Minding the Ps and Qs: Perseverance and Quality Studies Lead to Major Advances in Patients With Anaplastic Oligodendroglioma

Abstract

Almost 6 years ago, the results of two similar studies that described the outcomes for patients with anaplastic oligodendroglial (AO) tumors were published in Journal of Clinical Oncology. These studies were launched in 1994 and 1995 and built on the observations from the late 1980s and early 1990s that some patients with AO had dramatic and durable responses to chemotherapy. The Radiation Therapy Oncology Group (RTOG), in collaboration with four other North American–based cooperative groups, launched the RTOG 9402 trial. This phase III clinical trial compared the standard of care, external beam radiation, to preradiation chemotherapy using up to four cycles of intensive procarbazine, lomustine (CCNU), and vincristine (the iPCV regimen). Within 1 year of the initiation of the RTOG trial, the European Organisation for Research and Treatment of Cancer (EORTC) launched a study of patients with the same tumor type, but the experimental arm differed in that radiation was followed by up to six cycles of standard-dose PCV chemotherapy. When the results of these two trials were published in 2006, they both demonstrated a significant improvement in progression-free survival for patients who received the combination regimens, but there was no difference in overall survival. However, in both studies, approximately 80% of the patients who were randomly assigned to the radiation-only arms were treated with chemotherapy at tumor relapse (in contrast, only 50% of patients who were given up-front chemotherapy received chemotherapy salvage treatment). The conclusions in 2006 were that either treatment approach was acceptable, given that the patients who received only radiation as first-line treatment would then benefit from chemotherapy as second-line treatment. The editorial that accompanied these publications highlighted the need for patient outcomes measures such as neurocognitive and symptom burden consequences that might help determine whether early or late chemotherapy should be the standard of care. In other words, are the early toxicities from the chemotherapy offset by the preservation of function that results from the delay in tumor progression? These trials did not directly address these issues. However, both studies attempted to prospectively collect tumor tissues, although at the time that the studies were launched, no specific molecular markers were known. In 1998, the association of allelic loss of the short arm (p) of chromosome 1 and the long arm (q) of chromosome 19 with some AOs was published. Retrospective series strongly suggested that these changes were highly prognostic; subsequently, the status of 1p/19q was determined in the available tumor samples from both the RTOG and EORTC studies. The 2006 publications analyzed the survival outcomes, stratifying by the 1p/19q loss, and confirmed the prognostic importance of these chromosome changes, but survival was not improved by early chemotherapy in either the patients with 1p/19q loss or those without. However, in 2006, for the group with 1p/19q loss, the median survival had not been reached. As evidenced by the two articles that accompany this editorial, 6 years later the story has dramatically changed. Additional tumor samples were obtained from the original study participants and long-term follow-up data were obtained for both studies, now more than 17 years after their initiation. Remarkably, once again the two trials were complementary. Now with this long-term follow-up, there is clear evidence that for patients with AOs that contain the 1p/19q loss, early chemotherapy with radiation offers a significant improvement in overall survival compared with early radiation even with salvage chemotherapy at tumor relapse. This survival benefit was not found for patients with tumors that did not have the chromosomal deletions, highlighting the clinical importance of this molecular marker. These results have several important implications. These studies establish a new standard of care for patients with AO tumors that harbor the 1p/19q loss. No longer is radiation considered an adequate treatment for this patient population. As a result, the international cooperative group study of newly diagnosed AO with 1p/19q loss, CODEL, which compared radiation therapy with the combination of radiation and chemotherapy (temozolomide) and included an exploratory arm with chemotherapy (temozolomide alone), was halted because the control arm (radiation alone) is no longer viable. There are now ongoing discussions about a new trial design, with considerations ranging from comparing the PCV combination (used in these clinical trials) with temozolomide, an oral agent with a better toxicity profile and proven efficacy in glioblastoma. Further complicating the study design are the reports of tumor response with chemotherapy (PCV or temozolomide) alone, generating the question of whether to evaluate chemotherapy alone as first-line therapy, reserving a radiation-containing regimen for relapse. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 3 JANUARY 2