Adjuvant chemoradiotherapy beat radiotherapy alone for treatment of certain patients with World Health Organization (WHO)–defined low-grade glioma (LGG), according to researchers.
Prior results from this trial, NRG Oncology/RTOG 9802 (NCT00003375), demonstrated an increase in progression-free survival (PFS) and overall survival (OS) when procarbazine, lomustine, and vincristine (PCV) chemotherapy was added to radiation in patients with high-risk LGG.
The current results, published in the Journal of Clinical Oncology, displayed highly variable survival outcomes depending on molecular subgroup.
The initial report included only IDH1 R132H immunohistochemistry data because of limited tissue availability. However, retrospective retrieval of additional tissues subsequently enabled rigorous examination of the prognostic and predictive significance of these genetic biomarkers.
Prognostic and predictive
The trial included 251 patients with LGG (grade 2). Among the 106 eligible patients with WHO-defined molecular groups successfully profiled, 26 (24%) were IDH wild-type, 43 (41%) were IDH-mutant/non-codeleted, and 37 (35%) were IDH-mutant/codeleted.
After adjustment for clinical variables and treatment, multivariate analysis confirmed WHO-defined subgroup was a significant predictor of survival. All predictive analyses, however, were considered exploratory because of small sample sizes for patients with specific biomarker features in most cases.
In prognostic multivariable analyses, significantly favorable molecular subgroup associations were observed for OS in the IDH-mutant subgroups versus that in the wild type group (IDH-mutant/codeleted group HR, 0.18; P < .0001; IDH mutant/non-codeleleted group HR, 0.56; P = .048). Individually, the statistical significance was maintained for favorable OS for IDH1/2 mutations and 1p/19q codeletions.
In the predictive analyses, OS was longer for patients harboring IDH mutant/codeleted tumors receiving radiotherapy plus PCV than for those receiving radiotherapy alone (HR, 0.21; P = .029). The median OS was 13.9 years for radiotherapy and was not reached for PCV and radiotherapy.
PFS in the IDH-mutant/codeleted subgroup also was longer for patients receiving PCV (HR, 0.13; P < .001). The median PFS was 5.8 years for radiotherapy alone and was not reached for added PCV.
In the IDH-mutant/non-codeleted subgroup, OS was longer with PCV (HR, 0.38; P = .013). The median OS was 4.3 years for radiotherapy alone and 11.4 years when PCV was added.
PFS was also longer in the IDH-mutant/non-codeleted subgroup (HR, 0.32; P = .003). The median PFS was 3.3 years for radiotherapy and 10.4 years with PCV added.
IDH–wild type patients displayed no significant clinical benefit from the addition of PCV.
“Historically, many have thought that primarily patients with codeletions received benefit from PCV,” study author Erica H. Bell, PhD, of The Ohio State University in Columbus, said in an interview. “But we showed here that there is benefit in both IDH-mutant groups.”
Primary predictor
“Our evidence suggests that IDH mutation status could serve as the primary predictor of response to PCV in addition to radiotherapy in high-risk, low-grade gliomas and is a more accurate predictor of response than historical histopathological classifications,” Dr. Bell and colleagues wrote. “Consideration should be given for adjuvant PCV in the setting of high-risk, low-grade glioma patients harboring IDH mutations.”
High-risk was defined as being 40 years or older or having a subtotal resection biopsy.
“While both IDH mutant subgroups received benefit from the addition of PCV for both overall survival and PFS, the patients in the wild-type subgroup did not do well," Dr. Bell said. "We need to treat them more aggressively. We need to determine exactly what therapy modality they should receive. This is an active question in our field.”
“Another conclusion from the study,” she added, “is that upfront tissue collection and molecular subtyping are absolutely necessary for moving our field forward.”
Finding novel biomarkers and novel therapeutic targets remain as a further goal.
Dr. Bell commented that results of the CODEL trial of temozolomide in newly diagnosed 1p/19q-codeleted anaplastic glioma are widely anticipated.
“PCV is a very toxic treatment," she said. "If another agent that is less toxic, but just as efficacious, becomes available, we would rather use that. At this point, though, there are no head-to-head trials comparing temozolomide with PCV in codeleted populations.”
The current study was sponsored by the National Cancer Institute and The Ohio State University. The authors disclosed patents, royalties, and other intellectual property.
SOURCE: Bell EH et al. J Clin Oncol. 2020. doi: 10.1200/JCO.19.02983.