Photoselective Vaporization of the Prostate in the Management of Lower Urinary Tract Symptoms in Prostate Cancer Patients on Active Surveillance

Abstract

Objectives:

To demonstrate the safety and efficacy of photoselective vaporization of the prostate in alleviating refractory lower urinary tract symptoms in prostate cancer patients who are managed with active surveillance and to explore the association of this procedure with PSA levels and cancer progression rates.

Methods:

Between 2008–2018, active surveillance patients who had refractory symptoms and needed surgery were studied. Perioperative functional variables were collected and analyzed. Disease progression was defined as an upgrade or upstage on surveillance biopsies or mpMRI’s. Mean post-op scores were estimated using locally-weighted methods. The risk of progression was reported using Kaplan-Meier’s method.

Results:

Seventy-one patients were included in the study. The median age was 68 yrs and the median surveillance time before surgery was 4 yrs. At 12 months, there were substantial improvements in the mean International Prostate Symptom Score (18 to 5.9), maximum flow rate (6.8 to 14 ml/s), post-void residual (240 to 73ml), PSA (8.1 to 5.2 ng/ml), and prostate volume (85 to 57ml).

At 30-days, only two patients with grade-III complications. Late consequences included tissue regrowth in four and urethral stricture (requiring a single dilation) in three patients. PSA levels decreased by 36% at 12 months post-operatively. With a median follow-up of 3.7 years, seven men progressed and received radical treatment. At three years, the probability of remaining on surveillance was 93% (95% CI 87%- 100%).

Conclusions:

Photoselective vaporization of the prostate offers substantial relief of symptoms in active surveillance patients with refractory symptoms, without adverse effects on disease progression rates.

Introduction:

Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the US.¹ Approximately one-third of newly diagnosed PCa patients have low-risk disease,² for which Active surveillance (AS) is the primary treatment option.³ Active surveillance allows patients to avoid or delay the side effects of radical treatment without noticeable adverse oncological, psychological, or quality of life consequences.^4,5

The duration of surveillance has been steadily increasing as clinicians and patients become more confident in the safety of this strategy.^6,7 In the early years of AS adoption, less than 30% of AS patients were treatment-free at 10 years.⁸ In contemporary cohorts, more than half of AS patients will remain untreated at 15 years or longer.⁹

This increase in the adoption and duration of AS, together with the inherent older age at PCa diagnosis,⁸ will put a significant proportion of AS patients at risk of developing lower urinary tract symptoms (LUTS). These LUTS are linked to the age-related overgrowth of the benign component of the prostatic gland (BPH) rather than the concurrent malignant process.¹⁰ This overlap of the two underlying pathological processes is only expected to increase with the increasing number of aging AS patients.

Lower urinary tract symptoms are initially managed with oral medications. However, surgical management may become necessary for those who develop medication intolerance, symptoms progression, or significant consequences of chronic bladder outlet obstruction (BOO) such as bladder stones, recurrent urinary tract infections, and azotemia.¹¹

Without a diagnosis of malignancy, surgical management of BPH with LUTS typically involves endoscopic procedures such as transurethral resection (TURP), Holmium laser enucleation (HoLEP), and laser photo vaporization of the prostate (PVP).¹² However, in PCa patients with LUTS, the choice between these minimally-invasive procedures and the more radical cancer treatments, like radical prostatectomy, is more complicated.

Radical treatments in these patients are definite overtreatment of the underlying indolent malignant process and subject patients to potential life-long consequences.¹³ The alternative minimally-invasive BOO procedures have an established role in benign conditions but their safety, efficacy, and oncological impact in AS patients are not well-described in the literature. Therefore, the most appropriate treatment strategy in this scenario is yet to be defined

The purpose of this study is to report the safety, functional outcome, and oncological impact of a minimally invasive BOO procedure (PVP) in AS patients who required surgical management for their LUTS.

Materials and Methods:

This study is a retrospective analysis of AS patients who were enrolled in our institution’s AS program between 2008–2018. Institutional review board approval was obtained. Patients who underwent surgical intervention (PVP) for bothersome or refractory LUTS while on AS program were included in this analysis.

To enroll in our AS program, all men undergo confirmatory biopsy within 1 yr of diagnosis and undergo multiparametric prostate magnetic resonance imaging (mpMRI). If mpMRI was not performed prior to initial biopsy, it is completed prior to confirmatory biopsy. All confirmatory biopsies are MRI guided if a targetable lesion was identified. Based on our institution’s AS protocol, patients undergo PSA testing and DRE every 6 mo, repeat mpMRI every 18 mo, and follow-up mpMRI and biopsy at 3 yr after the initiation of AS.

Surgical intervention for LUTS was done using the GreenLight XPS 180W Laser System (Boston Scientific, Marlborough, USA). It was done when clinically indicated, irrespective of the timing of the protocol biopsies or mpMRI’s. We analyzed functional outcomes, early (≤ 30-day) and delayed (> 30-day) complications, and the risk of disease progression after PVP. Mean prostate specific antigen (PSA) levels, International Prostate Symptom Score (I-PSS), post-void residual (PVR), maximum urinary flow (Q-Max) on uroflowmetry, and prostate size on mpMRI after treatment was estimated using locally-weighed scatterplot smooth (LOESS). And then on follow up. Post-operative complications were classified according to the Clavien-Dindo Classification ¹⁴ and collected perioperatively, and later during routine follow up. Disease progression was defined as an upgrade or upstage on surveillance prostate biopsies or multiparametric magnetic resonance imaging (mpMRI) that triggered radical treatment. This risk was analyzed using Kaplan-Meier’s method. Measurements after progression were omitted. All analyses were conducted using R 3.6.1 statistical software.

Results:

Our institutional active surveillance program followed 990 PCa patients during the study period. Seventy-one patients underwent PVP for LUTS. Twenty-two (31%) of these patients had urinary retention requiring an indwelling Foley catheter or intermittent catheterization prior to PVP. Most men were grade group 1 (n=69, 97%) at PCa diagnosis and had been on active surveillance for a median of 4.0 years before PVP (Table 1). Twenty-eight patients (40%) had undergone a repeat (surveillance) biopsy before PVP.

Table 1.

Patient Characteristics.

Characteristic	N	N = 711
Age at PVP	71	68 (64, 74)
Diagnosis Gleason Grade Group	71
1		69 (97%)
2		2 (2.8%)
Diagnosis PSA, ng/ml	64	6.3 (4.0, 8.6)
Years from Diagnosis to PVP	71	4.0 (1.9, 6.0)
Highest Complication Grade within 30 days of PVP*
0		61 (86%)
I		4 (5.6%)
II		6 (8.4%)
III		2 (2.8%)
Medical Therapy Before PVP	71	68 (96%)
Indwelling Foley Before PVP	71	22 (31%)

¹Statistics presented: median (IQR); n (%), Dx: Diagnosis; PVP: Laser Photoselective vaporization of the prostate; PSA: Prostate Specific Antigen

^*:According to Clavien-Dindo Classification.

There were substantial improvements in functional outcomes across all time points during the first year. At 12 months, the mean IPSS scores (5.9 down from 18), QMax (14 ml/s up from 6.8 ml/s), PVR (73ml down from 240ml), PSA (5.2 ng/ml down from 8.1 ng/ml) and prostate volume (57ml down from 85ml) have all showed significant improvements (Figure 1 and Table 2).

Figure 1. Functional Outcomes After Photoselective Laser Vaporization of The Prostate in Active Surveillance patients.

PVP: Laser Photoselective Transurethral Vaporization of Prostate; PSA: Prostate Specific Antigen; IPSS: International Prostate Symptom Score; QMax: maximum urinary flow rate on Uroflowmetry; Prostate volume measured by prostate mpMRI in cubic centimeters

Table 2:

Timeline of the Functional Outcomes After Photoselective Laser Vaporization of The Prostate in Active Surveillance Patients.

Months since PVP	Mean Value (95% CI)	Percent Change from Baseline (95% CI)
PSA
0	8.1 (6.1, 11)	—
3	3.9 (3.1, 4.9)	−52% (−65%, −36%)
6	4.1 (3.3, 4.9)	−49% (−63%, −34%)
12	5.2 (3.9, 6.6)	−36% (−51%, −15%)
IPSS
0	18 (16, 20)	—
3	11 (7.9, 13)	−41% (−56%, −26%)
6	8.2 (6.1, 10)	−55% (−67%, −43%)
12	5.9 (4.1, 7.9)	−68% (−77%, −56%)
Post-void Residual
0	240	—
3	77	−68%
6	53	−78%
12	73	−70%
QMax
0	6.8	—
3	13	90%
6	13	88%
12	14	104%
Prostate Volume*
0	85 cc	—
3	83 cc	−3.1%
6	52 cc	−39%
12	57 cc	−33%

PVP: Photoselective vaporization of prostate; PSA: Prostate Specific Antigen; IPSS: International Prostate Symptom Score; QMax: maximum urinary flow rate on Uroflowmetry; cc: cubic centimeters

^*measured by prostate mpMRI.

With a median post-operative follow-up of 3.7 years, 32 patients (45%) had surveillance prostate biopsies and 22 patients (31%) had mpMRI. Seven men experienced prostate cancer progression and required radical treatment. Progression was confirmed by prostate biopsies that were triggered by significant rises in PSA (n=2), suspicious changes on MRI (n=2), or both PSA and MRI changes (n=3). Six of these patients were treated with external beam radiation therapy and one with radical prostatectomy. None of those 7 men developed urinary incontinence or strictures after their definitive cancer treatment. The progression-free probability after PVP was 100% at one year, 93% (95% CI 87%−100%) at 3 years, and 88% (95% CI 79%−98%) at 5 years (Figure 2).

Figure 2. Risk of Prostate Cancer Progression in Active Surveillance Patients after Photoselective Laser Vaporization of The Prostate.

PVP: Laser Photoselective Transurethral Vaporization of Prostate

Overall, complication rates within 30-days were low, with 61 (86%) reporting no complications (Table 1). Delayed consequences included: tissue regrowth requiring repeat PVP or catheterization (n=4, 5.6%), urethral stricture or meatal stenosis requiring a single dilation (n=3, 4.2%), and mild stress incontinence requiring one pad per day in one patient. Only one of the 22 patients who had initially presented with urinary retention developed tissue regrowth that required intervention.

Comment:

Endoscopic procedures for BOO have an established role in the setting of advanced prostate malignancy. For a long time, TURP and PVP have been used as palliative procedures that provide, at least temporarily, relief of symptoms in locally-advanced PCa.^15,16 Similarly, the role of endoscopic BOO procedures in benign prostatic enlargement is very well established, with multiple studies showing its safety and efficacy.^17–19 In localized prostate cancer, however, the role of these procedures remains largely unknown. To our knowledge, this is the first study that describes the efficacy and oncological impact of an endoscopic BOO procedure (PVP) in a localized, low-risk PCa patient cohort.

The demonstratable improvement in functional outcomes in this study is similar to what has been observed in PVP studies done in BPH patients. In the GOLIATH study, which is the only prospective randomized trial that compared 180W PVP to TURP,²⁰ the mean IPSS score in BPH patients decreased from 21.2 to 7.0 at 12-mon follow up. This response is quite similar to what’s observed in our study, where the mean IPSS scores decreased from 18 to 5.9 during the same follow-up period (a decrease of ~67% in both studies). The average decrease in PVR and increase in QMax at 12-mon follow up are also close in the two studies (60% vs. 70% improvement in PVR; 142% vs. 104% improvement in QMax at the GOLIATH and our study, respectively). Interestingly, our study showed comparable results to the GOLIATH study even though the mean prostate volume at baseline was almost double that at the GOLIATH study (85ml vs. 48.6ml). When compared to studies that reported on larger prostate sizes, the 12-mon average decrease in prostate volume in our study (33%) is close to what has been reported in the literature (40%).²¹ It is worthy to note however that some variations in size estimates are expected because of the different methods used in different studies (mpMRI vs. transrectal ultrasound).

These significant improvements in functional outcomes and the reduction in prostate size allowed many of our patients to become potential candidates for radiation therapy in the case of disease progression. In fact, six of the seven patients who progressed in our study have elected to undergo radiation therapy as the definitive treatment of their disease. It is unlikely that these patients would have been considered reasonable candidates for radiation therapy prior to the PVP since high IPSS is known to be associated with unfavorable outcome after radiation.²²

In our study, the average decrease in PSA during the first year of surgery is within what has been reported in BPH studies.²³ At our institution, we do not routinely use PSA level as the sole trigger for radical therapy initiation in AS patients. Nevertheless, it still plays an essential role in the surveillance process and has a recognized impact on the patients’ anxiety and quality of life.²⁴ It is evident that the decrease in PSA is related to the reduction of prostate size rather than any underlying malignant process. However, it is still conceivable that this PSA drop can provide considerable assurance to a significant subset of AS patients who are overly anxious about their PSA levels. The care team, on the other hand, should anticipate new baseline values and adjust the follow-up criteria (such as using PSA density and % free PSA) as needed. As evident in figure 1, PSA values will drop significantly early after PVP but they go up gradually over time.

The essential oncological aspect of this study is evaluating the impact of PVP on PCa disease progression. The progression rate after PVP were low, even though our patients had been on AS for a median of 4.0 years before PVP. This low progression rate can be explained by the subsequent decrease in PSA (which will eliminate some of the PSA-triggered mpMRI’s or expedited biopsies), or by a plausible selection bias where patients with known stable disease are preferentially selected for PVPrather than radical treatment.

Overall, the rate of disease progression in this cohort was not higher than our contemporary institutional rates that were recently published.⁹ This leads us to believe that PVP is, at least, not associated with additional or accelerated risk of disease progression in AS patients with relatively stable disease.

Another oncological aspect of this procedure is the potential missing of higher-grade PCa with tissue ablation. In contrast to TURP and HoLEP, ablative procedures do not remove tissues that can be evaluated pathologically and, hence, have a theoretical risk of missing PCa. A recent national study, however, showed that ablative techniques can miss clinically-significant PCa in only 0.26% of patients, which supports the oncological safety of this procedure.²⁵

The rates of early complications in our study are low. They are comparable to what has been reported in BPH^26,27 and in locally-advanced PCa patients.^16,28,29 Significant late consequences included tissue re-growth (n=4/71, 5.4%) and urethral strictures (n=3/71, 4.2%) requiring interventions. The rates of these consequences are also within the range of what has been reported in the BPH literature (2.2–10.2% and 1.7–7.7%, respectively).^17,30

Our study does have some limitations. As with any retrospective study design, selection bias and incomplete data are inherent potential limitations. Other limitations include the inability to analyze percent-free PSA and sexual function data. Percent-free PSA was not requested routinely on all patients. A large proportion of our patients were sexually inactive at the time of PCa diagnosis, which made subsequent sexual function evaluations less useful. Short follow up is possibly another limitation as longer follow up could potentially provide better estimates of PCa risk progression in this patient population.

Conclusions:

PVP is a safe and effective treatment option for PCa patients who develop bothersome LUTS while on active surveillance. Since patients primarily choose AS to preserve urinary function and quality of life, PVP provides excellent control of symptoms without compromising the prevailing rationale for AS. Larger cohort and longer follow-up are needed to delineate PSA changes over time and the durability of results.