Читать книгу Advances in Radiation Therapy - Группа авторов - Страница 32

Ideally, each patient with a malignancy who is eligible for radiation therapy should receive the most tumoricidal form of this this treatment with the lowest possible risk of toxicity. To overcome radiotherapy resistance, some patients would benefit from a more aggressive approach. This could be treatment intensification, for example by acceleration of the treatment to prevent the negative effects of accelerated tumor cell proliferation, or by boosting certain areas to specifically address intrinsic radioresistance, or a combination of radiotherapy with, for example, a hypoxic cell sensitizer or chemotherapy to reduce the radiotherapy resistance caused by hypoxia. For some patients, one of these approaches can be beneficial but for others could lead to unacceptable side effects. Therefore, it is highly desirable to make the selection upfront. The use of imageable biomarkers could be the key to a more patient-tailored treatment. Different biomarkers for hypoxia and proliferation that could be valuable for radiotherapy are discussed here, including their mechanism, the imaging procedure, quantification, and the value of the results.

© 2018 S. Karger AG, Basel

In recent decades, technological developments in treatment planning and image-guided radiotherapy have led to increased precision of radiation treatments. To make the next big step, a more patient-customized treatment is anticipated, with radiation doses as high as needed for a tumoricidal effect, and as low as possible to minimize the risk of healthy tissue toxicity. To achieve this goal, the biological effectiveness can be improved for instance by treatment acceleration, i.e., reducing the overall treatment time, or by combining radiotherapy with a radiosensitizer. Selecting the most appropriate treatment for a patient requires knowledge about the potential effect of different types of treatment on an individual level. Individual biological information, obtained by the imaging of biomarkers, could be the key to move from population-based to patient-tailored treatments [1].

There is no clear definition of “biomarkers,” but, in general, the term means “objective, quantifiable characteristics of a biological process that can be measured accurately and is reproducible” [2]. We use the term biomarker for quantifiable biological characteristics that can predict treatment efficacy, and, although a broad range of biomarkers can be included, e.g., patient weight, or pulmonary function, we confine ourselves to noninvasively imageable biomarkers that give an indication with respect to the biology of the tumor microenvironment.

In contrast to biopsies and characteristics derived from blood samples, imaging provides 3-dimensional (3D) information about tumor characteristics. At the cost of a relatively low resolution – that is relative to the microscopic or even molecular level at which resistance takes place – information is obtained for the whole tumor. In general, imaging can be performed repetitively and, apart from the additional radiation burden or administration of contrast fluid or radioactive compounds, it is noninvasive. Another advantage of imaging is its already defined role in diagnosis and patient management [1].

Since the early 1980s, when computed tomography (CT) imaging became widely used, tumor size has been the best-known imaging biomarker. Volumetric measurements also remain the basis for the evaluation of tumor response according to the RECIST-criteria. However, size is a biomarker reflecting the final part of a biological response, i.e., for a size reduction tumor cells must have died and been removed from the tissue. Thus, it is a “late” marker, delaying evaluation up to 12 weeks following radiotherapy since the principle of cell kill resulting from radiotherapy is predominantly caused by mitotic catastrophe. Receptor expression, proliferation, metabolism, vascularization, diffusion, and perfusion change can be detected earlier than a difference in size [3] (Fig. 1 a, b). Therefore, molecular and functional imaging are repeatedly suggested for early detection of treatment response, especially when targeted therapies are given, for instance in combination with radiotherapy [4–6]. Also, treatment modification to overcome radiation resistance, for instance modifying tumor cell hypoxia, may also be visualized at an earlier stage [7].

Many potential imaging biomarkers for the prediction of treatment response and treatment guidance have been described [8–12]. Before routine clinical use, these biomarkers have to bridge 2 “translational gaps”: first to become a reliable tool for medical research, and then to become a reliable, practical tool for clinical decision making [13]. Of the many tracers suggested to have potential, only a few make it into routine clinical practice. In radiotherapy, CT imaging (with or without i.v. contrast, 3D or 4D) is routinely used for treatment planning and evaluation. Magnetic resonance imaging (MRI) is increasingly being applied for target definition and treatment evaluation. Positron emission tomography (PET) is mainly used with fluorodeoxyglucose (¹⁸F-FDG), visualizing glucose metabolism as a surrogate for tumor activity, and used for diagnosis and tumor delineation. Mostly cone-beam CT or, to a lesser extent, albeit with a high potential, MRI is being applied for position verification.

Both PET and MRI can give more biological information than is currently obtained. Here, we focus on imaging biomarkers, mainly PET based, that can contribute to radiotherapy both for planning and evaluation purposes. These biomarkers should at least have the potential to allow the selection of patients benefiting from an adapted treatment (e.g., boost, hypofractionation, hypoxic cell sensitization) or exclude patients from radiotherapy that would not benefit because of radioresistance. Therefore, we will focus on 2 of the most important mechanisms of radioresistance: hypoxia and accelerated tumor cell proliferation [14] (Fig. 2).

For those who are not familiar with the technical aspects of PET, we begin by briefly explaining this technique. This is followed by the actual description of imaging hypoxia and proliferation biomarkers for radiotherapy – what do they exactly visualize and how can this be useful for radiotherapy?

Fig. 1 a. Before the change in size, other changes in tumor (cell) characteristics could be used to predict tumor development or the effect of radiotherapy. Since proliferation is an early biomarker, imaging of proliferation can be valuable for early response prediction or pretreatment patient selection. b Human tumor xenografted head and neck squamous cell carcinomas treated with a single dose of 10-Gy photons. Note the differences in rates of a changing microenvironment. Within 6–8 h a drastic reduction in hypoxia (pimonidazole, green) is observed lasting beyond the last time point at 28 h. The rate at which proliferation (BrdUrd, red) changes occur is faster and shorter; recovery of tumor cell proliferation can already be observed at 28 h. Blood vessels are blue (9F1). (Previously published by Bussink et al. [56].)