Protons 101: A path to greater impact - refocus on cancer outcomes and embrace technology.
To me, we're off the path, have at times confused important issues, and are losing ground in today's market.
This is an opinion piece in part prompted by the recent New England Journal breast publication. This editorial is focused on the paper, but at our field. This one has taken me far longer to write than most. It has been difficult to piece together. These are not simple issues. The US medical system is complex and needs refinement far beyond our field. But the paper, I think illustrates the need for discussion.
We will quickly look at the trial.
1300+ women, primary endpoint of the trial was local breast cancer recurrence (ref 1). In this low risk group of women (65 or older, hormone receptor positive, tumors less than 3cm, with clear margins and YEARS of adjuvant endocrine therapy), if you omitted radiation local recurrence risk increased 10x.
0.9% with radiation to 9.5% with radiation - at 10 years.
It did not affect overall survival. The discussion is largely the rationale for the exclusion of RT. Here are the conclusions.
Article Conclusions:
Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor–positive early breast cancer.
My Take:
A difference of 10% is not insignificant. Personally, with Gr3 or higher toxicity rates being often a few percent, I think this trial actually argues quite strongly for the inclusion of radiation in this segment of women, especially in the younger segment of women eligible. That said, it will be read by many as a successful de-escalation trial showing that radiation can safely be avoided. Look around online at different specialty opinions and I think the final assessment in this direction is quite clear.
Addendum: as if we needed proof, here is the WSJ headline, so yep negative slant.
The article is a de-escalation trial. In this trial, we de-escalate to exclude radiation altogether. Its a cost, toxicity, “good enough” argument. The central point of this editorial to try to describe how, at least in the US, our specialty has moved too far in this direction in our own trials, and in our own critiques of our own field. And what I believe this trial demonstrates is that this self-questioning of our own value is creeping more broadly across medicine.
(Note: Different markets require different calculus. The US has massive healthcare spending without broadly limited resources and our drug spending is excessive compared to the remainder of the world. These items might dramatically affect many of the points relating to business and economics.)
Our goals are noble.
I want to say clearly up front that my intent is not say that there is one clear answer. It is clearly wrong to use too many fractions just for personal financial gain. Using much more expensive equipment with no rationale for benefits places additional costs on the system. I understand and appreciate both of these arguments. I think a better analogy for this editorial would be that the pendulum has swung far too far in the direction of cost concern and too far from ideal cancer outcomes. This NEJM paper should serve as a wake up call. The argument I present below is for balance.
The idea and concept of reducing treatment to the very bare minimum number of visits is idealistic. I do agree with the vision that one day, a few radiation treatments will substitute for many surgeries. But we need to consider the path from here to there. And while there is inconvenience with additional appointments, and travel, and time from work, and parking, etc and those ARE real issues. In the context of cancer recurrence or greater treatment toxicity? I’m less convinced.
And let’s be clear, while we take the noble path, other specialties that, in my view, provide far less value / benefit swoop into acquire the funds we don’t fight for. That is reality. My concerns for our specialty revolve around two central issues in our field - fractionation and technology.
SBRT is the greatest new approach in our field of the last 30 yrs.
SBRT cures more patients. Yet, from my perspective, we seem confused at times. and discuss the benefits of SBRT as shorter treatments. Yes it does that, but SBRT is great because it improves outcomes. The fact that it reduces fractions is merely a side benefit - like a good side hustle in life, but the primary job is to get rid of the cancer and minimize harm.
Yet we seem to run and promote trials evaluating the following type of question: If the outcomes are about the same - you know statistically powered trials to access the newer shorter treatment is within say 5 or10% of the prior standard treatment outcomes - then that is good enough. The benefit has shifted from a tumor outcome (better control / less toxicity) to a vague “cost” decision or more simply a number of fractions comparison.
SBRT does far more. For lung cancer the cure rate went dramatically up. If we keep that as the principle, we’ll be ok. Shorter has to be better, or at least trending in that direction. Trending worse, but just not statistically inferior, should be almost entirely eliminated from our efforts. And maybe we haven’t gone quite there, but in places we have lost a consistent push for better tumor outcomes with less toxicity and opted to achieve “better” only via shorter / cheaper.
And we haven’t just had wins in SBRT. We see this type of win with whole breast hypofractionation. We moved from 5-5.5 weeks to 3 weeks and toxicity decreased and tumor control did not budge. In fact, tumor control was pretty consistently as good or slightly higher. That is the goal. It is clearly better. I see the same with hypofractionation in prostate cancer. I think PSA kinetics are, if anything, lower quicker. That is the direction we must head. Shorter with an improvement - not shorter and likely about the same - and those ARE different.
Ironically, radiation oncology is, generally speaking, the single highest rated specialty by patient satisfaction surveys. We have a great advantage of knowing our patients and seeing them regularly. We have time to discuss treatments and answer questions. We are often a sanctuary of calm in the craziness of cancer treatment. And yet we will argue profusely that 10 or 5 or 2 extra visits to our clinics are a huge QoL issue. Medical oncology clinics can schedule patients weekly or even twice weekly for months or years on end but we are concerned about 1 vs 2 or 5 vs 15 trips. We are our worst enemy at times.
To me it seems, we have confused the objective. Just because it is shorter, does not mean it is better. It should simply be better.
We are a technology based field.
We need high capital equipment to treat patients. Some like this fact, some do not. In addition to our perceived “hatred” of an extra radiation treatment fraction, we have adopted some idealistic concept that technology has costs and then, almost by definition, it is often bad and wasteful.
Radiation is a drop in the cost bucket and the reduction of 1 or 5 fractions from a course of treatment or the lack of new capital investment in our field is a distant rounding digit. For perspective, let’s look at the largest revenue drug in the US. Humira is a +21B dollar per year revenue drug in 2021 in the US. IF they were to run non-inferiority trials to reduce dosing from say 100% today to 90% with a 5%-10% non-inferiority limit using PRO surveys, I bet you could easily reduce to 90% or 80% dosing with very little clinical effect. Each 10% reduction in that SINGLE drug use represents approximately the entire CMS spend on radiation oncology for all sites and all indications per year (~2.4B). Our efforts to reduce fractions or decrease the capital expense of new machines amount to the revenue spent by large pharmaceutical companies on quarterly advertising campaigns for their drugs.
Meanwhile online we have radiation oncologists in leadership for our field referring to new machines that help us put more radiation in the tumor and less outside the tumor as no better than “make believe video games” because “phase III data doesn’t exist” (my wording paraphrasing from multiple posts). I get the ideal and noble path and the importance of proving value, but meanwhile look at the phase III data for IMRT in my prior post and look in the mirror at all the setup, immobilization devices, surface tracking etc that we all believe work yet little has proven phase III benefit. We are not as consistent as we, at times, claim to be.
Two examples of this perspective - MRI Linac and Protons.
The MIRAGE trial is not consistently touted as due to the capital investment in a ~7M (minimum) machine. The lead PI thinks it is the machine. But beyond the lead physician, our specialty can be seen arguing that it is as simple as a margin reduction trial and not a technology trial. Almost as if millions of dollars of capital investment into a clinic doesn’t help us achieve better results. And on the national level, ViewRay spends over 30M in research and development to better our field and improve our clinical outcomes. But nope, it is just margins or if they did it “this way” with the old machine vs. that new expensive MRI tech it would only be like $5 extra. I disagree.
And then protons. The PBT esophageal data is as strong of data as anything supporting IMRT over 3D (arguably stronger - the primary endpoint was clearly in favor of PBT and the post-operative complication rate was 7.6x for significant toxicities - like stroke and MI if treated with IMRT). Yet many seem to reference it as if it was negative. Clearly costs are different, the upfront capital and treatment cost are both greater with protons. From RO-APM development, Upper GI CMS cancer payments per episode were $32,419 for PBT vs. $17,433 for IMRT so there is a ~15k difference. But within our own field, rather than embracing the data, we point to cost and then question the validity of the pre-announced and pre-published primary endpoint. Again, it can’t be capital investment demonstrating improvements in outcomes.
In every aspect of our economy, capital investment moves us forward. Starbucks - a coffee shop - builds its company around technology to promote efficiency and “improve outcomes”. Yet, we are often the loudest critics questioning the value of capital investment in our own field. Often discounting results of this capital, even when good data says otherwise.
Meanwhile down the hall a drug is given. Its based on a study in the same weekly NEJM (ref 2). It is a new cancer drug study providing a benefit of “improvement in the radiographic PFS” of 5 months and it costs, lets say 100k per year. And medicine will rarely pause as it is prescribed and advertised year after year based on a clearly different standard.
Please remember the pendulum. This is not a right / wrong issue and clearly I strongly favor technology. This is a question of balance and my argument is that we have swung too far and are too divisive within our specialty and it is causing harm to the goals of our specialty.
We use high front end capital intensive technology and that has been the foundation of our specialty for over 50 yrs. SBRT would not be possible without technology improving the setup, planning, and accuracy of our treatments. The equipment IS very expensive on a front end evaluation but it delivers amazing value during its use period. We require technology and our technology must be constantly upgraded to attempt to counter the pharmaceutical spend that is likely 100x or more our fields annual capital outlay in the US.
In the US, our current path makes it more and more likely that INFERIOR pharmaceutical solutions beat a SUPERIOR radiation answer. If you don’t believe that vast financial spending differences can sway the balance point, you are simply wrong. Read the two articles in the NEJM back to back. We are already fighting with 1.5 hands behind our back due to the size of our field vs medical oncology spend. And our own field, at times, seems to wish to place a blindfold on our eyes because “that is the right thing to do”.
From the board room, the view is different.
I have a different perspective than most physicians. For the better part of a decade, I’ve been on boards. Boards of a pretty large, 500M+ revenue entity and I’ve watched how the boards function. Most physicians don’t have that experience, but here is a very simplistic look into that reality.
The CEO is hired to grow the business. Revenue, profits, or patient visits, patients or something, but grow the business. The board is often largely non-medical - businessmen, attorneys, politicians, etc. They understand the finances. They do not have patient overall survival on a dashboard. Finances yes, patient survival no.
All board meetings focus in part on finances. Some have other points of emphasis but all include finances. The CEO keeps his or her job by growing the business. The growing branches of the entity are generally favored and the shrinking entities become lower and lower priorities, especially if they can’t be “fixed”.
As a physician, I really dislike the above reality, but it is reality. Less fractions shrinks our reach on the balance sheet and it is a 1 in 100 board that understands and appreciates and encourages further reductions for a perhaps greater endpoint of patient QoL issues. Far more likely it means the simple math for time to recover capital if we buy xxx machine is simply longer and other investments appear more valuable to the institution. And it is this equipment you depend upon to fight back against Moderna spending $421M in a single quarter of 2021 improving products funding trial after trial.
And today we will have less impact on breast cancer
As radiation oncologists, a significant percentage of the patients in this trial will never have discussions with our specialty as of this week. The surgeon or medical oncologist or the patients themselves will read online and someone in the chain of referral will make the call to avoid treatment and the patient will never be seen by a radiation oncologist. Again, I have no financial cares on this issue - as close to zero as any physician you see have an opinion. I work at this point in my career because I want to, and I do not see this as a step forward. In general, I tend to recommend less treatment than most physicians and I’m disinclined to agree with this tradeoff for most women if the risk of recurrence increases by 9 in 100 women (a 10x avoidable increase with a well tolerated treatment). It might be in a prestigious journal, but I don’t believe it is good cancer treatment for many women now included between 65 and 70.
We need to square the up the goalposts.
First off, let me say what most have not said for the past decade or more.
If more fractions improve the cure rate and / or decrease toxicity, then yes - that should be the standard. It is fine to develop other alternative approaches with “compromises” (my term) offering perhaps slight decrements in control or slightly higher risk of toxicity but are performed in shorter approaches, but the standard achieves THE BEST control / toxicity profile. The other options of shorter with caveats should be left to individual discussions between the doctor and patient.
Back in the day, perhaps we needed a good push to limit fraction number. I don’t want to look backward, but rather, forward. And today, SBRT and hypofractionation have a very large foothold. These concepts are here today and will be here tomorrow. But trials like this current breast study paired with struggles in recruitment to our field are real warning signs that we are off the correct path for our specialty.
Again back to the article for example. I like partial breast. I like short treatments, but let’s be clear. APBI, in most trials, results in slightly higher recurrence rates (say 20% more relative risk of recurrence) and some trials demonstrate an increase in toxicity compared to whole breast. The data is NOT clearly one sided. A main touted benefit is that it is shorter. Ok I guess but that is our field arguing that APBI is “good enough” on tumor recurrence while toxicity results have been far less consistent. And that is the perceived “better” approach.
I’m not sure I agree. Perhaps we have figured out how to offset the toxicity risk of APBI by eliminating the bid approach and using IMRT - I *think* that is likely the case - I’ll feel more confident in about 5 yrs. Today, I hope the smaller trials that are 1/4th the size of the larger RAPID trial are, in fact, both reproducible outcomes.
But today we often argue strongly for even small drops in fractions with “costs” and “convenience” as the battle cry. I have seen nearly ZERO people on Twitter from the radiation oncology specialty argue for whole breast following the release of this paper. 100% of the arguments against this trial BEGIN with the premise of 5 fractions. That in and of itself discounts our value. I would not make this argument if it were near a 50/50 whole breast / APBI discussion, but it isn’t.
It is as if, 15 trips for 15 minute treatments isn’t worth 9 extra cancer recurrences - but 5! YES!! By pretty direct inference, it is those 10 extra trips that represent the difference between good value medicine and chasing profits (perhaps hyperbole, not by much).
Take for example, a physician who participated in the RAPID APBI trial and now opts for whole breast treatment due specifically to late cosmetic concerns. And add a boost because they know the surgeon is low volume? Gasp!! We are now at 20 or even… 21 fractions. They could certainly be seen as out of touch with leadership and maybe their integrity questioned for the use of sooo many treatments. That is not the correct path for our specialty, and yet it what we often project on public forums.
And this is a pervasive mantra throughout our field. There are a few trials where 1 fraction clearly appears worse than 2. Yet we persist to push for 1. We’ve begun to backtrack in lung using 10 fractions for central lesions because shorter was simply too risky and too toxic - in simple terms, we overshot trying to eliminate fractions. I could go on and on. Today we’re often on the razor edge of being too aggressive with fraction reduction. And yet we keep pushing for shorter somehow integrating number of treatments into the calculus of better, rather than prioritizing the BEST cancer control and the LEAST toxicity.
For example, is anyone looking at 10 fraction “SBRT like” treatment for high risk prostate cancer where we seem to be thinking that we need to push doses up 25% or so from say 40 to 50 Gy as we try to improve control rates? Hopefully we are, but I haven’t seen it. But I have seen going from 5 to 2. And while that may work, the other approach which almost certainly IS safer using more fractions to increase dose (say towards 70 in 10 fractions or something) we self eliminate. We are literally choosing fractions over prioritizing outcomes in ways. At times subtle. At times less so. And when we do this to ourselves, other specialties take note. We should focus on improving cancer outcomes and do it to the best of our ability.
Number of fractions is not a cancer endpoint.
I don’t believe we should have EVER accepted that simply reducing fractions with no change in outcomes was good enough. (yep, I’d eliminate this non-inferiority as a path to reduce fractions as standard of care - I’m too old perhaps). If you wish to create an alternate for special cases with caveats (say travel or true financial hardship or access to treatment in a timely fashion) fine, but clearly note that in the guidelines that it has compromises and has potential risks above the standard approach.
I laugh at prostate cancer fractionation / dosing. Per NCCN, you can pretty much do any fractionation to any dose you want for prostate cancer. In a very real way, we advertise “good enough” everywhere. Do we really believe all of those end in the same local control of tumor? or is it we don’t think it matters that much? Worst yet, perhaps we don’t know which is better to control the local cancer. Maybe we should figure that out more precisely and then present the best option.
To me, NOTHING we do today is good enough. We have to push for better. In every situation, we can refine and push and find some way to improve outcomes and / or reduce toxicity. And along with that improvement hopefully reduce fractions.
Our field is NOT so perfectly perfected that there is no room for improvement except for lessening fractions.
I will never believe that rationale. That line of thinking, in and of itself, does our field a great disservice. And let me be clear, if we aren’t offering “better” in a current disease site relative to surgery or drugs, we should have no role. But no other specialty sees clinic visits as a cancer outcome endpoint. They see the visits as opportunities to educate and inform and provide teaching and to grow their impact on patient care and we should embrace the great clinical relationships that have served our patients so well over the decades.
Sooner or later our self deprecating arguments will come home to roost. I think you see this in the New England journal article. And the reality is, you can debate in tumor boards or on Twitter all you want, but the New England Journal’s reach will have won in the majority of instances for the majority of patients. And today, we have less impact.
I know that has not been our intent, but we must find a balance point understanding the ramifications of the direction of our specialty for the markets in which we practice. And to me, over time, the seesaw has tipped from one direction to the opposite and we should reassess our attempts and keep the pendulum towards center for the betterment of our field.
I love our field. I believe we provide TREMENDOUS value. I’d encourage us to focus more on achieving the highest cure rate of the cancer and absolutely minimizing toxicity. That is the result that the vast majority of patients seek. I’m also hoping we get back to consistently embracing technology. We need large capital investments in our clinics to achieve the very best results and we must recognize that capital expenditure is a foundational pillar of our specialty.
We must compete in the market as a specialty to impact patient care more broadly. We have to aggressively represent our field for the wonderful work we do in promoting science and data driven improvements. We should utilize technology to expand and promote our advantages in cancer treatment. And we must be vocal supporting our field as we push to achieve the BEST cancer outcomes while arguing for the outstanding VALUE we represent. To me, that is the path forward.
REFRENCES:
Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer
DOI: 10.1056/NEJMoa2207586Rucaparib or Physician’s Choice in Metastatic Prostate Cancer
DOI: 10.1056/NEJMoa2214676