London-Cancer-Guidelines-managemen-of-skeletal-events-updated-v1

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
Page 7
Page 8
Page 8
5.
o Denosumab
o Zoledronic Acid
o Pamidronate
Appendices
o Appendix A: Blood Tests
o Appendix B: Referral Proforma letters and Forms
for dental referral
Page 9
Page 10
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 1 of 17
Version dated: February 2014
Review date: February 2016
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.
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 2 of 17
Version dated: February 2014
Review date: February 2016
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 contraindicated but intravenous bisphosphonates are considered appropriate.
Please refer to Breast Cancer Treatment guidelines for further guidance regarding Assessment of
Bone Health with Endocrine Treatment.
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 3 of 17
Version dated: February 2014
Review date: February 2016
3. Treatment Algorithm for Management SRE
New cancer patient requiring treatment for skeletal related events
Does the patient have:
o prostate cancer
o multiple myeloma
o Breast Cancer Treatment Induced Bone loss?
YES
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
NO
Does the patient have severe untreated hypocalcaemia or
hypercalcaemia of malignancy?
YES
Correct hypocalcaemia or treat the
hypercalcaemia of malignancy
(Refer to Hypocalcaemia guidelines or
Guidelines for the treatment of Hypercalcaemia
**Breast Cancer patients for treatment-induced bone loss in women who
of Malignancy)
experience premature menopause due to chemotherapy or has ovarian
suppression, ablation or removal.
OR
1st Line: Denosumab 120mg SC 4 weekly & Adcal D3
Breast cancer postmenopausal patient receiving treatment with aromatase
ONE tablet daily
inhibitors.
2nd Line (if cannot tolerate denosumab: Zoledronic
Where there is failure to achieve the required response on oral
Version:
1
Acid 4mg IV 3 or 4 weekly & Calcium supplement
bisphosphonates.
Where oral bisphosphonates are not tolerated at the
daily)
pamidronate
optimal
In patients
with
oesophageal
disease
Based
ondose.
the Barts
Health
Guideline
written
by: where
Chris oral
Watson and Checked
by or
Sarah
Slater if CrCl<29ml/min
bisphosphonates are contra-indicated but intravenous bisphosphonates
Reviewed
and Updated by Simon Jenkinson
are considered appropriate.
Page 4 of 17
Version dated: February 2014
Review date: February 2016
NO
1st Line: Denosumab 120mg SC 4 weekly &
Calcium supplement
2nd Line (if cannot tolerate denosumab:
Zoledronic Acid 4mg IV 3 or 4 weekly &
Calcium supplement or pamidronate if
<29ml/min
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.
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 5 of 17
Version dated: February 2014
Review date: February 2016
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








Common side effects
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.
Dyspnoea, diarrhoea, hypocalcaemia, hypophosphataemia, hyperhydrosis,
osteonecrosis of the jaw (see below)
Renal impairment
No dose reduction required, however closely monitor serum calcium
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 6 of 17
Version dated: February 2014
Review date: February 2016
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
Administration
4mg IV infusion every 6 months for breast cancer treatment related bone loss
in patients who cannot tolerate oral bisphosphonates or are contraindicated
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.
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 7 of 17
Version dated: February 2014
Review date: February 2016
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.
Dose
Pamidronate
Administration
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)
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
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 8 of 17
Version dated: February 2014
Review date: February 2016
Appendix A: Required Tests for IV Bisphosphonates and SC Denosumab
Drug
Dose
Frequency of Dosing
SC Denosumab*
120mg
IV Pamidronate
90mg
Every 4 weeks
Every 3 or 4 weeks
(depending of frequency of concurrent
chemotherapy)
N/A
N/A

FBC
LFT’s
Urea
Serum Creatinine
Corrected Serum Calcium
(Corr Ca2+)
Phosphate
N/A
N/A
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
Magnesium
For Patients with severe renal
impairment (CrCl <30ml/min)
U&E’s should be checked
every month.
*Blood results used to confirm IV chemotherapy can be used.
IV Zoledronic Acid
4mg
(Dose adjusted to Renal function see dose
adjustment table)
Every 3 or 4 weeks
(depending of frequency of concurrent
chemotherapy)
N/A
N/A

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.
Every 3 months and if low calcium
Every 3 months and if low calcium
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. 3 Edition. Caroline Ashley and Aileen Currie UK Renal Pharmacy Group
rd
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 9 of 17
Version dated: February 2014
Review date: February 2016
4.
South East Cancer Network Prevention of skeletal-related events guideline 2008
Version: 1
Based on the Barts Health Guideline written by: Chris Watson and Checked by Sarah Slater
Reviewed and Updated by Simon Jenkinson
Page 10 of 17
Version dated: February 2014
Review date: February 2016
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.
Department of Restorative Dentistry
1st Floor, Royal London Dental Hospital
New Road, Whitechapel E1 1BB
DATE
Telephone 020 7601 8701
URGENT REFFERAL for Restorative
Fax this form to 020 7377 7687
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
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
CONTACT NUMBER
GRADE
SHO 
SpR 
EMAIL
CLM 7.10
DENTAL CARE PATHWAY
FOR IV BISPHOSPHONATE/ SC Denosumab PATIENTS
BREAST ONCOLOGY/OTHER CLINIC
Decision to prescribe S/C Denosumab or IV
Bisphosphonates
If treatment very palliative
No acute
dental problems
If likely to be on treatment
long term
Patient has
no access to Dental Care
Fax referral PROFORMA to
Dental Hospital - Restorative
Patient has
General Dental Practitioner
Referral by
STANDARD LETTER to
dentist given to patient
DENTAL HOSPITAL/GDP ASSESSMENT
EXTRACTIONS
(Wait 3 weeks – check
soft tissue healing)
START TREATMENT
- do not stop for dental treatment/extractions
REGULAR DENTAL CARE
in GENERAL PRACTICE
Extraction
required/established
osteonecrosis
Refer to nearest Oral
Surgery/OMFS unit
ORAL PAIN
Refer to Dental
Hospital by
FAXED LETTER
letter advise if
urgent
Cause pain unclear
Refer to Restorative
for assessment/
treatment
Established osteonecrosis
Refer to Oral Surgery
+/- extractions
CLM 7.10