In light of the high bar that must be met for results to be truly practice-changing, and of the long period of time before survival results are mature in an indolent disease, the primary endpoint for clinical trials in anaplastic oligodendroglial tumors needs rethinking.
In the late 1980s, it was observed that highly malignant, radiotherapy-refractory, metastatic oligodendrogliomas could respond to chemotherapy, and that responses could be both robust and durable. However, it took 25 years to demonstrate conclusively that survival is significantly prolonged by the addition of chemotherapy to radiotherapy for the treatment of newly diagnosed 1p/19q codeleted anaplastic oligodendroglial tumors (AOTs).[3,4] These results, from Radiation Therapy Oncology Group (RTOG) trial 9402 and European Organisation for Research and Treatment of Cancer (EORTC) trial 26951[3,4] are thoroughly and thoughtfully reviewed here by Drs. Anderson and Gilbert. Yet, several issues remain unsettled.
First, it is unclear how to treat patients with AOTs without codeletion. Secondary analyses of RTOG 9402 and EORTC 26951 suggest that molecular factors other than 1p/19q codeletion also affect both response to treatment and prognosis. In particular, patients with isocitrate dehydrogenase (IDH)-mutated tumors, but without 1p/19q codeletion, may also benefit from chemoradiotherapy, albeit to a lesser degree than those with tumors harboring both codeletion and mutation. CATNON is an international phase III trial led by the EORTC. It is accruing well, and will investigate the benefit (or lack thereof) from temozolomide (Temodar) chemotherapy combined with radiotherapy vs radiotherapy alone in non–1p/19q-codeleted anaplastic gliomas; the trial will presumably also evaluate biomarkers such as IDH mutation. In the interim, one might argue that patients with IDH-mutated, non-codeleted tumors should receive both radiotherapy and PCV (procarbazine [Matulane], lomustine [CeeNU], and vincristine) as initial postoperative treatment. However, any modest survival benefit must be weighed against PCV toxicity. Longer survival that is poorer survival may not be viewed as “worth it” by some patients and practitioners.
Second, concerns about toxicity have also led the field away from radiotherapy altogether in the last 25 years. Both RTOG 9402 and EORTC 26951 used radiotherapy as the backbone, anchored in the premise that radiotherapy was the standard of care for all anaplastic gliomas because treatment with radiotherapy was clearly shown to improve survival in some of the original studies conducted by the Brain Tumor Study Group in the 1970s. However, most patients in those early trials had glioblastomas, not high-grade oligodendrogliomas. Many, if not most, neuro-oncologists now recommend chemotherapy alone for patients with codeleted tumors because they fear dementia in long-term survivors treated with radiotherapy. A German phase III trial suggested that initial chemotherapy could be followed by radiotherapy at recurrence without shortening survival. A retrospective study suggested that deferring radiotherapy at diagnosis did not adversely affect survival. The National Comprehensive Cancer Network guidelines include chemotherapy alone as a reasonable initial treatment strategy. Other prognostic factors may also need to be considered. For example, among those who are likely to survive longest (ie, young, asymptomatic patients who have undergone gross total resection of a tumor harboring 1p/19q codeletion, IDH mutation, methylguanine methyltransferase [MGMT]promoter methylation, and other favorable clinical and molecular prognostic factors), late toxicity from early radiotherapy is a serious consideration. CODEL is another international phase III study; this trial originally randomly assigned patients to receive radiotherapy alone or radiotherapy and temozolomide (or, in a smaller exploratory arm, temozolomide alone without radiotherapy). However, the trial was suspended following the realization that treatment with radiotherapy alone is inadequate for patients with 1p/19q codeleted tumors.[3,4] Hopefully the final trial design, the result of the revision process currently underway, will adequately address these issues through detailed neuro-cognitive evaluations of patients treated with chemotherapy alone vs chemoradiotherapy.
Third, the appropriate chemotherapy regimen for patients with AOTs harboring 1p/19q codeletion is undefined. For example, lomustine alone may be as effective as PCV, with less toxicity. More importantly, PCV is out of favor: in a retrospective study of treatment patterns over time, 98% of patients diagnosed with AOT from 2005 to 2007 who received chemotherapy were given temozolomide. It is possible that the efficacy of PCV is superior to that of temozolomide, but available data are inadequate to compare the regimens definitively.[10,15] Nevertheless, because PCV is perceived as so much more toxic, any survival differences following treatment with temozolomide vs PCV (alone or combined with radiotherapy) may not matter to the field unless such differences are both statistically significant and medically dramatic (ie, multiple years-akin to the doubling from 7.3 to 14.7 years seen in RTOG 9402).
In light of the high bar that must be met for results to be truly practice-changing, and of the long period of time before survival results are mature in an indolent disease, the primary endpoint for clinical trials in AOT needs rethinking. For example, RTOG 9402 and EORTC 26951 required an incubation of nearly 20 years from conception to final report, and a median follow-up of over 11 years in accrued patients. Pending these final reports, these studies were published in the interim as “negative,” even though this interpretation was contradicted by the final results.[16,17] As with a fine wine, patience was needed for the results to ferment. Yet this timeline suggests that survival, while the most definitive endpoint, may no longer be a practical endpoint in the coming years, given that the pace of scientific discovery is ever quickening, and new breakthroughs may turn questions that are considered interesting at study outset into irrelevant answers by study conclusion. Going forward, is it desirable to initiate a trial now that will require until the 2030s to mature? Both RTOG 9402 and EORTC 26951 demonstrated that progression-free survival is an earlier surrogate that appears valid in this context.[3,4,16,17]
Finally, the primary endpoint, from an efficacy perspective, may in fact be secondary for some patients. Quality of life and neurologic function are important, if not more important, considerations, leading some practitioners to advise (and some patients to prefer) deferring radiotherapy altogether-and to use temozolomide rather than PCV. Practical bedside neuro-cognitive testing and quality-of-life measures are increasingly incorporated into study design. However, understudied in neuro-oncology is the “relative value” (J. Gregory Cairncross, MD, personal communication) that practitioners and patients place on various outcome measures.
Some critical old questions have been answered. As with any good scientific endeavor, the answers have also raised new important questions.
Financial Disclosure: Dr. Lassman receives honoraria, research support, and/or serves on an advisory board for Merke Sharpe & Dohme.
1. Cairncross JG, Macdonald DR. Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol. 1988;23:360-4.
2. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90:1473-9.
3. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337-43.
4. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344-50.
5. Erdem-Eraslan L, Gravendeel LA, de Rooi J, et al. Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. J Clin Oncol. 2013;31:328-36.
6. Cairncross G, Wang M, Jenkins R, et al. IDH status predicts benefit from PCV with radiation therapy in anaplastic oligodendroglioma (RTOG 9402) [abstract]. Int J Radiat Oncol Biol Phys. 2012;84:S5.
7. Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303:1323-9.
8. Abrey LE, Louis DN, Paleologos N, et al. Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro Oncol. 2007;9:314-8.
9. Panageas KS, Iwamoto FM, Cloughesy TF, et al. Initial treatment patterns over time for anaplastic oligodendroglial tumors. Neuro Oncol. 2012;14:761-7.
10. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27:5874-80.
11. Lassman AB, Iwamoto FM, Cloughesy TF, et al. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol. 2011;13:649-59.
12. Neighbors LB, Ammirati M, Bierman PJ, et al. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology: central nervous system cancers (version 1.2013). 2013 [Updated December 21, 2012; cited 2013 March 10]. Available at: http://www.nccn.org.
13. Reiner AS, Panageas KS, Iwamoto FM, et al. Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors [abstract NO-15]. Neuro Oncol. 2011;13:iii43-iii44.
14. Levin VA, Edwards MS, Wright DC, et al. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980;64:237-44.
15. Vogelbaum MA, Wang M, Peereboom DM, et al. RTOG 0131: phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas â updated survival and progression free survival analysis [abstract NO-56]. Neuro Oncol. 2012;14:vi75-vi76.
16. Cairncross G, Berkey B, Shaw E, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24:2707-14.
17. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24:2715-22.
18. van den Bent MJ, Jaeckle K, Baumert B, Wick W. RTOG 9802: Good wines need aging. J Clin Oncol. 2013;31:653-4.