Ongoing and future clinical trials in particle therapy in the Nordic countries

Abstract

In the Nordic countries, as in the rest of the world, particle therapy as a radiotherapy modality, is evolving, albeit the hard evidence for the clinical benefit still is scarce. However, a common goal for the Nordic countries is to include a minimum of 80% of the patients treated with particle therapy into clinical trials. In this paper, we summarize the current status of clinical trials involving particle therapy in the Nordic countries, with an overview of both active and coming trials. So far, one is closed for inclusion and data are being analyzed, seven trials are actively recruiting patients and several more trials are underway. No common Nordic trial has yet been designed, nor is in the planning phase, and the authors will discuss the obstacles as well as the opportunities a common Nordic platform may represent.

Why is it relevant to discuss common Nordic particle therapy trials?

There is a growing interest in the Nordic countries to choose particles including protons as a radiotherapy option for selected indications, parallel to the situation internationally where the number of proton facilities has increased exponentially the last decades. The main reason is that proton therapy (PT) can deliver high conformal radiation doses on the tumor site and less unwanted dose to the surrounding healthy tissue. Thus, PT has the potential to reduce the adverse effects of radiotherapy and provide better outcomes for cancer patients and also reduce health-economic costs in the long run.

In the Nordic countries, there are today two running proton facilities, one in Uppsala, Sweden (clinically active since August 2015) and one in Aarhus, Denmark (active since January 2019), and in just a few coming years there will be another two facilities for protons (Oslo and Bergen, Norway) and one for Boron Neutron Capture Therapy (BNCT) (Helsinki, Finland). All these facilities are or will be part of public health care systems.

However, the indications and hence the number of patients considered for particle therapy is still quite limited and the knowledge and solid high-level clinical evidence so far is quite scarce. The selection of patients which today are accepted for PT varies between countries including close neighbors as the Nordic countries. There may be standard indications where all patients are offered PT (e.g., pediatric patients) or the decisions may be based on national or local multi-disciplinary tumor boards [1].

As PT is currently more expensive than conventional photon radiotherapy, it is important that solid research data are generated to justify its use and that long-term health economics data, besides the clinical benefit, are evaluated for all potential indications [1,2].

The basic common infrastructure is available

Common goal

The Nordic PT facilities will have the capacity and intention to treat a high proportion of patients within clinical trials, and 80–85% of PT patients in Sweden, Norway and Denmark are expected to be enrolled in a clinical trial. The majority of patients who receive BNCT in Finland will be enrolled in clinical trials as well.

At the moment, approximately 40% of patients treated with protons are included in a trial in Sweden and the number is increasing. The Skandion collaboration has revealed a lack of source of funding as well as needed logistics in Sweden. For Denmark, 2020 is still too early to evaluate if this goal is or can be achieved.

Public health care systems

The Nordic PT facilities are or will be part of public health care systems. The Nordic health care systems are quite similar, mainly public and financed mostly through regional and municipal taxes, where the state also contributes with some financial support [3]. For the populations, the healthcare is either free or there is a maximum amount/limit to what they have to pay including for prescription medicines. University hospitals work closely with the medical universities and colleges of education and research, which also means research is a part of the public health care system and in some extent also financed by the government.

Tradition for collaboration

There is a long tradition for collaboration in the Nordic countries in many areas, including research and clinical studies and there are several Nordic societies (e.g., head and neck cancer (SSHNO; sshno.org), anal cancer (NOAC; noac.dk), childhood cancer (NOPHO; nopho.org), Scandinavian Sarcoma Group (SSG; ssg-org.net), gynecological cancer (NSGO; nsgo.org)).

The populations are closely related, including the languages (except for Finnish), and contributing to a platform for collaborative studies, where patients have equal access to the studies, make the mobility easy to travel to relevant facility, and support and interchange patients between each other’s clinical studies. Also, as the Nordic countries are at different levels in PT. The social environments for the populations are similar which also make the extrapolation of the validity of the studies into general validity easier. Until all the countries are at full capacity and can meet their own demand, our trials should be freely accessible across borders, with a clear agreement on tariffs and reimbursements also for nonstandard indications tested in clinical trials.

Evidence based medicine – need for PT trials

The potential increase of the therapeutic ratio with PT means the same chance for cure but less risk of complications. PT has been used clinically for several decades, still limited data exist on treatment outcome outside pediatric cases and tumors in the central nervous system (CNS). There is very long list of indications, where conventional photon radiotherapy is causing significant morbidity, e.g., head and neck cancer, gastrointestinal cancer, thoracic malignancies and urogenital cancer. For these sites, the potential of PT is high, patients will recover faster from their treatment and live a better life with fewer side effects, but there is a need to demonstrate the clinical efficiency as well as the health economic aspects of PT. Trials creating high level of evidence, e.g., prospective randomized trials should be planned. Only if such trials are positive will PT become a standard option despite the high direct costs of the treatment compared to photons.

Randomized controlled trials (RCTs) demonstrating reduced morbidity are not straightforward to plan and conduct. The RCT methodology was developed for binary endpoints (death, recurrence, etc.), with strict rules for analysis and power calculation. RCT methodology is less well suited for assessing treatment-related side effects, which can be complex and assessed in many ways, observer-based, patient reported, functional assay and other ways, with arbitrary grading scales. Some side-effects also first appear many years after initial treatment (e.g., cardiac toxicity, stroke and secondary cancers). Innovative trial methodologies are emerging, e.g., trials using enriched populations, the Dutch model-based approach [4] but there is still no generally accepted alternative to RCT as the highest standard of evidence.

It is of outmost importance that robust data also on the health economical aspects of PT are generated to justify its use; data on clinical benefit and patient reported outcomes should be compared to the health care and other costs to determine investment and incremental costs from a health care and societal perspective, i.e., the incremental benefits need to be compared to the additional costs of PT.

RCT of novel technology can be difficult for several reasons. Access to the technology is needed in order to do the clinical testing, and if the technology is expensive, the payers will require first to see some evidence. This is the so-called Catch-22 dilemma. Another problem is that the new technology may be outdated and replaced before the outcome of a trial is available. Many clinical trials in radiation oncology have long recruiting times and late endpoints such as late side-effects. This latency can be due to high number of patients required for statistical reasons and/or due to slow accrual. The latter is especially true when a trial is conducted in a limited number of sites, e.g., in a single institution or a single country. With the increasingly high pressure on national health care, the possibility to conduct fast and large academic trials as part of the clinical routine within a single institution or country is often not possible.

Ongoing and planned trials so far in the Nordic countries

Sweden

Sweden was the first country in Scandinavia to offer PT. The Swedish national facility, the Skandion Clinic, works by the distributed model [5]. Since the clinicians at the participating departments will have access to virtually all cancer patients, the model is expected to be a firm base for efficient clinical research. This will secure an efficient inclusion of patients in e.g., clinical radiotherapy studies. The initial studies so far were initiated by individuals appointed by the medical directors of the departments of oncology at the university hospital together with interested oncologists/physicists and RTTs. The national work has been coordinated through several national meetings. The goal is that research should also be distributed. The ultimate vision of Skandion is that the 80% of patients treated with PT are in an RCT where one of the treatment arms were conventional RT (Table 1) [6].

Table 1. Overview of current Nordic clinical trials involving particle therapy.

Country	Trial	Principal investigator/coordinator	Tumor site	Design	Status/planned start date
Sweden	PRO-CNS NCT02797366	Malin Blomstrand ([e-mail])	CNS	Non-randomized	Active
	Protoncare	Karin Ahlberg ([e-mail])	All	Non-randomized	Closed
	Radtox	Ulla Martinsson ([e-mail])	Pediatric – all	Non-randomized	Active
	PROTHYM	Jan Nyman ([e-mail])	Thymus	Non-randomized	Active
	PRO-Hodgkin	Daniel Molin ([e-mail])	Hodgkin lymphoma	Non-randomized	Active
	Artscan V NCT03829033	Maria Gebre-Medhin ([e-mail])	Early tonsillary cancer	Phase II, randomized proton/photon	Active
	Artscan IV	Michael Gubanski ([e-mail])	HN reirradiation	Non-randomized	Active
	PROLOB	Zahra Taheri Kadkhoda ([e-mail])	Adjuvant breast cancer	Non-randomized	2020^a
	SWANCA	Björn Zachrisson ([e-mail])	Anal cancer	Randomized phase II proton/photon	2020^a
	PRORECT	Alexander Valdman ([e-mail])	Preoperative rectal cancer	Randomized phase II proton/photon	2020^a
	PROLUNG	Jan Nyman ([e-mail])	Lung cancer locally advanced disease, stage III or patients with T2-3N0 (stage IB–IIB) not suitable for surgery	Non-randomized	2020^a
Denmark	FAR-RMS EPSSG EudracCT 2018-000515-24	Akmal Safwat ([e-mail])	Rhabdomyosarcoma	Non-randomized	2020
	IWOT NCT03763422	Slavka Lucakova ([e-mail])	Low grade glioma	Randomized observation vs. PT/RT	2020
	SIOP High Risk Medulloblastoma	Astrid Sehested ([e-mail])	Medulloblastoma	Non-randomized	2020
	EEP II (SIOP) NCT02265770	Pernille Wendtland ([e-mail])	Ependymoma	Non-randomized	2020
	UMBRELLA EudraCT 2016-004180-39	Jesper Sune Brok ([e-mail])	Ewing sarcoma	Non-randomized	2020
	DAHANCA 35	Jeppe Friborg ([e-mail])	Pharynx/larynx cancer	Enriched population, randomized, proton/photon	2020^a
	DBCG proton trial NCT04291378	Birgitte Offersen ([e-mail])	Adjuvant breast caner	Enriched population, randomized, proton/photon	2020^a
	PROTECT	Marianne Nordsmark ([e-mail])	Preoperative esophageal cancer	Randomized, proton/photon	2021^a
	DNOG2 NCT04306432	Lene Haldbo-Classen ([e-mail])	Cognitive testing in CNS patients	Non-randomized	Active
	DAHANCA 37 NCT03981068	Kenneth Jensen ([e-mail])	HN reirradiation	Non-randomized	Active
	Liver	Britta Weber ([e-mail])	HCC and liver metastases	Non-randomized	Planning
	DCCG ReRad II	Camilla Kronborg ([e-mail])	Reirradiation rectal cancer	Non-randomized, dose escalation	2020^a
	DACG ReRad III	Camilla Kronborg ([e-mail])	Reirradiation anal cancer	Non-randomized, dose escalation	2021
	DGCG Cervical cancer	Lars Fokdal ([e-mail])	Postoperative and para-aortic	Non-randomized	Planning
	PROPROstat DAPROCA	Lise Bentzen ([e-mail])	Radical radiotherapy of prostate cancer	Enriched population, randomized, proton/photon	Planning
Finland	BNCT trial	Leila Vaalavirta ([e-mail])	HN reirradiation	Unknown	Planning

^a All potential start date may be adjusted due to the current corona pandemia.

Trials

PRO-CNS (NCT02797366)

A prospective non-randomized trial with the aim to prospectively collect as much information as possible on CNS patients treated with PT. Focus on side-effects, survival and on socio-economic factors, and dosimetric advantageous compared to historical cohorts. PRO-CNS was the first trial to be initiated and included also the first treated patients at Skandion. The study will stop for inclusion of patients in autumn 2020 and so far, more than 300 patients are included, with the majority of patients with glioma and meningioma.

PROTONCARE

Prospective collecting of patient reported toxicity and health related quality of life in short- and long-term perspective and experience of care. One of the initial studies with more than 200 patients included so far. This is the most active study-group with several publications and also a Ph.D. graduate [7].

Radtox registry

The registry records side-effects from life-long follow-up on all children treated with RT in Sweden. The study was already an established study before the clinical start of Skandion. It is a collaboration including Norway and Germany.

PROTHYM

A prospective, non-randomized phase II study including patients with thymic epithelial tumors, that are candidates for postoperative, adjuvant or for inoperable patients with localized disease, all treated with protons. Primary endpoints are toxicity (e.g., cardiac and pulmonary toxicity) and the local control at 5 year. The study is active since 2018 but the inclusion rate is slow, reflecting also that the diagnosis is quite rare.

PRO-Hodgkin

This is a multicenter phase II study of PT in patients with early stage Hodgkin lymphoma treated with induction chemotherapy. The study is performed in a non-inferiority setting comparing with a historical population-based consecutive Swedish material. The control group was treated according to the same principles, except that the RT was delivered with photons. The study was activated in February 2019 and the inclusion period is 5 years, including at least 75 patients treated with protons.

ARTSCAN IV

A non-randomized observational study of all reirradiation in patients with head and neck cancer with special focus on patients receiving PT. Patients treated with photons are also included and primary endpoint is loco-regional control, and secondary endpoints focus on early and late side effects, complications, quality of life and overall survival. The study was activated in 2019.

ARTSCAN V (NCT03829033)

Patients with early tonsillar cancer, candidates for unimodal and ipsilateral treatment with RT with curative intent are included. The patients are randomized in a 1:1 ratio between photons or protons, and primary endpoint is acute side effects at the end of treatment and late side effects one and five years after completion of treatment comparing the two RT modalities. The first initiated randomized phase II trial at the Skandion Clinic. The study was activated in the beginning of 2019 and the goal is to include 100 patients for 2–4 years.

PRO-LOB

A technical feasibility study for patients with breast cancer. It is non-randomized and with focus on optimal technical PT treatment, including positioning, fixation and planning. Endpoints are side-effects both as scored by clinicians but also by the patient. The study is estimated to include the first patient in a couple of months.

SWANCA

A randomized study designed to include patients with localized anal cancer, T2-T4 and/or N1, M0, comparing the acute hematological toxicity in patients treated with protons or photons. The protocol is still under construction but with the goal to start including patients late this year.

PRORECT

Preoperative short-course radiation therapy with protons compared to photons in high-risk rectal cancer, a prospective randomized phase II trial. Primary endpoint is the incidence of acute preoperative grade II–V gastrointestinal toxicity comparing the two RT modalities. The protocol is under final construction but with the goal to start including patients late this year.

PROLUNG

A phase II non-randomized study on PT of lung cancer with main focus on toxicity. The study is under construction.

Denmark

In Denmark, the aim is to include 80% of all PT patients into clinical trials. This ambition was included in the proposal for the Danish Centre for Particle Therapy and confirmed by the Danish National Board of Health and the Danish Government in the business case justifying the project and budget [8]. The planning and conduct of trials are done in a close collaboration with the Danish Multidisciplinary Tumor Groups (DMCGs; www.DMCG.dk). DMCGs already have a significant role in Danish cancer management, responsible for national treatment guidelines, national quality databases and coordination of national clinical trials. The DMCGs have taken the task of integrating PT into their work portfolio serious. During multiple bilateral meeting with DCPT, both standard indications and new trials have been developed (Table 1).

Randomized trials

The Danish RCT of PT versus photons so far include three tumor sites, head and neck, breast and esophagus. The trials use different selection methods and setup, which will be briefly described below.

DAHANCA 35

The Danish Head and Neck Cancer Group RCT for pharynx and larynx cancer patients will use comparative dose-planning and NTCP modeling to select candidates with a significant anticipated reduction in xerostomia and dysphagia and offer these patients randomization. Final endpoint, power calculation and start of accrual await a decision on the final NTCP model. Randomization will be 2:1, i.e., two out of three will receive PT. All six Danish head and neck cancer centers have started recruiting patients in the feasibility phase, in order to optimize treatment planning and referral pathways. Randomization is expected to start in 2020.

DBCG proton trial

The Danish Breast Cancer Group Proton Trial (NCT04291378) is an RCT in breast cancer, aiming to demonstrate reduced cardiac morbidity of protons for patients requiring loco-regional nodal irradiation. It is based on dose-planning studies of Stick et al. [9] showing that for patients where the dose–volume constraints to the heart and lungs cannot be met without compromising the target dose, a proton plan is always superior. The initial hypothesis has been confirmed in a larger multi-center planning study. A patient is candidate if mean heart dose ≥4 Gy or V17/20 lung ≥37%, no need for comparative treatment planning. An estimated 7% of all breast radiotherapy patients will be candidates (20% of the patients offered locoregional radiotherapy). Endpoints are radiation associated ischemic and valvular heart disease at 10 years after radiotherapy. One thousand and five hundred patients will be included in 3–5 years. Randomization is expected to start in 2020.

PROTECT

The Danish EsophagoGastric Cancer (DEGC) group PROTECT Trial (PROton versus photon Therapy for Esophageal Cancer – a Trimodality strategy (PROTECT)) compares preoperative proton versus photon chemoradiotherapy in locally advanced esophageal cancer. The RCT is developed by the DEGC in collaboration with partners from the European Particle Therapy Network (EPTN) [2]. The trial will test the hypothesis that dose reductions to critical OARs by PT will result in lower rates of treatment related complications. The primary endpoint is post-operative pulmonary complications. The trial is randomizing 1:1. A total of 440 patients are expected, with an expected enrollment period of four years. Randomization is expected to start in 2021.

Non-randomized prospective trials

The following non-randomized trials, where PT is the main study objective, are either active, being activated or on the drawing board.

DNOG2

Danish Neuro Oncology Group studies the neurocognitive function in patients who received RT or PT for tumors and the correlation between neurocognitive impairment and dose–volume parameters to pre-specified brain areas. A total of 120 patients will be included. Neurocognitive testing is performed before treatment and 1, 3 and 5 years after RT or PT.

DAHANCA37

An observational phase II trial of re-irradiation in head and neck cancer. 60 Gy/50 fx/10 fx/week EQD2 56 Gy. Weekly cisplatin, nimorazole for SCC. The study aims for 20 patients over two years. Primary endpoint is any new late toxicity grade ≥3. Approved by DAHANCA, DCPT and ethics, the first patients have been enrolled.

Liver tumors

Phase II trials are anticipated for primary treatment of hepatocellular carcinoma (HCC) and colorectal liver metastases, where treatment with photons is restricted by dose–volume constraints.

Lower GI

Re-irradiation of rectal cancer (ReRad II), a phase II dose escalation trial approved by the Danish Colorectal Cancer Group. First pilot patient to be treated 2020. A similar setup (ReRad III) for anal cancer re-irradiation, with expected start 2021.

Cervical cancer

The Danish Gynecologic Cancer Group are planning two prospective studies for cervical patients, with para-aortal involvement or in the postoperative setting, respectively.

Norway

Norway has the goal to include as many patients as possible into clinical trials, approximately 80%. The national group in Norway has just started their discussion on future proton studies, as there is still 3–4 years to the proton centers will open. A central research office for radiotherapy trials is under development. There are discussions on sending patients to clinical studies abroad. Today, it is possible to get reimbursement for PT abroad if PT is considered the standard treatment. At the time, there is no reimbursement or funding for the inclusion of patients in PT trials outside Norway.

There is a potential low grade glioma trial in collaboration with Sweden, with randomization between photons and protons including neuro-cognitive testing.

Finland

The only RT modality offering particle therapy in Finland is BNCT. With government-supported experience from initial trials in CNS tumors and recurrent head and neck cancer between 1990 and 2010 [10], a new BNCT clinic is now underway with US-based commercial collaboration. A new tentative clinical start is planned in late 2020 involving patients with recurrent head neck cancer and a clinical trial. Finland has no plans on building a PT facility, and pediatric patients and some adults with radioresistant tumors such as skull base chordomas are currently referred to PT mostly in Essen, Germany or Paul Scherrer Institute in Switzerland. However, increased demand for PT and growing collaboration between Nordic countries within this field will make participation in clinical trials of PT in Sweden, Denmark and Norway highly attractive for Finnish patients. To realize this initiative, a nationally coordinated reimbursement system under the auspices of Finnish Cancer Centre should be designed.

Hurdles and needs for common Nordic trials

So far, no common Nordic trials are active nor planned.

There may be many explanations for this: traditions and different standard care/guidelines and indications for PT treatment may contribute. Introducing and developing new techniques are always challenging and quite resource consuming. Technique collaboration between the current PT centers in Nordic countries has so far unfortunately been limited, possibly due to different timescales for introducing PT and use of different vendors. Hence, it has been more natural for the two centers to collaborate with other centers in Europe (e.g., for Århus with Manchester, UK, and for Skandion with Trento, Italy).

Reimbursement for PT and participation in academic driven trials is a key issue for the health economics and critical if PT is not considered a standard indication.

Larger common research funding applications both from Nordic options as well as EU funding might be a platform for busy clinicians, physicists and nurses/RTTs to establish research activity in the PT area.

Collaboration with the industry might be an option but is a politically sensitive area with little tradition in radiotherapy or PT. However, radiation therapy has rapidly developing technology driven by the industry, and high-quality evidence-based patient recruitment is also in the interest of the industry, since it will facilitate reimbursement [11]. The collaboration with researchers connected to the clinic may also strengthen and quicken the technical developments.

At the workshop in November 2019 one of the goals was to consider the potential for future common trials. Many issues were discussed, and several points were made:

• Create common guidelines and harmonization of current RT treatments for potential indications is essential and may be a focus area for Nordic cancer societies.

• All radiotherapy centers should participate/be included – national based to create a critical mass of patients to make the studies attractive.

• A platform for dummy runs to standardize delineation and proton treatment planning should be established as well as collaboration on technique development, e.g., how to handle moving targets as it is quite resource demanding.

• Find common roads for reimbursement for PT treatment when a diagnosis is not a standard indication for PT.

• Agreement on sending patients across the borders to make patients participate in each other studies; exchange study patients.

• Increasing the participation into international resource-demanding trials, e.g., pediatric patients into SIOP trials, may be facilitated by Nordic collaboration concentrating the treatments to few Nordic sites.

• A common Nordic consensus on which patients should be treated with PT and awareness of PT trials in the Nordic countries could facilitate recruitment of patients.

• A Nordic Collaborative PT Group might be an option with a home page with news, available trials, funding opportunities, contact persons, referral ways, etc.

Conclusions

So far, the Nordic collaboration is not involving clinical trials, but there was a strong consensus of the need at the workshop in Uppsala. There are several PT studies on the way in the Nordic countries. High-quality trials with sufficient patient accrual, new indications for PT, collaboration on technique development and the reimbursement for PT and academic trials are key issues. Addressing it from a Nordic perspective may not only strengthen PT but the whole radiotherapy community, providing cutting-edge treatments for our patients.

A new Nordic Collaborative Workshop for Particle Therapy is planned in 2020 in Denmark.

Acknowledgments

The authors thank all participants at the Nordic Collaborative Workshop for Particle Therapy 2019, in Uppsala, Sweden, with special thanks to Carl-Johan Brahme, Christina Vallhagen Dahlgren, Jon Espen Dale, Erik Lundin, Henriette Magelssen, Inger Marie Sandvik, Sigbjørn Smeland, Alexander Valdman, Damien Weber, Zahra Taheri-Kadkhoda and Bengt Glimelius.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.