Protons 101: What could/should a proton look like? Intro to the PRODOSC Trial
From an ideal perspective, what should the proton industry be looking to validate?
An introduction to a new concept trial:
PRODOSC Trial Structure
On this Substack, we have begun to look a little deeper at the data for proton therapy and the upcoming Oropharyngeal Randomized trial (ref 1) that is now closed to accrual. We have looked back, briefly at this point, at the relative lack of randomized prospective data that demonstrate value for protons in the treatment of cancer. We’ve looked at how MRI Linac has moved the bar using technology and how that industry is taking aggressive steps to define a clear use case using straightforward prospective trials. While there are important prospective trials on the horizon in proton therapy, to me, they remain quite limited in scope to single treatment sites.
So what might a radical proton trial design look like?
Back in 2019, there was a very nice publication that, at least in a retrospective fashion, demonstrated the “promise of protons”.
“The Promise of Protons” - Mark Storey MD
I first used this phrase a few years ago but I think it still works. It summarizes my vision and approach to evaluating data in the proton space. To me, and I fully believe that they are better for some cases, the “promise of protons” is not to use in them in very selected cases - not to cherry pick odd ball cases where there will never be randomized data. To me, the “promise of protons” is in the Bragg peak and in the dosimetry slides. Protons provide less dose to normal tissues and therefore must end with less toxicity across a broad spectrum of disease sites. It is the center of the marketing campaigns for these facilities. That is the bar that has been self-set by this industry and one that needs to be cleared.
The Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer. (ref 2)
This study (referenced below as Proton Concurrent Study) showed a dramatic reduction in Gr3 toxicity in a comparatively older and sicker group of patients when treated with protons rather than IMRT in the setting of concurrent chemotherapy for locally advanced cancers. Of course being a non-randomized retrospective trial, it is filled with confounders that may invalidate the entire conclusion, but to me, this is the type of trial that the proton industry should have been running since the evolution of pencil beam, lets say circa 2017-2018 once that technology had some install base. (ref 3 - timeline of US installs)
So the PRODOSC trial structure was my year 2020 attempt to re-create this retrospective study in a randomized prospective structure along with prospectively studied dosimetry metrics to help prove value for the proton industry. Realistically, my point was to create enough documentation to demonstrate that it is feasible and then outline, in some detail, the type of structure required. I started development towards the end of my first year in OKC. Then covid hit and I got knocked off the path. 2023 landed and brought a renewed focus.
This post begins to move that work here to my Substack.
Looking back, now with 3 years of hindsight, I still think this would be a great step forward for the industry and it is something the industry now needs to prove. Because, today, when posts like this appear on Twitter from educated trained radiation oncologists, there needs to be a better answer.
The proton industry now has capital investments well over several billion dollars and the appropriate window for clinical validation of their rationale is closing (many would say is long past due).
As of today, here are ASTRO Group 1 indications (ref 4) and looking at the list, I’d argue the tweet is pretty accurate.
On the basis of the above medical necessity requirements and published clinical data, disease sites that frequently support the use of PBT include the following:
•Ocular tumors, including intraocular melanomas
• Tumors that approach or are located at the base of skull, including but not limited to:
• Chordoma
• Chondrosarcomas
• Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated.
• Hepatocellular cancer
• Primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors when at least one of the four criteria noted above apply
• Patients with genetic syndromes making total volume of radiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients
• Malignant and benign primary CNS tumors
• Advanced (eg, T4) and/or unresectable head and neck cancers
• Cancers of the paranasal sinuses and other accessory sinuses
• Non-metastatic retroperitoneal sarcomas
• Re-irradiation cases (where cumulative critical structure dose would exceed tolerance dose)
Below is group 2 with qualifying language which represent most volume treated.
Today, we have both good and (to me) bad examples of proton therapy trials.
On the plus side are trials like:
US OPC Trial (ref 1)
TORPEdO: A phase III trial IMPT in HN cancer (ref 5)
DAHANCA 35: Proton Versus Photon Therapy for Head-neck Cancer (ref 6)
NHS Breast cancer trial - in those whom see heart dose reduction only (ref 7)
US RADCOMP Trial (ref 8)
On the downside are:
US OPC trial is a non-inferiority trial
US COMPARRE Trial (ref 9)
Note: I do not want to come across as dismissive of the massive work required to move these later trials forward. Hundreds, if not thousands, of hours went into the trials. But from my perspective too often in the US, too many stakeholders gain input and dilute the scientific question and these trials ultimately have significant issues in my assessment. (I have touched on this before with the NRG placing requirements on the US OPC trial, ref 1, but a longer discussion is needed in the future).
PRODOSC Trial:
“PRO”ton “DOS”imetry “C”omparison Trial.
Fundamentally, what does concept trial design propose to do?
From the design document:
Beyond the primary objectives, I have tried to outline a path in the trial documentation to measure and determine if and which know OAR reference metrics relate to any potential benefit. Comparative dosimetry data would be gathered prospectively via dual planning approaches. The trial documents include a proposed mechanism to evolve the dosimetry metrics as the randomization process occurs and assure some reasonable dosimetry variability in both both arms.
To me, this is more consistent with the promise of protons - a broad trial enrollment with simple validated primary objectives and secondary outcomes. It also attempts to provide a mechanism by which known dosimetry OAR differences can be evaluated within a prospective dataset.
Here is an early version graphic of this concept before more work and eventually simplifying the enrollment criteria to not require a comparative plan prior to discussion and patient consent:
In closing:
For protons to be successful a fulling their promise of improved outcomes, we should consider new trial structures beyond the scope of historical site by site approaches. There will NEVER be a large scale randomized trial in pediatric patients. Either we will find broad based indications for the technology via new trial approaches or we will continue to pick away at smaller and more focused sites. Head and neck cancer is the strongest opportunity BY FAR. The RADCOMP trial holds promise for a segment of breast cases and esophagus cancer with PBS likely would show much more improvement over the published passive scanning trial but a repeat of that trial is unlikely. And beyond those sites, progress will be slow if broader approaches are not pursued.
The retrospective study in high risk concurrent chemotherapy patients represents clear opportunity for the industry. It showed large scale toxicity reductions which, on my power calculations, appear to require no more than 312 patients to validate. But I want to be clear that even in this segment of concurrent chemotherapy cases, hypofractionation and SBRT will soon shut the door on the opportunity to demonstrate clear benefit over IMRT if action is not pursued quickly.
The “promise of protons” is to use technology to dramatically impact radiation oncology. The infrastructure with PBS is now in place. There are few excuses left. The industry should choose rationale targets, consider new methodologies and swing for a truly “big win.”
PRODOSC Documentation Trial Links:
PRODOSC Trial Design Document: 6 page overview document.
TIMELINE: A one page overview of the required data points and forms required.
ENROLLMENT: The one page enrollment form.
MED STAFF DOCUMENTATION: 2 forms, both single pages - one is completed at each follow-up event and one records ANC count for lymphopenia.
CHARLSON INDEX: Validated metric for relatively short-term mortality used to help ensure reasonable balance between arms.
PRO TOXICITY FORM: CTCAE toxicity forms for patients. This will include the shown form (which is adapted directly from CTCAE) and will include the validated EQ-5D-3L (not shown - copyrighted) assessment.
OVERVIEW OF DOSIMETRY METRICS: An 9 page document describing the rationale and data behind the metrics currently chosen for the trial.
EVOLVING METRIC PROCESS: Current proposed process which will adjust dosimetry metrics actively during the trial.
REFRENCES:
OPC Trial The Journey from Concept to Activation:
https://www.sciencedirect.com/science/article/pii/S1053429617301170?via%3DihubRetrospective Comparative Trial in Concurrent Chemoradiation Patients
https://jamanetwork.com/journals/jamaoncology/fullarticle/2757520Wikipedia - nice table on US install history
https://en.wikipedia.org/wiki/Proton_therapyASTRO Proton Therapy Model Policy
https://www.astro.org/uploadedFiles/_MAIN_SITE/Daily_Practice/Reimbursement/Model_Policies/Content_Pieces/ASTROPBTModelPolicy.pdfTORPEdO: Phase III UK Oropharyngeal Trial
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9702982/DAHANCA 35: Two parallel HN Trials from the Danish Group:
https://clinicaltrials.gov/ct2/show/NCT04607694
NHS Breast trial for patients at high risk of cardiac disease.https://www.theguardian.com/society/2023/jan/03/breast-cancer-patients-get-proton-beam-therapy-on-nhs-in-world-first-trial
US “Pragmatic” RADCOMP Breast cancer trial for all patients
https://clinicaltrials.gov/ct2/show/NCT02603341Prostate Cancer COMPPARE Trial:
https://clinicaltrials.gov/ct2/show/NCT03561220
www.protons101.com, home of the original Protons 101 website.
Content for the Protons101 blog written by Mark Storey MD.
Updated 2/7/2023 as RADCOMP should have been included in the closing.