Prostate Cancer Treatment Deferred (active surveillance/watchful waiting), Surgical & Radiation Therapy Comprehensive Review Article Part 5

Prostate Cancer Treatment Deferred Part 5

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Prostate Cancer

Treatment

Deferred (active surveillance/watchful waiting), Surgical & Radiation Therapy

Comprehensive Review Article

Part 5

Prof. Dr. Semir. A. Salim. Al Samarrai

Figure 1. Active Surveillance and Long-Term Outcomes in Early Stage Prostate Cancer

Treatment modalities:

The treatment modalities contain different criterias, after first modality in the deferred treatment (active surveillance/watchful waiting).

  • Deferred treatment (active surveillance/watchful waiting)

In localised disease a life expectancy of at least 10 years is considered mandatory for any benefit from active treatment. Data are available on patients who did not undergo local treatment with up to 25 years of

follow-up, with endpoints of overall survival (OS) and cancer specific survival (CSS). Several series have shown a consistent CSS rate of 82–87% at 10 years [1–6], and 80–95% for T1/T2 and ISUP grade < 2 PCas [512]. In three studies with data beyond 15 years, the DSS was 80%, 79% and 58% [3,5,6], and two reported 20-year CSS rates of 57% and 32%, respectively [3,5]. The observed heterogeneity in outcomes is due to differences in inclusion criteria, with some older studies from the pre-PSA era showing worse outcomes [5]. In addition, many patients classified as ISUP grade 1 would now be classified as ISUP grade 2–3 based on the 2005 Gleason classification, suggesting that the above-mentioned results should be considered as minimal. Patients with well-, moderately- and poorly differentiated tumours had 10-year CSS rates of 91%, 90% and 74%, respectively, correlating with data from the pooled analysis [7]. Observation was most effective in men aged 65–75 years with low-risk PCa [8].

Co-morbidity is as important as age in predicting life expectancy in men with PCa. Increasing co-morbidity greatly increases the risk of dying from non-PCa-related causes and for those men with a short life expectancy.

In an analysis of 19,639 patients aged > 65 years who were not given curative treatment, most men with a CCI score > 2 had died from competing causes at 10 years follow-up regardless of their age at time of diagnosis.

Tumour aggressiveness had little impact on OS suggesting that patients could have been spared biopsy and diagnosis of cancer. Men with a CCI score < 1 had a low risk of death at 10 years, especially for well or moderately-differentiated lesions [9]. This highlights the importance of assessing co-morbidity before considering a biopsy.

In screen-detected localised PCa the lead-time bias is likely to be greater. Mortality from untreated screen-detected PCa in patients with ISUP grade 1–2 might be as low as 7% at 15 years follow-up [10].

Consequently, approximately 45% of men with PSA-detected PCa are suitable for close follow-up through a robust surveillance programme. There are two distinct strategies for conservative management that aim to reduce over-treatment: AS and WW (Table 1).

Table 1. Definitions of active surveillance and watchful waiting

  • Active surveillance

Active surveillance aims to avoid unnecessary treatment in men with clinically localised PCa who do not require immediate treatment, but at the same time achieve the correct timing for curative treatment in those who eventually do [11]. Patients remain under close surveillance through structured surveillance programmes with regular follow-up consisting of PSA testing, clinical examination, MRI imaging and repeat prostate biopsies, with curative treatment being prompted by pre-defined thresholds indicative of potentially life-threatening disease, which is still potentially curable, while considering individual life expectancy.

Watchful waiting refers to conservative management for patients deemed unsuitable for curative treatment from the outset, and patients are clinically ‘watched’ for the development of local or systemic progression with (imminent) disease-related complaints, at which stage they are then treated palliatively according to their symptoms in order to maintain QoL.

Several cohorts have investigated AS in organ-confined disease, the findings of which were summarised in a systematic review [12]. More recently, the largest prospective series of men with low-risk PCa managed by AS was published [13]. Table 2 summarises the results of selective AS cohorts.

Table 2. Active surveillance in screening-detected prostate cancer (large cohorts with longer-term follow-up)

It is clear that the long-term OS and CSS of patients on AS are extremely good. However, more than one-third of patients are ‘reclassified’ during follow-up, most of whom undergo curative treatment due to disease upgrading, increase in disease extent, disease stage, progression or patient preference.

  • Watchful waiting

The Outcome of watchful waiting compared with active treatment showed the SPCG-4 study which was a RCT from the pre-PSA era, randomising patients to either WW or RP (Table 3) [14].

Table 3. Outcome of SPCG-4 at a median follow-up of 23.6 years

The study found radical prostatectomy (RP) to provide superior cancer-specific survival (CSS), overall survival (OS) and biochemical progression-free survival (PFS) compared to watchful waiting (WW) at a median follow-up of 23.6 years (range 3 weeks–28 years).

The overall evidence indicates that for men with asymptomatic, clinically localised PCa and with a life expectancy of < 10 years based on co-morbidities and/or age, the oncological advantages of active treatment over WW are unlikely to be relevant to them. Consequently, WW should be adopted for such patients.

  • Radical Prostatectomy

The second treatment modality with radical prostatectomy showed that the goal of RP by any approach is the eradication of cancer while, whenever possible, preserving pelvic organ function [15]. The procedure involves removing the entire prostate with its capsule intact and SVs, followed by vesico-urethral anastomosis. Surgical approaches have expanded from perineal and retropubic open approaches to laparoscopic and robotic-assisted techniques; anastomoses have evolved from Vest approximation sutures to continuous suture watertight anastomoses under direct vision and mapping of the anatomy of the dorsal venous complex (DVC) and cavernous nerves has led to excellent visualisation and potential for preservation of erectile function [16]. The main results from multi-centre RCTs involving RP are summarised in Table 4.

Table 4. Oncological results of radical prostatectomy in organ-confined disease in RCTs

Pre-operative preparation:

  • Pre-operative patient education

As before any surgery appropriate education and patient consent is mandatory prior to RP. Peri-operative education has been shown to improve long-term patient satisfaction following RP [17]. Augmentation of standard verbal and written educational materials such as use of interactive multimedia tools [18,19] and pre-operative patient-specific 3D printed prostate models has been shown to improve patient understanding and satisfaction and should be considered to optimise patient-centred care [20].

  • Pre-operative pelvic floor exercises

Although many patients who have undergone RP will experience a return to urinary continence [21], temporary urinary incontinence is common early after surgery, reducing QoL. Pre-operative pelvic floor exercises (PFE) with, or without, biofeedback have been used with the aim of reducing this early post-operative incontinence.

A systematic review and meta-analysis of the effect of pre-RP PFE on post-operative urinary incontinence showed a significant improvement in incontinence rates at 3 months post-operatively with an OR of 0.64 (p = 0.005), but not at 1 month or 6 months [22]. Pre-operative PFE may therefore provide some benefit, however the analysis was hampered by the variety of PFE regimens and a lack of consensus on the definition of incontinence.

  • Prophylactic antibiotics

Prophylactic antibiotics should be used; however, no high-level evidence is available to recommend specific prophylactic antibiotics prior to RP (See EAU Urological Infections Guidelines [23]). In addition, as the susceptibility of bacterial pathogens and antibiotic availability varies worldwide, any use of prophylactic antibiotics should adhere to local guidelines.

  • Neoadjuvant androgen deprivation therapy

Several RCTs have analysed the impact of neoadjuvant ADT before RP, most of these using a 3-month period. The main findings were summarised in a Cochrane review [24]. Neoadjuvant ADT is associated with a decreased rate of pT3 (downstaging), decreased positive margins, and a lower incidence of positive LNs.

These benefits are greater with increased treatment duration (up to 8 months). However, since neither the PSA relapse-free survival nor CSS were shown to improve, neoadjuvant ADT should not be considered as standard clinical practice.

  • Surgical techniques

Prostatectomy can be performed by open-, laparoscopic- or robot-assisted (RARP) approaches. The initial open technique of RP described by Young in 1904 was via the perineum [16] but suffered from a lack of access to pelvic LNs. If lymphadenectomy is required during perineal RP it must be done via a separate open retropubic (RRP) or laparoscopic approach. The open retropubic approach was popularised by Walsh

in 1982 following his anatomical description of the DVC, enabling its early control and of the cavernous nerves, permitting a bilateral nerve-sparing procedure [25]. This led to the demise in popularity of perineal

RP and eventually to the first laparoscopic RP reported in 1997 using retropubic principles, but performed transperitoneally [26]. The initial 9 cases averaged 9.4 hours, an indication of the significant technical and ergonomic difficulties of the technique. Most recently, RARP was introduced using the da Vinci Surgical SystemR by Binder in 2002 [27]. This technology combined the minimally-invasive advantages of laparoscopic RP with improved surgeon ergonomics and greater technical ease of suture reconstruction of the vesicourethral anastomosis and has now become the preferred minimally-invasive approach, when available.

In a randomised phase III trial, RARP was shown to have reduced admission times and blood loss, but not earlier (12 weeks) functional or oncological outcomes compared to open RP [28]. An updated analysis with follow-up at 24 months did not reveal any significant differences in functional outcomes between the approaches [29].

A systematic review and meta-analysis of non-RCTs demonstrated that RARP had lower peri-operative morbidity and a reduced risk of positive surgical margins compared with laparoscopic prostatectomy (LRP), although there was considerable methodological uncertainty [30]. There was no evidence of differences in urinary incontinence at 12 months and there was insufficient evidence to draw conclusions based on differences in cancer-related, patient-driven or ED outcomes.

  • Robotic anterior versus Retzius-sparing dissection

Robot-assisted RP has typically been performed via the anterior approach, first dropping the bladder to expose the space of Retzius. However, the posterior approach (Retzius-sparing [RS-RARP]) has been used to minimise injury to support structures surrounding the prostate.

Galfano et al., first described RS-RARP in 2010 [31]. This approach commences dissection posteriorly at the pouch of Douglas, first dissecting the SVs and progressing caudally behind the prostate.

All of the anterior support structures are avoided, giving rise to the hypothetical mechanism for improved early post-operative continence. Retzius-sparing-RARP thus offers the same potential advantage as the open perineal approach, but without disturbance of the perineal musculature.

Figure 2. Robotic Assisted Prostatectomy

Retzius-sparing-RARP )RS-RARP( has been recently investigated in RCTs leading to four systematic reviews and metaanalyses [32–34] including a 2020 Cochrane systematic review [35] and a large propensity score matched analysis [36]. The Cochrane review used the most rigorous methodology and analysed 5 RCTs with 502 patients. It found with moderate certainty that RS-RARP improved continence at 1 week post catheter removal compared to standard RARP (RR: 1.74). Continence may also be improved at 3 months post-operatively (RR: 1.33), but this was based on low-certainty data. Continence outcomes appeared to equalise by 12 months (RR: 1.01). These findings matched those of the other systematic reviews. However, a significant concern was that RS-RARP appears to increase the risk of positive margins (RR: 1.95) but this was also low-certainty evidence. A single-surgeon propensity score matched analysis of 1,863 patients reached the same conclusion as the systematic reviews regarding earlier return to continence but did not show data on margin status [36].

Based on these data, recommendations cannot be made for one technique over another. However, the trade-offs between the risks of a positive margin vs. earlier continence recovery should be discussed with prospective patients. Furthermore, no high-level evidence is available on high-risk disease with some concerns that RS-RARP may confer an increased positive margin rate based on pT3 results. In addition, RS-RARP may be more technically challenging in various scenarios such as anterior tumours, post-TURP, a grossly enlarged gland, or a bulky median lobe [37].

Figure 3. While the posterior wall of the anastomosis is being made, the silk suture is held continuously by the ProGrasp forceps under the same gentle traction, sufficient to present the urethra.

  • Pelvic lymph node dissection

A systematic review demonstrated that performing pelvic lymph node dissection (PLND) during RP failed to improve oncological outcomes, including survival [38]. Moreover, two RCTs have failed to show a benefit of an extended approach vs. a limited PLND on early oncologic outcomes [39,40]. However, it is generally accepted that eLND provides important information for staging and prognosis which cannot be matched by any other currently available procedure [38].

Extended LND includes removal of the nodes overlying the external iliac artery and vein, the nodes within the obturator fossa located cranially and caudally to the obturator nerve, and the nodes medial and lateral to the internal iliac artery. With this template, 94% of patients are correctly staged [41].

The individual risk of patients harbouring positive LNs can be estimated based on validated nomograms. The Briganti nomogram [42,43], the Roach formula [44] or the Partin and MSKCC nomograms [45] have shown similar diagnostic accuracy in predicting LN invasion. These nomograms have all been developed in the pre-MRI setting based on systematic random biopsy. A risk of nodal metastases over 5% can be used to identify candidates for nodal sampling by eLND during RP [46–48].

  • Sentinel node biopsy analysis

The rationale for a sentinel node biopsy (SNB) is based on the concept that a sentinel node is the first to be involved by migrating tumour cells. Therefore, when this node is negative it is possible to avoid an ePLND. There is heterogeneity and variation in techniques in relation to SNB (e.g. the optimal tracer) but a multidisciplinary collaborative endeavour attempted to standardise definitions, thresholds and strategies in relation to techniques of SNB using consensus methods [49].

  • Prostatic anterior fat pad dissection and histologic analysis

Several multi-centre and large single-centre series have shown the presence of lymphoid tissue within the fat pad anterior to the endopelvic fascia; the prostatic anterior fat pad (PAFP) [50–56]. This lymphoid tissue is present in 5.5–10.6% of cases and contains metastatic PCa in up to 1.3% of intermediate- and high-risk patients.

  • Management of the dorsal venous complex

Since the description of the anatomical open RP by Walsh and Donker in the 1980s, various methods of controlling bleeding from the dorsal venous complex (DVC) have been proposed to optimise visualisation [25]. In the open setting, blood loss and transfusion rates have been found to be significantly reduced when ligating the DVC prior to transection [57]. However, concerns have been raised regarding the effect of prior DVC ligation on apical margin positivity and continence recovery due to the proximity of the DVC to both the prostatic apex and the urethral sphincter muscle fibres. In the robotic-assisted laparoscopic technique, due to the increased pressure of pneumoperitoneum, whether prior DVC ligation was used or not, blood loss was not found to be significantly different in one study [58]. In another study, mean blood loss was significantly less with prior DVC ligation (184 vs. 176 mL, p = 0.033), however it is debatable whether this was clinically significant [59]. The positive apical margin rate was not different, however, the latter study showed earlier return to full continence at 5 months post-operatively in the no prior DVC ligation group (61% vs. 40%, p < 0.01).

Ligation of the DVC can be performed with standard suture or using a vascular stapler. One study found significantly reduced blood loss (494 mL vs. 288 mL) and improved apical margin status (13% vs. 2%) when using the stapler [60].

  • Nerve-sparing surgery

During prostatectomy, preservation of the neurovascular bundles with parasympathetic nerve branches of the pelvic plexus may spare erectile function [61,62].

Although age and pre-operative function may remain the most important predictors for postoperative erectile function, nerve-sparing has also been associated with improved continence outcomes and may therefore still be relevant for men with poor erectile function [63,64]. The association with continence may be mainly due to the dissection technique used during nerve-sparing surgery, and not due to the preservation of the nerve bundles themselves [63].

Extra-, inter-, and intra-fascial dissection planes can be planned, with those closer to the prostate and performed bilaterally associated with superior (early) functional outcomes [65–68]. Furthermore, many different techniques are propagated such as retrograde approach after anterior release (vs. antegrade), and athermal and traction-free handling of bundles [69–71]. Nerve-sparing does not compromise cancer control if patients are carefully selected depending on tumour location, size and grade [72–74].

  • Removal of seminal vesicles

The more aggressive forms of PCa may spread directly into the seminal vesicles (SVs). For oncological clearance, the SVs have traditionally been removed intact with the prostate specimen [75]. However, in some patients the tips of the SVs can be challenging to dissect free. Furthermore, the cavernous nerves run past the SV tips such that indiscriminate dissection of the SV tips could potentially lead to ED [76].

  • Techniques of vesico-urethral anastomosis

Following prostate removal, the bladder neck is anastomosed to the membranous urethra. The objective is to create a precisely aligned, watertight, tension-free, and stricture-free anastomosis that preserves the integrity of the intrinsic sphincter mechanism. Several methods have been described, based on the direct or indirect approach, the type of suture (i.e. barbed vs. non-barbed/monofilament), and variation in suturing technique (e.g., continuous vs. interrupted, or single-needle vs. double-needle running suture). The direct vesico-urethral anastomosis, which involves the construction of a primary end-to-end inter-mucosal anastomosis of the bladder neck to the membranous urethra by using 6 interrupted sutures placed circumferentially, has become the standard method of reconstruction for open RP [77].

The development of laparoscopic- and robotic-assisted techniques to perform RP have facilitated the introduction of new suturing techniques for the anastomosis. A systematic review and meta-analysis compared unidirectional barbed suture vs. conventional non-barbed suture for vesico-urethral anastomosis during robotic-assisted laparoscopic prostatectomy (RALP) [78].

Figure 4: Preparation of the urethra, bladder neck and the posterior suture

Although the review found slight advantages for continuous suturing over interrupted suturing in terms of catheterisation time, anastomosis time and rate of extravasation, the overall quality of evidence was low and no clear recommendations were possible. A recent RCT [79] compared the technique of suturing using a single absorbable running suture vs. a double-needle single-knot running suture (i.e. Van Velthoven technique) in laparoscopic RP [80]. The study found slightly reduced anastomosis time with the single running suture technique, but anastomotic leak, stricture, and continence rates were similar.

Figure 5: Placing the catheter and the anterior suture

Bladder neck management:

  • Bladder neck mucosal eversion

Some surgeons perform mucosal eversion of the bladder neck as its own step in open RP with the aim of securing a mucosa-to-mucosa vesico-urethral anastomosis and avoiding anastomotic stricture.

An alternative is to simply ensure bladder mucosa is included in the full thickness anastomotic sutures.

  • Bladder neck preservation

Whilst the majority of urinary continence is maintained by the external urethral sphincter at the membranous urethra (see below), a minor component is contributed by the internal lissosphincter at the bladder neck [81].

Preservation of the bladder neck has therefore been proposed to improve continence recovery post-RP. A RCT assessing continence recovery at 12 months and 4 years showed improved objective and subjective urinary continence in both the short- and long term without any adverse effect on oncological outcome [82].

Figure 6: Parachute the bladder neck down onto the urethra

  • Urethral length preservation

The membranous urethra sits immediately distal to the prostatic apex and is chiefly responsible, along with its surrounding pelvic floor support structures, for urinary continence. It consists of the external rhabdosphincter which surrounds an inner layer of smooth muscle.

Therefore, it is likely that preservation of as much urethral length as possible during RP will maximise the chance of early return to continence. It may also be useful to measure urethral length pre-operatively to facilitate counselling of patients on their relative likelihood of early post-operative continence.

  • Cystography prior to catheter removal

Cystography may be used prior to catheter removal to check for a substantial anastomotic leak. If such a leak is found, catheter removal may then be deferred to allow further healing and sealing of the anastomosis.

  • Urinary catheter

A urinary catheter is routinely placed during RP to enable bladder rest and drainage of urine while the vesicourethral anastomosis heals. Compared to a traditional catheter duration of around 1 week, some centres remove the transurethral catheter early (post-operative day 2–3), usually after thorough anastomosis with posterior reconstruction or in patients selected peri-operatively on the basis of anastomosis quality [83–86].

  • Use of a pelvic drain

A pelvic drain has traditionally been used in RP for potential drainage of urine leaking from the vesico-urethral anastomosis, blood, or lymphatic fluid when a PLND has been performed.

When the anastomosis is found to be watertight intra-operatively, it is reasonable to avoid inserting a pelvic drain. There is no evidence to guide usage of a pelvic drain in PLND.

  • Acute and chronic complications of surgery

Post-operative incontinence and ED are common problems following surgery for PCa. A key consideration is whether these problems are reduced by using newer techniques such as RALP. Systematic reviews have documented complication rates after RALP [30,87–90], and can be compared with contemporaneous reports after radical RRP [91]. A prospective controlled non-RCT of patients undergoing RP in 14 centres using RALP or RRP showed that 12 months after RALP, 21.3% of patients were incontinent, as were 20.2% after RRP (adjusted OR: 1.08, 95% CI: 0.87–1.34) [92]. Erectile dysfunction was observed in 70.4% after RALP and 74.7% after RRP. The adjusted OR was 0.81 (95% CI: 0.66–0.98) [92].

A systematic review and meta-analysis of unplanned hospital visits and re-admissions post-RP analysed 60 studies with over 400,000 patients over a 20-year period up to 2020. It found an emergency room visit rate of 12% and a hospital re-admission rate of 4% at 30 days post-operatively [93].

The intra-and peri-operative complications of retropubic RP and RALP are listed in Table 5.

Table 5. Intra-and peri-operative complications of retropublic RP and RALP

The early use of phosphodiesterase-5 (PDE5) inhibitors in penile rehabilitation remains controversial resulting in a lack of clear recommendations.

  • Effect of anterior and posterior reconstruction on continence

Preservation of integrity of the external urethral sphincter is critical for continence post-RP. Less clear is the effect of reconstruction of surrounding support structures to return to continence.

In addition, techniques used to perform both anterior suspension or reconstruction and posterior reconstruction are varied. For example, anterior suspension is performed either through periosteum of the pubis or the combination of ligated DVC and puboprostatic ligaments (PPL). Posterior reconstruction from rhabdosphincter is described to either Denonvilliers fascia posterior to bladder or to posterior bladder wall itself.

As there is conflicting evidence on the effect of anterior and/or posterior reconstruction on return to continence post-RP, no recommendations can be made. However, no studies showed an increase in adverse oncologic outcome or complications with reconstruction.

  • Deep venous thrombosis prophylaxis

EAU Guidelines recommendations on post-RP deep venous thrombosis prophylaxis (see table 6).

Table 6: Procedure-specific evidence summaries with recommendations for radical prostatectomies

For patients undergoing robotic radical prostatectomy without PLND, for those at low risk of VTE, the Panel recommends against use of pharmacologic prophylaxis (strong, moderate-quality evidence) and suggests against use of mechanical prophylaxis (weak, low-quality evidence); for those at medium and high risk, the Panel suggests against use of pharmacologic prophylaxis (weak, moderate-quality evidence) and suggests use of mechanical prophylaxis until ambulation (weak, low-quality evidence).

For patients undergoing robotic radical prostatectomy with standard PLND, for those at low risk of VTE, the Panel recommends against use of pharmacologic prophylaxis (strong, moderate-quality evidence); for those at medium risk, the Panel suggests against use of pharmacologic prophylaxis (weak, moderate-quality evidence); for those at high risk, the Panel suggests use of pharmacologic prophylaxis (weak, moderatequality evidence); and for all patients, the Panel suggests use of mechanical prophylaxis until ambulation (weak, low-quality evidence).

For patients undergoing robotic radical prostatectomy with extended PLND, for those at low risk of VTE, the Panel suggests against use of pharmacologic prophylaxis (weak, moderate-quality evidence); for those at medium risk, the Panel suggests use of pharmacologic prophylaxis (weak, moderate-quality evidence); for those at high risk, the Panel recommends use of pharmacologic prophylaxis (strong, moderate-quality evidence); and for all patients, the Panel suggests use of mechanical prophylaxis until ambulation (weak, lowquality evidence).

However, these recommendations should be adapted based on national recommendations, when available.

  • Early complications of extended lymph node dissection

Overall complication rates of 19.8% vs. 8.2% were noted for eLND vs. limited LND, respectively, with lymphoceles (10.3% vs. 4.6%) being the most common adverse event.

The third treatment modality with radiotherapy contain the intensity-modulated RT (IMRT) or volumetric arc radiation therapy (VMAT) with image-guided RT (IGRT) is currently widely recognised as the best available approach for External beam radiation therapy (EBRT).

  • External beam radiation therapy

Intensity-modulated )EBRT( and volumetric arc external-beam RT (VMAT) employ dynamic multileaf collimators, which automatically and continuously adapt to the contours of the target volume seen by each beam.

A meta-analysis by Yu et al., (23 studies, 9,556 patients) concluded that IMRT significantly decreases the occurrence of grade 2–4 acute GI toxicity, late GI toxicity and late rectal bleeding, and achieves better PSA relapse-free survival in comparison with 3D-CRT.

The advantage of VMAT over IMRT is shorter treatment times, generally two to three minutes. Both techniques allow for a more complex distribution of the dose to be delivered and provide concave isodose curves, which are particularly useful as a means of sparing the rectum.

  • Dose escalation

Local control is a critical issue for the outcome of RT of PCa. It has been shown that local failure due to insufficient total dose is prognostic for death from PCa as a second wave of metastases is seen 5 to 10 years later on [94]. Several RCTs have shown that dose escalation (range 74–80 Gy) has a significant impact on 10-year biochemical relapse as well as metastases and disease-specific mortality [95–102]. These trials have generally included patients from several risk groups, and the use of neoadjuvant/adjuvant HT has varied (see Table 7).

Table 7. Randomised trials of dose escalation in localised PCa

  • Hypofractionation

Fractionated RT utilises differences in the DNA repair capacity of normal and tumour tissue and slowly proliferating cells are very sensitive to an increased dose per fraction [103]. A meta-analysis of 25 studies including > 14,000 patients concluded that since PCa has a slow proliferation rate, hypofractionated RT could be more effective than conventional fractions of 1.8–2 Gy [104]. Hypofractionation (HFX) has the added advantage of being more convenient for the patient at lower cost.

Moderate HFX is defined as RT with 2.5–3.4 Gy/fx. Several studies report on moderate HFX applied in various techniques also including HT in part [105–115].

Moderate HFX should only be done by experienced teams using high-quality EBRT using IGRT and IMRT/ VMAT and published phase III protocols should be adhered to (Table 8).

Table 8. Major phase III randomized trials of moderate hypofractionation for primary treatment

Ultra-HFX has been defined as RT with > 3.4 Gy per fraction [115]. It requires IGRT and stereotactic body RT (SBRT).

Table 9 provides an overview of selected studies.

First results of a small (n = 30) randomised phase-II trial in intermediate-risk PCa of ‘ultra-high single dose RT’ (SDRT) with 24 Gy compared with an extreme hypofractionated stereotactic body RT regime with 5×9 Gy to the prostate, have been published recently (see Table 9) [116].

Table 9. Selected trials on ultra-hypofractionation for intact lacalised PCa

  • Neoadjuvant or adjuvant hormone therapy plus radiotherapy

The combination of RT with LHRH ADT has definitively proven its superiority compared with RT alone followed by androgen deprivation therapy (ADT) on relapse, as shown by phase III RCTs [117–121] (Table 10).

Table 10. Selected studies of use and duration of ADT in combination with RT for PCa

The question of the added value of EBRT combined with ADT has been clarified by 3 RCTs. All showed a clear benefit of adding EBRT to long-term ADT (see Table 11).

Table 11. Selected studies of ADT in combination with, or without, RT for PCa

  • Proton beam therapy

In theory, proton beams are an attractive alternative to photon-beam RT for PCa, as they deposit almost all their radiation dose at the end of the particle’s path in tissue (the Bragg peak), in contrast to photons which deposit radiation along their path. There is also a very sharp fall-off for proton beams beyond their deposition depth, meaning that critical normal tissues beyond this depth could be effectively spared. In contrast, photon beams continue to deposit energy until they leave the body, including an exit dose.

A RCT comparing equivalent doses of proton-beam therapy with IMRT is underway. Meanwhile, proton therapy must be regarded as an experimental alternative to photon-beam therapy.

Brachytherapy:

  • Low-dose rate brachytherapy

Low-dose rate (LDR) brachytherapy uses radioactive seeds permanently implanted into the prostate. There is a consensus on the group of patients with the best outcomes after LDR monotherapy [122] for low- or favourable intermediate-risk and good urinary function defined as an International Prostatic Symptom Score (IPSS) < 12 and maximum flow rate > 15 mL/min on urinary flow tests, as per NCCN definition [123]. In addition, with due attention to dose distribution, patients having had a previous TURP can undergo brachytherapy without an increase in risk of urinary toxicity.

  • High-dose rate brachytherapy

High-dose rate (HDR) brachytherapy uses a radioactive source temporarily introduced into the prostate to deliver radiation. The technical differences are outlined in Table 12.

Table 12. Difference between LDR and HDR brachytherapy

  • Acute side effects of external beam radiotherapy and brachytherapy

Gastro-intestinal and urinary side effects are common during and after EBRT. In the EORTC 22991 trial, approximately 50% of patients reported acute GU toxicity of grade 1, 20% of grade 2, and 2% grade 3. In the same trial, approximately 30% of patients reported acute grade 1 GI toxicity, 10% grade 2, and less than 1% grade 3. Common toxicities included dysuria, urinary frequency, urinary retention, haematuria, diarrhoea, rectal bleeding and proctitis [124].

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Author Correspondence:

Prof. Dr. Semir A. Salim. Al Samarrai

Medical Director of Professor Al Samarrai Medical Center.

Dubai Healthcare City, Al-Razi Building 64, Block D, 2nd Floor, Suite 2018

E-mail: semiralsamarrai@hotmail.com

Tel: +97144233669

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