Management of Acute Oncological emergencies

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Franklin Leonard Pitts
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1 Management of Acute Oncological emergencies Malignant Spinal cord compression (MSCC) Neutropenic sepsis Superior vena caval obstruction Hypercalcemia Hyponatremia Bowel obstruction Brain Metastasis with hydrocephalus Bone Metastasis

2 Malignant Spinal cord compression (MSCC)

3 MSCC - causes 5% incidence in known cancer pts 20% - MSCC is the first presentation of cancer Metastatic Breast, Lung, Prostate, Kidney Primary Myeloma, Lymphoma Sites 60% Thoracic, 30% Lumbosacral, 10% cervical >100 confirmed cases of MSCC at UHL in 2014

4 Method of spread Arterial seeding of the bone approx 90% 10% - Paraspinal mass gains access to epidural space via neural formamina Rarely vascular, intramedullary tumours

5 MSCC Red Flags Pain almost universal, precedes neurology by several weeks Motor depends on location, weakness, abnormal reflexes Sensory Numbness, parasthesias, unsteadiness Bladder & bowel

6 Management - MSCC Steroids & gastric protection Analgesia Urgent MRI of whole spine Surgery decompression & stabilisation of the spine Radiotherapy Chemotherapy e.g. lymphoma Hormonal manipulation e.g. prostate Ca

7 Case 1 40 F, Fit domestic, no personal H/o Malignancy 2 year H/o Mid / Low back pain Multiple GP visits Normal bloods & Myeloma screen Multiple Plain X-rays : Normal Chronic back pain A&E admission June 2013 Falls, Leg weakness Power 4/5, Right shoulder pain Admitted to Orthopedics

8 Case 1 -Investigations

9 Treatment options A) High dose steroids, surgical decompression of the spine, fixation of Humerus #, post op radiotherapy B) High dose steroids, Palliative radiotherapy to spine & humerus C) Best supportive care

10 Management High dose Dexamethasone Acute Oncology referral Sugical decompression & stabilisation of the spine Surgical fixation of Right humerus # Post operativetive Radiotherapy to spine and Humerus Histology Invasive ductal adenocarcinoma, ER+, HER2 ve consistent with Breast primary Started Tamoxifen, Denosumab June 2013 December 2015 : Fully mobile, independent, working, PS0

12 Spinal decompression Relieves compression Removes tumour Stabilises spine Leicester spinal surgeries

13 Baloon Kyphoplasty

14 Baloon Kyphoplasty

15 A little bit of evidence Lancet 2005

16 Patchell Randomised control trial 51 MSCC patients treated with RT and steroids 50 MSCC patients treated with steroids, surgery and then RT

17 Patchell

18 Patchell evidence Surgery significantly improved outcome More patients walking (84 % vs 57%) More patients walking longer (122 days vs 14 days) 32 patients entered study off legs RT alone: 3 patients able to walk Sx + RT: 10 patients able to walk

19 Patchell evidence No difference in overall survival Continence more likely to be preserved Reduces analgesia requirements

20 Patchell recommendations

21 Case 2 80 yrs male, IHD, DM, CKD, COPD PS2 4 weeks H/o progressive back pain, falls GP- spinal tenderness, PR Large hard prostate PSA 5000 (July 2014) Admission Power 3/5, MRI, bone scan

22 Investigations

23 Treatment options A) LHRH agonist, High dose steroids, surgical decompression of the spine, post op radiotherapy B) LHRH agonits, High dose steroids, Palliative radiotherapy to spine C) Best supportive care

24 Management High dose steroids Palliative radiotherapy LHRH antagonist (Degarelix) Rapidly achieves castrate levels of Testosterone (<3days) Vs 7-10 days with LHRH agonist. Bilateral orchidectomy Highly effective but rarely done Spinal surgery Inappropriate due to fitness, co morbidities April 2015: PSA <0.01, walks with stick, continent, PS1

25 Role of Dexamethasone in MSCC Interventions for the treatment of metastatic extradural spinal cord compression in adults.- Cochrane Database Syst Rev. 2008; Three trials provided insufficient evidence about the role of corticosteroids (n = 105, Overall ambulation RR 0.91, CI 0.68 to 1.23). Serious adverse effects were significantly higher in high dose corticosteroid arms (96 mg Vs 16mg) Dexathasone 16 mg daily with PPI is the standard of care in spite of very limited evidence

26 Radiotherapy in MSCC THE treatment of choice for MSCC (On its own or post surgery) Optimal dose fractionation unknown (SCORAD trial) 8GY single# / 20GY in 5#, 30GY in 10# Outcome highly variable, dependant on multiple factors Ambulatory status at presentation Primary Disease extent (Visceral mets) Presentation Disease course

27 Radiotherapy planning & treatment

28 Case 3 75 years, Known Metastatic Prostate cancer since 1999 bone metastasis On LHRH agonists Fit, no comorbidity Admitted via A&E Sudden complete loss of power in both legs, absent reflexes (March 2015)

30 MSCC Vascular causes MRI (MSK radiologist) Vascular (Ischemic)? Secondary to vertebral artery thrombus / embolus / compression by direct tumour. Rare occurrence Very poor neurological and overall outcome Radiotherapy is done for pain control only.

31 MSCC - Mobilisation Nurse flat with neutral spine alignment Determining spinal stability Tricky Stability determined by MRI findings, seek advice from Radiologist, Spinal surgeon

32 Supportive care Thromboprophylaxis 11 Management of pressure ulcers Bladder and bowel incontinence Postural hypotension Rehabilitation Discharge planning 11 NICE guideline 46

33 Treatment Objectives - Prevention Bisphosphonates & Denosumab Approx 35% reductions in skeletal related events. NICE approved for use in solid malignancy other than Prostate cancer Life style advice avoidance of strenuous activity

34 Treatment objectives Early detection & treatment Patient education known bone mets are now given MSCC information leaflets Staff education and training GP, Hospital doctors, specialist nurses Rapid access to MRI, Spinal surgery & Radiotherapy Good team working MSCC co ordinator, Spinal surgeons, Oncologists, Radiographers

CFU-M M-CSF Pre-fusion Osteoclast Multinucleated

Cytokines Osteoblasts Activated Osteoclast Bone

M-CSF = macrophage colony stimulating factor

35 RANK Ligand Is an Essential Mediator of Osteoclast Formation, Function, and Survival CFU-M M-CSF Pre-fusion Osteoclast Multinucleated Osteoclast RANKL RANK Hormones Growth factors Cytokines Osteoblasts Activated Osteoclast Bone Formation CFU-M = colony forming unit macrophage M-CSF = macrophage colony stimulating factor Adapted from Boyle WJ, et al. Nature. 2003;423: Bone Resorption

36 Skeletal Complication Risk: Incremental Benefits in Breast Cancer No bisphosphonate 64% risk at 2 yrs Pamidronate ~ 20% risk reduction Zoledronic acid Additional ~ 20% risk reduction Denosumab Additional 18% risk reduction 64% 51% 34% 27% Lipton A, et al. Cancer. 2000;88: Rosen LS, et al. Cancer. 2003;100: Stopeck A, et al. ECCO/ESMO Abstract 2LBA. Stopeck AT, et al. J Clin Oncol. 2010;28:

effect: about 5% in breast cancer population Who could get ONJ?

37 Osteonecrosis of the jaw (ONJ) What is ONJ? Exposed jawbone that does not heal Treated with surgery, antibiotics Rare side effect: about 5% in breast cancer population Who could get ONJ? Risk related to cumulative exposure Recent invasive dental procedure or poor oral health are risk factors Tooth extraction Dental implant

38 Malignant cord compression outcomes Early treatment = better functional outcome

39 Thank you

41 Treatment options A) High dose steroids, surgical decompression of the spine, post op radiotherapy B) High dose steroids, Palliative radiotherapy to spine C) Best supportive care

42 Patchell

43 Differential diagnosis Metastatic / Primary cancer Trauma / Herniated disc Osteoarthritis Infection / Inflammation

Denosumab vs Zoledronic Acid Pivotal Phase III SRE Prevention Trials In total, > 5700 patients with bone metastases Study 136 [1] Breast cancer (N = 2049) Study 103 [2] Prostate cancer (N = 1904)

44 Denosumab vs Zoledronic Acid Pivotal Phase III SRE Prevention Trials In total, > 5700 patients with bone metastases Study 136 [1] Breast cancer (N = 2049) Study 103 [2] Prostate cancer (N = 1904) Study 244 [3] Other solid tumors/mm (N = 1779) R A N D O M I Z A T I O N Denosumab 120 mg SC q4w + Placebo IV q4w Supplemental calcium and vitamin D Zoledronic Acid 4 mg IV q4w + Placebo SC q4w 1. Stopeck AT, et al. J Clin Oncol. 2010;28: Fizazi K, et al. Lancet. 2011;377: Henry DH, et al. J Clin Oncol. 2011;29:

45 SRE Rate: Denosumab vs ZA in Breast Cancer Patients With Bone Metastases 1.2 SREs per Patient per Yr % (P =.004) ZA Denosumab Stopeck AT, et al. J Clin Oncol. 2010;28:

Denosumab Binds RANK Ligand and Inhibits

Osteoclast RANKL RANK Denosumab Hormones Growth factors

Inhibited Osteoblasts Bone Formation Bone Resorption

46 Denosumab Binds RANK Ligand and Inhibits Osteoclast-Mediated Bone Destruction CFU-M Pre-Fusion Osteoclast RANKL RANK Denosumab Hormones Growth factors Cytokines Osteoclast Formation, Function, and Survival Inhibited Osteoblasts Bone Formation Bone Resorption Inhibited Provided as an educational resource. Do not copy or distribute.

47 ONJ Associated With Bone-Targeted Therapy in Patients With Bone Metastases All patients (N = 5723) Potential ONJ (n = 276) Positively adjudicated for ONJ (n = 89) Integrated analysis of pivotal denosumab SRE prevention trials Zoledronic acid (n = 37) 1.3% Denosumab (n = 52) 1.8% No significant difference between groups (P =.13) Saad F, et al. Ann Oncol. 2012;23:

48 ONJ Prevention Potential benefits of bisphosphonates typically outweigh small risks of ONJ How to prevent: See dentist before beginning bisphosphonate Pursue optimal preventative dental care Practice good oral hygiene In those with stable disease after prolonged therapy, can consider reducing frequency of treatment

49 Metastatic spinal cord compression Implementing NICE guidance 2 nd edition Oct 2011 NICE clinical guideline 75

50 Imaging It is important that MRI should be done quickly, dependent upon signs and symptoms

51 NICE Pathway The NICE metastatic spinal cord compression pathway covers Click here to go to NICE Pathways website

52 Treatment of spinal metastases and MSCC: 1 Nurse flat with spine in neutral alignment patients with severe mechanical pain suggestive of spinal instability or neurological symptoms or signs suggestive of MSCC until spinal and neurological stability are ensured

53 Treatment of spinal metastases and MSCC: 2 Start definitive treatment, if appropriate, before any further neurological deterioration and ideally within 24 hours of the confirmed diagnosis of MSCC

54 Treatment of spinal metastases and MSCC: 3 Carefully plan surgery to maximise the probability of preserving spinal cord function without undue risk to the patient, taking into account their overall fitness, prognosis and preferences

55 Treatment of spinal metastases and MSCC: 4 Ensure urgent (within 24 hours) access to and availability of radiotherapy and simulator facilities in daytime sessions, 7 days a week, for patients with MSCC requiring definitive treatment or who are unsuitable for surgery

56 Supportive care and rehabilitation Start discharge planning and ongoing care including rehabilitation on admission

Recognition & Treatment of Malignant Spinal Cord Compression Study Day

Recognition & Treatment of Malignant Spinal Cord Compression Study Day 11 th May 2017 Dr Bernie Foran Consultant Clinical Oncologist & Honorary Senior Lecturer Weston Park Hospital Outline of Talk Clinical