Milestones in the Use of Combined-Modality Radiation Therapy and Chemotherapy

Radiation therapy is now more than 100 years old. For the first 60 years, attempts to improve outcome were based on technical improvements in radiation sources, planning, and delivery and in exploration of altered fractionation. The concept of combining radiation therapy with chemotherapy was born shortly after the discovery of fluoruracil (as reviewed by McGinn et al). Indeed, we feel that among the most important developments in the treatment of locally advanced cancers in the last 50 years are the initiation of and continuing improvement in combining chemotherapy (and more recently, molecularly targeted therapies) with radiation therapy. Combined-modality therapy (CMT) has been shown in randomized trials to improve survival, compared with either radiation therapy or chemotherapy alone, in the treatment of high-grade gliomas and locally advanced cancers of the head and neck, lung, esophagus, breast, stomach, pancreas, and rectum. Furthermore, CMT permits organ conservation with high cure rates in cancers of the breast, larynx, and anus and sarcomas of the extremities. Thousands of patients are alive today with improved quality of life because of the development of CMT. Although CMT improves survival in multiple cancers, these gains have typically come at the price of increased toxicity. The increase in toxicity sometimes occurs because of irradiation of bone marrow (eg, cervical cancer) but, more commonly, results from damage to normal tissue that surrounds the tumor. Therefore, the traditional research on radiation therapy focusing on improving technical delivery through more precise targeting (which we will not discuss in this article), beneficial in its own right, has also permitted continued improvements in CMT by minimizing the toxicity of treatment of normal tissues. CMT can be used to improve control of the local disease through the additive killing of tumor cells by two different modalities (additivity) or through tumor selective synergy of agents with radiation therapy (synergy). If all the benefits of CMT were attributable to additivity, then sequential therapy and concurrent therapy should produce similar results. However, when sequential and concurrent therapies are compared directly for treatment of gross disease, concurrent therapy is more effective (and more toxic). There are at least two reasons why this could be the case. The most obvious is that concurrent chemotherapy increases the susceptibility of the tumor cell to radiation-induced killing compared with normal cells, so the effects of the drug need to be present at the time of irradiation. (Spalding and Lawrence provide a review of the biologic factors underlying CMT.) A second possible reason is that sequential treatment causes the protraction of total treatment time, which permits tumor cell repopulation during the course of treatment. For head and neck cancer treated with radiation therapy alone, protraction decreases tumor control, equivalent to a loss of approximately 0.75 Gy per day. Likewise, it has been proposed that the inferior results produced by chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone in anal cancer could be because of protraction of treatment. Sequential therapy has been successful in adjuvant treatment. The best example of successful sequential therapy may be in breast cancer, where the tumor bed after resection contains perhaps 1% of the cell numbers encountered with gross disease and where the use of chemotherapy or hormonal therapy contributes to the treatment of these residual cells before radiation therapy. Adjuvant radiation therapy for locally advanced soft tissue sarcoma presents a similar case. Radiation is sometimes administered before surgery (and chemotherapy afterward) or vice versa, with overall similar results. Thus, because surgery lowers the tumor burden, high tumor bed control rates can be achieved without the need to push the intensity of treatment to the edge of tolerability, and a greater emphasis can be placed on balancing multiple issues such as acute toxicity, cosmesis (for breast cancer), and function (for sarcoma). An additional factor is that the chemotherapeutic agents used for the treatment of breast and soft tissue sarcomas tend to produce substantial skin reactions when administred concurrently with radiation therapy, but similar reactions are deemed tolerable in head and neck cancer when required for cure. In addition to these purely local effects, CMT can improve survival through better systemic control. The most obvious mechanism by which improved systemic control can be achieved is through the treatment of occult metastatic disease by drug (which has been called spatial additivity). However, as is the case for local control, there may be more than one mechanism, in that improved local control can eliminate the source of metastasis. For instance, in the case of breast cancer, it is clear that local irradiation decreases both local recurrence and distant metastasis. This improvement emerged with the introduction of effective systemic chemotherapy, which prevented many women from succumbing to the early development of metastatic disease. This finding has led to the hypothesis that the effect of adjuvant radiation therapy on survival depends on the efficacy of adjuvant chemotherapy. If chemotherapy is either ineffective or very effective, radiation therapy as part of JOURNAL OF CLINICAL ONCOLOGY A S C O 50TH A N N I V E R S A R Y VOLUME 32 NUMBER 12 APRIL 2