Prevention of skeletal-related events in cancer patients

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Guidelines for prevention of skeletal-related events and treatment of bone metastases

Scope:

Prevention of skeletal related events caused directly by cancer (eg pathological fracture, spinal cord compression, radiation or surgery to bone, or tumour induced hypercalcaemia) and treatment of bone metastases with bisphosphonates or denosumab.

See alternative guidelines for:

  • treatment of tumour induced hypercalcaemia
  • patients on steroids for at least 3 months at doses of prednisolone of at least 7·5mg/day (or equivalent) or other bone-wasting drugs
  • additional information relating to use of bone-modifying agents in multiple myeloma

Responsibilities:

Patient group Prescribing* Monitoring Stopping Patient counselling
Metastatic breast cancer
Early breast cancer – IV treatment
Multiple myeloma
Prostate cancer
Lung cancer
Renal cancer
Other solid tumour
Consultant Raigmore Hospital  Consultant Raigmore Hospital
Early breast cancer - oral treatment Primary Care clinician according to Specialist letter Primary Care Primary Care clinician according to Specialist letter Raigmore Hospital and Primary Care

* Including initiation and continuation of prescribing, including vitamin D pre-treatment dose (where necessary) and calcium and vitamin D supplements

Indications and frequency of dosing
Patient group  First-/Second-line Duration

Metastatic cancer

  • with bone metastases
4 to 12-weekly IV zoledronic acid
OR 4 to 12-weekly subcutaneous denosumab
 As long as clinically appropriate
Early breast cancer
  • postmenopausal†
  • at higher risk of recurrence (10-year risk ≥ 12%)
  • receiving chemotherapy
6-weekly IV zoledronic acid for 3 cycles followed by
EITHER daily oral ibandronate
OR 6-monthly IV zoledronic acid 
 Up to 3 years
 Early breast cancer
  • postmenopausal†
  • at higher risk of recurrence (10-year risk ≥ 12%)
  • NOT receiving chemotherapy
Daily oral ibandronate OR  6-monthly IV zoledronic acid   Up to 3 years
 Multiple myeloma 4-weekly IV zoledronic acid
OR daily oral sodium clodronate
See Guideline: Bisphosphonate Use in Myeloma Patients 
 Prostate cancer
  • metastatic castrate-resistant
  • symptomatic bone metastases
3 to 4-weekly IV zoledronic acid  As long as clinically appropriate
 Lung cancer
  • symptomatic bone metastases
3 to 4-weekly IV zoledronic acid  Concurrently with first-line systemic anticancer treatment, stopped at the end of course; repeated during second-line treatment if required
Renal cancer
  • symptomatic bone metastases
3 to 4-weekly IV zoledronic acid  As long as clinically appropriate
(Note increased risk of osteonecrosis of the jaw with concurrent tyrosine kinase inhibitors)

 Other solid tumour*

  • symptomatic bone metastases
IV zoledronic acid may be considered a treatment option where there is evidence to do so As long as clinically appropriate

 NB: Onset of treatment effect of zoledronic acid may be 2 to 3 months from initiation of therapy.
† Adjuvant bisphosphonates are only recommended for use in women who are postmenopausal, unless the adjuvant/neoadjuvant treatment plan includes ovarian suppression therapy (i.e. GnRH agonist) or oophorectomy. Consultant decision.
*Non-formulary approval will be required.

Pre-treatment requirements
  1. Give a single oral dose of 100,000iu colecalciferol prior to starting treatment. Unless patient is already taking vitamin D supplements. Remember to check for prescribed and over-the-counter supplements.
  2. Measure serum adjusted calcium levels. Correct pre-existing hypocalcaemia before starting treatment.
  3. Assessment of dental health. All (except edentulous) patients must attend for a dental check-up before commencing therapy with a bisphosphonate or denosumab. Therapy must be postponed until healing from any remedial dental work is complete.
  4. Evaluation of renal function.
Monitoring
  • See drug information below
  • At each clinic appointment all patients must be asked about any dental problems (including pain, swelling or numbness in the mouth) and any ear problems (pain, discharge or infection)
  • Correct electrolyte abnormalities as per Electrolyte Working Group Guidelines.
Management of hypocalcaemia

If a patient develops hypocalcaemia despite being prescribed recommended doses of calcium and vitamin D supplementation:

  • Check that the patient is taking the supplements as prescribed
  • Consider whether there are factors which may affect the absorption of calcium supplements (eg administration with food)
  • Check, and if necessary, correct magnesium levels.

If there are no issues identified and the patient is asymptomatic, consider increasing the calcium supplementation. Contact local Biochemist or Endocrinologist for advice if patients have asymptomatic hypocalcaemia resistant to treatment.
If the patient is symptomatic (usually occurs when calcium < 1·9 mmol/L) contact Biochemist or Endocrinologist urgently due to potential risk of dysrhythmia and seizure. Symptoms of hypocalcaemia include: perioral and digital paraesthesiae, positive Trousseau’s and Chvostek’s signs, tetany and carpopedal spasm, laryngospasm, ECG changes (prolonged QT interval) and arrhythmia, seizure. Note: Severe symptomatic hypocalcaemia (including fatal cases) have been reported with denosumab. 

Adverse effects

a.   Osteonecrosis of the jaw
Patients with cancer are at higher risk for osteonecrosis of the jaw (ONJ). The risk is increased not only by the disease itself but by concurrent treatments. Bisphosphonates and denosumab increase the risk of ONJ. Tyrosine kinase inhibitors (TKIs) and anti-angiogenic systemic anticancer treatments (SACT) also increase the risk of ONJ. Patients should be advised of the risk of ONJ and counselled on appropriate precautions:

  • Maintenance of good oral hygiene
  • Routine dental check-ups during treatment
  • Advising doctor/dentist that they are receiving a bisphosphonate or denosumab, particularly if dental treatment or surgery is required
  • Reporting immediately any problems with mouth or teeth during treatment (eg loose teeth, pain, swelling, non-healing sores, or discharge)

b.   Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been very rarely reported with (mainly long-term) bisphosphonate or denosumab use. Other risks include steroid use, chemotherapy and other local factors such as infection or trauma. The possibility should be considered in patients who present with ear symptoms including chronic ear infections.

c.   Atypical femoral fractures
Bisphosphonates and denosumab have been reported to be associated with an increased risk of atypical femoral fractures. Patients should be advised to report any thigh, hip or groin pain.

d.   Gastro-intestinal irritation
Oral bisphosphonates can cause local irritation of the upper gastrointestinal mucosa. Caution should be used when oral bisphosphonates are given to patients with active upper gastrointestinal problems e.g. Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers. Patients must be advised to comply with dosing instructions and instructed to discontinue the bisphosphonate and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

Bisphosphonate drug interactions
  • Patients receiving NSAIDs in addition to bisphosphonates have developed renal dysfunction.
  • Additional risk of gastrointestinal irritation. Avoid/reduce if possible.
  • Caution with concomitant aminoglycosides due to risk of additive hypocalcaemia.
  • (Oral only) Impaired absorption with divalent metal ions: avoid administration with food, antacids and mineral supplements. See administration instructions.
Responsibilities of primary care clinician for breast cancer patients receiving ibandronic acid
  • Ensure pre-treatment requirements have been met.
  • Prescribe ibandronic acid 50mg tablets once daily (or at reduced frequency depending on renal function) as per specialist letter (duration of treatment stated on letter).
  • Ensure any other bisphosphonate, eg weekly alendronate or risedronate is stopped whilst patient is taking ibandronic acid.
  • Review current non-steroidal anti-inflammatory drugs (NSAIDs) use (increased risk of gastro-intestinal side-effects and potentially increased risk of renal dysfunction).
  • Review annually:
    • Medication review to check compliance; potential side-effects; tolerability of ibandronic acid; ensure patient and/or carer understands how to administer tablets; check oral hygiene advice is being followed.
    • Annual blood tests: renal function and serum adjusted calcium. Calculated creatinine clearance should be calculated for patients with BMI less than 20 since eGFR may overestimate renal function.
  • If ibandronate tablets are not tolerated or patient is unable to comply with dosing instructions, refer back to specialist for consideration of IV zoledronic acid 6 monthly as an alternative.
  • Inform consultant if ibandronate is discontinued for any reason.
Drug information

This information is not comprehensive. Refer to individual SPCs for further information.

 Drug  Administration   Monitoring frequency Dose Calcium supplementation 

Tests required:
Creatinine
eGFR/CrCl
Urea
Electrolytes, inc. AdjCa, Mg, Phos.
Bone profile

     CrCl (mL/min) Dose

Zoledronic acid

    
Intravenous
IV in 100mL sodium chloride 0·9% over 15 minutes.    
Prior to each dose      >60 4mg All patients unless contra-indicated. Starting dose 500mg calcium + 400iu vitamin D daily.    
 50 to 59 3·5mg
 40 to 49 3·3mg
 30 to 39 3mg
 <30 Contra-indicated
Sodium clodronate Oral
Take in the morning on an empty stomach with a glass of water. Refrain from eating, drinking (other than plain water) or taking any other oral medications for 60 minutes. Do not crush or dissolve tablet. Tablet may halved to aid swallowing.
At clinic appointments, min. 3-monthly, more frequently in renal impairment.  >50  1600mg daily Consider prescribing supplemental calcium + vitamin D in absence of hypercalcaemia. Adequate intake important.
30 to 49 1200mg daily
10 to 29 800mg daily
<10 Contra-indicated
Ibandronic acid  Oral
Take after an overnight fast (at least 6 hours) and before first food, drink or medicine of the day. Continue fasting at least 30 minutes. Swallow tablet whole with a full glass of water (180 to 240mL, approx. ½ pt) while standing or sitting upright. Do not lie down for 60 minutes after taking. Do not chew, suck or crush tablet. Water is only drink to be taken with ibandronate. 
At least every 12 months.   >50  50mg daily All patients unless contra-indicated. Starting dose 500mg calcium + 400iu vitamin D daily. 
 30 to 49 50mg on alternate days
<30 50mg once weekly
Denosumab Subcutaneous
Subcutaneous injection into thigh, abdomen or upper arm.

Prior to each dose.

Additional AdjCa 2 weeks after first dose.

120mg. No dose adjustment required in renal impairment. If CrCl <30 mL/min, patients are at greater risk of hypocalcaemia. All patients unless contra-indicated. At least 500mg calcium + 400iu vitamin D daily.

 AdjCa – adjusted calcium; Mg – magnesium; Phos – phosphate.

Summary of patient counselling points
  • Supply Patient Information Leaflet for adjuvant breast cancer patients
  • Maintain adequate fluid intake
  • Risk of osteonecrosis of the jaw:
    • maintain good oral hygiene and attend regularly for review at dentist
    • report mouth/dental symptoms promptly
    • avoid invasive dental procedures – discuss with prescriber
  • Risk of atypical fracture of femur: report thigh, hip or groin pain
  • Risk of osteonecrosis of the auditory canal: report any ear pain, discharge from the ear or ear infections
  • Importance of adherence to administration advice for oral bisphosphonates
  • Risk of GI irritation with oral bisphosphonates: seek medical attention if GI symptoms develop or worsen
  • Continue with calcium and vitamin D supplementation unless advised otherwise.
References

Guidelines adapted from WOSCAN Clinical Guidelines

  1. Healthcare Improvement Scotland and NHS Scotland, 2016. Scottish Palliative Care Guidelines. Hypercalcaemia. [online] Edinburgh: Scottish Partnership for Palliative Care. Available from: http://www.palliativecareguidelines.scot.nhs.uk/guidelines/palliative-emergencies/Hypercalcaemia.aspx (last updated 17 Feb 2016; accessed 14/8/17)
  2. Wang-Gillam A et al, 2008. Evaluation of vitamin D deficiency in breast cancer patients on bisphosphonates. The Oncologist, 13, pp821-7. doi:10.1634/theoncologist.2008-0013
  3. Himelstein AL et al, 2017. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial. JAMA, 317(1), pp48-58. doi:10.1001/jama.2016.19425
  4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2015. Adjuvant bisphosphonate treatment meta-analyses of individual patient data from randomised trials. Lancet, 386, pp1353-61. doi:10.1016/S0140-6736(15)60908-4
  5. Hadji P et al, 2016. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol, 27(3), pp379-90. doi: 10.1093/annonc/mdv617
  6. Electrolytes Working Group, NHS Highland, 2014. Guidelines for the treatment of low electrolytes. [online] Available from: http://tam.nhsh.scot/treatments-and-medicines/therapeutic-guidelines/nutrition-fluid-and-electrolytes/treatment-of-low-electrolytes-summary/  (accessed 11/9/18)
  7. Datapharm, 2017. Zoledronic Acid Accord 4 mg/5 ml concentrate for solution for infusion, last updated 9 Aug 2017. [online] Available from: http://www.medicines.org.uk/emc/medicine/28673 (accessed 14/8/17)
  8. Datapharm, 2017. Bonefos [sodium clodronate] tablets, last updated 23 Jun 2016. [online] Available from: http://www.medicines.org.uk/emc/medicine/311 (accessed 14/8/17)
  9. Datapharm, 2017. XGEVA [denosumab], last updated 28 Jun 2017. [online] Available from: http://www.medicines.org.uk/emc/medicine/24755 (accessed 14/8/17)
Glossary
Abbreviation Meaning
NSAIDs Non steroidal anti inflammatory drugs
ECG Electrocardiogram
eGFR Estimated glomerular filtration rate
BMI Body mass index
IV Intravenous
CrCl Creatinine clearance
GI Gastrointestinal
Editorial Information

Last reviewed: 31 December 2018

Next review: 31 December 2020

Author(s): Cancer Services Directorate

Approved By: TAM Subgroup of ADTC

Reviewer Name(s): Specialist Oncology Pharmacist

Document Id: TAM183