radical prostatectomy for prostate ca -- scandanavian study 18 yrs later

the Scandinavian prostate cancer group study just 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 prostate ca scandan 18 yrs nejm 2014 in dropbox, or 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).

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(From 7/26/12): Lots of press on the new PIVOT study in nejm (see psa PIVOT study watchful waiting nejm 2012 in dropbox), with 1/2 page spread in new york times, etc.  I only wish it were a better study...

 

--Attempt to enroll 2000 pts with clinically localized prostate ca, PSA<50, neg bone scan for mets to be randomized into radical prostatectomy vs observation,  but only able to recruit 731 (trouble getting men to be willing to be randomized).  So, pretty underpowered to start.  And, to make matters worse, 1/5 pts who agreed to participate did not adhere to assigned treatment group (further decreasing the chance to find a significant result).

 

--mean age 67. pickup by prostate cancer by psa screening, with average PSA 7.8. followup 10 yrs. No statistically signif diff in group with radical prostatectomy, with 5.8% dying from prostate ca or its treatment, vs 8.4% in those with observation -- absolute diff 2.9%, 12% RRR.  In prespecified group with psa>10, they did find reduced all-cause mortality with prostatectomy.

 

--21% of pts with surgery had adverse effect within 30 days of surgery (mostly wound infection, UTI, need for further surgery, and at 2 years- urinary incont with surgery 17.1% vs 6.3%, erectile dysfunction in 81% vs 44%, and no diff in bowel dysfunction)

 

So, what is the context here?

 

--prostate cancer is really common (17% lifetime risk in men, though risk of dying from prostate cancer closer to 3%). These numbers confirm that it is an important cause of death in men, but that there is likely both a significant overdiagnosis (most men die of other causes, well-known in many autopsy studies as well) and that it really is essential to determine a way to risk-stratify men to figure out who will benefit from more aggressive therapy

-- Other recent studies of significance:  (see BMJ review psa screening bmj 2010 and others in dropbox). Of note the recent European study (ERSPC) of 160K men, with  20% contamination (ie, men getting not what they were assigned to get) and followed 11 years found a 21% reduced risk of death from prostate cancer -- this was an absolute risk difference of 1.07 deaths per 1000 men, with 1055 men needing to get PSA screening and 37 addl cases of prostate cancer dx'd to prevent one death -- quite a high "overdiagnosis" rate. (see psa screen europ study 11 yrs nejm 2012 in dropbox).  The scandanavian study (see prostate ca scandan 10yrs jnci 2008, and followup prostate ca scandan 15 yr nejm 2011 in dropbox) of men randomized for mostly palpable clinically localized tumors (study mostly done prior to psa screening) randomized to radical prostatectomy vs watchful waiting, that after 15 yrs, the incidence of death from prostate cancer was 14.6 with surgery and 20.7% with observation, a 38% RRR, with NNT to avert one death of 15 overall and only 7 for men younger than 65.

--studies suggest that there is an orderly progression of prostate cancer, from PIN (prostate intraepitheralial neoplasia, the equivalent of CIN for cervical cancer), through increasing PSAs/more aggressive Gleason scores, to cancer. Studies above and others suggest that some men do worse, eg those with rapidly increasing PSAs, those with higher PSAs (such as those with PSA>10 in PIVOT), those with nodules picked up clinically (eg benefit in the Scandanavian study). Interestingly, the PIVOT study did find that the differences in all-cause mortality between the 2 groups decreased over time, “suggesting that longer followup would not alter” their findings (they also found the unexpected findings that “the effect of treatment … did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor” – all of this suggests to me that the study was too underpowered to be useful).There are some biomarkers currently being evaluated which may correlate with risk of more aggressive tumors. 

--one oblique suggestion that prostate cancer screening is successful is that there has been a 44% reduction in prostate-cancer specific mortality between 1993 and 2009, at a time when life expectancy is getting longer (and presumably men with slowly progressing cancer would be more likely to die from their cancer)

--it is really hard to do a good study,esp in the US, given the cancer-phobia, manifested both by the large number of men who want screening in spite of the lack of clear effectiveness and by the inability to recruit men into conservative management strategies (eg, the PIVOT’s study being unable to recruit more than 15% of eligible men into the study). the PLCO study in the NEJM, which found no benefit for screening, had 50% of the men in the control group still getting PSA testing!! This cancer-phobia is augmented by the self-serving promotion of PSA screening by the American Urology Assn, etc (National Prostate Awareness Week, other advertising….)

--so, what is to be done??? No one really knows and one can draw whatever conclusions one is predisposed to from these studies...  One possibility from these studies is to use different markers of more aggressive prostate cancer (those with rapidly increasing PSA, or PSA>10) instead of a cutpoint of 4 or less (the cutpoint of 4 is really pretty arbitrary – the higher the value the more likely to be cancer, as in the PIVOT study. BUT, psa is a pretty bad test in many ways. for example, biopsies done in the control group of the Prostate Cancer Prevention Trial found that of the 2950 men who never had a psa>4, prostate cancer was found in 449 (15%)!, with 32 of the 449 (6.6%) having psa <0.5!! (and of these 32, 4 -- ie, 12.5%-- had high grade cancer with gleason score of 7 or more!!!), and 17% of those with cancer having  psa <1, with 10%!!!! of them having high grade cancer.(see psa low and cancer nejm 2004 in dropbox).  one could also interpret these studies as US prev serv task force does: psa is a bad test, lots of overdiagnosis, lots of men with longterm side-effects from treatment, unevenness of outcomes from the studies that exist -- so, avoid psa testing. we need to figure out a good way to speak with patients, to help them make a decision, though it is difficult since the whole psa testing thing is so murky to us.