When do patient reported quality of life indicators become prognostic in breast cancer?

Previous studies have shown that various patient-reported quality-of-life (QL) indicators independently predict survival outcomes in metastatic breast cancer [1‐5] and other cancer types [5‐8]. By contrast, in studies of early-stage breast cancer, no clear relationship between QL indicators and survival has been reported [9‐11], though small studies have reported associations with appetite loss [12], future perspective [13], social wellbeing [14] and with physical and functional impairment [15], while a decrease in depression was reported to be associated with longer survival [16]. The reason for this discrepancy is uncertain. If the prognostic associations in advanced disease reflect patients’ perceptions of underlying disease severity, it may well be that at initial diagnosis of early-stage disease there are no such symptoms to perceive. The timing of the emergence of prognostic association of patient-reported QL indicators is therefore important because it might illuminate the mechanism for the association of such indicators with subsequent survival. The present study uses available individual-patient data from seven International Breast Cancer Study Group (IBCSG) adjuvant therapy trials that included QL assessments. We hypothesized that there may be a lead time prior to cancer relapse during QL indicators were prognostic for subsequent survival duration. Our primary objective was to examine the association between survival and QL indicators recorded at time points shortly before each patient’s date of disease relapse, and as a secondary aim to document the time course of the prognostic significance of the same QL indicators recorded at various intervals after relapse.

Between 1986 and 2000, seven IBCSG trials randomised a total of 8024 women with operable breast cancer to different systemic treatment comparisons. Trial VI randomised premenopausal women with node-positive cancer and investigated the optimal duration and timing of adjuvant chemotherapy [17]. Trial VII [18] and trial IX [19] investigated the value of adding chemotherapy to tamoxifen to treatment for postmenopausal women with node-positive and node-negative tumors, respectively. Trial VIII investigated the role of treatment with chemotherapy, endocrine therapy comprising ovarian suppression with goserelin, and the sequential use of these modalities in premenopausal and perimenopausal women with node-negative tumors [20]. Trial 13–93 examined the introduction of a treatment gap and the value of adding tamoxifen to chemotherapy in premenopausal women [21], while Trial 14–93 investigated the role of a treatment-free gap in postmenopausal women [22]. Trial 15–95 investigated dose-intensive chemotherapy in women with high-risk, node-positive breast cancer [23].

In all of these trials, QL was measured using validated single-item linear analog self-assessment (LASA) indicators of components of QL (physical wellbeing, mood, coping, and perceived health status) shown to be affected by breast cancer, surgery, chemo- and endocrine therapy [24‐27]. These were global indicators for physical well-being, mood, coping effort and perceived health status (utility). The specific indicators for side-effects were nausea/vomiting, appetite, flushing, and arm restriction. Mood and coping indicators are shown to be sensitive in identifying psychological distress, mood disorders and psychosocial dysfunction. The clinical relevance of global and specific LASA indicators has been confirmed in breast cancer trials that examined the impact of axillary clearance, chemo- and endocrine therapy, and by their association with performance status, tumor response, chemotherapy treatment benefit and toxicity, and survival duration. Each LASA indicator consisted of a 100-mm line, with scores ranged from 0 (best) to 100 (worst). The schedule of QL assessments was essentially similar in all trials, with regular early measures then additional assessment following relapse.

Of a total of 8024 patients, 3834 (47.8%) had a protocol-defined DFS event (first occurrence of breast cancer recurrence at local, regional, or distant site, contralateral breast cancer, second malignancy or death prior to a cancer event) during a median follow-up period of 12.1 years (range 0 to 21.5 years).. The patient and disease characteristics at trial entry, and QL data availability, are summarized in Table 1. Because we wanted to focus only on breast cancer relapse, we excluded 346 patients with a non-breast second primary malignancy, 223 who died without disease recurrence and 18 the nature of whose DFS event was unknown, leaving 3247 who had disease relapse in the main analytic cohort. Of these, 1243 (38%) had a relapse involving local or regional sites or contralateral breast and the remaining 2004 (62%) distant metastatic disease (Table 4 in Appendix 3).

Interest in the psychological correlates of prognosis in cancer has been longstanding. Our own studies in metastatic breast cancer [28] and melanoma [29] found a consistent positive effect of “minimization” of concern. In this study, using established QL indicators which had proven prognostic in metastatic disease [2, 9] we could not demonstrate any lead-time effect, in that none of the QL indicators, (apart from the possibly chance finding of mood at 2 months), measured at 1, 2, and 3 months before cancer relapse had prognostic significance for subsequent survival. By contrast, and in keeping with prior observations, the same indicators recorded at and after cancer relapse substantially predicted subsequent survival, with stronger association for QL indicators measured later in the course of relapsed disease. The hazard ratios observed after relapse represent large effect size: every 10 points worsening of physical well-being, at the median time of 1.3 months after progression, was associated with 7% increase in hazard of death. At median times of 5.8 and 10.1 months after progression, the corresponding hazards of death were increased to 8% and 13%, respectively for every 10 points worsening of physical well-being.

This study has several strengths. It is based on individual patient QL indicator data prospectively collected in almost 4000 patients from seven adjuvant clinical trials. Among these, 22.9% had available QL indicator data falling in the period prior to the time of relapse and 40.3% had QL indicator data soon thereafter, enabling prognostic analyses to be performed at various stages of the disease trajectory around the event of disease relapse.

There are also several limitations of this study. The findings remain hypothesis-generating, as none of these clinical trials were originally designed to answer the research questions addressed in this paper. Patients were classified in these trials as having disease progression if they had local recurrence and / or more distant metastatic disease. Patient’s self-perception of the severity of the disease might differ between those who developed a local recurrence versus those with distant metastasis and hence might potentially impact on the results. However, our sensitivity analysis (Table 4 in Appendix 3) does not suggest major differences in the result of all types of relapse versus those with distant metastases only. For feasibility reasons, in these large-scale phase-III international studies where trials were conducted in different cultures with different local settings and resources, key indicators relevant to patients with breast cancer were selected as an alternative to a comprehensive QL assessment [24, 25]. Because the time of relapse could not be prospectively known, QL indicator data were only available from 22.9% of patients at the chosen time points 1, 2 or 3 months before relapse. Moreover, these data were generally from patients who relapsed early during or immediately after completion of adjuvant systemic treatments (when QL indicator assessments were scheduled) rather than those who relapsed later. We do not have detailed clinicopathologic information about the sites of relapse in these patients and have therefore not attempted to separately assess the prognostic relevance of QL indicators after relapse at various different sites. Our multivariable analyses only adjusted for baseline factors at diagnosis of early-stage breast cancer. Thus, it is possible that QL indicator data might not be prognostic for survival after relapses confined, say, to soft tissues. We used QL indicators at various time points but did not examine for effects of change in the score. However, changes in QL indicator from baseline (at the commencement of adjuvant therapy) to before and during cancer relapse may be difficult to interpret because of the significant time gap for most of these patients, and the phenomenon of response shift [30‐32].

In conclusion, QL indicators measured at various intervals before cancer relapse did not have prognostic significance for subsequent OS. At and after cancer relapse, QL indicators substantially predicted subsequent OS, with stronger association for QL indicators measured in the later course of relapsed disease. Patients’ self-perception of the severity of the underlying disease after relapse might be a reason for the reported QL indicators and thus contributes to their prognostic significance.