1. Prostate Cancer Screening in the fit Chilean Elderly: a head to head comparison of total serum PSA versus age adjusted PSA versus primary circulating prostate cells (CPCs) to detect prostate cancer at initial biopsy.
Prof. NP Murray (1,2,), Dr. E Reyes (1), Dra. C Fuentealba (1) Dr. N Orellana (1), Dr. O Jacob (1)
(1) Hospital de Carabineros de Chile
(2) Universidad Mayor, Facultad de Medicina, Santiago, Chile.
Introduction: Prostate cancer is the most frequent cancer in the males population, and third cause of male cancer death in Europe. It is predominately a disease of older men with a median age at diagnosis of 68 years and 71% of prostate cancer deaths occur in men over 75 years. Although there is evidence that prostate cancer is more aggressive in the elderly this population is excluded from screening recommendations. This is because it is thought that the harm to benefit ratio of treatment increases with age, the likelihood of over-diagnosis is extremely high and comorbidity is important. However, the elderly can be classified into 4 groups according to their comorbidities, Group 1 comprises healthy men with controlled comorbidities, full independence in daily living activities and good nutritional status, a 75 yr old man in this group has a median life expectancy of 14 years and thus may benefit from prostate cancer screening.
An ideal biomarker would only detect clinically significant prostate cancer and be independent of benign disease. The detection of malignant circulating prostate cells (mCPCs) could be one candidate for the early detection of clinically significant prostate cancer in the healthy elderly.
We compare the use of age related PSA and total serum PSA with the detection of mCPCs to detect clinically significant cancer at initial biopsy.
Patients and Methods: A single center prospective study of patients in a Chilean prostate cancer screening program. All men with a PSA >4.0ng/ml underwent TRUS 12 core prostate biopsy. Age, PSA and biopsy results, defined as positive or negative for prostate cancer were registered. In men with cancer detected, the total Gleason score, number of positive cores and percent infiltrated were recorded. Epstein criteria were used to define small grade tumors.
After written consent, an 8ml venous blood sample was collected in EDTA (Vacutainer®). Mononuclear cells were separated using differential centrifugation and detected using anti-PSA monoclonal antibodies (Novocastro) and identified with immunocytochemistry using an alkaline phosphatase-anti alkaline phosphatase system with neo-fuschin as a chromogen. Positive samples underwent a second process using anti-P504S (DAKO) and identified using a peroxidase system with DAB as a chromogen.
A CPC was defined by ISHAGE criteria (1999) as a nucleated cell staining for PSA. P504S staining was classified according the AAP criteria as 0, 1+, 2+ and 3+, cells staining 2+ or 3+ in a circumferential, apical or granular pattern were classified as P504S positive.
Benign CPC P504S (-) Malignant CPC P504S (+)
A test was considered positive if mCPC was detected.
Ethical considerations: the study was performed in complete concordance with the Declaration of Helsinki. and approved by the Hospital Ethical Committee.
Results: 610 men underwent prostate biopsy, the details are shown in Table 1.
< 70 years
>70 years
Nº Patients
Mean age (SD)
398 (65%)
60 +/- 6.2 yrs
212 (35%)
74 +/- 4.5 yrs
Median PSA ng/ml (IQR)
5.59 ( )
6.24 (
p<0.04
Cancer detected
Criteria active surveillance
(34%)
34/134 (25%)
90 (43%)
22/90 (24%)
p=0.88
154/398 (39%) of men <70 years were mCPC (+), of 16 men mCPC (-) with a positive biopsy 14/16 complied with the criteria of active surveillance. 88/212 of men >70 years were mCPC (+), of 12 men mCPC (-) with a positive biopsy 10/12 (83%) complied with the criteria of active surveillance.
Total serum PSA is the only widely used
biomarker used for prostate cancer screening, although prostate specific it is not cancer specific, 70% of men with an increased PSA defined as >4.0ng/ml do not have prosatate cancer and thus undergo unnecesary biopsy with its risks. In elderly patients the specificity of the test decreases as a result of benign hyperplasia and prostatitis and as such age related serum PSA was proposed.
< 70 years mCPC
>70 years
mCPC
PSA
>6.5ng/ml
Value %
95% CI
Value
Specificity
86.4
91.8
61.0
Sensitivity
88.1
86.7
62.2
PPV
76.6
88.6
54.9
NPV
93.4
90.3
67.9
LR (+)
6.46
10.57
1.60
LR (-)
0.14
0.15
0.62
Comparing a cut-off PSA of >6.5ng/ml versus ng/ml
in men >70 years, there was a lower frequency of cancer detection, 34/108 (32%) versus 56/104 (54%) (p<0.001), as was the detection of clinically significant cancers, 20/34 (59%) versus 48/56 (86%) (p=0.009). In comparison with mCPC detection.
PSA >6.5ng/ml
mCPC
Cancers not detetcted
56/90 (62%)
12/90 (13%)
p<0.001
Clinically significant cancers missed
48/56 (86%)
2/12 (17%)
Biopsies avoided
108/212 (51%)
124/212 (59%)
p=0.03 .
Conclusions: An ideal biomarker is one that detects clinically significant cancer, does not detect indolent cancer and has a high negative predictive value to avoid unnecesary biopsies. The use of sequential mCPC detection appears to fulfill this criteria, men mCPC (-) could be considered as low risk and a biopsy avoided. In contrast a PSA >6.5ng/ml failed to meet these requirements, missing a significant number of clinically important cancers.
The use of sequential mCPC detection in this group of fit elderly men, significantly decreased the number of prostate biopsies without missing clinically significant cancers, it deserves multicenter studies to confirm these results.
This study was supported by a grant from the Hospital de Carabineros de Chile Research Fund..
Acknowledgements: To my wife, Ana María Palazuelos de Murray for her support and help in the redacting of this work.