Protons 101: Head and Neck Proton Trial Landscape: Europe to the rescue!!
There are some great radiation oncology trials for proton therapy coming out of Europe - today we'll look at two head and neck trials on the horizon that pair well with the US OPC data.
US and Europe: Very Different Medical Trial Markets
It seems that the US prospective trial structure has somewhat broken down. Look at the IMRT vs. 3D data review I did earlier here.
Less than one handful from the US. Yee Haw!! (sarcasm) Not one in head and neck cancer (ref 1). A ridiculously poor showing for a country with our wealth, our resources, and our ability to post on social sites about science. For a number of reasons, the US medical system is struggling to enroll in many areas where we need good clinical data.
Meanwhile, in recent years, Europe has been quite successful. Today, Europe is active enrolling many trials looking at whether protons outperform IMRT and can reduce toxicity. Per ESTRO, as of 2022, there are 19 phase II trials and 9 randomized prospective phase III trials actively enrolling patients (ref 2). Well done!!
The proton industry needs this help and this level of research to evaluate when and where and how protons might help us improve cancer treatments. Europe also does a far better job in sharing high capital expense equipment across their healthcare systems whereas we tend to strongly silo patients in the “best available option within our own system” approaches.
We do actually have a strong, well designed, US OPC trial (ref 3). It has completed accrual with I believe 442 patients randomized. But it isn’t perfect. IRB boards altered the structure and ultimately, it became a non-inferiority trial which will weaken the strength of the trial, if in fact, protons cause less toxicity.
But no fear. Look to Europe.
Two main European HN trials will address the question of proton therapy:
Above are examples of a Protons plan (left), IMRT (middle), and a 3rd (right) set of imaging showing the dose difference between the two approaches (literally subtracting the Proton plan from the IMRT plan). In a nutshell, this is the rational for running the trials. Protons give far less radiation but does that equate to less toxicity. Due to the cost, complexity, and some real physics / radiobiology concerns, this needs to be proven and not assumed to make a difference in outcomes.
Today we’ll just briefly review two head and neck trials enrolling patients.
TORPEdO Trial:
The trial is being conducted in the UK looking at proton therapy for oropharyngeal squamous cell carcinoma (ref 4).
Number of participants:
Planned sample size of 183 participants (122 IMPT: 61 IMRT).
Timeline:
TORPEdO recruited its first patient on 25th February 2020. There was a three-month hiatus to recruitment from March to May 2020 due to the first wave of the COVID-19 pandemic. As of 5th October 2022, the trial is open in 16 centres and is expected to complete recruitment by October 2023.
Endpoints:
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;
gastrostomy dependence or Common Terminology Criteria for Adverse Events (CTCAE) grade 3 wt loss (i.e. ≥ 20 % weight loss from baseline)
DAHANCA 35
Two trials out of the Danish Head and Neck Cancer Group. They are using either Gr2 or higher xerostomia or Gr4 or higher xerostomia risk to randomize patients according to normal tissue complication models (ref 5). Further details below.
Directly from the reference:
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).
(Note: 35D is the Gr2 dysphagia risk study and 35X is the Gr4 xerostomia risk study)
My Summary:
These two additional head and neck trials out of Europe are critical for the industry. Dr. Pierre Bianchard will perform a meta-analysis of the three trials: US OPC, TORPEdO, and DAHANCA 35.
To me, this will be BY FAR, the strongest current prospective dataset in head and neck cancer since the invention of IMRT.
This cumulative 3 prospective trial dataset will be the definitive radiation reference source for radiation oncology in head and neck cancer until at least 2030. 1200+ patients - ~730 total IMPT patients with ~490 IMRT patients - all treated in approximately the same time period. 3 regions of the world. THE HN reference dataset.
(If you doubt or think it is even close - please comment - medicine is a huge world and as always I could be missing something)
Radiation oncology will continue work around the edges at de-escalation, IO, smaller neck volumes, hypofractionation etc. In fact, I think non-proton / IMRT only hospitals (especially the larger ones) will fight like hell along these paths if the meta-analysis shows benefit for proton therapy to keep patients in “their silo”, but data wise, these three trials will be the gold standard for a number of years.
There is little doubt that the next few years will determine the trajectory of the proton therapy industry worldwide. Is it a routine clinical use machine? or something with FLASH and smaller, more limited indications? The central data piece, I believe, will come from these three head and neck cancer trials.
So if you look out on the horizon and don’t see many reasons that protons will be validated in the US market, look over the pond, the data are coming.
We always overestimate the change that will occur in the next two years and underestimate the change that will occur in the next ten. Don't let yourself be lulled into inaction.
Bill Gates
Note: More broadly the US does have several ongoing trials. The US trials on the horizon that hold major opportunity are the OPC trial referenced above, the RADCOMP breast trial, a national broad repeat of the MDACC esophageal trial with pencil beam proton therapy, a similar lung IMPT trial in ways repeating the negative lung trial with IMPT. (and then there are smaller CNS, hepatobiliary, and a large national prostate cancer trial which I covered earlier which I think holds less upside). It’s not that we aren’t trying, we just are going too slowly in my opinion.
REFERENCES:
Protons 101: A review of Prospective Randomized IMRT clinical data as of 2023. Self published link on Substack Storey MR
ESTRO ETPN 2022 Report
https://www.estro.org/ESTRO/media/ESTRO/Courses/2022/Course%20Images/EPTN-Report-2022.pdfComparing Intensity-Modulated Proton Therapy With Intensity-Modulated Photon Therapy for Oropharyngeal Cancer: The Journey From Clinical Trial Concept to Activation
https://doi.org/10.1016/j.semradonc.2017.12.002TORPEdO: A phase III trial of intensity-modulated proton therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9702982/DAHANCA 35: Proton Versus Photon Therapy for Head-neck Cancer (DAHANCA 35)
https://clinicaltrials.gov/ct2/show/NCT04607694