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Perspectives
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sumab (17%) compared to those receiving zoledronic acid (12%) (P=0.009).
In the USA we can calculate the cost of the drugs to Medicare by using the average sales price (www.cms.gov). This accounts for discounts and rebates and is a close esti- mate of the cost to Medicare. The patent for zoledronic acid expired in 2013, at which point the reimbursement cost decreased. The average sales price for 4 mg of zole- dronic acid is $48 and that for 120 mg of denosumab is $2044. The annual cost is therefore $576 for zoledronic acid, and $24,528 for denosumab – a difference of almost $24,000. In addition to this cost there is a mark-up of 4.3% that Medicare reimburses to providers. It should be noted that this mark-up may provide a financial incentive to the physician to prescribe the more expensive medica- tion, despite the higher cost to the patient and insurer. Finally, treatment centers also charge an infusion cost of approximately $140, billed with code 96413 (www.cms.gov). While these are the costs to Medicare, we must also recognize that the patient often shares a sig- nificant proportion of the cost. In 2015, the average annu- al Medicare beneficiary cost share was $527 for deno- sumab and $68 for zoledronic acid (www.cms.gov - 2015 Medicare drug spending data). The price of drugs is dif- ferent in other countries around the world; however, it is clear that everywhere in the world zoledronic acid is sig- nificantly cheaper than denosumab. This commentary is not intended to assess what was the most appropriate launch price of these drugs at the very different times of their being launched. The purpose is to discuss the most appropriate choice of therapy in 2018, when the prices are significantly different, due to one of the options being available in the significantly cheaper, generic form.
There is some additional convenience from using deno- sumab. Firstly, denosumab can be given subcutaneously which may be preferable to the intravenous administra- tion of zoledronic acid. Secondly, denosumab is dosed the same for all patients, and no adjustment is needed accord- ing to renal function, whereas dose adjustments are nec- essary for zoledronic acid. It is doubtful however, that this additional convenience justifies the additional annual cost in the USA of $24,000 per patient.
Recent data for zoledronic acid demonstrate equivalent efficacy in patients with bone metastases secondary to breast cancer, irrespective of whether the drug is given monthly or every 3 months.8 Could these data perhaps be extrapolated to patients with multiple myeloma? There are currently no good quality data regarding the use of denosumab every 3 months in patients with neoplastic bone disease.
In an era of financial challenges for healthcare, we, as physicians, must be careful stewards of finite healthcare resources. There appears to be no benefit from using denosumab instead of zoledronic acid in terms of overall
survival or skeletal events. In addition, the safety profile is very similar. There appears to be slightly more renal toxicity with zoledronic acid; however, this is balanced by the higher rates of hypocalcemia with denosumab. Although there was a demonstration of benefit in terms of progression-free survival, this finding should be treated with caution, as it emerged from a post hoc exploratory analysis. There are, however, significant differences in costs – both to society and to patients. Denosumab costs approximately $24,000 more per patient per year in the USA. Zoledronic acid is also considerably cheaper than denosumab in Europe as well. Perhaps the most appropri- ate management would be for all patients to receive zole- dronic acid, except those with a contraindication due to a low creatinine clearance. The reason for the high cost of new cancer drugs is complex. Without doubt, one of the many reasons is that the cost of drug development is high, partially related to the many regulatory require- ments. However, while cancer is still often an incurable disease, we must strive towards bringing forward new therapies that provide clinically meaningful benefits to our patients.9 In an era of medical bancruptcies and increasing healthcare costs, we owe it to both our patients and society to incorporate costs into clinical deci- sion-making.
References
1. RajeNS,RoodmanGD,WillenbacherW,etal.Impactofdenosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease. J Clin Oncol. 2017;35(15_suppl):8005.
2. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in post- menopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821-831.
3. Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48(4):677- 692.
4. Stopeck AT, Lipton A, Body J-J, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132-5139.
5. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resis- tant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-822.
6. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of deno- sumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14(9):901-908.
7. Raghav KP, Mahajan S, Yao JC, et al. From protocols to publications: a study in selective reporting of outcomes in randomized trials in oncology. J Clin Oncol. 2015;33(31):3583-3590.
8. Hortobagyi GN, Van Poznak C, Harker WG, et al. Continued treat- ment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: the OPTIMIZE-2 randomized clinical trial. JAMA Oncol. 2017;3(7):906-912.
9. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277- 1280.
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