The impact of endocrine therapy on patients with breast cancer: a review of the literature

The Breast (2002) 11, 1–12 r 2002 Harcourt Publishers Ltd doi:10.1054/brst.2001.0397, available online at http://www.idealibrary.com on

SPECIAL ARTICLE

The impact of endocrine therapy on patients with breast cancer: a review of the literature S. Coster and L. J. Fallowfield CRC Psychosocial Oncology Group, School of Biological Sciences, University of Sussex, Falmer, East Sussex, BN1 9QG, UK S U M M A R Y . This paper reviews studies which have examined the impact of endocrine therapy on the quality of life (QOL) of patients with breast cancer. In patients with primary disease, published studies suggest that endocrine therapies, such as tamoxifen, significantly increase both gynaecological and vasomotor symptoms. However, few studies have been able to demonstrate the impact which these symptoms have on patients’ QOL. This failure can be partially attributed to a range of methodological problems. Psychosocial research in advanced disease has largely consisted of randomized controlled studies with QOL as one of several study endpoints. Second generation treatments, such as aromatase inhibitors, have frequently been compared with older treatments, such as progestin therapies. Unfortunately, QOL data reported in these studies have tended to be fairly limited. Problems with existing QOL research in endocrine treatment are discussed and recommendations are made for further work. r 2002 Harcourt Publishers Ltd

events, although serious, are infrequent complications that must be balanced against reductions in mortality using adjuvant treatments.2 Due to the unique pharmacological action of tamoxifen, the treatment can also cause a range of persistent side-effects, including hot flushes, vaginal dryness and night sweats.3 Historically, patients with advanced disease who had failed on tamoxifen were treated with non-specific aromatase inhibitors, such as aminoglutethimide or the progestin, megestrol acetate. Both agents were also associated with a number of severe side-effects including rashes, excessive weight gain and nausea.4 However, the last decade has seen the development of specific secondand third-generation aromatase inhibitors, such as letrozole, anastrozole and exemestane. Phase III trials have clearly demonstrated the clinical superiority of these agents over conventional treatments for advanced disease. They have now established themselves as the second-line therapy of choice in post-menopausal women with advanced cancer. Treatment-related symptoms still occur with these newer agents but they have been championed as more tolerable alternatives, largely due to their specific pharmacological actions.5 Further research will establish the value of aromatase inhibitors as first-line treatments. Preliminary results

INTRODUCTION The purpose of this paper is to give an introduction to research examining the psychological and social impact of endocrine treatment in patients with breast cancer. Studies in the area are critically reviewed, and suggestions for future research are offered. Endocrine therapy is currently one of the most common forms of treatment for breast cancer. After primary surgery, women who have had oestrogen dependent tumours are advised to take endocrine treatment for up to 5 years, in order to prevent or delay the onset of disease. In palliative care, endocrine treatment is given with the aim of reducing distressing symptoms and prolonging survival. The anti-oestrogen tamoxifen is the gold standard adjuvant treatment in primary breast cancer but has been linked to an increased risk of adverse events, including endometrial cancer and eye problems.1 These Address correspondence to: Ms. S. Coster, CRC Psychosocial Oncology Group, School of Biological Sciences, University of Sussex, Falmer, East Sussex BN1 9QG, UK. Tel.: +44 (0) 1273 873 017 Received: 10 June 2001 Revised: 10 August 2001 Accepted: 17 August 2001

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already suggest that letrozole, for example, can replace tamoxifen as first-line therapy for post-menopausal women with metastatic breast cancer and also in neoadjuvant settings after surgery.6,7 Compared with patient-based evaluations of cytotoxic treatments, research into the impact of endocrine therapy on patients has been rather limited.8 Although symptoms such as hot flushes have been strongly associated with endocrine agents,9 neither their prevalence or their consequence on patients is clear.3,10 The perception that endocrine side-effects are no more problematic than those experienced during the menopause could certainly have diminished motivation to evaluate their impact.8 Unfortunately, side-effect profiles developed solely by clinicians can fail to be comprehensive; several studies have confirmed a marked disparity between doctors’, nurses’ and patients’ perceptions of endocrine treatment.11,12 Without comprehensive information on the impact of therapy, clinical staff cannot help patients to make informed decisions regarding their treatment programmes. For example, a woman with primary disease and a good prognosis, may not be willing to suffer treatment side-effects for the added protection provided by adjuvant therapy. Similarly, a patient with advanced cancer might not wish to extend their survival time if this time will be characterised by treatment related symptoms. A clear understanding of both the potential physical and psychological problems associated with cancer treatment is also needed to devise effective, ameliorative interventions. Such interventions can range from simply offering patients oestrogen creams to providing tailored emotional counselling. Without these interventions many patients will suffer the burden of side-effects unnecessarily, which could ultimately decrease their compliance with medication.

MEASURING QUALITY OF LIFE Before undertaking a review of studies that have used patient-focused quality of life (QOL) instruments, it is necessary to define what is meant by such a tool. Early attempts at quantifying patients’ QOL were based on the judgement of their clinician. It is now accepted that asking patients to complete questionnaires or checklists will provide more accurate and meaningful data. A plethora of self-report tools have been developed over the last few decades to evaluate the impact of illness or treatment on people with medical conditions. Within oncology, those tools most commonly used can be classified into one of five types of measure: study

specific; generic; domain-specific; cancer-specific; and, site/disease-specific. Generic tools are often multidimensional and assess functioning in a range of different areas. The Medical Outcomes Study 36-item short-form health survey (MOS SF-36)13 is an example of a generic tool that is used to measure overall well-being in general populations. Domain-specific tools are usually limited to assessing one or two dimensions in greater detail. The Hospital and Anxiety Scale (HADS)14 is an example of this type of measure, developed to assess anxiety and depression in patient samples. Unlike instruments designed for individual studies, generic and domain specific scales have often undergone rigorous psychometric testing. Many have been used extensively in clinical and research settings, and information may be available on normative values. However, both the length and complexity of some of these scales may make them unsuitable for use in clinical trials. More recently, a number of cancer-specific inventories have been developed, consisting of items which have particular relevance to cancer sufferers. They also tend to be multidimensional and can evaluate functioning across a range of domains including psychological, physical, emotional and social well-being. Examples of cancer inventories include the Functional Assessment of Cancer Therapy-General (FACT-G)15 and the Functional Living Index for Cancer (FLIC).16 Several instruments have been supplemented with disease sitespecific modules. The European Organisation for Research and Treatment of Cancer scale (EORTCQLQ C30), for instance, has a separate module for measuring the impact of breast cancer.17 A handful of questionnaires, including the FACT-ES,18 have also been tailored to evaluate particular types of treatment. The FACT-ES consists of a breast cancer inventory plus an additional module to assess the effects of endocrine treatment. The multidimensional nature of these cancer scales can remove the need for a battery of different inventories. They are ideal for clinical trial work, being brief and easy to complete. Unfortunately to maintain their brevity, only a few items are used to assess individual dimensions, and thus the information provided on each area of functioning can be limited. Fallowfield provides a discussion on the range of questionnaires that have been utilised in cancer studies.19

THE REVIEW A MEDLINE search conducted for the years 1981–2000 revealed a paucity of relevant QOL studies in both

The impact of endocrine therapy in breast cancer primary and advanced breast disease. Only studies utilising patient-based assessment measures were evaluated. Given the absence of randomized controlled trials, non-randomized studies were also included in the review. Much of the research conducted in adjuvant settings has focused heavily on tamoxifen treatment, perhaps reflecting the prominence of this agent in primary disease. Early adjuvant trials designed to determine the preventative value of tamoxifen in disease recurrence,20,21 paid little attention to the possible psychological impact of treatment. For this reason, the initial results of psychological assessments reported by the National Adjuvant Breast and Bowel Chemoprevention Study (NSABP1)22 were particularly influential. This randomized controlled trial (RCT) systematically evaluated dimensions of QOL in over 11 000 women receiving tamoxifen treatment for up to 5 years. Although one of the largest studies in this area, NSABP participants were women at high risk of developing breast cancer, but were currently disease-free. It is unclear as to the extent that these results can be generalized to patients who go on to develop breast cancer. To date, research conducted on women taking endocrine treatment after primary breast surgery has remained limited to a handful of small, cross-sectional studies. These studies have rarely compared different types of treatment, but have used domain-specific measures to answer specific research questions. The absence of large well-controlled studies is slowly being

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redressed, with psychological data from a series of adjuvant endocrine trials currently awaiting publication.23,24 In addition, several newly established trials of adjuvant endocrine treatment have incorporated quality of life assessments as one of several endpoints.25,26 Research into the effects of luteinizing hormone receptor hormone treatments (LHRH) in pre-menopausal women has been particularly limited to date. This could be due, in part, to the relative recency of their development, and results are now pending from LHRH trials that have also included QOL assessments.24 In contrast to adjuvant research, information on the impact of endocrine treatment in advanced disease has emerged almost entirely from RCTs. Typically, studies have compared the limitations of traditional second-line progestin treatments, with second- and third-generation aromatase inhibitors. These trials have tended to use cancer-specific, QOL measures which have been included as one of several study endpoints. Using these multidimensional scales, trials have been able to compare the effects of treatment in terms of global QOL and on particular areas of functioning. The effect of adjuvant endocrine treatment on sexual functioning The prevalence of gynaecological symptoms associated with endocrine treatment has prompted substantial interest in the impact of therapy on sexual functioning.

Table 1 Impact of endocrine treatment on sexual functioning Study

Tool

Day (1999) NSABP B-1

SF-36

Mortimer (1999)

Schover sexual history form

N

Menopausal status

11 064 Pre/peri/post

57 Post

Treatment

Design

Result

Tamoxifen vs placebo

RCT

K

Significant changes in arousal and interest

K

No reduction in sexual activity Negative feeling about intercourse No problems with arousal or frequency Decrease in frequency of sexual activity

Endocrine therapy

Crosssectional

K K

Lindley (1998) Ganz (1998)

GP B, Psychoonchology inventory CARES

86 Post

Endocrine therapy

Crosssectional

K

1098 Post

Endocrine therapy

Crosssectional

K K

McCaughan (1996)

DFSI

45 Post

Endocrine therapy

Crosssectional

K K

Endocrine treatment symptoms Absence of sexual functioning problems associated with therapy Endocrine treatment symptoms Absence of sexual problems associated with therapy

Methodlogical issues Findings relate only to disease free group a&b

a–c Posible recall bias a–c

a–c

a=non-controlled case series study; b=patient sample was on a range of endocrine therapies forming a non-randomized treatment group; c=questionable suitability of psychological assessments.

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Details of these studies are given in Table 1. Some have included patients of both pre- and post-menopausal status, although the samples in most studies have consisted largely of post-menopausal women. Results from the NSABP study suggested that after 36 months, significantly more patients taking tamoxifen suffered vasomotor and gynaecological symptoms compared with the control group. Accompanying these sideeffects, patients reported significant changes in their sexual functioning. A small but consistently larger proportion of patients on tamoxifen complained of problems with sexual functioning, interest, arousal and orgasm. These domains were assessed by items on the Medical Outcomes Study (MOS) sexual functioning sub-scale. However, despite a prevalence of symptoms that included vaginal dryness, there was no evidence that the number of sexually active patients in the experimental group had reduced since treatment. Excluding the NSABP trial, sexual research in adjuvant settings has been limited to cross-sectional studies containing a range of patients who have agreed to respond to a particular survey or interview. Mortimer et al. reported on a sample of patients who had been receiving tamoxifen treatment for up to 2 years.27 Using a detailed sexual history questionnaire28 the study reported that over 50% of patients complained of painful intercourse and nearly a third experienced vaginal tightness. Pelvic investigations, which were performed on a sub-set of women, showed a definite association between oestrogen effect in vaginal cells and a prevalence of gynaecological symptoms. This oestrogen effect did not, however, correlate negatively with frequency of sexual activity, desire, or ability to achieve orgasm. Despite the significant prevalence of gynaecological symptoms recorded, the authors also reported that sexual functioning in the sample was comparable to baseline data from the NSABP study.22 In three further cross-sectional studies, participants were receiving or had already completed a range of adjuvant treatments, including cytotoxic therapies.29–31 Given the greater toxicity of chemotherapy treatments, findings on side-effects and treatment impact in these studies cannot be confidently be attributed to endocrine treatment alone. Lindley31 attempted to evaluate sexual functioning in a group of patients who had completed adjuvant treatments up to 5 years previously. Using a questionnaire protocol derived from a non-breast trial, patients were asked to evaluate their sexual functioning at the time of the survey and to recall their sexual behaviour 1 year before their cancer diagnosis. Around a quarter of women remembered feeling a decreased interest in sex and reduced sexual activity before diagnosis, compared with 60% who were experiencing

these problems at the time of interview. Nearly half of the participants reported that problems with their sexual functioning were due to either the cancer itself or to treatment. The authors conclude that long-term problems are associated with adjuvant treatment, with the greatest changes observed for patients who became menopausal following treatment. However, using the FLIC questionnaire, no differences were detected between the quality of life of patients who had received chemotherapy, tamoxifen, or a combination of both. Results from this study might suffer from a general recall bias as patients were asked to rate their sexual behaviour before treatment retrospectively. Studies by Ganz29 and McCaughan30 compared cohorts of patients on either chemotherapy or endocrine treatment with patients receiving no adjuvant therapy. Using the sexual sub-scale of the Cancer Rehabilitation Evaluation System (CARES)32 Ganz reported that patients on chemotherapy experienced significantly more pain during intercourse than patients on endocrine treatments. McCaughan used the Derogatis sexual functioning inventory (DSFI)33 to assess sexual drive and satisfaction in patients receiving chemotherapy or endocrine treatment, compared with functioning in a patient sample on neither treatment. Many women who were receiving some form of treatment were taking a combination of therapies. Controlling statistically for patients who had also received endocrine therapy, patients on chemotherapy reported significantly more dyspareunia, difficulty with orgasm, and decreased libido; however, controlling for patients who had also received chemotherapy, patients on endocrine treatments reported no more sexual problems than patients receiving no adjuvant therapy at all. Chemotherapy was associated with poorer sexual functioning than endocrine therapy in both studies. This remained the case, despite patients on tamoxifen consistently reporting more hot flashes, night sweats, and vaginal discharge. Current research has largely failed to clarify the relationship between endocrine treatment and sexual behaviour. Although every study has reported a clear increase in the number of vasomotor and gynaecological problems experienced by women receiving tamoxifen, few have been able to evaluate the impact of these symptoms on the sex life of these women. The NSABP study was alone in reporting that tamoxifen treatment was clearly associated with poorer sexual functioning. However, it is possible that the disease free state of these women, could have contributed to different expectations of adjuvant treatment from those of women with primary cancer. Current research suggests that symptoms such as vaginal dryness may not significantly reduce patients’

The impact of endocrine therapy in breast cancer arousal or appetite to engage in sexual activity. It can be possible for patients to maintain good levels of intimacy despite suffering troubling side-effects from treatment. However, it is equally possible that inconclusive findings are attributable to problematic study methodologies. It may also reflect participants unwillingness to discuss sexual problems which transcend simple gynaecological complaints. Methodological problems with research on sexual functioning Patients’ frankness about sexual behaviour will vary between individuals, between different demographic groups, and can also depend on the nature of the research study. For this reason, researchers are aware that sexual problems associated with cancer treatment may be under-reported in patient interviews and surveys. Accurate disclosure can be encouraged through the selection of measurement tools with good face validity; however, there is little consensus on which tools are most suitable for use with cancer patients, and this is reflected by the sheer range of instruments which have been employed in sexual research. Some researchers believe that full diagnostic inventories, such as the DSFI, are too long and overly explicit for use in cancer studies. Other investigators have been content to limit sexual assessments to just a few items present on a generic inventory. A key problem facing researchers in this area is that the content validity of sexual inventories designed for diagnostic use in the general population has rarely been assessed with cancer populations. One research team has addressed this issue by developing the Sexual Activity Questionnaire (SAQ). This was developed to elicit sexual problems specifically in patients receiving tamoxifen treatment.34 Validation work has been promising, with the scale receiving acceptance among patients, whilst showing discriminant validity with women of different menopausal status. The questionnaire has been used in several chemoprevention studies.23,25,35 The dominance of cross-sectional designs in the cited studies utilising just one assessment in time, can make study comparisons equally problematic. For instance, there are inherent problems in comparing women currently receiving prophylactic treatment22 with patients who have completed therapy nearly 5 years previously.31 Agreement on the criteria for defining post-menopausal patients, would also be one way of improving uniformity between patient study populations. Cross-sectional studies have also failed to address the influence of the menopause on the reporting of vasomotor and sexual problems. Many patients who

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receive endocrine treatment in clinical practice and in research studies are peri- or post-menopausal. Several authors have reported a natural decline in sexual functioning after menopause36,37 and there is a danger that the prevalence of sexual problems in some patients may not just be a consequence of their cancer treatment. Accurate baseline assessments on patient’s existing ‘menopausal’ symptoms would allow more confident estimations of the subsequent effects of therapy. Given that adjuvant treatment can be administered for up to 5 years, such studies would also provide a clearer picture of the effects of tamoxifen across time. Ongoing longitudinal endocrine trials will hopefully go some way to improving research in this area. Sexual functioning is obviously a complex process that is dependent on many different areas. Few studies have been able to demonstrate that tamoxifen affects sexual fantasy or arousal. However, the role of oestrogen systems in this area of sexuality has not been confidently ascertained, and so an absence of findings is not surprising. Sexual arousal may be influenced by other hormones, or equally well predicted by psychological factors such as the relationship with partner prior to treatment. Many studies have found an association between endocrine treatment, painful intercourse, vaginal dryness and vaginal tightness. It is therefore interesting to note that the only study to find a decrease in sexual activity as a result of endocrine treatment relied on patients’ retrospective recall.31 It is also arguable whether the frequency of sexual activity can be taken as a reliable indicator of sexual dysfunction. It is not unusual for patients to successfully manage sideeffects with aids such as vaginal lubricants and report relatively normal functioning. In addition, the assumption that vaginal problems will assert a measurable impact on sexual enjoyment, discounts the range of nonpenetrative activities which may be enjoyed. It could be worth reconsidering present ways of assessing sexual behaviour during the development of future assessment tools. Affective disorders in patients receiving endocrine treatment Pharmacological research on the use of contraceptive pills and natural oestrogen withdrawal during menopause suggests that steroid hormones can influence womens’ moods. Researchers have suggested that endocrine treatment may similarly affect a patient’s mental or emotional health38 and several studies have attempted to investigate this idea (Table 2). As part of an overall QOL assessment, the NSABP trial compared the incidence of depressive illness in

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Table 2 Impact of adjuvant endocrine treatment on psychological morbidity Study

Tool

Shariff (1995)

IPAT Dep Scale STAI

42

Day (1999) NSABP B-1

CES-D MOS-SF36

11 064

Love (1991)

Study-specific

Couzi (1995)

Study-specific

Canney (1994) HADS

N

Menopausal status

Treatment

Design

Result

Post

Tamoxifen group

Prospective study

K

Increased depression associated with tamoxifen use

Pre/peri/post

Tamoxifen placebo

RCT

K

No increase of depression or psychological morbidity

140

Post

RCT

K

222

Post/pre

Tamoxifen vs placebo Endocrine therapy

Crosssectional

K

108

Post

Endocrine therapy

Crosssectional

K

No increase of depression or irritability Linear association between depression and endocrine side effects Linear association between anxiety and endocrine side effects

Methodological flaws No control group Selected patient group Findings relate only to disease free group. c a–c

a–c

a=non-controlled case series study; b=patient sample was on a range of endocrine therapies forming a non-randomized treatment group; c=questionable suitability of psychological assessments.

patients receiving adjuvant tamoxifen with those receiving no adjuvant treatment. The study employed the Center for Epidemiological Depression Scale (CEDS),39 a psychiatric diagnostic tool used widely throughout the US to detect affective disorders. Results from the NSABP1 indicated no variation between the occurrence of depression in the tamoxifen group and that found in the control sample. The MOS SF36 was also used to assess the emotional well-being of patients in both groups, but no differences were found in scores on the five-item mental health subscale. Equally, on the physical and mental component summaries of the MOS SF-36, no consistent differences emerged between the two groups. Women in both the tamoxifen and the control group showed levels of psychological functioning that in fact exceeded US normative values for the scale. With the exception of the NSABP study, research has been limited to studies with relatively small, sample sizes. A much smaller randomized trial compared tamoxifen therapy with a placebo treatment.40 Using a symptom checklist and a seven-item QOL tool designed for the study, Love et al. reported no differences between the two treatment groups in terms of insomnia, depression, irritability, or overall QOL. This was despite the fact that side-effect toxicity had significantly increased from baseline to 12 months in tamoxifen patients, but not in the placebo group. The study had a controlled design, but the reliability of findings are marred by the author’s use of an instrument with unreported psychometric properties. A single study, retrieved by this review, reported a definite association between depressive illness and the

use of tamoxifen.41 A group of patients, selected by a physician, were assessed at baseline and then 8 months after beginning tamoxifen therapy. All participants were screened before entering the study for existing psychiatric disorders. Patients answered questions on the IPAT depression scale42 and the state-trait anxiety scale,43 which have been used extensively with medical populations. Results indicated that group depression scores increased significantly from baseline to re-test at 8 months. Seventeen per cent of the sample obtained diagnostically significant scores on the IPAT depression scale and 12% had minimally elevated anxiety scores. The authors suggest that tamoxifen can cause depression in some patients and can be unsuitable for longterm adjuvant use. However, with only one follow-up assessment a 8 months, it is questionable as to whether this study addresses the problems of long-term treatment. As no comparison was possible with a sample of cancer patients who were not receiving treatment, the significance of these findings with a selected group of participants remains unclear. Studies to date have failed to clarify the relationship between tamoxifen therapy and emotional disturbance experienced by patients. Shariff,41 for example, proposes that depression results from hormonal imbalances caused by tamoxifen treatment. However, it is equally possible that affective disorders can result from the burden of persistent treatment side-effects. This particular study did not include a symptom checklist, and so the extent of problems experienced by the sample is unclear. A randomized trial,40 which did gather information on treatment symptoms, found no evidence of a relationship between persistent treatment toxicity

The impact of endocrine therapy in breast cancer and depression. In contrast, two case-series studies reported by Couzi3 and Canney44 suggested that sideeffects can be associated with an increase in depressive illness. Using a study-specific measure, Couzi found that depression seem to increase with the severity of hot flushes and night sweats experienced by tamoxifen patients. Similarly, Canney reported that 50% of patients in their study obtained borderline anxiety scores on the HADS, and that the disorder was associated with an increase of menopausal-type symptoms. These studies raise an interesting question but due to methodological flaws findings from both studies cannot be considered reliable. Research has yet to prove conclusively whether taking tamoxifen is associated with an increased risk of developing an affective disorder. The majority of studies to date have failed to find an association. Those studies which have suggested such an association have failed to clarify whether every patient is equally at risk, whether those experiencing toxic side-effects are more likely to develop psychological problems, or whether depression itself can lead to over-reporting symptoms. If depression is a possible consequence of treatment with tamoxifen, the origins of the disorder will have implications for both clinical intervention and long-term management. Methodological problems with research on affective disorders A range of different instruments have been used to assess the prevalence of affective disorders in breast cancer patients, including a number of unreliable studyspecific tools. However, even the use of validated, psychiatric scales can be problematic. Questionnaires used to detect depression in general populations, such as the General Health Questionnaire-28 (GHQ-28),45 do not always possess validity with cancer patients because of an over-reliance on somatic items. Instruments such as the HADS, designed for use with medical populations, are generally an improvement upon standard psychiatric measures. However, the sensitivity of any tool with a particular population can only really be assessed by direct comparison with psychiatric interview. Using such a technique, Hall et al.46 compared the prevalence of depression in a sample of cancer patients after breast surgery, using both a psychiatric interview and the HADS self-report scale. When patients were interviewed, 37% of the patient sample was diagnosed with a depressive illness. Using the HADS standard cutoff score of 11, only 14% were identified as suffering from depression. The authors reported poor sensitivity and specificity for the HADS with this population, and question the use of the tool as a research or screening

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instrument in breast cancer research. To date, very few psychiatric scales have received this degree of validation and so their sensitivity with breast cancer patients remains largely unknown. The need for well-controlled randomized studies in this area is obvious. Obtaining baseline data is the only way to ensure an accurate estimation of mood change during treatment. Given the already high prevalence of affective disorder in patients who have been diagnosed with cancer, such accuracy is particularly important. Some researchers have estimated that as many as 50% of cancer patients could suffer from depression following diagnosis.47,48 It is therefore imperative that research studies can distinguish between depression related to the patient’s condition and that resulting solely from cancer treatment. Measuring quality of life in advanced disease Unlike treatment for primary breast cancer, the gold standard endocrine therapy for patients with advanced disease is less established. Traditionally, second-line treatments, such as megestrol acetate have been used as less toxic alternatives to older aromatase inhibitors, such as aminoglutethimide. However, with the development of more tolerable second- and third-generation aromatase inhibitors, the choice of drugs available for advanced breast cancer has become vast. The results of numerous phase II and III trials have confirmed that third-generation aromatase inhibitors improve on the toxicity of aminoglutethimide, and that they are not associated with the excessive weight gain found with megestrol acetate treatment. In turn, aromatase inhibitors have been associated with generally milder sideeffects, such as gastro-intestinal disturbances and hot flushes.5 A proliferation of research has attempted to compare the efficacy of these new agents with traditional therapy. Many studies have evaluated the performance of new aromatase inhibitors against standard megestrol acetate treatment (Table 3). Quality of life has been used as an outcome measure in several of these trials. The minimal survival differences found between many of these new treatments may have encouraged researchers to value the psychological benefits of treatment as a study outcome. The prospective, randomised controlled designs featured by these studies are a considerable improvement on the poor methodology plagueing psychosocial research in adjuvant settings. Quality of life has often been included as an endpoint in these studies, but has rarely been the primary focus of the trial. For this reason, some studies have provided fairly limited information on psychological findings.

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Table 3 Impact of advanced endocrine treatment on QOL Study

Tool

N

Menopausal status

Treatment

Design Result

Methodological flaws

Budzar (1997)

RSCL

386

Post

MA vs anastrozole

RCT

K

–

Jonat (1996)

RSCL

378

Post

MA vs anastrozole

RCT

K

Goss (1999)

FLIC

452

Post

MA versus vorozole

RCT

K

Bernhard (1998)

Linear analogue scale (LASA) FLIC Rand MHI

177

Post

MA vs formestane

RCT

K

Improved psychological functioning with anastrozole QOL differences between treatments at 24 weeks insignificant Improved psychological functioning with vorozole No difference in QOL between treatments

131

Post

MA: low vs medium vs high dose

RCT

K

Better physical and psychological functioning with lowest dose No differences in body image No significant differences in QOL between treatments

c

Kornblith (1993)

Hayes (1995)

Body image sub-scale Visual analogue scale

K

648

Post

Tamoxifen vs toremifene

RCT

K

– c c

c

MA=megestrol acetate; a=non-controlled case series study; b=patient sample was on a range of endocrine therapies forming a nonrandomized treatment group; c=questionable suitability of psychological assessments.

Six studies evaluating endocrine treatments for advanced disease which used patient QOL measures, were retrieved. Two of these trials compared the tolerability and clinical efficacy of megestrol acetate with high and low doses of anastrozole, a new aromatase inhibitor.49,50 Both studies used the Rotterdam Symptom Checklist (RSCL) as an overall measure of QOL.51 The RSCL includes two primary sub-scales that measure physical and psychological domains, and has been validated against psychiatric interview with cancer patients.52 Neither study found any significant difference in side-effects experienced by patients receiving anastrozole or megestrol acetate, except predictably the occurrence of weight gain in the latter group. In one of these studies50 megestrol acetate was associated with an improvement in psychological functioning at 3 months, but at 6 months this was not significant. At 3 months, the second study49 found better physical functioning in patients on low-dose anastrozole compared to those receiving megestrol acetate, but better psychological functioning in patients on high-dose anastrozole compared to the megestrol acetate group. Unlike the first study, these differences remained significant at 6 months. A study by Goss compared megestrol acetate with the efficacy of vorozole, an aromatase inhibitor, among patients whose disease had progressed on tamoxifen.53 Quality of life was monitored using the FLIC scale, which is specifically designed for use with cancer patients. Although there was no significant difference in time to progression or survival between the treatment

groups, patients in the vorozole group reported significantly more nausea and hot flushes. Patients on megestrol acetate reported significantly more dyspnoea, increased appetite and weight increase. No differences between the two treatment groups emerged when results from the FLIC were analysed. However, Goss reported that patients on vorozole with complete, partial responses or stable disease, had significantly higher psychological well being compared to similar patients on megestrol acetate. Bernhard et al. reported on a trial comparing megestrol acetate treatment with formestane, another newly developed aromatase inhibitor.54 Along with overall survival and disease progression, the QOL of patients in the two treatment groups was compared using linear self-assessment scales (LASA). These scales covered several different areas of functioning and were administered every 2 months for 1 year. Patients’ QOL at baseline was strongly predictive of LASA scores once under treatment, but not of time to treatment failure. The study found no statistically significant differences in QOL between patients on either treatment. One trial that focused primarily on QOL compared the efficacy of three different doses of megestrol acetate in patients with advanced breast cancer. The study assessed both QOL and patient body image at baseline and 3 months after treatment.55 The authors hypothesised that patients receiving the highest dose of progestin would suffer the greatest weight gain and therefore the most psychological distress. Using the FLIC, the Rand Mental Health Inventory56 and a body

The impact of endocrine therapy in breast cancer image subscale,57 an association was found at 3 months between increasing dose and fatigue, and increased appetite and weight gain. Patients receiving low-dose treatment experienced significantly less side-effects than women in the high-dose group, reported better physical functioning, and less psychological distress. Patients who had reported the most bone pain on study entry, appeared to score more highly on QOL instruments at 3 months. The uncontrolled use of analgesics during the study, however, made it difficult to explore this area further. Interestingly, even though high doses were significantly associated with greater weight gain, no differences were found between treatment groups on the body image scale. In fact by 3 months, fatigue rather than body weight was found to be the greatest predictor of QOL. The authors also suggested that one of the biggest predictors of psychological distress at 3 months was the level of distress experienced pre-treatment. Only one of the studies retrieved did not feature a treatment group receiving megestrol acetate. This study compared toremifene therapy with second-line tamoxifen treatment.58 Toremifene is an anti-oestrogen, derived as an alternative to tamoxifen, providing similar clinical efficacy but with reduced toxicity. Along with disease progression, patients were monitored every 2 months using a study-specific QOL assessment. Using a visual analogue scale, all patients rated their mood, pain and overall enjoyment of life. No significant differences were found between treatments in terms of overall survival rates, or any of the QOL measures. Given the similar tolerability profiles of the two agents, the use of a non-validated scale without established sensitivity could be questioned. In conclusion, differences in QOL experienced by patients on megestrol acetate, vorozole, anastrozole and toremifene were small.50,54,55 Reported differences in psychological and physical functioning remain largely unexplained by patients’ reports of problematic symptoms. The only treatment side-effect consistently reported in studies appeared to be weight gain associated with megestrol acetate. However, the single study measuring the effect of weight gain from progestin treatment on patient body image was inconclusive.55 The authors of this particular study suggest that body image problems occurring after breast surgery could have superseded any further changes resulting from weight gain. Methodological problems with QOL research in advanced disease Given that studies in advanced disease have largely consisted of RCTs, methodological criticisms in this

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area lie not with the study designs but with the choice of QOL instrument. At least two studies comparing treatments for advanced disease have utilised the FLIC as their sole quality of life instrument.53,55 This is a cancer-specific QOL scale and although well validated, the appropriateness of the tool for use in clinical trials has been questioned. The FLIC consists of 22 items investigating pain, stress and ability to work or perform household chores. These are individually rated on a 13-point visual analogue scale. Some authors have criticised the number of items measuring each dimension and feel that it may not be sensitive to change over time.59 Studies cited in advanced disease that have not utilised the FLIC have still tended to rely upon visual or linear analogue rating scales to provide information on QOL.54,58 Unlike the Likert scales present on instruments such as the Rotterdam Symptom Checklist or the FACT-G, visual analogue scales have also been heavily criticised for being both confusing and time consuming for patients to complete.19 The International Breast Cancer Study Group opposes this view of linear scales and purports to have successfully used one-item linear QOL scales in a series of adjuvant chemotherapy trials. The group argues that these scales have been validated successfully in cancer populations. They also cite research showing good concurrent validity and responsiveness of a one-item question on mood, when directly compared with a 28item adjective checklist for assessing emotional wellbeing.60 Regardless of their reliability, such instruments do not always provide enough detail to capture the extent and effect of treatment related problems. The dominance of these scales in advanced breast cancer trials may certainly have contributed to limited findings in terms of quality of life. Inventories that do not provide precise information on treatment impact are also of limited value to clinicians hoping to use them to modify clinical practice.

CONCLUSION Several conclusions can be drawn from the literature. Firstly, research that has attempted to look at the impact of endocrine treatment on patient QOL has been scarce. The majority of studies in this review have concerned themselves largely with post-menopausal patients. As adjuvant endocrine therapy is increasingly being advocated in younger women, future studies will need to focus on the impact of treatment in premenopausal women. The work in adjuvant therapy has been characterised by methodological problems, such as small sample sizes

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The Breast

and poor study designs. Studies that have included symptom checklists have nearly always found evidence of vasomotor and gynaecological side-effects. However, few have been able to clarify the impact of these symptoms in terms of patient functioning. In metastatic disease, newer third-generation agents seem to improve the quality of patients’ lives in particular areas of functioning. Unfortunately, the insensitivity of many instruments used for assessment makes it difficult to account for small differences in QOL scores occurring between treatments.

IMPLICATIONS AND RECOMMENDATIONS FOR FURTHER RESEARCH One of the obvious comments to be made from this review is that QOL data are only as valid as the instruments chosen to assess them. Choosing an appropriate instrument for use in a particular study is certainly problematic. Coupled with the problems associated with non-validated study-specific questionnaires, the use of a psychometrically validated, cancerspecific QOL measures does not guarantee accurate and meaningful findings. King61 suggests that different conclusions can be drawn from the same studies depending solely on the type of tool employed. Studies directly comparing the EORTC-QLQ C30, and the FLIC have reported markedly different dimensionspecific results when the tools were used to assess the same study populations.62 Groenvold also argues that the use of standardized QOL tools in clinical trials does not guarantee that measures will be equally valid for every study.62 He stresses the importance of content validity which is the only way of ensuring that a scale is suitable to address a particular research question. Fallowfield proposes that most QOL instruments are not sufficiently contentspecific to provide a fully comprehensive account of the effects of endocrine therapy.18 As yet, the FACT-ES is the only cancer-specific QOL questionnaire that has an accompanying sub-scale for endocrine symptoms. The presence of an integrated checklist allows a relationship to be drawn between patient toxicity during treatment and overall QOL scores. It is designed to be particularly sensitive to the range of side-effects associated with endocrine agents. Early validation work using the FACT-ES has certainly shown good discriminant validity between different endocrine treatments groups and different stages of disease.18 The FACT-ES is currently being used in ongoing trials that are comparing a selection of endocrine treatments.

The use of tools that are valid to study questions, along with the introduction of new endocrine-specific measures, will hopefully provide a more rigorous way of assessing treatment impact. It is important that the quality of studies in psychosocial research continues to improve, and that positive or negative findings in research are not purely a consequence of inadequate study design. The increased inclusion of QOL measures in cancer trials is a step forward, in that it allows the administration of psychosocial assessments within much larger, randomised studies. The longitudinal designs of many of these trials can also provide essential information over different time points. However, it is important that QOL scores do not become just one more trial endpoint, providing limited data that is meaningless in real terms to patients and clinicians. The information collected from patients during research must genuinely enhance understanding of their treatment experiences.

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