EURURO-6107; No. of Pages 10 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Prostate Cancer
Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Erik Rud a,b,*, Eduard Baco c, Dagmar Klotz d, Kristin Rennesund c, Aud Svindland d,b, Viktor Berge c, Eskild Lundeby c, Nicolai Wessel c, Jon-Roar Hoff c, Rolf Eigil Berg c, Lien Diep e, Heidi B. Eggesbø a, Lars Magne Eri c,b a
Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway; b Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
c
Department of Urology, Oslo University Hospital, Oslo, Norway; d Department of Pathology, Oslo University Hospital, Oslo, Norway;
e
Department of Biostatistics, Epidemiology and Health Care Economics, Oslo University Hospital, Oslo, Norway
Article info
Abstract
Article history: Accepted February 27, 2015
Background: Magnetic resonance imaging (MRI) has the potential to help the surgeon tailor radical prostatectomy (RP) more accurately according to the location and extent of the tumour and thereby reduce the rate of positive surgical margins (PSMs). Objective: To evaluate the benefit of performing MRI prior to RP. Design, setting, and participants: This single-institution randomised trial included 438 patients between December 2009 and June 2012 who were scheduled for robotassisted laparoscopic prostatectomy. The study was registered (ClinicalTrials.gov identifier NCT01347320). Intervention: Patients were preoperatively randomly assigned to non-MRI or MRI groups. Outcome measurements and statistical analysis: The primary end point was the difference in the PSM rates between the two groups. Secondary end points were the rates of PSMs in clinical subgroups. Summary statistics were extracted from descriptive analyses, chi-square, or Fisher exact test, and logistic regression was used to analyse the data according to the intention-to-treat principle. Results and limitations: A total of 216 patients were randomised to non-MRI; 222 were randomised to MRI. There were 49 cases (23%) of PSMs in the non-MRI group and 43 cases (19%) in the MRI group (p = 0.4). The relative and absolute risk reduction was 15% and 4%, respectively. Patients with cT1 constituted 55% of the cohort, in which the rate of PSMs was 27% in the non-MRI group and 16% in the MRI group (p = 0.035). The relative and absolute risk reduction was 41% and 11%, respectively. A limitation was suboptimal communication between the radiologist and urologist. Conclusions: MRI prior to RP did not reduce the overall risk for PSMs in this patient cohort. However, at subgroup analysis we observed a possible benefit of MRI in patients with cT1. Patient summary: This study could not demonstrate a definite benefit of performing magnetic resonance imaging before surgery for all patients. However, there was a possible improved result in patients in which physical examination could not detect the cancer. # 2015 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Keywords: RCT Randomised controlled trial MRI Preoperative Prostate cancer Surgical margins Surgical benefit
* Corresponding author. Oslo University Hospital, Box 4959, Nydalen, 0424 Oslo, Norway. Tel. +47 934 45 684. E-mail address: [email protected] (E. Rud). http://dx.doi.org/10.1016/j.eururo.2015.02.039 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Rud E, et al. Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.02.039
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1.
Introduction
The role of magnetic resonance imaging (MRI) before radical prostatectomy (RP) is still under discussion, and routine MRI is not considered mandatory [1]. No randomised controlled trials (RCTs) have been conducted to evaluate the role of MRI prior to RP. Ideally, MRI should detect all significant cancer foci and give an accurate T classification for optimal surgical planning. Studies have demonstrated a 80–94% detection rate for the clinically dominant tumour, the so-called index tumour [2–4]. The index tumour is associated with extraprostatic extension (EPE) when relevant, the highest Gleason score (GS), or the largest volume, in that order of priority [5–7]. When present, the secondary and tertiary tumour is the two next highest ranking tumours according to the same criteria. The sensitivity of MRI for predicting T3 is limited, ranging from 13% to 95%, depending on patient selection and the method used [8,9]. The laterality of T3 is rarely reported, although it is highly relevant when planning treatment [5,10]. Preoperative detection of T3 disease is clinically important because T3 increases the risk of positive surgical margins (PSMs), that is, cancer present on the surface of the surgically removed prostate gland. PSMs are an indicator of nonradical surgery and therefore an important parameter when assessing the surgical quality of RP [11]. The aim of this RCT was to assess the ability of MRI before RP to reduce the rate of PSMs.
Table 1 – Baseline characteristics of 438 patients randomized to the non–magnetic resonance imaging (MRI) or MRI groups Non-MRI (n = 216)
MRI (n = 222)
63 6 8.2 (6.2–18.3)
62 6 7.8 (4.9–11.3)
Age, yr, mean SD PSA, ng/ml, median (IQR)
n cT stage 1c 114 41 2a 2b 41 14 2c 6 3a Gleason score in biopsy 79 6 79 7a 7b 20 8 37 1 9 D’Amico risk groups 55 Low 103 Medium High 58
%
n
%
53 19 19 6.5 2.8
125 48 25 14 10
56 22 11 6.3 4.5
37 37 9.3 17 0.5
70 89 27 28 8
32 40 11 12 3.6
25 48 27
57 114 51
26 51 23
IQR = interquartile range; MRI = magnetic resonance imaging; PSA = prostate-specific antigen; SD = standard deviation.
one envelope with another, and the envelope was disposed of after each allocation. A logbook registered every procedure and was controlled several times by the responsible statistician. The envelopes were prepared by the centre of Biostatistics and Epidemiology, Research Support Service, at Oslo University Hospital and kept accessible only to E.R., who also performed the randomisation. Patients were scheduled for
2.
Patients and methods
2.1.
Setting
This single-institution RCT was approved by the local regional committee for medical and health ethics (S-09143c2009/2183) and registered at ClinicalTrial.gov (NCT01347320). All patients signed a letter of consent.
2.2.
Study design
All patients scheduled for robot-assisted laparoscopic prostatectomy (RALP) at Oslo University Hospital, Aker, from December 1, 2009, to June 31, 2012, were candidates for the trial. Table 1 displays the baseline data of the patient cohort. During the study period, 675 patients were scheduled for RALP; 485 met the inclusion criteria, and 438 (90%) were included for intention-to-treat analyses (Fig. 1).
MRI within 2 wk.
2.5.
Sample size estimation
The rate of PSMs is highly associated with the incidence of pT3, and when planning the study, the incidence of pT3 was approximately 45%. For that reason, we expected the rate of PSMs in the non-MRI group to lie between 35% and 40%. A 20% difference in the rate of PSMs between the non-MRI and MRI groups was considered clinically relevant. With a significance level of 0.05, 91–151 in each group was required to provide 80% power with a two-tailed test for two independent proportions, assuming no dropout.
2.6.
Magnetic resonance imaging
The MRI radiologist had 2 yr of experience with prostate imaging at the start of the study. The radiologist was not systematically blinded to prostate-specific antigen (PSA), cT stage, and GS. All patients in the MRI group underwent 1.5-T MRI (Siemens, Erlangen, Germany) and six-
2.3.
Exclusion criteria
channel body matrix (Siemens). The time between biopsy and MRI was 11 7 wk (mean plus or minus standard deviation; range: 0–71) and
Exclusion criteria were previous relevant MRI of the prostate, contra-
between MRI and surgery was 1 4 wk (range: 0–25). No patients were
indications to MRI, and hip prosthesis.
excluded due to haemorrhagic artefacts or poor quality of the MRI.
2.4.
axial diffusion-weighted images (DWIs) using b50, b1000, and b2000. An
The sequences included 0.9-mm isotropic three-dimensional T2 and
Randomisation
apparent diffusion coefficient map was prepared from b50 and b1000. Allocation (1:1) of patients to either non-MRI or MRI was based on a
The MRI acquisition and postprocessing were previously reported in
permuted block randomisation procedure with undisclosed and variable
detail [12]. We used criteria for tumour detection and staging as
blocking factor. After consent was received, each patient was designated
previously specified [2,5,13–16]. Both T2 and DWI were used for
a unique, unchangeable sequentially numbered randomisation number,
detection and staging.
matching an opaque and sealed envelope, containing the corresponding
All patients also underwent axial and coronal T1-weighted imaging
intervention code (eg, non-MRI or MRI). It was not possible to replace
of the pelvis and the lumbosacral spine to evaluate possible lymph node
Please cite this article in press as: Rud E, et al. Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.02.039
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Number of patients referred to RALP during trial period (n = 675) Excluded (n = 189)
Enrolment
Randomised (n = 485)
MRI (n = 245)
Allocation
Previously performed MRI (112) Contraindications to MRI (23) Did not wish to participate (10) Treated at other hospital (9) Unknown (35)
no MRI (n = 240)
Excluded (n = 25) Withdrawn consent (3) No surgery was performed Referred to radiation or hormonal therapy (9) Cancelled surgery (10) Other (3)
Excluded (n = 23) Withdrawn consent (8) No surgery was performed Skeletal metastases on MRI (4) Referred to radiation therapy (1) Cancelled surgery (9) Underwent surgery in another country (1)
Patients included for intention-to-treat analysis (n = 222)
Patients included for intention-to-treat analysis (n = 216)
Underwent MRI (203) Did not undergo MRI (19) Contraindications to MRI (5) Change in surgical date (6) Did not meet (3) Other (6)
Underwent MRI (2) Previous MRI became known Referred to MRI and rebiopsy Did not undergo MRI (214)
RALP Fig. 1 – Trial profile using the Consolidated Standards of Reporting Trials 2010 guidelines. MRI = magnetic resonance imaging; RALP = robot-assisted laparoscopic prostatectomy.
and skeletal metastases. These findings are not discussed in this paper.
as a standard bilateral extrafascial dissection or as an extended excision.
The MRI examination was completed within 20 min.
The operator registered (1) the surgical plan before knowing the MRI results, (2) the surgical plan after knowing the MRI, and (3) the means by
2.7.
Communication with urologists prior to surgery
which the surgery actually was performed. We did not register whether MRI resulted in more extensive surgery anteriorly or at the bladder neck.
A schematic tumour map displaying the location and extent of the
The planned surgical approach was based on the preoperative
tumours (indicated in red), including possible EPE and seminal vesicle
parameters available that included transurethral ultrasound (TRUS),
invasion, was drawn manually for every patient (Fig. 2) and shown to
digital rectal examination (DRE), GS, tumour extent in biopsies, and
the surgeon before surgery in each case. In addition, the MRI information
patient’s wish. When available, MRI was also taken into consideration.
was registered in the electronic patient record system. Postoperatively, the surgeon completed a form, in which he reported whether, and in what way, MRI had changed the surgical approach.
2.8.
Surgery
RALP was limited to four experienced urologists at the department. The urologists had performed an average of 103 RALP procedures (range: 78–165), and a total of 415 laparoscopic prostatectomies (range: 296–585) at the start of the study. Figure 2 illustrates the possible approaches for the surgical dissection. The operations were classified as bilateral nerve-sparing surgery (BNS), unilateral nerve-sparing surgery (UNS), or non–nerve-sparing surgery
2.9.
Pathologic preparation and examination
Whole-mounted histologic sections were used as the reference standard. Specimen handling was previously described in detail [2]. The surgical margins were classified as positive when cancer tissue was present on the inked surface of the prostate specimen. The sector associated with each PSM was registered on a tumour map (Fig. 3). If a specific tumour affected the same sector as the site of the PSM, it was classified as responsible for the PSM. Each tumour and sector associated with PSMs was classified as detected by MRI or not.
2.10.
Clinical, radiologic, and pathologic T classification
(NNS). Nerve-sparing surgery included both intra- and interfascial
The staging results of the clinical examination and MRI were previously
dissection, as described by Walz et al [10]. The NNS could be performed
reported in detail [5] and are only briefly reported in Table 2.
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n
sio on ci ic si g ex x n n g e ri io in -spa xcis r a ve e p s er ed erv n-n nd Ne No Exte
Basis Right
Le
Basis NVB Middle
Apex
Middle
Ant. fibromuscular stroma
Transion zone Ant. lat. Post. med. Post. lat.
Apex
Fig. 2 – The 30-sector tumour map used for registration of all tumours at magnetic resonance imaging and histology served as the basis for correlation analysis. All suspected tumours were marked in red, and any extraprostatic extension was indicated. The map was then presented to the surgeon before surgery. The three possible planes of dissection are indicated with stippled lines. Extended and non–nerve-sparing surgery was combined for statistical analyses. Figure adapted by Kari C. Toverud from Girouin et al. Eur Radiol. 2007;17:1498–509, with permission from Springer. # Kari C. Toverud. Ant. = anterior; lat. = lateral; med. = medial; NVB = neurovascular bundle; Post. = posterior.
Preoperative DRE and TRUS, performed by urologists, classified all
3.
Results
patients as having clinically localised (cT1c or cT2a–c) or nonlocalised disease (cT3a–b). Due to a low number of cT3a–b cases, these patients were combined with cT2a–c in the statistical analyses. Correspondingly, MRI (rT) and histopathology (pT) classified all patients as localised (T2) or nonlocalised (T3).
2.11.
Statistical analyses
A total of 438 patients were included in this study, in which 216 were randomised to the non-MRI group and 222 were randomised to the MRI group (Fig. 1). Table 1 shows that the groups were well balanced. 3.1.
Magnetic resonance imaging tumour detection results
The rate of PSMs in the non-MRI and MRI groups was the primary end point. Clinical subgroups were defined according to the T classification, D’Amico risk groups, GS, and surgical procedures. The Pearson chi-square or Fisher exact test assessed differences in the rate of PSMs between the non-MRI and MRI groups and in clinical subgroups. The proportions of PSMs and odds ratios (ORs) with 95% confidence intervals (CIs) were used to describe the differences. Both absolute and relative differences (risk ratio) are reported. Differences in the ORs of the clinical subgroups were examined by the interaction term between the non-MRI and MRI group variable and the clinical subgroup variable using logistic regression. All analyses were performed according to the intention-to-treat principle. Two-sided p values were given and not corrected for multiple testing. IBM SPSS Statistics v.22 (IBM Corp., Armonk NY, USA) and MedCalc statistical software v.14.8.1 (MedCalc Software, Ostend, Belgium) were used for statistical analyses.
MRI tumour detection rates and staging results of this cohort were reported in two previous papers and are only mentioned briefly [2,5]. MRI detected 92% of the index tumour; it did not detect the index tumour in 16 patients. However, in 5 of these 16, MRI detected the second largest tumour with identical GS as the index tumour. In 11 patients with specimen GS 6 and 7, no tumour was found on MRI. 3.2.
Surgical procedures
The surgeons reported that MRI altered the surgical procedure on one or both sides in 59 patients (27%), of which 30 (51%) were cT1, 29 (49%) were cT2, and 49 (83%) were rT3. All changes were in the direction of a more radical excision. There was no difference in mean age, PSA, and GS in biopsy of
Please cite this article in press as: Rud E, et al. Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.02.039
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No MRI
MRI
Basic
Basic
Right
Middle
Le
Right
Ant. fibromuscular stroma
Middle
Transion zone
Le
Ant. fibromuscular stroma
Transion zone Ant. lat.
Post. med.
Ant. lat. Post. med.
Post. lat.
Post. lat.
Apex
Apex
Fig. 3 – Distribution of positive surgical margin (PSM) sites is marked with small circles. The PSM sites ventral to the basal urethra represent the bladder neck. Both the apex and the base are at high risk for PSMs. Figure adapted by Kari C. Toverud from Girouin et al. Eur Radiol. 2007;17: 1498–509, with permission from Springer. # Kari C. Toverud. Ant. = anterior; lat. = lateral; med. = medial; MRI = magnetic resonance imaging; Post. = posterior.
patients with adjusted surgery compared with those with nonadjusted surgery. BNS was performed in 35 of 90 patients (39%) classified as rT2 versus 15 of 110 (14%) for rT3 (p < 0.001). The overall rate of BNS, UNS, and NNS was 30%, 34%, and 35%, respectively. The absolute rate of BNS was 6.7% (95% CI, 2 to 16; p = 0.12) lower in the MRI group compared with
Table 2 – The performance of magnetic resonance imaging and digital rectal examination/transrectal ultrasound for detecting pT3 disease Sensitivity, % (95% CI) MRI All patients cT1 cT2–3 DRE/TRUS
the non-MRI group (Table 3). This difference was mainly due to a 13% (95% CI, 1–25; p = 0.024) lower rate of BNS in patients with cT2–3 (Fig. 4). 3.3.
There were 49 cases (23%) of PSMs in the non-MRI group and 43 (19%) in the MRI group (Table 4). The relative and absolute reduction was 15% (0.85; 95% CI, 0.6–1.2) and 4% (95% CI, 4 to 10; p = 0.4), respectively. The number needed to treat was 25, and two extra nerve resections (1.7%) were performed for each PSM avoided.
Specificity, % (95% CI)
3.4. 73 56 88 4
(63–81) (41–70) (76–95) (2–8)
Overall risk of positive surgical margins
65 70 55 98
(54–74) (57–81) (36–72) (95–99)
CI = confidence interval; DRE/TRUS = digital rectal examination/transurethral ultrasound; MRI = magnetic resonance imaging.
Risk of positive surgical margins in patient subgroups
MRI did not reduce the rates of PSMs in cT2–3, whereas in cT1, the relative and absolute reduction was 41% (0.59; 95% CI, 0.4–0.9) and 11% (95% CI, 2–22; p = 0.035), respectively (Tables 3 and 4). There was no benefit of MRI in any other subgroups.
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Table 3 – Positive surgical margin rate with respect to surgical procedure, cT stage, and Gleason score in biopsy Non-MRI (n = 216) Total
Bilateral nerve-sparing surgery DRE cT1 cT2–3 Gleason score in biopsy 6 7a 7b 8 9 All patients Unilateral nerve-sparing surgery DRE cT1 cT2–3 Gleason score in biopsy 6 7a 7b 8 9 All patients Non–nerve-sparing surgery DRE cT1 cT2–3 Gleason score in biopsy 6 7a 7b 8 9 All patients
MRI (n = 222) PSM
Total
PSM
n
%
n
%
n
%
45 28
49 67
11 2
24 7.1
46 14
51 33
34 26 8 5 73
53 54 62 63 NA 33
7 3 2 1 NA 13
21 12 25 20 NA 18
30 22 5 3 0 60
29 42
42 51
6 9
21 21
29 26 6 10
58 43 30 56
4 7 1 3
71
47
40 32 16 27 6 22 1 72
n
%
p
5 2
11 14
0.089 0.5
47 46 38 34 NA 25
2 5 0 0 NA 7
7 23 0 0 NA 12
0.11 0.3 0.2 0.4
40 40
58 49
7 7
16 19
0.7 0.7
14 27 17 30
23 35 14 8
42 57 70 44
1 8 3 2
4 23 17 25
0.3 0.7 0.8 0.8
15
21
80
53
14
18
0.6
51 43
14 7
35 23
39 43
49 57
8 14
19 30
0.15 0.3
48 46 40 58 11 47
3 7 3 8 0 21
19 26 50 36 0 29
17 32 9 16 8 82
52 54 60 42 89 53
2 10 5 3 2 22
12 30 50 19 25 27
0.6 0.7 0.8 0.2 0.6 0.7
p*
0.15
0.6
0.3 0.9
0.7
0.086
0.7
DRE = digital rectal examination; MRI = magnetic resonance imaging; NA = not available; PSM = positive surgical margins. The p value for interaction.
*
Rates of PSMs in patients with adjusted and nonadjusted surgery were 25% and 17%, respectively (8% difference; 95% CI, 4 to 22; p = 0.17). Most patients with PSMs underwent UNS or NNS; 36 of 49 (73%) in the non-MRI group and 36 of 43 (84%) in the MRI group (11% difference; 95% CI, 8 to 29; p = 0.2). For patients classified as rT3, the rate of PSMs was 25%; 89% of these patients underwent either UNS or NNS (Fig. 5). 3.5.
Distribution of positive surgical margins and the
4.
Discussion
The present study is the first RCT to evaluate the benefit of MRI prior to RALP. We could not demonstrate a significant reduction in the rate of PSMs for either the whole cohort or patients with pT3. However, we found a 41% lower rate of PSMs in patients with cT1 (p = 0.035), although this was not statistically significant in the context of multiple testing. The rate of PSMs varies significantly in the literature, and our results are within acceptable limits [17,18].
associated tumour 4.1.
There were 126 sites of PSMs in 92 specimens (Fig. 6). Sixty patients had a single PSM site; 32 had more than one. The index tumour was the responsible tumour in 89% of all cases of PSMs, and 60% were associated with EPE at the same location. MRI detected 92% of all tumours related to PSMs. The base and apex were at higher risk for PSMs (Fig. 3). The risk of ventral PSMs in the apex was higher in the non-MRI group (12%; 95% CI, 3 to 23; p = 0.072).
Effect of magnetic resonance imaging on surgical approach
MRI changed the surgical strategy in 29%, all in the direction of more radical excision. Other studies have reported that MRI affected the surgery in a radical direction in only 33–39% [19–21]. None of these studies had a control arm without MRI, making comparison difficult. Most of the patients with PSMs had undergone UNS or NNS in both the non-MRI and MRI group. Also, when MRI suggested T3, 89% of those with PSMs had undergone either
Please cite this article in press as: Rud E, et al. Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.02.039
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UNS or NNS (Fig. 5). This suggests that even more extended excisions are required to reduce the rate of PSMs. 4.2.
Rate of positive surgical margins in patients with cT1
Surprisingly, the greatest benefit of MRI was seen in patients with cT1. This was unexpected because the sensitivity of MRI for predicting pT3 in this group was poor (Table 2), and surgical procedures were not significantly different between the non-MRI and MRI group (Fig. 4). This suggests that the primary value of MRI was to provide the surgeon with accurate information about tumour location and extension, whereas staging was of secondary importance. 4.3.
Possible mechanisms for improved outcome in cT1
This study cannot explain the exact mechanisms for the reduced rate of PSMs in patients with cT1. However, one possibility may be excellent tumour visualisation on MRI, also in patients with cT1, whereas DRE and TRUS are normal. This probably favours selection of the proper surgical procedure, and it may have prevented dissection too close to the index tumour or changed the surgery in ways not registered in this study. For instance, in case of a ventral cancer with extraprostatic disease, it is possible to perform a combination of BNS and extended excision ventrally.
Fig. 4 – In patients with cT1, the relative risk of positive surgical margins (PSMs) was 41% lower in the magnetic resonance imaging (MRI) group, and there was a reduction in PSMs regardless of the surgical procedure. There was no significant difference in the surgery between the two groups. Unexpectedly, in patients with cT2–3, the overall PSM rate increased by 6% (95% confidence interval, S6 to 18; p = 0.4) in the MRI group, despite the fact that unilateral nerve-sparing surgery and non– nerve-sparing surgery were performed 13% more frequently in the MRI group. BNS = bilateral nerve-sparing surgery; MRI = magnetic resonance imaging; NNS = non–nerve-sparing surgery; PSM = positive surgical margins; UNS = unilateral nerve-sparing surgery.
4.4.
Importance of the index tumour and positive surgical
margins site
The index tumour was the source of PSMs in 89% of the cases (Fig. 6). This illustrates the relevance of locating the index tumour before surgery and is in accordance with a 2012 study [22]. However, despite the fact that MRI detected 98% of these tumours, the rate of PSMs did not improve for the whole cohort. If the MRI findings are
Table 4 – Rate of positive surgical margins in the non–magnetic resonance imaging (MRI) and MRI groups Non-MRI (n = 216)
All patients DRE cT1 cT2–3 D’Amico risk classification Low Medium High pT stage 2 3 Gleason score in specimen 6 7a 7b 8 9
Total, n
PSM, n
216
49
114 102
MRI (n = 222) %
Total, n
PSM, n
%
p
OR
95% CI
23
222
43
19
0.4
0.81
0.5–1.3
31 18
27 18
125 97
20 23
16 24
0.035 0.3 0.8*
0.51 1.53
0.3–0.9 0.7–2.9
55 103 58
7 24 18
13 23 31
57 114 51
3 25 15
5.3 22 29
0.38 0.93 0.41
0.1–1.6 0.5–1.7 0.4–2.1
111 105
9 40
8.1 38
103 119
5 38
4.9 32
0.58 0.76
0.2–1.8 0.4–1.3
59 83 44 23 7
9 17 11 9 3
15 20 25 39 43
57 87 48 22 8
7 14 14 6 2
12 16 29 27 25
0.78 0.75 1.21 0.58 0.44
0.3–2.3 0.3–1.6 0.5–3.1 0.2–2.1 0.1–4.0
*
p
0.029
0.8
0.7*
0.7
0.8*
0.8
CI = confidence interval; DRE = digital rectal examination; MRI = magnetic resonance imaging; OR = odds ratio. OR 1 indicates an increased risk. * The p value for interaction: A significant interaction p value indicates that the ORs of the subgroups are significantly different.
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Fig. 5 – Bilateral nerve-sparing surgery was chosen in 15 of 110 patients (14%) when magnetic resonance imaging (MRI) suggested T3 disease. For unknown reasons, the surgeon chose not to consider the MRI findings. Six of the patients turned out to have pT3 in which two had positive surgical margins (PSMs); the remaining nine were pT2 and one had PSM. In 95 of 110 patients (86%), the surgical procedure harmonised to a larger extent with the MRI finding; however, 24 of 27 patients (89%) with PSMs were found in this group. This illustrates that the degree of non–nerve-sparing excision was not sufficient. BNS = bilateral nerve-sparing surgery; MRI = magnetic resonance imaging; NNS = non–nerve-sparing surgery; NSM = negative surgical margins; PSM = positive surgical margins; UNS = unilateral nerve-sparing surgery.
Fig. 6 – The associated tumour for each case of positive surgical margins (PSMs) and whether magnetic resonance imaging (MRI) detected it or not. Also shown is whether the PSMs were associated with extraprostatic extension in the same area. MRI identified most tumours and sectors associated with PSMs, suggesting that the surgeons did not sufficiently consider the MRI findings. EPE = extraprostatic extension; MRI = magnetic resonance imaging; PSM = positive surgical margins.
included in the planning of surgical approach to a larger extent, it represents a considerable potential for improvement in the future. The MRI group experienced a lower rate of PSMs in the ventral apex (Fig. 3), although the prognostic value of this is controversial [23,24]. 4.5.
Magnetic resonance imaging protocol
This study used a simple MRI protocol, without contrast medium and endorectal coil, compared with the current
European Society of Urogenital Radiology recommendation [25]. Nevertheless, we achieved similar detection and staging results as those who have used the current recommendation [2,4,5,26,27]. This may indicate that a simple protocol is truly sufficient, although no studies have compared the different protocols on the same cohort, and direct comparison of results is difficult. Alternatively, our high rate of large tumours with pT3 resulted in extraordinary results. From a surgical point of view, it is critical to stress that MRI tumour detection is highly sensitive in most studies;
Please cite this article in press as: Rud E, et al. Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.02.039
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staging remains the weakest element. For this reason, urologists are encouraged to consider tumour location more than rT classification when deciding surgical strategy.
9
(eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
4.6.
Limitations
This study has some possible limitations. First, the study was underpowered to demonstrate a significant effect of MRI because the observed rate of PSMs was approximately half of the expected rate. Because all subgroup analyses were not defined a priori, one should interpret the findings in cT1 with caution and instead conduct future studies. Second, more patients were referred to radiation therapy in the non-MRI group after randomisation. This may be an indicator of more advanced disease, likely to result in PSMs. Consequently, it may have reduced the effect of MRI. Third, the radiologist was not fully blinded to clinical data. This might have affected the MRI results and consequently patient handling. Fourth, there was suboptimal communication between the radiologist and the urologist during this study. This is probably the most important reason why the difference in the rate of PSMs between the two groups was not larger. We believe the radiologists and the urologist should coinvestigate MRI images prior to surgery because only reading a written report or looking at a schematic drawing is suboptimal when planning surgery.
References [1] Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Update 2013. Eur Urol 2014;65:124–37. [2] Rud E, Klotz D, Rennesund K, et al. Detection of the index tumor and tumor volume in prostate cancer using T2w and DW MRI alone. BJU Int 2014;114:E32–42. [3] Turkbey B, Mani H, Aras O, et al. Correlation of magnetic resonance imaging tumor volume with histopathology. J Urol 2012;188: 1157–63. [4] Le JD, Tan N, Shkolyar E, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. Eur Urol 2015;67: 569–76. [5] Rud E, Klotz D, Rennesund K, et al. Preoperative magnetic resonance imaging for detecting uni- and bilateral extraprostatic disease in patients with prostate cancer. World J Urol. In press. [6] van der Kwast TH, Amin MB, Billis A, et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and prostate cancer volume. Mod Pathol 2010; 24:16–25. [7] Baco E, Ukimura O, Rud E, et al. Magnetic resonance imaging-
5.
Conclusions
We showed that the index tumour, usually detected by MRI, is the most frequent cause of PSMs. We did not find an overall reduction in the rate of PSMs in patients randomised to MRI, although subgroup analysis revealed a possible benefit in patients with cT1. Our study suggests more radical resection should be performed in the index tumour region and that future studies should focus on MRI-guided RP. In the MRI group, slightly more nerve resections were performed, which can be considered a potential negative effect of MRI. More studies are needed to evaluate the role of MRI before prostatectomy.
transectal ultrasound image-fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical prostatectomy specimens in 135 patients. Eur Urol 2015;67: 787–94. [8] Yacoub JH, Oto A, Miller FH. MR imaging of the prostate. Radiol Clin North Am 2014;52:811–37. [9] Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT. Imaging prostate cancer: a multidisciplinary perspective. Radiology 2007; 243:28–53. [10] Walz J, Burnett AL, Costello AJ, et al. A critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy. Eur Urol 2010;57:179–92. [11] Boorjian SA, Karnes RJ, Crispen PL, et al. The impact of positive surgical margins on mortality following radical prostatectomy during the prostate specific antigen era. J Urol 2010;183:1003–9.
Author contributions: Erik Rud had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Rud, Eggesbø, Eri. Acquisition of data: Rud, Klotz, Svindland, Wessel, Berg, Berge, Hoff, Rennesund, Lundeby. Analysis and interpretation of data: Rud, Eri, Baco. Drafting of the manuscript: Rud, Eri, Baco. Critical revision of the manuscript for important intellectual content: Rud, Eri, Baco, Eggesbø. Statistical analysis: Rud, Diep. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Rud, Eggesbø. Other (specify): None.
[12] Rud E, Baco E, Eggesbø HB. MRI and ultrasound-guided prostate biopsy using soft image fusion. Anticancer Res 2012;32:3383–9. [13] Sala E, Akin O, Moskowitz CS, et al. Endorectal MR imaging in the evaluation of seminal vesicle invasion: diagnostic accuracy and multivariate feature analysis. Radiology 2006;238:929–37. [14] Yu KK, Hricak H, Alagappan R, Chernoff DM, Bacchetti P, Zaloudek CJ. Detection of extracapsular extension of prostate carcinoma with endorectal and phased-array coil MR imaging: multivariate feature analysis. Radiology 1997;202:697–702. [15] Outwater EK, Petersen RO, Siegelman ES, Gomella LG, Chernesky CE, Mitchell DG. Prostate carcinoma: assessment of diagnostic criteria for capsular penetration on endorectal coil MR images. Radiology 1994;193:333–9. [16] Kim CK, Choi D, Park BK, Kwon GY, Lim HK. Diffusion-weighted MR imaging for the evaluation of seminal vesicle invasion in prostate cancer: initial results. J Magn Reson Imaging 2008;28:963–9.
Financial disclosures: Erik Rud certifies that all conflicts of interest,
[17] Yossepowitch O, Briganti A, Eastham JA, et al. Positive surgical
including specific financial interests and relationships and affiliations
margins after radical prostatectomy: a systematic review and
relevant to the subject matter or materials discussed in the manuscript
contemporary update. Eur Urol 2014;65:303–13.
Please cite this article in press as: Rud E, et al. Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.02.039
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[18] Novara G, Ficarra V, Mocellin S, et al. Systematic review and metaanalysis of studies reporting oncologic outcome after robotassisted radical prostatectomy. Eur Urol 2012;62:382–404. [19] Hricak H, Wang L, Wei DC, et al. The role of preoperative endorectal magnetic resonance imaging in the decision regarding whether to preserve or resect neurovascular bundles during radical retropubic prostatectomy. Cancer 2004;100:2655–63. [20] McClure TD, Margolis DJA, Reiter RE, et al. Use of MR imaging to determine preservation of the neurovascular bundles at robotic-assisted laparoscopic prostatectomy. Radiology 2012;262: 874–83.
lesion: implications for preoperative evaluation of tumor focality in prostate cancer. J Endourol 2012;26:503–8. [23] Dev HS, Wiklund P, Patel V, et al. Surgical margin length and location affect recurrence rates after robotic prostatectomy. Urol Oncol. In press. http://dx.doi.org/10.1016/j.urolonc.2014.11.005 [24] Fontenot PA, Mansour AM. Reporting positive surgical margins after radical prostatectomy: time for standardization. BJU Int 2013; 111:E290–9. [25] Barentsz JO, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012;22:746–57. [26] Somford DM, Hamoen EH, Fu¨tterer JJ, et al. The predictive value of
[21] Labanaris A, Zugor V, Takriti S, et al. The role of conventional and
endorectal 3 Tesla multiparametric magnetic resonance imaging
functional endorectal magnetic resonance imaging in the decision
for extraprostatic extension in patients with low, intermediate and
of whether to preserve or resect the neurovascular bundles during radical retropubic prostatectomy. Scand J Urol Nephrol 2009;43: 25–31. [22] Karavitakis M, Ahmed HU, Abel PD, Hazell S, Winkler MH. Margin status after laparoscopic radical prostatectomy and the index
high risk prostate cancer. J Urol 2013;190:1728–34. [27] Brajtbord JS, Lavery HJ, Nabizada-Pace F, Senaratne P, Samadi DB. Endorectal magnetic resonance imaging has limited clinical ability to preoperatively predict pT3 prostate cancer. BJU Int 2011;107: 1419–24.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Prostate Cancer
Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Erik Rud a,b,*, Eduard Baco c, Dagmar Klotz d, Kristin Rennesund c, Aud Svindland d,b, Viktor Berge c, Eskild Lundeby c, Nicolai Wessel c, Jon-Roar Hoff c, Rolf Eigil Berg c, Lien Diep e, Heidi B. Eggesbø a, Lars Magne Eri c,b a
Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway; b Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
c
Department of Urology, Oslo University Hospital, Oslo, Norway; d Department of Pathology, Oslo University Hospital, Oslo, Norway;
e
Department of Biostatistics, Epidemiology and Health Care Economics, Oslo University Hospital, Oslo, Norway
Article info
Abstract
Article history: Accepted February 27, 2015
Background: Magnetic resonance imaging (MRI) has the potential to help the surgeon tailor radical prostatectomy (RP) more accurately according to the location and extent of the tumour and thereby reduce the rate of positive surgical margins (PSMs). Objective: To evaluate the benefit of performing MRI prior to RP. Design, setting, and participants: This single-institution randomised trial included 438 patients between December 2009 and June 2012 who were scheduled for robotassisted laparoscopic prostatectomy. The study was registered (ClinicalTrials.gov identifier NCT01347320). Intervention: Patients were preoperatively randomly assigned to non-MRI or MRI groups. Outcome measurements and statistical analysis: The primary end point was the difference in the PSM rates between the two groups. Secondary end points were the rates of PSMs in clinical subgroups. Summary statistics were extracted from descriptive analyses, chi-square, or Fisher exact test, and logistic regression was used to analyse the data according to the intention-to-treat principle. Results and limitations: A total of 216 patients were randomised to non-MRI; 222 were randomised to MRI. There were 49 cases (23%) of PSMs in the non-MRI group and 43 cases (19%) in the MRI group (p = 0.4). The relative and absolute risk reduction was 15% and 4%, respectively. Patients with cT1 constituted 55% of the cohort, in which the rate of PSMs was 27% in the non-MRI group and 16% in the MRI group (p = 0.035). The relative and absolute risk reduction was 41% and 11%, respectively. A limitation was suboptimal communication between the radiologist and urologist. Conclusions: MRI prior to RP did not reduce the overall risk for PSMs in this patient cohort. However, at subgroup analysis we observed a possible benefit of MRI in patients with cT1. Patient summary: This study could not demonstrate a definite benefit of performing magnetic resonance imaging before surgery for all patients. However, there was a possible improved result in patients in which physical examination could not detect the cancer. # 2015 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Keywords: RCT Randomised controlled trial MRI Preoperative Prostate cancer Surgical margins Surgical benefit
* Corresponding author. Oslo University Hospital, Box 4959, Nydalen, 0424 Oslo, Norway. Tel. +47 934 45 684. E-mail address: [email protected] (E. Rud). http://dx.doi.org/10.1016/j.eururo.2015.02.039 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Rud E, et al. Does Preoperative Magnetic Resonance Imaging Reduce the Rate of Positive Surgical Margins at Radical Prostatectomy in a Randomised Clinical Trial? Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.02.039
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1.
Introduction
The role of magnetic resonance imaging (MRI) before radical prostatectomy (RP) is still under discussion, and routine MRI is not considered mandatory [1]. No randomised controlled trials (RCTs) have been conducted to evaluate the role of MRI prior to RP. Ideally, MRI should detect all significant cancer foci and give an accurate T classification for optimal surgical planning. Studies have demonstrated a 80–94% detection rate for the clinically dominant tumour, the so-called index tumour [2–4]. The index tumour is associated with extraprostatic extension (EPE) when relevant, the highest Gleason score (GS), or the largest volume, in that order of priority [5–7]. When present, the secondary and tertiary tumour is the two next highest ranking tumours according to the same criteria. The sensitivity of MRI for predicting T3 is limited, ranging from 13% to 95%, depending on patient selection and the method used [8,9]. The laterality of T3 is rarely reported, although it is highly relevant when planning treatment [5,10]. Preoperative detection of T3 disease is clinically important because T3 increases the risk of positive surgical margins (PSMs), that is, cancer present on the surface of the surgically removed prostate gland. PSMs are an indicator of nonradical surgery and therefore an important parameter when assessing the surgical quality of RP [11]. The aim of this RCT was to assess the ability of MRI before RP to reduce the rate of PSMs.
Table 1 – Baseline characteristics of 438 patients randomized to the non–magnetic resonance imaging (MRI) or MRI groups Non-MRI (n = 216)
MRI (n = 222)
63 6 8.2 (6.2–18.3)
62 6 7.8 (4.9–11.3)
Age, yr, mean SD PSA, ng/ml, median (IQR)
n cT stage 1c 114 41 2a 2b 41 14 2c 6 3a Gleason score in biopsy 79 6 79 7a 7b 20 8 37 1 9 D’Amico risk groups 55 Low 103 Medium High 58
%
n
%
53 19 19 6.5 2.8
125 48 25 14 10
56 22 11 6.3 4.5
37 37 9.3 17 0.5
70 89 27 28 8
32 40 11 12 3.6
25 48 27
57 114 51
26 51 23
IQR = interquartile range; MRI = magnetic resonance imaging; PSA = prostate-specific antigen; SD = standard deviation.
one envelope with another, and the envelope was disposed of after each allocation. A logbook registered every procedure and was controlled several times by the responsible statistician. The envelopes were prepared by the centre of Biostatistics and Epidemiology, Research Support Service, at Oslo University Hospital and kept accessible only to E.R., who also performed the randomisation. Patients were scheduled for
2.
Patients and methods
2.1.
Setting
This single-institution RCT was approved by the local regional committee for medical and health ethics (S-09143c2009/2183) and registered at ClinicalTrial.gov (NCT01347320). All patients signed a letter of consent.
2.2.
Study design
All patients scheduled for robot-assisted laparoscopic prostatectomy (RALP) at Oslo University Hospital, Aker, from December 1, 2009, to June 31, 2012, were candidates for the trial. Table 1 displays the baseline data of the patient cohort. During the study period, 675 patients were scheduled for RALP; 485 met the inclusion criteria, and 438 (90%) were included for intention-to-treat analyses (Fig. 1).
MRI within 2 wk.
2.5.
Sample size estimation
The rate of PSMs is highly associated with the incidence of pT3, and when planning the study, the incidence of pT3 was approximately 45%. For that reason, we expected the rate of PSMs in the non-MRI group to lie between 35% and 40%. A 20% difference in the rate of PSMs between the non-MRI and MRI groups was considered clinically relevant. With a significance level of 0.05, 91–151 in each group was required to provide 80% power with a two-tailed test for two independent proportions, assuming no dropout.
2.6.
Magnetic resonance imaging
The MRI radiologist had 2 yr of experience with prostate imaging at the start of the study. The radiologist was not systematically blinded to prostate-specific antigen (PSA), cT stage, and GS. All patients in the MRI group underwent 1.5-T MRI (Siemens, Erlangen, Germany) and six-
2.3.
Exclusion criteria
channel body matrix (Siemens). The time between biopsy and MRI was 11 7 wk (mean plus or minus standard deviation; range: 0–71) and
Exclusion criteria were previous relevant MRI of the prostate, contra-
between MRI and surgery was 1 4 wk (range: 0–25). No patients were
indications to MRI, and hip prosthesis.
excluded due to haemorrhagic artefacts or poor quality of the MRI.
2.4.
axial diffusion-weighted images (DWIs) using b50, b1000, and b2000. An
The sequences included 0.9-mm isotropic three-dimensional T2 and
Randomisation
apparent diffusion coefficient map was prepared from b50 and b1000. Allocation (1:1) of patients to either non-MRI or MRI was based on a
The MRI acquisition and postprocessing were previously reported in
permuted block randomisation procedure with undisclosed and variable
detail [12]. We used criteria for tumour detection and staging as
blocking factor. After consent was received, each patient was designated
previously specified [2,5,13–16]. Both T2 and DWI were used for
a unique, unchangeable sequentially numbered randomisation number,
detection and staging.
matching an opaque and sealed envelope, containing the corresponding
All patients also underwent axial and coronal T1-weighted imaging
intervention code (eg, non-MRI or MRI). It was not possible to replace
of the pelvis and the lumbosacral spine to evaluate possible lymph node
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Number of patients referred to RALP during trial period (n = 675) Excluded (n = 189)
Enrolment
Randomised (n = 485)
MRI (n = 245)
Allocation
Previously performed MRI (112) Contraindications to MRI (23) Did not wish to participate (10) Treated at other hospital (9) Unknown (35)
no MRI (n = 240)
Excluded (n = 25) Withdrawn consent (3) No surgery was performed Referred to radiation or hormonal therapy (9) Cancelled surgery (10) Other (3)
Excluded (n = 23) Withdrawn consent (8) No surgery was performed Skeletal metastases on MRI (4) Referred to radiation therapy (1) Cancelled surgery (9) Underwent surgery in another country (1)
Patients included for intention-to-treat analysis (n = 222)
Patients included for intention-to-treat analysis (n = 216)
Underwent MRI (203) Did not undergo MRI (19) Contraindications to MRI (5) Change in surgical date (6) Did not meet (3) Other (6)
Underwent MRI (2) Previous MRI became known Referred to MRI and rebiopsy Did not undergo MRI (214)
RALP Fig. 1 – Trial profile using the Consolidated Standards of Reporting Trials 2010 guidelines. MRI = magnetic resonance imaging; RALP = robot-assisted laparoscopic prostatectomy.
and skeletal metastases. These findings are not discussed in this paper.
as a standard bilateral extrafascial dissection or as an extended excision.
The MRI examination was completed within 20 min.
The operator registered (1) the surgical plan before knowing the MRI results, (2) the surgical plan after knowing the MRI, and (3) the means by
2.7.
Communication with urologists prior to surgery
which the surgery actually was performed. We did not register whether MRI resulted in more extensive surgery anteriorly or at the bladder neck.
A schematic tumour map displaying the location and extent of the
The planned surgical approach was based on the preoperative
tumours (indicated in red), including possible EPE and seminal vesicle
parameters available that included transurethral ultrasound (TRUS),
invasion, was drawn manually for every patient (Fig. 2) and shown to
digital rectal examination (DRE), GS, tumour extent in biopsies, and
the surgeon before surgery in each case. In addition, the MRI information
patient’s wish. When available, MRI was also taken into consideration.
was registered in the electronic patient record system. Postoperatively, the surgeon completed a form, in which he reported whether, and in what way, MRI had changed the surgical approach.
2.8.
Surgery
RALP was limited to four experienced urologists at the department. The urologists had performed an average of 103 RALP procedures (range: 78–165), and a total of 415 laparoscopic prostatectomies (range: 296–585) at the start of the study. Figure 2 illustrates the possible approaches for the surgical dissection. The operations were classified as bilateral nerve-sparing surgery (BNS), unilateral nerve-sparing surgery (UNS), or non–nerve-sparing surgery
2.9.
Pathologic preparation and examination
Whole-mounted histologic sections were used as the reference standard. Specimen handling was previously described in detail [2]. The surgical margins were classified as positive when cancer tissue was present on the inked surface of the prostate specimen. The sector associated with each PSM was registered on a tumour map (Fig. 3). If a specific tumour affected the same sector as the site of the PSM, it was classified as responsible for the PSM. Each tumour and sector associated with PSMs was classified as detected by MRI or not.
2.10.
Clinical, radiologic, and pathologic T classification
(NNS). Nerve-sparing surgery included both intra- and interfascial
The staging results of the clinical examination and MRI were previously
dissection, as described by Walz et al [10]. The NNS could be performed
reported in detail [5] and are only briefly reported in Table 2.
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n
sio on ci ic si g ex x n n g e ri io in -spa xcis r a ve e p s er ed erv n-n nd Ne No Exte
Basis Right
Le
Basis NVB Middle
Apex
Middle
Ant. fibromuscular stroma
Transion zone Ant. lat. Post. med. Post. lat.
Apex
Fig. 2 – The 30-sector tumour map used for registration of all tumours at magnetic resonance imaging and histology served as the basis for correlation analysis. All suspected tumours were marked in red, and any extraprostatic extension was indicated. The map was then presented to the surgeon before surgery. The three possible planes of dissection are indicated with stippled lines. Extended and non–nerve-sparing surgery was combined for statistical analyses. Figure adapted by Kari C. Toverud from Girouin et al. Eur Radiol. 2007;17:1498–509, with permission from Springer. # Kari C. Toverud. Ant. = anterior; lat. = lateral; med. = medial; NVB = neurovascular bundle; Post. = posterior.
Preoperative DRE and TRUS, performed by urologists, classified all
3.
Results
patients as having clinically localised (cT1c or cT2a–c) or nonlocalised disease (cT3a–b). Due to a low number of cT3a–b cases, these patients were combined with cT2a–c in the statistical analyses. Correspondingly, MRI (rT) and histopathology (pT) classified all patients as localised (T2) or nonlocalised (T3).
2.11.
Statistical analyses
A total of 438 patients were included in this study, in which 216 were randomised to the non-MRI group and 222 were randomised to the MRI group (Fig. 1). Table 1 shows that the groups were well balanced. 3.1.
Magnetic resonance imaging tumour detection results
The rate of PSMs in the non-MRI and MRI groups was the primary end point. Clinical subgroups were defined according to the T classification, D’Amico risk groups, GS, and surgical procedures. The Pearson chi-square or Fisher exact test assessed differences in the rate of PSMs between the non-MRI and MRI groups and in clinical subgroups. The proportions of PSMs and odds ratios (ORs) with 95% confidence intervals (CIs) were used to describe the differences. Both absolute and relative differences (risk ratio) are reported. Differences in the ORs of the clinical subgroups were examined by the interaction term between the non-MRI and MRI group variable and the clinical subgroup variable using logistic regression. All analyses were performed according to the intention-to-treat principle. Two-sided p values were given and not corrected for multiple testing. IBM SPSS Statistics v.22 (IBM Corp., Armonk NY, USA) and MedCalc statistical software v.14.8.1 (MedCalc Software, Ostend, Belgium) were used for statistical analyses.
MRI tumour detection rates and staging results of this cohort were reported in two previous papers and are only mentioned briefly [2,5]. MRI detected 92% of the index tumour; it did not detect the index tumour in 16 patients. However, in 5 of these 16, MRI detected the second largest tumour with identical GS as the index tumour. In 11 patients with specimen GS 6 and 7, no tumour was found on MRI. 3.2.
Surgical procedures
The surgeons reported that MRI altered the surgical procedure on one or both sides in 59 patients (27%), of which 30 (51%) were cT1, 29 (49%) were cT2, and 49 (83%) were rT3. All changes were in the direction of a more radical excision. There was no difference in mean age, PSA, and GS in biopsy of
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No MRI
MRI
Basic
Basic
Right
Middle
Le
Right
Ant. fibromuscular stroma
Middle
Transion zone
Le
Ant. fibromuscular stroma
Transion zone Ant. lat.
Post. med.
Ant. lat. Post. med.
Post. lat.
Post. lat.
Apex
Apex
Fig. 3 – Distribution of positive surgical margin (PSM) sites is marked with small circles. The PSM sites ventral to the basal urethra represent the bladder neck. Both the apex and the base are at high risk for PSMs. Figure adapted by Kari C. Toverud from Girouin et al. Eur Radiol. 2007;17: 1498–509, with permission from Springer. # Kari C. Toverud. Ant. = anterior; lat. = lateral; med. = medial; MRI = magnetic resonance imaging; Post. = posterior.
patients with adjusted surgery compared with those with nonadjusted surgery. BNS was performed in 35 of 90 patients (39%) classified as rT2 versus 15 of 110 (14%) for rT3 (p < 0.001). The overall rate of BNS, UNS, and NNS was 30%, 34%, and 35%, respectively. The absolute rate of BNS was 6.7% (95% CI, 2 to 16; p = 0.12) lower in the MRI group compared with
Table 2 – The performance of magnetic resonance imaging and digital rectal examination/transrectal ultrasound for detecting pT3 disease Sensitivity, % (95% CI) MRI All patients cT1 cT2–3 DRE/TRUS
the non-MRI group (Table 3). This difference was mainly due to a 13% (95% CI, 1–25; p = 0.024) lower rate of BNS in patients with cT2–3 (Fig. 4). 3.3.
There were 49 cases (23%) of PSMs in the non-MRI group and 43 (19%) in the MRI group (Table 4). The relative and absolute reduction was 15% (0.85; 95% CI, 0.6–1.2) and 4% (95% CI, 4 to 10; p = 0.4), respectively. The number needed to treat was 25, and two extra nerve resections (1.7%) were performed for each PSM avoided.
Specificity, % (95% CI)
3.4. 73 56 88 4
(63–81) (41–70) (76–95) (2–8)
Overall risk of positive surgical margins
65 70 55 98
(54–74) (57–81) (36–72) (95–99)
CI = confidence interval; DRE/TRUS = digital rectal examination/transurethral ultrasound; MRI = magnetic resonance imaging.
Risk of positive surgical margins in patient subgroups
MRI did not reduce the rates of PSMs in cT2–3, whereas in cT1, the relative and absolute reduction was 41% (0.59; 95% CI, 0.4–0.9) and 11% (95% CI, 2–22; p = 0.035), respectively (Tables 3 and 4). There was no benefit of MRI in any other subgroups.
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Table 3 – Positive surgical margin rate with respect to surgical procedure, cT stage, and Gleason score in biopsy Non-MRI (n = 216) Total
Bilateral nerve-sparing surgery DRE cT1 cT2–3 Gleason score in biopsy 6 7a 7b 8 9 All patients Unilateral nerve-sparing surgery DRE cT1 cT2–3 Gleason score in biopsy 6 7a 7b 8 9 All patients Non–nerve-sparing surgery DRE cT1 cT2–3 Gleason score in biopsy 6 7a 7b 8 9 All patients
MRI (n = 222) PSM
Total
PSM
n
%
n
%
n
%
45 28
49 67
11 2
24 7.1
46 14
51 33
34 26 8 5 73
53 54 62 63 NA 33
7 3 2 1 NA 13
21 12 25 20 NA 18
30 22 5 3 0 60
29 42
42 51
6 9
21 21
29 26 6 10
58 43 30 56
4 7 1 3
71
47
40 32 16 27 6 22 1 72
n
%
p
5 2
11 14
0.089 0.5
47 46 38 34 NA 25
2 5 0 0 NA 7
7 23 0 0 NA 12
0.11 0.3 0.2 0.4
40 40
58 49
7 7
16 19
0.7 0.7
14 27 17 30
23 35 14 8
42 57 70 44
1 8 3 2
4 23 17 25
0.3 0.7 0.8 0.8
15
21
80
53
14
18
0.6
51 43
14 7
35 23
39 43
49 57
8 14
19 30
0.15 0.3
48 46 40 58 11 47
3 7 3 8 0 21
19 26 50 36 0 29
17 32 9 16 8 82
52 54 60 42 89 53
2 10 5 3 2 22
12 30 50 19 25 27
0.6 0.7 0.8 0.2 0.6 0.7
p*
0.15
0.6
0.3 0.9
0.7
0.086
0.7
DRE = digital rectal examination; MRI = magnetic resonance imaging; NA = not available; PSM = positive surgical margins. The p value for interaction.
*
Rates of PSMs in patients with adjusted and nonadjusted surgery were 25% and 17%, respectively (8% difference; 95% CI, 4 to 22; p = 0.17). Most patients with PSMs underwent UNS or NNS; 36 of 49 (73%) in the non-MRI group and 36 of 43 (84%) in the MRI group (11% difference; 95% CI, 8 to 29; p = 0.2). For patients classified as rT3, the rate of PSMs was 25%; 89% of these patients underwent either UNS or NNS (Fig. 5). 3.5.
Distribution of positive surgical margins and the
4.
Discussion
The present study is the first RCT to evaluate the benefit of MRI prior to RALP. We could not demonstrate a significant reduction in the rate of PSMs for either the whole cohort or patients with pT3. However, we found a 41% lower rate of PSMs in patients with cT1 (p = 0.035), although this was not statistically significant in the context of multiple testing. The rate of PSMs varies significantly in the literature, and our results are within acceptable limits [17,18].
associated tumour 4.1.
There were 126 sites of PSMs in 92 specimens (Fig. 6). Sixty patients had a single PSM site; 32 had more than one. The index tumour was the responsible tumour in 89% of all cases of PSMs, and 60% were associated with EPE at the same location. MRI detected 92% of all tumours related to PSMs. The base and apex were at higher risk for PSMs (Fig. 3). The risk of ventral PSMs in the apex was higher in the non-MRI group (12%; 95% CI, 3 to 23; p = 0.072).
Effect of magnetic resonance imaging on surgical approach
MRI changed the surgical strategy in 29%, all in the direction of more radical excision. Other studies have reported that MRI affected the surgery in a radical direction in only 33–39% [19–21]. None of these studies had a control arm without MRI, making comparison difficult. Most of the patients with PSMs had undergone UNS or NNS in both the non-MRI and MRI group. Also, when MRI suggested T3, 89% of those with PSMs had undergone either
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UNS or NNS (Fig. 5). This suggests that even more extended excisions are required to reduce the rate of PSMs. 4.2.
Rate of positive surgical margins in patients with cT1
Surprisingly, the greatest benefit of MRI was seen in patients with cT1. This was unexpected because the sensitivity of MRI for predicting pT3 in this group was poor (Table 2), and surgical procedures were not significantly different between the non-MRI and MRI group (Fig. 4). This suggests that the primary value of MRI was to provide the surgeon with accurate information about tumour location and extension, whereas staging was of secondary importance. 4.3.
Possible mechanisms for improved outcome in cT1
This study cannot explain the exact mechanisms for the reduced rate of PSMs in patients with cT1. However, one possibility may be excellent tumour visualisation on MRI, also in patients with cT1, whereas DRE and TRUS are normal. This probably favours selection of the proper surgical procedure, and it may have prevented dissection too close to the index tumour or changed the surgery in ways not registered in this study. For instance, in case of a ventral cancer with extraprostatic disease, it is possible to perform a combination of BNS and extended excision ventrally.
Fig. 4 – In patients with cT1, the relative risk of positive surgical margins (PSMs) was 41% lower in the magnetic resonance imaging (MRI) group, and there was a reduction in PSMs regardless of the surgical procedure. There was no significant difference in the surgery between the two groups. Unexpectedly, in patients with cT2–3, the overall PSM rate increased by 6% (95% confidence interval, S6 to 18; p = 0.4) in the MRI group, despite the fact that unilateral nerve-sparing surgery and non– nerve-sparing surgery were performed 13% more frequently in the MRI group. BNS = bilateral nerve-sparing surgery; MRI = magnetic resonance imaging; NNS = non–nerve-sparing surgery; PSM = positive surgical margins; UNS = unilateral nerve-sparing surgery.
4.4.
Importance of the index tumour and positive surgical
margins site
The index tumour was the source of PSMs in 89% of the cases (Fig. 6). This illustrates the relevance of locating the index tumour before surgery and is in accordance with a 2012 study [22]. However, despite the fact that MRI detected 98% of these tumours, the rate of PSMs did not improve for the whole cohort. If the MRI findings are
Table 4 – Rate of positive surgical margins in the non–magnetic resonance imaging (MRI) and MRI groups Non-MRI (n = 216)
All patients DRE cT1 cT2–3 D’Amico risk classification Low Medium High pT stage 2 3 Gleason score in specimen 6 7a 7b 8 9
Total, n
PSM, n
216
49
114 102
MRI (n = 222) %
Total, n
PSM, n
%
p
OR
95% CI
23
222
43
19
0.4
0.81
0.5–1.3
31 18
27 18
125 97
20 23
16 24
0.035 0.3 0.8*
0.51 1.53
0.3–0.9 0.7–2.9
55 103 58
7 24 18
13 23 31
57 114 51
3 25 15
5.3 22 29
0.38 0.93 0.41
0.1–1.6 0.5–1.7 0.4–2.1
111 105
9 40
8.1 38
103 119
5 38
4.9 32
0.58 0.76
0.2–1.8 0.4–1.3
59 83 44 23 7
9 17 11 9 3
15 20 25 39 43
57 87 48 22 8
7 14 14 6 2
12 16 29 27 25
0.78 0.75 1.21 0.58 0.44
0.3–2.3 0.3–1.6 0.5–3.1 0.2–2.1 0.1–4.0
*
p
0.029
0.8
0.7*
0.7
0.8*
0.8
CI = confidence interval; DRE = digital rectal examination; MRI = magnetic resonance imaging; OR = odds ratio. OR 1 indicates an increased risk. * The p value for interaction: A significant interaction p value indicates that the ORs of the subgroups are significantly different.
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Fig. 5 – Bilateral nerve-sparing surgery was chosen in 15 of 110 patients (14%) when magnetic resonance imaging (MRI) suggested T3 disease. For unknown reasons, the surgeon chose not to consider the MRI findings. Six of the patients turned out to have pT3 in which two had positive surgical margins (PSMs); the remaining nine were pT2 and one had PSM. In 95 of 110 patients (86%), the surgical procedure harmonised to a larger extent with the MRI finding; however, 24 of 27 patients (89%) with PSMs were found in this group. This illustrates that the degree of non–nerve-sparing excision was not sufficient. BNS = bilateral nerve-sparing surgery; MRI = magnetic resonance imaging; NNS = non–nerve-sparing surgery; NSM = negative surgical margins; PSM = positive surgical margins; UNS = unilateral nerve-sparing surgery.
Fig. 6 – The associated tumour for each case of positive surgical margins (PSMs) and whether magnetic resonance imaging (MRI) detected it or not. Also shown is whether the PSMs were associated with extraprostatic extension in the same area. MRI identified most tumours and sectors associated with PSMs, suggesting that the surgeons did not sufficiently consider the MRI findings. EPE = extraprostatic extension; MRI = magnetic resonance imaging; PSM = positive surgical margins.
included in the planning of surgical approach to a larger extent, it represents a considerable potential for improvement in the future. The MRI group experienced a lower rate of PSMs in the ventral apex (Fig. 3), although the prognostic value of this is controversial [23,24]. 4.5.
Magnetic resonance imaging protocol
This study used a simple MRI protocol, without contrast medium and endorectal coil, compared with the current
European Society of Urogenital Radiology recommendation [25]. Nevertheless, we achieved similar detection and staging results as those who have used the current recommendation [2,4,5,26,27]. This may indicate that a simple protocol is truly sufficient, although no studies have compared the different protocols on the same cohort, and direct comparison of results is difficult. Alternatively, our high rate of large tumours with pT3 resulted in extraordinary results. From a surgical point of view, it is critical to stress that MRI tumour detection is highly sensitive in most studies;
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staging remains the weakest element. For this reason, urologists are encouraged to consider tumour location more than rT classification when deciding surgical strategy.
9
(eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
4.6.
Limitations
This study has some possible limitations. First, the study was underpowered to demonstrate a significant effect of MRI because the observed rate of PSMs was approximately half of the expected rate. Because all subgroup analyses were not defined a priori, one should interpret the findings in cT1 with caution and instead conduct future studies. Second, more patients were referred to radiation therapy in the non-MRI group after randomisation. This may be an indicator of more advanced disease, likely to result in PSMs. Consequently, it may have reduced the effect of MRI. Third, the radiologist was not fully blinded to clinical data. This might have affected the MRI results and consequently patient handling. Fourth, there was suboptimal communication between the radiologist and the urologist during this study. This is probably the most important reason why the difference in the rate of PSMs between the two groups was not larger. We believe the radiologists and the urologist should coinvestigate MRI images prior to surgery because only reading a written report or looking at a schematic drawing is suboptimal when planning surgery.
References [1] Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Update 2013. Eur Urol 2014;65:124–37. [2] Rud E, Klotz D, Rennesund K, et al. Detection of the index tumor and tumor volume in prostate cancer using T2w and DW MRI alone. BJU Int 2014;114:E32–42. [3] Turkbey B, Mani H, Aras O, et al. Correlation of magnetic resonance imaging tumor volume with histopathology. J Urol 2012;188: 1157–63. [4] Le JD, Tan N, Shkolyar E, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. Eur Urol 2015;67: 569–76. [5] Rud E, Klotz D, Rennesund K, et al. Preoperative magnetic resonance imaging for detecting uni- and bilateral extraprostatic disease in patients with prostate cancer. World J Urol. In press. [6] van der Kwast TH, Amin MB, Billis A, et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and prostate cancer volume. Mod Pathol 2010; 24:16–25. [7] Baco E, Ukimura O, Rud E, et al. Magnetic resonance imaging-
5.
Conclusions
We showed that the index tumour, usually detected by MRI, is the most frequent cause of PSMs. We did not find an overall reduction in the rate of PSMs in patients randomised to MRI, although subgroup analysis revealed a possible benefit in patients with cT1. Our study suggests more radical resection should be performed in the index tumour region and that future studies should focus on MRI-guided RP. In the MRI group, slightly more nerve resections were performed, which can be considered a potential negative effect of MRI. More studies are needed to evaluate the role of MRI before prostatectomy.
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Author contributions: Erik Rud had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Rud, Eggesbø, Eri. Acquisition of data: Rud, Klotz, Svindland, Wessel, Berg, Berge, Hoff, Rennesund, Lundeby. Analysis and interpretation of data: Rud, Eri, Baco. Drafting of the manuscript: Rud, Eri, Baco. Critical revision of the manuscript for important intellectual content: Rud, Eri, Baco, Eggesbø. Statistical analysis: Rud, Diep. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Rud, Eggesbø. Other (specify): None.
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Financial disclosures: Erik Rud certifies that all conflicts of interest,
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including specific financial interests and relationships and affiliations
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