ONCOLOGY.
No. 10
5
Concurrent Chemotherapy and Radiotherapy in Patients With Brain Tumors
By
Michael J. Glantz, MD
University of Massachusetts School of Public Health, Amherst, Massachusetts
Lyndon Kim, MD
Eastern Carolina University School of Medicine, Greenville, North Carolina
Hak Choy, MD
Department of Radiation Oncology, Vanderbilt University Medical
Center,Nashville, Tennessee
Wallace Akerley, MD
Brown University School of Medicine, Providence, Rhode Island
|
October 1, 1999
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(Drug information on paclitaxel) [Taxol], estramustine(Drug information on estramustine)
[Emcyt]); and specific action on hypoxic cell populations (eg, mitomycin(Drug information on 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(Drug information on 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.
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.
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
