Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone Sensitive Prostate Cancer Treated With Androgen Deprivation With Or Without Docetaxel.


Abstract

Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database ( ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA ≤ 0.2, > 0.2 to 4, and > 4 ng/dL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA ≤ 0.2 ng/dL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P ≤ .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached ≤ 0.2 ng/dL compared with > 4 ng/dL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA ≤ 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA ≤ 0.2 ng/dL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA ≤ 0.2 ng/dL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA ≤ 0.2 ng/dL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood of a lower PSA and improved survival.

Seminal vesicle carcinoma.


A 56-year-old man presented with a 29 day history of urgency and twice-hourly micturition. Physical examination was shown a cystic mass in the lower left abdomen. Intravenous urography showed right kidney hydronephrosis and hydroureter. CT scan of the pelvis showed a cystic mass behind the bladder, measuring 14·6 × 10·6 × 12·0 cm . Three-dimensional reconstruction of the pelvis showed a seminal vesicle adenocarcinoma (and the extruded and displaced bladder).

semvcyst

Prostate specifc antigen (PSA) before admission was 40·75 ng/mL. On admission, he was clinically stable, with serum PSA concentration of 28 ng/mL. Urine cytology examination measured three times was negative. Our presumptive diagnosis based on imaging results was a seminal vesicle diverticulum. No bladder tumours were found on cystoscopy and our patient had bilateral ureteral intubation and laparoscopic resection of the pelvic mass. Histopathological examination showed seminal vesicle papillary adenocarcinoma. Immunohistochemical staining was positive for CEA and CK7, negative for CA125, PSA and PsAP. Postoperative histologic examination confirmed the diagnosis of primary papillary adenocarcinoma of the seminal vesicle.

Source: Lancet

Urological Group’s Guidelines Recommend Against PSA Screening in Most Men.


The American Urological Association‘s new guidelines recommend prostate cancer screening only in men aged 55 to 69 and based on shared decision-making and the patient’s preferences. The guidelines put AUA‘s position more in line with other medical organizations.

In the 55-to-69 age group, one prostate-cancer death is prevented for every 1000 men screened over a decade. For men who decide to undergo prostate-specific antigen screening, AUA recommends testing every two years or more, rather than annual testing.

The group now recommends against routine PSA screening for men younger than 55 who are at average risk, those older than 69, and those with less than 10 to 15 years of expected life remaining.

The recommendations come less than a year after the U.S. Preventive Services Task Force recommended against routine PSA screening in all men.

Source:American Urological Association guidelines

Focused PSA Screening Strategy, Based on Empirical Data.


Three lifetime prostate-specific antigen tests (age: mid 40s, early 50s, and 60) are sufficient for at least half of men.

 

Swedish investigators have reported that 60-year-old men with blood prostate-specific antigen (PSA) levels 1 µg/L have 0.2% risk for prostate cancer within 25 years (JW Gen Med Oct 7 2010). In this study, the same investigators determined the associations between PSA levels at various ages and subsequent risk for metastatic prostate cancer and prostate cancer–related death.

From 1974 to 1984, 21,000 men (age, 52) provided baseline blood samples; 4900 provided additional samples 6 years later. During a median follow-up of 27 years, prostate cancer was diagnosed in 1369 men: Metastatic disease occurred in 241 men, and 163 prostate cancer–related deaths were recorded. Outcomes were as follows:

  • 15-year risk for metastatic prostate cancer was 0.6% for men in the highest PSA decile at age 40 (1.3 µg/L), 1.6% for men in the highest PSA deciles at ages 45 to 49 (1.6 µg/L), and 5.2% for men in the highest deciles at ages 51 to 55 (2.4 µg/L)
  • For men with PSA levels below the median at ages 45 to 49 (0.68 µg/L) and 51 to 55 (0.85 µg/L), 15-year risks for metastatic prostate cancer were only 0.1% and 0.3%, respectively
  • 44% of prostate cancer–related deaths within 30 years occurred in men in the highest PSA deciles at ages 45 to 49 (1.6 µg/L) and 51 to 55 (2.4 µg/L)

Comment: Based on these results, the authors recommend that screening not begin until age 45 and that men with PSA levels 1.0 µg/L undergo one repeat screening in their 50s and one at age 60 (those with PSA levels 1.0 µg/L at age 60 should not undergo further screening). They also suggest that men with PSA levels >1.0 µg/L at any age undergo more frequent screening and that men in the highest PSA deciles at ages 45 to 55 receive “particular focus,” because they contribute close to half of all deaths from prostate cancer before age 75. Although this strategy could be more efficient than the annual screening often conducted in the U.S., whether screening in this manner would prevent prostate cancer–related mortality is unclear.

 

Source:Journal Watch General Medicine

 

Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study.


Abstract

Objective To determine the association between concentration of prostate specific antigen (PSA) at age 40-55 and subsequent risk of prostate cancer metastasis and mortality in an unscreened population to evaluate when to start screening for prostate cancer and whether rescreening could be risk stratified.

Design Case-control study with 1:3 matching nested within a highly representative population based cohort study.

Setting Malmö Preventive Project, Sweden.

Participants 21 277 Swedish men aged 27-52 (74% of the eligible population) who provided blood at baseline in 1974-84, and 4922 men invited to provide a second sample six years later. Rates of PSA testing remained extremely low during median follow-up of 27 years.

Main outcome measures Metastasis or death from prostate cancer ascertained by review of case notes.

Results Risk of death from prostate cancer was associated with baseline PSA: 44% (95% confidence interval 34% to 53%) of deaths occurred in men with a PSA concentration in the highest 10th of the distribution of concentrations at age 45-49 (≥1.6 µg/L), with a similar proportion for the highest 10th at age 51-55 (≥2.4 µg/L: 44%, 32% to 56%). Although a 25-30 year risk of prostate cancer metastasis could not be ruled out by concentrations below the median at age 45-49 (0.68 µg/L) or 51-55 (0.85 µg/L), the 15 year risk remained low at 0.09% (0.03% to 0.23%) at age 45-49 and 0.28% (0.11% to 0.66%) at age 51-55, suggesting that longer intervals between screening would be appropriate in this group.

Conclusion Measurement of PSA concentration in early midlife can identify a small group of men at increased risk of prostate cancer metastasis several decades later. Careful surveillance is warranted in these men. Given existing data on the risk of death by PSA concentration at age 60, these results suggest that three lifetime PSA tests (mid to late 40s, early 50s, and 60) are probably sufficient for at least half of men.

Discussion

Overview of findings

PSA concentration can be used to predict of long term risk of metastasis or death from prostate cancer. It can identify a small group of men at greatly increased risk compared with a much larger group highly unlikely to develop prostate cancer morbidity if rescreening is delayed for seven or eight years. As PSA screening was extremely rare in this cohort, our findings can be used to design screening programmes by determining the age at which men should start to undergo screening and the interval between screenings. Men at low risk of death from prostate cancer without screening have little to gain from being screened but still risk overdiagnosis and overtreatment; men likely to die from prostate cancer without screening could avoid cancer specific mortality if they choose to be screened.

In an earlier paper, we showed that PSA concentration at age 60 had a strong association with the risk of death from prostate cancer by age 85 (AUC 0.90),7 with extremely low risk (≤0.2%) in men with PSA concentration below the median (≤1.0 µg/L). Taken together with our current data, this suggests a simple algorithm for prostate screening. All men with a reasonable life expectancy could be invited for PSA screening in their mid to late 40s. Men with a PSA concentration <1.0 µg/L would be advised to return for screening in their early 50s and then again at age 60, whereas men with PSA ≥1.0 µg/L would return for more frequent screening, with literature suggesting repeat tests every two or four years.19 The choice of 1.0 µg/L as a tentative threshold might vary according to preference. At age 60, men with PSA at median or lower—that is, ≤1.0 µg/L (or possibly below the highest quarter, ≤2.0 µg/L, depending on preference)—would then be exempted from further screening; men with a higher concentration would continue to undergo screening until around 70.1 Particular focus should be placed on men in the highest 10% of PSA concentrations at age 45-55, who will contribute close to half of all deaths from prostate cancer occurring before the age of 70-75. Some of these men will have concentrations above current thresholds for consideration of biopsy—such as 3 µg/L—and should be referred to a urologist. The remaining men could be told that, although they will probably not die from prostate cancer (with a mean risk of metastasis within 25 years close to 10%), they are at much higher risk than average and that it is especially important that they return for regular, frequent, and possibly more elaborate screening. It is also worth considering whether management of these men should become proactive, with reminder letters and attempts to follow-up non-compliers by telephone. Most importantly, the proposed PSA concentration of 1.0 µg/L to discriminate a low from a higher risk group is not suggested to serve as an indication for biopsy but rather be used to determine the frequency and intensity of subsequent monitoring.

What is known on this topic

  • Prostate specific antigen screening is widely used for the early detection of prostate cancer but remains highly controversial.
  • Focusing on the men at highest risk of prostate cancer metastasis and death could improve the ratio between benefits and harms of screening.
  • It is difficult to justify initiating PSA screening at 40 for men with no other significant risk factor
  • Men with PSA in highest 10th at age 45-49 contribute nearly half of prostate cancer deaths over the next 25-30 years
  • At least half of all men can be identified as being at low risk, and probably need no more than three PSA tests lifetime (mid to late 40s, early 50s, and 60)

What this study adds

Source: BMJ

 

 

 

 

 

 

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium.


Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC).

Methods:

Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m−2 intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (50% PSA reduction confirmed 28 days apart). According to the Simon two-stage design, 3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available.

Results:

In all, 53 patients received 2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m−2 during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity.

Conclusion:

This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.

Source: British journal of oncology

 

 

PSA Screening and Quality of Life.


Using simulation modeling, researchers estimated potential gains in quality-adjusted life-years from prostate-specific antigen screening.

Prostate-specific antigen (PSA) screening involves a tradeoff between potential mortality benefit and harms of overdiagnosis. In the European Randomized Study of Screening for Prostate Cancer (ERSPC), PSA screening lowered prostate cancer–related mortality at 11 years, but many men underwent surgery or radiation therapy for every death averted. Thus, researchers concluded previously that more analysis was needed “before general [screening] recommendations can be made” (JW Gen Med Mar 14 2012). Now, they present results of simulation modeling in which they integrated (1) ERSPC mortality outcomes, (2) probabilities of adverse diagnosis-related and treatment-related complications (e.g., incontinence, impotence), and (3) estimates of decrements in quality of life resulting from these adverse outcomes.

The model predicted that screening 1000 men (age range, 55–69) annually would extend the lives of 9 men for an average of 8 years each, adding about 73 life-years overall. However, when adverse effects on quality of life (experienced by all screened men who undergo biopsy and treatment) were factored into the model, the benefit of screening dropped from 73 nonadjusted life-years gained to 56 quality-adjusted life-years (QALYs) gained per 1000 men.

The authors then varied their estimates of adverse effects. Under the most favorable estimates, screening would add 97 QALYs per 1000 men; under the least favorable estimates, screening would result in 21 QALYs lost (meaning that screening would be harmful, on average).

Comment: This report reminds us that, at the population level, the value of PSA screening depends substantially on how men weigh the downstream benefits and harms of screening. One puzzling aspect of this theoretical analysis is its conclusion that screening would prevent 9 prostate cancer–related deaths per 1000 men; this benefit is ninefold larger than what actually has been demonstrated thus far in the ERSPC (1 death prevented per 1000 men screened, after mean follow-up of 11 years). Because this model assumes annual screening starting at age 55 and lifetime follow-up (whereas the ERSPC screened only every 4 years and started screening at various ages), the model’s larger mortality benefit is plausible. However, the huge difference between the estimated benefit and actual ERSPC results is surprising. The authors indirectly acknowledge this issue in their cautious conclusion: “Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made.”

Source: Journal Watch General Medicine

Radical Prostatectomy Confers No Mortality Benefit in Localized Cancer .


Radical prostatectomy does no better than observation in reducing overall or cancer-related mortality in patients with localized cancers, suggests a New England Journal of Medicine study. Editorialists note that the study was too small to be definitive.

Researchers randomized 731 patients diagnosed through prostate-specific antigen screening to either radical prostatectomy or observation. The primary outcome was all-cause mortality, and the secondary outcome was prostate cancer mortality.

After a median follow-up of 10 years, there was no advantage to prostatectomy over observation for either outcome, except among those with initial PSA values above 10 ng/mL. In these patients, prostatectomy was more advantageous.

Writing in Journal Watch Oncology and Hematology, Robert Dreicer agrees with NEJM‘s editorialists, who lament that the difficulty in recruiting patients led to an underpowered study. Dreicer sees these results as a prompt “to develop the next generation of studies to better identify and aggressively treat patients at risk.”

Source: NEJM

 

 

 

The USPSTF Recommendation on PSA Screening: Our Readers Have Spoken.


Results of an online poll and reader feedback about prostate-specific antigen screening.

After the U.S. Preventive Services Task Force (USPSTF) published its final recommendation opposing prostate-specific antigen (PSA) screening, we conducted an online poll of readers’ reactions. A total of 177 readers responded to the question “Please choose the statement that best fits your reaction to the USPSTF recommendation against PSA screening.”

As shown in the table, 78% of respondents agreed with the USPSTF recommendation, but a substantial proportion still will offer screening selectively. I’m guessing — based on informal discussions with other physicians — that some of these responses reflect concerns about litigation for failure to diagnose cancer.

Many readers shared their perspectives by posting “reader remarks” in response to our recent summary of the USPSTF recommendation (JW Gen Med Jun 7 2012). One reader will continue to screen because she “has probably saved the life” of several men with screening. She might be right: Even skeptics must concede that individual lives occasionally are saved by screening. After all, if enough men undergo prostatectomy, somewhere in the mix are men who eventually would have died of prostate cancer. But, the important question is this: How many people must undergo screening, biopsies, prostatectomies, and radiation therapy to benefit one person? The Task Force concluded that the number needed to screen (NNS) and number needed to treat (NNT) are too high and result in adverse outcomes for too many people, whereas advocates of screening believe otherwise. Nothing is wrong with arguing that a particular NNS or NNT is too high, as long as we remember that selection of “appropriate” cutoffs are value judgments and not scientific truths.

Another reader entitled his remark “Can’t tell who is saved.” He correctly implies that when a man survives (cancer-free) after treatment for PSA-detected cancer, we can’t determine whether his particular life was saved by screening. From the European randomized screening trial (JW Gen Med Mar 14 2012), we can infer that roughly 1 of every 30 patients who received treatment for screening-detected cancer had his life extended, but we don’t know which particular man was “saved” and which 29 underwent treatment unnecessarily.

Several respondents claimed that mismanagement of PSA results and overtreatment of patients with low-risk prostate cancer — and not PSA screening — are the real problems. In my view, both the PSA test and overtreatment are problematic. No screening test has perfect sensitivity and specificity, but PSA test accuracy is especially poor: Fully 25% of men with PSA levels between 2 and 4 ng/mL have prostate cancer (JW Gen Med Jun 8 2004), and many men with PSA levels between 4 and 10 ng/mL don’t have prostate cancer. Sensitivity and specificity can be refined somewhat by using age-specific cutoffs, change in PSA level over time, or other variations; but so far, these other approaches have not been tested rigorously in controlled studies. Management approaches are all over the map because clinicians don’t quite know what to do when PSA levels go up a little: Biopsy now? Repeat in 1 year? Repeat in 6 months? Give antibiotics for “prostatitis,” and repeat in 1 month? And, regarding overtreatment of men with low-risk cancer, thoughtful urologists have told me, “I agree that we overtreat. But if a patient who doesn’t really need surgery says, ‘I want my cancer treated,’ what are we supposed to do? If we don’t do the surgery, he’ll go elsewhere.”

Another reader suggested that PSA screening is most beneficial in men older than 75. However, in the European screening trial, among men 70 or older at the time of randomization, researchers noted a trend toward higher mortality in screened versus nonscreened men. And, in the largest treatment trial (prostatectomy vs. watchful waiting in men with localized cancer; JW Gen Med Sep 16 2008), prostatectomy was associated with lower mortality only in men younger than 65.

One final interesting comment: A physician reader notes that when patients ask him whether he gets PSA tests himself, he replies that he does not, even though “my father and father-in-law had prostate cancer.” In some clinical encounters, it might be appropriate to share one’s personal medical decisions. But, I believe that when patients ask about PSA testing, physicians should explain why they agree or disagree with screening and leave their own healthcare decisions out of the discussion.

Source: Journal Watch General Medicine.