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.