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Natasha Darras, BS Madhavan V. Pillai, MD Susan M. Parks, MD

Does Living Better Help People Live Longer? The Influence of Psychosocial Support in the Positive Outcome of Cancer Treatment. Natasha Darras, BS Madhavan V. Pillai, MD Susan M. Parks, MD. Learning Objectives.

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Natasha Darras, BS Madhavan V. Pillai, MD Susan M. Parks, MD

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  1. Does Living Better HelpPeople Live Longer?The Influence of Psychosocial Support in the Positive Outcome of Cancer Treatment Natasha Darras, BS Madhavan V. Pillai, MD Susan M. Parks, MD

  2. Learning Objectives • To review basic science research which sheds light on the mechanisms behind the positive impact of symptomatic care on the biology and behavior of the underlying cancer in patients • To discuss the most recent published studies showing the benefit of supportive care in helping cancer patients live longer with better quality of life • To examine the disconnect between conventional criteria for response to the treatment of cancer and the improvement in quality of life and survival in cancer patients • To recognize a subgroup of patients with breast cancer who seem to benefit from therapeutic intervention for their psychological and emotional problems

  3. Social Relationships and Health House, et al. Science July 1988

  4. “…my father told me of a careful observer, who certainly had heart-disease and died from it, and who positively stated that his pulse was habitually irregular to an extreme degree; yet to his great disappointment it invariably became regular as soon as my father entered the room.” -Charles Darwin

  5. Social Relationships and Health • Social isolation is associated with a risk of mortality that is the same as smoking or hypercholesterolemia House, et al. Social Relationships and Health. Science 2008.

  6. House, et al. Social Relationships and Health. Science 2008.

  7. Conclusions • Several studies over the past 50 years have shown that more socially isolated individuals have higher mortality rates, and the unmarried have higher mortality rates than the married • Clinical data suggest that the presence of or physical contact with another person can buffer the impact of stress, including in hospital settings such as intensive care units • Recent studies indicate that there is a positive association between social support and health, but more studies, better theories, and a better understanding of the psychological and biological processes affecting social relationships and health are necessary House, et al. Social Relationships and Health. Science 2008.

  8. Postponement of Death UntilSymbolically Meaningful Occasions Phillips, et al. JAMA April 11, 1990

  9. Background • An earlier study showed that Jewish mortality fell sharply below the expected level just before Passover and rose by an equal amount above expected immediately afterward, an example of postponement of death to reach a meaningful occasion Phillips, et al. Postponement of Death Until Symbolically Meaningful Occasions. JAMA 1990.

  10. Methods & Results • Examined all computerized records of the deaths of Chinese in California for 1960 through 1984; only included deaths from natural causes; used Jewish group and 2% simple random sample of all deaths (excluding Chinese and Jews) as controls • Mortality among Chinese dipped by 35.1% in the week prior to the Harvest Moon Festival (a symbolically meaningful occasion) and peaked by 34.6% in the week after • Largest to smallest dip/peak patterns: cerebrovascular diseases, heart diseases and finally malignant neoplasms Phillips, et al. Postponement of Death Until Symbolically Meaningful Occasions. JAMA 1990.

  11. Phillips, et al. Postponement of Death Until Symbolically Meaningful Occasions. JAMA 1990.

  12. Conclusions • The dip/peak pattern may occur because some people may be able to prolong life briefly until after a meaningful occasion, such as a holiday, birthday or anniversary Phillips, et al. Postponement of Death Until Symbolically Meaningful Occasions. JAMA 1990.

  13. Host Resistance Factors:The Interplay between the Biological Response to Stress and Cancer

  14. Protective and Damaging Effects of Stress Mediators McEwen, BS The New England Journal of Medicine January 15, 1998

  15. McEwen, BS. Protective and Damaging Effects of Stress Mediators. The New England Journal of Medicine 1998.

  16. McEwen, BS. Protective and Damaging Effects of Stress Mediators. The New England Journal of Medicine 1998.

  17. Conclusion • Allostatic load, or the ability to achieve stability through change when responding to stress, is increasingly important in the diagnosis and treatment of many illnesses • Allostatic load reveals the relationship between disease and psychosocial stressors; patients who appear to be isolated and have lack of control in the work environment have higher allostatic load • Identifies interventions aimed at reducing allostatic load in patients, including coping skills, recognizing their own limitations, relaxing and increasing social support McEwen, BS. Protective and Damaging Effects of Stress Mediators. The New England Journal of Medicine 1998.

  18. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival Sephton, et al. Journal of National Cancer Institute June 21, 2000

  19. Background • Normal cortisol levels are usually highest before awakening and decrease during the day, but patients with breast cancer consistently show flattened rhythms, consistently high levels and fluctuations • In patients with metastatic breast cancer, study examines association between diurnal variation of salivary cortisol, circulating natural killer cell counts and activity, prognostic indicators, medical treatment and psychosocial variables • Examines relationship between diurnal variation of salivary cortisol and subsequent survival Sephton, et al. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. Journal of National Cancer Institute 2000.

  20. Methods & Results • Salivary cortisol levels in patients with metastatic breast cancer were assessed at the beginning of the study at different hour intervals: 0800, 1200, 1700 and 2100 hours on each of 3 consecutive days • The slope of diurnal cortisol variation was calculated by log-regression model using sample cortisol concentrations, natural killer cell numbers were measured by flow cytometry, and the survival analysis was conducted by the Cox proportional hazards regression model • Results showed a relationship between diurnal cortisol rhythm and breast cancer survival • Early mortality occurred among patients with relatively “flat” rhythms, indicating a lack of normal diurnal variation, whereas patients with localized metastasis had more rhythmic cortisol profiles • “Flat” rhythms were also associated with lower counts and activity of natural killer cells Sephton, et al. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. Journal of National Cancer Institute 2000.

  21. Sephton, et al. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. Journal of National Cancer Institute 2000.

  22. Conclusion • Patients with metastatic breast cancer who have flattened diurnal cortisol rhythms have earlier mortality; thus, degree of loss of diurnal variation predicts early mortality in women with metastatic breast cancer • Suppression of natural killer cell count and function may be a predictor of survival and a marker of rapid disease progression • Flattened cortisol rhythms may reflect disease processes and/or physiologic and psychosocial stressors on the body • Identifying rhythm changes in cancer patients may be used to optimize timing of chemotherapy to minimize cytotoxicity Sephton, et al. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. Journal of National Cancer Institute 2000.

  23. Host Resistance Factors“Living better helps people live longer.” - medical oncologist • Through various body response mechanisms: • Endocrine • Immune • Autonomic Nervous System

  24. Disease Outcome • Large part determined by pathophysiology • Variability comes from host factors • Most important: response to stress • Activation of hypothalamic-pituitary (HPA) axis • Adaptive response to acute stress • Cumulative stress and HPA  Adverse physiologic consequences McEwen, BS. Protective and Damaging Effects of Stress Mediators. The New England Journal of Medicine 1998.

  25. Abnormal Cortisol Patterns • Affect expression of oncogenes: BRCA-1 • Retards apoptosis of malignant cells • Stimulates tumor proliferation • Activates hormone receptors Deng, CX. BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res. 2006. Sephton, et al. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. Journal of National Cancer Institute 2000. Antonova L, Mueller CR. Hydrocortisone down-regulates the tumor suppressor gene BRCA1 in mammary cells: a possible molecular link between stress and breast cancer. Genes Chromosomes Cancer 2008.

  26. Chronic Stress & Immune System • Suppresses and dysregulates immune function (animal studies and human data) • HPA hyperactivity in depression stimulates cytokines, which affect the brain and trigger sickness behavior • HPA dysregulation enhances pro-inflammation • Tumor cells co-opt mediators of proinflammation, which promote tumor progression and metastasis • Nuclear Factor – KB • Growth-promoting cytokines • Angiogenic factors • Elevated norepinephrine: triggers VEGF McEwen, BS. Protective and Damaging Effects of Stress Mediators. The New England Journal of Medicine 1998. Thaker PH, Lutgendorf SK, Sood AK. The neuroendocrine impact of chronic stress on cancer. Cell Cycle 2007.

  27. Quality of Life (QOL) indices are increasingly included as endpoints in the treatment of various metastatic solid tumors… This is a new approach separate from the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, a set of published rules which define when cancer patients improve or “respond” during cancer treatments; it is defined by objective assessments such as shrinkage in tumor size.

  28. The mystery of Sipuleucel-T…

  29. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer:“IMPACT” study Kantoff, et al. The New England Journal of Medicine July 29, 2010

  30. Background • Sipuleucel-T, an immunotherapy, has been shown to reduce risk of death in men with metastatic castration-resistant prostate cancer Kantoff, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate-Cancer: “IMPACT” Study. The New England Journal of Medicine 2010.

  31. Methods & Results • Phase III trial, double-blind, placebo-controlled • 512 patients: Sipuleucel-T vs. placebo; the primary endpoint was overall survival • The overall survival for Sipuleucel-T was 25.8 months in the Sipuleucel-T group vs. 21.7 months in the placebo group • In the Sipuleucel-T group, there was a relative reduction in risk of death of 22% as compared to the placebo group • There was no effect on time to disease progression • Reduction in PSA was observed only in 2.6% of 311 patients Kantoff, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate-Cancer: “IMPACT” Study. The New England Journal of Medicine 2010.

  32. Kantoff, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate-Cancer: “IMPACT” Study. The New England Journal of Medicine 2010.

  33. Kantoff, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate-Cancer: “IMPACT” Study. The New England Journal of Medicine 2010.

  34. Conclusions • The use of Sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer, but had no significant effect on time to disease progression or PSA levels Kantoff, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate-Cancer: “IMPACT” Study. The New England Journal of Medicine 2010.

  35. “Clinical Benefit” in Exocrine Pancreatic Cancer Tempero M. Chemotherapy of Pancreatic Cancer, Humana Press, Totowa, NJ 1998. Rothenberg ML, et al. A Phase II Trial of Gemcitabine in Patients with 5-FU Refractory Pancreatic Cancer. Ann. Oncol. 1996. Quality of Life indices are also increasingly included as endpoints in the treatment of exocrine pancreatic cancer “Clinical benefit” and survival are now accepted as accurate determinants of efficacy of treatment, even in the absence of traditional two-dimensional shrinkage in tumor measurements as an objective response to therapy “Clinical benefit” is often defined as a reduction in pain, an improvement in mood or a decrease in analgesic consumption

  36. New Endpoints in Hepatocellular Carcinoma Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. The New England Journal of Medicine 2008. In the systemic treatment of advanced hepatocellular carcinoma, the multicenter European SHARP trial demonstrated longer overall survival and longertime to radiologic progression among patients treated with sorafenib, a multikinase inhibitor Objective response rates, such as reduction in tumor size, were low

  37. An early study discusses the value of psychosocial support on the survival of cancer patients.

  38. Effect of PsychosocialTreatment on Survival ofPatients with MetastaticBreast Cancer Spiegel, et al. The Lancet October 14, 1989

  39. Background • Some previous studies had shown positive psychosocial effects of group therapy in cancer patients, including a suggestion of increased survival time • This particular study prospectively examined the effect of psychosocial intervention on patients with metastatic breast cancer Spiegel, et al. Effect of Psychosocial Treatment on Survival of Patients with Metastatic Breast Cancer. The Lancet 1989.

  40. Methods & Results • 86 women were randomly assigned to either a 1 year intervention consisting of weekly supportive group therapy with self-hypnosis for pain or a control group which did not receive self-hypnosis • Both groups had routine oncological care • At 10 year follow-up, survival time was 36.6 months in the supportive therapy group and 18.9 months in the control group Spiegel, et al. Effect of Psychosocial Treatment on Survival of Patients with Metastatic Breast Cancer. The Lancet 1989.

  41. Conclusions • Cancer patients may have improved survival with weekly supportive therapy Spiegel, et al. Effect of Psychosocial Treatment on Survival of Patients with Metastatic Breast Cancer. The Lancet 1989.

  42. A later replication study confirms the value of psychosocial support on cancer survival.

  43. Psychologic Intervention Improves Survival for Breast Cancer Patients: A Randomized Clinical Trial Andersen, et al. Cancer November 17, 2008

  44. Background • Test hypothesis that psychologic intervention would improve survival in newly diagnosed cancer patients Andersen, et al. Psychologic Intervention Improves Survival for Breast Cancer Patients: A Randomized Clinical Trial. Cancer 2008.

  45. Methods & Results • 227 patients who were surgically treated for regional breast cancer were randomized to psychologic intervention + assessment (with psychologic and behavioral measures) or assessment only • After several years, patients in the intervention arm had a reduced risk of breast cancer recurrence and death from breast cancer compared with patients in the assessment only arm Andersen, et al. Psychologic Intervention Improves Survival for Breast Cancer Patients: A Randomized Clinical Trial. Cancer 2008.

  46. Andersen, et al. Psychologic Intervention Improves Survival for Breast Cancer Patients: A Randomized Clinical Trial. Cancer 2008.

  47. Andersen, et al. Psychologic Intervention Improves Survival for Breast Cancer Patients: A Randomized Clinical Trial. Cancer 2008.

  48. Conclusion • Psychologic interventions can improve survival among patients with breast cancer after surgery and standard adjuvant treatment Andersen, et al. Psychologic Intervention Improves Survival for Breast Cancer Patients: A Randomized Clinical Trial. Cancer 2008.

  49. Case example • 48 year old female with breast CA was treated with lumpectomy. She was LN negative and ER-. • She works as an elementary school teacher but is currently out of work on leave. • She has two daughters, ages 9 and 11. Her husband works full time as an attorney. • She is back at her oncologist’s office for follow-up two weeks post operatively. What questions do you want to ask her?

  50. Case example • Explore her level of functional activity • What household chores is she doing? • Is she back at work? • Explore her back to work plan • Is she back at work yet? • If not, what are the barriers to her being back at work?

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