To the Editor
I read with great interest the article by Professor Marcel Durieux on the implications of anesthetic management and cancer recurrence,1 a concept that is becoming increasingly important, and I concur with his conclusions that the intriguing epidemiologic evidence presented in the Newsletter merits further intensive study.
Professor Durieux focuses on either the direct (i.e., mediated through local anesthetics) or indirect (i.e., mediated by their effect on reduction of stress hormones) effects of epidural or regional anesthesia as an explanation for the differences in cancer recurrence observed in 2 retrospective studies. An alternative explanation relies on the proangiogenic effects of opioids. He briefly refers to the possibility that mu opioids could have an effect on angiogenesis as proposed by Dr. Gupta and her study in breast cancer tumor growth.2 Our group has investigated the effects of opioids on models of angiogenesis and demonstrated that mu agonists in clinical concentrations trans-activate the VEGF receptors, and that opioid-induced angiogenesis is blocked by naloxone and the peripheral opioid antagonist methylnaltrexone.3
One randomized trial of patients receiving either intrathecal or comprehensive, i.e., systemic opiate cancer care, showed a dramatic difference in survival in those patients receiving intrathecal opiates.4 If there is an effect of opioids on tumor growth or recurrence, it may be particularly manifest in the perioperative period as there is no compelling clinical evidence that either opiates or opiate antagonists affect the development of new tumors. We examined this hypothesis in a study of new tumors from patients receiving methadone maintenance or chronic implanted naltrexone. Although the study was retrospective and small, some 4,000 patient years in all, we did not see a signal suggesting an effect of methadone or naltrexone on the development of new tumors.5 That an effect on tumor growth or recurrence is manifest in the perioperative period is further suggested by a very recent article demonstrating perioperative stimuli that activate disseminated tumor cells.6
One possible explanation for a selective effect during tumor surgery may reside in the effect of opioids on endothelial cell barrier integrity.7 We have recently demonstrated that mu opiates, in doses which can be used clinically, can alter the integrity of the endothelial barrier
in vitro. Thus, when cells may be shed into the circulation during surgery, the endothelial barrier integrity may not be intact.7 A recent clinical report suggests such an effect of opiates on endothelial barrier function.8 Such an explanation would explain the disparate findings that were observed in the epidemiologic studies during surgery and the observation that chronic opiate use does not increase the risk of cancer.
We would concur with Professor Durieux that this is an area which needs more complete investigation. The ability to vary the anesthetic regimen, or potentially to incorporate peripheral opiate antagonists to attenuate the proangiogenic effects of endogenous or exogenous opioids during surgery, represents an exciting new area for anesthesia.
Jonathan Moss, MD, PhD
Professor and Vice Chairman for Research
Anesthesia and Critical Care
Professor of the College
University of Chicago
Dr. Jonathan Moss serves as a paid consultant to Progenics Pharmaceuticals, has a financial interest in MNTX as a patent holder through the University of Chicago, and receives stock options from Progenics.
Durieux ME. Does anesthetic management affect cancer outcome? APSF Newsletter 2008;23(4):49,51.
Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002;62:4491-8.
Singleton PA, Lingen MW, Fekete MJ, et al. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res 2006;72:3-11.
Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002;20:4040-9.
Tait RJ, Hulse GK, Moss J: Does methadone maintenance therapy increase the risk of new cancers? [abstract] European Cancer Conference, Barcelona, Spain, October 23-27, 2007.
Weckermann D, Polzer B, Ragg T, et al. Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J Clin Oncol 2009;27:1549-56.
Singleton PA, Moreno-Vinasco L, Sammani S, et al. Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 2007;37:222-31.
Hainer C, Wente MN, Hallscheidt PJ, et al. Morphine-induced acute lung injury. J Clin Anesth 2008;20:300-3.