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Kendra Peterson, M.D., Nina Paleologos, M.D., Peter Forsyth, M.D., David R. Macdonald, M.D., and J. Gregory Cairncross, M.D., for the Oligodendroglioma Study Group
Department of Neurology, University of Minnesota, Minneapolis, Minnesota; Department of Neurology, Evanston Hospital, Evanston, Illinois; Department of Clinical Neurosciences, University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta, Canada; and Departments of Clinical Neurological Sciences and Oncology, University of Western Ontario and London Regional Cancer Centre, London, Ontario, Canada
The authors present their experience with salvage chemotherapy for oligodendroglioma, an uncommon brain tumor that responds predictably to PCV (procarbazine, lomustine (CCNU), and vincristine) when given as initial therapy. The authors reviewed the records of patients with oligodendrogliomas who received a second, third, or fourth cytotoxic regimen prescribed to combat tumor recurrence documented by computerized tomography or magnetic resonance imaging following an initial chemotherapy program. Initial regimens were prescribed at various time points: as neoadjuvant therapy prior to radiotherapy, as adjuvant therapy in conjunction with radiotherapy, or at recurrence following radiotherapy. Response criteria were based on measurable changes in tumor size following published guidelines. Twenty-three patients (14 men and nine women) aged 25 to 58 years (median 36 years) received 33 salvage regimens. When non-PCV chemotherapy had been the prior regimen, seven (88%) of eight patients responded to salvage chemotherapy, all seven (100%) responding to PCV. Administration of PCV was effective after regimens of carmustine and CCNU but was ineffective after prior administration of PCV. When PCV had been given any time previously, only four (19%) of 21 patients responded to salvage chemotherapy; however, four (40%) of 10 patients who received etoposide (VP-16)/cisplatin (CDDP) responded. Despite the small number of patients, two noteworthy trends emerge from these data: first, PCV is a highly effective salvage treatment when used at tumor recurrence following non-PCV chemotherapy regimens; second, the synergistic combination of VP-16 and CDDP may exert substantial antioligodendroglioma activity, and it warrants further evaluation.
Key Words * cisplatin * etoposide * procarbazine lomustine vincristine * chemotherapy * glioma * oligodendroglioma * PCV
Oligodendroglioma is a chemosensitive brain tumor. In striking contrast to other types of malignant glioma, anaplastic oligodendroglioma responds predictably to chemotherapy.[4] Responses have been observed to a variety of drugs,[13,57,10,13,16] principally alkylating agents, and PCV (procarbazine, lomustine (CCNU), vincristine)[11] has emerged as the treatment of choice. As currently configured, PVC displays substantial antioligodendroglioma activity. Nevertheless, recurrent tumors that previously had been irradiated are not cured by a course of PCV[1,37,10,16] and most newly diagnosed tumors are unlikely to be cured by a combination of PCV and radiation therapy.[6,14] In both instances, local regrowth is the rule. Dose intensification using bone marrow support is one strategy for improving the effect of PCV;[9,15] however, a careful search for other active compounds to augment, complement, or replace PCV may be rewarding.[17] Our experience using salvage chemotherapy in the treatment of patients with recurrent oligodendroglioma, including PCV as a salvage treatment, is summarized in this report.
Clinical Material and Methods
Patient Population
We reviewed the records of 23 patients with oligodendroglioma who received salvage chemotherapy: 15 patients were treated at the London Regional Cancer Centre, London, Ontario, Canada; five at Evanston Hospital, Evanston, Illinois; two at the University of Minnesota Medical Center, Minneapolis, Minnesota; and one at the Tom Baker Cancer Centre, Calgary, Alberta, Canada. Patients included in this study had either anaplastic oligodendrogliomas or symptomatic, enlarging, enhancing nonanaplastic tumors, called aggressive oligodendrogliomas by Macdonald and coauthors.[13]
Administration of Chemotherapy
Salvage chemotherapy was administered after radiotherapy in all patients. For the purposes of this report the chemotherapies are defined as second, third, and fourth regimens prescribed for computerized tomography (CT) or magnetic resonance (MR) imagingdocumented tumor recurrence following an initial chemotherapy program. The initial regimens had been prescribed at various time points: as neoadjuvant therapy prior to radiotherapy, as adjuvant therapy in conjunction with radiotherapy, or at recurrence following radiotherapy. Both PCV and intensive PCV (I-PCV) were administered as previously described;[2,11] the details of other salvage and initial chemotherapy regimens are summarized in Table 1.
As advocated by Macdonald and coauthors,[12] the responses to salvage chemotherapy were based on measurable changes in the largest cross-sectional area of the enhancing tumor on CT or MR images. Responses were defined as follows: complete response, disappearance of all enhancing tumor with the patient not using corticosteroid medications and appearing neurologically stable or improved; partial response, at least a 50% decrease in tumor size with the corticosteroid dose stable or reduced and the patient appearing neurologically stable or improved; progressive disease, at least a 25% increase in tumor size or any new area of tumor appearing on a follow-up image with the corticosteroid dose stable or increased and the patient appearing neurologically stable or worse; and stable disease, all other situations. (Minor responses (25%49% reduction in tumor size) were recorded; however, for the purposes of our analysis they were grouped with stable disease.) The same criteria had been used to assess patient responses to the initial chemotherapy. In situations in which there had been no evidence of disease on postoperative or postradiotherapy CT or MR images, patients were deemed not capable of being evaluated for response to initial chemotherapy. For both salvage and initial treatments, the duration of response or stable disease was defined as the interval in months from the start of chemotherapy to the date of CT or MRdocumented tumor progression; when progressive disease was evident at the time of the first evaluation (that is after one or two cycles of salvage chemotherapy), the duration of response was considered to be "0" months.
RESULTS
Twenty-three patients (14 men and nine women) aged 25 to 58 years (median 36 years) received at least one salvage chemotherapy regimen for a recurrent oligodendroglioma. Twenty-two of the patients had anaplastic oligodendrogliomas and one had an aggressive nonanaplastic tumor. Initial chemotherapies had been given as neoadjuvant treatment in six patients, as adjuvant treatment in three, and at tumor recurrence following radiotherapy in 14 patients (Table 2). Fifteen patients received a course of PCV (or I-PCV) as the initial regimen and were designated "Group A." Six of these patients received PCV (or I-PCV) as neoadjuvant treatment and nine received PCV (or I-PCV) after radiotherapy for recurrent tumor. Eight patients underwent another initial regimen (two patients received carmustine (BCNU); one patient, CCNU; two patients, aziridinylbenzoquinone (AZQ); two patients, melphalan; and one patient, fludarabine); these patients were designated "Group B." Three of these patients received their initial chemotherapy as adjuvant treatment and five received it after radiotherapy for recurrent tumor.
With respect to the initial chemotherapy, in Group A three patients had exhibited a complete response; eight, a partial response; one, stable disease; and three could not be evaluated. Thus 11 (92%) of the 12 assessable patients had initially exhibited a response to chemotherapy. The times to progression of disease after initial chemotherapy for the patients in Group A ranged from 6 to 54 months (median 15 months). In Group B one patient had shown a complete response to CCNU; three, a partial response (one to administration of BCNU and two to melphalan); and one patient, stable disease after receiving fludarabine. Two patients could not be evaluated (one had received BCNU and the other AZQ) and one patient displayed progressive disease after receiving AZQ. Thus four (67%) of six assessable patients had shown a response to the initial chemotherapy. The times to progression of disease after the initial chemotherapy for patients in Groups B ranged from 0 to 32 months (median 15 months).
Patients in Groups A and B received a total of 33 salvage chemotherapy regimens: 14 patients had one salvage regimen, eight had two, and one had three (Table 3). Patients in Group A (that is, those who received a course of PCV initially) had 17 salvage regimens and responded as follows: one patient exhibited a complete response to etoposide (VP-16)/cisplatin (CDDP); two patients had a partial response to VP-16/CDDP; three patients had stable disease (one after receiving melphalan; one after VP-16; and one after cyclophosphamide); and 11 patients showed progressive disease (five patients received VP-16/CDDP; one patient, VP-16; two patients, carboplatin; one, AZQ; one, thiotepa; and one, I-PCV). Times to progression of disease were 5, 11, and 12 months for responders and 4, 5, and 10 months for those with stable disease. (Note: two responders (Cases 9 and 13) were administered high doses of thiotepa followed by autologous bone marrow reconstitution after their responses were induced with VP-16/CDDP.) Patients in Group B (that is, those receiving chemotherapeutic drugs other than PCV initially) received 16 salvage regimens and responded as follows: one patient exhibited a complete response to PCV; eight showed a partial response (six to PCV; one to AZQ; and one to VP-16/CDDP); two patients who received melphalan had stable disease; and five displayed progressive disease after chemotherapy (one treated with AZQ; one with VP-16/CDDP; two patients with CDDP; and one with PCV). Times to progression of disease ranged from 4 months (response was ongoing when the patient died of leukemia) to 36 months (median 13 months) for responders and, 3 and 4 months for patients with stable disease.
Of the 21 patients who had been given PCV (or I-PCV) at any time previously, only four (19%) responded to salvage chemotherapy, all of whom responded to VP-16/CDDP. Of note, four (40%) of the 10 patients who received VP-16/CDDP responded, whereas VP-16, CDDP, and CBDCA were ineffective when used alone in two patients each. When chemotherapy did not include PCV as the prior regimen, seven (88%) of eight patients responded to salvage chemotherapy. All seven patients (100%) responded to PCV. The eighth exhibited progression of disease after a course of AZQ. Of note, both patients (Cases 17 and 18) who received PCV as a salvage regimen after prior treatment with a nitrosourea (BCNU or CCNU) showed a response, whereas no patient (Cases10 and 21) who received PCV as salvage therapy after remote prior treatment with PCV responded.
The standard dose of PCV was well tolerated after other initial regimens but post-PCV salvage therapies, especially those including a course of melphalan and cyclophosphamide, caused significant myelosuppression, which resulted in dose reductions and delays. Seventeen patients have died, 16 of progressive disease and one (Case 22) of acute leukemia. As of this writing, six patients (Cases 3, 5, 9, 13, 14, and 15) are alive with disease.
DISCUSSION
The cases described in this report were managed in various ways with regard to timing and type of treatment; however, all the patients had a specific type of aggressive glioma, namely oligodendroglioma. Despite the treatment variability, several interesting trends emerge from these data. First, the general usefulness of PCV chemotherapy in treating oligodendroglioma and the remarkable chemosensitivity of this tumor type are highlighted in this review; 92% of chemotherapy-naive patients with measurable disease reponded to administration of PCV (or I-PCV) and 67% responded to other initial alkylating agent regimens, notably those including BCNU, CCNU, and melphalan. Second, and perhaps most important in the context of this report, PCV is a highly effective salvage treatment for tumor recurrence following non-PCV chemotherapy regimens; 100% of PCV-naive patients responded to a course of PCV. Third, patients with oligodendrogliomas that respond to single-agent treatment with nitrosoureas may have durable responses to salvage therapy with PCV (two patients), but responders to an initial course of PCV may have PCV-resistant disease at recurrence (two patients). Finally, although the rate of response to salvage chemotherapy regimens in PCV-treated patients is low (19%), VP-16/CDDP may have considerable antioligodendroglioma activity; 40% of patients responded to this synergistic salvage regimen.
These assertions are based on our experience with relatively few patients, but if correct, they have implications for future studies of anaplastic or aggressive oligodendroglioma that address chemotherapy issues. First, PCV is a highly effective systemic therapy for malignant gliomas of oligodendroglial derivation. It is so effective that curative regimens, should they emerge in the next few years, almost certainly will be rooted in PCV. Strategies to support or replenish the bone marrow may be essential to the successful implementation of increasingly myelotoxic PCV-based therapies. Our group is currently evaluating the role of high-dose chemotherapy in the treatment of selected patients with newly diagnosed and recurrent aggressive oligodendrogliomas using autologous hematopoietic support. Second, because PCV is such a dependable salvage regimen, intentionally witholding this drug regimen while investigating the antioligodendroglioma properties of other compounds on chemotherapy-naive patients is a clinical research strategy worth considering. This might allow active agents to be identified more readily than would be possible in patients with recurrent disease rendered drug resistant by prior treatment with PCV. This strategy could be applied neoadjuvantly or at first recurrence after surgery and radiotherapy. Because PCV is a palliative treatment, we believe this approach can be justified on both ethical and scientific grounds. Third, durable responses to PCV in patients treated previously with BCNU or CCNU would suggest that procarbazine, vincristine, or both have significant antioligodendroglioma activity and are important components of PCV. Fourth, a course of VP-16/CDDP appears to be an active treatment for this disease; the response rate to administration of these drugs at recurrence in patients who have undergone a previous course of PCV was 40% and included a complete response in one patient. We have no data on response rate of chemotherapy-naive patients with oligodendroglioma to a regimen of VP-16/C DDP, but if it is comparable to that of PCV, it may prove to be a preferable initial therapy because VP-16/CDDP may be less likely to deplete bone marrow stem cells. Although on the bases of these data it is tempting to suggest that VP-16/CDDP is an active noncross-resistant regimen, worth adding to PCV (or I-PCV) in alternating cycles as advocated by Goldie and Coldman,[8] we have treated too few patients with salvage PCV after they have undergone a prior regimen of PCV to state with confidence that nonresponse in this situation is due to acquired PCV resistance or that retreatment with PCV has no therapeutic value.
Two final points merit comment. First, we have used various alkylating agentbased salvage regimens; however, in a recent description of a complete radiographic response to 5-fluorouracil/folinic acid in a patient with an anaplastic oligodendroglioma that was poorly responsive to PCV, Stewart, et al.,[18] raise the possibility that other classes of cytotoxic drugs, such as the antimetabolites, may display substantial antioligodendroglioma activity. Second, salvage chemotherapy regimens generally are evaluated in patients who responded to prior regimens rather than to those who do not respond. For this reason a bias emerges in favor of higher rates of response to second-line therapies in such studies; our results should be viewed in this light.
Acknowledgments
The authors thank P. Gray for preparing the manuscript. We also acknowledge the assistance of other members of the Oligodendroglioma Study Group, namely E. Dropcho, Indiana University Medical Center, Indianapolis, Indiana; L. DeAngelis, Memorial Sloan Kettering Cancer Center, New York, New York; S. Rosenfeld, University of Alabama at Birmingham, Birmingham, Alabama; and L. Swinnen, Loyola University Medical Center, Maywood, Illinois.
References
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2. Cairncross G, Macdonald D, Ludwin S, et al: Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 12:20132021,1994
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6. Duffan H, Albuquerque L, Ameri A, et al: Chemotherapy for newly diagnosed and recurrent anaplastic oligodendrogliomas and mixed gliomas: an analysis of 42 cases. Neurology 45(Suppl 4):261, 1995
7. Glass J, Hochberg FH, Gruber ML, et al: The treatment of oligodendrogliomas and mixed oligodendrogliomas-astrocytomas with PCV chemotherapy. J Neurosurg 76:741745, 1992
8. Goldie JH, Coldman AJ: Mathematic model for relating the drug sensitivity of tumors to the spontaneous mutation rate. Cancer Treat Rep 63:17271733, 1979
9. Kedar A, Maria BL, Graham-Pole J, et al: High-dose chemotherapy with marrow reinfusion and hyperfractionated irradiation for children with high-risk brain tumors. Med Pediatr Oncol 23:428436, 1994
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12. Macdonald DR, Cascino TL, Schold SC, et al: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:12771280, 1990
13. Macdonald DR, Gaspar LE, Cairncross JG: Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol 27:573574, 1990
14. Paleologos N, Macdonald D, Vick N, et al: Neoadjuvant (pre-radiation [RT] procarbazine, CCNU and vincristine (PCV) for anaplastic oligodendroglioma (AO) and aggressive oligodendroglioma (AgO). Neurology 45 (Suppl 4):387, 1995 (Abstract)
15. Saarinen UM, Pihko H, Makipernaa A: High-dose thiotepa with autologous bone marrow rescue in recurrent malignant oligodendroglioma: a case report. J Neurooncol 9:5761, 1990
16. Soffietti R, Chio A, Mocellini C, et al: Response of oligodendroglial tumors to PCV chemotherapy. Neurology 44 (Suppl 2):309310, 1994
17. Soffietti R, Chio A, Mocellini C, et al: Treatment with carboplatin of oligodendroglial tumors recurrent after PCV chemotherapy. Neurology 45 (Suppl 4):261, 1995
18. Stewart DJ, Dahrouge S, Soltys K: A phase II study of 5-fluorouracil plus folinic Acid in malignant gliomas in adults. J Neurooncol 23:249252, 1995
Manuscript received December 12, 1995.
Accepted in final form March 25, 1996.
Address reprint requests to: Kendra Peterson, M.D., Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, California 943055235.
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