- Email: [email protected]
Surviving cancer
Journal of Psychosomatic Research, Vol. 47, No. 6, pp. 497–503, 1999 Copyright 1999 Elsevier Science Inc. All rights reserved. 0022-3999/99 $–see front matter
S0022-3999(99)00060-4
EDITORIAL
SURVIVING CANCER: DO PSYCHOSOCIAL FACTORS COUNT? LESLIE G. WALKER,* STEVEN D. HEYS† and OLEG EREMIN‡ INTRODUCTION
The view that psychological factors are related to the onset and progression of malignant disease is not new. Almost 2000 years ago, the revered physician, Galen of Pergamum, averred, on the basis of his clinical experience, that women who developed breast cancer were more likely to have a melancholic than a sanguine temperament [1]. More recently, in 1870, the renowned surgeon James Paget wrote, “The cases are so frequent in which deep anxiety, deferred hope, and disappointment are quickly followed by the growth and increase of cancer that we can hardly doubt that mental depression is a weighty addition to the other influences favouring the development of the cancerous condition” [2]. Although a number of experimental studies in animals have found that various forms of stress increase the likelihood of developing different types of cancer [3], there are formidable problems in investigating the role of psychological factors in the genesis of cancers in homo sapiens. There are well-documented problems with the retrospective assessment of life events and dating the onset of the malignant process with precision is usually impossible [4]. Moreover, it is important not only to assess the occurrence of an event, but also the significance of that event for the individual concerned [5]. Several studies have been interpreted as showing a positive association between various life events and the onset of clinically evident cancer [6–8], but negative findings have also been reported [9]. Similarly, the etiological significance of mood and personality variables such as depression, emotional suppression, and social conformity remains unclear [10, 11]. PSYCHOSOCIAL FACTORS AND CANCER
Do psychosocial factors prolong survival? The possibility that psychological factors may alter the progression of malignant disease has also received attention [4]. A number of studies have examined the relationship between life events and relapse in breast cancer. As with their putative eti* Institute of Rehabilitation, University of Hull, Hull, UK. † Department of Surgery, University of Aberdeen, Aberdeen, UK. ‡ Department of Surgery, University of Nottingham, Nottingham, UK. Address correspondence to: Professor Leslie G. Walker, Institute of Rehabilitation, University of Hull, 215 Anlaby Road, Hull, HU3 2PG, UK. Phone: 01482 631826; Fax: 01482 635589; E-mail: [email protected]
497
498
Editorial
ological role, positive and negative results have been found [12–15]. Other studies have examined the relationship between coping strategies and disease outcome. Of particular note is a pioneering long-term follow-up study by Greer and colleagues who found that the fighting spirit and denial were associated with prolonged survival in women with breast cancer [16, 17]. These studies do not prove a causal relationship between coping style and survival. It could be, for example, that these coping strategies are manifestations of genetic factors that themselves influence the rate of disease progression. Alternatively, coping may be related to other factors relevant to outcome such as treatment compliance, characteristics of the tumor, nutritional state, and social support [18–20]. The most convincing evidence for a cause-and-effect relationship between psychosocial factors and the outcome of malignant disease comes from randomized, controlled clinical trials.
Randomized trials of psychosocial interventions In a landmark study, Spiegel et al. [21] carried out a 10-year follow-up of 86 women with metastatic breast cancer, some of whom had received group therapy consisting of a variety of interventions including peer group support, emotional expression, relaxation training, and autohypnosis. Although there was no statistically significant difference in the median survival of the patients receiving group therapy and the patients in the control group, the mean survival time of the patients receiving group therapy was 36.6 months compared with 18.9 months in the control group. The time from first metastasis to death was also increased in the patients who had received the group therapy. Subsequent analysis demonstrated that the results were not due to betweengroup differences in initial disease stage or to the amount of previous or subsequent radiotherapy, hormone therapy, or chemotherapy [21, 22]. However, the mechanism whereby the intervention enhanced survival is unclear in this study. The investigators themselves suggested that the intervention may have enhanced compliance with medical treatment, improved appetite and nutritional intake, and enabled patients to maintain a beneficial level of physical activity. In a detailed critique of this study, Fox [23, 24] pointed out that the survival curve for the control group lacks the expected right-skewed tail. He argued that the 12 patients in the control group who lived longest were an extremely aberrant sample because, according to other local data, they should have lived even longer than they did. Moreover, the survival curve for those receiving the intervention was similar to other local data for patients not receiving a psychosocial intervention. However, in a rejoinder, Spiegel et al. [25] considered that this post hoc interpretation of data could not be used to invalidate the significant treatment–control group difference in survival in the context of a randomized study. Fawzy et al. [26] evaluated disease recurrence and survival in 68 patients with malignant melanoma who participated in a brief group psychoeducational intervention. When the patients were followed-up between 5 and 6 years later, 10 of the 34 control patients had died compared with 3 of the 34 patients who had received the intervention. Multivariate analysis to take into account other possible reasons for differences in survival confirmed that the intervention per se had prolonged survival.
Editorial
499
Richardson et al. [27] also reported beneficial effects of psychosocial interventions. They compared the effects of three interventions designed to enhance compliance with medication and out-patient attendance in 94 patients with hematological malignancies. Patients were randomized to one of three educational interventions or a control condition. All patients randomized to an educational intervention were given a 1-hour interactive tape/slide presentation. In addition, some patients were given a home visit with, or without, a structured program to encourage them to take responsibility for medication. All three interventions enhanced treatment compliance. Multivariate analyses indicated that the educational interventions were associated with prolonged survival even when their beneficial effects on compliance were taken into account. More recently, Ratcliffe et al. [28] followed-up 63 patients with Hodgkin’s or nonHodgkin’s lymphoma. These patients had participated in a prospective, randomized, controlled trial to determine the effects of relaxation training and hypnotherapy in the control of chemotherapy-induced nausea and emesis. Five years after initial diagnosis, univariate analysis revealed that survival was related to age, stage of disease at presentation, and performance status. However, two psychosocial factors also achieved statistical significance, namely depression scores at diagnosis (Hospital Anxiety and Depression Scale [29]) and L-scores (thought in a medical context to be a measure of social conformity and the “cancer prone” [Type C] personality) (Eysenck Personality Questionnaire—Revised [30]). A subsequent univariate analysis (log-rank test) that stratified for L-scores showed a significant survival effect for the intervention (relaxation therapy with, or without, hypnotherapy) and the benefit appeared to be confined to patients with high L-scores [31]. Multivariate analysis using the Cox proportional hazards model found that early stage of disease at diagnosis, low depression scores, low scores on the L-scale, and (at the 0.058 level of significance) having a psychological intervention were independent prognostic factors for survival [28]. For various reasons, the investigators were cautious in their interpretation of the apparent advantage of the intervention on survival. A number of patients did not have troublesome chemotherapy side effects and, consequently, were not encouraged to practice relaxation or attend hypnotherapy. They were, of course, included in this intention-to-treat analysis. To date, published psychosocial intervention studies have not been designed primarily to demonstrate effects on survival. Unless the effects are very large and/or consistent across a range of interventions, it is not surprising that some studies have failed to demonstrate prolonged survival [32–35]. A number of studies designed to assess the impact of psychosocial interventions on survival, including Cunningham’s Healing Journey Program, are in progress and the results are awaited with great interest [25, 36–38]. If psychosocial interventions can influence survival in ways other than enhancing treatment compliance, what alternative mechanisms might be involved? Recent interest has focused on the possibility that these effects are mediated via psychoneuroimmunological mechanisms [18, 37, 39].
Psychosocial factors and the immune response Because the diagnosis and treatment of cancer are stressful experiences, the psychoneuroimmunological effects of stress on healthy individuals are of interest [40–
500
Editorial
42]. There is increasing evidence that psychological interventions can affect host defenses. However, can psychosocial factors modify the immune response to stress [43, 44]? To answer this question, 24 healthy volunteers were randomly allocated to an experimental intervention or to a control arm. The experimental intervention consisted of training in progressive muscular relaxation and cue-controlled relaxation for 3 weeks plus brief hypnotic suggestions immediately prior to exposure to an experimental stressor (doctor–patient role-play followed by feedback) on day 21. Subjects attended on three occasions (day 1, day 21, and day 22 or 23) and samples of blood were collected on these occasions for immunological analysis. Two samples of blood were taken at the second visit—one before exposure to the experimental stressor and one immediately thereafter. On exposure to the stressor, volunteers randomized to the experimental intervention showed increased lymphocyte proliferation in response to a mitogen (phytohemagglutinin) and enhanced circulating levels of interleukin-1 (IL-1). This suggests that the intervention improved the immune response to the experimental stressor. Changes in IL-1 following exposure to the stressor were positively correlated with Creative Imagination Scale [38] scores in the experimental group. Hypnotizability, therefore, may be an important moderator of the psychoneuroimmunological response to relaxation training and exposure to an acute stressor [46]. This study emphasizes the need to assess the possible interaction between the effects of interventions and response to a stressful experience; for example, coping with the diagnosis and treatment of malignant disease.
The effects of psychosocial interventions on the immune system in patients with cancer A prospective, randomized, controlled trial of relaxation training and guided imagery in 80 women with large or locally advanced breast cancer was recently carried out to assess the effects of this intervention on host defenses in patients with cancer. In addition to improving quality of life [47], the intervention increased the number and percentage of activated T cells (CD251), lowered the circulating level of tumor necrosis factor-alpha and enhanced lymphokine-activated killer (LAK) cell cytotoxicity. Although the two groups did not differ in natural killer (NK)-cell cytotoxicity, self-rated imagery quality was correlated with cytotoxicity at final followup [48]. Even in patients receiving immunosuppressive treatments (chemotherapy, surgery, radiotherapy), relaxation and imagery can produce immunological changes that may have clinical relevance. Fawzy et al. [26] found that their brief psychoeducational group intervention had demonstrable immunological effects. At the end of the intervention, which lasted only 6 weeks, there was a significant increase in the percentage of large granular lymphocytes (CD571). In addition, 6 months following the intervention there was an increase in NK cells (CD161 and CD561). However, although baseline NK activity was related to recurrence, changes in NK cell activity were not related to disease recurrence or to overall survival. The study, therefore, did not provide evidence that enhanced survival was a result of intervention-induced enhancement in NK-cell activity. Psychosocial factors and response to chemotherapy Another possible mechanism by which psychological factors may prolong survival is via response to medical treatment. We recently reported that psychological
Editorial
501
factors were important independent prognostic factors for clinical and pathological responses to cytotoxic chemotherapy in women with large or locally advanced breast cancer [49]. Stepwise multiple linear regression showed that the higher the level of mood disturbance before the first cycle of primary chemotherapy, the poorer the clinical and pathological response to chemotherapy. For example, pathological response to chemotherapy was affected independently by tumor size and by HADS depression score at the start of treatment. This finding provides further insight into how psychological factors may influence the survival of patients with cancer and extends the considerable literature linking quality of life to survival [50–55]. CONCLUSIONS
Evidence is accumulating that psychosocial interventions not only improve quality of life but may also prolong survival in patients with cancer. This may be achieved by means of a number of mechanisms, such as enhanced treatment compliance, better nutrition, a reduction in high-risk behaviors (e.g., unprotected sunbathing), alterations in coping strategies [56], improved quality of life, the provision of group or other social support, and direct effects on response to treatments such as chemotherapy. Although psychosocial interventions can alter host defenses, the clinical relevance of these changes in patients with cancer remains unclear. Just as the last decade saw a burgeoning of interest in psychosocial interventions to improve quality of life [57], the next decade will undoubtedly see considerable interest in the development and refinement of psychosocial interventions designed to prolong survival in patients with different types of cancer.
REFERENCES 1. Goldfarb C, Driesen J, Cole D. Psychophysiologic aspects of malignancy. Am J Psychiatry 1967; 123:1545–1552. 2. Paget J. Surgical pathology. London: Longman Green 1870. 3. Ben-Eliyahu S, Yirmiya R, Liebeskind JC, Taylor AN, Gale RP. Stress increases metastatic spread of a mammary tumor in rats: evidence for mediation by the immune system. Brain Behav Immunol 1991;5:193–205. 4. Watson M, Ramirez A. Psychological factors in cancer prognosis. In: Cooper CL, Watson M, eds. Cancer and stress: psychological, biological and coping studies. Chichester, UK: John Wiley & Sons 1991. 5. Hilakivi-Clarke L, Rowland J, Clarke R, Lippman ME. Psychosocial factors in the development and progression of breast cancer. Breast Cancer Res Treat 1994;29:141–160. 6. Chen CC, David AS, Nunnerly H, Mitchell M, Dawson JL, Berry H, Dobbs J, Berry H. Adverse life events and breast cancer: a case controlled study. BMJ 1995;311:1527–1530. 7. Courtney JG, Longnecker MP, Theorell T, Gerhardsson de Verdier M. Stressful life events and the risk of colorectal cancer. Epidemiology 1993;4:407–414. 8. Ginsberg A, Price S, Ingram D, Nottage E. Life events and the risk of breast cancer; a case control study. Eur J Cancer 1996;32A:2049–2052. 9. Roberts FD, Newcomb PA, Trentham-Dietz A, Storer BE. Self reported stress and risk of breast cancer. Cancer 1997;79:1055–1059. 10. Fox BH. Current theory of psychogenic effects on cancer incidence and prognosis. J Psychosoc Oncol 1983;1:17–31. 11. Fox BH. The role of psychological factors in cancer incidence and progression. Oncology 1995; 9:245–253. 12. Barraclough J, Pinder P, Cruddas M, Osmond M, Taylor AN, Perry M. Life events and breast cancer prognosis. BMJ 1992;304:1078–1081. 13. Barraclough J, Osmond M, Taylor AN, Perry M, Collins P. Life events and breast cancer prognosis. BMJ 1993;307:325.
502
Editorial
14. Ramirez AJ, Craig TJK, Watson JP, Fentiman IS, North WRS, Rubens RD. Stress and relapse of breast cancer. BMJ 1989;298:191–193. 15. Ramirez AJ, Richards MA, Gregory WM, Craig TJK, Watson JP, Fentiman IS. Life events and breast cancer prognosis. BMJ 1992;304:1632. 16. Greer S, Morris, T, Pettingale KW, Haybittle JL. Psychological response to breast cancer and 15 year outcome. Lancet 1990;335:49–50. 17. Pettingale KW, Morris T, Greer S, Haybittle JL. Mental attitudes to cancer: an additional prognostic factor. Lancet 1985;i:750. 18. Spiegel D, Kato PM. Psychosocial influences on cancer incidence and progression. Harvard Rev Psychiatry 1996;4:10–26. 19. Maunsell E, Brisson J, Deschennes L. Social support and survival among women with breast cancer. Cancer 1995;76:631–637. 20. Spiegel D, Sephton SE, Terr AI, Stites DP. Effects of psychosocial treatment in prolonging cancer survival may be mediated by immune pathways. Ann NY Acad Sci 1998;840:674–683. 21. Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet, 1989;ii:889–891. 22. Kogan MW, Biswas A, Pearl D, Carlson RW, Spiegel D. Effects of medical and psychotherapeutic treatment on the survival of women with breast carcinoma. Cancer 1997;80:225–230. 23. Fox BH. A hypothesis about Spiegel et al.’s 1989 paper on psychosocial intervention and breast cancer survival. Psycho-Oncol 1998;7:361–370. 24. Fox BH. Rejoinder to Spiegel et al. Psycho-Oncol 1998;7:518–519. 25. Spiegel D, Kraemer HC, Bloom JR. A tale of two methods: randomization versus matching trials in clinical research. Psycho-Oncol 1998;7:371–375. 26. Fawzy FI, Fawzy N, Hyun LS, Elashoff R, Guthrie D, Fahy JL, Morton DL. Malignant melanoma: effects of an early structured psychiatric intervention, coping and affective state on recurrence and survival 6 years later. Arch Gen Psychiatry 1993;50:681–689. 27. Richardson JL, Shelton DR, Krailo M, Levine AM. The effect of compliance with treatment on survival among patients with haematologic malignancies. J Clin Oncol 1990;80:356–364. 28. Ratcliffe MA, Dawson AA, Walker LG. Eysenck Personality Inventory L-scores in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Psycho-Oncol 1995;4:39–45. 29. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatry Scand 1983; 67:361–370. 30. Eysenck HJ, Eysenck SBG. Manual of the Eysenck Personality Scales (EPS Adult). London: Hodder & Stoughton 1991. 31. Walker LG. Hypnosis and cancer: host defences, quality of life and survival. Contemp Hypnos 1998; 15:34–39. 32. Gellert GA, Maxwell RM, Siegel BS. Survival of breast cancer patients receiving adjunctive psychosocial support therapy: a 10 year follow-up study. J Clin Oncol 1993;11:66–69. 33. Ilnyckyj A, Farber J, Cheang M, et al. A randomised controlled trial of psychotherapeutic interventions in cancer patients. Ann R Coll Phys Surg Can 1994;27:93–96. 34. Linn MW, Linn BS, Harris R. Effects of counselling for late stage cancer patients. Cancer 1982; 49:1048–1055. 35. Cunningham AJ, Edmonds CVI, Jenkins GP, Pollack H, Lockwood GA, Warr D. A randomised controlled trial of the effects of group psychological therapy on survival in women with metastatic breast cancer. Psycho-Oncol 1998;7:508–517. 36. Cunningham AJ. An experimental approach to the mind/cancer question. Adv J Mind-Body Health 1996;12:58–62. 37. Dreher H. The scientific and moral imperative for broad-based psychosocial interventions for cancer. Adv J Mind-Body Health 1997;13:38–49. 38. Goodwin PJ, Leszcz M, Koopmans J, Arnold A, Doll R, Chochinov H, Navarro M, Butler K, Pritchard KI. Randomised trial of group psychosocial support in metastatic breast cancer: the BEST study. Breast-Expressive Supportive Therapy. Cancer Treat Rev 1996;22(suppl A):91–96. 39. Lewis CE, O’Sullivan C, Barraclough J. The psychoimmunology of cancer. Oxford, UK: Oxford University Press 1994. 40. Walker LG, Eremin O. Psychoneuroimmunology: a new fad or the fifth cancer treatment modality. Am J Surg 1995;170:2–4. 41. Ader R, Felten DEL, Cohen N, eds. Psychoneuro-immunology, 2nd ed. San Diego, California: Academic Press 1991. 42. Herbert TC, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med 1993;55:364–369. 43. Gruzelier J, Clow A, Evans P, Lazar I, Walker LG. Mind–body influences on immunity: lateralised control, stress, individual difference predictors and prophylaxis. Ann NY Acad Sci 1998;851:487–494.
Editorial
503
44. Walker LG, Johnson VC, Eremin O. Modulation of the immune response to stress by hypnosis and relaxation training in normals: a critical review. Contemp Hypnos 1993;10:19–27. 45. Wilson SC, Barber TX. The Creative Imagination Scale as a measure of hypnotic responsiveness: applications to experimental and clinical hypnosis. Am J Clin Hypnos 1978;20:235–249. 46. Johnson VC, Walker LG, Whiting P, Heys SD, Eremin O. Can relaxation training and hypnotherapy modify the immune response to acute stress, and is hypnotisability relevant? Contemp Hypnos 1996; 13:100–108. 47. Walker LG, Walker MB, Ogston K, Heys SD, Ah-See AK, Miller ID, Hutcheon AW, Sarkar TK, Eremin O. Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. Br J Cancer 1999;80:262–268. 48. Walker LG, Walker MB, Simpson E, Fielden S, Ogston K, Segar A, Heys SD, Ah-See AK, Hutcheon AW, Eremin O. Guided imagery and relaxation therapy can modify host defences in women receiving treatment for locally advanced breast cancer. Br J Surg 1997;84(suppl 1):31. 49. Walker LG, Ogston K, Heys SD, Ah-See AK, Hutcheon AW, Eremin O. Psychological factors can predict response to primary chemotherapy in women with locally advanced breast cancer. Eur J Can (in press). 50. Addington-Hall JM, MacDonald LD, Anderson HR. Can the Spitzer Quality of Life Index help to reduce prognostic uncertainty in terminal care? Br J Cancer 1990;62:695–699. 51. Coates A, Gebski V, Signorini D, et al. Prognostic value of quality of life scores during chemotherapy for advanced breast cancer. J Clin Oncol 1992;10:1833–1838. 52. Coates A, Porzsolt F, Osoba D. Quality of life in oncology practice: prognostic value or EORTC QLQ-C30 scores in patients with advanced malignancy. Eur J Cancer 1997;33:1025–1030. 53. Earlam S, Glover C, Fordy C, Burke D, Allen-Mersh TG. Relation between tumour size, quality of life, and survival in patients with colorectal liver metastases. J Clin Oncol 1996;14:171–175. 54. Fraser SCA, Ramirez AJ, Ebbs SR, et al. A daily diary for quality of life measurement in advanced breast cancer trials. Br J Cancer 1993;67:341–346. 55. Morris JN, Sherwood S. Quality of life of cancer patients at different stages of the disease trajectory. J Chronic Dis 1987;40:545–553. 56. Walker LG, Walker MB, Ogston K, et al. Can the Type C personality be modified by relaxation therapy and guided imagery? Psycho-Oncol 1998;7:66–67. 57. Meyer TJ, Mark MM. Effects of psychosocial interventions with adult cancer patients: a meta-analysis of randomised experiments. Health Psychol 1995;14:101–108.
S0022-3999(99)00060-4
EDITORIAL
SURVIVING CANCER: DO PSYCHOSOCIAL FACTORS COUNT? LESLIE G. WALKER,* STEVEN D. HEYS† and OLEG EREMIN‡ INTRODUCTION
The view that psychological factors are related to the onset and progression of malignant disease is not new. Almost 2000 years ago, the revered physician, Galen of Pergamum, averred, on the basis of his clinical experience, that women who developed breast cancer were more likely to have a melancholic than a sanguine temperament [1]. More recently, in 1870, the renowned surgeon James Paget wrote, “The cases are so frequent in which deep anxiety, deferred hope, and disappointment are quickly followed by the growth and increase of cancer that we can hardly doubt that mental depression is a weighty addition to the other influences favouring the development of the cancerous condition” [2]. Although a number of experimental studies in animals have found that various forms of stress increase the likelihood of developing different types of cancer [3], there are formidable problems in investigating the role of psychological factors in the genesis of cancers in homo sapiens. There are well-documented problems with the retrospective assessment of life events and dating the onset of the malignant process with precision is usually impossible [4]. Moreover, it is important not only to assess the occurrence of an event, but also the significance of that event for the individual concerned [5]. Several studies have been interpreted as showing a positive association between various life events and the onset of clinically evident cancer [6–8], but negative findings have also been reported [9]. Similarly, the etiological significance of mood and personality variables such as depression, emotional suppression, and social conformity remains unclear [10, 11]. PSYCHOSOCIAL FACTORS AND CANCER
Do psychosocial factors prolong survival? The possibility that psychological factors may alter the progression of malignant disease has also received attention [4]. A number of studies have examined the relationship between life events and relapse in breast cancer. As with their putative eti* Institute of Rehabilitation, University of Hull, Hull, UK. † Department of Surgery, University of Aberdeen, Aberdeen, UK. ‡ Department of Surgery, University of Nottingham, Nottingham, UK. Address correspondence to: Professor Leslie G. Walker, Institute of Rehabilitation, University of Hull, 215 Anlaby Road, Hull, HU3 2PG, UK. Phone: 01482 631826; Fax: 01482 635589; E-mail: [email protected]
497
498
Editorial
ological role, positive and negative results have been found [12–15]. Other studies have examined the relationship between coping strategies and disease outcome. Of particular note is a pioneering long-term follow-up study by Greer and colleagues who found that the fighting spirit and denial were associated with prolonged survival in women with breast cancer [16, 17]. These studies do not prove a causal relationship between coping style and survival. It could be, for example, that these coping strategies are manifestations of genetic factors that themselves influence the rate of disease progression. Alternatively, coping may be related to other factors relevant to outcome such as treatment compliance, characteristics of the tumor, nutritional state, and social support [18–20]. The most convincing evidence for a cause-and-effect relationship between psychosocial factors and the outcome of malignant disease comes from randomized, controlled clinical trials.
Randomized trials of psychosocial interventions In a landmark study, Spiegel et al. [21] carried out a 10-year follow-up of 86 women with metastatic breast cancer, some of whom had received group therapy consisting of a variety of interventions including peer group support, emotional expression, relaxation training, and autohypnosis. Although there was no statistically significant difference in the median survival of the patients receiving group therapy and the patients in the control group, the mean survival time of the patients receiving group therapy was 36.6 months compared with 18.9 months in the control group. The time from first metastasis to death was also increased in the patients who had received the group therapy. Subsequent analysis demonstrated that the results were not due to betweengroup differences in initial disease stage or to the amount of previous or subsequent radiotherapy, hormone therapy, or chemotherapy [21, 22]. However, the mechanism whereby the intervention enhanced survival is unclear in this study. The investigators themselves suggested that the intervention may have enhanced compliance with medical treatment, improved appetite and nutritional intake, and enabled patients to maintain a beneficial level of physical activity. In a detailed critique of this study, Fox [23, 24] pointed out that the survival curve for the control group lacks the expected right-skewed tail. He argued that the 12 patients in the control group who lived longest were an extremely aberrant sample because, according to other local data, they should have lived even longer than they did. Moreover, the survival curve for those receiving the intervention was similar to other local data for patients not receiving a psychosocial intervention. However, in a rejoinder, Spiegel et al. [25] considered that this post hoc interpretation of data could not be used to invalidate the significant treatment–control group difference in survival in the context of a randomized study. Fawzy et al. [26] evaluated disease recurrence and survival in 68 patients with malignant melanoma who participated in a brief group psychoeducational intervention. When the patients were followed-up between 5 and 6 years later, 10 of the 34 control patients had died compared with 3 of the 34 patients who had received the intervention. Multivariate analysis to take into account other possible reasons for differences in survival confirmed that the intervention per se had prolonged survival.
Editorial
499
Richardson et al. [27] also reported beneficial effects of psychosocial interventions. They compared the effects of three interventions designed to enhance compliance with medication and out-patient attendance in 94 patients with hematological malignancies. Patients were randomized to one of three educational interventions or a control condition. All patients randomized to an educational intervention were given a 1-hour interactive tape/slide presentation. In addition, some patients were given a home visit with, or without, a structured program to encourage them to take responsibility for medication. All three interventions enhanced treatment compliance. Multivariate analyses indicated that the educational interventions were associated with prolonged survival even when their beneficial effects on compliance were taken into account. More recently, Ratcliffe et al. [28] followed-up 63 patients with Hodgkin’s or nonHodgkin’s lymphoma. These patients had participated in a prospective, randomized, controlled trial to determine the effects of relaxation training and hypnotherapy in the control of chemotherapy-induced nausea and emesis. Five years after initial diagnosis, univariate analysis revealed that survival was related to age, stage of disease at presentation, and performance status. However, two psychosocial factors also achieved statistical significance, namely depression scores at diagnosis (Hospital Anxiety and Depression Scale [29]) and L-scores (thought in a medical context to be a measure of social conformity and the “cancer prone” [Type C] personality) (Eysenck Personality Questionnaire—Revised [30]). A subsequent univariate analysis (log-rank test) that stratified for L-scores showed a significant survival effect for the intervention (relaxation therapy with, or without, hypnotherapy) and the benefit appeared to be confined to patients with high L-scores [31]. Multivariate analysis using the Cox proportional hazards model found that early stage of disease at diagnosis, low depression scores, low scores on the L-scale, and (at the 0.058 level of significance) having a psychological intervention were independent prognostic factors for survival [28]. For various reasons, the investigators were cautious in their interpretation of the apparent advantage of the intervention on survival. A number of patients did not have troublesome chemotherapy side effects and, consequently, were not encouraged to practice relaxation or attend hypnotherapy. They were, of course, included in this intention-to-treat analysis. To date, published psychosocial intervention studies have not been designed primarily to demonstrate effects on survival. Unless the effects are very large and/or consistent across a range of interventions, it is not surprising that some studies have failed to demonstrate prolonged survival [32–35]. A number of studies designed to assess the impact of psychosocial interventions on survival, including Cunningham’s Healing Journey Program, are in progress and the results are awaited with great interest [25, 36–38]. If psychosocial interventions can influence survival in ways other than enhancing treatment compliance, what alternative mechanisms might be involved? Recent interest has focused on the possibility that these effects are mediated via psychoneuroimmunological mechanisms [18, 37, 39].
Psychosocial factors and the immune response Because the diagnosis and treatment of cancer are stressful experiences, the psychoneuroimmunological effects of stress on healthy individuals are of interest [40–
500
Editorial
42]. There is increasing evidence that psychological interventions can affect host defenses. However, can psychosocial factors modify the immune response to stress [43, 44]? To answer this question, 24 healthy volunteers were randomly allocated to an experimental intervention or to a control arm. The experimental intervention consisted of training in progressive muscular relaxation and cue-controlled relaxation for 3 weeks plus brief hypnotic suggestions immediately prior to exposure to an experimental stressor (doctor–patient role-play followed by feedback) on day 21. Subjects attended on three occasions (day 1, day 21, and day 22 or 23) and samples of blood were collected on these occasions for immunological analysis. Two samples of blood were taken at the second visit—one before exposure to the experimental stressor and one immediately thereafter. On exposure to the stressor, volunteers randomized to the experimental intervention showed increased lymphocyte proliferation in response to a mitogen (phytohemagglutinin) and enhanced circulating levels of interleukin-1 (IL-1). This suggests that the intervention improved the immune response to the experimental stressor. Changes in IL-1 following exposure to the stressor were positively correlated with Creative Imagination Scale [38] scores in the experimental group. Hypnotizability, therefore, may be an important moderator of the psychoneuroimmunological response to relaxation training and exposure to an acute stressor [46]. This study emphasizes the need to assess the possible interaction between the effects of interventions and response to a stressful experience; for example, coping with the diagnosis and treatment of malignant disease.
The effects of psychosocial interventions on the immune system in patients with cancer A prospective, randomized, controlled trial of relaxation training and guided imagery in 80 women with large or locally advanced breast cancer was recently carried out to assess the effects of this intervention on host defenses in patients with cancer. In addition to improving quality of life [47], the intervention increased the number and percentage of activated T cells (CD251), lowered the circulating level of tumor necrosis factor-alpha and enhanced lymphokine-activated killer (LAK) cell cytotoxicity. Although the two groups did not differ in natural killer (NK)-cell cytotoxicity, self-rated imagery quality was correlated with cytotoxicity at final followup [48]. Even in patients receiving immunosuppressive treatments (chemotherapy, surgery, radiotherapy), relaxation and imagery can produce immunological changes that may have clinical relevance. Fawzy et al. [26] found that their brief psychoeducational group intervention had demonstrable immunological effects. At the end of the intervention, which lasted only 6 weeks, there was a significant increase in the percentage of large granular lymphocytes (CD571). In addition, 6 months following the intervention there was an increase in NK cells (CD161 and CD561). However, although baseline NK activity was related to recurrence, changes in NK cell activity were not related to disease recurrence or to overall survival. The study, therefore, did not provide evidence that enhanced survival was a result of intervention-induced enhancement in NK-cell activity. Psychosocial factors and response to chemotherapy Another possible mechanism by which psychological factors may prolong survival is via response to medical treatment. We recently reported that psychological
Editorial
501
factors were important independent prognostic factors for clinical and pathological responses to cytotoxic chemotherapy in women with large or locally advanced breast cancer [49]. Stepwise multiple linear regression showed that the higher the level of mood disturbance before the first cycle of primary chemotherapy, the poorer the clinical and pathological response to chemotherapy. For example, pathological response to chemotherapy was affected independently by tumor size and by HADS depression score at the start of treatment. This finding provides further insight into how psychological factors may influence the survival of patients with cancer and extends the considerable literature linking quality of life to survival [50–55]. CONCLUSIONS
Evidence is accumulating that psychosocial interventions not only improve quality of life but may also prolong survival in patients with cancer. This may be achieved by means of a number of mechanisms, such as enhanced treatment compliance, better nutrition, a reduction in high-risk behaviors (e.g., unprotected sunbathing), alterations in coping strategies [56], improved quality of life, the provision of group or other social support, and direct effects on response to treatments such as chemotherapy. Although psychosocial interventions can alter host defenses, the clinical relevance of these changes in patients with cancer remains unclear. Just as the last decade saw a burgeoning of interest in psychosocial interventions to improve quality of life [57], the next decade will undoubtedly see considerable interest in the development and refinement of psychosocial interventions designed to prolong survival in patients with different types of cancer.
REFERENCES 1. Goldfarb C, Driesen J, Cole D. Psychophysiologic aspects of malignancy. Am J Psychiatry 1967; 123:1545–1552. 2. Paget J. Surgical pathology. London: Longman Green 1870. 3. Ben-Eliyahu S, Yirmiya R, Liebeskind JC, Taylor AN, Gale RP. Stress increases metastatic spread of a mammary tumor in rats: evidence for mediation by the immune system. Brain Behav Immunol 1991;5:193–205. 4. Watson M, Ramirez A. Psychological factors in cancer prognosis. In: Cooper CL, Watson M, eds. Cancer and stress: psychological, biological and coping studies. Chichester, UK: John Wiley & Sons 1991. 5. Hilakivi-Clarke L, Rowland J, Clarke R, Lippman ME. Psychosocial factors in the development and progression of breast cancer. Breast Cancer Res Treat 1994;29:141–160. 6. Chen CC, David AS, Nunnerly H, Mitchell M, Dawson JL, Berry H, Dobbs J, Berry H. Adverse life events and breast cancer: a case controlled study. BMJ 1995;311:1527–1530. 7. Courtney JG, Longnecker MP, Theorell T, Gerhardsson de Verdier M. Stressful life events and the risk of colorectal cancer. Epidemiology 1993;4:407–414. 8. Ginsberg A, Price S, Ingram D, Nottage E. Life events and the risk of breast cancer; a case control study. Eur J Cancer 1996;32A:2049–2052. 9. Roberts FD, Newcomb PA, Trentham-Dietz A, Storer BE. Self reported stress and risk of breast cancer. Cancer 1997;79:1055–1059. 10. Fox BH. Current theory of psychogenic effects on cancer incidence and prognosis. J Psychosoc Oncol 1983;1:17–31. 11. Fox BH. The role of psychological factors in cancer incidence and progression. Oncology 1995; 9:245–253. 12. Barraclough J, Pinder P, Cruddas M, Osmond M, Taylor AN, Perry M. Life events and breast cancer prognosis. BMJ 1992;304:1078–1081. 13. Barraclough J, Osmond M, Taylor AN, Perry M, Collins P. Life events and breast cancer prognosis. BMJ 1993;307:325.
502
Editorial
14. Ramirez AJ, Craig TJK, Watson JP, Fentiman IS, North WRS, Rubens RD. Stress and relapse of breast cancer. BMJ 1989;298:191–193. 15. Ramirez AJ, Richards MA, Gregory WM, Craig TJK, Watson JP, Fentiman IS. Life events and breast cancer prognosis. BMJ 1992;304:1632. 16. Greer S, Morris, T, Pettingale KW, Haybittle JL. Psychological response to breast cancer and 15 year outcome. Lancet 1990;335:49–50. 17. Pettingale KW, Morris T, Greer S, Haybittle JL. Mental attitudes to cancer: an additional prognostic factor. Lancet 1985;i:750. 18. Spiegel D, Kato PM. Psychosocial influences on cancer incidence and progression. Harvard Rev Psychiatry 1996;4:10–26. 19. Maunsell E, Brisson J, Deschennes L. Social support and survival among women with breast cancer. Cancer 1995;76:631–637. 20. Spiegel D, Sephton SE, Terr AI, Stites DP. Effects of psychosocial treatment in prolonging cancer survival may be mediated by immune pathways. Ann NY Acad Sci 1998;840:674–683. 21. Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet, 1989;ii:889–891. 22. Kogan MW, Biswas A, Pearl D, Carlson RW, Spiegel D. Effects of medical and psychotherapeutic treatment on the survival of women with breast carcinoma. Cancer 1997;80:225–230. 23. Fox BH. A hypothesis about Spiegel et al.’s 1989 paper on psychosocial intervention and breast cancer survival. Psycho-Oncol 1998;7:361–370. 24. Fox BH. Rejoinder to Spiegel et al. Psycho-Oncol 1998;7:518–519. 25. Spiegel D, Kraemer HC, Bloom JR. A tale of two methods: randomization versus matching trials in clinical research. Psycho-Oncol 1998;7:371–375. 26. Fawzy FI, Fawzy N, Hyun LS, Elashoff R, Guthrie D, Fahy JL, Morton DL. Malignant melanoma: effects of an early structured psychiatric intervention, coping and affective state on recurrence and survival 6 years later. Arch Gen Psychiatry 1993;50:681–689. 27. Richardson JL, Shelton DR, Krailo M, Levine AM. The effect of compliance with treatment on survival among patients with haematologic malignancies. J Clin Oncol 1990;80:356–364. 28. Ratcliffe MA, Dawson AA, Walker LG. Eysenck Personality Inventory L-scores in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Psycho-Oncol 1995;4:39–45. 29. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatry Scand 1983; 67:361–370. 30. Eysenck HJ, Eysenck SBG. Manual of the Eysenck Personality Scales (EPS Adult). London: Hodder & Stoughton 1991. 31. Walker LG. Hypnosis and cancer: host defences, quality of life and survival. Contemp Hypnos 1998; 15:34–39. 32. Gellert GA, Maxwell RM, Siegel BS. Survival of breast cancer patients receiving adjunctive psychosocial support therapy: a 10 year follow-up study. J Clin Oncol 1993;11:66–69. 33. Ilnyckyj A, Farber J, Cheang M, et al. A randomised controlled trial of psychotherapeutic interventions in cancer patients. Ann R Coll Phys Surg Can 1994;27:93–96. 34. Linn MW, Linn BS, Harris R. Effects of counselling for late stage cancer patients. Cancer 1982; 49:1048–1055. 35. Cunningham AJ, Edmonds CVI, Jenkins GP, Pollack H, Lockwood GA, Warr D. A randomised controlled trial of the effects of group psychological therapy on survival in women with metastatic breast cancer. Psycho-Oncol 1998;7:508–517. 36. Cunningham AJ. An experimental approach to the mind/cancer question. Adv J Mind-Body Health 1996;12:58–62. 37. Dreher H. The scientific and moral imperative for broad-based psychosocial interventions for cancer. Adv J Mind-Body Health 1997;13:38–49. 38. Goodwin PJ, Leszcz M, Koopmans J, Arnold A, Doll R, Chochinov H, Navarro M, Butler K, Pritchard KI. Randomised trial of group psychosocial support in metastatic breast cancer: the BEST study. Breast-Expressive Supportive Therapy. Cancer Treat Rev 1996;22(suppl A):91–96. 39. Lewis CE, O’Sullivan C, Barraclough J. The psychoimmunology of cancer. Oxford, UK: Oxford University Press 1994. 40. Walker LG, Eremin O. Psychoneuroimmunology: a new fad or the fifth cancer treatment modality. Am J Surg 1995;170:2–4. 41. Ader R, Felten DEL, Cohen N, eds. Psychoneuro-immunology, 2nd ed. San Diego, California: Academic Press 1991. 42. Herbert TC, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med 1993;55:364–369. 43. Gruzelier J, Clow A, Evans P, Lazar I, Walker LG. Mind–body influences on immunity: lateralised control, stress, individual difference predictors and prophylaxis. Ann NY Acad Sci 1998;851:487–494.
Editorial
503
44. Walker LG, Johnson VC, Eremin O. Modulation of the immune response to stress by hypnosis and relaxation training in normals: a critical review. Contemp Hypnos 1993;10:19–27. 45. Wilson SC, Barber TX. The Creative Imagination Scale as a measure of hypnotic responsiveness: applications to experimental and clinical hypnosis. Am J Clin Hypnos 1978;20:235–249. 46. Johnson VC, Walker LG, Whiting P, Heys SD, Eremin O. Can relaxation training and hypnotherapy modify the immune response to acute stress, and is hypnotisability relevant? Contemp Hypnos 1996; 13:100–108. 47. Walker LG, Walker MB, Ogston K, Heys SD, Ah-See AK, Miller ID, Hutcheon AW, Sarkar TK, Eremin O. Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. Br J Cancer 1999;80:262–268. 48. Walker LG, Walker MB, Simpson E, Fielden S, Ogston K, Segar A, Heys SD, Ah-See AK, Hutcheon AW, Eremin O. Guided imagery and relaxation therapy can modify host defences in women receiving treatment for locally advanced breast cancer. Br J Surg 1997;84(suppl 1):31. 49. Walker LG, Ogston K, Heys SD, Ah-See AK, Hutcheon AW, Eremin O. Psychological factors can predict response to primary chemotherapy in women with locally advanced breast cancer. Eur J Can (in press). 50. Addington-Hall JM, MacDonald LD, Anderson HR. Can the Spitzer Quality of Life Index help to reduce prognostic uncertainty in terminal care? Br J Cancer 1990;62:695–699. 51. Coates A, Gebski V, Signorini D, et al. Prognostic value of quality of life scores during chemotherapy for advanced breast cancer. J Clin Oncol 1992;10:1833–1838. 52. Coates A, Porzsolt F, Osoba D. Quality of life in oncology practice: prognostic value or EORTC QLQ-C30 scores in patients with advanced malignancy. Eur J Cancer 1997;33:1025–1030. 53. Earlam S, Glover C, Fordy C, Burke D, Allen-Mersh TG. Relation between tumour size, quality of life, and survival in patients with colorectal liver metastases. J Clin Oncol 1996;14:171–175. 54. Fraser SCA, Ramirez AJ, Ebbs SR, et al. A daily diary for quality of life measurement in advanced breast cancer trials. Br J Cancer 1993;67:341–346. 55. Morris JN, Sherwood S. Quality of life of cancer patients at different stages of the disease trajectory. J Chronic Dis 1987;40:545–553. 56. Walker LG, Walker MB, Ogston K, et al. Can the Type C personality be modified by relaxation therapy and guided imagery? Psycho-Oncol 1998;7:66–67. 57. Meyer TJ, Mark MM. Effects of psychosocial interventions with adult cancer patients: a meta-analysis of randomised experiments. Health Psychol 1995;14:101–108.