Sunday, December 3, 2017

Questions to ask (and not ask) on a first urologist visit after a biopsy


  1. Am I a good candidate for surgery? What about anatomic abnormalities, previous hernia, effects of anesthesia, cardiovascular disease, diabetes or other comorbidities?

  2. I would like to get a second opinion on my biopsy slides from Epstein's lab at Johns Hopkins. (Here's the link.)

  3. What is my highest Gleason score? How many cores were positive? What was the highest percent of cancer in any core?

  4. What is my stage, and risk level? (You should  know your PSA – if you don’t, ask). How big is my prostate, and what is my prostate density?

    • If stage is T3 or T4: How can surgery be a good option if only the prostate capsule is taken out, leaving the rest behind? Aren’t the side effects of adjuvant radiation worse than if I had radiation at the start? (he may not know this.)

  5. Am I a candidate for active surveillance (why, why not), and if so, what are your Active Surveillance criteria and protocol? Why those and not something more or less stringent? Should I get a genetic test before deciding? Will that be covered by insurance?

  6. How many of the surgery technique you practice (whether robotic, laparoscopic or open) have you performed? (1000+ would be a good answer)

  7. Are you going to be doing all of the really important parts of my procedure yourself? (You need to be particularly careful about this at major training institutions where residents may be doing some parts of the surgery, or even the whole operation, while “your” surgeon is overseeing it.)

  8. In the last year, what was your positive surgical margin rate? (Should be less than 10% among men with stage pT2)

  9. What is your "trifecta" rate? (tricky because you don't want cherry-picked patients)

  10. What is your estimate of my risk for lasting incontinence; i.e., a pad or more after a year?

  11. What about lasting stress incontinence? climacturia? penile shrinkage? inguinal hernia? Peyronie’s? orgasmic pain or dysfunction?

  12. What kind of anastomosis technique do you use? (total - not just anterior)

  13. Will the bladder neck be spared? How will you maximize the urethral sparing?

  14. If you have positive biopsy cores near the apex: How will you ensure that all cancerous tissue is removed there?

  15. Will you take frozen sections and have a pathologist standing by to determine margins and how much of neurovascular bundles can be spared?

  16. What measures will you take to assure the integrity of the neurovascular bundles?

  17. What kind of penile rehab do you suggest?

  18. What kind of imaging (Bone scan, CT or MRI) is necessary for men at my risk level?

  19. Will you sample lymph nodes (PLND) or take extended lymph nodes (ePLND), or does it seem unnecessary for my risk level? If so, how will you find them (fluorescent dye)? How will you minimize risk of lymphocele and lymphedema?

  20. What kind of aftercare (including sexual rehab) will you provide, and how will we monitor side effects, and for how long? Will you regularly monitor my urinary and erectile recovery progress with validated questionnaires like EPIC and IPSS?

  21. How will I be monitored for recurrence? Will I get an ultrasensitive PSA test? How will you decide the point at which you would recommend I see a radiation oncologist? Do you use the Decipher test?

Questions not to ask:

  1. Is my age a factor in whether active surveillance is right for me? (only you can decide whether you are willing to live more years with the side effects of treatment, or whether you prefer to be treated while younger when side effects are apt to be less - see this link)

  2. What treatments should I consider and which is the best for me? (this would be asking your doctor to be an expert in treatments outside of his specialty, and also to know which benefits and risks are most important to you – he doesn’t have time or inclination to be expert in all therapies, and he’s not a mind reader.)

  3. If I were your father, what would you recommend? (You don’t know how he feels about his father (lol), and more importantly, what he would feel most comfortable with is not necessarily what you would feel most comfortable with. This is your decision to make and live with – don’t give up your power!)

Wednesday, November 22, 2017

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?

Saturday, November 18, 2017

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.






Saturday, November 4, 2017

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.






Thursday, October 26, 2017

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.

Thursday, October 19, 2017

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.

Monday, October 16, 2017

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.