bisphosphonate therapy - world health organization · bone metastases can cause skeletal-related...

$: BISPHOSPHONATE THERAPY - World Health Organization · Bone metastases can cause skeletal-related events (SREs) including fractures, spinal cord compression, hypercalcemia and significant$
BISPHOSPHONATE THERAPY

Union for International Cancer Control

2016 Review of Cancer Medicines on the WHO List of Essential Medicines

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Executive Summary

Bisphosphonates are powerful and specific inhibitors of osteoclasts and their use in

cancer patients prevents the increased bone resorption that accompanies metastatic bone

disease (1,2). Through this mechanism, bisphosphonates reduce complications or skeletal

related events (SREs) such as fractures, the need for palliative radiotherapy to relieve

pain, spinal cord compression and hypercalemia from bone metastases (3,4). They can

also reduce bone pain and analgesic requirements (5,6) and improve quality of life (7-9).

Up to 75% of prostate cancer patients, 70% of breast cancer patients and 30-40% of other

solid organ tumors will develop bone metastases (10). Additionally, almost all patients

with multiple myeloma will develop bone lesions during the course of the disease (11). In

the absence of a bisphosphonate, SREs occur in around one half to two thirds of patients

(depending on the underlying malignancy and concomitant cancer treatments) (9,12,13),

contributing significant morbidity to the clinical course of the underlying disease and

increasing the health care costs of treating advanced malignancy (3, 14).

Bisphosphonates reduce the number of patients with breast cancer experiencing an SRE,

extend the time to first and subsequent SREs and prevent around one third of all skeletal

morbidity (8,12,13,15). Zoledronic acid is the most effective agent (16-18) with a 41%

reduction in the overall risk of SREs when compared to placebo (19). Placebo controlled

trials have also shown benefits for oral clodronate (20-22), (intravenous (23,25) and oral

ibandronate (24,25) and pamidronate (8,9,15).

In hormone resistant prostate cancer, inhibition of bone resorption is also of clinical

relevance despite the osteoblastic nature of most prostate bone metastases (26,27).

However, only zoledronic acid has shown significant benefits in terms of reducing SREs

(12,28), although intravenous ibandronate has similar efficacy to palliative radiotherapy

for the acute relief of bone pain (6). In this disease setting, zoledronic acid decreased the




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number of patients experiencing an SRE by 9% (33% vs 44%), increased the median

length of time to first SREs (>420 days vs 321 days), reduced the overall risk of SRE by

36% and improved pain scores (12).

Similarly, in non-breast and non-prostate solid tumors (50% NSCLC and 50%

miscellaneous other solid tumors), zoledronic acid increased the median time to the first

event (230 days vs 163 days) and decreased the overall risk for SREs by 31% (12,29)

In multiple myeloma (30), bisphosphonates reduce vertebral fractures, SREs and bone

pain (relative risk of 0.74, 0.80 and 0.75, respectively) with oral clodronate (31,32),

pamidronate (33) and zoledronic acid (16,17) having similar effects on skeletal

morbidity. However, zoledronic acid improved overall survival when compared with oral

clodronate (34).

The current evidence supports the addition of bisphosphonates including zoledronic acid,

pamidronate, ibandronate, and clodronate to the EML. Of these, zoledronic acid has the

best efficacy and is the recommended bisphosphonate for solid tumors (3). In multiple

myeloma, pamidronate and zoledronic acid were equally efficacious and both are

considered as appropriate options (35,36).

The reviewers also discussed denosumab as an alternative to bisphosphonates.

Denosumab is a monoclonal antibody against RANKL that reduces SREs across all solid

tumors (37). However, denosumab is much more expensive than bisphosphonates which

are now generic medications and, although modest benefits compared to bisphosphonates

have been demonstrated, is not being recommended for inclusion in the Essential

Medicines List at this time due to the adverse economic impact this agent would have on

health care budgets.




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Public Health Relevance

The skeleton is one of the most common locations to which cancer metastasizes. The

propensity for solid tumor malignancies to metastasize to bone varies: 65-75% of patients

with advanced prostate cancer and 70% of patients who die of breast cancer will develop

bone metastases. The incidence of bone metastases is lower, 15-30%, in patients with

lung, colon, stomach, bladder and other cancers and only 5% of patients with certain GI

malignancies (10). In patients with multiple myeloma, 60% of patients will have bone

lesions at the time of presentation and nearly all patients will develop bone lesions during

the course of the disease (11)

Bone metastases can cause skeletal-related events (SREs) including fractures, spinal cord

compression, hypercalcemia and significant pain, which can then necessitate treatment

with radiation and/or chemotherapy or surgical intervention in the case of fractures or

spinal complications. In patients with bone metastases treated with systemic anticancer

treatments and no bisphosphonates, SREs occur in 46 to 64% of patients in two years

(depending on the underlying malignancy), contributing importantly to the significant

overall morbidity of advanced cancer (9,12,13).

Overview of Regimens

Solid tumor bone metastases (including breast cancer)

Zoledronic acid Intravenous infusion 4mg every 4-12 weeks (12,13,16)

Alternatives (breast cancer only)

Pamidronate Intravenous infusion 90mg every 4 weeks (8,15)

Ibandronate Oral 50mg daily (24)

Ibandronate Intravenous infusion 6mg every 4 weeks (23)

Clodronate Oral 1600mg daily (20,21,22)

Treatment should be continued throughout the course of the disease (3,4,7,38,39)




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Adminstration of zoledronic acid every 12 weeks may be as effective as the approved

every 4 weeks schedule (40-42).

Multiple Myeloma

Zoledronic acid Intravenous infusion 4mg every 4 weeks (16,17)

Alternatives

Pamidronate Intravenous infusion 90mg every 4 weeks (31,34)

Clodronate Oral 1600mg daily (32,33)

Treatment should be continued throughout the course of the disease. However, to reduce

the risk of treatment complications, interruption after 12-24 months should be considered

in patients in remission and restarted on progression (35,36).

Review of Benefits and Harms

The overall benefits of bisphosphonates in metastatic bone disease clearly exceed the

potential harms of treatment and are a recommended addition to standard anticancer

treatments across all tumor types (3,35,36,37,39,40).

Benefits

Breast cancer bone metastases

Zoledronic acid

Placebo controlled trial demonstrates 41% reduction in risk of skeletal event (19)

Similar reduction in proportion of patients experiencing an SRE as pamidronate (16) but

overall risk of SRE reduced by further 20% (17).

Pamidronate

Placebo controlled trials demonstrated significant reduction in SRE for both

chemotherapy (8) and endocrine therapy (15) treated patients. Overall benefits included

reduction in pain and improved quality of life (9).




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Ibandronate

Placebo controlled trials with both intravenous (23) and oral formulations (24)

demonstrated significant reduction in skeletal morbidity rate. Not approved in United

States

Clodronate

Relatively small placebo controlled trials have demonstrated significant benefits in

skeletal morbidity (20-22). Acute effects on bone pain less evident than with intravenous

aminobisphosphonates. Not approved in the United States

Prostate cancer bone metastases (castration resistant)

Zoledronic acid is approved worldwide for patients with castration resistant prostate

cancer on the basis of a randomized trial demonstrating significant reduction in

proportion of patients experiencing an SRE, prolonged time to first SRE and overall risk

reduction for SRE of 36% (12). Pamidronate ineffective in randomized trial conducted in

very advanced painful bone metastases (28). Use alongside androgen deprivation therapy

+/- docetaxel chemotherapy reduced SREs but did not improve survival (43).

Other solid tumor bone metastases

Randomised placebo controlled trial of zoledronic acid in a broad range of solid

tumors other than breast and prostate demonstrated significant reduction in

skeletal morbidity (13). Specific benefit clearly demonstrated in NSCLC and renal

cancer subsets (17). No randomized trial evidence to support use of any other

bisphosphonate in these disease settings

Multiple myeloma

Placebo controlled trial evidence for both pamidronate (31) and clodronate (32,33) in

multiple myeloma. Comparison of pamidronate with zoledronic acid suggested similar

efficacy (16,17). Zoledronic acid was more effective than oral clodronate in prevention of




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skeletal morbidity and extended survival by 3 months (34). Clodronate not approved in

United States.

Harms

Complications of treatment

There are several risks to treatment with bisphosphonates that require monitoring [3,44].

Intravenous bisphosphonates are commonly associated with the acute phase response

(fever and flu-like symptoms), bone/joint pain, Less common side effects include kidney

injury (45), ocular inflammation (46) and atrial fibrillation (47).

Osteonecrosis of the jaw (ONJ) is a significant clinical problem associated with long-

term bisphosphonate use (48). The frequency of ONJ is 1-2% of patients for each year on

monthly intravenous bisphosphonate therapy (49,50); the risk may be less with daily oral

agents or administration of intravenous treatment on a 3 monthly schedule (51). It is

recommended that patients have a dental exam and preventive dental work (such as tooth

extraction) performed prior to administration of bisphosphonate therapy and invasive

dental work should be avoided (51). When extraction or jaw surgery cannot be avoided,

prophylactic antibiotics should be given. The bisphosphonate should be discontinued

until healing is complete unless the patient has ongoing significant symptomatic bone

disease.

Patients are also at risk of hypocalcemia. Vitamin D supplementation is recommended

and most patients should be placed also on calcium supplementation, though this should

be individualized based on the characteristics of the malignancy and renal function (52).

Atypical femoral fractures (subtrochanteric and diaphyseal regions) can also occur rarely

(<1 in 1000) and may be related to long term suppression of bone remodeling induced by

bisphosphonate treatments (53).




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