Originally published as JCO Early Release 10.1200/JCO.2003.07.966 on November 10 2003

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Reversible Ovarian Ablation or Chemotherapy: Are We Ready for Quality of Life to Guide Adjuvant Treatment Decisions in Breast Cancer?

Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

HEALTH-RELATED QUALITY of life (HRQOL) measurement has been incorporated into randomized clinical trials in breast cancer since the 1980s. These measurements have provided valuable information about the experience of patients receiving a variety of treatments, and may also provide important prognostic information.¹ However, the contribution of HRQOL to treatment selection in breast cancer has been context-dependent. In a recent review,² we found that HRQOL measurements made important contributions to treatment selection when medical outcomes of the treatments studied were similar. This occurred mainly in the setting of local therapy for breast cancer (breast conserving therapy compared with mastectomy) and in the use of psychosocial therapies. HRQOL measurement has not played an important role in treatment selection in the adjuvant setting, as the majority of published trials identify survival benefit as the primary end point, making HRQOL a secondary consideration.

The study reported by de Haes et al³ in this issue of the Journal of Clinical Oncology represents one of the first randomized clinical trials in the adjuvant breast cancer setting in which HRQOL may guide treatment selection. The medical outcomes of this trial were recently published by Jonat et al⁴ in this journal. Premenopausal women with node-positive, stage II breast cancer were randomly assigned to receive 6 months of cyclophosphamide, methotrexate, and fluorouracil (CMF), or 2 years of monthly goserelin, a luteinizing hormone–releasing hormone analog that leads to reversible ovarian suppression in premenopausal women. In hormone receptor-positive patients, both treatments had equivalent effects on distant disease-free survival (hazard ratio for goserelin, 1.01; 95% CI, 0.84 to 1.20). Amenorrhea rates differed (95.1% v 58.6% at 6 months, and 22.6% v 76.9% at 3 years for patients on goserelin or CMF, respectively). Adverse effects of chemotherapy (nausea and vomiting, alopecia, infection, and diarrhea) were greater during the 6 months of chemotherapy in patients who received CMF, whereas adverse effects relating to estrogen suppression (vaginal dryness, hot flashes) were greater during the 2 years of treatment in patients who received goserelin. The authors concluded that "Goserelin offers an effective, well tolerated alternative to CMF in premenopausal patients with estrogen receptor-positive and node-positive early breast cancer." An accompanying editorial⁵ concurred, and also noted that neither of the two treatments studied in this trial (CMF or goserelin) may represent optimal chemotherapy or optimal endocrine therapy. Therefore, the trial results should be interpreted in light of current practice and ongoing clinical trials.

The current report formally presents the HRQOL results of this trial. HRQOL was measured using 39 items of the Rotterdam Symptom Checklist supplemented by two symptom items (hot flushes/sweating and weight changes), three social domain questions and an "effort to cope with illness" visual analog scale.³ Change in HRQOL from baseline was analyzed. Although the report details HRQOL results in patients with either hormone receptor-positive or receptor-negative breast cancer, results in the hormone receptor-positive subgroup (the group in whom therapeutic efficacy was equivalent) were similar to the overall results.

Overall HRQOL was better at 3 and 6 months in women randomized to goserelin, with no significant differences at 1, 2, and 3 years. The magnitude of the difference at 6 months was just over 6% of the range of the scale. Of even greater interest were the results for various components of HRQOL. During the first 6 months after randomization (the period during which CMF was administered) but not at 1, 2, or 3 years, patients receiving goserelin reported significantly less physical symptom distress, better activity levels, and reduced efforts to cope with breast cancer than patients receiving CMF. In contrast, hormonal symptoms and sexual interest were better in patients receiving CMF at 3 and 6 months and at 1 and 2 years, the period during which goserelin was administered. The opposite was seen at 3 years when goserelin was no longer administered, reflecting the fact that amenorrhea associated with goserelin treatment is reversible in the majority of patients, whereas amenorrhea associated with CMF administration is usually irreversible. The authors believe these HRQOL differences are clinically meaningful and, "coupled with the equivalent efficacy in ER-positive patients, these early benefits in QOL support the use of goserelin as an alternative to CMF in this patient population."³

Although focusing on overall HRQOL, which highlights the early benefits of goserelin, is a useful way of summarizing HRQOL information, the trade-offs between the early (first 6 months) improvements in HRQOL with goserelin, the intermediate (6 months to 2 years) benefits with CMF, and the late (3 years) beneficial effects seen with goserelin that may be of greatest potential interest to patients. These trade-offs will require patients and their physicians to balance different impacts of treatment on HRQOL at different time points, making decision-making challenging.

The first step in this decision-making process will be to communicate this HRQOL information to patients in a meaningful fashion. This will involve a description of how HRQOL differed at different time points, what attributes were measured, and the relevance of the differences in scores. What does a difference of 6 points on a 100 point overall HRQOL scale mean to an individual patient? Is it a minor difference that may not have a large impact on decision-making or is it a life-altering difference that will have a major impact on decision-making? How does one balance the detrimental effects of goserelin on hormonal symptoms and sexual interest that occur throughout the first 2 years of treatment with the detrimental effects of CMF on overall HRQOL, physical symptom distress, activity levels and efforts to cope during the first 6 months of treatment? Individual patients, and their physicians, will need assistance in understanding these differences and patients will need to incorporate their own values for each of these domains if they are to use this information to make informed treatment decisions. This need for a match between patient values and the choices they make has recently been highlighted by O’Connor et al.⁷ For some patients, the focus on individual symptoms such as sexual interest may predominate, and that symptom alone may drive treatment decisions. However, for the majority of patients, it is likely that this synthesis will be more complex and the decision-making process more difficult.

Many physicians will communicate this HRQOL information to patients and assist them in the decision-making process as part of routine consultation and care without any specific aids. However, there is growing evidence that the use of decision aids may facilitate this process. Two recent clinical trials have evaluated the use of decision aids in early breast cancer. Whelan et al⁸ evaluated a "Decision Board" to inform patients with node-negative breast cancer about the risks and benefits of adjuvant chemotherapy. Patients randomized to the Decision Board arm were better informed about breast cancer and about adjuvant chemotherapy, and they were more satisfied with the decision-making, although their ultimate treatment decision did not differ from those who received standard medical consultation alone. de Haes et al⁹ reached similar conclusions in a study of the effects of an interactive CD-ROM as a decision aid for patients making a choice between breast conserving therapy and mastectomy. Patients receiving the CD-ROM reported enhanced satisfaction with the information they received, their treatment decision, the decision-making process and overall communication. They also reported a positive effect on general health, physical functioning, and arm symptoms. Increased knowledge and enhanced satisfaction have frequently been reported when decision aids are used.⁷ As a result, the use of decision aids to communicate the complex HRQOL data reported by de Haes et al³ warrants careful consideration.

How might the results of this trial be used in clinical practice? They are of relevance to premenopausal women with node-positive, hormone receptor-positive breast cancer in whom a CMF type treatment is a reasonable therapeutic option. For these women, 2 years of adjuvant goserelin is a viable treatment alternative, leading to equivalent distant disease-free survival, but having different toxicities and HRQOL effects. Patients should be informed that overall HRQOL is better during the first 6 months of treatment if goserelin is used instead of CMF, but that this incremental benefit is modest. Many patients might prefer to select their treatment based on the different toxicity and HRQOL profiles of the two treatment options. For example, some patients may prefer the short-term detrimental effects on physical symptom distress, activity, and effort to cope when CMF is administered compared to the longer term adverse effects on hormonal symptoms and sexual interest when goserelin is administered—others may have the opposite preference.

The challenge of the HRQOL data presented by de Haes,³ which is also one of its greatest strengths, is that it does not lead to generalized treatment recommendations. Instead, it opens the door to highly individualized treatment decisions and a decision-making process that may be difficult for individual patients. This scenario challenges patients and physicians to thoroughly and thoughtfully embrace the decision-making process, and also challenges the research community to develop methods that will effectively assist patients in making these complex decisions.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

REFERENCES

1. Coates AS, Hurny C, Peterson HF, et al: Quality-of-life scores predict outcome in metastatic but not early breast cancer: International Breast Cancer Study Group. J Clin Oncol 18:3768–3774, 2000[Abstract/Free Full Text]

2. Goodwin PJ, Black JT, Bordeleau LJ, et al: Health-related quality-of-life measurement in randomized clinical trials in breast cancer: Taking stock. J Natl Cancer Inst 95:263–281, 2003[Abstract/Free Full Text]

3. de Haes J, Olschewski M, Kaufmann M, et al: Quality of life in goserelin-treated versus CMF-treated pre-/perimenopausal patients with node-positive early breast cancer. J Clin Oncol 21:4510–4516, 2003[Abstract/Free Full Text]

4. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628–4635, 2002[Abstract/Free Full Text]

5. Pritchard KI: Adjuvant therapy for premenopausal women with breast cancer: Is it time for another paradigm shift? J Clin Oncol 20:4611–4614, 2002[Free Full Text]

6. Sloan J: Asking the obvious question regarding patient burden. J Clin Oncol 20:4–6, 2002[Free Full Text]

7. O’Connor AM, Mulley AG, Wennberg JE: Standard consultations are not enough to ensure decision quality regarding preference-sensitive options. J Natl Cancer Inst 95:570–571, 2003[Free Full Text]

8. Whelan T, Sawka C, Levine M, et al: Helping patients make informed choices: a randomized trial of a decision aid for adjuvant chemotherapy in lymph node-negative breast cancer. J Natl Cancer Inst 95:581–587, 2003[Abstract/Free Full Text]

9. Molenaar S, Sprangers MA, Rutgers EJ, et al: Decision support for patients with early-stage breast cancer: Effects of an interactive breast cancer CDROM on treatment decision, satisfaction, and quality of life. J Clin Oncol 15:1676–1687, 2001

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