Magnetic resonance imaging does not improve the prediction of misclassification of prostate cancer patients eligible for active surveillance when the most stringent selection criteria are based on the saturation biopsy scheme

Authors


Guillaume Ploussard, INSERM U955 Eq07 Department of Urology, CHU Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94000 Créteil, France. e-mail: g.ploussard@voila.fr

Abstract

Study Type – Diagnostic (case series)

Level of Evidence 4

OBJECTIVE

  • • To investigate the role of magnetic resonance imaging (MRI) in selecting patients for active surveillance (AS).

PATIENTS AND METHODS

  • • We identified prostate cancers patients who had undergone a 21-core biopsy scheme and fulfilled the criteria as follows: prostate-specific antigen (PSA) level ≤10 ng/mL, T1–T2a disease, a Gleason score ≤6, <3 positive cores and tumour length per core <3 mm.
  • • We included 96 patients who underwent a radical prostatectomy (RP) and a prostate MRI before surgery.
  • • The main end point of the study was the unfavourable disease features at RP, with or without the use of MRI as AS inclusion criterion.

RESULTS

  • • Mean age and mean PSA were 62.4 years and 6.1 ng/mL, respectively. Prostate cancer was staged pT3 in 17.7% of cases.
  • • The rate of unfavourable disease (pT3–4 and/or Gleason score ≥4 + 3) was 24.0%. A T3 disease on MRI was noted in 28 men (29.2%).
  • • MRI was not a significant predictor of pT3 disease in RP specimens (P = 0.980), rate of unfavourable disease (P = 0.604), positive surgical margins (P = 0.750) or Gleason upgrading (P = 0.314).
  • • In a logistic regression model, no preoperative parameter was an independent predictor of unfavourable disease in the RP specimen.
  • • After a mean follow-up of 29 months, the recurrence-free survival (RFS) was statistically equivalent between men with T3 on MRI and those with T1–T2 disease (P = 0.853).

CONCLUSION

  • • The results of the present study emphasize that, when the selection of patients for AS is based on an extended 21-core biopsy scheme, and uses the most stringent inclusion criteria, MRI does not improve the prediction of high-risk and/or non organ-confined disease in a RP specimen.
Abbreviations
MRI

magnetic resonance imaging

AS

active surveillance

PSA

prostate-specific antigen

RP

radical prostatectomy

RFS

recurrence-free survival

OR

odds ratio

INTRODUCTION

Active surveillance (AS) is a strategy of managing patients expectantly with the intention to treat if signs of progression emerge [1–3]. Nomograms predicting insignificant prostate cancer have been developed, validated and updated [4–7]. However, the problem with prediction of insignificant disease resides in the over diagnosis of available tools. Some men are being classified with indolent disease although they have a truly significant cancer [8–10]. Published AS series have used different criteria largely based on centre experiences with no hard data. The most common clinical data used to define AS criteria are a Gleason score ≤6, PSA level ≤10 ng/mL and clinical stage T1–T2a disease. Recently, a prospective trial of AS has been opened in France and includes patients with a tumour length per core <3 mm in fewer than three cores [11]. Studies comparing entry criteria for AS protocols emphasized the risk of misclassification and the limitations of currently available AS criteria. Recent studies of repeat biopsies in men under AS have emphasized the risk of encountering upgraded and/or upstaged disease on the second pathological assessment [12–14].

The role of biopsy core number has previously been studied in AS series, and demonstrated to be an important factor improving the staging of low-risk prostate cancer patients [15]. The role of prostatic biopsies has changed. The actual importance of prostate biopsies has evolved from purely cancer detection to investigating as to how biopsy results can assist clinical management for patients. The inclusion of patients in AS protocols emphasizes the necessity of perfectly accurate staging strategies. To our knowledge, no series includes MRI as a selection criterion for patient inclusion in AS protocols. To date, a limited number of studies have assessed the yield of MRI in AS patient selection and follow-up. Although MRI has become an increasing imaging tool for characterization of low-volume prostate cancer, this predictive value has not been thoroughly assessed among prostate cancer patients eligible for AS [16,17].

In the present study, we investigated the role of prostate standard T2-weighted MRI in selecting patients for AS, testing the most stringent AS criteria reported in the literature in patients undergoing an extended 21-core biopsy scheme.

PATIENTS AND METHODS

The hospital’s ethics committee approved the study and the good clinical practice criteria were respected.

STUDY POPULATION

Between January 2001 and March 2008, we identified patients who have undergone a set of 21-core biopsies for high PSA velocity (>0.7 ng/mL per year), an abnormal DRE, a PSA level >4 ng/mL and/or a free-to-total PSA ratio <10% at our two institutions. Of all the patients in the database, we identified prostate cancer patients who met the following favourable criteria: PSA level ≤10 ng/mL, T1–T2a disease, a Gleason score ≤6, a life expectancy >10 years (<65 years old in the absence of comorbidities or an oncogeriatrics medical visit for men >65 years old). We only excluded patients who did not fulfil the pathological biopsy criteria as follows: tumour involvement <3 cores and tumour length per core <3 mm. We excluded patients who did not undergo a radical prostatectomy (RP). Thus, we identified 160 men who fulfilled these criteria. We also excluded 64 patients who did not undergo a prostate MRI before surgery. Each MRI examination was performed with at least a 6-week interval after the prostate biopsies. All the remaining 96 patients underwent a laparoscopic extraperitoneal RP.

Finally, the study population included 96 men who fulfilled criteria for AS on biopsies.

MRI studies were performed on a 1.5-T whole body MR scanner using a balloon-design endorectal coil inflated with 80 mL air. Conventional T2-weighted fast-spin echo images were obtained in three orthogonal planes and 3-mm slice thickness. Using established morphological and metabolic criteria for the endorectal MR imaging evaluation of prostate cancer, readers assigned a radiologically determined tumour stage that was based on the American Joint Committee on Cancer staging system. T1 tumours were not apparent on MR images, T2 tumours were visible on MR images but were organ confined, T3 tumours extended outside the capsule or into the seminal vesicles and T4 tumours invaded adjacent structures such as the bladder or rectum. Extracapsular extension was considered present if the tumour abutted the prostate capsule and demonstrated an irregular margin with the adjacent periprostatic tissue or if frank extension of the tumour outside the confines of the prostatic capsule was present. Readers were aware that the patients had biopsy-proved prostate cancer, but were unaware of other clinical and histopathological findings or future clinical management, including patient outcome. A single senior reader with >5 years of experience (M.B.) in endorectal MRI reviewed the MRI studies.

Data from clinical evaluation, biopsy and RP specimens were recorded into a prospective database. The rate of unfavourable disease in RP specimens was defined by a Gleason score ≤8 and/or a pT3 to pT4 stage. Biochemical recurrence was defined by a PSA level >0.2 ng/mL.

STUDY END POINTS

The main end point of the present study was the percentage of men with unfavourable disease features at RP, globally and in the case of MRI use as AS inclusion criterion (organ-confined disease vs non organ-confined disease on MRI). The unfavourable disease was defined by a Gleason score ≥4 + 3 and/or a pT3–4 cancer in the RP specimen. The number of men eligible for AS, the Gleason score upgrading and the biochemical recurrence-free survival (RFS) was also studied as a function of adjunction or not of MRI as an AS selection criterion. Tumours that were classified as stage T1 or T2 by the MR image readers were considered as eligible for AS. Patients with stage T3-4 tumours on MR images were not considered as candidates for AS.

STATISTICS

The qualitative data were tested using a χ2-test or Fisher’s exact test as appropriate, and continuous data were tested using the Student’s t-test. The Mann–Whitney U-test was used in the absence of a normal distribution. Biochemical RFS was calculated using the Kaplan–Meier method and curves were compared using a log-rank test. The limit of statistical significance was defined as P < 0.05. All analyses were performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA) software.

RESULTS

Characteristics of patients’ cohort are listed in Table 1. Mean age and mean PSA level were 62.4 years (range: 51 to 73.2) and 6.1 ng/mL (range: 1.8 to 10.0), respectively. Mean prostate volume was 51.7 g.

Table 1.  Patients’ cohort characteristics
 n = 96
PSA level, ng/mL 
 Mean6.12
 Range1.8–10.0
Age, years 
 Mean62.4
 Range51.0–73.2
 Clinical T2 stage, %12.5%
Prostate volume, g 
 Mean51.7
 Range12.0–192.0
BMI, kg/m2 
 Mean26.3
 Range19.4–44.8

Among the 96 low-risk patients, prostate cancer was staged pT3 in 17.7% of cases (Table 2). The rate of unfavourable disease (pT3–4 and/or Gleason score ≥4 + 3) was 24.0% in the overall cohort. Pathological examination of RP specimens revealed extraprostatic extension and seminal vesicle invasion in 16.7% and 1.0% of cases, respectively. In one case, no cancerous tissue was found in RP specimens (pT0). The 59-year-old patient who turned out to have a pT0 disease had a clinical T1c disease, a PSA level of 8 ng/mL, a prostate volume of 20 mL, a single positive core in prostate biopsy (tumour length 2 mm) and the absence of prostate cancer on MRI findings (iT0). Cancer was staged as pT2a, pT2b and pT2c in 27.1%, 2.1% and 52.1% of cases, respectively. Surgical margins were positive in 13.5% of specimens. Cancers were graded Gleason score 6 in 57.9% of cases, Gleason score 7 in 41.1% and Gleason score 8 in 1.1%.

Table 2.  Pathological findings in RP specimens in the overall cohort (n = 96) and in the restricted cohort of patients with T1–T2 disease on MRI (n = 68)
 Overall cohort (n = 96)T1–T2 disease on MRI (n = 68)P-value
pT3–4 disease17.7%17.6%0.980
Gleason score >642.2%38.8%0.314
Unfavourable disease: pT3 and/or Gleason score≥4 + 324.0%23.5%0.604
Positive surgical margins13.5%14.7%0.750
PSA failure 4.3% 4.9%1.00

Among the 96 patients, T3 disease on MRI was noted in 28 men (29.2%). The remaining 68 prostate cancers were classified as T1 or T2 disease on MRI. No seminal vesicle invasion was detected on MRI.

In the restricted cohort of the 68 men with T1–T2 disease on MRI, pathological findings in RP specimens did not differ significantly from those of the overall cohort. The MRI was not a significant predictor of pT3 disease in RP specimens (P = 0.980), rate of unfavourable disease (P =0.604), positive surgical margins (P = 0.750), Gleason upgrading (P = 0.314), or biochemical recurrence after RP (P = 1.00). Men with suspicious T3 disease on MRI were similar to those with T1–T2 disease concerning age (P = 0.251), prostate volume (P = 0.718) and PSA level (0.629).

Prostate cancer was staged pT3 in 17.6% of cases (Table 2). The rate of unfavourable disease (pT3–4 and/or Gleason score ≥4 + 3) was 23.5% among these 68 patients. Pathological examination of RP specimens revealed extraprostatic extension in 17.6%. No seminal vesicle invasion was found. Thus, incorporating MRI as a selection tool did not improve the prediction of non organ-confined disease or unfavourable disease.

In a logistic regression model, no preoperative parameter was an independent predictor of unfavourable disease in RP specimens (Table 3). The odds ratio (OR) of T3 disease on MRI was 1.11, and did not reach significance (P = 0.844).

Table 3.  Multivariate logistic regression model taking into account preoperative parameters (PSA, age clinical stage, prostate volume and MRI findings) for the prediction of unfavourable disease (pT3–4 and/or Gleason score ≥8) in RP specimens
 P-valueOR
PSA level, ng/mL0.4170.90
Age, years0.4041.04
Clinical stage, T1 vs T2 (%)0.8181.17
Prostate volume, g0.1200.98
MRI findings, T1–T2 vs T30.8441.11

After a mean postoperative follow-up of 29 months (range: 2.3–67.1), PSA failure was reported in 4.3% of patients. The MRI findings did not predict biochemical recurrence (Fig. 1). The RFS was statistically equivalent between men with T3 on MRI and those with T1–T2 disease (log-rank test; P = 0.853).

Figure 1.

Biochemical recurrence-free survival (RFS) curves stratified by the MRI findings: T1–T2 disease vs T3 disease on MRI studies (log-rank test: P = 0.853).

DISCUSSION

AS is an option in treatment decisions for men with suspected low-risk prostate cancer [1–3]. A consensus about the most accurate biopsy strategy remains elusive for men with minimal cancer who are amenable to AS [11,18–21]. The criteria for AS largely vary among different series and centres, with no strong, evidence-based data. Biopsy criteria such as the number of positive cores, tumour length (total or at any core) or percentage of cancer involvement at any core are predictive factors of tumour volume in RP specimens or biochemical failure after RP [6,22,23]. However, using the risk-stratification schemes based only on PSA level, DRE findings, biopsy Gleason score and extent of cancer involvement appears insufficient to identify cancers with a low risk of progression. Therefore, other factors, such as MRI, would provide additional significance [16]. Additional parameters such as PSA-DT <3 years or re-biopsy progression of the Gleason score might be additional factors indicating aggressive low-risk prostate cancer. The aim of such extended diagnostic strategies in the initial management would be to reduce the risk of misclassification and to preclude the need for rebiopsy in men who are eligible for AS.

In the present study, we investigated the role of prostate MRI in selecting patients for AS, testing the most stringent AS criteria reported in the literature. We chose to evaluate the MRI diagnostic yield in a cohort of patient undergoing an extended 21-core biopsy scheme. The pathological biopsy findings and the risk of Gleason score upgrading are clearly related to the biopsy core number [24,25]. We have also previously demonstrated that a 21-core biopsy scheme provided a better pathological assessment for men with low-risk prostate cancer than a 12-core biopsy scheme [15]. Compared with men eligible for AS only in a 12-core scheme, men eligible for AS with the use of a 21-core strategy had cancers with a lower extent of disease on biopsies, regardless of how the AS criteria are defined, and with a lower risk of non-organ-confined disease on the RP specimens. Transperineal mapping biopsy of the prostate might also provide superior staging information compared with standard transrectal biopsy, and improve the prostate cancer patient management [26].

Our present findings supported the hypothesis that standard MRI was not a useful maker to improve the selection for AS when an extended biopsy scheme was used.

Cabrera et al. [27] have previously reported that endorectal MR and MR spectroscopic imaging were not helpful in predicting disease progression in men with low-risk prostate cancer who select AS. These results were in line with our findings even if study criteria were not the same. Moreover, their staging distinguished between inapparent T1 and T2 tumours. The authors also suggested that the distinction between T2 and T3 tumours, as reported in our series, might hold more clinical importance by differentiating organ-confined from extracapsular disease.

The present study has several limitations. First, we evaluated a very stringent cohort of AS patients by studying the strictest AS criteria in patients undergoing an extended 21-core biopsy. Thus, our selection of patients was yet restrictive. Moreover, we examined a relatively small cohort of AS patients, and we cannot exclude the possibility that a larger study would have allowed detection of group differences. It is also noteworthy to emphasize that MRI could be an interesting tool to re-classify as low-risk patients those who were excluded from AS by the strict biopsy criteria. Second, we analysed the impact of MRI only as a dichotomous variables tool. Inapparent T1 or T2 tumours were pooled and compared with T3–T4 tumours, as the aim of the present study was to improve the prediction of pT3 cancers in RP specimens. Others parameters such apparent diffusion coefficient or tumour volume, may be more relevant.

T2-weighted images are the most routine images used in prostate assessment. However, these standard images had a low specificity. The use of routine T2-weighted images may underestimate the yield of MRI in AS selection and in detection of low-risk/low-volume prostate cancer, although the radiologists were highly experienced in detecting and staging prostate cancer with high accuracy. Others MRI parameters may have greater prognostic importance than standard T2-weighted sequences. The diagnostic performance of MRI in prostate cancer detection has been demonstrated to be improved by the addition of an apparent diffusion coefficient map to T2-weighted imaging [28]. The diffusion-weighted MRI has been shown to discriminate cancer tissue from benign peripheral tissue, and the apparent diffusion coefficient has been demonstrated to be lower in low-risk prostate cancer than in high- or intermediate-risk prostate cancer [29]. Van As et al. [30] have showed that the apparent diffusion coefficient was a significant predictor of adverse repeat biopsy findings and time to radical treatment in a prospective cohort of 86 AS men. However, their selection criteria for AS were less strict (Gleason score 6 or 7, PSA level <15, <50% of positive biopsy cores) and they did not correlate MRI findings and pathological parameters in RP specimens.

Limited data also suggest that MRI combined with magnetic resonance spectroscopic imaging could be relevant for low-risk patients’ assessment [31]. Futures studies should also investigate whether 3.0-T MRI provides a greater predictive value and help to better patients for AS. The 3.0-T MRI improves spectral resolutions of prostate imaging on T2-weighted sequences. Potential advantages are adequate imaging without an endorectal coil. However, his additional value for cancer staging has to be proven.

The initial assessment of the misclassification risk is important for patient management and treatment decision; however, it is surely not the best end point to address the conclusion in men eligible for AS. The evaluation of biochemical RFS rate should be included, as done in our series. However, the most important end point is cancer-specific survival rate. Nevertheless, as long as long-term oncological outcomes will not available from patients managed with AS, the misclassification rate will represent a major study point of AS strategy analysis and a necessary point of discussion between the urologist and his patient.

In conclusion, when the selection of patients for active surveillance is based on an extended 21-core biopsy scheme, and uses the most stringent inclusion criteria, MRI does not improve the prediction of high-risk and/or non organ-confined disease in a RP specimen. Our findings emphasize that routine MRI does not provide relevant added value for low-risk prostate cancer patients in such a restrictive context.

New MRI techniques, such as diffusion-weighted MRI, magnetic resonance spectroscopic imaging, or the use of 3.0-T MRI, provide significant improvements to routine T2-weighted MRI, and have to be assessed as prognostic tools in the selection of prostate cancer patients for AS. Further validation and cost-effectiveness of such techniques still need to be demonstrated for the characterization of low-volume prostate cancer.

CONFLICT OF INTEREST

None declared.

Ancillary