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Breast Cancer

Long-term Efficacy and Safety of Pamidronate Disodium in Treatment of Bone Metastases in Breast Cancer
Li-jun Di, Jun Ren, Ying Yan, Feng-ling Wan, Guo-gong Song, Jing Yu

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, China CLC number: R737.9, R730.53 DOI: 10.1007/s11670-009-0109-5 Document code: A Article ID: 1000-9604(2009)02-0109-06

ABSTRACT
Objective : To evaluate the long-term efficacy and safety of pamidronate disodium in patients with bone lesions secondary to advanced breast carcinoma. Methods: A retrospective chart review was conducted of 62 patients receiving intravenous pamidronate disodium for metastatic breast cancer. The proportion of patients experiencing at least one skeletal related event (SRE) after 12 months of therapy was determined. Results: The proportion of patients who had an SRE was 29.00% (18 individuals) and the median time to first event was greater than 350 days. Radiotherapy(11 individuals)and pathologic fracture(6 individuals)were the most frequent type of SRE, while cord compression(1 individuals) and hypercalcaemia(0 individuals) were rare. A total of 37 individuals had transient hypocalcaemia without any clinical symptom. No significant creatinine abnormalities were encountered. There were no clinically relevant changes of calcium ,phosphate and creatinine before and after therapy. Conclusion: Long-term treatment with pamidronate disodium significantly reduces and delays skeletal morbidity from osteolytic metastases . Prolonged therapy was well tolerated. This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. Key words: Pamidronate disodium, Skeletal related event, Bone metastases, Breast cancer

INTRODUCTION The skeleton is the most common site of metastatic disease and the most common site of first distant relapse in breast cancer. Metastasis to the skeleton occurs in approximately 65% 75% of patients with advanced breast cancer[1]. Bone metastases are associated with considerable skeletal morbidity, including severe bone pain that may require strong narcotics or palliative radiation therapy, pathologic fracture, spinal cord or nerve root compression, and hypercalcemia of malignancy
Received: Nov. 21, 2008; Accepted: Feb. 18, 2009 * E-mail: dilijun2006@Yahoo.com ** Corresponding author. E-mail: renjun9688@yahoo.com

(HCM), which can substantially reduce the quality of life and survival[2,3]. Randomised controlled studies have consistently demonstrated that the skeletal complications of metastatic breast cancer can be reduced and prevented by the regular administration of intravenous bisphosphonates[4,5]. To the knowledge of the investigators, there has been little report of the outcomes of patients receiving bisphosphonates outside the conduct of a clinical trial. 11 MATERIALS AND METHODS Study Cohort Sixty two women with Stage IV breast cancer

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and osteolytic metastases were included in this study. They had commenced intravenous pamidronate disodium for the prophylaxis or treatment of skeletal complications between November 1998 and June 2008. Relevant clinical information as well as the details of pamidronate disodium usage was recorded on each person for a period of more than 12 months from the time of commencement of bisphosphonate therapy. Patients were treated with a fixed dose of sodium pamidronate, 90/60 mg in more than 3 h infusion every 4 weeks to 5 weeks. The primary outcome measure used in this study was the proportion of patients experiencing at least one skeletal related event (SRE )in a 12 month period following the commencement of intravenous pamidronate disodium therapy. SRE were defined as either a pathological fracture, a bony lesion requiring intervention (surgery or radiotherapy) for pain or prevention of skeletal complications, spinal cord compression or hypercalcaemia (a serum calcium concentration above 12 mg per deciliter [3.0 mmol per liter] or elevated to any degree and requiring treatment)of malignancy. The total number of SRE did not include events occurring within 30 days of commencement of intravenous bisphosphonate therapy if they were related to the index presentation of bony disease. Simultaneous SRE (i.e. presenting on the same day) were counted as one event. Treatment of a single lesion with radiotherapy and surgery wasnot coded as separate SREs. Criteria for bone tumor response were based on plain radiography (XR), CT, MRI, or ECT every 6 month. Criteria as follows: (1) Complete response (CR): disappearance of all lesions on bone scan for at least 4 weeks. (2) Partial response(PR): decrease in the number ,the volume and the intensity of the lesions for at lease 4 weeks; (3) Stable disease(SD): no change in the number or the intensity of the bone metastases); and (4) Progressive disease(PD): increase in the volume of the lesions or detection of more than one new lesions. Statistical Analysis Descriptive statistics were used to define the characteristics of the samples and Kaplan-Meier (KM) estimates were used to calculate the proportion with an SRE. The KM technique was used to estimate the time from commencement of bisphosphonate administration to the first SRE. The Wilcoxon Sign-Rank Test was used to compare the changes in biochemical markers between before and after pamidronate disodium therapy. Crosstabs was determined using the x2 test. All data was analyzed using SPSS statistical software V15.0.

RESULTS Patient Characteristics and Pamidronate Disodium Administration The baseline clinical characteristics of the study cohort are shown in Table 1. The median follow-up time was 2.44 years(1.00-7.12 years). At initiation of bisphosphonates therapy the mean age of the group was 53.109.95 years and 9 individuals(14.52%) were more than 65 years. Most patients (82.3%) had multiple bone metastases. Common sites of bone lesions were vertebrate(73.6%), sternum and/or ribs (56.5%), pelvis(35.5%), long bone(12.9%), and cranium (12.9%). Thirty two individuals(51.6%) had only bone lesions without extra-osseous disease before the therapy of bisphosphonate. On average, skeletal disease had developed 4.313.06 years from the primary diagnosis of breast cancer, and most individuals had no chemotherapy or hormone therapy before the commencing of bisphosphonates. Twelve individuals had used to have at least one SRE before the commencing of bisphosphonates(8 individuals once, 3 individuals twice, 1 individual three times). The duration of bisphosphonates of the study cohort are shown in Table 2.Bisphosphonate therapy was commenced at a mean of 62115 days from the time of diagnosis of bone metastases and the duration of bisphosphonate therapy at a mean of 31.2517.50 months. Over the total duration of follow-up a mean of 29.2915.55 cycles of IV bisphosphonate were received, with an upper range of 68 cycles. Thirty two individuals(51.6%) had been treated with bisphosphonates more than 24 months, and 4 individuals more than 60 months. Bisphosphonates were commenced concurrently with chemotherapy and hormone therapy in 69.4% of the patients, only with hormonal therapy in 9.7% of the patients, and only with chemotherapy in 21% of the patients. The reasons for discontinuation of bisphosphonates within the fallow-up observation period were cancer death (13 patients); intolerance (0 patient) or not specified (1 patient). A significant number of patients remained on therapy despite being close to death from cancer progression. In the 13 patients who died within the study period, the time from last documented bisphosphonate infusion to death was between 1 and 125 days with a median of 53 days. Skeletal Complications The proportion of patients experiencing at least one SRE within 12 months of commencing bisphosphonates was 29% (18 individuals). The characteristics of these events, and the proportion

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of patients experiencing them, are described in Table 3. Spinal cord compression and surgery were rare events, occurring in only 1.6% of individuals within the first 12 months. The median time to the first occurrence of a SRE was greater than 365 days (Figure 1). Within the 12 month observation period, two of 18 individuals developed a second SRE. One individual developed a third SRE, and one a fourth SRE within 12 months of starting bisphosphonates. The median cycle from the commencing of bisphosphonates to the first SRE was 7 and 12 individuals had administrated at least 6 cycles before the first SRE. Median survival from start of bisphosphonates for all patients was 767 days, for patients with bone metastases only 1320 days, and for patients with extra-osseous metastases 692 days.

Figure 1. Kaplan-Meier estimates of the time to first skeletal related event from the date of first intravenous bisphosphonate infusion.

Table 1

Disease characteristics of patients N Percent ( ) 85.48 14.52 51.6 9.7 3.2 14.5 21.0 17.7 82.3 73.6 56.5 35.5 12.9 12.9 Table 2. The duration of pamidronate disodium administration The duration(month) 12 23 24 35 36 47 48 59 More than 60 months Total N 30 11 8 9 4 62 Percent( ) 48.4 17.7 12.9 14.5 6.5 100

Age 65 years 65 years Sites of extra-osseous disease None Liver Only Lung Only Other Multiple Number of bone lesions Single Multiple Sites of bone lesions Vertebrate Sternum and/or ribs Pelvis Long bone Cranium Treatment prior to bisphosphonates None Chemotherapy +/- hormone Hormone therapy alone SRE prior to bisphosphonates * Radiotherapy Pathological fracture Cord compression Treatment alone with bisphosphonates Hormone therapy alone Chemotherapy alone Chemotherapy+hormone

53 9 32 6 2 9 13 11 51 45 35 22 8 8

Table 3. Proportion of patients having each type of SRE in the first 12 months of intravenous bisphosphonate therapy(n=62) Proportion with event (%) Radiotherapy 11 * 17.7 Pathological fracture 6 9.7 Cord compression 1 1.6 Surgery 1 1.6 * 1 patient had two kinds of SRE, including radiotherapy and Type of SRE n pathological fracture.

54 3 5 9 2 2

87.1 4.8 8.1 14.5 3.2 3.2

Skeletal Lesions Response The response of bone lesions in 50 individuals could been evaluated. Most patients(58.1%) showed PD, and almost had new bone lesions. PR or CR was rare. Interestingly, the cumulative proportion of individuals developing a SRE within the first year of commencing bisphosphonates was comparable, about one third (Table 4). All patients with PD continued same bisphosphonates treatment, and did not change any other bisphosphonates.

6 13 43

9.7 1.0 9.4

112 Table 4. The skeletal lesions response at the end of first 12 months and SRE in patients with different response Responses n(%) SRE situation At least one SRE No SRE Proportion with event in the same response( %) 12(33.33) 24 3(30.00) 7 1(33.33) 2 0)0) 1 2(16.67) 10 18(29.00) 44

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significant difference between subjects commencing the therapy less than one month and the remainder of the cohort in the proportion of subjects with an SRE in the first 6 months (P=0.475). This data suggest that with the first 6 months of bone metastases, patients have more benefit with the earlier commencing of the bisphosphonate. Safety The laboratory values were determined at the end of the first 12 months and the last fallow-up. There were no clinically relevant changes in calcium analyses, phosphorus analyses, or kidney function tests for these patients receiving long-term bisphosphonate treatment(Table 5). The treatment was well tolerated. In 37 patients (37/62, 59.68%) a transient hypocalcemia was observed. In detail, 29 patients (46.7%) was grade I, 5 patients (8.1%) grade II, 1 patient(1.6%) grade III, and 2 patients(3.2%) grade IV. All the hypocalcemia was reversible and without any clinical symptom. Four cases (6.4%) of hypophosphatemia and no case of renal insufficiency were registered.

PD SD PR CR Unknown Total

36(58.1) 10(16.1) 3(4.8) 1(1.6) 12(19.4) 62(100)

On the other hand, bisphosphonate therapy was commenced less than one month from the time of diagnosis of bone metastases in 42 patients, more than one month in 20 patients. Interestingly, in the less than one month cohort, the cumulative proportion of individuals developing a SRE within the first 6 months of bone metastases was 26.19% (11 of 42 patients), and in the more than one month cohort 35% (7 of 20 patients). But there was no statistically

Table 5. Laboratory values at baseline and after bisphosphonate therapy

Study Entry No Calcium(mmol/L) Phosphorus(mmol/L) Creatinine(mmol/L) 51 50 49 12 months after Range 2.02-2.62 0.78-1.60 44-106 No 54 54 54 Last fallow-up No 62 62 62

x s
2.310.14 1.270.20 67.8814.28

x s
2.310.17 1.270.22 67.4616.22

Range 1.99-2.59 0.67-1.70 34-127

P 0.969 0.857 0.451

x s
2.320.18 1.230.27 66.0317.77

Range 1.91-2.76 0.41-1.8 34-124

P 0.426 0.952 0.638

DISCUSSION Hortobagyi et al[6] evaluated the efficacy of treatment with pamidronate disodium including 380 individuals.The median time to the occurrence of the first skeletal complication was greater in the pamidronate group than in the placebo group (13.1 vs. 7.0 months, P =0.005), and the proportion of patients with any skeletal complication was lower (43% vs. 56%, P =0.008). In conclusion, monthly infusions of pamidronate can protect against skeletal complications in women with stage IV breast cancer who have osteolytic bone metastases. The results of three other randomized clinical trials are comparable to the former study[4,5,7]. But the proportion of SREs in the current study(29%) are different from the results of these randomized controlled trials of intravenous bisphosphonates. In these latter studies, the proportion of individuals who experienced at least

one skeletal complication at 12 months from bisphosphonate commencement was 40%-50% in the treatment arm compared with 50%-60% in the placebo arm. We propose that the discrepancy between the results of the randomized controlled studies and our current audit relates primarily to the use of regular radiographic skeletal surveys in the trial setting . In practice, skeletal events are only identified on the basis of clinical suspicion and thus many bone lesions may be undetected and untreated. That is intensive exposure to skeletal surveys may result in the treatment of lesions which may never become clinically significant. On the other hand, the baseline population risk of a skeletal event is a further factor which may explain the discrepancies between the current audit and the results of previous randomized controlled studies. Patients with metastatic disease limited to bone are more likely to have pathologic fracture than those with concurrent solitary and bony

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metastases[8] . The percentage of individuals with metastatic disease limited to bone was 51.6% in current audit, but 60%-70% in these randomized clinical trials[4-6] . Liauw and Trinkaus also reported that the rate of clinically relevant SREs was substantially lower than the event rate observed in phase III clinical trials. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilization of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice[9,10]. Interestingly, patients who developed a SRE, most had more than 6 cycles of bisphosphonates. The use of these agents is hindered by a lack of data concerning drug scheduling, duration of use, indications for initiation and cessation. Just as the American Society of Clinical Oncology(ASCO) guidelines, Most patients of this audit remained on bisphosphonates except a declining performance status or poor tolerance[11] . The opinions as to whether bisphosphonates should be continued after progression of bony metastases are poor university. It is clear from the data reported by a survey oncologists (51.3%) continued the same bisphosphonates even when the patients had progressive bony metastases[12]. All patients in this audit continued the same pamidronate disodium. The optimal time for initiating bisphosphonates was under issue. Some experts would suggest that patients start with BP in the setting of newly diagnosed bone metastases along with chemotherapy and/or hormonal therapy[13]. In current study, the proportion of SREs within the first 6 months from the bone metastases was lower in patients who started bisphosphonates less than one month, although there was no statistically significant difference. As reported, infusion of bisphosphonates can cause electrolyte abnormalities. Although published data from clinical trials is often limited, in patients with bone metastasis from breast cancer, pamidronate clearly increases the incidence of hypocalcemia and hypophosphatemia compared with placebo. In the study of Major et al[14], hypocalcemia was most common during treatment of bone metastasis. About half of patients had hypocalcemia. In this audit, hypocalcemia is also the most common adverse effect. More than a half patients had with transient and reversible hypocalcemia. Further more, there was no statistically significant difference among the values taken before pamidronate, at the end of the first 12 months, and at the last fallow-up. The risk of renal failure is directly related to the drug infusion time and dosage. Using the recommended infusion time and dosage, the incidence of renal impairment was 9%-10% of patients[15] .

Previous treatments with bisphosphonates, advanced age, and multiple cycles of therapies increases the risk, but safe treatment beyond 7 years (68 cycles) has been reported in this audit. There were some old patients(more than 65 years) and some patients with long duration of bisphosphonates treatment in this study, but no case had renal impairment. Other rare adverse effect, such as osteonecrosis of the maxilla, nephrotic syndrome, or ocular complications, were not reported in this study for the reason of small sample size. In this small clinical practical cohort study, we reported the actual proportion of SRE in breast cancer patients with bone metastases. We hope the findings of this study provide an additional impetus to proceed with post-marketing evaluation of the use of bisphosphonates in clinical practice. REFERENCES
[1] [2] Coleman RE. Skeletal complications of malignancy [J]. Cancer 1997; 80(8 suppl):1588-94 Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies [J]. Cancer Treat Rev 2001; 27:165-76. Coleman RE. Efficacy of Zoledronic Acid and Pamidronate in Breast Cancer Patients: A Comparative Analysis of Randomized Phase III Trials [J]. Am J Clin Oncol 2002; 25(6 Suppl 1): s25-31. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group [J]. J Clin Oncol 1998; 16: 203844. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group[J]. J Clin Oncol 1999; 17: 84654. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group [J]. N Engl J Med 1996; 335:1785-91. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials[J]. Cancer 2000; 88:1082-90. Plunkett TA, Smith P, Rubens RD. Risk of complications from bone metastases in breast cancer. Implications for management[J]. Eur J Cancer 2000; 36: 476-82.

[3]

[4]

[5]

[6]

[7]

[8]

114 Liauw W, Segelov E, Lih A, et al. Off-trial evaluation of bisphosphonates in patients with metastatic breast cancer[J]. BMC Cancer 2005; 5: 89 [10] Trinkaus ME, Simmons C, Myers J, et al. Skeletalrelated events (SREs) in patients with bone metastases from breast cancer treated with intravenous(i.v.) bisphosphonates (BPs) in the nontrial setting[J]. Am Soc Clin Oncol 2008; Abstract No.1120. [11] Hillner BE, Ingle JN, Chelebowski RT, et al. American Society of Clinical Oncology 2003 Update on the role of bisphosphonates and bone health issues in women with breast cancer[J]. J Clin Oncol 2003; 21: 404257. [12] Verma S, Kerr-cresswell D, Dranitsaris G, et al. Bisphosphonate use for the management of breast [9]

www.springerlink.com/Chin J Cancer Res 21(2):109-114, 2009 cancer patients with bone metastases: a survey of Canadian Medical Oncologists[J]. Support Care Cancer 2004; 12: 8528. [13] Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel [J]. J Clin Oncol 2000; 18:1378-91. [14] Major PP, Coleman RE. Zoledronic acid in the treatment of hypercalcemia of malignancy: results of the international clinical development program[J]. Semin Oncol 2001; 28(2 Suppl 6): 1724. [15] Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates [J]. Ann Oncol 2006; 17: 89790.