Review The psychosocial impact of bone marrow transplantation: a review of the literature

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1 Bone Marrow Transplantation, (1998) 22, Stockton Press All rights reserved /98 $ Review The psychosocial impact of bone marrow transplantation: a review of the literature CS Neitzert 1, P Ritvo 1,2, J Dancey 1,2, K Weiser 1, C Murray 1 and J Avery 1 1 The Toronto Hospital, General Division, Toronto; and 2 University of Toronto, Toronto, Ontario, Canada Summary: Bone marrow transplant (BMT) is a procedure used for the treatment of a variety of cancers and malignant diseases. Recovery from this intensive process requires a long-term course, often accompanied by acute morbidity which includes various distressing physical symptoms. Recent literature has begun to explore the impact of this procedure on quality of life and psychosocial issues. While survivorship is often associated with a highly rated global quality of life, recovery from BMT is accompanied by several psychosocial difficulties which negatively impact patients. Fatigue is a common complaint, often hindering recipients for several years following their transplant. As well, reports of psychological distress, psychiatric symptoms, and/or mood disturbances such as anxiety or depression are not uncommon. Many patients also indicate interruption of sexual activity and increased sexual difficulty for several months following BMT. While some investigators have begun to examine hormone replacement therapy (HRT) as a treatment option for reducing sexual dysfunction, there is a general paucity of literature evaluating interventions for BMT survivors. This article reviews the literature examining various quality of life aspects including fatigue, psychosocial difficulties, and sexual functioning of patients during recovery from BMT. Limitations of past research are discussed and directions for future research suggested. Keywords: bone marrow transplantation; review; fatigue; sexual functioning; psychological distress Bone marrow transplantation (BMT) is an innovative procedure developed for treating malignant disease. The most common indications for BMT are Hodgkin s disease, non- Hodgkin s lymphoma, leukemia, metastatic breast cancer, and its use is increased as treatment technology improves, particularly with respect to reduced morbidity and increased life expectancy. Two types of BMT are currently most Correspondence: CS Neitzert, The Toronto Hospital, General Division, Department of Psychology, 585 University Avenue, Toronto, Ontario, Canada, M5G 2C4 Received 19 September 1997; accepted 9 April 1998 prevalent. Allogeneic transplantation uses donor blood and marrow and is most often employed in the treatment of hematological disorders. It may be associated with graftversus-host disease (GVHD), which involves attacks by donor marrow on the patient s organs and can result in serious complications. Autologous transplantation, by contrast, is used to treat several types of malignancies. Because the patient s own marrow is used, there is no GHVD risk. According to data available through the International Bone Marrow Transplant Registry (IBMTR), 4000 allogeneic BMT procedures and 6000 autologous BMT procedures were performed in North America in The same registry shows that in 1995, 4500 allogeneic BMT procedures and 8000 autologous BMT procedures were performed in North America, suggesting an increasing trend towards use of autologous transplantation where feasible. While the relapse and long-term survival rates for BMT vary with disease type and status, 1 estimates of between 50 and 60% have been projected for patients treated during first remission of leukemia. 1,2 Our initial review of research literature on BMT suggested that patients experienced a relatively high global quality of life following transplantation. Several investigators found that a majority of patients assessed reported satisfying and productive lives following BMT. 3 8 For example, Wingard et al 4 (1991) reported that 67% of their mixed autologous, syngeneic and allogeneic sample judged their global health to be good-to-excellent 6 months after BMT, with 65% reporting a return to work. Other reports indicated global improvements in health with increased time following transplant. In a longitudinal study of 58 recipients of autologous BMT, Chao et al 5 (1992) reported that at 90 days post-transplant about one-third of patients reported difficulty sleeping and poor appetite. One year following transplant, only 5% of these subjects reported difficulty sleeping and all reported normal appetites. Furthermore, 78% of this sample were employed at 1-year followup and 88% indicated above average or excellent life satisfaction. Such findings supported positive expectations about BMT recovery. However, our review of more specific reports indicated that a significant proportion of patients experience ongoing problems following transplantation. Reports of adverse symptoms have consistently cited fatigue, various physical problems, psychological distress, and impaired sexual functioning. More recent research on the quality of life of

2 410 patients has become increasingly empirically based, with several investigators conducting descriptive and discriminating analyses. While a review of all literature relating to psychosocial issues and BMT is beyond the scope of this paper, we have attempted to provide a thorough and comprehensive examination of the most salient empirical studies pertaining to issues of fatigue, psychological distress and sexual functioning in adult recipients. To locate these articles, we conducted an exhaustive literature search of Medline, PsycLit, CINAHL and Health Star using the following key words or phrases: bone marrow transplantation, sexual functioning, gonadal functioning, endocrinology, fatigue, quality of life, psychological distress. A summary of the most relevant studies and their findings can be found in Table 1. Physical symptomatology and fatigue The physical functioning of cancer patients is often limited by medical symptoms and BMT patients are no exception In an early cross-sectional investigation, Wolcott et al 13 (1986) evaluated the physical symptomatology of young adult ABMT patients (n = 26), assessed at a mean of 42 months post-treatment. Approximately 25% reported frequent, ongoing physical symptoms including diarrhea, dry mouth and abdominal cramps, and one-third described having a high number of infections within the past year. In a larger cross-sectional study, Haberman and colleagues 14 (1993) used an open-ended questionnaire to collect data on health problems among a sample of 125 BMT survivors, between 6 and 18.4 years post-transplant. A content analysis of their responses revealed a high incidence of sideeffects such as persistent colds, influenza, memory problems, fatigue, shingles, and pain. Among the symptoms reported, fatigue appears as one of the most common and distressing for cancer patients, with consistent reports of decreased physical abilities, increased need for rest, physical weakness and unusual tiredness. 9 11,15 19 For BMT patients, fatigue appears to be an especially significant and impairing problem. For example, a cross-sectional, descriptive study, conducted by Whedon et al 20 (1995), indicated that among 29 patients assessed, fatigue was the most frequently reported symptom, with 50% endorsing moderate to severe levels as many as 3 or more years after autologous transplant. These results were confirmed by a larger, multi-center study in which 200 BMT survivors, averaging 41 months post-transplant, were asked to rate their experience of physical symptomatology for both prevalence and severity (during the preceding week). These BMT patients perceived their physical health as significantly poorer than normative standards. Once again, fatigue was found to be the most frequently reported symptom, with 78% of the sample feeling consistently tired. As well, the participants rated fatigue symptoms among their most severe. 21 While these studies have demonstrated that fatigue is a disruptive and limiting symptom following BMT, the majority have been cross-sectional in design. One exception is a recent multi-center investigation which examined the energy level and sleep quality of 172 allogeneic and autologous BMT patients longitudinally, providing data of patient recovery over 5 years post BMT. At the initial assessment conducted 43.5 months post-transplant, 65% of patients indicated a current problem with energy level and 51% endorsed the presence of sleep difficulty. Approximately 30% of these patients rated their problem as moderate or severe. Furthermore, 40% of all participants noticed a decrease in both energy level and sleep quality specifically since receiving their cancer diagnosis. A second assessment with these individuals was conducted 62 months post-transplant, at which time patients reported continued problems with energy level and sleep quality. No significant temporal changes between initial and follow-up assessments were found, suggesting that for many BMT recipients, energy deficits and sleep difficulties remain a problem up to 5 years post-transplant. 22 In another longitudinal investigation, the quality of life of 125 BMT survivors was evaluated a mean of 10 years after transplant. Participants were asked to complete a number of questionnaires with respect to medical complications, psychological distress and health perceptions. Results indicated that BMT survivors continued to have several debilitating physical symptoms 10 years following treatment, with fatigue rated as their second most problematic concern. 8 While several descriptive studies have indicated that BMT recipients frequently complain of fatigue, weakness, decreased energy and insomnia in their long-term recovery from BMT, 4,8,13,14,20 26 most have not provided comparisons with normative samples. Two anomalous studies provide valuable insight into the experience of fatigue in BMT survivors. Hann and colleagues 27 compared symptoms among 43 post-bmt females, averaging 20 months since transplant, to 43 healthy control females with no prior cancer history. The BMT survivors showed significantly greater impairment in physical functioning, and reported significantly worse overall physical health. Distressing levels of fatigue were reported by 72% of these BMT survivors, and found to be significantly related to poorer overall physical health. In a similar study, Prieto and colleagues 28 collected cross-sectional data from 117 male and female post-bmt patients, a mean 55 months after transplant. Their analyses indicated that the BMT survivors reported significantly lower energy levels than the normative reference sample. In summary, research in fatigue has shown that a large proportion of BMT patients are impacted by fatigue as many as 10 years following the procedure. While many early studies were descriptive and cross-sectional in design, similar findings have been replicated in recent analyses which employ normative comparison samples and/or longitudinal designs. However, these data overall are limited in sample size, and by confounding variables such as diagnosis and secondary treatments. Further study with larger samples and comparison to normative control groups are necessary. Psychological distress The existing literature on BMT survivors suggests that a significant proportion of patients also experience a high degree of psychological or emotional distress following

3 Table 1 Studies evaluating the impact of bone marrow transplantation Author/Ref. Sample size Sample characteristics Method of recruitment Measures Procedure Results Fatigue and general functioning/psychological distress Wolcott et al (62% female) 27.9 (±8.3) years inclusion criteria: Profile of Mood State mailed recruitment letter Almost 25% recipients reported ongoing all allogeneic BMT 14.6 (±3.9) years survivors of UCLA (POMS); Simmons Scale; and those who responded symptoms, while 70% reported good health patients and their donors education study, BMT at least 1 Social Adjustment Self- were sent a questionnaire NS difference between donors and 42 (±21.7) months year prior, US resident, Report (SAS); current package recipients on POMS (although male post-bmt English-speaking, 18 demographic information cross-sectional recipients higher on several scales) years or over 15 25% recipients reported significant emotional distress also 15 25% reported low self-esteem, less-than-optimal life satisfaction Colon et al patients with median 31 days post- inclusion criteria: adult semi-structured interview interviewed as part of 21% met at least one DSM-III criteria leukemia (65% male) BMT patients with acute based on DSM-III standard follow-up 8% adjustment disorder; 8% substance all allogeneic BMT mean age 30 years leukemia hospitalized psychiatric criteria abuse disorder; 3% antisocial personality for BMT at University disorder; 2% organic affective syndrome; 2% of Minnesota Nov 1980 bereavement; 1% major depression; 1% May 1987 organic mental deficit; 1% V-code marital problem significant positive relationship between perceived support and improved survival significant negative relationship between depressive symptoms and survival rate Wingard et al (61% male) mean age 31 years inclusion criteria: all at Health Perception Scale; all survivors not in life- 67% rated global health good excellent 24% autologous, 71% (range 18 53) least 18 years, survivors Karnofsky Performance threatening relapse were sent 65% returned to work; 51% full-time allogeneic, 5% syngeneic 67% of sample had of BMT at Johns Rating; Physical & Social a questionnaire pkg. (86% 20% lost employment attended college Hopkins, who had BMT Functioning; Pain & Illness response rate) 80% felt social activities unimpaired 51% married at least 6 months prior Questionnaire retrospective 67% felt physical function abilities to study unimpaired 13% reported moderate severe pain Chao et al 5 58 (52% male) mean age 36 years inclusion criteria: designed a Quality of Life questionnaire administered 90 days post-bmt, QOL rating was % Hodgkin s, 36% (range 19 53) patients undergoing (QOL) questionnaire which at initial visit, telephone 1 year post-bmt, QOL rating was 8.9 non-hodgkin s, 19% 58% had college autologous BMT at included symptoms, questionnaire administered 90 days post-bmt 34% sleep difficulty, leukemia education Stanford, at least 18 appearance, sexual function every 3 months following 33% poor appetite, 34% experience frequent all autologous patients 57% married years of age, minimum and return to work as BMT for 1 year colds, 36% describe difficulty with sexual follow-up 1 year dimensions 98% response rate activity, 50% employed prospective design 1 year post-bmt, 5% difficulty sleeping, 0% poor appetite, 5% frequent colds, 14% sexual difficulties, 78% employed 1 year post-bmt 88% rate QOL aboveaverage to excellent Rodrigue et al adult patients mean 23 days prior to consecutive patients Beck Depression Inventory tested as part of routine BDI, STAXI, STAI patient scores not tested prior to BMT admission admitted to hospital for (BDI); Spielberger State- protocol prior to BMT significantly different from normative values (51% female) 92% Caucasian; 61% BMT August 1990 Trait Anxiety Inventory procedure BDI 15 in 20% of sample; significant married; disease duration November 1991 (STAI); State-Trait Anger positive association between disease duration 24.8 months; 32% college Expression Inventory; and depression education Medical Coping Modes 33% 1 s.d. above on STAI; 24% 1 s.d. Questionnaire; Minnesota Multiphasic Personality Inventory above on STAXI (Continued) 411

4 412 Table 1 Continued Syrjala et al allogeneic BMT mean age = 32 years; n = 67 pre-bmt; Sickness Impact Profile prospective design pre-bmt: 39% patients higher SIP score patients (58% male) 73% married; 38% college n = 34 (79% of (SIP); BDI; Brief Symptom patients assessed at four than normative values; 27% mild moderate education; 91% Caucasian survivors) at 90 day Inventory (BSI); Family timepoints: pre-bmt, 90 depression; 41% elevated anxiety scores assessment; n = 31 Relations Index; Ways of days post-bmt, 1 year post- mean anxiety and depression not found to (84%) at 1 year Coping Checklist BMT, 4.5 years post-bmt change over first year assessment; n = 22 emotional distress at 1 year predicted by (96%) at 4.5 year pre-bmt family conflict, marital status, assessment presence of GVHD 68% returned to full-time work by 2 years Andrykowski 200 (40% female) 38.5 (±10.7) years inclusion criteria: at POMS; SIP; Psychological eligible patients mailed significant effect of BMT-type on et al autologous BMT 41 (±8.3) months post- least 18 years old, at Adjustment to Illness Scale consent and questionnaire recovery of function with allogeneic group (54%), 93 allogeneic BMT least 1 year post-bmt, (PAIS); Recovery of package reporting poorer quality of life (46%) patients 30.2 (±36.8) months in disease remission, Function; Perceived Health recruited from 5 sites most frequently reported symptom feeling diagnosis to BMT English-speaking Questionnaire; Perceived cross-sectional tired (78%) 68% married, 60% some Quality Of Life greater age, lower level of education, college Questionnaire; Symptom more advanced disease all risk factors for Experience Report lower overall quality of life following transplant Bush et al (51% male) patients 38 (±7.6) years see Haberman et al 14 European Organization for see Haberman et al 14 74% report same or better QOL post-bmt (±7.6) years at at least 6 years post- Research and Treatment of cross-sectional 80% report good excellent current QOL time of transplant BMT Cancer QLQ-C30; POMS; 28 36% dissatisfied with sexual survival time 10.1 Ware Health Perception functioning (related to persistent physical (±2.5) years Inventory; Demands of problems) BMT Recovery Inventory; Long-term BMT Recovery Questionnaire 5% report QOL and health status as poor subjects report lower degree of fatigue/inertia than college and psychiatric samples Leigh et al patients (69% median 43 years of age 31 proceeded to Hospital Anxiety and Tyrer scale used only at pre-bmt: 22% report anxiety states, 19% male) undergoing BMT (range 17 57) transplant Depression Scale (HADS); pre-bmt depressive illness 19 autologous; 12 measured pre-bmt SAS; Present State Exam; measured at three time 2: 9% report anxiety states*; 31% allogeneic (n = 36); 3 5 months Tyrer Personality timepoints: pre-bmt; 3 5 depressive illness post (n = 22); 6 9 Assessment months post-bmt; 6 9 time 3: 6% report anxiety states; 19% months post (n = 16) months post-bmt depressive illness prospective design *anxiety significantly lower at time 2 for all patients; significant difference in change in anxiety from time 2 to time 3 between autologous and allogeneic patients (allogeneic became more anxious) (Continued)

5 Table 1 Continued Author/Ref. Sample size Sample characteristics Method of recruitment Measures Procedure Results Whedon et al (55% female) 35 (±9.26) years at inclusion criteria: all City of Hope Quality of questionnaires mailed to global QOL rating high 8.17 (±1.97) 41% lymphoma, 59% BMT BMT survivors at least Life BMT instrument; BMT survivors (85% 50% reported moderate severe fatigue leukemia, 28% breast 38.5 (±9.26) years at 18 years, English- qualitative questionnaire; response rate) 93% reported moderate severe distress cancer time of study speaking, had BMT at demographic information cross-sectional over illness s effect on family all Caucasian, (±19) months since least 1 year prior to lowest score was found on sexual (66%) married BMT study functioning sub-scale all ABMT 66% had returned to work Ahles et al (85% female) mean age (±9.38) inclusion criteria: Psychiatric Diagnostic short-term prospective baseline significantly higher STAI/POMS 20 breast cancer, 14 years suffering from breast Interview; STAI; BDI; design scores for hematologic patients; no hematologic disorder cancer or hematologic POMS; neuropsychologic tested three times: pre- differences when segregated based on prior disorder; years; battery BMT, 1 3 days post-bmt radiation or chemotherapy treatment first BMT; English- and 1 2 days predischarge hematologic patients more distressed than speaking breast cancer patients at baseline but decreased over time breast cancer patients less distressed at baseline, significantly increased at time 2, back to baseline at time 3 McQuellon 24 female breast mean age 44.2 (±6.3) all patients receiving The Functional Assessment pre-assessment part of NS between mean pre- and post-scores on et al 24 cancer patients years BMT treatment were of Cancer Therapy Bone standard procedure and post- overall quality of life, mood status or social undergoing autologous 92% Caucasian, 8% eligible Marrow Transplant Scale; measure completed over support status BMT African-American POMS; Centre for telephone after informed 33% patients reported depressive prior therapy 13% 50% at least some Epidemiological Studies consent letter returned (73% symptoms ( 16 on CES-D) after BMT lumpectomy, 75% college; Depression scale (CES-D); response rate) 30% reported problems with sexuality, mastectomy, 88% 75% married Medical Outcome Study- prospective depressive symptoms, and fatigue chemotherapy, 17% 67% less than 1 year Social Support Survey MOS-SSS and POMS the following concerns were reported: endocrine therapy post-diagnosis; 33% 1 2 (MOS-SSS); World Health administered at pre-bmt employment (25%), finances (42%), physical years post-diagnosis Organization Performance CES-D only administered at health (50%), frame of mind (25%), Rating post-bmt appearance (33%), health/life insurance (37%), personal/intimate relations (33%), planning for future (38%) Andrykowski 172 BMT recipients 39.1 years of age BMT patients in 5 POMS; Functional Living measured by interview at initial assessment: et al 22 45% allogeneic; 55% (±10.5) centres Index-Cancer; Symptom initial assessment; mailed in 65% subjects experienced problems with autologous 43.5 months post-bmt at least 18 years of Experience Report; Sleep, questionnaire 18 months energy level (30% moderate to severe) 62% male (±28.6) age, 12 months post- Energy, and Appetite Scale; following initial assessment 51% report sleep difficulty (31% moderate BMT; in disease Pittsburgh Sleep Quality to severe) remission Index 40% report increased impairment since cancer diagnosis follow-up at 18 months: no significant differences in energy level or sleep difficulty between initial and follow-up assessments (Continued) 413

6 414 Table 1 Continued Sutherland 231 allogeneic BMT age range years no selection criteria Medical Outcomes Survey questionnaries mailed to all BMT patients included: et al 26 survivors at time of BMT (no mean imposed, all allogeneic Short Form 36 (MOS SF- 251 BMT survivors, 93% QOL scores on MOS SF-36 significantly 54% male provided) BMT patients at 36); Satisfaction with Life response rate lower than normative values for 5/8 scales median follow-up after Princess Margaret Domains Scale Bone random sample of 100 (Physical Functioning, Role Functioning- BMT was 40 months, Hospital were included Marrow Transplantation; patients were sent same Physical, Role Functioning-Emotional, Social with a range of Princess Margaret Hospital questionnaires 2 weeks Functioning, General Health) months Symptom Experience later 71% response rate 105 patients 3 years post-bmt: Report cross-sectional design significantly lower than norm scores 7/8 MOS SF-36 scales (same scales as above plus Bodily Pain and Vitality) 126 patients 3 years post-bmt: significantly higher than norm scores 3/8 scales (Social Functioning, Vitality, Mental Health) and no other significant differences multivariate ANOVA with time since BMT as a factor GVHD (both acute and chronic), age at BMT, donor match all contributed significantly to variance in QOL scores Sexual functioning Cust et al females with mean age at BMT 25.7 inclusion criteria: investigator-designed sent questionnaire after 39% had been pregnant; 36% had children leukemia who had years English speaking, questionnaire about BMT (78% response rate) 81% vaginal dryness (distressing for 47%) received total body mean time from BMT leukemia, previously pregnancy and sexual retrospective 61% hot flashes; 36% night sweats irradiation and BMT to interview 4.2 years treated with BMT and functioning of 22 sexually active post-bmt: 91% (type unspecified) (range 8 months 9 years) total body irradiation vaginal dryness; 82% considerable pain 47% married during intercourse; 73% decreased libido; 64% difficulty achieving orgasm 27 took hormone replacement therapy for 6 months 81% said HRT eliminated all vasomotor symptoms; 11% some improvement; 7% reported no change Baruch et al males with history median age at diagnosis at least 18 years of HADS; investigator-designed 26 patients completed significant change in global self-rating of of hematological 27 years (range 11 44) age, at least 6 months questionnaire on past and sexual functioning sexual problems from pre- to post-bmt malignancy at time of study 33 post-bmt present sexual functioning; questionnaire and were (78% reported no problems prior to BMT 68% allogeneic, 32% years (range 19 49) blood pressure and sex tested in clinic, 20 others compared to 52% post-bmt) autologous time for BMT 58 hormones measured responded to questionnaire significant erectile failure, retarded months (range 6 154) mailed to them ejaculation, decreased libido, dry ejaculation significant correlations between sexual dysfunction and psychological morbidity, age, and decreased blood pressure problems with poor health in 50% subjects 4 males reported anxiety, 2 depression (Continued)

7 Table 1 Continued Author/Ref. Sample size Sample characteristics Method of recruitment Measures Procedure Results Mumma et al patients: 49 CO: 53% female, 90% diagnosed with Karnofsky Rating; semi- 92% response rate both men and women significantly poorer patients chemotherapy Caucasian, 51% married; leukemia, years structured interview; interviewed and body image than healthy controls; no only (CO); 21 patients aged 33 (±8) at time of diagnosis; Derogatis Sexual completed questionnaires at differences on sexual function had chemotherapy plus CBMT: 52% male; 90%at least 1 year post- Functioning Inventory; regular follow-up women report significantly lower sex BMT (CBMT) Caucasian; 24% married; treatment PAIS; BSI; POMS; Death appointment drive and satisfaction than healthy controls aged 26 (±5) Anxiety Questionnaire; increased time since treatment associated Impact of Event Scale with increased sexual activity but also associated with decreased sexual satisfaction and decreased body image subjects reporting higher psychological distress also report increased sex difficulties Vose et al (62% male) median age 31 (range 1 year post-bmt interview conducted over contacted by telephone 45% said appearance improved since BMT autologous BMT or 13 58) telephone retrospective 96% good appetite peripheral stem cell transplantation 76% employed/school full-time post-bmt vs 84% pre-bmt 33% report decreased libido, 40% decreased sexual functioning 38% males unable to achieve erection, 35% unable to ejaculate 44% females report hot flashes, 35% had menses but irregular physical activity same as before 28%; increased since BMT 58%, decreased 14% Baker et al (60.7% male) 30.6 years (range 18 at least 6 months post- Satisfaction with Life questionnaire mailed; 86% high degree overall satisfaction 24% autologous, 71% 53) BMT Domain Scale; POMS; response rate lowest ratings for physical strength, allogeneic, 5% syngeneic 91.1% Caucasian; 51% Rosenberg Self-Esteem retrospective design satisfaction with body, ability to attain (see Wingard et al 1991) married or living with Scale; Karnofsky Rating; sexual satisfaction partner; 13.9 years BMT Stress Scale; Bradburn women sig more negative affect than men education; 47 months post- Positive & Negative Affect self-esteem and current physical BMT (range 6 149) Scale functioning predictors of quality of life BMT at younger age related to higher degree of overall life satisfaction Spinelli et al post-menarchal, 5 pre-men group: normal menses at blood samples of luteinizing consecutive patients in all subjects had decreased estrogen, pre-menarchal females median 10 years, 100% diagnosis (in post- hormone (LH), follicle clinic increased FSH and LH following BMT all TBI/allogeneic leukemia, disease-bmt group); minimal 3 stimulating hormone (FSH), HRT offered to all 80% of pre-menarchal group developed BMT 1007 days months follow-up estrogen levels subjects under age 45 menses during follow-up post-men group: prospective design 6 months post-bmt 78% report 18 years n = 14 vasomotor symptoms, 61% genitourinary median 15 years, 93% symptoms, 94% of sexually active women leukemia, disease-bmt report sexual difficulties (vag dryness, 711 days; 18 years dysuria, dyspareunia, decreased libido or n = 60 median 30 years; frequency) 92% leukemia; disease- 49/74 given HRT 91% report decrease BMT 476 days in vasomotor symptoms; 42 81% report improved sexual functioning 13.5% postmenarchal group show ovarian recovery at follow-up (Continued) 415

8 416 Table 1 Continued Molassiotis BMT group n = 91: BMT: BMT or chemo at one PAIS; HADS; Rotterdam all long-term survivors higher depression in BMT group et al 38 67% male (±10.95) years of three clinics in UK; Symptom Checklist, in 3 centers invited to (P 0.02) 58% ABMT; 42% (±26.56) months 18+ years; at least 6 Norbeck Social Support participate contacted MC group higher physical symptom allogeneic post-bmt months post-bmt; not Questionnaire; Psychosexual individually at follow-up distress (P 0.05) 26% married; 31% MC group: in relapse; English- Functioning Questionnaire; appointments BMT significantly higher impotencecollege (±10.87) years speaking plus medical and retrospective study related sexual difficulties (20% of males vs maintenance chemo (±29.5) months demographic information response rates from 6% among MC males) n = 73: after first treatment BMT group 67% (range 45% males, 33% females in BMT group 52% male NS between groups on 60 71%); for MC group sexual life worse since BMT; 16% males 34% married; 38% any variables 62% (range 55 66%) and 13% females extremely dissatisfied college with current sexual activity (MC: 11%, 11%) no differences on psychological symptoms, or QOL measures between groups regression social adjustment, affirm & depression account for 73% of variance in QOL BMT group; physical symptom distress, social adjustment 53% for MC Marks et al 49 BMT group n = 30: BMT: between 16 and 65; Derogatis Interview for prospective study BMT group: 40% males, 53% females 50% female median age 38 (±10) BMT between July 1994 Sexual Functioning Self- patients contacted pre- reported global sexual dysfunction all 67% leukemia; 40% years control: and March 1995 at HU Report; Cancer admission or at admission reported sexual dissatisfaction amenorrheic median age 49 (±18) in Philadelphia Rehabilitation Evaluation prior to BMT control group: 56% males, 50% females 43% ABMT; 40% significant difference System; BSI 78% response rate global sexual dysfunction 33% reported sibling donor; 17% between groups in age, sexual dissatisfaction unrelated donor and amenorrhea among 20% BMT-men, 33% control-men control n = 15: females ejaculation problems; 13% BMT-men; 22% 60% male control-men erectile dysfunction no female 60% leukemia; all amenorrheic measures reported no association found between amenorrhea and sexual function no differences between genders or between groups on any variables Endocrine studies Benker et al allogeneic BMT median age 30 years evaluated 1 6 years blood samples to evaluate retrospective design pituitary-adrenal function remained stable survivors (57% female) (range 17 45) post-bmt endocrine function 17.4% incidence of hypothyroidism 39% panmyelopathy; GH significantly lowered; TSH 61% leukemia significantly elevated in irradiated patients; estradiol levels decreased in irradiated women, testosterone less pronounced; higher LH & FSH in irradiated men (Continued)

9 Table 1 Continued Author/Ref. Sample size Sample characteristics Method of recruitment Measures Procedure Results De Sanctis 30 prepubertal patients mean age 12.9 years prepared for BMT with blood samples to measure measured pre and post BMT females: 80% ovarian dysfunction; LH et al 51 (50% female) (range ) busulphan followed by FSH, LH, Leydig cell and compared to 14 levels 2.8 ( ) pre-bmt vs all allogeneic BMT; 3 developed GVHD and cyclophosphamide function in boys prepubertal healthy controls post-bmt (control value 0.5); FSH levels all with thalassaemia were appropriately treated 2.9 (2 6) pre-bmt vs post-bmt major mean 2.3 years (range (control range ) ) post-bmt males: LH levels 2.3 (2 6) pre-bmt vs post-bmt (control range ); FSH levels 2.4 (1 3.5) pre-bmt vs post-bmt (control range ); testosterone not different from controls Molassiotis 29 male patients BMT patients: 35.4 BMT patients at least 6 evaluated gonadal function response rates: 72.5% BMT psychological distress significantly higher et al 45 59% autologous, 41% (±12.6) years; 35.6 months post-bmt and psychosexual patients; 60% mixed in BMT and mixed patients vs controls allogeneic BMT (±23.3) months post-bmt adjustment patients; 74% controls longer-term BMT survivors similar 30 mixed diag cancer mixed: 45.1 (±8.9) psychosexual adjustment to mixed patients patients years; 13.5 months post- BMT and mixed patients significantly 119 healthy controls treatment higher psychosexual and gonadal dysfunction controls: 22.8 (±5.4) years vs controls 48.1% BMT patients dissatisfied with current quality of sexual life 38% impotence/erectile problems; 38% decreased libido; 21% altered body image Sanders et al 54 total of 1326 charts median time of 8.48 NA evidence of gonadal examined medical and 76 women had 146 pregnancies (53% female); of these, years (range ) recovery follow-up records prepubertal patients 28% females, 13% 196 female and 114 post-bmt males developed normal gonadal function male were prepubertal 16% recovered ovarian functioning increased incidence of pre-term babies and spontaneous abortion rate vs norms Keilholz et al patients (66% median 5 years post- investigated endocrine ovarian failure observed in all but 1 male) BMT function and bone female; estrogen insufficiency observed all autologous BMT median age 36 years metabolism 67% men elevated FSH levels (range 21 54) no evidence of osteopenia or hypothyroidism found 417

10 418 treatment. McQuellon et al 24 (1996) evaluated emotional distress in 24 females who had received autologous BMT treatment for breast cancer. They report 33% of their sample had scores above the cut-off for clinical depression on a short-form version of the Center for Epidemiological Studies Depression Scale (CES-D), when assessed approximately 9 months following treatment. In another small sample (n = 29), Whedon et al 20 (1995) found that as many as 93% reported moderate to severe psychological distress, defined by self-rating on a six-item, open-ended questionnaire administered an average of 37 months following transplant. Other investigations, using standardized instruments of measurement, have demonstrated significant emotional distress, 13 psychiatric symptoms, 29 and affective disturbances such as anxiety/depression following BMT For example, a carefully designed prospective study of 67 adult patients undergoing allogeneic BMT treatment evaluated psychosocial functioning at pre-transplant, 90 days post-transplant, and up to 6 years following transplant using the Brief Symptom Inventory (BSI). The results showed that while physical functioning improved significantly at 1-year posttransplant assessment, the elevated anxiety/depression levels found at 90 days post-treatment were sustained. While the overall mean scores were not significantly higher than normative samples, anxiety scores of 48% of the BMT patients and depression scores of 45% of the BMT patients were more than one standard deviation above the normal means. The investigators also noted mild to moderate impairment in physical and/or psychosocial performance among 30 40% of the 23 long-term survivors. 32 In a similar prospective study Leigh et al 34 (1995) assessed 36 adults prior to BMT, 3 5 months following BMT, and again 6 9 months post-transplant. The authors noted that overall 54% of the sample assessed before and at least once after BMT were reporting Hospital Anxiety and Depression Scale (HAD) scores of depression or anxiety above the clinical cut-off. Analyses showed that anxiety levels fluctuated over time with a significant decrease in score noted at the third assessment. In contrast, the authors found that the substantive depressive symptomatology observed in patients remained high up to 9 months post-transplant. Whereas 19% suffered from clinically diagnosed depressive illness at the pre-transplant measure, 31% met criteria at the second assessment, and 19% at the third assessment. For some BMT survivors, psychological symptoms after transplant can lead to severely dysfunctional states, as in the case studies reported by Molassiotis and Morris 36 (1997). They discuss two reports of attempted suicide following BMT, including one case that evolved into a psychotic episode, and another in which a patient experienced serious suicidal ideation during the period of isolation following transplant. While the authors acknowledge that steroid treatment may have induced the psychotic reaction, they also mention the intense physical limitations experienced by patients as potential factors contributing to severe depression and suicidal ideation. They recommend that all BMT patients be assessed more closely for depressive symptomatology during follow-up appointments. Although reference samples have been limited, some investigators have compared the psychological status of BMT recipients to normative samples or patients following other cancer treatments. Preliminary results indicate significantly higher levels of mood disturbance, tension and depressive symptoms in BMT patients when compared with lung cancer patients, testicular cancer patients and maintenance chemotherapy patients. 37,38 An investigation comparing psychological distress following BMT between patients with breast cancer and patients with hematological disorders demonstrated significantly different patterns of response over the course of short-term recovery. 39 While this study only examined patients up to several days following treatment, it provides information regarding the differential responses of disparate diagnostic groups which complicates the interpretation of previous data. Another study compared the results of 231 allogeneic BMT recipient scores on the Medical Outcomes Survey Short Form 36 (MOS SF-36) with those of a normative comparison sample. The results indicated that patient scores on five of eight quality of life subscales, including a rating of emotional functioning, were significantly lower than the normative sample. Further analyses determined a distinction in recovery based on time since transplant. Patients who had received BMT within the past 3 years demonstrated significantly lower scores on seven of the eight MOS SF-36 scales, including measures of physical functioning, emotional functioning, social functioning, general health, pain and vitality. Those patients who had received BMT more than 3 years prior to the study were found to have scores significantly higher than the normative population on three subscales (social functioning, vitality and general mental health), and not significantly different from the normative sample on the other five subscales. 26 These results indicate substantial improvement in quality of life and psychological functioning of patients after 3 years or more post-bmt compared with healthy populations. Additional prospective investigations conducted over similar periods of time and using comparison control samples consisting of other cancer groups and healthy individuals need to be conducted to add merit to these observations. Sexual functioning In her review of sexual functioning following cancer treatment, Andersen 40 (1990) found that a high percentage of cancer patients experienced some interruption in sexual function, depending on the course of cancer therapy received. Several reports have identified sexual dysfunction during recovery as a common problem among BMT survivors. Baruch et al 31 (1991) studied 46 males who had received BMT treatment for hematological malignancies. Whereas 22% of the patients had reported sexual problems prior to their transplant, 48% stated the presence of some degree of sexual difficulty following treatment. Results of numerous other studies have shown that between 26 and 82% of BMT patients note some degree of sexual dysfunction following transplantation. 5,7,8,24,41 47 In a multi-center study, Molassiotis et al 38 (1996) studied 91 adult BMT survivors in comparison with 73 patients with hematological malignancies being treated with maintenance chemotherapy. While the BMT group was assessed at an average

11 of 40 months post-bmt, the maintenance chemotherapy group was evaluated about 39 months after their first chemotherapy treatment. The authors reported significantly higher impotence-related problems among male BMT patients than males who received maintenance chemotherapy treatment. While not significant, the authors also noted a trend among the post-bmt males to report higher levels of sexual dysfunction. The only difference noted among the female participants was with respect to body image, with maintenance chemotherapy females reporting significantly higher concerns. An earlier study conducted by the same investigators compared sexual functioning in male BMT survivors (36 months post-transplant) with a mixed-diagnostic group of male cancer patients and a group of healthy male controls. Almost half (48%) of the BMT group were dissatisfied with their current sexual life while 38% reported low sexual interest. Twenty-one percent of BMT survivors reported altered body image, 38% had impotence-related problems, including erectile difficulties, and 17% stated they were experiencing moderate difficulties in their overall psychosexual adjustment. While no significant differences were found on sexual functioning variables between cancer groups, psychological distress was found to be significantly higher in the BMT patients, which the authors believed might have impacted their sexual functioning. Both BMT and cancer patients were found to have significantly worse scores on all aspects of sexual functioning, compared to healthy controls, with the exception of sexual desire. 45 In another study evaluating sexual functioning in BMT recipients, Altmaier et al 48 (1991) demonstrated much higher rates of sexual dysfunction in BMT patients relative to patients treated with chemotherapy alone as long as 2 years after treatment. More specifically, BMT patients stated that they experienced decreased desire (42% of patients), decreased sexual functioning (17% of patients), inability to function (25% of patients) and difficulties with their partners over sex (33% of patients). In comparison, while 33% of the chemotherapy group reported decreased desire, none of these patients reported decreased sexual functioning, functional inability or difficulties with their partners over sex. The reports of BMT patients indicate that they experience a variety of specific problems. In a cross-sectional follow-up study of 36 females treated with BMT, Cust et al 41 (1989) indicated that 6 months following treatment, 92% of the participants reported some experience of disruptive psychosexual symptoms, with 82% reporting pain during intercourse, and 81% experienced vaginal dryness. As well, 64% of these women reported difficulty achieving orgasm, and 73% reported that their desire for sexual activity had significantly decreased since treatment, perhaps in relation to their physical discomfort. In a similar study with both male and female BMT survivors, Vose et al 43 (1992) examined 50 autologous BMT recipients at least 1 year following transplantation. It was noted that 33% of all patients reported decreased interest in sexual activity, while 40% indicated that their sexual functioning remained substantially diminished. Among the male patients, the most commonly reported sexual problems were difficulty achieving erection (reported by 38% of males), and ejaculatory difficulty (reported by 35% of males). Among the female participants, distressing vasomotor symptoms were the most common complaint, with 44% reporting hot flashes. Taken together, these studies point to a high degree of difficulty with general sexual functioning following BMT therapy. However, many studies have failed to measure baseline (ie pre-treatment) sexual functioning, leaving it difficult to evaluate potential changes in sexual functioning that occur in relation to BMT treatment. Marks et al 49 (1996) found evidence of substantial self-reported sexual dysfunction among 30 patients prior to high-dose chemotherapy or BMT treatment, suggesting that these difficulties arise prior to transplant. However, this study did not provide analysis of post-treatment functioning, eliminating the opportunity to compare pre- and post-assessment impact. Furthermore, little research has been conducted using comparative samples such as healthy controls or cancer groups with varying treatment regimens or diagnoses, and studies are often limited by small sample sizes. Finally, as research on this topic is relatively recent, few studies have investigated sexual functioning longitudinally to determine what changes occur as a function of changes in physical condition. Endocrine studies In an effort to understand the physiological and psychosexual changes following BMT, researchers have assessed hormonal responses in long-term survivors. Benker et al 50 (1989) evaluated the growth hormone (GH) and thyroid stimulating hormone (TSH) levels in 23 recovering allogeneic BMT patients and found them to have remained significantly lower than control values between 1 and 6 years following transplant. Substantially lower levels of GH, TSH, estrogen levels, and some decreases in testosterone, accompanied by an increase in both follicle stimulating hormone (FSH) and luteinizing hormone (LH) severely limiting fertility have been reported in other investigations Although pregnancy has been observed in some cases, 57 its occurrence is rare among patients recovering from BMT. Few studies evaluating hormonal changes following BMT have been conducted using a prospective design. One such evaluation of adolescent survivors of allogeneic transplant conducted by De Sanctis et al 51 (1991), compared pre-transplant hormone levels with a post-transplant (mean = 2.3 years following BMT) assessment. Results clearly showed a substantial disruption in hormone levels following BMT relative to pre-treatment values, with females apparently sustaining a greater disturbance than males. It is unclear whether the pre-treatment levels were normative relative to control standards, as this information was not provided. Furthermore, as this study was conducted with adolescents it is unclear whether these results are generalizable to adult BMT patients. The long-term impact on hormone levels can be substantial, and BMT survivors frequently suffer not only sexual dysfunction but also infertility. In a retrospective review of 1326 patients, 76 women had a total of 146 pregnancies, some of which were in women who had undergone BMT treatment themselves, and some of which were carried by 419

12 420 partners of male BMT survivors. Among these individuals, Sanders et al 54 (1996) found a significantly increased rate of pre-term babies and spontaneous abortions compared with the normative standards among healthy women. This team of investigators estimated that as few as 16% of the women in this study had regained normal ovarian functioning. Hormone replacement therapy The findings that BMT survivors experience hormonal irregularities have given rise to the use of hormone replacement therapy (HRT) to treat sexual dysfunction in patients, with preliminary evidence demonstrating some benefits. Spinelli et al 58 (1994) prospectively followed 74 adult females undergoing allogeneic BMT over a period of several years. Immediately following treatment all participants were exhibiting evidence of ovarian disruption as a result of changes in their hormonal functioning. Six months after BMT, 94% of the 52 sexually active patients were reporting sexual difficulties which included vaginal dryness, dysuria, dyspareunia, decreased libido and/or decreased activity. To assist these patients, the investigators administered HRT with encouraging results. Of 49 women who received systemic HRT, 81% reported a dramatic improvement in their frequency and enjoyment of sexual activity and a substantial decrease in sexually related physical symptomatology. Cust et al 41 (1991) also administered hormone replacement therapy with apparent success: following BMT, 81% of subjects were experiencing vaginal dryness, 82% reported pain during intercourse, 73% noted decreased libido, and 64% reported difficulty achieving orgasm. By contrast, after 6 months of HRT, 81% of these women reported a substantial reduction in sexual difficulties and an improvement in their activity levels. While the results above suggest HRT may be a viable treatment option for women, there is a distinct absence of research on the benefits of this treatment for male BMT patients. Limitations of past research and future directions A number of methodological problems limit the applicability of available research. Many studies have used mixed patient samples, which include individuals who have received autologous and allogeneic forms of BMT, as well as patients who have received total body irradiation (TBI) and those who have not been irradiated. These mixed samples have been used, despite findings indicating significant differences between these groups in terms of treatment characteristics and treatment effects. 21,38 Past investigations have also grouped together patients who received differing pre-bmt courses of chemotherapy or radiation therapy. Different treatment regimens may be associated with distinctive physical and/or emotional side-effects impacting aspects of the quality of life of patients. As well, longitudinal studies are notably lacking with most investigations being cross-sectional and descriptive in nature. Small sample sizes are also a limitation of past research, with some studies using as few as 12 subjects. As Wingard 59 (1994) notes, study samples have been rarely stratified in terms of demographic variables such as socioeconomic status, age, disease or treatment, further limiting their generalizability to other patient populations. In a recent review of literature on BMT and QOL, Hjermstad and Kaasa 60 (1997) suggest that little detail is known about the specific patterns of experiences during recovery in the first years following BMT. Longitudinal examinations can provide more informed understanding of this process. Among the studies investigating the specific effects of BMT, there has also been a lack of agreement on standard assessment measures of quality of life, psychological distress, and sexual functioning, making meaningful comparisons between study samples difficult. In particular, global and quality of life assessments have been used interchangeably despite there being considerable differences between these assessment formats. Continued prospective research in functional status, psychosocial adjustment factors, and psychosexual functioning with reliable validated instruments, and more adequate sample sizes are necessary to definitively evaluate the apparent contrasts between global QOL reports and reports of specific types of post-treatment dysfunction and symptomatic distress. One likely explanation for the disparate results lies in appreciation that patients have for the effects of BMT in terms of survival, as it is indeed a life-saving treatment with few alternatives. Clearly, the subjects in these studies have been survivors for whom the treatment has been relatively successful, at least over the short term (the duration of most studies). It is only logical that these patients would be grateful for the treatment and their retained life expectancy, which would be reflected in their global QOL scores. However, it is important not to overlook the less positive reports concerning specific QOL indices. Post-treatment difficulties of BMT patients deserve a significant amount of attention, and indications of distress should not be neglected. Conclusion A thorough literature review illustrates a number of functional impairments that patients experience after bone marrow transplantation. In particular, fatigue, psychological distress and sexual dysfunction are reported with high incidence in a number of studies. Clearly, advances in treatment will result in improvements in quality of life and level of functioning for these patients. As previous research has been predominantly descriptive, future emphasis should be placed on prospectively evaluating therapeutic interventions that attempt to improve quality of life. Future research should also continue the examination of impact of BMT on sexual functioning and psychological distress, with particular emphasis on comparisons with healthy controls and other cancer groups. Preliminary results suggest HRT is a viable and beneficial treatment option in reducing sexual disturbances, although research in this area has been limited. Investigations must aim at determining which therapeutic methods help to eliminate debilitating symptoms, thereby enhancing both specific and global indices of quality of life for patients.