First-line chemotherapeutic treatment for oligodendroglioma, WHO grade 3—PCV or temozolomide? Free

Oligodendrogliomas, WHO grade 3, are rare primary brain tumors that account for only 1.7% of diffuse glioma in adults.¹ On a molecular level, oligodendrogliomas are defined by an isocitrate dehydrogenase (IDH) mutation and a full loss of the short arm of chromosome 1 and a full loss of the long arm of chromosome 19 (1p/19q co-deletion).² Patients with oligodendrogliomas have a better prognosis than those with astrocytomas, in part because these tumors exhibit unique and predictable chemosensitivity. Following surgery, initial management of oligodendroglial tumors incorporates chemotherapy with radiotherapy, but controversy surrounds which of two standard chemotherapeutic regimens, procarbazine, CCNU (ie, lomustine), and vincristine (PCV) chemotherapy or temozolomide, is superior. The definitive answer to this question will be determined by the outcome of the CODEL trial (NCT00887146). This phase III trial randomizes patients with oligodendrogliomas, WHO grade 3, to radiotherapy with concurrent and adjuvant temozolomide or radiotherapy with adjuvant PCV chemotherapy. Since long-term follow-up data are necessary to answer this question, results are not expected soon. In the absence of these data, some prospective and retrospective studies are helpful in evaluating the “better” chemotherapy. However, major limitations of these studies include the inclusion of patients diagnosed with oligodendrogliomas without confirmation of 1p/19q co-deletion, and various biases that influence which treatment is administered.

Two landmark phase III randomized controlled trials studied the effect of adding PCV to radiotherapy in patients with a grade 3 oligodendroglioma. Both the EORTC-26951 (n = 368) and the RTOG-9402 (n = 291) showed that adding PCV chemotherapy to radiotherapy gave a statistically significant longer progression-free survival (PFS), but a similar overall survival (OS) compared to radiotherapy alone.^3,4 Two other smaller trials (n = 20-62) studied the effect of upfront temozolomide in oligodendroglioma, WHO grade 3, deferring radiotherapy until progression.^5,6 Surprisingly, in these trials, survival approached what was found in combined chemoradiation. Only one prospective phase III study randomized patients between radiotherapy alone vs chemotherapy alone, and those randomized to chemotherapy, were treated with PCV or temozolomide.⁷ Although this study was not designed or powered to evaluate a difference in efficacy between these chemotherapeutic regimens, survival was slightly better in those treated with PCV. Additionally, up to 65% had grade 3 or grade 4 toxicities on PCV and 33% had to discontinue PCV chemotherapy earlier. In comparison, in those treated with temozolomide, just up to 39% of the patients grade 3 or grade 4 toxicities and no more than 10% had to discontinue treatment for reasons of toxicity.^3,4,7

In this edition of Neuro-Oncology Practice, Lamba et al describe a large nationwide retrospective cohort of patients with oligodendrogliomas, WHO grade 3. Only patients with a glioma that had histological features of oligodendroglioma and had a 1p/19q co-deletion were included. In addition, all had received radiotherapy and chemotherapy, either PCV or temozolomide.⁸ Over a time span of 9 years, 1414 patients diagnosed between 2010 and 2018 were extracted from the National Cancer Database (NCDB) in the United States. Patients were treated in 445 different centers. After a median follow-up of 3 years, 63.3% was still alive at the time of analysis. The unadjusted 5-year OS was significantly better for those treated with PCV (65.1%, 95% confidence interval 54.8-73.5) than for those treated with temozolomide (58.9%, 95% confidence interval 55.6-62.0, P = .04). However, after adjusting for known prognostic factors, such as age and extent of resection, there was no difference in OS between those treated with PCV and those treated with temozolomide (hazard ratio 0.81, 95% confidence interval 0.59-1.11, P = .18).

The results of Lamba et al are supported by another large (n = 1000) international multicenter retrospective series compared PCV chemotherapy with temozolomide in patients with anaplastic oligodendrogliomas.⁹ Not surprisingly, this study reported that survival was better for those treated with combined chemotherapy and radiotherapy than those treated with chemotherapy alone or radiotherapy alone. Similar to Lamba et al, after a follow-up of 5 years, for those treated with combined chemotherapy and radiation therapy, there was no difference in survival between those treated with PCV and those treated with temozolomide in PFS (P = .26) and OS (P = .62). The study reported by Lassman et al did not report treatment-related toxicity. In both retrospective studies, follow-up was short for a disease that is associated with a median survival that approaches 15 years. Consequently, long-term survival comparisons between the regimens cannot be determined from a review of these data.

Considering the above mentioned retrospective and prospective studies, PCV chemotherapy, compared to temozolomide, appears to furnish and improve PFS, but the OS is similar. However, despite greater published evidence for the use of PCV, temozolomide seems to be used more often in clinical practice, with reports over the last decade indicating that 71%-88% of patients with anaplastic oligodendrogliomas received temozolomide as front-line chemotherapy.^8,9 Reasons underpinning this observed preference for temozolomide include an oral formulation and excellent toxicity profile, including low risk of cumulative and prolonged myelosuppression. Temozolomide use in IDH-mutant gliomas has been reported to increase the incidence of an hypermutator phenotype. This phenomenon has not tempered the use of temozolomide as there is no clear evidence of detrimental impact on OS and overall efficacy.¹⁰ When chosen, PCV chemotherapy is more commonly prescribed to younger patients. In the study reported by Lamba et al, the median age of patients receiving PCV chemotherapy was 48 years vs 52 years for temozolomide, P = .008.⁸

The most recent guidelines from the European Association of Neuro-Oncology (EANO) and the American Society of Oncology (ASCO)/Society of Neuro-Oncology (SNO) recommend maximal safe surgical resection followed by radiotherapy and PCV chemotherapy for patients with an oligodendroglioma, 1p/19q co-deleted, WHO grade 3. Temozolomide is considered a reasonable alternative if there are potential concerns of PCV-related toxicity or intolerability.^11,12 Despite these recommendations favoring PCV chemotherapy, temozolomide appears to be the more commonly used first-line regimen. Although limited, the available evidence suggests that this approach is as efficacious and less toxic than PCV chemotherapy.

Conflict of interest statement. None.

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