The medical uses of ionizing radiation have expanded dramatically since Wilhelm Roentgen first discovered it at the end of the last century. In particular, it has proven to be an effective agent in the ongoing battle against cancer.
It is presumed that the essential target for radiation is cellular DNA where it acts through the formation of free radicals to directly or indirectly cause double-stranded breaks. It is these doublestranded breaks in the DNA that are felt to be the lethal lesion that malignant cells sustain from therapeutic radiation.
It is presumed that the essential target for radiation is cellular DNA where it acts through the formation of free radicals to directly or indirectly cause double-stranded breaks. It is these doublestranded breaks in the DNA that are felt to be the lethal lesion that malignant cells sustain from therapeutic radiation.
It was in the period of World War II that it was possible to induce lasting remissions and potential cures of hematological malignancies with nitrogen mustard (1), which was really the first chemotherapeutic agent put to widespread use in the treatment of malignant disease. Since that time, a multitude of other drugs have come and gone in the search for a cure.
A few drugs appear to have found a more lasting place in the therapeutic armamentarium, including doxorubicin, cisplatinum, cyclophosphamide, and 5-fluorouracil. A new generation of drugs with varied mechanisms of action has appeared in the last decade and also has the potential to remain as key in the treatment of cancers.
A few drugs appear to have found a more lasting place in the therapeutic armamentarium, including doxorubicin, cisplatinum, cyclophosphamide, and 5-fluorouracil. A new generation of drugs with varied mechanisms of action has appeared in the last decade and also has the potential to remain as key in the treatment of cancers.
These agents include paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine. Although oncologists and researchers have often tried to cure cancers with radiation alone or with various chemotherapeutic strategies, in general these have been met with limited success for any number of reasons, which will be outlined below.
The strategy of integrating different treatment modalities into a more comprehensive approach to both local control and the treatment of micrometastatic disease, often referred to as combined modality therapy, has been met with some success. Although the delivery of neoadjuvant and adjuvant chemotherapy may contribute to improved local control, it is less clearly demonstrable than with concurrent therapy. This chapter will focus on combined modality therapy with an emphasis on concurrent chemoradiation. It will attempt to set the background with an examination of the rationale and the difficulties that are inherent with concurrent therapy from the point of view of both the delivery of radiation and of chemotherapy.
Beyond this it will illustrate some of the gains achieved in therapy using a concurrent treatment approach. Finally it will focus on the potential for the future that lies in an increased understanding of the molecular players in neoplastic processes as well as the response of malignant cells to therapy with radiation and chemotherapy. The integration of new agents that are aimed against more specific cellular targets than either
radiation or traditional cytotoxic chemotherapy may significantly influence the success of combined modality therapy in the future.
TREATMENT PARADIGMS
Surgical therapy as a sole modality often fails because micrometastatic disease is already present at the time of surgery or because malignant cells are present beyond the surgical margins of the resection. Radiation therapy is sometimes added before or after surgical resection to decrease the possibility of local recurrence when it is felt that there is a high enough probability of residual malignant cells being present after surgery.
However, radiation therapy as both a sole modality of treatment or as an adjuvant or adjunctive therapy may fail to sterilize tumors because of micrometastases or because the dose of radiation that can be safely delivered is limited by the tolerance of the surrounding normal tissues. Certainly the explosion of new technology in the current computer age has improved our ability to deliver further radiation in a more conformal fashion.
However, in those malignancies that have a high propensity for distant spread of disease, delivery of higher doses of conformal radiation may not prove to be a satisfactory approach to the problem. Unfortunately chemotherapy rarely proves to have a curative role on its own in the treatment of solid tumors.
BIOLOGY COMPLICATES THE DELIVERY OF RADIATION The delivery of therapeutic radiation is limited by the tolerance of the surrounding normal tissues. Data have been compiled over many years that suggest which structures are able to tolerate certain doses with acceptable amounts of toxicity (2). This model for thinking about how to plan the delivery of radiation has changed considerably with the advent of new computer- and automation-driven technologies that allow for the more conformal delivery of dose to the gross tumor and to the clinical target volume.
New analytical tools called dose volume histograms, which allow for a definition of the dose delivered to a percentage of an organ, have begun to replace more traditional concepts of normal tissue tolerance. Although these technology-related advances allowfor the delivery of higher doses of radiation, this may only be an effective strategy in those tumors whose biology makes them amenable to a local therapy as the sole modality of treatment.
Those tumors that have a predilection for the early dissemination of micrometastases cannot be effectively treated by a local therapy alone. However, those tumors that tend to remain localized for longer periods of time may have several biologic reasons that underlie their resistance to radiation.
Chemoradiation In Cancer Therapy