Treatment Implications of Chromosomal Analysis in Anaplastic Oligodendrogliomas

ABSTRACT & COMMENTARY

Synopsis: Malignant brain tumors in adults are typically poorly responsive to chemotherapy. However, some patients with oligodendrogliomas respond well to chemotherapy, at times achieving durable complete remissions without the use of radiation therapy. This study reports the experience in 50 patients with histologically diagnosed anaplastic oligodendrogliomas, 48 of whom were treated with PCV chemotherapy. Chromosomal analysis was performed on paraffin-imbedded tissue. Isolated loss of 1p and 19q was associated with a 100% objective response rate in 17 patients. Median duration of response was greater than 31 months and median survival from diagnosis was greater than 123 months in this population. Patients with a loss of 1p who have other chromosomal abnormalities still respond to treatment, but their response durations are not durable. Patients in whom 1p was intact have much lower responses to chemotherapy with median response durations of less than 8 months. It is suggested that therapeutic decisions at the time of diagnosis can be based on the genetic subtype identified.

Source: Ino Y, et al. Clin Cancer Res. 2001;7:839-845.

Malignant gliomas have been classified on the basis of their histological appearance as astrocytomas, oligodendrogliomas, ependymomas, or mixed gliomas. For each type, surgical resection and radiation have typically been the mainstays of treatment. Cytotoxic chemotherapy has played a relatively minor role because responses are typically infrequent and, when they occur, brief. However, patients with oligodendrogliomas are much more likely to have a radiographically documentable response to chemotherapy, and some patients have had dramatic and gratifying long-term durable responses. Histological evaluation of patients with oligodendrogliomas has not provided prognostic criteria to identify those patients likely to respond. Allelic loss of chromosome 1p has been reported to correlate with response to chemotherapy and longer survival.1,2 Patients who lose 19q in addition to losing 1p may have particularly prolonged survival.2 In an effort to further identify biological subtypes by chromosomal analysis, Ino and colleagues, using formalin fixed paraffin embedded sections, carried out analyses for 1p, 19q, 10q, PTEN alteration, CDKN2A deletion, EGFR amplification, and TP53 mutations. Forty-eight of the 50 patients received chemotherapy with PCV. Thirty-four of these patients received radiation after chemotherapy, 5 received radiation concurrent with chemotherapy, and 11 were not irradiated. Median follow-up time from diagnosis was 107 months. Twenty-five patients responded to chemotherapy with 10 being complete responses. Of the 50 patients, 38 had tumors that were evaluable for radiographic response to chemotherapy. Response to chemotherapy was defined as radiographic decrease in tumor size of ³ 50% or the absence of disease progression 6 months after the start of chemotherapy. Four groups were identified. Groups 1 and 2 were characterized by 1p loss, while groups 3 and 4 had 1p intact. Group 1 included those patients whose chromosomal alterations involved only a loss of 1p and 19q. Group 2 included patients with 1p loss and some other genetic alteration. Group 3 included patients with 1p intact but with a TP53 mutation, while group 4 included patients with 1p intact and no TP53 mutation. Response rate and durations of response in groups 1-4 were 100%, 100%, 33%, and 18% and 31 months or longer, 11 months, 7 months, and 5 months, respectively. Ring enhancement was a strong negative predicator for response and segregated with 10q loss, PTEN alteration, CDKN2A deletion, and EGFR amplification as predictors of poor response to chemotherapy. Patients in group 1 typically had durable responses to chemotherapy. Patients in group 2 also responded to chemotherapy, but these responses were less durable. Patients in group 3 responded less frequently, and when they did, responses were of brief duration. Finally, the patients in group 4 seldom responded to chemotherapy and had an extremely poor prognosis.

COMMENT BY MICHAEL J. HAWKINS, MD

This study extends previous work in this area, demonstrating the prognostic significance and therapeutic implications of chromosomal analyses in patients with oligodendrogliomas. Treatment was relatively uniform with all patients initially receiving chemotherapy, with 48 (96%) treated with PCV. The relatively large number of patients with histologically similar tumors that were treated in a similar fashion permitted the definition of 4 distinct groups with differing responses to chemotherapy and/or survival durations. Many patients with isolated 1p, 19q loss were doing well with chemotherapy alone. In this group, with close follow-up, radiation therapy could possibly be delayed until tumor progression is documented. Patients in group 2 also have a high response to chemotherapy, but these responses tend to be less durable and would be expected to benefit from consolidatative or concurrent radiation therapy. Patients in group 3, while having a survival that is similar to those in group 2, tend to respond less well to chemotherapy. Patients in group 4 had particularly aggressive tumors and appeared to receive little or no benefit from PVC chemotherapy.

References

1. Cairncross JG, et al. J Natl Cancer Inst. 1998;90:
1473-1479.

2. Smith JS, et al. J Clin Oncol. 2000;18:636-645.