Special Feature

Stress and Poor Cancer Outcomes: It’s More Than Psychological

By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman reports no finanical relationships relevant to this field of study.

This article originally appeared in the November 2012 issue of OB/GYN Clinical Alert.

Synopsis: Chronic stress has been associated with development of several diseases and the release of several cytokines and growth factors known to support cancer growth and metastases. Pharmacological agents targeting the stress response, such as beta-blockers and prostaglandin inhibitors, have been associated with improved survivorship in patients with several solid tumors, including ovarian cancer. The relationship supports prospective clinical investigation, already underway.

Source: Diaz ES, et al. Impact of beta-blockers on epithelial ovarian cancer survival. Gynecol Oncol 2012; doi;10.1016/j.ygyno.2012.07.102.

Mediators of the autonomic response to stress, such as the catecholamines norepinephrine and epinephrine, promote cancer growth, metastasis, and progression in preclinical models. Pharmacological intervention with beta-blockers can abrogate this effect leading to improved patient outcomes. Further, retrospective data from studies of patients with non-ovarian tumors support this hypothesis. The authors of the current study set out to evaluate the effect in patients with ovarian cancer. Patients were collected retrospectively from an institutional database of primary ovarian cancer patients treated over a 10-year period with a minimum of 5 years of follow-up. Patients were considered beta-blocker users if there were documentation of agent use over two visits a minimum of 6 months apart. Standard intravenous paclitaxel and carboplatin was used in all recruited patients to minimize the impact of therapy on the primary endpoints of overall survival (OS) and progression-free survival (PFS). In all, 248 patients were identified; 68 (27%) were patients in whom anti-hypertensive agents were used. Of these, 23 (9%) of the total sample were taking beta-blockers, both selective beta and nonselective beta (and or alpha) agents. The cohorts were defined as beta-blocker users and other. The two cohorts were well matched for age, proportion of stage IV disease, grade 3 histology, percentage of non-serous histology, and optimal cytoreduction rates (which were near 90% for tumor residual < 1 cm). When compared to the non-beta-blocker group, those taking any form of a beta-blocker had a prolonged PFS (27 months vs 17 months, P = 0.05) and prolonged OS (56 months vs 48 months, P = 0.02, hazard ratio 0.56). This effect held true even when the beta-blocker users were compared to the other hypertensive non-beta blocker users and those whom were not hypertensive. In a multivariate analysis including known prognostic factors, beta-blocker use was the only independently associated factor to PFS and OS. The authors conclude beta blockade for the management of hypertension is associated with improved survivorship and supports the prospective investigation of beta-blocker therapy in ovarian cancer patients.

Commentary

The study presented appears to support the hypothesis that stress response mediation in ovarian cancer patients can have an impact on long-term outcomes, such as PFS and OS. The study also supports others done under similar pretenses demonstrating remarkably consistent results despite including diseases that arise from complex and divergent pathways.1,2 These observations suggest that central mechanisms for tumor invasion, spread, and progression exist and are mediated, in part, by effector factors from the autonomic nervous system. While the relationship of stress to cancer prognosis has been known for years, the mechanism through which this occurs and thus, the potential opportunities to interact with these response elements, is largely unknown. However, clues recently have come to light.

Perioperative Events Impact Long-term Outcomes

Four decades ago, an observation in preclinical cancer models suggested that removal of the primary tumor led to rapid growth of subclinical and known distant metastatic disease.3 In this body of work, an antiangiogenesis growth factor secreted by the primary tumor was discovered (endostatin), which led to the development of the field of biologically targeted antiangiogenesis therapeutic agents. Indeed, surgery is known to not only shift the angiogenic balance toward proangiogenesis, but also increase tumor cell shedding and increase the production of stimulatory growth factors. The latter, which includes catecholamines, prostaglandins, glucocorticoids, and opioids, have been extensively interrogated in preclinical models documenting their critical role in tumor cell proliferation, adhesion, locomotion, extracellular matrix invasion capacity, resistance to apoptosis with loss of cell-cell contact (a process termed anoikis), and secretion of proangiogenic factors.4,5 These factors also have significant impact on suppression of anti-metastatic cell-mediated immunity (CMI). Of particular relevance in the context of surgery is that these processes occur simultaneously and may leverage their effect on long-term outcomes by promoting initiation of the angiogenic switch, which could recruit dormant metastatic lesions to initial growth. In the clinic, should this hypothesis be true, it would suggest that brief interaction of the perioperative cascade could lead to long-term beneficial effects.

The Players and How they Work

Catecholamine and prostaglandin release are a common response to stress and tissue injury, both induced in operative/perioperative settings. Catecholamines act on beta-adrenoceptors, which have been identified to be present on tumor cells, inducing the release of several pro-angiogenic and pro-metastatic factors like VEGF, matrix metallopreteinases (MMP-2, MMP-9), and interleukins (IL-6, IL-8). Relatively recently it was discovered that this cascade appears to be driven through the beta-2 adrenergic receptor, which stimulates the cyclic AMP-protein kinase A pathway and leads to src-mediated focal adhesion kinase phosphorylation — all important (and targetable) processes driving the malignant phenotype. What was striking in these experiments was the efficacy of beta-2 blockade by commonly available antihypertensive agents in orthotopic ovarian cancer models.6,7 In the latter murine model, stress was induced not by surgery or tissue injury but by chronic stress induced by a claustrophobia-inducing, non-restraint enclosure device. In these experiments, tumor growth, enhanced under a constrained environment, was associated with massive release of catecholamines, whose effect was abrogated by treatment of beta-2 blockade.

Similarly, prostaglandins, particularly prostaglandin-E2, facilitate macrophage differentiation in the tumor microenvironment toward the M2 phenotype. This differentiation promotes tumor cell survival by modulating CMI and enhancing angiogenesis. In colon cancer for instance, COX-2 expression is associated with tumor size, stage, vascular density, depth of invasion, lymph node metastasis, recurrence, and overall survival. Both classes of compounds appear to work in concert to promote tumorigenesis; fortunately, both axes can be easily targeted clinically.

The Evidence

Currently, there are no prospective randomized, clinical trials addressing the effects of beta blockade perioperatively in cancer patients, but the retrospective evidence for its efficacy is interesting. The largest study reported on the effects of beta-blocker use and cancer survival was in breast cancer. In this registry study of women with stage I-IV invasive breast cancer diagnosed between 2001 and 2006 who were taking propranolol (n = 70) or atenolol (n = 525), patients were matched 1:2 to women not taking a beta-blocker (n = 4738).8 The primary outcome variables were of tumor invasion at diagnosis (T4), nodal/metastatic spread at diagnosis, and time to breast cancer-specific mortality. Propranolol users were significantly less likely to present with T4 lesions at diagnosis (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.07-0.85) or nodal/metastatic spread (OR, 0.2; 95% CI, 0.04-0.88) compared to matched nonusers. The cumulative probability of breast cancer-specific mortality was significantly lower for propranolol users compared with matched nonusers (HR, 0.2-0.6; 95% CI, 0.06-0.6). Interestingly, there was no difference in T4 or nodal/metastatic disease or mortality between atenolol users and matched nonusers. This trial supports the beta-adrenergic pathway’s importance in tumorigenesis as well as the differential effect of beta-2 blockade.

The experience with anti-prostaglandin therapy is more diverse and has been the subject of randomized clinical trials in several tumor types. A trial of low-dose aspirin for 1 year postoperatively in patients with gastric or esophageal cancer demonstrated a significantly improved 5-year survival rate (51% vs 41%) in low-stage, non-disseminated cases. In addition, three randomized trials of celecoxib (a COX-2 inhibitor) demonstrated significant tumor-specific effects in early breast cancer, transitional cell cancer of the bladder, and prostate cancer. In the former two sites, there was significant increase in tumor cell apoptosis, and in the latter, there was reduced tumor cell proliferation, vessel density, angiogenesis, and hypoxia inducing factor 1-alpha expression with a short (2-4 week) presurgical exposure.9,10 This further supports the hypothesis that specific tumor effects can be enabled by brief exposures of these compounds around the time of greatest expression of these pathways.

Where Do We Go from Here?

The study featured at the introduction identified that use of beta-blockers in women with newly diagnosed ovarian cancer was associated with prolonged survival. There are many questions not addressed in that report such as: Were these patients stressed? Did they take their antihypertensive agent around the time of surgery? Was a COX-2 inhibitor given in the perioperative period? Were epidurals used (reduces opioid and glucocorticoid secretion)? Would there be a difference in beta-2 blockade vs beta-1 blockade with a larger sample? Evidence presented would suggest that both beta-2 and prostaglandin blockade would have the greatest benefit to long-term outcomes if it could be safely administered. One significant question to address is safety of normotensive patients taking therapeutic beta-blockade in the perioperative setting. For ovarian cancer patients, the potential impact on long-term survival is not trivial. Fortunately, such a trial is already underway and should help to answer the feasibility of a larger randomized trial in women with ovarian cancer, the deadliest of all gynecologic cancers.

References

1. Yamaguchi K, et al. Significant detection of circulating cancer cells in the blood by reverse transcriptasepolymerase chain reaction during colorectal cancer resection. Ann Surg 2000;232:58-65.

2. Abramovitch R, et al. Stimulation of tumour growth by wound-derived growth factors. Br J Cancer 1999;79:1392-1398.

3. O’Reilly MS, et al. Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88:277-285.

4. Kerros C, et al. Reduction of cell proliferation and potentiation of Fas-induced apoptosis by the selective kappa-opioid receptor agonist U50 488 in the multiple myeloma LP-1 cells. J Neuroimmunol 2010;220:69-78.

5. Yang EV, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: Implications for stress-related enhancement of tumor progression. Brain Behav Immun 2009;23:267-275.

6. Sood AK, et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J Clin Invest 2010;120:1515-1523.

7. Thaker PH, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 2006;12:939-944.

8. Barron TI, et al. Beta blockers and breast cancer mortality: A population-based study. J Clin Oncol 2011;29:2635-2644.

9. Liu JF, et al. A preliminary study on the postoperative survival of patients given aspirin after resection for squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia. Ann Surg Oncol 2009;16:1397-1402.

10. Martin LA, et al. Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer. Breast Cancer Res Treat 2010;123:829-836.