An expanded molecular analysis of a phase 3, randomized Radiation Therapy Oncology Group (RTOG)-conducted trial shows the presence of the isocitrate dehydrogenase (IDH) gene mutation in anaplastic (malignant) oligodendroglial (OA) or oligoastrocytoma (AOA) tumors is associated with patients living longer when treated with chemo-radiotherapy (CRT) versus radiotherapy (RT) alone. The results were published online in the February 10, 2014 Journal of Clinical Oncology (JCO).
A previous report in the JCO (Jan 20, 2013:337-343) of RTOG 9402 long-term results (at 11 years patient follow up) showed the absence (codeletion) of chromosomes 1p and 19q in AO/AOA tumors was associated with a substantially better patient prognosis and near-doubling of median survival time when patients were treated with CRT compared to treatment with RT alone. “While these results were very encouraging, the prospect of a treatment strategy specifically tailored for tumors with chromosomal abnormality was confounded by the fact that a subset of long surviving patients with non-co-deleted tumors also significantly benefited from chemo-radiotherapy,” says primary author J. Gregory Cairncross, MD, Professor and Head of the Department of Clinical Neurosciences at the University of Calgary, Alberta, Canada.
This observation led investigators to explore whether IDH, the earliest known molecular alteration in oligodendroglial tumors, could serve as a biomarker to provide further insight about which patients would benefit from CRT. “We found the IDH mutational status identified patients with oligodendroglial tumors who did—and did not—benefit from chemotherapy with RT,” says Cairncross. The authors reported patients with codeleted and IDH mutated tumors lived longer after treatment with CRT compared to RT alone (14.7 vs. 6.8 years); those with non-codeleted mutated tumors also lived longer after CRT (5.5 vs. 3.3 years); and patients with non-codeleted, non-mutated AO/AOA were reported as receiving no discernible benefit from the addition of CRT to RT (1.0 vs. 1.3 years). “These data bring us closer to personalized therapy for patients with oligodendroglial tumors” says Cairncross, “and the finding of an IDH mutation related genetic feature in their blood closely linked to early benefit from PCV [procarbazine, lomustine and vincristine] plus RT is very intriguing.”
“The IDH gene mutation’s association with longer survival is an important observation and will prove helpful for future investigations,” says Walter J. Curran, Jr., MD, RTOG Group Chairman, senior author, and Executive Director of the Winship Cancer Center at Emory University in Atlanta. Also noted in the article is the availability of “two simple, reliable and inexpensive tests, well suited to biopsy samples” that give complementary information, and might help oncologists decide when to use CRT vs. RT alone for AO/AOA.
The RTOG 9402 trial A Phase III Intergroup Randomized Comparison of Radiation Alone vs. Pre-Radiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas was activated on July 1, 1994. Trial participants had a pathologically confirmed AO/AOA and were randomly assigned into one of two treatment arms. The 148 participants randomized to Arm 1 were treated with PCV (procarbazine, CCNU [lomustine] and vincristine) chemotherapy and radiation therapy (RT), and the 143 participants randomized to Arm 2 were treated with RT alone. The trial was conducted with four other National Cancer Institute (NCI)-supported cooperative groups.
The research project was supported by RTOG grants U10 CA21661 and U10 CA32115; NCCTG grant U10 CA25224; ECOG grants CA23318, CA66636, and CA2115; SWOG grant CA32102; and CCOP grant U10 CA37422 from the National Cancer Institute (NCI).