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.

"If all you have is a hammer, everything looks like a nail"

It was called "instrument bias" by Abraham Maslow and Abraham Kaplan, but for present purposes, we'll call it "specialty bias" - over-reliance on the tool one is most familiar with. Kishan et al. conducted a survey among urologists ("Uros") and radiation oncologists ("ROs") concerning their opinions about how best to treat high-risk patients in various situations from initial treatment to recurrence after initial treatment. They tabulated responses from:

• 846 ROs and 407 Uros
• 63% of ROs and 96% of Uros practiced in the US; the rest mainly in Australia and NZ
• They had a median of over 10 years of experience
• 41% of ROs and 51% of Uros were in private practice

Initial Treatment of High Risk Patients

ROs were 5 times more likely to believe that initial treatment with radiotherapy (RT) with androgen deprivation therapy (ADT) and with local salvage therapy, if needed, was preferred. They were also twice as likely to believe that it offered the patient equivalent outcomes as radical prostatectomy (RP) and salvage radiation (SRT), if needed. Uros were 4 times more likely to believe that RP ± SRT was the preferred treatment. Only 29% believed that RT had a place in initial treatment.

Preferred Initial Treatment	RO	Uro
RP±SRT	18%	71%
RT+ADT±local salvage	30%	6%
No preference	52%	23%

The "right" answer is...

Currently, the American Urological Association (AUA) and the American Society of Radiation Oncologists guidelines state:

"Clinicians should recommend radical prostatectomy or radiotherapy plus ADT as standard treatment options for patients with high-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)"

NCCN guidelines also list both as options. They note, however:

"A large, multicenter, retrospective cohort analysis that included 1809 men with Gleason score 9–10 prostate cancer found that multimodality therapy with EBRT, brachytherapy, and ADT was associated with improved prostate cancer-specific mortality and longer time to distant metastasis than either radical prostatectomy or EBRT with ADT. In addition, an analysis of outcomes of almost 43,000 men with high-risk prostate cancer in the National Cancer Database found that mortality was similar in men treated with EBRT, brachytherapy, and ADT versus those treated with radical prostatectomy, but was worse in those treated with EBRT and ADT . (MS25)

This can only be decided definitively by a randomized clinical trial, but given the difficulties of recruiting for such a trial, patients must make the decision based on lower level evidence.

Adjuvant RT (ART) and SRT for High-Risk Patients after RP

ROs were 2.7 times as likely to advocate for ART with undetectable PSA, and were twice as likely to believe that ART is underutilized. Conversely, Uros were 2.5 times more likely to approve of waiting until PSA has risen to 0.2 ng/ml. Most believed it is utilized appropriately (it is seldom utilized in this situation) or overutilized. About 2 in 5 ROs and Uros were OK with early SRT.

Two-thirds of ROs thought SRT was appropriate with 2 consecutive rises, or at any detectable level or any level under or equal to 0.1. Less than half of Uros held that belief. ROs were more likely than Uros to believe that SRT is underutilized.

ART Appropriate	RO	Uro
With undetectable PSA	43%	16%
Early SRT with detectable PSA < 0.2 ng/ml	42%	43%
Delayed SRT with PSA ≥ 0.2 ng/ml	16%	41%

ART Under/Over-Utilized	RO	Uro
Underutilized	75%	38%
Appropriately utilized	21%	43%
Overutilized	4%	19%

Lowest PSA at which SRT is Appropriate	RO	Uro
Detectable	15%	7%
≤ 0.1	21%	19%
At least 0.2	29%	35%
At least 0.4	4%	12%
At least 1.0	1%	7%
At least 2 consecutive rises	30%	20%

SRT Under/Over-Utilized	RO	Uro
Underutilized	65%	43%
Appropriately utilized	34%	52%
Overutilized	1%	5%

The "right" answer is...

The 2019 AUA/ASTRO guidelines state:

Guideline Statement 2. Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical margins, and extraprostatic extension should be informed that adjuvant radiotherapy, compared to radical prostatectomy only, reduces the risk of biochemical recurrence, local recurrence, and clinical progression of cancer. They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of three randomized controlled trials that addressed these outcomes indicated a benefit but the other two trials did not demonstrate a benefit. However, these two trials were not designed to identify a significant reduction in metastasis or death with adjuvant radiotherapy. (Clinical Principle)

 Guideline Statement 3. Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic extension because of demonstrated reductions in biochemical recurrence, local recurrence, and clinical progression. (Standard; Evidence Strength: Grade A)

Guideline Statement 8. Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA.  (Clinical Principle) 

"...patients should be advised that if recurrence is detected without evidence of distant metastases, then RT should be administered at the earliest sign of PSA recurrence ..."

The 2019 NCCN guidelines state:

Indications for salvage RT include an undetectable PSA that becomes subsequently detectable and increases on 2 measurements or a PSA that remains persistently detectable after RP. Treatment is more effective when pre-treatment PSA is low and PSADT is long.

Salvage for High-Risk Patients after RT

About 2/3 of Uros believed that RP and Cryo are appropriate salvage therapies after biochemical recurrence following primary RT (when imaging was negative for distant metastases). Very few thought salvage radiation or other ablation therapies were appropriate. Among ROs, most approved of salvage RP, but sizeable minorities felt that salvage brachytherapy and salvage cryo was appropriate. About 1 in 5 thought salvage SBRT or salvage HIFU was appropriate.

Salvage therapies after RT failure	RO	Uro
RP	56%	66%
LDR brachytherapy	34%	6%
HDR brachytherapy	42%	10%
SBRT	20%	5%
Cryoablation	40%	69%
HIFU	21%	13%

However, 2/3 of both ROs and Uros and agreed that salvage after RT was not as effective as salvage after RP.

Is salvage after RT as effective as SRT after RP?	RO	Uro
No	64%	66%
Yes	36%	34%

And most of both groups believe that focal salvage is inferior to whole gland salvage after RT failure. But Uros were much more likely to hold this belief vs ROs.

Focal salvage=whole gland salvage?	RO	Uro
No	56%	75%
Yes	44%	25%

The "right" answer is...

NCCN guidelines state:

Salvage RP is an option for highly selected patients with local recurrence after EBRT, brachytherapy, or cryotherapy in the absence of metastases, but the morbidity (ie, incontinence, loss of erection, anastomotic stricture) is high and the operation should be performed by surgeons who are experienced with salvage RP. 

Brachytherapy can be considered in men with biochemical recurrence after EBRT. In a retrospective study of 24 men who had EBRT as primary therapy and permanent brachytherapy after biochemical recurrence, the cancer-free and biochemical relapse-free survival rates were 96% and 88%, respectively, after a median follow-up of 30 months.Results of a phase 2 study of salvage HDR brachytherapy after EBRT included relapse-free survival, distant metastases-free survival, and cause-specific survival rates of 68.5%, 81.5%, and 90.3%, respectively, at 5 years.

HIFU also has been studied for treatment of radiation recurrence. Analysis of a prospective registry of men treated with HIFU for radiation recurrence revealed median biochemical recurrence-free survival at 63 months, 5-year OS of 88%, and cancer-specific survival of 94%.

For a discussion of salvage therapies after RT, see this link. Salvage after RT is generally as effective or better than SRT after RP. Focal salvage is as effective as whole gland salvage in many cases.

What to do about specialty bias

It is not surprising that specialists are more knowledgeable about, and more favorably disposed to their own field (otherwise, they're in the wrong job). However, there are knowledge gaps even within their own field. Many patients expect their doctors to be knowledgeable about their own field, and to be able to compare it to other therapies. We have seen that this is an unrealistic expectation. Here are some recommendations for patients:

• Don't expect a specialist to be knowledgeable outside his own field. Consult with a variety of specialists, if possible.
• Remember that it is radiation oncologists, not urologists, who treat and follow-up on SRT for surgical recurrences. ROs are more experienced than Uros at SRT.
• Salvage brachytherapy after RT recurrence is highly specialized - there aren't many practitioners with expertise. Salvage ablation and salvage SBRT specialists are even more rare. Patients should avoid salvage surgery due to its high morbidity.
• Second opinions are critical. Finding specialists may involve travel, which may be precluded by cost/insurance limitations.
• For patients who are inclined to research these topics themselves, they must be aware that the quality of research on all of these topics is low to moderate. There have been very few randomized clinical trials focussed on high risk patients, so we have to make informed judgments based on observational studies or single-arm, single-institution clinical trials in most situations. AUA, ASTRO and NCCN guidelines are updated and may be their best source of information (other than this blog 😉).

Focussing on physicians, the authors recommend interdisciplinary clinics, which might work well in academic centers. However, a substantial proportion of both ROs and Uros were in private practice. They also suggest continuing medical education, and cross-specialty training. Professional organizations typically do not currently require this. Uros do not typically attend ASTRO meetings, nor do ROs attend AUA meetings.

- with thanks to Dr. King for allowing me to see the full text and questionnaire.