Mood and Clinical Status in Patients With Multiple Myeloma By Peter M. Silberfarb, Keaven M. Anderson, Amy Chen Rundle, Jimmie C.B. Holland, M. Robert Cooper, and 0. Ross McIntyre Two hundred ninety patients with a recent diagnosis of multiple myeloma were studied psychologically at the time of initial treatment. Physician- and patientcompleted psychosocial scales were correlated with physical variables used to measure tumor load and physical status. A logistic regression model was used to analyze objective response to treatment. Indirect measures of response to treatment were obtained, and factors influencing survival duration were studied
using a Cox regression model. If physical variables were controlled, there were no significant correlations between psychologic scores on entry and response to treatment or survival duration. Thus, the notion that mood influences disease outcome once the disease process has begun in patients with multiple myeloma is not supported by this data set. J Clin Oncol 9:2219-2224. © 1991 by American Society of Clinical Oncology.
HE IMPORTANCE of a positive mind-set in fighting cancer to improve survival has been observed anecdotally by physicians and laypeople for years. Although no sound investigation has been devised to test this observation, common sense dictates its importance. Unfortunately, however, it also forms a basis for promulgating some of the unproven methods that often gain popularity in the treatment and management of cancer. There have been several interesting studies in humans implying that mental attitude can affect
Psychosocial performance is evaluated by physicians as well as by patients themselves.
T
disease outcome,'" whereas other studies indicate 8 no such relationship.'" Jamison et al' controlled
for some of the methodological weaknesses in prior studies and suggested that psychosocial variables did not play a large part in survival of 49 breast cancer patients with metastic disease. It is
apparent that controlling all physical variables, including known prognostic factors and stage of disease, are crucial to the proper interpretation of
this type of research. Studies of patients with multiple myeloma may shed some light on the intriguing interplay between psychologic and physical state because the tumor-cell load of the patient is easy to quantify and the many physical variables known to hold
prognostic importance for the disease are easily measured. The following study is such an attempt to assess the psychologic state of patients with recently diagnosed multiple myeloma while con-
trolling physical factors known to influence disease. The objective was to evaluate psychologic
functioning in multiple myeloma patients by means of several standard tests and to explore the associ-
ation of these findings with response and survival.
METHODS In 1977, we activated a study (Cancer and Leukemia Group B [CALGB] 7761) that tested four chemotherapeutic regimens in previously untreated patients with a diagnosis of multiple myeloma. The response and survival results from this clinical trial are reported elsewhere.' Briefly, patients were randomly assigned to treatment on regimens offering (1) a single alkylating agent, (2) sequential alkylating agents, (3) combination alkylating agents, or (4) combination alkylating agents plus doxorubicin. In addition, all patients received a tapering course of prednisone. The diagnosis of multiple myeloma was based on criteria devel1 oped by the Chronic Leukemia-Myeloma Task Force," and tumor-cell load was derived using the method developed by the Southwest Oncology Group." Study parameters included a history, a physical examination, the usual laboratory tests, bone marrow aspiration and biopsy, serum protein electrophoresis, and M component typing and quantification. These tests were performed at specified times during the study. In addition to monitoring symptoms, changes in the physical examination, renal function, M component level in serum and urine, pain, physical performance, and recalcification of bone lesions were assessed.
From the Dartmouth-HitchcockMedical Center,Lebanon; Cancer and Leukemia Group B Statistical Office, Lebanon, NH; Memorial Sloan-Kettering Hospital, New York, NY; and Bowman-Gray School ofMedicine, Winston-Salem, NC. Submitted July 17, 1989; acceptedJune 24, 1991. Supported by PublicHealth Service grantsfrom the National Cancer, National Institutes of Health, and Department of Health and Human Services; and Norris Cotton CancerCenter core grantno. CA-23108-13. Address repnnt requests to P.M. Silberfarb,MD, Department of Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756. 0 1991 byAmerican Society of Clinical Oncology. 0732-183X91/0912-0004$3.00/0
Journal of Clinical Oncology, Vol 9, No 12 (December), 1991: pp 2219-2224
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SILBERFARB ET AL
Strict criteria for indicating relapse or progression of disease were used to assess response duration, and changes in myeloma cell mass were assessed.' A direct response was defined as a reduction of serum or urinary M component to 50% of the initial value, healing of bone lesions, or 50% decrease in the area of measured soft tissue lesions. Indirect responses included specified improvement in hemoglobin, creatinine, serum calcium, performance, or pain. In addition, a bone marrow response was defined as a reduction of 200 per 1,000 nucleated marrow cells, if the initial marrow was composed of > 25% plasma cells. If the marrow contained 10% to 25% plasma cells, a reduction to 5% was defined as a response. Between 1977 and early 1982, 615 previously untreated multiple myeloma patients were entered onto this protocol. Patients were randomly assigned to the four treatment regimens. Almost half of the patients-290 of them-consented to participate in the additional psychosocial portion of the protocol. Psychosocial assessments were made for these 290 patients before initial treatment, at 12-week intervals, at remission or relapse, and at the end of 2 years of treatment. Four psychosocial data collection instruments were used. First, psychosocial functioning was evaluated by means of physician-rated global psychologic status on a 0 to 4 scale, ranging from superior functioning to life-threatening mental symptoms. Second, a physician-completed handicaprating scale was used, measuring employment limitation, social life restriction, emotional stability, intellectual dysfunction, and awareness of illness. Third, the Profile of Mood States (POMS), a popular self-report psychologic tool used to measure depression, tension, anger, vigor, fatigue, and confusion, was administered. Adjectives are rated on a five-point scale. POMS has been widely used in studying psychologic aspects of cancer. It is easily administered and has wide empirical acceptance. 12 Finally, we used a brief form of the Multiple Affective Adjective Check List (MAACL), which is a patient-completed scale that assesses anxiety, depression, and hostility by means of a series of adjectives that the patient checks."' A major reason for selecting the POMS and MAACL was their ease of administration in the medically ill. Characteristics such as age, tumor-cell load, and creatinine levels of participants at study entry and nonparticipants were categorized and compared using a x2 test. The log-rank test was used to compare survival time and time to response to treatment for participants and nonparticipants. Mean POM scores for male multiple myeloma patients and female multiple myeloma patients were calculated separately and compared with data from other previously 2 untreated adult patients with recent diagnoses of cancer." To study the association of handicap ratings and POMS scores with extent of disease, various measures of disease status (such as calcium, creatinine, serum M component) were broken into "low" and "high" groups to measure tumor-cell load and response. The psychosocial measurement scores of these two groups were then compared using a Wilcoxon test. Survival was analyzed using Cox's regression model for survival data. Each POMS and MAACL score, as well as total POMS, was fit in a univariate model to test for
differences in survival associated with that variable. Logistic regression was used to see if POMS or MAACL scores might be useful in predicting marrow response, indirect response, or direct response." RESULTS
This was one of the first attempts to study psychosocial functioning in the setting of a cooperative group chemotherapy trial. It was anticipated that compliance with the psychosocial portion of the protocol would be limited. Indeed, 290 patients-just under one half of the 615 assessable
patients-were entered on the psychosocial portion of the protocol. We analyzed multiple characteristics of patients completing psychosocial data (290) with those who did not complete psychosocial data (325) and found no difference between the two groups in age, sex, tumor-cell load, creati-
nine, or other prognostic variables. Participants were similar to nonparticipants in demographic as well as outcome measures such as survival and response to treatment. Table 1 summarizes demo-
graphic data at entry for the 290 patients in the psychosocial portion of the study. Upon entry onto the study, we asked patients three questions that we believed would be important for interpreting future emotional responses (Table 2). Religion was rather important to these patients, past emotional symptoms were uncommon, and answers were evenly distributed regarding whether the multiple myeloma had changed their lives. Table 3 lists entry psychosocial data on all patients as evaluated by physicians. Patients
were seen to be quite healthy psychologically on these variables (0, best; 4, worst) when they began treatment. Upon entry, patients also appeared to be quite healthy psychologically (Table 4) as judged by two self-report scales (POMS and
MAACL), with a higher score indicating greater distress. Adjectives describing how one felt during the past week including today were rated as to frequency on a five-point scale (0, not at all; 4,
extremely) in the POMS. In the MAACL, adjectives describing moods and feelings were to be checked if the patient felt that way that day. When POMS scores were compared with POMS data for
cancer patients (Table 4),12 the results were very similar. No statistically significant differences were found from the t-tests performed.
Unfortunately, the physician and patient were not asked the same questions regarding the pa-
tient's status upon entry onto the study; hence,
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PSYCHOLOGIC FUNCTION IN MYELOMA Table 1. Demographic Data for Participants
Sex Male Female Race White Black Other Unknown Age (years) < 40 40-49 50-59 60-69 > 70 Unknown Religion Protestant Catholic Jewish Other Unknown Education Grade school High school College Professional school Unknown Family income < $5,000 $5,000-s15,000 $15,000-$30,000 > $30,000 Unknown
N
%
157 133
54 46
selves as being more limited). For example, for the MAACL scores, 163 of the 498 patients (32.7%) felt very anxious, 77 of 276 (27.9%) felt very depressed, and 40 of 276 (14.5%) felt very hostile. In all three cases, the patients' physicians rated those patients as having mild "emotional instability." Likewise, for the POMS scores, most of the disagreement occurred such that physicians underrated tension, depression, vigor, and fatigue, and also underrated, but to a lesser degree, anger and confusion. Upon entry there were no significant statistical correlations between psychologic scores and physical variables, except that patients with high pain or poor performance scores had higher scores on the POMS and MAACL than did those with low pain or good performance scores. Therefore, patients who were worse physically were also worse psychologically. This is intuitively correct and consistent with clinical experience, thus supporting the view that our scales were sensitive to changes in mood and affect. There were differences in the various components of the handicap-rating scale at study entry when patients were separated into the physical groupings mentioned previously. However, these differences were also associated with known measures of prognosis. Higher ratings were always associated with higher creatinine levels, higher calcium levels, higher tumor-cell load, etc. There were no statistically significant differences between these physical groupings and patients' responses to the importance of religion, past emotional symptoms, or how illness had changed their physical and mental state. At 3 months, we compared the effects of the various treatments on POMS and MAACL scores and found no differences from study entry scores on the four treatment regimens. We then examined the relationship between positive response to treatment and length of survival and found no correlation between psycho-
213 60 3 14 9 30 77 97 57 20 167 58 22 23 20 97 134 32 9 18 62 116 43 12 57
different assessments were made. This means that ratings cannot be directly correlated with each other. It would have been useful, for example, to ask the patient about his/her awareness of illness so that one could see how the physician's rating of that question compared with the patient's own view. Nevertheless, the item of emotional instability rated by a physician could be roughly correlated with a patient's POMS and MAACL scores. In general, the patient ratings were more extreme in the negative direction (ie, patients rated them-
Table 2. Patient Self-Rating Upon Entry Into Study No. of Responses (%) Question Asked
Not At All
A Little
Moderately
Quite a Bit
How important is your religion to you? Did you have significant emotional symptoms in the past, before your illness? Has illness changed your physical and mental state?
9 (3)
18 (7)
56 (22)
177 (68)
167 (65)
47 (18)
21 (8)
22 (9)
37 (15)
61 (24)
61 (24)
90 (36)
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SILBERFARB ET AL Table 3. Physician Rating of Psychosocial Function of Patients Upon Entry to Study Rating Scale* (%)
Physician Rating of Patients Global psychosocial rating Psychosocial handicap rating Employment limitation Social life restrictions Emotional instability Intellectual dysfunction Awareness of illness
N
0
1
2
3
4
279
34
57
8
1
0
276 276 276 277 275
17 35 30 72 67
16 24 59 20 25
15 22 10 6 1
9 7 0 1 3
42 12 0 0 4
*Rating scale key: Global psychosocial rating: 0, superior functioning despite level of illness; 1, minor intermittent symptoms or stability maintained with effort; 2, moderate to marked emotional distress; 3, severe to profound mental symptoms; 4, life-threatening mental symptoms. Employment limitation: 0, usual work; 1, slightly less than usual work/housework; 2, work reduced by one half or more; 3, occasional work; 4, unable to work. Social life restrictions: 0, full social activities; 1, no new and fewer optional contacts; 2, contact only with family and close friends; 3, contact only with family; 4, contact with medical staff-family are visitors. Emotional stability: 0, normal emotional state; 1, mild emotional distress that requires no intervention; 2, moderate emotional symptoms requiring intervention; 3, severe symptoms requiring psychiatric intervention; 4, severe symptoms requiring psychiatric hospitalization or equivalent. Intellectual dysfunction: 0, none; 1, noticeable change but performing activities as usual; 2, significant change interfering with function; 3, severe loss of memory, orientation, requiring assistance in care; 4, no apparent intellectual function. Awareness of illness: 0, full awareness of illness; 1, occasionally acts unaware of illness; 2, frequently acts unaware-interferes with treatment; 3, usually acts unaware; 4, little or no awareness of illness.
logic scores and survival except on the POMS, where more vigor was associated with longer survival and more fatigue was associated with poor survival. However, if tumor-cell load was included in the Cox regression model, neither POMS vigor nor POMS fatigue was significantly associated with survival. Therefore, neither the patient-rated nor physician-rated mood states were related to survival. A logistic regression model was used for analyzing objective responses to treatment. Responses to treatment were grouped as either direct or indirect. 9 A direct response indicated objective improvement in either the serum M component, urine M component, soft tissue mass, bone lesions, or marrow. An indirect response was an improvement in the hemoglobin, creatinine, calcium, pain,
or performance. No association was found between these and the POMS or the MAACL scores. A Cox regression model was used for measuring survival duration. The POMS' subscores of vigor and fatigue likely reflected disease status; hence, they were predictive of survival duration. However, the results were not significant when tumorcell load was included in the model. Finally, because studies of cancer patients have suggested that denial might be associated with positive outcome, we looked at the association between awareness-of-illness scores as reported by physicians and survival and found no association after the usual medical prognostic factors were taken into consideration. Psychologic information was available on 24 patients at the time they relapsed. We compared
Table 4. Mean POM Scores for Multiple Myeloma Patients Versus Other Cancer Patients Males POMS Subtest Tension Depression Anger Vigor Fatigue Confusion Total
Multiple Myeloma Patients N Mean SD 128 127 126 127 126 125 106
12.0 10.5 5.8 13.4 9.7 7.4 37.4
7.4 9.4 6.4 6.8 6.6 5.2 31.2
Females Other Cancer Patients N Mean SD 457 457 457 457 457 457 457
12.5 10.3 6.0 14.5 9.9 6.9 31.2
7.2 10.1 6.4 6.8 7.6 5.0 33.7
Multiple Myeloma Patients
Other Cancer Patients
N
Mean
SD
N
Mean
SD
108 108 108 107 107 107 97
12.8 11.5 5.6 11.8 10.3 7.9 40.8
7.4 10.2 6.5 6.2 6.9 4.8 30.1
209 209 209 209 209 209 209
14.5 11.9 6.9 12.7 10.9 7.6 39.2
8.5 11.3 8.4 6.4 7.4 5.5 38.8
NOTE. Data for other cancer patients come from previously untreated adult patients with recently diagnosed cancer within CALGB trials 2 in 25 hospitals. Types of cancer include gastric, pancreatic, and lung (limited and extensive).'
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2223
PSYCHOLOGIC FUNCTION IN MYELOMA
this with study entry data for the same patients and found no change except that MAACL anxiety scores at the time of relapse, surprisingly, were less than on entry in 10 patients. Given the large number of tests performed and the relatively small amount of data, this result probably should not be considered significant. We also compared relapse data with psychologic data at 3 months and found no differences. DISCUSSION
The correlation between bereavement and increased risk of morbidity and mortality in humans has been noted frequently,14 although the specific link to cancer is less clear." Recently, there have been studies linking depression and cancer incidence. 6 ,"7 Studies of husbands of women dying of breast cancer demonstrated depression of immunologic functioning in these men,' 8 thus implicating the link between psychologic health and physical disease. Greer et al4 have implicated a woman's attitude toward illness as possibly predictive of survival in breast cancer patients. Spiegel et al6 studied patients with metastatic breast cancer 10 years after a year of weekly group therapy that emphasized self-hypnosis for pain relief. Patients in the intervention group survived significantly longer than the control patients. However, our study appears to contradict the notion that psychologic state, at least in multiple myeloma cancer patients, influences disease outcome once the disease process has begun. We found no significant correlation between psychologic scores on entry and response to treatment or survival duration if physical variables such as tumor-cell load and other known measures of prognosis were controlled. Mood states were not related to survival, whether as noted by physicians or patients. However, this study reports disease outcome and not quality of life, where positive emotions presumably would be important. Also,
we did not study social support and its effect on survival or response to treatment. Hislop et al"'9 recently reported the importance of a social support network as an independent prognostic factor in disease-free survival in women with breast cancer, and Stavraky et al2 have noted the importance of social support to the survival rate of lung cancer patients. Social support may have been a factor in the increased survival of breast cancer patients reported by Spiegel et al.6 However, the positive contribution of social support to the enhancement of survival in cancer patients is an area that requires further investigation before its import is embraced as fact. One of the limitations of the study was that physician and patient did not use the same rating scales to assess patient status; thus, it was difficult to assess directly the relationship between ratings. While this was not the main focus of the study, this information would have been relevant and interesting. Another limitation of our study is that there may have been selection biases in the study population. The participation rate for the psychosocial study was relatively low, as over one half those enrolled in the protocol did not choose to take part in the psychosocial portion. However, there were no differences between nonparticipants and participants with regard to age, sex, tumor-cell load, response to treatment, and survival. Our findings should not be construed as discouraging of a positive mental outlook for patients, as this clearly is tantamount to a positive quality of life. Instead, this study should be interpreted as further evidence to encourage multiple myeloma patients to rely on scientific medicine for treatment in addition to their psychologic strengths. ACKNOWLEDGMENT The authors thank Alice Kornblith and Roger Davis for statistical advice.
APPENDIX The following members of the Cancer and Leukemia Group B (and respective grants) participatedin this study: James R. Anderson, Harvard School of Public Health, Boston, MA (CA-33601): M. Robert Cooper, Bowman-Gray School of Medicine, Winston-Salem, NC (CA-03927); Edward S. Henderson, Roswell Park Memorial Institute, Buffalo, NY (CA-02599); Gibbons G. Cornwell, Dartmouth-Hitchcock Medical Center, Lebanon, NH (CA-04326); Irving Berkowitz, Wilmington Medical Center, Wilmington, DE (CA-37041); Nis I. Nissen, Finsen Institute, Copenhagen, Denmark; Robert Kyle, Mayo Clinic, Rochester, MN (CA-04646); J.L. Hutchinson, McGill Cancer Centre, Montreal, Canada (CA-31809); James F. Holland, Mount Sinai School of Medicine, New York, NY (CA-04457); Richard R. Silver, Cornell Medical Center, New York, NY (CA-07968); Sameer Rafla, Maimonides Hospital, New York, NY (CA-25119); Raymond Weiss, Walter Reed Army Medical Center,
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SILBERFARB ET AL
2224 APPENDIX (Cont'd)
Washington, DC (CA-26806); Rose Ruth Ellison, Columbia University, New York, NY (CA-12011); Mark Green, University of California at San Diego, San Diego, CA (CA-11789); Michael Perry, University of Missouri, Columbia, MO (CA-12046); Arlan Gottlieb, Upstate Medical Center at Syracuse, Syracuse, NY (CA-21060); Joseph Aisner, University of Maryland Cancer Center, Baltimore, MD (CA-31983); Louis Leone, Rhode Island Hospital, Providence, RI (CA-08025); Robert Carey, Massachusetts General Hospital, Boston, MA (CA-12449); Kanti Rai, Long Island Jewish Medical Center, New Hyde Park, NY (CA-11028); Franco Cavalli, Swiss Group, Inselspital, Bern, Switzerland; Farid Haurani, Thomas Jefferson Medical Center, Philadelphia, PA (CA-05462); Geoffrey Faulkson, H.F. Verwoerd Hospital, Pretoria, South Africa; Lucius Sinks, Georgetown University Hospital, Washington, DC (CA-21083); Peter Raich, West Virginia University Medical Center, Morgantown, WV (CA-28562); David Ontjes, University of North Carolina, Chapel Hill, NC; Albert B. Einstein, Jr, Virginia Mason Medical Clinic, Seattle, WA; and Norris Cotton Cancer Center core grant (CA-23108-13) for editorial and word processing assistance.
REFERENCES 1. Davies RK, Quinan DM, McKegney P, et al: Organic factors and psychological adjustment in advanced cancer patients. Psychosom Med 35:464-471, 1973 2. Derogatis LR, Abeloff MD, Melisaratos N: Psychological coping mechanisms and survival time in metastatic breast cancer. JAMA 242:1504-1508, 1979 3. Weisman AD, Worden JW: Psychosocial analysis of cancer deaths. Omega 6:61-75, 1979 4. Greer S, Moris T, Penningale KW: Psychological response to breast cancer: Effect on outcome. Lancet 2:785-787, 1979 5. Bloom JR: Social support, accommodation to stress and adjustment to breast cancer. Soc Sci Med 16:1329-1338, 1982 6. Spiegel D, Bloom JR, Kraemer HC, et al: Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 1:888-891, 1989 7. Cassileth BR, Lusk EJ, Miller DS, et al: Psychosocial correlates of survival in advanced malignant disease. N Engl J Med 312:1551-1555, 1985 8. Jamison RN, Burish TG, Wallston KA: Psychogenic factors in predicting survival of breast cancer. J Clin Oncol 5:768-772, 1987 9. Cooper MR, McIntyre OR, Propert K, et al: Single, sequential, and multiple alkylating agent therapy for multiple myeloma: A CALGB study. J Clin Oncol 4:1331-1339, 1986 10. Chronic Leukemia-Myeloma Task Force, National Cancer Institute: Proposed guidelines for protocol studies. II. Plasma cell myeloma. Cancer Chemother Rep 4:145-158, 1973
11. Durie BJ, Salmon SE: A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 36:842-852, 1985 12. Cella DF, Tross S, Orav EJ, et al: Mood states of patients after the diagnosis of cancer. J Psychosoc Oncol 7:45-53, 1989 13. Zuckerman M, Lubin B, Vogel L, et al: Measurement of experimentally induced affects. J Consult Psychol 28:418425, 1964 14. Lynch JJ: The Broken Heart. New York, NY, Basic Books, 1976 15. Bieliauskas LA, Garron DC: Psychological depression and cancer. Gen Hosp Psychiatry 4:187-195, 1982 16. Shekelle RB, Raynor WJ, Ostfeld AM, et al: Psychological depression and 17 year risk of death from cancer. Psychosom Med 43:117-125, 1981 17. Persky VW, Kempthorne-Rawson J, Shekelle RB: Personality and risk of cancer: 20-year follow-up of the Western Electric study. Psychosom Med 49:435-449, 1987 18. Schleifer SJ, Keller SE, Camerino M, et al: Suppression of lymphocyte stimulation following bereavement. JAMA 250:374-377, 1983 19. Hislop TG, Waxier NE, Coldman AJ, et al: The prognostic significance of psychosocial factors in women with breast cancer. J Chron Dis 40:729-735, 1987 20. Stavraky KM, Donner AP, Kincade JE, et al: The effect of psychosocial factors on lung cancer mortality at one year. J Clin Epidemiol 41:75-82, 1988
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using a Cox regression model. If physical variables were controlled, there were no significant correlations between psychologic scores on entry and response to treatment or survival duration. Thus, the notion that mood influences disease outcome once the disease process has begun in patients with multiple myeloma is not supported by this data set. J Clin Oncol 9:2219-2224. © 1991 by American Society of Clinical Oncology.
HE IMPORTANCE of a positive mind-set in fighting cancer to improve survival has been observed anecdotally by physicians and laypeople for years. Although no sound investigation has been devised to test this observation, common sense dictates its importance. Unfortunately, however, it also forms a basis for promulgating some of the unproven methods that often gain popularity in the treatment and management of cancer. There have been several interesting studies in humans implying that mental attitude can affect
Psychosocial performance is evaluated by physicians as well as by patients themselves.
T
disease outcome,'" whereas other studies indicate 8 no such relationship.'" Jamison et al' controlled
for some of the methodological weaknesses in prior studies and suggested that psychosocial variables did not play a large part in survival of 49 breast cancer patients with metastic disease. It is
apparent that controlling all physical variables, including known prognostic factors and stage of disease, are crucial to the proper interpretation of
this type of research. Studies of patients with multiple myeloma may shed some light on the intriguing interplay between psychologic and physical state because the tumor-cell load of the patient is easy to quantify and the many physical variables known to hold
prognostic importance for the disease are easily measured. The following study is such an attempt to assess the psychologic state of patients with recently diagnosed multiple myeloma while con-
trolling physical factors known to influence disease. The objective was to evaluate psychologic
functioning in multiple myeloma patients by means of several standard tests and to explore the associ-
ation of these findings with response and survival.
METHODS In 1977, we activated a study (Cancer and Leukemia Group B [CALGB] 7761) that tested four chemotherapeutic regimens in previously untreated patients with a diagnosis of multiple myeloma. The response and survival results from this clinical trial are reported elsewhere.' Briefly, patients were randomly assigned to treatment on regimens offering (1) a single alkylating agent, (2) sequential alkylating agents, (3) combination alkylating agents, or (4) combination alkylating agents plus doxorubicin. In addition, all patients received a tapering course of prednisone. The diagnosis of multiple myeloma was based on criteria devel1 oped by the Chronic Leukemia-Myeloma Task Force," and tumor-cell load was derived using the method developed by the Southwest Oncology Group." Study parameters included a history, a physical examination, the usual laboratory tests, bone marrow aspiration and biopsy, serum protein electrophoresis, and M component typing and quantification. These tests were performed at specified times during the study. In addition to monitoring symptoms, changes in the physical examination, renal function, M component level in serum and urine, pain, physical performance, and recalcification of bone lesions were assessed.
From the Dartmouth-HitchcockMedical Center,Lebanon; Cancer and Leukemia Group B Statistical Office, Lebanon, NH; Memorial Sloan-Kettering Hospital, New York, NY; and Bowman-Gray School ofMedicine, Winston-Salem, NC. Submitted July 17, 1989; acceptedJune 24, 1991. Supported by PublicHealth Service grantsfrom the National Cancer, National Institutes of Health, and Department of Health and Human Services; and Norris Cotton CancerCenter core grantno. CA-23108-13. Address repnnt requests to P.M. Silberfarb,MD, Department of Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756. 0 1991 byAmerican Society of Clinical Oncology. 0732-183X91/0912-0004$3.00/0
Journal of Clinical Oncology, Vol 9, No 12 (December), 1991: pp 2219-2224
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2219
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SILBERFARB ET AL
Strict criteria for indicating relapse or progression of disease were used to assess response duration, and changes in myeloma cell mass were assessed.' A direct response was defined as a reduction of serum or urinary M component to 50% of the initial value, healing of bone lesions, or 50% decrease in the area of measured soft tissue lesions. Indirect responses included specified improvement in hemoglobin, creatinine, serum calcium, performance, or pain. In addition, a bone marrow response was defined as a reduction of 200 per 1,000 nucleated marrow cells, if the initial marrow was composed of > 25% plasma cells. If the marrow contained 10% to 25% plasma cells, a reduction to 5% was defined as a response. Between 1977 and early 1982, 615 previously untreated multiple myeloma patients were entered onto this protocol. Patients were randomly assigned to the four treatment regimens. Almost half of the patients-290 of them-consented to participate in the additional psychosocial portion of the protocol. Psychosocial assessments were made for these 290 patients before initial treatment, at 12-week intervals, at remission or relapse, and at the end of 2 years of treatment. Four psychosocial data collection instruments were used. First, psychosocial functioning was evaluated by means of physician-rated global psychologic status on a 0 to 4 scale, ranging from superior functioning to life-threatening mental symptoms. Second, a physician-completed handicaprating scale was used, measuring employment limitation, social life restriction, emotional stability, intellectual dysfunction, and awareness of illness. Third, the Profile of Mood States (POMS), a popular self-report psychologic tool used to measure depression, tension, anger, vigor, fatigue, and confusion, was administered. Adjectives are rated on a five-point scale. POMS has been widely used in studying psychologic aspects of cancer. It is easily administered and has wide empirical acceptance. 12 Finally, we used a brief form of the Multiple Affective Adjective Check List (MAACL), which is a patient-completed scale that assesses anxiety, depression, and hostility by means of a series of adjectives that the patient checks."' A major reason for selecting the POMS and MAACL was their ease of administration in the medically ill. Characteristics such as age, tumor-cell load, and creatinine levels of participants at study entry and nonparticipants were categorized and compared using a x2 test. The log-rank test was used to compare survival time and time to response to treatment for participants and nonparticipants. Mean POM scores for male multiple myeloma patients and female multiple myeloma patients were calculated separately and compared with data from other previously 2 untreated adult patients with recent diagnoses of cancer." To study the association of handicap ratings and POMS scores with extent of disease, various measures of disease status (such as calcium, creatinine, serum M component) were broken into "low" and "high" groups to measure tumor-cell load and response. The psychosocial measurement scores of these two groups were then compared using a Wilcoxon test. Survival was analyzed using Cox's regression model for survival data. Each POMS and MAACL score, as well as total POMS, was fit in a univariate model to test for
differences in survival associated with that variable. Logistic regression was used to see if POMS or MAACL scores might be useful in predicting marrow response, indirect response, or direct response." RESULTS
This was one of the first attempts to study psychosocial functioning in the setting of a cooperative group chemotherapy trial. It was anticipated that compliance with the psychosocial portion of the protocol would be limited. Indeed, 290 patients-just under one half of the 615 assessable
patients-were entered on the psychosocial portion of the protocol. We analyzed multiple characteristics of patients completing psychosocial data (290) with those who did not complete psychosocial data (325) and found no difference between the two groups in age, sex, tumor-cell load, creati-
nine, or other prognostic variables. Participants were similar to nonparticipants in demographic as well as outcome measures such as survival and response to treatment. Table 1 summarizes demo-
graphic data at entry for the 290 patients in the psychosocial portion of the study. Upon entry onto the study, we asked patients three questions that we believed would be important for interpreting future emotional responses (Table 2). Religion was rather important to these patients, past emotional symptoms were uncommon, and answers were evenly distributed regarding whether the multiple myeloma had changed their lives. Table 3 lists entry psychosocial data on all patients as evaluated by physicians. Patients
were seen to be quite healthy psychologically on these variables (0, best; 4, worst) when they began treatment. Upon entry, patients also appeared to be quite healthy psychologically (Table 4) as judged by two self-report scales (POMS and
MAACL), with a higher score indicating greater distress. Adjectives describing how one felt during the past week including today were rated as to frequency on a five-point scale (0, not at all; 4,
extremely) in the POMS. In the MAACL, adjectives describing moods and feelings were to be checked if the patient felt that way that day. When POMS scores were compared with POMS data for
cancer patients (Table 4),12 the results were very similar. No statistically significant differences were found from the t-tests performed.
Unfortunately, the physician and patient were not asked the same questions regarding the pa-
tient's status upon entry onto the study; hence,
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2221
PSYCHOLOGIC FUNCTION IN MYELOMA Table 1. Demographic Data for Participants
Sex Male Female Race White Black Other Unknown Age (years) < 40 40-49 50-59 60-69 > 70 Unknown Religion Protestant Catholic Jewish Other Unknown Education Grade school High school College Professional school Unknown Family income < $5,000 $5,000-s15,000 $15,000-$30,000 > $30,000 Unknown
N
%
157 133
54 46
selves as being more limited). For example, for the MAACL scores, 163 of the 498 patients (32.7%) felt very anxious, 77 of 276 (27.9%) felt very depressed, and 40 of 276 (14.5%) felt very hostile. In all three cases, the patients' physicians rated those patients as having mild "emotional instability." Likewise, for the POMS scores, most of the disagreement occurred such that physicians underrated tension, depression, vigor, and fatigue, and also underrated, but to a lesser degree, anger and confusion. Upon entry there were no significant statistical correlations between psychologic scores and physical variables, except that patients with high pain or poor performance scores had higher scores on the POMS and MAACL than did those with low pain or good performance scores. Therefore, patients who were worse physically were also worse psychologically. This is intuitively correct and consistent with clinical experience, thus supporting the view that our scales were sensitive to changes in mood and affect. There were differences in the various components of the handicap-rating scale at study entry when patients were separated into the physical groupings mentioned previously. However, these differences were also associated with known measures of prognosis. Higher ratings were always associated with higher creatinine levels, higher calcium levels, higher tumor-cell load, etc. There were no statistically significant differences between these physical groupings and patients' responses to the importance of religion, past emotional symptoms, or how illness had changed their physical and mental state. At 3 months, we compared the effects of the various treatments on POMS and MAACL scores and found no differences from study entry scores on the four treatment regimens. We then examined the relationship between positive response to treatment and length of survival and found no correlation between psycho-
213 60 3 14 9 30 77 97 57 20 167 58 22 23 20 97 134 32 9 18 62 116 43 12 57
different assessments were made. This means that ratings cannot be directly correlated with each other. It would have been useful, for example, to ask the patient about his/her awareness of illness so that one could see how the physician's rating of that question compared with the patient's own view. Nevertheless, the item of emotional instability rated by a physician could be roughly correlated with a patient's POMS and MAACL scores. In general, the patient ratings were more extreme in the negative direction (ie, patients rated them-
Table 2. Patient Self-Rating Upon Entry Into Study No. of Responses (%) Question Asked
Not At All
A Little
Moderately
Quite a Bit
How important is your religion to you? Did you have significant emotional symptoms in the past, before your illness? Has illness changed your physical and mental state?
9 (3)
18 (7)
56 (22)
177 (68)
167 (65)
47 (18)
21 (8)
22 (9)
37 (15)
61 (24)
61 (24)
90 (36)
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2222
SILBERFARB ET AL Table 3. Physician Rating of Psychosocial Function of Patients Upon Entry to Study Rating Scale* (%)
Physician Rating of Patients Global psychosocial rating Psychosocial handicap rating Employment limitation Social life restrictions Emotional instability Intellectual dysfunction Awareness of illness
N
0
1
2
3
4
279
34
57
8
1
0
276 276 276 277 275
17 35 30 72 67
16 24 59 20 25
15 22 10 6 1
9 7 0 1 3
42 12 0 0 4
*Rating scale key: Global psychosocial rating: 0, superior functioning despite level of illness; 1, minor intermittent symptoms or stability maintained with effort; 2, moderate to marked emotional distress; 3, severe to profound mental symptoms; 4, life-threatening mental symptoms. Employment limitation: 0, usual work; 1, slightly less than usual work/housework; 2, work reduced by one half or more; 3, occasional work; 4, unable to work. Social life restrictions: 0, full social activities; 1, no new and fewer optional contacts; 2, contact only with family and close friends; 3, contact only with family; 4, contact with medical staff-family are visitors. Emotional stability: 0, normal emotional state; 1, mild emotional distress that requires no intervention; 2, moderate emotional symptoms requiring intervention; 3, severe symptoms requiring psychiatric intervention; 4, severe symptoms requiring psychiatric hospitalization or equivalent. Intellectual dysfunction: 0, none; 1, noticeable change but performing activities as usual; 2, significant change interfering with function; 3, severe loss of memory, orientation, requiring assistance in care; 4, no apparent intellectual function. Awareness of illness: 0, full awareness of illness; 1, occasionally acts unaware of illness; 2, frequently acts unaware-interferes with treatment; 3, usually acts unaware; 4, little or no awareness of illness.
logic scores and survival except on the POMS, where more vigor was associated with longer survival and more fatigue was associated with poor survival. However, if tumor-cell load was included in the Cox regression model, neither POMS vigor nor POMS fatigue was significantly associated with survival. Therefore, neither the patient-rated nor physician-rated mood states were related to survival. A logistic regression model was used for analyzing objective responses to treatment. Responses to treatment were grouped as either direct or indirect. 9 A direct response indicated objective improvement in either the serum M component, urine M component, soft tissue mass, bone lesions, or marrow. An indirect response was an improvement in the hemoglobin, creatinine, calcium, pain,
or performance. No association was found between these and the POMS or the MAACL scores. A Cox regression model was used for measuring survival duration. The POMS' subscores of vigor and fatigue likely reflected disease status; hence, they were predictive of survival duration. However, the results were not significant when tumorcell load was included in the model. Finally, because studies of cancer patients have suggested that denial might be associated with positive outcome, we looked at the association between awareness-of-illness scores as reported by physicians and survival and found no association after the usual medical prognostic factors were taken into consideration. Psychologic information was available on 24 patients at the time they relapsed. We compared
Table 4. Mean POM Scores for Multiple Myeloma Patients Versus Other Cancer Patients Males POMS Subtest Tension Depression Anger Vigor Fatigue Confusion Total
Multiple Myeloma Patients N Mean SD 128 127 126 127 126 125 106
12.0 10.5 5.8 13.4 9.7 7.4 37.4
7.4 9.4 6.4 6.8 6.6 5.2 31.2
Females Other Cancer Patients N Mean SD 457 457 457 457 457 457 457
12.5 10.3 6.0 14.5 9.9 6.9 31.2
7.2 10.1 6.4 6.8 7.6 5.0 33.7
Multiple Myeloma Patients
Other Cancer Patients
N
Mean
SD
N
Mean
SD
108 108 108 107 107 107 97
12.8 11.5 5.6 11.8 10.3 7.9 40.8
7.4 10.2 6.5 6.2 6.9 4.8 30.1
209 209 209 209 209 209 209
14.5 11.9 6.9 12.7 10.9 7.6 39.2
8.5 11.3 8.4 6.4 7.4 5.5 38.8
NOTE. Data for other cancer patients come from previously untreated adult patients with recently diagnosed cancer within CALGB trials 2 in 25 hospitals. Types of cancer include gastric, pancreatic, and lung (limited and extensive).'
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2223
PSYCHOLOGIC FUNCTION IN MYELOMA
this with study entry data for the same patients and found no change except that MAACL anxiety scores at the time of relapse, surprisingly, were less than on entry in 10 patients. Given the large number of tests performed and the relatively small amount of data, this result probably should not be considered significant. We also compared relapse data with psychologic data at 3 months and found no differences. DISCUSSION
The correlation between bereavement and increased risk of morbidity and mortality in humans has been noted frequently,14 although the specific link to cancer is less clear." Recently, there have been studies linking depression and cancer incidence. 6 ,"7 Studies of husbands of women dying of breast cancer demonstrated depression of immunologic functioning in these men,' 8 thus implicating the link between psychologic health and physical disease. Greer et al4 have implicated a woman's attitude toward illness as possibly predictive of survival in breast cancer patients. Spiegel et al6 studied patients with metastatic breast cancer 10 years after a year of weekly group therapy that emphasized self-hypnosis for pain relief. Patients in the intervention group survived significantly longer than the control patients. However, our study appears to contradict the notion that psychologic state, at least in multiple myeloma cancer patients, influences disease outcome once the disease process has begun. We found no significant correlation between psychologic scores on entry and response to treatment or survival duration if physical variables such as tumor-cell load and other known measures of prognosis were controlled. Mood states were not related to survival, whether as noted by physicians or patients. However, this study reports disease outcome and not quality of life, where positive emotions presumably would be important. Also,
we did not study social support and its effect on survival or response to treatment. Hislop et al"'9 recently reported the importance of a social support network as an independent prognostic factor in disease-free survival in women with breast cancer, and Stavraky et al2 have noted the importance of social support to the survival rate of lung cancer patients. Social support may have been a factor in the increased survival of breast cancer patients reported by Spiegel et al.6 However, the positive contribution of social support to the enhancement of survival in cancer patients is an area that requires further investigation before its import is embraced as fact. One of the limitations of the study was that physician and patient did not use the same rating scales to assess patient status; thus, it was difficult to assess directly the relationship between ratings. While this was not the main focus of the study, this information would have been relevant and interesting. Another limitation of our study is that there may have been selection biases in the study population. The participation rate for the psychosocial study was relatively low, as over one half those enrolled in the protocol did not choose to take part in the psychosocial portion. However, there were no differences between nonparticipants and participants with regard to age, sex, tumor-cell load, response to treatment, and survival. Our findings should not be construed as discouraging of a positive mental outlook for patients, as this clearly is tantamount to a positive quality of life. Instead, this study should be interpreted as further evidence to encourage multiple myeloma patients to rely on scientific medicine for treatment in addition to their psychologic strengths. ACKNOWLEDGMENT The authors thank Alice Kornblith and Roger Davis for statistical advice.
APPENDIX The following members of the Cancer and Leukemia Group B (and respective grants) participatedin this study: James R. Anderson, Harvard School of Public Health, Boston, MA (CA-33601): M. Robert Cooper, Bowman-Gray School of Medicine, Winston-Salem, NC (CA-03927); Edward S. Henderson, Roswell Park Memorial Institute, Buffalo, NY (CA-02599); Gibbons G. Cornwell, Dartmouth-Hitchcock Medical Center, Lebanon, NH (CA-04326); Irving Berkowitz, Wilmington Medical Center, Wilmington, DE (CA-37041); Nis I. Nissen, Finsen Institute, Copenhagen, Denmark; Robert Kyle, Mayo Clinic, Rochester, MN (CA-04646); J.L. Hutchinson, McGill Cancer Centre, Montreal, Canada (CA-31809); James F. Holland, Mount Sinai School of Medicine, New York, NY (CA-04457); Richard R. Silver, Cornell Medical Center, New York, NY (CA-07968); Sameer Rafla, Maimonides Hospital, New York, NY (CA-25119); Raymond Weiss, Walter Reed Army Medical Center,
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SILBERFARB ET AL
2224 APPENDIX (Cont'd)
Washington, DC (CA-26806); Rose Ruth Ellison, Columbia University, New York, NY (CA-12011); Mark Green, University of California at San Diego, San Diego, CA (CA-11789); Michael Perry, University of Missouri, Columbia, MO (CA-12046); Arlan Gottlieb, Upstate Medical Center at Syracuse, Syracuse, NY (CA-21060); Joseph Aisner, University of Maryland Cancer Center, Baltimore, MD (CA-31983); Louis Leone, Rhode Island Hospital, Providence, RI (CA-08025); Robert Carey, Massachusetts General Hospital, Boston, MA (CA-12449); Kanti Rai, Long Island Jewish Medical Center, New Hyde Park, NY (CA-11028); Franco Cavalli, Swiss Group, Inselspital, Bern, Switzerland; Farid Haurani, Thomas Jefferson Medical Center, Philadelphia, PA (CA-05462); Geoffrey Faulkson, H.F. Verwoerd Hospital, Pretoria, South Africa; Lucius Sinks, Georgetown University Hospital, Washington, DC (CA-21083); Peter Raich, West Virginia University Medical Center, Morgantown, WV (CA-28562); David Ontjes, University of North Carolina, Chapel Hill, NC; Albert B. Einstein, Jr, Virginia Mason Medical Clinic, Seattle, WA; and Norris Cotton Cancer Center core grant (CA-23108-13) for editorial and word processing assistance.
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