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atient Management Issuesn Metastatic Bone Diseaseavid Cameron

The main goals of bisphosphonate therapy are to prevent and treat skeletal events,minimize disability, and relieve pain without increasing the overall burden that bonemetastases (and their treatment) place on patients. The ease and convenience of treatmentare important to patients, and there are data suggesting that patients prefer oral therapyover intravenous drugs to help them maintain a normal life. Intravenous therapy withzoledronic acid and pamidronate is currently time-consuming; preparation, renal monitor-ing, infusion, and follow-up use valuable health care resources. Intravenous ibandronatecould help alleviate this burden because of its good renal safety profile. Although effica-cious, oral clodronate has compliance problems because of multiple dosing, large tabletsize, and gastrointestinal tolerability issues. Recent phase III trials of oral ibandronate haveshown efficacy similar to that of intravenous ibandronate, with no compliance or tolerabilityconcerns. Ibandronate appears to have several advantages over current therapies thatcould improve treatment acceptability and reduce the burden of disease on the health caresystem. Research continues into the efficacy, safety, and pharmacoeconomics ofibandronate.Semin Oncol 31:79-82 © 2004 Elsevier Inc. All rights reserved.

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ffective treatment of bone metastases in patients withadvanced breast cancer is crucial in limiting morbidity

nd disability. Although patient management requires a mul-idisciplinary approach, bisphosphonates in conjunctionith an antitumor agent have become the mainstay of treat-ent. The primary goals of bisphosphonate therapy are torevent skeletal events, relieve pain, improve quality of life,nd, where possible, survival. Treatment should also aim toimit toxicity, reduce the impact of disease on the health careystem, and take account of the patient’s lifestyle. The con-enience and simplicity of treatment is important to patientsecause they already have to cope with the substantial bur-en of the illness itself and the side effects of anticanceregimens. Metastatic bone disease can have a long clinicalourse, with a median survival of 2 to 3 years in advancedreast cancer.1 Patients need long-term bisphosphonates, ei-her for the rest of their life or at least until their performancetatus has substantially deteriorated. The most widely usedisphosphonates currently are intravenous (IV) zoledroniccid and pamidronate, and oral clodronate. Ibandronate,

estern General Hospital, Crewe Road, Edinburgh, UK, EH4 2XU.r Cameron serves as a research consultant and clinical investigator to

Roche Laboratories.ddress reprint requests to David Cameron, MD, Western General Hospital,

Edinburgh, UK. E-mail: david.cameron@ed.ac.uk

093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.oi:10.1053/j.seminocol.2004.07.027

hich is available in both IV and oral formulations, has noweceived approval in the European Union for the preventionf skeletal events in patients with bone metastases and breastancer.

reatment Options withntravenous Bisphosphonatesne of the main advantages of giving bisphosphonates intra-

enously in the hospital or clinic is that it guarantees compli-nce. It is also easy to arrange coordination with infusions ofhe patient’s other IV drugs, such as chemotherapy or mono-lonal antibody agents. However, there are a number of dis-dvantages to giving IV bisphosphonates. For outpatients,egular hospital visits are inconvenient, often taking severalours for travel and administration. Scheduling patients for

nfusions of other therapies can be complex. The preparation,dministration, and follow-up of bisphosphonate infusionsonsume valuable nursing time and resources.2,3 This canncrease when it is difficult to get venous access to give theisphosphonate. When peripheral venous access is not pos-ible (a particular problem in patients who have had multipleycles of chemotherapy) central venous catheterization issed, and complications of this approach can have a further

mpact on patients as well as health care resources and costs.

An important disadvantage for some IV bisphosphonates is

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80 D. Cameron

he recommended requirement for renal function monitoringefore each dose. This is because of the small risk of severe renal

mpairment. Updated guidelines from the American Society oflinical Oncology recommend that serum creatinine is moni-

ored before each dose of zoledronic acid or pamidronate, andhat infusion times of less than 2 hours for pamidronate or lesshan 15 minutes for zoledronic acid should be avoided.4 Reportsf severe, and sometimes fatal, renal damage from the Food andrug Administration Adverse Event Reporting System, ledhang et al5 to recommend discontinuing zoledronic acid if

enal function deteriorates.Infusion time is important when assessing the benefits of

isphosphonate therapy.6 A treatment with a short infusionime should be more convenient for the patient, translatingnto quality-of-life benefits and less time spent monitoringatients.2 Although zoledronic acid can be infused rapidlyver 15 minutes, the actual administration time is extendedy preinfusion of saline, drug preparation, set-up (eg, canula

nsertion) and safety follow-up. Similar factors apply to pam-dronate, which is infused more slowly over 2 hours. It canake about 1 hour to complete a single administration ofoledronic acid and up to 3 hours for pamidronate (Fig 1),2,3

nd these times do not include renal safety monitoring.Intravenous bisphosphonates that can be infused rap-

dly and without significant monitoring would be a bene-cial treatment option in metastatic bone disease. Phase IIIlinical trial data have shown that IV ibandronate has aenal safety profile comparable to that of placebo.7,8 Sonlike zoledronic acid and pamidronate, there is no rec-mmendation for serum creatinine monitoring beforeach dose and less need for corrective management ofymptomatic renal function deterioration. And althoughhe current recommended infusion time for IV iban-ronate is 1 hour, there is growing evidence that it coulde infused in 15 minutes, without renal toxicity.9,10 Theseenefits of ibandronate should reduce the impact of ad-

inistration time on patients and nurses. a

reatment Optionsith Oral Bisphosphonates

atients may dislike visiting the hospital for IV bisphospho-ate therapy because it is time-consuming, inconvenient, andnother clear reminder that they have cancer. Many patientslso become anxious about the IV infusion, anticipating pain,he needles, and the injection itself.11 In a study of 103 pa-ients with incurable cancer, the vast majority (89%) saidhey preferred to have palliative treatment orally rather thanntravenously, provided there was no compromise in eff-cacy.11 The patients felt that oral therapy would be moreonvenient, avoid the pain and difficulty of obtaining venousccess, and give them more control over the therapy environ-ent. Indeed, oral bisphosphonates would enable patients to

ead a more ordinary life by allowing them to make treatmentart of their daily routine.12 This would eliminate the burdenf regular hospital visits for the patient, health care staff, andlinic or hospital resources. Oral bisphosphonates are alsoarticularly suitable for long-term use and easy to combineith different dosing regimens. However, compliance should

lso be considered. It is difficult to monitor adherence accu-ately with oral drugs, and patients may confuse the dosingith concomitant oral regimens, a particular problem withlder patients or those with multiple medications. It is im-ortant to ensure that patients are properly informed aboutheir oral therapy to minimize such difficulties. For instance,atients who are concerned about forgetting to take their oraledication could have reminder strategies as part of their

herapy management program.11

Oral formulations need to be as efficacious as IV infusions,nd easy and convenient for patients to take. In phase IIIrials, oral ibandronate showed equivalent clinical benefits toV ibandronate in terms of its effects on preventing skeletalvents and relieving metastatic bone pain.7,13 Oral iban-ronate is given once daily, with a 30-minute post-dose fast,

Figure 1 Total administration times for IVzoledronic acid and pamidronate (excluding renalmonitoring).2,3

nd the tablet is much smaller than that of clodronate (about

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Patient management in metastatic bone disease 81

cm in length). In phase III trials, no patients withdrew fromifficulty in swallowing oral ibandronate.13

he Economic Issues ofisphosphonate Therapy

etastatic bone disease is a considerable burden on theealth care system. An estimated 25% to 40% of patients withreast cancer and bone metastases will need radiotherapy forone pain, 5% to 30% will develop hypercalcemia, and 17%o 50% will have vertebral fractures each year.14 A recenttudy from the United States assessed the effect of skeletalomplications on medical care costs in women with boneetastases from breast cancer.15 The results showed that total

osts per patient were $52,099 greater in patients with skel-tal-related events than in patients without these events.osts of care directly attributable to skeletal complicationsere $14,580 per patient.Bisphosphonate therapy could reduce the financial burden

f metastatic bone disease by reducing the rate at whichatients develop skeletal complications, with less time inospital, fewer orthopedic operations, and less need for ra-iotherapy and pain management. However, the costs of IVisphosphonate therapy are substantial, not just the expensef the drug itself but also the costs of nurse and technicianime for preparing and giving the infusion, hospital re-ources, and patient safety monitoring (eg, renal function forome IV bisphosphonates).14

At present, there are limited cost-effectiveness data on theenefits of bisphosphonates.7,16 Comparative cost analyses oftudies are prevented by the use of multiple outcomes, differ-nces in measurement of outcomes, and variations in the studyuration or population.13,17 Economic assessment of bisphos-honate therapy is also complicated by factors such as drugricing differences between countries and variations in the costsf skeletal-related events. For instance, the costs of surgery andehabilitation for hip fracture have been reported as US$12,000n Italy and US$30,000 in the United Kingdom and Unitedtates.6,18 Although oral clodronate has been available for severalecades, no studies have specifically assessed its economic ef-ects on patients with breast cancer, although one analysis re-orted that clodronate might be cost-saving if hospital costs forkeletal complications were reduced by �20%.19 A retrospec-ive analysis of resource consumption for a 1-year, placebo-ontrolled randomized trial of clodronate also included a roughost-effectiveness estimate (based on a 9% increase in skeletalvent-free survival and 64-day delay in bone events) of €9000or preventing one patient from having a skeletal event in 1ear.20 An economic analysis of treatment in myeloma showedhat clodronate reduced the mean costs of skeletal events by0% but increased overall management costs by 17%, althoughhis extra cost did not take quality-of-life benefits into account.21

Economic evaluations of IV pamidronate therapy haveiven different results. In a simple decision analysis model,sing the clinical data from a large, 1-year, randomized, pla-ebo-controlled trial in Canada, pamidronate saved 55 qual-

ty-adjusted days at a cost of US$12,155.22 The authors con-

luded that this was a reasonable cost to the health careystem for the quality-adjusted survival benefit. However, aubsequent US study found that the much higher cost ofamidronate as compared with European prices increasedhe total costs of treatment, despite reducing expenditure onkeletal events.6 The incremental costs per adverse eventvoided were very high, and the cost-effectiveness ratios wereS$108,200/quality-adjusted life year (QALY) with chemo-

herapy and US$305,300/QALY with hormonal therapy. Inn economic analysis in Europe, the marginal cost-effective-ess of pamidronate was US$40,063/QALY with chemother-py and US$27,857/QALY with hormonal therapy.18

With its shorter infusion time, zoledronic acid treatmentay be more cost-effective than pamidronate. In an evalua-

ion of resources used in zoledronic acid and pamidronatereatment in patients with metastatic bone disease, althougholedronic acid 4 mg increased the availability of infusionhairs compared with pamidronate 90 mg, the health careosts remained similar.3 Therefore, while the rapid infusionf zoledronic acid allows more patients to be treated, it doesot necessarily lower patient costs.Eliminating hospital visits with oral bisphosphonates

ould improve cost-effectiveness, as indicated by the limitedlodronate data, although this would depend on the ambu-atory drug-acquisition cost. However, savings should in-rease dramatically once patients no longer need to visit hos-ital for chemotherapy. Pharmacoeconomic studies areurrently evaluating the cost-effectiveness of ibandronate. AsV ibandronate has no mandatory requirement for renalafety monitoring and could reduce adverse-event manage-ent, it might be more cost effective than other IV bisphos-honates. Oral ibandronate is also more likely to be cost-ffective than IV agents because it would remove the need forospital visits for infusions, which are the most expensivespect of IV bisphosphonate therapy.

onclusionatients with bone metastases and advanced breast cancerlready have a heavy disease burden, so it is important toake bisphosphonate therapy as simple and convenient asossible, while maintaining efficacy and limiting side effects.ntravenous ibandronate may have advantages over currentlysed agents (zoledronic acid and pamidronate); emergingata indicate that it can be infused over 15 minutes and there

s no mandatory requirement for renal function monitoring.his means IV ibandronate could shorten the time patientspend at the hospital or clinic, and it might help to reduce theonsiderable financial burden of therapy. Moreover, the sim-le dosing regimen of oral ibandronate could make treatmentore acceptable to patients, with a convenient at-home dos-

ng schedule. By removing the need for infusion manage-ent, this treatment could considerably improve the cost-

ffectiveness of bisphosphonate therapy.

eferences1. Coleman RE: Skeletal complications of malignancy. Cancer 80:1568-

1594, 1997 (suppl 8)

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3. DesHarnais Castel L, Bajwa K, Markle JP, et al: A microcosting analysisof zoledronic acid and pamidronate therapy in patients with metastaticbone disease. Support Care Cancer 9:545-551, 2001

4. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of ClinicalOncology 2003 update on the role of bisphosphonates and bone healthissues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003

5. Chang JT, Green L, Beitz J: Renal failure with the use of zoledronic acid.N Engl J Med 349:1676-1679, 2003

6. Hillner BE, Weeks JC, Desch CE, et al: Pamidronate in prevention ofbone complications in metastatic breast cancer: a cost-effectivenessanalysis. J Clin Oncol 18:72-79, 2000

7. Body JJ, Diel IJ, Lichinitser MR, et al: Intravenous ibandronate reducesthe incidence of skeletal complications in patients with breast cancerand bone metastases. Ann Oncol 14:1399-1405, 2003

8. Bell R, Diel IJ, Body JJ, et al: Renal safety of ibandronate in patients withbone metastases from breast cancer: phase III trial results. Eur J CancerSuppl 2:132, 2004

9. Body JJ, Lichinitzer M, Andreeva N, et al: Safety of an intravenous (i.v.)loading dose of ibandronate followed by daily oral dosing in metastaticbone disease: results of an open-label study [abstract 735]. Proc Am SocClin Oncol 23:60, 2004

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