What is the preferred chemotherapy option between Temozolomide (temozolomide) and PCV (procarbazine, lomustine, vincristine) for low-grade glioma?

PCV vs Temozolomide in Low-Grade Glioma

Primary Recommendation

For high-risk low-grade gliomas requiring adjuvant chemotherapy, radiotherapy followed by PCV (procarbazine, lomustine, vincristine) is the standard of care and provides superior overall survival compared to radiotherapy alone, with the greatest benefit in patients harboring 1p/19q codeletion and IDH mutations. 1

Risk Stratification Determines Treatment Approach

High-Risk Patients (Require Adjuvant Therapy)

High-risk features include 3 or more of the following: age >40 years, KPS <70, tumor >6 cm, tumor crossing midline, or preoperative neurologic deficit beyond minor degree 1. Additional adverse factors include increased perfusion on imaging, absence of 1p/19q codeletion, and wild-type IDH1/IDH2 1.

For these high-risk patients, radiotherapy (50-54 Gy) followed by PCV chemotherapy is the Category 1 recommendation based on RTOG 9802 trial data showing overall survival prolongation from 7.8 years to 13.3 years. 1 This survival benefit was observed across histological subgroups, particularly in patients with IDH-mutant tumors, but notably not in IDH-wild-type tumors 1.

Low-Risk Patients

Low-risk features include: age ≤40 years, KPS ≥70, minor or no neurologic deficit, oligodendroglioma or mixed oligoastrocytoma histology, tumor <6 cm, 1p/19q codeletion, and IDH1/IDH2 mutation 1. After gross total resection, these patients may be observed without adjuvant therapy, though close follow-up is essential as >50% eventually progress 1.

Molecular Subtype Dictates Chemotherapy Choice

1p/19q Codeleted Tumors (Oligodendrogliomas)

Patients with 1p/19q codeletion derive the most significant benefit from PCV chemotherapy. 1, 2 These tumors demonstrate exquisite chemosensitivity and represent the most favorable candidates for chemotherapy 1. The survival advantage with RT plus PCV is most pronounced in this molecular subgroup 1, 2.

IDH-Mutant, 1p/19q Intact Tumors (Astrocytomas)

For IDH-mutant astrocytomas without 1p/19q codeletion, radiotherapy followed by PCV remains the standard based on RTOG 9802 extrapolation, though temozolomide is an acceptable alternative. 1 The 2021 EANO guidelines specifically recommend RT followed by PCV (or temozolomide chemoradiotherapy) for WHO grade 2 IDH-mutant astrocytomas requiring treatment 1.

IDH-Wild-Type Tumors

These biologically unfavorable tumors did not demonstrate benefit from PCV in RTOG 9802 1. For IDH-wild-type low-grade gliomas, radiotherapy followed by temozolomide (by MGMT status) may be preferred over PCV. 1, 2

Temozolomide as Alternative or Recurrent Disease Option

Temozolomide is included as a Category 2B recommendation for adjuvant therapy in low-grade gliomas based on nonuniform panel consensus 1. Phase II data showed 61% objective response rate with standard dosing and 20-52% with protracted schedules 1.

In the absence of randomized trial data directly comparing PCV to temozolomide in newly diagnosed low-grade gliomas, both regimens are considered acceptable for recurrence or progressive disease. 1 However, the NOA-04 trial demonstrated that chemotherapy alone (either PCV or temozolomide) is not superior to radiotherapy alone in anaplastic gliomas, suggesting alkylating agents alone are unlikely to match outcomes of RT followed by PCV 1.

Temozolomide Advantages

• Better tolerability profile with lower toxicity compared to PCV 2, 3
• Oral administration with simpler dosing schedule 1
• Main dose-limiting toxicity is myelosuppression (thrombocytopenia at 2-3 weeks) rather than delayed cumulative toxicity 1
• May be preferred in patients unable to tolerate PCV toxicity 2, 3

PCV Disadvantages and Toxicity Concerns

PCV carries significant neurotoxicity risk, particularly with intensive regimens. 4 Central neurotoxic side effects including focal neurological deficits, cognitive disturbances, EEG slowing, and cerebral atrophy have been documented 4. Delayed myelosuppression occurs at 4-6 weeks and can be cumulative, necessitating treatment interruptions or discontinuation 1. Standard PCV regimens are better tolerated than intensive schedules 4.

Practical Treatment Algorithm

1. Establish molecular diagnosis: Test for IDH mutation and 1p/19q codeletion status 1
2. Risk stratify: Determine if patient meets high-risk criteria requiring adjuvant therapy 1
3. For high-risk, 1p/19q codeleted tumors: RT (50-54 Gy) followed by PCV (Category 1) 1
4. For high-risk, IDH-mutant, 1p/19q intact tumors: RT followed by PCV or temozolomide chemoradiotherapy 1
5. For high-risk, IDH-wild-type tumors: Consider RT followed by temozolomide (by MGMT status) over PCV 1, 2
6. For recurrent disease: Either temozolomide or PCV acceptable; choice based on prior therapy and tolerance 1

Critical Caveats

• Chemotherapy is not a traditional mainstay of upfront treatment for low-grade gliomas 1
• Early radiotherapy prolongs progression-free survival but not overall survival when given upfront versus at progression 1
• The modified CODEL trial is addressing whether temozolomide-based chemoradiotherapy is similarly effective as RT followed by PCV, but results are pending 1
• Alkylating agent chemotherapy carries risk of inducing hypermutator phenotype associated with more malignant transformation, particularly concerning in IDH-mutant gliomas with longer life expectancy 1
• For recurrent high-grade glioma, the 5-day temozolomide schedule (200 mg/m² for 5 days) is superior to the 21-day schedule (100 mg/m² for 21 days) in terms of progression-free survival, overall survival, and quality of life 5