Myth: "Gleason 6 never progresses"

There is a lot of mythology about prostate cancer. One of the prevalent myths is that a Gleason score 6 (GS6) found with a biopsy, or even confirmed over many biopsies, never progresses. How did the myth get started and what is the truth, as we know it so far?

Metastases never come directly from GS6 in the prostate (true)

This is true. Donin et al. at NYU Langone looked at the records of 857 patients diagnosed as GS6 after a prostatectomy. 16 of them were found to have a significant recurrence and were treated with salvage radiation to the prostate bed. All but 2 of the treated patients had no further recurrence, indicating that there were no distant metastases. The remaining two were found to have actually had GS7 when their removed prostates were re-examined.

Ross et al. looked at records from Johns Hopkins, UCSF,  Baylor and Henry Ford and found 22 cases (out of 14,123 examined) where pelvic lymph node metastases were found during prostatectomies of GS6 patients. 19 of those were re-reviewed, and all were found to have a higher Gleason score than the initial pathology assessment. Lymph node metastases were never associated with a GS6. Similarly, Liu et al. searched the 2004-2010 SEER database to find 21,960 GS6 patients who had pelvic lymph node dissection along with their prostatectomy. Only 0.48% were found to have lymph node metastases. Unfortunately, their prostate specimens were not available for re-review. Wenger et al. looked at the 2004-2011 SEER database, the 2004-2013 National Cancer Database, and  2004-2013 patient records at the University of Chicago; lymph node metastases were found in 0.2%, 0.18%, and 0%, respectively, among the GS6, post-prostatectomy records. Of the 24 patients at U. of Chicago who had a recurrence, all but 3 were local. The 3 non-local recurrences were all found to have been GS7 on pathological re-review.

In a Dutch study of 449 GS6 post-prostatectomy patients treated from 1985-2013 with over 8 years of median follow-up, Kweldam et al. found that there were no lymph node metastases, no distant metastases, and no prostate-cancer related deaths.

Not only does true GS6 never metastasize, it rarely eats into surrounding tissue. Anderson et al. looked at post-prostatectomy records of 2,502 GS6 patients from the University of Chicago and Northwestern treated from 2003-2014. Only 7 of them were found to exhibit extraprostatic extension (stage pT3a), and it was only focal in every case. There were no cases of seminal vesicle invasion (stage pT3b) or invasion of organs adjacent to the prostate (stage pT4). Hassan et al. at Johns Hopkins looked at post-prostatectomy records of 3,288 GS6 patients treated from 2005-2016. 3.9% exhibited focal extraprostatic extension, 2.4% exhibited significant (non-focal) extraprostatic extension, and there was only one case of seminal vesicle invasion.

A GS6 at biopsy may not be a true GS6 (true)

In a study at Johns Hopkins among low-risk patients who decided to have a prostatectomy, Epstein et al. reported that 36% were upgraded from a GS6 to a higher grade. Lotan et al. report a similar amount of upgrading (40%) even if a 32-core saturation biopsy was used. Multiparametric MRI targeting can find GS7 or greater tumors if they are large enough (> 2 cc), but Bratan et al. reported that the GS7 detection rate was only 63% for tumors < 0.5 cc, and 82-88% for tumors 0.5-2.0 cc. An NIH study used mpMRI imaging on patients who immediately afterwards had a prostatectomy. The mpMRI was evaluated by their expert readers who looked for cancers larger than 5 mm and  with grades of at least GS 3+4. The mpMRI missed 16% of clinically important tumors.

Multiple biopsies over the years can increase the odds of finding any cancer that is GS7. Even if a single mpMRI-targeted biopsy misses 37% of small GS7 tumors, the odds that two such biopsies will miss it is 37% x 37% = 14%. Three biopsies drop the odds to 1 in 20, and the odds of missing it on 4 biopsies is 1 in 53. Multiple biopsies are used in most active surveillance protocols, and their frequency can be slowed if there is no evident progression. Some of the increased detection with multiple biopsies will be due to better detection of what was always there, some will be due to grade progression (see below), and it really doesn't matter which is which. 

A GS6 may progress into something else that can metastasize (true)

GS6 is a relatively indolent type of prostate cancer. Most of it never progresses to higher grades, but some of it will, given enough time. In the longest-running active surveillance study in North America, Klotz reports that 55% of low-risk patients have been able to avoid treatment due to grade progression for 20 years. Conversely, 45% did have grade progression. Only 25% had progressed in the first 5 years, 37% by 10 years, and 45% by 15 years. After that, cases of progression came to a halt. An  active surveillance model at Johns Hopkins, which had strict annual biopsies, attempted to separate the misclassifications from the true grade progression. They estimated that the true grade progression rate in the first 10 years was 12%-24%. A similar model estimated the rate of total grade progression (true progression plus correction of prior misclassification) at about 4% per year during the first ten years, and they determined that the time for those GS6s that progressed to a GS7 took an average of 14 months.

Watkins et al. reported that GS6 patients had a low risk of recurrence after prostatectomy unless they had positive surgical margins. 8-year freedom from biochemical recurrence was 95% with no positive margins, but only 74% if there were any positive margins. GS6 left in the body can still proliferate and progress.

A large retrospective study at Harvard reported that among the 410 deaths from prostate cancer in an advanced prostate cancer cohort, 42 (10%) were originally biopsy-diagnosed as GS 6. GS 6 doesn't often turn into something lethal, but it can.

Further evidence of grade progression comes from a cohort of 1041 Swedish patients who had a PSA test but were not biopsied at that time. Gleason score was found to be correlated with the "lead time" between the date of the elevated PSA (3.0-10.0) and the biopsy when symptoms occurred. The diagnosis of higher grade cancers rose steadily throughout the up to 30 years of lead time in the study. Inversely, the diagnosis of low grade cancers dropped steadily with lead time. The low grade cancers converted to high grade cancers over time.

(update July 2020) Salami et al. found that certain molecular "fingerprints" existed in the cancers that were GS6 and remained in their cancers after the patients progressed to higher grades.


There are some risk factors that can help distinguish the GS6s that will progress from the ones that won't (partly true)

There are several risk factors associated with higher grade cancers (e.g., PSA, PSA density, age, and African-American); however, none of them have a cutpoint that discriminates between those who will progress from GS6 and those who won't. Ellis et al. at Johns Hopkins showed that the number of positive biopsy cores (≤6 or >6) did predict grade progression at prostatectomy to some extent:

• 23% were upgraded if there were ≤6 positive cores
• 34% were upgraded if there were >6 positive cores
• But it had little effect on the recurrence-free survival following prostatectomy . 

Perineural invasion (PNI) noticed in the biopsy may be prognostic for progression on GS6, especially when both PNI and a high percentage of cancer in cores are found (see this link). Johns Hopkins has tables from which a patient with PNI may estimate his risk that the cancer is not confined to the prostate capsule based on GS, PSA, and the highest % cancer in a biopsy core.

Genetic risk can sometimes identify patients who are at higher risk for grade progression than their low risk NCCN designation would indicate. Prolaris and Oncotype Dx will usually indicate genetic risk in line with NCCN risk group, but sometimes they may find higher risk than expected. Recently, Decipher has begun to offer genomic risk scores based on biopsy samples. There is some evidence that there may be wide genetic diversity of the multiple tumors within a man's prostate. Just as a single biopsy may miss a high grade cancer, the biopsy cores sent for genetic analysis may not include the one or ones with higher genetic risk. These tests are expensive ($3,000-$4,000) and may not be covered by insurance (always get preauthorization!).

PSA inconsistently goes up with grade, and some high grade disease puts out low levels of PSA. Compared to total PSA, the PSA-derived biomarkers (e.g., Free PSA, PHI, 4Kscore, IsoPSA) have higher detection rates of high grade prostate cancer, as do PCA3, TMPRSS2:ERG fusion, and Select MDx.

How does GS6 progress to higher grades? What can we do about it?

There is very little certainty about the changes that occur at the molecular level when GS6 cancer progresses, and what drives those changes. Sowalsky et al. found that Gleason pattern 4 glands that were intermixed or adjacent to Gleason pattern 3 glands shared characteristic genetic markers that indicated they had a common origin. Whether the pattern 4 cells were cloned directly from pattern 3 cells or arose from  a common precursor cell is not clear. The authors suggest that a genetic aberration called "PTEN loss" may distinguish pattern 3 cells that might progress from the kind that might not progress.

VanderWeele et al. did a genetic analysis of 4 patients who had both GS6 and GS8 tumors in the same prostate. Two of the men also had lymph node metastases that were analyzed. They found that the GS6 and GS8 cells shared 9% of the characteristic genes they looked for. That suggested that GS6 did not directly morph into GS8, but arose from an early common ancestor long before. On the other  hand, the GS8 shared 81% of those characteristic genes with the lymph node metastases, indicating recent progression.

Haffner et al. did a genetic analysis of a metastasis from a patient who recently died of prostate cancer. They also analyzed tissue samples taken from the man's earlier prostatectomy and lymph node dissection. They found that the lethal metastasis was much more closely related to a small bit of pattern 3 cancer in the prostate rather than to the pattern 4 cancer in the "index lesion" (the largest, highest grade tumor in the prostate) or to the lymph node metastasis. The lymph node metastasis, however, was not clonally related to the pattern 3 cancer, and seems to have arisen from a different source. The authors suggest that PTEN loss and loss of another tumor-suppressor gene called TP53 may distinguish the potentially lethal pattern 3 cancer from the innocuous kind.

Palapattu et al. used MRI/Ultrasound fusion biopsy to take sequential cores from exactly the same place on study entry and one year later from 31 low-risk men on active surveillance. 35% progressed to a higher grade (pattern 4 or 5) in the same site in that year. It was from the same tumor because it had characteristic gene expression in almost every case. They found several suspicious genetic mutations. Mutations in the genes SPOP and IDH1 were common to both the low grade and high grade cells in one patient each, suggesting they may be responsible for progression. In one patient, a TP53 mutation was found in the later high grade core, but not the earlier low grade core, suggesting it is the result of something else that caused progression. Mutations in SPOP and BRCA2 were found in only the later cores in two patients who did not yet progress, perhaps suggesting increased potential for progression. As opposed to the studies that suggest a common progenitor cell for low and high grade cancer, this study suggests that genetic abnormalities and accumulating genetic breakdown are the sources of grade progression.

These studies are beginning to offer clues as to why GS6 sometimes progresses. There are biomarkers like Ki67, p53, and VPAC that may predict progression. Histological analysis may detect PTEN loss and TP53 loss, as well as mutations in SPOP, IDH1, and BRCA2 in tumor genes. While we currently lack widely available means to predict progression, active surveillance with periodic biopsies remains our best tool for finding progression while it is still curable.

Unfortunately, there are no medicines that can prevent grade progression from occurring, or reverse it after it does occur. Perhaps someday, CRISPR or zinc fingers will be used, but that is many years away.

Radiation-induced fatigue

One of the annoyances associated with radiation treatments given over a long duration is a growing feeling of fatigue. Radiation-induced fatigue reaches a peak by the end of therapy, but may not completely disappear for a year (see this link). There are many open questions about exactly what it is, what causes it, and what can be done about it.

It is a prevalent morbidity associated with external beam radiation therapy (EBRT) for every kind of cancer. Hickok et al. reported it among 372 EBRT patients treated for a variety of cancers. The incidence of fatigue for those treated for prostate cancer was 42% at baseline, increasing to 71% by week 5. Fatigue severity of at least 4 on a 5-point scale increased from 13% at baseline to 20% by week 5. They also found that:

• Prostate cancer patients had lower incidence of fatigue compared to other cancers
• Fatigue severity was not associated with age, gender or total dose of EBRT

Chao et al. examined the records of 681 prostate radiation patients treated with 6-9 weeks of radiation therapy for prostate cancer at the University of Pennsylvania. Their fatigue level (on a scale of 0-3) was assessed at baseline and at the end of radiation therapy. They found that fatigue was higher :

• in younger men (<60 years of age)
• in men who were depressed
• in men who started hormone therapy before radiation
• in men who did not get anti-nausea medication

Fatigue returned to baseline levels by 3 months post-EBRT in the vast majority of patients.

Miaskowski et al. also found that younger men and those suffering from depression were more susceptible.

Luo et al. did not detect any correlation with age among locally advanced patients, but did detect an association with PSA, Gleason score and stage. Since all 97 patients in their study received androgen deprivation therapy, it is impossible to isolate the effects of each. Tumor burden has always been associated with fatigue in cancer patients.

There is a psycho/social dimension to radiation-induced fatigue. Stone et al. found that there were associated deteriorations in global quality of life, cognitive functioning, and social functioning, most likely as a result of the fatigue. Nausea/vomiting, pain, insomnia, diarrhea, were associated morbidities. Financial difficulties were associated as well. Baseline levels of fatigue and anxiety were associated with higher levels of post-radiation fatigue.

Others have found that fatigue increases with the number of treatments (but not the dose), and the size of the radiation field. In fact, with 5-treatment SBRT, fatigue scores were never meaningfully elevated. Chao found there was no difference between photons and protons in inducing fatigue.

It is impossible to separate cause from effect in these associational studies. Muscle weakness has been associated with fatigue (see this link and this one), but is that because the radiation causes muscle weakness, or because fatigue makes men less likely to exercise with resultant muscle weakness? Our minds may interpret the feeling of muscle weakness as fatigue. It is also difficult to separate the effect of adjuvant hormone therapy, which may cause lassitude and muscle loss from lack of testosterone.

Emotional status is another variable that may both contribute to fatigue and result from it. Stress causes increased production of cortisol at first, but over time, negative feedback may cause adrenal insufficiency, creating a feeling of fatigue. Depression and anxiety are normal reactions to a cancer diagnosis, and the process of going through multiple treatments undoubtedly exacerbate those emotions. Whether psychogenic or somatogenic, the mind changes the body, and the body changes the mind.

Biochemical pathways

We know surprisingly little about the physical process that leads to the feeling of fatigue. The hope is that by learning more, we can design interventions that may block the fatigue process. Holliday et al. hypothesized that fatigue was caused by sleeplessness or by inflammatory cytokines (which can cause flu-like symptoms). In their small study of 28 men at MD Anderson, they found that sleep actually increased, and there was no relationship between cytokines and degree of fatigue (this contradicted a mouse model).

Radiation may induce anemia in susceptible individuals. Feng et al., in a study of 35 men, found that red blood cells, hematocrit, and hemoglobin levels dropped as radiation therapy and adjuvant androgen deprivation therapy progressed. Perceptions of fatigue correlated with reduction in those "heme" markers.

Mitochondria  are the energy factories of our cells. They mostly use a process called "oxidative phosphorylation" to generate energy. Hsiao et al. found that genes necessary for the patency of mitochondrial energy production were significantly more impaired in men who received radiation than in men on active surveillance. Mitochondrial enzymes have been shown to play a role as well.

There is some evidence that nerve inflammation from radiation may cause fatigue. Saligan et al.  found that the SNCA gene, which is over-expressed as a result of neural inflammation, overexpressed the protein alpha-synuclein, a neuroprotectant. This may one day become a biomarker for radiation-induced fatigue. "Neurotrophic factors" are released by nerves that have been exposed to radiation. They have been implicated in psychological states like fatigue and depression.

Hsiao et al. found that worsening fatigue scores were associated with impairment of genes related to  B-cell immune response, antigen presentation, and protection from oxidative damage. The same group also found an association with IFI27, a gene responsible for inducing cell death in irradiated cells.

What can be done about it?

Unfortunately, we do not yet have a pill for it. Ritalin had been proposed, but placebo-controlled studies have proven it to be ineffective in brain tumor patients receiving EBRT and in cancer patients in general (interestingly, a placebo was effective). It is doubtful that a stimulant will be effective in prostate cancer patients receiving EBRT, although patients have anecdotally reported some success with modafinil.

Erythropoietin may be useful off-label in some cases if significant anemia is detected, but there are no clinical trials supporting such use.

Anti-nausea medication may be beneficial, but the ones that cause drowsiness should be avoided.

Until there is a pill, the best interventions are:

(1) Avoid protracted radiation therapy. Now that eight randomized clinical trials have proven that moderately hypofractionated EBRT (20-26 treatments)  is no less effective than conventionally fractionated EBRT (39-44 treatments), there is no longer any reason, other than in exceptional cases, to endure the longer fatiguing schedule. SBRT (4 or 5 treatments) entails no meaningful increase in fatigue. High-risk patients may avail themselves of brachy-boost therapy that includes only 20 EBRT treatments. Patients getting salvage radiation will still have to endure 35-40 treatments, although current and past clinical trials suggest that that may no longer be necessary in the future.

(2) Exercise. In a small randomized controlled trial, Monga et al. found that an 8-week structured cardiovascular exercise program prevented fatigue, while improving depression, cardiovascular fitness, strength, flexibility and sense of well-being. Hojan et al. found that those high-risk patients randomized to supervised moderate intensity physical exercise had significantly less fatigue compared to controls. Their levels of inflammatory cytokines were lower, as was their functional capacity, blood counts, and quality of life. Steindorf et al. compared outcomes among 160 women undergoing radiation for breast cancer who were randomly assigned to 12-week muscle resistance training or muscle relaxation training. Resistance exercise resulted in significantly lower radiation-induced fatigue and better quality of life. Segal et al. showed that  the combination of cardiovascular and resistance exercise in men with prostate cancer decreased fatigue, with longer lasting improvements attributable to resistance training. Windsor et al. found that even moderate walking throughout the duration of EBRT treatments prevented fatigue and improved physical functioning.

Exercise has another important benefit during radiation therapy -- it may improve the effectiveness of radiation and reduce its toxicity. Some tumors are radioresistant due to hypoxia -- not enough oxygen penetrates the deepest tumor tissue. Oxygenation is necessary for radiation to create the free radicals that destroy the cancer DNA. This positive effect of exercise has so far only been studied in rats and awaits clinical verification. Paradoxically, good oxygenation is what keeps healthy cells healthy. Kapur et al. showed that aerobic exercise reduced rectal toxicity during EBRT.

Patients complain that exercise is the last thing they feel like doing when they are fatigued and depressed. Well-meaning friends and loved ones may offer deleterious advice to rest and take things easy. In all of the above clinical trials, patients had supervised exercise training. If one can afford it, this would be a good time to hire a personal trainer who would force one to work out, whether one wants to or not. Perhaps family and friends can be enlisted to "crack the whip" rather than encourage relaxation. Both cardiovascular training and muscle resistance training are important. Some hospitals and cancer support organizations offer exercise programs for cancer patients. Of course, permission from one's doctor is required.

(3) Stress reduction. Patients and their physicians should be alert to signs of depression and anxiety.  Antidepressant medications (e.g., Lexapro) may serve double duty because they have been found to reduce the severity of hot flashes in patients who are on androgen deprivation therapy. Wellbutrin (bupropion) is an antidepressant that also has stimulant side effects. Most anxiolytic drugs (e.g., benzodiazepines) will only increase fatigue. However, practicing mindfulness-based stress reduction has been shown to reduce anxiety and depression in cancer patients. Yoga may be useful as well.

Why did biochemical control not translate into a survival increase after brachy boost therapy?

The first randomized clinical trial to prove that brachy boost (BB) therapy had better oncological outcomes among high risk patients was Sathya et al. (2005). After 5 years, 36% of those high-risk patients who received the brachy boost had a PSA recurrence vs. 66% of those who received external beam radiation (EBRT) only. In an update, the authors report that overall survival was not significantly different in the two groups. This seems to call into question whether PSA recurrence is a useful surrogate endpoint for survival, or if it is, under what circumstances?

Dayes et al. provided a 14-year median update on the original study and added further comments in this "Beyond the Abstract" essay. The 104 patients in the original study who were treated between 1992 and 1997 had the following characteristics and treatments:

• Median age was 66
• 60% were high risk, 40% intermediate risk
• All had a negative pelvic lymph node dissection, negative bone scan and CT
• Brachy boost (BB) comprised 35 Gy of Ir 192 over 48 hours plus 40 Gy of EBRT in 20 fractions for a total of 75 Gy [sic].
• EBRT-only compromised 66 Gy delivered in 33 fractions using 2DRT (an outmoded external beam technology).
• None received androgen deprivation as part of their radiation therapy, nor afterwards unless PSA reached 20 ng/ml.

As of the update on the 104 patients (with only 5 lost to follow-up):

• Mortality from any cause was 67% among the BB patients, 77% among the EBRT-only patients -- not significantly different
• Prostate cancer-specific mortality was 18% among the BB patients, 23% among the EBRT-only patients - not significantly different
• Incidence of metastases was 20% among the BB patients, 28% among the EBRT-only patients - not significantly different
• Improvement in PSA control was maintained: 47% higher rate of biochemical recurrence-free survival among the BB group

There was a biopsy given 2 years after treatment to 87 of the 104 men in the original study

• In the BB group, 24% had a positive biopsy and 6% were metastatic
• In the EBRT-only group, 51% had a positive biopsy and 6% were metastatic

The authors conclude:

Despite ongoing benefit with respect to biochemical disease control, long term follow up out to 2 decades failed to demonstrate improvements in other important outcomes such as development of metastatic disease, deaths from prostate cancer and deaths from any cause. 

Increased biochemical (PSA) control usually translates into increased survival later on. That correlation is well-characterized. So why did it not in this case?

This study, with a sample size of only 104 (51 BB, 53 EBRT-only), was not large enough to detect statistically significant survival differences. We note that directionally there was an improvement in survival even though the difference wasn't big enough for 95% confidence. Also, 40% were intermediate risk patients who are slower to have detectable metastases and are more likely to die of other causes. By contrast, the ASCENDE-RT trial of LDR brachy boost therapy recruited 398 men, 30% were intermediate risk, and may eventually be able to demonstrate overall survival differences with longer follow-up.

We have to acknowledge that the doses delivered in this study were below what is now considered curative, and the findings here are to a large extent irrelevant. I am at a loss to explain how a hot iridium implant could be left in a patient for 48 hrs without doing serious damage or cooking the prostate to a crisp.  Perhaps they used cooler implants back then.  I can only trust that Dr. Sathya is correct in not making a correction for the lack of fractionation, which would be typical. It seems the BB dose was sub-optimal as demonstrated by the fact that in a quarter of men, the cancer was left alive in the prostate. EBRT-only was worse - leaving cancer alive in the prostates of twice as many men. Although they dissected some pelvic lymph nodes that they could find, we now know that even with improved modern lymph node detection methods, we miss 44% of positive lymph nodes (see this link). The 6% who were metastatic might have been caught with some of our new PET scans. So, in both groups, there was a lot of cancer left behind. Many high-risk radiation patients today would have had whole-pelvic radiation and would have had hormone therapy for up to two years. This highlights the importance of expanding the treated area, using escalated doses, and adding systemic therapy when the probability is high that the cancer might have escaped the prostate.

Even though BB wasn't curative for many high risk patients, it is disappointing that death was not delayed by reducing the tumor burden. There are several clinical trials of treating the prostate (with surgery or radiation) even after metastases have been detected, thereby hoping to prolong survival by reducing the load of cancer cells. Metastasis-directed radiation is sometimes given in this hope as well. Both of those therapies decrease PSA, at least temporarily. But only treating PSA serves no purpose if that is the only outcome. If this study is any indication, the cancer will catch up and replace the killed cells with no net survival benefit. I hope that is not the case.

How anticipating regret and quick decisions can lead to poor decision making

An essay in the New England Journal of Medicine describes the cognitive components of regret. They opine that regret always involves self-recrimination and not just disappointment over poorer than expected outcomes.

They breakdown treatment regret into different causes:

• "Process Regret" occurs when patients do not consider information about all available choices before making a decision.
• "Role Regret" arises when a patient gives in to pressure from others to change his decision.
• Active decisions can lead to more regret than passive decisions when the outcome turns out poorly.
• "Omission Bias" is the tendency to avoid active decisions, even when in our best interest.
• "Commission bias" may occur when the patient is distraught and believes that immediate decisive action is needed.
• Regret is lower when things are going poorly anyway; higher when there is a downturn of fortunes.

But there is another kind of regret that is equally counterproductive. In fact, it can lead to our making poor treatment decisions. "Anticipated regret," the fear of future self-recrimination, can cripple the patient's decision process, and ironically lead to "treatment regret" farther down the road. They offer the following advice to physicians, but I think that we as peers should heed it as well:

"We should recognize that anticipated regret can leave a patient mired in decisional conflict, unable to choose. For these patients, it is vital to bring anticipated regret to the surface by openly discussing their fears and helping them gain a clear perspective on the risks and benefits of their options in order to move forward. To mitigate the possibility of future experienced regret, we as doctors can try to reduce the emotional temperature and, when feasible, avoid having patients make their decisions while in a hot state. Except in the most urgent circumstances, physicians can set in motion a deliberate process, exploring all treatment options to avert process regret. When patients are heavily influenced by others in making a decision, we can also be alert to the possibility of role regret.

Here's their essay.

My personal belief is that regret - either of the past or anticipated - is a destructive emotion that causes distress. The best way I know to avoid it is by practicing Mindfulness to keep us in the present moment as much as possible and less in an a past that we can no longer change or a future that we cannot reliably anticipate.

I have also come to believe that no doctor ought to accept as final any prostate cancer primary treatment decision made by a low, intermediate or high risk patient within a month of receiving his diagnosis, and preferably within 3 months. The emotional temperature has too strong an effect on decision making, and time is our friend in this regard. Similarly, doctors should insist that second opinions have been acquired.

A new study by Hirasawa et al. confirms others that demonstrate that waiting 6 months or more (median 7.6 months) from biopsy to surgery among patients with localized prostate cancer (low risk to high risk) had no effect on 5 year rates of biochemical recurrence. It also had no effect on whether nerve bundles were spared, pathological upgrading or upstaging, positive margins, or positive lymph node detection. A similar study has demonstrated the same thing when the eventual treatment choice was radiation, comparing  those who waited more than 3 months with those who had treatment within 3 months,. There is no medical reason to rush this primary treatment decision.

Does Lu-177-PSMA-617 increase survival?

We have enthusiastically reported the encouraging outcomes of the early clinical trials of the radiopharmaceutical Lu-177-PSMA, most recently at this link. Based on reduction in PSA, it performs well. But medicines have no real benefit if all they do is treat PSA. We want medicines that increase survival.

Rahbar et al. reported the outcomes of 104 patients treated with Lu-177-PSMA-617 at University Hospital Muenster, Germany. All patients had metastatic castration-resistant prostate cancer (mCRPC) and had already received docetaxel and at least one of abiraterone or enzalutamide. After the first of an average of 3.5 cycles, they had the following outcomes:

• 67% of patients had some PSA decline
• 33% of patients had a PSA decline of at least 50%
• Median overall survival was 56 weeks (13 months)

The authors conclude:

177Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced mCRPC pretreated with chemotherapy, abiraterone and/or enzalutamide. 

But is this conclusion justified? It's hard to know without a prospective clinical trial where patients are randomized to receive the radiopharmaceutical or standard-of-care. The best we can do is look at the overall survival from clinical trials involving patients with symptomatic mCRPC. In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), overall survival was:

• 14 months with Xofigo
• 11 months with placebo

The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival. There have been a couple of small trials of "third-line" medicines after docetaxel and abiraterone were used.

In a non-randomized trial among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 9 months with cabazitaxel

In a Danish study among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 5 months with enzalutamide

So these data suggest that Lu-177-PSMA-617 may have prolonged life more than third-line treatment with another taxane or another hormonal agent. However, we expect much cross-resistance between abiraterone and enzalutamide, and resistance building up with prolonged use of taxanes. It is always hazardous to compare patient outcomes or declare success when they have not been randomized. Certainly there is enough suggestive data to warrant a Phase 3 randomized clinical trial.

Record 10-year SBRT study among low risk patients

Alan Katz has now published the study with the longest-running follow-up of any study of external beam radiation therapy for prostate cancer among low risk patients, in this case, using SBRT. 10-year follow-up among intermediate and high-risk patients will be presented at next year's ASTRO meeting. This study ties in longest length of follow-up with the Memorial Sloan Kettering (MSK) study of IMRT. IMRT involves 40-45 radiation treatments over the course of about 9 weeks; SBRT shortens the number of treatments to 4 or 5 over the course of about 11 days.

Focusing on their low risk cohort only, the Katz study has a distinct advantage over the MSK study in sample size:

• The Katz study started with 230 low risk patients and, because of later start dates and some loss to follow-up, had 57 evaluable low-risk patients who were tracked for 10 years.
• The MSK study started with 49 low risk patients and, because of later start dates and loss to follow-up, ended with only 2 patients tracked for 10 years.
• Median follow-up was 108 months for Katz and 99 months for MSK

The IMRT study used a prescribed dose of 81 Gy in 45 fractions. The Katz study used a dose of 35 Gy in 5 fractions on 42 patients and 36.25 Gy in 5 fractions on 188 patients (average = 36 Gy). The biologically effective dose for cancer control was 17% higher in the Katz study.

It is risky to compare SBRT and IMRT when patients are not randomized to treatment with one or the other. There has been such a randomized trial, and partial results have been reported (see this link). The median age was the same in both studies (69 years of age), and the same definitions for the low risk category, and for biochemical failure were used. To highlight some of the differences and similarities in outcome:

• 10-year biochemical disease-free survival was 94% for Katz vs. 81% for MSK
• 10-year distant metastasis free-survival was 98.4% for Katz and 100% for MSK
• No prostate cancer-related deaths at 10 years in either study

Late-term urinary and rectal side effects were infrequent and mild in both studies:

• Late-term urinary side effects:
• Grade 2: 9%, Grade 3: 3% in the Katz study
• Grade 2: 9%, Grade 3: 5% in the MSK study
• Late-term rectal side effects:
• Grade 2: 4%, Grade 3: 0% in the Katz study
• Grade 2: 2%, Grade 3: 1% in the MSK study

Of those who were previously potent before radiation, 56% were potent (sufficient for intercourse) 10 years later (median age 79) in both studies.

Other interesting outcomes of the Katz study included:

• Median PSA fell to 0.1 ng/ml after a median of 48 months
• 21% experienced a PSA bounce along the way.
• Cure rates were independent of whether patients received 35 Gy or 36.25 Gy
• Urinary toxicity was higher in the group that got the higher dose
• Rectal toxicity was no different in the two groups
• Patient-evaluated urinary and rectal function declined acutely but returned to baseline within a year
• Sexual function declined by 23% at 6-12 months, and continued to decline by 38% by 8 years. It is unknown what percent of that decline was age related (but see this link).

Looking at the higher local control rates of SBRT and HDR brachytherapy, Dr. Katz sees evidence that IMRT is sub-optimal in delivering biological effective dose. He also believes that no more than 35 Gy in 5 fractions is necessary to achieve that control, and that it would minimize side effects.

Of course, probably half of the low risk men in this study might have gone those ten years without needing any kind of treatment at all. But for those who may not want or may not be good candidates for active surveillance, SBRT is a low cost, low bother, low side-effect alternative that delivers high rates of long-term oncological control.

Amazingly, I still hear that there are insurance companies that will not cover SBRT because longer follow-up is needed. Dr. Katz had already reported the nine-year follow-up (see this link), and with this addition and the 10-year higher-risk update at ASTRO next year, it's hard to see what any objection might be.

Dr. Katz is to be congratulated for continuing to update his study for 10 years. It is a lot of work to follow up with so many patients, and collect and tabulate their reported outcomes. He is a radiation oncologist not associated with a large tertiary care facility that might have more resources at its disposal.

A new Lu-177-PSMA ligand has good results in a new study

Targeted nuclear medicine has shown some impressive outcomes in several small studies, mostly conducted in Germany. Most of the studies have used a radioactive beta-particle emitter, Lutetium 177, attached to a ligand that has high and specific affinity for prostate cancer cells. Most medicines developed for this purpose have a ligand that attaches to Prostate-Specific Membrane Antigen (PSMA), a protein found on 90% of all prostate cancer cells. The ligand for Lu-177-PSMA has to have a "grappling hook" on one end (called a chelator) that holds onto the Lu-177. On the other end is a "magnet" of sorts that binds tightly to the PSMA. The beta particles then kill the cell that the ligand attaches to and some nearby cells as well.

There are also ligands that attach to prostate cancer proteins other than PSMA, and radioactive elements other than Lu-177 that are in clinical trials. This is a rapidly developing field.

The new ligand is called PSMA-I&T (imaging and therapy) or sometimes PSMA-DOTAGA. The ligand used in most of the other studies was PSMA-617 (also known as PSMA-DKFZ) or PSMA-J591. The ideal ligand attaches strongly to PSMA in prostate cancer tumors and to nothing else. Importantly, it should not accumulate in the kidneys to a great extent because it could damage them.

Last year, the Central Clinic of Bad Berka, Germany reported on 56 patients treated with Lu-177-PSMA-I&T (see this link). 80% of treated patients had a PSA response and toxicity was minor. Heck et al.  at the Technical University of Munich reported on 19 metastatic castration-resistant patients who were treated with 7.4 GBq per cycle and up to 4 cycles.

• In 56%, PSA decreased by at least 30%
• In 33%, PSA decreased by at least 50%
• In 11%, PSA decreased by at least 90%
• Complete remission of metastases in 5%
• Metastases stayed stable in 63%
• Metastases progressed in 32%
• Performance status was stable or improved in 74%
• In those with bone pain, it was reduced partially or completely in 58%
• Mild (Grade 1 or 2) toxicities included dry mouth (37%), anemia (32%), and platelet loss (25%)
• There were no severe (Grade 3 or 4) toxicities.
• There was no kidney toxicity up to 40 GBq (see this link)

(Update 11/2018) Heck et al. updated the above with information on 100 patients. They were heavily pre-treated with a median of 3 pre-treatments. In fact, they were required to have had Zytiga or Xtandi, and at least one cycle of taxane chemo. They were all mCRPC and 35% had visceral metastases. They may have had up to 6 cycles of Lu-177-PSMA-617 (average was 3.2 cycles).

• In 38%, PSA decreased by at least 50%
• Median clinical progression-free survival was 4.1 months
• Median overall survival was 12.9 months
• Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%)

A meta-analysis looked at the PSMA-I&T and PSMA-617 ligands in relation to the PSMA-J591 ligand. With a combined sample size of 369 patients across 10 studies, Calopedos et al. reported that:

• 68% of patients had some PSA decline
• 37% of patients had a PSA decline of at least 50%
• More patients had a PSA decline with the PSMA-I&T and PSMA-617 ligands, but there was a wide range of outcomes

These early indicators look good. Even if it just stabilizes performance status and mitigates bone pain in these end-stage patients, there is an important benefit. Of course, what we really want to see is evidence that it increases overall survival

While PSMA-I&T was developed to be a good ligand for imaging purposes as well as therapeutic purposes, a recent study found that, when used with Ga-68 (a positron emitter), PSMA-HBED-CC (also known as PSMA-11) was slightly better at detecting metastases (see this link). Another PSMA ligand, DCFPyL, that incorporates the positron emitter F18 into the ligand more tightly (avoiding chelation, which can easily be reversed), seems to be superior to the Ga-68-PSMA-HBED-CC PET tracer (see this link). Both DCFPyL PET and Ga-68-HBED-CC PET are in numerous clinical trials in the US and Canada. Lu-177 is a gamma emitter that can be seen by a gamma camera or via SPECT. However, it is usually used in conjunction with a positron-emitter in order to obtain a superior image.

Readers may wish to read these other articles on this subject:

Will Lutetium-177-anti-PSMA be the next Xofigo?
Lu-177-PSMA update
Lu-177-PSMA: another update
First in-human trial of Actinium-225-PSMA-617
Ac-225-PSMA-617 extends survival (update)
Ac-225-PSMA-617 (update)
I-131-MIP-135, a new radiopharmaceutical, in clinical trial at Memorial Sloan Kettering

Focal salvage ablation for radio-recurrent prostate cancer

When there is a recurrence after primary radiation treatment, it is very tempting to try to identify the site(s) of local recurrence within the prostate and prostate bed and only treat those. The hope is that we can destroy any remaining cancer while keeping toxicity to the bladder, rectum, and neurovascular bundles to a minimum. The alternative to treating just the identifiable recurrence sites (focal or hemi-gland treatment) is to treat the whole gland. We saw that whole gland re-treatment with brachytherapy or SBRT seems to have good oncological and toxicity outcomes. But the standard of care, other than salvage surgery, has been salvage whole gland cryotherapy.

Cryotherapy is one kind of tissue ablation technique - it irreversibly destroys prostate tissue, both healthy and cancerous. Other kinds of ablation techniques include High Intensity Focused Ultrasound (HIFU), Irreversible Electroporation (IRE), Photodynamic Therapy (PDT), and Focal Laser Ablation (FLA). There have been small clinical trials of a few types of salvage focal ablation.

Focal Cryotherapy

Abreu et al. compared outcomes of 25 patients who had hemi-gland cryotherapy to 25 patients who had whole gland cryotherapy between 2003 and 2010.

• 5-year biochemical failure free rate was 54% in the hemi-gland group and 86% in the whole gland group.
• New incontinence afflicted none of the hemi-gland group and 13% of the whole gland group.
• Potency preservation occurred in 2 of 7 in the hemi-gland group, but none of the whole gland group
• Fistula occurred in none of the hemi-gland group and in one patient in the whole gland group.

Li et al. reported the COLD Registry data on on 91 radio-recurrent patients treated with salvage focal cryotherapy between 2002 and 2012.

• 3-year biochemical disease-free survival was 72%
• 5-year biochemical disease-free survival was 47%
• 4 of 14 patients (29%) had positive biopsies
• 3 patients (3%) suffered a fistula
• 6 patients (7%) suffered urinary retention
• 5 patients (6%) suffered incontinence requiring pads
• Half of previously potent patients were able to have intercourse.

Weske et al. reported on 55 radio-recurrent patients treated with salvage focal cryotherapy at Columbia University Medical Center between 1994 and 2011.

• 5-year disease-free survival was 47%
• 10-year disease-free survival was 42%

While whole gland salvage had very good oncological results, the toxicity was unacceptable. Focal therapy has undoubtedly improved over the years, but oncological results could be a lot better, and potency preservation was poor. Could another kind of focal ablation do better?

Focal HIFU

The Ahmed/Emberton group in the UK reported the outcomes 150 radio-recurrent men treated with focal HIFU between 2006 and 2015.

• 3-year biochemical failure free survival was 48%
• 100% for low risk patients
• 61% for intermediate risk patients
• 32% for high risk patients
• 3-year composite endpoint-free survival was 40% (endpoints= PSA recurrence+positive imaging+positive biopsy+systemic therapy+metastasis detected+death from prostate cancer)
• 100% for low risk patients
• 49% for intermediate risk patients
• 24% for high risk patients
• Complications included: 
• urinary tract infection in 11%
• bladder neck stricture in 8%
• fistula in 2%
• inflammation around the pubic bone in 1 patient
• They did not report potency preservation

Focal Irreversible Electroporation (IRE)

IRE or NanoKnife has gained interest because it is less of a thermal-type ablation than cryotherapy or HIFU. (See this link and this one for recent reports on its use as a primary therapy.) It is not FDA-approved for use in the US, so its use is limited to clinical trials. An Australian group working under Phillip Stricker, conducted a pilot test on 18 radio-recurrent patients.

With median 21 month follow-up, Scheltema et al. reported:

• 85% (11 of 13 patients) had mpMRI-undetectable cancer in the ablation zone
• 1 had an out-of-field recurrence
• 1 had a false-positive out-of-field recurrence
• Biochemical failure-free survival (bFFS) was 83% using the nadir+2 definition and 78% using the nadir+1.2 definition.
• 80% had biopsy-proven no evidence of disease on follow-up
• Incontinence requiring pads was suffered by 27%
• Potency preservation was reported by 33% (2 of 6 patients)

Salvage Surgery

For comparison, it is useful to note the outcomes of salvage surgery in radio-recurrent patients. In a recent meta-analysis, Matei et al. show that the 5-year biochemical recurrence free survival is about 50%. Incontinence rates among patients of surgeons who reported on 25 or more salvage surgeries was 47%. Erectile dysfunction was most often 100% (range 72-100%). Other serious complications included anastomotic stricture (closing off of the urethra where it was re-joined) in 18%, and rectal injury in 7%.

Salvage surgery sets a low bar.

Salvage Whole Gland Ablation

As another point of comparison, we can briefly look at the outcomes of salvage whole gland ablation. In two meta-analyses, Mouraviev et al. and Finley and Belldegrun looked at outcomes of salvage whole gland cryoablation. Focusing on the most recent trials, which used the most recent technology, biochemical failure-free rates ranged from 50% to 74%. In the study with the longest follow-up, Chin et al. reported biochemical failure free rates of 34% at 10 years and 23% at 15 years. Using up-to-date techniques, incontinence rates average 22% and impotence was mostly in the 60-80% range.

Crouzet et al. reported on 418 radio-recurrent patients treated with salvage HIFU from 1995-2009.
The 5-year biochemical failure-free survival was 58%, 51% and 36% for patients who were low-, intermediate-, and high-risk, respectively, before their primary treatment. 42% suffered incontinence requiring pad use, 8% required an artificial urinary sphincter, 18% suffered bladder outlet obstruction or stenosis, 2% suffered a fistula, and 2% suffered pubic bone osteitis. They did not evaluate erectile function, but in primary whole-gland HIFU treatment, about 60% of previously potent men had diminished potency after treatment. We would expect further loss of erectile function after salvage treatment.

Importance of Imaging

Good imaging is critical to the success of any salvage therapy after radiation failure. A full body PET scan with CT or MRI must be used to rule out distant metastases. The newly approved Axumin PET scan, now becoming widely available, has good detection rates (89%) when PSA is above 2.0 ng/ml, as it is at the time of a biochemical recurrence after primary radiotherapy. The biochemical failure-free survival (bFFS) numbers are sure to improve over time due to better selection of salvageable cases.

The other use of imaging is to detect the site of recurrence within the prostate. This may be followed with a multiparametric MRI-targeted biopsy or a template-mapping biopsy to precisely localize the cancer for focal ablation.

Caveats

It is only since multiparametric MRIs and better PET scans became prevalent that researchers realized that up to half of post-radiation recurrences are local (see this link). Therefore, it is relatively recently that investigators started to explore salvage therapies beyond salvage surgery and salvage cryoablation. Consequently, the sample size and the length of follow-up in many clinical trials is too small to draw reliable conclusions. The Chin et al. study demonstrates that treatment failures may not show up for 15 years. Whether those late failures are due to occult metastases or incomplete salvage ablation in that early trial is unknown.

We do not yet have a consensus on how to measure success. Researchers often use the Phoenix criterion (nadir+2) that was developed for external beam radiation. Some argue that the Stuttgart criterion (nadir + 1.2) which was developed for primary ablation therapy is a better measure. Because nadir PSA of 0.5 or less after radiotherapy is prognostic for long-term success, many look for that benchmark. Certainly, follow-up mpMRI and targeted biopsy are prudent steps to take 2 years after salvage ablation. However, it is necessary to have a radiologist and pathologist who are practiced at reading an mpMRI and biopsy, respectively, after both radiotherapy and ablation. There are few in the US who meet that qualification.

Another caveat is technological evolution and the learning curve. Cryotherapy is now using third-generation machines that are increasingly precise at forming "ice balls" while protecting nearby healthy tissue. HIFU is in its second generation, and IRE is relatively new. As technologies evolve and as practitioners gain more experience, we expect to see more complete ablation of the cancer and more sparing of the bladder and neurovascular bundles. Studies with longer follow-up may have used machines that are now obsolete. Studies with short follow-up may reflect practitioners on the beginning of their learning curve.

Focal ablation as primary therapy often (20-30% of the time) requires "re-dos." The retreatment may be necessitated by incomplete ablation within the ablation zone or missed bits of recurrent cancer outside of  the ablation zone. Multiple treatments undoubtedly add to cost and toxicity. Follow-up is too short for most studies to know what the eventual "re-do" rate will be.

Summary Table

Below is a table showing some oncological and toxicity outcomes for select studies of various salvage therapies after primary radiation failure. It is meant to be illustrative only - patient selection varied widely. My main purpose is to help patients understand the wide range of salvage therapies, other than salvage surgery and salvage whole gland cryotherapy, that are now becoming available to them.

	Length of follow-up	Number in trial	bFFS	Grade 3 or 4 urinary toxicity	Impotence	Reference
SBRT (whole gland)	2 years	29	82%	6%	60%	1
HDR brachy (whole gland)	3 years	61	60%	2%	NA	2
LDR brachy (whole gland)	3 years	37	60%	NA	NA	2
LDR brachy after LDR brachy (focal)	3 years	15	73%	none	13%	3
HDR brachy (focal)	3 years	15	61%	7%	NA	4
Cryo (focal)	5 years	91	47%	16%	50%	5
HIFU (focal)	3 years	150	48%	NA	NA	6
IRE (focal)	21 months	18	83%	27%	67%	7
Surgery	50 months average	1407 (32-404 in each)	~50%	65%	72%-100%	8
Cryo (whole gland)	45 months average	1385 (12-121 in each)	50%-74%	22%	60%-80%	9
HIFU (whole gland)	5 years	418	58% LR 51% IR 36% HR	62%	> 60%	10

Previous articles on the subject of salvage after primary radiation:
Local recurrence (Mayo)
Local recurrence (MSK)
Salvage SBRT
Salvage HDRBT and LDRBT
Salvage LDRBT after LDRBT
Salvage whole gland cryo