guideline for the management of skeletal related...

Version: 1 Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater Reviewed and Updated by Simon Jenkinson of 17 Version dated: February 2014 Review date: February 2016

Guideline for the Management of Skeletal Related Events

1. Treatment/Prevention of Skeletal Events related to Metastatic Disease

Page 2

2. Prevention of Osteoporotic Fractures in Cancer Patients

Page 3

3. Treatment Algorithm for Management of SRE’s

Page 4

4. Specific Drug Information and Adverse Effects

Page 6

o Denosumab Page 7 o Zoledronic Acid Page 8 o Pamidronate Page 8 5. Appendices

o Appendix A: Blood Tests Page 9 o Appendix B: Referral Proforma letters and Forms

for dental referral

Page 10


Treatment/Prevention of Skeletal Events related to Metastatic

Disease

First line: Denosumab (XGEVA®) 120mg S/C except prostate and multiple

myeloma patients- given every 4 weeks only*

This is indicated for patients with bone metastasis due to breast cancer/other solid

tumours except prostate tumours and multiple myeloma.

NICE TA268 (October 2012)

Denosumab is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal

cord compression or surgery to bone) in adults with bone metastases from breast cancer and from solid tumours other than

prostate if:

o bisphosphonates would otherwise be prescribed AND

o the manufacturer provides denosumab with the discount agreed in the patient access scheme.

Denosumab is not recommended for preventing skeletal-related events in adults with bone metastases from prostate cancer.

Patients receiving denosumab should be prescribed 500mg calcium and 400iu Vitamin D

supplements e.g. Adcal D3 tablets, one to be chewed daily.

Patients with prostate cancer or multiple myeloma should receive Zoledronic acid 4mg IV

first line every 3 or 4 weeks instead of denosumab. If the patient has CrCl <29ml/min then

Pamidronate 90mg should be prescribed every 3 or 4 weeks- see guidance in section f

regarding administration

*Zoledronic Acid 4mg IV every 3 or 4 weeks first line can be used for providers who

are unable to implement NICE TA268

Second line: Zoledronic Acid 4mg IV (dose adjusted to renal function) every 3 or

4 weeks

This is indicated for patients who cannot tolerate denosumab or are hypersensitive to it.

Patients receiving zoledronic acid should be prescribed 500mg calcium and 400iu Vitamin D

supplements e.g. Adcal D3 tablets, one to be chewed daily.

If the patient has CrCl <29ml/min then Pamidronate 90mg should be prescribed every 3 or

4 weeks- see guidance in section f regarding administration.


Breast Cancer Treatment Induced Bone Loss

Zoledronic Acid 4mg IV (dose adjusted to renal function) every 6 months.

Approved for two groups of patients:

1. Breast Cancer patients for treatment-induced bone loss in women who experience premature menopause due to chemotherapy or has ovarian suppression, ablation or removal.

2. Breast cancer postmenopausal patient receiving treatment with aromatase inhibitors. In both groups of patients one of the conditions below MUST apply:

o There is failure to achieve the required response on oral bisphosphonates. o Oral bisphosphonates are not tolerated at the optimal dose o The patient with oesophageal disease where oral bisphosphonates are contra-

indicated but intravenous bisphosphonates are considered appropriate. Please refer to Breast Cancer Treatment guidelines for further guidance regarding Assessment of Bone Health with Endocrine Treatment.


Does the patient have severe untreated hypocalcaemia or hypercalcaemia of malignancy?

1st Line: Denosumab 120mg SC 4 weekly &

Calcium supplement 2

nd Line (if cannot tolerate denosumab:

Zoledronic Acid 4mg IV 3 or 4 weekly & Calcium supplement or pamidronate if <29ml/min

Correct hypocalcaemia or treat the hypercalcaemia of malignancy (Refer to Hypocalcaemia guidelines or

Guidelines for the treatment of Hypercalcaemia of Malignancy)

Does the patient have: o prostate cancer o multiple myeloma o Breast Cancer Treatment Induced Bone loss?

NO YES

NO

1st Line: Denosumab 120mg SC 4 weekly & Adcal D3

ONE tablet daily 2

nd Line (if cannot tolerate denosumab: Zoledronic

Acid 4mg IV 3 or 4 weekly & Calcium supplement daily) or pamidronate if CrCl<29ml/min

New cancer patient requiring treatment for skeletal related events

For Prostate and Multiple Myeloma Patients:

o Zoledronic acid 4mg IV 3 or 4 weekly (Frequency of zoledronic acid depends on frequency of concurrent chemotherapy)

For Breast Cancer Treatment induced bone loss**:

o Zoledronic Acid 4mg IV 6 monthly

YES

**Breast Cancer patients for treatment-induced bone loss in women who experience premature menopause due to chemotherapy or has ovarian suppression, ablation or removal. OR Breast cancer postmenopausal patient receiving treatment with aromatase inhibitors. Where there is failure to achieve the required response on oral bisphosphonates. Where oral bisphosphonates are not tolerated at the optimal dose. In patients with oesophageal disease where oral bisphosphonates are contra-indicated but intravenous bisphosphonates are considered appropriate.

3. Treatment Algorithm for Management SRE


Specific Drug Information and Adverse Effects

a. Osteonecrosis of the Jaw

All oncology/haematology patients starting Denosumab or bisphosphonate therapy should

be informed about the rare but serious risk of developing osteonecrosis of the jaw.

The patient's dentist practitioner should be made aware of the intention to commence

Denosumab/bisphosphonate treatment and asked to perform a dental examination prior to

the first dose being administered.

See referral forms and algorithm in the appendices. Please note the multiple myeloma

patients pathway with dental assessment/Maxillo-Facial surgery review is yet to be

determined. Please contact Dr Jamie Cavenagh.

Once treatment has started, patients should receive 6 monthly dental reviews and avoid

invasive dental procedures if at all possible.

b. Symptom Control of flu-like Syndrome with IV Bisphosphonates

Paracetamol can be recommended for symptom control of flu-like syndrome, fever, myalgia

or arthralgia. These symptoms tend to occur with the first two doses, and then are less likely

to occur with subsequent treatment.

c. Femoral Fractures

Femoral fractures have been reported with bisphosphonate/denosumab therapy, primarily in patients receiving long-term treatment for osteoporosis.

These transverse or short oblique fractures can occur anywhere along the femur from just

below the lesser trochanter to just above the supracondylar flare.

These fractures occur after minimal or no trauma and some patients experience thigh or

groin pain, often associated with imaging features of stress fractures, weeks to months

before presenting with a completed femoral fracture.

Fractures are often bilateral; therefore the contralateral femur should be examined in

bisphosphonate/denosumab-treated patients who have sustained a femoral shaft fracture.


Discontinuation of bisphosphonate/denosumab therapy in patients suspected to have an

atypical femur fracture should be considered pending evaluation of the patient, based on an

individual benefit risk assessment.

During bisphosphonate or Denosumab treatment patients should be advised to report any

thigh, hip or groin pain and any patient presenting with such symptoms should be

evaluated for an incomplete femur fracture.

Drug Specific Information

d. Denosumab

Dose 120mg subcutaneously every 4 weeks

XGEVA 120mg solution for injection

Administration XGEVA should be administered under the responsibility of a healthcare professional.

Before administration, the XGEVA solution should be inspected visually. Clear, colourless to slightly yellow solution may contain trace amounts of

translucent to white proteinaceous particles. Do not inject the solution if it is cloudy or discoloured. Do not shake

excessively. To avoid discomfort at the site of injection, allow the vial to reach room

temperature (up to 25°C) before injecting and inject slowly. Inject the entire contents of the vial as slow subcutaneous injection into

the thigh, abdomen or upper arm.

A 27 gauge needle is recommended for the administration of denosumab. Do not re-enter the vial.

Common side effects Dyspnoea, diarrhoea, hypocalcaemia, hypophosphataemia, hyperhydrosis,

osteonecrosis of the jaw (see below)

Renal impairment No dose reduction required, however closely monitor serum calcium


e. Zoledronic Acid

Dose 4mg IV infusion every 3-4 weeks (for practical reasons so any IV chemotherapy can be given on the same day) for bony disease/pain caused by metastatic disease 4mg IV infusion every 6 months for breast cancer treatment related bone loss in patients who cannot tolerate oral bisphosphonates or are contraindicated

Administration In 100ml 0.9% Sodium Chloride over 15 minutes

Common side effects Fever, flu-like syndrome (bone pain, fever, fatigue and rigors) -see symptom

control below, nausea, myalgia/Arthralgia, renal impairment, electrolyte

imbalances, hypophosphataemia, osteonecrosis of the jaw (see below) May

need oral metoclopramide when required with each course, if nausea is severe

Renal impairment Creatinine clearance should be estimated using the Cockcroft and Gault

formula. The appropriate zoledronic acid starting dose is recommended below.

Creatinine Clearance (ml/min) Dose of Zoledronic Acid Volume of Zoledronic

Concentrate (4mg/5ml)

≥60 4mg 5ml

50-59 3.5mg 4.4ml

40-49 3.3mg 4.1ml

30-39 3.0mg 3.8ml

<29 Not Recommended -

Note:

If creatinine clearence deteriorates from baseline value, a doctor should be informed and

consideration should be given to withholding zoledronic acid until the serum creatinine

recovers or stabilises. Zoledronic acid will be kept as stock on most wards now and so the

creatinine clearance should be assessed by the prescriber and nurse prior to administration.

Zometa is not recommended for patients presenting with severe renal impairment prior to

initiation of therapy, which is defined for this population as CrClr < 30 ml/min

If a patient’s dose of zoledronic acid is reduced due to poor or deteriorating renal function,

the patients zoledronic acid dose should remain the same even if the renal function

subsequently improves.


If the dose of zoledronic acid was reduced in previous cycle, the updated creatinine clearance

results must be checked before administering the dose and biochemistry results no greater

than 7 days old should be used.

f. Pamidronate

Dose 90mg IV infusion (if Crcl <10ml/min- see renal impairment) Every 3 to 4 weeks (for practical reasons so any IV chemotherapy can be given on the same day)

Administration In 500ml 0.9% Sodium Chloride over 90 minutes

Common side effects Fever, flu-like syndrome (bone pain, fever, fatigue and rigors)-see symptom

control below, nausea, myalgia/arthralgia, renal impairment, electrolyte

imbalances, hypophosphataemia, osteonecrosis of the jaw (see below)

Renal impairment Patient with established or suspected renal failure the infusion rate should

NOT exceed 20mg/hr – see table below

Creatinine Clearance (ml/min) Dose of Pamidronate Rate of infusion

>10ml/min 90mg 90min

<10ml/min 60mg 4.5 hours

Notes:

Creatinine Clearance is calculated using the Cockroft and Gault Formula:

Creatinine Clearance (CrCl)= (140- Age [in years]) Weight[in kg] F

Serum Creatinine [in mol/l]

Where in males F= 1.23

Where in females F= 1.04


Appendix A: Required Tests for IV Bisphosphonates and SC Denosumab

*Blood results used to confirm IV chemotherapy can be used.

References

1. NICE Guidelines TA265 Denosumab for the prevention of skeletal related events in adults with bone metastasis from solid tumours. October 2012

2. www.medicines.org.uk accessed January 2012

3. Renal Drug Handbook. 3rd

Edition. Caroline Ashley and Aileen Currie UK Renal Pharmacy Group

Drug SC Denosumab* IV Pamidronate IV Zoledronic Acid

Dose 120mg 90mg 4mg (Dose adjusted to Renal function see dose

adjustment table)

Frequency of Dosing Every 4 weeks Every 3 or 4 weeks (depending of frequency of concurrent

chemotherapy)

Every 3 or 4 weeks (depending of frequency of concurrent

chemotherapy)

FBC N/A N/A N/A

LFT’s N/A N/A N/A

Urea For patients who have no renal impairment

U&E’s should be checked for the first month only as baseline.

The serum calcium should be checked one month after the baseline and then subsequently every 2 months

For Patients with severe renal impairment (CrCl <30ml/min)

U&E’s should be checked every month.

Biochemistry should be taken prior to each dose however results from the previous visit may be used if renal function and calcium were within

normal limits and stable. Where a patient’s renal function is not stable, biochemistry results within the previous 7 days

should be used.

Biochemistry should be taken prior to each dose however

results from the previous visit may be used if renal function and calcium were within normal limits and stable.

Where a patient’s renal function is not stable, biochemistry results within the previous 7 days should be

used.

Serum Creatinine

Corrected Serum Calcium (Corr Ca2+)

Phosphate

Magnesium Every 3 months and if low calcium Every 3 months and if low calcium

http://www.medicines.org.uk/


4. South East Cancer Network Prevention of skeletal-related events guideline 2008

Appendix B: Referral Proforma letters and Forms for dental referral

}Date of ref

Consultant Oncologist

Diagnosis date

Treatment given dates

Proposed treatment with name of bisphosphonate/Denosumab

Other relevant MH and medication

Patient ID

Including easiest phone contact

Dear Dentist

The above patient has been receiving treatment in the oncology clinic here at

Hospital. A decision has been made to prescribe {insert drug name} therapy.

It is therefore essential that this patient has an oral health assessment and any necessary extractions

as soon as possible. Once your patient starts IV bisphosphonate/denosumab therapy they will always

be at increased risk of osteonecrosis which is often very difficult to treat.

Therefore we attach some guidelines for this initial assessment and treatment and for the future

management of your patient. These have been produced in conjunction with our oral surgery and

restorative dental consultant colleagues. If you have any medical queries, please contact the

consultant oncologist above.

Please ask your patient to contact us as soon as any necessary dental extractions have been carried

out. Your help with this patient’s care is very much appreciated.

Yours faithfully

ADVICE FOR GENERAL DENTAL PRACTITIONERS

ON DENTAL CARE FOR PATIENTS WHO HAVE BEEN PRESCRIBED

S/C DENOSUMAB or IV BISPHOSPHONATE THERAPY

THE ORAL HEALTH ASSESSMENT/DENTAL TREATMENT

PRIOR TO THERAPY

1. Provide a comprehensive clinical and radiographic examination

2. Identify and control periodontal disease, dental caries and endodontic

disease

3. Give preventative advice and treatment as appropriate

4. Arrange extraction of teeth that are unrestorable/not easily restorable

as soon as possible. Examples could be a retained root, a tooth with chronic

infection and failed root canal treatment or a tooth with advanced bone loss

and a deep periodontal pocket

5. Evaluate third molars, if recent, frequent episodes of pericoronitis arrange

extraction

6. Ensure dentures are comfortable and atraumatic and sharp edges are

eliminated from teeth or restorations

7. Arrange for regular oral health review

DENTAL CARE OF PATIENTS RECEIVING THERAPY

1. PERMITTED TREATMENTS

All routine dental treatment under local anaesthesia can be carried out as

required. This includes scaling and root planning, routine restorations, crowns

and bridges and root canal treatment

2. AVOID

All surgical procedures involving the exposure of bone including extractions and

implant placement

3. EXTRACTIONS

These may be unavoidable when dental pain or infection cannot be resolved with

conservative measures or if the tooth has a mobility score of > 3. In this case you

should refer your patient to your local oral surgery/maxillofacial unit

4. OSTEONECROSIS

This can arise from trauma such as an extraction, dental disease such as apical

periodontitis or periodontal disease, or spontaneously. Signs can include delayed

healing of soft and hard tissues after an extraction and exposure of bone with

surrounding soft tissue inflammation. It can be symptomless or lead to

tenderness of the area and can cause severe pain due to secondary infection. If

osteonecrosis is suspected it is essential you refer to your local oral

surgery/maxillofacial unit as soon as possible. As early treatment can improve

the outcome of this condition which is difficult to manage.

URGENT REFFERAL for Restorative

Dental Assessment

for patient prior to S/C Denosumab or IV Bisphosphonate therapy

PATIENT

NAME HOSPITAL NUMBER

DOB MALE FEMALE

ADDRESS

POSTCODE

HOME TELEPHONE

MOBILE TELEPHONE

OUT PATIENT IN PATIENT Ward Name Tel number & extension

Department of Restorative Dentistry

1st Floor, Royal London Dental Hospital

New Road, Whitechapel E1 1BB

Telephone 020 7601 8701

Fax this form to 020 7377 7687

DATE

TREATMENT DETAILS

TYPE OF TUMOUR

DATE OF TUMOUR DIAGNOSIS

TREATMENT GIVEN AND DATES

DATE PLANNED FOR IV BISPHOSPHONATE or S/C Denosumab

OTHER RELEVANT MEDICAL HISTORY/MEDICATION YES NO

DETAILS

REFERRER

CONSULTANTS NAME

SPECIALTY

(if not consultant ) NAME GRADE SHO SpR

CONTACT NUMBER EMAIL

CLM 7.10

DENTAL CARE PATHWAY FOR IV BISPHOSPHONATE/ SC Denosumab PATIENTS

If treatment very palliative

If likely to be on treatment long term

BREAST ONCOLOGY/OTHER CLINIC Decision to prescribe S/C Denosumab or IV

Bisphosphonates

DENTAL HOSPITAL/GDP ASSESSMENT

Patient has no access to Dental Care

Fax referral PROFORMA to Dental Hospital - Restorative

Cause pain unclear Refer to Restorative for assessment/ treatment

EXTRACTIONS (Wait 3 weeks – check

soft tissue healing)

Patient has General Dental Practitioner

Referral by STANDARD LETTER to dentist given to patient

REGULAR DENTAL CARE in GENERAL PRACTICE

No acute dental problems

START TREATMENT - do not stop for dental treatment/extractions

Established osteonecrosis Refer to Oral Surgery +/- extractions

ORAL PAIN Refer to Dental Hospital by FAXED LETTER letter advise if urgent

Extraction required/established osteonecrosis Refer to nearest Oral Surgery/OMFS unit

CLM 7.10

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