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The concurrent chemoradiation paradigm—general principles

Nature Clinical Practice Oncology volume 4, pages 86–100 (2007)Cite this article

Abstract

During the past 20 years, the advent of neoadjuvant, primary, and adjuvant concurrent chemoradiotherapy has improved cancer care dramatically. Significant contributions have been made by technological improvements in radiotherapy, as well as by the introduction of novel chemotherapy agents and dosing schedules. This article will review the rationale for the use of concurrent chemoradiotherapy for treating malignancies. The molecular basis and mechanisms of action of combining classic cytotoxic agents (e.g. platinum-containing drugs, taxanes, etc.) and novel agents (e.g. tirapazamine, EGFR inhibitors and other targeted agents) with radiotherapy will be examined. This article is part one of two articles. In the subsequent article, the general principles outlined here will be applied to head and neck cancer, in which the impact of concurrent chemoradiotherapy is particularly evident.

Key Points

  • Concurrent chemoradiotherapy has improved cancer care during the past two decades in multiple diseases, and can be used in the neoadjuvant, primary (definitive), or adjuvant setting

  • Chemotherapy or targeted agents can increase the efficacy of radiation

  • Radiosensitizing effects (interaction within the radiation field) can be additive or supra-additive

  • Multiple mechanisms underlie radiosensitizing properties of chemotherapeutic agents and include increased radiation damage, inhibition of DNA repair, cell-cycle synchronization, increased cytotoxicity against hypoxic cells, inhibition of prosurvival pathways, and abrogation of rapid tumor cell repopulation

  • Radioresistance occurs through multiple mechanisms, such as a large tumor burden, hypoxia, rapid tumor cell repopulation, as well as the constitutive or acquired activation of radioresistance signaling pathways

  • In addition to the classic chemotherapeutic agents with radiosensitizing properties (i.e. cisplatin and paclitaxel), several novel agents show promising interactions with radiation (e.g. EGFR inhibitors, pemetrexed, tirapazamine, and potentially several other targeted therapies)

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Figure 1: Rationale for adding chemotherapy to radiation.
Figure 2: Schematic example of an isobologram depicting the combination of radiation and a systemic agent.
Figure 3: Schematic dose–response curves for tumor and normal tissue damage with radiation.
Figure 4: Cell-cycle schematic and respective sensitivity to chemotherapeutic agents.
Figure 5: Increased DNA damage by addition of cisplatin to radiation.

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Acknowledgements

The authors would like to acknowledge the generous help of Dr Blase Polite and Dr Samir Undevia in reviewing organ-specific data.

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  1. TY Seiwert is a fellow in the Department of Medicine, JK Salama is an instructor in the Department of Radiation and Cellular Oncology, and Director of the Hematology/Oncology Section in the Department of Medicine, University of Chicago Cancer Research Center, Pritzker School of Medicine, The University of Chicago, and EE Vokes is the John E Ultmann Professor of Medicine and Radiation and Cellular Oncology, Pritzker School of Medicine, The University of Chicago, IL, USA.,

    Tanguy Y Seiwert, Joseph K Salama & Everett E Vokes

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  1. Tanguy Y Seiwert
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  2. Joseph K Salama
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  3. Everett E Vokes
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Correspondence to Tanguy Y Seiwert.

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Competing interests

EE Vokes has been a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, ImClone, OSI and sanofi-aventis. The other authors declared they have no competing interests.

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Seiwert, T., Salama, J. & Vokes, E. The concurrent chemoradiation paradigm—general principles. Nat Rev Clin Oncol 4, 86–100 (2007). https://doi.org/10.1038/ncponc0714

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