Combined-Modality Therapy for Low-Grade Gliomas: Balancing Toxicity, Delivery Logistics, and Survival Benefit


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The results of RTOG 9802 take a step forward in the right direction, given the significantly improved overall and progression-free survival for high-risk low-grade gliomas with combined-modality therapy.

—John Suh, MD

Low-grade gliomas account for 15% of all primary brain tumors and represent a heterogeneous group of glial neoplasms. Although these tumors have been termed low-grade, this is a misnomer, especially for some grade II gliomas, which may exhibit a more aggressive behavior and variable natural history.

John Suh, MD

John Suh, MD

Grading of these tumors involves evaluation of key morphologic features, including mitotic activity, nuclear atypia, endothelial proliferation, and necrosis. Before the impact of molecular markers and mutations was known, various prognostic factors for survival were proposed by the Radiation Therapy Oncology Group (RTOG) and European Organization for Research & Treatment (EORTC): age ≥ 40 years, extent of surgical resection, astrocytoma histology subtype, tumors measuring ≥ 6 cm, tumors crossing the midline, and the presence of preoperative neurologic deficits.1,2

Recently, the incorporation of genomic analysis into prognostic models has determined that molecular markers (1p19q co-deletion, IDH mutation, and TP53 mutation status) are better predictors of survival than histologic subtype.3 For example, a low-grade glioma without an IDH mutation behaves more like a glioblastoma than a low-grade glioma. 

Older Prospective Trials

Several prospective studies have evaluated the role of radiation therapy and surgery in patients with low-grade gliomas. The RTOG and EORTC tested the impact of radiotherapy dose escalation4,5 and the use of upfront vs delayed radiation therapy in phase III trials.6 Collectively, these trials showed no benefit in terms of overall or progression-free survival based on radiotherapy dose but did demonstrate a significant benefit in progression-free survival (5.3 years vs 3.4 years, P < .0001) for patients undergoing early radiation therapy compared with delayed radiation therapy.

The RTOG performed a phase II prospective evaluation of the natural history of patients younger than age 40 who underwent a neurosurgeon-determined gross total resection.7 The importance of residual disease was established in this study; the 5-year recurrence rates for patients with < 1 cm, 1 to 2 cm, and > 2 cm of residual disease were 26%, 68%, and 89%, respectively. 

RTOG 9802

My colleagues and I recently reported the long-term results of RTOG 9802,8 summarized in this issue of The ASCO Post. This phase III study of 251 eligible patients enrolled from 1998 to 2002 investigated the addition of procarbazine, lomustine, and vincristine (PCV) to radiation therapy alone in patients with high-risk low-grade gliomas (< 40 years who had undergone a biopsy/subtotal resection or ≥ 40 years and had undergone biopsy or any degree of resection). The initial report in 2012 showed a survival advantage for the addition of PCV among 2-year survivors.2 The updated results demonstrated significantly improved overall and progression-free survival, regardless of the tumor type.8 The combined group had a longer median overall survival than did patients who received radiation alone (13.3 vs 7.8 years, hazard ratio = 0.59, P = .003). The progression-free survival at 10 years was 51% for the radiation therapy plus PCV arm compared with 21% for the group that received radiation therapy alone (P < .001).

Although the overall and progression-free survival rates clearly favored the radiation plus PCV arm, the side effects from combined-modality therapy were significantly higher than those from the radiation therapy alone group, especially grade 3 or 4 hematologic toxicities. Of note, patients with the oligodendroglioma subtype were most likely to have IDH1 R132H mutations. On multivariable analysis, the presence of the IDH1 R132H mutation was identified as an independent prognostic factor for better overall and progression-free survival. Those with the mutation still benefited significantly from receiving radiotherapy plus PCV rather than radiotherapy alone (P = .02 for overall survival; P < .001 for progression-free survival). 

Is Combined-Modality Therapy Standard of Care?

Although RTOG 9802 is the first trial to demonstrate a significant survival benefit for high-risk low-grade gliomas treated with combined-modality therapy, the results have caused a conundrum in terms of what should be standard of care for these patients. Given the concerns about the hematologic toxicities and the logistics of delivering PCV, temozolomide has been used frequently over the past decade, as it is orally given, better tolerated by patients, and standard for patients with glioblastoma.

Unfortunately, no prospective trials have compared temozolomide with PCV in patients with low-grade gliomas. We do know that radiation therapy and concurrent daily temozolomide followed by up to 12 cycles of adjuvant temozolomide is safe and effective based on RTOG 0424, which was a single-arm phase II trial for high-risk low-grade gliomas.9 With a median follow-up of 4.1 years, the median survival has not been reached, and the 3-year survival of 73.1% compares favorably with historical studies. The ECOG E3F05 study, a phase III trial for patients with low-grade gliomas with uncontrolled symptoms, tumor progression based on serial magnetic resonance imaging, or age ≥ 40 years was suspended in early 2014 and should provide additional information regarding the potential benefit of radiation therapy with concurrent temozolomide followed by adjuvant temozolomide compared with radiation therapy alone. Since a trial comparing PCV and temozolomide is unlikely, physicians and patients will need to determine the value of a more toxic regimen in which a survival benefit has been clearly demonstrated vs one that has been extrapolated without level 1 evidence. 

Future Trials

As our understanding of the biology of low-grade gliomas expands, future trials will become more targeted and patient-centric. Ultimately, the hope is that our understanding of tumor biology will lead to better selection of treatments for these patients to improve survival, minimize toxicities, and maintain or improve quality of life. Additional clinical trials are needed to further our knowledge of low-grade gliomas, and the results of RTOG 9802 take a step forward in the right direction, given the significantly improved overall and progression-free survival for high-risk low-grade gliomas with combined-modality therapy. ■

Disclosure: Dr. Suh has received research support from and is a consultant for Varian Medical Systems and has received travel funds from Elekta.

Dr. Suh is Chairman, Department of Radiation Oncology, Rose Ella Burkhardt Brain Tumor & Neuro-oncology Center, Taussig Cancer Institute, Cleveland Clinic.

References

1. Pignatti F, van den Bent M, Curran D, et al: Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076-2084, 2002.

2. 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 30:3065-3070, 2012.

3. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al: Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481-2498, 2015.

4. Karim AB, Maat B, Hatlevoll R, et al: A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 36:549-556, 1996.

5. Shaw E, Arusell R, Scheithauer B, et al: Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: Initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol 20:2267-2276, 2002.

6. 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 366:985-990, 2005.

7. Shaw EG, Berkey B, Coons SW, et al: Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: Results of a prospective clinical trial. J Neurosurg 109:835-841, 2008.

8. Buckner JC, Shaw EG, Pugh SL, et al: Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374:1344-1355, 2016.

9. Fisher BJ, Hu C, Macdonald DR, et al: Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: Preliminary results of Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys 91:497-504, 2015.


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