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David Spiegel, MD1 BACKGROUND. This study was designed to replicate our earlier finding that inten-
Lisa D. Butler, PhD1 sive group therapy extended survival time of women with metastatic breast can-
Janine Giese-Davis, PhD1 cer. Subsequent findings concerning the question of whether such psychosocial
Cheryl Koopman, PhD1 support affects survival have been mixed.
Elaine Miller, RN, MPH1 METHODS. One hundred twenty-five women with confirmed metastatic (n 5 122)
Sue DiMiceli, BA2 or locally recurrent (n 5 3) breast cancer were randomly assigned either to the sup-
Catherine C. Classen, PhD3 portive-expressive group therapy condition (n 5 64), where they received educa-
Patricia Fobair, LCSW, MPH4 tional materials plus weekly supportive-expressive group therapy, or to the control
Robert W. Carlson, MD5 condition (n 5 61), where they received only educational materials for a minimum
Helena C. Kraemer, PhD1 of 1 year. The treatment, 90 minutes once a week, was designed to build new bonds
of social support, encourage expression of emotion, deal with fears of dying and
1
Department of Psychiatry and Behavioral death, help restructure life priorities, improve communication with family mem-
Sciences, Stanford University School of Medicine, bers and healthcare professionals, and enhance control of pain and anxiety.
Stanford, California. RESULTS. Overall mortality after 14 years was 86%; median survival time was 32.8
2
SoluGenics LLC, Palo Alto, California. months. No overall statistically significant effect of treatment on survival was
3 found for treatment (median, 30.7 months) compared with control (median, 33.3
Department of Psychiatry, University of Toronto,
Toronto, Ontario, Canada. months) patients, but there was a statistically significant intervention site-by-
4
condition interaction. Exploratory moderator analysis to explain that interaction
Department of Radiation Oncology, Stanford Uni-
revealed a significant overall interaction between estrogen-receptor (ER) status
versity School of Medicine, Stanford, California.
and treatment condition (P 5 .002) such that among the 25 ER-negative partici-
5
Department of Medicine/Oncology, Stanford Uni- pants, those randomized to treatment survived longer (median, 29.8 months)
versity School of Medicine, Stanford, California.
than ER-negative controls (median, 9.3 months), whereas the ER-positive partici-
pants showed no treatment effect.
This study was made possible by National Insti- study and takes responsibility for data integrity Seplaki, Krista Thorne Yocam, Thai Nguyen,
tute for Mental Health grant 5R01MH047226 and data analysis accuracy; Study concept and Trina Kurek, Rita Halbach, Christopher Biggs,
with additional funding from the National Cancer design: Spiegel, Fobair, Carlson, Kraemer; Data Susan Diamond Moore, Susan Weisberg, Meg
Institute, the American Cancer Society PF-4185, acquisition: Spiegel, Butler, Giese-Davis, Miller, Marnell, Frank Stockdale, Eric Neri, Sandie
The John D. and Catherine T. MacArthur Founda- Classen, Fobair; Data analysis and interpretation: Sephton, Amanda Kovattana, Catherine Byers,
tion, and the Fetzer Institute. The study sponsors Spiegel, Giese-Davis, Butler, Koopman, DiMiceli, Christine Blasey, Bill Moyers, referring commu-
had no role in the design and conduct of the Carlson, Kraemer; Drafting of the manuscript: nity physicians, the Stanford Oncology Day
study, collection, management, analysis, interpre- Spiegel, Butler, Giese-Davis; Critical revision of Care Center, and the patients and their
tation of the data, or preparation, review, or the manuscript for important intellectual content: spouses and families who participated in the
approval of the manuscript. Spiegel, Butler, Giese-Davis, Koopman, Miller, study.
DiMiceli, Classen, Fobair, Carlson; Statistical
ClinicalTrials.gov Identifier: NCT00226928. http:// analysis: Giese-Davis, Butler, Koopman, DiMiceli,
Address for reprints: David Spiegel, MD, Depart-
www.clinicaltrials.gov Kraemer; Funding acquisition: Spiegel, Butler,
ment of Psychiatry and Behavioral Sciences,
Koopman, Giese-Davis; Administrative, technical,
Stanford University School of Medicine, Stanford,
This article was presented at the annual meeting or material support: Miller, Carlson; Study super-
CA 94305-5718; Fax: (650) 498-6678; E-mail:
of the American Psychiatric Association, May 20, vision: Spiegel, Butler, Koopman, Carlson.
dspiegel@stanford.edu
2006, Toronto, Canada.
The authors acknowledge the contributions of
The authors of this article contributed as fol- Irvin Yalom, Jane Benson, Xin-Hua Chen, Karin Received February 26, 2007; revision received
lows: Dr. Spiegel had full access to all data in the Calde, Leslie Kinder, Lynne LoPresto, Julie April 10, 2007; accepted April 24, 2007.
CONCLUSIONS. The earlier finding that longer survival was associated with sup-
portive-expressive group therapy was not replicated. Although it is possible that
psychosocial effects on survival are relevant to a small subsample of women who
are more refractory to current hormonal treatments, further research is required
to investigate subgroup differences. Cancer 2007;110:1130–7. 2007 American
Cancer Society.
TABLE 1
Demographic Variables at Baseline (Mean [SD] or Number of Cases [% of Total Sample])
Total sample
Age at randomization* 53.3 (10.8) 53.1 (10.6) 54.8 (10.48) 54.8 (11.4) 48.4 (7.9)
Education, y* 15.9 (2.4) 16.1 (2.7) 17.1 (2.7) 15.6 (2.4) 15.5 (2.4)
Ethnicity (% white) 50 (82.0) 59 (92.2) 32 (88.9) 51 (87.9) 26 (83.9)
Income
Below $39,999 21 (34.4) 14 (21.9) 10 (27.8) 19 (32.8) 6 (19.4)
$40,000–$79,999 22 (36.1) 24 (37.5) 13 (36.1) 18 (31.0) 15 (48.4)
Above $80,000 18 (29.5) 25 (39.1) 13 (36.1) 20 (34.5) 10 (32.3)
Did not respond 0 1 (1.6) 0 1 (1.7) 0
Currently employed (% yes) 33 (54.1) 37 (57.8) 24 (66.7) 21 (36.2) 25 (80.6)
Hours worked per wk* 31.6 (13.3) 32.2 (11.7) 33.5 (10.7) 25.4 (16.5) 34.8 (9.2)
No. of children 2.1 (1.5) 2.6 (2.4) 2.3 (2.4) 2.7 (2.0) 1.9 (1.2)
No. of people in household 2.2 (1.0) 2.4 (1.2) 2.2 (1.1) 2.2 (1.0) 2.4 (1.1)
TABLE 2
Prognostic Variables at Baseline (Mean [SD] or Number of Cases [% of Total Sample])
Total sample
Age at initial diagnosis, y 47.2 (10.3) 47.2 (10.2) 48.6 (10.2) 48.7 (10.5) 42.8 (8.5)
Age at recurrence, y* 50.9 (10.1) 51.3 (10.5) 52.5 (10.0) 52.7 (10.9) 46.5 (8.0)
Premenopausal at randomization <50 y* (%) 26 (42.6) 25 (39.1) 15 (41.7) 18 (31.0) 18 (58.1)
Disease free interval, mo from initial diagnosis to metastasisy 44.5 (34.7) 47.7 (36.4) 46.6 (38.9) 48.0 (33.8) 42.1 (35.3)
Months from recurrence/metastasis to study randomization 28.7 (48.2) 22.2 (27.0) 29.0 (47.9) 24.9 (35.7) 22.1 (33.1)
Dominant location of metastasis or recurrence
Chest wall or regional lymph nodes (%)y 20 (32.8) 18 (28.1) 10 (27.8) 16 (27.6) 12 (38.7)
Bone (%) 22 (36.1) 28 (43.8) 13 (36.1) 21 (36.2) 16 (51.6)
Viscera (%) 19 (31.1) 18 (28.1) 13 (36.1) 21 (36.2) 3 (9.7)
Estrogen receptor status
Negative (%) 12 (21.4) 13 (21.0) 6 (17.1) 13 (24.1) 6 (20.7)
Positive (%) 44 (78.6) 49 (79.0) 29 (82.9) 41 (75.9) 23 (79.3)
Chemotherapy (%) 31 (50.8) 29 (45.3) 17 (47.2) 33 (56.9) 10 (32.3)
Hormone therapy (%) 47 (77.0) 50 (78.1) 28 (77.8) 44 (75.9) 25 (80.6)
5) systemic treatment received since metastasis and/or tion [SD] 5 55.6) and with metastasis for an average of
recurrence (none, chemotherapy only, hormonal ther- 2 years (25.4 months, SD 5 38.8).
apy only, chemotherapy and hormonal therapy), and 6)
institution (Stanford Oncology Day Care, Kaiser Medi- Survival
cal Center, community oncologist). Randomization Participant survival or death was determined for all
was conducted for overall assignment to treatment ver- participants by research staff communication with par-
sus control condition. On average, participants had ticipants, family members, and/or physicians, or by
been initially diagnosed with primary breast cancer 6 consulting the Social Security Death Index, and then all
years (71.5 months) before study entry (standard devia- reported deaths were confirmed by death certificate.
1134 CANCER September 1, 2007 / Volume 110 / Number 5
TABLE 3
Cox Regression on Survival for Treatment Versus Control by Site for
Women With Metastatic Breast Cancer (N 5 125)
Hazard 95% CI
B SE Wald df P ratio lower-upper
Cox regression analysis included condition, dummy variables for N-1 Sites. (Stanford and San Francisco)
and the interaction between Condition and Sites. All variables were centered.
B indicates Cox regression; SE, standard error of the mean; df, degrees of freedom; P, probability; CI, con-
fidence interval.
currence more among ER-negative than ER-positive addition, randomization was determined by computer
women.43 Breast cancer is coming to be understood program, but it was conducted by the project director
as a family of diseases, as gene array analysis of rather than someone independent of the project, and
mRNA expression is showing considerable heteroge- patients were randomized for the study as a whole, not
neity of breast cancer subtypes44,45 with wide variabil- by site.
ity in prognosis and treatment response. In particular,
ER-positive and ER-negative tumors come from dif- Conclusion
ferent cell lineages (luminal vs basal), further explain- Although the present study failed to replicate earlier
ing resistance to hormone-related treatments among findings of psychotherapy treatment effects on sur-
ER-negative patients,46 who have poorer overall prog- vival, it is clear that group psychotherapy is emotion-
nosis.47 Thus, it is possible that any putative effect of ally beneficial for metastatic breast cancer patients.
psychosocial support on survival among ER-positive Being confronted with their worst fears as they see
women has been superseded by highly effective hor- others die of the same illness, with help in managing
monal treatments, which may also have effects the strong emotions that understandably arise, is
on hypothalamic-pituitary-adrenal (HPA) functioning emotionally helpful for patients and not physically
that is affected by stress management. Outcome harmful. Picturing and even watching the manner of
among ER-negative women is less affected by hormo- one’s own death does not hasten it. As both medical
nal treatments, leaving room for the impact of other treatment and psychosocial support have improved
treatments such as chemotherapy, specific oncogene- and our understanding of breast cancer has become
targeted monoclonal antibodies, or effects of psycho- more sophisticated, more targeted treatments of
social intervention on stress response systems in the both types may enhance overall effectiveness.
body. However, conclusions about the effect of group
therapy in this subgroup of patients awaits further REFERENCES
study and replication. 1. Spiegel D, Bloom JR, Yalom I. Group support for patients
Recognition of the need for psychosocial support with metastatic cancer. A randomized outcome study. Arch
for cancer patients has increased substantially over Gen Psychiatry. 1981;38:527–533.
2. Spiegel D, Bloom JR. Group therapy and hypnosis reduce
the past few decades as has the availability of sup-
metastatic breast carcinoma pain. Psychosom Med. 1983;45:
port groups for cancer patients.48 When we started 333–339.
our original trial in the late 1970s, our main problem 3. Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psy-
was convincing patients randomized to group ther- chosocial treatment on survival of patients with metastatic
apy to participate in this novel intervention. In the breast cancer. Lancet. 1989;2:888–891.
4. Kogon MM, Biswas A, Pearl D, Carlson RW, Spiegel D.
current study that started in the 1990s, the recruit-
Effects of medical and psychotherapeutic treatment on
ment challenge had changed. Control patients who the survival of women with metastatic breast carcinoma.
were not assigned to group treatment were disap- Cancer. 1997;80:225–230.
pointed. Indeed, 1 control patient demanded a list of 5. Kuchler T, Henne-Bruns D, Rappat S, et al. Impact of psy-
names of other control patients in the study so that chotherapeutic support on gastrointestinal cancer patients
undergoing surgery: survival results of a trial. Hepatogas-
she could start a support group (we did not comply
troenterology. 1999;46:322–335.
with this request). Also, breast cancer patients are 6. McCorkle R, Strumpf NE, Nuamah IF, et al. A specialized
now far less likely to be alone emotionally with their home care intervention improves survival among older post-
illness because there is greater public understanding, surgical cancer patients. J Am Geriatrics Soc. 2000;48:1707–
acceptance, and support.49 1713. Comment in: J Am Geriatr Soc. 2000;48:1732–1733.
7. Fawzy FI, Fawzy NW, Hyun CS, et al. Malignant melanoma.
Effects of an early structured psychiatric intervention, cop-
Limitations ing, and affective state on recurrence and survival 6 years
As noted above, there are several limitations to the later. Arch Gen Psychiatry. 1993;50:681–689.
present study, including significant baseline differ- 8. Fawzy FI, Canada AL, Fawzy NW. Malignant melanoma:
ences across sites in age at randomization, education, effects of a brief, structured psychiatric intervention on
survival and recurrence at 10-year follow-up. Arch Gen Psy-
and hours worked per week. There was also a signifi- chiatry. 2003;60:100–103.
cant site-by-condition interaction for disease-free 9. Richardson JL, Shelton DR, Krailo M, Levine AM. The effect
interval and dominant location of recurrence or metas- of compliance with treatment on survival among patients
tasis, leading to apparent differences in treatment with hematologic malignancies. J Clin Oncol. 1990;8:356–364.
effects across sites that were likely driven by imbal- 10. Linn MW, Linn BS, Harris R. Effects of counseling for late
stage cancer. Cancer. 1982;49:1048–1055.
ances in the prognostic variables. These imbalances 11. Ilnyckyj A, Farber J, Cheang M, Weinerman B. A rando-
might have been produced by our efforts to stratify for mized controlled trial of psychotherapeutic intervention in
prognostic variables in a sample of modest size. In cancer patients. Ann R Coll Phys Surg Can. 1994;27:93–96.
1138 CANCER September 1, 2007 / Volume 110 / Number 5
12. Edelman S, Lemon J, Bell DR, Kidman AD. Effects of group 32. Early Breast Cancer Trialists’ Collaborative Group
CBT on the survival time of patients with metastatic breast (EBCTCG). Effects of chemotherapy and hormonal therapy
cancer. Psychooncology. 1999;8:474–481. for early breast cancer on recurrence and 15-year survival:
13. Cunningham AJ, Edmonds CVI, Jenkins GP, Pollack H, an overview of the randomised trials. Lancet. 2005;365:
Lockwood GA, Warr D. A randomized controlled trial of the 1687–1717. Comments in: ACP J Club. 2005;143:58. Lancet.
effects of group psychological therapy on survival in 2005;365:1665–1666.
women with metastatic breast cancer. Psychooncology. 33. Kraemer HC, Frank E, Kupfer DJ. Moderators of treatment
1998;7:508–517. outcomes: clinical, research, and policy importance. JAMA.
14. Goodwin PJ, Leszcz M, Ennis M, et al. The effect of group 2006;296:1286–1289.
psychosocial support on survival in metastatic breast can- 34. Kraemer HC, Stice E, Kazdin A, Offord D, Kupfer D. How
cer. N Engl J Med. 2001;345:1719–1726. do risk factors work together? Mediators, moderators, and
15. Kissane DW, Love A, Hatton A, et al. Effect of cognitive- independent, overlapping, and proxy risk factors. Am J Psy-
existential group therapy on survival in early-stage breast chiatry. 2001;158:848–856.
cancer. J Clin Oncol. 2004;22:4255–4260. 35. Kraemer HC. Pitfalls of multisite randomized clinical trials
16. Spiegel D. Effects of psychotherapy on cancer survival. Nat of efficacy and effectiveness. Schizophr Bull. 2000;26:533–
Rev Cancer. 2002;2:383–389. 541.
17. Newell SA, Sanson-Fisher RW, Savolainen NJ. Systematic 36. Yalom ID, Greaves C. Group therapy with the terminally ill.
review of psychological therapies for cancer patients: over- Am J Psychiatry. 1977;134:396–400.
view and recommendations for future research. J Natl Can- 37. Fox BA. A hypothesis about Spiegel et al.’s 1989 paper on
cer Inst. 2002;94:558–584. psychosocial intervention and breast cancer survival. Psy-
18. Chow E, Tsao MN, Harth T. Does psychosocial intervention chooncology. 1998;7:361–370.
improve survival in cancer? A meta-analysis. Palliat Med. 38. Goodwin PJ, Pritchard KI, Spiegel D. The Fox guarding the
2004;18:25–31. clinical trial: internal vs. external validity in randomized
19. Edwards AG, Hailey S, Maxwell M. Psychological interven- studies [letter]. Psychooncology. 1999;8:275. Comment in:
tions for women with metastatic breast cancer. Cochrane Psychooncology. 1999;8:366–367.
Database Syst Rev. 2004:CD004253. Comment in: Evid 39. Kissane DW, Grabsch B, Clarke DM, et al. Supportive-ex-
Based Nurs. 2004;7:110. pressive group therapy for women with metastatic breast
20. Smedslund G, Ringdal GI. Meta-analysis of the effects of psy- cancer: survival and psychosocial outcome from a ran-
chosocial interventions on survival time in cancer patients. domized controlled trial. Psychooncology. 2007;16:227–
J Psychosom Res. 2004;57:123–131; discussion, 133–135. 286.
21. Spiegel D. Commentary on meta-analysis of the effects of 40. Riggs BL, Hartmann LC. Selective estrogen-receptor modu-
psychosocial interventions on survival time and mortality lators – mechanisms of action and application to clinical
in cancer patients by Geir Smedslund and Gerd Inger Ring- practice. N Engl J Med. 2003;348:618–629.
dal. J Psychosom Res. 2004;57:133–135. 41. Smith IE, Dowsett M. Aromatase inhibitors in breast can-
22. Spiegel D, Giese-Davis J. Depression and cancer: mechanisms cer. N Engl J Med. 2003;348:2431–2442.
and disease progression. Biol Psychiatry. 2003;54:269–282. 42. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-re-
23. Evans DL, Charney DS, Lewis L, et al. Mood disorders in ceptor status and outcomes of modern chemotherapy for
the medically ill: scientific review and recommendations. patients with node-positive breast cancer. JAMA. 2006;295:
Biol Psychiatry. 2005;58:175–189. 1658–1667.
24. Classen C, Butler LD, Koopman C, et al. Supportive-expres- 43. Chlebowski RT, Blackburn GL, Elashoff RE, et al. Dietary
sive group therapy and distress in patients with metastatic fat reduction in postmenopausal women with primary
breast cancer: a randomized clinical intervention trial. Arch breast cancer: Phase III Women’s Intervention Nutrition
Gen Psychiatry. 2001;58:494–501. Study (WINS) [abstract]. ASCO Meeting Abstracts. 2005;23:
25. Efron B. Forcing a sequential experiment to be balanced. 10.
Biometrika. 1971;58:403–417. 44. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of
26. Spiegel D, Classen C. Group Therapy for Cancer Patients: A human breast tumours. Nature. 2000;406:747–752.
Research-Based Handbook of Psychosocial Care. New York: 45. Sorlie T, Tibshirani R, Parker J, et al. Repeated observa-
Basic Books; 2000. tion of breast tumor subtypes in independent gene
27. Spiegel H, Spiegel D. Trance and Treatment: Clinical Uses expression data sets. Proc Natl Acad Sci U S A. 2003;100:
of Hypnosis. Washington, DC: American Psychiatric Pub- 8418–8423.
lishing; 2004. 46. Kristensen VN, Sorlie T, Geisler J, et al. Gene expression
28. Giese-Davis J, Koopman C, Butler LD, et al. Change in profiling of breast cancer in relation to estrogen receptor
emotion-regulation strategy for women with metastatic status and estrogen-metabolizing enzymes: clinical impli-
breast cancer following supportive-expressive group ther- cations. Clin Cancer Res. 2005;11(2 pt 2):878s–883s.
apy. J Consult Clin Psychol. 2002;70:916–925. 47. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression
29. Kraemer HC, Robinson TN. Are certain multicenter rando- patterns of breast carcinomas distinguish tumor subclasses
mized clinical trial structures misleading clinical and pol- with clinical implications. Proc Natl Acad Sci U S A.
icy decisions? Contemp Clin Trials. 2005;26:518–529. 2001;98:10869–10874.
30. Kraemer HC, Blasey CM. Centering in regression analyses: 48. Gore-Felton C, Spiegel D. Enhancing women’s lives: the
a strategy to prevent errors in statistical inference. Int J role of support groups among breast cancer patients.
Methods Psychiatr Res. 2004;13:141–151. J Spec Group Work. 1999;24:274–287.
31. Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and 49. Pohls UG, Renner SP, Fasching PA, et al. Awareness of
USA breast cancer deaths down 25% in year 2000 at ages breast cancer incidence and risk factors among healthy
20–69 years. Lancet. 2000;355:1822. women. Eur J Cancer Prev. 2004;13:249–256.