Concurrent Chemotherapy and Radiotherapy in Patients With Brain Tumors

ABSTRACT: Because treatment for most brain tumors remains inadequate, there has been a sustained interest in using concurrent chemotherapy and radiotherapy to improve local control, prolong overall survival, and reduce treatment-related toxicity. Unfortunately, many currently available radiosensitizers are either ineffective against brain tumors or have a reduced ability to cross the blood-brain barrier when administered systemically. Many agents also have overlapping toxicities with cranial irradiation or enhance the toxicity of radiation in a way that potentially compromises care. Finally, the addition of chemotherapy to cranial irradiation complicates the assessment of tumor response. Despite these barriers, trials with a number of promising agents are currently under way. These trials have already provided crucial insights into the pharmacokinetics, clinical pharmacology, and practical management of brain tumor patients with concurrent chemotherapy and radiotherapy. These findings should rapidly lead to the safer and more effective use of combined-modality therapy in patients with central nervous system cancer. [ONCOLOGY 13(Suppl 5):78-82, 1999]

Introduction

Despite decades of intensive clinical investigation, treatment for most primary and metastatic brain tumors remains inadequate. For malignant gliomas in particular, tumor recurrence after first-line therapy (tumor resection and cranial irradiation) is almost inevitable, and the overwhelming majority of tumors—90% to 95%—recur at or within 2 cm of the site of the original lesion.[1-4] While the local recurrence rate is slightly reduced when stereotactic radiosurgery or interstitial radiation implants are used, local control is still not achieved in the vast majority of tumors,[5-7] and sometimes significant toxicity results.[8-11] For this reason, there has been a sustained interest in the use of concurrent chemotherapy and radiotherapy as a technique to improve local control and overall survival, while maintaining a tolerable side-effect profile.

The Ideal Radiosensitizer

Essential properties of the ideal brain tumor radiosensitizer are summarized in Table 1. The ideal agent should be nontoxic or should produce easily tolerable side effects that do not overlap with those associated with cranial irradiation. It should also enhance the efficacy of radiation. The three most common mechanisms for radiosensitization are inhibition of radiation damage repair (eg, purine and pyrimidine analogs); perturbation of cell cycling to increase the fraction of G₂/M-phase cells (eg, vinca alkaloids, paclitaxel [Taxol], estramustine [Emcyt]); and specific action on hypoxic cell populations (eg, mitomycin [Mutamycin], RSR 13). The agent should also possess independent activity against the tumor. Because of the low proportion of cycling cells in most brain tumors,[12-14] the radiosensitizer should be non–cell-cycle specific and should be amenable to dose-intense or prolonged-infusion schedules. Finally, because quality of life and efficiency of care are critical issues, the agent should, like cranial irradiation itself, be adaptable to outpatient administration. Although these requisites of the ideal radiosensitizer are obvious and noncontroversial, currently available agents are lacking in several important areas (Table 2).

Effectiveness

While radiosensitizing potency is the essential property of a radiation-enhancing agent, intrinsic activity against brain tumors is also necessary, both to increase cell killing locally and to sterilize tumor micrometastases that fall outside of the radiation field. If radiosensitizers lack such intrinsic antitumor activity and fail to sterilize micrometastases located outside the radiation ports, their use may simply shift the pattern of brain tumor recurrence to more distant intracranial sites without prolonging disease-free overall survival.

Another concern commonly mentioned in the context of brain tumor chemotherapy is the potential for reduced passage of systemically administered chemotherapy across the blood-brain barrier. This is probably a minor issue for most small molecule radiosensitizers, regardless of their lipid solubility,[15-19] but may be important for complex biomolecules, monoclonal-antibody–directed treatments, and other immunotherapies. [20,21]

Brain tumor treatment also presents unique challenges in response evaluation,[22] including technical concerns about the timing of imaging procedures,[23] confounders of apparent radiographic response,[24] and the inability of routine imaging studies to distinguish between residual or recurrent tumor and treatment-induced necrosis.[25-27]

Feasibility

Added to these barriers are challenges to the feasibility of combining a radiosensitizing agent to cranial irradiation. Any agent adds to the expense of treatment, particularly if hospitalization is necessary, and any agent will require additional treatment time, which detracts from quality of life.

Toxicity

If toxicity from the radiation sensitizer is encountered, cranial irradiation may have to be delayed or curtailed, thus compromising care. In addition to the risk of side effects from the radiosensitizing agent itself, the potential for additive toxicity (eg, cisplatin [Platinol] and hearing loss), synergistic toxicity (eg, methotrexate and leukoencephalopathy), and limitation of treatment options at the time of tumor recurrence (eg, the difficulty of administering nitrosoureas to patients who previously received mitomycin) must all be factored into the selection of a radiosensitizer.

Promising Agents and Exciting Discoveries

Despite these significant barriers to the use of radiosensitizers in patients with brain tumors, a number of ongoing studies with promising agents are currently under way (Table 3), and additional studies are planned. While dramatic improvements over conventional therapy have yet to be realized, crucial insights have been gained that will dramatically alter our approach to brain tumor therapy and the design of future therapeutic trials over the next several years.

The first of these insights is pharmacokinetic. Numerous studies conducted over the last several years with a wide range of chemotherapeutic agents have provided compelling evidence that dosing guidelines established in patients with non–nervous system cancers frequently do not apply to patients with brain tumors, and often represent dramatic underestimates of the appropriate drug doses for those patients (Table 4). In many studies, maximum tolerated doses are twice as high in brain tumor patients as in those with extraneural cancers. In other studies, treatment at maximum tolerated doses established in patients with extraneural cancer produced little response, but also minimal or no toxicity, in brain tumor patients.

In retrospect, potential explanations for this finding are easy to enumerate. In adults with primary brain tumors, bone marrow and other organ involvement by tumor is extraordinarily rare. More importantly, most patients with brain tumors are receiving one or more drugs (eg, corticosteroids, anticonvulsants, H2-receptor antagonists, antidepressants) that stimulate the cytochrome P-450 enzyme system and accelerate chemotherapy drug metabolism. This finding raises the possibility that some drugs previously found to have little or no activity against nervous system tumors actually have not received an adequate trial. It also suggests that separate dose escalation and pharmacokinetic studies must be performed for patients with central nervous system cancers.

A second surprise relates to the access of orally or intravenously administered drugs to brain tumors. Despite persistent concerns about the blood-brain barrier, several recent studies suggest that brain tumor drug concentrations usually parallel serum concentrations.[15,16,18,19,44] Thus, treatment failures probably reflect lack of drug activity rather than restricted access. In contrast, brain tumor and cerebrospinal fluid drug levels often differ significantly, and cerebrospinal fluid drug levels cannot act as a surrogate measure for brain tumor levels.[20,21,45,46] (Cerebrospinal fluid levels may, however, reflect drug levels in the normal brain, and normal-appearing brain around tumors may be infiltrated with tumor cells.)

A recent flurry of phase I chemotherapy trials has produced a third revelation. Just as the “brain tumor” maximum tolerated dose often differs dramatically from that in non–brain tumor patients, the nature of the dose-limiting toxicity may also differ (Table 5). In many cases, that dose-limiting toxicity involves the central (encephalopathy, seizures, hallucinations)[40] or peripheral nervous system (paresthesias, peripheral neuropathy).[32,37] In some cases, the toxicity is novel; in others, the side effect is also observed in non–brain tumor patients, but at a much lower frequency. This shift in the spectrum of dose-limiting toxicity toward nervous system manifestations probably results from the higher maximum tolerated doses being administered (analogous to the nervous system toxicity that limits some high-dose chemotherapy regimens in the transplant setting) and the fact that most patients already have underlying nervous system injury.

A final realization provided by recent studies is the frequency with which concurrent chemotherapy and radiotherapy result in accelerated central nervous system radiation toxicity (Table 6). In part, chemotherapeutic agents may lower the threshold of radiation injury in normal nervous system tissue.[47-53,56] Radiation may also increase the permeability of central nervous system vasculature to chemotherapeutic agents, permitting exposure to higher drug doses.[57-61] This realization will necessitate a more careful assessment of long-term outcome, with a particular focus on late radiation effects. It will also necessitate more careful attention to other known risk factors, such as extremes of age (young and old), radiation dose and fractionation, preexisting vascular risk factors, and the probability of long-term survival.

Conclusions

Local control over most primary brain tumors remains an elusive goal, and patients usually die from a tumor that recurs and progresses at the site of the original lesion. For this reason, strategies to enhance the effect of conventional cranial irradiation make good practical sense and have been aggressively sought. The characteristics of an ideal brain radiosensitizer are intuitively obvious—minimal toxicity, high radiosensitizing potency, independent activity against the tumor, and ease of administration—but have been hard to achieve. Nevertheless, a number of promising agents are currently under investigation, and ongoing investigations have recently led to the discovery of several important principles of brain tumor therapy relating tumors to drug pharmacokinetics, access of agents to brain, and the spectrum of toxicities in patients treated with concurrent chemotherapy and cranial irradiation. These should lead rapidly to the safer and more effective use of concurrent chemotherapy and radiotherapy in the treatment of patients with nervous system cancers. Ultimately, these findings should also lead to improved survival and quality of life from novel treatment approaches.

References:

1. Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastomas. Neurology 30:907-911, 1980.

2. Choucair AK, Levin VA, Gutin PH, et al: Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg 65:654-658, 1986.

3. Wallner KE, Galicich JH, Krol G, et al: Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405-1409, 1989.

4. Liang BC, Thornton AF Jr, Sandler HM, et al: Malignant astrocytomas: Focal tumor recurrence after focal external beam radiation therapy. J Neurosurg 75:559-563, 1991.

5. Bashir R, Hochberg F, Oot R: Regrowth patterns of glioblastoma multiforme related to planning of interstitial brachytherapy radiation fields. Neurosurgery 23:27-30, 1988.

6. Agbi CB, Bernstein M, Laperriere N, et al: Patterns of recurrence of malignant astrocytoma following stereotactic interstitial brachytherapy with iodine-125 implants. Int J Radiat Oncol Biol Phys 23:321-326, 1992.

7. Sneed PK, Gutin PH, Larson DA, et al: Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost. Int J Radiat Oncol Biol Phys 29:719-727, 1994.

8. Wen PY, Alexander E III, Black PM, et al: Long-term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas. Cancer 73:3029-3036, 1994.

9. Loeffler JS, Alexander E III, Shea WM, et al: Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol 10:1379-1385, 1992.

10. 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. Int J Radiat Oncol Biol Phys 21:601-606, 1991.

11. Loeffler JS, Alexander E, Wen PY, et al: Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma. J Natl Cancer Inst 82:1918-1921, 1990.

12. Coons SW, Pearl DK: Mitosis identification in diffuse gliomas: Implications for tumor grading. Cancer 82:1550-1555, 1998.

13. Hoshino T, Prados M, Wilson CB, et al: Prognostic implications of the bromodeoxyuridine labeling index of human gliomas. J Neurosurg 71:335-341, 1989.

14. Zuber P, Hamou MF, de Tribolet N: Identification of proliferating cells in human gliomas using the monoclonal antibody Ki-67. Neurosurgery 22:364-368, 1988.

15. Norman D, Stevens EA, Wings SD, et al: Quantitative aspects of contrast enhancement in cranial computed tomography. Radiology 129:683-688, 1978.

16. Groothuis DR, Vriesendorp FJ, Kupfer B, et al: Quantitative measurements of capillary transport in human brain tumors by computed tomography. Ann Neurol 30:581-588, 1991.

17. Vick NA, Bigner DD: Microvascular abnormalities in virally induced canine brain tumors: Structural bases for altered blood-brain barrier function. J Neurol Sci 17:29-39, 1972.

18. Stewart DJ: Human central nervous system pharmacology of antineoplastic agents: Implications for the treatment of brain tumors, in Chatel M, Darcel F, Pecker J (eds): Brain Oncology, Biology, Diagnosis and Therapy, pp 387-395. Dordrecht, Martinus Nijhoff, 1987.

19. Grossman SA, Wharam M, Sheidler V, et al: Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma. J Clin Oncol 15:2596-2603, 1997.

20. Collins JM, Riccardi R, Trown P, et al: Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: Comparison of intravenous, intramuscular, and intraventricular delivery. Cancer Drug Deliv 2:247-253, 1985.

21. Saris SC, Rosenberg SA, Friedman RB, et al: Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier. J Neurosurg 69:29-34, 1988.

22. Perry JR, DeAngelis LM, Schold SC Jr, et al: Challenges in the design and conduct of phase III brain tumor therapy trials. Neurology 49:912-917, 1997.

23. Forsyth PAJ, Petrov E, Mahallati H, et al: Prospective study of postoperative magnetic resonance imaging in patients with malignant gliomas. J Clin Oncol 15:2076-2081, 1997.

24. Watling CJ, Lee DH, Macdonald DR, et al: Corticosteroid-induced magnetic resonance imaging changes in patients with recurrent malignant glioma. J Clin Oncol 12:1886-1889, 1994.

25. Di Chiro G, Oldfield E, Wright DC, et al: Cerebral necrosis after radiotherapy and/or intraarterial chemotherapy for brain tumor: PET and neuropathologic studies. Am J Roentgenol 150:189-197, 1988.

26. Glantz MJ, Hoffman JM, Coleman RE, et al: Identification of early recurrence of primary central nervous system tumors by [18F] fluorodeoxyglucose positron emission tomography. Ann Neurol 29:347-355, 1991.

27. Schwartz RB, Holman BL, Polak JF, et al: Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: Association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy. J Neurosurg 89:60-68, 1998.

28. Friedman HS, Dugan M, Kerby T, et al: DNA mismatch repair analysis and response to Temodal in newly diagnosed malignant glioma (abstract 1457). Proc Am Soc Clin Oncol 17:378a, 1998.

29. Carde P, Timmerman D, Koprowski C, et al: Gadolinium-texaphyrin (GD-TEX) radiation sensitizer: Improved survival in a phase IB/II trial in patients with brain metastases (abstract 1463). Proc Am Soc Clin Oncol 17:379a, 1998.

30. Kleinberg L, Grossman SA, Piantadosi S, et al: Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme. J Clin Oncol 17:2593-2603, 1999.

31. Rosenthal DI, Close LG, Lucci JA III, et al: Phase I studies of continuous-infusion paclitaxel given with standard aggressive radiation therapy for locally advanced solid tumors. Semin Oncol 22(suppl 9):13-17, 1995.

32. Glantz MJ, Choy H, Kearns CM, et al: Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas. J Clin Oncol 14:600-609, 1996.

33. Adelstein DJ, Likavec MJ, Sharan VM, et al: Intravenous 5-fluorouracil infusion and simultaneous radiotherapy in glioblastoma multiforme (abstract). Proc Am Soc Clin Oncol 6:71, 1987.

34. Hug V, Hort G: Mitomycin for treatment of brain parenchymal disease [letter]. J Clin Oncol 6:1787, 1988.

35. Halperin EC, Herndon J, Schold SC, et al: A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain: CNS Cancer Consortium. Int J Radiat Oncol Biol Phys 34:793-802, 1996.

36. Nicholas MK, Sweeney PJ, Masters G, et al: Phase I trial of vinorelbine with concurrent radiotherapy in malignant glioma: Diminished toxicities at conventional doses (abstract 1574). Proc Am Soc Clin Oncol 17:408a, 1998.

37. Gertler SZ, Macdonald D, Goodyear M, et al: NCIC CTG phase II study of gemcitabine in patients with malignant glioma (IND.94) (abstract 1491). Proc Am Soc Clin Oncol 17:387a, 1998.

38. Friedman AH, Ashley DM, Kerby T, et al: Topotecan treatment of adults with primary malignant glioma (abstract 1503). Proc Am Soc Clin Oncol 17:390a, 1998.

39. Friedman HS, Petros WP, Friedman AH, et al: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17:1516-1525, 1999.

40. Chang SM, Kuhn JG, Rizzo J, et al: Phase I study of paclitaxel in patients with recurrent malignant gliomas: A North American Brain Tumor Consortium report. J Clin Oncol 16:2188-2194, 1998.

41. Fetell MR, Grossman SA, Fisher JD, et al: Preirradiation paclitaxel in glioblastoma multiforme: Efficacy, pharmacology, and drug interactions. J Clin Oncol 15:3121-3128, 1997.

42. Prados MD, Schold SC, Spence AM, et al: Phase II study of paclitaxel in patients with recurrent malignant glioma. J Clin Oncol 14:2316-2321, 1996.

43. Grossman SA, Hochberg F, Fisher J, et al: Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. Cancer Chemother Pharmacol 42:118-126, 1998.

44. Fine RL, Balmaceda C, Bruce J, et al: Deposition of paclitaxel into normal and malignant brain tumor tissue (abstract 741). Proc Am Soc Clin Oncol 17:192a, 1998.

45. Glantz MJ, Choy H, Kearns CM, et al: Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. J Natl Cancer Inst 87:1077-1081, 1995.

46. Shapiro WR, Young DF, Mehta BM: Methotrexate: Distribution in cerebrospinal fluid after intravenous, ventricular, and lumbar injections. N Engl J Med 293:161-166, 1975.

47. Bleyer WA, Griffin TW: White matter necrosis, mineralizing microangiopathy, and intellectual abilities in survivors of childhood leukemia: Associations with central nervous system irradiation and methotrexate therapy, in Gilbert HA, Kagan AR (eds): Radiation Damage to the Nervous System: A Delayed Therapeutic Hazard, pp 155-174. New York, Raven Press, 1980.

48. Posner JB: Side effects of radiation therapy, in Posner JB (ed): Neurologic Complications of Cancer, pp 311-337. Philadelphia, FA Davis, 1995.

49. Wehbe T, Glantz M, Choy H, et al: Histologic evidence of a radiosensitizing effect of Taxol in patients with astrocytomas. J Neurooncol 39:245-251, 1998.

50. Poisson M, Hauw JJ, Pouillart P, et al: Malignant gliomas treated after surgery by combination chemotherapy and delayed radiation therapy. Part II. Tolerance to irradiation after chemotherapy. Acta Neurochir 51:27-42, 1979.

51. Rosenblum MK, Delattre JY, Walker RW, et al: Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: A pathologic study. J Neurooncol 7:269-281, 1989.

52. Burger PC, Mahaley MS Jr, Dudka L, et al: The morphologic effects of radiation administered therapeutically for intracranial gliomas: A postmortem study of 25 cases. Cancer 44:1256-1272, 1979.

53. Van Tassel P, Bruner JM, Maor MH, et al: MR of toxic effects of accelerated fractionation radiation therapy and carboplatin chemotherapy for malignant gliomas. Am J Neuroradiol 16:715-726, 1995.

54. Huang TS, Huang SC, Hsu MM: A prospective study of hypothalamus pituitary function after cranial irradiation with or without radiosensitizing chemotherapy. J Endocrinol Invest 17:615-623, 1994.

55. Ogilvy-Stuart AL, Shalet SM, Gattamaneni HR: Thyroid function after treatment of brain tumors in children. J Pediatr 119:733-737, 1991.

56. Pratt RA, DeChiro G, Week JC Jr: Cerebral necrosis following irradiation and chemotherapy for metastatic choriocarcinoma. Surg Neurol 7:117-120, 1977.

57. Storm AJ, van der Kogel AJ, Nooter K: Effect of x-irradiation on the pharmacokinetics of methotrexate in rats: Alteration of the blood-brain barrier. Eur J Cancer Clin Oncol 21:759-764, 1985.

58. Qin D, Ma J, Xiao J, et al: Effect of brain irradiation on blood-CSF barrier permeability of chemotherapeutic agents. Am J Clin Oncol 20:263-265, 1997.

59. Krueck WG, Schmiedl UP, Maravilla KR, et al: MR assessment of radiation-induced blood-brain barrier permeability changes in rat glioma model. Am J Neuroradiol 15:625-632, 1994.

60. Rubin P, Gash DM, Hansen JT, et al: Disruption of the blood-brain barrier as the primary effect of CNS irradiation. Radiother Oncol 31:51-60, 1994.

61. Levin VA, Edwards MS, Byrd A: Quantitative observations of the acute effects of x-irradiation on brain capillary permeability: Part I. Int J Radiat Oncol Biol Phys 5:1627-1631, 1979.