Principles of Chemoradiation: Theoretical and Practical Considerations

Introduction

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(Drug information on fluorouracil) with radiation in a preclinical study.[3] 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(Drug information on 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.[8] 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.[11] 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 radiation–dose-modifying agent in current use; however, the reader is directed to several fine reviews that provide more detail, particularly with respect to specific drugs and radiosensitization.[12-14]

The “Ideal” Radiation Modifier

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” radiation modifier.

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.

Radiation Sensitizers

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,[15] with double-strand DNA breaks as the lethal lesion.[16] 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,[17] as well as compromise repair systems[18], as discussed below.