Prostate cancer update: 2013 Dr Robert Huddart Cancer Clinic London
Recent developments Improved imaging New radiotherapy technologies Radiotherapy for advanced disease Intermittent hormone therapy New drugs
Koh and Sohaib, Radiol Clinic N Am 2012
Potential applications Pre diagnostic MRI (to select patients for biopsy) Targeting biopsies Checking patients with negative biopsy for rebiopsy Surveillance follow up Detection of recurrence Targetted radiotherapy
NNT screen is 1410 to prevent 1 CaP death NNT is 48 to prevent 1 CaP
Traditional pathway New pathway Raised PSA Raised PSA Biopsy MRI assessment MRI for staging No tumour tumour Observed and Biopsy on progression Biopsy
18F-Choline PET/CT Conventional imaging (CT, MRI) suffers from inadequate specificity, particularly in the detection of LN metastases. Excellent for bony metastases (sensitivity 79%, specificity 97%) Has high specificity (96% 1 ), but limited sensitivity (66%) for nodal mets (nodes often small +limit of PET resolution =3-5mm) 1. Beheshti M, et al. Radiology. 2010 Mar;254(3):925-33. 2. Beheshti M, et al. Mol Imaging Biol. 2010 Jun;12(3):360.
10.1.2012 10.1.2012 MRI 5.11.2010 CT 4.11.2010
Applications of Choline PET Intra prostatic targeting Staging high risk patients Detection of recurrence in High PSA patients
Radiotherapy developments Intensity Modulated Radiotherapy Image guided radiotherapy Fiducial markers Online imaging Stereotactic radiotherapy
IMRT: More precise dose distributions
Developments in Radiotherapy: IGRT Fiducial markers
Cone beam CT
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Why is this important? More accuracy allows smaller margins that can reduce toxicity More focused therapy allows dose escalation Fewer bigger treatments (convenience, More effective?)
Lancet Oncol 2007 8 475-87 PSA control 71% 60% 74 Gy 64 Gy Bowel dysfunction UCLA-PCI
Locally advanced prostate cancer Take home message: Effective treatment helps (cures) more patients than treating localised cancer
Hormones and RT better than RT alone in locally advanced CaP
Hormones and Radiotherapy for locally advanced prostate cancer PRO7 trial Warde et al Significant survival benefit with greater benefit than prostatectomy v watchful waiting
New treatments Initial therapy Castration treatments
LHRH Analogues Antiandrogens LHRH Analogue LHRH LHRH Brain Pituitary Brain Pituitary LH ACTH LH ACTH Testis Adrenal Gland Testis Adrenal Gland Prostate Cancer Antiandrogen Prostate Cancer
Degarelix: LHRH Antagonists Klotz et al
Tombal et al 2010: Secondary analysis of RCT Eur Urol 57 836-842
LHRH Antagonists (Degarelix) For Rapid testosterone suppression Drawbacks Skin reactions Larger injection than LHRHa Best For: Immediate primary treatment of symptomatic patients Precise place to be defined No good for: No specific ci
Issue with LHRH therapy Bone health Risk of cardiovascular disease
Intermittent Hormone therapy Crook et al 2012 NEJM 367 895-903 Qol : Global scores trend for IHT NS Less Hot flashes, urinary symptoms, fatigue and better sexual desire
New therapies
New drugs proven to improve survival in castrate resistant prostate cancer pre 2009 Docetaxel
Advanced Prostate Cancer Algorithm 2009 Dexamethasone 0.5mg LHRH Anti androgen Docetaxel Mitoxantrone Stilboesterol
New drugs proven to improve survival in Castrate resistant prostate cancer 2010-2012 Abiraterone (Zytiga) [NICE approved] Enzalutamide Alpharadin Carbazitaxel [London CDF] Sipuleucil-T
Abiraterone inhibits CYP450c17: One enzyme, two functions A key enzyme in androgen synthesis
Abiraterone: antitumour activity 70% of patients PSA fall by 50% 50% of patients PSA fall by 90% Patients with measurable disease > 50% objective response rate HRPC is still hormone driven!
Abiraterone phase III trial COU-301 Increased Toxcities: Fluid retention (31% v 22%, Hypokalaemia (17% v 8%), cardiac events 10% v8% NS) De Bono et al N Engl J Med. 2011 May 26; 364(21): 1995 2005.
Ryan et al Abiraterone:Pre chemotherapy
Enzalutamide phase III Potent androgen receptor inhibitor Super casodex
TROPIC trial: Carbazitaxel v Mitozantrone in Post Docetaxel CRPC Carbazitaxel new generation taxane- active in docetaxel resistant tumours DeBono et al 2010 Lancet 376 1147-54
Radionuclides Alpha emitters are big and have low penetration Alpha-emitter, Radium-223 is safe given in repeated doses and may alter natural history
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Postdocetaxel or unfit for docetaxel STRATIFICATION Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S E D 2:1 N = 922 6 injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT00699751.
IMPACT study Kantoff et al 201 NEJM 363 411-22 Dendritic cell vaccine
Advanced Prostate Ca algorithm 2007 Dexamethasone 0.5mg LHRH Anti androgen Docetaxel Mitoxantrone Stilboesterol
LHRH Advanced Prostate Ca algorithm 2014? Anti androgen Abiraterone Docetaxel Denusumab? Enzalutamide Carbazitaxel Alpharadin Other treatments? Experimental therapies Stilboesterol
Bisphosphonates? Time to skeletal event Saad et al. JNCI 94(19) 2002
Figure 2 Kaplan-Meier curves of key efficacy endpoints () Time to symptomatic bone metastasis Matthew R Smith, Fred Saad, Robert Coleman, Neal Shore, Karim Fizazi, Bertrand Tombal, Kurt Miller, Paul... Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial The Lancet Volume 379, Issue 9810 2012 39-46 http://dx.doi.org/10.1016/s0140-6736(11)61226-9
Conclusions Many new developments have occurred in prostate cancer in the last 5 years Treatment algorithms are changing Positive impact on prostate cancer patients Cost!
Quiz
After the bones which is the commonest sites of prostate cancer metastases a. Brain b. Liver c. Para aortic lymph nodes d. lung e. Pleura
Which of these statements about PSA are true? a. PSA is a serine threonine protease found in seminal fluid b. It is elevated in 80% of patients with metastatic prostate cancer d. Response in PSA acts as a good surrogate for improved survival e. Doubling in PSA in <6 months tends to indicate the presence of metastatic disease
Which of these side effects is more common after Bicalutamide rather than treatment with a LHRH agonist 2. 1. Impotence 2. Hot flushes 3. Muscle weakness 4. Gynaecomastia 5. Osteoporosis
Which of these treatments has been proven to improve survival after docetaxel? Denusomab Strontium Enzalutamide Dexamethasone Mitoxantrone
Which of these treatments has been approved by NICE for treatment of CRPC? Mitoxantrone Enzalutamide Abiraterone Carbazitaxel Sipuleucil T