Northern Illinois University @ MindSay 
If you are a physicist, or play one on TV, the title probably misled you.
Addressed here is the nascent explosion of proton therapy facilities. The number of such facilities in the U.S. is set to triple in the next five years from 5 to 15. The first antiproton facility is not yet on the drawing board, but the possibility has already been discussed.
But this is not about the two anti-up quarks and one anti-down quark type of antiprotons, nor about matter versus antimatter. This is more about "does it matter?". The proton’s most important current competitor is the lowly photon (x-ray). This series of posts is an introduction to the coming contest between the $5million photon facilities and the $150million proton facilities.
In the shadow of the Fermi National Accelerator Laboratory (Fermi Lab’s official academic partner has been University of Chicago), Northern Illinois University is constructing a multi-gantry proton radiation treatment facility. NIU does not have a medical school or any clinical facilities of any kind. None the less NIU elected to enter the field of medical care at the extreme edge of the technological imperative spectrum with a capital construction budget of about $160 million.
Strangely enough, NIU appears to be on the inside track to get their facility built. In an odd twist of Illinois law, non health care entities have a lower bar (i.e., Certificate of Exemption) to get over than health care organizations that actually have experience in the field. Central DuPage Hospital was denied a Certificate of Need to build a proton facility a few miles from the NIU's planned location.
Amateur physicists have known about the theoretical advantages of protons for medical treatment of cancer for at least 50 years. Robert Wilson, builder of Fermi Lab, pointed out in 1946 an important property of protons – the Bragg Peak and predicted great things for therapeutic protons ("Radiological Use of Fast Protons", R. R. Wilson, Radiology, 47:487-491 (1946)).
Oversimplified, Bragg described the relationship between beam strength and distance to energy delivery. Wilson helped to build the Harvard Cyclotron, which was used from 1962 until 2002 to treat 9000 patients with protons. Ironically, given their advertised virtue of sparing normal tissue, the first use of protons to treat cancer was to destroy normal tissue…the pituitary gland in patients with breast cancer in order to stop hormone production to stop the growth of hormone dependent cancers. Of course, protons have been eclipsed for this purpose with medicines that temporarily deplete the pituitary instead of destroying it....an even more effective way to spare normal tissues.
Protons give up most of their energy in a sharp “Bragg” peak at precise distance. This allows (with some considerable high tech manipulation to "blur" the peak into a precise volume) the radiation therapist to “paint” a tumor mass with multiple pencil beams of protons, while delivering very little radiation to surrounding tissue (there is virtually no "exit beam" beyond the Bragg Peak). Marrying the CAT scan to a moveable accelerator permits astonishingly precise radiation delivery…so called intensity modulated proton therapy (impt).
What about the proton’s lowly antagonist, the photon? In the little over 100 years since Wilhelm Conrad Roentgen was tinkering with a Crooke’s tube and noticed x-rays (photons), photon radiation treatment has come a long way. The crude (and dangerous) experiments that killed one of the Doctors Curie (and some of their patients) have now resulted in very high energy linear accelerators dedicated to photon treatment of cancer. (Pierre Curie was killed by a more primitive kind of physics – a carriage wreck).The kilovoltage machines of the 50’s gave way to the cobalt 60 units of the 70’s. With the latest iteration of linear accelerators married to “4D” conformal algorithms (which even compensate for normal movements like breathing) and multiple beam intensity modulated radiation treatment (imrt), photon therapy is also precise. These aren't your grandfather's photons. They are highly trained photons on steroids.
This begs the astonishingly simple question: “How close is close enough in cancer treatment?”
"There is nothing new to be discovered in physics now. All that remains is more and more precise measurement" - Lord Kelvin, ~1900
Ok, I could be mistaken about proton therapy.
Even Lord Kelvin missed a few future possiblities that physicists discovered in the last century, including the very existence of protons (the term was coined by Rutherford, and it first appeared in print in 1920).
Still, I believe that universal proton therapy is premature. The road side of medical technology is littered with "advances" that should have marked progress but didn't. For each type of cancer there may be some (likely small) subset of patients for whom the astonishingly precise measurement of radiation dose and volume can result in incrementally improved cure rates through local control, while still minimizing morbidity. I prefer a few proton facilities equipped with the latest IMPT where carefully selected patients could only be treated as part of clinical trials designed by experts from all disciplines. I would prefer studies designed to objectively measure quality and quantity of life, not surrogates like psa's and imaging shadows. I also prefer world peace.
The technological imperative has once gain prevailed, and the age of proton therapy is upon us. Unintended consequences will occur, though not easily predicted.
The first unintended consequence of proton prolifertion will be an expansion in the total number of patients treated. Because protons are perceived to result in few side effects, a belief among caregivers and patients will be fostered that there is nothing to lose by treatment. If significant morbidity is cut in half but double the number of patients are treated, the total morbidity will be unchanged. Currently proton therapy costs twice as much as photons (at least). Under this set of assumptions costs will quadruple at a time when health care costs in general are exploding.
Quadrupling costs would be justified if survival and quality of life were incrementaly improved. How likely is this to be the case for prostate cancer? About 15% of patients who are diagnosed with prostate cancer die from the disease, and autopsy studies suggest the actual number of prostate cancers is much higher than the 190,000 diagnosed. Natural history studies indicate that a diagnosis of early stage prostate cancer has very little effect on survival ("natural history" means "untreated"), yet these are the cancers most amenable to "cure". But try telling a patient he has "mild" cancer and then advocate watchful waiting. His first question will be: then why did you look for it? His second is likely to be: how can I find a new doctor?
Anatomic stage provides a measure of disease progression. SEER data (crude as it is) based on historic stage shows that 91% of prostate cancer cases are diagnosed while the cancer is still confined to the primary site or after the cancer has spread to regional lymphnodes (localized or regional stage); 5% are diagnosed after the cancer has already metastasized (distant stage) and for the remaining 4% the staging information was unknown. The corresponding 5-year relative survival rates were: 100.0% for localized/regional; 31.9% for distant; and 79.1% for unstaged. Not much room for improvement exists for stage I cancer, at least in terms of survival, and no local treatment will improve survival for those who present with distant spread.
The trick is to find the small subset of intermediate risk prostate cancer patients (perhaps about 15% of the total) who still have local disease at diagnosis but who have a relatively poor prognosis, and then to treat them without vastly expanding the total number of people treated. Since risk stratification has a large element of subjectivity built in, I suspect the latter condition will not prevail.
A second unintended yet inevitible consequence of creating capacity to treat 1600 plus more patients per year (as in the case of th NIU faciltiy) in a market that already has ample radiation treatment capacity will be another escalation in the medical marketing wars. Loma Linda has advertised nationally for years, making claims for protons that push the evidence based envelope.
A roughly fifty year cycle seems to exist for medical hucksterism. In 1850 when the famous gastrophysiologist Wlliam Beaumont recruited a new physician to his private practice in St. Louis he placed a small ad in local newspapers announcing that his new partner had special expertise in diseases of the eye. Beaumont was immediately viciously attacked by colleagues and nearly drummed from the corps of the local medical society.
The then newly created (1849) American Medical Association had borrowed heavily from Thomas Percival's treatise (A Scheme of Professional Conduct Relative to Hospitals and other Medical Charities 1772) on medical "ethics" when it drafted its code of conduct. Advertising was eschewed. By 1900 US newspapers were full of boiler plate ads for patent medicine, medical devices and doctors claiming superior skills or unique services. By 1950 the rules of 1850 had regained the ascendency and physicians were "allowed" only a briefly run "toombstone" in newspapers to simply announce their presence in a community.
By 2000, the advertising cycle was in full upswing again. The "ethical" prescription drug industry (the adjective had been applied to distinguish what has become "big pharma" from the snake oil salesman) went from no ad's aimed at the general public in 1950 to near the top of the spending list by 2000. Last year, Glaxo was the 7th largest spender on ads, spending $2.4 billion, and Johnson & Johnson came in 9th with $2.3 billion in spending, placing the health care giant ahead of Unilever, Toyota and Sony.
Percival's code had been drafted at the behest of a London hospital in an attempt to regulate the relationships between physicians and hospitals and among the physicians themselves. In 2008 individual physicians were largely out of the ad wars. Rather, health care "systems" now "market" themselves with claims that they are either more caring or more skillful (and usually both) than their competitiors.
And so the proton facilities with their $100+ million in bonded indebtedness will advertise for patients. They will compete with each other on a local, regional and national level. It is not accidental that NIU's new facility is across the street from DuPage Airport and its 8000 foot runway, and in the shadow of Fermi Lab's Wilson Hall. (Ironically, Fermi Lab is in a state of decline, having been eclipsed by the more powerful accelerator in Cern.)
NIU has announced that it will enter into an agreement with the Northwestern University Faculty to provide the clinical expertise at its new center. A search of the Northwestern cancer center web site (http://pubs.cancer.northwestern.edu/abstracts/search?do_pagination=1&page=1) for faculty publications containing the word "proton" yielded 59 hits. But none of the 59 papers seem to have anything at all to do with treating patiients with protons. Basically, NIU, which lacks a medical school, will credential and privilege physicians to use its clinical facility. How will NIU judge the compentency of these physicians and what experience with proton therapy will be required? Who at NIU has the clinical experience and expertise to make these decisions? How will prospective patients be informed about these issues? Advertisements?
Check this site to see how the M.D. Anderson Proton Center (for-profit) is to be marketed by M.D. Anderson Cancer Center, which "leased" its name to the center. http://hcrenewal.blogspot.com/2005/10/m-d-anderson-cancer-center-leases-its.html First the marketing agreement to promote the center, then the science to see if it is actually better.
The protonless health care systems will tout their competing services, such as their daVinci robots, brachytherapy, imrt guided photons and expertise in medical oncology. The have-nots will not so gently point out that "to a man who only has a hammer, the whole world looks like a nail" and that proton-only facilities are dominated by mad physicists and unidimensional clinicians. They will do this until they install their own $15 million proton machines. Then they will advertise protons. All this collateral spending will cost many millions.
A third unintended consquence will be to ensure the continued immortality of Will Rogers, who said: "When the Okies left Oklahoma and moved to Califormia, they raised the average intelligence level in both states."
The Will Rogers Phenomenon will occur when both of these conditions are met: The element being moved is below average for its current set. Removing it will, by definition, raise the average of the remaining elements. The element being moved is above the current average of the set it is entering. Adding it to the new set will, by definition, raise the average.
Proton therapy will be declared superior by it's proponents. These proponents will obtain transrectal ultrasounds, transrectal MRI's, CT's, psa's, psa velocity, free psa and other tests to "stage" patients. Historically many of these tests were unavailable or not done in the photon era. More staging most often results in up-staging, which meets the conditions of the Will Rogers Phenomenon.
For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004.The "new" Gleason score readings (high scores indicate poor prognosis) were an average of 0.85 points higher (95% confidence interval [CI], 0.79–0.91; P < .001) than the same slides read in 1990 to 1992. As a result (thanks to Will Rogers), Gleason score-standardized prostate cancer mortality for these men was artifactually improved from 2.08 to 1.50 deaths per 100 person years—a 28% decrease even though overall outcomes were unchanged.
Given the right pathologists and a little staging leeway, most any new treatment will look great. Perhaps surgery looks better than radiation for younger men with prostate cancer (at least according to one widely quoted paper) simply because surgery results in very accurate staging.
For those who prefer more formal cost-effectiveness methodology (like insurance companies), analysis indicates that proton therapy for prostate cancer does not appear to be cost-effective when measured by commonly acceptable parameters, according to a study by researchers from Fox Chase Cancer Center (JCO 2007; 25: 3603-3608). Quality-adjusted survival was similar for both modalities in each age group as measured by QALY: The incremental cost effectiveness ratio was calculated to be $63,578/ QALY for a 70-year-old-man and $55,726/QALY for a 60-year-old man.Quality-adjusted survival was similar for both modalities in each age group as measured by QALY: The incremental cost effectiveness ratio was calculated to be $63,578/QALY for a 70-year-old-man and $55,726/QALY for a 60- year-old man.
"When even the brightest mind in our world has been trained up from childhood in a superstition of any kind, it will never be possible for that mind, in its maturity, to examine sincerely, dispassionately, and conscientiously any evidence or any circumstance which shall seem to cast a doubt upon the validity of that superstition. I doubt if I could do it myself." - Mark Twain
I am a skeptic, in spite of Mark's good advice. The problem is, time will not tell. Prospective randomized trials comparing survival for surgery, brachytherapy, photons and protons for intermediate prognosis prostate cancer patients will not be done. Carbon ion radiation may replace protons, and might be the next half-way technology to usurp the technological imperative. Neither Lewis Thomas nor Thomas Hardy would have been surprised if it happens.
Since these discussions are in the overall context of the proton-antiproton conundrum, a few preliminaries are needed before addressing the “Close” question as it pertains to radiation treatment.
Back to the NIU $160 million proton center. To treat patients the center will need to at least break even financially in the long run. Their estimate is that this will mean they will need 1600 patients per year. The Harvard Cyclotron treated 9000 patients in 40 years (225 per year), and for much of that period it was the only proton center in the country (Loma Linda opened in 1990).
The new NIU center will have multiple gantries and several treatment vaults, so it is in reality the equivalent of 4 or 5 Harvard Cyclotrons. Plus NIU is one of at least five multiple gantry/vault facilities that will open soon to add to the five that are now operating. So who will be among the 1600 patients that NIU plans to treat?
A consensus has developed that pediatric cancers are likely to be best treated by protons because of the effect of radiation on normal and still developing tissue. This consensus is not based on the highest level of evidence, which would require randomized clinical trials. But small numbers make such trials close to impossible. About 10,000 cases of pediatric cancer occur in the US every year. About a third of these malignancies are leukemias, and only about 10% of leukemia patients get cranial radiation at low total doses where protons are likely not an advantge. So even if all other pediatric cancer patients received proton radiation, that would total about 7000 per year. Soon there will be at least 30 proton vaults in the US, or about 230 pediatric cancer patients per vault per year.
For what other cancers does a consensus exist that protons are superior to other options? The short answer is none. Some adult spinal cord tumors and tumors of the base of the skull might benefit from protons, but fortunately there are only a handful of such cases per year….no more than a few per U.S. proton vault per year. So for the financial viability of the NIU proton center, other patients with more common cancers, like prostate, lung breast and rectum will need to receive protons.
Prostate cancer patients are obvious candidates for proton therapy recruitment. The Loma Linda proton faility claims to have treated 12,000 prostate cancer patients since about 1990. The disease is very common…190,000 U.S. cases per year or about 6300 per proton vault. But controversy swirls around every aspect of prostate cancer and treatments can range from none to many combinations of combined surgery, beam radiation, brachy (seed implant) radiation and hormones.
Swedish researchers estimate that about a third of diagnosed prostate cancer is “non-lethal” and may not require curative treatment. If this is the case, then the 190,000 falls to about 130,000. The median age at diagnosis for prostate cancer is 72. Many elderly patients with other medical conditions will die from other causes. (Ironically, sick patients are more likely to have their prostate cancer discovered because they are visiting doctors and getting PSA’s, ct scans, rectal exams, etc. This phenomenon when viewed by clinical epidemiologists has been referred to as “Berkson's Fallacy”). This further will reduce the possible appropriate candidates for protons, perhaps by another third to roughly 100,000. The actual number of optimal candidates for proton therapy is probably much smaller yet than 100,000.
Who will compete for these 100,000 patients? About 10,000 urologists and 4000 radiation oncologists were in practice in the US in 2000. Most prostate cancer patients initially are evaluated by urologists for diagnosis and staging. For each urologist the order of magniude of patieints eligible for curative treatment is about 10 per year. What choices will the urologist suggest? Radical prostatectomy can be performed by most urologists. Some are now using a "da Vinci Robot" to perform less invasive radical prostatecomy. Alternatively, the urologist can collaborate with a radiation oncologist to perform "brachy therapy" - the insersion of radioactive seeds into the prostate. Some patients, particularly older ones with higher risk for surgery will be referred for external beam therapy or may receive no initial treatment.
Next: How Close is Close Enough for Radiation, Part II.
“You can scarcely tell the difference between them except in price. Medicare pays about $50,000 to treat prostate cancer with protons, almost twice as much as with X-rays." A.L. Zeitman, M.D. *
This quote comes from a December 2007 article in the New York Times and the "difference" to which Dr. Zeitman refers is between photons and protons for prostate cancer treatment. Dr Zeitman is the lead author of one of the few reports of controlled trials using proton therapy. His group treated prostate cancer with either "conventional" (~70 gy) dose radiation or "high" dose (~80 gy) radiation. Both groups got the final 20 or 30 gray via protons, not photons. So this was not a comparison of protons and photons per se. "All patients received conformal photon (x-ray) therapy to a fixed dose of 50.4 Gy."
Here is the bottom line quoted from Dr. Zeitman's 2005 Journal of the AMA paper: "Although this trial validates the use of proton-beam therapy, it did not test whether this modality is more or less efficacious than other less expensive and more commonly available conformal techniques or, for that matter, than brachytherapy or surgery."
Reading the technical aspects of the JAMA paper gives some idea of "how close is close enough" at least for the designers of the trial, so I will quote it here [emphasis added]:
Conformal radiation therapy was given in 2 phases. Phase 1 used conformal proton beams to treat the prostate alone. The applied proton-beam dose was corrected to a photon equivalent using a radiobiological effectiveness ratio of 1.1. Dose is thus expressed not as gray (Gy) but as gray equivalents (GyE). Either 19.8 GyE or 28.8 GyE was given, depending on randomization, in either 11 or 16 fractions (1.8-GyE fractions). The clinical target volume was the prostate, with a 5-mm margin. An additional 7 to 10 mm was added for a planning target volume, according to the technical requirements of the treating machines at the 2 participating institutions. Thus, the planning target volume varies in order to deliver identical treatment. Planning was performed using 3-dimensional computed tomography–based techniques. Patient position and beam arrangement differed according to the experience of the participating institutions. At Loma Linda University Medical Center, patients were treated in the supine position using opposed lateral 250-mV proton beams. At the Massachusetts General Hospital, patients were treated in the lithotomy position using a single 160-mV proton beam directed through the perineum.
In phase 2, all men, regardless of trial group, were planned to receive 50.4 Gy delivered with photons in 1.8-Gy fractions to the prostate and seminal vesicles. Patients were treated in the supine position, and radiation was delivered using high-energy (10-23 mV) beams. A combination of 4 beams (anterior, posterior, and right and left lateral) was used. The clinical target volume included the prostate and seminal vesicles, with a margin of 10 mm for potential microscopic infiltration by tumor. The total treatment time when both phases were combined was 8 weeks in the conventional-dose group and 9 weeks in the high-dose group.
Basically in this trial 10mm was deemed "close enough" to ensure that all the potential little arms and fingers of the cancer crab were included in the treatment. Is this "radical" radiation treatment "Halstedian" enough (to use the an analogy to breast cancer surgery) or is it too much? Do the little fingers of the crab (bathed as they are in relatively high oxygen levels and thus more vulnerable to radiation compared to the central core of the cancer) require the same high (and possibly damaging to the host) dose?
As pointed out by Schulz and Kagan (Physics Today, 2003), "surgery is the primary treatment for more than 80% of all cancers at most hospitals, and for good reasons. For example, when treating esophageal cancer, it is standard practice for a surgeon to resect several centimeters of apparently normal tissue above and below the cancerous region to assure that microscopic disease has not been left behind. Subsequent pathological staging provides guidelines about the likely course of the disease and whether follow-up treatments will be required. Despite what would appear to be an aggressive and definitive approach, the five-year survival rate for esophageal cancer patients is around 15%. The results for other, more common cancers are not so dismal: about 60% for the colon and 80% for the bladder. In the context of surgical experience, one must wonder how the millimeter precision of proton-beam dose distributions will benefit the patient."
Who knows how close is close enough for radiation volume and dose?
I contend that no one knows. About $750 million dollars in capital alone is about to be spent to build another 25 proton treatment vaults in the next few years. The NIU facility will cost $160 million if it comes in on budget. Another similar facility has been proposed 6 miles away. Within a 50 mile radius of these facilities are about 25 high energy linear photon accelerators, few running at capacity. Many of these accelerators are married to CAT scans for conformal therapy and some have been equipped for even more precise "intensity modulated radiation treatment." In addition, close by is what is billed as the world's busiest dedicated prostate cancer brachytherapy center.
Of course, prostate cancer is not the only prevalent malignancy that could be treated with protons, but even less is known about proton use in these others. Almost a decade ago some were already predicting still birth for proton therapy. (Intensity-modulated conformal radiation therapy and 3-dimensional treatment planning will significantly reduce the need for therapeutic approaches with particles such as protons. MED PHYS 26: 1185, 1999.)
The megacost NIU type of proton facility will face "down market" competition from vendors like Still River and TomoTherapy. Lower cost, single vault systems are under development that can be retrofitted into existing linear accelerator vaults. Because proton therapy per se already has FDA approval, Still River expects that clinical trials will not be required (i.e. regulators need only be satisfied that the system can fire a proton beam, and that it is safe and effective). In the absence of complete FDA clearance, Still Rivers Systems has entered into a contract with its first customer, Washington University, in St Louis, MO, to construct a one-room proton-therapy facility onsite. This is due to be installed early in 2008, and in March 2008 Wash U was advertising on-line for a proton therapy physicist ("The Department of Radiation Oncology at the Washington University School of Medicine has an exceptional opportunity for experienced proton therapy physicist to immediately join our proton therapy program based on the Still River System 250 MeV proton system"). Meanwhile, Tufts New England Medical Center, Boston, MA, has filed for state permission to commence using protons for cancer treatment, in anticipation of a favourable FDA decision.
In a new technology transfer pact, Lawrence Livermore National Laboratory has licensed its compact proton therapy technology to TomoTherapy Incorporated (NASDAQ: TTPY) of Madison, Wis., through an agreement with the Regents of the University of California. TomoTherapy expects to provide DWA-based proton therapy systems for less than $20 million and that these units would be installed in existing radiation therapy facilities. TomoTherapy will fund development of the first clinical prototype, which will be tested on patients at UC Davis Cancer Center. If clinical testing is successful, TomoTherapy will bring the machines to market.
NIU's proposal assumes a "16 state referral base" of about 70 million people. Missouri and Indiana are two of the 16, and one has a proton facility and the other will beat NIU to market by about two years. Wisconsin, home of TomoTherapy, is also among the 16 states. Ionically, within the decade many academic and community hospitals will likely have their own small proton facilities.
NIU needs about 1600 patients per year to by ecomincally viable. The University of Chicago, which constantly touts itself in advertisements as being on the "Forefront of Medicine" treats about 2000 patients, virtually all with photon radiation, per year at four clinical centers that include two different medical schools.
The stampede to proton therapy is an example of Lewis Thomas' "technological imperative" run amuck. We are building proton treatment facilites because we can. The miraculous technology can deliver cancer killing radiation with incredible precision. We just don't know the precise vulnerability, size, or location of the target, or in many cases whether we should shoot at it at all.
*Dr. Zeitman has nicely summarized his position with inspiration from the Thomas Hardy (1912) poem, The Convergence of the Twain (Lines on the loss of the Titanic). See the Journal of Clinical Oncology Vol 25, No 24 (August 20), 2007: pp. 3565-3566.
Next: The Law of Unintended Consequences - Possible Epiphenomena of the Proton Stampede.
Oh, Lord Jesus, please not again.
"At least two people have been shot and several injured at Northern Illinois University outside Chicago, CNN affiliates are reporting."
http://www.cnn.com/2008/US/02/14/university.shooting/index.html