Low Dose Rate Brachytherapy Monotherapy at the Mayo Clinic

The Mayo Clinic reported the 10-year oncological results on 974 consecutive low and intermediate risk patients treated with low dose rate brachytherapy (I-125 seeds) monotherapy from 1998 to 2013.

Patients were treated as follows:

• 90% of the prostate received 159 Gy (median dose) of 1-125 seeds
• 26% received some ADT (mainly to shrink the prostate)

Patient characteristics (number (%)) were as follows:

• Gleason 6: 783 (80%)
• Gleason 3+4 :153 (16%)
• Gleason 4+3:  38 (4%)
• Stage T 2b or 2c: 24 (2.5%)
• PSA ≥ 10: 93 (10%)
• Low risk: 693 (71%)
• Intermediate risk: 281 (29%)

While they did not routinely collect data on the percent of positive biopsy cores, they did define an "unfavorable intermediate risk" cohort as having Gleason 4+3 or multiple intermediate risk factors.

With median follow-up of 6 years, there were only 45 cases of biochemical failure, and 10 deaths from any cause. The 10-year biochemical recurrence-free survival was:

• 85% overall
• 90% among low risk men
• 74% among intermediate risk men

The following hazard ratios were significant on multivariate analysis:

• Gleason score 4+3: 7.0
• Use of ADT: 0.3
• PSA (per unit increase): 1.17
• Unfavorable intermediate risk : 3.75

Predominant Gleason pattern 4 also affected the rate of distant metastases and prostate cancer-specific survival. Use of ADT did not. Local recurrence was only 2%.

Radiation dose was consistently escalated, so the effect of dose differences failed to meet statistical significance. Patient selection has changed over the years. Low risk men are routinely steered towards active surveillance. Multiparametric MRI is now used to stage intermediate risk candidates in order to find those where cancer is likely to have escaped the prostate capsule or penetrated the seminal vesicles -- those patients may be offered multimodal radiation with both external beam therapy and a brachy boost. While use of monotherapy was rare among those with GS 4+3, it is probably much rarer today. Monotherapy seems to be sufficient in favorable intermediate risk men.

This study had similar results to those reported by Cleveland Clinic (see this link). It also affirms that monotherapy is all that's needed for favorable intermediate risk (see this link), and that brachy boost therapy is needed for unfavorable risk patients (see this link). These are reflected in current guidelines (see this link). The use of ADT beyond cytoreduction does not seem to be necessary, at least in high risk men receiving brachy boost therapy (see this link). This study did not address the toxicity of brachytherapy, which should be discussed with one's brachytherapist.

With thanks to Brian Davis for allowing me to read the full text of his study.

Questions to ask a low dose rate (seeds) brachytherapist

Questions for LDR brachytherapists

1.     How many have you performed?

2.     How has your practice of brachytherapy changed over the years?

3.     What is your 5-yr freedom from recurrence rate for patients at my risk level? What proportion of your recurrences were local?

4.     What kind of urinary and rectal reactions can I expect? How long can I expect them to last? What medications or interventions do you typically give for that? Should I expect those symptoms to recur later?

5.     What is your rate of serious (Grade 3) adverse events? Do you see urinary strictures? Urinary retention requiring catheterization? Fistulas? Rectal bleeding requiring argon plasma or other interventions?

6.     For how long should I refrain from sex with a partner?

7.     For how long should I refrain from close contact with people and pets?

8.     Among men who are previously potent, what percent of your patients return to baseline?

9.     Do you recommend ED meds as protective?

10. What kind of dose with which isotope do you use? Would adjuvant IMRT be given with that? Would hormone therapy be given with that?

11. How do you prevent seed migration?

12. Do you use “intra-operative planning” or some other technique to guide placement and assure adequate seed distribution? Do you use a template with ultrasound guidance, cone-beam CT or some other method?

13. What do you set as dose limits for organs at risk? How do you assure that urinary sphincters, the urethra, and the rectum are spared?

14. Do you do a follow-up CT or MRI after a month?  How often do you find you have to go in again to treat cold spots?

15. How will we monitor PSA? What kind of PSA pattern can I expect?

16.  What kind of aftercare (including sexual rehab) will you provide, and how will we monitor side effects, and for how long? Will you regularly monitor my urinary and erectile recovery progress with validated questionnaires like EPIC and IPSS?

17.  In your practice, what percent of men experience biochemical recurrence?
    • What % of those have been local?
    • If there should be a biochemical (PSA) recurrence, what would the next steps be?
    • Have you ever used SBRT, brachy, or cryo for salvage after a local LDR brachy failure, and was that focal or whole gland?

18.  Are you open to email communications between us?

Brachy boost therapy should be reserved for unfavorable risk patients

The ASCENDE-RT trial showed that oncological outcomes were improved among both intermediate risk and high risk men who were treated with external beam radiation (EBRT) and a brachytherapy boost (LDR-BT) to the prostate and adjuvant androgen deprivation therapy (ADT) (see this link). A new study from the University of Michigan suggests that the benefit in intermediate risk men is exclusively among those who have been diagnosed with unfavorable intermediate risk prostate cancer.

They used the NCCN definitions:

• Favorable intermediate risk: Gleason score 3+4 and PSA< 10 ng/ml and stage T1/T2a and <50% of biopsy cores were positive
• Unfavorable intermediate risk: All other intermediate risk

Abugharib et al. retrospectively reported the outcomes of 579 intermediate risk men treated with either EBRT alone or EBRT+LDR-BT between 1995 and 2012. After a median follow-up of 7.5 years:

• The 10-year biochemical recurrence free survival was 92% for the brachy boost therapy vs. 75% for EBRT alone
• Recurrences were cut in half (hazard ratio= 0.48) by the brachy boost after correcting for known confounders
• The improvement due to the boost was only seen in the "unfavorable intermediate risk" group, but not in the favorable intermediate risk group.
• 10-year distant metastasis-free survival did not differ by risk group.
• 6-year cumulative incidence of grade 3 urinary toxicity was 3.5 times higher among men who received brachy boost therapy.
• Toxicity was transient and resolved completely in 57%, partially in 29%, and persisted in only 1 patient.

We recall that ASCENDE-RT reported nearly identical oncological and toxicity outcomes:

• Among those with intermediate-risk prostate cancer, 9-year bPFS was 94% for the brachy boost cohort vs. 70% for EBRT-only.
• Late term Grade 3 GU toxicity reached 19% for the brachy-boost group vs. 5% for the EBRT-only group (3.8 times higher).

Although this was not a randomized clinical trial like ASCENDE-RT, the similarity helps lend credence to their study.

There was a randomized clinical trial RTOG 0232 (see this link) that also showed no benefit to the brachy boost among favorable intermediate risk men.

While ten years is not long enough to evaluate differential effects on metastases and mortality, we may infer from the large difference in the 10-year failure rate that those differences will probably eventuate in more metastases and deaths later on.

It appears that men with unfavorable intermediate risk prostate cancer may benefit from brachy boost therapy. However, men with favorable intermediate risk prostate cancer are at risk of much greater long-term urinary toxicity with no oncological benefit whatever. We can reasonably infer that men with low risk prostate cancer, who may be safely watched with active surveillance, would derive no benefit and only greater toxicity from the combination therapy. Unfortunately some clinics, notably the Radiotherapy Clinics of Georgia, infamously treat even low risk patients with brachy boost therapy (which they market as ProstRCision).

Revised ASCO/CCO brachytherapy guidelines

The publication of the ASCENDE-RT clinical trial (discussed here) has led to a revision in the brachytherapy guidelines (available here) issued by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO). The guidelines are for patients who choose radical therapy rather than active surveillance. They based their guidelines only on randomized clinical trials that included brachytherapy as an option.  They exclude high dose rate brachytherapy (HDR-BT) as a monotherapy because it has not been proven in a randomized clinical trial.

Their guidelines suggesting which therapies are suitable are stratified by patient risk level:

Low Risk

• Low dose rate brachytherapy (LDR-BT) alone
• External Beam Radiation Therapy (EBRT) alone, or
• Radical prostatectomy (RP)

Intermediate Risk

For favorable intermediate risk patients (no Gleason score> 3+4, no more than half the cores positive, PSA<10, and stage<T2b):

• LDR-BT alone

For other intermediate risk patients:

• EBRT with or without androgen deprivation therapy (ADT) and a brachy boost (LDR-BT or HDR-BT) to the prostate.

High Risk:

• EBRT and ADT and a brachy boost (LDR-BT or HDR-BT)

They make the following qualifying statements:

• Patients should be counseled about all their management options (surgery, EBRT, active surveillance, as applicable) in a balanced, objective manner, preferably from multiple disciplines.
• Recommendation for low-risk patients is unchanged from initial guideline, because no new randomized data informing this question have been presented or published since.
• Patients ineligible for brachytherapy may include: moderate to severe baseline urinary symptoms, large prostate volume, medically unfit, prior transurethral resection of the prostate, and contraindications to radiation treatment.
• ADT may be given in neoadjuvant, concurrent, and/or adjuvant settings at physician discretion. It is noted that neoadjuvant ADT may cytoreduce the prostate volume sufficiently to allow brachytherapy
• There may be increased genitourinary toxicity compared with EBRT alone.
• Brachytherapy should be performed at a center following strict quality-assurance standards.
• It cannot be determined whether there is an overall or cause-specific survival advantage for brachytherapy compared with EBRT alone, because none of the trials were designed or powered to detect a meaningful difference in survival outcomes.

Neither the patient nor the doctor should take these to be their only options. ASCO/CCO only included options for which there is Level 1 evidence; that is, evidence from  randomized comparative clinical trials. Patients, doctors and insurance providers should make treatment decisions based on the full array of available clinical data, understanding that higher level evidence carries more weight.

Brachy Boost: The gold standard for progression-free survival of high risk prostate cancer

Several randomized clinical trials have established the superior oncological outcomes of the combination of external beam radiotherapy with a high dose rate brachytherapy boost (see this link). Last year, the results of the first randomized clinical trial of the combination of external beam radiotherapy with low dose rate brachytherapy, the ASCENDE-RT trial, was presented at the 2015 Genitourinary Conference (reported here). We now have the full details of the oncological outcomes (toxicity outcomes will be reported separately).

Morris et al. reported on 398 intermediate (31%) and high risk (69%) patients treated at 6 facilities in British Columbia and Toronto. All patients received 12 months of androgen deprivation beginning 8 months before radiation therapy. and continuing 4 months after the start. Androgen deprivation consisted of a GnRH agonist (Eligard or Suprefact) with an antiandrogen (bicalutamide or flutamide) given for the first 4 weeks. The radiation treatment was either of:

• EBRT-only: 78 Gy in 39 fractions using 3D-CRT
• Brachy boost: 46 Gy in 23 fractions of EBRT (3D-CRT) + 115 Gy of I125 seeds

It is worth noting that the brachy boost dose used in this trial is compared to an EBRT dose that is considered to be high enough to be curative by today's standards.

With 6.5 years of median follow-up, the 9-year biochemical progression-free survival (bPFS) was:

• 85% for the brachy boost cohort vs. 65% for EBRT only
• The hazard ratio was 2.3 (i.e., those getting EBRT only were 2.3 times as likely to relapse compared to those getting the brachytherapy boost)
• Among those with high-risk prostate cancer, 9-year bPFS was 83% for the brachy boost cohort vs. 62% for EBRT-only.
• Among those with intermediate-risk prostate cancer, 9-year bPFS was 94% for the brachy boost cohort vs. 70% for EBRT-only.
• Among those who did not relapse, the median nadir PSA was 0.01 ng/ml (54% undetectable) for the brachy boost cohort vs. 0.25 for EBRT-only (8% undetectable).
• In this length of follow-up, metastases, prostate cancer-specific mortality, and overall mortality were rare events, and were not statistically significantly different. Median age was 68.

This analysis did not address toxicity outcomes, but, as previously reported, the improved oncological outcomes came at the expense of toxicity:

• Late term Grade 2 or higher genitourinary (GU) toxicity was higher for the brachy-boost group. 
• Late term Grade 3 GU toxicity reached 19% for the brachy-boost group vs. 5% for the EBRT-only group. 
• Late term gastrointestinal (GI) toxicity was similarly mild for both groups.

The use of 3D-CRT rather than IMRT (which is now the more prevalent form of EBRT) probably affected toxicity, especially with the wider field of the brachy-boost therapy.

This should establish brachy boost therapy (using either a high dose rate or low dose rate brachy boost) as the gold standard for oncological control for high risk prostate cancer. Perhaps equivalent outcomes with less toxicity may be achievable for both high risk and intermediate risk patients using high dose rate brachy monotherapy, SBRT monotherapy, or SBRT boost therapy. But for now, those are experimental approaches in high risk patients. The optimal duration of ADT use has yet to be defined. Patients with pre-existing urinary conditions should approach boost therapy with caution.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

note: Thanks to Dr. James Morris for allowing me to review the full text.

Can brachytherapy spread prostate cancer?

In an earlier commentary (see this link), we looked at the available evidence that invasive procedures, including surgery, biopsy, and brachytherapy, could spread prostate cancer. There have been very few cases reported where it is likely that brachytherapy has spread prostate cancer: 5 cases from seeds migrating to the lungs (see this link), and one case where a catheter probably spread the cancer to the bladder wall during high dose rate brachytherapy (see this link).

Tsumura et al. report the results of their study to determine whether circulating tumor cells (CTCs) were dislodged from the prostate into systemic circulation by brachytherapy. They took blood samples from 59 patients before and immediately following brachytherapy.

• 30 patients were treated with a combination of hormone therapy, external beam radiation, and high dose rate brachytherapy (HDRBT) for high risk or locally advanced prostate cancer.
• 29 low- and intermediate-risk patients were treated with low dose rate brachytherapy (LDRBT) as a monotherapy.

The blood samples were analyzed using CellSearch technology. They found that:

• None of the samples taken before brachytherapy had any CTCs
• CTCs were detected immediately after brachytherapy in 7 patients (11.8%), 13.3% among LDRBT patients, 10.5% among HDRBT patients.
• There was no statistically significant association with risk category, clinical stage, tumor volume, Gleason score, PSA, prostate volume, needle concentration, age, hormone therapy or type of brachytherapy.

While it is too soon to know whether those CTCs will cause a recurrence in the 7 brachytherapy patients, a similar study done by Eshwege et al. before and after prostatectomy suggests that they will not. In that study, there was increased risk of recurrence only if CTCs were found before the prostatectomy. The additional shedding of tumor cells during the procedure did not correlate with recurrence within 5 years.

Even high risk/advanced prostate cancer cells are not capable of survival outside of the prostate environment. To metastasize, they must first undergo a series of genetic alterations called epithelial-to-mesenchymal transition (EMT). Some researchers believe that small numbers of such metastatic-capable cancer cells may exist in small numbers within the prostate. If so, it seems to be a rarity.

Brachytherapy alone is enough for favorable intermediate risk patients

RTOG 0232 was a large clinical trial conducted to determine whether low dose rate brachytherapy (BT) alone was of equal benefit compared to external beam radiation therapy with a brachytherapy boost (EBRT+BT) in intermediate risk patients.

The study was conducted at 68 cancer centers in the US and Canada from 2003 to 2012. 588 intermediate risk men were treated. For the purposes of this study, “intermediate risk” was defined as:

• Stage T1c – T2b, and
• Either Gleason Score of 7 and PSA less than 10 ng/ml, or
• Gleason score of 6 and PSA between 10 and 20 ng/ml

They did not collect detailed data and report separately those who would now be classified as “favorable intermediate risk” by the Zumsteg definition (Gleason score 3+4, less than half the biopsy cores positive, and otherwise low risk). However, Howard Sandler, the Principal Investigator, wrote:

It was deliberately a favorable intermediate group largely. At the time (2002) we felt that combination therapy was mandatory for the more advance patients and we weren’t comfortable randomizing to brachy alone for those patients.

So it is important that we do not generalize their findings to unfavorable intermediate-risk or high-risk patients.

The patients were treated as follows:

• BT: 145 Gy of I-125 seeds or 125 Gy of Pd-103 seeds
• EBRT+BT: 45 Gy of EBRT and a boost with 110 Gy of I-125 seeds or 100 Gy of Pd-103 seeds

After 5 years of follow-up:

• Progression-free survival was 85% for EBRT+BT patients, 86% for BT patients (no difference)
• Acute grade 3 (serious) side effects were suffered by 8%  in each group.
•  Late-term grade 3 (serious) side effects were higher (12%) in the EBRT+BT compared to 7% in the BT group

o   Urinary side effects: 7% in the EBRT+BT group vs. 3% in the BT group

o   Rectal side effects: 3% in the EBRT+BT group vs. 2% in the BT group

So, the addition of external beam radiation added nothing to cancer control, at least out as long as 5 years. While side effects were low for both groups, combination therapy increased them.

We saw recently in an analysis of the patients at Cleveland Clinic who were treated exclusively with BT only (see this link, especially the section on intermediate risk), that progression-free survival was very good for “low intermediate risk” patients. Furthermore, Drs. Stone and Zelefsky agreed that the combination therapy is unnecessary for this group, especially when treated with a sufficient brachytherapy dose. Radiotherapy Clinics of Georgia has built a business out of treating even low-risk patients with the combination therapy. This is now proved to be an overtreatment that is needlessly toxic.

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?

LDRBT, IMRT and SBRT Quality of Life

Some of the leading lights in radiation oncology have collaborated on a study by Evans et al. of patient-reported quality of life (QOL) following various primary radiation treatments for prostate cancer. They analyzed three monotherapies (all without hormone therapy): low dose rate brachytherapy (LDRBT), intensity-modulated radiation therapy (IMRT), and stereotactic body radiation therapy (SBRT). It did not include high dose rate brachytherapy or proton therapy.

Because this study was so far-reaching in its scope and its findings, it is worth taking a close, detailed look at it. I will break it into three parts. In the first part, we’ll look at the basis of the study – how the study was designed and carried out, and what does it purport to tell us. In Part 2, we will look at some of the more important findings of the study. And in Part 3, we will discuss the implications and caveats of its findings, and draw conclusions.

PART 1. THE BASIS OF THE STUDY

The purpose of the study was to evaluate three primary radiation therapies – LDRBT, IMRT and SBRT – with respect to the patient-perceived side effects of those treatments, and to do so in a standardized and consistent manner. While this was a prospective study, it was not a randomized comparison, which is the gold standard for doing that. However, it does provide the doctor and patient with more information on what they can reasonably expect, across those treatments, than we’ve ever had before.

Data was provided by several of the top institutions in the US:

LDR or IMRT

Michigan (2 sites)

Mass General

Beth Israel Deaconess

MD Anderson

Cleveland Clinic

Washington University (St Louis)

SBRT

Georgetown

21st Century (2 sites)

The number of patients in the two-year follow up:

• ·        LDRBT: 243 patients
• ·        IMRT: 140 patients
• ·        SBRT: 272 patients

I don’t know how they selected which doctors and medical centers to include. In addition, the study was done with the assistance of the PROSTQA Study Consortium, a blue-ribbon panel of top researchers. They previously published much of this data on IMRT and LDRBT in 2008 (see this link). The SBRT data are new. Their results are a good indicator of outcomes from top practitioners at major treatment centers, and are not a good indicator of expected outcomes in community practice. I’m sure that many patients have favorite doctors whose work was not represented in this study, and they will argue that these results are not representative.

Because this was not set up as a randomized comparison of treatments, differences in patient selection may skew the results. Importantly, the LDRBT cohort is 5 years younger (65 years, median) than the other two groups (69 years, median). In all quality-of-life studies, younger patients do better. They are less likely to suffer deleterious effects of radiation, and they are more resilient in their recovery. Paralleling the difference in age at baseline, the baseline sexual QOL was best for LDRBT, and the baseline prostate symptom scores were best for LDRBT, followed by IMRT and SBRT.

The instruments they used to evaluate quality of life were EPIC-26 and SF-12. Patient-reported assessments have an advantage over physician-reported toxicity reports. The physician data depends on the patient to voluntarily tell the doctor about all adverse events, which is useful for highest grade events (3 or 4), but is less reliable for low grade events (1 or 2) that the patient might never bring to the doctor’s attention. Some men “tough it out,” some see their PCP instead (who may be more accessible), and some worry about even the most minor events. The survey instruments used here are standardized and validated, and guide the patient through a detailed assessment of the QOL issues that have been found to matter most. Patients filled them out at baseline, at 1-2 months, 6, 12, and 24 months. EPIC scores are based on scale of 0 (worst) to 100 (best). Although they also measured such qualities as general physical and mental status, and vitality/well-being, none of these were impacted by treatments.

IMRT and LDRBT patients were treated from 2003 to 2006; SBRT patients from 2007 to 2011. Contemporary best practice was observed as follows:

·        LDRBT: 144 Gy prescribed dose for I-125, US-guided, transperineal placement, I-125 or Pd-103 used, and 3-5 mm margins (more details here)

·        IMRT:76-79 Gy in 1.8-2.0 Gy increments, and 0.5-1.5 cm margins.

·        SBRT: 35-40 Gy in 5 fractions, fiducials or Calypso image guidance, and 3-5 mm margins.

There were two kinds of urinary problems that were measured: urinary incontinence (leakage, dribbling, control & pad use) and urinary irritation/obstruction (frequency, pain/burning, weak/incomplete). Bowel issues comprised urgency, frequency, leakage, bleeding and pain. The sexual domain comprised ability to have erections, their firmness, and frequency when needed; also, quality of orgasms and overall sexual function.

All of the study’s findings relate to how much patient evaluations changed compared to their baseline evaluations in the urinary, rectal and sexual quality of life domains. We expect that the radiation therapies that do the least damage will show the least deterioration in the patient perceptions in each domain.

Because the study was not randomized, and it did not attempt to match triplets of patients on their demographics and co-morbidities, we have the difficulty of comparing results in different kinds of patients. The analysis of patient characteristics across treatments revealed only one real glaring discrepancy – LDRBT patients were 5 years younger than the rest. The authors made some attempt to restore comparability by only looking at sexual scores among patients who were 60 years of age or older, but such analyses were limited in their published results. In my opinion, they ought to have computed age-adjusted scores in all domains. The failure to do so will compound the difficulties in interpreting results as they carry their tracking into the future when the aging of the study population has greater effects.

PART 2. DETAILED FINDINGS

In this part we’ll look at the results of their analysis. The authors did a great job of compiling a vast amount of information. Even so, in some cases, I wish more of the information had been presented (I was able to see the full text). Perhaps they will reveal more of the details in future analyses of this rich database.

Change from Baseline

The following table shows the EPIC score change from baseline after two years among patients having each kind of therapy. The last column shows, for reference, the minimum amount of change that has been found to be clinically important for that set of symptoms.

	LDRBT	IMRT	SBRT	Minimal Clinically Detectable Change
Urinary- irritative/obstructive	-6*	+2	0	5-7
Urinary - incontinence	-6*	-5*	-3	6-9
Bowel	-7*	-8*	-1	4-6
Sexual†	-24*	-21*	-14*	10-12

* Change is statistically significant

†Among those with scores over 60 at baseline (to help compensate for age-related differences).

Sexual status was the domain that was most affected by all the treatments. For LDRBT, it had the greatest deterioration. Deterioration in urinary and bowel scores were statistically significant and clinically meaningful in patients who had LDRBT. IMRT also had its greatest impact on sexual status, and not much different from LDRBT. Other than sexual status, only IMRT bowel scores deteriorated meaningfully; urinary status returned to near baseline. SBRT had the smallest change in sexual status, albeit large enough to be meaningful. Bowel and urinary status returned to baseline.

Minimal Clinically Detectable Change

The authors also looked at what% of patients suffered a minimal clinically detectable (MCD) change in each of those components of their quality of life over time. The typical pattern was a sharp increase at 1 or 2 months (acute effects). In all but sexual scores, that was followed by improvement. Predictably, urinary irritation/obstructive were most impacted, reaching about 90% at two months for LDRBT, and significantly better at all time points for IMRT and SBRT. The proportion who had MCD bowel symptoms and sexual symptoms was consistently more favorable for SBRT than for LDRBT or IMRT.

As a measure of the severity of symptoms, the authors looked at the % of patients who suffered an MCD increase of twofold or more over baseline after two years:

	LDRBT	IMRT	SBRT
Urinary (all)	45%	25%	18%
Bowel	25%	30%	11%
Sexual†	35%	33%	20%
None of the above	34%	40%	65%
All of the above	8%	7%	2%

In general, large clinical deteriorations in QOL were about twice as frequent for LDRBT compared to SBRT, with IMRT falling in the middle.

Symptom Severity over Time

As another measure of symptom severity, the table below shows the% change versus baseline in the proportion who rated their symptoms as moderate to severe, at 1-2 months and at 2 years:

	LDRBT		IMRT		SBRT
	2 mos.	24 mos.	2 mos.	24 mos.	1 mo.	24 mos.
Urinary (all)	+33%	+7%	+27%	+3%	+8%	-3%
Bowel	+14%	+6%	+16%	+6%	+7%	-2%
Erectile dysfunction†	+21%	+19%	+11%	+16%	+5%	+11%

† inability to have erections, among patients of all ages

Moderate to severe acute urinary and rectal side effects increased markedly for LDRBT and IMRT. For SBRT, they increased much less and returned to slightly better than baseline levels.

Keeping in mind that LDRBT patients were a median of 5 years younger than the other two groups, the increase in erectile dysfunction among LDRBT patients is troubling.  As we saw in a recent study, the deterioration occurs earlier than was previously thought. For SBRT, in contrast, there was only a +5% increase in erectile dysfunction severity at two months after treatment, but that increased to +11% by two years. Nevertheless, that was still lower than the other two therapies.

PART 3. DISCUSSION

In this section, we will make an attempt to explain the findings of the study and draw whatever conclusions we can from them.

We have seen a very consistent pattern across all the measures of QOL and in all of the domains: LDRBT patients did worst, SBRT patients did best, and IMRT patients were in between. Why should that be? Let’s examine a few hypotheses:

Patient selection/non-random

This was not a randomized comparative trial, so it is possible that the LDRBT patients selected were, for some reason, more prone to the damaging effects of radiation. This argument is weakened by the fact that they were 5 years younger, and their urinal, rectal and erectile function at baseline were better than in the other two groups.

Better practitioners not represented

Some of the top LDRBT practitioners like Peter Grimm, Michael Zelefsky, Brian Moran, and Gregory Merrick, to name a few, were not represented here. One could also argue in the other direction that some of the most experienced SBRT practitioners, like Christopher King, Alan Katz, and Debra Freeman, were not represented here. Their results might have increased comparative favorability of the SBRT results still further. However, the results do seem to be comparable to those reported by Katz and the 8-institution consortium.

Time of treatment

IMRT and LDRBT results were based on best practice in 2003-2006, while SBRT was based on patients treated in 2007-2011. There were technological improvements in both modalities since then that might make their outcomes more comparable to SBRT. As radiation technology continues to evolve, it becomes problematic to choose among them based on past performance.

Hypofractionation spares healthy tissue

Hypofractionation (SBRT or HDRBT) – radiation applied in fewer treatments (or fractions) – has been found to kill cancer cells more efficiently than normal fractionation (IMRT) or continuous fractionation (LDRBT). Because prostate cancer is especially susceptible to hypofractionation (technically, we say it has a low alpha/beta ratio of about 1.5), and because healthy nearby early-responding tissues are less susceptible (they have a higher alpha/beta ratio of about 10), healthy tissues are better spared by it.

A convenient measure for comparing the dose seen by nearby healthy tissues is something called the biologically effective dose (BED). We can compute for each modality the maximum BED experienced by nearby early-responding tissues that are responsible for acute side effects. With SBRT (7.5 Gy X 5 fractions), the BED to those tissues is 30% less than the dose from IMRT (1.8 Gy X 44 fractions). For LDRBT (144 Gy I-125 Rx dose), the maximum BED to those tissues is 56% greater than the dose from IMRT. ). Making comparisons solely on BED is problematic because LDRBT radiation is extremely short range, so a lower proportion of the bladder and rectum surface may be exposed to that maximum dose.

Dose constraints

Radiation oncologists set strict dose constraints for the bladder, urethra, rectum, and sometimes to the penile bulb, limiting the volume of those organs that receive potentially toxic doses. However, there is only so much that doses can be limited if they are to effectively kill the cancer in the prostate. I don’t know what dose constraints were set for the three modalities examined in this study. We can only assume that they used best practices.

Imaging

The imaging of the pelvic organs both in planning and in the application of radiation makes a large difference in toxicity. This is where SBRT shines. SBRT commonly uses a fused image of a CT and MRI with fiducials or transponders in place for planning. This helps to precisely predetermine, down to less than a millimeter, where all the beams will be directed. These practices can be used with IMRT as well. However, with IMRT, the images are aligned only once per session, whereas with SBRT, the images are aligned continually throughout the session. We recently saw how disastrous SBRT could be without intra-fractional motion tracking. LDRBT seed placement is commonly accomplished under ultrasound image guidance, using computerized intra-operative planning. The ultrasound can help the doctor see where the needles are going, but it can’t see the seeds well. Even stranded seeds tend to move, the prostate is moved by each needle insertion, and the prostate swells throughout the procedure, so that it is impossible to know where their final position will be. An image is obtained about a month later, after the swelling subsides, to check for major discrepancies in seed positions and to give an after-the-fact reading of the doses absorbed by organs at risk.

Late term effects

This study tracked patients for two years, which is long enough for most of the late-term side effects to show up. However, some will inevitably show up even later. Some tissues, particularly some in the bowel, are “late responding” to radiation damage. Late responding tissues are relatively more sensitive to the concentrated radiation of SBRT (they have an alpha/beta ratio of 3-5), so it is possible that SBRT’s advantage will decrease with longer follow up.

CONCLUSIONS

Although one can quibble over methodological issues in comparing the modalities, SBRT certainly provides excellent quality of life to treated patients. SBRT also is the most convenient of the treatments, requiring only five short visits, no intrusive procedures (other than fiducial placement), and no anesthesia. LDRBT is the winner on cost of treatment, with a $17,000 median Medicare reimbursement, followed by SBRT ($22,000) and IMRT ($31,000). However, a full cost analysis should also include the costs of managing the side effects of treatment, which seem to be much lower for SBRT and higher for LDRBT. Based on the findings of this study, and approximately equivalent oncological control for the 3 modalities in favorable risk patients, it is hard to justify IMRT. Availability is an issue: IMRT is available everywhere, while there is less access to excellent practitioners of SBRT (usually as CyberKnife®) and LDRBT. Some insurance still will not cover SBRT, although that is less often a barrier now.

An oft-heard argument against SBRT is that there’s not enough long-term data. SBRT is the youngest of the three modalities, used against prostate cancer since 2003. The longest-running SBRT study, has 7 years of follow up on 515 patients. For comparison, robotic prostatectomy has been used since 2000, and has never been proven superior to open surgery in a randomized comparative trial. IMRT, likewise, has never been evaluated in a comparative randomized trial, and in its current form, using dose escalation and precision IGRT techniques, was only begun in the mid-1990s. The longest-running IMRT study, at Memorial Sloan Kettering, has 10 years of follow up on 170 patients. LDRBT has been used, in some form, for over a hundred years. However, in its modern form with dose escalation and intra-operative planning methods, there are no studies older than 15 years that have any decisional value. I have often bemoaned the problem of “irrelevance” in long-term clinical studies: by the time we get the results, technology and practice have changed so much that the results have become irrelevant in making decisions among the best available therapies.

While this study raises the hypothesis that SBRT may be superior to IMRT and LDRBT, it is prudent for the patient to keep them all in his consideration set at least until the results of randomized comparative trials become available. This study should influence patients and clinicians to give serious consideration to SBRT.

Later this year, we will have the early results from Sweden of a randomized clinical trial of SBRT versus IMRT in intermediate-risk patients. There are several more comparative trials that are scheduled for completion in the coming years. If they confirm the results of this study, it will be difficult to justify IMRT as first-line therapy. Unfortunately, as far as I know, there are none planned comparing SBRT and LDRBT. There are few institutions that offer both modalities (Memorial Sloan Kettering is an exception), so randomization would be problematic.