Clinical investigation: Brain
Importance of the mini-mental status examination in the treatment of patients with brain metastases: a report from the radiation therapy oncology group protocol 91-04

Presented as a Poster at the 40th Annual Meeting of ASTRO, Phoenix, Arizona, October 24–29th, 1998.
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Abstract

Purpose: Little information is available on the importance of pretreatment Mini-Mental Status Exam (MMSE) on long-term survival and neurologic function following treatment for unresectable brain metastases. This study examines the importance of the MMSE in predicting outcome in a group of patients treated with an accelerated fractionation regimen of 30 Gy in 10 daily fractions in 2 weeks.

Materials and Methods: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastases were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. Two hundred twenty-four patients were entered on the accelerated fractionated arm, and 182 were eligible for analysis (7 patients were judged ineligible, no MMSE information in 29, no survival data in 1, no forms submitted in 1).

Results: Average age was 60 years; 58% were male and 25% had a single intracranial lesion on their pretherapy evaluation. KPS was 70 in 32%, 80 in 31%, 90 in 29%, and 100 in 14%. The average MMSE was 26.5, which is the lower quartile for normal in the U.S. population. The range of the MMSE scores was 11–30 with 30 being the maximum. A score of less than 23 indicates possible dementia, which occurred in 16% of the patients prior to treatment. The median time from diagnosis to treatment was 5 days (range, 0–158 days). The median survival was 4.2 months with a 95% confidence interval of 3.7–5.1 months. Thirty-seven percent of the patients were alive at 6 months, and 17% were alive at 1 year. The following variables were examined in a Cox proportional-hazards model to determine their prognostic value for overall survival: age, gender, KPS, baseline MMSE, time until MMSE below 23, time since diagnosis, number of brain metastases, and radiosurgery eligibility. In all Cox model analyses, age, KPS, baseline MMSE, time until MMSE below 23, and time since diagnosis were treated as continuous variables. Statistically significant factors for survival were pretreatment MMSE (p = 0.0002), and KPS (p = 0.02). Age was of borderline significance (p = 0.065) as well as gender (p = 0.074). A poorer outcome is associated with an increasing age, male gender, lower MMSE, and shorter time until MMSE below 23. Improvement in MMSE over time was assessed; 62 patients died prior to obtaining follow-up MMSE, and 30 patients had a baseline MMSE of 30 (the maximum), and, therefore, no improvement could be expected. Of the remaining 88, 48 (54.5%) demonstrated an improvement in their MMSE at any follow-up visit. Lack of decline of MMSE below 23 was seen in long-term survivors, with 81% at 6 months and 66% at 1 year of patients maintaining a MMSE above 23. Analysis of time until death from brain metastases demonstrated that decreasing baseline MMSE (p = 0.003) and primary site (breast vs. lung vs. other p = 0.032) were highly associated with a terminal event.

Conclusion: While gender and perhaps age remain significant predictors for survival, MMSE is also an important way of assessing a patient’s outcome. Accelerated fractionation used in the treatment of brain metastases (30 Gy in 10 fractions) appears to also be associated with an improvement in MMSE and a lack of decline of MMSE below 23 in long-term survivors.

Introduction

Radiation therapy remains the standard treatment for patients with brain metastases, especially those with multiple lesions. Various reports have generally identified age of the patient at the time of treatment as the single most important prognostic factor, although good performance status, absence of systemic disease, complete resection performed, and location of the primary site (such as breast or lung) have also been associated with increased survival. Recently, the Radiation Therapy Oncology Group (RTOG) completed a Phase III comparison of accelerated fractionation (AF) or accelerated hyperfractionation (AH) in the treatment of patients with central nervous system (CNS) metastases. Additional information on the value of performance status as identified by a Mini-Mental Status Examination (MMSE) or Karnofsky Performance Status (KPS) was obtained in these patients and its importance, relative to outcome, is reported here.

Section snippets

Methods and materials

From 1991 to 1995, the RTOG conducted Protocol 91-04. This was a Phase III trial in patients with known CNS metastasis. Prior to initiating patient entry, all participating institutions submitted the protocol design and consent form to their Institutional Review Board for approval. Informed consent was obtained from all patients. Eligibility requirements included proof of an underlying primary tumor with a measurable brain lesion (or lesions) by CT or MRI. Additionally, a KPS of at least 70 and

Results

This study accrued a total of 445 patients between October of 1991 and September of 1995. Sixteen patients were either ineligible or not analyzable: 9 were ineligible, 1 canceled, 2 were awaiting submission of appropriate forms, and 4 had no on-study forms. Two hundred twenty-four patients received accelerated fractionation. For this analysis, all patients had to be eligible according to the protocol guidelines and have treatment and survival data. Patients without pretreatment MMSE were also

Discussion

Multiple other studies have demonstrated the poor outcome usually expected in patients with CNS metastasis. Previous RTOG studies have explored a series of different fractionation schedules. The initial experience utilizing various accelerated-fractionation regimens was summarized by Borgelt et al. (4). Four treatment regimens consisting of 40 Gy in 4 weeks, 40 Gy in 3 weeks, 30 Gy in 3 weeks, or 30 Gy in 2 weeks were reviewed. The overall response to treatment was equivalent among all of the

Conclusions

Long-term survival of selected patients with CNS metastases is 17% at 1 year and 5% at 2 years after treatment with 30 Gy in 10 fractions in 2 weeks. Studies attempting to improve upon these results through the use of radiosensitizers, radioprotectors, or stereotactic radiosurgery are currently ongoing.

Although gender and age may be predictors of survival, KPS and MMSE are also highly correlated with outcome.

MMSE and primary site remain important determinants of time until death from CNS

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This paper was supported by grants CA21661 and Ca32115 from the National Cancer Institute and from funding through Pharmacyclics Inc. Its contents are solely the responsibility of the authors and do not necessarily represent the views of the National Cancer Institute or Pharmacyclics Inc.

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