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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2707-2714 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.3414 Phase III Trial of Chemotherapy Plus Radiotherapy Compared With Radiotherapy Alone for Pure and Mixed Anaplastic Oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402
From the University of Calgary, Calgary, Alberta; McGill University, Montreal, Quebec; University of Toronto, Toronto, Ontario, Canada; American College of Radiology; Thomas Jefferson University Medical Center, Philadelphia, PA; Wake Forest University Medical Center, Winston-Salem, NC; Mayo Clinic, Rochester, MN; Foundation for Cancer Research, Phoenix, AZ; University of Texas Southwestern Medical Center, Dallas, TX; and the University of Wisconsin, Madison, WI Address reprint requests to Gregory Cairncross, MD, Foothills Medical Centre, Department of Clinical Neurosciences, 1403 29th St NW, Calgary, Alberta, T2N 2T9, Canada; e-mail: jgcairnx{at}ucalgary.ca
PURPOSE: Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are treated with surgery and radiotherapy (RT) at diagnosis, but they also respond to procarbazine, lomustine, and vincristine (PCV), raising the possibility that early chemotherapy will improve survival. Furthermore, better outcomes in AO have been associated with 1p and 19q allelic loss. PATIENTS AND METHODS: Patients with AO and AOA were randomly assigned to PCV chemotherapy followed by RT versus postoperative RT alone. The primary end point was overall survival. The status of 1p and 19q alleles was assessed by fluorescence in situ hybridization.
RESULTS: Two hundred eighty-nine eligible patients were randomly assigned to either PCV plus RT (n = 147) or RT alone (n = 142). At progression, 80% of patients randomly assigned to RT had chemotherapy. With 3-year follow-up on most patients, the median survival times were similar (4.9 years after PCV plus RT v 4.7 years after RT alone; hazard ratio [HR] = 0.90; 95% CI, 0.66 to 1.24; P = .26). Progression-free survival time favored PCV plus RT (2.6 years v 1.7 years for RT alone; HR = 0.69; 95% CI, 0.52 to 0.91; P = .004), but 65% of patients experienced grade 3 or 4 toxicity, and one patient died. Patients with tumors lacking 1p and 19q (46%) compared with tumors not lacking 1p and 19q had longer median survival times (> 7 v 2.8 years, respectively; P CONCLUSION: For patients with AO and AOA, PCV plus RT does not prolong survival. Longer progression-free survival after PCV plus RT is associated with significant toxicity. Tumors lacking 1p and 19q alleles are less aggressive or more responsive or both.
Anaplastic oligodendroglioma (AO) is a histologically distinct high-grade glioma that, when copopulated by neoplastic astrocytes, evokes a diagnosis of anaplastic oligoastrocytoma (AOA).1 In recent years, the histologic criteria for the diagnosis of AO and AOA have liberalized, and as a result, the rate of diagnosis of both has increased. Today, up to 25% of newly diagnosed malignant gliomas are designated AO or AOA.1 Standard treatment for AO and AOA consists of maximum surgical resection and radiotherapy (RT).2 Although seldom curative, long survival is relatively common after such treatment. Median survival time is also relatively long, ranging from 3 to 5 years.3 In North America, initial treatment for AO and AOA has often included chemotherapy with carmustine or procarbazine, lomustine, and vincristine (PCV). Chemotherapy at diagnosis has been justified on the basis of weak evidence of a survival benefit in studies of adjuvant carmustine for malignant glioma (trials populated largely by patients with glioblastoma).4 Early chemotherapy for oligodendroglioma was reinforced by the discovery that AO and AOA are often chemotherapy sensitive, responding dramatically on computed tomography (CT) or magnetic resonance imaging (MRI) after exposure to PCV.5,6 To test the hypothesis that PCV plus RT is a better initial treatment than RT alone for AO and AOA, the Radiation Therapy Oncology Group (RTOG) and four other oncology cooperatives undertook a randomized trial, which opened in 1994. Anticipating that chromosomal analysis might identify clinically important subsets of patients,7 paraffin sections and blood were requested from all participants, and during the trial, the potential prognostic and predictive value of 1p and 19q allelic loss in AO was reported.8,9
Patients age  18 years with a newly diagnosed, supratentorial AO or AOA were eligible. Anaplasia was based on an evaluation of the following five microscopic features: tumor cellularity, nuclear pleomorphism, mitotic activity, vascular proliferation, and necrosis. To be high grade, the tumor had to contain two anaplastic features, one of which was frequent mitoses or endothelial proliferation. To be an oligoastrocytoma, a 25% or greater oligodendroglioma component was required. The diagnosis was confirmed by central pathology review on all patients before random assignment. Eligible patients also had a Karnofsky performance score (KPS) of 60 and adequate hematologic, pulmonary, renal, and hepatic function (absolute neutrophil count 1.5 x 109/L, platelets 150 x 109/L, oxygen diffusing capacity 60%, serum creatinine  1.5x the upper limit of normal [ULN], total bilirubin 1.5x ULN, and liver function tests < 2x ULN). Patients with other serious illnesses or pregnancy were ineligible. All study centers had institutional review board approval, and all patients consented in writing.
Study Design and Treatment
Except for timing, RT was prescribed identically in the experimental and control arms. Patients randomly assigned to PCV plus RT were required to begin RT within 6 weeks of the final dose of chemotherapy. The total RT dose was 59.4 Gy in 33 fractions (1.8 Gy each), administered 5 days a week (Monday through Friday). Megavoltage irradiation (
Corticosteroid medications were permitted for cerebral edema, antiemetics were permitted for nausea or vomiting, and anticonvulsants were permitted for seizures. Deletions of chromosomes 1p and 19q were evaluated by fluorescence in situ hybridization analysis on tumor tissue sections as described elsewhere.10 The primary end point was overall survival. Secondary end points were progression-free survival, frequency of severe (
Surveillance and Follow-Up
Statistical Analysis
Patients From July 1994 to March 2002, 289 eligible patients from 76 institutions were randomly assigned to PCV plus RT (n = 147) or RT alone (n = 142); 50% were enrolled at 12 centers. Ten randomly assigned patients (five in each arm) were declared ineligible. In the experimental arm, the reasons for ineligibility were varied and included the following: pregnancy (n = 1), missing baseline KPS (n = 1), failure to obtain a planning MRI (n = 1), incorrect diagnosis (n = 1), and missing documentation of central pathology review (n = 1). In the control arm, the reasons for ineligibility pertained to the diagnosis (n = 2) or central review process. Sixty-nine percent of participants were under age 50 years, 60% were male, 88% had debulking surgery, 90% had a KPS 80, and 74% had an AO or oligodendroglioma-dominant AOA. Moreover, the treatment groups were well balanced with respect to age, sex, KPS, imaging features, extent of resection, pure versus mixed histology, degree of anaplasia (moderate v high), and corticosteroid requirements at baseline (Table 1). Unstained sections were available for fluorescence in situ hybridization analysis on 206 (71%) of 289 eligible patients; 1p and 19q deletion status was successfully ascertained in 201 patients (70%). The median duration of follow-up was 5.1 years (range, 3 to 93 months).
Patient Disposition and Treatment Delivery The median time from diagnosis to the start of treatment was 5 weeks (range, 1 to 14 weeks) in the experimental arm and 6 weeks (range, 1 to 12 weeks) in the control arm (Table 2). Chemotherapy was delivered per protocol in 72% of patients; minor or acceptable variations occurred in 17% and 6% of patients, respectively. In 4% of patients, PCV was either administered incorrectly or could not be verified. Fifty-four percent of patients received four cycles of PCV (wholly or partly), 22% received three, 10% received two, 12% received one, and 1% did not receive PCV despite being randomly assigned to PCV plus RT. Forty-eight percent of patients completed all four cycles of the dose-intensive PCV formulation used in the study. The reasons for stopping PCV were progression or death, toxicity, patient refusal, and physician preference. RT was administered per protocol or acceptably in 76% of PCV patients and in 82% of controls; unacceptable variations occurred in 6% and 8% of patients, respectively. Because of progression, death, or patient preference, RT was stopped in 10% of patients in the experimental arm and 5% of patients in the control arm. RT delivery could not be confirmed in 7% of patients in the experimental arm and 5% of patients in the control arm.
Survival Thirty-eight months after the last patient was enrolled, 158 (55%) of 289 patients had died (75 of 147 patients in the experimental arm and 83 of 142 patients in the control arm). The unadjusted HR for death after PCV plus RT versus RT alone was 0.90 (95% CI, 0.66 to 1.24; log-rank P = .26), indicating that survival was not prolonged by PCV plus RT at diagnosis. The median survival time was 4.9 years in the PCV plus RT group and 4.7 years in the RT group (Table 3 and Fig 1). Progression-free survival time was prolonged by PCV plus RT (HR = 0.69; 95% CI, 0.52 to 0.91; log-rank P = .004). Median progression-free survival time was 2.6 years with PCV plus RT compared with 1.7 years with RT alone (Fig 2).
Safety Patients randomly assigned to the experimental arm experienced significant toxicity. Sixty-five percent of patients (94 of 144 patients) had a grade 3 (48 of 144 patients, 33%) or 4 (46 of 144 patients, 32%) toxic reaction on PCV. The most frequent severe toxicities were hematologic (n = 80), neurologic (cognitive or mood change and peripheral or autonomic neuropathy, n = 19), GI (nausea and vomiting, n = 13), hepatic (n = 6), and dermatologic (n = 6). One corticosteroid-dependent patient developed a severe pulmonary infection while neutropenic and died. Serious toxicities were uncommon during RT. Twelve patients (8%) in the PCV plus RT arm and seven patients (5%) in the RT arm had grade 3 or 4 toxicity (Table 4). Late toxicities were uncommon, occurring in 4% and 5% of patients in the experimental and control groups, respectively. No instances of dementia or radionecrosis have been reported in either group.
Treatment at Progression For patients randomly assigned to RT, PCV at recurrence was recommended. In May 2005, 177 (61%) of 289 patients had experienced progression, including 76 (52%) of 147 patients in the experimental arm and 101 (71%) of 142 controls. Rates of salvage chemotherapy differed significantly between the groups. At progression, 81 (80%) of 101 patients assigned to RT received salvage chemotherapy compared with 29 (37%) of 76 patients assigned to PCV plus RT. In the control arm, the cytotoxics used at progression were PCV (n = 21), temozolomide (n = 10), both PCV and temozolomide (n = 11), or neither PCV nor temozolomide (n = 12) or were unspecified (n = 27). In the experimental arm, a variety of cytotoxics was used, often temozolomide (n = 14). Response to salvage chemotherapy was not recorded. Other therapies at progression included second surgery, focused reirradiation, and investigational maneuvers. Rates of second surgery also differed significantly between the groups. Sixty-one (60%) of 101 patients in the control group had second surgery compared with 30 (39%) of 76 patients assigned to PCV plus RT. Whether differences in the intensity or effectiveness of treatment at recurrence had a disproportionately favorable influence on the overall survival of patients in the control group is open to speculation.
Chromosomal Analysis
There was no effect of treatment on survival analyzed by genotype (Fig 4). For 1p- and 19q-deleted patients, the HR for death after PCV plus RT versus RT alone was 0.81 (95% CI, 0.40 to 1.65; log-rank P = .28; median survival time, not reached v 6.6 years, respectively). Similarly, for patients with tumors with other genotypes, treatment had no effect on survival (HR = 0.91; 95% CI, 0.58 to 1.42; log-rank P = .33; median survival time, 2.7 years for PCV plus RT v 2.8 years for RT only). The lower risk of progression after PCV plus RT compared with RT only was statistically significant only for the patients with both 1p and 19q deletions (HR = 0.42; 95% CI, 0.24 to 0.75; log-rank P = .001; median progression-free survival time, not reached v 2.6 years, respectively; Fig 5). For the other patients, initial treatment had no significant effect on the risk of progression (HR = 0.78; 95% CI, 0.51 to 1.18; log-rank P = .12; median progression-free survival time, 1.4 years for PCV plus RT v 1.0 years for RT only).
Cox Multivariate Regression Analysis The influence of genetic and clinical variables on survival was analyzed in the Cox proportional hazards models with assigned treatment, age, KPS, and number of anaplastic features as fixed covariates. Loss of 1p, loss of 19q, younger age, normal neurologic function, moderate anaplasia, debulking surgery, and unifocality on baseline imaging were independently associated with longer overall survival time, whereas sex, race, tumor histology, and corticosteroid use were not. Loss of 1p, PCV therapy, younger age, moderate anaplasia, and unifocality predicted longer progression-free survival time. Loss of 19q was not associated with progression-free survival in the final Cox model.
This study, conceived in the early 1990s, tested the hypothesis that a dose-intensive PCV formulation administered immediately before RT would prolong the survival of patients with newly diagnosed AO and AOA compared with RT alone, which was then the standard of care for all types of anaplastic glioma. The idea that a recognizable subtype of malignant glioma might be cured by intensive initial therapy was an exciting prospect in 1994.12,13 Instead, this study and a similar trial in Europe14 demonstrate that PCV plus RT at diagnosis is not a better initial management strategy for AO and AOA compared with RT alone. Because most patients in the control group received PCV or similar chemotherapy at progression, one could argue that this study actually tested the hypothesis that intense initial therapy with PCV and RT is superior to sequential treatment for AO and AOA; it is not. This result stands in sharp contrast to the findings in the study by Stupp et al,15 in which the survival of patients with glioblastoma was prolonged by temozolomide plus RT at diagnosis. Why might early chemotherapy be effective for glioblastoma, a chemotherapy-resistant cancer, but not oligodendroglioma, a chemotherapy-sensitive cancer? Two possibilities come to mind. First, compared with glioblastoma, AO and AOA have favorable natural histories, which is a characteristic that may be a more important determinant of survival than any combination or sequence of noncurative therapies, like PCV and RT. Second, temozolomide, which also alkylates DNA, is well tolerated compared with PCV. Temozolomide can be administered daily during RT without significant myelosuppression,15 whereas toxicity precludes chemoradiotherapy with PCV. The fact that progression-free survival was prolonged by adding PCV to RT at diagnosis suggests that early chemotherapy may have the potential to improve overall survival as well. Such potential might be realized by a drug like temozolomide, which is less toxic and can be administered daily with RT. Indeed, temozolomide has significant antioligodendroglioma activity.16,17 During the trial, retrospective studies drew attention to a possible association between 1p and 19q allelic loss and radiographic response to PCV, durable response to PCV, long progression-free survival after RT, and long overall survival in patients with AO.8,9,18-23 In this study, tumor tissue was available for analysis in 71% of patients. Codeletion of 1p and 19q was detected in 46% of assessable patients. Patients whose tumors harbored a codeletion of 1p and 19q lived far longer than all other patients. In the Cox multivariate regression analysis, 1p loss and 19q loss were independent predictors of overall survival, suggesting that tumors with 1p or 19q loss, but especially a codeletion, have a more favorable natural history, response to treatment, or both. Indeed, tumors with 1p and 19q codeletion are a clinically and biologically distinct subgroup of oligodendrogliomas. A post hoc analysis of the interaction of treatment and genotype showed that treatment assignment had no effect on survival. For both the 1p and 19q codeleted patients and the other patients, adding PCV to RT at diagnosis did not prolong life. Of note, the progression-free survival benefit observed in patients randomly assigned to PCV plus RT was only statistically significant in the 1p and 19q subset. This finding provides further evidence that loss of 1p and 19q is both a predictive and prognostic marker in AO and AOA, supporting earlier results linking this codeletion with radiographic response to PCV.8 Whether 1p and 19q loss is a relative or absolute marker of chemotherapy sensitivity is unresolved by these data. This study successfully examined the treatment of an uncommon brain tumor, demonstrating that multimodality treatment at diagnosis is no more effective in prolonging survival than a measured approach to initial treatment, using RT and chemotherapy sequentially, as needed. Although progression-free survival was prolonged by early intensive treatment, PCV plus RT at diagnosis was accompanied by substantial chemotherapy-related toxicity. Finally, this study confirmed the biologic and clinical importance of allelic loss of chromosomes 1p and 19q in AOs and AOAs, setting the stage for future trials designed specifically for patients with 1p and 19q codeletion.
The following cooperative groups, institutions, and investigators supported the trial: Radiation Therapy Oncology Group: Akron City Hospital, Akron, OH (William Demas, MD); Albert Einstein Medical Center, Philadelphia, PA (Sucha Asbell, MD); Christiana Care Health System, Newark, DE (Adam Raben, MD); Cleveland Clinic Foundation, Cleveland, OH (John Suh, MD); Community Clinical Oncology Programs (CCOPs) in Columbus, OH (Larry Berk, MD), Greenville, SC (Jeannette Wilcox, MD), Kansas City, MO (William Stephenson, MD), Metro-MN, St Louis, MN (Paul Sperduto, MD), Ochsner Clinic, New Orleans, LA (Carl Kardinal, MD), Southeast Cancer Control Consortium, Winston-Salem, NC (James Atkins, MD), and Upstate Carolina, Spartanburg, SC (James Bearden, MD); Southern Nevada Cancer Research Foundation, Las Vegas, NV (Raul Meoz-Mendez, MD); Cross Cancer Institute, Edmonton, Alberta, Canada (Dorcas Fulton, MD) Dana-Farber Cancer Institute, Boston, MA (William Shipley, MD); Dartmouth Hitchcock Medical Center, Lebanon, NH (Eugen Hug, MD); Foundation for Cancer Research and Education, Phoenix, AZ (David Brachman, MD); Fox Chase Cancer Center, Philadelphia, PA (Andre Konski, MD); Hamilton Regional Cancer Center, Hamilton, Ontario, Canada (Anthony Whitton, MD); Hopital Notre-Dame du CHUM, Montreal, Quebec, Canada (Karl Belanger, MD); Johns Hopkins Medical Center, Baltimore, MD (Ding-Jen Lee, MD); Louisiana State University Health Science Center, New Orleans, LA (Jill Gilbert, MD); London Regional Cancer Center, London Ontario, Canada (Gregory Cairncross, MD); LDS Hospital, Salt Lake City, UT (William Sause, MD); Mayo Clinic, Rochester, MN (Jan Buckner, MD); McGill University, Montreal, Quebec, Canada (Luis Souhami, MD); M.D. Anderson Cancer Center, Houston, TX (Ritsuko Komaki, MD); Medical College of Wisconsin, Milwaukee, WI (Elizabeth Gore, MD); New York University Medical Center, New York, NY (Michael Gruber, MD); Radiological Associates of Sacramento, Sacramento, CA (Christopher Jones, MD); State University of New York Health Science Center, Brooklyn, NY (Marvin Rotman, MD); Thomas Jefferson University Medical Center, Philadelphia, PA (Walter Curran, MD); Tom Baker Cancer Centre, Calgary, Alberta, Canada (Peter Forsyth, MD); University of Alabama Birmingham Medical Center, Birmingham, AL (Ruby Meredith, MD, PhD); University of California Davis Medical Center, Davis, CA (Janice Ryu, MD); University of California San Francisco, San Francisco, CA (Michael Prados, MD); University of Kentucky Medical Center, Louisville, KY (Roy Patchell, MD): University of Pennsylvania Medical Center, Philadelphia, PA (Peter Phillips, MD); University of Rochester, Rochester, NY (Paul Okunieff, MD); Wake Forest University Medical Center, Winston-Salem, NC (Edward Shaw); Washington University, St Louis, MO (Jeff Michalski, MD), and Wayne State University, Detroit, MI (Lisa Rogers, MD). Southwest Oncology Group: Cleveland Clinic Foundation, Cleveland, OH (Thomas Budd, MD); CCOPs—Columbus, Columbus, OH (Philip Kuebler, MD, PhD) Montana, Billings, MT (Patrick Cobb, MD), St Louis, St Louis, MO (Bethany Sleckman, MD), Northwest, Puget Sound, WA (Dustan Osborne, MD), and Wichita, Wichita, KS (Dennis Moore, MD); Henry Ford Hospital, Detroit, MI (Robert Chapman, MD); Loyola University, Chicago, IL (George Kovach, MD); Ohio State University, Columbus, OH (Paul Manuszak, MD); Providence Hospital, Southfield, MI (Howard Terebelo, MD); Puget Sound Oncology Consortium, Puget Sound, WA (Alex Spence, MD); University of Colorado, Denver, CO (Russell Tolley, MD); University of Michigan, Ann Arbor, MI (Laurence Baker, DO); University of New Mexico, Albuquerque, NM (Cheryl Willman, MD); University of Texas Southwestern, Dallas, TX (Karen Fink, MD, PhD); and University of Utah, Salt Lake City, UT (Thomas Warr, MD). North Central Cancer Treatment Group: Medcenter One Health Systems, Bismarck, ND (Edward Wos, DO); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA (Martin Wiesenfeld, MD); Iowa Oncology Research Association CCOP, Des Moines, IA (Roscoe Morton, MD); Michigan Cancer Consortium, Ann Arbor, MI (Philip Stella, MD); Meritcare Hospital CCOP, Fargo, ND (Preston Steen, MD); Geisinger Clinic and Medical Center CCOP, Danville, PA (Albert Bernath, MD); Illinois Oncology Research Association CCOP, Peoria, IL (John Kugler, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, OH (Paul Schaefer, MD); Mayo Clinic and Mayo Foundation, Rochester, MN (Steven Alberts, MD); and CentraCare Clinic, St Cloud, MN (Harold Windschitl, MD). National Cancer Institute of Canada Clinical Trials Group: British Columbia Cancer Centre, Fraser Valley Centre, Surrey, British Columbia, Canada (Alexander Agranovich, MD); Toronto Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada; and University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada (Normand Laperierre, MD). Eastern Cooperative Oncology Group: Beth Israel Deaconess Hospital, Boston, MA (Michael Atkins, MD); Guthrie Clinic for Education and Research, Sayre, PA (Goran Broketa, MD); Hennepin County Medical Center, Minneapolis, MN (Daniel Schneider, MD); St Anthony's Medical Center, Rockford, IL (Laura Cisneros, MD); University of Florida Medical Center, Gainesville, FL (Robert Marsh, MD); and Western Michigan Cancer Center, Kalamazoo, MI (Raymond Lord III, MD).
The authors indicated no potential conflicts of interest.
We are indebted to the patients who agreed to participate in this study and also to the nurses and managers at participating institutions, office staff of the participating groups, and staff in the pathology and molecular genetics laboratories of the Mayo Clinic whose support was critical to the success of this large trial.
Supported by National Cancer Institute Grants No. U10 CA21661 and U10 CA32115 to the Radiation Therapy Oncology Group; U10 CA25224 to the North Central Cancer Treatment Group; CA23318, CA66636, and CA2115 to the Eastern Cooperative Oncology Group; and U10 CA37422 to Community Clinical Oncology Programs. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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ABSTRACT
INTRODUCTION
