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
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]
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 tumors90% 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.
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 noncell-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).
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-antibodydirected treatments, and other immunotherapies. [20,21]
Brain tumor treatment also presents unique challenges in response evaluation, including technical concerns about the timing of imaging procedures, confounders of apparent radiographic response, and the inability of routine imaging studies to distinguish between residual or recurrent tumor and treatment-induced necrosis.[25-27]
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.
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.
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 nonnervous 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 nonbrain 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) 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 nonbrain 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.
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 obviousminimal toxicity, high radiosensitizing potency, independent activity against the tumor, and ease of administrationbut 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.
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