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Defining Clinical Benefit in Postmenopausal Patients With Breast Cancer Under Second-Line Endocrine Treatment: Does Quality of Life Matter?

From the Swiss Institute for Applied Cancer Research Coordinating Center and Institute of Medical Oncology, Inselspital, Bern; Department of Medicine C, Kantonsspital, and Bürgerspital, St Gallen; Cantonal Institute of Oncology, Ospedale San Giovanni, Bellinzona; Division of Gynecology, Centre Médical Universitaire, Geneva; and Cantonal Institute of Oncology, Ospedale Civico, Lugano, Switzerland.

Address reprint requests to Jürg Bernhard, PhD, Swiss Institute for Applied Cancer Research Coordinating Center, Effingerstr 40, 3008 Bern, Switzerland.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: In endocrine therapy trials in advanced breast cancer, patients with response (complete response/partial response [CR/PR]) and patients with stable disease for at least 6 months (SD_6m) have shown similar survival and therefore are often defined as a population with clinical benefit (patients with CR/PR or SD_6m). We evaluated the impact of response and/or clinical benefit on quality of life (QL) in postmenopausal patients under second-line endocrine treatment after failure of tamoxifen.

PATIENTS AND METHODS: One hundred twenty-eight of 177 eligible patients of a randomized trial (Swiss Group for Clinical Cancer Research 20/90) receiving either formestane (250 mg intramuscularly biweekly) or megestrol acetate (160 mg orally daily) were analyzed. The baseline characteristics (with the exception of site of metastases) were balanced among patients with CR/PR, SD_6m, and progressive disease (PD). Patients completed QL indicators at baseline and at 1, 3, 5, 7, 9, and 11 months. Responders were separately compared with nonresponders (patients with SD_6m or PD) and with patients with SD_6m, and patients with clinical benefit were compared with patients with PD by analysis of covariance with adjustment for baseline scores.

RESULTS: Overall, 88% (557 of 634) of expected QL forms were received. In the comparison of responders versus patients with both SD_6m and PD, responders indicated better physical well-being (P = .004) and mood (P = .02) at month 3. Compared only with patients with SD_6m, responders showed no significant difference in baseline QL and time to treatment failure (328.5 v 340 days). While under treatment, responders reported significantly better physical well-being (months 3 to 11), mood (months 5 to 11), coping (months 5 to 9), and appetite (months 7 to 11) and less dizziness (month 9) than patients with SD_6m. The changes between baseline and months 5 and 7, respectively, indicated improvement in responders but heterogeneous patterns in patients with SD_6m.

CONCLUSION: Although the CR/PR and SD_6m groups had similar times to treatment failure, patients with CR/PR reported better QL, suggesting more beneficial response to second-line endocrine treatment. Patients' subjective perspective should be taken into account in this mainly palliative setting. Future trials should be designed so that the CR/PR and SD_6m groups are investigated separately.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN ADVANCED BREAST CANCER under endocrine therapy, patients with stable disease lasting for at least 6 months (SD_6m) show similar survival to patients with partial response (PR).^1,2 Hence, the clinical benefit obtained by SD_6m has been classified as being comparable to that obtained by PR, and SD_6m has been included in overall response rates in endocrine trials.^3,4 Recently, Robertson et al⁵ confirmed these findings in patients with local/regional and metastatic breast cancer under endocrine therapy. They reported no significant difference in survival from first-line or second-line endocrine therapy in patients who obtained complete response (CR), PR, or SD_6m. Regarding clinical practice, progressive disease (PD) has been suggested to be the clinically relevant point at which treatment must be changed.⁵

In metastatic breast cancer, currently available treatments are mainly palliative. Therefore, patients' subjective perspective is a key issue in defining clinical benefit. We questioned whether similar survival times in patients responding to endocrine therapy with either SD_6m or CR/PR would imply similar quality of life (QL). We expected better coping and mood in patients with CR/PR because reduction of tumor burden is associated with hope.

We evaluated QL under second-line endocrine treatment by response and clinical benefit in postmenopausal patients with breast cancer who had failed tamoxifen (TAM) treatment. Patients were treated within a randomized trial of the Swiss Group for Clinical Cancer Research comparing formestane with megestrol acetate (MGA).⁴ There was no significant difference between the treatments with regard to response rate, time to treatment failure,⁴ or QL.⁶

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The Trial
The trial was planned to test differences in time to treatment failure and toxicity between formestane (250 mg intramuscularly every 2 weeks) and MGA (160 mg orally daily). Details are described elsewhere.⁴ In brief, postmenopausal patients with objective evidence of histologically and/or cytologically proven breast cancer and measurable or nonmeasurable but assessable advanced disease were eligible. Patients must have had failed previous adjuvant and/or palliative treatment with TAM, irrespective of the best response. Previous adjuvant chemotherapy was allowed, but it had to be completed more than 12 months before enrollment on the trial. Further inclusion criteria were Swiss Group for Clinical Cancer Research/Eastern Cooperative Oncology Group performance status of 0 to 2 and appropriateness of endocrine therapy as decided by the treating physician. Informed consent was obtained from all patients. Patients were randomized after being stratified for institution, type of treatment, and best response to previous TAM treatment (adjuvant TAM v palliative TAM with PR/CR v palliative TAM with SD/PD v palliative TAM with unknown/not assessable response). In November 1992, the inclusion criteria were modified to allow pretreatment with one chemotherapy regimen for advanced disease. The following toxicity ratings were included in this analysis: weight gain ( 3 kg), thromboembolism (superficial phlebitis, deep vein thrombosis, or pulmonary embolism), hypertension (> 150 mmHg systolic or > 90 mmHg diastolic; for hypertensive patients, an increase in systolic pressure 30 mmHg or in diastolic pressure 15 mmHg) (all yes/no),⁴ sleep problems, and tremor or neurologic disturbance (both World Health Organization and International Union Against Cancer scores of 0, 1, or 2 v 3 or 4). Treatment failure was defined by documented disease progression, patient refusal, or unacceptable toxicity.

QL Assessment
Linear analog self-assessment (LASA) indicators were used to measure selected components of QL previously shown to be affected by advanced breast cancer and endocrine treatment. Each LASA indicator consisted of a 10-cm line anchored at both ends with words describing the minimal and maximal extremes of the dimension being measured; physical well-being ("good" to "lousy"), mood ("happy" to "miserable"),^7,8 and coping/perceived adjustment ("How much effort does it cost you to cope with your illness?" "no effort at all" to "a great deal of effort") (Perceived Adjustment to Chronic Illness Scale)⁹ were assessed as global indicators with a one-page form. In addition, tiredness, appetite/sense of taste disturbance,⁸ hot flushes,¹⁰ and dizziness were included as specific indicators of symptoms and side effects (all with anchors "none" to "severe"). The time frame was related to the preceding 2 weeks. Conceptual and methodologic aspects of this approach are summarized elsewhere.¹⁰ The QL form was used in three languages (German, French, and Italian).

In this advanced-disease multicenter trial, a detailed QL assessment was not feasible. Therefore, we followed a different strategy. Given that the primary purpose was to compare the two treatments with regard to patients' overall QL, and not to determine specific reactions associated with the two drugs, we defined the limited set of indicators described above to evaluate outcome. Responses on the global LASA indicators are expected to reflect the summation of the meaning and importance of various factors for each patient.¹⁰ Although less precise for specific treatment effects, these measures are expected to be sensitive to the wide spectrum of reactions seen among patients on endocrine treatments and to detect changes on single dimensions; this approach is suitable for comparison of QL between response groups across treatments. In patients with advanced breast cancer, some of these indicators have shown significant independent prognostic value for survival.¹¹ They discriminated between the effects of endocrine and cytotoxic treatment, between responders and nonresponders,¹² and between different chemotherapy regimens.¹³

The QL assessment schedule was defined with regard to the known large variation in time to treatment failure (ie, dropouts because of disease progression) in these patients: QL indicators were assessed at randomization, at 1, 3, 5, 7, 9, and 11 months thereafter, and at treatment failure; this strategy is suitable for summary measures over time. Patients were instructed by nurses or physicians to fill in the QL forms at clinical visits to the hospital, using a standardized and pretested written example. Reasons for missing QL data were recorded. Sociodemographic data were assessed by nurses or physicians at study entry. All QL indicators were scored by measuring in millimeters from 0 to 100 and were reversed, with higher numbers reflecting better QL (eg, fewer symptoms).

Statistical Analyses
All patients with QL forms available both at baseline and at one or more subsequent time points were included in this analysis. In this sample, as in the total sample,⁶ treatment did not significantly affect QL. Hence, we could combine patients from both treatment arms for the following analyses.

"Responders" were defined as patients with CR or PR as best response receiving study treatment for at least 8 weeks,⁴ and "nonresponders" were defined as patients with SD_6m (ie, SD as best response and time to treatment failure > 180 days) or PD (ie, not CR, PR, or SD_6m). "Benefiters" referred to patients with clinical benefit (ie, CR, PR, or SD_6m).

According to different grouping criteria, comparisons were performed among three groups (ie, patients with CR/PR v patients with SD_6m v patients with PD) as well as between two groups (ie, responders v nonresponders, benefiters v patients with PD, and responders v patients with SD_6m).

The biomedical baseline characteristics (age, menopausal status, performance status, type of and best response to previous TAM, site of metastases) of this sample were compared among the three groups by ² test or, in case of too few numbers, by exact test. For age as a continuous variable, the Kruskal-Wallis test was used.

Baseline QL scores were compared by the Kruskal-Wallis test (three groups) or the Wilcoxon rank sum test (two groups). Subsequent QL assessments, including the last available assessment on treatment before treatment failure (last assessment),¹⁴ were compared between groups by analysis of covariance (ANCOVA) with baseline assessment scores as covariates. Because a preliminary analysis showed some significant differences in baseline scores between groups, interaction between baseline score and group was included in the ANCOVA if it was significant. The intercepts (ß₀) and slopes (ß₁) of the linear regression of subsequent scores on baseline values were compared between groups by using their difference, denoted as ß₀ and ß₁, respectively. Differences in intercept (ß₀) correspond to differences in scores between groups in case of a baseline value of 0. A slope (ß₁) of 0 means that subsequent scores are not correlated with baseline values. Differences in slope between groups (ß₁) mean that correlation between subsequent scores and baseline values are not the same in these groups. An example is shown in Fig 1. Because of the high attrition rate in patients with PD, comparisons including this group were made only up to month 3.

View larger version (12K): [in this window] [in a new window]   Fig 1. Fitted ANCOVA model and raw data for physical well-being at month 3. Higher scores indicate better physical well-being. The solid line and 1 refer to responders, and the dotted line and 2 refer to nonresponders.

In addition, the prevalence of weight gain and physician-rated toxicity in patients with CR/PR versus SD_6m was investigated by Fisher's exact test. The effects of these toxicities on QL were investigated for the last assessment by analysis of variance (ANOVA). Given that toxicity may differ between treatment arms, treatment was also included as a covariate.

To keep results easily comparable, no transformation was applied in a few ANCOVAs and ANOVAs with nonnormal distribution or unequal variance. This analysis is mainly exploratory. No adjustment was made for multiple testing. All tests were two-sided.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Description of the Sample
The biomedical characteristics of the total sample (n = 177 eligible randomized patients) are described elsewhere.⁴ In brief, approximately 11% of all patients had negative estrogen and 22% had negative progesterone receptor status, half had received TAM as adjuvant treatment, and half had received TAM as palliative treatment. The two arms were well balanced at study entry with the exception of weight and tumor localization; patients in the formestane arm had a significantly higher mean weight and significantly less frequent liver metastases. The median age was 65 years (range, 43 to 87 years).

Feasibility issues of QL assessment in this trial are described elsewhere.⁶ Overall, 88% (557 of 634) of expected QL forms at baseline and on study treatment were received. One hundred twenty-eight (72%) of the 177 eligible patients had QL forms available both at baseline and at one or more time points truly under treatment (ie, not contaminated by treatment failure) and were included in this analysis. The biomedical baseline characteristics of this sample were compared among patients with CR/PR, SD_6m, and PD. The only statistically significant differences were related to the site of metastases. Among responders, bone metastases (42%) were less frequent than among patients with SD_6m (72%) or PD (71%); among patients with SD_6m, lymph node (17%) and skin (8%) metastases were less frequent than among patients with PD (41% and 11%, respectively) or response (54% and 31%, respectively).

Impact of Response
At baseline, patients with response reported a trend toward better scores in physical well-being (P = .07) and tiredness (P = .06) compared with patients with SD_6m or PD (Table 1). During the first month of treatment, there was no difference in QL by response. At month 3, responders reported better physical well-being (n = 74; ß₀ = 36.0, P = .004; ß₁ = -0.3, P = .05). This indicates that the difference between responders and nonresponders had a maximum of 36 when the baseline score was 0 and decreased by 0.3 when the baseline score increased by one point; hence, the difference was more marked in patients with worse baseline scores, as illustrated in Fig 1. Responders also indicated better mood (n = 72; ß₀ = 12.6, P = .02) at month 3.

Similarly, at the last assessment, responders reported better physical well-being (n = 126; ß₀ = 40.5, P = .003; ß₁ = -0.4, P = .03) and mood (n = 124; ß₀ = 46.6, P = .0001; ß₁ = -0.5, P = .003). Because of the relatively short time to treatment failure, nonresponders after the month-3 assessment consisted mainly of patients with SD_6m. Thus, more detailed results are given for the following comparison between patients with response and patients with SD_6m.

Impact of Clinical Benefit
The question of clinical benefit was investigated first by comparing responders, patients with SD_6m, and patients with PD at baseline and at last assessment. At baseline, the three groups showed a trend toward different scores in physical well-being (P = .13) and tiredness (P = .12) in the expected direction, with tiredness scores in patients with stable disease being between those of the other groups (Table 1). Under treatment (last assessment), the responders indicated better physical well-being and mood compared with patients with SD_6m or PD (Fig 2); the difference in appetite was mainly between patients with clinical benefit (CR/PR or SD_6m) and patients with PD.

View larger version (23K): [in this window] [in a new window]   Fig 2. Fitted ANCOVA models and raw data at last assessment for physical well-being (A), mood (B), and appetite (C). Higher scores indicate better QL. The solid line and 1 refer to responders, the dotted line and 2 refer to patients with SD6m, and the dashed line and 3 refer to patients with PD.

Second, patients with clinical benefit were compared with patients exhibiting PD. At baseline, the benefiters again showed a trend toward better scores in physical well-being (P = .08) and tiredness (P = .09) as well as in appetite/sense of taste disturbance (P = .09) (Table 1). At the last assessment, the benefiters reported better physical well-being (n = 126; ß₀ = 8.9, P = .04), mood (n = 124; ß₀ = 34.6, P = .0004; ß₁ = -0.4, P = .005), and appetite/sense of taste disturbance (n = 127; ß₀ = 39.0, P = .0004; ß₁ = -0.4, P = .002).

Comparing Response with Stable Disease
Responders were compared separately with patients with SD_6m. There was no significant difference in time to treatment failure (328.5 v 340 days) or in baseline QL scores between the two groups. Under treatment, these two groups consistently differed during the whole observation period in various QL indicators. The results of indicators significantly affected at least at one time point are summarized in Table 2. Responders reported better physical well-being from month 3 up to and including month 11, better mood at months 5 to 11, better coping at months 5 to 9, better appetite at months 7 to 11, and less dizziness at month 9. This effect was present also for the last assessment of physical well-being and mood.

At the last assessment, weight gain of 3 kg or more was observed in 12 of 26 patients treated with MGA and in eight of 33 patients treated with formestane. There was no significant difference in weight gain between patients with response and patients with SD_6m. The effect of weight gain on QL indicators was not significant. Similarly, hypertension did not differ significantly between the response groups, and its effect on QL was minor. Thromboembolism (n = 1), severe sleep problems (grade 3, n = 1), and tremor or neurologic disturbance (grade 3, n = 0) had too low a prevalence in this subgroup for further investigation.

Of particular importance is patients' QL at months 5 and 7. These time points reflect the critical window for the definition of SD_6m. The distributions of changes from baseline in the three global indicators are shown separately for month 5 (Fig 3) and month 7 (Fig 4). In responders, the changes indicated substantial improvement in the majority of patients, ranging from 7% (physical well-being, month 5) to 19% (mood, month 7) of the full-scale range (0 to 100) across scales and both time points. In contrast, about half of the patients with SD_6m reported stable or somewhat worse scores, and the others reported either an improvement or a considerable deterioration.

View larger version (17K): [in this window] [in a new window]   Fig 3. Distributions of differences in QL measures between baseline and month 5. Positive values indicate an improvement in all measures. The bold line refers to the median, and the x refers to the mean.

View larger version (17K): [in this window] [in a new window]   Fig 4. Distributions of differences in QL measures between baseline and month 7. Positive values indicate an improvement in all measures. The bold line refers to the median, and the x refers to the mean.

Baseline Effects
In the ANCOVA models reported above, baseline scores were, in most cases (88%), strongly and positively correlated with subsequent assessments for all QL measures (slope, 0.2 ß₁ 1.08, .0001 P .05). In other words, baseline scores were strongly predictive for the QL under treatment, although they were not significantly associated with subsequent response or clinical benefit. Finally, there was no significant association between initial performance status and response (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We evaluated QL under second-line endocrine treatment by response and clinical benefit in postmenopausal patients with breast cancer after failure of TAM. Compared with responders, nonresponders showed a trend toward worse physical well-being and tiredness already at baseline. This finding primarily reflects the biologic heterogeneity of disease. It is in line with the results of an earlier study¹² and confirms these indicators' sensitivity to the course of disease, as shown in a comparison of prefailure and postfailure QL.¹⁵ As expected, responders showed better physical well-being and mood under treatment, although not yet at the month-1 assessment. Given that endocrine agents may take months to induce a measurable CR or PR, response is expected to discriminate only later in the treatment course.

Following the established definition of clinical benefit,^1,2,5 we split the nonresponders into patients with SD_6m and patients with PD. Patients with SD_6m reported better physical well-being, mood, and appetite/sense of taste under treatment compared with patients with PD, as implied by the definition of clinical benefit.

In regard to the comparison of responders and patients with stable disease, similar QL was observed at baseline. Under treatment, however, patients with response reported consistently better scores in mood and, beyond our expectation, in physical aspects during the whole observation period. In particular between months 5 and 7, the differences between responders and patients with stable disease were of a magnitude comparable to the mean changes between prerecurrence and postrecurrence QL assessed by the same three global indicators in adjuvant trials.¹⁵ Although the situation of this trial is different, this finding underlines the clinical relevance of the difference in QL between patients with response and patients with stable disease under second-line endocrine treatment.

In addition, the changes in physical well-being, mood, and coping between baseline and the critical window of months 5 to 7 were different in responders compared with patients with SD_6m. In accordance with clinical knowledge, the majority of the responders reported a substantial improvement. In contrast, among patients with SD_6m there were heterogeneous patterns, suggesting that the benefit induced by stable disease is not the same as the benefit of response.

In summary, similar time to treatment failure between patients with response and patients with SD_6m does not necessarily result in similar QL. Given that currently available treatments are mainly palliative, patients' subjective perspective must be taken into account in definingclinical benefit. Although clinical benefit defined as CR/PR or SD_6m is a useful end point from a biomedical point of view, it is not appropriate if QL considerations are included. Therefore, clinical trials should be designed a priori for separate investigation of the CR/PR and SD_6m groups. This requires larger sample sizes than a design restricted to clinical benefit as the main end point.

What are the clinical implications of these findings? Taking into consideration the heterogeneous changes among the patients with SD_6m, progression of disease may not be the only clinically relevant point at which second-line endocrine therapy should be changed. This decision must be made on an individual basis, with the individual profile of symptoms and side effects taken into account. For example, a patient with bone as the dominant site of disease and symptoms not responding to second-line endocrine therapy but achieving stable disease may have suboptimal palliation only. In this case, switching to third-line endocrine therapy or to chemotherapy is indicated and could help to induce and maintain a better QL. The addition of radiotherapy to painful lesions or the initiation of a potent bisphosphonate therapy should also be considered. In contrast, a patient with two or three nodular lung metastases achieving stable disease under second-line endocrine therapy may maintain a relatively good QL until disease progression.

Submission rates of QL forms were good and comparable with those in similar studies.^3,16 Given the high rate of treatment failures across the whole observation period, we used the last available assessment before failure as a summary measure.¹⁴

This measure consistently discriminated between responders and nonresponders, and between responders and patients with SD_6m, with regard to mood and physical well-being. In other words, irrespective of survival time, a main subjective effect of response as distinguished from SD_6m seems to be physical and not solely emotional. Whether this effect reflects patients' psychologic response to good news or the remission itself cannot be answered by our study. It is worth noting that the effect on physical well-being was clearly stronger than that on mood and was consistent over time. QL measures in metastatic disease, and in particular physical ratings, are likely to reflect the status of the underlying disease. This has been shown for baseline scores¹¹ as well as for changes under intermittent versus continuous chemotherapy.¹³ Nevertheless, the magnitude of the observed differences in our trial makes the distinction between CR/PR and SD_6m essential from a QL point of view.

In conclusion, from patients' perspective, response to second-line endocrine treatment is suggested to be more beneficial than SD_6m, despite similar time to treatment failure. In our data, patients' experiences differed substantially from investigators' assumptions regarding the suitable end point for endocrine therapy trials. This finding needs further investigation. It may affect the design, analysis, and interpretation of clinical trials in this mainly palliative setting.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Howell A, Mackintosh J, Jones M, et al: The definition of the ‘no change’ category in patients treated with endocrine therapy and chemotherapy for advanced carcinoma of the breast. Eur J Cancer Clin Oncol 24:1567-1572, 1988[Medline]

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3. Jonat W, Howell A, Blomqvist C, et al: A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer 32A:404-412, 1996

4. Thürlimann B, Castiglione M, Hsu Schmitz SF, et al: Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: A phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Eur J Cancer 33:1017-1024, 1997

5. Robertson JFR, Willsher PC, Cheung KL, et al: The clinical relevance of static disease (no change) category for 6 months on endocrine therapy in patients with breast cancer. Eur J Cancer 33:1774-1779, 1997

6. Bernhard J, Castiglione-Gertsch M, Hsu Schmitz S-F, et al: Quality of life in postmenopausal patients with breast cancer after failure of tamoxifen: Formestane versus megestrol acetate as second-line hormonal treatment. Eur J Cancer (in press)

7. Coates A, Fisher Dillenbeck CF, McNeil DR, et al: On the receiving end: II. Linear analogue self-assessment (LASA) in evaluation of aspects of the quality of life of cancer patients receiving chemotherapy. Eur J Cancer Clin Oncol 19:1633-1637, 1983[Medline]

8. Coates A, Glasziou P, McNeil D: On the receiving end: III. Measurement of quality of life during cancer chemotherapy. Ann Oncol 1:213-217, 1990[Abstract/Free Full Text]

9. Hürny C, Bernhard J, Bacchi M, et al: The Perceived Adjustment to Chronic Illness Scale (PACIS): A global indicator of coping for operable breast cancer patients in clinical trials—Swiss Group for Clinical Cancer Research (SAKK) and the International Breast Cancer Study Group (IBCSG). Support Care Cancer 1:200-208, 1993[Medline]

10. Bernhard J, Hürny C, Coates AS, et al: Quality of life assessment in patients receiving adjuvant therapy for breast cancer: The IBCSG approach—The International Breast Cancer Study Group. Ann Oncol 8:825-835, 1997[Abstract/Free Full Text]

11. Coates A, Gebski V, Signorini D, et al: Prognostic value of quality-of-life scores during chemotherapy for advanced breast cancer. J Clin Oncol 10:1833-1838, 1992[Abstract]

12. Baum M, Priestman T, West RR, et al: A comparison of subjective responses in a trial comparing endocrine with cytotoxic treatment in advanced carcinoma of the breast. Eur J Cancer 16:223-226, 1980 (suppl)

13. Coates A, Gebski V, Bishop JF, et al: Improving the quality of life during chemotherapy for advanced breast cancer: A comparison of intermittent and continuous treatment strategies. N Engl J Med 317:1490-1495, 1987[Abstract]

14. Tandon PK: Application of global statistics in analyzing quality of life data. Stat Med 9:819-827, 1990[Medline]

15. Hürny C, Bernhard J, Coates AS, et al: Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer: International Breast Cancer Study Group. Lancet 347:1279-1284, 1996[Medline]

16. Bernhard J, Cella DF, Coates AS, et al: Missing quality of life data in cancer clinical trials: Serious problems and challenges. Stat Med 17:517-532, 1998[Medline]

Submitted June 27, 1998; accepted January 6, 1999.

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