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
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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