Clinical investigation: brain
Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas

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Abstract

Introduction: Allelic loss of the short arm of chromosome 1 predicts radiographic response to chemotherapy and long overall survival times in patients with anaplastic oligodendrogliomas. Using a database of patients with oligodendrogliomas in whom chromosome 1p status was known, we explored whether allelic loss of 1p also predicted longer duration of tumor control when radiotherapy was part of the initial treatment of these patients.

Materials and Methods: We measured progression-free survival following radiotherapy in a cohort of patients with World Health Organization (WHO) Grade II and WHO Grade III oligodendrogliomas. The effects on progression-free survival of patient age, Karnofsky performance score (KPS), tumor grade when irradiated and chromosome 1p status were examined by univariate and multivariate statistical analyses. For the subset of patients with newly diagnosed anaplastic oligodendrogliomas, relationships between use of chemotherapy, chromosome 1p status and progression-free survival were also examined.

Results: Fifty-five patients (29 male, 26 female; ages 18–75 years; median, 44 years; KPS 50–90, median 80) were irradiated for either a WHO Grade II (n = 19) or Grade III (n = 36) oligodendroglioma. Twenty-eight patients had chemotherapy immediately prior to radiotherapy, and 27 had chemotherapy at progression following radiotherapy. The median radiation dose was 54 Gy in 30 fractions. Loss of heterozygosity (LOH) at chromosome 1p was evident in 36 tumors and absent in 19. Overall median progression-free survival after radiotherapy was 40.4 months. Median progression-free survival was 55.0 months for patients whose tumors harbored 1p loss vs. 6.2 months for those patients whose tumors retained both copies of chromosome 1p (p < 0.001). On both univariate and multivariate analyses, chromosome lp loss was the principal independent predictor of longer progression-free survival for patients with Grade II and III oligodendrogliomas. For Grade III oligodendrogliomas, chemotherapy as an adjunct to radiotherapy prolonged tumor control for those patients whose tumors harbored allelic loss of chromosome 1p (p = 0.004).

Conclusion: These data suggest allelic loss of chromosome 1p in patients with oligodendroglial neoplasms predicts longer progression-free survival among patients receiving radiotherapy ± chemotherapy as part of their initial treatment. Chromosome 1p loss may be an important stratification variable in future therapeutic trials of oligodendroglioma.

Introduction

Oligodendrogliomas are primary neoplasms of the central nervous system thought to arise from the oligodendrocyte or a precursor cell committed to oligodendroglial differentiation. Oligodendrogliomas comprise at least 5–10% of all the glial tumors that occur in adult patients with some reports suggesting that up to 25% of gliomas may be oligodendroglial in derivation (1). Accurate diagnosis of oligodendrogliomas is an important issue in clinical neurooncology (2) because overall survival and response to treatment may be substantially better for patients with oligodendroglial neoplasms. Recently, molecular markers of oligodendrogliomas have been identified, which may supplement the traditional histologic diagnosis of these tumors. In particular, allelic loss of chromosome 1p has emerged as an important molecular signature of oligodendrogliomas, occurring in 50–70% of both low-grade and anaplastic tumors (3). Anaplastic oligodendrogliomas may also demonstrate losses of chromosomes 9p, 10q, and 19q as well as TP53 gene mutations, although these molecular alterations are not specific to oligodendroglial neoplasms (4).

An oligodendroglial component in either a low- or high-grade glioma generally predicts longer progression-free and overall survival for patients with such lesions 5, 6. These analyses have included both irradiated and nonirradiated cases. It has also been demonstrated that anaplastic oligodendrogliomas may be remarkably chemosensitive. For unknown reasons, oligodendrogliomas often respond dramatically to a combination chemotherapy regimen that includes procarbazine, lomustine, and vincristine, called PCV (7). Moreover, response to PCV may be a predictable occurrence. Allelic loss of chromosome 1p has been associated with high radiographic response rates and long survival times for patients with anaplastic oligodendrogliomas receiving this nitrosourea-based chemotherapy regimen (4). In the present study, we sought to determine whether chromosome 1p status was predictive of tumor control among patients who received radiotherapy as part of their treatment for an oligodendroglial tumor.

Section snippets

Clinical material

Cases in this report were retrieved from a database of patients who had received chemotherapy for an oligodendroglial neoplasm at a regional cancer centre in Canada from 1985 to 1998. Only patients in the database whose tumors had been irradiated and also examined for allelic loss of chromosome 1p were selected for this analysis. The histologic diagnosis of oligodendroglioma was confirmed on central pathology review by one of the authors (D.N.L.). The tumors were graded using the World Health

Results

Fifty-five patients from the database met the eligibility requirements for this analysis. There were 29 male patients and 26 female patients with a median age at diagnosis of 44 years (range, 18–75 years). At the time of radiation, their median Karnofsky performance score was 80 (range, 50–90). Tumor grade at the time of radiation was Grade II in 19 instances and Grade III in 36. Chemotherapy was administered at tumor progression following radiotherapy in 27 patients; 19 of the 27 had

Discussion

Patients with oligodendroglial tumors are more likely to respond to contemporary chemotherapies than are patients with astrocytic tumors (11). Patients with oligodendrogliomas are also more likely to enjoy longer progression-free and overall survival times following treatment than are patients with astroglial neoplasms of comparable grade 5, 6, 12. These more favorable characteristics of oligodendrogliomas notwithstanding, there remains considerable heterogeneity in clinical outcomes among

Acknowledgements

The authors wish to thank Jacqueline Robertson for her secretarial support with the manuscript.

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