The management and treatment options for secondary bone disease. Dr Jason Lester Clinical Oncologist Velindre Cancer Centre

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1 The management and treatment options for secondary bone disease Dr Jason Lester Clinical Oncologist Velindre Cancer Centre

$castrate-refractory$ prostate cancer

2 Aims Overview of bone metastases management in castrate-refractory prostate cancer Radiotherapy Bisphosphonates Strontium Summary Newer therapies (brief)

3 Introduction 5% at diagnosis have bone metastases 75% with locally advanced disease go on to develop bone metastases Complications include: Pain Poor mobility Loss of function Spinal cord compression Urinary incontinence Fecal incontinence Paralysis Hypercalcaemia (rarely)

Case History 65 year old man GP referral to urology June 07 with a history of frequency, dysuria PSA 136 ng/ml Bone scan June 07 showed metastases Prostate biopsy July 07

4 Case History 65 year old man GP referral to urology June 07 with a history of frequency, dysuria PSA 136 ng/ml Bone scan June 07 showed metastases Prostate biopsy July 07 showed Gleason = 7 adenocarcinoma Admitted as an emergency on August 07 with lower back pain PMH: Hypertension. Type 2 Diabetes. Medication: Aspirin, Metformin, Ramipril

5 Bone scan

6 Case History Aug 07 Seen by Oncology as an inpatient Already had first Zoladex implant Admitted to lumbar discomfort for several months No focal neurology Pain resolved Information given on the STAMPEDE trial

7 STAMPEDE trial (old protocol)

8 Case History Aug 07: Randomised to Arm A No skeletal symptoms Continued on Zoladex Feb 08: PSA rising (no symptoms) Bicalutamide added

9 Case history May 08 Transient response to bicalutamide No PSA response to withdrawal Remained pain-free PS 1 10 cycles of docetaxel plus prednisolone completed Jan 09 with >50% reduction in PSA

10 Case History March 09 PSA rising Pain in the lower lumbar spine PS 1 Bone scan, CT Palliative radiotherapy to his lower spine

11 Palliative RT to lower spine April 09 L3 to S3 Single field Side effects: Tiredness Temporary increase in pain Loose motions Skin redness Skin pigmentation

12 Palliative radiotherapy Achieves complete or partial pain relief in 70% Usually 1 or 5 treatments used Onset of analgesic effect is variable Usually a least a week to kick-in Side effects depend on area treated

13 Palliative radiotherapy Pain recurs in the majority of patients Can be repeated to the same area if needed only if effective the first time Concerns with retreatment to spinal cord rarely if ever a clinical issue

14 CT May 09

15 CT May 09 Progression of bony disease No soft tissue disease

16 Case History June 09 Complete resolution of pain in lower spine with RT No radiological disease outside the skeleton Pain now outside RT field pelvis, mid thoracic spine Options?

17 Case History June 09 Discussed Zometa, strontium, clinical trial Zometa 4mg i.v 4-weekly started Generalised skeletal pain weeks 1 and 2 Increase in analgesia Pain rapidly settled Continued on Zometa

Bisphsophonates Osteoclasts destroy old bone Osteoblasts build new bone PTHrP IL-6 Osteoclast TGF-, BMP IGFs, FGF Bone mets produce chemicals that make

18 Bisphsophonates Osteoclasts destroy old bone Osteoblasts build new bone PTHrP IL-6 Osteoclast TGF-, BMP IGFs, FGF Bone mets produce chemicals that make the osteoclasts work harder, weakening bone and causing pain Zoledronic acid reduces the activity of osteoclasts This can reduce pain and strengthen bone

19 Zometa side effects Temporary increase in pain Flu-like symptoms Headache Nausea Osteonecrosis of the jaw Kidney damage

20 Case History Sept 09 Seen in clinic PSA rising - doubling time 6 months Right sacral pain radiating down the right leg and numbness in right foot Zometa stopped Xray pelvis RT to pelvis provisionally booked

21 Xray Pelvis Sept 09

22 RT to pelvis Sept 09

23 Case history Oct 09 RT to pelvis improved pain Further pain throughout spine new areas and previously treated areas Rising PSA PS 1 Wanted to go back on Zometa What now?

24 Case history Oct 09 Restarted Zometa MRI spine CT Strontium discussed

25 MRI Spine Oct 09

26 Case history Oct 09 MRI no evidence of cord compression CT no evidence of soft tissue disease Consented for strontium 89

taken up by bone Most effective in prostate cancer

27 Strontium 89 Radiotherapy intravenous bolus Beta particle emitter Strontium next to calcium in the periodic table taken up by bone Most effective in prostate cancer Reduces bone pain and analgesic use Reduces need for palliative RT

28 Strontium 89 Takes 1-2 weeks to reduce pain Lasts 2 6 months Can be repeated every 3 months Currently use restricted to castrate resistant disease

29 Strontium 89 side effects Increased pain starting 2-3 days after treatment and lasting 2-3 days Flushing Diarrhoea Fever Chills Bone marrow suppression (platelets)

30 Strontium 89 Patient needs to be continent Adequate bone marrow function low volume bone metastases No or minimal disease outside the bones Life expectancy of at least 3 months

31 Case history Dec 09 No side effects from Strontium Reported general improvement in pain FBC satisfactory PSA continued to rise with shortening doubling time

32 Case report update Currently on Abiraterone PSA has fallen Skeletal pain under control..

Summary treatment of bone metastases Hormones are an effective

resistant disease, disease-modifying treatments can be effective for

pain Zometa can help control pain and reduce skeletal-related events

33 Summary treatment of bone metastases Hormones are an effective treatment for bone pain in hormone-naïve patients In castrate resistant disease, disease-modifying treatments can be effective for pain Palliative radiotherapy can be used to treat localised areas of pain Zometa can help control pain and reduce skeletal-related events Strontium can be an effective treatment for pain, but DO NOT use as a last resort therapy

34 Summary treatment of bone metastases Sequencing of bone therapies depends on: hormonal status/previous treatment symptoms extent of disease co-morbid disease planned future treatment

35 Denosumab Monoclonal antibody against RANK Ligand protein, which activates osteoclasts

36 Denosumab Subcutaneous injection given every 4 weeks No flu-like symptoms No acute increase in pain Can cause low calcium No evidence of a survival benefit

37 Overall Survival Benefit of Radium-233 Chloride (alpharadin) in the treatment of patients with symptomatic bone mets in Castration-resistant Prostate Cancer Inclusion criteria Progressive, symptomatic CRPC with at least 2 bone mets on bone scintigraphy No known visceral mets Receiving BSC Previously either docetaxel ineligible, received or refused docetaxel Randomized 2:1 n = injections of radium-223 (50kBq/kg IV) every 4 weeks (n = 615) Matching Placebo (n = 307) Pts stratified according to: Prior docetaxel use Baseline alkaline phosphatase level Current bisphosphonate use

2 months for placebo Safety and tolerability data were highly

38 Alpharadin Radium-233 significantly improved median survival by 2.8 months 14.0 months for radium-223 and 11.2 months for placebo Safety and tolerability data were highly favourable - Low incidence of myelosuppression Grade 3 / 4 neutropenia (1.8% vs 0.8%)

39 The management and treatment options for secondary bone disease Dr Jason Lester Clinical Oncologist Velindre Cancer Centre

Advanced Prostate Cancer. November Jose W. Avitia, M.D

Advanced Prostate Cancer. November Jose W. Avitia, M.D Advanced Prostate Cancer November 4 2017 Jose W. Avitia, M.D In 2017 161,000 new cases of prostate cancer diagnosed in US, mostly with elevated PSA 5-10% will present with metastatic disease In 2017: 26,000