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ORIGINAL ARTICLE
Year : 2023 | Volume
: 34
| Issue : 4 | Page : 187-193
Digital rectal examination still plays a crucial role of predicting outcomes in the prostate cancer patients undergoing primary total prostate cryoablation
Kuan-Hung Lin, Tsung-Yi Hsieh, Chung-Hsin Chen, Yeong-Shiau Pu
Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
Correspondence Address:
Chung-Hsin Chen
Department of Urology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/UROS.UROS_139_22
Purpose: In the management of prostate cancer (PC), outcome prediction using clinical stages determined via magnetic resonance imaging (MRI) or digital rectal examination (DRE) is controversial. Materials and Methods: Patients with PC who received primary total prostate cryoablation (PTPC) at our institution between October 2008 and March 2021 were enrolled in this study. The primary outcome was biochemical recurrence (BCR), which was defined according to the Phoenix criteria. The concordance of clinical stages determined via DRE and MRI was measured using the weighted kappa coefficient. The Cox proportional-hazards models were used to assess the BCR risks. Results: A total of 230 patients with a median age of 70 years were included in the analysis. The consensus rate of clinical T stages between DRE and MRI was 60.9% with fair concordance (κ = 0.310). DRE upstaged 25 (10.9%) patients, whereas MRI upstaged 65 (28.3%) patients. During the median follow-up duration of 83.1 months, BCR occurred in 78 patients. The univariate analysis of BCR revealed that initial prostate-specific antigen, Gleason sum, and DRE-determined T stage (T3a–b vs. T1-2c; hazard ratio [HR] 1.88; 95% confidence interval [CI] 1.2–2.94) were statistical predictors of BCR. However, no significant association was observed between MRI-determined T stage and BCR (T3a–b vs. T1-2c; HR 1.30; 95% CI 0.83–2.02). The multivariate models consisting of DRE-determined T stage were better than those consisting of MRI-determined T stage based on the Akaike information criteria. Conclusion: In the patients who underwent PTPC, DRE was a valuable technique for evaluating preoperative tumor status and predicting outcomes.
Keywords: Biochemical recurrence, cryoablation, digital rectal examination, magnetic resonance imaging, outcome prediction, prostate cancer
Prostate cancer (PC) is the second most commonly diagnosed cancer and the sixth leading cause of death in men worldwide. In 2020, about 1.5 million new cases of PC and 375,000 deaths were estimated worldwide.[1],[2] Biochemical recurrence (BCR) after the definitive treatment for localized PC is associated with an increased risk of developing distant metastasis and mortality.[3] The predictors of BCR include findings from digital rectal examination (DRE), prostate-specific antigen (PSA) at diagnosis, and Gleason score.[4],[5] Magnetic resonance imaging (MRI) has been frequently used in clinical evaluation. However, it still has not replaced DRE, the traditional method, on the role of evaluating clinical staging. DRE is considered a subjective test with potential interobserver variability and underestimates the extent of anteriorly located tumors.[6],[7] Contrarily, MRI exhibits higher sensitivity than DRE in the detection of nonorgan-confined PC and leads to significant upstaging of the clinical T stage and risk group.[8],[9] In recent years, MRI has been incorporated into the treatment guidelines of the National Comprehensive Cancer Network (NCCN) recommendations, especially for patients with a high risk of PC.[10]
Many BCR-related studies have focused on localized PC following radical prostatectomy (RP). Current therapies for localized PC include RP, radiation therapy (RT), cryoablation, high-intensity focused ultrasound, and watchful waiting.
Cryoablation is a minimally invasive and feasible local treatment for PC. It has the advantages of short hospital stay, minimal anesthesia, and rapid recovery, and provides benefit to older patients or those with multiple comorbidities.[11],[12],[13] A previous study has suggested that prostate cryoablation is an effective treatment option for men with a high risk of PC.[14] No studies have compared DRE and MRI staging in patients with PC who underwent primary total prostate cryoablation (PTPC). This study was designed to compare the outcome prediction between DRE and MRI in patients with PC who underwent PTPC.
Materials and MethodsPatient population
Patients with localized PC who underwent PTPC at our institution from October 2008 to March 2021 were prospectively enrolled in this study. Those who underwent focal or hemi-gland cryoablation were excluded. In addition, patients with PSA ≥50 mg/mL were excluded as most of them developed BCR. The Research Ethics Committee of the National Taiwan University Hospital has reviewed and approved our study (202204097RINA) on June 23, 2022. Informed consent has been waived by the Research Ethics Committee. A portion of the study population has been previously reported.[15]
Clinical information collection
The prospectively collected information were patient age, PSA at diagnosis, biopsy Gleason score (presented with International Society of Urological Pathology grade),[16] prostate volume, T stage determined via DRE and MRI, the number of cryoprobes used, neoadjuvant androgen deprivation therapy (ADT), follow-up PSA values, and the patterns of disease recurrences. The purpose of neoadjuvant ADT lasting over 12 weeks was to reduce prostate size when the anterior–posterior diameter of the prostate exceeded 35 mm so as to facilitate PTPC. ADT following cryoablation was given to selected patients with a high risk of PC.
All DRE staging and PTPC procedures were performed by a single surgical team. All patients were followed up using the same protocol, which included PSA examination every 3 months in the 1st year, every 6 months in the 2nd to the 5th year, and then annually. The primary outcome was time to BCR, which was defined according to the Phoenix criteria indicating a PSA increase of ≥2 ng/mL above the nadir, calculated from the serial follow-up PSA value.[5],[17] The multiparametric MRI with either 3 or 1.5 T plus endorectal coil was used for the patients to determine tumor stages. These images were independently reviewed by radiologists.
Statistical consideration
Contingency tables were established for comparisons using the Chi-squared test. Nonparametric data were evaluated using the Kruskal–Wallis test to compare the medians among the groups. The degree of agreement between DRE and MRI staging was measured using the weighted kappa coefficient. Log-rank test and Cox proportional-hazards models were used to assess the BCR risk. Three multivariate models were tested to compare the BCR prediction between DRE and MRI staging. Model 1 included both DRE and MRI staging as well as other significant parameters identified in the univariate analysis, whereas Models 2, and 3 excluded MRI and DRE staging, respectively. All three models were used with a bidirectional stepwise regression process. All analyses were conducted using the IBM SPSS Statistics V22.0 (IBM Corporation, Armonk, New York, US). Furthermore, all tests were two-tailed, with P < 0.05 indicating statistical significance.
ResultsPatient demographics
This study enrolled 289 consecutive patients with PC who underwent PTPC. A total of 56 patients were excluded because of PSA ≥50 ng/mL (n = 13) or receiving focal/hemi-gland cryoablation (n = 43). In addition, three patients with missing MRI data were excluded. The remaining 230 patients were included in the final analysis [Figure 1]. The patients were classified into three groups based on the clinical T stage of DRE [Table 1] and MRI [Table 2]. The patients' median age was 70 years (range, 48–88 years), and the median PSA at diagnosis was 10.7 ng/mL (range, 2.0–45.9 ng/mL). Those with PSA <10, 10–20, and >20 ng/mL accounted for 47.4%, 31.7%, and 20.9% of the entire cohort, respectively. Biopsy Gleason sums of 6, 3+4, 4+3, and 8–10 were observed in 29.1%, 30.9%, 20.0%, and 20.0% of the patients, respectively. The median prostate volume was 27.7 mL (range, 11.9–81.9 mL), and the median cryoablation number was 6 (range, 5–9). A total of 16 patients received 3-month neoadjuvant ADT (n = 16, 7.0%), whereas 19 patients (n = 19, 8.3%) received 12-month ADT following cryoablation under the setting of a clinical trial.[18] BCRs occurred in 33.9% (n = 78) of the patients during the median follow-up duration of 83.1 months (range, 2–114 months).
Table 1: Demographics of prostate cancer patients stratified by digital rectal examination T staging
Figure 1: Flow diagram of patient selection into the study cohort. PC: Prostate cancer, PSA: Prostate-specific antigen, MRI: Magnetic resonance imaging
Table 2: Demographics of prostate cancer patients stratified by magnetic resonance imaging T stagingWith the stratification of the T stage determined via DRE [Table 1], the patients with higher T stage had higher PSA at diagnosis, higher Gleason sum, and higher BCR rate. On the other hand, when MRI was used to determine the T stage [Table 2], the patients with higher T stage had higher PSA at diagnosis. However, no differences were observed in Gleason sum and BCR rate. Regardless of the methods used for determining the T stage, patient age, prostate volume, the number of cryoprobes used, and neoadjuvant hormone therapy were similar among the groups.
Association of clinical T stage determined via digital rectal examination and magnetic resonance imaging
With the classification of T stage as T1-2c, T3a, and T3b, the consensus rate between DRE and MRI was 60.9% (n = 140) with fair concordance (κ = 0.310) [Table 3]. DRE upstaged 25 (10.9%) patients, whereas MRI upstaged 65 (28.3%) patients compared with the other method. The clinical T1-2c diseases were more frequently determined via DRE (n = 156, 67.8%) than via MRI (n = 120, 52.2%). However, MRI allocated more T3a (n = 89, 38.7%) and T3b (n = 21; 9.1%) cases than DRE (n = 61, 38.7%; n = 13, 5.7%).
Biochemical recurrence
During the median follow-up duration of 83.1 months, BCRs occurred in 78 (33.9%) patients. The BCR-free survival curves for the DRE-and MRI-determined clinical T stages [[Figure 2]a and [Figure 2]b, respectively] and risk classification [[Figure 2]c and [Figure 2]d, respectively] are illustrated. With the stratification of the clinical stages, the DRE-determined T1c–2b diseases were associated with longer BCR-free duration than either T3a or T3b [log-rank test: P = 0.005, [Figure 2]a]. However, the MRI-determined T stages did not successfully predict the BCR-free duration [Figure 2]b.
Figure 2: (a) BCR-free survival curves for DRE based clinical T stage, (b) BCR-free survival curves for MRI based clinical T stage, (c) BCR-free survival curves for DRE-determined risk stratification, (d) BCR-free survival curves for MRI-determined risk stratification. MRI: Magnetic resonance imaging, BCR: Biochemical recurrence, DRE: Digital rectal examinationIn the univariate analysis of BCR in our cohort, higher PSA at diagnosis (hazard ratio [HR] 2.56 and 3.33, 95% confidence interval [CI] 1.48–4.44 and 1.87–5.93 for PSA 10--<20 and 20--<50 ng/mL, respectively), higher Gleason sum (4 + 3: HR 2.04 95% CI 1.05–3.97; 8--10: HR 3.34, 95% CI 1.74–6.41; reference: Gleason sum 6), and higher DRE-determined T stage (HR 1.88; 95% CI 1.2–2.94) statistically predicted BCR [Table 4]. However, the MRI-determined T stage, prostate size, the number of cryoprobes used, age, and neoadjuvant hormone therapy were not associated with BCR.
Table 4: Univariable and multivariable analyses of biochemical failure in prostate cancer patients after primary cryoablationThe multivariate analysis revealed that higher PSA value and Gleason sum were associated with BCR in all models [Table 4]. The DRE-determined T stage did not significantly predict BCR in Model 1 (HR 1.24; 95% CI 0.76–2.05) and Model 2 (HR 1.21; 95% CI 0.74–1.98). Similarly, the MRI-determined T stage did not significantly predict BCR in Model 1 (HR 0.88; 95% CI 0.55–1.43) and Model 2 (HR 0.92; 95% CI 0.57–1.48). Among these three multivariate models, Model 2 had the lowest Akaike information criterion (728.05) and Bayesian information criterion (748.68). This indicated that Model 2, which consisted of DRE-determined T stage, has better goodness of fit than Model 3, which consisted of MRI-determined T stage. Compared with the full model, namely, Model 1, both Models 2 and 3 presented similar performance in predicting BCR based on the likelihood ratio test (P = 0.61 and 0.39 for Model 1 vs. Model 2 and Model 1 vs. Model 3, respectively).
DiscussionAlthough this study demonstrated fair concordance of tumor T stage determined via DRE and MRI, MRI upgraded tumor stages more frequently than DRE. Furthermore, the DRE-determined stages predicted BCR more accurately than the MRI-determined stages. Although the T stage determined by either DRE or MRI was not a statistically significant prognosticator of BCR, the model consisting of DRE-determined T stage had better prediction performance than that consisting of MRI-determined T stage. This finding indicated that DRE did not lose its clinical role of being a prognosticator in the current clinical practice in which MRI is frequently used.
Advanced local or nonorgan-confined diseases, such as extraprostatic extension (T3a) and seminal vesicle invasion (T3b), were significantly associated with poor prognosis and higher recurrence rate after primary definitive therapy.[19] Therefore, most guidelines recommended more aggressive treatments for these diseases.[20],[21] Based on the NCCN guidelines, for example, clinical T3 stage, or higher is categorized as either high-or very high-risk localized PC, for which RT with long-term ADT or RP has been suggested. Contrarily, active surveillance, or observation has been recommended for patients with low-or very low-risk localized PC.[20] An accurate staging method would facilitate the decision-making regarding the treatment strategy and prediction of patient outcomes.
Our study demonstrated that more frequent upstaging was observed in MRI than in DRE. For example, 57 (36.5%) of 156 patients with DRE-determined T1-2c were classified as having MRI-determined T3a–b. Contrarily, DRE showed a higher stage in 21 (17.5%) of the patients (n = 120) with MRI-determined T1-2c. Our findings were consistent with those of a previous study that investigated the impact of MRI on the EAU risk classification in 180 patients who underwent robot-assisted RP. Draulans et al. found that MRI up-and downstaged risks in 31% and 4% of patients, respectively, compared with the stages determined by the pathological reports.[8] Marcus et al. found a similar phenomenon in the impact of MRI on the NCCN risk classification. They observed an upstaging risk in 26% of the patients (n = 71).[22] The results of the present study indicated that MRI indeed has a migration impact on the higher risk stratification. To the best of our knowledge, this is the first study to investigate stage migration via MRI in patients who underwent prostate cryoablation but not RP.
Although there was fair concordance between the DRE-and MRI-determined T stages in our cohort, the findings obtained from DRE seemed to be more associated with BCR than those from MRI in the analysis using either the Cox proportional-hazards model or Kaplan–Meier method. Theoretically, the clinical T stages were associated with tumor outcomes in patients with PC who received definitive local treatment.[23],[24],[25] The MRI-determined T stages were significantly higher than the DRE-determined ones, indicating that the upgraded T stage by MRI was not supported by the corresponding tumor outcomes. We speculated that MRI had higher sensitivity but lower specificity to nonorgan-confined diseases (above T3a) than DRE.[9] MRI increased staging may lead to poor BCR prediction, as our findings. It can also explain why BCR occurred more frequently in nonorgan-confined PC in the DRE-based risk group than in the MRI-based risk group.
PSA at diagnosis, Gleason sum, and DRE-determined T stage were significant predictors of BCR in the univariate analysis, but neither the DRE-, nor MRI-determined T stage were independent factors in the multivariate analysis of our cryoablation cohort. However, the DRE-and MRI-determined clinical T stages were significantly associated with BCR in patients who underwent RP.[2] The reasons for the contrasting conclusions regarding patients receiving RP and prostate cryoablation may include, but not limited to, the following points. First, the differences in operation principles and procedures may contribute to the patient outcomes. For example, the preservation of neurovascular bundles may significantly increase the risk of local recurrence in patients receiving RP.[26],[27] However, we did not attempt to preserve neurovascular bundles in patients who underwent prostate cryoablation, indicating that cryoablation reduced the risk of local recurrence at the areas of bilateral neurovascular bundles. Logically, the minimal extraprostatic extension could be ablated via cryoablation but might be preserved using RP with neurovascular bundle preservation. MRI can identify or predict the microextension of prostate tumors, which would be totally ablated by rearranging the location and freezing duration during prostate cryoablation. Therefore, the outcomes did not significantly differ between T1-2c and T3a determined via MRI. This may be the reason why the MRI-determined T stage was not found to be a predictor of BCR in patients who underwent prostate cryoablation. Second, the statistical power was not sufficient to identify the small BCR predictive value of MRI in our cohort due to the relatively small sample size. Nevertheless, the DRE-determined T stage still exhibited a statistically significant value in predicting BCR in our cohort. This finding indicated that DRE was a better method for evaluating precryoablation tumor status than MRI. Third, the criteria for BCR were different for RP and PTPC. At present, there are no unified criteria for BCR following cryoablation and no consensus on the cutoff value of PSA for BCR. In this study, we used the Phoenix criteria, which were used by previous studies for BCR following PTPC.[14] However, the Phoenix criteria are less stringent compared with the BCR criteria for patients who underwent RP. The use of more stringent criteria for BCR following RP may lead to easier identification of BCR cases. The difference in the cutoff values for BCR may influence patient outcomes. This may be the reason why the DRE-and MRI-determined clinical T stages were significantly associated with BCR in patients who underwent RP but not in those who underwent PTPC.
This study had several limitations. First, all the enrolled patients were from a single center. This may limit the generalization of our findings to other institutes. Contrarily, the treatment bias between the operators was minimal. Second, the statistical power was insufficient for an extensive analysis due to the relatively small sample size. However, we still observed a difference in the BCR predictive value between DRE and MRI. Third, selection bias of the patients undergoing PTPC may exist. Prostate cryoablation is not recommended for patients with great tumor burden. The fourth limitation is the retrospective nature of this study. However, the consecutive patients and prospectively collected variables mitigated the bias.
ConclusionAlthough the consensus rate of the MRI-and DRE-determined clinical T stages was fair, MRI significantly upstaged the clinical T stages compared with DRE. Neither the DRE-nor the MRI-determined T stages were significant predictors of BCR in patients who underwent prostate cryoablation. The DRE-determined T stages revealed the value predicting BCR in the univariate Cox proportional-hazards model and Kaplan–Meier method. Hence, DRE is still considered a practical technique for evaluating the preoperative tumor status of patients undergoing prostate cryoablation.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Financial support and sponsorship
Nil.
Conflicts of interest
Prof. Chung-Hsin Chen and Dr. Yeong-Shiau Pu, the editorial board members at Urological Science, had no roles in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
References
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