Radiation oncologists who have been hesitant to add chemotherapy to radiotherapy for postoperative treatment of low-grade glioma in adults because of potential effects on cognitive function can now be reassured about chemo-radiotherapy.
An analysis of the Radiation Therapy Oncology Group (RTOG) 9802 trial, now available online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2013.53.1830), shows that cognitive function at five years post-therapy was the same for patients receiving both chemotherapy and radiotherapy as for those receiving radiotherapy alone.
Rather than having impaired cognitive function, some patients in both groups actually had improvements over presurgery baseline.
More recently, a related part of the study also showed, according to an announcement from the Radiation Therapy Oncology Group and the National Cancer Institute in February—that at almost 12 years of follow-up, median overall survival improved with the use of the same chemotherapy—procarbazine, lomustine, and vincristine (PCV)—plus radiation therapy: 13.3 years versus 7.8 years for patients receiving radiation therapy alone.
These reports from RTOG 9802 are based on outcomes of 251 high-risk patients with World Health Organization grade 2 glioma age 40 or older with any extent of resection, or age 18 to 39 with subtotal resection/biopsy; 126 patients were randomly assigned to radiation therapy alone (54 Gy) and 125 to radiation therapy plus PCV.
Another 111 patients age 18 to 39 with gross total resection served as low-risk controls.
The results are practice changing, the researchers said. “Both oncologists and patients can have more confidence in pursuing a potentially new standard of care—combining radiation and chemotherapy—for low-grade glioma,” said the first author of the JCO study, Roshan S. Prabhu, MD, of Southeast Radiation Oncology Group at Levine Cancer Institute in Charlotte, N.C.
Edward G. Shaw, MD, co-lead investigator of RTOG 9802 and Professor of Radiation Oncology at the Brain Tumor Center of Excellence at Wake Forest Baptist Health Medical Center, said in the RTOG/NCI announcement that patients who are deemed appropriate candidates for radiation therapy should be encouraged to receive chemotherapy as well, understanding both the potential benefits and risks.
The initial results of the randomized, prospective RTOG 9802 trial, with Shaw as first author, were published in 2012 (JCO 2012;30:3065-3070), showing that the addition of PCV to radiation therapy provided a progression-free survival benefit, but not an overall survival benefit.
The study by Prabhu et al reporting on cognitive function was based on the initial analysis of those patients as assessed by Mini-Mental State Examination (MMSE) at baseline and at years 1, 2, 3, and 5.
Patients in both randomly assigned arms had a statistically significant average MMSE score increase over time with no difference between arms, but this was mainly in patients with a good neurologic function score and right lateralization.
In a telephone interview, Prabhu speculated that the improvement in cognitive function could be due to reduction in tumor volume, reduction of edema, or cytokine production related to the tumor or to changes in the tumor microenvironment.
He added, however, that more sensitive neurocognitive assessments may detect changes not apparent through use of the MMSE alone as a measure of cognitive function. There have been reports over the years that chemotherapy with radiotherapy extends overall survival.
The more intensive chemo-radiotherapy regimen may allow a progression-free survival benefit, Prabhu said, but it raises the question of what is more detrimental—the intensive treatment or tumor recurrence.
The study did address the risk-benefit ratio in terms of cognitive therapy. “Chemo brain” after chemotherapy has been reported any number of times, but Prabhu pointed out that this has been shown mainly in treatment of breast and other tumors, rather than central nervous system tumors.
“In breast cancer or non-CNS cancer, cognitive functioning is as good as it will be before treatment, and can really only go down from there with intensive treatment,” he said. “The paradigm in brain tumors, however, is that the tumor itself causes cognitive dysfunction—when you test patients before treatment they already have cognitive dysfunction.”
The theory is that by effectively treating the low-grade glioma, even with more intensive treatment, cognitive function may be improved. The anatomy involved is the hippocampus, he explained, and both radiation and chemotherapy are known to have detrimental effects on the hippocampus that lead to worsened short-term recall.
“It's short-term recall that worries patients and their caregivers most because they quickly notice it,” he said.
Prabhu said researchers are now testing different methods to reduce the effects of cancer treatment on cognitive function. He cited the publication last year of the RTOG 0614 trial (Neuro-Oncology 2013;15:1429-1437), which showed that memantine, a drug used to treat Alzheimer's disease, delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving whole-brain radiotherapy (OT 12/10/12 issue).
And a Phase II study reported at last year's American Society for Radiation Oncology Annual Meeting as Abstract LBA1 (OT 11/25/13 issue) showed that conformal avoidance of the hippocampus during whole-brain radiotherapy for brain metastases was associated with memory preservation.
A question now arises, he said, whether the effects of PCV are translatable to the alkylating agent temozolamide, which many clinicians are substituting for PCV: “There is a lot of resistance to giving chemotherapy because of the potential effects on the cognitive domain, and many patients come in asking specifically how treatment will affect their thinking. When you don't have evidence, it's hard to recommend that treatment, but with this paper there is now published evidence that it is not detrimental to neurocognitive functioning, and in fact most patients actually get better over time.”
Asked for his opinion for this article, the first author of the ASTRO abstract, Vinai Gondi, MD, Director of CNS Radiation Oncology at Cadence Brain Tumor Center and Proton Center in Warrenville, Ill., and Clinical Assistant Professor at the University of Wisconsin School of Medicine and Public Health, noted that the role of chemotherapy in addition to radiotherapy for patients with low-grade gliomas has been controversial ever since the initial findings of RTOG 9802 demonstrated a progression-free survival benefit, especially in light of the expected increased toxicity profile of PCV chemotherapy.
But the updated findings from RTOG 9802, he said, will be practice-changing, and upfront chemo-radiotherapy as defined by RTOG 9802 should be the new standard of care for high-risk low-grade gliomas. “The now apparent overall survival benefit is practice-affirming for those who have believed in the use of upfront chemo-radiotherapy for high-risk low-grade gliomas, and practice-changing for those who have not.”
Still, whether to adopt PCV chemotherapy or the now more commonly employed temozolomide remains controversial, he added.
Gondi said that the initial results from RTOG 0424, presented at last year's ASCO Annual Meeting (Abstract 2008), demonstrated promising overall survival in comparison with a historical control with the use of temozolomide and radiotherapy for patients with high-risk low-grade gliomas, although the definition of high-risk features varied slightly from that of RTOG 9802.
The major limitation of the Prabhu study, Gondi continued, is the relative insensitivity of the MMSE mini-mental status examination to capture all cognitive domains, and relatively small cognitive effects of upfront intensified therapy with chemo-radiotherapy may still exist. In addition, the study does not address the potential cognitive impact of disease progression and subsequent therapy at time of progression.
This is particularly relevant in the setting of observation for low-risk low-grade gliomas, Gondi said, adding that this question is currently being investigated in RTOG 0925, being led by Ali Choucair and Nadia Laack.