for the Evaluation of Novel Techniques in Particle Therapy
Schmid, T.E. (Munich); Multhoff, G. (Neuherberg)
Clinically relevant progress has been made in the diagnosis and treatment of cancer in recent decades; however, this progress varies substantially between cancer types and between countries with variable access to health care resources. Five-year survival rates have improved beyond 50% for breast cancer and colon cancer, whereas lung cancer is associated with poor survival of <20% and only very little progress has been made with overall survival improvements of 2–4% in Europe and North America [1].
Advances in biological disease characterization has accelerated progress in many cancer types. In non-small cell lung cancer (NSCLC) and melanoma – previously associated with a devastating prognosis in metastatic state – patients with an activating driver mutation (EGRF, ALK, BRAF) achieve long-term survival when treated with targeted drugs or, since recently, with immune checkpoint inhibition. The field of radiation oncology has advanced in parallel with the progress in medical oncology and has improved the precision of cancer treatment and outcome for our cancer patients. Radiation oncology is characterized by the interaction of technology and cancer and patient biology, and by the interdisciplinary and multi-professional practice of cancer treatment and research. Consequently, progress has been achieved in the 3 distinct fields of: (a) radiobiology and combined modality treatment, (b) radiotherapy technology, and (c) particle therapy [2, 3].
Better understanding of radiation and cancer biology is a major driving force of innovation towards better radiotherapy [4]. For radiation oncology, the main areas of ongoing development include combinations with immunotherapy, targeting of the tumour microenvironment, and integration of imaging biomarkers for individualized treatments [3]. These areas are covered in dedicated sections and reflect the current status and future perspectives. While checkpoint inhibition leads to unprecedented and sometimes longlasting remission rates in some types of cancer, such as malignant melanoma, it is becoming more and more evident that the majority of cancers are resistant to immunotherapy. Resistance to immunotherapy either from the beginning (primary resistance) or later during the course of treatment after an initial response (secondary or acquired resistance) is a remaining challenge and an area of intense research [5]. Conceptually, one strategy to overcome resistance is the use of combinatorial approaches of different immunotherapies with other treatment modalities, such as radiation, chemotherapy, and targeted agents. Better understanding of immunotherapy and radiation biology might result in the definition of a new role for radiotherapy. Interestingly, mechanisms of resistance to immunotherapies include a suppressive tumour microenvironment and tumour hypoxia, i.e., well-established factors of resistance to radiotherapy and targeted agents. This functional link may suggest novel approaches, such imaging strategies and therapeutic manipulations, leading to better prediction and treatment adaptation of rational combinations in the future [6].
Radiation oncology has participated in the rapid progress made in computational sciences and biomedical engineering. As a consequence, radiation therapy is planned and delivered in a very different way compared to the standards of the last century. As a non-invasive treatment, radiation oncology is an imaging-based and imaging- driven treatment modality. Multimodality imaging for target and organ-at-risk definition using CT, MRI, and PET imaging has become the standard of care in many cancer sites and has improved accuracy and reproducibility. For example, FDG-PET is a mandatory component of NSCLC staging [7] and MRI-based prostate segmentation is a mandatory component of radical radiotherapy planning for prostate cancer [8]. Functional imaging for biological disease characterization has been explored for many years but is still at a research stage and has not yet become a standard of care [9]. Recent research has evaluated the potential of quantitative computational image analysis for the comprehensive characterization of medical images [10, 11] , a methodology called radiomics. Radiotherapy treatment planning is today using intensity-modulated techniques in routine clinical practice, which has improved dosimetric treatment characteristics and, subsequently, clinical outcome [12, 13]. Current progress is aiming to identify the optimal patienttailored individual treatment plan with improved accuracy and reliability; different solutions have been proposed using, for example, libraries of previous treatments, multi-criteria optimization, and Pareto navigation [14, 15]. Continuous reassessment of cancer biology and target geometry, and its integration into treatment by adaptive re-planning, is currently being explored in particular in the context of hybrid devices of combined linear accelerators and MRI [16]. Stereotactic radiotherapy has been practiced for decades for the treatment of benign and malignant brain tumours, and technological advances of highly conformal treatment planning and image-guided treatment delivery has allowed its transfer to the body part in the form of stereotactic body radiotherapy (SBRT) [17]. Today, SBRT is the standard of care for medically inoperable early-stage NSCLC [18] and outcomes appear similar to results achieved by the gold standard of surgery [19]. The characteristics of SBRT to achieve very high rates of local tumour control in a few noninvasive and ambulatory treatment sessions is the rational to explore its potential in many other cancer types. SBRT appears highly promising not only in early cancer stages, but in particular in the stage of oligometastatic disease, when integrated into and combined with effective systemic treatment [20–22].
Particle therapy represents one of the most promising improvements in radiation oncology in recent years. Particle therapy has distinct physical properties leading to a reduction of integral dose compared to photons. On top of that, ion beam therapy has to be divided into protons with almost comparable biological effect to photons, and carbon ions or other heavier charged particles with an increased relative biological effectiveness. So, on the one hand there is proton radiotherapy, where indications are comparable to photons, and on the other hand there is high-LET particle beams, where clinical trials are necessary to determine the tumours that are most sensitive to them. The rationale for proton beams is mainly reducing the dose exposure to normal tissue and for carbon ions treating radioresistant tumours, such as slow-growing tumours. To date, there are already many trials showing promising results of ion beam therapy in different oncological settings. For example, ion beam therapy in paediatric patients has reduced integral dose exposure, which in turn
