A very large clinical trial (~10,000 women) is underway to assess the usefulness of the Oncotype Dx gene profile for selecting treatment for early stage estrogen receptor positive breast cancer: the TAILORx Trial.  The trial sponsors will ask women with breast cancer to undergo Oncotype Dx testing (for which they will be billed $3650) and then assign them to three risk groups based on their recurrence score. (The groups are defined using different cut-off’s for this trial than those used for the study done on the NSABP B-20 tumors.)  Women in the low risk score group will get hormonal treatment (tamoxifen or one of the newer “aromatase inhibitor” class of drugs). Women in the high risk group will get chemotherapy and hormone therapy. The women in the intermediate group will be randomly assigned to receive either hormone treatment alone or a combination of hormone and chemotherapy.

 

A least four concerns make this trial seem premature. First, the chemotherapeutic "validation" of Oncotype Dx is based on one small, old chemotherapy trial. Second, TAILORx does not incorporate many other old and new prognostic indicators that might trump Oncotype Dx in some circumstances. Third, not enough information exists about how the Oncotype Dx score might interact in a confounding way with specific hormone treatments, chemotherapy drugs, and regimens. Finally, far too many non-random, non-blinded choices are afforded to patients and physicians in TAILORx to make for decent "science".

 

TAILORx is based on a retrospective analysis of a small, non-random sample of assays performed on preserved tissue. The ability to use this old material to obtain reproducible gene profiles is an amazing technological feat, to be sure. But only 651 of about 2300 patient results were available. The chemotherapy used in the NSABP B-20 dates to the 1970's. Substantial evidence supports a conclusion that these regimens improve prognosis for many patients. But two of the agents (methothrexate and 5-fu) are not often employed today. The third agent, cytoxan, has lost popularity over concerns that it may lead to late complications like second malignancies. Meta-analysis of the many thousands of patients treated with chemotherapy indicates that the B-20 drugs are not as effective as newer drugs like the taxols and adriamyin.

 

So inspite of the fact that the paper describing the results for the 651 patients uses the word "prospective" five times, it is actually a retrospective survey, not a clinical trial. This might matter for a woman who is enrolled in TAILORx because she cannot be sure that the Oncoype Dx group studied really is representative of the group she is in. And remember that much of the power of the argument for Oncotype Dx is contained in the one subgroup that contained only 47 patients.

 

A second concern revolves around the lack of  consideration of many other older and newer prognostic variables when deciding whether a patient falls into "Group 2" (the intermediate risk group) as defined here:

 

Group 2 (Primary study group; ODRS 11-25): Patients are stratified according to tumor size (≤ 2.0 cm vs ≥ 2.1 cm), menopausal status (postmenopausal vs premenopausal vs perimenopausal), planned chemotherapy (taxane-containing [i.e., paclitaxel, docetaxel] vs nontaxane-containing), and planned radiotherapy (whole breast with no boost planned vs whole breast with boost planned vs partial breast irradiation planned vs no planned radiation therapy [for patients who have had a mastectomy]). Patients are then randomized to receive either hormonal therapy alone or combination chemotherapy and hormonal therapy.

 

For example, tumor size, tumor dna ploidy, quantitative level of estrogen receptor, tumor lymphovascular invasion, per cent of dividing cells ("s phase"), Ki 67 expression and many other features and meaurements have been used to stratify patients for risk of treatment failure. (Some of these features can make a woman with a very small tumor (<1 cm) eligible for inclusion in the trial, an acknowledgement of their possible importance). And of course, clinical features on presentation may predict risk of failure. Mammographically discovered cancers may have a different prognosis compared to those discovered by the patient feeling a mass, for example.

 

Under TAILORx rules, a 48 year old woman with a palpable 4.9 cm cancer that is high grade with lymphatic invasion, weakly estrogen receptor positive, Ki 67 expression and an S phase of 20 and a Oncotype Dx score of 23 (intermediate risk) could be randomly assigned to tamoxifen alone.

 

Some will argue that the hypothetical patient described above would be unlikely to have an Oncotype Dx score as low as 23. (The B-20 Oncotype Dx analysis used 18 to 31 to define the intermediate risk group. The range was changed to 11-25 for TAILORx, possibly because her2+ patients are excluded - more on this below.) This is probably true, since the Oncotype Dx score does correlate to some extent with many "traditional" indicators. However, if the above hypothetical patient exists, few cancer physicians would advise tamoxifen alone. This would result in one of two outcomes for our hypothetical patient.

 

First, the woman would not likely be offered the TAILORx trial. Or, if she were offered the trial and the randomization resulted in tamoxifen alone, she would be advised to withdraw from the trial and receive chemotherapy. Either way, the results from TAILORx will be compromised. If patients on the "edges" of the "groups" are manipulated to get the "right" treatment, the trial results will be of little use, because the "borderline" cases are the very ones that present the most difficult decisions, and the Will Rogers phenomenon will be in play to distort the results.

 

A third concern that may make TAILORx premature is the paucity of information about how the Oncotype Dx predictive power might be affected by the choice of hormone and chemotherapy agents. The TAILORx protocol allows each physician to choose a chemotherapy regimen and/or hormone agent. Some might still choose the B-20 CMF and tamoxifen regimen for patients perceived to be at lower risk (within the intermediate group), while others might choose "dose dense" taxol containing aggressive treatment for a patient like the hypothetical one described above. There are many reasons why this may lead to errors.

 

The gene for glutathione S-transferase (GST) GSTM1 is one of the 16 predictor genes in Oncotype Dx. The presence of this gene tends to improve prognosis. The problem is that this gene also affects the metabolism of some cancer drugs. Anticancer drugs that have been shown to be substrates for GSTs are, for example, chlorambucil, melphalan, cytoxan metabolites, and steroids.  Indirect evidence for a role of GSTs in modulating drug effects through deactivation of drug-generated hydroperoxides or other reactive oxygene species exists for adriamycin, mitomycin C, carboplatin, and cisplatin, but not taxol. Some have postulated for other malignancies like acute leukemia in children that gstm1 confers a favorable prognosis because it changes chemotherapy metabolism. Oncotype Dx does not identify which patients have one copy of GSTM1 (a null polymorphism) and which have two copies. Remember B-20 chemotherapy often included cytoxan but never taxol. 

 

Another gene in Oncotype Dx is her2. Patients with tumors that express her2 are exluded from TAILORx. This gene is a prototype marker for chemotherapy selection since the drug Herceptin works very well when it is expressed and not at all if it isn't. B-20 contained a number of her2 positive patients and herceptin was not available in that era. So the Oncotype Dx used in TAILORx is a different one than the one tenuously "validated" in B-20. If the her2 gene is a totally independent predictor, the change might not matter. But her2 does interact with other cancer genes, for example the Src family. Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the Nobel Prize.

 

Bag1 is another gene in Oncotype Dx and it interacts with the estrogen receptor (alpa) mechanisms which can control cancer growth. Does it interact with tamoxifen (studied in B-20) the same way as the aromatase inhibitors included in TAILORx (but not in B-20)? BAG1 seems to predict respone to tamoxifen but how it predicts benefits from other hormones or chemotherapy is less clear.

 

TAILORx is constructed on a tenuous foundation based on a very small number of observations (remember the 47 patieint subgroup) and on many exrapolations based on assumptions. Some of these may seem niggling, such as the fact that B-20 used age 70 and tumor size 4cm as cut offs and TAILORx uses 75 and 5 cm. Yet B-20 found a suggestion that age and chemotherapy effectivenes interact and that tumor size affects prognosis.

 

And, one more thing: how can "partial breast radiation" be allowed in a non-random way? This would imply that partial breast radiation has become an acceptable "standard of care". Where are the appropriately powered randomized trials that support this implication? Don't be fooled into thinking that an analysis of this non-randomly assigned "stratification" can answer any useful question.

 

Stratification (i.e., prospective randomization within smaller, rigidly predefined clinical subroups) is often employed in clinical trials (though purists might argue that this is unnecessary in trials with a large number of outcome events).  But TAILORx is not stratified by rigidly predefined criteria. Rather it will permit thousands of patients and physicians to choose among a rich buffet of treatment options related to local therapy ((type of node sampling (any type among many permitted), type of mastectomy (any type among many), lumpectomy (any type among many), radiation (type of radiation, partial/whole radiation), chemotherapy (literally thousands of combinations and permutations of drugs and doses) and hormones (serms and aromatase inhibitors).)

 

Stratification might make sense if it were based on close to totally objective (not really ever possible in the real world) and independent classifications. Stratification makes no sense if it based on thousands of differing views and biases related to the risks and benefits of a multitude of differing therapies. Those decisions will be largely based on the very risk assessment conderations that the TAILORx trial is supposed to answer.

 

"Although technological advances will further improve our understanding of breast cancer and will contribute to tailoring treatment to the individual patient, our experience with adjuvant CMF over 30 years confirms that the effects of such a regimen are long lasting and may benefit patients with favourable and unfavourable prognostic indicators, at the cost of minimal long term sequelae." This is how Dr. Bonadonna himself described in 2005 (emphasis added) results from the chemotherapy regimen that is still often called "Bonadonna CMF". "Tailoring treatment" is the holy grail but TAILORx is designed too clumbsily to trump 30 years of better designed clinical trials.

 

Monks from the Order of the Brothers of the Statistic will study the scripture that flows from TAILORx and will be able to devine all the potential biases and confounders by utililizing probabilistic testing based on dubious underpinnigs that may well result in some very "significant" and small "p" numbers. Cultists who worship at that particular altar of "evidence based" medicine will travel about with their power point slides of life table graphs and p values carried to the fourth decimal point, Genomic Health will turn a profit for the first time and its shares will skyrocket, and another level of the temple known to heretics as the "House of Cards" will have been constructed.

 

Or maybe the results will look so powerful that even a skeptic like me will be convinced (or fooled).

 

TAILORx may be another example of the technological imperative in action. TAILORx reflects the fervent need of patients and doctors for a simple "black box" method for making difficult choices. The admonition of H.L. Mencken bears remembering: "For every complex problem, there is a solution that is simple, neat, and wrong."

 

 

A serious question for women with breast cancer and their physicians is whether chemotherapy should be employed after the initial breast surgery. This decision is particularly vexing for situations where the prognosis is relatively good, but not good enough. Patients whose cancers have estrogen receptors and who do not have any spread to the lymph nodes comprise such a group. And the group is large, perhaps half the women with breast cancer.

 

A decade or so ago the results from the National Surgical Adjuvant Breast Project chemotherapy trial B-20 were reported. This trial suggested chemotherapy was of benefit before the menopause with a step down in usefulness with menopause and then a continuing decline with age. Thus tamoxifen plus chemotherapy seemed wise up until roughly the age of 60 (the trial did not include women over 70).  The chemotherapy employed in B-20 were regimens that date to the 1970's. Many experts believe that newer regimens are more effective.

 

B-20 revealed that the degree of estrogen positivity was possibly important, with women with lower levels benefiting more from the chemotherapy and tamoxifen combination. The advent of gene profiling, like the proprietary “Oncotype Dx”, seems to have resolved the chemotherapy issue for many patients and physicians. Is this rational or simply another example of the technological imperative?

 

“The RS [Oncotype Recurrence Score] assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit” is the conclusion in a paper in the Journal of Clinical Oncology in 2006. Based largely on this study, Oncotype Dx appears with favorable mention in the American Society of Clinical Oncologists and National Comprehensive Cancer Network guidelines. Genomic Health, the company that sells the Oncotype Dx test, uses these guidelines and the JCO paper in its marketing.

 

The 12 page JCO report is chock full of sophisticated analysis, such as “linear fit of the likelihood of distant recurrence as a continuous function of recurrence score” analyses and various multivariate models. But what is the basis for the statement that Oncotype “predicts the magnitude of chemotherapy benefit”?

 

A glance at “Fig. A2” on page 11 tells the story. Figure A2 gives 12 year “overall survival” comparisons for four groups: tamoxifen versus combined tamoxifen/chemo for all patients lumped together, and the corresponding comparisons for good, intermediate, and poor Oncotype Dx score groups. Seven of the eight groups have 12 year survival ranging from about 92% for the low score tamoxifen alone group to about 82% for both intermediate groups, and the tamoxifen/chemotherapy high risk group.

 

Only the high Oncotype risk score tamoxifen alone group jumps off the page. This group has a 12 year survival of only 60%. But the tamoxifen alone group with high risk Oncotype scores consists of only 47 patients. Where did these 47 patients come from? They came from a study (B-20) done by the NSABP and reported in 1997 and included 2363 patients with breast cancer, negative lymph nodes and positive estrogen receptors. The 47 unlucky patients were about 2% of the total enrolled patients in NSABP B-20.

 

Are the 47 patients representative of all the Oncotype high risk patients in B-20? It is hard to say. Samples of the original breast tumors were available for only 670 patients and testing was successful in 651. So, only about ¼ of the B-20 patients are included in the Oncotype study. If this sample were random, probabilistic analysis might be intact. But the absence of material to test was not random. Some of the tumor samples were “used up” in other studies, and not saved in others. Presumably these other studies were focused on something specific and not random.

 

And what about the “overall survival” of 60%? Is that real? Again, it is hard to say. “Deaths before distant recurrence [was] considered [a] censoring event”. This means that a patient who was killed in an auto crash would be counted as alive but lost to follow up rather than counted as a death. But what if the crash was caused by a blood clot caused by the tamoxifen? And, since both chemotherapy and tamoxifen are thought to increase clots, what if several more patients in the combined group than in the tamoxifen died of strokes or heart attacks?

 

Oncotype is being used by patients and physicians all over the country to decide upon chemotherapy based on the 47 patients. Perhaps by a coincidence, the 12 year survival for both the Oncotype intermediate and high risk combined tamoxifen/chemotherapy groups was nearly identical at 82%. There were 212 such patients.

 

However, the 47 high risk tamoxifen alone group had survival 22% less than any other group. What are the possible explanations for the remarkably bad outcome for the 47 patients? Perhaps it is as it seems – tamoxifen alone is inadequate for high risk patients. Still it seems odd that the worst prognosis group had almost exactly the same survival experience as the intermediate group when the treatment was both chemotherapy and tamoxifen. If the understanding is that tamoxifen is good for estrogen receptor positive patients and chemotherapy adds something for some patients, how is it that the combination gives the same results for both intermediate and high risk patients?

 

Maybe the 47 were just very unlucky and the 117 high risk patients who got the combination therapy were astonishingly lucky to get the same results as the intermediate group. To account for this possibility, tests of statistical significance are performed. Using one of these (Cox proportional hazard test), there is less than one chance in a thousand that the 22% difference in survival is “random”, according to the analysis done by the authors. The tests for statistical significance assume random allocation of treatment. The original B-20 trial was randomized but the Oncotype study was not based on a random sample from that trial and was retrospective.

 

In addition, the “significance testing” was not said to have been corrected for the fact that many comparisons were made. The degree of confidence one takes away from a retrospective study full of potentially confounding variables and assumptions that violate basic probabilistic underpinnings is not as high as the statistical significance level might otherwise imply.

 

The authors of the JCO paper claim that their test “predicts the magnitude of chemotherapy benefit.” This seems not quite right. The magnitude of benefit from tamoxifen/chemo was identical in the intermediate and high risk score groups. What the test may have predicted in those 47 patients with high scores was a poor outcome with tamoxifen alone. One would think that the suggestion that Oncotype should serve as the basis for treatment selection for 100,000 women should not be based on the experience of an undefined 47 patient “chunk sample”.

 

The test costs about $3650. About 100,000 women may have er positive, node negative cancer diagnosed this year. That’s $365 mil for just one test in a complicated setting where many other images and tests will be required. Oncotype Dx should be verified by a prospective randomized trial that is appropriately stratified. Such a trial is underway.

 

More on this later.

"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. 

 

 

 

 

 

 

 

 

“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.

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.