Introduction

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In 2006, a substantial proportion of patients receiving radiation therapy for cancer will receive concurrent treatment with systemic chemotherapy or a biological agent. Indeed, the practice of oncology has become more multidisciplinary than ever before, and radiation oncologists with good familiarity regarding concurrent radiation/drug regimens will be best positioned to optimize patient outcome and anticipate toxicities. In the coming years, a series of new molecular agents will enter oncology practice thereby further increasing the options for concurrent treatment regimens. In this issue of Seminars, we focus on the evolving use of concurrent radiation plus systemic therapy in oncology practice.

Much has transpired since Steel proposed a classical framework to define interactions between combined radiation and chemotherapy in 1979. In this issue, Wilson provides a timely update regarding concurrent chemoradiation treatment strategies with a focus on biological interaction mechanisms, and factors that may influence the impact of new molecular agents on radiation response. Although there are many new systemic agents on the horizon, the most common single agent delivered concurrently with radiation in 2006 remains cisplatinum. The article by Hao reviews the status of concurrent platinum-based chemoradiation regimens using two upper aerodigestive tract cancers (head and neck (H&N) and esophagus) as examples. For each tumor type, the clinical evidence and current state of practice is reviewed, as well as comment regarding future directions for research.

Increasing numbers of patients are now receiving hormonal therapy concurrent with radiation therapy, and this is particularly common for men with prostate cancer. The article by Lee reviews the current status of combined radiation and hormonal therapy for patients with prostate cancer, and provides concise recommendations for optimal treatment regimens based on review of the clinical data. We still know relatively little regarding specific mechanisms of interaction between hormonal therapy and radiation, and this field remains ripe for further preclinical and clinical investigation.

Two of the most compelling clinical datasets highlighting the potential value of concurrent radiation with new drugs have recently emerged for glioblastoma multiforme (GBM) and advanced H&N cancer. The article by Zhang and Chakravarti reviews a landmark Phase III trial demonstrating significant survival improvement for GBM patients treated with the combination of radiation and temozolomide (TMZ) versus radiation alone that has redefined global practice standards. This article summarizes proposed action mechanisms for TMZ and discusses the potential value of patient selection using MGMT methylation status from biopsy material. The article by Harari and Huang reviews a landmark Phase III trial demonstrating significant survival improvement for advanced H&N cancer patients treated with addition of the EGFR inhibitor cetuximab to radiation. Tracing the story line of EGFR inhibitors from preclinical to clinical fruition suggests that some of the most potent future results may ultimately derive from combining EGFR inhibitory agents with radiation therapy.

For the future, a broad series of promising new molecular targeting agents are moving through clinical trials with potential for FDA approval in coming years. In the area of antiangiogenic and antivascular agents, bevacizumab has recently gained FDA approval and is rapidly advancing in global use for colorectal and lung cancer patients. Comparatively little is known regarding detailed mechanistic actions of these promising new agents in concert with radiation, and the article by O’Reilly provides a superb review of this emerging field. The final articles by Choudhury and Chinnaiyan offer a glimpse into the future regarding several molecular targets that afford particular promise for modulation in combination with radiation in cancer therapy. Highlighting targets such as ATM-ATR, DNA repair molecules, IGF-1R and PI3 kinase, preclinical and early clinical data are previewed with rationale regarding future possibilities for combination approaches.

In recent years, several striking examples of improved clinical outcome using concurrent radiation plus systemic therapy (over radiation alone) have been established. Many promising new molecular cancer agents will enter oncology practice in the near future. The emerging data suggests that several of these new molecular therapies may achieve their greatest impact when delivered in combination with radiation therapy. This is an unprecedented time in our history for systematic preclinical and clinical investigation of radiation/drug interactions to improve ultimate outcome for our cancer patients.