• © 2007 by American Society of Clinical Oncology

Concomitant Chemoradiotherapy

This edition of the Journal of Clinical Oncology focuses on preclinical and clinical studies of the interaction of chemotherapy and radiation. In recent years, many studies investigating the concomitant administration of the two modalities have been completed, generating much new knowledge. New mechanisms of interactions of cytotoxic as well as targeted agents with radiation have been identified, and significant progress has been made in the treatment of a variety of solid tumors. A concurrent chemoradiotherapy regimen represents the best current standard therapy option for many patients with regionally advanced solid tumors, and improves the probability of cure.

The general clinical goal of administering chemotherapy and radiation simultaneously is to improve both locoregional and systemic tumor control. The classic foundation of the chemotherapy/radiation interaction includes spatial interaction, radiation sensitization, and toxicity independence. Spatial interaction recognizes that radiation therapy will work locoregionally (ie, within the irradiated field), while chemotherapy will work systemically. While this definition allows for some chemotherapy antitumor activity within the radiated field, the major goal for chemotherapy is to eradicate systemic micrometastases. Notably, simultaneous administration of the two modalities is not a prerequisite for spatial interaction to occur. Another goal of concomitant chemoradiotherapy is to increase the efficacy of radiation (ie, radiation sensitization). Sensitization addresses the fact that clonogenic radioresistance will ultimately cause treatment failure within the irradiated field after single-modality radiotherapy for many patients with intermediate-stage solid tumor. Toxicity independence postulates that this goal can be achieved without an increase of in-field adverse effects and implies an improved therapeutic ratio.

Radiation sensitization has been described for most cytotoxic agents. Possible sensitizing mechanisms have included synergistic DNA damage, inhibition of repair of radiation damage, hypoxic cell sensitization, cell cycle synchronization, inhibition of rapid repopulation of tumor cells, and suppression of radiation resistance pathways, including activation of the epidermal growth factor (EGFR) signaling pathway among many others. Similarly, targeted agents have been shown to result in radiation sensitization. Currently of major interest in this regard are inhibitors of EGFR as well as antiangiogenic agents. EGFR inhibitors in particular have already been shown to have clinical value as radiation sensitizers in advanced head and neck cancer. We have reached a juncture where many opportunities exist for the integration of physically targeted radiotherapy with biologically targeted molecular therapy.

Genetically engineered radiation enhancers are also of interest. For example, tumor necrosis factor (TNF) radiosensitizes in the preclinical setting; however, its high toxicity when administered systemically prohibits its simultaneous administration with radiation. To circumvent this problem, the TNF gene has been linked to a radiation inducible promoter and adenoviral vector. Thus, when this agent is injected into a tumor, it is hoped that the virus will infect the tumor cell, and that subsequent radiation will lead to activation of the promoter and local production of TNF with resultant radiation sensitization.

A third major goal of clinical studies of chemoradiotherapy is to shift the therapeutic ratio and increase antitumor efficacy to a greater effect than treatment-related short-term and long-term toxicities. Most clinical experience to date demonstrates that improved antitumor efficacy is achieved at the cost of increased short-term toxicities such as mucositis, esophagitis, and increased myelosuppression. However, increased acute toxicity may be acceptable if increased efficacy can be documented as increased actual long-term survival rates and/or functional organ preservation. Concurrent chemoradiotherapy also exacerbates long-term toxicities including fibrosis and dysphagia/swallowing. For example, as nonsurgical organ preservation strategies have become a standard in many patients with advanced larynx cancer, increased attention has shifted to studies of actual organ function post-treatment. There is a pressing need to develop better diagnostic and management tools to evaluate organ function after chemoradiotherapy. Such efforts are necessary because functional toxicities are more difficult to quantify than objective end points such as survival. These challenges can lead to systemic under-reporting bias concerning toxicity.

Amelioration of toxicity through the use of modifying drugs has also been pursued. Such studies of “protectors” carry the intrinsic risk of also protecting the tumor, and need to be pursued with caution. Administration of cytokine growth factors has been studied. Clinical experience to date does not suggest a protective major role both for erythropoietic or granulopoietic stimulating factors. In fact, erythropoiesis-stimulating agents have been associated with decreased survival rates in two head and neck cancer trials and in one breast cancer trial. Keratinocyte growth factors are currently under investigation and may offer clinical benefit in the future. It is important to recognize that targeted therapy may be directed towards the protection of normal tissue.

These and other issues are addressed by the outstanding investigators who have contributed to this edition of the Journal. With respect to specific organ sites, we have elected to focus on intermediate-stage malignancies of the head, neck, and chest, as well as brain tumors where chemoradiotherapy has most solidly been established as a standard therapy option. These articles focus on definition of current regimens and ongoing developmental efforts including the integration of induction chemotherapy approaches with concomitant chemoradiotherapy, integration of anti-EGFR or antiangiogenic agents, and other novel cytotoxics.

It is our hope that as translational research increases our understanding of mechanisms of interaction of systemic agents with radiation, we will be able to define more effective and less toxic therapies in the future.