Chemotherapy After Radiation Extends Survival in Unfavorable-Risk Low-Grade Glioma

Patients with grade 2 gliomas treated with a chemotherapy regimen of procarbazine, lomustine (CCNU) and vincristine (PCV) after radiation therapy (RT) lived significantly longer and had significantly slower disease progression than patients treated with RT alone, according to results of a multi-center study, which included Cleveland Clinic.

While the survival benefits of RT+PCV treatment are substantial, the combination therapy’s toxicities are greater than with RT alone. That means patients and their physicians will need to consider whether the potential survival gains warrant additional toxic effects.

“Perhaps the most encouraging result is the number of long-term survivors with unfavorable-risk, low-grade glioma,” or LGG, reports John Suh, MD, Chairman of Cleveland Clinic Cancer Center’s Department of Radiation Oncology and a co-author of the study published in the New England Journal of Medicine. “This is the first trial to demonstrate a significant survival benefit for high-risk LGG patients treated with combined modality therapy.

“However, the hematologic toxicities of RT+PCV are greater and the logistics of delivering PCV can be complex,” Dr. Suh says. “Temozolomide has been used frequently in the past decade, given its oral administration, better tolerance and its establishment as standard therapy for glioblastoma. Unfortunately, no prospective trials have compared temozolomide to PCV in LGG patients. Physicians and patients will need to determine the value of a more toxic regimen in which a survival benefit has been clearly demonstrated compared to one that has been extrapolated without level 1 evidence.”

LGG’s variable course

LGGs, which constitute between 5 and 10 percent of all adult primary brain tumors, are a heterogeneous group of tumors with a variable and potentially long course. They typically affect young patients. Progression occurs in nearly all patients, and nearly all die prematurely. Treatment is a balancing act — administering therapy to extend progression-free and overall survival while maintaining quality of life by minimizing treatment-related morbidity, including seizures, cognitive decline and neurologic deficits.

In general, LGG treatment paradigms have involved immediate surgery and RT, or upfront surgery alone with delayed RT until the time of tumor progression. Surgery typically is not curative and the timing of postoperative RT is controversial, particularly when considering its acute and delayed side effects and their impact on patients’ quality of life.

Treatment decisions are guided by prognosis and must involve the timing of RT as well as the decision to add chemotherapy. Risk factors for poor prognosis include age older than 40, tumors 6 cm or larger, neurologic function score > 1, tumors crossing midline and astrocytoma-dominant histology. More recently, tumor molecular markers including elevated proliferative index, absence of a 1p19q co-deletion and absence of mutations in the IDH1/2 genes have also been determined to predict poor outcomes.

Previous studies had shown that various chemotherapy regimens caused tumor regression in patients with recurrent LGGs. In particular, two small nonrandomized trials demonstrated that the PCV combination given as initial therapy produced favorable response rates in a meaningful proportion of patients.

Those findings prompted an initiative to test the PCV regimen in a prospective, randomized trial comparing outcomes in unfavorable-risk LGG patients (defined as age >40 and/or subtotal resection of a supratentorial WHO grade 2 glioma) who received chemotherapy with and without RT. Patients were accrued from 1998 to 2002.

Initial results of the RTOG 9802 protocol, published in 2012, showed that RT+PCV significantly improved progression-free survival (PFS) but not overall survival (OS). Between years zero and two post-diagnosis, OS and PFS were similar for the RT-alone and RT+PCV cohorts; however, post hoc subset analysis showed that beyond two years, the RT+PCV combination provided an advantage in both PFS and OS, suggesting that chemotherapy produced a delayed benefit.

This study presents RTOG 9802’s long-term results.

Treatment details

Between 1998 and 2002, 251 patients with supratentorial grade 2 glioma received either RT alone or RT+PCV with Cleveland Clinic being one of the lead enrollers on this study. Patients aged 18-39 were eligible if they underwent a subtotal resection or biopsy, while those aged 40 and older were included if they underwent a biopsy or resection of any of the tumor.

The dose of 54 Gy was delivered by external beam in 30 fractions of 1.8 Gy/fraction, five days a week over six weeks to a gross tumor volume defined by MRI plus a 2 cm margin. Chemotherapy was administered within a month of RT completion and consisted of six cycles of PCV repeated at eight-week intervals, dosed as follows:

• Procarbazine: 60 mg/m2 orally per day on days 8-21
• CCNU: 110 mg/m2 orally on day one
• Vincristine: 1.4 mg/m2 intravenously on days eight and 29

Patients underwent a Mini-Mental State Examination (MMSE) at baseline and a preoperative and postoperative MRI. Both MMSE and MRI were repeated during treatment and at protocol-specified points until tumor progression, with MMSE ending at five years.

Separation of the survival curves

In contrast to early results from RTOG 9802, the more mature analyses found the RT+PCV group had an approximate 5.5-year benefit in OS, with an additional 20 percent in long-term survivors.

With a median follow-up time of 11.9 years, survival was as follows:

PFS: 10.4 years for RT+PCV versus 4.0 years for RT alone
OS: 13.3 years for RT+PCV versus 7.8 years for RT alone
5-year overall survival rate: 72 percent for RT+PCV versus 63 percent for RT alone
10-year overall survival rate: 60 percent for RT+PCV versus 40 percent for RT alone

Dr. Suh offers several thoughts on the late separation of the survival curves. “First and foremost, longer follow-up permits a greater number of events to occur, which increases the power to detect statistically significant differences,” he says. “There is also the possibility that two-year survivors had favorable molecular features and more complete resections, allowing the maximal benefit of PCV to be realized.

“It should also be emphasized that the survival curves cross,” Dr. Suh says. “Although there were no PCV-related deaths, it is possible that patients receiving PCV experience side effects that decrease their functional status, precluding salvage therapies that may prolong survival.” Dr. Suh also notes that the trial was not stratified by molecular status at randomization because it began in 1998—thus imbalanced molecular features may have influenced initial results.

Toxicity, morbidity and cognition

As expected, the frequency and severity of toxic effects were greater in the RT+PCV group. Most were grade 1 or 2, which is consistent with the effects of other multi-agent regimens. Only four patients required transfusions and no chemotherapy-induced malignancies or deaths attributable to either RT or PCV have occurred. Although late toxicities are a potential concern, no grade 3 or greater events have been reported in the RT+PCV cohort, compared to two in the RT-only arm.

An unexpected finding involved improved cognitive function among both study cohorts during the course of the trial. Twelve percent of patients in the RT+PCV group had increased cognitive function scores from baseline at five years, compared with 5 percent in the RT-only group. Although the MMSE is a relatively insensitive tool that may miss some cognitive changes, the apparent cognition benefits from more aggressive therapies probably reflect the lack of tumor progression, Dr. Suh says.

Treatment decisions

Even with the encouraging survival findings in this long-term analysis, Dr. Suh says some physicians may still have reservations about administering the older PCV regimen based on its profile compared to temozolomide, the standard of care in grade 3 and 4 gliomas.

No prospective trials have analyzed temozolomide versus PCV for low-grade gliomas although a trial for 1p/19q codeleted anaplastic gliomas was recently modified to include high-risk low grade gliomas. , according to Dr. Suh. Therefore, physicians and patients must weigh the value of a more toxic regimen with a clearly demonstrated survival benefit versus one with better tolerability but only an extrapolated survival benefit, he says.

“Physicians will need to decide whether the higher side effects of RT+PCV justify its routine use or if temozolomide should be used, given its ease of administration and established use in malignant gliomas,” he says.

Plans to conduct additional analyses for various molecular subsets are underway to better determine which patients will benefit most from PCV and to personalize treatment recommendations accordingly.

“As our understanding of the biology of low-grade glioma matures, future trials will become more targeted and patient-centric,” Dr. Suh says. “For now, the results of this trial provide a strong foundation to improve OS, PFS and quality of life for high-risk, low-grade glioma patients.”

Photo Credit: ©Russell Lee