Current imaging paradigms in radiation oncology

The technological revolution in imaging during recent decades has transformed the way image-guided radiation therapy is performed. Anatomical imaging (plain radiography, computed tomography, magnetic resonance imaging) greatly improved the accuracy of delineating target structures and has formed the foundation of 3D-based radiation treatment. However, the treatment planning paradigm in radiation oncology is beginning to shift toward a more biological and molecular approach as advances in biochemistry, molecular biology, and technology have made functional imaging (positron emission tomography, nuclear magnetic resonance spectroscopy, optical imaging) of physiological processes in tumors more feasible and practical. This review provides an overview of the role of current imaging strategies in radiation oncology, with a focus on functional imaging modalities, as it relates to staging and molecular profiling (cellular proliferation, apoptosis, angiogenesis, hypoxia, receptor status) of tumors, defining radiation target volumes, and assessing therapeutic response. In addition, obstacles such as imaging-pathological validation, optimal timing of post-therapy scans, spatial and temporal evolution of tumors, and lack of clinical outcome studies are discussed that must be overcome before a new era of functional imaging-guided therapy becomes a clinical reality.     

Cost-effective PET investigations in oncology

The authors have reviewed the financial considerations of oncological FDG PET examinations by the guidelines of the Health Care Financing Administration (USA). By critical assessment of large number of clinical investigations,the cost-effectiveness of FDG PET scans has been confirmed in the following cases: differential diagnosis of solitary pulmonary nodule, diagnosis,staging and restaging of non-small cell lung cancer, colorectal cancer, malignant lymphomas, melanoma malignum, esophageal neoplasms and cancers of the head and neck. The role of this method in breast cancer is currently under intensive investigation. Due to the correct staging, PET examinations in these indications enable the clinicians to choose the optimal treatment ensuring the maximum probability of recovery and being cost-effective as unnecessary medical interventions become avoidable.     

New perspectives of PET/CT in oncology

The fusion of PET and computed tomography, which provide metabolic and structural images, respectively, has improved the diagnostic precision of PET in oncology. Some current procedures in the PET/CT acquisition as contrast enhanced CT/PET, the use of PET/CT in radiotherapy planning and the PET-MRI can drastically change the approach of oncologic patients. Finally, inclusions of PET/CT in oncologic diagnostic algorithm and prognostic nomograms are pending issues.     

Global radiation oncology waybill

Background/aim

Radiation oncology covers many different fields of knowledge and skills. Indeed, this medical specialty links physics, biology, research, and formation as well as surgical and clinical procedures and even rehabilitation and aesthetics. The current socio-economic situation and professional competences affect the development and future or this specialty. The aim of this article was to analyze and highlight the underlying pillars and foundations of radiation oncology, indicating the steps implicated in the future developments or competences of each.

Methods

This study has collected data from the literature and includes highlights from discussions carried out during the XVII Congress of the Spanish Society of Radiation Oncology (SEOR) held in Vigo in June, 2013. Most of the aspects and domains of radiation oncology were analyzed, achieving recommendations for the many skills and knowledge related to physics, biology, research, and formation as well as surgical and clinical procedures and even supportive care and management.

Results

Considering the data from the literature and the discussions of the XVII SEOR Meeting, the “waybill” for the forthcoming years has been described in this article including all the aspects related to the needs of radiation oncology.

Conclusions

Professional competences affect the development and future of this specialty. All the types of radio-modulation are competences of radiation oncologists. On the other hand, the pillars of Radiation Oncology are based on experience and research in every area of Radiation Oncology.     

Current concepts in clinical radiation oncology

Based on its potent capacity to induce tumor cell death and to abrogate clonogenic survival, radiotherapy is a key part of multimodal cancer treatment approaches. Numerous clinical trials have documented the clear correlation between improved local control and increased overall survival. However, despite all progress, the efficacy of radiation-based treatment approaches is still limited by different technological, biological, and clinical constraints. In principle, the following major issues can be distinguished: (1) The intrinsic radiation resistance of several tumors is higher than that of the surrounding normal tissue, (2) the true patho-anatomical borders of tumors or areas at risk are not perfectly identifiable, (3) the treatment volume cannot be adjusted properly during a given treatment series, and (4) the individual heterogeneity in terms of tumor and normal tissue responses toward irradiation is immense. At present, research efforts in radiation oncology follow three major tracks, in order to address these limitations: (1) implementation of molecularly targeted agents and ‘omics’-based screening and stratification procedures, (2) improvement of treatment planning, imaging, and accuracy of dose application, and (3) clinical implementation of other types of radiation, including protons and heavy ions. Several of these strategies have already revealed promising improvements with regard to clinical outcome. Nevertheless, many open questions remain with individualization of treatment approaches being a key problem. In the present review, the current status of radiation-based cancer treatment with particular focus on novel aspects and developments that will influence the field of radiation oncology in the near future is summarized and discussed.     

Cerenkov radiation energy transfer (CRET) imaging: a novel method for optical imaging of PET isotopes in biological systems

Background

Positron emission tomography (PET) allows sensitive, non-invasive analysis of the distribution of radiopharmaceutical tracers labeled with positron (β⁺)-emitting radionuclides in small animals and humans. Upon β⁺ decay, the initial velocity of high-energy β⁺ particles can momentarily exceed the speed of light in tissue, producing Cerenkov radiation that is detectable by optical imaging, but is highly absorbed in living organisms.

Principal Findings

To improve optical imaging of Cerenkov radiation in biological systems, we demonstrate that Cerenkov radiation from decay of the PET isotopes ⁶⁴Cu and ¹⁸F can be spectrally coupled by energy transfer to high Stokes-shift quantum nanoparticles (Qtracker705) to produce highly red-shifted photonic emissions. Efficient energy transfer was not detected with ^99mTc, a predominantly γ-emitting isotope. Similar to bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET), herein we define the Cerenkov radiation energy transfer (CRET) ratio as the normalized quotient of light detected within a spectral window centered on the fluorophore emission divided by light detected within a spectral window of the Cerenkov radiation emission to quantify imaging signals. Optical images of solutions containing Qtracker705 nanoparticles and [¹⁸F]FDG showed CRET ratios in vitro as high as 8.8±1.1, while images of mice with subcutaneous pseudotumors impregnated with Qtracker705 following intravenous injection of [¹⁸F]FDG showed CRET ratios in vivo as high as 3.5±0.3.

Conclusions

Quantitative CRET imaging may afford a variety of novel optical imaging applications and activation strategies for PET radiopharmaceuticals and other isotopes in biomaterials, tissues and live animals.     

Application of optical imaging and spectroscopy to radiation biology

Optical imaging and spectroscopy is a diverse field that has been of critical importance in a wide range of areas in radiation research. It is capable of spanning a wide range of spatial and temporal scales, and has the sensitivity and specificity needed for molecular and functional imaging. This review will describe the basic principles of optical imaging and spectroscopy, highlighting a few relevant applications to radiation research.     

Small animal PET imaging

Positron emission tomography (PET) is well established as an important research and clinical molecular imaging modality. Although the size differences between humans and rodents create formidable challenges for the application of PET imaging in small animals, advances in technology over the past several years have enabled the translation of this imaging modality to preclinical applications. In this article we discuss the basic principles of PET instrumentation and radiopharmaceuticals, and examine the key factors responsible for the qualitative and quantitative imaging capabilities of small animal PET systems. We describe the criteria that PET imaging agents must meet, and provide examples of small animal PET imaging to give the reader a broad perspective on the capabilities and limitations of this evolving technology. A crucial driver for future advances in PET imaging is the availability of molecular imaging probes labeled with positron-emitting radionuclides. The strong translational science potential of small animal and human PET holds great promise to dramatically advance our understanding of human disease. The assessment of molecular and functional processes using imaging agents as either direct or surrogate biomarkers will ultimately enable the characterization of disease expression in individual patients and thus facilitate tailored treatment plans that can be monitored for their effectiveness in each subject.     

Recent initiatives for radiation oncology resident education in radiation and cancer biology

Nearly all residents from accredited radiation oncology residency programs in the United States are required to take the American College of Radiology (ACR) In-Training examination each year. The test is comprised of three sections: Clinical Radiation Oncology, Radiological Physics, and Radiation (and Cancer) Biology. Here we provide an update on changes to the biology portion of the ACR exam. We also discuss the availability and use of the ACR and biology practice exams as assessment and teaching tools for both the instructors of radiation and cancer biology and the residents they teach.     

Evidence based radiation oncology with existing technology

Aim

To assess the real contribution of modern radiation therapy (RT) technology in the more common tumoral types in Central America, Caribbean and South America.

Background

RT is an essential tool in the management of cancer. RT can be either palliative or of curative intent. In general, for palliative radiotherapy, major technologies are not needed.

Materials and methods

We analyzed the contribution of RT technology based on published evidence for breast, lung, gastric, gallbladder, colorectal, prostate and cervix cancer in terms of disease control, survival or toxicity with especial focus on Latin America.

Results

Findings indicate that three dimensional conformal radiation therapy (3D RT) is the gold standard in most common type of cancer in the studied regions. Prostate cancer is probably the pathology that has more benefits when using new RT technology such as intensity modulated radiation therapy (IMRT) versus 3DRT in terms of toxicity and biochemical progression-free survival.

Conclusions

In light of the changes in technology, the ever-increasing access of developing countries to such technology, and its current coverage in Latin America, any efforts in this area should be aimed at improving the quality of the radiotherapy departments and centers that are already in place.     

New perspectives in radiation oncology: Young radiation oncologist point of view and challenges

AimTo assess the role of the young radiation oncologist in the context of important recent advancements in the field of radiation oncology, and to explore new perspectives and competencies of the young radiation oncologist.BackgroundRadiation oncology is a field that has rapidly advanced over the last century. It holds a rich tradition of clinical care and evidence-based practice, and more recently has advanced with revolutionary innovations in technology and computer science, as well as pharmacology and molecular biology.Materials and methodsSeveral young radiation oncologists from different countries evaluated the current status and future directions of radiation oncology.ResultsFor young radiation oncologists, it is important to reflect on the current practice and future directions of the specialty as it relates to the role of the radiation oncologist in the comprehensive management of cancer patients. Radiation oncologists are responsible for the radiation treatment provided to patients and its subsequent impact on patients’ quality of life. Young radiation oncologists must proactively master new clinical, biological and technical information, as well as lead radiation oncology teams consisting of physicists, dosimetrists, nurses and technicians.ConclusionsThe role of the young radiation oncologist in the field of oncology should be proactive in developing new competencies. Above all, it is important to remember that we are dealing with the family members and loved ones of many individuals during the most difficult part of their lives.     

PET imaging of the basal ganglia

The present chapter reviews PET imaging in basal ganglia disorders; Parkinson's disease is used as a model of these disorders because the neurochemical pathobiology of this disease is well known and great advances in the imaging area have been achieved. Other basal ganglia disorders including Tourette's syndrome, dystonia, Huntington's chorea and Wilson's disease are also dealt with. With PET and SPECT techniques, the whole integrative dopaminergic network of neurons can be studied, which plays an important role in differential diagnostics. Furthermore, pharmacological effects of medication can be visualized and the role of stereotaxic neurosurgery can be evaluated. Finally, functional imaging gives clues about the prognosis and rehabilitation aspects of the basal ganglia disorders.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

In vivo respiratory-gated micro-CT imaging in small-animal oncology models

Micro-computed tomography(micro-CT) is becoming an accepted research tool for the noninvasive examination of laboratory animals such as mice and rats, but to date, in vivo scanning has largely been limited to the evaluation of skeletal tissues. We use a commercially available micro-CT device to perform respiratory gated in vivo acquisitions suitable for thoracic imaging. The instrument is described, along with the scan protocol and animal preparation techniques. Preliminary results confirm that lung tumors as small as 1 mm in diameter are visible in vivo with these methods. Radiation dose was evaluated using several approaches, and was found to be approximately 0.15 Gy for this respiratory-gated micro-CT imaging protocol. The combination of high-resolution CT imaging and respiratory-gated acquisitions appears well-suited to serial in vivo scanning.     

In vivo imaging of apoptosis in oncology: an update

In this review, data on noninvasive imaging of apoptosis in oncology are reviewed. Imaging data available are presented in order of occurrence in time of enzymatic and morphologic events occurring during apoptosis. Available studies suggest that various radiopharmaceutical probes bear great potential for apoptosis imaging by means of positron emission tomography and single-photon emission computed tomography (SPECT). However, for several of these probes, thorough toxicologic studies are required before they can be applied in clinical studies. Both preclinical and clinical studies support the notion that 99mTc-hydrazinonicotinamide-annexin A5 and SPECT allow for noninvasive, repetitive, quantitative apoptosis imaging and for assessing tumor response as early as 24 hours following treatment instigation. Bioluminescence imaging and near-infrared fluorescence imaging have shown great potential in small-animal imaging, but their usefulness for in vivo imaging in humans is limited to structures superficially located in the human body. Although preclinical tumor-based data using high-frequency-ultrasonography (US) are promising, whether or not US will become a routinely clinically useful tool in the assessment of therapy response in oncology remains to be proven. The potential of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) for imaging late apoptotic processes is currently unclear. Neither 31P MRS nor 1H MRS signals seems to be a unique identifier for apoptosis. Although MRI-measured apparent diffusion coefficients are altered in response to therapies that induce apoptosis, they are also altered by nonapoptotic cell death, including necrosis and mitotic catastrophe. In the future, rapid progress in the field of apoptosis imaging in oncology is expected.     

PET: A biological imaging technique

Like in vivo autoradiography, PET provides a means to image and measure rates of biological processes throughout the distributed and interrelated systems of the entire living brain. In addition, both techniques can track and image the functional interactions of the brain with other systems throughout the entire body. Technological advances are yielding higher image spatial resolution and Electronic generators for automated synthesis of positron labeled compounds. The expanding number of labeled compounds (>500) is providing a growing number of biological assays (i.e., substrate metabolism, pre and post synaptic processes, enzyme activity, interaction of medical and illicit drugs with biological systems of the brain, immune system, membrane processes). Studies of normal cerebral function focus on mapping evoked responses of various components of motor, visual, somatosensory, memory and cognitive functions. Cerebral development, neuronal plasticity, and compensatory reorganization to lesions or surgery are active areas of investigation. Various types of assays have been used to identify specific biological alterations, map progression and determine therapeutic responses in a wide variety of neuropsychiatric disorders and drug abuse.Special issue dedicated to Dr. Louis Sokoloff.