It has long been recognized that cellular and tissue oxygenation is a major determinant of radiosensitivity.31,32 For several decades, oxygen was considered to be a radiation dose modifier as in vitro/in vivo radiobiology data suggested that the oxygen enhancement ratio (OER) is 2.5-3.0 for low-LET radiation (X-rays, photons) and 1.5-2.0 for intermediate-LET radiation (protons). More recently, experimental and limited clinical data suggest that the OER for both low- and intermediate-LET radiation are lower at lower doses typically used daily in treating human cancers. Although the underlying mechanism of the oxygen-modifying effect is not exactly known, the leading model suggests that cellular oxygen acts as a radiosensitizer by forming radicals such as peroxides in DNA, resulting in a fixation or persistence of ionizing radiation (IR) damage.
It is now known that two different forms of hypoxia exist in human cancers. Chronic hypoxia results from a tumor outgrowth of its blood supply, and variable levels or gradients of chronically low oxygen tension exist beyond the physiologic diffusion distance of oxygen through the interstitial (extra-vascular) tissue compartment.33 It is hypothesized that these chapter 3
chronic hypoxic tumor areas (volumes) contain clonogenic and radioresistant hypoxic tumor cells. It is also recognized that reoxygenation of these chronically hypoxic tumor cells can occur, at least experimentally.33,34 A second type of tumor hypoxia also exists and is termed acute or perfusion-limited hypoxia. Acute tumor hypoxia results from transient alterations in tumor vasculature.34
Over the past decade, several clinical studies have demonstrated that hypoxic tissue (defined as areas of oxygen tension less than 2.5mmHg) exist in up to 50% to 60% of a wide range of locally advanced solid tumors including primary brain tumors, soft tissue sarcomas, and melanoma as well as carcinomas of the breast, head and neck, pancreas, and cervix.35 Although trials of several hypoxic radiosensitizers have been negative, it is now realized that proper patient (tumor) selection was not performed in the design of these trials.36 Current trials such as the accelerated radiotherapy, carbogen, and nicotinamide (ARCON) trials in Europe, particularly in head and neck cancer and bladder cancers, are selecting patients with biochemically confirmed hypoxic tumors for testing this approach.37
Hypoxia also causes altered gene expression in human tumors with associated changes in tumor microenvironment. The best characterized transcription factor is hypoxia-inducible factor 1 (HIF-1).38 The changes in gene expression in hypoxic tumors are similar to changes in normal cells to adapt to a hypoxic stress such as trauma and subsequent wound healing. However, these hypoxia-regulated genes, when upregulated in human tumors, lead to resistance not only to radiation therapy but also to different types of chemotherapy.39 The clinical targeting of HIF-1a to selectively kill or inhibit hypoxic tumor cells is now in early trials using drugs such as radamycin.39 The advantage of targeting HIF-1 is the observed rapid response to changes in oxygenation, making it a good target for both acute and chronic hypoxic tumor cells. Such new targeted approaches in radiation oncology are discussed later in this chapter.
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