Protons 101: Prostate Cancer: Summary of Current Data

LAST UPDATED: August 2019 to reflect the new August 3rd Lancet randomized prostate cancer trial.

Summary of Current Prostate Cancer Outcome Data for Patients Treated with Radiation:

Below is a table summarizing recent trials that have been published on prostate cancer. This table simply attempts to summarize current data comparing external beam radiation (both 3D which is older and IMRT which is new since around 2000) to Proton Therapy. It does not include brachytherapy or true SBRT cases.

IMRT is by far the most prevalent form of radiation treatment for prostate cancer and therefore, by default, has been considered the “gold standard” to compare other treatments to – and that is what this table does – it compares Proton Therapy trials to large current (and prior) external beam series.

In total, over 7000 patients are represented. Follow-up is not consistent – newer studies benefit from fewer years of follow-up. These are many of the largest / landmark trials – all published since 2013.

The below table compares current proton therapy published data to current IMRT published data Table includes: number of patients, ADT (percent of men on hormonal treatment), follow-up in months, percentage of patients who remain disease free at the time of the study for Low, Intermediate, High risk patients in the trial, and finally side effect rates for the GI/Rectum or GU/bladder. Grade 3 is generally a procedure required and grade 2 is generally a medicine or prescription was required. Grade 2 side effects are in parenthesis.
The above table compares current proton therapy published data to current IMRT published data

Table includes: number of patients, ADT (percent of men on hormonal treatment), follow-up in months, percentage of patients who remain disease free at the time of the study for Low, Intermediate, High risk patients in the trial, and finally side effect rates for the GI/Rectum or GU/bladder. Grade 3 is generally a procedure required and grade 2 is generally a medicine or prescription was required. Grade 2 side effects are in parenthesis.

Prostate Data Proton Compare
The above table compares current proton therapy published data to current IMRT published data
Table includes: number of patients, ADT (percent of men on hormonal treatment), follow-up in months, percentage of patients who remain disease free at the time of the study for Low, Intermediate, High risk patients in the trial, and finally side effect rates for the GI/Rectum or GU/bladder. Grade 3 is generally a procedure required and grade 2 is generally a medicine or prescription was required. Grade 2 side effects are in parenthesis.

My assessment of the data:

On my look, the photon data (the lower entries in the table) are not as good as the proton data when data is viewed at a very high level. Either you can find trials that have high control rates OR low side effects, but you don’t see both.

A few notes on a couple of series: First: the Spratt (2013) data. It shows excellent control rates and very limited toxicity for grade 3 and higher side effects. The odd part regarding that data is that those patients were treated to 86.4 Gy – much higher than is accepted today. So on some level, those patients must have had more and more trouble as years went by. Otherwise, the standard dose in today’s treatment of prostate cancer would be 85 Gy or higher. I struggle to find the rationale for the move away from that dose in the medical literature. Second: the other notably good result is he Jolnerovski data at 97.5% control for Low Risk disease. It should simply be noted, that trial is 41 patients in the low risk group. All were treated to 70Gy – 74Gy. Great results. Low risk prostate cancer does very well with radiation in general to doses at current levels. The bladder toxicity is still noted to be high for the entire cohort of 277 patients.

I THINK THE TABLE IS MOST INTERESTING FOR INTERMEDIATE RISK PATIENTS

If you look at the Intermediate Risk patients, the difference is even more pronounced on the disease free survival side than the difference seen in the low risk patients. For example every recent proton trial published for intermediate grade disease is in the 90%+ disease free survival rate whereas no trials for IMRT have achieved that number (and the two closest to meeting that mark have grade 2 toxicity over 20%). Today, intermediate risk prostate cancer is the largest group of patients that I see. Most doctors these days are doing a good job in active surveillance (watching) the earliest prostate cancers. Most men who present today to my clinic are in the intermediate risk category. We’ve shown (historically) that they need treatment and the goal then becomes the long-term cure of the disease. Control rates in the table above show APPROXIMATELY a failure rate at 2x the failure rate of proton therapy for patients treated with IMRT. That is what the table looks like. The current Widmark non-inferiority trial showed that the hypofractionated arm achieved a mathematical control rate of 78% or better. That is the simplified statement of the math of that non-inferiority trial.

Finally, a statement on high risk patients. To me, this group is the most difficult to assess. The numbers of patients are smaller, the staging and extent of the field size has more variance, the use of ADT and length enters into the equation. The proton data holds up very well and appears superior again. That said, there is good data with pelvic treatment and brachytherapy as an alternative approach so I don’t have as much clarity in this area.

IMRT is deemed to be the “gold standard” due to its prevalence, not because of randomized trial results or because it was first to use high doses.

The history of radiation oncology is that proton therapy has been treating prostate cancer patients to high doses of nearly 80 Gy for ~25 years through the experience at Loma Linda. This pattern – 7920 Gy equivalent in 44 treatments is the most consistent pattern of treatment and has a long and strong track record. On the other side of the radiation technique spectrum, brachytherapy likewise has been delivering very high dose directly to the prostate for 30 years. Many IMRT programs started around the year 2000 and most do treat to doses >75 Gy. It replaced 3D conformal radiation as the standard based simply upon improved radiation plan dosimetry. 78 Gy became the standard largely following release of the MD Anderson randomized trial comparing 70 Gy to 78 Gy showing that higher doses were far more effective at controlling disease (long term data published in 2008 – I helped publish the acute side effect data in 2000 – special thanks to Alan Pollack).

Note: NCCN says they are equivalent treatments. They offer 16 “equivalent” external radiation options currently.

I think that is important to say as well. We do well with treatment for prostate cancer. The above looks at the fractionated radiation data. Like I said, It doesn’t include surgery, brachytherapy, or the various stereotactic approaches that are coming into use. So it is a limited view, there are lots of good options and treatment technique comparisons are difficult. But protons deliver less dose to the patient, they are more targeted, and the data; at least from my view; appears to mirror those facts. I don’t believe there are near as many “equivalent” options, but that is a discussion for a different post.

There is a randomized study available comparing IMRT to Proton Therapy.

We’re trying to obtain an answer in a methodical way. Ideally, you don’t use table to compare outcomes, you use studies. There is a large ongoing trial in place. I think over the next 5 – 7 years, it will give more information about what are our better options. It will be slow to accrue but if you are interested in helping to move science forward, it is one I encourage you to ask about.

Prostate Data Ref

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Dr. Mark Storey MD
Medical Director, Oklahoma Proton Center