Safety limits of SBRT dose escalation

In a recent commentary, we saw that the lack of a standard of care for SBRT dose escalation may put patients at risk when dose limits are pushed beyond what is customarily considered effective and safe. Hannan et al. have now published their efficacy findings. Further details of the IRB-approved clinical trial specs are available here.

Between 2006 and 2011, the researchers at several institutions conducted a dose escalation trial utilizing SBRT on 91 men treated for low and intermediate risk prostate cancer. Among those men:

• ·      64% were intermediate risk, defined as:

o   Either GS 6 and PSA between 10 and 20 ng/ml , or

o   GS 7 with PSA≤ 15 ng/ml and clinical stage ≤ T2b

• ·      36% were low risk by the NCCN definition.

All patients received 5 treatments or fractions. The first 15 patients were treated with 45 Gy, the next 15 with 47.5 Gy, the next 15 with 50 Gy. Because that last group did not exhibit their predefined “maximally tolerated dose” in the short term, an additional 47 patients also received the 50 Gy dose.

The cancer control was excellent. At 5 years after treatment:

• ·      98.6% were free from biochemical failure
• ·      100% were free from metastases
• ·      None had died of prostate cancer
• ·      Overall survival was 89.7%

Toxicity was another matter. There were no reports of serious acute urinary toxicity. However, late-term urinary toxicity of grade 3 or greater was reported in 5.5% of patients. For the purposes of their analysis, acute toxicities were those observed within 9 months of treatment, and late-term toxicities were those observed between 9 and 18 months.

Rectal toxicity was reported in detail earlier by Kim et al. and merit a closer look:

• ·      Among those who received 45 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   No acute grade 2 toxicity was observed.

o   Late-term grade 2 toxicity was observed in 1 patient (of 15).

• ·      Among those who received 47.5 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   Acute grade 2 toxicity was observed in 4 of 15 patients (27%)

o   Late-term grade 2 toxicity was observed in 5 of 15 patients (33%).

• ·      Among the 61 patients who received 50 Gy there was:

o   One case of serious (grade 3) acute toxicity and one case of life-threatening (grade 4) acute toxicity.

o   3 cases (5%) of serious (grade 3) late-term toxicity and 2 cases (3%) of life-threatening (grade 4) late-term toxicity.

o   2 of the patients developed rectourethral fistulae, and 5 required diverting colostomies.

We note that even at the lowest dose level given in this trial (45 Gy), they were delivering much more than the customary SBRT dose of 36.25 Gy. Because this study began with such a high dose, it did not succeed in its objective of finding an optimal dose. It did, however, find the dose that created dose-limiting toxicity. At 50 Gy, they were delivering a dose that is bioequivalent to more than twice the customary and safe IMRT dose (80 Gy in 40 fractions). This is especially troubling when we realize that 36% were low-risk patients who might have delayed treatment with active surveillance.

There are many aspects of this study that are hard to understand. It’s hard to understand why they didn’t start at a more reasonable dose level. Dr. Alan Katz reported excellent cancer control with extremely low toxicity using only 35 Gy (see this link). With the sharp increase in acute grade 2 toxicities at 47.5 Gy, it’s hard to understand why the researchers did not pull the plug before patients were seriously harmed. It’s also hard to understand how the internal review board (IRB) did not question the ethics of this study.

(Update 2/6/2019) In a small (n=26) prospective dose-finding study of 40 Gy (n=9), 45 Gy (n=10) and 50 Gy (n=7) among low and intermediate risk patients, Potters et al. reported freedom from biochemical failure of 92%, 100% and 100% respectively with 67 months of follow-up. There were no Grade 3 toxicities, and toxicity was about equal in all groups. Quality of life returned to baseline in all groups within 2 years.

We have observed (see this link) that there is a lot more to SBRT safety than simply setting the prescribed dose. Careful planning, image guidance and accurate delivery are equally important. In the right hands, SBRT is among the safest and most effective of all radiation therapies, with excellent convenience and relatively low cost. In fact, I chose it for myself.

SBRT Registries

Patient registries are potentially a rich source of information with which to evaluate outcomes. They often include patient characteristics, details of the therapies they received, and outcomes tracked over time. They provide full population data of all patients treated at participating centers, and can provide very large amounts of data over time.

Like a clinical trial, there are specific and uniform definitions used in capturing patient and treatment data, allowing for comparability on a variety of variables. Registries and clinical trials are internal review board (IRB) approved for ethical standards and must comply with HIPAA laws (patients must consent, and patient names are not entered in). In the US, they both have an insurance advantage as well: Medicare, Medicaid and insurance companies may cover the costs of clinical trials and registries for treatments that they would not ordinarily cover. In some situations, they will only provide coverage if the patient is enrolled in a registry or clinical trial.

Unlike a clinical trial, there are usually no detailed patient inclusion and exclusion criteria, and the treatments may vary from center to center and from patient to patient. Because patients are not excluded from the database, registries are capable of providing very large databases for analysis. There is no randomization, so there is selection bias – patients who received different treatments may have been selected for specific reasons. The quality of the data is only as reliable as the clinician entering it, and it is not necessarily subject to peer review as publication of clinical trial results are. As with other large database analyses, it may be possible to find matched cases for control, but that is not the same as randomization. While clinical trials have a hypothesis to be proved or disproved, a registry provides data for quality improvement and for generating hypotheses.

Registries are difficult and expensive to establish and maintain. The American Board of Radiology attempted to create a national brachytherapy registry, but abandoned those efforts in 2015 when issues in its development and implementation “proved to be more daunting and costly than initially anticipated.” In 2012, the American Society of Radiation Oncologists (ASTRO) announced plans to implement a National Radiation Oncology Registry (NROR) with Prostate Cancer as its first focus. A pilot was completed in June 2015, and there are plans for expansion.

The Registry for Prostate Cancer Radiosurgery (RPCR) was established in 2010. There are 45 participating sites in the US, and the database included nearly 2000 men as of 2014. They collect three kinds of data for each patient: screening, treatment, and follow-up.

Screening data include age, performance status, rationale for radiosurgery, initial TNM stage, Gleason score, number of positive biopsy cores, use of hormonal therapy, and several baseline measures, including pre-treatment PSA, IPSS, International Index of Erectile Function (IIEF-5) score, Bowel Health Inventory score, and Visual Analog pain score.

Treatment data include radiation delivery device details, treatment dates, dosimetry (e.g., doses, schedules, targets, margins, including doses to specific organs at risk: rectum, bladder, penile bulb, and testicles), and how image tracking was performed.

Follow-up data include periodic tracking of the baseline data collected at screening, as well as physician-reported toxicity. RPCR encourages sites to record follow-up data every 3 months for the first 2 years following SBRT treatment and every 6–12 months thereafter, for a minimum of 5 years.

Some interim findings have been published by Freeman et al. So far, they have only reported 2-year data on 1,743 patients. Oncological control was reported as biochemical disease-feee survival:

·      Low Risk: 99% (n=111)

·      Favorable Intermediate Risk: 97% (n=435)

·      Unfavorable Intermediate Risk: 85% (n=184)

·      High Risk: 87% (n=168)

There was no severe late-term urinary toxicity, and one patient developed severe late-term rectal bleeding. Erectile function was preserved in 80% of men under 70 years of age, and 55% of men over 70.

The other SBRT registry is called the Radiosurgery Society Search Registry (RSSearch Registry) and includes data from 17 community centers treating prostate cancer patients. There were 437 prostate cancer patients enrolled between 2006 and 2015. The data collected is similar to the RPCR Registry. All patients in their first report were treated using the CyberKnife platform (this registry was originated by Accuray, the manufacturer of CyberKnife), although they allowed other platforms in later enrollments.

Davis et al. recently reported their interim findings. Oncological control was reported as 2-year biochemical disease-fee survival:

·      Low Risk: 99.0% (n=189)

·      Intermediate Risk: 94.5% (n=215)

·      High Risk: 89.8% (n=33)

There was no severe (grade 3) acute urinary or rectal toxicity, and very little grade 2. There was no severe (grade 3) late-term urinary or rectal toxicity. The highest incidence of grade 2 late term symptoms was 8% with urinary frequency, They did not collect baseline data on sexual function.

Both of these registries are administered by Advertek. The results of the RSSearch Registry were reported in Cureus, which is their own publication. RPCR results were published in Frontiers in Oncology, which is an independently peer-reviewed journal. It is important to note this because questions about the reliability of the data may arise.

If these data look a little too good to be true… well, let’s dig a little deeper. The biochemical disease-free survival figures only reflect 2 years of follow-up. In that short amount of time, many patients have not yet reached their nadir PSA let alone had time to rise 2 points above that nadir. Most of the low-risk patients and many of the intermediate-risk patients would not have had a rise of 2 points in their PSA even if they’d had no treatment.

The toxicity data are very suspect. Unlike a clinical trial where experienced researchers are carefully evaluating patients on a regular schedule, patient evaluations by community clinicians are haphazard. The clinicians may introduce affirmation bias into their assessments – they have incentive to make their numbers look good. The best way to evaluate toxicity is with patient-reported outcomes on validated, guided-response questionnaires, like EPIC. This was not done in either of these registries. 

I think SBRT is actually quite a good therapy (I chose it for myself!), but we have to look to other sources for more reliable data. With longer term follow-up, the cancer control data from these registries may become more reliable, and may help us generate better hypotheses about which treatment variants work best and on which patient groups.

SBRT has equivalent toxicity with 5 treatments and 12 treatments

Lukka et al. reported one-year outcomes of the RTOG 0938 trial designed to test whether SBRT done in 5 treatments of fractions has equivalent and acceptable toxicity compared to SBRT in 12 fractions.

This was a multi-institutional US /Canadian study among 246 low risk men. They were randomly assigned to one of two SBRT treatment regimens:

• Arm 1: 36.25 Gy delivered in 5 fractions twice a week for 2 ½ weeks.
• Arm 2: 51.6 Gy delivered in 12 fractions 5 days a week for 2 ½ weeks.

These doses are approximately equivalent in biologically effect for cancer control and in their expected effect on healthy tissues. Men were allowed to be treated on several different SBRT platforms, including CyberKnife, VMAT and protons.

This is the planned 1-yr quality-of-life analysis, with future analyses to be performed after 2 and 5 years.  The EPIC questionnaire was used to assess bowel, urinary, and sexual quality-of-life.

•     Bowel changes > 5 points are considered clinically significant.

o   Any such change affecting ≤ 35% of men was considered to be acceptable.

o   Any such change affecting ≥ 55% of men was judged to be unacceptable.

•   Urinary changes  > 2 points are considered clinically significant.

o   Any such change affecting ≤ 40% of men was considered to be acceptable.

o   Any such change affecting ≥ 60% of men was considered to be unacceptable.

• Sexual score changes ≥ 11 points are considered clinically significant

After 1 year of follow-up, patient-reported clinically significant changes were noted in:

• Bowel changes were acceptable: 29.8% in Arm 1 and 28.4% in Arm 2
• Urinary changes were borderline acceptable: 45.7% in Arm 1 and 42.2% in Arm 2
• Sexual score changes: 32.9% in Arm 1 and 30.9% in Arm 2
• Disease-free survival at two years: 93.3% in Arm 1 and 88.3% in Arm 2
• None of the differences between Arm 1 and 2 were statistically significant

Physician-reported toxicities were as follows:

• Acute urinary: Grade 3 – 2 patients (1.7%)
• Acute rectal: Grade 3 – 2 patients (1.7%), Grade 4 – 1 patient (1.1%)
•  Late urinary: Grade 3 – 1 patient (0.8%)
•  Late rectal: Grade 3 – 2 patients (1.7%)

Both treatment regimens substantially met the study’s toxicity requirements, and confirm that 5 fractions are as toxicity-free as 12 fractions. These outcomes are in line with historical controls based on conventional IMRT treatment regimens. Of course, only a randomized clinical trial (like this one, which proved there were no differences in oncological or toxicity outcomes) can compare IMRT and SBRT.

9-year SBRT outcomes

Katz and Kang have posted their 9-year SBRT outcomes on 515 patients. This represents the longest tracking of SBRT outcomes -- just one year short of the IMRT tracking reported by Alicikus et al. on a starting cohort of 170 patients treated at Memorial Sloan Kettering Cancer Center.

The patients were treated between 2006-2010 using the CyberKnife platform.

• ·      324 were low risk, 139 intermediate risk, and 52 were high risk according to NCCN definitions.
• ·      70 patients received adjuvant ADT for up to one year.
• ·      158, all with Gleason score<4+3, received 35 Gy in 5 fractions.
• ·      357 received 36.25 Gy in 5 fractions
• ·      Median age was 69
• ·      Median PSA was 6.5 ng/ml

After a median followup of 84 months:

• ·      Oncological Control:

o   9-yr freedom from biochemical failure was:

§  95% for low-risk men

§  89% for intermediate risk men

§  66% for high-risk men

o   Median PSA nadir was .1 ng/ml

o   No difference in biochemical control for the lower vs. the higher radiation dose.

o   99.6% prostate cancer survival

o   86% overall survival

• ·      Toxicity:

o   Late rectal toxicity:

§  Grade 2: 4%

o   Late urinary toxicity:,

§  Grade 2: 9.5%

§  Grade 3: 1.9%

§  Grade 2 or 3: 6.9% for the lower radiation dose vs. 13.2% for the higher dose.

o   Patient-reported bowel and urinary quality-of-life (EPIC questionnaire) declined at one month then returned to baseline by 2 years. Sexual quality-of-life declined by 29% at last followup.

These are clearly excellent results for any kind of radical therapy. The authors conclude:

“These long-term results appear superior to standard IMRT with lower cost and are strikingly similar to HDR therapy.”

While it’s tempting to conclude that neither the higher dose of radiation, with its greater toxicity, nor the addition of ADT conferred any incremental benefit, that can only be proved with a randomized clinical trial. Until so proven, it must be understood as only a good hypothesis to be discussed by patients with their radiation oncologists. It is also worth noting that these reflect the outcomes of one very expert practitioner. There is an SBRT registry currently collecting data across many treatment centers.

The reported outcomes are nearly identical to those reported at 7 years (see this link and this link and this link), indicating very stable control and no additional late term toxicity with longer followup. In light of that, its low cost, convenience, and the fact that the standard of care, IMRT, has only one more year of follow-up on a much smaller sample size, it’s difficult to understand why some insurance companies still balk at covering SBRT for low and intermediate risk patients. Medicare does cover it.

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?

SBRT for Oligometastatic Recurrence

Although the theory of the existence of a temporarily stable oligometastatic stage in prostate cancer is more than 20 years old, it remains unknown whether there is any benefit to pursuing curative or progression-delaying radiation if there are only a few metastases detected at recurrence. All of the studies so far have been very small, single-institution studies, lacking randomization, control groups, or consistent treatments. Ost et al. have pooled much of the existing data into a meta-analysis focusing only on those patients whose few metastases at recurrence were treated with SBRT.

In all, they identified 119 patients from 6 studies with the following characteristics:

• ·      3 or fewer metastases were identified at recurrence any time after radical treatment.

o   One in 72%, two in 19%, three in 9%

o   163 metastases detected

o   Median time from diagnosis to detection: 4.7 years

• ·      Primary metastasis sites were nodal (60%), bone (36%), or visceral (4%).
• ·      Detection was via Choline PET/CT (77%), FDG PET/CT (20%), and MRI (3%).
• ·      Median PSA at detection was 4.0 ng/ml, with a doubling time of 5.6 mos.
• ·      Adjuvant ADT was used in half the cases for a median of 2 months (range: 1-8 mo.)

o   Excluded if ADT>12 months or ongoing at time of metastasis detection.

• ·      Primary therapy was RP only (18%), RT (25%), or RP+aRT/sRT (57%).

After a median follow up of 3 years after SBRT treatment of metastases:

• ·      Distant progression was detected in 61%.

o   Distant progression-free survival was 31% at 3 years, 15% at 5 years.

o   Median distant progression-free survival was 21 months.

o   70% had 3 or fewer metastases at time of progression.

• ·      Median time to start of palliative ADT was 28 months.

o   Half received a second course of SBRT.

• ·      Local progression-free survival was 93% at 3 years; 92% at 5 years.

o   Local progression was significantly greater at lower SBRT doses.

o   Local progression occurred at 18 months without adjuvant ADT, 25 months with adjuvant ADT, but the difference wasn’t statistically significant.

• ·      Overall survival was 95% at 3 years, 88% at 5 years.
• ·      Late Grade 2 GI toxicity was 3%, none greater.

The metastasis-directed SBRT treatment did an excellent job at eradicating the specific metastases at which it was directed, and the toxicity was remarkably low. However, that did not halt the cancer’s progression, except in 15% at 5 years, and presumably in fewer after longer follow up. The question remains, however, did the treatment slow down the cancer, allowing for many extra months and perhaps years of survival, and especially of symptom-free survival? After all, we were happy to get even a few months of extra survival out of our newest drugs like Xtandi, Zytiga, and Jevtana. There was no distant progression in these closely watched patients for almost 2 years, and even then, the metastatic burden was low. Given that there was almost no toxicity risk, should routine SBRT treatment of oligometastases at recurrence be a new standard of care?

That’s a very hard question to answer, even with the pooled data in this study. The problem is that we don’t know what would have happened had they not been treated. Were these patients really slow to progress, or do they only appear to be because they were so closely watched with advanced imaging from a very early point (lead-time bias)?

Some have theorized that there is a type of slowly metastasizing prostate cancer that these studies are selecting for – in that case, it is just a characteristic of that particular type of low-metastases prostate cancer and not the treatment that is slowing progression. We have seen so far in the CHAARTED trial that low-burden metastatic disease progresses and responds differently to docetaxel and ADT compared to polymetastatic prostate cancer. One study found that there is a microRNA that may distinguish between the oligometastatic type and the polymetastatic type. This hints at a distinct phenotype that may be particularly amenable to oligometastatic treatment. If so, perhaps we will eventually be able to identify biomarkers to select candidates for it.

On the other hand, a recent study that found that cancer often spreads from metastasis to metastasis bolsters the claim that oligometastatic treatment may be at least partially effective in all cases. To determine which hypothesis is true we’ll need clinical trials. Almost all of the studies on SBRT for oligometastases are very small, and have taken place in Europe. I am not aware of any planned clinical trial in the US. There are only a few Phase 2 trials in Spain, Germany, and Canada.

Because most of the detected oligometastases were in the pelvic lymph nodes, there is a special opportunity for lymph node-only treatment. Arguably, the entire pelvic lymph node area, and not just individual detected nodes, ought to be treated, and this was done in about 40% of the cases. There may be micrometastases that are too small to be detected in the pelvic lymph system. That area is typically not treated during primary radiation therapy, or during adjuvant/salvage radiation treatment. It may, in some cases be amenable to additional radiation if previous treatment was not too wide, was long ago, and anatomic considerations (e.g., visceral fat) allow for it. Recent analyses by Rusthoven et al. and by Abdollah et al. found a survival benefit to such whole pelvic salvage radiation (type unspecified), but Kaplan et al. failed to find a benefit. Salvage SBRT whole pelvic treatment for recurrent patients with positive nodes has yet to be explored in sufficient numbers of patients to draw conclusions about it.

With the growing number of test sites for the new generation of high-accuracy PET scans (e.g., C-11 Choline, Ga-68-PSMA, PET/MRI, etc.), it may become increasingly possible to detect advanced prostate cancer in the oligometastatic stage. SBRT treatment centers are also increasingly available, and the treatments are brief (typically 1-3 fractions), relatively inexpensive, and apparently very safe. As long as patient expectations are reasonable – that treatment may be able to delay, but not cure - it’s hard to argue against its use.