Treating Anaplastic Oligodendrogliomas and WHO Grade 2 Gliomas: PCV or Temozolomide? The Case for Temozolomide

In 2013, the results of two prospective phase III studies evaluating procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy with radiation therapy (RT) in patients with newly-diagnosed anaplastic oligodendrogliomas suggested that the addition of chemotherapy significantly prolonged survival.[1,2] In Radiation Therapy Oncology Group (RTOG) trial 9402, anaplastic oligodendroglioma patients with 1p/19q codeletion who received 4 cycles of intensive PCV (CCNU 130 mg/m² orally on day 1; procarbazine 75 mg/m² orally daily on days 8 through 21; and vincristine 1.4 mg/m² intravenously on days 8 and 29) followed by RT had a significantly longer survival-14.7 years, compared with 7.3 years for those who received RT alone.[1] However, there was no improvement in median survival in patients with noncodeleted tumors who received PCV/RT. Similar results were reported for European Organisation For Research and Treatment of Cancer (EORTC) trial 26951, which compared RT followed by 6 cycles of standard-dose PCV vs RT alone.[2] In this study, median overall survival was not reached in the RT/PCV group, compared with 112 months in the RT group (hazard ratio, 0.56; 95% confidence interval, 0.31–1.03).[2]

More recently, RTOG 9802 showed that the addition of PCV chemotherapy to RT improved median survival to 13.3 years (compared with 7.8 years with RT alone) in patients with “high-risk” grade II gliomas, defined as gliomas occurring in patients who receive less than gross total tumor resection or who are > 40 years of age.[3] These three studies established RT + chemotherapy as the standard of care for patients with newly diagnosed grade III anaplastic oligodendrogliomas or “high-risk” grade II gliomas.

Since there is level 1 evidence for PCV, should this be the standard chemotherapy?[4]

Prior to the results of these studies becoming available, most neuro-oncologists in North America had replaced PCV with TMZ, which is less toxic and which, in conjunction with RT, had shown greater efficacy than RT alone for glioblastomas.[5] The ongoing intergroup “CODEL” trial (National Clinical Trials Identifier NCT00887146)-which directly compares RT followed by PCV vs RT with concurrent and adjuvant TMZ vs TMZ alone-will address the relative effectiveness of the two therapies, but these results will not be available for many years. In the meantime, patients should probably be treated with the much better tolerated TMZ.

There is no definitive evidence that PCV is more effective than TMZ for gliomas. In the Medical Research Council (MRC) Brain Tumor Working Group study, the addition of PCV chemotherapy to RT did not improve survival in patients with newly diagnosed high-grade gliomas compared with RT alone.[6] Although most patients had glioblastomas, 17% (113 patients) had anaplastic gliomas. PCV did not produce a survival advantage in this subgroup. In contrast, the EORTC/National Cancer Institute of Canada (NCIC) trial showed that the addition of TMZ to RT in patients with newly diagnosed glioblastoma significantly increased median survival by 2.6 months.[5] Similarly, in the MRC Clinical Trials Unit BR12 study comparing TMZ with PCV in patients with recurrent high-grade gliomas, including 103 patients with grade 3 gliomas, there was no survival advantage for PCV.[7] There was also no difference in time to treatment failure between PCV and TMZ in the Neuro-Oncology Working Group of the German Cancer Society (NOA)-04 trial in anaplastic gliomas,[8] although the numbers were relatively small and the study was not powered to compare the two regimens. These data suggest that TMZ is more effective than PCV for glioblastoma, and while the relative efficacy of the two agents in anaplastic oligodendrogliomas is unknown, there is no clear evidence supporting a greater benefit for PCV.

The PCV regimen is undoubtedly more toxic than TMZ. In the RTOG study that utilized the intensive PCV regimen, 65% of patients experienced grade 3/4 toxicities,[1] while in the EORTC trial, 32% of patients had grade 3 and 15% had grade 4 hematologic toxicity.[2] Overall, 38% of patients in the PCV arm of the EORTC trial discontinued therapy because of toxicity. Moreover, the marrow suppression in some patients was long-lasting, potentially reducing the possibility of administering full-dose chemotherapy at recurrence. In contrast, in the EORTC/NCIC trial of TMZ + RT for newly diagnosed glioblastoma, only 16% of patients experienced grade 3/4 hematologic toxicities.[5] Similarly low rates of toxicity have been reported in more recent trials involving TMZ.[9,10]

There is evidence that not all the components of PCV cross the blood-brain barrier. Although lomustine and procarbazine probably do achieve adequate intratumoral concentrations in gliomas, vincristine does not appear to cross the blood-brain barrier.[11] If this regimen were developed today, vincristine would not be included; it is unlikely to contribute to the efficacy of the regimen and undoubtedly adds toxicity.

It is currently unknown whether patients with anaplastic oligodendrogliomas benefit more from PCV than from TMZ. There is no evidence that PCV is more effective than TMZ for the treatment of glioblastoma. However, there is unequivocal evidence that PCV is more toxic than TMZ, and there are data suggesting that the vincristine component probably does not pass through the blood-brain barrier. Unless the CODEL trial shows that PCV is superior to TMZ, patients with anaplastic oligodendrogliomas can reasonably be treated with RT and TMZ.

Financial Disclosure:Dr. Wen receives speaker fees from Merck. Dr. Rinne has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337-43.

2. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344-50.

3. Buckner JC, Pugh SL, Shaw EG, et al. Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG. J Clin Oncol. 2014;32(suppl 5):abstr 2000.

4. Villano JL, Wen PY, Lee EQ, et al. PCV for anaplastic oligodendrogliomas: back to the future or a step backwards? A point/ counterpoint discussion. J Neuro-Oncol. 2013;113:143-7.

5. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-96.

6. Medical Research Council Brain Tumour Working Party randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001;19:509-18.

7. Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol. 2010; 28:4601-8.

8. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27:5874-80.

9. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699-708.

10. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709-22.

11. Boyle FM, Eller SL, Grossman SA. Penetration of intra-arterially administered vincristine in experimental brain tumor. Neuro Oncol. 2004;6:300-5.