Establishing and expanding the indications for proton and particle therapy

The present issue of Acta Oncologica is devoted to the emerging field of proton and particle therapy in the management of cancer. This editorial is written to highlight recent trends in the proton and particle therapy field exemplified with the papers collected in this issue while at the same time also celebrating the 50th anniversary of Acta Oncologica, pointing out the long-standing contributions of the journal to support further progress of proton and particle therapy.

Acta Oncologica has ever since its beginning had a firm base in the Stockholm and Uppsala regions in Sweden, a region very much connected to the origin and further development of proton and particle therapy. The first ever treatment of a cancer patient with protons took place in Uppsala in 1957, and the outcome of these pilot investigations was reported in Acta Radiologica [1,2], the forerunner journal of Acta Oncologica [3]. Decades later, the region has also been home to scientific discussions concerning the potential use of nuclei heavier than protons, primarily carbon ions [4–6], ultimately leading to the first Nordic hospital-based proton therapy facility, located in Uppsala (Skandionkliniken). Some years ago Acta Oncologica published the results of the Swedish expert-opinion based evaluation and estimation of the clinical need for proton therapy across all relevant tumor sites [7]; these estimates have been used in many later reports as essential input when scaling the need for proton therapy for facilities planned to serve a given patient population or health service region. In 2011, an Acta Oncologica supported symposium on particle therapy was held in Uppsala, jointly organized by Swedish and Danish scientists interested and involved in this field [8]. The symposium lead to a series of publications on proton and particle therapy that appeared in a dedicated issue of the journal, including also very timely and useful review papers authored by leading scientists in this field [9–12].

The present issue of Acta Oncologica contains a number of original contributions to the proton and particle therapy field, including also a series of clinical outcome reports. Such data is very much in demand to further establish and expand the clinical indications for these promising treatment modalities. According to the PTCOG web site, more than 20 proton/particle therapy facilities are currently in the construction phase; in addition, a large number of regional and national projects are in the ‘paper phase’, including the Nordic countries. Indeed, the current indications for proton or carbon ion therapy that are firmly established count only a modest number of tumor entities, most of them being relatively rare diseases. However, believing in the first ‘commandment of radiotherapy’ – There are no radio-resistant tumors, only radio-sensitive normal tissues – the improved treatment conformality that can be achieved using current state of the art spot-scanning treatment is very likely to also lead to improved treatment outcomes. For the same reason, the radiotherapy community has not performed any randomized trials comparing photon-based treatment with conventional three-dimensional (3D) conformal versus intensity-modulated radiotherapy (IMRT). The question of what level of scientific evidence is required for the introduction of proton/particle therapy has been a topic for much scientific discussion during the past years [13,14], and it continues [15]. Although clinical trials are needed to fully clarify the role of protons and carbon ions for a number of tumor sites, it is important to keep in mind that we are able to calculate the effects of radiotherapy (both the delivered doses and also their projected biological effects) with fairly high accuracy, particularly so when changes in anatomy and geometry during treatment are accounted for. So-called treatment planning studies may therefore serve as a very useful means of providing the first indications for the benefit for protons and other particles for a given patient group [7]. Indeed, the principle of patient-specific head-to-head treatment planning comparison has been incorporated into the patient selection schemes of several upcoming proton and particle therapy facilities. This issue contains several examples of planning studies [16–19] providing further fuel to such developments.

Prostate cancer, with it high prevalence, straightforward treatment planning approach, relative dearth of adjacent critical structures and biochemical indices of disease control remains an attractive target for proton and heavy ion therapy. It is therefore not surprising that a substantial number of the papers published on proton therapy in the past five years have concerned themselves with this subject, and this issue of Acta Oncologica is no exception. Henderson and associates [20] at the University of Florida Proton Therapy Institute (UFPTI) have performed an in-depth analysis of the long-term effects of proton beam therapy on genitourinary (GU) functioning in patients treated for low- and intermediate-risk disease. Overall they found a low rate of moderate-severe late toxicity which compares very favorably with patients treated with IMRT [21] who in fact received a substantially lower dose than the proton patients. In this series, the only significant variable predicting for GU toxicity was the presence of pre-treatment symptoms requiring medical management; prostate volume and normal-tissue volumes did not influence morbidity. Their results are virtually identical to the morbidity findings in the PROG 95-09 dose-escalation trial [22], and do seem to allow for further dose-escalation in both a standard and hypo-fractionated manner. Similarly, Kil and colleagues [23] from UFPTI have employed a novel approach, measuring the effect, if any, of proton beam prostate radiotherapy on serum testosterone levels, to support with clinical data the physically measured very low out-of-field radiation doses generated by several phantom studies [24–26]. By demonstrating the absence of any apparent decrease in serum testosterone after proton therapy as compared to what has been observed in some IMRT-based reports [27], they have confirmed the results of several physical measurement-based analyses and, hopefully, have put to rest once and for all many of the oft-quoted concerns over scattered radiation during proton beam therapy previously expressed by Hall [28].

The physical characteristics of protons, as well as prior clinical experience in other anatomic sites (uveal melanoma, hepatocellular carcinoma, lung cancer) [29–31], make protons an appealing modality also in hypo-fractionated radiotherapy of prostate cancer. In this issue, Kim and colleagues [32] give us a report of a phase II, prospective, randomized trial of hypo-fractionated proton beam therapy in stage T1-T3 prostate cancer patients. The patients were assigned to one of five different dose schedules, all of which were based on treatment schemes previously hypothesized by Fowler [33], and all of which were designed to be iso-effective with 72 Gy given in 36 fractions. In all five arms treatment was acutely well tolerated with only 5% of patients experiencing Grade 2 GU morbidity and no acute Grade 3 or higher gastrointestinal (GI) or GU incidents. Similarly, late effects were relatively rare with Grade 2 GI and GU rates of 13% and 7%, respectively, and only 2% of patients experiencing a Grade 3 event. These rates compare very favorably with published standard and hypo-fractionated series for this tumor site [34–37]. Biochemical disease-free survival rates were also in line with published reports [38,39]. The low morbidity and comparable rates of tumor control are extremely encouraging and provide impetus for further optimization of proton-based hypofractionation strategies in this setting. The high fractionation sensitivity as an intrinsic property of prostate carcinomas supports the use of hypo-fractionation [40].

In another clinical report in this issue, Combs and colleagues [41] from the University of Heidelberg's Ion Therapy (HIT) Center and the German Cancer Research Center present encouraging early results on 70 patients treated with either proton or combined proton/carbon ion therapy for meningiomas. This study echoes recent reports of scanning-based proton therapy indicating a clinically meaningful benefit of particle therapy specifically in the treatment of complex benign and histologically aggressive meningiomas [42]. The incorporation of ⁶⁸Ga-DOTATEC as diagnostic tool to further distinguish and ‘draw the line’ between tumor contour versus normal tissue emphasizes the need for parallel precision radiotherapy with equal degrees of precision in diagnostic imaging and treatment delivery verification. In this series, patients with high-grade meningiomas were treated with combined proton/carbon ion therapy. This novel approach seeks to combine the physical advantages of one particle (protons) with the biologically increased effectiveness of a second particle (carbon ions). The advent of ‘multi-ion therapy facilities’ opens a new era and new frontiers of radiobiological and clinical research in the ultimate quest for the ideal radiotherapy particle modality.

Looking to the technical delivery aspects of radiotherapy, the introduction of image-guidance strategies to actively account for geometrical uncertainties is one of the recent success stories of conventional photon-based treatment. In proton and particle therapy, such strategies appear to be even more important, as these treatment modalities tend to be more sensitive to any uncertainties influencing the treatment geometry and the range of the particles. This issue contains three treatment planning studies exploring these issues for intensity-modulated proton therapy, in the setting of both cranial and pelvic tumor sites. Hopfgartner and colleagues [43] investigated the consequences of both target and normal tissue dose/volume histogram parameters when treatment was subject to realistic (3 mm) set-up errors. Beam configurations of different complexity were studied, and as could be expected they observed that plans with the highest number of beams were most robust towards geometrical uncertainties. The study of Thörnqvist et al. [44] focused on the effects of target dose degradations in the treatment of locally advanced prostate cancer, when the prostate, seminal vesicles and the pelvic lymph nodes are irradiated. Using a repeat computer tomography imaging material, it was shown that the residual deformations of the seminal vesicles – and to a lesser extent, of the lymph nodes – following image-guidance, can severely degrade the treatment plan quality. Similarly, variability in the amount and location of intestinal gas may influence proton plans more than photon plans [16]. Just like in photon-based therapy, it seems that adaptive planning and treatment strategies to increase the robustness of proton therapy may be required to take full advantage of the potentially higher dose conformity of such plans.

If one truly believes that the only absolutely ‘safe’ dose of radiation to normal tissue is zero, then the case for particle beam therapy, especially in the curative setting, is compelling [45–50]. The papers presented in this issue of Acta Oncologica represent a sampling of the ongoing clinical research in this area and demonstrate some of the approaches that can be taken outside of the context of a classic clinical trial to identify, establish and expand the indications for charged particle therapy.

Declaration of interest: Eugen Hug declares a conflict of interest as he is holding stock options with Procure Proton Treatment Centers Inc.