The median survival time of adults with supratentorial malignant glioma treated in clinical studies with surgery, 6 weeks of external-beam radiotherapy, and carmustine (BiCNU) is approximately 1 year. This poor survival time is almost certainly optimistic, since only a select subgroup of patients end up participating in clinical trials-ie, those with a better prognosis. For elderly patients and/or those with poor functional status, median survival time ranges from 16 to 40 weeks. A regimen of surgery plus 2 to 3 weeks of radiotherapy appears to achieve a survival duration equivalent to that of long courses of chemoradiotherapy at less cost in time and money, and perhaps with less caregiver stress. Since the incidence of brain tumors in the elderly is rising and the size of the elderly population is increasing, it is appropriate to investigate the role of less aggressive therapy for what will be a growing number of malignant glioma patients with a poor prognosis.
The outlook for the majority of adult patients with malignant gliomas has not improved since the Brain Tumor Study Group (BTSG) trials of the 1970s ascertained a benefit from 55 to 60 Gy of fractionated external-beam radiotherapy and carmustine (BiCNU) following surgery [1-5]. The median survival time of patients who participate in formal clinical trials is approximately 1 year [2-4,6-12]. This dismal figure is almost certainly an overestimate, since powerful selection factors lead patients with better prognostic factors to enter clinical trials [8,9,13,14]. Patient age, functional status, and tumor grade are the most important prognostic factors [1,7,15]. It is only in the subgroup of patients with more favorable prognostic signs that selection of therapy has any impact on survival .
In 1960 Bouchard and Pierce reported that life expectancy in patients with glioblastoma multiforme was better in those who received radiotherapy than in those treated with surgery alone . Unfortunately, only 4% of patients in the combined-modality treatment group were alive at 10 years.
The BTSG conducted several randomized prospective postoperative clinical trials in patients with malignant gliomas [1,3,5]. In the first of these studies, the four treatment arms included surgery plus: supportive therapy alone, carmustine alone, 50 to 60 Gy of whole-brain radiotherapy alone, and carmustine plus radiotherapy. The vast majority of the patients (90%) were classified as having glioblastoma multiforme, 9% had anaplastic astrocytoma, and 1% had other anaplastic gliomas.
The approximate median survival times, in weeks, for the four treatments were: supportive care, 14; carmustine, 19; radiotherapy, 36; and carmustine plus radiotherapy, 35. The difference in survival times between radiotherapy and either carmustine alone or supportive care was statistically significant. This study thus constituted the first demonstration, in a randomized trial, that radiotherapy significantly increased median survival time for patients with glioblastoma multiforme.
In a subsequent BTSG trial (trial 7201), median survival time for treatment that included methyl-CCNU but not radiotherapy was 24 weeks. Significantly better survival times were seen with conventional radiotherapy alone (36 weeks), radiotherapy plus methyl-CCNU (42 weeks), or conventional radiotherapy plus carmustine (51 weeks).
In the third major BTSG study (trial 7501), radiotherapy plus methylprednisolone achieved a median survival time of 40 weeks, and radiotherapy plus methylprednisolone plus carmustine attained a survival time of 41 weeks. Significantly better survival times were reported with both radiotherapy plus procarbazine (47 weeks) and radiotherapy plus carmustine (50 weeks) [1-3].
Over a decade after BTSG trial 7201, the Central Nervous System Cancer Consortium (CNSCC) conducted a randomized trial of conventional radiotherapy plus carmustine vs conventional radiotherapy plus diaziquone (AZQ). The median survival time from randomization of all patients was 351 days, corresponding to approximately 69 weeks after diagnosis. Since randomization in this study occurred approximately 8 weeks after completion of radiotherapy, or 15 to 20 weeks after diagnosis, this median survival time is based on a subpopulation of patients who survived and maintained a Karnofsky performance status (KPS) of at least 50% for 4 to 5 months after diagnosis. This explains why the overall median survival in this study exceeds that reported in most other trials [6,11].
Adjuvant Chemotherapy--Among the most extensively examined areas in the treatment of malignant gliomas is the use of adjuvant chemotherapy. Phase II trials of the nitrosoureas documented a 10% to 40% response rate for recurrent tumors . Because of this activity, carmustine and methyl-CCNU were utilized in adjuvant chemotherapy trials. Based on the previously cited BTSG trials, many would argue that the best standard therapy of patients with malignant gliomas should include nitrosourea chemotherapy. However, only one of the three BTSG randomized trials that evaluated adjuvant chemotherapy and included a no-chemotherapy arm showed a statistically significant benefit of chemotherapy.
There are almost a limitless variety of "new" chemotherapy programs to be tested in malignant gliomas or "old" programs to be recycled with slight changes. A host of single- and multi-agent programs have been tried, including carmustine; lomustine; methyl-CCNU; bleomycin (Blenoxane); procarbazine, lomustine, plus vincristine (Oncovin); AZQ; and mitomycin (Mutamycin) plus mercaptopurine [11,12,18].
To approach the question of the role of adjuvant chemotherapy in malignant gliomas, Fine et al performed a meta-analysis of the combined results from 16 randomized trials involving more than 3,000 patients . They found a survival benefit attendant to the use of chemotherapy, and that benefit occurred earlier in patients with anaplastic astrocytoma than in those with glioblastoma multiforme.
The survival times for malignant glioma following surgery, conventional radiotherapy, and chemotherapy seem to have plateaued over the past 25 years. In the free market of ideas, various "new" therapies are held out as innovative and potentially efficacious. Some of these alleged new ideas are, in fact, previously investigated, venerable concepts that have resurfaced [19,20]. Examples include multiple daily fractions of external-beam radiotherapy ; interstitial brachytherapy1 [21-25]; localized or whole-body hyperthermia [26,27]; dose escalation with conventional fractionated radiotherapy [28,29]; radiosensitization with metronidazole, bromodeoxyuridine (BUDR), iododeoxyuridine (IUDR), and neutron/boron capture [30-34]; radiolabeled monoclonal antibodies; high-dose chemotherapy with autologous bone marrow rescue; and gene therapy with retroviral vectors.
Radiosurgery--Stereotactic radiosurgery is a popular area of current clinical investigation. Radiosurgery utilizes multiple beams to tightly concentrate radiation dose to the tumor with relative sparing of normal tissue. The most commonly used radiation sources for radiosurgery are high-energy x-rays produced by a linear accelerator; cobalt-60 gamma rays, as provided by the commercially available Gamma Knife (Elekta Instruments, Decatur, Georgia); and particle beams, such as the Harvard cyclotron beam.
Either before or following fractionated external-beam radiotherapy, a radiosurgery "boost" may be given to the bulk of the tumor-provided that the tumor volume does not exceed the limits of the technology, ie, equal to or less than 3 to 4 cm. Fewer than 20% of malignant gliomas meet this criterion [9,13,35]. Multiple noncoplanar beams can be used as a boost for such larger lesions. To improve the tolerance of normal tissues for radiosurgery of larger volumes, the therapy is more highly fractionated. Thus, at some point, highly fractionated radiosurgery intellectually merges with precision conventional external-beam radiotherapy.
Study after study shows that patient age, tumor grade (glioblastoma multiforme vs anaplastic astrocytoma), and patient performance status are the pretreatment variables most predictive of outcome [10-12,15,36,37]. In many clinical trials, the benefit of a new therapy becomes less apparent in patients over 45 to 55 years of age who have poor performance status. This observation is underscored by the fact that only a select subgroup of malignant glioma patients are entered into clinical trials-individuals who are unlikely to be representative of the broader population. If the data supporting the benefit of full-dose radiotherapy plus carmustine, as evidenced by clinical trials, are derived from a highly select population, then conventional wisdom in support of such therapy may fairly be called into question.
Selection Bias in External-Beam Radiotherapy Plus Chemotherapy Clinical Trials--Researchers from the University of Western Ontario investigated selection bias in clinical trials of anaplastic glioma . They collaborated with our group at Duke in a prospective randomized clinical trial comparing AZQ to carmustine following surgery and radiotherapy for malignant gliomas [6,11]. Because of the Ontario provincial cancer care network, it was possible to assess the percentage of patients in a catchment area of approximately 1.1 million persons who ultimately entered the trial. It was also possible to evaluate how the loss of patients from the study biased the survival predictions.
Of 217 initial patients with a clinical and radiographic diagnosis of malignant glioma, 20 were too old and disabled to undergo a biopsy to establish a tissue diagnosis. Of the remaining 197 adults who had a biopsy-proven supra-tentorial malignant glioma, the investigators studied how many remained eligible for the study.
The eligibility criteria were a Karnofsky performance score 50% or greater, the absence of other medical conditions precluding chemotherapy, and signed informed consent. At diagnosis, 100% of the 197 patients met these eligibility criteria. Three weeks later, at the start of radiotherapy, 68% were still eligible. Six weeks later, at the end of radiotherapy, 47% were eligible. Eight weeks later, when offered randomization between the two drugs, 40% of the patients remained eligible. Seventy percent of these remaining patients agreed to be randomized (28% of the initial 197 patients).
The major reason patients became ineligible for the study were a decrease in KPS, followed by significant medical problems precluding participation and irregularities in the administration of external-beam radiation that violated the protocol. Study patients lived significantly longer than nonstudy patients (60 vs 25 weeks, P = .0001). One can imagine that the results might have been even more dramatic if an age cut off, ie more than 70 years, had been included as a criterion for eligibility. When one considers the fact that patients with progressive tumor during radiotherapy are excluded from randomized studies of post-radiotherapy chemotherapy, case selection is seen to be even more profound.
Selection Bias in Brachytherapy Clinical Trials--In a corollary study, the Western Ontario group collaborated with Gutin of the University of California at San Francisco and Leibel of Memorial Sloan-Kettering Cancer Center . They took records of 101 malignant glioma patients treated with conventional fractionated external-beam radiotherapy and adjuvant chemotherapy and asked two experienced surgeons and a radiotherapist to designate each patient as either eligible or ineligible for adjuvant brachytherapy. None of the patients had received such therapy. Overall, 32% of the patients were deemed eligible for brachytherapy. In a similar review conducted by the Radiation Therapy Oncology Group (RTOG) of their experience, 25% of patients were eligible for adjuvant brachytherapy . Eligible patients lived longer than ineligible ones (16.6 vs 9.3 months), were younger, and had larger initial surgical resections and better function. These findings suggest that better outcome following adjuvant brachytherapy for malignant glioma is strongly influenced by patient selection.
Recently, Curran et al published a recursive partitioning analysis of prognostic factors uncovered in three RTOG malignant glioma trials involving 1,578 patients . Patients were grouped according to a variety of prognostic factors.
Median survival time ranged from a high of 58.6 months for the 9% of patients less than 50 years of age who had anaplastic astrocytoma and normal mental status to a low of 4.6 months for the 17% of patients 50 years of age or older who had a KPS less than 70% and normal mental status and who received 54.4 Gy or less of external-beam radiation therapy. Since the RTOG trials were confined to patients 70 years of age or younger, it is likely that the study overrepresented the patient cohort with better prognostic factors.
Thus, inclusion of patients with poor prognostic factors in a study may obscure the potential benefit of aggressive therapy in patients with the more favorable prognosis. Conversely, inclusion of patients with good prognostic factors may falsely promote the usefulness of aggressive therapy.
The effects of case selection are summarized in Figure 1. This analysis of data from the published literature clearly shows that patients ultimately treated in clinical trials at academic medical centers constitute a small minority of malignant glioma patients. We are subjecting a large number of patients to forms of therapy that have the potential to benefit very few. As the incidence of brain tumors among the elderly increases, this problem will become more apparent .
1. Leibel SA, Sheline NG: Radiation therapy for neoplasms of the brain. J Neurosurg 66:1-22, 1987.
2. Shapiro WR, Green SB, Burger PC, et al: Randomized trial of three chemotherapy regimens and two radiotherapy regimens in post operative treatment of malignant gliomas: Brain tumor cooperative trial 8001. J Neurosurg 71:1-9, 1989.
3. Shapiro WR: Therapy of malignant adult brain tumors: What have clinical trials taught us? Semin Oncol 13:38-45, 1986.
4. Sheline GE: Radiotherapy for high grade gliomas. Int J Radiat Oncol Biol Phys 18:794-803, 1990.
5. Walker MD, Alexander Jr E, 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, 1978.
6. Schold Jr SC, Herndon II JE, Burger PC, et al: Randomized comparison of diaziquone and carmustine in the treatment of adults with anaplastic gliomas. J Clin Oncol 11:77-83, 1993.
7. Curran WJ, Scott CB, Horton J, et al: Recursive partitioning analysis of prognostic factors in three radiation therapy oncology group malignant glioma trials. J Natl Cancer Inst 85:704-710, 1993.
8. Curran WJ, Scott CB, Nelson JS, et al: Survival comparison of radiosurgery eligible and ineligible malignant glioma patients treated with hyperfractionated radiation therapy and BCNU: A report of RTOG 83-02. J Clin Oncol 11:857-862, 1993.
9. Curran WJ, Scott CB, Weinstein AS, et al: Survival comparison in brachytherapy eligible and ineligible malignant glioma patients treated with twice-daily radiation therapy and BCNU:
A report of RTOG 83-02 (abstract). Radiother Oncol 24:511, 1992.
10. Deutsch M, Green SB, Strike TA, et al: Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant gliomas. Int J Radiat Oncol Biol Phys 16:1389-1396, 1989.
11. Halperin EC, Gaspar L, Imperato J, et al: An analysis of radiotherapy data from the CNS Cancer Consortium's randomized prospective trial comparing AZQ to BCNU in the treatment of patients with primary malignant brain tumors. Am J Clin Oncol (CCT) 16:277-283, 1993.
12. Halperin EC, Herndon J, Schold SC et al: A phase III randomized prospective trial of external beam radiotherapy (ERT), mitomycin C (MITO), BCNU, and 6-mercaptopurine (6-MP) for the treatment of adults with anaplastic glioma of the brain (abstract). Int J Radiat Oncol Biol Phys 30(suppl 1):214, 1994.
13. Florell RC, MacDonald DR, Irish WD, et al: Selection bias, survival, and brachytherapy for glioma. J Neurosurg 76:179-183, 1992.
14. Winger MJ, MacDonald DR, Schold Jr SC, et al: Selection bias in clinical trials of anaplastic glioma. Ann Neurol 26:531-534, 1989.
15. Stenning SP, Freedman LS, Bleehen NM: Prognostic factors for high-grade malignant glioma: Development of a prognostic index-a report of the Medical Research Council Brain Tumor Working Party. J Neurooncol 9:47-55, 1990.
16. Bouchard, J, Pierce CB: Radiation therapy in the management of neoplasms of the central nervous system, with a special note in regard to children: Twenty years' experience, 1939-1948. Am J Roentgenol 84:610-628, 1969.
17. Wilson CB, Gutin P, Baltry EB: Single-agent chemotherapy of brain tumors: A five year review. Arch Neurol 33:739-744, 1976.
18. Fine HA, Dear KBG, Loeffler JS, et al: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71:2585-2597, 1993.
19. Brada M: Back to the future-radiotherapy and high grade gliomas. Br J Cancer 60:1-4, 1989.
20. Halperin EC: Multiple-fraction-per-day external beam radiotherapy for adults with supratentorial malignant gliomas. J Neurooncol 14-255-262, 1992.
21. Drake CJ, Pfalzner PM, Linell EA: Intracavitary irradiation of malignant brain tumors. J Neurosurg 20:428-434, 1963.
22. Gutin PH, Prados MD, Phillips TL, et al: External irradiation following by interstitial high activity I-125 implant "boost" in the initial treatment of malignant gliomas NCOG study 6G-8202. Int J Radiat Onc Biol Phys 21:601-606, 1991.
23. Gutin PH, Phillips TL, Wara WM, et al: Brachytherapy of recurrent malignant brain tumors with removable high activity iodine-125 sources. J Neurosurg 60:61-67, 1984.
24. Sacks E: Treatment of glioblastomas with radium. J Neurosurg 11:119-121, 1954.
25. Mundinger F: Treatment of brain tumors with radioisotopes. Prog Neurol Surg 1:202-257, 1966.
26. Hynynem K, Lulu B: Hyperthermia in cancer treatment. Invest Radiol 25:824-834, 1990.
27. Stea B, Cetas C, Cassady JR, et al: Interstitial thermo-radiotherapy of brain tumors: Preliminary result of a phase I clinical trial. Int J Radiat Oncol Biol Phys 19:1463-1472, 1990.
28. Salazar OM, Rubin P, MacDonald JV, et al: Patterns of failure in intra-cranial astrocytomas after irradiation: Analysis of dose and field factors. Am J Roentgenol 126:279-292, 1976.
29. Salazar OM, Rubin P: The spread of glioblastoma multiforme as a determining factor in the radiation treated volume. Int J Radiat Onc Biol Phys 1:627-630, 1976.
30. Barth RF, Soloway AH, Fairchild RG: Boron neutron capture therapy for cancer. Sci Am 100-107, October, 1990.
31. Fulton DS, Urtsan RC, Schin JH, et al: Misonidazole combined with hyperfractionation in the management of malignant gliomas. Int J Radiat Oncol Biol Phys 10:1709-1712, 1984.
32. Green SB, Byar DP, Strike TA, et al: Randomized comparisons of BCNU, streptozotocin, radiosensitizer, and fractionation of radiotherapy in the post operative treatment of malignant glioma (Study 7702) (abstract C-1018). Proc Am Soc Clin Oncol, p 260, 1984.
33. Greenberg HS, Chandler W, Dias RF, et al: Intra-arterial bromodeoxyuridine radiosensitization in radiation treatment of malignant astrocytomas. J Neurosurg 69:500-505, 1988.
34. Griffin TW, Davis R, Laramore G, et al: Fast neutron radiation therapy for glioblastoma multiforme-results of an RTOG study. Am J Clin Oncol (CCT) 661-667, 1983.
35. Flickinger J, Loeffler JS, Larson DA: Stereotactic radiosurgery for intracranial malignancies. Oncology 8:81-98, 1994.
36. Nelson DF, Diener-West M, Horton J, et al: Combined modality approach to the treatment of malignant glioma-re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up; A joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group. Natl Cancer Inst Mono 6, 1988.
37. Prados MD, Gutin PH, Phillips TL, et al: Highly anaplastic astrocytoma: A review of 357 patients treated between 1977 and 1989. Int J Radiat Oncol Biol Phys 23:3-8, 1992.
38. Davis DL, Hoel D, Fox J, et al: International trends in cancer mortality in France, West Germany, Italy, Japan, and Wales, and the U.S.A. Lancet 336:474-481, 1990.
39. Costanza M, Buechler M, Munzenreider J, et al: Radiation plus adjuvant CCNU (1-[2-chloral ethyl]-3-cyclohexanol-1-nitrosourea) vs CCNU, hydroxyurea, and vincristine in the treatment of malignant glioma. Int J Radiat Onc Biol Phys 5:1589-1592, 1979.
40. Simpson WJ, Platts ME: Fractionation study in the treatment of glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1:639-644, 1976.
41. Gaspar LE, Fisher BJ, McDonald et al: Supratentorial malignant gliomas: Patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys 24:55-57, 1992.
42. Hernandez JC, Maruyama Y, Yaes R, et al: Accelerated fractionation radiotherapy for hospitalized glioblastoma multiforme patients with poor prognostic factors. J Neurooncol 9:41-45, 1990.
43. Levin VA, Wilson CB, Davis R, et al: Phase III comparison of BCNU, hydroxyurea and radiation therapy for the treatment of primary malignant gliomas. J Neurosurg 51:526-532, 1979.
44. Picard JD, Bailey S, Sanderson H, et al: Steps toward cost-benefit analysis of regional neurosurgical care. Br Med J 301:629-635.
45. Bauman GS, Gaspar LE, Fisher BJ, et al: A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme. Int J Radiat Onc Biol Phys 29:835-840, 1994.
46. Hercbergs AA, Tadmor R, Findler G, et al: Hypofractionated radiation therapy and concurrent cisplatin in malignant cerebral gliomas: Rapid palliation in low performance status patients. Cancer 64:816-820, 1989.
47. Newall J, Ransohoff J, Kaplan B: Glioblastoma in the older patient: How long a course of radiotherapy is necessary? J Neurooncol 6:325-327, 1988.
48. Peschel RE, Wilson L, Haffty B, et al: The effect of advanced age on the efficacy of radiation therapy for early breast cancer, local prostate cancer, and grade III/IV gliomas. Int J Radiat Oncol Biol Phys 26:539-544, 1993.
49. Tamura M, Nakamura M, Kunimine H, et al: Large dose fractionated radiotherapy in the treatment of glioblastoma. J Neurooncol 7:113-119, 1989.
50. Whittle IR, Denholm SW, Gregor A: Management of patients aged over 60 years with supratentorial glioma: Lessons from an audit. Surg Neurol 36:106-111, 1991.
51. Curran W J: Should patients with histologically unverified brain tumors receive cranial irradiation? Int J Radiat Oncol Biol Phys 28:549-550, 1994.
52. Halperin EC, Bentel G, Heinz ER, et al: Radiation therapy treatment planning and supratentorial glioblastoma multiforme: An analysis based on post mortem topographic anatomy with CT correlations. Int J Radiat Onc Biol Phys 17:1347-1350, 1989.