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Brachytherapy grew rapidly in the late 1990s, and may have unseated external beam radiation (XBR) as the second most popular treatment for prostate cancer. Recently it has come under attack by surgeons who perform radical prostatectomy (RP), a procedure that accounts for an estimated 60% to 70% of all treatments for this disease (excluding hormone therapy). GARP believes that criticisms of "implant-only" brachytherapy are valid. However, GARP is tremendously impressed by the inroads that simultaneous implant/conformal beam radiation therapy is making. In fact, we believe that this improved technique is significant enough that it will unseat RP as the gold standard in treatment for prostate cancer. The transition will not be devoid of bumps in the road. First of all, the number of implant-only brachytherapy procedures could fall faster than simultaneous irradiation could pick up the slack. Secondly, it is quite likely that palladium-103 implants, which account for40% of all seeds sold, could completely lose favor with brachytherapists who would then use iodine-125isotopes. In this in-depth report, GARP describes the background and dynamics of trends in prostate cancer treatment and how these trends may create market opportunity for iodine-125 seed manufacturers. 

The history of modern prostate cancer treatment is best seen through its principal protagonists. GARP would like to commend several doctors who have been pioneers in the field. These include Dr. Walsh in the area of surgery, Drs. Ragde & Blasko in brachytherapy, and Dr. Critz in the area of combination brachytherapy external radiation therapy. GARP believes that the findings of Dr. Critz are receiving significant recognition and could extend to have a major impact upon his peers and the radioisotope seed business.  

Dr. Patrick Walsh, Chairman of the Brady Urological Institute at Johns Hopkins, is the acknowledged giant in the field of urologic oncology. RP has been performed for decades, but took a major leap forward in 1982. In that year, Dr. Walsh discovered that the nerves controlling erections do not pass through the prostate. Two years later he perfected what is now known as nerve-sparing RP. Today, nearly all RP operations are nerve sparing. US News & World Report has recognized his clinic as the #1 of its kind for over a decade. Dr. Walsh is eager to uphold its reputation and publishes statistics that rank among the world's highest success rates for RP operations.  

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Most importantly, his findings have been peer-reviewed and published in major journals. GARP believes that the Internet may play a key role in disseminating the results of Dr. Critz to the public as well as to his peers. He clearly states complex ideas in layman's terms. A tour de force of his views is presented in www.prostrcision.com/pages/faq.html, which is on his clinic's web site. Additionally, he has become recognized as a leading authority on the topic within his profession. In May 1999 at its annual meeting in Dallas, the Society for Urologic Oncology of the American Urological Association (AUA) sponsored a "structured debate" featuring Dr. Critz, Dr. Walsh, and Dr. D'Amico, who represented brachytherapy, surgery, and external radiation respectively. Notably absent was an advocate of implant-only therapy.  

Clearly the most important finding of this debate was the analysis by Dr. Critz of the PSA nadir (the lowest PSA achieved after treatment) needed after irradiation for men to be cured of prostate cancer. Several years ago Dr. Critz showed that the post-treatment PSA nadir goal after radiotherapy for prostate cancer was, at a maximum, 0.5 ng/ml, and that men must achieve this goal to be cured. Because it can take several years for the PSA to fall to its lowest levels, at the 1999 Dallas AUA meeting Dr. Critz analyzed men treated with simultaneous irradiation via the transperineal implant technique with minimum 5 year follow-up. This analysis with modern techniques, allowing time to achieve ultimate nadir, demonstrated that for men to be cured of prostate cancer they must achieve and maintain an undetectable PSA nadir, less than or equal to 0.2 ng/ml.  

Dr. Critz's involvement with brachytherapy began in the late 1970s. He quickly surmised that the techniques of that era were crude and likely to be ineffective. Although he mastered the old style, retropubic method (one hand inserts seeds through an abdominal incision, another feels for placement through the rectum) he understood that all of the prostate's tissue would not get irradiated due to uneven spacing, and cancer cells outside the prostate due to microscopic capsular penetration would not be treated by seeds alone. By 1984, he had defined his innovative approach of combining external beam radiation after seed implantation, a unique process of simultaneous irradiation, and he began to enroll the first patients that are now in his 15-year data. Most radiation oncologists reverse Critz's sequence, administering 5 weeks of external beam radiation (XBR) prior to brachytherapy, and then only in high-risk patients. Critz believes this pre-implant "softening" with XBR adds little value since it separates the external beam irradiation from the implant, producing sequential doses rather than simultaneous exposure. Because Iodine-125 has a 60-day half-

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life, by performing the I-125 seed implant first followed three weeks later by 6-7 weeks of conformal beam irradiation, the cancer is irradiated simultaneously from two sources. Simultaneous irradiation intensifies the radiation dose through a synergistic effect on both cancerous and normal prostate cells.  

The surge of popularity of implant-only brachytherapy in the late 1990s may be linked to its promotion as a treatment that is as effective as surgery but spares the side effects of impotence and incontinence. GARP is aware of many reports from well-known brokerage firms that took this stance. However, this is a rather simplistic view. While brachytherapy definitely has fewer side effects than RP, one must understand that this is because it is a technique that is generally limited to within the confines of the prostate gland. However, surgical findings show that 50% of newly diagnosed men with early stage prostate cancer go on to discover that their cancer has spread outside the prostate capsule into surrounding tissues. In a few cases, these men could be cured through surgery since the possibility of excising areas outside the prostate exists, and external beam radiation could be used as a follow-up. This does not guarantee survival, and it almost always leads to incontinence and impotence. Even if a surgeon removes tissue near the prostate, frequently a few cancer cells have escaped beyond this zone like dandelion seeds in the wind. Given the choice of ineffective local treatment with seeds alone, it has unquestionably still been better to choose to live with pads and without sex than to be dry and die. GARP believes that many investors in shares of the ragenics turned a blind eye to this fundamental difference between RP and seed implant. This may explain why that company's valuation became quite effervescent in 1997 and early 1998, accelerated by the thrill generated when Drs. Ragde & Blasko published their very encouraging 7-year results. Incidentally, these cure rates were not calculated by PSA nadir 0.2 ng/ml but were calculated with higher nadir levels, which added to the good results.  

Ragde and Blasko's 10-year data, recently published by Dr. Ragde in late 1998, pricked this bubble of excitement. Instead of achieving a "plateau" of success (e.g. stability in the number of cancer-free patients overtime), between 7 and 10 years after treatment patients increasingly exhibit rising PSA levels. Specifically, their series' PSA monitored cancer freedom fell from 79% to 55% in that short 3 year span. The 55% cure rate reported by Dr. Ragde 10 years after treatment was calculated with PSA nadir 0.2 ng/ml and included men treated with not only with seed implant alone but also men treated with sequential external beam irradiation followed by seeds. The 10-year cure rate with ultrasound transperineal 1-125 implant only was less than 50%.It is particularly notable that all three debaters at the 1999 AUA annual meeting (Critz, Walsh, & D'Amico) took issue with the efficacy of implant-only brachytherapy.
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there is a synergistic effect, but it only happens if XBR is added after implantation. Finally, the conformal simultaneous XBR delivered in prostRcision treatment aids in reaching cells that may be in cold spots after post-implant trauma and can also reach selected tissue immediately outside the gland, where microscopic capsule penetration cancer cells may escape.  

Generally XBR is used to treat men who are not good candidates for surgery for health reasons other than the cancer. Also, very often surgeons recommend it in cases where they suspect that the disease has spread outside the prostate capsule. In these instances, surgery may not save the patient but it would probably cause incontinence and impotence and as always there is a small risk of life threatening complications during the procedure. Even adjusting for the bias of such high-risk patients, XBR has a poor track record with only 10%biochemical disease freedom after 10-years.

Dr. Critz stopped using the retropubic implant method in 1992 and began using ultrasound guided transperineal implantation as a part of simultaneous irradiation. However, his 10-year results with these patients treated by simultaneous irradiation with the obsolete retropubic implant method are equivalent to RP with 67%biochemical disease freedom. Given the deficiencies of the old-style technique, it is clear that simultaneous radiation is highly effective. When patients who have received implants with ultrasound guidance are also considered in Dr. Critz's statistics, his 10-year success ratio rises to 72%. This is considerably better than Ragde & Blasko's overall 55% success ratio after 10 years for men treated with implant only or with external beam irradiation followed by implant. Moreover, Critz reports that his disease free results achieve a plateau with no further failures after 8.5 years, whereas the steep decline between years 7 and 10 for implant-only statistics suggest that their patients are not "cured." One other danger faces implant-only patients. Drs. Ragde& Blasko may have exceptional operating room abilities. However, newly minted brachytherapists (of which there are many) only receive 2 days of classroom training and often are not terribly skilled at establishing a close, uniform placement pattern.  

GARP believes that Critz's simultaneous radiation technique is superior to surgery and could emerge as the gold standard eventually. When looking at summary statistics of the 10-year data, Critz's approach has a slight edge over radical prostatectomy, weighing in at a 72% success ratio compared to 68% for RP under Dr. Walsh.  Observers should note that there has not been much room for improvement in how a prostate gland gets removed since Walsh's discoveries in 1982. In contrast, the tools of the brachytherapy trade keep getting refined. The progression from retropubic to ultrasound guided to simultaneous radiation seems logical, even if this last rung on the ladder is not in the mainstream of thought in the investment and patient community.  Moreover, improvements could occur from here. At a minimum, due to the 10-year 

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Some other aspects of Dr. Critz's technique apply to this group of men. While Critz treats the whole prostate, he takes care to concentrate seeds in the "Peripheral Zone" of the prostate, an area near its edge as the name implies (see ultrasound photo below), where most cancers are located. Seeds are also placed outside the prostate in areas of likely extra capsular spread, such as the seminal vesicles and apex. These refinements, combined with the extension of conformal beam radiation into surrounding areas, probably account for the dramatically better results with intermediate risk patients.  

Interestingly, Dr. Critz uses iodine-125 instead of palladium-103 for some very specific reasons. Iodine has 30% more energy than palladium-103 (28kV vs. 21kV). It also has along window of activity (60-day half-life, versus 17 days for palladium-103). Iodine-125 is less likely to create cold spots because its higher energy can penetrate deeper into tissue when the prostate gland swells after brachytherapy, and also because its energy still gets released long after the swelling recedes. There are very few researchers that exclusively focus on palladium-103. GARP also finds it odd that Dr. Blasko, who is a paid consultant for Theragenics (until recently the only maker of palladium-103 seeds) has not updated a1995 abstract describing 5-year results of palladium implant only therapy. This study, long apart of Theragenics' marketing material, focused exclusively on that isotope. In contrast to this single report on palladium, Blasko's peer-reviewed publications reporting outcome include only those men treated with iodine-125. 

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the nature of the disease, it took nearly a decade for both innovations to begin to fall into disrepute. A clear-headed look at the rise of implant-only brachytherapy in the late 1990s would have to acknowledge that the field is especially ripe for statistical manipulation. The disease progresses slowly. The outcome of treatment is highly dependent upon patient selection. The disease tends to appear in men over 65. Mortality from other causes often strikes before the cancer does. There are multiple benchmarks for measuring outcomes. All these factors combine to make it difficult even for experts to compare each other's findings. The bottom line is that it takes a long time to die of this disease. No matter what treatment an early-stage patient receives, he is likely to be alive in 10 years. Moreover, there is a good chance his cancer probably will not show signs of metastasis yet. It's a researcher's delight.  

Thus, instead of valid comparative studies, there is a plethora of game playing which favors authors' interests, be they surgeons, brachytherapists, or radiation oncologists. The game is played in the following way. First, load the deck with patients that aren't too sick to begin with. Refer anyone at in the upper-intermediate risk level to a radiation oncologist for XBR. Next, publish frequently within a 3-7 year window after making a study, because the disease progresses so slowly that high survival and "disease free" PSA readings are assured.  If you make it to 10 years without completely horrible outcomes, define "success" in such a way that "disease free" statistics are favored by your treatment modality and loosely enough such that the success ratio is high.  This has clearly happened in the radiotherapy community but will change when radiotherapy cure rates are calculated by PSA nadir 0.2 ng/ml. Finally, don't bend the rules so much that massive peer review objections result or prestigious journals such as Cancer won't publish the results. If all else fails, publish outside of the top five medical journals, circulate the results widely among potential patients, advertise about a miraculous new prostate cancer cure, and laugh all the way to the bank. 

 Doubtlessly GARP is overstating the state of affairs in the analysis above. Researchers are well meaning and set out to cure diseases. However, there are vested interests when years of specialization and the building of practices are at stake. Once one is heavily committed down one path, it is difficult not to admit that another approach could be better. The easiest choice is to make slight adjustments in one's thinking which justify previous decisions. Predictably, surgeons defend surgery, brachytherapists advocate brachytherapy, and radiation oncologists favor XBR. Unless GARP laid out the case for game playing the way we did, the investment community would not see the forest for the trees.