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In Reply

McMaster University, Hamilton, Ontario, Canada

Paul E. Goss

Harvard University Medical School, Boston, MA

James N. Ingle

Mayo Clinic, Rochester, MN

Donsheng Tu, Lois Shepherd, Joseph L. Pater

National Cancer Institute of Canada Clinical Trials Group, Kingston, ON, Canada

This et al raise important concerns regarding the importance of participant compliance in assessing quality of life. In the MA-17 quality-of-life substudy,¹ we adopted guidelines that are commonly used by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) to analyze quality-of-life data.² As stated in the referenced article and in This et al's letter, we defined compliance with quality-of-life assessment as the number of patients completing assessments at designated time points divided by the number of patients still on study and expected to complete an assessment. This approach is used because in a randomized trial in which patients are accrued over a number of years, patients will be followed for different periods of time. Because the MA-17 trial was stopped after a median follow-up of 30 months, the majority of "missing" assessments at later time points occurred because patients had not been followed that long—it was not that these patients had "dropped out." For example, approximately 37% of patients on both arms with baseline assessments had follow-up times of less than 24 months. Among those who had been followed for 24 months, approximately 18% in both treatment arms were off protocol treatment before the scheduled 24-month clinical assessment, and thus were not expected to complete the quality-of-life assessment at that time. Among the patients who discontinued protocol treatments before their 24-month assessment, the major reasons were patient refusal (49% of patients receiving letrozole [LET] and 45% of patients receiving placebo [PLAC]), toxicity (24% of patients receiving LET and 22% of patients receiving PLAC), recurrence (10% of patients receiving LET and 15% of patients receiving PLAC), death or other illness (4% of patients receiving LET and 5% of patients receiving PLAC). The overall proportion of patients who would not be expected to undergo the 24-month assessment (53% for patients receiving LET and 56% for patients receiving PLAC) is similar in both treatment arms, and it is unlikely to have had a substantial impact on the interpretation of the quality-of-life results.

For the main evaluation of quality of life in the trial, we used a response analysis in which we included all patients who had completed a baseline assessment and at least one subsequent assessment to minimize the effect of dropouts. This type of analysis does lend itself to examining the duration of deterioration, but in view of the infrequent yearly assessments and the short duration of follow-up, this was not possible in this study.²

We agree with This et al that the long-term evaluation of aromatase inhibitors on quality of life is an important clinical question. The MA-17 quality-of-life substudy is the largest study to date evaluating quality of life in patients receiving aromatase inhibitors and the only large adjuvant trial with a placebo control. Although follow-up is still relatively short, more than 700 patients have completed a quality-of-life assessment at 36 months. Further follow-up will be necessary to look at the long-term impact of letrozole. Recent reports from other trials of aromatase inhibitors suggest that the effects at 5 years are consistent with earlier reported results.³

We believe that a double-blind randomized trial remains the best design to evaluate the impact of hormonal therapy on quality of life because postmenopausal women's quality of life is likely to deteriorate over time unrelated to therapy, and such a design avoids the problem of selection bias and false attribution.⁴ On the basis of this and the reasons stated in the preceding paragraphs, we stand by our conclusions regarding the generalizability of the study findings.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Timothy J. Whelan AstraZeneca (A); Novartis (A) Paul E. Goss Novartis (A) Novartis (A); Pfizer (A) James N. Ingle AstraZeneca (A); Novartis (A) AstraZeneca (A); Novartis (A); Pfizer (A) Lois Shepherd Novartis (C) Joseph L. Pater Novartis (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. Whelan TJ, Goss PE, Ingle JN, et al: Assessment of quality of life in MA.17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23:6931-6940, 2005[Abstract/Free Full Text]

2. Osoba D, Bezjak A, Brundage M, et al: Analysis and interpretation of health-related quality-of-life data from clinical trials: Basic approach of the National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 41:280-287, 2005[CrossRef][Medline]

3. Cella D, Fallowfield L: ATAC Trialists' Group: Five-year quality of life (QOL) follow-up of adjuvant endocrine therapy for postmenopausal women in the Arimidex (A), Tamoxifen (T), Alone or in Combination (ATAC) Trial. J Clin Oncol 23:23S, 2005 (abstr 577)

4. Whelan T, Pritchard K: Managing patients on endocrine therapy: Focus on quality-of-life issues. Clin Cancer Res 12:1056-1060, 2006

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