When is whole pelvic radiation needed for salvage?

Patients who elect to have post-prostatectomy radiation for recurrent prostate cancer face a couple of important decisions:

(1) Should the radiation be limited to the prostate bed (PBRT)? OR
(2) Should one treat all the pelvic lymph nodes at the same time (whole pelvic radiation - WPRT)? And if so, is the oncological outcome likely to be better if one has androgen deprivation therapy (ADT) along with it?

There is an ongoing prospective randomized clinical trial (RTOG 0534) to help answer these questions. But results are not expected until the end of 2020. Meanwhile, the best we can do is look at how patients have done in the past. Ramey et al. conducted a retrospective analysis of 1861 patients treated at 10 academic institutions between 1987 and 2013. The treatments and patient characteristics were as follows:

• All had post-prostatectomy PSA> 0.01 ng/ml (Median was 0.5 ng/ml)
• All had post-prostatectomy Gleason scores ≥ 7
• None had detected positive lymph nodes
• 1366 had PBRT without ADT,  250 with ADT
• 176 had WPRT without ADT, 69 with ADT
• Median salvage radiation dose was 66 Gy
• More than half of GS 8-10 patients got ADT, whereas most GS 7 patients did not
• 60% had extraprostatic extension
• 21% had seminal vesicle invasion
• 60% had positive surgical margins

After a median follow-up of 51 months, the 5-year freedom from biochemical failure outcomes are shown in the following table.

             5-Year Freedom from Biochemical Failure

	PBRT	WPRT	TOTAL
With ADT	51%	66%	55%
Without ADT	48%	60%	50%
TOTAL	49%	62%	51%
Among GS 7:
With ADT	56%	70%	59%
Without ADT	52%	66%	54%
TOTAL	53%	67%	56%
Among GS 8-10:
With ADT	45%	64%	49%
Without ADT	34%	44%	35%
TOTAL	37%	53%	44%

WPRT with ADT had the best outcomes in total and in each Gleason score category. Two-thirds of salvage patients had 5-year cancer control with the combination, whereas only about half had oncological control without them. The differences were especially marked among those with GS 8-10. There was significant improvement even in men with GS 7; however, they did not have the data to ascertain whether they were GS 3+4 or GS 4+3. Adjuvant ADT improved outcomes whether it was used in conjunction with WPRT or PBRT. On multivariate analysis, both WPRT and ADT independently increased freedom from biochemical failure. Higher radiation dose, lower PSA, lower Gleason score, Stage T2, and positive surgical margins decreased the risk of failure.

Neither WPRT nor ADT made any difference in the rate of metastases, which were low at 5 years post-prostatectomy.

Toxicity and quality of life, which would be the only reasons not to give WPRT and ADT to all salvage radiation patients, were not evaluated in this study. Also lacking were data on duration and type of adjuvant ADT

This study is congruent with a couple of retrospective studies (see this link and this one), but incongruent with a couple of other retrospective studies (see this link and this one). The present study is the largest and most recent dataset of them, and corrects for the effects of other variables in a way that the two opposing studies did not.

We saw previously that adjuvant ADT has been proven in a randomized clinical trial to improve oncological outcomes of salvage radiation after prostatectomy (see this link).

While we await the more definitive data from RTOG 0534, this builds the case that both WPRT and ADT should be included in the salvage radiation treatment of men with prostatectomy-diagnosed Gleason scores of 8-10, and at least some of those with Gleason score of 7. There are several open questions:

• Is there a benefit for GS 3+4, or only for GS 4+3 or higher?
• Is there a benefit when higher salvage radiation doses (70-72 Gy) are used, or with hypofractionated protocols that raise the biologically effective dose?
• What is the optimal duration of adjuvant ADT?
• Would any of the newer hormonal therapies (e.g., Zytiga or Xtandi) or other systemic therapies improve outcomes?
• What are the trade-offs with toxicity and quality of life?
• What is the optimal treatment field for WPRT, and should it vary with individual anatomy and comorbidities, given its potential toxicity?
• Can we use the newer PET scans or USPIO MRI to help decide if WPRT is necessary?
• Can we identify any subsets (e.g., low PSA, stage T2, GS 3+4) that would not benefit from the additional treatment?

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.