I wish I had ejaculated more!

More frequent ejaculation is associated with lower incidence of prostate cancer, according to an update of the Health Professionals Follow-Up Study.

This isn't news. In 2004, they reported the incidence of prostate cancer among men who ejaculated 21+ times per month compared to those who ejaculated 4-7 times per month. They corrected for known risk factors like family history of prostate cancer, BMI, height, smoking, use of Vitamin E, diabetes, and other diet and lifestyle risks. From 1992-2000, they were asked to remember their ejaculation frequency when they were 20-29 years of age, when they were 40-49 years of age, and in the past year. (All the men in the study were at least 40 years of age.)

• Those who ejaculated most frequently in their 20s were 11% less likely to be diagnosed with prostate cancer later.
• Those who ejaculated most frequently in their 40s were 32% less likely to be diagnosed with prostate cancer later.
• Those who ejaculated most frequently in the last year were 51% less likely to be diagnosed with prostate cancer later.
• Over their lifetime so far, those who ejaculated most frequently in the last year were 33% less likely to be diagnosed with prostate cancer later.

The full text of the earlier study is available at this link.

The update adds 10 more years of follow-up to their earlier report. The update included:

• 31,925 men vs. 29,342 in the early report
• 480,831 man-years of data  vs. 222,426 in the early report
• 3,839 cases of prostate cancer vs. 1,449 cases in the early report

The update reports:

• Those who ejaculated most frequently in their 20s were 19% less likely to be diagnosed with prostate cancer later.
• Those who ejaculated most frequently in their 40s were 22% less likely to be diagnosed with prostate cancer later.
• The abstract doesn't report the hazard ratios for ejaculation frequency in the last year or during their lifetime-to-date.
• All of the associations are statistically significant and clinically meaningful.

This is based on recollections of their ejaculatory frequency in their 20s and 40s, and may represent a romantic view of their younger days. But the pattern holds for ejaculations in the last year too, at least in the earlier report. Ejaculatory frequencies are correlated by age: those who ejaculated most frequently in their 20s, also ejaculated most frequently in their 40s and in the past year.

It may well be true that there is a causal connection. It is possible that the prostate tissue increases in tone, just as muscle tissue does, and degenerative changes may be caused by disuse.

It may also be true that men who have higher testosterone levels ejaculate more frequently and have lower incidence of prostate cancer. We know that the converse is true - men with historically lower natural levels of testosterone (called hypogonadal) have higher incidence of prostate cancer.

Whatever the explanation, increasing one's ejaculatory frequency seems to be a prudent measure worth taking. It carries no risk, and has obvious benefits.

Dose Escalation for Salvage Radiation

In the late 1990s and early 2000s, the advent of more accurate linear accelerators (linacs) and image-guidance technology for delivering therapeutic X-rays to prostate cancer changed the dose that could be safely given. In the late 1980s, the typical dose was only in the mid-60 Gy range. By the early 2000s most of the top prostate cancer treatment centers were delivering 80 Gy (at 1.8 or 2.0 Gy per treatment) with higher cure rates and lower toxicity. Dose escalation for primary treatment of prostate cancer was a resounding success and became the standard of care.

However, dose escalation was not utilized appreciably in salvage radiation treatment (SRT) after prostatectomy. The reasons doses were kept lower in the salvage setting were that:

• Toxicity might be higher because radiation could be especially damaging when applied to tissue that had been cut or stressed by surgery.
• Without the shielding effect of the prostate in place, sensitive structures like the bladder neck, the rectum, the penile bulb, and the urethra would receive the full brunt of the radiation.
• Unlike the relatively large tumors in an intact prostate, the cancer in the prostate bed was small or microscopic and didn’t need as large a dose of radiation to eradicate it.

Current guidelines by the American Urological Association (AUA) and The American Society of Radiation Oncologists (ASTRO) establish a minimum dose of 64-65 Gy for SRT, but do not establish an optimum dose, citing lack of available evidence. At the top treatment centers, radiation oncologists routinely deliver doses as high as 70 Gy, but seldom higher. The outstanding question is: what is the optimum dose for SRT? That is, what dose offers the best chance at a cure with acceptable toxicity?

The Dose/Response Curve

Radiation oncologists talk about an S-shaped “dose/response curve.” At the bottom of the “S,” we know that at very low radiation doses there is very little “response,” meaning very few cancer cells are killed. At a certain radiation level, a lot more cancer cells are killed, and even a small increase in dose will kill a lot more cancer cells. This is called the “steep” part of the dose/response curve. After the steep part, adding more dose doesn’t kill a lot more cancer cells, but it begins to kill off healthy cells, increasing toxicity. The optimal dose is reached just before this happens at the top of the steep part. Below is what a dose/response curve looks like:

The Study

Dr. Christopher King (see this link) analyzed data from 71 studies, representing 10,034 patients treated who received SRT between 1996 to 2015 to see if the data conformed to a dose/response curve. He found an excellent fit:

• SRT dose was the single most important factor correlated with recurrence-free survival
• PSA at the time of SRT was the second most important factor
• Other factors (stage, Gleason score, positive margins, lymph node invasion, and use of adjuvant ADT) were less important.
• At an SRT dose of 66 Gy, half the patients were recurrence-free after SRT
• Recurrence-free survival increased by 2 percentage points for each additional Gy of SRT dose.
• The dose/response curve for SRT fit almost perfectly to the dose/response curve for primary RT.

Because the curves seem to be identical whether it was for primary therapy or for salvage therapy, it implies that even the microscopic prostate cancer cells lingering in the prostate bed require as much radiation to finish them off as the larger tumors within the prostate. This radioresistance will not surprise those of us who have noticed the improved cancer control patients get with a brachytherapy boost given for primary radiation therapy.

How much better cancer control can we expect?

It’s hard to know how high recurrence-free survival can get if the dose is increased. The statistics suggest that increasing the SRT dose from 66 Gy to 76 Gy will increase recurrence-free survival from 50% to 70% at 5 years of follow-up. But this is unknown territory, and in some patients, undetectable distant metastases will have already occurred. Of the 71 studies reviewed in this meta-analysis, only 4 included doses above 70 Gy. Dr. King is proposing a clinical trial where patients are randomized to receive 66 Gy or 76 Gy.

76 Gy for SRT – is that safe?

Only one study included a dose this high. Ost et al. treated 136 patients. 5-year biochemical recurrence-free survival was 56%, but patients were treated fairly late – median PSA had already reached 0.8 ng/ml by the time SRT began, and most had adverse pathology findings. They report reasonable late toxicity: 4 patients (3%) suffered a grade 3 urinary event, and 1 case of a grade 3 rectal adverse event. However, they do note that a lot of the grade 2 toxicity seemed to be chronic rather than transient. 39% suffered long-lasting grade 2 urinary toxicity, and 18% suffered from long-lasting grade 2 rectal toxicity. I assume patients will be excluded from Dr. King’s clinical trial if they still have urinary issues from surgery. There is no data on the effect of dose escalation on erectile dysfunction.

There has been one randomized clinical trial of SRT dose escalation in the modern era. The SAKK 09/10 trial found little difference in acute toxicity symptoms at 70 Gy compared to 64 Gy, but patient-reported urinary symptoms worsened.

Can SBRT be used instead of IMRT?

There have been a few clinical trials of hypofractionated SRT that seem promising (see this link). UCLA will be starting a trial next year as well. An IMRT dose of 76 Gy is biologically equivalent in its cancer control to 5 SBRT treatments totaling 33 Gy.

The challenges for SBRT are greater than for IMRT. Because the dose per treatment is so high, even a small “miss” can increase toxicity and reduce effectiveness. It is difficult to use fiducials in the prostate bed, and the soft tissue is highly deformable and subject to motion from the bowels and bladder. The radiation oncologist will have to use soft tissue landmarks and site them multiple times per treatment. A filled bladder and good bowel prep are important, as is a very fast linac. Careful planning and strict adherence to dose constraints to organs at risk are essential.

Implications for pelvic lymph node treatment

If prostate cancer in the prostate bed requires almost 80 Gy, what can we infer about microscopic cancer that has spread to pelvic lymph nodes? It would seem that that cancer would be equally radioresistant. The pelvic lymph nodes area is often treated with a dose of about 50 Gy. Unfortunately, as the radiation field increases to extend to the entire pelvic area, many more organs are subject to toxic reactions. The enteric tissue of the small bowel is particularly prone to late reactions. In a database analysis at Fox Chase Cancer Center, patients treated with 56 Gy to the whole pelvis for high-risk prostate cancer may have had gastrointestinal reactions as long as 9 years later. We await the findings of randomized clinical trials (RTOG 0534 and PRIAMOS1) to tell us whether such treatment is effective.

Discuss with your radiation oncologist

Although Dr. King’s meta-analysis is impressive in the amount of data represented, it is not a randomized trial that would change clinical standards on its own. Even so, it is certainly worth discussing with one’s radiation oncologist before committing to a treatment plan. There are many considerations for the patient  - especially his current status with regard to urinary and erectile function. For patients with few adverse pathology findings (e.g., long PSA doubling time, low Gleason score, no obvious capsular penetration), the risk of extra toxicity may not be worthwhile. It’s a judgment each patient must make for himself.



Note: Thanks to Dr. Christopher King for allowing me to see the full text of his study.

PORTOS: a gene signature that predicts salvage radiation success

Salvage radiation is curative in roughly half of all cases. There are many factors that contribute to an unfavorable prognosis, including waiting too long, high PSA and rapid PSA doubling time, adverse post-surgery pathology (stage, Gleason score, positive margins), and high Decipher or CAPRA-S score. But, other than a detected distant metastasis, none can predict failure of salvage therapy. For the first time, there seems to be a genetic signature that predicts when adjuvant or salvage radiation  (A/SRT) will succeed.

The study is all the more impressive because of the many top prostate cancer researchers attached to it, representing a collaborative effort from many top institutions: Harvard, University of Michigan, Johns Hopkins, Northwestern University, University of California San Francisco, Mayo Clinic and others.

The process

Zhao et al. started with data on 545 patients who had a prostatectomy at the Mayo Clinic between 1987 and 2001. They attempted to find patients who were matched on pre-RP PSA, Gleason score, stage, and positive margins, but differed on whether they received A/SRT or not. They also had to have complete information on diagnosis and whether they eventually had metastatic progression. This yielded 98 matched pairs. They then did complex genetic screening of archived tissue samples from those prostatectomy patients, focusing on 1800 genes that have been implicated in response to DNA damage after radiation. They found 24 genes that were correlated with occurrence of metastases after salvage radiation. After correcting for other factors, they determined what they call a “Post Operative Radiation Therapy Outcomes Score (PORTOS).” A PORTOS of zero (called a “low” PORTOS) means it predicts no benefit from salvage radiotherapy. A PORTOS greater than zero (called a “high” PORTOS) predicts a benefit from salvage radiation.

Validation

The next phase was to predict how well the 24-gene signature would predict salvage radiation success in a larger data set. They analyzed 840 patient records from patients treated at the Mayo Clinic from 2000-2006, Johns Hopkins (1992-2010), Thomas Jefferson University (1999-2009) and Durham VA Medical Center (1991-2010). They were able to find 165 matched pairs – half treated with A/SRT, half with no radiation. Tissue samples were screened and scored, and 10-year incidence of detected metastases was obtained. 1 in 4 men were categorized as “high PORTOS,” 3 in 4 were “low PORTOS.”

In the “high PORTOS” group: 

• Only 4% suffered metastatic progression if they had A/SRT
• 35% suffered metastatic progression if they did not have A/SRT
• They had an 85% reduction in 10-year incidence of metastases after A/SRT, which was statistically significant.

In the “low PORTOS” group:

• 32% suffered metastatic progression if they had A/SRT
• 32% suffered metastatic progression if they did not have A/SRT

None of the other prognostic tools (Decipher, CAPRA-S, or Prolaris) that are sometimes used to predict metastases after prostatectomy could predict the response to A/SRT.

Caveats

This should be interpreted with caution for several reasons:

It was retrospective, and therefore subject to selection bias. That is, the physicians may have decided on the basis of patient characteristics or other disease characteristics not captured here to give A/SRT to some patients, but not to others. Only a prospective, randomized trial can tell us if the association with PORTOS is the cause of the differential response.

Among the disease characteristics the researchers were unable to capture for this study were the time between prostatectomy and A/SRT, PSA at time of A/SRT/maximum PSA reached, nadir PSA achieved after prostatectomy, PSA doubling time, extent of positive margins, Gleason score at the positive margin, and comorbidities. Patients were not treated uniformly with respect to radiation dose received and duration of adjuvant androgen deprivation therapy (ADT). Only 12% received any adjuvant ADT, and only 12% received adjuvant (rather than salvage) radiation.

Metastases were detected by bone scan and CT. Lymph node dissection, if performed, was limited. It was detected in 4% of the “low PORTOS” group, but in none of the “high PORTOS” group. It is unclear how today’s newer PET scans would affect outcomes.

Radioresistance

Prostate cancer has long been known to be radioresistant relative to other cancers. To understand radioresistance, we must first understand how ionizing radiation (X-rays or protons) kills cancer cells. The radiation causes a chemical reaction with water and oxygen to generate molecules known as “reactive oxygen species” or ROS. One such ROS molecule, the hydroxyl radical, inserts itself into the cell’s DNA to break both strands of the double helix, called “double strand breaks.” The cell dies when it can’t replicate because of those double strand breaks.

Radiobiologists cite 5 reasons for radioresistance:

1. Hypoxia

Prostate cancer thrives in an oxygen-poor environment, and often does not have a good blood supply that brings oxygenation. It therefore requires more radiation to provide adequate ROS, especially into thick tumors.

2. Cell-Cycle Phase

As a cancer cell attempts to build new DNA and replicate, it goes through several phases. In one of those phases, the “S phase,” the cell is building new DNA. It is particularly radioresistant in this phase. Radiotherapy is typically carried out over a period of time in multiple fractions, rather than in a single shot, to allow the cancer cells to cycle into more radiosensitive phases. However, in a recent lab study, McDermott et al. showed that fractionated radiation increases the population of radioresistant S-phase prostate cancer cells.

3. Repair of DNA damage

Non-cancerous cells that can’t repair the DNA damage, commit suicide (called apoptosis). Many non-cancerous cells are able to repair the DNA damage and survive. Fractionation gives them time to self-repair. Cancerous cells usually lack that DNA-repair mechanism and most cannot undergo apoptosis. If they are not killed immediately, they die when they try to replicate. However, some cancerous cells may escape destruction by turning the genetic cell repair mechanism back on.

4. Repopulation

Some cancers grow so quickly that fractionated radiation gives them time to grow back between treatments. This is not the case for prostate cancer.

5. Inherent radioresistance

Some kinds of cells are inherently impervious to radiation damage; muscle, nerves, and stem cells are radioresistant, as are melanoma and sarcoma. Prostate cancer stem cells, thought to play a role in prostate cancer proliferation, are inherently radioresistant. A recent lab study showed that radiation may paradoxically activate stem-cell like features of prostate cancer cells, turning them into radioresistant stem cells.

How should PORTOS be used?

GenomeDx is already supplying PORTOS to post-prostatectomy patients who order Decipher. Should it be used to guide A/SRT decision-making? Given the caveats (above), there are many uncertainties in how predictive it actually will be when it is used prospectively in larger patient populations. But the information is certainly interesting.

I wonder whether PORTOS reflects a genetic change that occurs in local prostatic cancer cells as they undergo a change (called “epithelial-to-mesenchymal transition” (EMT)) into metastatic-capable cells. Or is it a genetic characteristic, there from the start? A recent study showed that 12% of men with metastases have faulty DNA-repair genes. (This included 16 DNA-repair genes, compared to the 24 in the PORTOS study). Such faults occurred in 5% of men with localized prostate cancer, and 3% in men with no prostate cancer. DNA-repair mutations seem to accumulate as the cancer progresses. It may well be that PORTOS is an early detector of systemic micrometastases. Perhaps it will be found to be redundant to detection of small metastases using new PET indicators. I would love to see a PORTOS analysis on metastatic tissue as well (lymph node, bone and visceral) and maybe on circulating tumor cells to see whether radioresistance is an acquired trait of PC progression. If it is an early indicator of metastatic progression, it may already be too late for primary radical therapy.

While a “high” PORTOS suggests that A/SRT will be curative, only a quarter of the men had a high PORTOS. Does that really mean that three-quarters of recurrent men should give up on curative therapy? If PORTOS is not an indicator of EMT, I hope that those recurrent cancers still can be cured. But it may mean that certain adjuvant measures may be required, including higher radiation doses, systemic therapies that are known to enhance radiation effectiveness, and investigational adjuvant therapies.

•      A/SRT doses are typically in the range of 66-70 Gy. Some A/SRT studies used doses as high as 72-76 Gy. With modern IGRT/IMRT technology, such doses may be delivered with acceptable toxicity. Also, if larger lesions can be identified with the new PET scans and multiparametric MRIs, it may be possible to deliver a simultaneous integrated boost dose to those lesions.

•      ADT has been shown to reduce hypoxic cancer survival and inhibit DNA repair. It is possible that prolonged neoadjuvant use, perhaps with second-line hormonal agents (Zytiga or Xtandi) may improve radiation cell kill. Docetaxel, which has shown limited usefulness in non-metastatic patients, may prove useful in low-PORTOS situations. Perhaps immunotherapy can play a role as well.

•     There are many investigational agents that may enhance radiosensitization. PARP1 inhibitors (e.g., olaparib) and heat shock protein inhibitors may prove useful in restoring radiation sensitivity (see this link). PI3K/mTor inhibitors and HDAC inhibitors (e.g., vorinostat) may increase cell kill in hypoxic conditions (see this link) and to cancer stem cells (see this link). Cell oxygenation may be enhanced by a measure as simple as 15 minutes of aerobic exercise before each treatment (see this link). There are common supplements like resveratrol and soy isoflavones, and drugs like statins, aspirin, and metformin that have shown promise as radiosensitizers in lab studies.

It is possible that PORTOS may also prove useful in predicting radiation response among newly diagnosed unfavorable risk patients. GenomeDx  currently requires whole-mount prostate specimens. I don’t know if PORTOS can be done on biopsy cores, or if it provides any prognostic information beyond what the conventional risk factors (PSA, Gleason score, stage and tumor volume) provide. It would have to be similarly validated before we would be able to incorporate it in primary therapy decision-making.

This test is very expensive. For now it only is available along with Decipher, which costs about $4,000. Medicare may cover it, but private insurance may or may not. Always get pre-authorization first.

Lu-177-PSMA-617: Another update

Because there is great interest in systemic therapies for metastatic prostate cancer, I want to provide readers with the latest news about the Lu-177-PSMA-617 trials in Germany.

I recently reported (see this link) on 74 patients – 31% had PSA declines greater than 50%. A new report by Rahbar et al. expands the patient base to include PSA data on 99 patients and toxicity data on 121 patients treated at 12 therapy centers.  After median follow-up of 16 weeks, and up to 4 therapy cycles:

·      45% had a PSA decline greater than 50%

o   40% after a single cycle

·      18/121 patients (15%) had serious or life-threatening hematotoxicity, affecting red blood cells (10%), platelets (4%), and white blood cells (3%)

·      Xerostomia (loss of saliva) occurred in 8%

This is a very encouraging PSA response. For comparison, only 13% had a PSA reduction greater than 50% in the Xofigo clinical trial. However in that trial, 66% had a 50%+ decline in bone alkaline phosphatase, which may be a better biomarker for bone metastases. The hematotoxicity was identical.

What we really want to know is whether the treatment increases survival, and whether it is any better than Xofigo in doing so. The potential benefit of Lu-177-PSMA-617 is that it can treat non-osseous metastases too. We await future clinical trials to prove its benefit.

Urinary and sexual healing improved by waiting to start salvage radiation

Salvage radiation adds to the side effects of surgery and may halt the progress made towards healing. Healing takes time. On the other hand, we have learned that adjuvant or early salvage radiation has better oncological outcomes than waiting, the earlier the better (see this link).  Two new studies help us better understand the trade-offs.

Zaffuto et al. examined the records of 2,190 patients who had been treated with a prostatectomy. Their urinary and sexual outcomes were evaluated based on whether they received:

1. no radiation
2. adjuvant radiation (prior to evidence of recurrence, usually administered 4-6 months following prostatectomy), or
3. salvage prostatectomy (after PSA reached 0.2 ng/ml)

They also looked at outcomes based on when they were treated with radiation:

1. Less than a year after surgery, or
2. A year or more after surgery

With median follow-up of 48 months, the 3-year outcomes were as follows.

Erectile function recovery rates were:

• 35.0% among those who received no radiation
• 29.0% among those who waited to receive salvage radiation
• 11.6% among those who had adjuvant radiation
• 34.7% among those who waited for a year or more before initiating salvage radiation
• 11.7% among those who had radiation within a year

Urinary continence recovery rates were:

• 70.7% among those who received no radiation
• 59.0% among those who waited to receive salvage radiation
• 42.2% among those who had adjuvant radiation
• 62.7% among those who waited for a year or more before initiating salvage radiation
• 43.5% among those who had radiation within a year

Van Stam et al. looked at their database of 241 patients who were treated with salvage radiation and 1005 patients who only received a prostatectomy but no radiation afterwards. All patients were last treated between 2004 and 2015, and had up to 2 years of follow-up afterwards.

After adjusting for patient characteristics, they found that:

• Salvage radiation patients had significantly worse recovery of urinary, bowel, and erectile function.
• Patients who waited more than 7 months before receiving salvage radiation had better sexual satisfaction scores and better urinary function recovery.

So what is one to do: treat earlier for better odds of cancer control, or treat later for better urinary and sexual function recovery? We have seen that adjuvant radiation is rarely likely to be necessary, and that early salvage radiation can probably be just as effective. But what if PSA is already high and rising rapidly? One solution might be to use hormone therapy to halt the cancer progression while tissues heal. That may help with urinary function, but is apt to interfere with recovery of sexual function. This remains a difficult decision, which is why discussions with an experienced radiation oncologist should begin at the earliest detectable PSA (over 0.03 ng/ml) on an ultrasensitive test. Most of all, the patient must do the self-analysis to understand which trade-offs he is willing to make.

Sexual function was no worse when fewer external beam radiation treatments were used

The HYPRO trial was designed to detect whether hypofractionation (fewer radiation treatments) was inferior to conventional fractionation. Their previous report looked at outcomes on late-term urinary and rectal function. Here, they report on sexual function outcomes.

To briefly recap, 820 intermediate/high risk patients were randomly assigned to one of two external beam radiation treatment protocols:

• Conventional fractionation: 78 Gy in 39 treatments
• Hypofractionation: 64.6 Gy in 19 treatments
• 39% had adjuvant hormone therapy lasting up to 6 months

It should also be noted that men were 71 years of age at the time of treatment.

After median follow-up of 37 months:

• Among those with partial or full erectile function at baseline, erectile dysfunction occurred in 34.4% among those who had hypofractionation and 39.3% among those who had conventional fractionation. The difference was not statistically significant.
• Orgasmic function among those who did not have hormone therapy was higher for the hypofractionation group. The difference was statistically significant.
• Overall, sexual function scores declined after treatment, but there was no difference between two treatments.

Two other randomized clinical trials also reported no difference in sexual function. Both the Fox Chase trial (see this link) and the M.D. Anderson trial (see this link) found hypofractionation made no difference in sexual outcomes. This should give some comfort to patients and radiation oncologists considering hypofractionation.

Brachytherapy alone is enough for favorable intermediate risk patients

RTOG 0232 was a large clinical trial conducted to determine whether low dose rate brachytherapy (BT) alone was of equal benefit compared to external beam radiation therapy with a brachytherapy boost (EBRT+BT) in intermediate risk patients.

The study was conducted at 68 cancer centers in the US and Canada from 2003 to 2012. 588 intermediate risk men were treated. For the purposes of this study, “intermediate risk” was defined as:

• Stage T1c – T2b, and
• Either Gleason Score of 7 and PSA less than 10 ng/ml, or
• Gleason score of 6 and PSA between 10 and 20 ng/ml

They did not collect detailed data and report separately those who would now be classified as “favorable intermediate risk” by the Zumsteg definition (Gleason score 3+4, less than half the biopsy cores positive, and otherwise low risk). However, Howard Sandler, the Principal Investigator, wrote:

It was deliberately a favorable intermediate group largely. At the time (2002) we felt that combination therapy was mandatory for the more advance patients and we weren’t comfortable randomizing to brachy alone for those patients.

So it is important that we do not generalize their findings to unfavorable intermediate-risk or high-risk patients.

The patients were treated as follows:

• BT: 145 Gy of I-125 seeds or 125 Gy of Pd-103 seeds
• EBRT+BT: 45 Gy of EBRT and a boost with 110 Gy of I-125 seeds or 100 Gy of Pd-103 seeds

After 5 years of follow-up:

• Progression-free survival was 85% for EBRT+BT patients, 86% for BT patients (no difference)
• Acute grade 3 (serious) side effects were suffered by 8%  in each group.
•  Late-term grade 3 (serious) side effects were higher (12%) in the EBRT+BT compared to 7% in the BT group

o   Urinary side effects: 7% in the EBRT+BT group vs. 3% in the BT group

o   Rectal side effects: 3% in the EBRT+BT group vs. 2% in the BT group

So, the addition of external beam radiation added nothing to cancer control, at least out as long as 5 years. While side effects were low for both groups, combination therapy increased them.

We saw recently in an analysis of the patients at Cleveland Clinic who were treated exclusively with BT only (see this link, especially the section on intermediate risk), that progression-free survival was very good for “low intermediate risk” patients. Furthermore, Drs. Stone and Zelefsky agreed that the combination therapy is unnecessary for this group, especially when treated with a sufficient brachytherapy dose. Radiotherapy Clinics of Georgia has built a business out of treating even low-risk patients with the combination therapy. This is now proved to be an overtreatment that is needlessly toxic.

5-year SBRT trial: high cancer control, low toxicity

(9/10/2018)
Meier et al reported the results of a 5-year multi-institutional trial, (also reported at the 2017 ASTRO meeting), finding that SBRT had high rates cancer control and low toxicity.

This was a prospective clinical trial in which all 21 institutions treated 309 patients according to the same protocol. The institutions were community, regional and academic hospitals across the US. All patients were low (56%) or intermediate risk (44%). Of the 137 intermediate risk patients,  61% were favorable and 39% were unfavorable intermediate risk. The treatment was:

• 40 Gy in 5 treatments to the prostate
• 36.25 Gy to the seminal vesicles in intermediate risk patients
• No concurrent or adjuvant androgen deprivation therapy was allowed.

At five years after SBRT treatment, the following oncological outcomes were reported:

• 97.1% had no biochemical progression; that is, no increases in PSA to over 2 ng/ml from the lowest value achieved 
  o 97.3% for low risk patients, compared to 92.3% for IMRT historically
  o 97.1% for intermediate risk patients, compared to 91.3% for IMRT historically
       - 100% among favorable intermediate risk
       - 93.1% among unfavorable intermediate risk

By five years after SBRT treatment, the late toxicity outcomes were reported:

• No grade 3 (serious) rectal side effects
• Grade 2 rectal side effects in 2%

• Grade 3 (serious) urinary side effects in 4 of the 309 patients (1.3%)
• Grade 2 urinary side effects in 12%

These are certainly excellent outcomes, and are in-line with or better than retrospective SBRT studies that have previously been reported. So far, the longest running SBRT single institution study has been reported by Alan Katz (see this link). I’ve heard that a ten-year update is in the works. That will be as long and larger than the longest running IMRT trial.

SBRT is about half the cost of IMRT, and at only 5 treatments, is certainly a lot less bother for the patients. It has excellent outcomes even without adjuvant ADT in unfavorable intermediate risk patients. With large long-term studies now available, it is difficult to understand why some insurance companies still don’t cover it.

Toxicity equal for SBRT and conventional external beam radiation

There has been some question as to whether the toxicity of delivering very high doses of external beam radiation per treatment (or fraction) in fewer fractions (called “extreme hypofractionation” or SBRT) would be high compared to conventional dose rates per fraction. While SBRT practitioners have reported very low toxicity rates (see table in this link), there has always been some doubt because there may have been some bias in how patients were selected in the various studies.

The HYPO-RT-PC trial was the first trial ever to randomly assign patients to one kind of radiation or the other. Between 2005 and 2015, they enrolled 1200 intermediate-risk patients in Scandinavia to receive either:

1.  Conventional fractionation: 78 Gy in 39 fractions
2. SBRT: 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

There were a few differences from some US practices:

• “Intermediate risk” was defined as one or two of the following 3 risk factors:

1. Stage T1c-T3a (T3a is a high risk factor in the commonly used US definition)
2. PSA> 10 ng/ml (PSA> 20 ng/ml is a high risk factor in the commonly used US definition)
3. Gleason score ≥7 (Gleason scores greater than 7 are a high risk factor in the commonly used US definition)

• 80% of the men were treated with a technology called 3D-CRT, which is seldom used for external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic.

• SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

The toxicity results are based on 866 patients who had 2-year follow-up results. There were some differences in acute toxicity:

• Acute urinary toxicity was 27.6% for the SBRT group and 22.8% for the conventional fractionation group, but the difference was not statistically significant.
• Acute rectal toxicity was 9.4% for the SBRT group and 5.3% for the conventional fractionation group. The difference was statistically significant, but narrowed by 3 or 6 months.

Neither physician-reported toxicity nor patient-reported late-term toxicity differed by the fractionation schedule they received. By two years:

• Late-term urinary side effects were reported by 5.4% of the SBRT group and 4.6% of the conventional fractionation group. The difference was not statistically significant.
• Late term rectal side effects were reported by 2.2% of the SBRT group and 3.7% of the conventional fractionation group. The difference was not statistically significant.
• Impotence was reported by 34% of both groups, up from 16% at baseline.
• Patient-reported bother from urinary, rectal and sexual side effects were not different.

Given their use of the largely outmoded 3D-CRT technology, it was not surprising that acute toxicity would be elevated. I’m frankly surprised that late-term toxicity was not higher for SBRT.

They plan to present their findings on oncological outcomes at a future time.

Very early salvage radiation has up to 4-fold better outcomes and saves lives

Another  subject that has come up a lot recently is when to have salvage radiation. It is always a pressing decision for those 30% of prostatectomy patients who have detectable PSA after prostatectomy. We have seen (see this link) that a low PSA on an ultrasensitive PSA test, as low as 0.03, can be a predictor of full biochemical recurrence later. This latest analysis of this subject looked at how treating sooner rather than later was associated with better cancer control and survival.

Abugharib et al. examined the records of 657 men who had salvage radiation therapy (SRT) from 1986 to 2013 at the University of Michigan and the University of Texas Southwestern. They were all discovered to have detectable PSA following prostatectomy. Researchers were looking for evidence to confirm or contradict their hypothesis that earlier SRT had better outcomes.

They defined "earlier" in two ways:

1. At a lower PSA. Because of the treatment dates, there was relatively little data from ultrasensitive PSA tests. They divided PSA at the time of SRT into three categories:

• 0.01-0.2 ng/ml - the "very early salvage" cohort
• >0.2 - 0.5 ng/ml - the "early salvage" cohort
• >0.5 ng/ml - the "later salvage" cohort (0.5 was selected because the median PSA was 0.4 ng/ml)

2. At an earlier time from completion of prostatectomy

• < 9 months   
• 9-21 months
• 22-47 months
• > 48 months

They looked at "outcomes" in four ways:

1. freedom from biochemical recurrence (PSA> 0.2 ng/ml) after SRT
2. freedom from starting salvage, life-long androgen deprivation therapy (ADT) after SRT
3. freedom from detectable metastases after SRT
4. prostate cancer specific survival

After a median follow-up of 9.8 years, they found:

• The time in months since completion of prostatectomy had no bearing on any of the outcomes.
• The PSA at which they were treated has a major impact on all outcomes.
• The "early salvage" group had outcomes that were about twice as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
• The "later salvage group" had outcomes that were about four times as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
• 91% of the variance in biochemical recurrence after SRT was explained by the PSA at which patients were treated.
• Adjuvant ADT, which was given to 24% of patients for a median of 6 months (range 4-24 months), was significantly associated with freedom from biochemical recurrence after SRT. There were 40% fewer failures. 

Researchers did not have data on PSA doubling time and velocity, and the number who had persistently elevated PSA, all of which almost certainly would affect outcomes. Perhaps such other variables as the length of the positive margins and the Gleason score there ought to be incorporated into a fuller analysis.

Patients who were treated at an early sign of detectable PSA  (0.2-0.5) were twice as likely to develop metastases and die of prostate cancer as those who were treated at the earliest PSA (below 0.2). Those who waited for PSA to rise above 0.5 ng/ml were four times as likely to develop metastases and die from prostate cancer compared to those treated when PSA first became detectable.

We have three large randomized clinical trials proving that outcomes are diminished by about half by waiting rather than treating within the first 6 months, even before there are detectable PSAs (called adjuvant radiation). But few elect to have adjuvant radiation, and the number has been declining (see this link). To avoid overtreatment and protect patients from perhaps unnecessary side effects of SRT, early salvage has emerged as a compromise.

The authors point out that it may take 7 months or more for adequate healing of urinary and erectile complications (see this link). Also, this is an important decision for the patient, which he ought not make hastily. Yet here, more than in the primary therapy decision, very early action can save lives. As a compromise, they suggest early use of neoadjuvant ADT (prior to SRT) which could slow the cancer down and give tissues more time to heal. The extra time may help the patient recover better urinary function, if not erectile function.

They recommend,

"Our data would suggest potentially a traditional cut-off of 0.2 to define biochemical failure may be too late, and that at the first sign of a detectable PSA that SRT (or SRT + ADT) should be initiated."

This remains a difficult decision, and the patient with a detectable PSA after surgery should begin discussions with a good radiation oncologist as soon as possible. Age and comorbidities enter into the decision as well. Unfortunately at these low PSAs, even the most accurate of the new generation of PET scans are incapable of finding distant metastases that might help rule out those cases where SRT would be futile. Nomograms and Decipher scores may help in cases where the decision is equivocal.