Clinical Indications for Carbon Ion Radiotherapy

Clinical Oncology 30 (2018) 317e329 Contents lists available at ScienceDirect

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Overview

Clinical Indications for Carbon Ion Radiotherapy O. Mohamad *y, S. Yamada y, M. Durante zx * University

of Texas e Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA Hospital of the National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan z Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute of Nuclear Physics (INFN), University of Trento, Povo, Trento, Italy x Department of Physics, University Federico II, Monte S. Angelo, Naples, Italy y

Received 29 October 2017; accepted 20 November 2017

Abstract Compared with photon and proton therapy, carbon ion radiotherapy (CIRT) offers potentially superior dose distributions, which may permit dose escalation with the potential for improved sparing of adjacent normal tissues. CIRT has increased biological effectiveness leading to increased tumour killing compared with other radiation modalities. Here we review these biophysical properties and provide a comprehensive evaluation of the current clinical evidence available for different tumour types treated with CIRT. We suggest that patient selection for CIRT should move away from the traditional viewpoint, which confines use to deep-seated hypoxic tumours that are adjacent to radiosensitive structures. A more integrated translational approach is required for the future as densely ionising C-ions elicit a distinct signal response pathway compared with sparsely ionising X-rays. This makes CIRT a biologically distinct treatment compared with conventional radiotherapy. Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Key words: Carbon ion; high LET; indications; radiation; radiotherapy; RBE

Introduction More than half of all cancer patients receive radiotherapy during the course of their illness, but only a small percentage of those are treated with particle therapy [1,2]. Most patients who receive particle radiotherapy are treated with proton beams, with a relatively smaller number receiving heavier ions, including carbon [3]. Compared with photon therapy, particles have physical advantages warranting a superior dose distribution, which allows a more accurate tumour targeting and dose escalation with better sparing of nearby organs. Within the field of particle therapy, different nuclei have different physical and biological properties [4]. Carbon ions, for Author for correspondence: M. Durante, Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute of Nuclear Physics (INFN), University of Trento, Via Sommarive 14, 38123 Povo, Trento, Italy. Tel: þ39-0461-283294. E-mail address: [email protected] (M. Durante).

example, have a better dose distribution and increased biological effectiveness compared with protons. A Brief History The use of particles in radiotherapy was initially proposed in 1946 by physicist Robert Wilson [5]. It was several years before the first patient received proton beams at the Lawrence Berkeley National Laboratory in California in 1954. The patient had a pituitary gland tumour. The first case series with proton radiotherapy was published in 1958 [6]. Starting in 1975, physicians at the Lawrence Berkeley National Laboratory treated hundreds of patients with other ions, including carbon ions, for various indications. Unfortunately, the programme was shut down in 1992 due to financial constraints. The accumulated experience from the USA together with a growing community of particle therapy advocates from Europe and Japan led to the treatment of thousands of patients with proton and other particle beams. In 1994, the National Institute of Radiological Sciences

https://doi.org/10.1016/j.clon.2018.01.006 0936-6555/Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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Fig 1. Percentage depth dose curves for carbon, proton and photon beams showing clear physical advantages for carbon ion beams.

(NIRS) treated the first patient with carbon beams at the Heavy Ion Medical Accelerator in Chiba, marking the second birth of carbon ion radiotherapy (CIRT). Soon after, in 1997, € r Schwerionenforschung (GSI) started a the Gesellschaft fu treatment programme in Darmstadt, Germany, followed by the Heidelberg Ion Therapy Center in 2009. Currently, more than 11 CIRT centres are in operation (Japan [five], Germany [two], Italy [one], China [two], and Austria [one]) [7] and several others are under construction.

Physical and Biological Advantages We have previously reviewed the physical and biological characteristics of carbon ion beams for cancer treatment [8,9]. Here, we will only briefly review some of the major properties of CIRT, how these characteristics contribute to their enhanced clinical efficacy and how they should be considered in designing clinical trials. Physical Advantages Given their physical charge, mass and high initial energy, heavy particles such as carbon ions transfer their energy in

matter as a function of depth. As such, and in contrast to photons where the maximum dose (Dmax) is close to the skin surface, little ionisation energy is deposited at or near the surface with CIRT, but rather most energy is deposited at a well-defined depth with a relatively well-defined range. This peak of dose distribution is called the Bragg peak. By manipulating the beam line and/or weighting different energies, the whole depth of any particular tumour can be irradiated with CIRT with a high peak-to-plateau ratio and no exit dose. This extended Bragg peak is call the spread-out Bragg peak [10,11] (Figure 1). Carbon beams have less Coulomb interactions and subsequently sharper lateral penumbra compared with proton beams [9]. These physical characteristics impart a superior dose distribution to CIRT that is not paralleled in other radiotherapy modalities. This has been repeatedly shown in dosimetric studies [12e14] with even more improved dose distribution with scanning compared to passive beams (Figure 2). Notably, this advantageous dose distribution is not perfect given the range uncertainty at the distal end of the Bragg peak [15] and its sensitivity to set-up variation, and inter-fractional anatomic change [16] and tumour motion [17]. Nonetheless, CIRT is believed to have the capacity of delivering higher energy to deep-seated tumours while simultaneously sparing nearby radiosensitive structures better than photon- or protonbased therapies. Biological Advantages To better understand the radiobiological characteristics of CIRT, it is important to mention their superior linear energy transfer (LET) values when compared with either photons or protons. LET is defined as the energy transfer from a radiation beam to the medium it traverses per unit length. This increased LET of carbon beams leads to significantly different biological effects at the DNA level. This measure of biological potency is termed relative biological effectiveness (RBE), which is the ratio of dose from a particular radiotherapy modality needed to cause the same amount of tumour kill as a reference dose, which is usually X-rays of 250 kVp. Thus, RBE for photons is 1. Although RBE

Fig 2. Dose distribution by passive (A) and scanning (B) beams using carbon ion radiotherapy for pancreas cancer showing a clear reduction in the dose to the spinal cord and left kidney with scanning beams.

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Here we will summarise the most recent clinical data and the current accepted indications for CIRT in the countries and centres where it is available. CIRT is still considered an ‘experimental treatment’ for most tumour sites. So far, although some trials are accruing, there has not been any randomised clinical trials comparing CIRT with other treatment modalities and all the discussed trials are at best single-arm phase II efficacy trials.

currently the only curative option, but most patients present with unresectable disease [26] and locally advanced pancreatic cancers (LAPC) continue to have poor outcomes with photon radiotherapy and/or chemotherapy [27]. Two reasons justify a dose-escalation and high RBE approach for pancreas cancer: the high rates of local recurrence with a significant burden of severe local symptoms and the possibility of converting unresectable cases to resection with all the survival benefits of resected pancreatic cancer. For such reasons, CIRT, with its advantageous dose distribution and OER, has been investigated as definitive treatment (with concurrent gemcitabine) in patients with LAPC with excellent outcomes and a remarkable overall survival of 48% at 2 years [28]. More recent data on patients with LAPC who received CIRT with concurrent chemotherapy showed an impressive 2 year overall survival of 60% (Figure 3; data not yet published). A prospective trial from Germany is currently investigating CIRT for LAPC with concurrent and adjuvant gemcitabine [29]. Further dose escalation is being planned in Japan for patients with LAPC [30]. Interestingly, a randomised phase III clinical trial, an international collaboration between the USA, Japan, Italy and South Korea, will start accruing patients with LAPC comparing CIRT with photon intensity-modulated radiotherapy (IMRT), both with concurrent gemcitabine. CIRT has also been tested as a preoperative treatment for pancreatic cancer to reduce the risk of postoperative local recurrence [31]. The results were recently updated in abstract form and showed an excellent safety profile and local control for all patients and encouraging overall survival for patients who received surgery but not for the unresectable cases [32]. Neoadjuvant CIRT for resectable or borderline resectable pancreatic cancer is promising, but solid evidence for its efficacy or superiority to other radiotherapy modalities is still lacking.

Gastrointestinal Malignancies

Hepatocellular Carcinoma

Pancreas Cancer

Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality and liver transplantation is the only curative treatment currently. Advanced photon-based stereotactic radiation (SBRT) has shown excellent local control

is a complex entity usually dependent on LET of the test radiation, physical dose, irradiated tumour type, depth of tumour, end point, etc., RBE for protons is generally considered to be 1.1 (despite the fact that proton RBE increases at the end of the range), whereas that of carbon ions has been generally accepted to be in the 2e3 range or higher [18,19]. This higher RBE is directly related to the ability of carbon ions to induce a more complex DNA damage compared with photons or protons. These complex DNA damages probably overwhelm the cell repair capacity and thus lead to increased tumour kill [20,21]. This cell kill capacity in CIRT is independent of the cell cycle unlike photon radiotherapy where cell kill is cell cycle dependent [22]. Another important phenomenon to define is the oxygen enhancement ratio (OER), which is the ratio of doses of certain radiation quality required to produce the same cell kill in normoxia compared with hypoxia. OER approaches 3 for photon radiotherapy and is considerably lower for charged particles. The higher the LET, the lower the OER [23]. Thus, unlike photons, CIRT killing is relatively independent of oxygen tension or the production of oxygen radicals and does not require free O2 for DNA damage. CIRT therefore is more effective against hypoxic radioresistant tumours [24].

Current Evidence

Pancreatic cancers are known to be hypoxic and radioresistant to photon radiotherapy [25]. Surgery is

Fig 3. Overall survival curve for patients with locally advanced pancreas cancer (LAPC) treated with carbon ion radiotherapy and Gemcitabine by the Japan Carbon-ion Radiation Oncology Study Group.

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[33]. However, dosimetric studies have shown an advantage for CIRT in terms of target conformity and normal liver sparing compared with SBRT [12]. Moreover, HCC is believed to manifest enhanced radiosensitivity with CIRT [34]. Similar to SBRT, proton radiotherapy has shown excellent local control with HCC and given the improved biological effectiveness and dose distribution, CIRT has been theorised to further improve outcomes [35]. A few clinical trials and retrospective studies evaluated CIRT for HCC patients with excellent local control [36e39]. With appropriate patient selection, current CIRT treatments can be completed in four fractions and ongoing trials are investigating one or two fraction treatments for selected patients. Although local control is equivalent to SBRT, CIRT showed lower high-grade acute and late toxicity [40] and it is believed that local control after CIRT will be improved compared with SBRT in larger tumours. To the best of our knowledge, no current trials are investigating this comparison. Nor are trials comparing CIRT with other HCC treatment modalities such as radiofrequency ablation or chemo-embolisation. Recurrent Rectal Cancer Recurrent cancers are usually associated with increased hypoxia and are resistant to photon radiotherapy [41]. Recurrent rectal cancer specifically is associated with significant symptoms, low quality of life scores and poor overall outcomes [42]. In addition, achieving acceptable treatment plans is extremely difficult in patients previously treated with radiotherapy. Thus, CIRT represents an attractive treatment modality for patients with recurrent rectal cancers. Indeed, initial results of clinical trials for patients with recurrent rectal cancer are encouraging with excellent local control and overall survival whether patients have received surgical resection only for their primary tumours [43] or they have been previously irradiated [44]. The results of CIRT for locally recurrent rectal cancer after surgery have been recently updated in abstract format. Acute and late toxicities are minimal and not exceeding grade 3. At the optimal dose, local control and overall survival at 5 years are 89% and 52%, respectively [45], which are remarkable compared with photon radiotherapy for similar indications [46]. Similarly, CIRT has shown promising results in patients with isolated para-aortic lymph node recurrence after surgical resection of primary colorectal cancer [47].

Head and Neck Malignancies Many of the head and neck cancers have suboptimal outcomes and a poor adverse events profile with conventional photon radiotherapy. Given the radioresistance/hypoxia of head and neck malignancies and the intricate anatomy of the head and neck, CIRT seems to be an ideal modality for such tumours given the high RBE and the ability to reduce normal tissue complications. Very promising initial results were reported for a heterogeneous mix of head and neck cancers [10]. These initial results were succeeded by a multitude of reports for different indications, which will be reviewed here. Notably, squamous cell carcinomas (SCC) of the oropharynx, oral cavity and larynx, which represent the majority of head and neck malignancies, are not commonly treated with CIRT. Adenoid Cystic Carcinoma Adenoid cystic carcinoma (ACC) tumours are rare and only account for about 2% of all head and neck cancers and a minor fraction of all salivary gland tumours [51]. Given the slow growing nature of these tumours, a large percentage of patients usually present in the advanced stage. Moreover, given their propensity for peri-neural invasion, target volumes are usually enlarged to include possible routes of spread along nerves. Although surgery with or without postoperative radiotherapy is the mainstay treatment for early stage cases, high LET radiotherapy (including carbon and neutron beams) is reserved for incompletely resected and inoperable patients whose outcomes with surgery and/or conventional radiotherapy are poor [52e54]. Clinical studies have shown significant radiosensitivity and good outcomes after proton or neutron therapy [55e57]. Prospective trials using IMRT with CIRT boost for inoperable or incompletely resected ACC (Germany) showed improved local control and overall survival with acceptable toxicity compared with IMRT alone [58e60]. Likewise, CIRT alone without photon beams (Japan) has shown excellent local control and overall survival with relatively mild toxicities for locally advanced [61e65] and recurrent ACC [64,66]. The prospective ACCEPT phase I/II trial is currently testing the combination of cetuximab and IMRT/carbon boost in incompletely resected or inoperable ACC cases [67].

Oesophageal Cancer Other Non-squamous Cell Carcinomas of the Head and Neck The current standard of care for advanced oesophageal cancer is neoadjuvant chemoradiation with photons followed by surgery [48]. Despite the large volumes treated and respiratory motion, CIRT is technically feasible for oesophageal cancers [49]. However, the experience so far has been modest, at best. Only one study reported preoperative CIRT for early and advanced oesophageal cancer without any significant toxicity and with an encouraging pathological complete response [50]. Further clinical trials are underway in Japan to further investigate the utility of CIRT in oesophageal cancer.

Most of the head and neck non-squamous cell carcinoma cases treated with CIRT have been ACC. However, many studies have reported the outcomes of advanced and recurrent head and neck adenocarcinoma, mucoepidermoid carcinoma and olfactory neuroblastoma, among others. CIRT has shown reproducible and equivalent outcomes for these cancers similar to ACC [61,68,69]. Locally advanced head and neck adenocarcinoma also showed promising results with CIRT with acceptable toxicity. Patients who developed visual loss had tumours close to the optic nerve

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[70,71]. CIRT was also considered safe and efficacious for patients with mucoepidermoid carcinoma [72]. Although SCCs are not typically treated with CIRT, carbon beams have shown promising results in patients with locally advanced SCC of the external auditory canal and middle ear [73]. A clinical trial is currently investigating induction chemotherapy followed by IMRT/CIRT boost with concurrent cetuximab for locally advanced head and neck SCC [74]. Uveal and Mucosal Melanoma Uveal melanoma is classically treated with surgery, proton therapy or brachytherapy [75]. CIRT has shown excellent outcomes for choroidal melanoma [76,77]. A meta-analysis comparing brachytherapy with charged particle therapy showed that local recurrence and adverse events (retinopathy and cataract formation) are lower in the particle therapy group despite a similar enucleation rate and overall survival [78]. Regarding mucosal melanoma, CIRT has shown good local control but progression-free and overall survival are still poor, reflecting the need for systemic therapy to reduce the rate of distant metastases [79e82]. Indeed, a multicentre retrospective study of CIRT in patients with mucosal melanoma showed that concurrent chemotherapy (dimethyl triazeno imidazole carboxamide) was a significant prognostic factor for overall survival [83]. Currently, concurrent chemotherapy is standard for patients receiving CIRT for mucosal melanoma at the NIRS. Small retrospective series showed comparable results between carbon and proton therapies for this malignancy, but it is difficult to make conclusions given the small number of cases [79,84].

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report using CIRT for a heterogeneous group of sarcoma patients showed promising results with acceptable toxicity [91]. Since then, multiple studies have reported excellent local control and functional outcomes using CIRT for unresectable retroperitoneal sarcomas [92], unresectable sacral chordomas [93], unresectable non-skull base chondrosarcoma [94], unresectable osteosarcoma of the trunk [95], unresectable spinal sarcomas [96], primary sarcomas of the extremities [97], unresectable malignant peripheral nerve sheath tumour [98] and unresectable Ewing’s sarcomas [99]. When compared with surgical resection in small retrospective series, CIRT had improved local control and preservation of urinary-anorectal function in patients with sacral chordomas [100] and improved functionality in patients with pelvic chondrosarcoma [101]. Unresectable or incompletely resected pelvic bone or soft tissue sarcomas are in general considered good candidates for CIRT [102]. A study is currently testing particle therapy (proton radiotherapy with carbon boost) for patients with unresectable osteosarcoma [103].

Lung Malignancies Non-small Cell Lung Cancer

Because dose escalation is difficult in the skull base region, local control of skull base chordomas has been suboptimal with X-rays. However, results have improved with proton therapy [85]. Chondrosarcomas, on the other hand, had better outcomes. That being said, skull base chordomas and chondrosarcomas are another example of good indications for CIRT. Multiple studies have investigated the safety and efficacy of CIRT for skull base chordomas and chondrosarcomas and long-term outcomes have been reported. Results have been reproducible from both Germany and Japan and showed excellent local control and overall survival compared with historical reports using photons [86e88]. CIRT has also shown good outcomes in reirradiating locally recurrent skull base chordomas and chondrosarcomas [89]. A phase III clinical trial is currently randomising patients with skull base chordomas to proton versus carbon radiation [90].

Lung cancer is among the most common malignancies and usually the most common cause of cancer-related mortality globally [104]. The gold standard treatment of early stage non-small cell lung cancer (NSCLC) is surgical resection. However, many patients are not able to undergo surgery due to old age or simultaneous cardiac or pulmonary disease. In these situations, radiotherapy provides an alternative treatment, especially SBRT [105,106]. Despite the high conformality of SBRT, CIRT still has better dose distribution in early and advanced stage lung cancer, which makes it more suitable for patients with underlying cardiac or interstitial lung disease [13,14]. Clinical trials investigating CIRT for early stage lung cancer have shown excellent local control and acceptable overall survival [107], even when single fraction CIRT is used [108,109] or when CIRT is used in the setting of in-field recurrence of previously irradiated NSCLC [110]. Interestingly, CIRT has shown a lower risk of radiation-induced pneumonitis [111], which makes it more useful for patients with interstitial lung disease [112]. Retrospective studies comparing proton and CIRT for T2a-T2b or stage I NSCLC showed equivalent outcomes and toxicities between the two groups [113,114]. CIRT for locally advanced NSCLC is less established, but early clinical data are very promising [115,116]. Many clinical trials in all centres globally are currently accruing patients to further evaluate CIRT for NSCLC.

Extra-cranial Bone and Soft Tissue Sarcoma

Prostate Cancer

Bone and soft tissue sarcomas represent a major indication and probably the best candidates for CIRT. Indeed, this is the only tumour type where CIRT is currently covered under the National Healthcare Insurance in Japan. An initial

High-risk Prostate Cancer

Skull Base Chordoma and Chondrosarcoma

High-risk prostate cancer has suboptimal outcomes with conventional photon irradiation. Dose escalation with low

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dose rate prostate brachytherapy achieved excellent rates of freedom from biochemical failure compared with an external beam boost (and compared with historical data of external beam radiation only studies) at the expense of increased genitourinary and gastrointestinal adverse events and reduced health-related quality of life scores [117e119]. Although there are no clinical trials comparing photon with CIRT for high-risk prostate cancer, current studies have shown excellent biochemical freedom from progression, an excellent toxicity profile with no grade 3 adverse events and good health-related quality of life outcomes [120e123]. In a large multi-institutional retrospective analysis with 1215 patients with high-risk prostate cancer, CIRT showed a remarkable 5 year biochemical recurrence-free survival and cancer-specific survival of 92% and 99%, respectively, without any grade 3 adverse events [124]. Prostate cancerspecific mortality was 4.3% in high-risk patients treated with CIRT and long-term hormone therapy [125]. Although CIRT has been used for low- and intermediate-risk prostate cancer, it is unlikely that CIRT will become indicated for these cancer types given the excellent outcomes and adverse events profile with photon radiotherapy, especially SBRT [126]. A recently completed phase II clinical trial compared acute toxicity between CIRT and proton radiotherapy for patients with prostate cancer with equivalent results [127]. In the Hospital of Charged Particles at the NIRS in Chiba, Japan, the prostate is the most treated cancer site with CIRT [128].

Gynaecological Malignancies Cervical Cancer Cervical cancer is a good example of a candidate for CIRT [129]. It is deep-seated, surrounded by radiosensitive organs (rectum, bladder, bowel), hypoxic and radioresistant [130]. Several phase I and II clinical trials evaluated the use of CIRT for locally advanced cervical cancer (SCC and adenocarcinoma). After initial dose escalation and adjustment for field design and dose constraints, oncological outcomes and adverse events were very encouraging [131e135]. The rate of distant metastasis is still relatively high and concurrent chemotherapy regimens are to be explored. A very limited number of patients received concurrent cisplatin without major adverse events [136]. More work is needed to define the exact indications for CIRT in patients with cervical and other gynaecological cancers.

Paediatric Tumours and Other Malignancies Several other malignancies have been treated with CIRT over the past 24 years. However, clear indications have not been established for a multitude of reasons. CIRT, for example, has been reluctantly used for the treatment of paediatric tumours due to the fear of severe adverse events

and/or the concern of an increased risk of second malignancies [137e139]. The few available reports with short follow-up did not show any second malignancies. Likewise, very few publications are available for highgrade brain tumours [140,141]. Notably though, the Japanese data of CIRT for glioblastoma compares favourably with the standard of care (maximal surgical resection followed by chemoradiation with temozolomide). Despite the infiltrative nature of high-grade brain tumours, a current phase II trial is investigating CIRT in patients with recurrent or progressive high-grade gliomas compared with photon radiotherapy [142]. Other brain tumours have been treated with CIRT, including low-grade gliomas [143] and high-risk meningiomas [144,145], but such experiences are still in the maturation process. Similarly, despite the increased radiosensitivity of typically radioresistant triple-negative breast cancer cell lines to carbon ions [146], the experience of using CIRT for breast cancer has been limited, mostly due to difficulties with setup reproducibility and inter-fractional variations. Interestingly, the reported cases used CIRT to definitively treat early stage T1N0M0 oestrogen receptor-positive invasive ductal carcinomas [147,148]. CIRT is unlikely to become indicated for the more common breast cancers, but some cancer subtypes (triple negative or inflammatory) may respond better compared with photon radiotherapy. More efforts are needed to investigate these questions.

Discussion As discussed above, carbon ion beams have distinctive biological and physical properties compared with photonor proton-based treatments. These advantages make it possible to treat a multitude of radioresistant malignancies as well as other malignancies requiring high doses that cannot be achieved conventionally due to their location and/or proximity to radiosensitive structures. Although dosimetric advantages are clear, the current evidence supporting CIRT is level 2b, at best, without any randomised phase III clinical trial comparing carbon beams with any other radiation modality. Designing large randomised clinical trials for radiotherapy in general is difficult given the large number of variables that need to be controlled. Along the same lines, designing phase III trials comparing CIRT with photon or proton radiotherapy is not trivial. The sparse distribution of CIRT centres globally (only 11 operating centres globally) and the financial issues related to insurance coverage and treatment reimbursement makes accrual for such trials difficult. Even if these logistical and technical issues are to be solved, the ethical question of randomising a patient to an arm that is known to have, at the least, inferior dose distribution remains to be addressed. These dilemmas always arise every time a new technology emerges in radiation oncology and in other fields in medicine. We have seen a similar situation before with proton therapy and a similar concern was raised [149,150]. Unfortunately, randomised clinical trials were not systematically carried out and now,

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as we switch to value-based reimbursement models in the USA, proton therapy is under heavy scrutiny [151]. The particle therapy community is urged to be judicious in their approach to starting clinical trials and expanding CIRT. Although the next few years will bring significant technological improvements with accelerators becoming smaller and cheaper, the initial capital cost of particle therapy centres and the annual maintenance costs will continue to exceed those of photon therapies [152]. Still, the cost-effectiveness of CIRT could be possibly proven if evidence-based patient selection and hypofractionated treatments are adopted [153e155]. The anticipated benefits of CIRT in terms of prolonging survival, reducing late side-effects and reducing the subsequent healthcare costs dealing with recurrences and treatment-related morbidities are believed to make up for the increased treatment costs. Other modifications to the beam line, such as replacing custom collimators with multileaf collimators and eliminating custom range compensators, are associated with a significant cost reduction in daily treatments [156]. Whenever clinical trials are to be carried out, an integrated translational approach should be implemented. Patient selection should move away from the classical description of a good candidate tumour for CIRT being ‘hypoxic, near radiosensitive organ at risk and deep-seated’. For example, a panel of hypoxia genes could be tested and the hypoxia signatures could be used to stratify patients between conventional photon radiotherapy and CIRT [157]. Furthermore, future clinical trials should use advanced statistical methods, mathematical modelling in patient selection and disease-specific end points. If appropriate patients and/or useful end points are not selected, no clinically significant differences will be found between CIRT and the ever-improving proton- and/or photon-based radiotherapy. We believe strongly that our knowledge of biophysics and cancer biology should be used to steer the evolution of CIRT in the right direction. We have irrefutable evidence that CIRT has major physical, biological and dosimetric advantages over photon and proton beams and the current clinical evidence shows promising results in many cancer types. Thus, the mapping and construction of CIRT centres, including their numbers and geographical location, should reflect the number of cases expected to be treated in the respective populations. As clinical evidence grows, the number of centres can grow simultaneously. With the expected improvement in oncological outcomes (local control, overall survival), improvement in functional outcomes (for example, ambulation in patients with sacral chordomas) and reduction of adverse events (for example, decreased rectal toxicities in high-risk prostate cancer), CIRT has the potential to have an overall improved costeffectiveness profile over photons as long as the number of centres and infrastructure cost are closely matched to the expected incidence of the indicated cases in a particular geographical region. Needless to say, these centres are expected to operate with optimal workflow and at maximum capacity.

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Conclusions CIRT is capable of increasing tumour control and reducing normal tissue complications but it should be able to do that more efficaciously than protons or X-rays. Due to the high infrastructure costs, transnational collaborations are required to provide the necessary evidence of benefit. Compared with other radiotherapy modalities, heavy ion therapy is still in its infancy and the possible technological advancements are exciting. Adoption of LET painting [158,159], mixed beam strategy (such oxygen ions for hypoxic tumours) [160], combination with immunotherapy [161] or chemotherapy [162] and improvement of motion management technologies [17] are all anticipated improvements in the next decade. There are currently several phase III clinical trials comparing C-ions with X-rays or protons (reviewed in [149]). The results of these comparative trials will be decisive for the future of CIRT.

Acknowledgements Funding for research in this field at TIFPA comes from the CSN5 experiment MoveIT.

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