Was there Selection Bias in the PIVOT trial?

[pjoshea13]

"Findings question validity of large PCa trial"

"Cheryl Guttman Krader

"Feb 14, 2019

"San Francisco—According to the updated report from the Prostate Cancer Intervention versus Observation Trial (PIVOT), radical prostatectomy had no significant benefit over observation for reducing mortality among men with clinically localized disease.

"The appropriateness of applying those findings to patients seen in daily practice is questionable, however, considering information from an analysis assessing the external validity of PIVOT, said Firas Abdollah, MD, at the 2018 AUA annual meeting in San Francisco.

"To evaluate the generalizability of the PIVOT results, Dr. Abdollah and colleagues compared the characteristics of its patient population with those of prostate cancer patients within three nationwide databases—the Surveillance, Epidemiology, and End-Results (SEER) population-based registry, the National Cancer Database (NCDB) hospital based-registry, and the Prostate, Lung, Colorectal and Ovarian (PLCO) trial.

"Relative to all three external populations, men in PIVOT were older and had more comorbidities, the authors found. The differences between cohorts in age and general health might explain why the all-cause mortality rate was also much higher in PIVOT compared with the other prostate cancer patient populations, said Dr. Abdollah, fellow in uro-oncology and robotic surgery, Henry Ford Health System, Detroit.

“Our findings point to a sampling bias in PIVOT and indicate that the men who enrolled in PIVOT are not representative of those we are seeing in clinical practice. Clinically localized prostate cancer has a protracted course, and perhaps the older, sicker men in PIVOT did not have a long enough life expectancy to benefit from treatment,” added Dr. Abdollah, working with Mani Menon, MD, and colleagues.

"Men from the external databases were included for the comparisons if they had characteristics matching those used for the PIVOT inclusion criteria: age ≤75 years, T1-T2NxM0 prostate cancer, PSA <50 ng/mL, and life expectancy ≥10 years.

"PIVOT included 731 men enrolled between 1994 and 2002. The comparator groups were comprised of 2,847 men enrolled in the PLCO trial between 1993 and 2001, 60,089 men entered into SEER between 2000 and 2004, and 63,303 men registered in the NCDB between 2004 and 2005.

“The databases that we used capture a wide variety of clinical settings and are very representative of men seen in clinical practice,” Dr. Abdollah told Urology Times.

"The mean age at diagnosis was 67 years for men in PIVOT, which was older than for the SEER, NCDB, and PLCO cohorts (61.3, 60.2, and 65.8 years, respectively), and the between-group difference was statistically significant comparing PIVOT with the SEER and NCDB populations. Charlson comorbidity index (CCI) was not reported in SEER, but the proportion of men with no comorbidities (CCI of 0) was significantly smaller in PIVOT than in the NCDB and PLCO databases (56% vs. 96.4% and 94%, respectively).

"The overall mortality rates in the PIVOT, SEER, NCDB, and PLCO cohorts were 64%, 23%, 9%, and 8.1%, respectively. Dr. Abdollah noted that the median follow-up in PIVOT, which was 12.7 years, is similar to that for the SEER database (12.3 years), whereas the median follow-up for men in the PLCO trial and NCDB was only 7.5 and 9 years, respectively.

“The shorter follow-up for the latter two cohorts could only partly explain their lower overall mortality rates,” said Dr. Abdollah.

“Interestingly, the overall mortality rate for a subgroup of men from SEER that we excluded from our comparative analysis because they had not been given a recommendation for surgery was 50%. Presumably, these individuals were not recommended definitive treatment because of pre-existing conditions, and yet their mortality rate was still lower than that reported in PIVOT.”

urologytimes.com/prostate-c...

-Patrick

[cujoe]

Thanks & Keep 'em coming, Patrick

[FCoffey]

Even if the bias is real, the difference in outcomes is so small that it reaches statistical significance only in a large trial, and only if a weight of zero is assigned to quality of life.

[NPfisherman]

Thanks for posting Patrick... PIVOT was 1994-2002 for data... I believe that it was biased on review of the information...

The fact that this info was during this period prior to gold nanoparticles, TOOKAD, HIFU, etc... says it is meaningless in today's newer options...

Here is what Dr Evan Yu said in an article on OncLive

"However], trials are ongoing, and some of them are also looking at eradicating the primary lesion of the prostate. Theoretically, there's a rationale for this, because the primary will shed lesions—micrometastases—that will set down and create more metastases. Ablating those [metastases] at a lower-volume disease state might be ideal. With that being said, there are studies reading out [that are evaluating] ablation of the primary prostate lesion of a patient with metastatic disease."

I agree with Nalakrats.... Remove the Mother Ship.... using your option of choice...RP, TOOKAD, HIFU, etc... like Dr Yu says...ablating micrometastases at lower volume disease just makes sense...

All the best

Fish

[Hidden in reply to NPfisherman]

Good to hear a doctor expressing this opinion.

[NPfisherman in reply to Hidden]

Indeed...even with older men with medical issues, there are new options available that are just less risky for those patients...

Dr Evan Yu is a young gun...hope all of them are thinking this way...

George71 posted a reply with results on TOOKAD vs Active Surveillance in another post, which showed clear benefits of treatment with TOOKAD... My philosophy on AS is waiting for the beast to raise its ugly head is nonsense--bludgeon the beast... These newer options like HIFU, TOOKAD, nanoparticles, etc are just better options for older men that are higher surgical risk...it just puts more time on the clock with potential/ possible cure as a dividend...

Have a good day,

Fish

[tallguy2 in reply to NPfisherman]

If I were attending this fall's NYC Prostate Cancer Conference the question I would ask is: what is medicine doing to help men like some of us INTERCEPT this beast before it leaves the prostate gland? Today's SOP of waiting until the PSA hits 4.0 and then doing a biopsy was too late for many of us.

And then, if we have sufficient clinical trials, we can also learn whether or not interception of, say, Gleason 9 disease well before PSA=4.0 has any long-term outcome benefits. There is MUCH more research to be done.

[NPfisherman in reply to tallguy2]

Agreed...a better blood/saliva/or urine test to pick it up when it starts and hit it earlier with HIFU, TOOKAD, radiation, pick your weapon...would cut the number of men on this hell ship by an incredible amount... More is being done but more needs to be done...

Fish

[Sxrxrnr1]

2014 report

nejm.org/doi/full/10.1056/N...

2018 report

2minutemedicine.com/radical...

Late 2018 report

nejm.org/doi/full/10.1056/N...

Bottom line

* Similar finding to Pivot finding, just as mass PSA scanning was between European and American studies.

* Treatment of some value to younger men, very sketchy evidence to treat for older men at diagnoses. Some value under 65 years of age at diagnoses, very limited at over 65, mainly due to co-morbities more common in older men.

* Less than 3 years of overall life expectancy achieved at 25 plus years.

* Extremely limited value to treatment for low G scores.

* Major differences in QOL life in treating verses not treating.

I have followed this study closely(and later Pivot study) since my diagnoses at 65 years of age 13 plus years ago. Had a major influence on my decision how I myself chose to respond to it.