Metastasectomy in renal cell carcinoma: where are we now?

PURPOSE OF REVIEW: Metastatic RCC has a variable natural history. Treatment choice depends on disease and patient factors, but most importantly disease burden and site of metastasis. This article highlights key variables to consider when contemplating metastasectomy for RCC and provide a narrative review on the evidence for metastasectomy in these patients. RECENT FINDINGS: Tumour subtype is associated with differing patterns of recurrence. Patients with single or few metastatic sites have better outcomes, and those with greater time interval from initial nephrectomy. Local recurrence is particularly amenable to minimally invasive surgical resection and is oncologically sound. Very well selected cases of liver or brain metastases may benefit from metastectomy, although lung and endocrine metastases have more favourable outcomes. Although site and burden of disease is important, the key determinate of outcome in metastasectomy depends mostly on the ability to achieve a complete resection. Adjuvant treatment is not currently advocated. SUMMARY: Metastasectomy should be generally reserved for cases where complete resection is achievable, unless the goal of treatment is to palliate symptoms. This field warrants ongoing research, particularly as systemic therapy and minimally invasive surgical techniques evolve. Elucidating tumour biology to inform patient selection will be important in future research.

The impact of the extent and location of positive surgical margins on the risk of biochemical recurrence following radical prostatectomy in men with Gleason 7 prostate cancers.

BACKGROUND: Positive surgical margins (PSM) after radical prostatectomy (RP) have been associated with increased risk of biochemical recurrence (BCR). This is heavily influenced by other clinicopathological factors. This study aims to assess the impact of the extent and location of PSM on BCR following RP for Gleason 7 carcinoma of the prostate (CaP). MATERIALS AND METHODS: All men treated with RP between 2008 and 2017 in our region for localized or locally advanced Gleason 7 CaP, were included. Clinical (age, year, preoperative prostate specific antigen) and pathological (prostate weight, positive or negative surgical margins, International Society of Urological Pathology [ISUP] grade, T stage) data were collected. PSM were subcategorised according to Extent into favourable (unifocal and <3 mm in length) or unfavourable (multifocal or ≥3 mm in length), and Location into apical only or others. The outcome was the risk of BCR which was calculated with univariable and multivariable regression models and reported as hazard ratio (HR) with 95% confidence interval (CI). RESULTS: The cohort constituted of 1433 men. Majority had ISUP 2 (71.2%) or localized (62%) disease. Men with PSM (n = 506) were at greater risk of BCR when compared to those with negative margins (adjusted HR = 1.52, [CI: 1.14-2.04], p = .005). Similar observation was demonstrated for both PSM location subgroups. As for the PSM extent category, only men with unfavourable PSM demonstrated an increase in BCR risk over negative margin (adjusted HR = 1.67, [CI: 1.23-2.28], p = .001). CONCLUSIONS: Within this study settings, PSM were generally associated with increased BCR risk. This, however, was not demonstrated in favourable PSM extent cases. Observation rather than active treatment in these men should be considered.

Detection of clinically significant cancer in the anterior prostate by transperineal biopsy.

OBJECTIVE: To determine the incidence of clinically significant prostate cancer (csPCa) detected exclusively in the anterior prostate using transperineal prostate biopsy. PATIENTS AND METHODS: Histopathology results of all patients who underwent transperineal prostate biopsy between February 2016 and March 2018 at a single institution were assessed for distribution of cancer within the prostate. Patients with cancer found exclusively in the anterior prostate were then compared to those with any cancer found in the posterior or lateral prostate with International Society of Urological Pathology Grade Group 2-5 cancers being considered csPCa. RESULTS: A total of 508 patients were included. Overall, 12.0% of the cohort had csPCa detected only in anterior biopsies. When stratified by prostate-specific antigen (PSA) level, 6.6% of men with a PSA level of 4.1-10.0 ng/mL and 8.2% of men with a PSA level of >10.0 ng/mL had csPCa detected in the anterior prostate alone. CONCLUSION: Transperineal biopsy has the ability to diagnose anteriorly located csPCa that would potentially have been missed by the transrectal approach.

Radical treatment of localised prostate cancer in the elderly.

Elderly men are more likely to be diagnosed with aggressive cancer, but are often inappropriately denied curative treatment. Biological rather than chronological age should be used to decide if a patient will profit from radical treatment. Therefore, every man aged >70 years should undergo a health assessment using a validated tool before making treatment decisions. Fit elderly men with intermediate- or high-risk disease should be offered standard curative local treatment in keeping with guidelines for younger men. Vulnerable and frail elderly men warrant geriatric intervention before treatment. In the case of vulnerable patients, this intervention may render them suitable for standard care. When considering radical prostatectomy outcomes a 'bifecta' of oncological control and continence is appropriate, as erectile dysfunction (although prevalent) has a much smaller impact on quality of life than in younger patients. Radiotherapy is an alternative to radical prostatectomy in men with a life expectancy of <10 years. Primary androgen-deprivation therapy is not associated with improved survival in localised prostate cancer and should only be used for symptom palliation. Further elderly-specific research is needed to guide prostate cancer care.

Patients with medical risk factors for chronic kidney disease are at increased risk of renal impairment despite the use of nephron-sparing surgery.

OBJECTIVE: To determine whether patients with normal preoperative renal function, but who possess medical risk factors for chronic kidney disease (CKD), experience poorer renal function after partial nephrectomy (PN) for renal cell carcinoma (RCC) compared with those without risk factors. PATIENTS AND METHODS: The effects of age, hypertension (HTN) and diabetes mellitus (DM) on estimated glomerular filtration rate (eGFR) were investigated in 488 consecutive operations for RCC performed during 2005-2012 at six Australian tertiary referral centres; 156 patients underwent PN and 332 patients underwent radical nephrectomy (RN). We used chi-squared test and binary logistic regression to analyse new-onset CKD, and multiple linear regression to investigate determinants of postoperative eGFR. RESULTS: The development of new-onset eGFR of <60 mL/min was related to undergoing RN rather than PN (risk ratio [RR] 2.7, P < 0.001), older age (RR 1.6, P < 0.001) and the presence of HTN (RR 1.6, P = 0.001) and DM (RR 1.5, P = 0.003). Patients undergoing PN were still at risk of new-onset CKD if medical risk factors were present. Whereas 7% of patients undergoing PN without CKD risk factors developed new-onset eGFR <60 mL/min, this figure increased to 24%, 30% and 42% for older age, HTN and DM, respectively. Patients with eGFR of 45-59 mL/min were more likely to progress to more severe forms of CKD and end-stage renal failure than those with eGFR of ≥60 mL/min. On multivariate analysis, RN, rather than PN, age and the presence of DM (but not HTN), predicted both the development of new-onset eGFR of <60 mL/min (R(2) = 0.37) and new-onset eGFR <45 mL/min (R(2) = 0.42). CONCLUSION: Patients with medical risk factors for CKD are at increased risk of progressive renal impairment despite the use of PN. Where feasible, nephron-sparing surgery should be considered for these patients.

Minimally invasive interventions for lower urinary tract symptoms: What sits between medical therapy and transurethral resection of the prostate.

BACKGROUND: There are a variety of medical and surgical treatment options available today for the management of lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction due to benign prostatic hyperplasia (BPH). OBJECTIVE: The aim of this paper is to highlight the various treatment options available for the management of bladder outlet obstruction secondary to BPH and discuss the benefits and potential drawbacks of each. DISCUSSION: Lifestyle and dietary modification and medical therapies, such as an alpha-1 blocker as monotherapy, should be considered as first-line when initially counselling a patient for LUTS secondary to bladder outlet obstruction due to BPH. If bothersome LUTS persist despite medical management, or if medical management is not suitable or preferable, then surgical interventions can be considered. The mainstay of surgical intervention has traditionally been transurethral resection of the prostate (TURP); however, the treatment landscape is rapidly evolving with the development of minimally invasive procedures.

Can initial clinical assessment exclude thoracolumbar vertebral injury?

INTRODUCTION: The aim of this study was to test the hypothesis that all blunt trauma patients, presenting with a Glasgow coma scale (GCS) score of 15, without intoxication or neurological deficit, and no pain or tenderness on log-roll can have any thoracolumbar fracture excluded without imaging. MATERIALS AND METHODS: All patients diagnosed with a thoracolumbar fracture presenting to the emergency department of a major trauma centre and having an initial GCS score of 15 were included in the study. Variables collected included type of fracture, mechanism of injury, the presence of pain or tenderness on log-roll, ethanol levels and prehospital opioid analgesia. RESULTS: There were 536 patients with thoracolumbar fractures, of which 508 (94.8%) patients had either pain, tenderness or had received prehospital opioid analgesia. A small subgroup of 28 (5.2%) patients who received no prehospital opioid analgesia, did not complain of pain and had no tenderness to the thoracolumbar spine elicited on log-roll. This subgroup was significantly older (p=0.033) and a high proportion of patients (64.3%) had a concurrent fracture of the cervical spine. Within this subgroup, a clinically significant unstable thoracic fracture was present in three patients, with all three patients exhibiting symptoms and signs of neurological injury or having a concurrent cervical vertebral fracture. CONCLUSIONS: In this population of blunt trauma patients with a GCS score of 15, not under the influence of alcohol or prehospital morphine administration, the absence of pain or tenderness on log-roll can exclude a clinically significant lumbar vertebral fracture, but does not exclude a thoracic fracture.

Red Out: Bleeding During Robotic Retroperitoneal Lymph Node Dissection and Strategies To Manage It.

Robotic retroperitoneal lymph node dissection is emerging as an attractive minimally invasive technique to remove residual and recurrent retroperitoneal masses in patients with germ cell malignancies. It has huge potential benefits for patients in terms of lower rates of blood loss, ileus, postoperative pain, and scarring, and faster return to full activity. Inadvertent injury to the great vessels, lumbar tributaries, and other vessels is not uncommon and requires a calm but strategic management response. A thorough knowledge of the standard anatomy, specific pathology, and anatomic variations will help robotic surgeons in managing intraoperative haemorrhage. We describe the anatomy of the retroperitoneal vessels, surgical case selection, and the technical and nontechnical skills essential for success in this complex and high-risk procedure. Patient summary: Robot-assisted surgical removal of lymph nodes from the area behind the abdominal cavity is a complex operation that has minimal bleeding if all goes well. However, as it involves operating on the major abdominal blood vessels, there is a risk of life-threatening bleeding that the operating team must be able to rapidly control. Effective teamwork and a range of advanced technical skills are required to respond to any serious bleeding.

The prostatic middle lobe: clinical significance, presentation and management.

The role of the prostatic middle lobe in the presentation and management of benign prostatic hyperplasia (BPH) is under-appreciated. Middle lobe enlargement is associated with intravesical prostatic protrusion (IPP), which causes a unique type of bladder outlet obstruction (BOO) via a 'ball-valve' mechanism. IPP is a reliable predictor of BOO and the strongest independent factor for failure of medical therapy necessitating conversion to surgical intervention. Men with middle lobe enlargement tend to exhibit mixed symptoms of both the storage and the voiding types, but symptomatology will vary depending on the degree of IPP present. Initial assessments such as uroflowmetry and post-void residual volumes are inadequate to detect IPP and could confound the clinical picture. Radiological evaluation of prostate morphology is key to assessment as it provides important prognostic information and can help with operative planning. Treatment strategies employed for BPH should consider the shape and morphology of prostate adenomata, specifically the presence of middle lobe enlargement and the degree of associated IPP.

The effect of oral anticoagulation on the prevalence and management of haematuria in a contemporary Australian patient cohort.

OBJECTIVE: • To examine the effect of oral anticoagulation (OA) on the prevalence and inpatient management of haematuria in a contemporary Australian patient cohort. PATIENTS AND METHODS: • Patients across all inpatient units who had diagnosis-related group (DRG) coding for haematuria were identified from April 2010 to September 2011. • A retrospective chart review was performed to identify the type of anticoagulation (if any), requirement for bladder irrigation or blood transfusion, length of stay (LOS) and cause of haematuria. • Patients for whom the anticoagulation status was uncertain were excluded from analysis. • Statistical significance was determined by Pearson's chi-square tests and Student's t-tests. RESULTS: • In all, 335 admissions with DRG coding for haematuria were identified from hospital records, of which 268 admissions had clear documentation of anticoagulation. There were 118 emergency admissions and 150 elective admissions for day case cystoscopy. The mean age of the patients was 66 years and the male:female ratio was 5:1. In all, 123 admissions were for patients on some form of anticoagulation (46%). • Patients were on anticoagulation in 53% of the 118 emergency admissions for gross haematuria. These comprised patients on aspirin (28%), clopidogrel (4%), warfarin (10%), combined aspirin and warfarin (1%) and combined aspirin and clopidogrel (10%). • The use of OA was a significant predictor of the need for intervention among the 118 emergency admissions (86% vs 62%, P = 0.003). • In particular, dual antiplatelet therapy in the form of aspirin and clopidogrel was associated with an increased requirement for bladder irrigation (92%) when compared with patients on other forms of anticoagulation (84%) or none at all (62%, P = 0.01). • The mean LOS for patients admitted to hospital with haematuria was 5.6 days. Patients on warfarin had a statistically significant longer LOS than the other groups (13.7 vs 4.5 days, P < 0.001). A cause for haematuria was identified in 120 of the 234 patients (51%). Of these, the most common was benign prostatic hyperplasia (21%), followed by bladder urothelial carcinoma (17%). CONCLUSION: • In our cohort of patients, about half of all admissions with haematuria were for patients on some form of OA. • OA use increased the need for intervention, especially for patients on dual antiplatelet therapy.

The impact of health-policy-driven subsidisation of prostate magnetic resonance imaging on transperineal prostate biopsy practice and outcomes.

Background: From 1 July 2018, the Australian Medicare Benefits Schedule (MBS) introduced rebates for multi-parametric magnetic resonance imaging (mpMRI) for the workup for prostate cancer (PCa). We aimed to determine if subsidisation of mpMRI prior to transperineal biopsy altered our institution's prostate biopsy practice patterns and outcomes. Methods: All patients who underwent transperineal prostate biopsy at an Australian tertiary institution from 1 January 2017 to 1 January 2020 were identified. Patients with known PCa were excluded. Patients were stratified into two groups: a pre-subsidisation cohort comprising patients biopsied prior to the introduction of mpMRI subsidisation on 1 July 2018 and a post-subsidisation cohort comprising patients biopsied after 1 July 2018. Histopathological results were compared with further stratification based on mpMRI results. Clinically significant cancer was defined as ISUP Grade Group ≥ 2. Results: Six hundred and fifty men fulfilled the inclusion criteria. Three hundred and sixty-one patients were in the pre-subsidisation cohort and 289 in the post-subsidisation cohort. Of the patients in the pre-subsidisation group, 36.3% underwent a pre-biopsy mpMRI compared with 77.5% in the post-subsidisation group. Of the patients in the pre-subsidisation group, 59.6% had positive biopsies (p = 0.024) compared with 68.2% in the post-subsidisation group. The rate of clinically significant PCa was lower in the pre-subsidisation group (39.1%) compared with the post-subsidisation (49.5%, p = 0.008). The negative predictive value of mpMRI for clinically significant PCa was 86.5%. Conclusion: Our institution experienced a reduction of negative prostate biopsies and an increase in clinically significant PCa within transperineal biopsy specimens after the Australian healthcare system introduced financial subsidisation of mpMRI.

Advances in prostate cancer.

BACKGROUND: Prostate cancer is a common tumour type in Australian men. OBJECTIVE: The aim of this article is to review important changes in prostate cancer diagnosis and management over the past five years, particularly as they pertain to general practice. DISCUSSION: The management of prostate cancer has changed significantly in recent years, particularly the use of imaging, with the introduction of prostate magnetic resonance imaging as routine in the diagnostic pathway, and the increasing use of prostate-specific membrane antigen positron emission tomography for early stratification in the salvage setting for failure of primary treatment in localised disease. In addition, upfront combinations of androgen deprivation therapy with other systemic treatments have yielded significant gains in overall survival for patients with metastatic disease. There has also been an increasing recognition of the association between germline DNA repair defects and progressive disease, and interest in the potential to identify patients for therapies that target these defects. There have been significant changes in how prostate cancer is diagnosed and managed in the past five years, with the introduction of new clinical pathways that were unprecedented just a decade previously.

Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression.

BACKGROUND: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. METHODS: We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. RESULTS: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014). CONCLUSIONS: CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.

A Retrospective Comparison of Transrectal and Transperineal Prostate Biopsies: Experience of a Single Surgeon.

Background: Transrectal ultrasound-guided prostate biopsy (TRUS) is the gold standard for undertaking prostate biopsy, however, it has been associated with higher rates of post-biopsy sepsis than transperineal prostate biopsy (TP). Objective: To compare complication rates between transrectal prostate biopsy and TP for a single surgeon. Materials and Methods: Data were collected for all prostate biopsies undertaken by a single experienced urologist through his private rooms between February 2012 and March 2018. In total, 693 cases were included (560 individual men) in the final analysis (transrectal = 276 and transperineal = 417). All patients were followed up 2 weeks post-biopsy, and complications were recorded (sepsis, urinary tract infection [UTI], bleeding, and acute urinary retention [AUR]). Results: Complications occurred in 37 cases (transrectal = 3 and transperineal = 34). Sepsis occurred in one case following transrectal biopsy (0.36%) and two cases following TP (0.48%). UTI occurred in two cases following transrectal biopsy (0.72%) and two cases following transperineal (0.48%). Bleeding occurred in one case following TP (0.24%). The most common complication was AUR, which occurred in 28 cases following TP (6.71%). Conclusions: Data from this study compared complication rates for both transperineal and transrectal prostate biopsies in a single-surgeon study.

Prostatic nerve subtypes independently predict biochemical recurrence in prostate cancer.

OBJECTIVE: To describe nerve subtypes involved by perineural invasion (PNI) in prostate cancer and their relationship with clinicopathological parameters and recurrence risk. METHODS: 141 prostatectomy specimens from men with localized prostate cancer and known perineural invasion were analyzed. Index tumor blocks were stained for perineural invasion and sympathetic/parasympathetic markers. For 98 patients with complete staining, nerves from up to three hotspot regions of intraprostatic perineural invasion were classified according to autonomic subtype and perineural invasion status. Findings were correlated with prospectively collected clinicopathological data. Biochemical recurrence predictors were tested in univariable and multivariable models. RESULTS: Most intra-prostatic nerves contained sympathetic and parasympathetic fibres, irrespective of perineural invasion status. A fraction was purely sympathetic (5% PNI, 2% non-PNI) or double-negative (non-adrenergic, non-nitrergic; 1% PNI, 1% non-PNI). Perineural invasion nerve count was associated with higher pathological stage. Although total perineural invasion or non-perineural invasion nerve count did not predict biochemical recurrence, two subtypes were found to be independent predictors: pure sympathetic non-perineural invasion nerves (HR 6.79, p = 0.03) and non-adrenergic, non-nitrergic PNI nerves (HR 10.56, p < 0.005). CONCLUSIONS: Pure sympathetic nerve density without tumour invasion and perineural invasion specifically involving non-adrenergic, non-nitrergic fibres are independent predictors of biochemical recurrence post prostatectomy, supporting a role for the autonomic nervous system in prostate cancer progression.