The importance of radiotherapy dose escalation and long-term ADT for success

 Localized prostate cancer (PCa) is highly curable. We usually divide localized PCa into 3 risk categories: low-risk, intermediate-risk, and high-risk of recurrence after treatment. Even high-risk PCa is highly curable - 80+% of patients are cured in clinical trials of various radiation therapy regimes (see this link, for example). With new PET scans recently approved for high-risk patients, patients who truly have localized PCa have every hope of achieving even better cure rates.

This begs the question: what do we mean by "cured." What most patients mean is that no recurrence will ever be detected. The first sign of recurrence is a rising PSA more than 2.0 ng/ml over the lowest PSA achieved (nadir). This is called a "biochemical recurrence" (BCR). Other deleterious events may happen. An undetected ("occult") metastasis may grow. The patient may die due to some other cause. If the former never happens, it is called "metastasis-free survival (MFS)." It is highly dependent on the technology used to detect occult metastases. If the latter never happens within the time patients are tracked after treatment, it is called "overall survival (OS)." It is highly dependent upon other diseases ("comorbidities"), treatments given, and the length of follow-up. Often, there are undetermined variables (called "confounders") that tilt OS in one direction or another. Only BCR is relevant for the patient making a therapy choice for his localized prostate cancer.

As we saw previously (at this link), the MARCAP consortium has found that the duration of androgen deprivation therapy (ADT) given along with ("adjuvant to") radiation therapy depends on how the radiation is delivered to high-risk patients - either 12 months for brachy boost therapy or 26 months for external beam radiation therapy. Kishan et al. has analyzed a large number of clinical trials to answer the following questions:

1. What is the role of radiation dose escalation in minimizing BCR?
2. What is the role of long-term vs short-term ADT in minimizing BCR?

• They defined "high dose" radiation as any dose equivalent to greater than or equal to 74 Gy (or its equivalent)
• They defined "long-term" (LTADT) as any duration longer than 18 months, while "short-term" (STADT) was defined as 3-6 months.

For high-risk patients, compared to treating them with low-dose RT without ADT:

• Adding high dose RT (without ADT) reduced BCR by 26%
• Adding short-term ADT reduced BCR by 36%
• Adding high dose RT and STADT reduced BCR by 55%
• Adding low dose RT and LTADT reduced BCR by 61%
• Adding high dose RT and LTADT reduced BCR by 69%

Intermediate risk patients were treated before NCCN distinguished "favorable" intermediate-risk from "unfavorable" intermediate-risk (see this link). For intermediate-risk patients, taken as a whole, compared to treating them with low-dose RT without ADT:

• Adding high dose RT (without ADT) reduced BCR by 21%
• Adding short-term ADT reduced BCR by 32%
• Adding high dose RT and STADT reduced BCR by 46%
• Adding low dose RT and LTADT reduced BCR by 55%
• Adding high dose RT and LTADT reduced BCR by 74%

In both risk groups, long-term ADT provided greater benefit than high dose RT, but combining LTADT with high dose RT provided the best cure rates. 

There are some seeming contradictions between this meta-analysis and the DART 01/05 randomized clinical trial. The purpose was to see if there was a difference in biochemical disease-free survival (bDFS) among intermediate and high-risk patients treated with high-dose radiation and either 28 months or 4 months of ADT. At 5 years of follow-up (see this link), the LTADT group had a significantly higher bDFS than the STADT group. The difference was particularly noticed among the high-risk subgroup. However, with 10 years of follow-up, the difference was no longer significant. 

• For the total, the bDFS was 70% for LTADT vs 62% for STADT (not statistically significant)
• For the high-risk subgroup, the bDFS was 67% for LTADT vs 54% for STADT (not statistically significant)

At least for the high-risk subgroup, the difference was large but not statistically significant. What happened?

What happened was a quarter of the men in the study died in the interim (median age was 72 at the start). Only 3% died of prostate cancer. Many of the men who would have shown no biochemical progression had they lived were eliminated from the trial because they died of other causes. This is called "survivorship bias." The high dropout rate due to death from other causes tells us that follow-up of such trials beyond 5 years will introduce bias into our most important endpoint. It is also another reason that "overall survival" is not a useful endpoint when patients are older. Men with less than 10 years of expected survival due to age or comorbidities should consider watchful waiting rather than any kind of radical treatment. Patients can determine their actuarial expected survival with this calculator: (scroll down to "Male Life Expectancy").

Optimal duration of adjuvant ADT depends on the type of radiation used for high-risk patients

No one wants to have androgen deprivation therapy (ADT), even if it is for a limited time. It has been known for a long time that it improves oncological outcomes when given with ("adjuvant to") radiation therapy in patients with high-risk prostate cancer. Several randomized clinical trials (RCTs) have tried to find the best duration to use it, but it is difficult to arrive at reliable optimization points- it would involve varying the duration for a large number of high risk patients. Kishan et al. have taken an innovative approach to solving this problem by combining several RCTs and a multi-institutional observational study. Unlike typical "meta-analyses," they compared similar patients across three studies.

The three studies they used in their analysis were:

1. The high-risk patients in the DART 01.05 GICOR RCT (see this link), which randomized patients to 28 months or 4 months of adjuvant ADT in patients getting high dose external beam radiation (EBRT-only). They found that 28 months is better than 4 months, but is there a duration that is less than 28 months for EBRT-only?
2. The patients in the TROG 03.04 RADAR RCT (see this link), which randomized patients to 18 months or 6 months of adjuvant ADT in patients getting varying doses of EBRT or high dose rate brachy boost therapy (BBT). They found that 18 months is better than 6 months for BBT, but is there a duration that is less than 18 months for BBT?
3. The patients in a multi-institutional (retrospective, non-randomized) study who received varying durations of adjuvant ADT and EBRT-only or brachy boost therapy for their high risk PCa (see this link).

They used distant metastasis-free survival (DMFS) as the endpoint of interest because it has been found to correlate well with eventual overall survival. They went back to the original patient-level data to extract comparable patients when comparing them across studies. This retained many of the advantages of each of the three studies. While this innovative approach does not constitute the highest level of evidence (Level 1), it offers a degree of reliability that goes beyond simple observational studies.

They used two statistical methods to look at the data. In one analysis, they divided the durations into three parts: 

• ≤6mo.
• >6 - 18 mos
• >18 mos

In another analysis (called "cubic splines") they found the best fit for the continuous data. Both analyses led to similar conclusions.

The best estimates for the best minimum adjuvant ADT duration are:

• at least 26.3 months for EBRT-only
• at least 12 months for BBT

But, one might object, didn't Nabid's PCS IV trial show that 18 months is as good as 36 months (see this link)? Kishan points out that only about half of the cohort in that trial who were supposed to get 36 months of ADT actually got that much. And nearly a quarter of the 36-month cohort actually received less than 21 months. The only data we've seen so far has been analyzed by the dose they were intended to get, not by what they actually got. Also, why were the drop-out rates so high? The DART RCT had 95% compliance with the full 28 months, even though the radiation doses given were much higher.

There is a trade-off: BBT can come with severe late-term urinary side effects (among 19% in the ASCENDE-RT RCT), while the late-term urinary side effects are milder for EBRT-only (only 2.5% in DART). Only the patient can decide if he is willing to take on 12 months of ADT with BBT vs over twice as long for EBRT-only, given the higher expected radiation toxicity with BBT.

Which is better: EBRT+2 years of ADT or BBT+1 year of ADT?

Patel et al. looked at the use of the two therapies at many of the top cancer centers. They found there was no significant difference in the occurrence of distant metastases or in prostate cancer-specific survival.

There are several unanswered questions:

• As we have seen (see this link), brief intense use of abiraterone or other advanced hormone therapy may obviate the need for longer ADT.
• Decipher genomic analysis may indicate which patients may be able to get away with less hormone therapy, and which need more. The PREDICT-RT RCT will eventually answer this question.
• Does SBRT monotherapy or HDR brachy monotherapy still require adjuvant ADT? Those therapies can have almost as high a biologically effective dose as BBT but with fewer side effects. This study suggests that 12 months of ADT is beneficial with even the highest dose radiation, but future clinical trials will give a more reliable answer.
• Standard-of-care dictates 2-3 years of adjuvant ADT when enlarged pelvic lymph nodes are found by CT or MRI. What is the optimum duration when cancerous pelvic lymph nodes are only detected with a PSMA PET scan and not by CT? What about when they are too small to be detected by any kind of imaging, and their presence is only suggested by risk characteristics?
• What duration of adjuvant ADT minimizes biochemical recurrence-free survival and the need for any salvage treatment?
• Will these estimates hold up if tested in an RCT?

Gay men should never* have a prostatectomy

After over 10 years with gay prostate cancer support groups, I have come to believe that radical prostatectomies (RP) cause special and needless suffering in gay men and should never be used in them. Two great resources for gay men faced with this decision are these:

The Effects of Radical Prostatectomy on Gay and Bisexual Men's Mental Health, Sexual Identity and Relationships: Qualitative Results from the Restore Study

Threat of Sexual Disqualification: The Consequences of Erectile Dysfunction and Other Sexual Changes for Gay and Bisexual Men With Prostate Cancer

Gay men suffer more from prostate cancer

The distress caused by a prostate cancer treatment is worse for gay men than for straight men (Hart, Ussher, Rosser). The excess distress among the "boomer" cohort may be rooted in a lower perception of societal status to begin with (discussed in The Velvet Rage), and the adoption of dominant culture point-of-view of gay men as hypermasculine or effeminate, and hypersexualized. The greatest threat to the identity of gay men with prostate cancer is the loss of erectile function.

"Just cut it out"

"Cancer panic" is a type of anxiety familiar to everyone who has had a cancer diagnosis. It is often followed by generalized depression and grieving over one's mortality. Anxiety and depression are the enemies of understanding. There is very little input that can occur. From the doctor's point of view, a great deal of information is imparted. But from the patient's point of view, all he may hear is "cancer blah blah blah."

For most of us, cancer seems to be an unvaryingly lethal disease. We all have loved ones who have died, sometimes painfully, from various types of cancer. The fact that prostate cancer is uniquely slow growing and we have biomarkers and diagnostic tests that often allow it to be cured is lost on many of us, if not intellectually, at least emotionally.

"Just cut it out" is a very natural first reaction. Often, well-meaning family and friends reinforce that initial reaction.

Results the same or better with radiation or active surveillance

The ProtecT clinical trial randomized men with localized prostate cancer to either active monitoring, radical prostatectomy (RP), or external beam radiation (EBRT). After 10 years there was no difference in oncological outcomes. While ProtecT didn't break down results by risk level (almost everyone was favorable risk), we now know that 55% of low-risk men are able to go without treatment for 20 years so far without grade progression (Klotz). Favorable intermediate-risk men have similar 10-year results with RP or SBRT. Unfavorable intermediate-risk men seem to have superior results with radiation (see this link), and high-risk men have much better results with brachy boost therapy than surgery (Kishan et al. 2018).

There were marked differences, however, in quality-of-life in ProtecT. There was higher risk of lasting incontinence and erectile dysfunction after prostatectomy.

Among men who were previously potent, only 35% maintained potency 2 years after nerve-sparing prostatectomy (Sanda et al, 2008). It was similar to EBRT in men who were 10 years older. Using better radiation techniques (like SBRT) has resulted in 2-year potency preservation of 79% (Chen et al.). Of course, active surveillance results in no incremental potency loss.

Age

Younger men do better with any therapy - RP or RT. When we are younger, our tissues are more resilient. Some have used that as an excuse for younger men to avoid active surveillance. In fact, there is no age at which active surveillance is not preferable in terms of long-term side effects (see this link and Lee et al.).

It has been argued that the risk of a second primary malignancy due to radiation is a major risk factor in younger patients. This recent study found that the "Probability of Second Malignancy was similar between SBRT and radical prostatectomy." It is tremendously difficult to attribute second malignancies to radiation. Hensley et al. has shown that men who have had bladder cancer (removed by cystectomy) are more prone to prostate cancer. The best estimates of risk are less than 1% (see this link and this one). Arguably, younger men have more intact DNA repair mechanisms.

Young, unpartnered and gay men are particularly impacted by "marginalisation, isolation and stigma—relating to men's sense of being “out of sync”; the burden of emotional and embodied vulnerabilities and the assault on identity." (Matheson et al.) A recent Pew study reported that gays are much more likely to be single than straights, especially gays over 45 (AARP). Gay men of all ages do not have the social support system of their straight counterparts.

Aging without expected erectile function is especially a problem for gay men (Ussher et al.)

Erectile Dysfunction

Even among men who are able to regain erections sufficient for vaginal penetration, they are seldom able to regain erections sufficient for anal penetration. At Memorial Sloan Kettering, arguably one of the best institutions at providing quality RP, "only 4% of men who were ≥ 60 years old with functional erections pre-surgery achieved back-to-baseline erectile function." (Nelson et al.) I would guess that drops to near zero for anal penetration.

As mentioned, erectile dysfunction is the single largest emotional and social problem for gay men, who are mostly single at the age when they are treated for prostate cancer. Gay men more than straight men face an identity crisis because their identities have been sexualized. With only 35% maintaining potency after RP, and even fewer left with erections sufficient for anal intercourse, they are effectively excluded from the dating market and face a lifetime of social isolation. Ussher et al. (2017) calls it "sexual disqualification"- exclusion from gay life.

The sudden loss of potency destroys many pre-existing relationships. Partners look for sexual satisfaction elsewhere, and often leave relationships as a result. Depression is a common result. There have been no studies of suicide following RP among gay men, an unmet need.

While orgasm is still achievable without an erection, many men do not find it worth the bother.

Loss of Ejaculate

While women can fake orgasms, men can't. We either ejaculate at orgasm, or we don't have an orgasm. Ejaculation is how men communicate that "it was good for me." Men are disappointed when their partners do not "cum." RP removes all ejaculate except for Cowper's gland secretions. RT reduces ejaculation, but in a recent trial of SBRT patients at Georgetown, only 15% were without ejaculate after 2 years. Anejaculation excludes men from relationships with other gay men. It is more bothersome to gay men (Wassersug et al.)

Ejaculation is how we've signaled orgasm to ourselves since puberty. Getting used to orgasms without ejaculation takes some psychological readjustment, whether gay or straight.

Perceived size loss

Another rarely discussed adverse effect of RP is size loss. Men are very conscious of size and compare themselves to others. Size is seen as a surrogate for masculinity, and many think that sufficient size is necessary for mutual pleasure. Size loss is difficult to measure objectively, but the perception of size loss can be patient-reported (but usually isn't). In a patient-reported study of 1411 men, 55% of men report size loss after RP (Carlsson et al.)That loss had a negative effect on their quality of life. Some patients complain that even sitting down to pee they are unable to point their micropenis into the toilet. Gay men with such size loss universally do not undress in front of others.

Climacturia

Shooting urine at orgasm (climacturia) is another non-regularly reported side effect of RP. Incidence was as high as 44% at 3 months post RP and 36% at 24 months post RP (Mitchell et al.). For many men, gay or straight, it is embarrassing and bothersome. Many give up sex because of it.

Penile sensitivity/dysorgasmia

Because of damage to the pudendal nerve during RP, some men report penile pain (usually temporary) or loss of sensitivity (maybe permanent). Perhaps related is reported pain during orgasm(this seldom occurs). This is often not reported.

Anal Pleasure

I've heard mixed reports about whether receptive anal sex (bottoming) is as pleasurable post-prostatectomy. Some feel that pushing against the prostate and pushing out cum is an important source of pleasure. Others feel that filling the rectum is all that's necessary. Ussher reports that many men who are in relationships who previously enjoyed "topping" switched to bottoming when they could no longer perform. Many were unhappy about switching roles. This has only been qualitatively researched.

Myths

There are two myths that are prevalent about radiation, and they affect decision-making among gays and straights equally. The first myth is that salvage after radiation is nearly impossible. While it is true that surgery after radiation is fraught with peril and should never be done, it is untrue that no salvage is possible. In fact, salvage after RT often has better results both oncologically and in terms of side effects compared to salvage RT after surgery (see this link). More to the point, with 10-year biochemical recurrence-free survival after RT over 95% for favorable risk, and over 80% for the highest risk patients, and with better PSMA PET patient selection, salvage should not be an overriding concern. It is a mistake to think that one can always have salvage. Side effects are always worse than if RT had been given originally.

The other myth is that with radiation, side effects crop up with time. One need only look at the patient-reported outcomes in the 6 years of the ProtecT trial to see it isn't true (see this link). With radiation, acute side effects are highest in the first 6 months and decrease afterward. That is not to say there are no late-term effects, but it is extremely rare for an entirely new side effect to occur later that has never occurred before. Erectile dysfunction naturally increases over time as men age. In a very elegant study, Keyes et al. showed that half of the long-term decline in erectile function among men getting brachytherapy was due to normal aging. ED does occur with radiation, but there is significantly less.

ADT

It is worth mentioning that those with advanced prostate cancer who must use ADT, often complain of their loss of masculinity. When RT is used for high-risk localized prostate cancer, adjuvant ADT is temporary. However, if proper preventive measures aren't taken (e.g., penis pump), there could be permanent size loss.

Lack of Research

The major instruments/questionnaires for evaluating quality-of-life after treatment, EPIC and SHIM, do not ask about most of the above adverse effects of treatments. Indeed, they do not ask men if they have sex with other men. What does not get measured, does not get acted upon. If there are any solutions to the above adverse effects of RP, they are not being studied intensively, if at all.

Most urologists have no idea if their patients are gay or straight. Sometimes they bring their male partner if they have one. But most often they are not out to their doctor because they are fearful that their doctor may have anti-gay attitudes and will somehow provide lesser treatment.

Advice

Slow it down!: For men diagnosed with localized prostate cancer, there is ample time to make a decision. Treatment delays have been studied (see this link), and treatment delays of 3 months, even in high-risk men, do not make a difference in outcomes. Your initial cancer panic will subside with time, and you will be able to make a more reasonable decision. Doctors should never accept a treatment decision within one month of diagnosis, and probably not even within 3 months, especially with the approval of PSMA PET scans for unfavorable risk patients. If your diagnosis is low-risk, join an active surveillance program. Even some favorable intermediate-risk men with small amounts of pattern 4 can buy time on active surveillance.

Tell your doctor that you're gay. Very few are bigots in major cities. If you live in Buttfuck, KY you should not have a prostatectomy there anyway. Remember that your doctor is of limited use in helping you grapple with the emotions necessary or even provide much of the information necessary to make this decision, and won't be there to pick up the pieces afterwards. A recent NY Times article described a novel program at Nothwestern University in Chicago to help gay men after prostate cancer treatment.

Join a support group. One can read all about this stuff, but things like loss of ejaculate and size loss won't be real to you unless you experience them. The next best thing is talking to a live person who has experienced them. (This is called the "availability heuristic," by the way.) It is one thing to understand intellectually, but quite another to feel it. Seeing a grown man cry about his micropenis has more impact than reading that penile shortening occurs.

Go into psychotherapy/ learn mindfulness: We all have baggage about cancer. Learn what kind of baggage you are carrying and whether you are hampered by it. If you can, take a class in mindfulness. With practice, it will help you stay in the present moment instead of ruminating endlessly about low probability future outcomes.

Talk to a Radiation Oncologist: We all started with a urologist. Sometimes, he did your biopsy. Many are trained as surgeons. Some surgeons are "hot dogs" who believe they can cure the common cold. They usually recommend surgery, because it's what they do. (If they don't believe in surgery, they wouldn't be a surgeon.) Get out and find a radiation oncologist before you make a treatment decision.

Don't ask the doctor what he would do if you were his father! This is probably the question patients most often ask, but shouldn't. You are asking one specialist to also be a specialist in another therapy. A doctor well-trained in shared decision-making will deflect your question: "what more can I tell you, so that you feel able to make this decision for yourself?" Even if the doctor is gay, he is not you - he has his own set of concerns and biases.

*OK, there are exceptions, but very few.

(1) There are very few men who are super-sensitive to radiation cannot have it. 

(2) Some men have BPH to such a degree that radiation will inflame the prostate and cause the urethra to close up. Most such men can have a TURP procedure before radiation. TURPs usually cause reverse ejaculation (semen goes up into the bladder). But it is also necessary to wait several months before radiation begins; otherwise, there is risk of incontinence. 

(3) Men with a history of intractable relapsing prostatitis. 

There may be other reasons - I encourage patients to tell me about any.

For suggested questions to ask on interviews, see the following links:

• Questions to ask (and not ask) on a first urologist visit after a biopsy
• Questions to ask on a first visit for primary radiation therapy (IGRT/IMRT)
• Questions to ask an SBRT specialist
• Questions to ask a low dose rate (seeds) brachytherapist
• Questions to ask a high dose rate (temporary implant) brachytherapist
• Questions for an adjuvant or salvage radiation doctor
• Questions to ask yourself
• I didn't add focal ablation because we now have definitive proof that it doesn't work (see this link)

Exceptions to "early salvage" radiation treatment for recurrence after prostatectomy

Three major randomized clinical trials and a meta-analysis have proved that for most men waiting for early signs of recurrence after prostatectomy (e.g., 3 consecutive PSA rises or PSA of 0.1 or 0.2 ng/ml) to give radiation gave the same outcome as immediate ("adjuvant") radiation (see this link). But there are exceptions. In some men, adjuvant treatment is better. In some men, early salvage may overtreat them.

Adjuvant Radiation Therapy

Tilki et al. did a retrospective study of 26,118 men given prostatectomies at several hospitals in Germany, UCSF, and Johns Hopkins. 2, 424 of them had "adverse pathology" defined as:

• positive lymph nodes, or
• Gleason score = 8-10, and
• Stage T3 or T4

Patients were treated with adjuvant (within 6 months of prostatectomy) radiation therapy (ART), salvage radiation therapy (SRT) after PSA rose above 0.2 ng/ml (biochemically recurrent - BCR), or no radiation therapy. They matched patients on age, initial PSA, and positive/negative margin status. 10-year all-cause mortality was:

• for men with adverse pathology including positive lymph nodes:
• 14% for ART
• 27% for no RT
• 28% for SRT
• for men without positive lymph nodes:
• 5% for ART
• 25% for no RT
• 22% for SRT
• for men with no adverse pathology:
• 8% for ART
• 9% for no RT
• 8% for SRT

This suggests that for men with adverse pathology, ART improves outcomes over early SRT.

Delela et al. found that a high Decipher score can tip the balance toward adjuvant radiation.

No/Delayed SRT

At the other end of the risk spectrum are men with such low risk for clinical recurrence, that salvage radiation can be delayed, perhaps indefinitely. This is based on the observation that while 40% of post-prostatectomy patients may experience a BCR, only 30% of BCR patients develop a clinically relevant recurrence, and all but 16% die of something else before the recurrent cancer kills them. We saw the results of a retrospective study that suggested that those at lower risk of progression (low PSA, Gleason score, and stage) and receiving a higher dose of SRT may not need adjuvant ADT. 

In a major review for the European Urological Association, Van den Broeck et al. reviewed 77 studies covering 20,406 patients who were biochemically recurrent (conventionally measurable PSA) after prostatectomy. They sought to define the patient and disease characteristics that determined which of the BCR cancers led to distant metastases and death from prostate cancer. They found that the following risk characteristics defined a "low risk" BCR prostate cancer that could be safely watched:

• PSA doubling time > 1 year
• Gleason score < 8
• Interval to biochemical failure > 18 months

Tilki et al. validated the EAU study in a retrospective study of 1,125 patients. Preisser et al. validated the study retrospectively among 2,473 men. Pompe et al. validated the risk group in a retrospective study of 1,821 men. To date, there has been no prospective validation in a randomized clinical trial.

(update 5/4/23) Tilki et al. found that if there was one high-risk feature (stage T3/4 or GS 8-10) and PSA ≤ 0.25, salvage radiation provided no survival benefit. However, the survival benefit was significant if PSA>0.25. This suggests that post-prostatectomy patients with a high-risk feature must not wait for the results of a PSMA PET/CT (which usually is uninformative below PSA of 0.5), but should have salvage radiation as soon as they are biochemically recurrent.

Zaorsky et al. point out some additional characteristics of recurrent patients who may be safely watched:

• PSA < 0.5 ng/ml at time of recurrence
• Age > 80 years of age
• Significant comorbidities
• No distant metastases detected with PET/CT imaging (Ferdinandus et al)

It is undoubtedly better to have a low Decipher score as well.

Lacking prospective validation, this is a decision that should be carefully discussed between the patient and the radiation oncologist.

Whole-pelvic radiation therapy for high-risk patients

The decision about whether or not to treat the entire pelvic lymph node area along with the prostate (called whole pelvic radiation therapy (WPRT)) or to treat just the prostate with a margin around it (called prostate-only radiation therapy (PORT)) has long been a matter of judgment. Now we have proof of its benefit in most high-risk patients.

Murthy et al. reported the results of "POP-RT," a randomized clinical trial conducted among 224 high-risk and very high-risk patients treated at the Tata Memorial Hospital in Mumbai, India between 2011 to 2017. What sets this trial apart from previous trials that had equivocal results (like RTOG 9413 and GETUG-01) are the rigorous patient selection criteria and the now-proven treatments they received.

80% of patients were screened using PSMA PET/CT to rule out those with already-detectable lymph node or distant metastases. The rest were staged using bone scan/CT. Local staging (T1-4) was done with CT, MRI, and physical examination. Patients had to have a probability of microscopic lymph node metastases of greater than 20% using the Roach formula:

Probability of cancer in pelvic lymph nodes = (⅔ x PSA) + (10 x (Gleason score - 6))

This meant that high-risk patients had to have the following risk characteristics:

• If Gleason Score 8-10: Any PSA, T1- T3a N0 M0 
• If Gleason Score 7: PSA > 15, T1-T3a N0 M0 
• If Gleason Score 6: PSA > 30, T1-T3a N0 M0
• Also, any other "Very High Risk" including T3b-T4 N0 M0, with any Gleason Score, any PSA, if their Roach probability was > 20%
• In this group of patients, the median Roach probability was about 40% and the median PSA was 28 ng/ml.

Treatment consisted of dose-escalated IMRT and 2 years of adjuvant androgen deprivation therapy (ADT):

• Prostate dose= 68 Gy in 25 fractions or treatments (equivalent to about 81 Gy in 40 treatments)
• Pelvic lymph node dose = 50 Gy in 25 treatments (note: this is somewhat higher than the 45 Gy in 25 treatments that is usually given)
• Pelvic lymph nodes up to the aortic bifurcation were treated, which conforms to current RTOG specs.
• ADT was started 2 months before IMRT and continued for a total of 2 years
• Note: this trial began before ASCENDE-RT proved the superiority of brachy boost therapy, but used a higher IMRT dose and longer ADT. This high-dose IMRT/long-term ADT treatment was proven effective by the DART 01/03 GICOR trial.

After median follow-up of 68 months, the oncological results were:

• 5-year biochemical failure-free survival was 95% for the WPRT group vs. 81% for the PORT group.
• 5-year disease-free survival, which means they had no PSA progression and no radiographic progression, was 90% for WPRT (15 recurrences) vs 77% for PORT (36 recurrences).
• 5-year metastasis-free survival, which is a good surrogate endpoint for overall survival, was 95% for WPRT vs 88% for PORT
• Younger patients (< 66) derived more benefit from WPRT
• Among those with recurrences, most (52%) of the recurrences in the PORT arm were in pelvic lymph nodes, whereas few (12.5%) were nodal recurrences in the WPRT arm.

Murthy et al. also reported on toxicity and patient-reported quality of life outcomes comparing the two treatments.

• Acute grade 2 or greater GI toxicity was 33% for WPRT vs 25% for  PORT (not statistically different)
• Acute grade 2 or greater GU toxicity was 33% for WPRT vs 24% for PORT (not statistically different)
• Late-term grade 2 or greater GI toxicity was 8.2% for WPRT vs 4.5% for  PORT (not statistically different)
• Late-term grade 2 or greater GU toxicity was 20.0% for WPRT vs 8.9% for PORT (statistically different)
• Very few patients in either arm suffered serious (grade 3) toxicity. There was no grade 4 toxicity.
• While higher rectal radiation doses were not associated with higher bowel toxicity, higher bladder doses were associated with higher urinary toxicity.
• Patient-reported outcomes were not significantly different for urinary, bowel or sexual adverse effects.
• (update 3/24) no significant changes at 75 months.

It is worth noting that cancer in the Indian population is generally more progressed than in the US population at the time of diagnosis. Those with Stage T3b/T4 (seminal vesicle invasion and invasion into surrounding organs) accounted for 47% of this group, whereas it's a rare finding in the US because of more prevalent earlier PSA testing. Another difference is that 27% of patients had a previous TURP, which is high compared to the US. It is possible that the high TURP rate may have contributed to extra urinary toxicity seen in men getting WPRT.

Given the relatively mild side effect profile with no clinically significant difference to patients, WPRT should be the standard of care for high-risk patients at high risk of pelvic lymph node involvement. In 2027, we will have the results of a much larger, multi-institutional randomized trial (RTOG 0924) of WPRT vs PORT. Also, there was no increase in second malignancies due to the expanded coverage in this study.

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.

Pseudoscience

Many patients read "sciency" sounding posts on the internet and youtube videos. They follow poor advice, thinking it is scientific. I compiled this checklist for the patient who is wondering if what he saw is science or fake news. Often, it looks like science because there are a lot of footnotes. I adapted a document I saw on Twitter.  I have added to it and added some explanation below:

Some Characteristics of Pseudoscience

1. Is UNFALSIFIABLE (can’t be proven wrong); makes vague or unfalsifiable claims.

2. Relies heavily on ANECDOTES, personal experiences, testimonials, “professional” opinions, and preclinical (test tube or animal) studies. IGNORES “LEVELS OF EVIDENCE,” and GRADE given by professional consensus.

Note: For every 10,000 compounds screened->250 (2.5%) are entered into a preclinical study 

-> 5 (2%) are tested in clinical trials -> 1 gets FDA approval

3. CHERRY PICKS confirming evidence while ignoring/minimizing disconfirming (especially higher level) evidence.

4. Uses TECHNOBABBLE: Words that sound scientific but don’t make sense.

5. Lacks PLAUSIBLE MECHANISM: No way to explain it based on existing knowledge, or deficient evidence for the proposed mechanism.

6. Is UNCHANGING: doesn’t self-correct or progress.

7. Makes EXTRAORDINARY/EXAGGERATED CLAIMS with insufficient clinical evidence.

8. Professes CERTAINTY; talks of “proof” with great confidence. Ignores statistical confidence intervals and power.

9. Commits LOGICAL FALLACIES: Arguments contain errors in reasoning.

10. Lacks PEER REVIEW: Goes directly to the public (e.g. YOUTUBE videos, blogs, direct-to-patient presentations only), avoiding scientific scrutiny.

11. Claims there is a CONSPIRACY (e.g., Big Pharma/FDA conspiracy) to suppress their ideas.

12. OVERSIMPLIFIES biochemistry (e.g. alkaline water, reducing sugar intake, antioxidants or anti-inflammatories will slow cancer)

13. Ignores INTERACTIONS with other substances, bioavailability, biochemical feedback effects, microbiome, substance purity, or adulteration

14. Claims “causation” when only “ASSOCIATION” has been demonstrated. (See the Bradford-Hill checklist) 

15. LACK OF DISCUSSION of potential biases, missing confounding variables, effects that may have changed over time and/or with improved technology.

16.  INAPPROPRIATE STATISTICS AND RESEARCH METHODS. Non-valid endpoints or subset conclusions, lack of pre-announced endpoint and subsets, lack of power to detect endpoint within sample size and timeframe, poor choice of surrogate endpoint or subsets, "p hacking," biases in retrospective studies.

17. Failure to disclose CONFLICTS OF INTEREST or sponsors.

#15 and #16 require some explanation:

Surrogate endpoints: Ideally, we would have long-term follow-up until death ("overall survival") for every trial. This is impractical, particularly for prostate cancer that has a very long natural history. ICECAP has identified "metastasis-free survival" as an appropriate surrogate for overall survival in trials involving men with localized prostate cancer.  The appearance of metastases has been suggested as appropriate for men with recurrent PCa but requires validation. Biochemical recurrence-free survival is only useful for predicting the success of a therapy for localized prostate cancer. PSA doubling time is definitely inappropriate without a control group. Radiographic progression-free survival seems to be a good surrogate endpoint in men who are metastatic and castration-resistant (see this link and this one). If the pattern holds, PSA-based endpoints are inadequate (see this link and this one) and only metastasis-based endpoints are adequate. Typically, trials are only powered (have enough sample size) to reliably detect differences in their primary endpoint.

Subset conclusions: Because there is only enough sample size to reliably detect differences in the primary endpoint, subset analysis is suspect. Using subset analysis, Spears et al. showed that men diagnosed on Mondays did not benefit from abiraterone - a ridiculous conclusion. They also showed that men diagnosed with metastases (M1) benefited while men diagnosed without metastases (M0) did not. Both conclusions are inappropriate. In the case of men without metastases, there were only 34 deaths among the 460 patients in the treatment group and 44 deaths among the 455 patients in the treatment group - not enough to prove a statistically significant effect with 95% confidence. However, with time, there may be enough deaths to achieve a statistically significant effect, so we have to be cautious about labeling it as ineffective in the M0 subgroup.

"P hacking" or "data-dredging"/positive results bias occurs when researchers do not announce before the study begins exactly which subgroups or variables will be looked at and which measures will be used to judge success or failure. They are going on a fishing expedition to find at least some variable or subgroup with statistically significant results. Because of random probabilities, if there are enough variables there will almost always be some that have statistically significant outcomes, like the "Monday diagnosis" subgroup above. Starting in 2000, all peer-reviewed journals required researchers to state upfront what they would be looking for. This made a large change in the number of positive results reported (see this link). Journals often would not print negative findings. In 2017, NIH and the FDA required the sponsors of all clinical trials listed in clinicaltrials.gov to provide results whether positive or negative. Policing and compliance are spotty.

Biases in retrospective studies and database analyses: Common biases are selection bias, ascertainment bias, lead-time bias, length bias, survivorship bias, confounding by unmeasured variables, and others.

Lower salvage radiation dose - are outcomes the same?

A large randomized clinical trial, SAKK 09/10, found that a salvage radiation dose of 64 Gy over 32 treatments had equivalent biochemical outcomes compared to 70 Gy over 35 treatments.

They treated 350 patients from 2011 to 2014 at 28 hospitals in Germany, Switzerland, and Belgium. They were treated with either 3D-CRT (44%) or more modern radiation techniques. None had positive lymph nodes. Key patient characteristics were as follows:

• Biochemically recurrent after prostatectomy (median PSA= 0.3 ng/ml)
• Positive margins in 45%
• Gleason score ≥ 8 in 18%
• No detectable tumors

After 6.2 years of follow-up, outcomes were as follows:

• Freedom from biochemical progression (FFBP) was enjoyed by 65% of those who got 64 Gy vs 73% of the 70 Gy group. This difference is not statistically different (p=0.11).
• Local recurrences (only) occurred in 9% of the 64 Gy group vs 2% of the 70 Gy group. This difference is statistically significant (p= 0.005)
• Regional recurrences (only) occurred in 11% of the 64 Gy group vs 17% of the 70 Gy group. This difference is not statistically significant (p= 0.11)
• Distant recurrences (any) occurred in 15% of the 64 Gy group vs 15% of the 70 Gy group.
• In an earlier report, acute urinary toxicity of Grade 2 or greater occurred in 14% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• In an earlier report, acute rectal toxicity of Grade 2 or greater occurred in 17% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• Late urinary toxicity of Grade 2 or greater occurred in 29% of the 64 Gy group vs 30% of the 70 Gy group (not different)
• Late rectal toxicity of Grade 2 or greater occurred in 12% of the 64 Gy group vs 22% of the 70 Gy group (different)
• Patient-reported outcomes were not different between the two dose regimens.

Oncological Outcomes

The stated purpose of SAKK 09/10 was to detect a difference in 6-year FFBP, and they detected no difference. But is that enough to change practice? The ICECAP working group cautions  that 5-year metastasis-free survival, but not biochemical recurrence-free survival, is a good surrogate endpoint when overall survival would take too long to obtain in trials of primary therapy for localized prostate cancer. For trials of salvage therapy of recurrent prostate cancer after prostatectomy, some early analysis suggests that the 5-year occurence of distant metastases may be a good surrogate endpoint. 6-year FFBP used in this trial is probably not a good surrogate endpoint.

Focusing our attention on the actual cancer progression instead of just PSA progression, we see that the higher dose did significantly better at preventing local progression of the cancer. If the trial were to run 15 years, we might see a very meaningful difference between the curative powers of the two dose regimens. Furthermore, as shown in the SPPORT trial, salvage treatment of pelvic lymph nodes, even when none is detectable, may slow progression or possibly cure some patients with regional micrometastatic progression. 

There may be other ways to improve outcomes:

• Using the expanded prostate bed delineation guidelines may improve local control.
• As PSMA PET/CT becomes more widely available, it will be possible to detect more loco-regional cancer for boost doses, and eliminate salvage treatment from patients who already have small distant metastases (see this link). 
• The use of genomic tests, like Decipher Genomic Classifier (GC), may aid in selecting patients in whom higher doses are needed. In a subset analysis, among Decipher "high GC-risk" patients, FFBF was 51% for 70 Gy vs 39% for 64 Gy patients; among Decipher "low GC-risk" patients, FFBF was 75% for 70 Gy vs 69% for 64 Gy patients (update) FFBF was 45% for GC-high patients vs 71% for GC-low patients. 
• There is a clinical trial at UCLA that will determine whether raising the biologically effective dose (BED) using SBRT (34 Gy/ 5 fractions) gives good outcomes compared to historical controls. The BED is equivalent to 85 Gy if given in fractions of 1.8 Gy.
• There is a clinical trial in France that will determine whether adjuvant hormone therapy intensification with Erleada improves results.
• Keeping in mind that very few patients in this trial had Gleason scores of 8-10, and none had detectable gross tumors at or near the prostate, those patients may still be good candidates for dose intensification (as well as adjuvant ADT).

Toxicity Outcomes

If there is no cost to the patient in terms of increased toxicity, there is no reason not to increase the dose. The patients were unable to detect a difference in urinary, rectal, or sexual outcomes. There was a difference in physician-reported late-term rectal toxicity that deserves further attention.

Compared to acute urinary toxicity, late-term urinary toxicity is about twice as bad in both dosing regimens, although the ratings are not different between regimens. Compared to acute rectal toxicity, late-term rectal toxicity was 29% lower for the 64 Gy dose group, but marginally higher for the 70 Gy dose group. The authors believe that rectal dose constraints could be tightened with IMRT.

For comparison, MSK reported that using 70 Gy as a salvage dose, late-term urinary toxicity (Grade≥2) was 17% (vs 30% in this trial) and late-term rectal toxicity (Grade≥2) was 5% (vs 22% in this trial). They also reported that IMRT improved rectal toxicity over 3D-CRT, while no difference was observed in this trial.

The reason for these atypical results is mysterious, although physician-reported toxicities are notoriously unreliable.

So, lacking more reliable endpoints and considering that patients did not notice any difference in their quality of life based on dose intensification, the decision on what dose to use is best based on a discussion with the radiation oncologist.

(update 04/22/2022) Beck et al. report that adherence to treatment guidelines was poor in the SAKK 09/10 trial. This may explain the mysterious toxicity results as well as being responsible for worse freedom from biochemical progression.

Brief, intense radiation and hormone therapy for very high risk prostate cancer

(updated)

As we've seen, brachy boost therapy seems to have the best oncological results for men with very high-risk prostate cancer. But brachy boost therapy entails 20-25 external beam radiation treatments plus the invasive placement of radioactive seeds or needles plus at least 18 months of testosterone suppression. While the oncological results are excellent, with about 80% cure rates, there is significant risk of serious late-term urinary retention. In some men, testosterone never fully recovers.

McBride et al. reported the early results of the AASUR trial. The goal of the trial was to find a treatment with equivalent oncological outcomes, but one that is easier on the patient, with less risk of long-term toxicity. They recruited 64 patients at 4 top institutions (Memorial Sloan Kettering, Johns Hopkins, University of Michigan, and Thomas Jefferson University). All patients were "very high risk," defined as:

• any Gleason score (GS) 9 or 10, or
• 4 or more cores of GS 8, or
• 2 high-risk features (stage T3/4, GS 8, or PSA>20)
• No metastases (N0, M0)

Patients were treated with:

• SBRT (7.5-8.0 Gy x 5 treatments)
• 6 months of Lupron, Erleada, and Zytiga

After 30 months of follow-up:

• 90% were free of biochemical failure
• Median PSA at the last follow-up was 0.1
• PSA remained undetectable in 40%
• Testosterone rose to non-castrate levels at a median of 6.5 months after hormone therapy ended, and almost all rose to >150 ng/dl
• 23% experienced transient serious toxicities, mostly hypertension
• Quality of life scores at 1 year held for urinary and rectal domains but declined in sexual and hormone domains.

How do these results compare to other trials of radiation+ADT in high-risk patients?

Lin et al. used whole pelvic IMRT with an SBRT boost to the prostate and 2 years of ADT in 41 high- and very high-risk patients. With 4 years of follow-up, they reported 92% biochemical recurrence-free survival (bRFS).

Hoskin et al. used high dose rate brachytherapy as a monotherapy in 86 high-risk patients. Most (80%) had adjuvant ADT for a median of 6.3 months (range 1-40 months). With 4 years of follow-up, they report 87% biochemical recurrence-free survival (bRFS) among high-risk patients.

Zapatero et al. reported the results of the DART 01.03 GICOR trial of escalated dose IMRT with either short-term (4 months) or long-term (28 months) ADT. There were 185 high-risk patients with about half getting each ADT protocol. About a quarter received simultaneous radiation of their pelvic lymph nodes. With 5 years of follow-up, they report 76% bRFS among high-risk patients who got short-term ADT and 88% bRFS among high-risk patients who got long-term ADT.

(Update) Murthy et al. reported results of a trial where 224 men with ≥ 20% risk of pelvic lymph node metastases were screened with PSMA PET scans and were randomized to get whole pelvic radiation with a boost to the prostate or prostate-only radiation. They all received 2 years of adjuvant ADT. With 5 years of follow-up, they reported 95% bRFS. 

This table summarizes these trials:

	AASUR	SBRT boost (Lin)	HDR-BT (Hoskin)	IMRT DART  GICOR	IMRT DART  GICOR	IMRT POP-RT
follow-up	2.5 yrs	4 yrs	4 yrs	5 yrs	5 yrs	5 yrs
Radiation	SBRT	IMRT+ SBRT boost	HDR-BT  monotherapy	IMRT  (dose escalated)	IMRT  (dose escalated)	WP:50Gy/25fx boost:18Gy/25fx
Coverage  area over  prostate	SV	Whole pelvic	±SV (if MRI+)	• SV • 27%  whole pelvic	• SV • 19%  whole pelvic	Whole pelvic
Adjuvant  hormone  therapy	ADT+Zytiga+Erleada	93% ADT	80% ADT	ADT	ADT	ADT
Duration of  hormone  therapy	6 mos.	2 yrs	6.3 mos.	4 mos.	28 mos.	2 yrs
Risk	VHR	78% HR 22% VHR	HR	HR	HR	≥20% LN risk
bRFS	89%	92%	87%	76%	88%	95%

HR=high risk VHR=very high risk SV=seminal vesicles bRFS=biochemical recurrence-free survival: PSA stayed lower than nadir+2.0 ng/ml

2.5 years of follow-up is too early to draw valid conclusions. We see that most of the trials had higher bRFS even with much longer follow-up; however, only AASUR recruited very high-risk patients exclusively. ICECAP has shown that only metastasis-free survival is a valid surrogate endpoint for overall survival. A trial on high-risk patients will have to run for 8-10 years to collect a sufficient number of metastases to draw valid conclusions, so we can only look at this as an early signal.

Treatment of Pelvic Lymph Nodes

We know that the time to be able to see the first few cancerous pelvic lymph nodes is often several years, so 2.5 years of follow-up tells us little. The newly approved PSMA PET scans will be able to rule out the larger metastases (>5 mm), but will never be able to find metastases smaller than that. Waiting for visibility to make the decision to treat is a bad idea. By the time some lymph nodes are large enough or rapidly growing, the risk of spread outside the pelvic lymph node drainage area increases, and the hope of a cure may vanish.

The PSMA PET/CT is nevertheless worthwhile. While a negative scan does not change the treatment decision, a positive scan may detect occult metastases or pelvic lymph nodes that may benefit from a higher spot dose and more intense or longer hormone therapy.

We rely on validated formulas to tell us the probability that there are microscopic pelvic lymph node metastases. Two of the popular formulas are the Roach Equation (discussed here) and the Yale Formula (discussed here).

There is a risk of overtreatment. Many high-risk patients will never require pelvic lymph node treatment, and we are awaiting evidence (RTOG 0924) that such treatment will improve survival. As we have seen, bRFS is improved.

However, the only risk is that toxicity will be higher when the whole pelvis is treated. Murthy et al. showed that even at higher doses of pelvic lymph node radiation, there was no increase in acute toxicity, late gastrointestinal toxicity, and no deterioration in patient-reported quality of life scores.

Arguably, 25 extra IMRT treatments to the pelvic lymph nodes represent a patient inconvenience over the 5 SBRT prostate-only treatments. In the UCLA and Sunnybrook high-risk SBRT trials (discussed here), the pelvic lymph nodes may be treated (to 25 Gy) within the same 5 treatments. So far, with limited follow-up, cancer control is high and toxicity is low.

Hormone therapy intensification

The DART 01.05 GICOR trial proved that long-term (28 months vs 4 months) ADT improves survival in high-risk patients even when treated with dose-escalated IMRT. Nabid et al. proved that 18 months is often as good as 36 months. AASUR suggests that by including both Zytiga and Erleada, the duration of hormone therapy can be shortened. But the sexual and hormone quality of life did diminish. This raises questions that can only be answered in an expanded randomized clinical trial:

• Are all 3 medications (Zytiga, Erleada, and Lupron) necessary for the benefit? The ACIS trial found that adding Erleada increased radiographic progression-free survival in mCRPC patients. There was no such synergy found in adding Xtandi to Zytiga in this non-randomized trial.
• Do they add much to Lupron alone if whole pelvic radiation is given?
• Does Lupron alone for, say, 9 months, with whole-pelvic SBRT (as in the UCLA trial) afford the same benefit with less toxicity? And would Orgovyx instead of Lupron allow for earlier testosterone recovery?
• Can genomics (Prolaris or Decipher of biopsy tissue) identify patients who might benefit from the combined hormone therapy?