Tailoring Chemotherapy for Low-Grade Gliomas

In this issue of ONCOLOGY, Drs. Strowd, Holdhoff, and Grossman provide a comprehensive discussion of the role of chemotherapy for low-grade gliomas.[1] Although grade II gliomas tend to have a less aggressive course than their high-grade counterparts, the outcome is still fatal in the majority of patients, frequently through progression into a higher histologic grade. Given their peak incidence during the third and fourth decades of life, grade II gliomas can significantly shorten life expectancy and have a significant impact on patients’ quality of life.

The recently reported long-term results of the Radiation Therapy Oncology Group (RTOG) intergroup trial 9802 created level 1 evidence to guide use of chemotherapy in newly diagnosed patients with grade II gliomas, and established a new standard of care for high-risk patients, as defined in the trial eligibility criteria-that is, patients ≥ 40 years of age or those < 40 years of age who underwent a subtotal resection or biopsy.[2] With a median follow-up of 11.9 years, patients in the radiation therapy (RT)-PCV (procarbazine, lomustine [CCNU], vincristine) arm had a median progression-free survival time of 10.4 years vs 4.0 years in the RT arm and lived significantly longer (13.3 vs 7.8 years; hazard ratio [HR] = 0.59; P = .03), despite the fact that more patients in the RT arm received salvage treatment at progression, including chemotherapy and resection of the recurrent tumor. The latter finding indicates that timing of chemotherapy during the natural history of this disease matters. Similar to other solid tumors, the efficacy of PCV in the adjuvant setting could simply be explained by a lower tumor burden, since PCV in this case is administered immediately following surgery and RT. Alternatively, administration of PCV in this setting could also have a positive impact on the pattern of molecular evolution of these tumors during the disease course.[3]

Although these results cannot be directly compared across studies, the outcomes of patients treated with RT-PCV in RTOG 9802 also appear promising in the context of outcome data from other contemporary randomized comparative trials in low-grade glioma. For example, in the European Organisation for Research and Treatment of Cancer (EORTC) 22845 trial,[4] which compared early vs late RT administration in patients with low-grade glioma, the median overall survival was comparable in the two arms (7.4 years vs 7.2 years, respectively) and very consistent with the survival outcomes in the RT-only arm of RTOG 9802. The outcome data on 111 patients who were excluded from RTOG 9802 because they were considered low-risk (age < 40 years following gross total resection) are also revealing. With a median follow-up of 4.4 years at the time of the report, progression-free survival at 5 years for these untreated patients with grade II disease was 48% (vs 44% and 61% in the RT-alone and RT-PCV arms of RTOG 0825, respectively). Updated outcome data from these 111 patients, as well as data from the ongoing observational trial RTOG 0925, will be of great interest, since the existing data indicate that at least a subgroup of “low-risk” patients do not fare well and can possibly benefit from more aggressive management at diagnosis.

Among “high-risk” patients with grade II glioma, as defined by the eligibility criteria of RTOG 9802, is treatment benefit limited to specific subgroups? Although molecular analysis of baseline tumor tissue deriving from this trial has been planned, results are not yet available and cannot be used to guide management. Of note, the majority of the patients in RTOG 9802 had oligodendrogliomas or mixed oligoastrocytomas, with only approximately one-fourth of these patients having astrocytomas. Associations between histology and outcome will be of great interest as part of the final report of RTOG 9802, but it is likely that these will be exploratory and underpowered, especially for the less common pure astrocytoma histology.

The two recently reported trials in anaplastic glioma, RTOG 9402[5] and EORTC 26951,[6] with treatment arms (RT vs RT-PCV) similar to those of RTOG 9802, can provide potentially important insights, however. In both studies, the similarly striking survival benefit with addition of PCV chemotherapy was limited to patients with 1p19q codeleted tumors. In RTOG 9402, patients with IDH mutations also benefited from treatment, even in the absence of 1p19q codeletion.[7] Based on the frequency of these two molecular alterations in low-grade gliomas, it can be expected that the majority of grade II glioma patients harbor one or both of these predictive markers. In addition, a CpG island hypermethylated phenotype and the MGMT gene promoter methylation (MGMT-STP27) status predicted benefit from treatment with PCV in EORTC 26951.[8]

With the aforementioned trial results taken together, and until results of the molecular analysis of RTOG 9802 become available, RT-PCV should be the new standard of care at diagnosis for all high-risk grade II glioma patients. It is reassuring that, with the exception of the acute reversible toxicity, the addition of PCV in RTOG 9802 did not result in an increased incidence of long-term neurocognitive toxicity (although only assessed by the Mini-Mental State Examination), and no secondary malignancies such as leukemias or myelodysplastic syndrome have been reported.

Clinical trial participation should also be encouraged for these patients whenever possible. Although the intergroup low-grade glioma trial E3F05 is temporarily closed, the CODEL trial (N0577) for 1p19q codeleted anaplastic glioma patients has been amended to also allow participation of patients with low-grade glioma and 1p19q codeletion. CODEL, in its current design, randomizes patients to RT-PCV vs RT-temozolomide vs single-agent temozolomide. The recent evidence that incorporation of chemotherapeutic interventions can result in relatively long survival times for patients with low-grade glioma, even if they belong to a high-risk group, highlights the need to also preserve neurocognitive function and health-related quality of life in these patients. Therefore, patient-reported outcomes and neurocognitive evaluation need to be carefully incorporated into, and considered in endpoint definitions for, ongoing and future trials.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Strowd RE III, Holdhoff M, Grossman SA. The use of chemotherapy for grade II gliomas. Oncology (Williston Park). 2014;28:1036-43.

2. 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 5s):abstr 2000.

3. Johnson BE, Mazor T, Hong C, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343:189-93.

4. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366:985-90.

5. 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.

6. 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.

7. Cairncross JG, Wang M, Jenkins RB, et al. Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol. 2014;32:783-90.


8. van den Bent MJ, Erdem-Eraslan L, Idbaih A, et al. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and oligoastrocytomas. A report from EORTC study 26951. Clin Cancer Res. 2013;19:5513-22.