PracticeUpdate: Haematology & Oncology | Vol 1.No.3 - 2016

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The ever changing landscape for prostate cancer care in Australia

Interview with Dr Homayoun (Homi) Zargar, MD, FRACS (Urol)

Urological surgeons Dr Homi Zargar and Dr Rajesh Nair give PracticeUpdate a review of clinically relevant new research in prostate cancer, focusing on those that could potentially impact clinical practice in Australia. PSA testing in Australia

and Dr Rajesh Nair, FRCS (Urol), FEBU, MSc

The STAMPEDE trial STAMPEDE is a randomised controlled trial using a multi-arm, multi-stage platform design. It recruited 2962 men with high-risk localised (24%), node-positive (15%) or metastatic prostate cancer (61%) to four separate treatment arms: ADT alone, ADT plus zoledronic acid, ADT plus docetaxel, or ADT plus zoledronic acid and docetaxel. 6 The addition of docetaxel demonstrated sig- nificance in both its primary endpoint of overall survival (77 vs 67 months; P = 0.003) and sec- ondary endpoint of failure-free survival (37 vs 21 months; P < 0.0001) compared with ADT alone. Thus, docetaxel with standard therapy improved overall survival by an average of 10 months in men with newly diagnosed, hormone-naive, advanced prostate cancer. For the subset of patients with metastatic disease, the average improvement in overall survival was even higher at 22 months. Adding zoledronic acid to standard therapy did not affect survival, and adding the combination of zoledronic acid and docetaxel was not more effective than adding docetaxel alone. What does the future hold? We need to identify men with prostate cancer early. With further development of technology, hopefully we can utilise imaging in conjunction with PSA testing for identifying and stratifying patients with prostate cancer. More sophisticated imaging in combination with genomic markers can help identify patients who might benefit from lymph node dissection and assist in the adoption of patient-specific lymph node dissection tem- plate. Image-guided surgery holds the promise of identifying cancer margins intraopertively. Genomics can play a significant role in stratify- ing patients according to their risk, differentiating men presenting with similar diagnostic results but having different cancer biology. So genomic tests can guide us in the better identification of patients requiring early treatment and in the modification of treatment depending on the patient’s genetic makeup, as part of our quest toward delivering precision medicine. References 1. Moyer VA; US Preventive Services Task Force. Ann Intern Med 2012;157:120-134 2. Weiner AB, Matulewicz RS, Eggener SE, et al. Prostate Cancer Prostatic Dis 2016 Jul 19. doi: 10.1038/pcan.2016.30. [Epub ahead of print] 3. Yaxley JW, Coughlin GD, Chambers SK, et al. Lancet 2016 July 26. doi: 10.1016/S0140-6736(16)30592-X. [Epub ahead of print] 4. Van Leeuwen P, Emmeett L, Ting F, et al. BJU Int 2016 May 21. doi: 10.1111/bju.13540. [Epub ahead of print] 5. Sweeney CJ, Chen YH, Carducci M, et al. N Engl J Med 2015;373:737-746 6. James ND, Sydes MR, Clarke NW, et al. Lancet 2016;387:1163-1177

those achieved with open radical prostatectomy. Yet, secondary outcomes show a different picture: RARP patients demonstrate less blood loss (443 vs 1338 ml, P = 0.001), less postoperative pain and a shorter hospital stay (1.5 vs 3.2 days, P = 0.0001) compared with ORP patients. While a highly commendable study, there are a number of methodological oversights which are unlikely to see a change in the number of RARPs performed in Australia or worldwide. This study does not control for individual surgical experience, trainee involvement, and outcome parameters re- corded at 12 weeks represent too short a follow-up period to allow for meaningful comparison. If any- thing, this study allows one to view robotic surgery in a favourable light. A lesser-experienced surgeon can deliver functional and oncological outcomes that an experienced open surgeon can deliver by adopting robotic techniques. (See page 5.) Australia has led the charge in the research and utilisation of [ 68 Ga]gallium-labelled prostate- specific membrane antigen ligand ( 68 Ga-PSMA) positive emission tomography (Ga-PSMA PET/ CT). There is an increasing bank of evidence demonstrating that Ga-PSMA PET can present lesions suspicious for prostate cancer with excel- lent contrast and a high detection rate even when the level of prostate specific antigen is low. Van Leeuven and colleagues from Sydney recently reported 300 consecutive patients with prostate cancer; 70 of whom developed biochemi- cal recurrence following radical prostatectomy. Those with a PSA of ≥ 0.05 and <1.0 ng/mL underwent Ga-PSMA-PET/CT. 4 They demonstrated that Ga-PSMA-PET/CT in patients with intermediate or high-risk prostate cancer has 95% specificity and 64% sensitivity for detecting lymph node metastases. Even at PSA levels <0.5 ng/mL, it appears to be useful for re-staging of prostate cancer in patients with rising PSA levels who are being considered for salvage radiotherapy. Managing metastatic prostate cancer The sands are shifting in the way patients with metastatic prostate cancer are managed. The CHAARTED 5 and STAMPEDE 6 trials demon- strated significant survival advantages with the addition of upfront chemotherapy to traditional androgen deprivation therapy (ADT) when man- aging these patients. The CHAARTED trial The Eastern Cooperative Oncology Group (ECOG) phase 3 randomised CHAARTED trial evaluated whether the addition of upfront chemotherapy to ADT improved overall survival in patients with hormone-sensitive metastatic prostate cancer. A total of 790 patients diagnosed with hormone-sensitive metastatic prostate can- cer were randomised to ADT alone vs ADT with the addition of docetaxel at a dose of 75 mg/m 2 every 3 weeks for 6 cycles started within 4 months of the initiation of ADT. 5 The results reported were in favour of adding docetaxel to ADT in men with hormone-sensitive metastatic prostate cancer. ADT plus docetaxel re- sulted in a median overall survival of 57.6 months (P = 0.0003) compared with 44 months in the ADT-alone arm. In stratifying the patients accord- ing to high vs low-volume disease, the benefit for docetaxel therapy was found to be more apparent in the high-volume metastatic group. 68 Ga-PSMA positive emission tomography in prostate cancer

In 2012, on the back of two large randomised trials – the Prostate, Lung, Colorectal and Ovar- ian cancer screening study (PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial – the US Preven- tive Services Task Force issued a recommenda- tion against prostate-specific antigen (PSA)-based screening for prostate cancer. It suggested that the potential harms of PSA-testing outweighed the benefits offered by curative prostate cancer care. 1 Following this recommendation, a drop in PSA testing and overall prostate cancer incidence was observed in the US, which translated to a reduction in radical prostatectomies there.

Genomic tests can guide us in the better identification of patients requiring early treatment and in the modification of treatment depending on the patient’s genetic makeup, as part of our quest toward delivering precision medicine.

In Australia, a similar decline in rates of PSA testing has been observed since 2012 following the widely publicised USPSTF recommendation. It remains to be seen whether this translates to a reduction in the number of local treatments. A controversial study evaluating the increasing incidence of metastatic prostate cancer in the United States was reported by Weiner and col- leagues. 2 His group evaluated the role of relaxed screening following the USPSTF recommenda- tions and whether this led to changes in the incidence of advanced and metastatic prostate cancer at diagnosis. All men diagnosed with prostate cancer in the National Cancer Data Base (2004–2013) at 1089 different healthcare facilities in the US were evaluated. The annual incidence of metastatic prostate cancer increased by 72% from 2007 to 2013. The greatest (92%) increase in metastatic prostate cancer was seen in men aged 55–69 years. These results did not take into account a num- ber of confounding events and observations. For example, changes in aggregate screening before the USPSTF recommendations, alterations in the biological aggressiveness of prostate cancer, and improved sensitivity and use of imaging when iden- tifying those patients with metastatic disease were not accounted for. It is unlikely that these results are transferrable to anAustralian population where PSA screening has always remained opportunistic. Robot-assisted laparoscopic prostatectomy vs open radical retropubic prostatectomy There has been a significant lack of data com- paring robot-assisted laparoscopic radial prosta- tectomy (RARP) and open radical prostatectomy (ORP). Yaxley et al from Queensland reported the early oncological and functional outcomes following a randomised controlled multicentre phase 3 study published in The Lancet this year. 3 A total of 326 patients with newly diagnosed localised prostate cancer were randomised to RARP and ORP. Primary outcome parameters reported included urinary and sexual function, and oncological outcomes determined by surgical margin status, and evidence of disease progression at 6 and 12 weeks post operatively. Urinary function and sexual function were simi- lar at 12 weeks post prostatectomy. Positive surgical margin rates were also similar at 10% vs 15% in the ORP vs RARP groups, respectively (P = 0.0021). Robot-assisted laparoscopic radical prostatectomy is associated with clinical outcomes similar to

Dr Zargar is a urological surgeon with fellowship training in uro-oncology and advanced laparoscopic and robotic surgery. He is Consultant Urologist at the Royal Melbourne Hospital and Senior Clinical Lecturer, Department of Surgery at the University of Melbourne. Dr Nair is a UK-trained urological surgeon undergoing advanced fellowship training in robotics and uro-oncology at the Royal Melbourne Hospital.

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