The Precision Prostatectomy: an IDEAL Stage 0, 1 and 2a Study

IDEAL stage 0: conceptualization of the technique and preclinical simulation

We retrospectively analyzed 100 consecutive whole-mount radical prostatectomy specimens from patients that had undergone robotic radical prostatectomy (January 2016–January 2017) and satisfied the following criteria: (1) prostate-specific antigen (PSA) ≤15 ng/mL, (2) stage ≤cT2, (3) dominant unilateral lesion with Gleason score ≤4+3 with any number of cores or % cores involved ipsilaterally on transrectal ultrasound (TRUS) prostate biopsy, and (4) no primary Gleason score ≥4 contralaterally on TRUS prostate biopsy; these inclusion criteria were based on prior focal therapy studies.10 17 In the IDEAL stage 0 part of the study, we examined the whole-mount radical prostatectomy specimens, to

1. Map the CaP lesions, including grade and tumor diameter.

2. Determine the distribution of lesions that were below the size limit of mp-MRI detection, usually defined as 10 mm in diameter or 0.5 cm∧3.18

3. Simulate a “what if” scenario to examine residual cancer rates, if these men were treated with focal or hemiablation rather than with conventional prostatectomy.

4. Use the risk estimates generated in this stage to develop a novel technique—the precision prostatectomy—that removes the entire hemi prostate and seminal vesicle complex on the side of the index lesion, but leaves a thin rim of prostatic capsule (5–10 mm) on the side contralateral to the dominant lesion.

IDEAL stage 1/2a: study population, informed consent and surgical technique

We examined the feasibility of precision prostatectomy in eight carefully selected men who were desirous of focal therapy to the prostate (IDEAL stage 1/2a). These men were evaluated and treated over a 6-month period, between January and July 2017, allowing a minimum follow-up of 24 months. All men placed high priority on preservation of erectile function and sought out the treating surgeon specifically requesting focal therapy. No man was a candidate for active surveillance, and all met the following criteria: (1) PSA ≤15 ng/mL, (2) stage ≤cT2, (3) dominant unilateral lesion with Gleason score ≤4+3 with any number of cores or % cores involved ipsilaterally on TRUS prostate biopsy, (4) no primary Gleason score ≥4 contralaterally on TRUS prostate biopsy, and (5) preoperatively potent without phosphodiesterase type 5 (PDE-5) inhibitors. Data collection was under an ongoing protocol approved by the Institutional Review Board, and in compliance with Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations. Informed consent was obtained from all patients. The patients were apprised of the experimental nature of the procedure, and the fact that the risks could not be accurately estimated given the novelty of the procedure. Patients were required to review the informational material for at least 7 days before they were considered for precision prostatectomy. Failing this in-home evaluation, patients were assigned to conventional radical prostatectomy.

Patient positioning, port placement, developing the space of Retzius and prostatic pedicle dissection followed our standard anterior Vattikuti Urology Institute technique of prostatectomy.19 20 However, in the precision prostatectomy, standard nerve-sparing radical prostatectomy was undertaken on the side of the dominant lesion. On the contralateral side, the dissection was started anterior to the vas deferens/seminal vesicle complex, preserving all layers of Denonvilliers' fascia, with the included erectogenic nerves.21 22 The dissection was continued 5–10 mm into the prostatic capsule, deliberately attempting to leave behind a thin rim of prostatic capsule (5–10 mm) along with the seminal vesicle/ejaculatory duct complex. Systematic needle biopsies (via a suprapubic approach) were taken from the remnant prostatic tissue, and sent for frozen section analysis. Completion prostatectomy was performed if the frozen biopsies showed residual cancer. Vesicourethral anastomosis was performed as previously described.19 20 The patients received a Foley or suprapubic tube per patient choice.

For the stage 1/2a study, our goals were to assess:

1. The safety and feasibility of the technique.

2. Continence and potency outcomes.

3. Short-term oncological control as assessed by biochemical recurrence (using the American Urological Association (AUA) definition of biochemical recurrence following radical prostatectomy or the ASTRO criteria used for radiation or focal therapy) and protocol biopsies of residual tissue.

IDEAL stage 0 and 1/2a: variables, endpoints and definitions

For each patient (stage 1/2a), the following clinical parameters were noted: age at surgery, body mass index, comorbidities, American Society of Anesthesiologists score, preoperative PSA, clinical tumor stage (cT), and biopsy Gleason score, total number of cores on biopsy, number of positive cores on biopsy and percentage core positivity. Operative parameters collected included total operative time, console operative time, estimated blood loss, intraoperative complications and need to convert to radical prostatectomy. Pathological parameters collected included pathologic Gleason Score, pathological tumor stage (pT) and surgical margin status (negative vs positive). The prostatectomy specimens were sectioned and processed according to the previously described methodology by Ruijter et al.23 Briefly, after fixation and marking of surgical planes with dye, radical prostatectomy specimens were cut into serial parallel transverse 4 mm thick slices. Following histological processing and complete embedding, 4 µm tissue sections were stained with H&E. All the tumor nodules were outlined in ink on the coverslips of all the slides. The whole tumor was mapped and reconstructed, and the three-dimensional (3D) shape and size of the tumor was determined. For calculating the maximum dimension of tumor, apart from the largest dimension on a single slide, the longitudinal contiguous tumor dimension across sequential sections was also taken into account. This dimension was calculated by multiplying the thickness of slice by the number of sections in which tumor was present. Postoperative complications noted included need for blood transfusion, urinary tract infections, lymphoceles, deep venous thrombosis (DVT), pulmonary embolus (PE), pneumonia, myocardial infections and death for 30 days after surgery. Preoperative and postoperative urinary and sexual function assessments were performed using the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF-5) questionnaires. Postoperative PSA was collected at 4, 8 and 12 months postoperatively. Biochemical recurrence (BCR) was defined using American Urological Association (AUA) criteria for BCR following radical prostatectomy.24 All patients were followed for at least 12 months.

Definitions: for stages 0 and 1/2a, unilateral disease (preoperative) was defined as cancer limited to only one side of the prostate on 12 or more cores of TRUS-guided biopsy, while bilateral disease included both sides (the same definition was utilized for whole-mount analysis). A dominant lesion on biopsy was defined as the lesion with the highest grade, and in case, two or more lesions had the same Gleason score, the lesion with the greatest core length positivity was designated as the dominant lesion. A dominant nodule was the lesion with highest grade on final pathology, and similar to the dominant lesion on biopsy, if two or more nodules had the same Gleason score, the larger nodule was designated as the dominant nodule. Clinically significant cancer was defined as a lesion with Gleason score ≥3+4, based on prior focal therapy studies.10 11

Nomenclature: A focus group of 30 men, including those in this report, were asked to come up with a name for the procedure or to choose from a menu of options: focal surgery, focal prostatectomy, subtotal prostatectomy, precision surgery, precision prostatectomy or capsule preserving prostatectomy. The consensus of the men was precision prostatectomy (29/30 men), with term “Menon” added on by patient request because a majority wanted to assign the credit (or the blame) to the treating surgeon (Menon precision prostatectomy (MPP)).

Statistical analyses

Descriptive statistics of categorical variables focused on frequencies and proportions. Medians and (IQR) were reported for continuously coded variables. Kaplan-Meier estimates were constructed to assess 12-month urinary continence and sexual potency rates. Statistical analyses were performed using the R statistical package (R Foundation for Statistical Computing, Vienna, Austria), considering a statistical significance at two-sided p<0.05.

IDEAL stage 0: baseline characteristics

The median (IQR) age and PSA were 61 (58–66) years and 5.1 (4.1–7.8) ng/mL, respectively, in the 100 patients in the preclinical study. The clinical stage was cT1 in 79% (n=79) of the patients, and cT2 in the remaining. The biopsy Gleason was 3+3 in 21% (n=21), 3+4 in 53% (n=53) and 4+3 in 26% (n=26). The median (IQR) number of cores positive on biopsy were 4 (3–6). On transrectal biopsies, 48 men had disease located to one half of the prostate and 52 had bilateral disease.

IDEAL stage 0: whole-mount radical prostatectomy specimen analysis, and MPP and focal HIFU simulation analysis

In prostate mapping studies of the whole-mount radical prostatectomy specimens, 96% of the patients had cancers involving at least a part the peripheral zone, defined as within 5–10 mm of the prostatic capsule; the remaining 4% patients had anterior zone tumors only. Seventy-one per cent (71%) of the men had clinically significant disease (Gleason score ≥7) in the peripheral zone, within 5–10 mm of the prostatic capsule (figure 1).

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In all 100 patients, a dominant nodule was identifiable. Ninety-eight men had additional satellite lesions smaller than 0.5 cc in volume—46 on the side of the dominant lesions and 52 in the contralateral lobe. Seventy-two per cent (72%) of the patients had bilateral disease on whole-mount analysis (figure 1 provides further details).

If all 100 men in the modeling cohort had been treated with focal ablation, all men except 1 would have had residual Gleason ≥6 cancer. Further, only 25 patients would have qualified for focal therapy, given the recommended prostate weight cut-off of 40 g for HIFU. In these 25 men, 44% would have had residual Gleason 3+4, 16% Gleason 4+3, 4% Gleason 4+4% and 4% Gleason 4+5 disease (figure 2), given that focal HIFU spares 5–10 mm of peripheral tissue on the treatment side and does not treat the contralateral side. Thus, only 8 men of the original 100 would have been eligible and completely treated in the modeling cohort. With hemiablation, 44 men would have had complete cancer ablation, 56 men would have had residual cancer and 21 would have clinically significant cancer (Gleason 7 or higher).

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In the simulation analysis, if these men had undergone MPP with preservation of 5–10 mm of tissue on the contralateral side, no patient of the 48 with unilateral disease would have had clinically significant cancer (≥Gleason 7) in the preserved tissue. If patients with bilateral disease (n=52) had undergone MPP, 19.2% would have had Gleason 3+4% and 7.6% Gleason 4+3 disease left behind (figure 3). Hence, overall in these 100 patients, 14% of the patients would have had clinically significant (Gleason 3+4, n=10, Gleason 4+3, n=4) disease left behind after simulated MPP, while 86% would have avoided whole-gland therapy.

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IDEAL stage 1/2a: baseline characteristics, modifications to technique and outcomes

Baseline characteristics are provided in table 1. Eight patients underwent MPP. Median (IQR) age and PSA were 54 (52–57) years and 4.4 (3.8–6.1) ng/mL, respectively. All patients were potent preoperatively with a median IIEF-5 score of 24. The majority of the patients had cT1 disease, 62.5% (n=5). The biopsy Gleason score was 3+4 in 50% (n=4); the remaining 4 had 3+3 disease. The median (IQR) number of cores positive on biopsy were 3.5 (2–5). Seventy-five (n=6) per cent of the patients had unilateral disease on biopsy. None of the eight patients met the Epstein criteria for active surveillance.25

Two surgeons (MM and WJ) were involved in the procedure, with MM being the supervising surgeon in all cases. Median (IQR) console time was 134 (108–148) min. Hemostasis was accomplished with a cautery: no hemostatic agents were used. There were no complications intraoperatively or postoperatively. None of the procedures were converted to conventional radical prostatectomy (table 2). One modification to technique was made during the series: intraoperative ultrasound was introduced after the first two cases, to measure the depth of residual tissue left in situ. This was between 4 and 10 mm in all six men, confirming that the intent had been achieved. On final pathology, five men (62.5%) had pT2c disease. No patient had a positive surgical margin on the side of the radical prostatectomy, while two patients had a positive margin at the site of precision prostatectomy, but a negative frozen section of the capsular tissue. One of the two patients with positive surgical margins on the specimen site had Gleason 3+4 disease at the affected margin, while the other had Gleason 3+3. Follow-up protocol biopsy of the remnant tissue showed focal Gleason six cancer in the former patient, and no cancer in the latter.

At 12 months from surgery, all patients had recovered urinary continence and sexual potency. The median (IQR) time to urinary continence was 1 (1–2.5) month and for sexual potency was 4 (4–10) months, with seven of the eight (87.5%) patients potent by 4 months. The median (IQR) 12-month IPSS and IIEF-5 scores were 3 (2–4) and 21 (19–25), respectively. The median (IQR) PSA was 0.2 (0.1–0.4) ng/mL at 12 months, and the PSAs remained stable at 24–30 months of follow-up. Per the AUA definition for biochemical recurrence following radical prostatectomy, two of the eight (25%) patients had biochemical recurrence within 12 months (table 2). None (0%) of the patients would have been considered to have a biochemical recurrence, per the ASTRO criteria.26 The PSA values of the two patients with BCR (per the AUA criteria) were 0.4 and 0.7 ng/mL at 12 months.

Two men with an undetectable PSA and excellent functional outcomes declined protocol biopsies. Four men had protocol biopsies in the absence of PSA recurrence, and none had evidence of cancer (median (range) cores: 8 (8-15)). Two patients with PSA recurrence (one with a positive and one with a negative surgical margin) underwent prostate transrectal ultrasound-guided biopsy at 12 months. Both patients had focal Gleason 3+3 cancer in the remnant and are on active surveillance. All four patients without biochemical recurrence had a combination of benign prostatic tissue and fibromuscular tissue on biopsies. No patient had required additional therapy at their last follow-up (24–30 months).