Ongoing European Randomized Proton Trials (REFERENCE SERIES)
A summary of great prospective trial work out of Europe
www.protons101.com
Home to the musings of a radiation oncologist - with a slant on protons and dose and optimizing cancer outcomes.
Getting trials done is tough. But, it seems it must be harder in the US than elsewhere. And then, in the proton world, pair that with insurance denials and the inherent financial pressures on the proton industry and you get… well, not much as we need. There are some finally coming (think oropharynx, lung, esophageal, breast, and prostate), but elsewhere…
Elsewhere, there seems to be large-scale progress and today, we’ll jump across the old pond and look at 11 prospective randomized controlled trials in proton therapy. For many in the US market wondering how and when there will be data for proton therapy, I’d suggest refocus on western Europe.
In total these trials aim to enroll 5200+ patients on Phase III Randomized Controlled Trials alone - covering site like glioma, head and neck, breast, esophagus, rectal, prostate. Heck, there is even one trial looking at Carbon and Hadron therapy that puts proton therapy into the “conventional radiotherapy” arm. Pause and let that sink in.
Trials, Trials and more Trials:
As I’ve said previously, I don’t expect wins in all of these, but I do think in places, we are very likely to determine that there is real value in toxicity reduction based on improved dosimetry with proton therapy.
We’ll walk through the above highlighted phase III prospective randomized controlled trials in order - links are in the title name rather in a reference section below - hopefully for easier access.
The descriptions come directly from the trial pages and are the authors descriptions.
Note: the only real editorial comment is in the summary at the end of the document - this is a summary consolidated medical literature document primarily. But I think it serves to drive home where the industry is today.
PROSPECTIVE RCTs for PROTON THERAPY
PRO-GLIO CNS PROton Versus Photon Therapy in IDH-mutated Diffuse Grade II and III GLIOmas (PRO-GLIO)
Glioma Norway / Sweeden - 225 patients
Detailed Description:
PRO-GLIO aims at establishing proton irradiation as standard radiotherapy for IDH-positive diffuse glioma grade II and III patients. First, PRO-GLIO will show that proton therapy is safe, despite the infiltrative nature of these tumors. Second, the HRQOL and neuropsychological investigating part of PRO-GLIO will show that patients irradiated with protons have a better outcome in this regard than those irradiated with photons. Inclusion criteria are a diagnosis of grade II or grade III IDH-mutated diffuse glioma, good performance status, indication for radiotherapy and age between 18 and 65 years.
Patients will be randomized to proton or photon radiotherapy and the study work will be divided in three work packages (WP).
In WP1, survival data will be the main focus, but the estimation of QALY will also be an important part - concentrating on differences between the two study arms. If there is truly no difference between the proton and photon radiotherapy on the probability of FIFS after two years, then 224 randomized patients (112 in each treatment group) are required to be 80% certain that the upper limit of a two-sided 95% confidence interval will exclude a difference in favor of the photon radiotherapy of more than 15%. This assumes a 0.8 probability of FIFS in the control arm, and no drop-outs.
In WP2, a battery of validated neuropsychological tests will be used to test the cognive abilities of the patients. All patients will be testes using an internet-based test (Cog-State) and 1/3 of patients will also have an in-depth neuropsychological evaluation. The two methods will be compared.
In WP3, a battery of patient-reported outcome measures (PROMS) questionnaires will be used to establish which subjective challenges this patient group struggles the most with.
Primary Outcome Measures :
First intervention free survival (FIFS) at 2 years [ Time Frame: 2 years ]
GRIPS Glioblastoma Radiotherapy Using IMRT or Proton Beams (GRIPS)
Glioblastoma Heidelberg - 326 patients
Brief Summary:
Radiation therapy is an integral part of the multimodal primary therapy of glioblastomas. As the overall prognosis in this tumor entity remains unfavorable, current research is focused on additional drug therapies, which are often accompanied by increases in toxicity. By using proton beams instead of photon beams, it is possible to protect large parts of the brain which are not affected by the tumor more effectively. An initial retrospective matched-pair analysis showed that this theoretical physical benefit is also clinically associated with a reduction in toxicity during therapy and in the first few months thereafter. The aim of the GRIPS study is to prospectively test this clinical benefit in a randomized, open-label Phase III study. Patients are treated in the study using either modern photon radiation techniques (standard arm) or proton beams (experimental arm). The primary endpoint is the cumulative toxicity CTC grade 2 and higher in the first 4 months. Secondary endpoints include overall survival, progression-free survival, quality of life, and neurocognition.
Primary Outcome Measures :Cumulative rate of toxicity [ Time Frame: from start of radiotherapy until progress (max. month 4) ] Cumulative rate of toxicity ≥ grade 2 (until progress (max. month 4))
DAHANCA 35: Proton Versus Photon Therapy for Head-neck Cancer (DAHANCA 35)
Head and Neck Cancer Denmark - 600 participants.
Detailed Description:
DAHANCA 35 is two parallel conducted, but separate randomized studies, within the same trial (DAHANCA 35D and DAHANCA 35X) by the Danish Head-Neck Cancer Study Group (DAHANCA). In patients with squamous cell carcinoma of the pharynx or larynx planned for primary radiotherapy a proton and a photon doseplan is prepared. If proton radiotherapy reduces the anticipated absolute risk of dysphagia >= grade 2 (DAHANCA scale, DAHANCA 35D) or severe xerostomia >= grade 4 (EORTC Head-Neck 35, DAHANCA 35X) more than 5%, the patient is randomised to either proton therapy or photon therapy, 2:1. The anticipated risk of xerostomia and dysphagia is estimated using Normal-Tissue Complication Models (NTCP). Patient are analysed according to the primary endpoint (dysphagia and/or xerostomia) after which they were enrolled. DAHANCA 35D is expected to enroll 360 patients and DAHANCA 35X 240 patients (in total 600 patients).
Primary Outcome Measures :
Dysphagia >= grade 2 [ Time Frame: Six months after end of radiotherapy ]
The rate of observer-reported dysphagia >= grade 2 measured by the DAHANCA late toxicity score (grade 0-4, with 0 being best)
Xerostomia = grade 4 [ Time Frame: Six months after end of radiotherapy ]
The rate of patient-reported xerostomia measured by the EORTC Quality of life questionnaire (QLQ) Head-Neck (HN) 35 (grade 1-4, with 1 being best)
TORPEdO: TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer
Head and Neck Cancer UK - 183 patients.
Status: In follow-up
Trial details:
TORPEdO is a phase III, multicentre, randomised trial to assess whether intensity modulated proton therapy (IMPT) compared with intensity modulated radiotherapy treatment (IMRT) reduces toxicity in oropharyngeal squamous cell carcinoma.
183 patients will be recruited from UK sites over a 3.5 year period, with patients randomised to IMPT being treated at either The Christie NHS Foundation Trust or University College London Hospitals NHS Foundation Trust. Patients will receive treatment for 6.5 weeks, and will be followed up for a further 5 years.
Primary objective:
To assess whether IMPT compared with IMRT reduces treatment-related toxicities in patients with locally advanced oropharyngeal squamous cell carcinoma.
The co-primary endpoints measured at 12 months after completion of chemoradiotherapy are:
University of Washington Quality of Life Questionnaire version 4 (UW-QoL v4.0) physical composite score;and
Gastrostomy dependence or Common Terminology Criteria for Adverse Events (CTCAE) grade 3 wt loss (i.e. ≥ 20 % weight loss from baseline)
The DBCG Proton Trial: Photon Versus Proton Radiation Therapy for Early Breast Cancer
Breast Denmark - 1502 patients
Detailed Description:
Adjuvant breast cancer radiation therapy (RT) is standard for all patients operated with breast conservation and for patients diagnosed with large tumours and/or node-positive disease. Around 65% of all breast cancer patients treated with RT have whole breast RT without nodal RT, whilst the remaining 35% are treated with loco-regional RT (target is breast / chest wall and regional nodal volumes). RT leads to fewer local and regional recurrences, a decrease in breast cancer death and improves overall survival. Since 2014, when the DBCG IMN study showed overall survival gain from internal mammary node (IMN) RT, IMN RT has been standard for all high-risk patients in Denmark. IMN RT causes a significant increase in dose to the heart and lung, thus heart and lung sparing RT techniques based on deep inspiration breath hold (DIBH), volumetric arc therapy and tomotherapy are increasingly used to lower dose to heart and lung whilst maintaining dose to breast and nodal targets. These advanced techniques are used in all DBCG departments routinely. Despite using advanced RT techniques, some patients still receive high RT dose to heart and lung.
Proton therapy (PT) has not been widely used nor investigated for adjuvant breast cancer RT, because there are only few proton centres. However, due to the properties of PT it is possible to achieve optimal dose coverage of relevant targets and at the same time ensure low dose to organs at risk compared with photon RT. In an energy-dependent manner, PT will deposit the majority of its dose in tissue depths defined by the Bragg peak. In practice, this translates into i) the ability to deliver the peak energy to target volumes of irregular 3-dimensional shape using pencil-beam scanning technology, ii) a sharp dose fall-off following deposition of energy in the target and iii) reduction of the integral dose to the patient. Within millimeters, the exit dose drops off from 90% to 10%, resulting in the virtual absence of an exit dose. The effectiveness, safety and feasibility of PT has been reported in few small cohort studies with limited follow up, and there is a lack of clinically controlled randomised trials documenting benefit from PT, evaluated either as higher tumour control and/or as fewer morbidities.
This trial tests standard photon RT versus experimental proton RT for selected early breast cancer patients.
Primary Outcome Measures :
Radiation associated ischaemic and valvular heart disease [ Time Frame: 10 years after RT ] The following incidences heart diseases according to ICD10: ischaemic heart disease codes I20-25 and valvular heart disease codes I00-09, I01.0, I09.2, I34-39
PARABLE: Proton beAm theRApy in patients with Breast cancer: evaluating early and Late-Effects
Breast Cancer UK - 192 patients
Plain English Partial Summary of Trial:
Design and methods: To confirm that PBT reduces rare but life-threatening side effects such as heart attacks compared with RT would need over 10,000 patients in a clinical trial lasting 15-20 years. This is not feasible and would mean large numbers of patients being exposed to less than optimal treatment in the meantime. We plan an efficient clinical trial using average heart dose, a short term predictor for later heart damage, to deliver a result much earlier. We will invite 192 breast cancer patients who have at least a 2 in 100 predicted lifetime risk of serious heart side effects from their planned RT to receive either PBT (Manchester/London) or RT (local centre). The choice of PBT or RT will be decided randomly by computer to minimise bias. We will compare average heart dose received with PBT to that received with RT and use symptoms reported by patients at 2 years after treatment to compare other side effects in and around the breast. Outcomes and side effects will be collected for 5 years and NHS databases will be used to collect even longer-term effects. We will assess whether patients accept randomisation and address any inequality of access. Patient & Public Involvement (PPI): Patients as equal partners have contributed at all stages, including discussions at 7 national meetings and 2 patient focus groups. PPI has shaped the design by confirming that the main outcomes are important to patients, that 3-week PBT is acceptable and that outcome data should be collected beyond 5 years. Communication of Results: We will present results at international conferences, publish in peer reviewed medical journals and produce lay summaries for a diverse audience together with our PPI partners.
Aims & objectives:
PARABLE aims to show that PBT reduces predicted risk of late serious heart toxicity with no increase in other shorter-term side effects. PARABLE's specific objectives are: (i) Change international practice for breast PBT early with a primary outcome analysis at 2 years' follow-up (ii) Improve understanding of PBT biological models through a mechanistic study with potential benefit for all cancer patients needing PBT.
PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy (PROTECT)
Esophageal cancer UK, Europe 396 participants
Detailed Description:
PROTECT is a unblinded international multicenter randomized phase III study for patients with operable EC or EGC receiving nCXT (standard of care) or nCPT (intervention). The study will be open-label for the patient and the treating physician.
The radiation dose is either 41.4 Gy in 23 fractions, five fractions per week or 50.4 Gy in 28 fractions, five fractions per week. Prior to trial opening, each proton center will determine a single dose regimen for all patients treated in that specific proton center and its assigned photon centers.
The protocol prescribes that all referring centers will use the same chemotherapy regimen, which is weekly carboplatin (AUC 2), and paclitaxel (50 mg/m2), five cycles, irrespective of choice of dose regimen. Chemotherapy is a non-investigational drug.
Prior to referral to any proton therapy center, patients will be randomed (1:1) to either nCXT or nCPT. Only patients randomized to the PT arm will be referred to a PT center. Randomization will be performed centrally using an online 24-hour web-based system maintained by the Clinical Trial Office at Aarhus University Hospital, ensuring allocation concealment to the clinical investigators. The method of randomization will be stratified permuted blocks of size 4 and 6 (selected randomly) with the following strata:
Histopathology (non-squamous vs squamous cell carcinoma)
Planned surgical technique (open versus minimal invasive/robotic or hybrid)
Proton center and sites assigned to this center (which will deliver the nCXT)
Primary Outcome Measures :
Pulmonary complications [ Time Frame: from randomization until 90 days after surgery ]
Incidence of pulmonary complications during and following nCPT or nCXT and surgery
Sweden rectal cancer - 254 patients
Detailed Description:
The aim of this study is to investigate whether proton beam radiotherapy in locally advanced rectal cancer can offer meaningful reductions in acute gastrointestinal toxicity compared to standard treatment with photons which may improve patient's tolerability of neoadjuvant chemotherapy.
There are currently no published clinical reports evaluating the use of proton therapy in the upfront treatment of locally advanced rectal cancer. There are further no published randomized trials comparing radiotherapy with photon vs proton in locally advanced rectal cancer.
This is a prospective randomized trial, initially run at the limited number of centres but later expanded to other centres participating in the Skandion network. Patients will be treated with short course 5 x 5 Gy radiation scheme with either photons (standard arm) or protons (Skandion clinic) followed by four to six cycles of combination chemotherapy (capecitabine and oxaliplatin) and surgery. The rectal tumour will be removed by TME/PME surgery or more extensive surgery if required because of tumour extent.
All patients will receive at least 4 courses of CAPOX (Capecitabine b.i.d.1000 mg/m2 day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day 1 every 3 weeks) week 3-14, followed by surgery at week 17-20.
Primary Outcome Measures :
Incidence of acute grade 2-5 gastrointestinal toxicity [ Time Frame: From start of radiotherapy to planned start of the third (3) CAPOX cycle (week 9-10 of the trial) ]
The incidence of acute preoperative grade 2-5 gastrointestinal toxicity according to CTCAE v5.0 associated with proton vs. photon radiotherapy
Prostate, Denmark - 400 pts
ABSTRACT The Danish Prostate Cancer Group is launching the randomized trial, PROstate PROTON Trial 1 (NCT05350475), that compares photons and protons to the prostate and pelvic lymph nodes in treatment of high-risk prostate cancer. The aim of the work described in this paper was, in preparation of this trial, to establish a strategy for conventionally fractionated proton therapy of prostate and elective pelvic lymph nodes that is feasible and robust. Proton treatments are image-guided based on gold fiducial markers and on-board imaging systems in line with current practice. Our established proton beam configuration consists of four coplanar fields; two posterior oblique fields and two lateral oblique fields, chosen to minimize range uncertainties associated with penetrating a varying amount of material from both treatment couch and patient body. Proton plans are robustly optimized to ensure target coverage while keeping normal tissue doses as low as is reasonably achievable throughout the course of treatment. Specific focus is on dose to the bowel as a reduction in gastrointestinal toxicity is the primary endpoint of the trial. Strategies have been established using previously treated patients and will be further investigated and evaluated through the ongoing pilot phase of the trial.
Primary Outcome Measures :
Late gastrointestinal (GI) toxicity at year 2 compared to baseline using Expanded Prostate Cancer Index Composite-26 (EPIC-26) [ Time Frame: 2 years ]
Patient Reported Outcome The investigators aim at reducing gastro-intestinal toxicity grad 2 more than 5 points, which is considered clinically significant, measured by mean points, which is considered clinically significant.
Prostate Heidelberg - 897 patients
Methods/ design:
The PAROS trial is a prospective, multicenter and randomized phase III trial for men with localized prostate carcinoma after surgery. Post-prostatectomy patients will be randomized to either normofractionated radiotherapy (nRT) with photons (70.0/ 2.0 Gy), or hypofractionated radiotherapy (hRT) with photons (57.0/ 3.0 Gy) or hRT with protons (57.0/ 3.0 Gy relative biological effectiveness [RBE]). Block randomization is stratified by Gleason Score (≤ 7 vs. > 7) and treatment indication (adjuvant vs. salvage). The trial is planned to enroll 897 patients. The primary objective is to show an improvement in the bowel-score according to EORTC QLQ-PR25 after proton therapy compared to photon irradiation (week 12 vs. baseline). Secondary aims are non-inferiority of hRT compared to nRT with regard to biochemical progression-free survival (bPFS), overall survival (OS), quality of life and toxicity.
Primary Objective:
The primary objective is to show an improvement in the bowel-score according to EORTC QLQ-PR25 after proton therapy compared to photon irradiation (week 12 vs. baseline).
ETOILE A randomized controlled phase III study comparing hadrontherapy with carbon ions versus conventional radiotherapy – including photon and proton therapy – for the treatment of radioresistant tumors: the ETOILE trial
Sarcoma France C+ centers 250 patients
Methods:
The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas.
In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France.
The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted.
To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study.
MY SUMMARY:
There they are - 11 prospective trials!! I think, even if you just quickly look over them, they demonstrate detail and insight into the direction the field is headed. To me, they are run with strong and relevant primary objectives. And many come with much longer lists of secondary objectives looking at a range of related questions for our field.
So if you are “betting the under” on proton therapy showing benefit or today sitting on the sideline hoping the center down the block just dries up, just realize the odds aren’t in your favor. Protons are coming - with data. And data that in places will likely far exceed anything supporting IMRT and perhaps many SBRT indications on strength. I agree with broad IMRT usage and love our advances in SBRT. I agree with their use today, but if and when data comes out of some of these trials, I believe this data will force some difficult discussions - if they are proven beneficial.
I’m honestly surprised that as of 2023, there is so little data. That said, I made assumptions back in the days prior to leaving Arkansas and I’ve learned a ton in the last half decade. I still think I was correct then and correct now when saying, I believe protons represent a better path for some patients, but it is nice to see great scientist doing the important work of helping to clearly demonstrate the value of this technology.
“We always overestimate the change that will occur in the next two years and underestimate the change that will occur in the next ten.” Bill Gates
For me, two years has shifted to beyond four years, but there is still hope for the 10 year mark.
Looking ahead, I believe there will be some areas where they are proven superior (not all but many) and unlike Europe where they are focusing on normal tissue probability models to help access and patient prioritization, here in the US, we’re very likely going to need to need a massive restructuring of the walls that administrators of large hospital institutions have built around their business models. To me, you are more likely to win a parlay bet on these 11 trials than the under. This Substack is out here now so that you can follow along in this journey as we wait for the data. If it lands where I believe some will, it should be an interesting ride.
Next week, a bit of radiation oncology history and a look at why this data is critical to the success or failure of the proton industry.
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Fantastic summary! Thanks for putting this together.