Unilateral Prostate Cancer Cannot be Accurately Predicted in Low-Risk Patients

Volume 77, Issue 3, Pages 784-787 (1 July 2010)  IJROBP 

Hemiablative therapy (HAT) is increasing in popularity for treatment of patients with low-risk prostate cancer (PCa). The validity of this therapeutic modality, which exclusively treats PCa within a single prostate lobe, rests on accurate staging. We tested the accuracy of unilaterally unremarkable biopsy findings in cases of low-risk PCa patients who are potential candidates for HAT.

Methods and Materials

The study population consisted of 243 men with clinical stage ≤T2a, a prostate-specific antigen (PSA) concentration of <10 ng/ml, a biopsy-proven Gleason sum of ≤6, and a maximum of 2 ipsilateral positive biopsy results out of 10 or more cores. All men underwent a radical prostatectomy, and pathology stage was used as the gold standard. Univariable and multivariable logistic regression models were tested for significant predictors of unilateral, organ-confined PCa. These predictors consisted of PSA, %fPSA (defined as the quotient of free [uncomplexed] PSA divided by the total PSA), clinical stage (T2a vs. T1c), gland volume, and number of positive biopsy cores (2 vs. 1).

Results

Despite unilateral stage at biopsy, bilateral or even non-organ-confined PCa was reported in 64% of all patients. In multivariable analyses, no variable could clearly and independently predict the presence of unilateral PCa. This was reflected in an overall accuracy of 58% (95% confidence interval, 50.6–65.8%).

Conclusions

Two-thirds of patients with unilateral low-risk PCa, confirmed by clinical stage and biopsy findings, have bilateral or non-organ-confined PCa at radical prostatectomy. This alarming finding questions the safety and validity of HAT.

With the implementation of prostate-specific antigen (PSA) screening in clinical practice, a substantial proportion of newly diagnosed prostate cancers (PCa) are detected at an early stage. Recent estimates suggest that almost 50% of newly diagnosed cases of PCa in the United States qualify as low-risk patients, according to the D'Amico classification

Recent reports also indicated that approximately 20% of PCa tumors at radical prostatectomy (RP) are confined to a single prostate lobe 3, 4. To decrease patient morbidity, which may be associated with radical treatment, these tumors may be treated with hemiablative therapies (HAT) 5, 6, 7, 8, 9. However, the safety of HAT and the validity of clinical staging have been questioned by different groups of investigators from the United States 10, 11, 12. In those studies, large proportions of men showed contralateral PCa (65% to 72%) despite clinical and biopsy evidence of unilateral disease.

In the current study, we tested the hypothesis that unilateral PCa at prostate biopsy may also frequently be bilateral in a European cohort of men. Moreover, we attempted to identify predictors of pathology-confirmed unilateral disease.

Discussion 

Historically, PCa was invariably considered to be multifocal in nature  However, recent reports suggest that the proportion of unilateral PCa at RP increased from 8% between 1988 and 1995 to 17% between 2001 and 2006. This number may be increasing further, especially in light of lower PSA biopsy thresholds  and serial prostate biopsies. Indeed, the rate of clinically insignificant PCa may be as high as 30% when 12-core-biopsy schemes are used, even in the initial biopsy setting. Based on the established health-related quality-of-life detriments related to whole-gland treatment modalities, such as RP, external radiotherapy, or brachytherapy, some investigators suggest the use of HAT for men with biopsy evidence-proven unilateral low-risk PCa The danger of such an approach may be related to the inability of core biopsies to detect the presence of contralateral PCa. Such limitation has been reported from the United States and could significantly undermine the safety and the validity of HAT.

We addressed this potential limitation of core biopsy in the current study. Specifically, we assessed the rate of bilateral and/or extraprostatic disease at RP in patients with clinically localized, low-risk PCa (defined as a PSA concentration of <10 ng/ml, a clinical stage of ≤T2a, and a biopsy-proven Gleason sum of ≤6), with a maximum of two unilateral biopsy cores from a ≥10-core biopsy. Our findings indicate that despite the absence of PCa in one lobe, the rate of bilateral disease was as high as 57.6% The overall rate of bilateral and/or extraprostatic PCa was 64%. When only one positive biopsy core was considered, the rate of bilateral disease and/or extraprostatic disease was 60%, and when two positive biopsy cores were recorded, this proportion increased to 74%. These proportions of missed contralateral cancers are extremely alarming and clearly question the validity of HAT. Interestingly, some investigators suggest that patients with even more aggressive disease characteristics, such as a biopsy-proven Gleason score of 3 + 4, may also be considered for HAT. These individuals are at an even higher risk of bilateral or extraprostatic cancer. Therefore, the criteria considered in the current report may be interpreted as relatively stringent, especially when only one positive core is considered.

Our univariable and multivariable logistic regression models demonstrate that the accuracy of unilateral PCa prediction using standard clinical parameters is only slightly better than a flip of a coin. Taken together, our findings clearly indicate the inability of current ≥10-core-biopsy regimens to safely exclude the presence of bilateral PCa. Consequently, it may be unsafe to administer HAT, since as many as 60% to 70% of individuals will actually harbor bilateral disease and may be at risk of local or distant recurrence due to untreated active disease.

Ours is the first European report of results indicating the failure of the ≥10-core prostate biopsy scheme to accurately identify men with truly unilateral disease. Moreover, unlike previous reports, our study is the first to assess the accuracy of potential predictors of organ-confined, unilateral PCa. Our findings showed that the combined accuracy of all predictor variables was only 58%.

Our reported rate of bilateral disease in patients with biopsy-proven unilateral disease is in accordance with that of previous reports from the United States, where a similar phenomenon was observed. For example, Scales  examined the records of 261 PCa patients with clinical stage ≤T2a, a PSA level of <10 ng/ml, biopsy evidence of a Gleason score of ≤6, and a maximum of two ipsilateral positive biopsy cores on at least sextant biopsy. The rate of unilateral, organ-confined disease at RP was only 35%, and none of the tested variables (age, ethnicity, PSA, number of positive biopsy cores, clinical stage, and biopsy Gleason sum) independently predicted bilateral disease. Tareen  retrospectively examined data from 590 men with unilateral PCa, according to at least sextant core biopsy, and found the presence of bilateral disease at RP in 72% of the cases. Again, none of the examined variables, including the presence or absence of high-grade prostatic intraepithelial neoplasia, was statistically significantly associated with the presence of unilateral disease.

Our study is not devoid of limitations. Like all other analyses that examined the rate of undetected contralateral PCa, our study is retrospective. Moreover, we had no information about the number and extent of previously negative prostate biopsies. This information may help to better discriminate between patients with overt vs. undiagnosed contralateral PCa. However, due to the elevated rate of contralateral disease (58%), it is unlikely that this knowledge would modify the significance and clinical pertinence of our findings. We also did not have information about the volume and grade of undetected contralateral tumors at RP. This information could help identify individuals with insignificant contralateral PCa, which, during follow-up, may not lead to clinically relevant or detectable relapses. Finally, we had no longitudinal observational data for actual patients who underwent HAT for clinically unilateral PCa to assess the rates of disease relapse, progression, and death.

Despite these limitations, our findings question the validity and safety of HAT, and further studies are required before uncontrolled (outside of clinical trials) use of HAT is adopted into clinical practice.

Conclusions 

Our study indicates that even in patients with low-risk PCa, the prediction of unilateral, organ-confined disease cannot be made with any degree of confidence. Until new disease markers allow better staging stratification, clinicians and patients need to be aware that the absence of PCa in unilateral biopsy cores does not exclude the presence of bilateral disease. This finding should be considered during the informed consent process, when unilateral treatment modalities are considered.