Towards clinical evidence in particle therapy: ENLIGHT, PARTNER, ULICE and beyond

Since the middle of the 20th century, particle therapyhas been in focus for patient treatments. In 1946, Robert Wilson proposed the use of charged particles for tumor therapy, and since then, the clinical use of protons and heavier ions, mainly carbon ions, has become more widespread [1]. The first clinical evidence was obtained in Berkeley, treating radiation-resistanttargets with various ion species [2–14]. The main advantage of particle beamsderive from their physical properties: through an inverted dose profile, regions within the entry channel of the beam can be spared of dose, while a steep dose deposition can be directed in an energy-dependent manner into the defined treatment volume ( Bragg Peak). The following dose fall-off spares tissue behind the target volume, thus reducing integral dose significantly compared to when using photons. Heavier charged particles, such as carbon ions or oxygen, are additionally associated with an increased relative biological effectiveness(RBE), while the RBE of protons is commonly accepted to be about 1.1 [15, 16]. Recent observation, however, suggests that this may be an oversimplification. Carbon ion radiotherapy is currently available in only a few centers worldwide: mainly in Japan, with two centers in Europe (CNAO, Pavia, Italy and HIT, Heidelberg, Germany). For proton therapy, treating centers are more widespread throughout the USA and Asia, with a few centers in Europe. Most clinical data has been reported as smaller series within Phase I/II trials, or retrospectively assembled data from patient subgroups, most indications being sarcomas, malignant salivary gland tumorsor ocular melanoma[2, 17–22]. The only large randomized trial comparing protons to photons was performed in patients with prostate cancer, where proton therapywas applied as a boost in the experimental arm to a higher total dose than in the control arm[23, 24]; this trial did show a benefit in terms of biochemical progression-free survival, with overall comparable toxicity [25]. Over the years, photon treatments have improved and modern intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) approaches enable the radiation oncologistto deliver doses of ∼80 Gy to the prostate safely. This is not the dose concept and technical background that was implemented in that trial. Therefore, controversy remains about the real value of this trial, i.e. comparing ‘protons vs photons’, or comparing ‘high dose vs low dose’. Currently, the cost of particle therapyis a multiple of that of photon treatments, due to the size of structures, the complexity of technology required, the resulting investment and also the high running cost; additionally, capacity for treatment is still limited [18, 26, 27]. Therefore, current discussions focus on the indications for particle therapy. Therefore, besides seeking technical improvement and developments to make particle therapyless costly and more widely available, four main clinical foci are of importance: design of clinical trials comparing protons, carbon ions and advanced photon techniques for selected tumor indications; identification of prognostic markers, i.e. molecular characteristics, imaging properties or normal tissue qualities stratifying patients; better understanding of patient- and tumor-specific RBE for protons and heavier ions alike; integration of particles into multimodal treatment with systemic approaches together with surgery. Integrating such novel tools into modern radiation oncology requires large-scale preclinical and clinical research in the fields of biology, physics and medicine. To bring together the expertise of various researchers of all stages, and to educate newcomers into the field through dissemination of knowledge, joint European structures were generated as a platform to incorporate protons and heavier ions into modern radiation oncology concepts.