Despite advances and refinements in cancer
treatment and an emphasis toward early detection, the vast majority
of human malignancies are not effectively treated. Knowledge of the
complex nature of human cancer is increasing exponentially as modern
molecular biology and genetics reveal potential targets to combat and
perhaps some day prevent this dreadful disease. Yet, there is still a
need to fully develop and optimize combined-modality cancer treatment
to help patients who will not have the opportunity to benefit from
the molecular biology revolution.
The combined use of radiation therapy and chemotherapy in cancer
treatment is a logical and reasonable approach that has already
proven beneficial for several malignancies. Local control of the
primary tumor mass (which can often be achieved by high-dose
radiation), combined with systemic chemotherapy to control metastatic
disease, should provide effective means to combat such a highly
complex disease. Moreover, the finding that many chemotherapy drugs
enhance the effects of radiation provides even more impetus to
integrate both modalities.
The genesis of concurrent chemoradiation dates back to the 1950s when
investigators began searching for chemical agents that might enhance
the effects of radiation.[1,2] In 1958, Heidelberger et al obtained
potentiation of activity by combining fluorouracil with
radiation in a preclinical study. They treated transplanted murine
tumors with fluorouracil 20 mg/kg/day for 7 days and radiation doses
of either 15 or 20 Gy. These pioneering studies were later translated
into clinical trials, often with contradictory results, such as those
observed in the treatment of lung cancer.[4,5] However, a major
breakthrough was achieved in the early 1970s when, encouraged by the
results obtained with chemoradiotherapy at the Mayo Clinic on
gastrointestinal cancers,[6,7] Nigro and colleagues used a
combination of fluorouracil and mitomycin concurrent with radiation
as neoadjuvant treatment in patients with cancer of the anal canal.
They reported that three of three patients achieved complete
responses. In two of the three patients, an abdominoperineal
resection was performed 2 months after treatment. Histological
examination of tissue specimens confirmed a pathologic complete
response. The other patient refused surgery but was alive and
clinically free of disease 14 months after the treatment. Even though
the study included only a small number of patients, the results of
this initial pilot study (and subsequent clinical trials) were so
dramatic, they prompted a paradigm shift in the thinking of
oncologists away from exonerative surgery for anal cancer. Since the
1970s, numerous chemoradiation trials have been performed with
differing levels of success in a variety of cancer histologies.
It is most reasonable to ponder why chemoradiation is so successful
in the treatment of one cancer histology and yet only provides
varying levels of success in others. Furthermore, it is also
reasonable to explore the limitations of chemoradiation. The major
limitation of combining two modalities has been cumulative
normal-tissue toxicity. Either modality when used alone may cause
major normal-tissue toxicity, which in some instances can be life
threatening. The onset of normal-tissue toxicity limits the dose
achievable by either modality alone and thus compromises the
administration of the drug or radiation dose. Most experimental
models and a number of clinical trials using combined drugs and
radiation simultaneously show that normal-tissue toxicity may be
enhanced even further.[9,10] Thus, a major barrier in the use of
radiation or chemotherapy to treat cancer either alone or in
combination is lack of specificity.
A photon beam, no matter how well shaped or conformed to the
dimensions of the tumor, will undoubtedly irradiate some normal
tissue. The radiosensitivities of tumor and normal tissues are often
similar, or, unfortunately in some cases, the tumor cells may be more
resistant than surrounding normal tissues. Radiation alone can and
does damage normal tissue if threshold doses are exceeded. Systemic
drug therapy theoretically exposes all tissues, normal and tumor
alike, to cytotoxic action. Often, normal-tissue toxicity exceeds
tumor cytotoxicity, or effective tumor-cell cytotoxicity is
compromised by reducing the dose to reduce normal-tissue toxicity to
an acceptable level. During chemotherapy, patients frequently relapse
after initial treatment and become progressively less responsive to
second- or third-line treatments. Combined-modality therapies
complicate these issues further. These are the harsh realities of
combined-modality therapy that must be dealt with if cancer treatment
is to improve using multimodality approaches.
Rational and systematic cooperation on the part of basic scientists
and clinicians offers the possibility to forge treatment approaches
that work. This article will focus on several aspects of
combined-modality therapy that should be considered. Space does not
permit the review of each radiationdose-modifying agent in
current use; however, the reader is directed to several fine reviews
that provide more detail, particularly with respect to specific drugs
When considering using the combination of a chemotherapy drug(s) (or
radiation-modifying agent[s]) with radiation, it is important to
understand the mechanism(s) of action of each modality, how these
mechanisms might overlap to enhance one or the other, and how to
effectively time each agent to yield maximum benefit. It
is perhaps worth asking the question, If one could design an
ideal radiation modifier, what would be its characteristics? Table
1 highlights the characteristics of an ideal
Consideration of an ideal modifier may be a lofty
aspiration, yet it nonetheless provides a standard for which to aim.
In principle, the ideal radiation modifier portrayed in Table
1 allows for more radiation dose to be delivered to the tumor
(in the case of a protector) and more effective dose (in
the case of a sensitizer). Most experimental tumors and most human
primary tumors respond to radiation treatment in a dose-dependent
manner with respect to response and cure. The more dose delivered to
the tumor, the greater the likelihood of tumor cure. Likewise, an
ideal radiation sensitizer has effective antitumor
activity against metastatic disease, a major determinant of
long-term, disease-free survival. In reality, an ideal
radiation modifier does not yet exist, but we can use the
characteristics of an ideal radiation modifier as a standard as new
chemoradiation agents become available.
The major reason to consider the use of a radiation sensitizer is to
improve local control of disease. A radiosensitizer may not have a
direct anticancer effect (as is the case for some hypoxic cell
radiosensitizers), or it may be one of a variety of anticancer drugs
that, in addition to radiosensitization, exhibits antitumor effects
alone. Understanding the mechanism of action of a specific
radiosensitizer can affect the way it is used in the clinic. In
general, the mechanism by which agents sensitize cells to radiation
can be categorized into three broad areas, as discussed below.
Increase in Initial Damage
Radiation-induced cellular effects result from the production of free
radical species and/or direct ionization of target molecules. The
exact identification of critical cellular structures or molecules and
the specific type of damage rendered by radiation are not completely
known. However, considerable evidence points to DNA as the critical
target for radiation damage, with double-strand DNA breaks as the
lethal lesion. Cells die following radiation treatment by
mitotic-linked death and/or programmed cell death (apoptosis). An
agent that causes more initial damage to critical cellular targets
would be expected to enhance the cytotoxic effects of radiation if
repair systems become saturated. Halogenated pyrimidines, which in
part enhance the radiation response by increasing damage, have been
used in chemoradiation studies. Incorporation of halogenated
pyrimidines into cellular DNA has been shown to increase DNA
damage, as well as compromise repair systems, as discussed below.
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