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Keywords:

  • early prostate cancer;
  • feasibility;
  • prostatectomy;
  • brachytherapy;
  • decision aid

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1

Objective

  • To determine the feasibility of a phase III randomised controlled trial of brachytherapy vs radical prostatectomy (RP) in men with low–intermediate risk localised prostate cancer.

Patients and Methods

  • This parallel, two-group, multicentre, randomised controlled feasibility trial enrolled men with histologically confirmed localised, low-risk prostate cancer and good performance status from five UK hospitals.
  • Participants were randomly allocated (1:1) by remote computer allocation to receive a decision aid (DA) DVD or standard information (control group), followed by a second randomisation (1:1) to brachytherapy or RP.
  • There was no ‘blinding’ of staff or patients.
  • Primary outcome was feasibility: a recruitment rate of six patients per centre over the last 6 months of recruitment would deem a phase III trial feasible.

Results

  • Between May 2009 and May 2011, 30 patients were randomised (15 in the DA group and 15 in the control group), and four continued to the second treatment randomisation (one from the DA group and three from the control group).
  • One patient was allocated and received brachytherapy and three RP.
  • SABRE 1 closed early due to poor recruitment. All patients were analysed.
  • Screening logbook analysis showed that the main reasons for declining trial entry were a wish to choose treatment or opting for active monitoring.
  • Results from the DA questionnaire (completed by 10 men) showed that four of the men ‘felt surgery and radiotherapy had been proven in a high quality trial’ and seven felt ‘they should make their treatment decision while knowing their doctors opinion’.

Conclusion

  • Recruitment to a RP vs brachytherapy trial in localised prostate cancer was not feasible by the use of this two-step randomisation using a DA and previous trials in early prostate cancer have had similar difficulties in recruitment, with only a few achieving their accrual target.
  • The best treatment method for treating low-risk prostate cancer is still unproven in a head-to-head trial and the increasing number of options will make choices correspondingly more difficulty without good quality comparative research.
  • More sophisticated techniques for recruitment may be more successful in future trials in this patient population.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1

Prostate cancer is the commonest cancer in men in the UK, with an annual incidence of >40 000 cases [1]. There is no formal national screening programme but increased patient and doctor knowledge of the PSA test has increased opportunistic prostate cancer screening, with the effect that there has been a downward stage-shift to more early stage disease.

In the UK, there is no consensus about the best management of these patients. There are at least four common, yet quite different, approaches to the management of favourable-risk (low or intermediate risk) localised prostate cancer: active surveillance, surgery, brachytherapy, and external-beam radiotherapy (EBRT). However there is no level 1 evidence comparing any of these approaches in favourable-risk disease [2, 3].

Furthermore, new treatments for early prostate cancer, e.g. cryotherapy, high-intensity focussed ultrasound and photodynamic therapy, are being developed and are offered privately, in overseas clinics or in trials. With such a wide array of treatment options, this can provide uncertainty for patients as to the best choice without adequate data for guidance. These developing treatments are predominantly minimally invasive procedures, similar, in that sense, to prostate brachytherapy. Once brachytherapy has been evaluated in a randomised trial against a traditional ‘standard’ treatment in terms of efficacy and toxicity, it may serve as a more appropriate comparator for any of the newer prostate cancer treatments in future randomised trials.

Active surveillance is an option more commonly used in Europe than the USA and can be popular with patients because of the absence of treatment-related side-effects. In low-risk disease, where the risk of death is low in the first 10 years after diagnosis, active surveillance results in deferral or postponement of up-front radical treatment.

Brachytherapy as a minimally invasive option has inherent benefits but has not been compared directly against the ‘gold standard’ radical prostatectomy (RP) in a randomised controlled trial (RCT). The most recent National Institute for Clinical Excellence (NICE) guidance [4] on low-dose rate brachytherapy (NICE 2005) considered ‘… low dose rate brachytherapy to be an established procedure’ and that ‘… the results are comparable with those achieved with surgery or external-beam radiotherapy in well-selected patients’. They concluded that ‘further research and audit should address quality of life, clinical outcomes and long-term survival’.

The present study compared brachytherapy, in a randomised fashion, with RP, one of the accepted standard treatments for early prostate cancer. The design of the study was a simple one-to-one randomisation, which was felt to be easy for patients and investigators to understand and would be suitable for patients who did not wish to pursue active surveillance or EBRT as an option (EBRT and active surveillance have been compared with RP in the UK Medical Research Council [MRC] the Prostate Testing for Cancer and Treatment [ProtecT] study that has not as yet reported).

It was felt that the profile of patients who choose brachytherapy as an option more closely resembles that of patients choosing RP rather than EBRT, and RP is widely regarded as the ‘gold standard’ curative treatment for localised prostate cancer and therefore an appropriate comparator for brachytherapy.

If prostate brachytherapy had been more widely available at the time of the development of the ProtecT study then it may have been logical for it to have been included as a fourth randomisation option.

Difficulties Recruiting to Surgical and Prostate Trials

Recruiting to surgical and in particular prostate cancer surgical trials is notoriously difficult. Many previous randomised trials in early prostate cancer have failed to recruit successfully. The LopeRA feasibility trial (RCT of laparoscopic, open and robot-assisted prostatectomy as treatment for organ-confined prostate cancer) randomised patients to open or laparoscopic RP and found strong patient preferences and an unwillingness to travel to other hospitals hampered recruitment [5]. A Canadian phase III trial (START) comparing active surveillance with radical treatment closed early due to poor recruitment. Another North America study, SPIRIT (A Randomised Trial of Radical Prostatectomy versus Brachytherapy for Patients with T1c or T2a N0 M0 Prostate Cancer) was designed to compare the outcome of patients treated with brachytherapy vs RP [6]. A multidisciplinary education session was used in SPIRIT to attempt to aid recruitment; however, most patients still declined randomisation. The authors concluded that men who understand their treatment options and trial rationale presented by representatives from competing treatment methods may be more likely to consent to random assignment. SPIRIT unfortunately closed due to poor accrual; however, excellent patient recruitment was achieved in one Canadian centre, showing that, in the right circumstances, patients are willing to accept this randomisation.

ProtecT randomised patients with screen-detected prostate cancer between active monitoring, RP and radical conformal EBRT [7]. ProtecT embedded qualitative research within the trial design that led to changes to information and presentation of treatments subsequently improving recruitment. The trial is currently in follow-up having successfully recruited to target [8]. Factors in ProtecT hindering randomisation included terminology used by recruiters (e.g. using the word ‘trial’ could be interpreted by patients as monitoring or ‘try and see’ and suggested using the word ‘study’ instead); order of presentation of treatment options and unconvincing presentation of randomisation and clinical equipoise. If recruiters were not completely committed to their position of equipoise they found patients would question randomisation. Overall, Donovan et al. [8] found that through information documents to recruiters and an intensive training programme their randomisation rate went from 40 to 70% [9].

Reasons for poor recruitment are multifactorial and information gathering by patients using the internet may have a strong impact on patient choice and move them from a position of equipoise.

SABRE 1 (Surgery Against Brachytherapy – a Randomised Evaluation) was designed as a feasibility trial with a plan to follow on to a phase III trial to investigate oncological outcomes between RP and brachytherapy in a direct trial. Recognising that qualitative research is costly but using the lessons learnt that randomisation rates were critically dependent on the way in which information about treatment options is presented informed the design of SABRE 1.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1

In this multicentre two-group parallel, randomised controlled feasibility trial, inclusion criteria included men with histologically confirmed prostate cancer; biopsy performed ≤ 6 months; clinical stage T1/2; PSA level of <15 ng/mL; either Gleason score ≤ 6 (no tertiary grade 4 or 5); with a PSA level of <15 ng/mL or Gleason sum score 7 (no tertiary grade 5) with a PSA level < 10 ng/mL (PSA test < 3 months before treatment intervention); TRUS prostate volume of ≤ 50 mL and WHO Performance Status 0/1. Satisfactory haematological and biochemical indices, written consent and a life expectancy of >10 years were also mandatory.

This was a feasibility trial using a two-step randomisation design (Fig. 1). First randomisation was to decision aid (DA) with a decision aid DVD or standard information (control group) alone, followed by the second randomisation to treatment allocation (RP or brachytherapy) both in a 1:1 allocation.

figure

Figure 1. SABRE consort diagram.

Download figure to PowerPoint

Men with biopsy confirmed prostate cancer were approached for consent to the first stage at, or soon after their biopsy result by urological surgeons, oncologists or research nurses. Only men with good risk prostate cancer could continue on to treatment randomisation. Patients were recruited from five UK hospitals. Oncologists and surgeons participating in the trial had to meet skills verification criteria and comply with quality assurance.

Standard dosage and techniques for brachytherapy and surgery were used and protocol treatment details are listed in appendix 1.

DA Intervention

Our hypothesis was that problems with accrual in previous trials may have been due to a lack of clinical equipoise by physicians and surgeons; so giving a DA directly to patients may overcome this by increasing patient involvement in decision-making. The DA was a 30-min DVD produced by the Foundation for Informed Decision Making and successfully piloted by the National Informed Decision Making Project run by Action on Urology under the auspices of the NHS Modernisation Agency. It described the standard treatment options available to patients, provides detailed information about treatment outcomes in relation to individual patient characteristics and seeks to help patients apply their own personal values to their treatment decision. The aims of the DA were to improve patient knowledge and expectation; for patient involvement in decision making; to lower decisional conflict; to improve agreement between patient values and treatment choice and to help explore how individual values impact the decision-making process. There are no published data on the effect of DAs on randomisation rates to treatment trials. The control, standard information comprised of booklets about prostate cancer and treatment, further contact details and access to a urology specialist nurse as occurs in routine local clinical practice.

Outcomes and Assessments

Primary outcome for the DA randomisation was the proportion of patients consenting to the treatment randomisation. For the treatment randomisation; primary outcome was feasibility of randomisation in terms of average accrual rate per centre during the last 6 months of recruitment.

Secondary outcomes included decisional quality after treatment; compliance with allocated treatment; clinical failure; PSA relapse; patient reported health-related quality of life and toxicity.

Patients were followed up at 1 and 4 month after treatment for decisional quality. Treatment follow-up was at 4-monthly intervals for 2 years, 6-monthly from 2 to 5 years then annually until 10 years.

Sample Size and Statistical Analysis

Treatment randomisation was expected to be difficult. As a feasibility study we wished to determine the rate of recruitment in the limited number of centres involved, so this trial was not powered to detect a difference between the two treatment interventions. The trial planned to recruit 400 patients to the DA randomisation, which was sufficient to detect a doubling in the acceptance rate for the treatment randomisation (from 1 in 10 (10%) in the control arm to 1 in 5 (20%) on the DA arm), with 80% power and a two-sided 5% significance level.

Randomisation was by a remote computer method. For practicality patients and investigators were not ‘blinded’. The randomisation sequence for both randomisations was generated by a third party with no clinical involvement in the trial using 1:1 allocation, random block sizes of 2, 4, 6 and 8 and stratification for centre and risk for the treatment randomisation and stratification for centre only for the DA randomisation. Centres wanting to randomise an eligible patient telephoned the University of Southampton Clinical Trials Unit who logged onto the web-based randomisation system and obtained the result.

Accrual rate during the last 6 months of this trial was measured to determine the potential success of the Phase III SABRE 2 trial. The aims of the feasibility study were not just to determine whether this randomisation is possible, but to define the likely rate of accrual in the Phase III trial. More than six patients per centre accrued during the last 6-month period would indicate that a large Phase III trial could recruit successfully (one patient per centre per month). Decisional quality was assessed by the Decisional Quality Assessment Questionnaire, based on one used in the NHS Modernisation Agency Action on Urology Project. This questionnaire consists of 10 questions that assess the patients' knowledge concerning the treatment of localised prostate cancer, and their values and preferences.

SABRE1 received ethical approval from the Office for Research Ethics Committees Northern Ireland (08/NIR03/77) and was conducted in compliance with ICH-GCP (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use-Good Clinical Practice); International Standard Randomised Controlled Trial Number Register (ISRCTN) registration number 88144169. The University of Southampton Clinical Trials Unit was involved in trial design, trial set-up, trial management, randomisation and all statistical aspects of the trial.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1

SABRE1 closed early in May 2011 due to poor recruitment with five sites open. The recruitment period was 24 months. At time of trial closure 30 patients had entered the first DA randomisation (15 allocated to each group) and four patients continued on to treatment randomisation.

Analysis of screening logbooks showed large differences by site in successful recruitment. The percentage of patients considered going through to first randomisation varied from 7 to 100%. The centre with 100% record only considered three patients, as it was the last to open. Overall 10.5% patients considered for the trial were randomised. In all, 286 patients were considered by the five sites with 230 provisionally suitable. In all, 77% (128/166) of eligible patients were given information on the trial, and 23% (30/128) of those patients consented to first randomisation. There was a large attrition rate from first to second randomisation. The primary outcome for first randomisation; the proportion of patients consenting to treatment randomisation was 6.7% for patients allocated to the DA arm (one of 15) and 20% for patients allocated to the control arm (three of 15); 27% overall. Of the four patients who agreed to continue on to treatment randomisation (one patient received brachytherapy and three surgery; Figure 1, consort diagram). The primary outcome for the second randomisation, the rate of patient accrual was 0.2 per site per month in the last 6 months of recruitment, and the trial was prematurely closed by the trial steering committee as it was felt unlikely to reach target accrual despite best efforts.

Analysis of screening logbooks showed that the main reasons for declining were a wish to choose treatment or opting for active monitoring (Table 1).

Table 1. Screening logbook details
Reasons for declining trial as detailed in screening logbooksNumber of patients
Wants active monitoring34
Wants radiotherapy/brachytherapy14
Wants surgery11
Decided on treatment type (not specified)1
Significant urinary tract problems2
‘Refused’13
Not fit for one treatment type9
Private patient1

In all, 10 patients who took part in the randomisation part 1 (DA) completed the DA questionnaire, of which four received the DA and six in the control group received standard information only (Table 2). The questionnaire was split into ‘facts’ (how well information about their condition and their options was given); ‘values’ (what is important to the patient and their preferred way of life) and ‘making choices’ (how much patients wish to be involved). Half of men completing the questionnaire did not know whether there was a difference in long-term side-effects (sexual problems, urinary problems or both) between EBRT/brachytherapy or surgery. Only four of the 10 men (four in the control group, none in the DA group) felt ‘both surgery and radiotherapy had been proven in a high-quality trial to most improve chances of living for 10 years’, with four of the 10 men (two in the in control group, two in the DA group) answering ‘don't know’.

Table 2. DA questionnaire replies (10 replies)
QuestionDA group (n = 4), n/NControl group (n = 6), n/NTotal (n = 10), n/N
1. ‘What matters most to you?’ Number of patients replying ‘very important’   
Avoid dying3/46/69/10
Avoid surgery1/40/61/10
Decrease chance of urinary dysfunction2/42/64/10
Decrease chance of sexual problems2/42/64/10
2. ‘Who should decide on best treatment for you?’   
Doctor (while knowing my opinion)1/40/61/10
My doctor and I together0/42/62/10
I should (while knowing my doctor's opinion)4/43/67/10
3. ‘Do you feel you made the right (treatment) choice?’   
Yes4/46/610/10

In all, six of the 10 men (three in the control group and three in the DA group) completing the questionnaire thought most men would die of something else rather than prostate cancer, eight of the 10 men (five in the control group and three in the DA group) thought less than half or no men would experience their cancer returning after EBRT or surgery. In making a treatment decision most (nine of the 10 men: all six in the control group and three of the DA group) felt it was very important to do everything possible to avoid dying of prostate cancer, four of the 10 men (two in the control group and two in the DA group) to decrease chances of urine problems, four of the 10 men (two in the control group and two in the DA group) to decrease chances of sexual problems, and only one man (in the DA group) felt it was very important to avoid surgery. In all, seven of the 10 men (three in the control group and all four in the DA group) felt that they should make their treatment decision, while knowing their doctors opinion.

We asked patients that had been allocated the DA and subsequently declined treatment randomisation if they found the DA helpful in making a treatment choice. 37% (six of 15) found it helpful, 13% (two of 15) unhelpful and 47% (seven of 15) declined to answer. Of the 26 patients declining treatment randomisation, three wished to choose active surveillance, two brachytherapy, four surgery and 16 unknown.

Our patient numbers are too small to make firm conclusions about barriers to recruitment but in a qualitative analysis by recruiting clinicians and trial staff we felt overall that despite the original aims of the DA, it may have contributed to patients taking a stance and subsequently refusing randomisation. In addition, the first appointment discussion with a patient may have had an impact in contributing to patients expectations of their treatment method that was hard to shift. We also found that engagement by all key members of the multidisciplinary team was crucial.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1

There is still controversy on how to manage early prostate cancer, the fifth most common cancer worldwide with 899 000 cases diagnosed in 2008 [1]. Four commonly used treatment options are available with RP acting as the reference standard. However, with few randomised trials comparing different treatments and speciality bias adding to the controversy, it is challenging for both physicians and patients to choose the right option. Surgery has the advantage of pathological examination of the prostate gland but increased urinary complications and erectile dysfunction rates. EBRT with no anaesthesia risk is available to a wider group of perhaps less fit patients with fewer urinary side-effects and greater potency preservation but increased rectal complications. Brachytherapy has improved incontinence and erectile dysfunction rates; increased urinary retention but reduced rectal side-effects than EBRT [10]. Active surveillance by definition has no associated physical side-effects other than periodic repeat prostate biopsy and/or imaging and is therefore initially attractive to patients, especially when presented as a valid option without detriment to mortality [11]. However, there are ramifications with 10–50% of patients subsequently proceeding to active treatment and a possible psychosocial impact related to uncertainty and anxiety [12]. With all management options in common use it becomes increasingly important to minimise toxicity and develop less invasive techniques and provide strong comparator evidence on oncological outcomes. SABRE2 was conceived to inform decision-making for this group of patients comparing RP to brachytherapy where there is little level 1 evidence to direct practice. The present trial SABRE1, a feasibility study, was designed to identify whether patient accrual was possible to avoid a costly phase III trial that ultimately failed to recruit. In terms of its primary endpoint, SABRE1 achieved this by showing clearly that unfortunately recruitment to this trial was not feasible in the UK with limited resources (unlike the MRC ProtecT study that was well resourced). A protocol amendment in 2011 was made to remove the first randomisation point (DA) as this was thought to be distracting but recruitment did not improve.

Our aim was to address the commonly inadequate recruitment to surgical trials by informing patients of their treatment options early to encourage equipoise and reduce clinician bias influence. A novel trial design incorporating additional information (DA DVD) failed to improve recruitment. Our recruitment rate of eligible approached patients was 23%, comparable to a large USA study of screen-detected patients with prostate cancer, the Prostate Cancer Intervention versus Observation Trial (PIVOT) where 15% of men accepted randomisation. However, PIVOT did reach its recruitment target but had to screen 13 022 men, of which 5023 were probably eligible and potentially interested in participating [11, 13]. Another two-step randomisation process was used in the ProtecT feasibility trial, where initial randomisation was to a nurse or Urologist for a trial information appointment had high (90%) recruitment rate to the information appointment [14]. After this 67% of men counselled by the nurse and 71% of men who saw the urologist agreed to randomisation in the treatment trial. However, this trial was unique in that detailed qualitative research and considerable training of nurses and feedback to recruiters took place. Study costs were high. This high recruitment rate has not been replicated.

Analysis of the decisional questionnaire used in SABRE, although limited by small numbers does give some insight into the thought processes of men with early prostate cancer. As one would expect, most rated a wish to survive their prostate cancer as very important. However, despite either standard or standard and DA information a large majority still were unsure of the different side-effect profile between treatments, yet most felt the decision should be their own (with clinician knowing their decision).

Moreover the concept of removing choice (by randomisation) requires very careful discussion. Donovan et al [8] and Mills et al. [9] found that both patients and recruiters in ProtecT had difficulty with randomisation and equipoise in particular. Randomisation could be useful as a way of resolving the dilemma of choice, attempting the randomisation before the end of the information appointment and informing patients they would have time to consider if their allocated treatment was acceptable were all methods for improving acceptability of the trial. In a systematic review of reasons for non-entry of eligible patients into surgical RCTs showed that the three most commonly reported patient-related reasons for non-entry were preference for one form of treatment, dislike of the idea of randomisation, and the potential for increased demands on the patient [15]. The recruiting researcher necessarily has influence on recruitment rate. A study investigating the personality dimensions of surgeons and physicians, and tolerance towards uncertainty by questionnaire showed that surgeons were significantly more extrovert (P < 0.001) less neurotic (P < 0.001) and less tolerant of uncertainty (P = 0.007) than physicians. There was no difference in attitude towards RCTs [16]. In addition, there is no mandatory formal training of researchers on how to obtain informed consent other than following ICH-GCP guidelines. A more historical study analysed 82 taped recordings of consultations of patients with cancer about clinical trials [17]. That study found most clinicians explained the treatments and side-effects in detail but only 25% explained randomisation in implicit and explicit (with a layman's explanation) terms and 83% never checked patient's understanding.

With an increasing number of potential treatments for early prostate cancer, the choice for patients and clinicians will correspondingly become increasingly difficult unless good quality research can show the pros and cons. Alternatives to the ‘gold standard’ RCT are patient preference, comprehensive cohort (relying on sufficient numbers of ‘indifferent’ patients) and randomised consent (Zelen), where patients are randomised before consent. More recently the ‘cohort multiple randomised controlled trial’ design [18] has been proposed but this has both methodological and ethical limitations and may be difficult to apply to this patient population. It is clear that only a few prostate RCTs have successfully recruited when offering very different treatment arms. Expensive embedded qualitative research may be the method to recruit patients successfully but this is not feasible in the current economic climate. We conclude that more sophisticated techniques are required in the future perhaps embracing and using the technology that gives patients much more information before they come to the clinic. SABRE1 has however shown the value of a small feasibility trial in saving time, money and effort by testing feasibility in a real-life scenario.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1

Funder: Cancer Research UK.

The Clinical Trials Awards and Advisory Committee (CTAAC) reference: C328/A8692.

The National Cancer Research Network (NCRN) reference: 11061813.

We acknowledge the patients, the research staff from all sites and University of Southampton Clinical Trials Unit for their hard work supporting this trial.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1
Abbreviations
EBRT

external-beam radiotherapy

ICH-GCP

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use-Good Clinical Practice

MRC

Medical Research Council

NICE

National Institute for Clinical Excellence

PIVOT

the Prostate Cancer Intervention versus Observation Trial

ProtecT

the Prostate Testing for Cancer and Treatment (study)

RCT

randomised controlled trial

RP

radical prostatectomy

SABRE

Surgery Against Brachytherapy – a Randomised Evaluation

Appendix 1

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  10. Appendix 1

Arm Rx1 Radical Prostatectomy

The surgical technique for radical prostatectomy may be retropubic, transperineal, laparoscopic or robotic. Surgery will take place within 6 months of randomisation.

Pelvic lymph node surgery is permitted at the discretion of the treating surgeon.

Unilateral or bilateral nerve-sparing techniques may be used at the discretion of the treating surgeon.

The following information must be described in the pathology report on the radical prostatectomy specimen:

  1. Histological type and Gleason grade recorded by order of prevalence, i.e. most extensive, second most extensive and third (tertiary), if present.
  2. Presence or absence of extraprostatic extension.
  3. Presence or absence of seminal vesicle invasion.
  4. The number and laterality of lymph nodes sampled the number of positive lymph nodes, and the presence or absence of extracapsular extension.
  5. The presence and location of positive surgical resection margins (apex, base and circumferential).

Arm Rx2 Brachytherapy

The procedure will be performed within 6 months following randomisation. It will be performed under general or regional anaesthesia.

Intravenous antibiotic coverage, such as Gentamicin, is recommended at induction of anaesthetic. In addition oral Ciprofloxacin 500 mg bd (twice daily) for 5 days is recommended. Alpha-blockers may be given at the discretion of the treating clinician.

A transrectal ultrasound probe attached to a stabilised stepping unit should be used. Planning must be via transrectal ultrasound. The urethra should be visualised using aerated gel in a catheter.

Isotope: Either iodine 125 or palladium 103 is acceptable.

Technique: Seeds may be implanted using pre-loaded needles or a MICK® applicator.

Dose: For palladium 103 the dose will be 125.00 Gy, minimum peripheral dose (NIST 1999 specification). For iodine 125 the minimum peripheral dose will be between 145.00 Gy to 160.00 Gy, (NIST 1999 specification) depending on local protocol

Peripheral loading is advisable to limit the dose to the urethra to less than or equal to 150% of the prescribed dose.

Seed activity: Palladium 103, 1–1.6 millicuries (37–59.2 mBq). Iodine 125, 0.28–0.5 millicuries (10.36–18.5) per seed.

The clinical target volume: Pre-implant (intraoperative) TRUS definition of the prostate.

Planning target volume: An expansion of the target volume is recommended as follows: 3–5 mm each lateral border, caudal and cephalad border. The anterior and posterior margin should be 0–3 mm.

Post-implant dose calculations: Post implant target volume is the volume of the prostate defined following brachytherapy on CT scan obtained 4–6 weeks after brachytherapy. The V100 (percentage of prostate volume receiving 100% of the prescribed dose), V150 (percentage of prostate volume receiving 150% of the prescribed dose), V200 percentage of the prostate volume receiving 200% of the prescribed dose and the D90 the dose delivered to 90% of the prostate volume.

Post implant CT scan involves 2–3 mm thin slices taken through the prostate from 2 cm superior to 2 cm inferior to the prostate gland.