Radiation plus PCV chemotherapy may become 
standard of care for anaplastic oligodendrogliomas

Antonio Omuro, MD

This is an important study that, along with RTOG study 9402, finally provides proof-of-concept that oligodendroglial tumors benefit from chemotherapy. The concept that anaplastic oligodendrogliomas are chemosensitive tumors is not new, dating back to the 1990s. However, preliminary results of both RTOG 9402 and EORTC 26951 studies, published in the 2000s, suggested that the addition of chemotherapy improved PFS but not OS in these tumors. At the time, the lack of survival benefit was explained by the fact that salvage chemotherapy was as effective as upfront chemotherapy. Finally, mature data from both of those studies suggest that the timing of chemotherapy does matter, and it is no longer appropriate to treat these tumors with radiotherapy alone. However, how to apply results from these trials — initiated almost 20 years ago — to current practice remains an open question.

PCV is a highly toxic chemotherapy. While data from these studies were maturing, the use of temozolomide became increasingly popular, boosted by the positive results observed in glioblastoma, a tumor in which PCV failed to improve outcomes. Moreover, the use of temozolomide without radiotherapy also has been suggested as a potential alternative in an attempt to avoid radiotherapy-related long-term neurotoxicity, a problem with particular relevance in this glioma subtype because many patients survive long enough to experience delayed radiotherapy effects.

Unfortunately, the use of temozolomide has not been prospectively validated. The only randomized study properly investigating this agent in 1p/19q deleted anaplastic oligodendroglioma will have to be redesigned, given that the proposed control arm was radiotherapy alone, without PCV. Moreover, long-term follow-up and mature data clearly are essential for sound conclusions.

Will the community wait another 15 years to know the answer and go back to PCV in the meantime? Only time will tell. Given the fast pace at which molecular characterization of these tumors is evolving, it is not implausible that by the time current studies are finally reported, other more attractive therapeutic options will be available. The discovery of IDH-1 mutations as an early and important event driving tumorigenesis in this glioma subtype has provided important insights and opened a whole new venue for investigation.

The bottom line is that we learned chemotherapy works in this disease, but as of now the optimal treatment remains controversial, with no standard of care established. In this situation, the best we can do is to make every effort to enroll patients in clinical trials to expedite completion of accrual and get our answers earlier.

Roger J. Packer, MD

The management of adult malignant gliomas remains highly problematic. Of all the subtypes of high-grade gliomas in adults, the one tumor subtype with the best responsiveness to treatment has been oligodendrogliomas. Groundbreaking work by Cairncross and colleagues 2 decades ago demonstrated that these tumors, at the time of recurrence, were responsive to treatment with procarbazine, lomustine and vincristine (Cairncross G. J Clin Oncol. 1994;12:2013-2021). Since that time, temozolomide has also been shown to be an effective agent. However, it has been difficult to prove that this sensitivity to alkylating agents can be translated into improvements in OS in newly diagnosed patients and, furthermore, what — if any — parameters are predictive of response to treatment.

Relatively large, prospective randomized trials have been undertaken, both in North America and in Europe, to determine the efficacy of adjuvant chemotherapy with the PCV regimen in newly diagnosed patients following surgery and local radiotherapy. Initial analysis of both studies demonstrated an increase in PFS but could not clearly show an increase in OS.

Since the completion of these two large randomized trials, there is increasing evidence that the presence of an abnormality of the short arm of chromosome 1 (1p deletion) and the long arm of chromosome 19 (19q deletion) may be predictive of chemotherapy responsivity. Other biomarkers also have been identified that may be associated with improved outcome, including methylation of the methyl-guanine methyl transferase (MGMT) gene promoter and mutations of the isocitrate dehydrogenase (IDH) gene.

The paper by van den Bent and colleagues reporting the long-term follow-up of the European Organization for Research and Treatment of Cancer (EORTC) prospective, randomized oligodendroglioma study provides important clinical information. This study, which follows the cohort of the European study for 10 years, finds that the addition of adjuvant chemotherapy with the three-drug regimen resulted in improved OS as well as PFS. This was independent of a retrospective analysis of a variety of different molecular parameters, including 1p/19q codeletion. However, 1p/19q codeletion was found to be predictive of an even more pronounced response to treatment, and when those patients were separated out from the group as a whole, the benefit of adjuvant chemotherapy was less marked. Overall, survival was also found to be better in patients with methylated MGMT promoter and IDH-mutated tumors; however, on multivariate analysis only, IDH mutation and 1p/19q abnormalities were independently associated with improved outcome.

As the authors suggest, these results make a strong case for radiation plus alkylator therapy as being the standard of care after surgery for anaplastic oligodendrogliomas, especially in 1p/19q codeleted tumors. An argument can be made that temozolomide could be used instead of the three-drug regimen. In patients with recurrent disease, the PCV regimen and the temozolomide treatment were found to be essentially of equal efficacy. The general consensus is that the temozolomide has less short-term toxicity; however, temozolomide has not yet been shown to have equal efficacy as PCV in the adjuvant setting in newly diagnosed patients.

In addition, this extended analysis of the EORTC study demonstrates two other important findings. The first is the importance of utilizing information from well-done prospective studies to its fullest. Given the financial climate, there is pressure to limit follow-up on patients on studies. If the EORTC had decided to stop data capture after 5 years of follow-up, these important new understandings of the treatment of anaplastic oligodendrogliomas would not have been discovered. Second, as a medical community, the field of neuro-oncology is in a molecular era, and analysis of the impact of molecular genetic findings on outcome is crucial to determine the true efficacy of treatment and better understanding of disease.

To date, there is no clear explanation of why 1p19q codeleted tumors should be more responsive to treatment. Clearly, in patients with malignant gliomas, including malignant oligodendrogliomas, work still needs to be done. It is likely that for progress to be made, it will have to be in molecularly defined populations of patients, each with likely different responsivities to therapy. This will be even more important in the analysis of therapies that are "molecularly targeted," which are already well into clinical trials.