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Chemoradiation strategies for patients with malignant glioma
Chemoradiation Strategies for Patients With Malignant Glioma Walter]. Curran,]r Malignant gliomas afflict approximately 10,000 patients annually in North America. Typical median survival time for patients with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) ranges from 10 to 12 months and 30 to 40 months, respectively. Randomized controlled trials in the 1960s and 1970s demonstrated that cranial radiation therapy (RTI plus surgery significantly improved median survival; these results have not been reproduced, although more recent trials have established the critical nature of full-dose RT in postoperative therapy. These trials also established the value of adding chemotherapy to RT, particularly in patients under age 60. More recent randomized trials evaluated various chemotherapy regimens as alternatives to nitrosurea, different RT techniques, and preirradiation multiagent chemotherapy. Several observations in the late 1980s led to the development of independent research strategies for patients with GBM tumors, AA lesions, and patients with anaplastic oligodendroglioma, includ-
ing selective use of brachytherapy, various radiosensitizing agents, and the development of a novel statistical approach to patient grouping by prognostic characteristics and survival (RPA classes). Induction chemotherapy before radiation also has been evaluated and is currently being tested in an Intergroup randomized trial. Other clinical trials evaluating new chemotherapy and radiosensitizing agents including tirapazamine, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), and topotecan currently are under way. It is unlikely that anyone systemic or multiagent regimen will substantially change the natural history of malignant glioma. Substantial opportunities for improved survival will only come when attempts to improve both surgical and radiotherapeutic approaches to this disease are exploited simultaneously with new drug development programs. Copyright© 1997 by WH. Saunders Company
alignant gliomas affiict approximately 10,000 patients per year in North America. Despite improvements in operative and perioperative management, radiotherapeutic techniques, and supportive management, little progress has been made in prolonging survival for the majority of patients with malignant glioma. Since the publication of the Brain Tumor Study Group (BTSG) 6901 study results in the late 1970s, the standard management of most patients with malignant glioma has been maximal surgical resection without compromise of neurologic function, followed by postoperative cranial radiation therapy (RT) to 60 Gy with or without nitrosoureabased chemotherapy.l Typical median survival times (MSTs) for patients with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) with such approaches are 10 to 12 months and 30 to 40 months, respectively. 2
early 1970s, several trials randomized patients to postoperative regimens containing cranial RT or to surgery alone. In both BTSG 690 I and the trial conducted by the Scandinavian Glioblastoma Study Group,3 there was a doubling or greater of MST favoring the RT-containing arms. In these two trials, the MSTs for patients receiving combined therapy versus surgery alone were 35 and 16 weeks and 44 and 21 weeks, respectively. Unfortunately, no such major improvements have been observed since those trials. These trials did establish the critical nature of using full-dose RT as a component of postoperative therapy. Additionally, both BTSG 690 I and its successor trial, BTSG 7201, demonstrated a small but statistically significant difference in survival favoring the arms containing RT and either carmustine or lomustine chemotherapy, particularly among patients under age 60. 1,4 These trials created the standard of care for the past 20 years. During the 1970s and 1980s, a number of randomized trials compared alternative systemic regimens plus cranial RT with a nitrosourea/RT regimen. These approaches included other chemotherapeutic agents such as hydroxyurea, procarbazine, and VM265 and RT sensitizers such as misonidazole. 6 Unfortunately, no survival advantages were reported from any of these trials. Since the mid-1980s, several randomized trials have evaluated the influence of using a radiotherapeutic "boost" technique on survival. Because the vari-
M
Randomized Trials: Designs and Results The randomized trials conducted by the cooperative groups could be simplistically categorized in the following manner. In the late 1960s and From the Department ofRadiation Oncology,jifferson Medical College, ThomasJifferson Universiry, Philadelphia, PA. Address reprint requests to Walter j. Curran, Jr, MD, Department of Radiation Oncology,Jifferson Medical College, ThomasJdftrson Universiry, 111 S 11th St, Philadelphia, PA 19107. Copyright © 1997 by WB. Saunders Company 1053-1296/97/0703-0206$5.00/0
Seminars in Radiation Oncology, Vol 7, No 3, Suppl2 (july), 1997: pp 33-36
33
34
Walter]. Curran,}r
able in these trials was the total RT dose and the techniques employed (altered fractionation, brachytherapy, or stereotactic radiosurgery), the systemic therapy employed was a standard agent such as carmustine. In the past 2 years, at least three randomized cooperative group trials have been activated evaluating the value ofpreirradiation multiagent chemotherapy among selected malignant glioma patients. Further details regarding these trials are provided here.
Patient Selection Until the late 1980s, clinical trials were designed to enroll any newly diagnosed malignant glioma patient. Several observations at that time led to the development of independent research strategies for patients with GBM tumors, AA lesions, and those with anaplastic oligodendroglioma (AO). The observations included two from the Northern California Oncology Group (NCOG) and two from the Radiation Therapy Oncology Group (RTOG). In a phase II trial of 106 patients evaluating removable highactivity iodine-125 brachytherapy, NCOG reported that the survival of AA patients appeared comparable to NCOG historic controls but was superior for GBM patients.7 Based on this finding, follow-up University of California at San Francisco (UCSF) trials included brachytherapy in the management of GBM patients when possible and excluded brachytherapy from AA patient trials. The NCOG also reported an encouraging phase II experience with the halogenated pyrimidine bromodeoxyuridine (BUdR) for AA patients but not for GBM cases. H This led to an independent phase III trial of BUdR for AA patients initially conducted by the UCSF group and ultimately adopted by the RTOG and the Southwest Oncology Group. A phase 1111 trial conducted by the RTOG evaluating the halogenated pyrimidine iododeoxyuridine (IUdR) for AA patients also concluded that such an approach warranted phase III testing. The RTOG reported a novel statistical approach to its malignant glioma patient database called recursive partitioning and ana(ysis (RPA). Based on groupings of patients by prognostic characteristics and survival outcome, a total of six RPA "classes" of patients with malignant glioma were identified, with MSTs ranging from 4 to 59 months. Additionally, the rapid accrual of patients with malignant glioma to the large randomized trial run by the RTOG from 1990 to 1994 evaluating hyperfractionated RT (90-06) confirmed that sufficient patient numbers are avail-
able to conduct distinct trials for specific malignant glioma subgroups.
Preirradiation Chemotherapy The management of several malignancies historically managed with RT alone has been selectively improved with the use of two or more cycles of preirradiation multiagent chemotherapy. Included in this group is stage III non-small cell lung cancer, central nervous system lymphoma, and bulky Hodgkin's disease. In order to benefit from pre-RT chemotherapy, at least two criteria must be met. First, there must be a reasonable likelihood of tumor response to the induction chemotherapy, and second, the patient must be sufficiently asymptomatic as to not require immediate RT. Among malignant glioma patients, those patients most likely to sustain a therapeutic response to induction chemotherapy are those with AO. These tumors, which constitute 5% to 8% of most malignant glioma series, demonstrated a 75% response rate to the regimen of procarbazine, lomustine, and vincristine (PCV) in a prospective National Cancer Institute of Canada trial. lO This experience has led to the current Intergroup randomized trial comparing four cycles of PCV followed by cranial RT with cranial RT alone. This trial was initiated in 1994, is coordinated by the RTOG, open in four other cooperative groups, and scheduled to accrue 200 to 300 patients. Despite a low response rate to chemotherapy among GBM patients and the symptomatic nature of most GBM tumors, induction chemotherapy also has been evaluated for this patient cohort. Investigators at Johns Hopkins University and the University of Pittsburgh report a phase II experience using continuous infusion carmustine and cisplatin prior to cranial RT.ll Although no obvious advantage over standard therapy was clearly demonstrated, this regimen is now being tested in a phase III Eastern Cooperative Oncology Group trial versus immediate standard RT and concurrent carmustine for GBM and AA patients. The same agents using a different schedule also are being tested in a similar phase III trial within the North Central Cancer Treatment Group. It is likely that the therapeutic benefit of pre-RT chemotherapy will only be observed among chemosensitive malignant glioma patients who have relatively asymptomatic lesions or who have undergone an aggressive surgical resection.
Chemoradiationflr Malignant Glioma
New Agents Currently, the RTOG has taken the POSItIon that there is no sufficiently promising phase II experience for radiosurgery-ineligible GBM patients to warrant a phase III trial. Therefore, the group has embarked on a series of phase I and II trials testing new systemic agents with cranial RT. By partitioning enrolled patients into RPA "classes," the group hopes to identify which phase II survival data are sufficiently promising to warrant phase III testing. Each of the approaches has its own rationale, and some of the new agents have a unique interaction with ionizing RT. Tirapazamine (WIN 59075) is a benzotriazine compound exhibiting substantial differential toxicity for hypoxic cells. The combination of tirapazamine with RT may result in greater than additive hypoxic cell toxicity. Preclinical laboratory data supported the theory that tirapazamine will increase the effectiveness of RT against hypoxic tumor cells. 12 Based on these data and clinical support for hypoxia as a contributor to the treatment-resistant nature of malignant gliomas, the RTOG launched a phase II trial of tirapazamine at a dose of 159 mg/m 2 for 12 doses during cranial RT for radiosurgery-ineligible GBM patients. A total of 55 patients were enrolled at this dose level, and subsequently the trial was reopened at a tirapazamine dose of 260 mg/m 2 for 12 doses. The trial is expected to complete accrual in early 1997. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a chemotherapeutic agent approved for use in advanced breast and ovarian cancers with demonstrated evidence of radiosensitization in preclinical tumor models, including astrocytoma cell lines. 13 It appears that paclitaxel can increase the fraction of cells in the most radiosensitive time periods of the cell cycle, G2 and M. A phase I trial of weekly paclitaxel with cranial RT for malignant glioma demonstrated a maximal tolerated dose approaching 250 mg/m 2/wk. 14 Based on this experience, the RTOG is conducting a phase II trial of this agent on a weekly basis for 6 weeks concurrently with cranial RT for GBM at a dose of 225 mg/m 2/wk. Topotecan is a chemotherapeutic agent that exerts its action through inhibition of topoisomerase I. This action can enhance RT damage by preventing DNA repair and cell survival recovery.15 Because modest activity as a single agent was observed among patients with recurrent malignant gliomas, topotecan's potential in conjunction with cranial RT war-
35
ranted further attention. The RTOG is currently conducting a phase I dose-escalation study of topotecan concurrent with cranial RT. The current dose under study is 1.5 mg/m 2 every 3 weeks. After establishment of the maximally tolerated dose, a phase II trial of approximately 55 patients will be conducted.
Future Directions It is unlikely that anyone systemic agent or multiagent regimen will substantially change the natural history of malignant glioma among affiicted patients. A substantial improvement in survival will come only when improvements in the locoregional management are coupled with progress in the systemic management of the disease. Specifically, the substantial opportunities to improve both the surgical and radiotherapeutic approaches to this disease need to be exploited simultaneously with new drug development programs. The substantial progress made in our understanding of glioma pathogenesis should also contribute to these endeavors.
References I. Walker MD, Alexander EJr, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: A cooperative clinical trial.J Neurosurg 49:333-343, 197H 2. Curran WJJr, Scott CB, HortonJ, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Nat! Cancer Inst 85:704-710,1993 3. Kristiansen K, Hagen S, Kollevold T, et al: Combined modality therapy of operated astrocytomas grade III and N. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: A prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 47:649-652, 19H1 4. Walker MD, Green SB, Byar DP, et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N EnglJ Med 303:1323-1329, 19HO 5. Shapiro WR, Green SB, Burger PC, et al: Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group 800 I.J Neurosurg 71: 1-9, 1989 6. Nelson DF, Diener-West M, Weinstein A'l, et al: A randomized trial of misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of malignant glioma after surgery: Final report of an RTOG study. Int J Radiat Oncol BioI Phys 12: 1793-1 HOD, 1986 7. Gutin PH, Prados MD, Phillips TL, et al: External irradiation followed by an interstitial high activity iodine-125 implant "boost" in the initial treatment of malignant gliomas: NCOG Study 6G-82-2. IntJ Radiat Oneol Bioi Phys 21:601-606,1991 8. Levin VA, Prados MR, Wara WM, et al: Radiation therapy and
36
WalterJ. Curran,]r
bromodeoxyuridine chemotherapy followed by procarbazine, lomustine, and vincristine for the treatment of anaplastic gliomas. Int] Radiat Oneal Bioi Phys 32:75-H3, 1995 9. Urtasun RC, Cosmatos D, Oelrowe], et al: lododeoxyuridine (IUdR) combined with radiation in the treatment of malignant glioma: A comparison of short versus long intravenous dose schedules (RTOG H6-12). Int] Radiat Oneal Bioi Phys
27:207-214,1993 10. Cairncross G, Macdonald 0, Ludwin S, et al: Chemotherapy for anaplastic oligdendroglioma: The National Cancer Institute of Canada Clinical Trials Group.] Clin Oncol 12:20132017,1994 II. Gilbert MR, Lunsford LO, Kondziolka D, et al: A phase" trial of continuous infusion chemotherapy, external beam radiotherapy, and local boost radiotherapy for malignant gliomas. Proc Am Soc Clin Oncol 12: 176, 1993 (abstr 500) 12. Brown]M, Lemmon ML: Fractionation increases the antitu-
13. 14.
15.
16.
mor eHect of adding a hypoxic cytoxin to irradiation, in Dewey WC, Edington M, Fry RJM, ct al (eds): Radiation Research: A Twentieth Centul)' Perspective. San Diego, CA, Academic Press, 1992, PI' 807-H 12 Tishler RH, Geard CR, Hall E], et al: Taxol sensitizes human astrocytoma cells to radiation. Cancer Res 52:3495-3497, 1992 Glantz M, Choy H, Cole B, et al: Phase I study of wcekly, outpatient Taxol and concurrent cranial radiation in adults with astrucytomas. Proc Am Soc Clin Oncol 14: 146, 1995 (abstr 279) Mattern MR, Hofmann GA, McCabe FL, et al: Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor toputecan (SK&F 104864). Cancer Res 51:5813-5lJI6, 1991 Eisenhauer EA, Wainman N, Boos G, et al: Phase II trials of topotecan in patients (PTS) with malignant glioma and soft tissue sarcoma. Proc Am Soc Clin Oneal 13:175, 1994 (abstr
4HH)
ing selective use of brachytherapy, various radiosensitizing agents, and the development of a novel statistical approach to patient grouping by prognostic characteristics and survival (RPA classes). Induction chemotherapy before radiation also has been evaluated and is currently being tested in an Intergroup randomized trial. Other clinical trials evaluating new chemotherapy and radiosensitizing agents including tirapazamine, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), and topotecan currently are under way. It is unlikely that anyone systemic or multiagent regimen will substantially change the natural history of malignant glioma. Substantial opportunities for improved survival will only come when attempts to improve both surgical and radiotherapeutic approaches to this disease are exploited simultaneously with new drug development programs. Copyright© 1997 by WH. Saunders Company
alignant gliomas affiict approximately 10,000 patients per year in North America. Despite improvements in operative and perioperative management, radiotherapeutic techniques, and supportive management, little progress has been made in prolonging survival for the majority of patients with malignant glioma. Since the publication of the Brain Tumor Study Group (BTSG) 6901 study results in the late 1970s, the standard management of most patients with malignant glioma has been maximal surgical resection without compromise of neurologic function, followed by postoperative cranial radiation therapy (RT) to 60 Gy with or without nitrosoureabased chemotherapy.l Typical median survival times (MSTs) for patients with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) with such approaches are 10 to 12 months and 30 to 40 months, respectively. 2
early 1970s, several trials randomized patients to postoperative regimens containing cranial RT or to surgery alone. In both BTSG 690 I and the trial conducted by the Scandinavian Glioblastoma Study Group,3 there was a doubling or greater of MST favoring the RT-containing arms. In these two trials, the MSTs for patients receiving combined therapy versus surgery alone were 35 and 16 weeks and 44 and 21 weeks, respectively. Unfortunately, no such major improvements have been observed since those trials. These trials did establish the critical nature of using full-dose RT as a component of postoperative therapy. Additionally, both BTSG 690 I and its successor trial, BTSG 7201, demonstrated a small but statistically significant difference in survival favoring the arms containing RT and either carmustine or lomustine chemotherapy, particularly among patients under age 60. 1,4 These trials created the standard of care for the past 20 years. During the 1970s and 1980s, a number of randomized trials compared alternative systemic regimens plus cranial RT with a nitrosourea/RT regimen. These approaches included other chemotherapeutic agents such as hydroxyurea, procarbazine, and VM265 and RT sensitizers such as misonidazole. 6 Unfortunately, no survival advantages were reported from any of these trials. Since the mid-1980s, several randomized trials have evaluated the influence of using a radiotherapeutic "boost" technique on survival. Because the vari-
M
Randomized Trials: Designs and Results The randomized trials conducted by the cooperative groups could be simplistically categorized in the following manner. In the late 1960s and From the Department ofRadiation Oncology,jifferson Medical College, ThomasJifferson Universiry, Philadelphia, PA. Address reprint requests to Walter j. Curran, Jr, MD, Department of Radiation Oncology,Jifferson Medical College, ThomasJdftrson Universiry, 111 S 11th St, Philadelphia, PA 19107. Copyright © 1997 by WB. Saunders Company 1053-1296/97/0703-0206$5.00/0
Seminars in Radiation Oncology, Vol 7, No 3, Suppl2 (july), 1997: pp 33-36
33
34
Walter]. Curran,}r
able in these trials was the total RT dose and the techniques employed (altered fractionation, brachytherapy, or stereotactic radiosurgery), the systemic therapy employed was a standard agent such as carmustine. In the past 2 years, at least three randomized cooperative group trials have been activated evaluating the value ofpreirradiation multiagent chemotherapy among selected malignant glioma patients. Further details regarding these trials are provided here.
Patient Selection Until the late 1980s, clinical trials were designed to enroll any newly diagnosed malignant glioma patient. Several observations at that time led to the development of independent research strategies for patients with GBM tumors, AA lesions, and those with anaplastic oligodendroglioma (AO). The observations included two from the Northern California Oncology Group (NCOG) and two from the Radiation Therapy Oncology Group (RTOG). In a phase II trial of 106 patients evaluating removable highactivity iodine-125 brachytherapy, NCOG reported that the survival of AA patients appeared comparable to NCOG historic controls but was superior for GBM patients.7 Based on this finding, follow-up University of California at San Francisco (UCSF) trials included brachytherapy in the management of GBM patients when possible and excluded brachytherapy from AA patient trials. The NCOG also reported an encouraging phase II experience with the halogenated pyrimidine bromodeoxyuridine (BUdR) for AA patients but not for GBM cases. H This led to an independent phase III trial of BUdR for AA patients initially conducted by the UCSF group and ultimately adopted by the RTOG and the Southwest Oncology Group. A phase 1111 trial conducted by the RTOG evaluating the halogenated pyrimidine iododeoxyuridine (IUdR) for AA patients also concluded that such an approach warranted phase III testing. The RTOG reported a novel statistical approach to its malignant glioma patient database called recursive partitioning and ana(ysis (RPA). Based on groupings of patients by prognostic characteristics and survival outcome, a total of six RPA "classes" of patients with malignant glioma were identified, with MSTs ranging from 4 to 59 months. Additionally, the rapid accrual of patients with malignant glioma to the large randomized trial run by the RTOG from 1990 to 1994 evaluating hyperfractionated RT (90-06) confirmed that sufficient patient numbers are avail-
able to conduct distinct trials for specific malignant glioma subgroups.
Preirradiation Chemotherapy The management of several malignancies historically managed with RT alone has been selectively improved with the use of two or more cycles of preirradiation multiagent chemotherapy. Included in this group is stage III non-small cell lung cancer, central nervous system lymphoma, and bulky Hodgkin's disease. In order to benefit from pre-RT chemotherapy, at least two criteria must be met. First, there must be a reasonable likelihood of tumor response to the induction chemotherapy, and second, the patient must be sufficiently asymptomatic as to not require immediate RT. Among malignant glioma patients, those patients most likely to sustain a therapeutic response to induction chemotherapy are those with AO. These tumors, which constitute 5% to 8% of most malignant glioma series, demonstrated a 75% response rate to the regimen of procarbazine, lomustine, and vincristine (PCV) in a prospective National Cancer Institute of Canada trial. lO This experience has led to the current Intergroup randomized trial comparing four cycles of PCV followed by cranial RT with cranial RT alone. This trial was initiated in 1994, is coordinated by the RTOG, open in four other cooperative groups, and scheduled to accrue 200 to 300 patients. Despite a low response rate to chemotherapy among GBM patients and the symptomatic nature of most GBM tumors, induction chemotherapy also has been evaluated for this patient cohort. Investigators at Johns Hopkins University and the University of Pittsburgh report a phase II experience using continuous infusion carmustine and cisplatin prior to cranial RT.ll Although no obvious advantage over standard therapy was clearly demonstrated, this regimen is now being tested in a phase III Eastern Cooperative Oncology Group trial versus immediate standard RT and concurrent carmustine for GBM and AA patients. The same agents using a different schedule also are being tested in a similar phase III trial within the North Central Cancer Treatment Group. It is likely that the therapeutic benefit of pre-RT chemotherapy will only be observed among chemosensitive malignant glioma patients who have relatively asymptomatic lesions or who have undergone an aggressive surgical resection.
Chemoradiationflr Malignant Glioma
New Agents Currently, the RTOG has taken the POSItIon that there is no sufficiently promising phase II experience for radiosurgery-ineligible GBM patients to warrant a phase III trial. Therefore, the group has embarked on a series of phase I and II trials testing new systemic agents with cranial RT. By partitioning enrolled patients into RPA "classes," the group hopes to identify which phase II survival data are sufficiently promising to warrant phase III testing. Each of the approaches has its own rationale, and some of the new agents have a unique interaction with ionizing RT. Tirapazamine (WIN 59075) is a benzotriazine compound exhibiting substantial differential toxicity for hypoxic cells. The combination of tirapazamine with RT may result in greater than additive hypoxic cell toxicity. Preclinical laboratory data supported the theory that tirapazamine will increase the effectiveness of RT against hypoxic tumor cells. 12 Based on these data and clinical support for hypoxia as a contributor to the treatment-resistant nature of malignant gliomas, the RTOG launched a phase II trial of tirapazamine at a dose of 159 mg/m 2 for 12 doses during cranial RT for radiosurgery-ineligible GBM patients. A total of 55 patients were enrolled at this dose level, and subsequently the trial was reopened at a tirapazamine dose of 260 mg/m 2 for 12 doses. The trial is expected to complete accrual in early 1997. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a chemotherapeutic agent approved for use in advanced breast and ovarian cancers with demonstrated evidence of radiosensitization in preclinical tumor models, including astrocytoma cell lines. 13 It appears that paclitaxel can increase the fraction of cells in the most radiosensitive time periods of the cell cycle, G2 and M. A phase I trial of weekly paclitaxel with cranial RT for malignant glioma demonstrated a maximal tolerated dose approaching 250 mg/m 2/wk. 14 Based on this experience, the RTOG is conducting a phase II trial of this agent on a weekly basis for 6 weeks concurrently with cranial RT for GBM at a dose of 225 mg/m 2/wk. Topotecan is a chemotherapeutic agent that exerts its action through inhibition of topoisomerase I. This action can enhance RT damage by preventing DNA repair and cell survival recovery.15 Because modest activity as a single agent was observed among patients with recurrent malignant gliomas, topotecan's potential in conjunction with cranial RT war-
35
ranted further attention. The RTOG is currently conducting a phase I dose-escalation study of topotecan concurrent with cranial RT. The current dose under study is 1.5 mg/m 2 every 3 weeks. After establishment of the maximally tolerated dose, a phase II trial of approximately 55 patients will be conducted.
Future Directions It is unlikely that anyone systemic agent or multiagent regimen will substantially change the natural history of malignant glioma among affiicted patients. A substantial improvement in survival will come only when improvements in the locoregional management are coupled with progress in the systemic management of the disease. Specifically, the substantial opportunities to improve both the surgical and radiotherapeutic approaches to this disease need to be exploited simultaneously with new drug development programs. The substantial progress made in our understanding of glioma pathogenesis should also contribute to these endeavors.
References I. Walker MD, Alexander EJr, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: A cooperative clinical trial.J Neurosurg 49:333-343, 197H 2. Curran WJJr, Scott CB, HortonJ, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Nat! Cancer Inst 85:704-710,1993 3. Kristiansen K, Hagen S, Kollevold T, et al: Combined modality therapy of operated astrocytomas grade III and N. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: A prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 47:649-652, 19H1 4. Walker MD, Green SB, Byar DP, et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N EnglJ Med 303:1323-1329, 19HO 5. Shapiro WR, Green SB, Burger PC, et al: Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group 800 I.J Neurosurg 71: 1-9, 1989 6. Nelson DF, Diener-West M, Weinstein A'l, et al: A randomized trial of misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of malignant glioma after surgery: Final report of an RTOG study. Int J Radiat Oncol BioI Phys 12: 1793-1 HOD, 1986 7. Gutin PH, Prados MD, Phillips TL, et al: External irradiation followed by an interstitial high activity iodine-125 implant "boost" in the initial treatment of malignant gliomas: NCOG Study 6G-82-2. IntJ Radiat Oneol Bioi Phys 21:601-606,1991 8. Levin VA, Prados MR, Wara WM, et al: Radiation therapy and
36
WalterJ. Curran,]r
bromodeoxyuridine chemotherapy followed by procarbazine, lomustine, and vincristine for the treatment of anaplastic gliomas. Int] Radiat Oneal Bioi Phys 32:75-H3, 1995 9. Urtasun RC, Cosmatos D, Oelrowe], et al: lododeoxyuridine (IUdR) combined with radiation in the treatment of malignant glioma: A comparison of short versus long intravenous dose schedules (RTOG H6-12). Int] Radiat Oneal Bioi Phys
27:207-214,1993 10. Cairncross G, Macdonald 0, Ludwin S, et al: Chemotherapy for anaplastic oligdendroglioma: The National Cancer Institute of Canada Clinical Trials Group.] Clin Oncol 12:20132017,1994 II. Gilbert MR, Lunsford LO, Kondziolka D, et al: A phase" trial of continuous infusion chemotherapy, external beam radiotherapy, and local boost radiotherapy for malignant gliomas. Proc Am Soc Clin Oncol 12: 176, 1993 (abstr 500) 12. Brown]M, Lemmon ML: Fractionation increases the antitu-
13. 14.
15.
16.
mor eHect of adding a hypoxic cytoxin to irradiation, in Dewey WC, Edington M, Fry RJM, ct al (eds): Radiation Research: A Twentieth Centul)' Perspective. San Diego, CA, Academic Press, 1992, PI' 807-H 12 Tishler RH, Geard CR, Hall E], et al: Taxol sensitizes human astrocytoma cells to radiation. Cancer Res 52:3495-3497, 1992 Glantz M, Choy H, Cole B, et al: Phase I study of wcekly, outpatient Taxol and concurrent cranial radiation in adults with astrucytomas. Proc Am Soc Clin Oncol 14: 146, 1995 (abstr 279) Mattern MR, Hofmann GA, McCabe FL, et al: Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor toputecan (SK&F 104864). Cancer Res 51:5813-5lJI6, 1991 Eisenhauer EA, Wainman N, Boos G, et al: Phase II trials of topotecan in patients (PTS) with malignant glioma and soft tissue sarcoma. Proc Am Soc Clin Oneal 13:175, 1994 (abstr
4HH)