Introduction

Parts of this chapter are reproduced from Worthington et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Parts of this chapter are reproduced from Hashim et al.2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Scientific background and review of current literature

The prostate gland sits at the exit of the bladder like a collar, and as men get older their prostates enlarge, causing benign prostatic enlargement and benign prostatic obstruction (BPO). The resulting urethral obstruction can cause either urinary retention (the inability to pass urine) or bothersome voiding lower urinary tract symptoms (LUTS) secondary to BPO, such as slow and intermittent urinary stream. These conditions can severely affect a man’s quality of life, resulting in worsening physical and social functioning, vitality and mental health.3 Bothersome LUTS secondary to BPO with an International Prostate Symptom Score (IPSS) of ≥ 11 points and a maximum urine flow rate (Qmax) of < 15 ml/second affects 2.5 million men aged 40–79 years in the UK, with 44,000 new cases diagnosed annually.4 If medical therapy fails to improve LUTS, men often request surgery to reduce these. The aim of the surgery is to relieve the obstruction to allow men to void better, and to prevent the complications associated with BPO. These can include renal failure, urinary tract infections and bladder stones, as well as the persistence of bothersome LUTS.

Around 25,000 prostate operations are performed annually in the UK to relieve BPO. Transurethral resection of the prostate (TURP), the gold-standard operation, accounts for around 80% of these. TURP has been used widely for the past 40 years, and, although generally a successful procedure, it is associated with small but significant risks. It has a 30-day mortality rate of 0.3%, as well as a range of morbidities, including transurethral resection (TUR) syndrome (1%), which is due to the absorption of irrigating fluid leading to confusion and collapse; haemorrhage during the operation (transfusion rate 5%); and subsequent urinary tract infections (up to 20%).5 These morbidities result in delayed discharge and increased re-admissions, increased primary care resource utilisation, considerable distress to patients and additional costs to the NHS.1

The well-known risks of both mortality and morbidity from TURP have meant that many alternatives have been assessed. Various laser alternatives have been marketed, but uptake has been slow, owing in part to a long learning curve, or to inferior performance in terms of clinical outcomes. However, although the uptake of laser techniques has been slow historically, there does seems to have been a significant increase over the past few years. Hospital Episode Statistics data do not provide a clear indication of the proportion of procedures carried out using laser techniques as there is variation and overlap in coding. Considering only operations specifically coded as laser cases [OPCS Classification of Interventions and Procedures (OPCS-4) M65.46], the number increased in England by 45% from 2341 in 2012/13 to 3387 in 2016/17. However, this is still a relatively small proportion (≈14%) of the total number of cases of endoscopic resection of the prostate, which has remained reasonably constant at around 25,000. This is despite the commonly accepted advantages of laser prostatectomy, including lower risk of perioperative complications, shorter catheterisation time and reduced hospital stay.7

National Institute for Health and Care Excellence (NICE) clinical guidelines 978 currently recommend offering TURP or holmium laser enucleation of the prostate (HoLEP) as BPO surgery. However, since the last update to the guidelines, in 2016 NICE recommended the use of the GreenLight XPS^TM Laser Therapy System (Boston Scientific Corporation, Marlborough, MA, USA) for certain patients.9 According to the current guidelines, any other lasers should be subject to a clinical trial before being used widely.

The current form of the HoLEP technique was originally described by Gilling et al.10 in 1998. In the HoLEP procedure, the holmium laser is used to remove the prostatic lobes, which are then morcellated in the bladder before being removed. Although HoLEP is a long-established, effective procedure (recommended by NICE since 200311), with the key benefit that it can be undertaken regardless of prostate size, it has a recognised limitation in that it has a long learning curve, which reduces its generalisability. NICE8 recommends that this procedure be performed only in centres specialising in the technique or that have mentorship arrangements in place.

The GreenLight XPS laser involves the photoselective vaporisation of prostatic tissue. NICE has recommended it only since 2016 in its medical technologies guidance 29.9 Currently NICE has deemed that there is insufficient evidence to recommend its use in high-risk patients, such as those with an increased risk of bleeding, prostates larger than 100 ml, or urinary retention. The NICE review concludes that the GreenLight XPS is at least as effective as TURP but can more often be carried out as a day-case procedure, given appropriate service redesign.

This study has evaluated a new laser technique called thulium laser transurethral vaporesection of the prostate (ThuVARP). Thulium is a continuous laser technology and has a tunable wavelength of between 1.75 and 2.22 µm, which is similar to that of holmium technology.12 However, holmium is pulsed, making vaporesection time-consuming. This thulium laser technique was chosen for evaluation in this trial because it vaporises and resects the prostate, thereby using a surgical technique similar to TURP, enabling a short learning curve and meaning that it can be quickly put into widespread use.

The thulium laser was first made available in the UK in 2004 and it had been compared with TURP in one randomised controlled trial (RCT) in China at the time that the UNBLOCS trial was funded.13 Based on this RCT and on one non-randomised prospective controlled trial in patients with small and medium-sized prostates,14 the European Association of Urology (EAU) guidelines on laser technologies in 2012 stated that ThuVARP showed efficacy equivalent to that of TURP.15 However, the thulium patients had shorter catheterisation and hospitalisation times and fewer adverse events than patients undergoing TURP (intraoperative and postoperative bleeding), with level 1b evidence [individual RCTs conducted with narrow confidence intervals (CIs)].1 Subsequent EAU guidelines on the treatment of non-neurogenic male LUTS, published in 2017, reviewed the 4-year follow-up of the RCT conducted in China,16 as well as other, new studies. The guidelines concluded that thulium enucleation may be an alternative to TURP and HoLEP in men with moderate to severe LUTS, leading to both immediate and medium-term objective and subjective improvements (level of evidence 1b).

Zhang et al.17 reported equal outcomes for ThuVARP and HoLEP in treatment of urinary tract symptoms, and similar efficacy and safety. ThuVARP was statistically superior to HoLEP in blood loss and inferior to HoLEP in operation time; however, this was clinically negligible.

In its guidelines on male LUTS (updated in 2015),8 NICE stated that the evidence base was inadequate to allow clear guidance in terms of the clinical effectiveness and cost-effectiveness of laser vaporesection techniques. NICE identified that research in this area, in the form of a RCT, would help to inform future guidance on the use of laser vaporesection techniques in men with LUTS or urinary retention who need surgery.1

Rationale for the trial

The general population has an increased life expectancy, resulting in an ageing population. As BPO is a disease seen in older men, the number of patients with the condition is expected to grow by almost 50% by the year 2025, increasing the need for BPO surgery.4 Furthermore, the age of men undergoing the operation is increasing (41% of the TURP operations in 2016–17 were carried out on patients aged > 75 years); therefore, the risks of surgery associated with TURP will continue to grow. There is, therefore, sustained interest in the condition and an increasing need to find safer techniques than TURP. The potential advantages of reduced blood loss, shorter hospital stay and earlier return to normal activities make laser vaporesection techniques attractive to both patients and health-care providers. A potential advantage of ThuVARP is that it would allow urologists to operate on a wider range of men, including those men who are more frail and older, but with less risk. However, there is uncertainty about the extent of improvement to symptoms and quality of life in the short and longer term, which this trial addresses, and the procedure has not yet been widely taken up across the UK.

An additional reason for the early evaluation of ThuVARP is the promise it offers to convert BPO surgery from an inpatient operation to a day-case procedure. Shortened stay is becoming more important to the NHS because of the growing cost of inpatient beds, a shortage of inpatient beds owing to an ageing and increasingly comorbid population, and the risk that longer hospital stays present for these patients, for example of hospital-acquired infections.

In summary, although there has been little existing work on ThuVARP, the promising initial evidence from one RCT suggested that ThuVARP has equivalent clinical effectiveness to TURP, although this was in a single centre in China. Our randomised study was designed to provide the high-quality evidence, in a NHS setting with a range of patient-reported, clinical effectiveness and cost-effectiveness outcomes, to underpin and inform future NICE guidance.1

Study aims and objectives

The key aim of the UNBLOCS (UriNary oBstruction relieved by Laser Or Conventional Surgery) trial was to determine whether or not ThuVARP is equivalent to TURP in men with BPO treated in the NHS in terms of a patient-reported symptom severity score (IPSS) and the clinical measure of Qmax.

The following primary question was addressed:

• What is the relative clinical effectiveness of ThuVARP and TURP in improving patient-reported LUTS as measured by the IPSS patient-reported questionnaire, and the objective measure of maximum urine flow rate (Qmax), 12 months after surgery?

The secondary research questions were:

1. How do the two procedures compare in terms of perioperative outcomes?
2. What is the cost-effectiveness of ThuVARP compared with that of TURP in terms of quality-adjusted-life-years (QALYs: the primary economic outcome), IPSS and Qmax?
3. What is the comparative impact of each treatment on patient-reported LUTS, erectile function, quality of life and general health?
4. What is the comparative satisfaction of men with each type of surgery?
5. What is the comparative effectiveness of these operations in men who present with LUTS as opposed to men who present with urinary retention?
6. What are men’s experiences of both procedures, including those men presenting with LUTS and those men presenting with urinary retention?