- Email: [email protected]
Patients' preferences for adjuvant chemotherapy in early breast cancer: a review of what makes it worthwhile?
Choosing adjuvant chemotherapy
Review
Patients’ preferences for adjuvant chemotherapy in early breast cancer: a review of what makes it worthwhile? Vlatka Duric and Martin Stockler
Adjuvant chemotherapy for early breast cancer improves survival but is unpleasant and inconvenient. Women and clinicians need information about the magnitude of survival benefits considered sufficient to make the side-effects and inconvenience worthwhile. We sought studies that quantified the minimum required survival benefit by asking women who had experienced adjuvant chemotherapy. Four studies involving 512 women were appraised and summarised. All studies referred to chemotherapy given between 1980 and 1996, but the methods varied widely, especially the way in which women were recruited and questioned. However, the results were remarkably consistent. Most women said that small improvements in survival were sufficient to make adjuvant chemotherapy worthwhile. Women with dependants, social support, and milder side-effects judged smaller benefits worthwhile. Age, education, employment, and income status were not predictive of the women’s responses. Optimum decision-making about the relative benefit of adjuvant chemotherapy requires upto-date information from women receiving current chemotherapy and supportive regimens. Lancet Oncol 2001; 2: 691–97
Adjuvant chemotherapy improves disease-free and overall survival in women with early breast cancer, increasing 10-year survival by about 10% for women aged under 50 and by about 3% for women aged 50–69, with larger gains for those at greater risk.1 These modest improvements might translate into average life-expectancy gains of 1 to 3 years, depending on individual circumstances. The expected benefits for each woman depend on her baseline risk, predicted by the extent, histology, and receptor status of her tumour. However, adjuvant chemotherapy has side-effects and is inconvenient; it is unnecessary for some and ineffective for others. The important question is not whether it works, but in which subgroups it works well enough to justify its side-effects and inconvenience (Figure 1).2 The benefits and harms of adjuvant chemotherapy are not equally apparent to individual women or clinicians. The acute side-effects of chemotherapy such as hair loss, nausea, fatigue, and risk of infection have an immediate and obvious effect on quality of life.3,4 The impacts of rare long-term sideeffects, such as cardiac dysfunction and myelodysplasia, are vivid and striking. On the other hand, the benefits of THE LANCET Oncology Vol 2 November 2001
Figure 1. Weighed in the balance – many factors need to be taken into account when deciding whether adjuvant chemotherapy for early breast cancer is worthwhile.
adjuvant chemotherapy are delayed and less apparent to patients or clinicians. Individual preferences regarding the relative importance of these outcomes are crucial for optimum decision-making about whether or not to have adjuvant chemotherapy. Women facing this choice can gain unique insights from the recorded judgment of women who have experienced adjuvant chemotherapy for early breast cancer first-hand. We undertook a systematic review of studies that quantified the benefits that make adjuvant chemotherapy for early breast cancer worthwhile by asking women who had experienced it. The purpose of this review is to VD and MS are at the NHMRC Clinical Trials Centre, University of Sydney, Australia. MS is also at the Department of Public Health and Community Medicine, University of Sydney, Department of Medicine, University of Sydney, and Sydney Cancer Centre, Royal Prince Alfred and Concord Repatriation General Hospitals, NSW, Australia. VD is also at the Department of Psychological Medicine, University of Sydney. Correspondence: Dr Martin Stockler, Sydney Cancer Centre GH6, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW, 2050 Australia. Tel: +612 9515 5494. Fax: +612 9519 1546. Email: [email protected]
691
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Review
Choosing adjuvant chemotherapy
summarise the views of women who have experienced chemotherapy, for the benefit of future women and clinicians facing this decision. The minimum benefits considered sufficient in these studies are not intended to be quantitative guidelines for the prescription of adjuvant chemotherapy. Selected findings from the studies are tabulated and described with simple summary statistics.
Findings Four studies involving 512 women from Australia, USA, and Italy were published between 1992 and 2000. The baseline characteristics of the women, their disease, and treatment are summarised in Table 1. Most of the women had chemotherapy during the late 1980s and early 1990s. The distributions of age, disease stage, and treatment types reflect the use of adjuvant chemotherapy during this time. Most women were younger than 60 years, were married, and had at least a high-school education. About half were employed. The differing proportions of women with stage I disease (0%,9 25%,6 and 48%5) reflect the years in which the women were treated and the wider use of adjuvant chemotherapy for node-negative breast cancer in the USA. Less than 25% of the women had either breast-conserving surgery or adjuvant radiotherapy. Few details were available about the chemotherapy that the women received. The limited information showed that cyclophosphamide, methotrexate, fluorouacil (CMF), and doxorubicin-containing regimens were most common, and a tiny proportion of women received high-dose chemotherapy with stem-cell support. However, no women were reported to have received taxanes or trastuzumab
(herceptin). The methods used in each study are described in Table 2. The primary purpose of Simes and Coates’ study was to establish preferences,9 but the others had additional goals. Two studies used face-to-face interviews supported by visual aids,7,9 whereas the other two used mailed questionnaires.5,6 Three studies sought women treated or reviewed consecutively and had response rates of over 75%.5,7,9 The study by Ravdin and colleagues was the largest, but had the lowest response rate (21%), because not all women who were sent questionnaires by post had received adjuvant chemotherapy.6 All the studies presented women with a range of possible survival benefits aiming to quantify the smallest benefit that would make the side-effects and inconvenience of treatment worthwhile. In three studies,5-7 the order in which the benefits were presented was fixed in a linear increasing fashion; in Simes and Coates’ study the ordering was randomly allocated to be either increasing or decreasing.9 Variations over time and between interviewers were addressed only in studies using face-to-face interviews. In Simes and Coates’ study,9 repeated interviews 3 to 6 months apart gave comparable results (Spearman’s coefficient of 0.6 to 0.7). These correlations are substantial, but they overestimate reliability because not all participants completed two interviews and because they ignore systematic changes over time. In Zimmermann and colleagues’ study,7 there was little difference between preferences elicited 2 months apart, despite differences in how the questions were framed. There were substantial differences in the wording and nature of the questions. Interviewers in two studies asked women to imagine themselves in hypothetical situations,
Table 1. Baseline characteristics of studies, women, their disease, and treatment Simes & Coates8
Lindley et al. 5
Ravdin et al. 6
Zimmermann et al.
1992
1998
19986
20007
Number of women
104
55
318
35
Country
Australia
USA
USA
Italy
Trial characteristics
8
Age median or mean (range)
5
49
54
49
52
(29–67)
(29–86)
(< 40 – > 70)
(39–66)
Married (%)
73
67
74
97
Employed (%)
52
61
··
43
Educated to high school level or above (%)
88
> 65
96
··
I
0
48
25
··
II
100
51
73
··
Lumpectomy
9
17
-
23
Mastectomy
91
83
-
77
18
19
-
18
Any
100
64
100%
100
CMF
100
··
39
··
··
46
··
Stage of breast cancer at diagnosis (%)
Initial surgery (%)
Adjuvant radiotherapy (%) Adjuvant chemotherapy (%)
Doxorubicin containing (eg AC, FAC, CAFM) 0 0
··
4
··
Treatment duration
High-dose with stem-cell support
1982–87
1988–91
1980–96
1981–96?
Years preferences were elicited
1986–87
··
1996
··
C, cyclophosphamide; M, methotrexate; F, fluorouracil; A, doxorubicin
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Choosing adjuvant chemotherapy
Table 2. Description and appraisal of methods used in fair studies of patients preferences Method
Simes & Coates 19929
Lindley et al. 19985
Ravdin et al. 19986
Zimmermann et al. 20007
Stated purpose
To ask women who had received CMF as adjuvant treatment to rate the benefit that would make treatment worthwhile
To evaluate the QOL of patients who survived 2- 5 years since initiation of adjuvant cytotoxic or hormonal therapy and to characterise relations between QOL and physical symptoms, sexual function, and preferences about adjuvant treatment
To survey survivors to define what they had been told about their prognosis and the value of adjuvant therapy, what they estimated their prognosis to be with and without adjuvant therapy, and what improvement they would have found minimally worthwhile
To examine the effects of framing of outcome and probabilities of cancer occurrence on the treatment preference that patients indicate for hypothetical scenarios
Response rate 104/129 (81%) (interviewed/approached)
86/111 (77%)
562/2600 (21%)
35/40 (88%)
Identification and recruitment Survey instrument
Consecutively women treated
Volunteer consumers
Women consecutively reviewed in clinic Interview
Questionnaire
Questionnaire
Women consecutively reviewed in clinic Interview
Method of administration Face to face
Postal survey and telephone call
Postal survey
Face to face
Number of interviewers
2
?
NA
1
Was inter-rater reliability reported?
No
NA
NA
NA
Was intra-rater ? reliability reported
Yes
NA
NA
NA
Use of visual aids
Yes
?
?
Yes
Starting point for questions
Without chemotherapy
With chemotherapy
Without chemotherapy
Without chemotherapy
Discussion of framing effects
Yes
Yes
No
Yes
Discussion of anchoring Yes effects
No
No
Yes
Ordering of questions
Randomised
Fixed
Fixed
Fixed
Ordering of benefits presented
Increasing or decreasing
Increasing
Increasing
NR
Nature of question
Preferred option
Expected benefit
Worthwhile benefit
Preferred option
Subject of question
Woman herself
Woman herself
Woman herself
Hypothetical woman
General format of questions
Series of choices between having or not having adjuvant chemotherapy given different levels of benefit.
‘…what potential improvement in cure rate or prolongation of survival women would expect in exchange for receiving adjuvant chemotherapy?’
‘Given your experiences with treatment, would taking more treatment after surgery have been worthwhile for you if it extended your life by the following...?’
Series of choices between having or not having adjuvant chemotherapy given different levels of benefit
NA, not applicable; NR, not reported; QOL, quality of life
and then to make a series of choices between paired options with and without chemotherapy.7,9 The questionnaires in the two other studies asked women to choose from a range of options.5,6 Lindley and colleagues’ questionnaire asked women what benefit they would ‘expect’ or ‘anticipate’; Ravdin and coworkers’ questionnaire asked whether ‘…taking more treatment after surgery would have been worthwhile if…’. There was also substantial variation in precisely how the adjuvant chemotherapy was specified. For example, Coates and colleagues described adjuvant chemotherapy as ‘6 months of the treatment you received’, whereas Ravdin and colleagues described it simply as ‘more treatment after surgery’. Three studies used survival without chemotherapy as the starting point, asking how much better it would have to be to make chemotherapy worthwhile.6,7,9 Lindley’s study used survival with chemotherapy as the starting point, and asked how much worse it would have to be without chemotherapy to make it worthwhile. THE LANCET Oncology Vol 2 November 2001
Minimum worthwhile benefits The minimum benefits considered sufficient to make adjuvant chemotherapy worthwhile are summarised in Table 3 and illustrated in Figures 2 and 3. All studies except the one by Zimmermann and colleagues asked questions framed in terms of extra months of life expectancy. All studies asked questions framed in terms of improvements in the percentage chances of survival or cure. Additional life expectancy of six monthswas considered sufficient to make adjuvant chemotherapy worthwhile by 52% of women, and an extra 12 months was considered sufficient by 74% (Figure 2). An extra 24 months of life expectancy was considered insufficient by 9% of women. A 1% improvement in the chance of survival or cure was considered sufficient to make chemotherapy worthwhile by 50% of women, and a 5% improvement was considered sufficient by 72% (Figure 3). A 10% improvement was considered insufficient by 13% of women (range 8–17%). These findings were remarkably 693
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Choosing adjuvant chemotherapy
Table 3. Cumulative proportions of women considering adjuvant chemotherapy worthwhile for given improvements in outcome Simes & Coates 19929
Lindley et al. 19985*
Ravdin et al. 19986
Zimmermann et al. 20007
All combined
Number of patients
104
55
318
35
512
Life expectancy without chemotherapy
5 years
< 5 years†
Unspecified
27 46 77 89 99
57 72 90 98 NR
44 51 70 90 98
5 year survival 65, 85
Cure‡ 30, 40, 45, 75, 85, 90
Unspecified
5 years survival 50, 70, 85
48 74 83 94 97
NR 69 83 88 93
51 73 88 93 99
NR 63 92 95 95
Improvement with chemotherapy 3 months 6 months 12 months 24 months > 24 months Percentage chances of benefit without chemotherapy
42 52 74 91 98
Improvement with chemotherapy (%) 1 5 10 20 > 20
50 72 87 93 98
NR, not reported; *In this study, women were told survival would be 5 years with chemotherapy and were asked how much time they would expect to lose in exchange for not having the chemotherapy; †Includes only 55 women who had chemotherapy; ‡Includes 55 women who had chemotherapy and 31 women who did not.
consistent between the studies, despite the many differences in their methods.
Predictors of preferences All four studies explored characteristics that might predict or influence the minimum benefit considered worthwhile. These analyses are summarised in Table 4. Each study assessed different features, and even if the same one was being assessed (eg side-effects) the way it was ascertained was quite different. Patients’ support was the only demographic characteristic associated with elicited preferences. Women who were living with and supporting dependants considered smaller benefits worthwhile,9 as did women who reported having full support available for themselves. The nature of the support was not specified (emotional, financial, etc). Demographic characteristics that were not predictive of the women’s responses in any study included age, education,
employment, income, ethnicity, and marital status. Psychological characteristics that might affect preferences were not addressed in any of the studies. Spread to lymph nodes was the only disease characteristic reported to be predictive. Women with nodepositive disease considered smaller benefits worthwhile according to Ravdin and colleagues’ study. The absence of adjuvant radiotherapy was the only characteristic of treatment identifiable at baseline that was associated with a smaller minimum worthwhile benefit for chemotherapy. Whether or not endocrine therapy was used did not influence preferences for chemotherapy. Women who experienced less severe side-effects from chemotherapy considered smaller benefits worthwhile in two studies,5,9 but not in a further one.6 Women’s preferences were not influenced by either the interval between treatment and the elicitation of preferences, or by whether or not breast cancer had recurred. Simes & Coates (n=104) Lindley et al. (n=55) Ravdin et al. (n=318) Zimmermann et al. (n=35)
100 90 80 70 60 50 40 30 20 10 0
Proportion of women (%)
Proportion of women (%)
Simes & Coates (n=104) Lindley et al. (n=55) Ravdin et al. (n=318) Zimmermann et al. (n=35)
1
5 10 20 Absolute improvement in chances (%)
>20
Figure 2. Proportion of women who considered adjuvant chemotherapy worthwhile for various improvements in the chances of survival or cure.
694
100 90 80 70 60 50 40 30 20 10 0 3
6 12 24 Extra months of life expectancy
>24
Figure 3. Proportion of women who considered adjuvant chemotherapy worthwhile for various increases in life expectance.
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Choosing adjuvant chemotherapy
Method-related factors that might influence preferences were not a major focus of these studies. In the study by Simes and colleagues,9 women considered smaller increments in survival time worthwhile when faced with a hypothetical life expectancy of 5 years, compared with 15 years. Interestingly, however, there was almost no difference in the minimum percentage improvements worthwhile when working from baselines of 65% or 85%. Lindley and colleagues reported that the cure rate without chemotherapy did not affect the minimum worthwhile benefit. Framing the question positively or negatively did not affect elicited preferences in the study by Zimmermann and coworkers.7
Discussion In these four studies women who had experienced adjuvant chemotherapy for early breast cancer were asked what survival benefit was needed to make it worthwhile. Simes and Coates’ study was specifically designed to address this question;9 the other studies sought this information as a secondary objective. All the women in Simes’ study received the same adjuvant chemotherapy (oral CMF) for stage II breast cancer during the 1980s. Lindley and colleagues’ study did not specify the kinds of chemotherapy received, and it included some women who had not received chemotherapy; these women considered larger benefits necessary to make hypothetical adjuvant chemotherapy worthwhile. The study by Ravdin and colleagues was the largest and included information about the kinds of chemotherapy received. Half of the women studied considered a 1% improvement in their chances (of survival or cure) or a 6-month prolongation of their life expectancy sufficient to make the side-effects and inconvenience of adjuvant
chemotherapy worthwhile. However, there was substantial heterogeneity: 13% of women considered a 10% gain insufficient, and 9% of women considered a 24-month prolongation of life expectancy insufficient. All studies included a few women (1% to 2%) who considered no improvement sufficient to make the chemotherapy they experienced worthwhile. How accurately can these variations between women be predicted? Women with dependants and better social supports perceived smaller benefits to be sufficient. Women who perceived themselves to be at higher risk, either because of shorter hypothetical life expectancies, or because of spread to lymph nodes, considered smaller benefits worthwhile. However, after taking these factors into account, there is still substantial variation between individuals, and an individual’s preferences cannot be predicted from her baseline characteristics. It is therefore imperative to allow women to declare their preferences and to incorporate these in decision making. None of the studies assessed the influence of psychological factors on women’s preferences. However, because the diagnosis and treatment of breast cancer are highly stressful and decisions about adjuvant chemotherapy are made within a few weeks of diagnosis and surgery, there is a need for more information about the effects of psychological characteristics on preferences and decision making. Further work should include women who choose not to have adjuvant chemotherapy, and who were excluded from our analysis. These women would probably consider larger benefits necessary. The theory of cognitive dissonance suggests that women are likely to remember their experience of chemotherapy in a way that vindicates their decision to have it.
Table 4. Characteristics assessed for their influence on the minimum benefit considered worthwhile by patients Characteristics found to be predictive*
Simes & Coates 19929
Lindley et al. 19985
Personal
Dependants needing full support of the woman
Experienced chemotherapy
Ravdin et al. 19986
Zimmermann et al. 20007
More support available to woman Disease-related
Lymph nodes involved with cancer
Treatment-related
Fewew side-effects No radiotherapy
Methods-related
Shorter life expectancy
Fewer disruptions
Characteristics not found to be predictive Personal
Age Education Employment
Disease-related
Recurrence
Treatment-related
Time since treatment Use of endocrine therapy
Methods-related
Different % chances without chemotherapy
Age Education Income Marital status Ethnicity Current QOL
Age Education
Hospital admission for side-effects Framing of question
QOL, quality of life *These were associated with women considering smaller benefits worthwhile.
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Review Search strategy and selection criteria MEDLINE, EMBASE, CANCERLIT, and reference lists were searched for studies that assessed the preferences of women for adjuvant chemotherapy in early breast cancer. The following search terms were used: ‘explode breast neoplasms’ and ‘explode antineoplastic agents’, and the text words ‘early or adjuvant’ and ‘preference or utility or attitude or expectation’. Studies were included if they quantified the magnitude of benefits considered sufficient to make adjuvant chemotherapy for early breast cancer worthwhile by asking women who had adjuvant chemotherapy for early breast cancer. Studies were excluded if only qualitative judgments were sought (eg would you make the same decision again?), if the women surveyed had not experienced adjuvant chemotherapy, or if the questions did not refer to adjuvant chemotherapy for early breast cancer. The electronic search identified three studies published as journal articles.5–7 Examination of reference lists revealed another six studies, only one of which met our inclusion criteria (a book chapter previously known to us,8 and recently accepted for journal publication).9 The remaining studies that addressed related questions or populations were excluded from the main analysis, but are discussed later in the paper.10–14
In addition to the four studies discussed above, which estimated the minimum benefits considered worthwhile by women who had experienced adjuvant chemotherapy for early breast cancer, we have considered five studies that addressed related questions. Slevin and colleagues surveyed 100 cancer patients, 938 doctors, 303 nurses, and 100 lay people to quantify the minimum benefits considered necessary to make a hypothetical intensive chemotherapy regimen for advanced cancer worthwhile.10 Their study confirmed that patients with advanced cancer considered very small benefits sufficient to make intensive chemotherapy worthwhile. The benefits had to be larger for doctors than for patients, much larger for nurses, and even larger for lay people. Hayman and colleagues assessed 97 women’s preferences for adjuvant radiotherapy after conservative surgery for early breast cancer.11 They found that women were very fearful of local recurrence and that even small reductions of this risk as a result of radiotherapy were considered worthwhile. Demographic, disease and treatment characteristics were not predictive of their preferences. McQuellan and colleagues asked 115 women with early breast cancer their opinions about hypothetical scenarios involving chemotherapy for advanced breast cancer.12 There was substantial heterogeneity among the women and the treatments, but again, many women rated small improvements sufficient to make intensive chemotherapy worthwhile. Beisecker and colleagues interviewed 21 women who had completed adjuvant chemotherapy for node-negative breast cancer.13 Nineteen of the women reported that given the same circumstances, they would choose to have 696
Choosing adjuvant chemotherapy
chemotherapy if faced with the same decision, knowing what they now knew. Levine and colleagues reported on the development of a clinical decision aid for women with early breast cancer considering adjuvant chemotherapy.14 The instrument was piloted in 37 women with high-risk, node-negative breast cancer; 34 chose to have adjuvant chemotherapy. These studies confirm that people with cancer consider small benefits sufficient to make unpleasant and inconvenient anticancer treatments worthwhile. They also indicate that people who have experienced a treatment consider much smaller benefits worthwhile than people who have not experienced it. It seems that the less direct a person’s experience of a treatment or condition, the larger the benefit they consider necessary to justify it. The clinical implications of our findings is that small benefits are important to many women with breast cancer, not that adjuvant chemotherapy should be recommended for all women with a prospect of a 1% improvement. When discussing this information with women considering adjuvant chemotherapy, it is important to explain its sources, strengths and weaknesses. The use of adjuvant chemotherapy for early breast cancer has evolved substantially in the past 10 years. It is being used in a greater proportion of women at lower risk and in older women. The intensity and duration of treatment have changed. Supportive therapy for the prevention and treatment of side-effects has improved,4 and the incorporation of new drugs with additional toxic effects is being evaluated in current trials. Decision-makers need information about contemporary chemotherapy and supportive regimens given for current indications. Ideally, this information would come from randomised trials that allow direct comparisons of the benefits considered necessary to make competing regimens worthwhile.
Conclusions The minimum benefit needed to make the side-effects and inconvenience of treatment worthwhile is a key element in clinical decision-making. The judgments of women who have experienced chemotherapy offer unique insights to women and clinicians facing decisions about adjuvant chemotherapy. The available data indicate that most women who have experienced adjuvant chemotherapy for early breast cancer consider small benefits sufficient to make it worthwhile. Information is needed from women who have received current generation chemotherapy and supportive care. Research is also needed to find out how best to present this information to women facing such decisions in the future. Acknowledgments
Vlatka Duric is supported by grants from the University of Sydney Cancer Fund, the Australian Cancer Society and the ANZ Breast Cancer Trials Group. References
1 Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–42. 2 Lippman ME, Hayes DF. Adjuvant therapy for all patients with breast cancer. J Natl Cancer Inst 2001; 93: 80–82. 3 Coates AS, Abraham S, Kaye SB, et al. On the receiving end: patient THE LANCET Oncology Vol 2 November 2001
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Choosing adjuvant chemotherapy
4 5 6 7
8
9
perception of the side effects of chemotherapy. Eur J Cancer Clin Oncol 1983; 19: 203–08. Griffin AM, Butow PN, Coates AS, et al. On the receiving end V: patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol 1996; 7: 189–95. Lindley C, Vasa S, Sawyer WT, Winer EP. Quality of life and preferences for treatment following systemic adjuvant therapy for early breast cancer. J Clin Oncol 1998; 16: 1380–87. Ravdin PM, Siminoff IA, Harvey JA. Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 1998; 16: 515–21. Zimmermann C, Baldo C, Molino A. Framing of outcome and probability of recurrence: Breast cancer patients’ choice of adjuvant chemotherapy (ACT) in hypothetical patient scenarios. Breast Cancer Res Treat 2000; 60: 9–14. Coates AS, Simes RJ. Patient assessment of adjuvant treatment in operable breast cancer. In: Introducing new treatments for cancer: practical, ethical and legal problems. London: John Wiley and Sons. 1992: 447–58. Simes RJ, Coates AS. Patient preferences for adjuvant
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11
12 13 14
chemotherapy of early breast cancer: how much benefit is needed? J Natl Cancer Inst Monogr 2001 (in press). Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 1990; 300: 1458–60. Hayman JA, Fairclough DL, Harris JR, Weekes JC. Patient preferences concerning the trade-off between the risks and benefits of routine radiation therapy after conservative surgery for earlystage breast cancer. J Clin Oncol 1997; 15: 1252–60. McQuellan RP, Muss HB, Hoffman SL, et al. Patient preferences for treatment of metastatic breast cancer: a study of women with earlystage breast cancer. J Clin Oncol 1995; 13: 858–68. Beisecker AE, Cook MR, Ashworth J, et al. Side-effects of adjuvant chemotherapy: perceptions of node-negative breast cancer patients. Psychooncology 1997; 6: 85–93. Levine MN, Gafni A, Markham B, MacFarlane D. A bedside decision instrument to elicit a patient’s preference concerning adjuvant chemotherapy for breast cancer. Ann Intern Med 1992; 117: 53–58.
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Review
Patients’ preferences for adjuvant chemotherapy in early breast cancer: a review of what makes it worthwhile? Vlatka Duric and Martin Stockler
Adjuvant chemotherapy for early breast cancer improves survival but is unpleasant and inconvenient. Women and clinicians need information about the magnitude of survival benefits considered sufficient to make the side-effects and inconvenience worthwhile. We sought studies that quantified the minimum required survival benefit by asking women who had experienced adjuvant chemotherapy. Four studies involving 512 women were appraised and summarised. All studies referred to chemotherapy given between 1980 and 1996, but the methods varied widely, especially the way in which women were recruited and questioned. However, the results were remarkably consistent. Most women said that small improvements in survival were sufficient to make adjuvant chemotherapy worthwhile. Women with dependants, social support, and milder side-effects judged smaller benefits worthwhile. Age, education, employment, and income status were not predictive of the women’s responses. Optimum decision-making about the relative benefit of adjuvant chemotherapy requires upto-date information from women receiving current chemotherapy and supportive regimens. Lancet Oncol 2001; 2: 691–97
Adjuvant chemotherapy improves disease-free and overall survival in women with early breast cancer, increasing 10-year survival by about 10% for women aged under 50 and by about 3% for women aged 50–69, with larger gains for those at greater risk.1 These modest improvements might translate into average life-expectancy gains of 1 to 3 years, depending on individual circumstances. The expected benefits for each woman depend on her baseline risk, predicted by the extent, histology, and receptor status of her tumour. However, adjuvant chemotherapy has side-effects and is inconvenient; it is unnecessary for some and ineffective for others. The important question is not whether it works, but in which subgroups it works well enough to justify its side-effects and inconvenience (Figure 1).2 The benefits and harms of adjuvant chemotherapy are not equally apparent to individual women or clinicians. The acute side-effects of chemotherapy such as hair loss, nausea, fatigue, and risk of infection have an immediate and obvious effect on quality of life.3,4 The impacts of rare long-term sideeffects, such as cardiac dysfunction and myelodysplasia, are vivid and striking. On the other hand, the benefits of THE LANCET Oncology Vol 2 November 2001
Figure 1. Weighed in the balance – many factors need to be taken into account when deciding whether adjuvant chemotherapy for early breast cancer is worthwhile.
adjuvant chemotherapy are delayed and less apparent to patients or clinicians. Individual preferences regarding the relative importance of these outcomes are crucial for optimum decision-making about whether or not to have adjuvant chemotherapy. Women facing this choice can gain unique insights from the recorded judgment of women who have experienced adjuvant chemotherapy for early breast cancer first-hand. We undertook a systematic review of studies that quantified the benefits that make adjuvant chemotherapy for early breast cancer worthwhile by asking women who had experienced it. The purpose of this review is to VD and MS are at the NHMRC Clinical Trials Centre, University of Sydney, Australia. MS is also at the Department of Public Health and Community Medicine, University of Sydney, Department of Medicine, University of Sydney, and Sydney Cancer Centre, Royal Prince Alfred and Concord Repatriation General Hospitals, NSW, Australia. VD is also at the Department of Psychological Medicine, University of Sydney. Correspondence: Dr Martin Stockler, Sydney Cancer Centre GH6, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW, 2050 Australia. Tel: +612 9515 5494. Fax: +612 9519 1546. Email: [email protected]
691
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
Choosing adjuvant chemotherapy
summarise the views of women who have experienced chemotherapy, for the benefit of future women and clinicians facing this decision. The minimum benefits considered sufficient in these studies are not intended to be quantitative guidelines for the prescription of adjuvant chemotherapy. Selected findings from the studies are tabulated and described with simple summary statistics.
Findings Four studies involving 512 women from Australia, USA, and Italy were published between 1992 and 2000. The baseline characteristics of the women, their disease, and treatment are summarised in Table 1. Most of the women had chemotherapy during the late 1980s and early 1990s. The distributions of age, disease stage, and treatment types reflect the use of adjuvant chemotherapy during this time. Most women were younger than 60 years, were married, and had at least a high-school education. About half were employed. The differing proportions of women with stage I disease (0%,9 25%,6 and 48%5) reflect the years in which the women were treated and the wider use of adjuvant chemotherapy for node-negative breast cancer in the USA. Less than 25% of the women had either breast-conserving surgery or adjuvant radiotherapy. Few details were available about the chemotherapy that the women received. The limited information showed that cyclophosphamide, methotrexate, fluorouacil (CMF), and doxorubicin-containing regimens were most common, and a tiny proportion of women received high-dose chemotherapy with stem-cell support. However, no women were reported to have received taxanes or trastuzumab
(herceptin). The methods used in each study are described in Table 2. The primary purpose of Simes and Coates’ study was to establish preferences,9 but the others had additional goals. Two studies used face-to-face interviews supported by visual aids,7,9 whereas the other two used mailed questionnaires.5,6 Three studies sought women treated or reviewed consecutively and had response rates of over 75%.5,7,9 The study by Ravdin and colleagues was the largest, but had the lowest response rate (21%), because not all women who were sent questionnaires by post had received adjuvant chemotherapy.6 All the studies presented women with a range of possible survival benefits aiming to quantify the smallest benefit that would make the side-effects and inconvenience of treatment worthwhile. In three studies,5-7 the order in which the benefits were presented was fixed in a linear increasing fashion; in Simes and Coates’ study the ordering was randomly allocated to be either increasing or decreasing.9 Variations over time and between interviewers were addressed only in studies using face-to-face interviews. In Simes and Coates’ study,9 repeated interviews 3 to 6 months apart gave comparable results (Spearman’s coefficient of 0.6 to 0.7). These correlations are substantial, but they overestimate reliability because not all participants completed two interviews and because they ignore systematic changes over time. In Zimmermann and colleagues’ study,7 there was little difference between preferences elicited 2 months apart, despite differences in how the questions were framed. There were substantial differences in the wording and nature of the questions. Interviewers in two studies asked women to imagine themselves in hypothetical situations,
Table 1. Baseline characteristics of studies, women, their disease, and treatment Simes & Coates8
Lindley et al. 5
Ravdin et al. 6
Zimmermann et al.
1992
1998
19986
20007
Number of women
104
55
318
35
Country
Australia
USA
USA
Italy
Trial characteristics
8
Age median or mean (range)
5
49
54
49
52
(29–67)
(29–86)
(< 40 – > 70)
(39–66)
Married (%)
73
67
74
97
Employed (%)
52
61
··
43
Educated to high school level or above (%)
88
> 65
96
··
I
0
48
25
··
II
100
51
73
··
Lumpectomy
9
17
-
23
Mastectomy
91
83
-
77
18
19
-
18
Any
100
64
100%
100
CMF
100
··
39
··
··
46
··
Stage of breast cancer at diagnosis (%)
Initial surgery (%)
Adjuvant radiotherapy (%) Adjuvant chemotherapy (%)
Doxorubicin containing (eg AC, FAC, CAFM) 0 0
··
4
··
Treatment duration
High-dose with stem-cell support
1982–87
1988–91
1980–96
1981–96?
Years preferences were elicited
1986–87
··
1996
··
C, cyclophosphamide; M, methotrexate; F, fluorouracil; A, doxorubicin
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Table 2. Description and appraisal of methods used in fair studies of patients preferences Method
Simes & Coates 19929
Lindley et al. 19985
Ravdin et al. 19986
Zimmermann et al. 20007
Stated purpose
To ask women who had received CMF as adjuvant treatment to rate the benefit that would make treatment worthwhile
To evaluate the QOL of patients who survived 2- 5 years since initiation of adjuvant cytotoxic or hormonal therapy and to characterise relations between QOL and physical symptoms, sexual function, and preferences about adjuvant treatment
To survey survivors to define what they had been told about their prognosis and the value of adjuvant therapy, what they estimated their prognosis to be with and without adjuvant therapy, and what improvement they would have found minimally worthwhile
To examine the effects of framing of outcome and probabilities of cancer occurrence on the treatment preference that patients indicate for hypothetical scenarios
Response rate 104/129 (81%) (interviewed/approached)
86/111 (77%)
562/2600 (21%)
35/40 (88%)
Identification and recruitment Survey instrument
Consecutively women treated
Volunteer consumers
Women consecutively reviewed in clinic Interview
Questionnaire
Questionnaire
Women consecutively reviewed in clinic Interview
Method of administration Face to face
Postal survey and telephone call
Postal survey
Face to face
Number of interviewers
2
?
NA
1
Was inter-rater reliability reported?
No
NA
NA
NA
Was intra-rater ? reliability reported
Yes
NA
NA
NA
Use of visual aids
Yes
?
?
Yes
Starting point for questions
Without chemotherapy
With chemotherapy
Without chemotherapy
Without chemotherapy
Discussion of framing effects
Yes
Yes
No
Yes
Discussion of anchoring Yes effects
No
No
Yes
Ordering of questions
Randomised
Fixed
Fixed
Fixed
Ordering of benefits presented
Increasing or decreasing
Increasing
Increasing
NR
Nature of question
Preferred option
Expected benefit
Worthwhile benefit
Preferred option
Subject of question
Woman herself
Woman herself
Woman herself
Hypothetical woman
General format of questions
Series of choices between having or not having adjuvant chemotherapy given different levels of benefit.
‘…what potential improvement in cure rate or prolongation of survival women would expect in exchange for receiving adjuvant chemotherapy?’
‘Given your experiences with treatment, would taking more treatment after surgery have been worthwhile for you if it extended your life by the following...?’
Series of choices between having or not having adjuvant chemotherapy given different levels of benefit
NA, not applicable; NR, not reported; QOL, quality of life
and then to make a series of choices between paired options with and without chemotherapy.7,9 The questionnaires in the two other studies asked women to choose from a range of options.5,6 Lindley and colleagues’ questionnaire asked women what benefit they would ‘expect’ or ‘anticipate’; Ravdin and coworkers’ questionnaire asked whether ‘…taking more treatment after surgery would have been worthwhile if…’. There was also substantial variation in precisely how the adjuvant chemotherapy was specified. For example, Coates and colleagues described adjuvant chemotherapy as ‘6 months of the treatment you received’, whereas Ravdin and colleagues described it simply as ‘more treatment after surgery’. Three studies used survival without chemotherapy as the starting point, asking how much better it would have to be to make chemotherapy worthwhile.6,7,9 Lindley’s study used survival with chemotherapy as the starting point, and asked how much worse it would have to be without chemotherapy to make it worthwhile. THE LANCET Oncology Vol 2 November 2001
Minimum worthwhile benefits The minimum benefits considered sufficient to make adjuvant chemotherapy worthwhile are summarised in Table 3 and illustrated in Figures 2 and 3. All studies except the one by Zimmermann and colleagues asked questions framed in terms of extra months of life expectancy. All studies asked questions framed in terms of improvements in the percentage chances of survival or cure. Additional life expectancy of six monthswas considered sufficient to make adjuvant chemotherapy worthwhile by 52% of women, and an extra 12 months was considered sufficient by 74% (Figure 2). An extra 24 months of life expectancy was considered insufficient by 9% of women. A 1% improvement in the chance of survival or cure was considered sufficient to make chemotherapy worthwhile by 50% of women, and a 5% improvement was considered sufficient by 72% (Figure 3). A 10% improvement was considered insufficient by 13% of women (range 8–17%). These findings were remarkably 693
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Table 3. Cumulative proportions of women considering adjuvant chemotherapy worthwhile for given improvements in outcome Simes & Coates 19929
Lindley et al. 19985*
Ravdin et al. 19986
Zimmermann et al. 20007
All combined
Number of patients
104
55
318
35
512
Life expectancy without chemotherapy
5 years
< 5 years†
Unspecified
27 46 77 89 99
57 72 90 98 NR
44 51 70 90 98
5 year survival 65, 85
Cure‡ 30, 40, 45, 75, 85, 90
Unspecified
5 years survival 50, 70, 85
48 74 83 94 97
NR 69 83 88 93
51 73 88 93 99
NR 63 92 95 95
Improvement with chemotherapy 3 months 6 months 12 months 24 months > 24 months Percentage chances of benefit without chemotherapy
42 52 74 91 98
Improvement with chemotherapy (%) 1 5 10 20 > 20
50 72 87 93 98
NR, not reported; *In this study, women were told survival would be 5 years with chemotherapy and were asked how much time they would expect to lose in exchange for not having the chemotherapy; †Includes only 55 women who had chemotherapy; ‡Includes 55 women who had chemotherapy and 31 women who did not.
consistent between the studies, despite the many differences in their methods.
Predictors of preferences All four studies explored characteristics that might predict or influence the minimum benefit considered worthwhile. These analyses are summarised in Table 4. Each study assessed different features, and even if the same one was being assessed (eg side-effects) the way it was ascertained was quite different. Patients’ support was the only demographic characteristic associated with elicited preferences. Women who were living with and supporting dependants considered smaller benefits worthwhile,9 as did women who reported having full support available for themselves. The nature of the support was not specified (emotional, financial, etc). Demographic characteristics that were not predictive of the women’s responses in any study included age, education,
employment, income, ethnicity, and marital status. Psychological characteristics that might affect preferences were not addressed in any of the studies. Spread to lymph nodes was the only disease characteristic reported to be predictive. Women with nodepositive disease considered smaller benefits worthwhile according to Ravdin and colleagues’ study. The absence of adjuvant radiotherapy was the only characteristic of treatment identifiable at baseline that was associated with a smaller minimum worthwhile benefit for chemotherapy. Whether or not endocrine therapy was used did not influence preferences for chemotherapy. Women who experienced less severe side-effects from chemotherapy considered smaller benefits worthwhile in two studies,5,9 but not in a further one.6 Women’s preferences were not influenced by either the interval between treatment and the elicitation of preferences, or by whether or not breast cancer had recurred. Simes & Coates (n=104) Lindley et al. (n=55) Ravdin et al. (n=318) Zimmermann et al. (n=35)
100 90 80 70 60 50 40 30 20 10 0
Proportion of women (%)
Proportion of women (%)
Simes & Coates (n=104) Lindley et al. (n=55) Ravdin et al. (n=318) Zimmermann et al. (n=35)
1
5 10 20 Absolute improvement in chances (%)
>20
Figure 2. Proportion of women who considered adjuvant chemotherapy worthwhile for various improvements in the chances of survival or cure.
694
100 90 80 70 60 50 40 30 20 10 0 3
6 12 24 Extra months of life expectancy
>24
Figure 3. Proportion of women who considered adjuvant chemotherapy worthwhile for various increases in life expectance.
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Method-related factors that might influence preferences were not a major focus of these studies. In the study by Simes and colleagues,9 women considered smaller increments in survival time worthwhile when faced with a hypothetical life expectancy of 5 years, compared with 15 years. Interestingly, however, there was almost no difference in the minimum percentage improvements worthwhile when working from baselines of 65% or 85%. Lindley and colleagues reported that the cure rate without chemotherapy did not affect the minimum worthwhile benefit. Framing the question positively or negatively did not affect elicited preferences in the study by Zimmermann and coworkers.7
Discussion In these four studies women who had experienced adjuvant chemotherapy for early breast cancer were asked what survival benefit was needed to make it worthwhile. Simes and Coates’ study was specifically designed to address this question;9 the other studies sought this information as a secondary objective. All the women in Simes’ study received the same adjuvant chemotherapy (oral CMF) for stage II breast cancer during the 1980s. Lindley and colleagues’ study did not specify the kinds of chemotherapy received, and it included some women who had not received chemotherapy; these women considered larger benefits necessary to make hypothetical adjuvant chemotherapy worthwhile. The study by Ravdin and colleagues was the largest and included information about the kinds of chemotherapy received. Half of the women studied considered a 1% improvement in their chances (of survival or cure) or a 6-month prolongation of their life expectancy sufficient to make the side-effects and inconvenience of adjuvant
chemotherapy worthwhile. However, there was substantial heterogeneity: 13% of women considered a 10% gain insufficient, and 9% of women considered a 24-month prolongation of life expectancy insufficient. All studies included a few women (1% to 2%) who considered no improvement sufficient to make the chemotherapy they experienced worthwhile. How accurately can these variations between women be predicted? Women with dependants and better social supports perceived smaller benefits to be sufficient. Women who perceived themselves to be at higher risk, either because of shorter hypothetical life expectancies, or because of spread to lymph nodes, considered smaller benefits worthwhile. However, after taking these factors into account, there is still substantial variation between individuals, and an individual’s preferences cannot be predicted from her baseline characteristics. It is therefore imperative to allow women to declare their preferences and to incorporate these in decision making. None of the studies assessed the influence of psychological factors on women’s preferences. However, because the diagnosis and treatment of breast cancer are highly stressful and decisions about adjuvant chemotherapy are made within a few weeks of diagnosis and surgery, there is a need for more information about the effects of psychological characteristics on preferences and decision making. Further work should include women who choose not to have adjuvant chemotherapy, and who were excluded from our analysis. These women would probably consider larger benefits necessary. The theory of cognitive dissonance suggests that women are likely to remember their experience of chemotherapy in a way that vindicates their decision to have it.
Table 4. Characteristics assessed for their influence on the minimum benefit considered worthwhile by patients Characteristics found to be predictive*
Simes & Coates 19929
Lindley et al. 19985
Personal
Dependants needing full support of the woman
Experienced chemotherapy
Ravdin et al. 19986
Zimmermann et al. 20007
More support available to woman Disease-related
Lymph nodes involved with cancer
Treatment-related
Fewew side-effects No radiotherapy
Methods-related
Shorter life expectancy
Fewer disruptions
Characteristics not found to be predictive Personal
Age Education Employment
Disease-related
Recurrence
Treatment-related
Time since treatment Use of endocrine therapy
Methods-related
Different % chances without chemotherapy
Age Education Income Marital status Ethnicity Current QOL
Age Education
Hospital admission for side-effects Framing of question
QOL, quality of life *These were associated with women considering smaller benefits worthwhile.
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Review Search strategy and selection criteria MEDLINE, EMBASE, CANCERLIT, and reference lists were searched for studies that assessed the preferences of women for adjuvant chemotherapy in early breast cancer. The following search terms were used: ‘explode breast neoplasms’ and ‘explode antineoplastic agents’, and the text words ‘early or adjuvant’ and ‘preference or utility or attitude or expectation’. Studies were included if they quantified the magnitude of benefits considered sufficient to make adjuvant chemotherapy for early breast cancer worthwhile by asking women who had adjuvant chemotherapy for early breast cancer. Studies were excluded if only qualitative judgments were sought (eg would you make the same decision again?), if the women surveyed had not experienced adjuvant chemotherapy, or if the questions did not refer to adjuvant chemotherapy for early breast cancer. The electronic search identified three studies published as journal articles.5–7 Examination of reference lists revealed another six studies, only one of which met our inclusion criteria (a book chapter previously known to us,8 and recently accepted for journal publication).9 The remaining studies that addressed related questions or populations were excluded from the main analysis, but are discussed later in the paper.10–14
In addition to the four studies discussed above, which estimated the minimum benefits considered worthwhile by women who had experienced adjuvant chemotherapy for early breast cancer, we have considered five studies that addressed related questions. Slevin and colleagues surveyed 100 cancer patients, 938 doctors, 303 nurses, and 100 lay people to quantify the minimum benefits considered necessary to make a hypothetical intensive chemotherapy regimen for advanced cancer worthwhile.10 Their study confirmed that patients with advanced cancer considered very small benefits sufficient to make intensive chemotherapy worthwhile. The benefits had to be larger for doctors than for patients, much larger for nurses, and even larger for lay people. Hayman and colleagues assessed 97 women’s preferences for adjuvant radiotherapy after conservative surgery for early breast cancer.11 They found that women were very fearful of local recurrence and that even small reductions of this risk as a result of radiotherapy were considered worthwhile. Demographic, disease and treatment characteristics were not predictive of their preferences. McQuellan and colleagues asked 115 women with early breast cancer their opinions about hypothetical scenarios involving chemotherapy for advanced breast cancer.12 There was substantial heterogeneity among the women and the treatments, but again, many women rated small improvements sufficient to make intensive chemotherapy worthwhile. Beisecker and colleagues interviewed 21 women who had completed adjuvant chemotherapy for node-negative breast cancer.13 Nineteen of the women reported that given the same circumstances, they would choose to have 696
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chemotherapy if faced with the same decision, knowing what they now knew. Levine and colleagues reported on the development of a clinical decision aid for women with early breast cancer considering adjuvant chemotherapy.14 The instrument was piloted in 37 women with high-risk, node-negative breast cancer; 34 chose to have adjuvant chemotherapy. These studies confirm that people with cancer consider small benefits sufficient to make unpleasant and inconvenient anticancer treatments worthwhile. They also indicate that people who have experienced a treatment consider much smaller benefits worthwhile than people who have not experienced it. It seems that the less direct a person’s experience of a treatment or condition, the larger the benefit they consider necessary to justify it. The clinical implications of our findings is that small benefits are important to many women with breast cancer, not that adjuvant chemotherapy should be recommended for all women with a prospect of a 1% improvement. When discussing this information with women considering adjuvant chemotherapy, it is important to explain its sources, strengths and weaknesses. The use of adjuvant chemotherapy for early breast cancer has evolved substantially in the past 10 years. It is being used in a greater proportion of women at lower risk and in older women. The intensity and duration of treatment have changed. Supportive therapy for the prevention and treatment of side-effects has improved,4 and the incorporation of new drugs with additional toxic effects is being evaluated in current trials. Decision-makers need information about contemporary chemotherapy and supportive regimens given for current indications. Ideally, this information would come from randomised trials that allow direct comparisons of the benefits considered necessary to make competing regimens worthwhile.
Conclusions The minimum benefit needed to make the side-effects and inconvenience of treatment worthwhile is a key element in clinical decision-making. The judgments of women who have experienced chemotherapy offer unique insights to women and clinicians facing decisions about adjuvant chemotherapy. The available data indicate that most women who have experienced adjuvant chemotherapy for early breast cancer consider small benefits sufficient to make it worthwhile. Information is needed from women who have received current generation chemotherapy and supportive care. Research is also needed to find out how best to present this information to women facing such decisions in the future. Acknowledgments
Vlatka Duric is supported by grants from the University of Sydney Cancer Fund, the Australian Cancer Society and the ANZ Breast Cancer Trials Group. References
1 Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–42. 2 Lippman ME, Hayes DF. Adjuvant therapy for all patients with breast cancer. J Natl Cancer Inst 2001; 93: 80–82. 3 Coates AS, Abraham S, Kaye SB, et al. On the receiving end: patient THE LANCET Oncology Vol 2 November 2001
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4 5 6 7
8
9
perception of the side effects of chemotherapy. Eur J Cancer Clin Oncol 1983; 19: 203–08. Griffin AM, Butow PN, Coates AS, et al. On the receiving end V: patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol 1996; 7: 189–95. Lindley C, Vasa S, Sawyer WT, Winer EP. Quality of life and preferences for treatment following systemic adjuvant therapy for early breast cancer. J Clin Oncol 1998; 16: 1380–87. Ravdin PM, Siminoff IA, Harvey JA. Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 1998; 16: 515–21. Zimmermann C, Baldo C, Molino A. Framing of outcome and probability of recurrence: Breast cancer patients’ choice of adjuvant chemotherapy (ACT) in hypothetical patient scenarios. Breast Cancer Res Treat 2000; 60: 9–14. Coates AS, Simes RJ. Patient assessment of adjuvant treatment in operable breast cancer. In: Introducing new treatments for cancer: practical, ethical and legal problems. London: John Wiley and Sons. 1992: 447–58. Simes RJ, Coates AS. Patient preferences for adjuvant
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chemotherapy of early breast cancer: how much benefit is needed? J Natl Cancer Inst Monogr 2001 (in press). Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. BMJ 1990; 300: 1458–60. Hayman JA, Fairclough DL, Harris JR, Weekes JC. Patient preferences concerning the trade-off between the risks and benefits of routine radiation therapy after conservative surgery for earlystage breast cancer. J Clin Oncol 1997; 15: 1252–60. McQuellan RP, Muss HB, Hoffman SL, et al. Patient preferences for treatment of metastatic breast cancer: a study of women with earlystage breast cancer. J Clin Oncol 1995; 13: 858–68. Beisecker AE, Cook MR, Ashworth J, et al. Side-effects of adjuvant chemotherapy: perceptions of node-negative breast cancer patients. Psychooncology 1997; 6: 85–93. Levine MN, Gafni A, Markham B, MacFarlane D. A bedside decision instrument to elicit a patient’s preference concerning adjuvant chemotherapy for breast cancer. Ann Intern Med 1992; 117: 53–58.
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