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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 4024-4025 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.8686
In ReplyDepartment of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, WI
Oncology Clinical Development, Pharmacyclics, Sunnyvale, CA Dr Vordermark appropriately focuses on the important issue of avoiding selection bias in post whole-brain radiation therapy evaluation in patient with brain metastasis, and adroitly recognizes that our strategy of analyzing identical patients surviving at 4 and 15 months following treatment achieves this in large measure. We obviously concur with Dr Vordermark that this type of analysis is recommendable for future prospective studies of neurocognitive function (NCF) and quality of life (QOL) in patients with brain metastasis. In all such analysis, it is essential to report compliance. In our analysis, 15 patients survived beyond 15 months, and nine of them completed NCF tests (compliance rate 60%).1 For the 4 months' data that Dr Vordermark requested, 124 patients survived beyond 4 months, among whom 63 to 75 patients finished evaluation of different NCF tests, resulting in a compliance rate of 51% to 60%, identical to rates in other trials and also emphasizing the similar compliance rates at 4 and 15 months. In our analysis, only those patients who had NCF test scores at each time point were analyzed for NCF changes. Using delayed recall as an example, we found that among the 124 patients surviving at 4 months, 70 patients (56%) completed it. Among the 54 patients (44%) who did not complete the test, 13 patients (10%) returned for at least one subsequent test. For the 41 patients who did not return for further testing, 16 patients (13%) died before the next test. The most common cause for noncompliance was a missed visit due to low-performance status. For patients who showed up for a visit, the compliance is much higher (eg, we published that 77% to 87% of tests were completed by patients in this trial who had a 6-month visit2). These results are consistent with the notion that in a patient population with poor prognosis, consistently high compliance is difficult to achieve as patients' condition deteriorates over time. As Dr Vordermark pointed out, compliance rates in the range of 80% in patients with brain metastases are unrealistic. Regine et al3 reported in patients with brain tumors (81% with brain metastases) that the overall compliance rate for administration and completion of the five NCF measures and a QOL instrument decreased from 95% at enrollment to 70% 1 month after treatment. Similar compliance rates are seen in other patient populations with metastatic disease. For example, Maughan et al4 found that among the 12-week survivors in a metastatic colon cancer trial, only 43% had valid QOL data at baseline, 6 weeks and 12 weeks. In a similar patient population, compliance at 6 months was 56%.5 Even in a relatively favorable group of patients with localized head and neck cancer treated with curative intent, QOL questionnaire compliance at 12 months was 65% and 75%, respectively, in the two arms of a randomized phase III trial of radiotherapy with or without cetuximab.6 Poor compliance rates constitute a potential limitation with any patient-reported outcome. Patients able to complete the tests and questionnaires may very likely have a better outcome than those who cannot. Although it is impossible to evaluate noncompliant patients, as Dr Vordermark states, reporting the compliance rate certainly aids in interpreting the generalizability of the results. In our study, we followed a fixed cohort of compliant 15-month survivors and showed that these had stable or improving NCF scores over time. We believe that this is a valid and important observation, adding to the literature on the trade-off between disease control on one hand and normal tissue effects of whole brain irradiation on the other. Any strategy that improves compliance is critical in studying the true NCF changes in patients with brain metastasis. A pilot study preceding our trial reported high patient acceptance and compliance rate.7 Although it was a small study with short follow-up, it suggested that higher compliance is possible, perhaps through test-simplification. However, this could result in reduced sensitivity for detecting subtle NCF changes, and could also weaken the results from the possible learning effects of repeated testing relying on a simplified test. Strategies such as home-based testing, telephone follow-up, Internet forms, caregiver input, and so on are being used to improve compliance. Ultimately, the challenges in assessing and analyzing NCF and QOL data in this patient population do not detract from the huge clinical relevance of these end points. Some data analytic strategies, like the ones used in our study, are less prone to problems with interpretation of study findings and should be considered in future trials. 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. Employment or Leadership Position: Markus Renschler, Pharmacyclics (C) Consultant or Advisory Role: Minesh P. Mehta, Schering-Plough (C), Pharmacyclics (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Li J, Bentzen SM, Renschler M, et al: Regression after whole-brain radiotherapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 25:1260-1266, 2007 2. Meyers CA, Smith JA, Bezjak A, et al: Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: Results of a randomized phase III trial. J Clin Oncol 22:157-165, 2004 3. Regine WF, Schmitt FA, Scott CB, et al: Feasibility of neurocognitive outcome evaluations in patients with brain metastases in a multi-institutional cooperative group setting: Results of Radiation Therapy Oncology Group trial BR-0018. Int J Radiat Oncol Biol Phys 58:1346-1352, 2004[CrossRef][Medline] 4. Maughan TS, James RD, Kerr DJ, et al: Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: A multicentre randomised trial. Lancet 359:1555-1563, 2002[CrossRef][Medline] 5. Wietzke-Braun P, Schindler C, Raddatz D, et al: Quality of life and outcome of ultrasound-guided laser interstitial thermo-therapy for non-resectable liver metastases of colorectal cancer. Eur J Gastroenterol Hepatol 16:389-395, 2004[CrossRef][Medline] 6. Curran D, Giralt J, Harari PM, et al: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25:2191-2197, 2007 7. Herman MA, Tremont-Lukats I, Meyers CA, et al: Neurocognitive and functional assessment of patients with brain metastases: A pilot study. Am J Clin Oncol 26:273-279, 2003[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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