery. If this antiangiogenic properties (14). Also seen in fig. 4 is what appears to be the leading 10. Krebs MG, Hou JM, Ward TH, Blackhall FH, Dive C. Circulating tumour cells: their utility in cancer management and predicting outcomes. examination, the first peak consists of two distinct groups centered at 10 months and 30 observation holds up to further scrutiny, it could mean that the simple use of this safe and edge of the late broad peak. If so, this would be the first such sighting. 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. months. This pattern was not explainable by accepted theories. effective anti-inflammatory agent at the time of surgery might eliminate most early Are the missing early relapses never to happen or are they merely postponed to 12. Pachmann K. Tumor Cell Seeding During Surgery—Possible Contribution to Metastasis Formations. Cancers 2011, 3, 2540-2553.
become late relapses? Whatever their source, cancer cells in circulation probably 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.
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 Balkwill et al writes that if genetic damage is the “match that lights the fire” of cancer, then have half life of a few days or less. Unless injected into more hospitable 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.
to growing deposits. To explain the first peak, we postulated that events such as induction of inflammation is the “fuel that feeds the flames” and that inflammation affects both the surroundings such as tissue, these cells will likely harmlessly die off. These data 15. Wallace TA, Martin DN, Ambs S. Interactions among genes, tumor biology and the environment in cancer health disparities: examining the angiogenesis at the time of surgery provoked sudden exits from dormant phases to active survival and proliferation of already initiated cancer cells (3). Since Virchow first proposed and our analysis suggest that at least for some patients the early relapses evidence on a national and global scale. Carcinogenesis. 2011 Aug;32(8):1107-21. growth and then to detection, which appeared to explain the particularly sharp early relapse in 1863 that tumors could originate from sites of chronic inflammation, it has been well apparently avoided in the Forget et al data do not show up later.
*M. Retsky has a patent pending for treatment of early stage cancer. No other conflicts of interest reported. mode within 10 months most predominant among premenopausal patients with positive established that chronic inflammation both contributes to cancer progression and While there is much worthwhile interest in personalized cancer treatment, that may This presentation is the intellectual property of the author/presenter. Contact for permission to reprint and or distribute.
We acknowledge the support of Komen Foundation Grant: 100484
nodes. The remainder of the relapses within the first 40 months we suggested to be surgery- predisposes tissue to various types of primary and metastatic cancer (4). not be the only way to solve the early relapse problem.
induced growth of previously dormant single malignant cells. We acknowledge the support of Komen Foundation Grant: 100484

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