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

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.

Conclusion

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.

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