JCO commentary on RCTs for protons

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trublu

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Herein lies an important lesson that will save you all tons of time in your careers:

When basic principles lead you to be certain a new therapy is better than standard of care, it's unethical to test it in a randomized trial.

I'll alert the FDA.
 

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Wow, a tremendously interesting article thanks for posting that. I found it amusing that the authors did not disclose any conflict of interests at the end of the editorial. What about the fact that they both have $$$ proton machines at their institutions?!

Still, they do make some cogent points. The bottom line is that most technology advances in RadOnc (they mentioned Cobalt machines and then Linacs) were not subjected to rigorous scrutiny in RCTs. Dosimetry is not a clinical trial but at least we have some way of assessing dose distribution.

Of course the most common tactic to justify the cost of protons is simply to create a distraction. Medical oncologists and cardiologists are jacking Medicare dollars with their questionable interventions as well. On the whole, protons are just a drop in the bucket vs unecessary stents or systemtic therapies that increase survival by a couple of months but cost $25K.

I don't think anything will ever change, this is the way it will always be. The only thing we can hope for is that our field is small enough to remain under the radar. Given the vast number of proton machines coming on-line in the coming years with the strong possibility of much smaller devices to generate protons, I think it is safe to say that costs will go down.

The thing that surprises me that most about the editorial is the arrogance of it all. Of course, everyone knew what they were thinking but to come out and rail against RCTs in (ironically) one of the seminal oncology journals that publish RCTs is really beyond the pale.
 
there is, how shall i say, a little bit of controversy in the field over that commentary.
 
Gfunk6 said:
The thing that surprises me that most about the editorial is the arrogance of it all. Of course, everyone knew what they were thinking but to come out and rail against RCTs in (ironically) one of the seminal oncology journals that publish RCTs is really beyond the pale.
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I'm honestly kind of ashamed of the medical profession reading that. Every year we lose more autonomy and influence over what is covered and what isn't. And judging by that article, maybe that's a good thing.

According to Dr. Cox's reasoning, if we spend millions of dollars to prevent one case of grade 2 proctitis it is money well spent. Apparently every manner of cost/benefit analysis is unethical, because we should always be taking the thing with the higher benefit. What a realistic view (that happens to coincide with MDA's 100 million dollar financial investment).
 
Wow. I have the same reaction as everyone else.

I think the comment that if it was just as cheap as x-rays, no one would be arguing is pointless. It is way more expensive, so that's not really debatable.

The ALLHAT trial a few years ago for hypertension showed that generic HCTZ was just as effective for first line therapy for uncomplicated HTN as an ACE-I, ARB, CCB, or B-blocker. And, it is 1/2 to 1/50 of the cost. It basically brought back HCTZ, and saved Medicare (and patients) loads of money. So many people were convinced that the newer drugs were better.

The idea that something newer and theoretically better doesn't have to be tested is concerning. Especially a faculty member at the pre-eminent cancer center in the world saying that is the case.

-S
 
what really concerns me is the black and white nature of this entire debate--that protons are either the savior of the field, or the "dark side" of medicine. I was nearly kicked out of an interview (i exaggerate) because, when asked, I said that protons are a worthwhile investment for a select number of academic institutions. My rationale was that--despite the lack of evidence--development and use of protons is akin to that of an "orphan drug" for a rare condition. The trouble is that money is really polluting the whole issue. Those without protons, or the financial means to get them, are outspokenly against them. Those who have found a donor or interested investor seem to be eager to describe promising future of the technology. What is missing is the data--and it seems that money may stand in the way of that data being collected and published. I mean, if we cannot count on Harvard or MD Anderson to be objective about this technology, what have we come to?
 
IRISH22 said:
what really concerns me is the black and white nature of this entire debate ...
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I agree with this sentiment. The issue, even from a scientific (much less an economic and ethical) point of view, is not as cut and dried as the article makes it out to be. I was at the AAPM meeting last summer, and several physicists presented on the uncertainties associated with treating with protons. One memorable talk was entitled "What you see is not what you get", emphasizing that the superior treatment plans created with proton modeling might not actually represent the dose that is received by the patients. Significant (>1 cm) uncertainty may exist both due to the uncertainty in Bragg peak location, and the deformation of the dose cloud due to patient motion or internal organ motion. (As I side note, I spent one day in the Midwest Proton Therapy Institute in Bloomington, IN. They told me that they needed to replan a CNS case once because someone had a head cold and their sinuses filled up, which significantly changed proton attenuation through the frontal sinus). To summarize:
Advantage: Protons stop.
Disadvantage: We don't know where.

Will protons be better than linacs in RCT? I'm not sure. I would have clinical equipoise to enroll patients in a RCT, at least in something like prostate cancer. I would volunteer for such a trial if I had prostate cancer.

I heard Dr. Cox lecture last spring, and the majority of one talk was devoted to the need for randomized trials for proton therapy. I don't know why he changed his mind. Maybe the physics issues are not as big as was thought this summer. Even without a large RCT, we will at least get some data from comparing long-term outcomes after proton therapy with long term outcomes from x-rays done concurrently at other institutions. If huge benefits to protons are seen in these comparitive studies, that would be wonderful. If small benefits or no benefits are seen, questions about patients selection, etc, will still cloud the issue.
 
are there any RCT's showing that robotic prostatectomies improve cure & impotency rates or reduce morbidity as compared to an open/laparascopic radical prostatectomy?

(id say that 75% of the prostatecomies at my institution are robotic...)

are there any RCT's for any disease site showing that robotic surgeries are better than their traditional surgical counterparts?

(gyn, gynonc, neuro and even thoracic surgeons are now delving into robotic surgery at my institution)

how about intra-op MRI guidance for brain surgery?

and in our field....daily kv or weekly cbct imaging affecting outcomes? imrt for improving outcomes in the setting of breast conservation thereapy (and im not talking cosmesis...as an aside, is the cosmesis worth the extra 20k?)

many fields which introduces new technology do not have to prove (through an RCT) that the new, more expensive technology is better than the traditional, less expensive counterpart.
 
It seems to me that the advantage of protons lies in enabling us to do things we would not have otherwise been able to do with photons. For example, base of skull tumors (e.g. chordomas and chondrosarcomas) can be treated to higher doses than are possible with IMRT. Re-treatments of tumors near critical structures become more feasible. There is decreased dose-wash, which may be advantageous, especially in young patients. Depending on who you ask, IMRT may carry a significant risk for young patients due to the large volume of tissue receiving low-dose irradiation. These things would be difficult to test in a randomized fashion (esp. the effect of volume of tissue receiving irradiation, as the data would take ~15-20 years or more to collect).

In the interest of full disclosure, my residency program is loosely affiliated with the Midwest Proton Radiotherapy Institute. However, I am a resident, and thus have no financial interest.
 
Actually, most proton centers (and all in the U.S.) use passive modulation to create a proton field. That results in neutron scatter, and gives a larger integral dose to a patient than X-Ray IMRT.

Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. http://www.ncbi.nlm.nih.gov/pubmed/16618572

IndyXRT said:
It seems to me that the advantage of protons lies in enabling us to do things we would not have otherwise been able to do with photons. For example, base of skull tumors (e.g. chordomas and chondrosarcomas) can be treated to higher doses than are possible with IMRT. Re-treatments of tumors near critical structures become more feasible. There is decreased dose-wash, which may be advantageous, especially in young patients. Depending on who you ask, IMRT may carry a significant risk for young patients due to the large volume of tissue receiving low-dose irradiation. These things would be difficult to test in a randomized fashion (esp. the effect of volume of tissue receiving irradiation, as the data would take ~15-20 years or more to collect).

In the interest of full disclosure, my residency program is loosely affiliated with the Midwest Proton Radiotherapy Institute. However, I am a resident, and thus have no financial interest.
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one of our residents is doing a nice study on secondary cancers from protons. the integral dose issue is the key.
 
radonc said:
are there any RCT's showing that robotic prostatectomies improve cure & impotency rates or reduce morbidity as compared to an open/laparascopic radical prostatectomy?
QUOTE]

i am also at an institution where the majority of RPs are robotic assisted. it is well documented, atleast here, that the average hospital stay is cut in half and pts return to work 2 weeks sooner compared to the open procedure. it is a significant overall cost savings to the institution if the volume is high enough and the pt in terms of productivity if the recovery time is shortened. as compared to protons where you really need a RCT to prove decreased toxicity for all the reasons sighted above, this is an easily measurable cost benefit. not a valid comaparison by my estimation.
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qwert said:
Actually, most proton centers (and all in the U.S.) use passive modulation to create a proton field. That results in neutron scatter, and gives a larger integral dose to a patient than X-Ray IMRT.

Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. http://www.ncbi.nlm.nih.gov/pubmed/16618572
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There is some disagreement about the exact extent of secondary neutrons (as in the discussion about CT scans, Hall is at one end of the spectrum), but they do exist. That's why in the new gantry rooms MPRI is using a scanning proton beam rather than passive scatter (they tell me the neutron contamination is significantly reduced, although I have not laid eyes on the data myself).
 
Wm Tell said:
I agree with this sentiment. The issue, even from a scientific (much less an economic and ethical) point of view, is not as cut and dried as the article makes it out to be. I was at the AAPM meeting last summer, and several physicists presented on the uncertainties associated with treating with protons. One memorable talk was entitled "What you see is not what you get", emphasizing that the superior treatment plans created with proton modeling might not actually represent the dose that is received by the patients. Significant (>1 cm) uncertainty may exist both due to the uncertainty in Bragg peak location, and the deformation of the dose cloud due to patient motion or internal organ motion. (As I side note, I spent one day in the Midwest Proton Therapy Institute in Bloomington, IN. They told me that they needed to replan a CNS case once because someone had a head cold and their sinuses filled up, which significantly changed proton attenuation through the frontal sinus). To summarize:
Advantage: Protons stop.
Disadvantage: We don't know where.
Click to expand...


The summer before last, the AAPM meeting had an undercurrent of buzz concerning this very issue. It seems that the beam energy was slightly enough different at a proton institution to cause a geographic miss based on planning. No one was talking about it very much in public.

Herein lies the problem. Those who have it publically (billboards, radio, TV) tout its advantages. Those who don't detract. If we had had early trials with other modalities (neutrons), we might not have had the early toxicity/morbidity and mortality issues that later became apparent. While protons are not high LET particles, there are perhaps greater dosimetric uncertainties than we realize, and more opportunity for things to go wrong dosimetrically. Like most things, when they work well, they really work well.

But that is off topic from what I think is the more important lesson to be learned from this article. That is the ethics of cash flow and how it alters the thinking process from one of science and scientific inquiry to that of advocacy, absent hard information, be it in an RCT or a preponderance of well documented case evidence. And, of course the cash flow that results from (or does not result from, as the case may be) that advocacy position.

I suggest that those with influence in their respective programs, have a special "ethics" journal club and gather a bunch of these articles, not for rigorous review, but to demonstrate how these articles are born, how they influence the decision making processes and how we as a community can and should respond.
 
There are a number of cancer types where Protons may indeed provide a local-control and survival advantage for our patients. Those types usually make up a very small fraction of all of our patients.
Tomotherapy is an excellent technique as well and you can indeed irradiate several tumors to higher doses with tomotherapy than you would have done it with 3D-CRT.
Does that mean that every institution needs proton therapy and tomotherapy? Nope. Leave it to the experts. And send your patients away to them, if you feel they have a chance of getting a better treatment there, that will either enhance their survival or drastically limit their side effects.
 
radonc said:
many fields which introduces new technology do not have to prove (through an RCT) that the new, more expensive technology is better than the traditional, less expensive counterpart.
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Of course, that doesn't make this the right thing to do. I fear we risk contributing to the ballooning of health care costs which may, eventually, result in resources being allocated for us, not by us. Without evidence that we're moving in the right direction with protons, might this be too risky a gamble to take?
 
Wm Tell said:
I heard Dr. Cox lecture last spring, and the majority of one talk was devoted to the need for randomized trials for proton therapy. I don't know why he changed his mind. Maybe the physics issues are not as big as was thought this summer.
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To be frank, I don't think physics has anything to do with it; rather, I think he's found himself in the middle of a bit of a controversy, and he's decided to defend at all costs a therapy he believes in.

Wm Tell said:
If huge benefits to protons are seen in these comparitive studies, that would be wonderful. If small benefits or no benefits are seen, questions about patients selection, etc, will still cloud the issue.
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Selection bias, absolutely. Also, we'll never know how differences in technique - apart from the beam used - impact these patients. Because of the increased risk of uncertainties, proton patients are often set up differently than, say, IMRT patients. If all prostate patients treated with protons are treated with a rectal balloon in place, for example, who is to say whether improved outcomes are due to protons, themselves, or due to better target localization?

Without a trial, we'll never, ever know.
 
Reality - Protons are effective for treating tumors
Reality - Protons are good for specific locations - ie chordomas, pedi cases
Reality - The biological effect may be more than photons (MGH personal communications)
Reality - Protons are ridiculously expensive

Fiction - Protons signicantly reduce toxicity for prostate cancer (Zietman, et al)
Fiction - Protons are the panacea we've all been waiting for.

The reality here is that while protons are being hailed as the next replacement to all Linacs, just as Linacs were to cobalt, this is just a crazy, far fetched idea.

The rationale for a randomized trial is really to show whether this technology has a real role in our armamentarium for common things - ie prostate cancer. Why should medicare or private payers spend $50,000 for protons for prostate when you can do it for less than half with IMRT, and about $10K for seeds. Without some for of data showing a benefit, I can't see how the payors will adopt this costly treatment, if there is no benefit.

Also, we're getting greedy as a specialty - we've milked IMRT so much that we've now got a target on our backs. In 2000, the total medicare expense for IMRT charges was $200 mil, and in 2006 it was $800mil. You can't believe that an increase that large does not get noticed. WIth protons, notice that many of the units being bought are free-standing, ie Procure - and those people are going to lose their shirts, as they'll either have to take no payment or extreme cuts in reimbursement.

Don't let the technology changes get you all caught up - in the end we still have to pay for this. It will likely be in your taxes when you are an attending.

My 2 cents
 
newbie is really experienced. Very contextual points.

And Yes the MGHers believe the radiobiological effect is more than we say (1.1).Perhaps the Dude can tell us why they think that?
 
Not sure of the exact reason....but I know Tarbell and Yock have talked about the RBE is actually a little higher than expected - probably has to do with the stopping of protons and an enormous release of energy at that point. But I know the MGH folks are a little cautious, especially w/ the pedi patients around the chiasm w/ protons.
 
interesting.
It strikes me as one of those experiential things. Not much lit. I once asked Loeffler what RBE he used and he just went with the 1.1.
 
Interesting thread. I have couple comments. (somehow SDN is eating my paragraphs, sorry about that.) My admittedly limited understanding of the RBE issue is that the overall RBE is ~1.1 across the entire beam path. It is significantly higher in the Bragg peak range, but since 1) we don't know exactly where the peak is (see uncertainty comments above) and 2) treatment planning typically isn't done (and for proton planning may not even allow yet) dose-calculation as function of RBE, 1.1 is just used for expediency. I think there are some efforts at PSI to dose-paint with the high RBE regions to where the tumor is in prostate, but I am not sure how far they are getting with it. About secondary cancers, an interesting paper from PSI is (PMID 17459608) "The impact of dose escalation on secondary cancer risk after radiotherapy of prostate cancer." (Schneider U, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):892-7. Epub 2007 Apr 24.). They calculate that compared to 70 Gy 3D-CRT photons, dose escalating 6 MV IMRT gives 18% higher risk of secondary cancers, dose escalating 15 MV IMRT gives 25% higher risk of secondary cancers, and dose escalating spot-scanned IMPT gives 41% lower risk of secondary cancers. Also, the actual measured neutron data from Loma Linda are apparently nowhere near as high as those used for the Hall article. One can model anything; it's all about the assumptions. I think we will just have to wait for secondary cancers to manifest to settle it. As for the RCT question, it's very interesting. IMRT is widely adopted and widely reimbursed, yet to my knowledge there are only 3 randomized trials comparing IMRT to conventional therapy - and none of these was performed in the US and they were all published only within last 2 years, well after IMRT adoption. One of these 3 is in breast, and that's one site that's actually not routinely reimbursed. Still, the reasons for IMRT adoption are better dosimetry and better reimbursement, exactly the same reasons for protons. SBRT is another example; it is very nicely reimbursed, without any RCT data whatsoever. And that doesn't even touch on prostate Cyberknife. The only reason for the public outcry is indeed that protons are at the moment quite a bit more expensive (by my estimate by factor ~4-5x, excluding facilities). Overall, I very highly doubt we will ever see an RCT in the US. I have been in business before going into radonc, and my personal feeling about protons is colored by that. I think the market will sort it out. Specifically, the benefits will either be perceived by CMS and insurances to be worth it (based on gut feel and/or patient demand and/or dosimetry and/or data), in which cases it will be reimbursed, or they won't reimburse and protons won't become widespread. The society at large will decide if it wants it and if it has money for it. At the end of the day, that's how decisions are made about adopting new technology in the US. I suspect protons will settle out somewhere around IMRT/Gamma Knife reimbursements, in which case some of the facilities that are spending large sums of money might take a bloodbath, but can use it as a loss leader showing their cancer centers are at the forefront. Don't forget, radiation oncology is a really really small piece of the US health care pie. The entire US spending for radiation oncology (as I recall, maybe wrongly) is in the neighborhood of $1.2 billion. Avastin alone, which produces somewhat marginal benefit in metastatic cancer, is projected to have 2008 US sales of $2.8 billion. So protons aren't really all that significant ...
 
If we're worrying about reimbursement, then we've missed the point. The issue is how the tools- and this includes avastin- are used. Applying basic principles to clinical decision making is reasonable. When reimbursements facilitates our clinical decision making in absence of data (or spite of it) we need to regroup.
 
interesting green journal article v86:2 (148): "should positive phase 3 clinical trial data be required before proton beam therapy is more widely adopted? No". By Suit et al.

Steph
 
But should it be widely used for things like prostate cancer, where there is likely no significant clinical benefit (see Zietman, ASTRO 2008), and likely to overutilize our medicare dollars.

If we adopt protons widely, we can all pretty much say goodbye to ever seeing medicare.
 
Just curious if there is any animal data or if anyone knows of any.
 
stephew said:
interesting green journal article v86:2 (148): "should positive phase 3 clinical trial data be required before proton beam therapy is more widely adopted? No". By Suit et al.

Steph
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Why publish this in the green journal, I wonder?
 
trublu said:
Herein lies an important lesson that will save you all tons of time in your careers:

When basic principles lead you to be certain a new therapy is better than standard of care, it's unethical to test it in a randomized trial.

I'll alert the FDA.
Click to expand...

I understand that Dr. Cox is under some heat regarding his financial disclosure with JCO
 
Recent addition to the red journal. May be of interest to this discussion...

Dose–Volume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer

Carlos Vargas M.D.*, Corresponding Author Contact Information, E-mail The Corresponding Author, Amber Fryer B.S.*, Chaitali Mahajan M.D.*, Daniel Indelicato M.D.†, David Horne C.M.D.*, Angela Chellini B.S.*, Craig McKenzie C.M.D.*, Paula Lawlor C.M.D.*, Randal Henderson M.D.*, Zuofeng Li D.Sc.*, Liyong Lin Ph.D.*, Kenneth Olivier M.D.† and Sameer Keole M.D.*
†Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL
*University of Florida Proton Therapy Institute, Jacksonville, FL
Received 24 April 2007; revised 2 July 2007; accepted 4 July 2007. Available online 27 September 2007.

Purpose
The contrast in dose distribution between proton radiotherapy (RT) and intensity-modulated RT (IMRT) is unclear, particularly in regard to critical structures such as the rectum and bladder.

Methods and Materials
Between August and November 2006, the first 10 consecutive patients treated in our Phase II low-risk prostate proton protocol (University of Florida Proton Therapy Institute protocol 0001) were reviewed. The double-scatter proton beam plans used in treatment were analyzed for various dosimetric endpoints. For all plans, each beam dose distribution, angle, smearing, and aperture margin were optimized. IMRT plans were created for all patients and simultaneously analyzed. The IMRT plans were optimized through multiple volume objectives, beam weighting, and individual leaf movement. The patients were treated to 78 Gray-equivalents (GE) in 2-GE fractions with a biologically equivalent dose of 1.1.

Results
All rectal and rectal wall volumes treated to 10–80 GE (percentage of volume receiving 10–80 GE [V10–V80]) were significantly lower with proton therapy (p < 0.05). The rectal V50 was reduced from 31.3% ± 4.1% with IMRT to 14.6% ± 3.0% with proton therapy for a relative improvement of 53.4% and an absolute benefit of 16.7% (p < 0.001). The mean rectal dose decreased 59% with proton therapy (p < 0.001). For the bladder and bladder wall, proton therapy produced significantly smaller volumes treated to doses of 10–35 GE (p < 0.05) with a nonsignificant advantage demonstrated for the volume receiving &#8804;60 GE. The bladder V30 was reduced with proton therapy for a relative improvement of 35.3% and an absolute benefit of 15.1% (p = 0.02). The mean bladder dose decreased 35% with proton therapy (p = 0.002).

Conclusion
Compared with IMRT, proton therapy reduced the dose to the dose-limiting normal structures while maintaining excellent planning target volume coverage.

http://dx.doi.org.lp.hscl.ufl.edu/10.1016/j.ijrobp.2007.07.2335
 
The article in the above post doesn't show a thing.....other than the dosimetry is superior. We already know that protons has superior dosimetry, but to try to justify a $50,000 treatment vs. a $8-15K treatment on dosimetry data alone will not fly. MGH already showed superior dosimetry, but as Zietman himself stated at ASTRO - he couldn't say there is any significant clinical beneft.

Also, a previous poster mentioned data on cyberknife and how payers are paying high reimbursement with no data. That is simply not true. There is now significant data on hypofraction of 50-60Gy on medically inoperable early stage NSCLC with great clinical results - local control of 90% or better. This is certainly better than any experience of external beam RT in a conventional manner, and helps justify this technology. Cyberknife is not a cheap capital purchase and insurers realize this. And the reimbursement has been declining yearly (except for this year).
 
xraydude said:
The article in the above post doesn't show a thing.....other than the dosimetry is superior. We already know that protons has superior dosimetry, but to try to justify a $50,000 treatment vs. a $8-15K treatment on dosimetry data alone will not fly. MGH already showed superior dosimetry, but as Zietman himself stated at ASTRO - he couldn't say there is any significant clinical beneft.

Also, a previous poster mentioned data on cyberknife and how payers are paying high reimbursement with no data. That is simply not true. There is now significant data on hypofraction of 50-60Gy on medically inoperable early stage NSCLC with great clinical results - local control of 90% or better. This is certainly better than any experience of external beam RT in a conventional manner, and helps justify this technology. Cyberknife is not a cheap capital purchase and insurers realize this. And the reimbursement has been declining yearly (except for this year).
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Definitely agree with you for SRS of the lung -- there is def good data from Japan as well from the US. However the Cyberknife data for prostate is a different story....
 
xraydude said:
The article in the above post doesn't show a thing.....other than the dosimetry is superior. We already know that protons has superior dosimetry, but to try to justify a $50,000 treatment vs. a $8-15K treatment on dosimetry data alone will not fly. MGH already showed superior dosimetry, but as Zietman himself stated at ASTRO - he couldn't say there is any significant clinical beneft.

Also, a previous poster mentioned data on cyberknife and how payers are paying high reimbursement with no data. That is simply not true. There is now significant data on hypofraction of 50-60Gy on medically inoperable early stage NSCLC with great clinical results - local control of 90% or better. This is certainly better than any experience of external beam RT in a conventional manner, and helps justify this technology. Cyberknife is not a cheap capital purchase and insurers realize this. And the reimbursement has been declining yearly (except for this year).
Click to expand...

Well, the local control is certainly good with stereotactic body radiation therapy (SBRT). However, you certainly don't need a Cyberknife to do SBRT. In fact, some of the original U.S. data came from our institution (Indiana University), and it was done with two standard linear accelerators without MLCs (we used cerrobend blocks to shape the fields and milled cerrobend compensators to modulate the dose).
 
Here are a couple of interesting editorials published in the latest issue of JCO re: the original RCTs for protons editorial.

1. "Protons and Parachutes" by Joel Tepper

This is a response to the original JCO editorial. Very well written IMO and is a good summary of the prevailing opinion on this message board.

2. Counter-reply by Michael Goitein and James Cox

This reply is, IMO, even more outrageous than the first editorial. You should read the whole reply but here are some choice quotes,

". . . the burden of proof is on the shoulders of those wishing to conduct an RCT to show that the arms are substantially comparable."

". . . consider the case of a trial between protons and x-rays in which protons deliver the same dose as the x-rays within the target volume. Without doubt, the protons would deliver an overall lower dose to the normal tissues outside the target volume . . . We cannot see how the two arms could be considered to be equipoise and therefore, how randomization could be justified in the case of such a trial."

equipoise = An ethical requirement of clinical trials, equipoise means that the researchers are not certain which arm will receive the best treatment.

". . . we fail to see how one can ethically conduct a trial in which equipoise is not achieved, purely to learn if the extent of the benefit is worth the cost."

And the best two lines of the whole repy . . . [drum roll please]

"There is no lack of people worrying about how to cut costs (and corners). Rather than identifying with them, let those of us who are dedicated to cancer care be advocates for the patient."
 

Attachments

The cynic in me would like to think that some of these pro-proton editorials were ghost-written by companies that make them. (See: http://jama.ama-assn.org/cgi/content/full/299/15/1833)

I should also add that in addition to Tepper's letter, a bunch of other letters and comments were also e-published in the same issue of JCO, all of which were referred to by Goitein and Cox in their reply:

Introduction by the Editors of JCO
http://jco.ascopubs.org/cgi/reprint/JCO.2008.17.4136v1

Macbeth & Williams, "Proton Therapy Should Be Tested in Randomized Trials"
http://jco.ascopubs.org/cgi/reprint/JCO.2008.16.5514v1

Brada et al, "Evidence for Proton Therapy"
http://jco.ascopubs.org/cgi/reprint/JCO.2008.16.5670v1

Lewis, "On Equipoise and Emerging Technology"
http://jco.ascopubs.org/cgi/reprint/JCO.2008.16.5191v1

Glatstein et al, "Should Randomized Control Trials Be Required for Proton Radiotherapy? An Alternative View"
http://jco.ascopubs.org/cgi/reprint/JCO.2008.17.1843v1

Morgan, "A Patient's Perspective on Randomized Clinical Trials for Proton Radiotherapy"
http://jco.ascopubs.org/cgi/reprint/JCO.2008.16.5605v1
 
Doctor&Geek said:
I should also add that in addition to Tepper's letter, a bunch of other letters and comments were also e-published in the same issue of JCO, all of which were referred to by Goitein and Cox in their reply
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Thanks for the links, I really need to get my hands on that issue!

The patient's editorial is quite infuriating. It demonstrates the arrogance of the American patient/consumer who demands whatever therapy is marginally better despite the exoirbant cost.
 
Gfunk6 said:
The patient's editorial is quite infuriating. It demonstrates the arrogance of the American patient/consumer who demands whatever therapy is marginally better despite the exoirbant cost.
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I don't subscribe to this view. Mr. Morgan is expressing his view based on the information that he was provided, which if true, would present a valid argument in favor of protons. Far from arrogance, he may be misinformed, a result in part of his caretakers (his urologist) failure to communicate to Mr. Morgan an unbiased and balanced opinion of proton therapy. Even if there was some arrogance involved, remember we're talking about a patient with cancer - we can and should be forgiving.

That said, the key line is:

Given that the medical community seems to agree that the proton
beam is superior to x-rays in the delivery of radiation, albeit at a
higher cost, what else do you have to know? Moreover, in attempting
to learn more through trials, are you putting participants at risk?
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As pointed out in the other editorials, the medical community is most certainly not in agreement that the proton beam provides a definitive clinical benefit to patients. Which is precisely the reason why we're debating theoretical benefits vs. real benefits and equipoise.
 
In this week's JAMA theme issue on cancer:

Patient-Reported Long-term Outcomes After Conventional and High-Dose Combined Proton and Photon Radiation for Early Prostate Cancer

James A. Talcott, MD, SM; Carl Rossi, MD; William U. Shipley, MD; Jack A. Clark, PhD; Jerry D. Slater, MD; Andrzej Niemierko, PhD; Anthony L. Zietman, MD

JAMA. 2010;303(11):1046-1053.

Context Increased radiation doses improve prostate cancer control but also increase toxicity to adjacent normal tissue. Proton radiation may attenuate adverse effects.

Objective To determine long-term, patient-reported, dose-related toxicity.

Design, Setting, and Patients We performed a post hoc cross-sectional survey of surviving participants in the Proton Radiation Oncology Group (PROG) 9509&#8212;a randomized trial comparing 70.2 Gy vs 79.2 Gy of combined photon and proton radiation for 393 men with clinically localized prostate cancer (stage T1b-T2b, prostate-specific antigen <15 ng/mL, and no radiographic evidence of metastasis). The estimated 10-year biochemical progression rate for patients receiving standard dose was 32% (95% confidence interval, 26%-39%) compared with 17% (95% confidence interval, 11%-23%) for patients receiving high dose (P < .001). We surveyed 280 of the surviving 337 patients (83%) from April 2007 to September 2008.

Main Outcome Measures Prostate Cancer Symptom Indices, a validated measure of urinary incontinence, urinary obstruction and irritation, bowel problems, and sexual dysfunction, and related quality-of-life instruments.

Results At a median of 9.4 years after treatment (range, 7.4-12.1 years), participants' demographic and clinical characteristics were similar. Patient-reported outcomes were reported as mean (SD) scale score for standard dose vs high dose: urinary obstruction/irritation (23.3 [13.7] vs 24.6 [14.0]; P = .36), urinary incontinence (10.6 [17.7] vs 9.7 [15.8]; P = .99), bowel problems (7.7 [7.8] vs 7.9 [9.1]; P = .70), sexual dysfunction (68.2 [34.6] vs 65.9 [34.7]; P = .65), and most other outcomes were also similar, although patients receiving standard dose whose cancers had more often progressed expressed less confidence that their cancers were under control (mean [SD] scale score for standard dose, 76.0 [25.4] vs high dose, 86.2 [17.9]; P < .001). Many patients characterized their urinary and bowel function as normal despite reporting symptoms that, for other prostate cancer patients before and early after cancer treatment, caused substantial distress.

Conclusion Among men with clinically localized prostate cancer, treatment with higher-dose radiation compared with standard dose was not associated with an increase in patient-reported prostate cancer symptoms after a median of 9.4 years.
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