Wednesday, November 30, 2016

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.

Monday, November 28, 2016

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.

Tuesday, November 1, 2016

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.


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.


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.


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.