Rethinking risk stratification for radiation therapy

In 2016, we looked at the Candiolo risk stratification system for radiation therapy. To my knowledge, it has not been prospectively validated or widely adopted. In the intervening 5 years, a number of things have changed:

• Active surveillance has become the treatment of choice for many patients with low-risk PC, and for some with favorable intermediate-risk PCa.
• We have the first large randomized trial (ProtecT) of external beam radiation vs. surgery vs "active monitoring" demonstrating 10-year oncological equivalence for favorable-risk patients.
• Multiparametric MRI is increasingly used to find higher grade cancer. (We won't discuss whether this has been a net benefit, as Vickers et al. doubts).
• Multiparametric MRI has also been used for staging by some doctors. (See this new predictive nomogram for surgery based on MRI staging and size).
• Multiparametric MRI has been used to detect local recurrence.
• Decipher and other genomic tests of biopsy tissue have been used to independently assess risk.
• PSMA PET scans have recently been FDA-approved for unfavorable risk patients to rule out distant metastases.
• PSMA PET and Axumin PET scans have been FDA-approved to determine radiographic recurrence.
• NCCN has added the distinction between favorable and unfavorable intermediate-risk, as described by Zumsteg et al. 
• The use of brachytherapy has declined.
• Several new hormone therapies (abiraterone, enzalutamide, apalutamide, and darolutamide) have been approved for metastatic patients.

Prognostic vs Predictive Risk Stratification

There is a new staging system called "STAR CAP." It shows a patient's prognosis of dying in 5 years or 10 years from prostate cancer (Prostate Cancer-Specific Mortality - PCSM) after availing themselves of whatever standard therapies they choose. This was an enormous undertaking. The researchers looked at the records of 19,684 men with non-metastatic (those with positive pelvic lymph nodes were included) prostate cancer who were treated at 55 sites in the US, Canada, and Europe between January 1992 and December 2013. Treatment may have consisted of radiation of any kind (7,263 patients) or prostatectomy (12,421 patients). They may have also had androgen deprivation therapy and salvage therapy. They may have also had docetaxel (2004) and Provenge (2010) therapy; Xofigo was approved in May 2013, so some few may have had it. Follow-up ended in December 2017. The patients were split equally into "training" and "validation" cohorts. Secondarily, they validated it using 125,575 men in the SEER database. It has also been independently validated in Europe for prostatectomy patients, 

They used 5 risk factors (except for pelvic lymph nodes (N stage))  to assign points (similar to CAPRA and Candiolo), in the following groupings:

• Age: ≤50. 51-70, 71+
• T stage: T1, T2a-b, T2c/T3a, T3b/T4 (based on physical examination, not imaging)
• N stage: N0. N1 (based on CT)- note: only 22 patients were N1 in the training cohort
• Gleason score: 6, 3+4, 4+3, 4+4/3+5,4+5, 5+3/5+4/5+5
• Percent positive cores: ≤50%, 51-75%, 76-100%
• PSA: ≤6, >6-10, >10-20, >20-50, >50-200

It divides patients into 9 risk groups (3 low (IA-C), 3 intermediate (IIA-C), and 3 high (IIIA-C)) based on how likely they are to die of their prostate cancer after all their therapies. Interested patients can use this handy nomogram.

Their system outperforms the AJCC prognostic stage groups (8th edition) or the NCCN system if they were used to predict prostate cancer mortality.

Their system is necessarily limited by the risk factors available in the large databases they used to train and validate their model. That means that there may be risk factors that are not accounted for, including:

• genomic risk
• % pattern 4 in GS 3+4 (this may be important in determining prostatectomy risk and risk of staying on active surveillance. It is often not reported on biopsies.
• Multiparametric MRI for staging and tumor volume
• PSA density and perineural invasion
• Use of 5aris (Proscar or Avodart)
• Use of PSMA PET scans to better select patients for local therapy

The STAR CAP system is also limited by how prostate cancer mortality is ascertained. For example, if a man dies of a blood clot in his lungs, heart, or brain, was that because the cancer increases blood clots, or was that a competing cause of death?

Decision-making

For most patients with localized prostate cancer, their cancer is not likely to be lethal after well-done therapies, at least not for a long time. Patients who are correctly diagnosed with localized PCa and treated for it will usually die of something else - their prognosis is excellent. What patients want to know is which therapy gives them the best chance of a cure and what side effects they can reasonably expect - their predicted outcomes are more important than their prognosis.

I often counsel patients to try to stay in the present moment, and not be concerned with what may or may not happen down the line. The patient is rightly concerned with making the best treatment decision he can make given what he currently knows about his cancer. If his cancer progresses, there are potentially curative salvage therapies for both surgery and radiation. If his cancer progresses after salvage therapy, his cancer can often be managed with a variety of systemic therapies for many years. The list of systemic therapies is growing rapidly. It doesn't help the patient to know the percent of patients who died in the past, given the therapies that were available then (The STAR CAP cohort goes back to 1992!). The patient wants to know his odds of a given therapy working for him now - a predictive model.

A good example of such a predictive model is the Memorial Sloan Kettering (MSK) nomogram for predicting prostatectomy outcomes. It is based on the outcomes of over 10,000 men and is continually updated. Like STAR CAP, CAPRA, and Candiolo, it includes patient age and % positive cores, as risk factors. While it also provides 10-yr and 15-yr prostate cancer survival estimates (also, see this MSK nomogram that uses comorbidities and actuarial survival tables to calculate 10- and 15-yr survival probabilities), it tells the patient what his progression-free survival (PFS) probability is if he is like the average man with his risk characteristics who chooses prostatectomy as his treatment. They define "progression-free survival (PFS)" as a PSA of less than 0.05 ng/ml and no evidence of clinical recurrence. It also shows the probability of adverse pathology after prostatectomy.

I know of no such comparable nomogram for radiation therapies. What is needed is a large predictive model for each of the major types of radiation therapies: external beam radiation, brachytherapy monotherapy, and the combination of external beam radiation and brachytherapy. It also needs to include whether whole pelvic treatment and androgen deprivation therapy (and its duration) are used with it. 

Building such a database is an enormous undertaking. No one institution has enough primary radiotherapy patients to create a reliable sample for all risk strata and for modern best practice. Unlike surgery, which has changed little in its effectiveness over time (even nerve-sparing surgery didn't change that), the effectiveness of radiation therapy changed a lot with dose escalation. Perhaps ASTRO or a multi-institutional consortium can create a registry to hold the data.

While patients making a treatment decision want to compare predictive outcomes across the treatments available to them, there are many reasons why such comparisons are difficult. The only valid way of comparing treatments is via a prospective randomized trial, like ProtecT. As we saw in the MSK nomogram, PFS or biochemical recurrence-free survival (bRFS) depends on the definition of PSA recurrence. MSK uses a PSA of 0.05 ng/ml as their definition of PSA progression after prostatectomy. Radiation therapies define biochemical recurrence as "nadir+2.0 ng/ml." It is impossible to say if these are comparable benchmarks. Perhaps future definitions of local recurrence after radiotherapy will include detection by mpMRI or one of the PSMA radioindicators that are not urinarily excreted that are in trials now.

The patient also needs to understand his likelihood of incurring the side effects associated with each treatment. ProtecT again provides the only direct comparison, but that is limited to prostatectomy, external beam radiation, and active monitoring. We know that side effects may increase with brachy boost therapy,  use of ADT, and whole pelvic treatment.

Case Examples

(1) a 65-year-old man in good health, recently diagnosed with GS 4+3, 7 cores out of 12 were positive, stage T1c (nothing felt by DRE), bone scan/CT negative, and PSA of 7.5 ng/ml. Here's how the various staging systems categorize him:

• STAR CAP: Stage IIB  (IIA-C is intermediate risk) 5-yr PCSM:1.1%   10-yr PCSM:4.4%
• CAPRA Score: 6 - high risk (6-10 is high risk)
• AJCC Prognostic Stage Group: IIC (IIA-C is intermediate risk)
• NCCN: Unfavorable intermediate risk 
• recommended options: RP+PLND, EBRT+ADT (4-6 mos.), Brachy boost therapy ± ADT (4-6 mos.)
• Candiolo score: 162 (intermediate range is 117-193) 
• 5-yr bPFS= 80% 10-yr bPFS=60%
• MSK pre-op nomogram: 10-yr and 15-yr PCSM: 1%
• 5-yr PFS=58% 10-yr PFS=42%
• Organ confined= 34%, EPE=63%, N1=14%, SVI=16%
• Multi-institutional SBRT consortium (Kishan et al.) reported 7-yr bRFS of 85% for unfavorable intermediate-risk (NCCN)
• 10-yr bRFS was reported (Abugharib et al.) to be 92% for brachy boost therapy among unfavorable intermediate-risk (NCCN) with relatively high late-term urinary toxicity
• 5-yr bRFS was reported (Kittel et al.) to be 81% for low dose rate brachytherapy monotherapy among unfavorable intermediate-risk (NCCN)

So brachy boost therapy is far more successful than surgery for unfavorable intermediate-risk patients. SBRT monotherapy may be better than either EBRT or LDR brachytherapy monotherapy because of the higher biologically effective dose.

(2) A 55 y.o. man in good health, GS 3+4 (10% pattern 4), 3/12 positive biopsy cores, perineural invasion, Stage T1c, PSA 4.5 ng/ml

• STAR CAP: Stage IC  (1A-C is low risk) 5-yr PCSM:0.5%   10-yr PCSM:2%
• CAPRA score: 2 (0-2 is low risk)
• AJCC Prognostic Stage Group: IIB (IIA-C is intermediate risk)
• NCCN: favorable intermediate risk
• recommended options: active surveillance, EBRT, brachytherapy monotherapy, RP±PLND
• Candiolo score: 86 (low risk 57-116) 
• 5-yr bPFS= 85% 10-yr bPFS=74%
• MSK pre-op nomogram: 10-yr and 15-yr PCSM: 1%
• 5-yr PFS=90% 10-yr PFS=83%
• Organ confined= 77%, EPE=21%, N1=2%, SVI=2%
• Multi-institutional SBRT consortium (Kishan et al.) reported 7-yr bRFS of 91% for favorable intermediate-risk (NCCN)
• 5-yr bRFS was reported (Kittel et al.) to be 90% for low dose rate brachytherapy monotherapy among favorable intermediate-risk (NCCN)

So, all therapies for favorable intermediate-risk patients have "success" rates in the same range (85%-91% at ~5 years) independent of the chosen therapy. This is consistent with what we saw in the ProtecT trial. However, he isn't a good candidate for active surveillance because of his biopsy-detected perineural invasion (see this link).

(3) A 72 y.o. man with heart stent but otherwise healthy, GS 4+5, 8/12 positive biopsy cores, Stage T3a (felt bulge), PSA 15 ng/ml, neg. bone scan/CT

• STAR CAP: Stage IIIB (IIIA-C is high risk) 5-yr PCSM: 6%   10-yr PCSM:21.2%
• CAPRA score: 8 (6-10 is high risk)
• AJCC Prognostic Stage Group: IIIC (IIIA-C is high risk)
• NCCN: high/very-high risk (2 high risk features)
• recommended options: EBRT+ADT (1.5-3 yrs), brachytherapy boost therapy + ADT (1-3 yrs), RP+PLND
• Candiolo score: 256 (high risk 57-116) 
• 5-yr bPFS= 67% 10-yr bPFS= 43%
• MSK pre-op nomogram: 10-yr PCSM: 4% 15-yr PCSM: 10%
• 5-yr PFS=12% 10-yr PFS=7%
• Organ confined= 1%, EPE=99%, N1=71%, SVI=79%
• Kishan et al. reported that for Gleason 9/10 patients at UCLA and Fox Chase, 10-year bRFS was 70% for brachy boost therapy, 60% for EBRT, and 16% for prostatectomy. While surgery by itself is inferior to radiation therapies for these very high-risk patients. Surgery+ salvage RT has success rates that seem to be closer.

In this case, age and the heart stent probably rule out surgery. His expected lifespan argues against watchful waiting. Brachy boost therapy and 18 months of adjuvant ADT (with cardiologist agreement) is a preferred option. Pelvic lymph nodes should be treated because of the high risk of pelvic lymph node invasion. If possible, a PSMA PET scan should be used to rule out distant metastases.

For patient decision-making, prognostic risk groups like STAR CAP, AJCC, and CAPRA are useless. The NCCN risk groups were based on prostatectomy bRFS. Counts of positive cores already used in the NCCN schema help differentiate very low risk from low risk, favorable intermediate-risk from unfavorable intermediate-risk, and high-risk from very high-risk. It is not clear that age is a risk factor that determines the oncological success of any therapy (although it undoubtedly affects toxicity). As we can see from these prototype cases, we are more needful of a risk stratification system/nomograms for the various radiation therapies similar to the MSK pre-op nomogram.

SBRT for High-Risk Patients

As we have seen, SBRT is a preferred therapy for low and intermediate-risk patients (see this link). It is effective, safe, convenient, and relatively inexpensive. However, its use for high-risk patients remains controversial.

Amar Kishan has accumulated data from 8 institutions that have used SBRT for 344 high-risk patients. They were treated as follows:

• They received from 35 Gy-40 Gy in 5 treatments (7-8 Gy per treatment)
• 72% received adjuvant ADT for a median of 9 months
• 19% received elective nodal radiation

After a median follow-up of 49.5 months:

• 4-year biochemical recurrence-free survival  (bRFS)was 82%
• Higher dose, longer ADT, and nodal radiation were associated with better bRFS
• 4-year metastasis-free survival was 89%
• Late grade 3 GU toxicity was 2.3%
• Late grade 3 GI toxicity was 0.9%
• Toxicity was associated with dose and ADT use

Although the results of different prospective trials aren't comparable, the following table gives an idea of 4-6 year outcomes of prospective trials of high-risk patients using various therapies.

	Follow-up	bRFS	BED	ADT (median)	Late GU Toxicity Grade ≥3
SBRT (1)	4 yrs	82%	198-253 Gy	9 mos.	2.3%
Surgery+SRT (2)	5 yrs	78%	154 Gy	6 mos.	8% (3)
HDR-BT (4)	5 yrs	91%	227-252 Gy	6.3 mos.	3-16%
LDR- Brachy Boost (5)	5 yrs	86%	227 Gy	12 mos.	19%
HDR-Brachy Boost (6)	6 yrs	88%	267 Gy	12 mos.	2.5%
IMRT (7)	5 yrs	88%	174 Gy	28 mos.	2.5%

SBRT = stereotactic body radiation therapy,. External beam radiation (EBRT) concentrated in 5 treatments

bRFS= biochemical (PSA) recurrence-free survival

BED= biologically effective dose (comparable effectiveness)

ADT= androgen deprivation therapy used for a limited time to improve outcomes

late GU toxicity ≥3 = serious urinary side effects requiring intervention, occurring more than 3 months after therapy

HDR-BT = high dose rate brachytherapy (temporary implants)

LDR-BT = low dose rate brachytherapy (permanent implants/seeds)

Brachy Boost therapy - External beam radiotherapy (EBRT) with a boost of radiation to the prostate using brachytherapy 

IMRT = intensity-modulated radiation therapy, usually given in about 40 treatments

(1) https://www.redjournal.org/article/S0360-3016(21)00068-7/pdf

(2) https://riskcalc.org/ProstateCancerAfterRadicalProstatectomyNew/ with GS 8

(3) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext

(4) https://www.redjournal.org/article/S0360-3016(11)00552-9/abstract

(5) https://www.redjournal.org/article/S0360-3016(16)33484-8/abstract

(6) https://www.thegreenjournal.com/article/S0167-8140(18)30238-X/fulltext

(7) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext

As we've seen (see this link), brachy boost therapy is the gold standard for long-term recurrence-free survival. At about 5 years, however, all therapies seem to be about equally effective, with biochemical recurrence-free survival in the range of 78-91%. However, they differ markedly in the incidence of serious late-term urinary side effects. For LDR Brachy Boost therapy, the risk of urinary retention is high, while the risk of incontinence and urinary retention is elevated among patients having salvage radiation (SRT). External beam monotherapy, using either IMRT or SBRT, had a low risk of serious late-term urinary side effects (and almost no risk of serious rectal side effects).

IMRT, as a primary therapy for high-risk patients, requires long-term use of ADT to be effective. The DART RADAR trial showed that for high-risk patients, 6 months of adjuvant ADT wasn't nearly enough. Nabid suggests that 18 months of adjuvant ADT may be optimal when paired with IMRT. SBRT seems to be equally effective with less adjuvant ADT, but the optimal duration is yet to be determined.

The question that will only be resolved with longer follow-up is whether the recurrence rates are stable after 4 years, or whether they will deteriorate with longer follow-up. In the ASCENDE-RT trial of brachy boost therapy vs external beam radiation only, biochemical recurrence rates were similar after 5 years. Recurrence increased at a rate of 5% per year among those treated with EBRT alone, but only at a rate of 1% per year if they got the brachy boost. There was similar stability of outcomes when HDR brachytherapy was used. Recurrence after salvage radiation increased from 22% at 5 years to 30% at 10 years. There is every reason to believe that SBRT, which uses biologically effective doses (BED) of radiation similar to brachy boost therapy, will follow a stable recurrence pattern over time, but that remains to be shown.

Ensuring the safety of patients is critical, and high-risk patients are usually treated with wider margins that can affect toxicity. As we saw, SBRT there are many factors that must be considered when giving radiation this intense (see this link).

The first randomized trial (see this link) of radiation delivered in 6 treatments compared to 39 treatments to intermediate to high-risk patients proved that the cancer control and toxicity were similar. Another randomized trial (PACE-B) has already shown that the toxicity is lower with SBRT. An ongoing arm of that trial (PACE-C) is focusing on high-risk patients.

NCCN has included SBRT as a reasonable standard-of-care option for high-risk patients (Table 1 Principles of Radiation Therapy PROS-E 3 of 5 in NCCN Physicians Guidelines 3.2020). Due to the pandemic, an international panel of radiation oncologists is recommending that high-risk patients consider its use (see this link).

ProtecT Randomized Clinical Trial: Patient outcomes by treatment received - active monitoring, prostatectomy, or radiation

In an earlier article (see this link), we looked at the only trial that randomized men with localized prostate cancer to either "active monitoring" (AM), radical prostatectomy (RP), or external beam radiation (EBRT). AM was less restrictive than today's active surveillance protocols (it included men who were not low risk) and it did not include mpMRI or follow-up biopsies. EBRT was lower dose than contemporary guidelines, included short-term ADT for everyone, and used a more toxic technique (3D-CRT) than IMRT prevalent today. RP was open and nerve-sparing. The earlier analysis categorized patients according to the treatment they were randomized to receive, rather than the treatment they actually received. They did this because it eliminates "selection bias" - patients switched to the treatment that they or their doctors believed would benefit them most. Now, the authors report patient outcomes according to the treatment they actually received.

1. Treatment choice/ oncological outcomes

In the first year, 78% of patients received the treatment they were randomly assigned. Higher risk men chose radical treatment rather than AM. Conversely, men with low-risk PC were less likely to opt for EBRT.

In the ten years of follow-up, there were only 17 prostate cancer deaths out of 1643 men randomized in the trial. The pooled, adjusted risks and the percent of the AM group that suffered each oncological outcome after 10 years of follow-up were:

• 69% lower risk of prostate cancer death for radical therapy (RP or EBRT) vs AM 
• 1.8% PC deaths among AM
• 64% lower risk of metastases or death for radical therapy (RP or EBRT) vs AM 
• 6.0% metastases or death among AM
• 77% lower risk of progression for radical therapy (RP or EBRT) vs AM 
• 24% progression among AM
• 47% lower risk of salvage ADT for radical therapy (RP or EBRT) vs AM 
• 8.8% salvage ADT among AM
• No statistically significant differences between RP and EBRT

The inferior performance of their AM protocol was predictable (see this link - Section 3). Their AM protocol did not include mpMRI confirmation, biopsy follow-up, and allowed some higher-risk patients.


2. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AM or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 24% were incontinent by the end of two years, with little improvement from that point. Incontinence increased slowly in the AM group as they elected to have radical treatment.


Table 1. Incontinence: The percent who used one or more pads per day

Time point	AM	RP	EBRT
Baseline	0%	1%	0%
6 months	0%	55%	1%
1 year	1%	32%	2%
2 years	3%	24%	2%
3 years	3%	23%	2%
4 years	5%	20%	2%
5 years	5%	20%	2%
6 years	7%	21%	2%

b. Nocturia

The researchers examined the question of whether nighttime urination was more frequent after therapy. On this dimension, only EBRT had a clinically detectable effect, and it was only at the 6 month mark. After that, it returned quickly to AM levels. RP returned to baseline level.

Table 2. Nocturia - Twice or more per night

Time point	AM	RP	EBRT
Baseline	20%	22%	20%
6 months	24%	35%	65%
1 year	23%	26%	36%
2 years	28%	23%	32%
3 years	31%	25%	32%
4 years	33%	25%	33%
5 years	35%	23%	36%
6 years	38%	25%	34%

3. Rectal Adverse Outcomes

The researchers asked the trial participants whether they had blood in their stools half the time or more. There were no discernable effects of AM or RP. Blood in stools peaked at a low level (8%) of those who had EBRT.

Table 3. Blood in stools more than half the time

Time point	AM	RP	EBRT
Baseline	1%	1%	1%
6 months	1%	1%	4%
1 year	1%	0%	4%
2 years	0%	1%	7%
3 years	1%	1%	8%
4 years	1%	1%	8%
5 years	2%	1%	8%
6 years	1%	2%	6%

4. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AM. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was possible for 5% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 13% at 2 years but did not recover appreciably beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AM cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they aged and elected to have radical therapies, predominantly surgery. 

For the EBRT cohort, erectile function had dropped to a minimum value of 18% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 34% at 3 years. At 6 years, potency was twice ads high as those who had RP. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point	AM	RP	EBRT
Baseline	68%	66%	63%
6 months	59%	5%	18%
1 year	60%	6%	34%
2 years	54%	13%	32%
3 years	49%	14%	34%
4 years	43%	15%	31%
5 years	40%	16%	28%
6 years	35%	15%	29%

Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation

Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.

Myth #3: Over time, erectile function is about the same for surgery and radiation.