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

April 15, 2015

In most cases, PCV chemotherapy will provide an edge in outcomes over TMZ for glioma patients, primarily because of the former regimen’s use of multiple drugs and their complementary interactions.

Rationale for the PCV Combination

The combination chemotherapy regimen PCV is an acronym for the three drugs that comprise it-procarbazine, CCNU (or lomustine), and vincristine-and was developed based on clinical experience with these three drugs,[1] and on experimental rodent studies.[2,3] The main drug in PCV is CCNU, a DNA cross-linking alkylating agent that readily crosses the intact blood-brain barrier[4] and that has been effective both as a single agent and in combination with procarbazine and vincristine in the treatment of low- and high-grade gliomas.[5-7]

Procarbazine is also an alkylating agent and biotranforms to an azoxy intermediate that activates methyl- and benzyl-carbonium ions.[8] It has antitumor activity against a variety of cancers, but, like all monofunctional alkylating agents, does have carcinogenic and mutagenic properties.[9,10] In addition, the monofunctional (single-strand) DNA adducts produced by procarbazine have been shown to potentiate nitrosourea (BCNU [carmustine], CCNU) cytotoxicity and DNA cross-linking in glioma cell lines.[11,12]

Vincristine is a vinca alkaloid that binds to the microtubular proteins of the mitotic spindle, leading to mitotic arrest and cell cycle phase-specific cell death. Unlike CCNU and procarbazine, which readily cross the blood-brain barrier, vincristine is highly restricted in its blood-brain barrier penetration.[13,14] Thus, its use in the treatment of gliomas has been somewhat problematic for me and others. Nonetheless, vincristine remains a constant in the PCV combination, most likely because it is given only twice in a 6-week course-and because it will penetrate some regions of infiltrative tumor, albeit not as well as CCNU or procarbazine.

PCV has been in wide use throughout most of the Western Hemisphere and Europe for decades, and thus has figured prominently in clinical trials of all grades of gliomas. Efficacy has been shown for PCV against glioblastoma,[15-18] anaplastic astrocytoma,[19] and anaplastic oligodendroglioma,[19,20] as well as against astrocytoma and oligodendroglioma.[20-22]

The Appeal of Temozolomide

With the advent of temozolomide (TMZ) and its use in the treatment of gliomas, a new opportunity arose for patients and physicians. TMZ is a methylating and monofunctional alkylating agent.[23] Like procarbazine, it has carcinogenic and mutagenic potential. What differentiated TMZ from CCNU and procarbazine was the fact that TMZ was well tolerated by patients. It produced nausea/vomiting in only about 50% of patients, and it had very predictable myelosuppression, allowing treatment on a number of schedules-in particular, the commonly used 5-days-every-28-days schedule-with modest myelosuppression.[24,25] In all trials, TMZ was found to be active against gliomas of all stages.[26-41] In addition, clinical investigators liked TMZ because it was relatively easy to prescribe, it had predictable toxicity, and patients had few side effects compared with PCV.

PCV is more toxic than TMZ at several levels. PCV is toxic to blood-forming stem cells, leading to unpredictable myelosuppression and nadir count durations, and thus making it hard to adhere to a 6-week treatment course. In addition, CCNU and procarbazine are both highly emetogenic and require strong antinausea medication to control vomiting. Procarbazine is also likely to produce anorexia over the course of multiple therapies. This has made administration of PCV at times difficult, and has led many physicians to limit the number of courses and, at times, to discontinue therapy earlier than planned.

TMZ treatment, on the other hand, has been continued for a year, and in some cases 2 years. My personal preference is not to use a methylating agent like TMZ for more than 1 year, and even this may be too long, as methylating agents are highly carcinogenic and apt to lead to mutations and second malignancies. Indeed, TMZ has been implicated in hypermutation and glioma stage transformation.[42]

So why use TMZ? It would clearly be illogical to think that TMZ, a methylating agent, would be superior to a drug combination that includes a cross-linking ethylating and carbamoylating drug, a methylating and benzylating drug, and a drug directed at mitotic spindles and cell division. The attraction of TMZ is the possibility it provides of offering 12 treatment courses (of 4 weeks each) in a year, as opposed to only 6 or 7 courses (of 6 to 8 weeks each) of PCV in a year. In addition, patients receiving PCV generally feel more fatigued and anorexic than those receiving TMZ. But is that enough of a difference to prefer TMZ over PCV for many gliomas?

Let’s Look at Outcomes

What is the value of PCV as compared with TMZ in the treatment of anaplastic oligodendrogliomas? Our metric is overall survival (OS) and, to a lesser extent, progression-free survival (PFS) and quality of life. We therefore must look to randomized studies for these answers. In a 2008 Cochrane meta-analysis, Quon and Abdulkarim found that PCV chemotherapy in addition to standard treatment of surgery and radiotherapy (RT) did not improve OS in patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas but did improve PFS.[43] On the other hand, in a prospective randomized European Organisation for Research and Treatment of Cancer (EORTC) trial of 388 patients randomized to either RT or RT + PCV, it was shown that the addition of 6 cycles of PCV after 59.4 Gy of RT increased both OS and PFS in anaplastic oligodendroglial tumors.[44] In a parallel Radiation Therapy Oncology Group (RTOG) study, 291 patients were randomized to either RT or RT + PCV; the researchers found no difference in median survival between the two treatment groups (4.6 years for PCV + RT vs 4.7 years for RT). However, patients with chromosome 1p/19q codeleted tumors who were treated with PCV + RT lived longer than patients with codeleted tumors who were treated with RT alone (14.7 vs 7.3 years, respectively).[45]

Although TMZ has not been as extensively studied in anaplastic oligodendroglioma populations (since patients with chromosome 1p/19q codeletion do better with alkylating agents), one would assume that TMZ would control tumor growth as does PCV. Whether differences in tumor cell kill between the two therapies lead to shorter PFS or OS is a subject of study. In an open-label study of TMZ in 36 anaplastic oligodendroglioma patients with chromosome 1p/19q codeletion who were treated with pre-irradiation TMZ followed by TMZ during radiation, the PFS was 2.4 years.[46] Regarding the Neuro-Oncology Working Group of the German Cancer Society (NOA) study NOA-04, a multi-arm randomized European trial of 274 patients with anaplastic gliomas, Wick et al judged that no appreciable difference between adjuvant TMZ and PCV could be observed.[47] More conclusive studies are needed to determine whether the differences between these therapies will be deemed sufficient to justify the use of the more toxic PCV.

For low-grade gliomas, many clinicians, when they feel compelled to treat with chemotherapy, will use TMZ instead of PCV. This may change, based on mature analysis of the long-ongoing RTOG 9802 study (median follow-up, 11.9 years) of 251 eligible patients with low-grade gliomas (astrocytoma, oligoastrocytoma, and oligodendroglioma) who were randomly assigned to either 54-Gy RT or RT with adjuvant PCV (up to 6 courses). This study showed a PFS gain (median PFS, 4.0 vs 10.4 years; P = .002) and an OS gain (median OS, 7.8 vs 13.3 years; P =.03) for the RT-followed-by-PCV arm.[21,48] The researchers concluded that for grade 2 glioma patients > 40 years of age, and for those who receive less than gross total tumor resection, post-irradiation adjuvant PCV prolongs both OS and PFS, but that patients with astrocytoma or astrocytoma-dominant oligoastrocytoma and males have worse outcomes. At this time, there is no similar study of TMZ in this patient population available for comparison.


In most cases, PCV chemotherapy will provide an edge in outcomes over TMZ for glioma patients, primarily because of the former regimen’s use of multiple drugs and their complementary interactions. On the other hand, for some patients, especially those with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, TMZ may offer a viable chemotherapy option, although it is far from ideal. Thus, I suspect that most neuro-oncologists have had patients who were treated with TMZ and did very well. The greater problem in the neuro-oncology community is the abject failure of the pharmaceutical industry and academia to discover and develop new types of anticancer therapies for glioma patients.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


1. Gutin PH, Wilson CB, Kumar AR, et al. Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors. Cancer. 1975;35:1398-404.

2. Levin VA, Wilson CB. Correlations between experimental chemotherapy in the murine glioma and effectiveness of clinical therapy regimens. Cancer Chemother Pharmacol. 1978;1:41-8.

3. Levin VA, Edwards MS, Wright DC, et al. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980;64:237-44.

4. Montgomery JA. Chemistry and structure-activity studies of the nitrosoureas. Cancer Treat Rep. 1976;60:651-64.

5. Levin VA, Hoffman WF, Pischer TL, et al. BCNU-5-fluorouracil combination therapy for recurrent malignant brain tumors. Cancer Treat Rep. 1978;62:2071-6.

6. Levin VA, Prados MD. Treatment of recurrent gliomas and metastatic brain tumors with a polydrug protocol designed to combat nitrosourea resistance. J Clin Oncol. 1992;10:766-71.

7. Goerne R, Bogdahn U, Hau P. Procarbazine-a traditional drug in the treatment of malignant gliomas. Curr Med Chem. 2008;15:1376-87.

8. Weinkam RJ, Shiba DA. Metabolic activation of procarbazine. Life Sci. 1978;22:937-45.

9. Weiss HD, Walker MD, Wiernik PH. Neurotoxicity of commonly used antineoplastic agents (first of two parts).N Engl J Med. 1974;291:75-81.

10. Ogawa K, Hiraku Y, Oikawa S, et al. Molecular mechanisms of DNA damage induced by procarbazine in the presence of Cu(II). Mutat Res. 2003;539:145-55.

11. Meer L, Schold SC, Kleihues P. Inhibition of the hepatic O6-alkylguanine-DNA alkyltransferase in vivo by pretreatment with antineoplastic agents. Biochem Pharmacol. 1989;38:929-34.

12. Mineura K, Izumi I, Kuwahara N, Kowada M. O6-methylguanine-DNA methyltransferase activity in cerebral gliomas. A guidance for nitrosourea treatment? Acta Oncologica. 1994;33:29-32.

13. Levin VA, Landahl HD, Freeman-Dove MA. The application of brain capillary permeability coefficient measurements to pathological conditions and the selection of agents which cross the blood-brain barrier. J Pharmacokinet Biopharm. 1976;4:499-519.

14. Levin VA. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem. 1980;23:682-84.

15. Levin VA, Silver P, Hannigan J, et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990;18:321-4.

16. Levin VA, Uhm JH, Jaeckle KA, et al. Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. Clin Cancer Res. 2000;6:3878-84.

17. Jeremic B, Jovanovic D, Djuric LJ, et al. Advantage of post-radiotherapy chemotherapy with CCNU, procarbazine, and vincristine (mPCV) over chemotherapy with VM-26 and CCNU for malignant gliomas. J Chemother. 1992;4:123-26.

18. Kappelle AC, Postma TJ, Taphoorn MJ, et al. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology. 2000;56:118-20.

19. Levin VA, Hess KR, Choucair A, et al. Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. Clin Cancer Res. 2003;9:981-90.

20. Van den Bent M, Hoang-Xuan K, Brandes AA, et al. Long-term follow-up results of EORTC 26951: a randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodenrogliomal tumors (AOD). J Clin Oncol. 2012;30:

21. 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;32:5s.

22. Lebrun C, Fontaine D, Bourg V, et al. Treatment of newly diagnosed symptomatic pure low-grade oligodendrogliomas with PCV chemotherapy. Eur J Neurol. 2007;14:391-8.

23. Clark AS, Stevens MF, Sansom CE, Schwalbe CH. Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA. Anti-cancer Drug Des. 1990;5:63-8.

24. Brada M, Moore S, Judson I, et al. A phase I study of SCH 52365 (temozolomide) in adult patients with advanced cancer. Proc Am Soc Clin Oncol. 1995;14:A1521.

25. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83:588-93.

26. Friedman HS, Dolan ME, Pegg AE, et al. Activity of temozolomide in the treatment of central nervous system tumor xenografts. Cancer Res. 1995;55:2853-7.

27. Bower M, Newlands ES, Bleehen NM, et al. Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol. 1997;40:484-8.

28. Friedman HS, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000;6:2585-97.

29. Schwenka J, Ignoffo RJ. Tomozolomide-a new option for high-grade astrocytomas. Cancer Pract. 2000;8: 311-3.

30. Yung WK. Temozolomide in malignant gliomas. Semin Oncol. 2000;27(3 suppl 6):27-34.

31. Brandes AA, Ermani M, Basso U, et al. Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study. Ann Oncol. 2001;12:255-7.

32. Macdonald DR. Temozolomide for recurrent high-grade glioma. Semin Oncol. 2001;28(4 suppl 13):3-12.

33. van den Bent MJ, Keime-Guibert F, Brandes AA, et al. Temozolomide chemotherapy in recurrent oligodendroglioma. Neurology. 2001;57:340-2.

34. Groves MD, Puduvalli VK, Hess KR, et al. Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. J Clin Oncol. 2002;20:1383-8.

35. Lashford LS, Thiesse P, Jouvet A, et al. Temozolomide in malignant gliomas of childhood: a United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. J Clin Oncol. 2002;20:4684-91.

36. Brada M, Viviers L, Abson C, et al. Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol. 2003;14:1715-21.

37. Quinn JA, Reardon DA, Friedman AH, et al. Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol. 2003;21:646-51.

38. van den Bent MJ, Taphoorn MJ, Brandes AA, et al. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003;21:2525-8.

39. Hoang-Xuan K, Capelle L, Kujas M, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol. 2004;22:3133-8.

40. Levin N, Gomori JM, Siegal T. Chemotherapy as initial treatment in gliomatosis cerebri: results with temozolomide. Neurology. 2004;63:354-6.

41. Weller M, Steinbach JP, Wick W. Temozolomide: a milestone in the pharmacotherapy of brain tumors. Fut Oncol. 2005;1:747-54.

42. Johnson BE, Mazor T, Hong C, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2013;??

43. Quon H, Abdulkarim B. Adjuvant treatment of anaplastic oligodendrogliomas and oligoastrocytomas. Cochrane Database Syst Rev. 2008;CD007104.

44. 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.

45. 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.

46. Mikkelsen T, Doyle T, Anderson J, et al. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009;92:57-63.

47. 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.

48. Shaw EG, Wang M, Coons SW, et al. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012;30:3065-70.