Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer
Br J Cancer
vol. 98, 25 - 33, 2008
Abstract
Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, −2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.
Commentary
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A: Evidence from an article that is shown in a human (double-blind, when appropriate), randomized trial, meta-analysis or both
On the basis of well-designed randomized controlled trials,1-4 high-dose chemotherapy (HDC) with stem cell support has proven to be more toxic and no more efficacious than standard-dose chemotherapy for cases of both high-risk and metastatic breast cancer. This approach of hitting the most serious cases of breast cancer with the most aggressive or intense form of chemotherapy was initially viewed as promising based on the results of single-arm trials demonstrating results that appeared superior to historical outcomes from standard therapy.5 Accrual to randomized trials was difficult due to patients' and physicians' preferences, with the majority of patients treated off-protocol or in single-arm studies.6
In this context, 2 recent publications, one by Bernhard and colleagues in the British Journal of Cancer and one by Crump and colleagues1 in the Journal of Clinical Oncology present results that are important both for the clinical information they provide and for their fulfillment of the obligation between researcher and trial participants to analyze and publicize trial results, even when the trial is negative.
The article by Crump and colleagues presented the results of a randomized multicenter trial conducted by the National Cancer Institute Clinical Trials Group, in which 386 patients with metastatic breast cancer were treated with induction chemotherapy, and those with a significant response (224) were randomized to HDC versus standard-dose chemotherapy. Although this trial was underpowered and closed early because of poor accrual following negative results from similar randomized trials, it provided further evidence that there was no benefit in terms of survival from HDC and a substantial cost, in this case a 6% incidence of 100-day mortality from the more intensive approach. Scant details of the longitudinal quality of life analysis are provided, but it appears that quality of life was substantially worse during chemotherapy although comparable between study arms by 6 months after treatment.
The message of higher toxicity and worse quality of life during therapy with recovery to baseline or better by several months after treatment is mirrored in the study by Bernhard and colleagues. This publication reported the quality of life and quality-adjusted time without symptoms and toxicity (Q-TWiST) analysis for a randomized trial of HDC versus standard-dose adjuvant chemotherapy conducted by the International Breast Cancer Study Group. This trial also failed to show a significant benefit for HDC over standard-dose therapy, but quality of life improved to better than baseline by several months after completion of either therapy.7
In general, the principle that “more is better” when it comes to cytotoxic chemotherapy for breast cancer has been discredited; however, given the emerging understanding of the heterogeneity of this disease, it is not impossible that there will be a subset of patients for whom this hypothesis merits further testing in the future among carefully selected patients in a well-designed randomized clinical trial. If so, these trials suggest that quality of life differences should not preclude a more intense, but more effective therapy. Of course, the hope is that we will identify pathways and targeted agents that will allow us to improve outcomes with little additional toxicity, as has been demonstrated for patients with HER-2–positive breast cancer in both the metastatic and adjuvant settings.8,9 These HDC studies highlight the importance of randomized trials, even when the experimental therapy seems promising and the need for continued efforts to find better strategies to improve outcomes for women with high-risk and metastatic breast cancer.
