Denosumab for Bone Pain in Metastatic Breast Cancer
April 1, 2013 5 minutes read
Denosumab for Bone Pain in Metastatic Breast Cancer
Abstract & Commentary
By Gary R. Shapiro, MD, Medical Director, Cancer Center of Western Wisconsin, New Richmond, WI. Dr. Shapiro reports no financial relationships relevant to this field of study.
Synopsis: Denosumab is more effective than zoledronic acid at preventing pain in women with advanced breast cancer and bone metastases. Although fewer denosumab-treated patients reported increased analgesic use from no/low use at baseline to strong opioid use, the time to pain improvement and the time to decreased pain interference with daily activities were similar between those using denosumab and zoledronic acid.
Source: Cleeland CS, et al. Pain outcomes in patients with advanced breast cancer and bone metastases: Results from a randomized, double-blind study of denosumab and zoledronic acid. Cancer 2013;119:832-838.
This randomized, double-blind, double-dummy Phase 3 study was designed to compare the effect of denosumab with zoledronic acid on pain due to breast cancer bone metastases. None of the women in this international study of 2046 women with breast cancer and radiographic evidence of one or more bone metastases had received prior intravenous or oral bisphosphonates for the treatment of bone metastases. Eligible patients were randomized to receive either a monthly subcutaneous injection of denosumab 120 mg and intravenous placebo or subcutaneous placebo and a monthly intravenous infusion of zoledronic acid 4 mg (with appropriate dose adjustments for renal function). Patients completed the Brief Pain Inventory-Short Form at baseline and monthly thereafter. The proportion of patients receiving hormonal treatment or chemotherapy for their breast cancer while on this study was balanced between the denosumab and zoledronic acid treatment groups.
The median time from initial diagnosis of bone metastases to randomization was 2 months, and approximately 33% of patients already had experienced a skeletal related event (SRE) by then. Approximately 53% of women in the denosumab group and 49% in the zoledronic acid group reported no or mild pain at baseline. Patients in both of these groups had worsening pain severity as the study progressed, but fewer women who received denosumab reported a clinically meaningful worsening from their baseline pain: 15% relative difference (5% absolute difference) with an almost 4-month delay (P = 0.002) in the median time to pain worsening to moderate or severe with denosumab (9.7 months) compared with zoledronic acid (5.8 months). Denosumab also delayed the time that it took for pain to interfere with daily activity (decreased pain interference) by 1 month compared with zoledronic acid (16.0 months vs 14.9 months, P = 0.09). The proportion of patients with meaningful improvement in their worst pain score was similar between the treatment groups, ranging from 26% at 1 month to 16% at 18 months for denosumab and from 26% at 1 month to 18% at 18 months for zoledronic acid. The median time to meaningful improvement in the worst pain score also was similar between the treatment groups, 2.7 months for denosumab and 2.8 months for zoledronic acid (P = 0.72). The time to meaningful decrease in pain interference was similar between the groups: denosumab 2.9 months, zoledronic acid 3.2 months (P = 0.92).
Compared to those in the zoledronic acid group, fewer denosumab-treated patients reported increased analgesic use from no/low use at baseline to strong opioid use (relative difference, 20%; absolute difference, 2%). Among patients who had no/low analgesic use at baseline, the median time to strong opioid analgesic use was not reached in the denosumab arm, and was 29.5 months in the zoledronic acid arm (P = 0.27).
Commentary
The majority of women with metastatic breast cancer eventually will develop bone metastases and are at risk for SRE such as pain, spinal cord compression, pathologic fractures, and hypercalcemia. Randomized clinical trials have demonstrated that bisphosphonates reduce SRE and pain associated with bone metastases,1 and that zoledronic acid may be superior to pamidronate in those with lytic breast cancer bone metastases.2
In 2010, Stopeck et al reported that denosumab was superior to zoledronic acid in preventing SREs in patients with breast cancer and bone metastases, and that women who are candidates for bisphosphonate therapy also should be considered for treatment with denosumab.3 Using data from that study, Cleeland et al examined the effect of these agents on pain outcomes: pain severity, analgesic use, and the degree to which pain interferes with common dimensions of feeling and function (pain interference). This is the first study to analyze how these agents affect the length of time until significant pain develops.
Cleeland et al found that denosumab was more effective at extending the time to significant increases in pain and pain-related functional interference as well as the time to first use of strong opioid analgesics compared with zoledronic acid, particularly among patients who had no or mild pain at baseline. Both agents had comparable levels of pain palliation.
Though both zoledronic acid and denosumab are extremely well tolerated, they have somewhat different side effect profiles. Hypocalcemia occurs more frequently with denosumab, and zoledronic acid causes more kidney-related problems and acute phase reactions. Osteonecrosis of the jaw is an infrequent risk of both (1-2%). The long-term risks of denosumab and the optimal duration of treatment are not known.
The subcutaneous route of denosumab administration is certainly an advantage over the zoledronic acid intravenous route, but its main benefit over zoledronic acid is that it delays the onset of cancer pain and pain-related functional interference. Consequently, these women, especially those with no or only mild pain at baseline, enjoy a prolonged period of pain control without suffering the side effects of the stronger opioid analgesics. One hopes that these important quality-of-life benefits also apply to those with bone metastases from other tumor types, but additional studies are needed before extrapolating these findings beyond breast cancer.
References
1. Rosen LS, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735-1744.
2. Rosen LS, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36-43.
3. Stopeck AT, 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;28:5132-5139.
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