Stereotactic body radiation therapy (SBRT) consists of the delivery of precise, conformal, hypofractionated, and ablative therapy in a single or a small number of fractions to extracranial regions. Over the last decade, it is rapidly being integrated into mainstream radiation oncology practices. The indications for SBRT continue to grow, as does the technology associated with its delivery. This chapter presents a detailed overview of clinically relevant topics including patient selection and outcomes, and the technological aspects of planning and delivery of SBRT. The tumor streams covered in this chapter are lung, liver, spine, pancreas, renal cell carcinoma, adrenal, prostate, and head and neck. The chapter concludes by highlighting two novel areas, cardiac arrhythmias and pediatric oncology, in which the use of SBRT is emerging.
Different immunotherapy concepts developed over recent decades include immune checkpoint inhibition, vaccination, and T cell-engaging therapies, as well as effectors on the immunosuppressive tumour microenvironment. For all these immunotherapy approaches, combination studies with tumour irradiation have been performed in vivo and in the clinic. The results point towards possible opportunities for combination therapies to improve patient outcome.
Target volume definition is of obvious importance in successful radiotherapy. Single-energy CT scans remain the standard, but FDG-PET-CT scans aid the determination of which lymph nodes should be included in the gross tumor volume and to fine-tune areas of cancer involvement. FDG-PET-CT imaging remains the gold standard in clinical practice. Hypoxia and proliferation tracers are still investigational, as is PET-guided redistribution of the radiation dose within the tumor. Contrast-enhanced CT as well as 4D CT scans contain information such as the characteristics of the lungs that are related to individual radiosensitivity, ventilation, and perfusion. Dual-energy CT imaging holds promise for the future for characterization of both tumor and normal tissues. The assessment of response after radiotherapy on the basis of CT scans remains difficult because of inflammatory and fibrotic changes. RECIST is still the standard. FDG avidity suffers from too high rates of false positive and false negative signals and is therefore not recommended, except on clinical indication.
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.
The increasing number of centers providing proton or carbon beam therapy underlines the growing importance of charged particle therapy within the spectrum of cancer radiotherapy. Whereas protons are more widely used around the world, carbon ions, which are known to bear a higher efficacy as compared to protons, are still neglected to some extent, especially due to a lack of clinical data on adverse side effects. Yet, an increasing amount of clinical data indicates the distinguished efficacy of carbon ion therapy. Notwithstanding, the radiobiological mechanisms of particle radiation are not completely understood and lag behind advances in technology, which potentially enable new therapy regimens. However, an increased knowledge is required for their application with maximal benefit and sufficient risk estimation. Differential gene expression, distinct molecular mechanisms and signal pathways in the radiation response, and systemic effects, such as increased immunogenicity, and the possibilities of combined treatments arising from them, are important fields of particle radiobiology in which new discoveries and advances have occurred. These aspects are contemplated with respect to an individualization of radiotherapy; radiation type and treatment regimen might be chosen on the basis of the radiosensitivity of the individual and the cancer type. Here, we provide an update on a few recent findings and advances in particle radiobiology. A comprehensive essay on the basics of particle radiobiology is beyond the scope of this article. The focus is directed on a few subjects currently undergoing intense study and which are of current interest with respect to advances in therapy.
Particle therapy is characterized by distinct physical properties leading to a reduction of integral dose compared to photons. While protons have an almost comparable biological effect, carbon ions and other heavier charged particles offer an increased relative biological effectiveness. The potential clinical benefit has been pointed out by several groups. Most likely, for protons, children have the largest margin of benefit since their normal tissue is very sensitive to radiation, and curative treatments lead to extremely long-term survivors having a lot of scope for long-term side effects. Many clinical studies, mostly of a retrospective nature, have shown promising results for various tumor types being treated with proton and heavy ion radiotherapy. Further clinical trials are needed in order to evaluate the opportunities of ion beam therapy and its prognostic influence on the general outcome, and many studies are currently recruiting patients. The aim here is to summarize current knowledge, possible clinical rationales, and indications for ion beam therapy.
Treatment planning for radiotherapy has become unthinkable without computer algorithms for dose optimization. Although the need for optimization algorithms originated from the complexity of treatment delivery technology such as intensity-modulated radiotherapy, volumetric-modulated arc therapy, and robotic stereotactic radiotherapy, the focus has shifted to refining goals and methods of optimization itself. Dose optimization chiefly advances in 3 directions: human interface and automation, compensation of changing patient geometries, and diversification/individualization of radiation dose prescription. Traditionally, dose optimization requires the definition of numerical treatment goals, followed by an interactive trial-and-error process to adjust the correct, patient-specific balance of these goals. Being both operator dependent and time consuming, methods are needed that produce high-quality treatments efficiently, with the long-term objective of autonomous dose optimization. Expedient treatment planning is also key to treatment adaptation to changes in patient geometry. Despite all efforts to image and adapt at treatment time, some residual uncertainties remain and must be compensated via treatment planning. Reformulations of the dose optimization problem are joined with various image-based 4D patient models to ensure treatment robustness against geometric uncertainties. Robust optimization leads to a deviation from customary dose prescription in favour of more predictable dose delivery. The dose distribution can be individualized further by additional functional image information, aiming to guide the dose towards undertreated volumes and away from overtreated ones, also known as dose-painting. Multimodal imaging is increasingly integrated into treatment planning, making it a natural consequence to supplant computed tomography by magnetic resonance imaging to establish MR-based radiotherapy.
Preclinical mouse models that allow the evaluation of novel techniques in radiotherapy using charged particles like protons or heavier ions are discussed here. Focused beams of protons or carbon ions offer distinct physical characteristics that might contribute to an overall improved risk-benefit profile in radiotherapy. In the last decade, novel concepts in radiotherapy aimed to optimize the delivery of high radiation doses to the tumor while sparing the surrounding healthy tissue. 2D in vitro tumor cell cultures provide experimental models to determine the radiosensitivity of isolated cells to different radiation qualities. However, these cell culture models are not capable of mimicking the complexity and heterogeneity of 3-dimensionally growing clinical tumors with their individual tumor microenvironment. Therefore, small animal tumor models are urgently needed to study radiation responses after particle radiotherapy in vivo. Here we describe the recent developments and the accurate testing of novel techniques in particle radiotherapy using up-to-date preclinical animal models.
The tumor microenvironment comprises multiple different cell types and structural and functional components, and defines a unique tumor milieu on the individual tumor level. Several biological processes in the microenvironment are pivotal for tumor growth, like the formation of an intact tumor vasculature and the composition of the extracellular matrix. Furthermore, tumor heterogeneity also derives from the complex and dynamic interactions of the tumor cells with the stromal compartment during tumor growth and in response to treatment, and thereby represents a major treatment hurdle. Here we give an overview of the different entities of the tumor microenvironment and present their role in radiation resistance. Dynamic changes in response to irradiation will be outlined, and relevant approaches to target critical elements of the tumor microenvironment will be discussed. We are only now starting to understand how these different entities cooperate biologically, and thereby determine tumor aggressiveness and treatment resistance on the individual level. At the same time, these dynamic and even treatment-induced interactions within the tumor represent promising targets for novel combined treatment modalities with radiotherapy.
Germ cell tumors (GCTs) represent a group of biologically complex malignancies that affect patients at different sites within the body and at different ages. The varying nature of these tumors reflects their cell of origin which is the primordial germ cell, which normally gives rise to ovarian and testicular egg and sperm producing cells. These cells retain an ability to give rise to all types of human tissues, and this is illustrated by the different kinds of GCTs that occur. In adolescent and young adult (AYA) patients, GCTs predominantly present as testicular, ovarian or mediastinal primary GCTs, and represent some of the most complex therapeutic challenges within any AYA practice. The varying types of GCTs, defined by primary site and/or age at presentation, can look very similar microscopically. However, there is growing evidence that they may have different molecular characteristics, different biology and different requirements for curative treatments. Whilst in adult testicular GCTs there is evidence for an environmental cause during fetal development and a genetic component, these causative factors are much less well understood in other GCTs. GCTs are some of the most curable cancers in adults, but some patients exhibit resistance to standard treatments. Because of this, today's clinical research is directed at understanding how to best utilize toxic therapies and promote healthy survivorship. This chapter explores the biology, behavior and treatment of GCTs and discusses how the AYA group of GCTs may hold some of the keys to understanding fundamental unanswered questions of biological variance and curability in GCTs.
The pattern of cancer seen in young people changes with increasing age, transitioning from childhood- to adult-type cancer in adolescence and the third decade. The risk factors, presentation and biology of cancer in young adults differ from those in the older adult population. Factors of particular significance in adolescents and young adults (AYAs) include genetic predisposition to adult-type cancer, diagnostic uncertainty, long-term morbidity and considerations of fertility. New systemic therapies are being introduced that can prolong life and even increase the chance of cure, but the impact on AYAs is uncertain, as these patients are often under-represented in clinical trials. Here, we discuss the management of AYAs with 3 of the most common cancers affecting adults, when they emerge in the AYA populations, and therefore are currently met by medical oncologists - breast cancer, colorectal cancer and melanoma.
Embryonal tumors classically occur in young children, some principally within the first year of life. Prospective national and international clinical trials during recent decades have brought about progressive improvements in survival, and associated biological studies have advanced our understanding of tumor biology, in some cases allowing biological tumor characteristics to be harnessed for therapeutic benefit. Embryonal tumors continue to occur, albeit less commonly, during childhood, adolescence and throughout adulthood. These tumors are less well understood, usually not managed according to standardized protocols and rarely included in clinical trials. Survival outcomes are generally poorer than their childhood equivalents. We present here a summary of the published literature on embryonal tumors that present ectopically during adolescence and adulthood. We show that for some tumors protocol-driven treatment, supported by accurate and complete diagnostics and staging, can result in equivalent outcomes to those seen during childhood. We make the case that clinical trial eligibility criteria should be disease-based rather than age-based, and support improvements in dialogue between children's and adults' cancer clinicians to improve outcomes for these rare tumors.
Awareness of the need for collaboration across pediatric and adult cancer to care for adolescents and young adults (AYAs) arose from the recognition of the unique characteristics of AYAs with cancer. Neither pediatric nor adult oncology hospital departments are able to provide age-appropriate care single handedly. The best way to bridge the gap in care of AYA cancer patients is to centralize aspects of their care within dedicated AYA care programs, including the following essential components: provision of developmentally appropriate and multidisciplinary (supportive) care, availability of AYA inpatient and outpatient facilities and healthcare professional AYA expertise as collaboration between adult and pediatric departments. Barriers are related to the slowly emerging evidence of benefit, cultural differences (collaboration between pediatric and adult oncology professionals), administrative and logistic challenges (small number of AYAs makes it difficult to create an AYA program in every hospital) and financial aspects (dependency on philanthropic funds). The sustainable development of an AYA program requires acceptance as a standard of care at the clinical and patient community and at government level. To improve the quality, equity and quantity of research and innovation in AYA cancer care across the world, it is necessary to join forces and collaborate in international networks to study issues such as the features of quality care, collaboration between pediatric and adult clinical teams, trial groups and professional societies, and AYA-specific groups such as Critical Mass, Canteen or European Network for Teenagers and Young Adults with Cancer.
Within this chapter, we begin with the invaluable context of the experience of living after cancer as a young person. Then we move to describe the growing body of data indicating the consequences of cancer in patients diagnosed aged as teenagers and young adults (YAs). We identify that, while the variation in definitions used in the literature hamper firm conclusions, specific patterns of substantial morbidity are observed which are distinct from those seen in younger children. When combined with the epidemiology, the overall burden of late effects of adolescents and YA cancer and its treatment are a substantial public health problem. The progress in parts of Europe and the US in bringing together outcomes into medium-sized data sets, combined with the gaps in the data and remaining uncertainties, mean that the time is right for international epidemiological ascertainment of these adverse effects. There are potential benefits for commencing prospective clinical as well retrospective epidemiological study designs.
The inclusion of teenagers and young adults (TYAs) in cancer clinical trials is focal point for many countries with a specific TYA program. This objective has arisen from data which suggests that lower trial entry may, in part, contribute to lesser survival gains observed in this group when compared to children and some older adult cancers. In this chapter, we discuss obstacles to clinical trials and innovative therapies for TYA. Limited clinical trial availability is discussed in the context of the rarity of TYA cancers and our limited understanding of cancer biology in this group, other obstacles include inappropriate age eligibility criteria, limited accessibility to available trials, a lack of physicians and patients awareness and poor acceptability of trial design. We propose several strategies which could be applied to overcome these obstacles, some ready for implementation and others which require further exploration. Strengthening pediatric and adult oncology collaboration at the individual level and through oncology societies will undoubtedly positively impact accrual to trials for TYA, as will abolishing the use of age as a barrier to drug and trial access. This will allow us to create biologically driven trials and facilitate early new drug access and the creation of biobank collections to drive our understanding of the biology of cancers in this age group. Involving multiple stakeholders in trial design will facilitate acceptable trials to both healthcare professionals and young people themselves. The support of the multidisciplinary TYA team and a culture of research embedded within this are the keys to improving access and participation of TYA in cancer trials.
Lymphomas are one of the commonest malignancies in adolescents and young adults (AYA) accounting respectively for 22% of all cancers in patients aged 15-24 years (16% for Hodgkin lymphoma (HL) and 6% for non-HL (NHL)). The distribution of NHL subtypes in this age group differs strikingly from the distribution in children and in older adults with 4 main subtypes accounting for the majority of the cases: diffuse large B-cell lymphoma (DLBCL) including primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma or anaplastic large cell lymphoma. Age-related differences in tumor biology have been demonstrated mainly in DLBCL but there is still a need for biological studies to better understand agerelated differences in this age group. AYA patients currently diagnosed with HL and NHL have 5-year survival expectations exceeding 90 and 75%, respectively. Different therapeutic strategies are often used in children and adult lymphoma and the dispersion of lymphoma care between adult and pediatric hematologist-oncologists results in heterogeneous strategies for each subgroup according to age. The impact of these different strategies on outcomes is not easy to evaluate given the paucity of population-based data focused on this age group, taking into account tumor biology and the lack of a uniform staging system. Given the excellent results obtained with current therapies, the challenge now is to develop strategies aimed at reducing acute and long-term toxicity in most patients while maintaining high cure rates and to identify patients at high risk of failure requiring new strategies including more selective targeted therapies. (C) 2016 S. Karger AG, Basel
The definition of soft tissue and bone sarcomas include a large group of several heterogeneous subtypes of mesenchymal origin that may occur at any age. Among the different sarcomas, rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma and osteosarcoma are aggressive high-grade malignancies that often arise in adolescents and young adults. Managing these malignancies in patients in this age bracket poses various clinical problems, also because different therapeutic approaches are sometimes adopted by pediatric and adult oncologists, even though they are dealing with the same condition. Cooperation between pediatric oncologists and adult medical oncologists is a key step in order to assure the best treatment to these patients, preferably through their inclusion into international clinical trials.
Each original paper needs an abstract of up to 250 words structured with subheadings as follows: Background/Aims, Methods, Results, Conclusions. Structured abstracts are not needed for Reviews and Novel Insights from Clinical Practice. Footnotes: Footnotes should be avoided. When essential, they should be numbered consecutively and appear at the foot of the appropriate page. Acknowledgements: Include all sources of funding for the research presented in the manuscript and substantive contributions of individuals regarding the research or manuscript. All possible conflicts of interest should also be given here. Abbreviations: Abbreviations (with the exception of those clearly well-established in the field) should be explained when they are first used. Units of measurement: Measurements should be expressed in SI units wherever possible. Drug names: Use generic names of drugs (first letter: lowercase) whenever possible. Registered trade names (first letter: uppercase) should be marked with the superscript registration symbol ® or TM when they are first mentioned. Tables and illustrations: Tables and figures must be numbered (e.g. Figure 1, Figure 2) and submitted as separate files. Tables require a heading and figures a legend, which must provide sufficient information for either to stand alone. Each figure and table must be cited in the text numerically. Tables should be in Word format. b/w half-tone and color figures must have a final resolution of 300 dpi after scaling to final size, line drawings 1200 dpi. Color figures must be in RGB format. All figures should be in a common format such as PSD, TIF, PNG, EPS or WMF. Vector graphics should be in PPT, AI or EPS format. D ow nl oa de d by : 54 .7 0. 40 .1 1 12 /2 5/ 20 17 1 :3 9: 07 P M
