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).

Unwarranted conclusions about oligometastatic treatment

Some patients wonder, if they just have a couple of metastases, why can't those be "zapped" by a few quick SBRT treatments and thereby be cured of their prostate cancer? Or, even if they can't be cured, can't the cancer's progression be slowed down?

To address those questions, we have to understand what is called the "natural history" of prostate cancer progression. Even high-risk prostate cancer is quite a different sort of thing from metastatic prostate cancer. High-risk prostate cancer cells, for example those with Gleason score 5+5, are incapable of thriving outside the prostatic environment. At some point they undergo a genetic transition called epithelial-to-mesenchymal transition (EMT), after which they can freely move throughout the body in the lymph, blood or the spaces around nerves, and plant themselves and accumulate in distant locations. Sometimes those microscopic metastases can circulate for a long time before planting themselves somewhere new. Sometimes they can plant themselves but do not proliferate appreciably for a long time. Sometimes they can alter the tissue environment in a new place (especially bone tissue) so it is more amenable to clumping and proliferation. Sometimes those cells get caught in lymph nodes (lymph nodes may be thought of as filters to catch cellular debris, including cancer cells) and proliferate there. All of these processes occur simultaneously.

Let's try to gain an understanding of how many cancer cells are in systemic circulation at a given time. We have found that a count of 5 or more circulating tumor cells (CTC) per 7.5 ml of blood is associated with metastatic progression (the prostate is also always shedding cells, healthy and cancerous, that are not capable of metastatic progression). So a 200 lb. man with no detectable metastases and with a CTC count of 5, who has 6.5 liters of blood, will have at least 4,300 circulating tumor cells. In addition, there will be many thousands more lodged in and between tissues. Now, to be detectably metastatic with today's best imaging technology, a clump of tumor cells must be at least 4 mm long. The cancer cell may be about 10 μm, so there are at least 200,000,000 of them before the smallest metastasis becomes detectable. All of those cancer cells are constantly shedding and forming new daughter metastases elsewhere. So cancer cells may be circulating, clumping, and growing for a long time before they form a big enough clump to be detectable.

It should be clear that there is no possibility of a cure without systemic treatment. Currently, we have no systemic treatments that can cure metastatic prostate cancer.

How long does it take to go from the first microscopic metastasis to the point where it is detectably metastatic? That's impossible to know with any accuracy for a given individual. What we do know is that on average it takes 8 years from the time a man is biochemically recurrent after prostatectomy to the time when the first bone metastases are detected on a bone scan (see this link). That represents the accumulation of perhaps a billion cells in one place. It may be years more before the next bone metastasis is detected. Lymph node metastases are the slowest progressing of all the kinds that prostate cancer causes. It is not unusual for many years to pass between new detectable lymph node metastases. The new PET scans detect metastases much earlier, when the tumors are 80% smaller.

Now we can come back to the question of whether early detection and treatment of metastases can at least slow progression and increase survival. A C-11 Choline PET/CT may be able to reliably detect metastases when the PSA is only about 2 ng/ml, rather than 20 ng/ml for a bone scan. The newer PSMA-based PET/CTs may detect metastases even earlier, say at about 0.5 ng/ml. So, if any treatment is given when metastases are detected this early, and then we find that it takes a very long time - many years - to detect subsequent metastases, did the treatment delay progression? This effect is called "lead-time bias."

Adding to the confusion is the fact that those big clumps of detectable cancer cells are the source of much of the PSA. When those detected metastases are "zapped," the cancer cells in them no longer secrete PSA and the cancer is controlled locally. We also know that old clumps of cancer are a rich source for new tumor cells. Is it possible that reducing at least that local source of metastatic cells will slow progression?

The only way to answer this question with any assurance is to conduct a randomized clinical trial. Some patients will get the treatment, in this case SBRT to the detected metastases, and the other patients will get standard of care -- hormone therapy. Then we will be able to see how long it takes for new distant metastases to be detected for the treated group as compared to the control group; and more importantly, did the treated group survive longer?

Triggiani et al. retrospectively report on patients at several centers in Italy (for some reason, most of these studies have been done in Italy) who had 3 or fewer detected metastases treated with SBRT.

• About 100 patients with a recurrence after primary treatment with metastases detected by Choline PET scan (the oligo-recurrent group)
• 41 castration-resistant patients with metastases detected by bone scan/CT (the oligo-CRPC group)

After a median of 20-23 months of follow-up, distant progression-free survival was:

• 43% after 2 years for the oligo-recurrent group
• 22% after 2 years for the oligo-CRPC group

The authors conclude:

"Stereotactic body radiotherapy seems to be a useful treatment both for oligo-recurrent and oligo-CRPC."

We are now ready to understand why this is an unwarranted conclusion. There is no way to know, based on the data they provided, whether the treatment was "useful" or not. We have no way of knowing what the distant progression-free survival would have been had they not received the SBRT treatment. Inexplicably, several groups from Italy also reached such unwarranted conclusions.

In fact, in a meta-analysis with longer-running follow-up data, Ost et al. (commented on here) found that for oligo-recurrent patients, distant progression-free survival was:

• 31% after 3 years, and only
• 15% after 5 years

In other words, the vast majority (85%) of men with SBRT-treated oligometastatic recurrence had detectably relapsed within 5 years. Given the lead-time bias and the slow rate of detectable early progression anyway, it is impossible to say that the radiation treatment accomplished anything. Until we have some proof, patients should approach metastatic treatment for anything but palliative purposes with caution. There is currently no evidence, none, that treatment of metastases has any effect on survival.

In spite of the lack of evidence, if a radiation oncologist looking at the patient's anatomy finds metastatic radiation to be safe, then there is little reason other than cost to abstain from it. However, a patient is taking a survival risk if he puts off hormone therapy in order to find metastases, especially in light of early evidence from the TOAD study.

Treatment of pelvic lymph nodes is a special case. If a patient is able to detect any metastatic pelvic lymph nodes, and he is convinced that he should have treatment at all, he should consider treatment of the entire pelvic lymph node field rather than isolated pelvic lymph nodes. One has to treat what one can't see as well as what one can see; again, provided that it is safe to do so. Safety may be questionable because of anatomy, lack of visceral fat, history of bowel inflammation, and previous pelvic radiation. The evidence for efficacy is mixed. Some retrospective data analyses (Rusthoven, Abdollah, Jegadeesh) found a survival benefit, while some did not (Kaplan and Johnstone). These retrospective studies are notoriously confounded by selection bias (i.e., the patients who got the therapy were the most likely to improve anyway). We await the outcomes of the randomized clinical trials before we have a more definitive answer.

There are currently several randomized clinical trials that have begun. Few are large enough or scheduled to run long enough to detect a survival benefit for prostate cancer. So far, the trials are in London, Montreal, France, Ghent, Italy and at Johns Hopkins.

SBRT Dose Escalation

Is there an optimum treatment dose for SBRT? At the low end of the spectrum, Alan Katz found that 35Gy in 5 fractions gave equivalent oncological outcomes with less toxicity compared to 36.5 Gy. At the other end of the dose spectrum, a clinical trial pushed the dose as high as 50 Gy in 5 fractions with disastrous consequences (see this link).  A trial of high dose rate brachytherapy, which is radiologically similar to SBRT, failed to find an optimum dose.

But radiation safety is not only just about dose. We saw that two treatment schedules using the same prescribed dose (40 Gy in 5 fractions) had disparate toxicity outcomes (see this link). In fact, the 12 month toxicity outcomes of Dr. King's high-risk study were recently presented and look excellent (see this link). It's also worth noting once again the outcomes of the 5-year multi-institutional SBRT clinical trial that used 40 Gy in 5 fractions and had excellent oncological and toxicity outcomes (see this link).

Helou et al. reported the outcomes of their SBRT (they call it SABR, but it's the same thing) trials at the Sunnybrook Health Sciences Centre in Toronto, Canada. There were sequential trials conducted from 2006-2014:

• 35 Gy/5 fractions/29 days - 82 low risk men only
• 40 Gy/5 fractions/11 days or 29 days - 177 low and intermediate risk men

A few (12) men had up to 6 months of androgen deprivation to shrink their prostates prior to radiation.

As an early measure of oncological effectiveness, they used PSA at 3 years (PSA3Y) after radiation. After correcting for the other variables like age, baseline PSA, T stage, and ADT use, the dose received remained the biggest predictor of PSA3Y. Median PSA3Y was:

• 0.64 ng/ml in those who received 35 Gy
• 0.27 ng/ml in those who received 40 Gy
• The difference was significant in both low risk men and intermediate risk men

The use of PSA3Y as a surrogate endpoint for biochemical recurrence is controversial. Because prostate cancer progresses very slowly and radiation, at the very least, reduces the cancer burden, it can take at least 5 years, and as long as 10 years, before we start to see concrete evidence that such therapy is curative. Also, a longer time until the nadir is achieved has been found to be correlated with failure-free survival (see this link). Nadir PSA has been proven to be a strong predictor of a lasting cure (see this link), but no one can tell when the nadir will be reached. In a recent study comparing the PSA at 1000 days after SBRT or HDR brachytherapy to the PSA at 1000 days after conventional IMRT, Kishan et al. reported that the PSA was lower for SBRT/HDR-BT. While the downward slope was about the same for the first 1000 days, the slope was steeper afterwards for SBRT/HDR-BT, indicating that a lower nadir would be achieved.

After correcting for confounders like age, baseline urinary function, and time between treatments, late term urinary toxicity of grade 2 or higher was 17 times greater among those who received 40 Gy compared to those who received 35 Gy.

The authors previously reported late term rectal toxicity. After 2 years, the cumulative probability of  grade 2 or higher rectal toxicity was suffered among:

• 5% of the men who received 35 Gy with 4mm margins
• 27% of the men who received 40 Gy with 5 mm margins
• 42% of the men who received 40 Gy with 5 mm margins +  30 Gy to seminal vesicles received 

Grade 3 and 4 rectal toxicity was especially high (10%) in the group that had their seminal vesicles irradiated. There were 3 cases of fistulas that may be attributable to rectal biopsies. [Patients should be very careful about the use of any kind of instrumentation within at least 6 months of radiation. That includes cystoscopies and colonoscopies.] Since this study, the authors have changed their radiation planning to include faster (VMAT) linacs and improved rectal dose constraints. Other changes that might mitigate rectal toxicity may include use of intrafractional tracking, rectal immobilization, and a rectal spacer.

There was clearly a trade-off between SBRT dose and late-term side effects of treatments. Perhaps we will one day be able to identify those cancers that are curable with a lower dose, and treat only those with the more radio-resistant cancers with a higher dose. Some believe that such techniques as simultaneous integrated boosts or heterogeneous planning may cure the cancer in the prostate better with less damage to organs at risk. But they remain to be proved in randomized clinical trials.

Note: Thanks to Dr. Andrew Loblaw for allowing me to review the full text of the study.

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.

Conflicting messages after surgery for high-risk patients from radiation oncologists and urologists

In spite of the data suggesting that brachy boost has better outcomes for high risk patients, it is being utilized less often and surgery is being utilized more often. After surgery, the high-risk patient is monitored by his urologist (Uro). If the urologist fears a recurrence, he may (1) refer his patient to a radiation oncologist (RO) for adjuvant or salvage radiation therapy (A/SRT), (2) refer his patient to a medical oncologist if he believes the recurrence is metastatic and incurable, or (3) he may continue to monitor the patient. The rate of utilization of A/SRT has been dwindling in spite of three major randomized clinical trials that proved that ART has better outcomes than waiting. If the patient does get to see a radiation oncologist, he may be advised to be treated soon, in conflict with the urologist advising him to wait. This puts the patient in a difficult situation.

Kishan et al. report the results of a survey among 846 ROs and 407 Uros. The researchers sought their opinions about under which conditions they would offer a high-risk post-prostatectomy patient A/SRT. For the purposes of their survey, they defined "adjuvant RT" as radiation given before PSA has become detectable, and "salvage RT" as radiation given after PSA has become detectable. "Early salvage RT" means PSA is detectable but lower than 0.2 ng/ml.

The following table shows the percent of ROs and Uros who agreed with each survey question:

	RO	Uro
ART underutilized	75%	38%
ART overutilized	4%	19%
SRT underutilized	65%	43%
SRT overutilized	1%	5%
SRT when first PSA is detectable	93%	86%
ART when first PSA is undetectable	43%	16%
Early SRT when first PSA is undetectable	42%	43%
SRT when first PSA is undetectable	16%	41%
Recommend SRT if PSA is:
Detectable	15%	7%
2+ consecutive rises	30%	20%
>0.03-0.1	8%	8%
>0.1-0.2	13%	11%
>0.2-0.4	29%	35%
>0.4	5%	19%
Recommend ART if pathology report is adverse:
Positive margin	80%	47%
Extraprostatic Extension (pT3a)	60%	32%
Seminal Vesicle Invasion(pT3b)	68%	47%
Local organ spread (pT4)	66%	46%
Pelvic lymph node (pN1)	59%	29%
Gleason score 8-10	20%	20%
Prefer SRT	12%	25%
Recommend adjuvant ADT with ART if:
Positive margin	14%	12%
Extraprostatic Extension (pT3a)	15%	11%
Seminal Vesicle Invasion(pT3b)	29%	25%
Local organ spread (pT4)	36%	37%
Pelvic lymph node (pN1)	65%	46%
Gleason score 8-10	46%	28%
No ADT	22%	31%
Recommend whole pelvic A/SRT if:
Positive margin	6%	9%
EPE	12%	9%
SVI	25%	22%
pT4	30%	30%
pN1	82%	64%
GS 8-10	36%	24%
No role	12%	24%
Other	13%	3%

In contrast to Uros, ROs are more likely to believe that both ART and SRT are underutilized. Uros believe that are used about right. ROs often see patients too late if they see them at all.

When the first PSA is detectable, both kinds of doctors would recommend SRT. When the first PSA is undetectable, 43% of ROs would recommend ART nonetheless, while only 16% of Uros would recommend ART.

Most of the ROs would treat when they see 2 consecutive rises in PSA, or if the PSA was detectable and under 0.2. Most (54%) Uros would wait until PSA was over 0.2.

Over half the ROs would recommend ART to high risk patients demonstrating any of several adverse pathological features: positive margins, stage T3/4, or positive pelvic lymph nodes. The majority of Uros would not recommend ART to high risk patients with those adverse pathologies.

The majority (65%) of ROs would include adjuvant ADT if there were positive lymph nodes. Uros were less likely to recommend adjuvant ADT based on lymph node involvement and Gleason score.

While most of both groups would have added whole pelvic radiation for patients with positive lymph nodes, 82% of ROs would, but only 64% of Uros.

ROs, knowing that a locally advanced cancer can suddenly become metastatic, and therefore incurable, would like to give A/SRT as soon as possible. Uros, who treat patients for the combined effect of surgery and radiation on urinary and sexual function, would like to wait as long as possible. The patient is caught in the middle of this difficult decision. Some have recommended beginning neoadjuvant ADT at the lowest detectable PSA and extending that time for as long as needed  to give urinary tissues maximum time to heal. Whatever the high-risk patient may eventually decide is in his best interest, he should meet with an RO immediately after surgery to hear both sides of the issue. Uros are blocking access to information that the patient needs.