Rationale for chemoradiotherapy

The rationale for combining chemotherapy (CT) and radiotherapy (RT) is based mainly on two ideas, one being spatial cooperation and the other the enhancement of radiation effects. Spatial cooperation is effective if CT is sufficiently active to eradicate subclinical metastases and if the primary local tumor is effectively treated by RT. In this regard, no interaction between RT and CT is required, but differing toxicities are needed so that both modalities can be used at effective dosages. To enhance RT by CT, five major mechanisms of CT-RT interactions are required. CT can enhance RT effects by: (1) direct enhancement of the initial radiation damage by incorporating drugs into DNA, (2) inhibiting cellular repair, (3) accumulating cells in a radiosensitive phase or eliminating radioresistant phase cells, (4) eliminating hypoxic cells, or (5) inhibiting the accelerated repopulation of tumor cells. However, virtually all chemotherapeutic agents enhance radiation damage to normal tissues as well. Consequently, therapeutic benefits are only achieved if the enhanced tumor response is greater than that for normal tissues. Due to the complex interaction between CT and RT, the sequence of CT and RT is important. Clinical results of induction CT followed by RT are disappointing, and improvements in local control rates of RT by induction CT have not been observed. On the other hand, clinical trials, including metaanalyses, have clearly shown that CT given concurrently with RT results in improved local control and survival. Although acute toxicities are inevitably increased in concurrent chemoradiotherapy (CRT), no significant increases in late toxicities were reported in most clinical trials. Thus, a therapeutic benefit was observed with the use of concurrent CRT.