SUMMER EDITION 2022 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE Supported by: This publication is intended for registered healthcare professionals only. Dr Lance Coetzee Urologist, Robotic Surgeon and Founder of the Prostate Cancer Foundation of South Africa.
SUMMER EDITION 2022 Editor Prof Shingai Mutambirwa - Urologist MBChB, MMed (Urology) Medunsa Headof Urology - SefakoMakgathoHealth Sciences University Chairman - The South African Urological Association Academic committee Chairman - Medical and ScienticAdvisory Board of The Prostate Cancer Foundation Editorial Board Dr. Sheynaz Bassa - Clinical and RadiationOncologist MBChB (Univ of Natal), FCRad (Onc) SA Head of Department: RadiationOncology Steve Biko Academic Hospital and The University of Pretoria Dr Jireh Serfontein - Medical Sexologist MBChB (Pret.), Dip HIVManagement, MMed Sexual Health (Univ. Sydney) Clinical head: My Sexual Health Pretoria Editorial and PublishingOfce Maria Philippou Randburg 2194 Enquiries 082 3355 444 Publisher Maria Philippou AndrewOberholzer Disclaimer All rights reserved. No editorial matter published in Urology, Urooncology and Sexology Updatemay be reproduced in any form or languagewithout written permission from the publishers. While every effort is made to ensure accurate reproduction, the Prostate Cancer Foundation, the authors, publishers and their employees or agents shall not be responsible or in any way liable for any errors, omissions or inaccuracies in the publication whether arising fromnegligence or for any consequences arising there from. The inclusion or exclusion of any product does not mean that the Prostate Cancer Foundation, the publisher or the editorial board advocates or rejects its use either generally or in any particular eldor elds. This publ icat ion is intended for registered heal thcare professionals only. If you received this publication or a link to this publication in error, please do not directly or indirectly use, print, copy, forward, or discloseany part of this publication. Please delete the copy or link to the publication and notify the publisher. Cover: Dr Lance Coetzee Urologist, Robotic Surgeon and Founder of the Prostate Cancer Foundation of South Africa. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE CONTENTS 1 ARAMIS: A Phase III Study of darolutamide in Men with Highrisk Non-metastatic Castrationresistant Prostate CancerMAM_DAR-ZA-0015-1 Prole on Dr Lance Coetzee The Development of Thermal Therapy for Bladder Cancer Part 2 A practical approach to the management of metastatic hormone sensitive prostate cancer (mHSPC) – feedback from SAUA Astellas Trade Symposium Are we underdosing patients with erectile dysfunction with PDE5 inhibitors? Will sildenal be the next breakthrough for treatment Alzheimer's disease? Thanks to Everyone Who Supported The Prostate Cancer Foundation's Suit Up September Campaign to Help Raise Awareness About Prostate Cancer People on the move Transforming Surgery: Versius Surgical System Southern African Prostate Cancer Study (SAPCS) creating a roadmap for Precision Health Jumping the river - orgasms without erections The 2023 Hollard Daredevil Run for Prostate and Testicular Cancer The Prostate Cancer Foundation and Astellas teamed up this September to make a difference in the ght against prostate cancer 2 10 12 22 26 30 32 34 38 40 43 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE 28 29
2 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE ARAMIS: A Phase III Study of darolutamide in Men with High-risk Non-metastatic Castration-resistant Prostate Cancer MA-M_DAR-ZA-0015-1 Summary • Darolutamide is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration1 resistant prostate cancer (nmCRPC). • ARAMIS, a Phase III, randomized, double-blind, placebo-controlled multinational study, evaluated the efcacy and safety of darolutamide in men being treated with androgen deprivation therapy (ADT*) for nmCRPC with a high risk of developing metastases (PSADT of ≤ 10 months and PSA ≥ 1,2,3 2ng/ml). Patients (N = 1509) were randomized 2:1 to receive darolutamide 600 mg tablets orally twice daily plus ADT* versus matching placebo plus ADT*. * Common previous hormonal therapies for prostate cancer (received by ≥10% of all patients) included leuprolide (52%), goserelin (32%), triptorelin (29%), bicalutamide (66%), utamide (13%), and cyproterone (11%). In the primary analysis of the Phase III ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) signicantly prolonged metastasis free survival (MFS) (median 40.4 months) compared to placebo plus ADT 1,3 (median 18.4 months). In the nal analysis of the ARAMIS trial: • Darolutamide plus ADT signicantly improved overall survival (OS), with a 31% reduction in risk of death compared with placebo plus ADT, in men with nmCRPC (hazard ratio [HR] 0.69; 95% condence interval [CI] 0.53-0.88, 2 P=0.003) • Treatment with darolutamide plus ADT signicantly improved all other secondary endpoints, including time to pain progression (HR 0.65; 95% CI 0.53-0.79, P<0.001), time to cytotoxic chemotherapy (HR 0.58; 95% CI 0.440.76; P<0.001), and time to rst symptomatic skeletal event (SSE) (HR 0.48; 95% CI 0.29-0.82, 2 P=0.005) • The nal analysis of the safety prole of darolutamide was generally consistent with 2,4 the primary analysis. The incidences of treatment-emergent adverse events were similar between patients who received darolutamide plus ADT and those who 2-4 received placebo + ADT. The AE with an incidence of ≥10% was fatigue (13.2% in the darolutamide group versus 8.3% in the placebo group). No new safety signals were 2 observed in the nal analysis. CLINICAL DATA ARAMIS Trial Background Study Design ARAMIS a global, randomized, double-blind, placebo-controlled phase 3 trial evaluated the efcacy and safety of darolutamide plus ADT versus placebo plus ADT in men with nmCRPC (Error! 1-3 Reference source not found.). Men with nmCRPC and a prostate-specic antigen doubling time (PSADT) of ≤10 months were randomized 2:1 to receive either darolutamide 600 mg twice daily 2,3 plus ADT or placebo plus ADT. The primary endpoint was metastasis free survival (MFS). Secondary outcomes included overall survival (OS), time to pain progression (TPP), time to rst cytotoxic chemotherapy, time to rst symptomatic skeletal events (SSE), and safety. 1-3 Figure 1. ARAMIS Trial Design This is a CPD accredited article, please click on the link below to complete the questionnaire for CPD points: https://bayerag.eu.qualtrics.com /jfe/form/SV_3Og96dqvI7GYvyu
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4 Patient Baseline Characteristics and Demographics Patient demographics (Table 1) and baseline clinical characteristics (Table 2) were well-balanced between 2,3 the study groups. 3 Table 1. ARAMIS: Patient Demographics Age, median, years Age group, n (%) <65 65 - 74 75 – 84 ≥85 Race, n (%) *Asian Black or African American Other White Weight N Missing, n Median, kg Geographical region, n (%) North America Asia Pacic Rest of the world Darolutamide N=95574.0 113 (11.8) 373 (39.1) 384 (40.2) 85 (8.9) 122 (12.8) 28 (2.9) 9 (0.9) 760 (79.6) 953 2 82.40 108 (11.3) 119 (12.5) 728 (76.2) Placebo N=55474.0 84 (15.2) 216 (39.0) 209 (37.7) 45 (8.1) 71 (12.8) 24 (4.3) 6 (1.1) 434 (78.3) 552 2 82.00 76 (13.7) 67 (12.1) 411 (74.2) Total N=150974.0 197 (13.1) 589 (39.0) 593 (39.3) 130 (8.6) 193 (12.8) 52 (3.4) 15 (1.0) 1194 (79.1) 1505 4 82.00 184 (12.2) 186 (12.3) 1139 (75.5) Darolutamide N=955 n (%) 667 (69.8) 4.84 (4.39) 18.7 (9.0) 924 (96.8) 650 (68.1) 305 (31.9) 27 (2.8) 217 (22.7) 711 (74.5) 177 (18.5) 727 (76.1) 51 (5.3) 792 (82.9) 163 (17.1) Placebo N=554 n (%) 371 (67.0) 4.89 (4.65) 19.8 (9.7) 522 (94.2) 391 (70.6) 163 (29.4) 17 (3.1) 142 (25.6) 395 (71.3) 103 (18.6) 420 (75.8) 31 (5.6) 396 (71.5) 158 (28.5) Total N=1509 n (%) 1038 (68.8) 4.86 (4.45) 19.1 (9.3) 1446 (95.8) 1041 (69.0) 468 (31.0) 44 (2.9) 359 (23.8) 1106 (73.3) 280 (18.6) 1147 (76.0) 82 (5.4) 1188 (78.7) 321 1.3) 3 Table 2. ARAMIS: Patient Characteristics Baseline PSADT ≤6 months, n (%) PSADT, months, mean (median) PSA, ng/mL, mean (median) No baseline osteoclast- target therapy, n (%) ECOG PS, n (%) 0 1 Gleason total score (Factor1 + Factor2), n (%) Missing <7 ≥7 Prior hormonal therapy, n (%)103 (18.6) 1 ≥2 Not applicable* Baseline presence of regional pathological lymph nodes by central imaging review, n (%) No Yes UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
5 ARAMIS Trial Findings Metastasis-Free Survival (MFS) After a median follow-up of 17.9 months, darolutamide plus ADT demonstrated a statistically signicant improvement in MFS of 40.4 months [95% CI 34.33 – NR] vs 18.4 months [95% CI 15.51 – 22.34] in the placebo plus ADT arm and reduced the risk of metastasis or death by 59% compared to placebo [HR .41 (95% CI 0.34 – 0.50); P <0.001]. This improvement in MFS (Figure 2) was consistent among patients irrespective of baseline characteristics, therapy and demographics. See 3 Table 3 and Figure 1. 1,3 Figure 2. ARAMIS Trial Metastasis-Free Survival The results from the secondary endpoints also favored darolutamide plus ADT. Exploratory endpoints evaluated at the primary analysis included PFS, time to PSA progression, time to rst prostate cancer-related invasive procedure, and time to initiation of subsequent anti-neoplastic therapy, all of which favored darolutamide plus ADT. Overall Survival (OS) Following the primary data cutoff, the ARAMIS study was unblinded on November 30, 2018, and nal data collection cutoff was November 15, 2019. The median follow-up was 29.1 months for the overall study population (11.2 additional months following 2 the primary analysis for MFS). Patient Crossover and Disposition in ARAMIS: At the time of study unblinding, 170 patients from the placebo group crossed over to receive open- 2 label darolutamide plus ADT. At the time of the data cutoff for the nal analysis, 49% (466/954) of patients originally randomized to darolutamide plus ADT were still receiving treatment with darolutamide and 86% (147/170) of patients in the crossover group were still receiving darolutamide. The median treatment exposure for darolutamide group was 18.5 months for the double-blind period and 25.8 months in the combined double-blind and 2 open-label periods. The nal analysis was performed after 254 deaths (148 [16%] in the darolutamide group and 106 [19%]) in the placebo group. Darolutamide plus ADT signicantly reduced the risk of death by 31% (HR 0.69; 95% CI 0.53-0.88, P=0.003) in men with nmCRPC in the nal analysis of the ARAMIS trial. Median OS in months was not reached for both 2 treatment arms (Figure 3). UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
6 2 Figure 3. Overall Survival NE, not estimable. 2 The treatment effect for OS in the pre-specied subgroup analysis is presented in Figure 4 below. 2 Figure 4. Overall Survival Subgroup Analysis CI, condence interval; ECOG, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NE, not estimable; PSA, prostate-specic antigen. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
7 Other Secondary and Exploratory Endpoints Once the OS results had achieved statistical signicance, the other secondary endpoints were 2 evaluated hierarchically in sequence. Time to pain progression was evaluated using data from the primary analysis as no additional data were collected for this endpoint beyond that 2,4 time. Secondary endpoints were signicantly improved by darolutamide and exploratory endpoints favored darolutamide. See Table 3 3 below. Subsequent Therapy In the placebo group, 56% of patients (309/554) received subsequent darolutamide or other life- prolonging therapy while 15% of patients (141/955) in the darolutamide group received subsequent 2 life-prolonging therapy. Subsequent life-prolonging therapy for both groups are presented in Table 4 2 below. Safety In the nal analysis (18.5 months for the doubleblind period and 25.8 months for the combined double-blind and open-label periods) of ARAMIS, the safety prole of darolutamide was consistent with the primary analysis (median exposure of 14.8 2,3 months). Overall, adverse events (AEs) were similar between the darolutamide plus ADT and placebo + ADT groups (reported in 85.7% of patients in the darolutamide plus ADT group and 79.2% of patients receiving placebo plus ADT during the double-blind period) and no new safety signals were observed in the nal analysis despite the longer treatment 2,3 exposure. Table 5 shows the Treatment Emergent Adverse Events (TEAEs) for the total safety population (N = 1508) in the primary analysis. TEAEs (all grades) occurring in ≥5% of patients reported in Table 6 below, in the darolutamide versus placebo arms, respectively, included fatigue (including asthenia) (12.1% [115/954, vs 8.7% [48/554]). Other TEAEs occurring in ≥5% in the darolutamide arm included back pain (8.8%), arthralgia (8.1%), diarrhea (6.9%), hypertension (7.3%), constipation (TEAEs occurring in 6.3%), pain in extremity (5.8%), anemia (5.6%) and hot ush (5.2%). Approximately 14% of TEAEs led to a dose modication in the darolutamide arm versus 9.4% of TEAEs in the 2 placebo arm. NE, not estimable. Endpoint, median (months) Secondary Endpoints Time to pain progression Time to initiation of cytotoxic chemotherapy Time to rst SSE Exploratory Endpoints Time to rst prostate cancer- related invasive procedure Time to initiation of subsequent antineoplastic therapy Patients who discontinued study treatment, n (%) Received life-prolonging therapy Life-prolonging therapy for CRPC received: Darolutamide Docetaxel Abiraterone, abiraterone acetate Enzalutamide Sipuleucel-T Cabazitaxel Darolutamide + ADT N=955 40.3 NE NE NE NE Placebo + ADT N=554 25.4 NE NE NE NE HR (95% CI) 0.65 (0.53-0.79) 0.58 (0.44-0.76) 0.48 (0.29-0.82) 0.42 (0.28-0.62) 0.36 (0.27-0.48) P-value <0.001 <0.001 0.005 <0.001 <0.001 3 Table 3. Outcomes of Secondary and Exploratory Endpoints Daro + ADT N=955 141 (15) – 82 (9) 29 (3) 28 (3) 1 (0.1) 1 (0.1) Daro + ADT N=955 141 (15) – 82 (9) 29 (3) 28 (3) 1 (0.1) 1 (0.1) 2 Table 4. Subsequent Life-Prolonging Therapies Daro, darolutamide. ADT, Androgen depravation therapy. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
8 After a median follow-up of 17.9 months, treatment 4 discontinuations were similar between both arms. Discontinuations due to adverse events occurred in 8.9% of patients in the darolutamide arm vs 8.7% of patients in the placebo arm. Discontinuations due to metastasis occurred in 11.7% vs 23.3% of patients; and discontinuations due to investigator judgment occurred in 5.7% vs 16.4% of patients, in the darolutamide vs placebo arms, respectively. Discontinuations due to protocol deviation and to other reasons unspecied occurred in 1.4% vs 1.3% and 0.6% vs 0.4% in the darolutamide vs placebo arm, respectively. Additionally, 7.1% vs 14.1% of patients in the darolutamide vs placebo arm respectively decided not to continue trial participation. It should be noted that one person in the darolutamide arm was randomized but did not 2 receive treatment. A total of 55 deaths (Grade 5 event) occurred during the trial with 3.9% of deaths occurring in the darolutamide arm versus 3.2% 3 occurring in the placebo arm. See Table 5 below. The incidence of discontinuations due to AEs was unchanged from the primary analysis while the incidences of serious AEs and Grade 5 AEs between the treatment groups during the double- blind period were comparable with the primary 2,3 analysis (Table 5). In the placebo-darolutamide crossover group, 70.0% experienced an AE and 4.7% experienced an AE leading to discontinuation 2,3 (Table 5). 2,3 Table 5. Summary of Treatment-Emergent Adverse Events (TEAEs) Daro, darolutamide. In line with the primary analysis, fatigue was the only AE present in more than 10% of patients during the double-blind period (13.2% in the darolutamide group and 8.3% in the placebo group) while the incidence of 2 all other AEs that occurred in ≥5% of patients was generally similar between groups. AEs of interest are 2 presented in Table 6. ARAMIS trial TEAEs Any AE, n (%) Grade 3 or 4 Grade 5 Serious Leading to permanent discontinuation of study drug Daro + ADT N=954 794 (83.2) 236 (24.7) 37 (3.9) 237 (24.8) 85 (8.9) Placebo + ADT N=554 426 (76.9) 108 (19.5) 18 (3.2) 111 (20.0) 48 (8.7) Daro + ADT (double blind period) N=954 818 (85.7) 251 (26.3) 38 (4.0) 249 (26.1) 85 (8.9) Placebo + ADT (double blind period) N=554 439 (79.2) 120 (21.7) 19 (3.4) 121 (21.8) 48 (8.7) Placebo-Daro Crossover N=170 119 (70.0) 27 (15.9) 2 (1.2) 26 (15.3) 8 (4.7) Final Analysis Primary Analysis UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
9 n (%) a Fatigue b Bone fracture Falls (including accident) Weight decreased (any event) c Asthenic conditions d Rash Seizure f Mental impairment disorders f Depressed mood disorders Hypertension Hot ush f,g,h Cardiac arrhythmias i Coronary artery disordersf, f,j Heart failure Grade 3-4 4 (0.4) 10 (1.0) 9 (0.9) 0 2 (0.2) 2 (0.2) 0 3 (0.3) 1 (0.1) 33 (3.5) 0 17 (1.8) 19 (2.0) 4 (0.4) Any grade 126 (13.2) 52 (5.5) 50 (5.2) 40 (4.2) 38 (4.0) 30 (3.1) 2 (0.2)e 19 (2.0) 21 (2.2) 74 (7.8) 57 (6.0) 70 (7.3) 38 (4.0) 18 (1.9) EAIR (per 100 subject years) 8.9 3.4 3.3 2.6 2.5 2.0 0.1 1.3 1.4 4.9 3.8 4.6 2.5 1.2 Any grade 46 (8.3) 20 (3.6) 27 (4.9) 14 (2.5) 17 (3.1) 6 (1.1) 1 (0.2) 10 (1.8) 10 (1.8) 36 (6.5) 25 (4.5) 24 (4.3) 15 (2.7) 5 (0.9) Grade 3-4 5 (0.9) 5 (0.9) 4 (0.7) 0 2 (0.4) 1 (0.2) 0 0 0 13 (2.3) 0 4 (0.7) 2 (0.4) 0 EAIR (per 100 subject years) 7.4 3.2 4.3 2.2 2.7 1.0 0.2 1.6 1.6 5.8 4.0 3.8 2.4 0.8 2,3 Table 6. Incidence and Exposure-Adjusted Incidence of Treatment-Emergent Adverse Events of Interest Placebo + ADT (double blind) N=554 Darolutamide + ADT (double blind) N=954 EAIR, exposure-adjusted incidence rate; TEAE, treatment-emergent adverse event. a. In the primary analysis, this category combined the following MedDRA, version 20.0 terms: asthenic conditions, disturbances in consciousness, decreased strength and energy, malaise, lethargy, asthenia, and fatigue. In the nal analysis, this only included fatigue. b. Combined term comprising MedDRA terms of any fractures and dislocations, limb fractures and dislocations, skull fractures, facial bone fractures and dislocations, spinal fractures and dislocations, and thoracic cage fractures and dislocations c. Combined term comprising MedDRA terms of asthenic conditions, disturbances in consciousness, decreased strength and energy, malaise, lethargy, and asthenia d. MedDRA labeling grouping, including preferred terms of rash, rash macular, rash maculo-papular, rash papular and rash pustular e. One additional incidence of seizure occurred in the darolutamide group during the open-label period, in a patient with a history of epilepsy f. MedDRA High Level Group term g. Grade 5 events occurred in 2 patients receiving darolutamide in the double-blind period and 3 patients receiving placebo in the double-blind period h. An imbalance in the incidence of cardiac arrhythmias between the darolutamide and placebo groups was observed at baseline i. Grade 5 events occurred in 3 patients receiving darolutamide in the double-blind period, 1 patient receiving placebo during the double-blind period and 1 patient in the crossover group j. Grade 5 events occurred in 7 patients receiving darolutamide in the combined double-blind and open-label periods, and 3 patients receiving placebo during the double-blind period. At baseline, 3% (31/955) of patients in the darolutamide group and 6% (32/554) of patients in the placebo group used concomitant bone-sparing agents (i.e., drugs affecting bone structure and mineralization [such as bisphosphonate and denosumab], vitamin D and analogues, calcium and calcium combinations, uorides and 3,4 calcitonins). CPD Accreditation ® For any further information on Nubeqa (darolutimide) please contact your Bayer representative or Lynda Woods Customer Sales and Marketing Manager: Oncology South Eastern West Africa lynda.woods@bayer.com +27 82 651-2639 References/Enclosure(s): 1. Darolutamide [Prescribing Information]. Darolutamide PI. SAHPRA approval 15 March 2022 2. Fizazi K, Shore N, Tammela TL, et al. Darolutamide and overall survival in nonmetastatic castration- resistant prostate cancer. N Engl J Med. 2020; 38 (11): 1040-1049 3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. 4. Data on le. Bayer HealthCare Pharmaceuticals, Whippany, NJ. Approval number MA-M_DAR-ZA-0015-1 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
10 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE Profile on Dr Lance Coetzee UROLOGIST AND CHAIRMAN OF THE PROSTATE CANCER FOUNDATION With over 1300 robotic assisted laparoscopic prostatectomies behind him, Dr Lance Coetzee is one of South Africa's highest volume robotic prostate cancer surgeons. He is recognized both locally and internationally as a leader in the eld of prostate cancer. He is a Senior Consultant Urologist (Uro-oncology and Reconstructive Urology) in the Department of Urology at the University of Pretoria and has a private practice at the Urology Hospital in Pretoria. In 2007 he founded the Prostate Cancer Foundation of South Africa and has served as its chairman since its inception. We asked him some questions about his life, his career, and his passion for prostate cancer What inspired you to specialize in urology? It was due in part due to fate. During my housemanship the person who was due to take over from me was unable to, so I stayed on. I was then posted to 1 Military hospital for my military service, and when they heard that I had some urology experience they placed me in the urology department. I was originally thinking more of becoming a thoracic surgeon, but my stint in the urology department at 1 Military hospital fortunately steered me in a different direction. How difcult was it to make the transition from open surgery or laparoscopic to robotic surgery? I had done a lot of open surgery, so it was a fairly easy transition. Laparoscopic surgery is almost counterintuitive and makes the transition more difcult. If you know the operation well, it's really just about adjusting to the platform and getting over the nger troubles. For a a radical prostatectomy, robotic surgery is actually easier than open surgery. You don't have to open up the patient, you just place the ports in and you are immediately in the eld that you are going to be working in. You can also access small spaces buried behind the pubic bone that you can't see with open surgery. The instrumentation is so much more precise, and the superior vision allows for a much better nerve sparing procedure. I believe that in experienced hands, robotic surgery is better able to preserve continence and potency, and there is far less blood loss and a shorter hospital stay. In fact, we are now able to operate on older patients who would previously have been disqualied from having their prostate cancer surgically managed, because of the much more invasive nature of open surgery.
11 What inspired you to start the Prostate Cancer Foundation? Back in 2005 I was chatting to one of the pharmaceutical brand managers at the time, Bev Pretorius from Sano, and we realised that there was a real vacuum in terms of the knowledge of prostate cancer amongst not only the general public, but also amongst GP's. There was a desperate need to raise awareness about the importance of early detection in order to move the diagnostic line back to the point when the disease is potentially curable. We were losing too many otherwise healthy men to a potentially curable disease because of ignorance, and that was the initial drive that inspired us to start the organisation. We linked up with some of the other prostate cancer foundations in Australia and the UK to nd out how they had gone about establishing their organisations and launched The Prostate Cancer Foundation of South Africa in 2007. In the past few years, the Prostate Cancer Foundation has gained a lot more recognition, what do you attribute this to? The Foundation has gone from strength to strength in the past few years. Having strong leadership in the executive board, with clear vision has been critical. But the Foundation grew to a point where we needed someone fulltime to manage it, and we appointed Andrew Oberholzer as the CEO in 2011. This made a huge difference and enabled the organisation to sort out all of the compliance issues which a board of volunteers simply doesn't have time for. Under Andrew's leadership the organisation has blossomed. The organization was restructured around 2014 into three separate divisions, a Medical and Scientic Advisory Board comprising of the healthcare professionals involved in diagnosing and treating prostate cancer, a Patient Affairs Board where prostate cancer survivors can get involved, and a Marketing Board where pharmaceutical and medical corporate members have representation. This enabled us to have a more focused approach, and we have been better able to identify the needs of each group and develop programmes and strategies to meet these. The prostate cancer landscape is changing rapidly, what do you think will be the biggest game changer in the diagnosis and treatment of prostate cancer in the next 10 years? The technology in all the different treatment arms is evolving rapidly. This includes surgery, pharmacology and radiation. However, the biggest game changer is likely to be genetic sequencing which will enable us to select the patients that really need treatment and manage other patients more conservatively. I think that we are already quite far down the road with this, but it's still very expensive. This will hopefully change in the next 10 years and genetic sequencing will be more affordable and therefore more widely available. As one of the busiest surgeons in South Africa, how have you managed to balance, work, family and recreation? There's denitely a price to pay and I haven't always been able to spend as much time with my family as I would have liked to. We weren't able to take long breaks at the end of the year, but instead opted for lots of short high impact, high quality breaks. I must give a lot of credit to my wife, who is a strong and independent person and who was able to to take on a lot of the responsibility for bringing up our kids when I couldn't be there. I have a lot of interests and when I turned 50, I tackled the challenge of obtaining a pilot's licence and then a commercial pilot's licence. This was a great diversion. My wife and I love the bush and enjoy wildlife photography. We have been lucky to visit a lot of interesting places including the Arctic. We also enjoy y shing and have visited some of the best y shing areas in the world. Dr Lance Coetzee taking some time out to land a 110cm Goliath Tiger Fish UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
12 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE The Development of Thermal Therapy for Bladder Cancer Part 2 Dr S Cornish Urologist Hyperthermia for bladder cancer treatment began a gradual process of acceptance from the 1980’s when the rst animal experiments were conducted in the laboratories. Some drugs have become associated with chemohyperthermia of supercial bladder cancer, and I will briey mention the history of intravesical chemotherapy. Chemotherapy for bladder cancer rst came to light in the early 1960’s when the drug Thiotepa, which is an organophosphate compound, was rst instilled into a bladder through a urethral catheter. The drug works as an alkylating agent binding to one of the DNA strands and preventing mitosis. It was developed by Cyanamid of the United States and registered in 1959. It is still used today to treat bladder cancer. Prior to this development agents such as podophyllum extract, phenol, and glycerin had been used intravesically with a modicum of success. Mitomycin C then came on the scene. It is derived from the Streptomyces bacteria and discovered in the 1950’s by Japanese scientists desperate to shake off the shackles of shame inicted by the WWII. Dr Kitasato, who went on to found the Kitasato Institute was principally interested in deriving new antibiotics akin to Alexander Fleming and his Penicillin. He employed Dr Hata who discovered Leucomycin, an antibiotic. Then three years later in 1956 Dr Hata discovered Mitomycin A and B. These two drugs had antibiotic and some anti-tumoral activity. Further analysis detected Mitomycin C in a more alkaline broth. This molecule had a high anti-tumour activity, and it went on to be registered for cancer therapy. Mitomycin C went on to become the most commonly used chemotherapeutic agent for bladder cancer treatment. His urological interests lie in cancer therapies and diagnosis, urinary incontinence, prostate enlargement therapy and fertility management. Kitasato Institute is now a part of the Kitasato University, but the original 1915 building has been brought and rebuilt in the Meijimura Museum, "an open-air museum for preserving and exhibiting Japanese architecture of the Meiji period
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14 Gemcitabine was developed in Dr Hertel's lab at Eli Lilly and Company during the early 1980s. It was meant to be an antiviral drug, however testing revealed it attacked leukaemia cells. Further research indicated it was effective against pancreatic cancer as a standalone drug. It also became used with Cisplatin to treat metastatic cancer. As is often the case it was registered for use in other countries before the USA where it was developed. Gemcitabine works by being incorporated into DNA as a faulty base. The drug masks itself from cellular repair mechanisms by allowing normal bases to be incorporated alongside the drug. The faulty base causes an irreparable error that inhibits further DNA synthesis and hence cell death is inevitable. Intravesical gemcitabine was initially reported as a treatment option for BCG-refractory non-muscleinvasive bladder cancer patients by a group led by Dr Dalbagni in 2002. Larger studies followed after 2010 initially by Dr Di Lorenzo. The drug has become recognised as an effective agent with relatively low toxicity. Docetaxel is another agent that has been used for chemohyperthermia therapy in the bladder. It has not been so widely studied as Mitomycin and Gemcitabine. Docetaxel was patented in 1986 and became available clinically in 1995. It is one of a family of drugs known as taxanes. Docetaxel is a more potent semisynthetic derivative of paclitaxel, derived from extracts of the leaves of the European yew tree (Taxus baccata). The cytotoxic activity of docetaxel is exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule disassembly. This leads to inhibition of mitotic cell division between metaphase and anaphase. The accumulation of microtubules also induces apoptosis though this is not its main mechanism of action. Docetaxel has been associated with Gemcitabine in combination for chemohyperthermia. Other drugs which have been shown to be efcacious in supercial bladder cancer include Doxorubicin, Epirubicin, and Valrubicin which are anthracycline antibiotics. They do not seem to have been used in hyperthermic studies. A drug known as EO9 or Apaziquone initially showed superior outcomes to Mitomycin and Gemcitabine, but the drug seems to have died a phase II death. Etoposide, another drug used for intravesical chemotherapy, actually has reduced efcacy when combined with heat. The role of immunotherapy deserves a mention at this point following the pioneering work of Professor Lamm in the 1970’s which saw chemotherapy for the bladder displaced by BCG. I invoked the name of Imhotep from 2600 BC in my previous article on the history of hyperthermia. Imhotep induced infection with incision and poultice to treat tumours. The immunotherapy brigade saw this as an immune response rather than from the fever induced. William Coley and his Toxin were also thought to be efcacious from an immune response rather than a thermal effect. In 1929 a study on cadavers showed that those infected with tuberculosis had a lower incidence of cancer compared with control studies. Who ever thought that TB was useful in health instead of a scourge? Research exploded in the early seventies on BCG therapy for various cancers starting with melanoma and rapidly encompassing other tumours. Unfortunately, just like hyperthermia nearly died an ignoble death, BCG immune therapy crashed as it just did not work except in bladder cancer. Lamm surmised that “it may simply be that bladder cancer is the ideal condition for the application of this immunotherapy.” BCG has remained the stalwart of treating recurrent supercial bladder cancer through into current times though cracks are starting to show in its foundations as hyperthermia therapy research gains traction. BCG not only medically but economically is coming under pressure. The low cost and therefore low protability of BCG has resulted in recurrent shortages that threaten both bladder cancer patients and children at risk for tuberculosis and other serious infections. BCG has been hung by its own petard as its low cost and therefore low protability mean less enthusiasm for its manufacture. Everyone involved in intravesical therapy today knows of the vagaries of BCG availability. Perhaps recombinant technologies will lead to a revival of its production as prots once again can be realised more readily for the medical industry. Professor Donald Lamm of Phoenix, Arizona UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
15 Now I turn to all the advantages of heat in the ght against cancer. I alluded to these in the previous article but now I will go into some greater detail. So, what does heating actually do. Thermotherapy has been divided into three different ranges. Firstly, there is the range 38 to 40 °C which is physiological; then there is 41 to 43 °C, which is the therapeutic hyperthermic range; and lastly there is greater than 43°C which is deleterious to the body. Physiological Heat Interleukin-1 (IL-1) is produced when an infection or other immune trigger occurs. The IL-1 directly affects the brain, and a signal is sent via integratory pathways to the hypothalamus which is the heat regulatory centre. An efferent response from the hypothalamus will cause appropriate effector body organs to raise the body temperature. On tumour cells, heat in this range has a direct cytotoxic affect but with minimal growth arrest, there is an increase in vascular blood ow within the tumour and a myriad of affects occur within the immune system. These affects include cellular enhancement in that there is activation of natural cells, phagocytes and dendritic cells with cross priming of CD8 T cells and improved movement of lymphocytes. In addition, heat shock proteins undergo increased production and lastly there is an increase in cytokines, chemokines and cell adhesion molecules. Therapeutic Heat In this thermal range the cytotoxic effect is more profound and there is a linear relationship with the thermal input. There is a direct effect on mitosis because RNA and DNA synthesis is impaired and DNA repair mechanisms are curtailed. The vascular alterations allow improved oxygenation to the tumour tissue and improved drug delivery. The immune effects are the same as in the physiological range. Deleterious Heat In this range cytotoxicity is more profound and exponential. There is apoptosis and indiscriminate cell damage. The vascular changes reduce blood ow due to damage to the endothelial cells, increased wall permeability and the presence of microthrombi. The immune response wanes as heat shock proteins are reduced and all the cellular responses are damaged resulting in immunosuppression. Delving deeper into the physiology of therapeutic heat I will look at the three aspects of tumour destruction as summarised above. Direct Cytotoxicity Cytotoxicity targets mitosis and repair mechanisms. This cytotoxicity is reversed when the heat is withdrawn. A linear growth arrest occurs targeting the S phase mainly but also slowing the M phase of mitosis. The S phase suppression is due to prolonged reduction in DNA synthesis and a brief reduction in RNA synthesis. Tumour cells, which are not normal, evade apoptosis mechanisms by rapidly dividing because cell arrest mechanisms are blocked. This prevents the apoptotic mechanisms from coping efciently. The slowed mitosis allows the apoptotic pathways breathing space to perform their function optimally. Interestingly the G phase of mitosis is protected by the accumulation of heat shock proteins. The raised temperature interferes with protein repair mechanisms. Proteins are damaged by the concomitant chemotherapy, and this will amplify the chemotherapeutic effect by signicantly enhancing cell apoptosis. Improved Vascularisation Increasing the temperature of tissues leads to vasodilatation. This allows better blood ow and more of a chemotherapeutic drug will be carried to the target tissue. As tumour tissue is already well endowed with a maximised blood supply, going beyond the therapeutic range will cause normal tissue to steal blood ow from the cancerous tissue as it seeks to heal itself. A better blood ow permits increased oxygenation of cancerous tissue. Research in the last hundred years showed that solid cancers have regions of mild to severe hypoxia due to abnormal vascular function. Research started in 1909 when Dr Schwarz rst observed how changes in vascular function affected radiosensitivity of tissues. The Germans continued to dominate the research into the 1920’s when oxygen was demonstrated as pivotal for radiosensitivity and glycolysis described in tumour cells when confronted with increased oxygen levels. Cancer cells adapt by having an altered UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
16 cellular metabolism as well as increasing resistance to chemotherapeutic drugs and radiotherapy. The better oxygenation can be directly toxic to the cancer cells; it improves tissue healing and reduces resistance to chemotherapy. Enhanced Immunity The level of immune system enhancement is determined by the temperature of the heated tissues and the duration of the thermal therapy. The consequence of heat therapy is that the immune system adapts to augment tumourocidal activity. The increased temperature stimulates increased activity of dendritic cells, natural killer cells and phagocytic cells. Dendritic cells can assimilate antigen to stimulate other cells useful in antitumour activity. Natural killer cells which obviously naturally seek out and destroy tumour cells become super killer cells and phagocytes function better to clear up cellular debris. There is upregulated production of heat shock proteins and chaperone tumour related antigens which are released by cancer cells in the presence of heat, radiotherapy, and chemotherapy. These proteins are taken up by dendritic cells which then present these antigens to CD8 T cells and Macrophages. This antigen interaction stimulates production of cytokines and interleukins. These released proteins are proapoptotic and proinammatory culminating in increased tumourocidal activity. The heat shock proteins attach to tumour cell walls like labels making easier identication for the immune system to target. These proteins can also enter tumour cells causing disruption and cell toxicity. Lastly for this article intercellular adhesion molecules have augmented production so that there is increased trafcking of lymphocytes to the target region. The story is actually more complicated but for brevity and clarity I have tried to depict the cellular effects of hyperthermia simplistically. The Physics of Bladder Hyperthermia The physics involved in bladder chemohyperthermia are wonderfully complicated but there are a few easy truths to assimilate. I will concentrate on only treatment for non-muscle invasive bladder tumours (NMIBC) for this article. Thermotherapy has been developed to treat muscle invasive disease but at present this falls outside the domain of the urologist. The understanding of thermodynamics for deep muscle thermotherapy brings to mind the cliché that it is outside of the scope of this article. Various institutions have vied to create mathematical models of the uid dynamics and heat transfer inside bladders but for multiple reasons of which I will mention a few the process is incredibly difcult. The above diagram will remind readers of the principles of heat transfer. These concepts are important to contemplate when one considers thermal therapy of any form. The bladder is an organ with a complex shape varying from an empty tetrahedron to a full pseudosphere. Its position and shape and dimensions all vary continuously depending on gender, the degree of lling and the state of adjacent organs. Trying to understand ow which is invariably turbulent as uid leaves and enters the bladder either from the kidneys or via the catheter in a constantly changing shape can be considered challenging. The changing volume during the therapy also affects heat transfer within the uid. Add to that the issue that thermal gradients can be non-uniform within the uid bathing the bladder wall due to salinity variances and bubbles of gas which have completely different heat transfer physics and one ends up with seriously complex mathematical models. The average bladder wall thickness in a healthy subject is 3.0 mm for a female and 3.3 mm for a male. The average depth of the urothelial layer and the lamina is about 1 mm. This is the depth that we focus on when treating NIMBC which includes Tis; Ta; and T1 tumours. The applied heat needs to penetrate to this depth to reach the goal of effective chemo thermotherapy. The technological hurdles are much easier to surmount with NMIBC using uncomplicated thermal conduction heating solutions. Heat applied to the wall of the bladder via warmed uid in the bladder is taken up by the process of conduction. This simply involves the transfer of heat energy from a region of higher temperature to a region of lower temperature. This process will continue until equilibrium is reached. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
17 Within the bladder there is blood circulating at a temperature of 37°. This blood will through a process known as convection carry heat away from the bladder wall. Therefore, the warmed solution within the bladder must be maintained at the optimum temperature to keep the supercial layer at the required temperature. There are broadly speaking two solutions to keep the contents of the bladder at the magical 43 to 44 °C. Firstly one can insert a warming device into the bladder. This was the basis of the rst system developed in the 1980’s. Warming the uid within the bladder makes modelling of thermal gradients a lot more complicated. Urine contains salts and the urine moving around in the bladder has varying solute concentrations. This urine obviously mixes with the chemotherapeutic agent. The RF transmitters, using frequencies in the microwave range, built into the catheter will warm the urine differently depending on the salt concentration at a particular point in the bladder. The RF energy also penetrates the bladder wall as radiant energy and warms the tissues directly so that heat transfer is not reliant solely on conduction. This can have a positive effect in maintaining temperature in deeper tissues to improve the chemothermal therapeutic effect. It can also result in unplanned and random hot spots which can damage the bladder and surrounding tissues. Another negative point is that cold spots can also occur reducing the effectiveness. The second solution is to instil into the bladder already warmed uid which is constantly replaced so that cooling does not occur. This is the basis of two other solutions to be discussed a little later. This means the uid bathing the walls of the bladder is at a constant temperature and modelling becomes easier. This method relies on conduction only to heat the tissues. Using a rapid circulation counteracts the turbulent ow across the surface of the bladder and leads to a uniform temperature over the entire urothelium. There is a feeling that this method has a disadvantage in that the bladder wall is not warmed as well from radiant energy supplied by a microwave source built into the bladder. On the other hand, the uniform warming means no dangerous temperature spikes in the bladder wall. The input temperature of the uid can be relied on as the maximum thermal temperature of the bladder tissue. A thermal difference of only 6 to 7 °C is considered by some researchers to be a suboptimal for heating the bladder wall. Yet the temperature change occurs over a short distance, so the gradient is steep. This gradient permits heat penetration of 2 to 3 mm into the bladder wall which should be ample for NIMBC. The safety of this system has led to a rapid acceptance amongst the urological community. The heat transfer that occurs to the bladder wall is not instantaneously in the optimum range when a system is switched on. Modelling has shown that there is a period of changing thermal milieu until a steady state is reached which can be up to fteen minutes. Also important is the requirement to prevent an accumulation of heat. This is important in systems that heat the bladder contents in situ. The bladder contents need to be recycled and passed through a cooling device otherwise runaway temperatures inside the bladder could occur. Systems that heat the uid containing the drug outside the body are less complex at holding the temperature at the required level. I have merely scratched the surface of the complex physics and engineering involved in this treatment modality, but I hope I have given the reader some understanding. Turning to the actual drugs used as the partner in chemo thermotherapy. I will use Mitomycin C (MMC) as the drug example as it has been studied extensively. The key takeaway aspect from the drug point of view is that there is greater uptake of the drug into the tissues, so you get more bang for your buck. In the pre thermotherapy situation Mitomycin proved to be inferior to BCG. It was found that the Mitomycin plasma levels were highest shortly after the TURBT when there was a denuded surface in the bladder. Even these levels where ten times lower than the level that causes myelosuppression. As the bladder healed the plasma levels of Mitomycin declined after each weekly instillation of MMC. Two weeks after the TURBT the plasma levels were already two to fourfold lower. The depth of penetration followed a logarithmic curve. Roughly for each 500 microns the MMC concentration fell by 50%. The urothelium however constitutes the major barrier and the tissue concentrations are thirty times lower just under the mucosa than that in the bladder uid. There are various chemical and physical methods to increase the permeability of the urothelium. In this article I will address only the physical thermal effect. The impermeability of the bladder mucosa is due to the tight cell junctions of the Umbrella cells and enhanced by the negatively charged GAG layer. The GAG layer prevents diffusion of substances. The Umbrella cells will only allow active transport of certain molecules. Heat supplies greater energy to the chemotherapeutic molecules assisting the drug to penetrate the tissues more readily. Mitomycin C crosses cell membranes by active transport. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
18 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE When heat was added to the equation changes occurred in the mean plasma concentration of the drug. In comparator trials the plasma concentrations reached were at least double after thirty minutes in the thermal group and this was maintained until sixty minutes. Prior to thirty minutes there was a time dependent improvement presumably because the applied heat caused a gradual increase in permeability of the urothelium. It has been noted that when a tumour is present at the time of chemo thermotherapy the plasma levels rise even higher presumably because of the increased vascularity of tumours. Fortunately, multiple tumours do not seem to result in a toxic dose. Furthermore, within the tumour tissue itself there is an up to ten-fold increase in drug concentration due to parameters of tumour tissue described earlier in the article. Mitomycin is metabolised in the target cells to three forms that are directly cytotoxic. The drug metabolism increases proportionally by fty percent for each 1°C rise in temperature thereby enhancing cancer cell destruction. You may ask does the heat not damage the drug and the answer seems to be no. There was almost no difference in the concentration levels of drug in the urine after treatment comparing thermal to non-thermal therapy controls. HIVEC Devices Hyperthermia can be delivered as a local, regional or as a whole-body therapy. With bladder cancer I will be considering local therapy only in its intravesical format. The bladder readily lends itself to this form of treatment as it is readily accessible from the outside and valves at the ureteric junctions and at the bladder neck mean the treatment can be conned solely to the bladder. There are machines that can deliver regional bladder hyperthermia. This hardware is extremely expensive and is unlikely to be purchased by a urologist. This hardware heats the bladder from the outside and can heat the entire bladder wall and the peri-vesical tissue. Work is being conducted to look at treating muscle invasive bladder tumours with this treatment modality. At last, I will now introduce the technologies developed for local chemohyperthermia of NIMBC. The story of chemohyperthermia starts back in 1972 when Thiotepa was used in conjunction with thermotherapy up to 44°C for low stage bladder tumours. The initial trials were not very successful with many side effects. In the 1980’s an existing microwave technology was combined with Mitomycin to develop the rst intravesical chemothermotherapy. Synergo The Synergo system was developed to improve chemo hyperthermia in the bladder by placing the heating source inside the bladder so no longer did energy have to travel from the outside to reach the bladder. This concept was akin to brachytherapy of the prostate instead of external beam radiation, a technique well known to urologists. A small diameter intraluminal microwave antenna was developed that was embedded in a multilumen catheter. The source of the microwave radiation was thus signicantly simplied bringing the cost of the treatment down. The microwave antenna not only heated the uid in the bladder lumen but also the bladder wall through radiation. By circulating the uid and cooling it the designers could achieve higher energy levels in the antenna. The greater energy meant improved penetration of heat through the bladder uid and into the bladder wall. The system has had several iterative improvements with time. However due to issues already mentioned it remained a tool of thermotherapists mainly. The
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