The first randomized clinical trial comparing active surveillance, surgery and external beam radiation tells us little :-(

This was supposed to be HUGE! The first clinical trial ever where patients were randomly assigned to active surveillance (AS), radical prostatectomy (RP) or external beam radiotherapy (EBRT). The results were published in The New England Journal of Medicine (see this link). They started signing up men in the UK in 1999 and continued recruitment for 10 years. By 2009, they screened over 82,000 men for prostate cancer and found 1,643 men with newly diagnosed localized prostate cancer who were willing to be randomized to initial treatment with AS, RP or EBRT, about a third in each. They then followed them for a median of ten years to see how well they did with each therapy. Imagine the effort involved! Sounds good so far -- what could go wrong?

The bottom line was that all 3 therapies did about the same in preventing death. AS was found to cause higher rates of disease progression and metastases. We will explore why below.

There were several problems that arose.

1. They planned to detect mortality differences, but couldn't.

They thought there would be more deaths in the ten years of follow-up, but almost all the men defied those expectations. That's partly because of all the great new life-prolonging drugs that became available in the 21st century; drugs like docetaxel, Xtandi, Zytiga, and Xofigo. Also, in a clinical trial, patients are very closely diagnosed, treated, and monitored. They get far better care than the average patient in community practice. There were only 17 prostate-cancer related deaths

Men also survived longer because of progress in treating other diseases. But most of all, men lived longer because they frequently visited doctors as part of the study, during which they were  closely monitored for other illnesses. There were only 152 deaths from all other causes, only 9% of the total sample size. Men were 50 to 69 years of age  (62 years median) at the start of the study and were tracked for 10 years. On average, based on US actuarial tables, about 18% should have died from all causes. So the mortality rate was half of what was expected. On the average, men in the UK live two years longer than men in the US - not enough to account for the difference.

No worries. Instead of looking for mortality differences, the researchers had a secondary objective to look for differences in disease progression and rates of metastases. Those are excellent surrogate endpoints. But...

2. The intended treatment wasn't always what patients wound up doing

Although men were randomized to one of the 3 therapies, a lot of the men apparently changed their minds, as was their right. The authors of the study analyzed everything based on the intended treatment at the time they were randomized. This is how they said they would analyze the data, and they stuck with the plan. The switching that occurred was as follows:

• Of the 545 men randomly assigned to AS,  482 (88%) stayed with it at least for 9 months. The rest decided to have surgery, radiation, no therapy, or dropped out.
• Of the 553 men randomly assigned to RP, 391 (71%) did have surgery within the first 9 months following randomization. Most of the remainder switched to AS, the rest to radiation or other treatment, and a few chose no treatment or dropped out.
• Of the 545 men randomly assigned to EBRT, 405 (74%) did have EBRT within the first 9 months following randomization. Most of the remainder switched to AS, the rest to surgery, other treatment, no treatment or dropped out.
• In all, 22% of the men did not have the therapy they were originally randomized to, yet they are including in the analysis as if they did. It is unknown how this may have skewed the findings.

3. Their AS protocol was nothing like contemporary protocols.

     a. Inclusion criteria were much less restrictive

In contemporary AS protocols, almost all men are in the "low risk" category. "Low Risk" means they are stage T1c or T2a, their Gleason score is 6, and their PSA is less than 10. Some of the more restrictive AS programs, like Johns Hopkins, also include the "Epstein criteria." That means there were no more than 2 positive cores, no more than 50% cancer in any positive cores, and the PSA density must be less than 0.15 ng/ml/g. For the first time this year, NCCN included AS as an option for men with Gleason score 3+4 if no more than half the cores were positive, but only if they were otherwise low risk.

In the ProtecT trial, the only inclusion criterion was that the men had to have localized prostate cancer. See this link for their protocol. This means that they allowed men who were higher stage (T2b and T2c), higher grade (Gleason score ≥ 7), and higher PSA (PSA could be as high as 10-20 ng/ml). In fact, they previously reported that, among the AS cohort:

• 10% had an initial PSA between 10 and 20 ng/ml
• 22% had an initial Gleason score≥ 7 (2% were GS 8-10)
• 25% had a clinical stage of T2 - they do not break that into subcategories, presumably most were T2a

So, many of those higher risk men would have been screened out of a contemporary AS program. The authors did not analyze this higher risk subgroup to tell us how many of the 33 cases of metastases or 112 cases of clinical progression were among them, but they do report (Table 2) that of the 8 prostate-cancer deaths in the AS group, 5 were among men with Gleason score ≥ 7 at diagnosis (vs. 2 each for RP and EBRT). The remaining 3 deaths among those diagnosed as Gleason 6 was similar to the number for RP (3) and EBRT (2). It seems that all extra deaths were attributable to higher Gleason scores in their AS program.

     b. Monitoring of men on AS was below contemporary standards.

In contemporary AS protocols, there is always a confirmatory follow-up biopsy within a year of the first screening biopsy. The repeat biopsy schedule varies from that point on, and may be every year, as it was originally at Johns Hopkins. Some AS protocols utilize mpMRI to search for suspicious areas and only biopsy as suspicion arises, others implement a biopsy schedule that may vary depending on the findings of the last biopsy. Some do TRUS biopsies, some do mpMRI-targeted biopsies, some combine the two, and some do follow-up transperineal template-mapping biopsies. But all good AS programs include follow-up biopsies.

In the ProtecT trial, patients were screened for a high PSA (> 20 ng/ml), emergent symptoms, or a 12-month PSA increase ≥ 50%. So those who had a form of prostate cancer with a low PSA output (such as some of those with predominant Gleason pattern 5) would never be discovered until symptomatic metastases occurred. I don’t know what percent ever got a second biopsy.

We recently saw what happened in Göteborg when there was no pre-determined biopsy schedule: 54 out of 474 men (11%) failed on AS. They used a similar monitoring system as the ProtecT trial: quarterly, and then semi-annual PSA tests, and re-biopsy at the discretion of the doctor.

I sometimes talk to patients who get periodic PSA tests and claim they are on active surveillance. They are putting themselves in danger. Time and again, PSA kinetics have been rejected as a sole indicator of progression for very good reasons, mainly (1) PSA is affected by many non-cancer causes, and (2) some of the most virulent prostate cancer cells put out very little PSA. There is no substitute for confirmatory and follow-up biopsies.

Let's put perspective just how egregious a difference it is when active surveillance does not include follow-up biopsies. Current estimates are that one in three TRUS-guided biopsies (12 through the rectum) will miss a higher grade of cancer. So, if one biopsy failed to detect a higher grade cancer with odds of 33%, then the odds of missing it on two biopsies is (.33) squared, etc. As the following table shows, the odds of missing the higher grade cancer with annual biopsies for ten years is about 1 in a hundred-thousand.

Biopsy	Odds of missing higher grade in ALL the biopsies
1st	33%
2nd	11%
3rd	4%
4th	1%
5th	0.4%
6th	0.1%
7th	0.04%
8th	0.01%
9th	0.005%
10th	0.001%

Now, at Johns Hopkins, for example, it was their active surveillance policy to have annual biopsies, and they used the Epstein criteria discussed above. After 15 years of follow-up, the metastasis-free survival rate was 99.4%. Laurence Klotz at Sunnybrook in Toronto has the longest running trial of active surveillance in North America. They allowed some patients as high as favorable intermediate risk, and while there was always a confirmatory biopsy in the first year, their biopsy schedule was not as rigorous as Johns Hopkins. After 20 years, of follow-up, they report metastasis-free survival of 97.2%. In the ProtecT trial, there were 33 men out of the 545 men in the AS cohort - 6.1% had already been diagnosed with metastases after only 10 years of follow-up. The outcomes of the AS cohort are very out-of-line compared to active surveillance programs that have more rigorous selection criteria and monitoring protocols.

Selection criteria	Biopsy schedule	Active Surveillance Program	Follow-up	Metastasis-free survival
Strictest: Epstein protocol	Annual	Johns Hopkins	15 years	99.4%
Less strict: favorable risk only	Confirmatory and periodic thereafter	Sunnybrook	20 years	97.2%
Any localized regardless of PSA or grade	none	ProtecT	10 years	93.9%

4. Their EBRT protocol was below today's standards.

In the years prior to 1999 when they were planning this study, there were very different radiation therapies in place than have now become standard of care. This is a problem with all long-term clinical trials involving radiation technology. By the time we get the results, they are irrelevant because the technology and understanding has progressed so much. For an expanded discussion of this issue, see this link.

They used an older technology (3D-CRT) to deliver only 74 Gy in 37 treatments while adding 3-6 months of hormone therapy before and during treatment. Now, with IGRT/IMRT technology, the patients would safely receive about 80 Gy. Low and favorable risk patients probably do not benefit from adjuvant ADT -- it adds sexual side effects without adding to cancer control in most of them. Some have questioned whether the increase is justified for low or intermediate risk patients (see this link), but, as we saw, 10 years is not long enough to judge that, and there is no consequence to the higher dose in terms of side effects. It is entirely possible that the low dose they gave patients only delayed progression but did not cure the cancer.  If that is true, we may see the EBRT outcomes deteriorate when they present their planned 15-year follow-up.

ProtecT was a vast and expensive undertaking. It will probably never be repeated, and there isn't likely to ever be a US equivalent. Sadly, we can't learn very much from their current analysis of this major study, although it may yield more fruit with some subsequent analyses.

How long is long enough? Length of follow-up on clinical trials for primary treatments

Many of us are faced with the difficulty of choosing a primary therapy based on data from clinical trials with follow-up shorter than our life expectancy. How can we know what to expect in 20 or 30 years? This is quite apart from the fact that most published studies only tell us how the treatment worked for a chosen group of patients treated by some of the top doctors at some of the top institutions – they never predict for the individual case that we really want to know about; i.e., “me.” The issue of length of follow-up is particularly problematic for radiation therapies, although it may be too short for surgery and active surveillance studies as well. How can we make a reasonable decision given the uncertainty of future predictions?

I may have missed some studies, but the longest follow-up studies I have seen for each primary therapy treatment type are as follows:

• HDR brachy monotherapy - 10 years (CET/Demanes)
• HDR brachy+EBRT - 15 years (Kiel, Germany)
• IMRT - 10 years (MSKCC)
• LDR brachy monotherapy - 12 years (UWSeattle & Mt. Sinai)*
• LDR brachy+EBRT - 25 years (RCOG)
• Protons- 10 years (Loma Linda)
• SBRT - 9 years (Katz)
• Robotic RP - 10 years (Henry Ford Hospital, Detroit)
• Laparoscopic RP - 10 years (Heilbronn, Germany)
• Open RP - 25 years (Johns Hopkins)
• Active Surveillance - 20 years (Toronto)

*Mt. Sinai published a study with longer follow-up (15 years); however, all patients were treated from 1988 to 1992, before modern methods were used, and such results are irrelevant (see below) for decision-making today.

On a personal note, I was treated at the age of 57 and had an average life expectancy of 24 years, possibly more because I have a healthy lifestyle and no comorbidities. So there were no data that could help me predict my likelihood of cause-specific survival and quality of life out to the end of my reasonably expected days. What's more, the therapies with the longest follow-up (open RP, brachy boost) also have the highest rates of serious side effects. With my low-risk cancer, there seemed little need to take that risk with my quality of life.

While we may be tempted to wait for longer follow-up, (1) we don't always have that luxury, and (2) there very likely will not be any longer follow-up. Not only is follow-up expensive, there are also the problems of non-response, drop-outs, and death from other causes. The median age of patients in radiation trials is typically around 70, so many will leave the study. The 10-yr Demanes study, for example, started with 448 patients, but there were only 75 patients with 10 years of follow-up. The “10-year” study of IMRT at MSKCC started with 170 patients, but only 8 patients were included for the full ten years! After the sample size gets this small, we question the validity of the probability estimates, and there is no statistical validity in tracking further changes. (It is worth noting that IMRT became the standard of care without longer term or comparative evidence.)

An even bigger problem is what I call irrelevance. Technological and medical science advances continue at so brisk a pace that the treatment techniques ten years from now are not likely to resemble anything currently available (another argument for active surveillance, if that's an option). Dose escalation, hypofractionation, IGRT technology, intra-operative planning, VMAT, variable multi-leaf collimators, on-board cone-beam CT, and high precision linacs - all innovations that have mostly become available in the last 15 years - have dramatically changed the outcomes of every kind of radiation therapy, and made them totally incomparable to the earlier versions. Imagine shopping for a new MacBook based on the performance data of the 2000 clamshell iBook. By the time we get the long-term results, they are irrelevant to the decision now at hand.

What we want to learn from long-term clinical trials are the answer to two questions: (1) Will this treatment allow me to live out my full life? and (2) what are the side effects likely to be? To answer the first question, researchers look at prostate cancer-specific survival. It’s not an easy thing to measure accurately – cause of death may or may not be directly related to the prostate cancer. We usually look at overall survival as well. For a newly diagnosed intermediate risk man, prostate cancer survival is often more than 20 years, so we can’t wait until we have those results to make a decision. Taking one step back, we look at metastasis-free survival, but that is often over 15 years. Sometimes there is clinical evidence of a recurrence before a metastasis is detected (e.g., from a biopsy or imaging). More often, the only timely clue of recurrence is biochemical – a rise in PSA over some arbitrary point. That point is set by consensus. Researchers arrived at the consensus after weighing a number of factors, especially its correlation with clinically-detected progression. Biochemical recurrence-tree survival (bRFS), or its inverse, biochemical failure (BF), is the most commonly used surrogate endpoint.

We might be comfortable if outcomes seem to have reached a plateau. For some of the above studies, we are able to look at some of the earlier reported biochemical failure rates compared to those measures reported at the end of the study (ideally broken out by risk group).

• ·      In the Demanes Study, the 10-year results are virtually unchanged from the 8-year results.
• ·      In the Kiel study of HDR brachy boost, the 5-, 10- and 15-year BF was 22%, 31%, and 36%.
• ·      In the RCOG study of LDR brachy boost, the 10-, 15-, 20- and 25-year BF was 25%, 27%, 27%, and 27%
• ·      In the Mt. Sinai study of LDR brachy, the 8- and 12-yr BF was 12% and 10% for low risk; 19% and 16% for intermediate risk; 35% and 36% for high-risk patients.
• ·      In the MSKCC study of IMRT, the 3-, 8- and 10-yr BF was 8%, 11%, and 19% for low risk; 14%, 22% and 22% for intermediate risk; 19%, 33% and 38% for high risk patients.
• ·      In the Katz SBRT study, the 5- and 7-year BF was 2% and 4% for low-risk, 9% and 11% for intermediate-risk, and 26% and 32% for high-risk patients.
• ·      For comparison, the 5- 10- 15- and 25- year recurrence rates for prostatectomy at Johns Hopkins were 16%, 26%, 34% and 32%.

For most of the therapies, HDR & LDR brachy monotherapy, LDR brachy boost therapy, and SBRT, the failure rates remained remarkably consistent over the years. However, for surgery and IMRT, failure rates increased markedly in later years. Most of us can’t wait 25 or more years to see if a therapeutic option remains consistent or not, and for radiation, the results would almost assuredly be irrelevant anyway.

Ralph Waldo Emerson is misquoted as saying, “Build a better mousetrap, and the world will beat a path to your door.” An important criterion for decision-making when there is only limited data is our answer to the question: Is this a better mousetrap? Arguably, robotic surgery was only an improvement over open surgery, and not an entirely new therapy requiring separate evaluation. It has never been tested in a randomized comparison, and I doubt we will ever know for sure. Arguably, IMRT was simply a “better mousetrap” version of the 3DCRT technique it largely superseded and didn’t need a randomized comparison to prove its worth. Was HDRBT monotherapy just an improvement over HDRBT+EBRT? Was SBRT just an improvement over IMRT, or should we view it as a variation on HDRBT, which it radiologically resembles by design? There are no easy answers to any of these questions. However, as a cautionary note, I should mention that proton therapy was touted as more precise because of the “Bragg peak effect,” yet in practice seems to be no better in cancer control or toxicity than IMRT.

There is also the problem of separating the effect of the therapy from the effect of the learning curve of the treating physician. Outcomes are always better for patients with more practiced physicians. The learning curve has been documented for open and robotic surgery, but less well documented for radiation therapies. Patients treated early (and perhaps less skillfully) in a trial are over-represented in the latest follow-up, and there may be very little follow-up time on the most recently (and perhaps more skillfully) treated patients.

So when do we have enough data to make a decision? That comfort level will vary among individuals. I was comfortable with 3-year data based on choosing a theoretically “better mousetrap”, and many brave souls (thank God for them!) are comfortable with clinical trials of innovative therapies. In the end, everyone must assess for himself how long is long enough. For doctors offering competing therapies and for some insurance companies, there never seems to be long enough follow-up. I suggest that patients who are frustrated by those doctors and insurance companies challenge them to come up with concrete answers to the following questions:

• ·      What length of follow-up do you want to see, and why that length?
• ·      What length of follow-up was used to determine the standard of care?
• ·      Do you need to see prostate-cancer specific survival, or are you comfortable with an earlier surrogate endpoint?
• ·      What is the likelihood of seeing longer term results, and will there be any statistical validity to them if we get them?
• ·      Have outcomes reached a plateau already?
• ·      What evidence is there that toxicity outcomes change markedly after 2 years?
• ·      Will the results still be relevant if we wait for longer follow-up?
• ·      Is the therapy just a “better mousetrap” version of a standard of care?
• ·      Are my results likely to be better now that there are experienced practitioners?

Can invasive procedures spread prostate cancer?

Prostate cancer is seldom spread by invasive procedures such as biopsies, prostatectomy, TURP, LDR brachytherapy, HDR brachytherapy, or insertion of fiducials for image-guided radiotherapy. We know this because those procedures have high cure rates. Nevertheless, there have been isolated case reports of such inadvertent cancer dissemination occurring.

Mechanism of unintended cancer dissemination

Two direct mechanisms have been proposed as ways in which invasive procedures may facilitate the spread of cancers:

(1) by direct implantation from invasive instruments like biopsy needles or surgical knives, and

(2) by release of tumor cells into the bloodstream or lymph.

It is likely that only a few, less prevalent types of prostate cancer cells are amenable to spreading by invasive procedures. The most prevalent types of prostate cancer are incapable of survival outside of the prostatic environment. Several studies have now shown that true Gleason 6 tumors have never been known to metastasize. However, that does not preclude their eating into adjoining tissue, or possibly evolving to higher Gleason grade. Only cells that have some major alterations in their genetic structure are capable of moving through and beyond the prostate. Cancer stem cells spread readily yet are not always detected.

Detection

Until very recently, we lacked the technology to detect the very small foci of cancer cells that may have been accidentally seeded. Those foci have been found only when they grew much larger. That has occurred as long as 19 years later in one case, and then suspicion was raised because it recurred in such an unusual spot (the perineum). The advent of multiparametric MRIs has enabled us to see much smaller foci of recurrences than we have before, with the potential to see foci as small as 4 mm in length (Barchetti and Panebianco). The limit of detection may be even lower for the new generation of PSMA-antibody-based radiotracers coupled with the new PET/MRI scanners. Even so, if the cancer is in a more usual place, such as the anastomosis, how do we distinguish a cancer placed by instrumentation from one that grew there naturally?

Circulating tumor cells may be found with CellSearch® or ADNA® tests.

Biopsy

Biopsies can break off rogue cancer cells and plant them along the needle tract. This has been observed in breast cancer, liver cancer, and rarely in other cancer biopsies as well (Shyamala et al.) Although the cells are planted there, they do not remain viable for long outside of their host environment (Loughran et al.) and usually do not produce tumors. There have been isolated cases of tumors produced by needle-tracking of prostate cancer biopsies. In 1987, Haddad and Somain found 15 such cases of prostate tumors that had to have arisen following transperineal biopsies.

In 1991, Bastacky, Walsh and Epstein at Johns Hopkins found that tumor growth along the needle track was evident in the periprostatic soft tissue in 2% of the prostatectomy specimens they examined. Unlike earlier reports that only found needle tracking in transperineal biopsies of high-grade tumors, they found it in transrectal biopsies of Gleason 7 tumors as well. A recent literature review by Volanis et al. found 42 case reports of needle-tract seeding.

Another way that biopsies can potentially spread cancer is by release of isolated cells into systemic circulation. Tumor cells are less sticky than healthy cells, so they may be more easily dislodged by invasive procedures. In a recent study by Ladjevardi et al., the researchers looked at the peripheral blood (from their arms) of 38 men (23 patients with PC, 15 patients without PC) before and after prostate biopsy. They examined the blood for presence of epithelial cells that might have become dislodged by the biopsy. They found cellular material in 83% of the men who had PC, but only in 13% of the men who did not have PC. This does not mean that the epithelial cells were tumor cells, or if there were, that they were viable. The most viable kinds of tumor cells are mesenchymal rather than epithelial, but those were not searched for. It would be interesting to see this experiment repeated with CellSearch® or ADNA® technology, which can detect and distinguish circulating tumor cells.

Surgery

Some cancers are easily spread through inoculation by surgical instruments. For this reason, surgeons try to avoid cutting into the tumor. With unifocal tumors (e.g., breast cancer) the surgeon cuts a margin around the tumor. But with prostate cancer, where tumors are almost always multifocal and can be anywhere in the prostate, surgeons try to remove the entire prostate in one piece. Sometimes, surgeons slice through the tumor at the margin, leaving behind a positive surgical margin (PSM). Sometimes this is inevitable, but experienced surgeons typically have a lower PSM rate. At Johns Hopkins, for example, the PSM rate is as low as about 10%. The cancer left behind may continue to grow, may become non-viable after detachment, or may get cleaned up by the immune system. It is unknown at this time whether tumor cells detached by the cut at the PSM seed new tumors.

A similar effect may occur when an attempt is made to spare neurovascular bundles. In a study of 9,915 patients treated at Memorial Sloan Kettering and Ottawa Hospital from 1985-2010, 6% had prostate incision. Those who had bilateral nerve-sparing had incision rates over twice as high as those who did not have nerve-sparing surgery, after adjustment for confounders. Patients who had robotic surgery had incision rates almost twice as high as those who had open or laparoscopic surgery. Risk of prostate incision has decreased over time, presumably with surgeon’s experience.

Another difficulty arises where the surgeon must detach the prostate from the urethra, which runs right down the middle. The surgeon scrapes prostate tissue away from the urethra, and cuts it as far away as he can from the bladder neck on top, and the urethral sphincter, on the bottom. He then joins the two ends together, which is called an anastomosis. This procedure may leave cancerous tissue behind. In a recent CT/MRI study of post-prostatectomy tissue, 76% of recurrences after surgery were found to occur at the anastomosis. How many of those were from cancerous tissue that was left behind, and how many from contamination of the surgical blade?

Sometimes, especially with laparoscopic procedures on large prostates, the surgeon is forced to cut the prostate up into smaller pieces that he can remove through the port – a process known as morcellation. This may be especially risky for releasing cancer cells into systemic circulation. In April 2014, the FDA discouraged the use of morcellation on the uterus or uterine fibroid tumors because of the high risk of cancer spread associated with the process. Sometimes surgeons will recommend hormone therapy to their patients with especially large prostates in order to perform robotic surgery without morcellation. To my knowledge, there have been no studies of the effect of morcellation on prostate cancer spreading.

Spread of cancer at the laparoscopic port site is exceedingly rare. A 2004 study looked at 10,912 urologic laparoscopic procedures across 50 different treatment centers, and found only 10 cases of port seeding and 3 cases of peritoneal spread from the procedure. There have been only a handful of cases reported since then. Robotic laparoscopic surgery is responsible for only 3 documented cases of port site and/or peritoneal spread: one case in Japan, one case in Korea, and one case in Turkey.

Cancer cells may be released into systemic circulation by surgery. A study of circulating epithelial tumor cells in breast cancer patients found that the serum-detected cell numbers did increase in some patients following surgery, and the increase was sustained in some, indicating viability. A study of bladder cancer circulating tumor cells using CellSearch® found an increase following transurethral bladder resection. Eschwège et al. found increased numbers of prostate epithelial cells in the serum after surgery, but found no association with metastatic progression or survival. To my knowledge, there has not yet been a study specifically of circulating tumor cells pre- and post-prostatectomy.

There is not enough documented proof that the magnitude of cancer spread by surgery is large enough to be of concern. However, the potential for cancer spreading by poor surgical technique is one more reason to find the most experienced surgeon possible.

Low Dose Rate (LDR) Brachytherapy or “Seeds”

Implanting seeds is a highly invasive procedure, with 70 or more radioactive seeds injected into the prostate. In a Japanese study among 616 consecutive patients receiving LDR brachytherapy between 2003-2010, 5 patients had a pulmonary metastasis after clinical recurrence. Pulmonary metastases are rare, but they were hormone-responsive, which suggests a prostate cancer origin. The authors note that they may have been caused by seed migration to the lungs. All of those 5 had high Gleason scores, and only one had neoadjuvant hormone therapy.

High Dose Rate (HDR) Brachytherapy

Raleigh et al. at UCSF recently reported the first case of prostate cancer seeding following HDR brachytherapy treatment for a man with high risk PC treated with a combination of HDR brachytherapy and EBRT. The cancer recurred at the site where an HDR brachytherapy catheter was known to have touched the patient's bladder. The authors conclude:

"This case is the first report of prostate cancer recurrence in the bladder wall after brachytherapy and raises questions about prostate cancer biology, brachytherapy technique, and the timing of brachytherapy boost relative to whole pelvic radiotherapy for prostate cancer."
 

I hope that readers will not be dissuaded by these reports from seeking diagnostics and therapies they may be considering. There are risks with any invasive procedure, but it is important to keep the relative magnitude of those risks in perspective. I think these case studies are useful insofar as they are generative of hypotheses. It is clearly an area ripe for further scientific inquiry.