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1130

Effects of Supportive-Expressive Group Therapy on


Survival of Patients With Metastatic Breast Cancer
A Randomized Prospective Trial

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.

ª 2007 American Cancer Society


DOI 10.1002/cncr.22890
Published online 23 July 2007 in Wiley InterScience (www.interscience.wiley.com).
Effects of Supportive-Expressive Group Therapy on Breast Cancer Survival/Spiegel et al. 1131

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.

KEYWORDS: metastatic breast cancer, survival, group therapy, randomized clinical


trial, estrogen receptor status, stress, distress, psychosocial support.

tions,20 although the small number of studies and


D oes living better mean living longer with cancer?
Considerable interest in this topic has been gen-
erated since the possibility was raised that intensive
diversity of treatments and cancers makes this a dif-
ficult distinction to sustain.21 Other systematic
group psychotherapy may result not only in im- reviews have found the evidence to be divided but
proved mood,1 better coping,1 and reduced pain,2 the results to be not random, with some studies
but also in longer survival.3 Our original study, begun showing a survival advantage for psychosocial inter-
in the 1970s, was a randomized trial in which we vention, others showing no difference, but none
had initially hypothesized better emotional outcome showing a survival disadvantage for those given psy-
but not longer survival. The treatment and control chosocial support.16,22,23 This study was designed as
groups were well balanced on prognostic variables, a replication trial of our original finding.
and we found a mean 18-month survival advantage
that was not accounted for by differences in medical
treatment.4 Since then, 3 other published rando- MATERIALS AND METHODS
mized trials5–8 and 1 matched cohort trial9 also Research Participants
found that psychosocial treatment for patients with a Patients were eligible for study if they had a very
variety of cancers produced both psychological and high risk for death from breast cancer and were
survival benefits. However, 6 other published stu- selected on the basis of having metastatic and/or
dies,10,11 4 involving breast cancer patients,12–15 recurrent breast cancer. Other inclusion criteria
found no survival benefit for those treated with psy- included an ability to speak English, the absence of a
chotherapy. Three of these studies reported only second cancer or other life-threatening illness, and
transient12 or no psychological benefit of any willingness to participate in group treatment if ran-
kind.11,13 The quality of the psychosocial intervention domized to that condition. Enrolling 125 women into
may be 1 variable that is critical to medical out- this study was determined to have better than 90%
come.16 An intervention that does not help emotion- power to detect effects of the treatment condition on
ally is not likely to provide physical benefit. However, survival corresponding to a standardized mean dif-
3 other studies10,14,15 showed a positive psychological ference between average survival times of approxi-
effect but no survival advantage. The quality of the mately .64, based upon results from our prior study,3
group therapy in the Goodwin et al. study14 was indicating a 67% probability (area-under-the-curve
attested to by reductions in distress and pain, with [AUC]) that a treatment subject would live longer
even greater psychological benefit found among than a control subject and a 34% probability that a
those who were more anxious and depressed initially. control subject would outlive a treatment subject.
Likewise, Kissane et al.15 reported reduced anxiety, a A total of 155 women were screened between
trend toward improved family functioning, and 1991 and 1996, but 30 were not randomized; 12
greater satisfaction with treatment among women dropped out because of disease progression, 7 were
with primary breast cancer offered Cognitive-Existen- found to be ineligible after medical record review;
tial Group Therapy, but neither found a survival and 11 decided they did not want to continue in the
advantage. study (see Fig. 1).
One systematic review17 and 2 meta-analy- The 125 participants were enrolled at 1 of 3
18,19
ses that examined survival at specific time treatment intervention sites by location. Twenty-eight
points after intervention found no effect of psy- women were recruited through the Oncology Day
chotherapy on cancer survival time. However, Care Center at Stanford University Medical Center,
another meta-analysis reported an overall survival 37 through letters sent to community oncologists
advantage for individual, but not group, interven- (including Kaiser Permanente patients), 6 were
1132 CANCER September 1, 2007 / Volume 110 / Number 5

FIGURE 1. Consort diagram.

referred by oncology social workers, and 54 were Randomization


self-referred from brochures distributed in the com- Participants were randomized by the project director, a
munity and notices in local newspapers and breast research nurse, who used computer-assisted adaptive
cancer newsletters. All continued to receive standard randomization based on a biased coin-design method
cancer treatment throughout the study. Only 1 to promote comparability of medical status in treat-
patient in the present trial was treated with trastuzu- ment and control conditions25 of the following vari-
mab (Herceptin).24 Analysis is by intention-to-treat ables: 1) dominant location of metastasis (chest wall/
(N 5 125), with the characteristics of the final sam- regional lymph nodes, bone, viscera), 2) estrogen-re-
ple presented in Tables 1 and 2. All participants gave ceptor status (positive, negative, unknown), 3) disease-
written informed consent for participation in a pro- free interval (time from initial diagnosis of breast can-
tocol approved by the Stanford University School of cer to first metastasis and/or recurrence at <1 year,
Medicine Human Subjects Committee. 1–3 years, >3 years), 4) age (<50 years, 50 years),
Effects of Supportive-Expressive Group Therapy on Breast Cancer Survival/Spiegel et al. 1133

TABLE 1
Demographic Variables at Baseline (Mean [SD] or Number of Cases [% of Total Sample])

Total sample

Control Treatment San Francisco Stanford San Jose


Demographic variables at baseline n 5 61 (%) n 5 64 (%) n 5 36 (%) n 5 58 (%) n 5 31 (%)

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)

* Significant main effect for site, P < .05.

TABLE 2
Prognostic Variables at Baseline (Mean [SD] or Number of Cases [% of Total Sample])

Total sample

Control Treatment San Francisco Stanford San Jose


Prognostic variables at baseline n 5 61 n 5 64 n 5 36 n 5 58 n 5 31

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)

* Significant main effect for site, P < .05.


y
Significant site-by-condition interaction, P < .05.

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

Intervention Condition longer subsequent survival. Overall mortality was 86%,


The weekly 90-minute therapy sessions involved 3–15 close enough to our a priori level of 90% that no subse-
participants (patients only, not family members) and quent change would affect our conclusions. Survival
were led by 2 therapists; study therapists included a analysis was by intent-to-treat, and all 125 women
psychiatrist, psychologists, and social workers. Differ- who were randomized were included in analyses.
ent therapists led the groups at each site, but 1 (D.S.) One treatment participant never attended group, 2
led the Stanford group, attended groups at the other 2 dropped out after 1 or 2 sessions, and 2 began attend-
sites, and supervised all therapists. The supportive- ing only a year or more after randomization. Demo-
expressive therapy model involved the creation of a graphic and medical variables are described in Table l.
supportive environment where participants were en- In the primary a priori analysis, Cox proportional
couraged to confront their problems, strengthen their hazards analysis was used to test for effects of the
relationships, and find enhanced meaning in their condition (group therapy plus education or educa-
lives. The intervention was semistructured, with thera- tion only), site, and the site-by-condition interaction,
pists trained to facilitate discussion of the themes (site was included to test whether or not treatment
listed, as material emerged in an emotionally expres- effects on survival generalized across sites).29 A pre-
sive rather than didactic format. The themes included liminary analysis examined potential imbalance in
1) building new bonds of social support, 2) facilitating assignment to condition and site, with baseline con-
the expression of emotion, 3) confronting fears of dying tinuous demographic and medical status variables
and death including dealing with the deaths of group tested by 2-way analysis of variance, including site,
members, 4) reordering life priorities, 5) improving condition, and the site-by-condition interaction (with
support from and communication with family and independent variables and the interaction term all
friends, 6) enhancing communication with physicians, centered).30 The significance of baseline categorical
and 7) learning to use self-hypnosis for anxiety and variables was, likewise, tested by logistic regression
pain control.24,26–28 There were 3 treatment groups, 1 at with site, condition, and the site-by-condition inter-
each site, and they met weekly for 90-minute sessions. action (centered).
Although the basic treatment period was 1 year, partici- Whereas the a priori hypothesis was unidi-
pants were invited to remain in the groups for as long rectional, all tests of statistical significance were 2-
as they wished, and most continued to participate as tailed. After the primary survival analysis was com-
long as their health permitted, up to 12.5 years. The pleted, which included tests of site as a moderator of
psychological efficacy of the intervention in this trial treatment outcome, 3 additional exploratory analyses
was demonstrated by previously reported significant were conducted to examine possible sources of treat-
reductions in mood disturbance, traumatic stress ment-effect differences across sites as follows: loca-
symptoms,24 and pain, and improvements in emotion tion of metastatic spread, disease-free interval, and
regulation.28 None of these significant psychosocial estrogen-receptor status. The first 2 variables were
treatment outcomes differed by site.24,28 chosen because of significant baseline site-by-condi-
tion effects, and analyses were conducted to examine
Control Condition possible sources of survival differences across sites.
To ensure full participation and cooperation, we Estrogen-receptor status was chosen because the
offered a self-directed education intervention to all most important medical treatment difference bet-
women in the study, so the experimental comparison ween our original study and the current one is the
was group therapy plus education versus education advent of hormonal therapies for women with estro-
alone. All participants were given a form from which gen-receptor positive tumors.31,32 For each of these
to select materials to take home on loan. The selec- analyses, Cox proportional hazards analysis was used
tion of 30 books, 15 pamphlets, 5 videotapes, and 7 to test for effects of the moderator, condition, site,
audio tapes covered a wide range of topics related to and all interactions of site with the moderator and
medical and emotional aspects of breast cancer. Par- with condition (all centered) on survival. As explora-
ticipants were also given a 1-year membership to a tory analyses, these are not definitive tests but
consumer health library in their community. Thirty- hypotheses for future research.
two (53%) control patients and 35 (55%) treatment
patients used these resources.
RESULTS
Data Analysis Overall median survival time was 32.8 months from
The primary hypothesis of the current study was that study entry, 33.3 months for the educational control
randomization to group psychotherapy would result in sample and 30.7 months for the treatment group. Cox
Effects of Supportive-Expressive Group Therapy on Breast Cancer Survival/Spiegel et al. 1135

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

Condition 20.07 0.21 0.12 1 0.731 0.93 0.62–1.40


Stanford site 0.45 0.25 3.12 1 0.078 1.56 0.95–2.56
San Francisco site 0.44 0.28 2.48 1 0.115 1.55 0.90–2.67
Condition 3 Stanford 20.62 0.51 1.52 1 0.218 0.54 0.20–1.45
Condition 3 San Francisco 21.41 0.56 6.38 1 0.012 0.24 0.08–0.73

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.

proportional hazards analysis of survival with condi-


tion (treatment, control), site (San Francisco, San Jose,
or Stanford), and site-by-condition interactions (all FIGURE 2. Kaplan-Meier survival curves for treatment and control groups
centered) indicated that there was no overall sig- by ER-negative and ER-positive status. Cox proportional hazards interaction
nificant effect of treatment on survival, hazard B 5 21.84 (Wald 5 9.76, P 5 .002) for overall interaction between ER sta-
ratio 5 0.93 (95% confidence interval [CI], 0.62 to 1.40; tus and group condition.
P 5 .73; see Table 3). There was a statistically signi-
ficant site-by-condition interaction, specifically a dif-
ference between the treatment effects at the San free interval could not account for site differences in
Francisco and San Jose sites. At the San Francisco site, treatment effects on survival. Estrogen-receptor (ER)
control group median survival was 18.4 months (95% status was selected for the third post hoc moderator
CI, 6.8–30.0), and treatment group median survival analysis because ER status identified those patients
was 51.0 months (95% CI, 2.6–99.3). At the San Jose who were refractory to the major medical treat-
site, control group median survival was 70.6 months ment advance, which was the advent of hormonal
(95% CI, 13.9–127.2), and treatment group median sur- therapies for women with ER-positive tumors,
vival 29.8 months (95% CI, 26.0–33.5). Whereas at between the first study conducted in the 1970s and
Stanford, control group median survival was 32.8 the current trial.31 There was a significant interac-
months (95% CI, 13.2–52.4), and treatment group me- tion between ER status and condition (Cox propor-
dian survival was 28.4 months (95% CI, 18.8–38.0). tional hazards interaction B 5 21.84, Wald 5 9.76,
When we examined baseline differences in site P 5 .002) within the entire sample, as well as the
and site-by-condition interaction, we found the fol- expected significant effect of ER status on survival
lowing results and used these to guide subsequent (Cox proportional hazards B 5 .63, Wald 5 4.53,
analyses. There were significant differences across P 5 .033). Also, the statistically significant site-by-
sites (but not between treatment and control sam- condition interaction disappeared (P 5 .66) when ER
ples) in age at randomization, education, and hours status was included in the analysis. Figure 2 presents
worked per week. There was a significant site-by- the survival curves for ER-positive and ER-negative
condition interaction for disease-free interval and status by treatment and control group. It can be seen
dominant location of recurrence or metastasis (chest that although there are no significant treatment
wall or regional lymph nodes vs bone or viscera). effects in the ER-positive group (control-group me-
Because we found them to be unbalanced across dian survival, 42.5 months; treatment-group median
sites, we examined location of metastatic spread survival, 30.7 months), the treatment versus control
(bone and viscera vs chest wall) and disease-free differences in the ER-negative group (control-group
interval at baseline in exploratory moderator ana- median survival, 9.3 months; treatment-group me-
lyses30,33–35 to identify possible sources of the sign- dian survival, 29.8 months) are similar to those
ificant site-by-condition differences in survival. reported in our earlier study.3 That study was con-
However, in these moderator analyses, the site differ- ducted at a time when hormonal treatments were
ences in treatment effects on survival persisted, indi- less widely used and when overall survival was
cating that location of metastatic spread and disease- shorter.31 Furthermore, the treatment-control differ-
1136 CANCER September 1, 2007 / Volume 110 / Number 5

TABLE 4 months, respectively) compared with those of the


Outside Group and Other Therapy Participation Assessed During the original study participants (mean 5 37.0 months and
First Year of the Study mean 5 22.9 months, respectively). Thus, the current
Control Treatment sample had far longer overall survival, likely reflect-
Participation during study period n 5 61 (%) n 5 64 (%) ing both sample differences and recent improve-
ments in breast cancer treatment.31,32 Our earlier
No. of groups attended 1.0 (1.11) 0.8 (0.91) study3 had been criticized by Fox37 because survival
Participation in groups outside study 38 (62.3) 37 (57.8)
in the control arm was not consistent with Surveil-
Participation in cancer groups 26 (42.6) 14 (21.9)
Participation in therapy outside study 12 (19.7) 16 (25.4) lance, Epidemiology, and End Results [SEER] registry
survival data, although it was noted that the internal
comparison between treatment and control groups
ences among ER-negative patients were consistent in a randomized trial is more telling than matching
across all 3 treatment sites. to an external comparison group.38 Nonetheless, the
Since our earlier study,3 the availability of com- overall finding of this study is consistent with that of
munity cancer support groups has increased. We Goodwin et al.14 and Kissane et al.39 in finding no
examined participation by women in both control effect of group psychotherapy on survival time of
and treatment conditions in additional support women with metastatic breast cancer.
groups (both cancer and noncancer groups), volun- The source of the statistically significant differen-
teer activities, and individual or couple’s therapy (Ta- tial effects of treatments across sites cannot be defi-
ble 4). As would be expected, women in the control nitively determined, but it does not affect the overall
condition participated in significantly more cancer finding. The reduction in distress and improvement
groups outside the study (control: 26 of 61 [42.6%]; in emotion regulation provided by group therapy
treatment: 14 of 64 [21.9%], chi-square 5 5.90, obtained at all 3 sites,24,28 so differences in adher-
P 5 .02, logistic regression with site, condition, and ence to the treatment model are not likely to account
the site-by-condition interaction, all centered). How- for differences in survival outcome. Moderator analy-
ever, they did not differ in the total number of addi- sis is useful to search for subpopulations that may
tional support groups in which they participated be differentially responsive to treatments.33 In an ex-
(control: mean 5 1.0, standard deviation 5 1.1; treat- ploratory moderator analysis, we found a significant
ment: mean 5 0.8, standard deviation 5 0.9, 2-way treatment effect by ER status on survival suggesting
analysis of variance, site, condition, and the site-by- that, among ER-negative patients (21% of our sam-
condition interaction, all centered). A similar number ple), random assignment to group psychotherapeutic
of women in each condition participated in indivi- treatment was associated with significantly longer
dual, couple’s, and family therapy outside the study survival, whereas the same is not true for those with
(control: 12 of 61 [19.7%]; treatment 16 of 64 [25.4%], ER-positive status. Furthermore, when ER status was
chi-square 5 .58, P 5 .45). included in the analysis, site-by-treatment interac-
tions seen in the primary analysis disappeared, and
ER-negative treatment patients lived longer than ER-
DISCUSSION negative controls at each of the 3 sites. Although this
Although this study failed to replicate our original was exploratory, there are several reasons to believe
finding of enhanced survival among women ran- that differences in estrogen-receptor status may be
domly assigned to a year of supportive-expressive crucial to breast cancer prognosis and treatment
group psychotherapy in the overall sample, it did response. Significant advances have been made in
replicate the inconsistency of results found since improving hormonal therapies that use selective
then between different studies. The median survival estrogen response modifiers and aromatase inhibitors,
of 32.8 months in this study is substantially longer as well as in improving risk:benefit ratios of targeted
than the 17.6 months reported by Goodwin et al. in chemotherapies.40,41 Indeed, survival with metastatic
the BEST trial (who analyzed her results earlier than breast cancer has improved substantially since the
we did)14 and the 17 months in our earlier trial,36 mid-1980s.31,32 Recent studies have shown that
suggesting sample differences. The control partici- among ER-positive patients, hormonal treatments are
pants in the present study had much longer survival, sufficiently effective that chemotherapy adds rela-
a median of 33 months. This is particularly notable tively little to survival, whereas improved chem-
given similarities in the disease-free interval and otherapy treatment regimens make a considerable
time from metastasis to study entry of the current difference among ER-negative women.42 Similarly, a
participants (mean 5 46.1 months and mean 5 25.4 diet intervention has been found to reduce risk of re-
Effects of Supportive-Expressive Group Therapy on Breast Cancer Survival/Spiegel et al. 1137

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
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