University of Sydney and Sydney Cancer Centre, Royal Prince Alfred and Concord Hospitals, NSW
Alan Coates is a pioneer of quality of life research in oncology. This paper reviews three threads in his extensive program of quality of life research that have had enduring influences on how we think about cancer and manage it. The studies produced counterintuitive conclusions to three pragmatic questions: 1) How long should chemotherapy continue in responding patients with advanced cancer? 2) Is baseline quality of life prognostic in people with advanced cancer? 3) What benefits are needed to make adjuvant chemotherapy worthwhile? This research was done predominantly in people with breast cancer and melanoma, but its implications extend to the management of all malignancies.
Chemotherapy can improve QoL by shrinking tumours and improving cancer-related symptoms, but it can impair QoL by damaging normal tissues and causing treatment related side-effects. A major practical question for patients with advanced cancer who are responding to chemotherapy is whether it is better to continue it until disease progression, or to stop after some number of cycles, reserving further cycles for subsequent progression.
The seminal trial addressing this question was designed by Alan Coates and reported in the New England Journal of Medicine in 1987. This Australia New Zealand Breast Cancer Trials Group study compared two strategies for giving chemotherapy in advanced breast cancer: continuing it until disease progression (continuous) versus stopping it after three cycles and restarting at evidence of further progression (intermittent).1 The underlying hypothesis was that intermittent chemotherapy would be preferable because it would give equivalent anti-cancer effects with less toxicity.
The results were unexpected and controversial. QoL improved during the first three cycles of chemotherapy despite its side-effects. More importantly, QoL was better with continuous chemotherapy than with intermittent. Subsequent follow-up showed that continuous chemotherapy also yielded superior survival duration.2 This trial established that chemotherapy could improve both length and QoL in people with advanced cancer. It remains one of the strongest pieces evidence that chemotherapy is beneficial in advanced cancer.3
The observation that changes in QoL were significant predictors of survival in this trial raised the question of whether baseline QoL scores might also be prognostic.1
Subsequent studies in advanced breast cancer showed that QoL scores were highly significant predictors of survival, regardless of whether they were assessed by patients or their doctors.4 The prognostic significance of QoL scores was corroborated in a trial of adding interferon to dacarbazine for advanced melanoma,5 and subsequently, in patients with a range of metastatic cancers being treated in routine clinical practice in several countries.6 Observations of women in early breast cancer trials showed that ratings of QoL after they relapsed were associated with overall survival, but ratings before relapse were not associated with outcome.7
These findings suggested that the association between QoL and survival was related to cancer-related symptoms. They were compatible with a simple explanation that patients perceived disease progression before it was clinically evident, but also with a more complex causal relationship where QoL influenced survival duration.
Subsequent observational studies showed that differences in coping styles and adjustment strategies were associated with differences in overall survival8 and in QoL over time in patients with melanoma that was localised9 or metastatic.10 Styles of coping and adjustment were also associated with survival in women with metastatic breast cancer.11 These studies suggested that the use of minimisation and avoidance were associated with longer survival and led to a randomised trial to test the benefits of encouraging patients to use these coping styles and adjustment strategies.
International randomised trials in the 1970s and 1980s established that adjuvant chemotherapy could improve relapse free and overall survival in early breast cancer, but that it also had measurable adverse effects on QoL. These adverse effects on QoL were transient and seemed minor compared with patients’ adaptation and coping after diagnosis and surgery.12 Investigators concluded that this finding should encourage patients and doctors to choose appropriate adjuvant therapy with less concern for initial toxicity.
These observations were taken further in the seminal study of patients’ preferences for adjuvant chemotherapy in early breast cancer conducted by Alan Coates and John Simes.13,14 They interviewed 100 women who had adjuvant chemotherapy to determine the benefits they considered necessary to make the experience of adjuvant chemotherapy worthwhile. The majority of women considered small benefits (a few extra percentage points or months) sufficient to warrant the side-effects and inconvenience of adjuvant chemotherapy. Subsequent studies corroborated these findings for other countries, treatments and eras.15,16 Even more interesting were the subsequent findings that women considered larger benefits necessary to make adjuvant endocrine therapy worthwhile.17,18
Quality-adjusted survival analysis was another novel approach to incorporating patients’ attitudes and opinions into judgements about adjuvant chemotherapy. This method for formally integrating the effects of adjuvant chemotherapy on length and QoL also supported the conclusion that adjuvant chemotherapy was worth considering for most women with early breast cancer.19
Alan Coates has made a substantial, enduring contribution to thinking and practice in oncology. These studies have shown how to improve the decision making and treatment for people affected by cancer. They also provide a shining example of how to combine compassion, open-mindedness and rigour.
1. Coates A, Gebski V, Bishop JF, Jeal PN, Woods RL, Snyder R, et al. Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. New England Journal of Medicine. 1987; 317(24):1490-5.
4. Coates A, Gebski V, Signorini D, Murray P, McNeil D, Byrne M, et al. Prognostic value of quality-of-life scores during chemotherapy for advanced breast cancer. Journal of Clinical Oncology. 1992; 10(12):1833-8.
5. Coates A, Thomson D, McLeod GR, Hersey P, Gill PG, Olver IN, et al. Prognostic value of quality of life scores in a trial of chemotherapy with or without interferon in patients with metastatic malignant melanoma. European Journal of Cancer. 1993; 29A(12):1731-4.
7. Coates AS, Hurny C, Peterson HF, Bernhard J, Castiglione-Gertsch M, Gelber RD, Goldhirsch A. Quality-of-life scores predict outcome in metastatic but not early breast cancer. Journal of Clinical Oncology 2000; 18(22):3768-74.
8. Brown JE, Butow PN, Culjak G, Coates AS, Dunn SM. Psychosocial predictors of outcome: time to relapse and survival in patients with early stage melanoma. British Journal of Cancer. 2000; 83(11):1448-53.
9. Brown JE, King MT, Butow PN, Dunn SM, Coates AS. Patterns over time in quality of life, coping and psychological adjustment in late stage melanoma patients: an application of multilevel models. Quality of Life Research. 2000; 9(1):75-85.
12. Hurny C, Bernhard J, Coates AS, Castiglione-Gertsch M, Peterson HF, Gelber RD, et al. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. Lancet. 1996; 347(9011):1279-84.
13. 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. p. 447-458.
16. Duric V, Stockler MR, Heritier S, Boyle F, Beith J, Sullivan A, Wilcken NJC, Coates AS, Simes RJ. Patients’ preferences for adjuvant chemotherapy in early breast cancer: what makes AC and CMF worthwhile now? Ann Oncol. 2005; 16: 1786-94.
17. Thewes B, Meiser B, Duric V, Stockler MR, Taylor A, Stuart-Harris R, et al. What survival benefits do premenopausal early breast cancer patients need to make endocrine therapy worthwhile? Lancet Oncol. 2005; 6(8):581-8. UI: 16054569.
18. Duric V, Fallowfield L, Saunders C, Houghton J, Coates AS, Stockler MR. Patients’ preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile. Brit J Cancer. 2005; 93: 1319-23.
19. Goldhirsch A, Gelber RD, Simes RJ, Glasziou P, Coates AS. Costs and benefits of adjuvant therapy in breast cancer: a quality-adjusted survival analysis. Journal of Clinical Oncology. 1989; 7(1):36-44.