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New concepts for phase I trials: evaluating new drugs combined with radiation therapy

Nature Clinical Practice Oncology volume 2, pages 456–465 (2005)Cite this article

Abstract

The rationale for delivering concomitant chemoradiation is not only to increase tumor cell kill but also to achieve a synergistic effect of chemotherapy and radiation. Combination of chemotherapy and radiotherapy has yielded encouraging results in patients with locally advanced diseases. Our increased knowledge of cancer at the molecular level has transformed our understanding of tumor radiation resistance. Preclinical models have shown that several biologic agents designed to target specifically these molecular processes are radiosensitizing agents. Many of these agents are in the process of clinical evaluation with radiotherapy. The translation of these findings into the clinical setting will be feasible only if early phase I trials demonstrate their safety when combined with ionizing radiation. The combination of new drugs and radiation might not necessarily be equivalent to the toxicity of the new drug plus the usual toxicity of radiation. The doses and schedule to be explored for the new drug might vary from those assessed for the new drug alone. Inappropriate evaluation of a combination regimen can result in unjustified abandonment of a combination, or adoption of a regimen at toxic dose levels because of poor toxicity monitoring. Beside the 'in field' radiation dose-dependant symptoms, 'outside the field' symptoms that are not dose dependant might be identified. Specific and long-term clinical evaluation will be required to identify potentially harmful interactions. It will be necessary to rethink phase I strategies, toxicity endpoints, and trial designs and concepts in order to fully optimize these regimens.

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Figure 1: Evolution of radiosensitization concepts to improve tumor response to ionizing radiation.
Figure 2: Schematic graph reflecting the ideal antitumor efficacy, molecular target effect and toxicity as a function of dose for a hypothetical molecular based agent combined with ionizing radiation.
Figure 3: Clinical development steps of a new drug–radiation combination.

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Acknowledgements

E Deutsch is supported by a Fondation de France/Federation des centres anticancereux Medical Scientist Training Program Grant.

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Authors and Affiliations

  1. Radiation Oncology Department at the University of Pennsylvania, Philadelphia, USA

    Eric Deutsch

  2. Department of Radiation Oncology, Laboratoire UPRES EA2710 radiosensibilité des tumeurs et des tissus sains, at the Institut Gustave Roussy, Villejuif, France

    Eric Deutsch

  3. Assistant Professor, Medical Oncology Department, Phase I Trials Unit, at the Institut Gustave Roussy, Villejuif, France

    Jean Charles Soria

  4. Professor in the Medical Oncology Department, Phase I Trials Unit, at the Institut Gustave Roussy, Villejuif, France

    Jean Pierre Armand

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Correspondence to Eric Deutsch.

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Competing interests

JC Soria received clinical trial research support from AstraZeneca, Sanofi Aventis, Bristol-Myers Squibb, and Pharmacia. JC Soria has received occasional honoraria from AstraZeneca and Sanofi Aventis. E Deutsch received clinical research support from GlaxoSmithKline, AstraZeneca and Lilly.

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Deutsch, E., Soria, J. & Armand, J. New concepts for phase I trials: evaluating new drugs combined with radiation therapy. Nat Rev Clin Oncol 2, 456–465 (2005). https://doi.org/10.1038/ncponc0295

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