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Cancer- prostate

Primary Care Corner with Geoffrey Modest MD: Prostatectomy not help for localized ca

1 Aug, 17 | by

by Dr Geoffrey Modest

The 19.5 year follow-up of the PIVOT study (Prostate Cancer Intervention vs Observation Trial) confirmed their prior observations at the 12-year mark, showing that for men with localized prostate cancer, surgery was not significantly associated with decreases in all-cause or prostate cancer specific mortality (see Wilt TJ. N Engl J Med 2017;377:132).

 

Details:

— From 1994 to 2002, 731 men with localized prostate cancer were randomized to radical prostatectomy vs observation. This study provides patient-reported outcomes data through 2014

— Mean age at the beginning of the study was 67, PSA 7.8. All patients had to have histologically-confirmed, clinically localized prostate cancer (stage TI-T2NxM0) of any grade diagnosed in the prior 12 months, and PSA needed to be <50, age <75, negative results on bone scan for metastatic disease, and life expectancy of >10 years

—  Mortality outcomes were assessed locally at the site of care, but there was blinded central histopathological reclassification after the local assessment was done

— Endpoints included all-cause mortality (primary endpoint);  prostate cancer mortality (which included prostate cancer treatment related mortality); local, regional, systemic, and PSA progression; additional treatments; adverse events requiring treatment; and patient reported outcomes of urinary incontinence, erectile and sexual dysfunction, worry about health, “bother” due to prostate cancer treatment, physical discomfort, satisfaction with sexual functioning, and functional limitations due to prostate cancer or its treatment

— of the 364 men assigned to radical prostatectomy, 78.8% had surgery (281 had definitive surgery, 6 had positive nodes and surgery incomplete, 25 had radiation); of the 367 assigned to observation, 36 had surgery, 1 incomplete surgery due to positive nodes, 38 radiation (and almost all completed by 4-5 years after randomization). local progression leveled off at 5 years; systemic progression leveled off after 8 years

 

Results:

— 281 of 364 men assigned to surgery (61.3%) and 254 of 367 assigned to observation (66.8%) died, not quite statistically significant (p=0.06). The absolute difference in risk of death was 3.1 percentage points in 8 years, increasing to 5.5 percentage points in this study. Median follow-up from randomization to death or end of follow-up was​ 12.7 years.

— Deaths attributed to prostate cancer or its treatment occurred in 27 men (7.4%) assigned to surgery and 42 men (11.4%) assigned to observation, almost significant, p=0.06. Deaths that were considered to be definitively due to prostate cancer treatment occurred in 4.9% assigned to surgery and 6.0% assigned observation.

— on looking at the graphs: local progression was by 3-4 years after randomization, with level curves thereafter; regional progression was mostly between 6-15 years, again mostly level curves though these were less smooth and with smaller numbers; PSA increases began at 3 years, curves splayed with surgery benefit, then paralleled around 10 years

–Among men assigned to surgery, 41% had disease progression, and 34% received treatment for disease progression; in those assigned to observation, 68% had disease progression and 60% had treatment. Local cancer progression occurred in 34% vs 62%, in surgery vs observation groups; regional in 9 vs 14% and systemic progression in 10 vs 15%

–Subgroup analyses showed:

— age at diagnosis: no difference statistically, though trend favoring surgery was more impressive in those < 65 years old

— race: no difference between white vs black

— PSA: no difference if it was < 10 vs > 10

— risk category (D’Amico risk or one based on tumor stage, histologic score, and PSA level): of the 6 categories (low, intermediate, or high risk; all as determined locally and centrally) only locally assessed intermediate risk patients had a statistically significant 20% decreased risk with

— The Forest plot did show that for each subgroup analysis, including Gleason score above or below 7, all showed a trend showing prostatectomy benefit, however none of these reached significance, either for death from any cause or death from prostate cancer (though it should be noted that the number of patients in subgroup categories were quite low).

–adverse events:

–erectile dysfunction in 15 vs 5% (for surgery vs observation), incontinence in 17 vs 4%.

— The use of absorbent pads because of urinary incontinence was greater through 10 years in men treated with surgery, with absolute differences exceeding 30 percentage points at all times measured.

— Erectile dysfunction, decreases in sexual function/activity/interest/satisfaction were much greater through 5 years in men assigned to surgery.

— urinary incontinence and erectile/sexual dysfunction, as well as limitations in activities of daily living were each greater with surgery than observation through 10 years

— Worry about health did not differ between the 2 groups, though men assigned to surgery were more likely to report” bother” due to prostate cancer or treatment, physical discomfort, and limitations of daily activity for 2 years but not at later time points.

 

Commentary:

 

–These findings are consistent with those of the Scandinavian Prostate Cancer Group Study as well as the Prostate Testing for Cancer And Treatment trials, the latter compared surgery or radiation with active monitoring and delayed radical intervention based primarily on PSA results

— as a perspective, only 9.4% of these patients died from prostate cancer, the absolute difference in all-cause mortality was 5.5 percentage points and for prostate cancer mortality was 4.0 percentage points over almost 20 years, suggesting that the long term mortality attributable to prostate cancer with the above screening criteria/methodology is quite low

— however, despite these low numbers in patients with localized prostate cancer (less than 3% for metastatic progression, less than 1% for prostate cancer specific mortality), studies suggest that observation, PSA-based monitoring, and active surveillance with delayed radical intervention are used infrequently, even among older men.

–There are several issues with this study.

–This clearly reflects radical prostatectomy as the tested intervention. Radiation therapy in its many forms was not evaluated.

​–how does one explain the fact that prostate cancer mortality is quite high (3rd leading cause of death in men, 1 in 39 die from prostate cancer) yet screening does not seem to help so much?? Perhaps there really is large diversity in what we call or see under the microscope as “prostate cancer”.  One patient with localized prostate cancer may go on for decades never receiving treatment, yet another with the apparent same microscopic findings and even D’Amico risk may progress quickly and perhaps no treatment would help. There was a study done many years ago which (as I remember was in JAMA and from the Prostate Cancer Prevention Trial database) found that those who had more rapid increase in their PSA (PSA velocity), even initially if the PSA was “normal”, did just as poorly if they had surgery or not. Lending some further support to this possibility was that for those who did progress in the above study, this happened early (within the first few years) with little apparent increase subsequently. Given the frequency of prostate cancer, it would be very important to have a more refined and accurate risk stratification, so that the nonprogressors do not have the aggressive treatment (with the clear and pretty immediate adverse effects), those with aggressive disease who do not benefit from surgery don’t get it, and a middle group that perhaps does benefit, does get it.

​–though they did look at Gleason grade, this is a little difficult to assess here since there have been subsequent revisions in the grading system which make it hard to compare the old with the new, the newer system attributing higher Gleason scores.

–The study also did not control for potential confounders, though they do note that these would likely decrease any observed benefit from active intervention​

–And, we do not have information about what happened to those on observation who had evidence of cancer spread. did they have surgery? radiation? nothing? did it matter?
–It is a little unnerving that there was such a difference in the histopathology scoring from the local hospitals to the central site (as in prior blogs, there are quite profound differences in radiologic interpretations as in mammograms as well as histopathology in several studies, and these studies are typically done by the foremost academic centers where one might expect more consistency).  Leaves us in primary care in a significant quandry: when do we trust/act on/submit patients to awful further procedures or treatments if there is a real possibility that another radiologist or pathologist would have a totally different read? and how many bad things are missed because of an error in the opposite direction??. for example, see blog  

 

so,

There are a few points here:

— the study adds impressive long-term follow-up that localized prostate cancer does not seem to increase either all-cause mortality or prostate-specific mortality significantly. And one might imagine that some of the 3% who have metastatic progression might have less so with regular PSA monitoring and biopsy vs active surveillance programs

— surgery does decrease the risk of disease progression, either by PSA or by local/regional/systemic progression.  this suggests that followup is important, but that there are still a pretty large group (30+%) in those in the observation group who did fine, and the risk of erectile dysfunction (15%)  and incontinence (17%) requiring treatment was pretty high.  And, the long-term difference in even prostate-cancer specific mortality as well as all-cause mortality (the really important clinical outcomes) was small and not statistically significant

— The study clearly reflected surgery and not other modalities of prostate cancer therapy. However many patients still receive surgery, and it certainly seems appropriate that they be aware of the findings of the study, which seems to reflect a trend to benefit but quite real adverse effects.

— my sense from the literature is that there is more impetus to do PSA screening, after a lull of many years. I certainly do not know the right answer here. My guess is that there is a real subset of patients who have early prostate cancer who do better with surgery, and this is reflected in the fact that all of the subgroup analyses and the overall results do show a trend to better outcomes with surgery. But the fact that these surgical benefits are only a trend in this really long study strongly suggests that a large % of people getting surgery will get no benefit and the exposure to significant risks. so, it is hard for me to recommend screening without a better tool to risk-adjust patients and select those truly at increased risk for prostate cancer or all-cause mortality who might benefit.

Primary Care Corner with Geoffrey Modest MD: PSA screening shenanigans??

2 Dec, 14 | by EBM

By: Dr. Geoffrey Modest

There was an editorial in the NY Times on 11/26/14 written by the pathologist who discovered PSA in 1970 (and writer of a book on it, called “The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster”).  There was also a recent interview of him by Eric Topol.

Untitled

 

His basic comments:

–In reviewing the European Randomized Study of Screening for Prostate Cancer (ERSPC), and the Swedish Goteberg study (which was the basis for the European one) and had a 44% reduction in prostate cancer deaths, they refused to allow outside investigators to review the data. The 11-year followup reported in NEJM from the whole  ERSPC was 29% reduction in those adherent to the study (see DOI: N Engl J Med 2012; 366:981-990)

–There were inherent concerns about about the methadology, including transferring 60% of the data from Goteberg to the ERSPC, strongly tipping the balance of the 7-country study by this one country which showed such a dramatic positive result.

–There were significant conflicts of interest in the investigators, being involved in companies that market PSA tests or related technologies.

So, just muddies the water a bit more (and who would have thought they could be muddier). The US study, also reported in NEJM (see DOI: N Engl J Med 2009; 360:1310-1319), did not find benefit from screening, though had its own issues (much contamination of the groups). Ablin might also have his own issues: he discovered the PSA test, targeted it for use as a marker to follow known prostate cancer and not a screening test, may be promoting his book, etc. But it is certainly concerning if the most positive study (ERSPC) is potentially biased by a single Swedish study, and they will not release their data for review…..

Primary Care Corner with Geoffrey Modest MD: Low-risk prostate cancer and specialist recommendations

8 Sep, 14 | by EBM

interesting study of perceptions and suggestions of US radiation oncologists and urologists on the effectiveness of active surveillance for patients with prostate cancer (see Med Care 2014;52: 579–585). baseline is that there are general concerns that prostate cancer is greatly overtreated, and that active surveillance (AS) is appropriate (and in fact recommended) for low-risk prostate cancer (clinically localized disease, PSA in 4-10 range, Gleason 6 or less). results:

–national survey of radiation oncologists and urologists about perceptions of AS, done from nov 2011 to april 2012, with 717 completing survey

–71.9% thought AS effective and 80% thought it was underused

–BUT for a case patient of a 60yoM  diagnosed with low-risk prostate cancer, these specialists recommended radical prostatectomy in 44.9%, brachytherapy in 35.4% and AS only in 22.1%. though specialists in academic med centers more likely to recommend AS, with OR 2.35.

–and, lest anyone is surprised, urologists vs radiation oncologists were more likely to recommend surgery (OR of 4.19) and less likely to recommend radiation treatment (OR 0.13 for brachytherapy and OR 0.11 for external beam radiation)

so, 230K patients are diagnosed each year with prostate cancer. and estimated 100K with clinically-localized disease, qualifying for AS. clinical guidelines do recommend AS with close disease monitoring by frequent PSA tests, digital rectal exams and  biopsies; but most patients are treated with XRT or surgery and only 10% get AS. clearly, a key barrier to AS is that the specialists involved in the care of these patients (radiation oncologists, urologists) are in fact more aggressive than the recommendations (and, indeed, more aggressive than what they even said — that up to 80% thought AS was underused). given their inherent conflicts-of-interest, seems to me that primary care providers (and general oncologists) should be stronger advocates for patients with low-risk prostate cancer.

geoff

 

Primary Care Corner with Geoffrey Modest MD: Radical prostatectomy for prostate cancer

28 Mar, 14 | by EBM

the Scandinavian prostate cancer group study published their 18 year followup of radical prostatectomy vs watchful waiting in men with localized prostate cancer (study prior to PSA testing, and was largely of men with palpable nodules). see DOI: 10.1056/NEJMoa1311593. this follows their 15 year followup published a couple of years ago. in brief,
–695 men with early prostate cancer randomized to surgery vs watchful waiting, followed up to 23.2 years, though overall analysis at 18 year mark: 
63 deaths from prostate cancer in surgery group and 99 in watchful waiting (18% vs 29%, RR 0.56), absolute diff of 11% and NNT to prevent one death = 8
–200 deaths from all causes in the surgery group and 247 in the watchful waiting group (56.1% vs 68.9%, RR 0.71, abs diff 12.8%)
–androgen-deprivation therapy in fewer pts in surgery group vs watchful waiting, (42.5 vs 67.4%, abs diff 25%)
–benefit of surgery largest in men younger than 65 and those with intermediate-risk prostate cancer (eg gleason score <8), though also reduced risk of metastases in older men.
–both death from any cause and death from prostate cancer were significantly lower in those <65yo (RR 0.50, abs risk reduction ARR 25.5% for death from any cause; and RR 0.45, ARR 15.8% for prostate ca deaths. both NS for those >=65yo).  distant mets with RR 0.49 and ARR 15.8% in <65yo and RR 0.75 and ARR 6.6% if >=65yo.
–no evidence that effect diminished over time
so, my general assessment of this update is not really different from the last one. will append my blog from 7/26/2012 below on the PIVOT study with comments on Scandanavian one. of course, one major concern with the scandanavian study is that about 90% of the men were randomized after prostate cancer detected on rectal exam (which has worse prognosis than picking up with PSA), so current applicability a bit murky).
geoff

Primary Care Corner with Geoffrey Modest MD: Selenium and vitamin E may increase risk of prostate cancer

28 Feb, 14 | by EBM

New study in JNCI attempted to sort out diverse findings on prostate cancer development in men supplemented with selenium or vitamin D or both. (see DOI:10.1093/jnci/djt456). Previous data has shown:

–From the selenium and vitamin E cancer prevention trial (SELECT) in 2001, a prospective study of 35,533 men randomized to one of 4 groups (selenium 200 mcg/d plus vitamin E 400 IU/d, vitamin E plus placebo, selenium plus placebo, or just placebo), there was no benefit from these interventions, and a significantly increased risk of prostate cancer by 17% with vitamin E supplementation alone
–The nutritional prevention of cancer trial (NPC), a study of 928 men who lived in an area of the US with low soil selenium levels, found that men with moderate or low selenium levels and given supplementation with selenium had a decrease in prostate cancer risk by 75%.  This was not found in men who had high plasma selenium levels at baseline.

this current study was a cohort study comparing 1739 men with prostate cancer (489 with Gleason 7-10) from the SELECT trial with a randomly selected subcohort of 3117 men, also a from the SELECT trial.  They assessed whether selenium and vitamin E supplementation effect on prostate cancer was conditional on baseline selenium status.  Findings:

–Toenail selenium levels at baseline was not associated with prostate cancer risk
–Supplementation with selenium only or selenium plus vitamin E had no effect on prostate cancer in men with low baseline selenium levels in their toenails, but found a 91%  increased risk of high grade prostate cancer in men with a higher baseline selenium status.
–Vitamin E supplementation alone had no effect among men with high selenium status at baseline, the but had an increased risk of prostate cancer by 63% (total, low-grade, and high-grade) in men with lower selenium baseline status.
–When these investigators assessed the data using the cutpoints of the NPC trial above for baseline selenium concentrations, they could not reproduce any positive effect of supplementation. (though note that the NPC study was much smaller than the SELECT one).
–a couple of caveats to the current study: Toenail selenium concentrations are  not a perfect measure of actual selenium absorption and metabolism, and does not measure the functional activity of selenium-dependent proteins in prostate and other tissues.  Also there were very few black patients involved in the SELECT trial.

So, bottom-line, supplementation with selenium and vitamin E did not help, and in certain groups (e.g. selenium supplementation in those with high baseline selenium levels, and vitamin E supplementation alone in those with low selenium levels) was associated with increased prostate cancer risk.  We do know from many different studies that good nutrition is associated with lower levels of heart disease and cancer.  However, we repeatedly find in the studies that micronutrient supplementation often does not reproduce these results, and in some cases (e.g. beta-carotene and lung cancer in smokers) is harmful.  The issue here, as I pointed out in many prior blogs about micro-nutritional supplementation, is that there is likely an important interplay between the different nutritional components to foods as well as a balance of the amounts of each one, and there is been a long evolutionary history of humans consuming an array of appropriate vegetables, for example, which provide the appropriate mix.  The reductionist approach of trying to isolate specific micronutrients as a magic bullet to prevent disease and then supplementing with a supraphysiologic dose is therefore both conceptually problematic and typically clinically unsuccessful (with the possible exception to vitamin D, which is not largely nutritionally-derived, and deficiency may well create problems in those in untoward northern climates).

geoff

 

Primary Care Corner with Geoffrey Modest MD: Aspirin use and prostate cancer

21 Feb, 14 | by EBM

I had posted a couple of articles in the lancet suggesting that aspirin protected against incident cancer and cancer mortality, including in those with metastatic disease. New observational study of 6000 men with prostate cancer (localized adeno, rxd with radical prostatectomy or xrt) and followed 70 months found that, irrespective of the prostate ca therapy, those who happened to be taking aspirin had much lower prostate-specific mortality (3% vs 8%), with dec in both disease recurrence and bony mets. The decrease was particularly impressive in those with “high-risk” disease, wtih prostate-specific mortality 4% vs 19%. Although they looked at all anticoag therapies, the effect was primarily seen with aspirin.  See doi: 10.1200/JCO.2011.41.0308.  So, observational study, but adds to the lancet studies, and prior studies that aspirin/nsaids help prevent colon cancer.

Geoff

Primary care corner with Dr Geoffrey Modest: Prostate screening conundrum continues

25 Nov, 13 | by EBM

There have been a couple of articles of note on prostate cancer and screening.

 

One was in this week’s New England Journal of Medicine (see DOI: 10.1056/NEJMsa1201141). The impetus for the study was to determine if urologists purchasing their own office-based, expensive intensity-modulated radiation therapy (IMRT) equipment were more likely to use this form of radiation therapy vs urologists who do not own the equipment.  The researcher looked at Medicare claims from 2005 through 2010 in 2 samples: 1 was in private practice groups with 35 urologists self-referring for IMRT who started using this equipment during this time period versus 35 groups not owning this therapy; the other study was of a group of 11 non-self-referring urologists at National Comprehensive Cancer Network centers compared to 11 self-referring urology groups in private practice.  The intention of the second study was to compare urologists who were likely to practice on the basis of clinical evidence and unlikely to derive personal financial benefits from the services, versus 11 matched self-referring private urology practices in close proximity to the centers.  Findings:

–for the 35 private practice urology groups, the rate of IMRT use by self-referring urologists increased from 13.1 to 32.3%.

–for 35 non-self-referring urology groups during the same time period, the rate of a IMRT use increased only from 14.3 at 15.6%.

–For those urologists working at National Comprehensive Cancer Network centers, the use of IMRT remained stable at 8% but increased to 33% in the 11 matched nearby self-referring urology groups.

–The mean cost estimate of her IMRTwas $31,574, approximately twice that of a radical prostatectomy or brachytherap

Not surprising.  Similar findings have been found for using advanced imaging techniques, clinical laboratory testing, and pathology services by self-referring physicians.  There is also an increased use of surgery in physician-owners of specialty hospitals. Although the feds prohibit much self-referral, there are notable exceptions, including for radiation therapy.

 

The second article which came out several months ago was an update of the American Urologic Association guidelines for early detection of prostate cancer (see: http://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm). There were several changes in these guidelines over prior ones.  They still focus on PSA screening, given that there is little evidence supporting the clinical efficacy of DRE, PSA derivatives (eg free PSA, PSA velocity, etc), or novel biomarkers such as PCA3.  They do acknowledge several harms from screening, including that more than 75% of people with a PSA greater than 3 have no cancer on biopsy, the cumulative risk of having at least one false positive test after 4 rounds of annual testing was around 13%, and over-diagnosis of prostate cancer was on the order of 66% (approximately 1/3 of the screen-detected cases).  Their general recommendations are as follows:

–Not screen men under age 40

–Not do routine screening in men between 40 and 54 years of age at average risk. They recommend individualized decisions on prostate cancer screening in these younger men at higher risk (e.g. positive family history, or African-American men)

–For men aged 55-69, “the panel recognizes that the decision to undergo PSA screening involves weighing the benefits of preventing prostate cancer mortality in one man for every one thousand men screened over a decade against the known potential harms associated with screening and treatment.  For this reason, the panel strongly recommends shared decision-making for men aged 55-69 years that are considering PSA screening, and proceeding based on a man’s values and preferences.”

–The screening interval of 2 years or more may be preferred over annual screening to reduce the harms of screening, preserving the majority of benefits and reducing over-diagnosis and false positives.

–Not screening men over 70 or men with a less than a 10-15 year life expectancy.

so, these new guidelines definitely reflect a softening of their position on screening. still clearly supports screening with the caveat that there should be shared decision-making.  pretty hard to do that when we, as trained medical providers able to decipher the intricacies of the different studies and their methodologies, are pretty clueless as to what to do.  I will also follow this post with a prior discussion–see below.

geoff

From March 2013:

in one of my precepting sessions, the question came up about the utility of finasteride as well as the predictive accuracy of PSA screening.  finasteride does do well in decreasing prostate volume, though it takes months to work. but i wanted to circulate 2 important articles (both from the prostate cancer prevention trial), which i think sheds light on these issues.

1. prostate cancer prevention trial — 7 year study of 19K men >55yo, with PSA <3 and nl DRE, randomized to finasteride 5mg/d vs placebo. rationale of study is high prevalence of prostate cancer in men (17% lifetime risk). found that prostate cancer was reduced by the prophylactic administration of finasteride by 25% (24% in the placebo group, and 18% with finasteride). BUT, higher incidence of high-grade prostate cancer (Gleason scores 7-10) in the finasteride group (6.4%) vs the placebo group (5.1%).  also sexual side-effects of finasteride. but, bottom line, concern that there may be more high-grade, potentially lethal prostate cancers with finasteride.

2. prostate cancer in those with low PSAs — this looked at the placebo group at the end of the above 7 year study, where they did a prostate bx in 3K men in the placebo group who never had PSA>4 or abnl DRE. rather striking findings as follows:

-15.2% had prostate cancer, breakdown as follows:

-psa <0.5, 6.6% with prostate cancer (!!!)

-psa 0.6-1, 10%

-psa 1.1-2, 17%

-psa 2.1-3, 24%

-psa 3.1-4, 27%

-of those who had prostate cancer, 15% of them had high grade cancers (Gleason 7-10), breakdown as follows:

-psa <0.5, 12.5% of those in that psa group with cancer had high grade lesions

-psa 3.1-4, 25% with high grade lesions.

bottom line, increasing psa is associated with more cancers and high-grade cancers, BUT psa is a pretty miserable test, does very poorly in terms of its sensitivity (and, if you lower the sensitivity to a cutpoint of 3 or 2, the number of biopsies done in the population increases dramatically and you still seem to miss a fair number of even high grade cancers).

hope this is helpful.

geoff

Primary care corner with Geoffrey Modest: finasteride doesnt worsen prostate CA survival

27 Aug, 13 | by EBM

recent publication looked at the longterm effects of finasteride (see N Engl J Med 2013;369:603-10, DOI: 10.1056/NEJMoa1215932).  the 15-year survival rates were no different between groups (78.0% with finasteride and 78.2% with placebo).  the 10-yr survival rates for men with low-grade prostate cancer was 83% with finasteride and 80.9% with placebo; for high-grade prostate cancer: 73.0% vs 73.6%

so, pretty clear that not so useful to try to prevent prostate cancer with finasteride (to me, would have been surprising to be beneficial, since the high grade tumors are more dysplastic and less likely to respond to normal endocrine stimulation which is blocked by finasteride). but, at least this study shows that finasteride is pretty benign (i have been hesitant to use it for BPH because of the initial findings, but will use more now if indicated clinically).   

geoff

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