There is more to it than words...

We can argue about PSA testing until the cows come home. It is easy to say that GS6 is harmless but as it stands in today's world we need more than words…

In a recent issue of the Journal of Urology there is an article by Swedish researchers who investigated low-risk prostate cancer among men diagnosed with PCa in the recent past (2007 – 2011).

In those 5 years some 45,532 men in Sweden were diagnosed with various stages of prostate cancer. Of those, 17,437 (38.3%) were diagnosed with GS6. The objective of the researchers (Stattin P et al) was to clearly identify those low-risk PCa men that qualified for active surveillance (AS). Because of certain limitations, only 13,159 (28.9%) of the GS6 patients met the AS guidelines and of those low-risk patients, 4,500 chose radical prostatectomy. These surgically treated men were younger (median age 62) and had smaller prostate glands (median volume 35 ml) and a median PSA of 6.1 ng/ml.

“Results
Among Swedish men with clinically localized Gleason 6 prostate cancer approximately 50% had adverse pathology at radical prostatectomy. Of the men who met the study inclusion criteria of 6 different active surveillance protocols, adverse pathology was present in 33% to 45%. Predictors of adverse pathology were older age, higher prostate specific antigen, prostate specific antigen density greater than 0.15 ng/ml/cm3, palpable disease and extent of cancer greater than 4 mm on biopsy. Larger prostate volume had an inverse relationship with adverse pathology.”

As you can see these results are important for men here who contemplate doing AS. These results could affect all low-risk men treated with forms of treatment other than surgery too.

In reviewing this article:
1. The number of low-risk cancer patients diagnosed is clearly related to the use of PSA in a population.
2. In Sweden the use of PSA testing is not as high as it is in the USA
3. With reduced PSA testing there is more advanced disease at diagnosis. This is not a good thing.
4. This is one of the reasons Sweden has one of the highest prostate cancer mortality in the World.

AS should be the main strategy to avoid over treatment. Until better diagnostics are available men need to be careful in avoiding treatment while avoiding progression. To promote AS without more accurate information simply because GS6 will never or hardly ever progress is a disservice to uninformed patients. The fact that the results of this Swedish study show more advanced disease at diagnosis is an indication that in the absence or reduced PSA testing PCa can progress to more lethal forms of the disease. This should be well understood by all men as they age…

RalphV

Source:
Stattin P et al.
Population Based Study of Predictors of Adverse Pathology among Candidates for Active Surveillance with Gleason 6 Prostate Cancer. The Journal of Urology
Volume 191, Issue 2 , Pages 350-357, February 2014

Well said. This simply means that anyone with PCa needs to be vigilant and take action at any sign of progression.
Bob

Ralph,

How did the study define "adverse pathology"?

Thanks, Ralf, good to hear from you again.

David

Hello Ralph,

Good to hear from you again.

I'm not sure the stuff you quoted answered RCS's question. Those factors all "predict" adverse pathology but they don't tell us what it is. If you are older, or have a higher PSAD, or more positive cores that seems to mean you are more at risk of "adverse pathology" whatever that is...

PeterDisAbelard. said...
Hello Ralph,

Good to hear from you again.

I'm not sure the stuff you quoted answered RCS's question. Those factors all "predict" adverse pathology but they don't tell us what it is. If you are older, or have a higher PSAD, or more positive cores that seems to mean you are more at risk of "adverse pathology" whatever that is...

The cited study tried to predict these adverse pathologies for men BEFORE surgery. These men all qualified for AS protocols before surgery but the surgical pathology was different from the diagnostic one.
"Materials and Methods
From 2007 to 2011, 13,159 men were diagnosed with Gleason 6, clinical stage T1c/T2 prostate cancer in the NPCR (National Prostate Cancer Register of Sweden). Of these men 4,500 underwent radical prostatectomy, including 2,205 with data on the extent of prostate cancer in the biopsy cores. Logistic regression was used to examine variables associated with adverse pathology (defined as upgrading to Gleason 7 or greater, or up staging to pT3 or greater) in the full group and in potential candidates for active surveillance using 6 current published protocols."

In simpler words, the diagnostic biopsy used to decide for AS was not accurate in49% of the men treated with surgery. This is the uncertainty that exists today at diagnosis. That is why men need to understand the limitations of the current diagnostic tools and seek as much information about the true extent of their disease rather than accept that their GS 6 is representative of their prostate condition. Add to that GS6 at 50 years of age can be different than GS6 at an older age. Age has to be considered in making an AS decision. Current AS protocols do not limit age for inclusion but include life expectancy as a limit.

RalphV

That was not in the conclusion Ralph please help me where it says 49%?

"Conclusions
More than a third of men meeting the most stringent active surveillance criteria had adverse pathology at radical prostatectomy in this population based cohort. Active surveillance programs should consider prostate specific antigen density and extent of cancer on biopsy for patient selection.
Key Words: prostatic neoplasms, watchful waiting, pathology, prognosis, neoplasm grading
Abbreviations and Acronyms: AS, active surveillance, GS, Gleason score, PCa, prostate cancer, PSA, prostate specific antigen, PSAD,PSA density, RP, radical prostatectomy
 
Many studies have demonstrated the frequent disparity between Gleason scores reported on prostate biopsy and at radical prostatectomy. In a recent review Epstein et al reported that about a third of cases with a biopsy Gleason score of 5-6 were upgraded at RP.1
This issue is particularly germane to men with presumed low risk prostate cancer considering active surveillance, for whom accurate pretreatment risk stratification is paramount. As reviewed by Dall'Era et al, in most AS programs candidates are chosen based on GS, clinical stage and PSA based parameters.2 Depending on the particular inclusion criteria 4% to 82% of men were eligible for AS, and conversion to active treatment was reported in 11% to 33% of men on AS, with changes in tumor histology as the most common reason for discontinuing AS.2
A recent consensus conference concluded that AS is underused.3 However, the limitations of current clinical staging and disparities in selection criteria among current protocols are important in evaluating obstacles for expanding the use of AS.
In this study we examined trends and predictors of upgrading/up staging in men with low risk prostate cancer who are potential candidates for AS from a large population based Swedish cohort. We hypothesized that upgrading and up staging remain common, but that additional predictors beyond PSA, clinical stage and GS could improve risk classification. These results are clinically important to lend insight into which factors are most essential to consider in the selection of men for AS and subsequent monitoring which is currently not standardized across institutions."
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This is consistent with JHU.There is no follow up because this is not a level 1 study. It is a retrospective view that recommends that more biomarkers be used for men selected for AS.

And I concur

Thank you for replying Ralph,

Per the NCI on the study I posted the NCI is critical of the Stattin paper as noted:

jnci.oxfordjournals.org/content/102/13/950.full

From JNCI:

CONTEXT AND CAVEATS

Prior knowledge
Treatment of localized prostate cancer is controversial.

Study design
Retrospective study in a nationwide cohort of patients with localized prostate cancer who were 70 years or younger. These patients received surveillance (including active surveillance and watchful waiting) or treatment with curative intent (including radical prostatectomy and radiation therapy). A subgroup of patients with low-risk prostate cancer was also studied. The cumulative incidence of death from prostate cancer and competing causes was calculated.

Contribution
For the combination of low- and intermediate-risk prostate cancers, calculated cumulative 10-year prostate cancer–specific mortality was 3.6% in the surveillance group and 2.7% in the curative intent group. For those with low-risk disease, the corresponding values were 2.4% in the surveillance group and 0.7% in the curative intent group. The 10-year risk of dying from competing causes was 19.2% in the surveillance group and 10.2% in the curative intent group.

Implications
The low 10-year prostate cancer–specific mortality observed among patients with low-risk prostate cancer in the surveillance group indicates that surveillance may be a suitable treatment option for many patients with low-risk disease.

Limitations
The observational design resulted in a strong selection bias in which a higher proportion of healthy patients with prostate cancer with adverse factors were assigned to radical prostatectomy than to surveillance. No information was available on tumor extent in core biopsy specimens, serum PSA levels after the date of diagnosis, or progression to metastatic disease. The median follow-up time was limited to 8.2 years.

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To level the point that patients need to be diligent, I agree that men that are selected for AS remember the "A" in AS and they be diligent in their approaches to monitoring their diagnosis with caution that they may need to at some point make a treatment choice.

I believe that the Stattin et al papers are indeed loaded with Urologist bias but even still they note that there are many patients that are eligible for and should be selected for AS as opposed to immediate radical therapy.

There is more to this than words. There is also anti-AS bias.

Ralph,

Thank you for the definition. If I understand the results (correctly) 49% of the Swedish guys who were G6 and chose surgery ended up with a worse case then they thought going into surgery. This is significantly greater than the percentage I had previously heard (15 to 30%). Maybe it's the lingonberries. Thanks.

ralfinaz, you the man. As a 41 yr old G6 with a palpable tumor, I appreciate your eloquent advocacy for those of us who "don't really have cancer." I had never heard the term "adverse pathology" but as they told me at Hopkins, "...you might be G6 but the fact we can feel a nodule makes "it" a little more worrisome." AS is like reading tea leaves, contrary to what it's devotees and shills might argue. Thanks again, ralfinaz.

An Australian study gives a different take on the safety of AS. Even when progression occurs and a patient is treated there was a 100% chance of of no metastasis and a 99% chance of no reoccurrance. So even if the surgical results reflect a worse status, the actual results are similar to those receiving immediate treatment.

A new paper in BJU International reports on data from a total of 650 Australian patients managed on active surveillance for low-risk, localized prostate cancer.
The study data reported by Thompson et al. focuses in particular on whether the use of saturation biopsies or transperineal biopsies affected the oncologic outcomes of their patients as compared with standard transrectal biopsies, but also provide key survival information.
The study is a retrospective analysis of prospectively collected data from two cohorts of patients with low-risk, localized prostate cancer (managed at two different Australian centers). All patients were enrolled between 1998 and 2012, and monitoring biopsies were carried out the patients in one of four possible ways:
Using standard, systematic 6- to 12-core systematic biopsies given either transrectally or transperineally
Using saturation biopsies (i.e. > 12 biopsy cores) given either transrectally or transperineally
Here are the core results reported by the authors:
The median and mean follow-up periods were 55 months and 67 months, respectively.
Rates of survival during the follow-up period were
Prostate cancer-specific survival, 100 percent
Metastasis-free survival, 100%
Biochemical recurrence-free survival after treatment, when treatment became necessary, 99 percent
Radical treatment-free survival at 5 years, 57 percent
Radical treatment-free survival at 10 years, 45 percent
Median time to treatment, when treatment became necessary, 7.5 years.

This study shows that monitoring AS patients is an effective strategy and those that underwent treatment because of progression had 7.5 years without treatment SEs and treatment had a 99% success rate which is much better than the reoccurrance rate for primary surgery on low risk patients. A progression from a G6 to a G7 while on AS does not necessarily mean worse treatment results as is also pointed out in the Hopkin's study that showed delay and immediate treatment had the same results. The key is the monitoring program so patients with progressing cancers can be identified and treated when necessary.

Clock,
The main reason is that men enrolled in an AS program have to meet certain criteria even if they are low risk, such as number of positive cores and % core involvement. So as a group their risk characteristics are more favorable than your normal G6 or low risk patient. Just because you are a G6 it doesn't necessarily mean you should go on AS; you also need other favorable stats that classify one as low risk or very low risk. The volume of cancer present has a significant impact on the reoccurrance rate, so even if you are discovered to have a G7 through monitoring or the tumor is seen to get larger by biopsy or scan it will be caught early enough to give a very favorable outcome. Primary treatment outcome for the range of G6 is about 95%, but that includes G6 with large tumor volume as well as those that already have extra capsular extensions. These are always excluded for any AS programs and referred to immediate treatment. The whole purpose of AS is to catch those progressions early and it seems to do a very good job in that regard.

Tony,
In what do you base your conclusion? Find a post of mine in which I have negated the potential value of AS in preventing overtreatment. Find one here or anywhere else in the past 22 years of advocacy where I have tried to change anyone's preference about they should do for their cancer. Show me where are my dangerous and inappropriate comments.

RalphV