© 2005 Foundation for Promotion of Cancer Research
A Multicenter and Open Label Clinical Trial of Zoledronic Acid 4 mg in Patients with Hypercalcemia of Malignancy
1 Department of Oncology/Hematology, National Cancer Center Hospital East, Kashiwa, Chiba, 2 Department of Internal Medicine and 8 Department of Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, 3 Department of Medical Oncology, National Cancer Center Hospital, Tokyo, 4 Department of Breast Oncology, Saitama Cancer Center, Kitaadachi-gun, Saitama, 5 Department of Internal Medicine, National Hospital Organization Nishigunma National Hospital, Shibukawa, Gunma, 6 Department of Palliative Care Unit, Shakaihoken Kobe Central Hospital, Kobe and 7 Department of Chemotherapy, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
For reprints and all correspondence: Hironobu Minami, Department of Oncology/Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577 Japan. E-mail: hminami{at}east.ncc.go.jp
Received May 10, 2004; accepted October 19, 2004
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Background: Hypercalcemia of malignancy is a serious complication of cancer. The objective of this study was to investigate the efficacy and safety of zoledronic acid, a new-generation bisphosphonate and the most potent inhibitor of bone resorption identified to date, for hypercalcemia of malignancy in Japanese patients.
Methods: Patients with hypercalcemia of malignancy, defined as an albumin-corrected serum calcium level 
12.0 mg/dl, were treated with a single dose of zoledronic acid, 4 mg, by 15 min infusion. Clinical end-points included the proportion of patients with complete response, which was defined as a decrease of corrected serum calcium 
10.8 mg/dl by day 10, and time to relapse, which is defined as the duration in days between the date of infusion and last available corrected serum calcium <11.6 mg/dl.
Results: Twenty-seven patients were enrolled in this study and 25 patients were evaluable for the efficacy of zoledronic acid. The mean corrected serum calcium level decreased from 14.5 to 9.6 mg/dl by day 10. The complete response rate was 84%. The median time to relapse was 23 days, ranging from 0 to 56 days. The most frequently observed adverse event was fever (38°C). Electrolyte abnormalities suspected to be drug related including grade 3 or 4 hypocalcemia, hypophosphatemia and hypokalemia were observed in 11 patients; however, all patients were asymptomatic. No serious adverse events associated with renal toxicity were reported.
Conclusions: Zoledronic acid is well tolerated and is effective for hypercalcemia of malignancy in Japanese patients.
Key Words: bisphosphonate • hypercalcemia • zoledronic acid
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Hypercalcemia of malignancy (HCM) is among the most common and most serious complications of malignancy in the late stage. It occurs in 5–10% of all cancer patients at some point during the course of their disease, frequently in patients with cancer of the lung, breast, kidney, or head and neck, and adult T-cell leukemia. The early symptoms of HCM are mild and can be difficult to distinguish from symptoms of the underlying disease or the side effects of cancer therapy. If left untreated, it can progress rapidly and may become life-threatening. Patients who develop HCM generally have a short life expectancy, ranging from weeks to months (1). Treatment of HCM is important considering its life-threatening nature and symptoms such as anorexia, nausea, polyuria, confusion and coma.
Bisphosphonates are potent inhibitors of bone resorption and are the most effective therapy for HCM. Bisphosphonate compounds can be divided into two distinct pharmacological classes with different mechanisms of action depending on whether they contain a nitrogen atom in their side chains (2). Non-nitrogen-containing bisphosphonates, which are first-generation bisphosphonates, including etidronate and clodronate, are metabolized intracellularly to cytotoxic, non-hydrolyzable analogs of ATP that may inhibit ATP-dependent intracellular enzymes in osteoclasts (2). Nitrogen-containing bisphosphonates, which are second- or third-generation bisphosphonates including pamidronate, alendronate and ibandronate, inhibit protein prenylation, which leads to loss of membrane localization of small G proteins such as Ras, Rho and Rac. Consequently, osteoclasts may undergo apoptosis (2). They are more potent than the first-generation bisphosphonates and have been used for the treatment of HCM.
Zoledronic acid (ZOMETA; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a newer nitrogen-containing bisphosphonate that has been shown in preclinical studies to be more potent than currently available bisphosphonates including pamidronate. Zoledronic acid was 850-fold more effective than pamidronate in inhibiting the induction of hypercalcemia in rats, and 100-fold more potent than pamidronate in inhibiting calcium release in an in vitro calvaria assay (3).
Zoledronic acid at doses of 2, 4 and 8 mg/body was well tolerated in a phase 1 study for Japanese cancer patients with bone metastases (4). This phase 1 study also demonstrated that 4–8 mg of zoledronic acid was more effective with respect to suppressing markers of bone resorption than the lower dose, suggesting that these dose levels might be more potent to inhibit osteoclast activity.
For treating HCM, randomized, controlled clinical studies were conducted in the USA, Canada, Australia and European countries to compare the efficacy and safety of zoledronic acid and pamidronate (5). The complete response rate and time to relapse among patients treated with zoledronic acid 4 or 8 mg were superior to those among patients treated with pamidronate 90 mg, while maintaining a similar safety profile. Zoledronic acid at a single dose of 4 mg was nearly as effective as 8 mg, and the differences between the two doses were not statistically significant. Therefore, zoledronic acid at a single dose of 4 mg was recommended and has been approved for treatment of HCM in many countries since 2000.
A multicenter study was conducted to investigate the efficacy and safety of zoledronic acid in Japanese patients with HCM.
|
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
This clinical study was conducted at seven hospitals in Japan between July 2001 and May 2002. The institutional review boards of the study hospitals approved the protocol. Written informed consent was obtained from each patient before participation in the study; however, if the patient was in a severe diminished state of consciousness due to HCM, written consent could be obtained from a relative such as the patient's spouse. In that case, the patient's informed consent to continue in the study was obtained after his/her level of consciousness was improved.
PATIENTS
Patients aged 20 years and older with histological or cytological confirmation of cancer and hypercalcemia, defined as an albumin-corrected serum calcium (CSC) 12.0 mg/dl, were eligible. The CSC was calculated by the following formula: CSC (mg/dl) = patient's measured serum calcium (mg/dl) + 0.8 x [mid-range serum albumin of each institutional laboratory standard (g/dl) – patient's measured albumin (g/dl)]. Patients who had a history of allergic reaction to bisphosphonates or who had been treated with bisphosphonates for HCM within 3 months of study entry were excluded, as were patients who exhibited serum creatinine >4.5 mg/dl or who were treated with calcitonin within 72 h of study entry. Patients who were treated with newly initiated antineoplastic cytotoxic chemotherapy or hormonal therapy 6 days before or 10 days after the initial administration of this study drug, or with any investigational drugs within 1 month of study entry were also excluded. Additional exclusion criteria were for patients who were severely dehydrated, could not tolerate intravenous hydration, or suffered from hyperparathyroidism, adrenal insufficiency, vitamin D intoxication, milk alkali syndrome, sarcoidosis or other granulomatous disease, or multiple endocrine neoplasia syndromes.
TREATMENT
Patients were treated with a single dose of 4 mg of zoledronic acid via a 15 min intravenous infusion followed by hydration with 500 ml of saline over 2 h. Then patients were followed-up for 56 days or until relapse defined as CSC11.6 mg/dl. Patients who were refractory to the initial therapy or who relapsed within 56 days after the initial treatment could be re-treated with a single dose of 4 mg of zoledronic acid and followed-up for 28 days or until relapse.
ASSESSMENT OF SAFETY AND EFFICACY
Efficacy was assessed by the CSC level, which was measured on days 4, 7, 10, 14, 17, 21, 24 and 28, and weekly thereafter up to day 56. Efficacy was also assessed by improvement of the symptoms of HCM on days 4, 7, 10 and 56. The improvement of symptoms, i.e. depressed level of consciousness, anorexia, nausea, vomiting, fatigue and mouth dryness, was defined as an improvement in the grade as evaluated according to the National Cancer Institute's Common Toxicities Criteria version 2 in comparison with those before treatment.
Safety was evaluated by clinical findings, adverse events, vital signs, routine blood chemistries, hematological values and urinalysis. The severity of adverse events was graded according to the National Cancer Institute's Common Toxicities Criteria version 2.
STATISTICAL METHODS
The determination of the sample size was based on the proportion of patients achieving a complete response (CR), which was defined as a decrease of CSC below 10.8 mg/dl by day 10, using Fleming's single-stage procedure. The CR rate representing a level of activity of definitive interest was considered to be 85% as expected from the efficacy of zoledronic acid 4 mg reported by Major et al. (5). A minimal threshold response rate was considered to be 60%, based on the CR rate of pamidronate 45 mg in three previous Japanese clinical trials for treatment of HCM (in-house data of Novartis). Thus, the required sample size was calculated to be 25, based on a hypothesis of an anticipated efficacy rate of 85%, threshold efficacy rate of 60%, alpha = 0.05 (two-sided) and beta = 0.2.
Primary analysis was based on the CR rate by day 10. The proportions of patients who achieved a CR by day 4 and/or day 7 were also evaluated. The change from baseline in CSC was also assessed at days 4, 7 and 10. For patients with missing CSC values, the last CSC observation available was carried forward. The time to relapse was defined as the number of days from the date of study drug infusion to the date of the last CSC <11.6 mg/dl. All patients who did not achieve a CR had their time to relapse set to zero and were not censored. Patients who died after a CR was achieved but before documentation of relapse were assumed to have relapsed on the day the last CSC was obtained. All other complete responders who discontinued or completed the study without documented relapse were censored on the last day on which CSC was obtained. Duration of CR was calculated using rules similar to time to relapse, except that the duration was based on the day of onset of the CR rather than the start date of the infusion. Duration of CR was calculated only for the subset of patients who had a CR. Time to relapse and duration of CR were estimated by the Kaplan–Meier method.
The impact of the baseline CSC (13.6 or <13.6 mg/dl), with or without bone metastases, cancer type (breast/myeloma or other) and the parathyroid hormone-related protein (PTHrP, 2.0 or >2.0 pmol/l) on whether the patient achieved a CR was analyzed by Fisher's exact test. Log rank test was also used to analyze the impact of the above-mentioned demographic factors on the time to relapse.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
CHARACTERISTICS OF THE PATIENTS
Twenty-seven patients were enrolled in the study and 26 patients were treated with zoledronic acid. One patient withdrew his consent before study drug infusion. Table 1 lists the characteristics of the treated patients. Half of the patients (13 out of 26) had a poor performance status of 3 or 4, and 24 patients had symptoms associated with HCM. Twenty-one out of 26 patients had an elevated (>2 pmol/l) PTHrP at baseline. As one patient died due to progressive disease without any CSC values after administration of the study drug, this subject could not be included in the efficacy analysis.
|
CR RATE AND TIME TO RELAPSE
The primary efficacy variable, CR rate by day 10, was 84% [95% confidence interval (CI), 63.9–95.5%] (Fig. 1). Approximately half of patients treated with zoledronic acid reached CR by day 4.
|
The CSC level decreased in all patients after zoledronic acid treatment (Fig. 2). Finally, four out of 25 patients did not achieve CR; however, their CSC levels decreased to
11 mg/dl including a patient whose CSC was lowered by >5 mg/dl from baseline. The mean CSC level decreased from 14.5 mg/dl before treatment to 9.6 mg/dl on day 10. The mean (±SD) change in CSC level from day 1 (baseline) to days 4, 7 and 10 was –3.30 (±1.63), –4.67 (±1.84) and –4.89 mg/dl (±1.97), respectively.
|
The median time to relapse was 23 days, ranging from 0 (not CR) to 56 days (95% CI, 16–29 days). In patients who achieved CR, the median duration of CR was 22 days (95% CI, 11 to >56 days).
EFFICACY ACCORDING TO SELECTED SUBGROUP
The CR rate and time to relapse were compared between patients with a baseline CSC of 13.6 or <13.6 mg/dl, with or without bone metastases, with breast/myeloma or other cancer types and with PTHrP 2.0 or >2.0 pmol/l (Table 2). Although there were only five patients with the lower value, there was a significant difference in time to relapse according to the baseline PTHrP (P = 0.004).
|
CLINICAL SYMPTOMS ASSOCIATED WITH HCM
Clinical symptoms associated with HCM, including depressed level of consciousness, anorexia, nausea, vomiting, fatigue and mouth dryness, improved in accordance with decreasing CSC level. The proportions of patients in whom each symptom was improved at day 10 were 88.9% (eight out of nine), 68.2% (15 out of 22), 64.7% (11 out of 17), 75.0% (three out of four), 66.7% (14 out of 21) and 64.7% (11 out of 17), respectively.
RE-TREATMENT WITH ZOLEDRONIC ACID
Seven patients who relapsed within 56 days after having achieved a CR and one patient who did not achieve a CR to the initial treatment were re-treated with a 4 mg dose. The mean baseline CSC before the re-treatment was 12.8 mg/dl (range, 11.7–15.2), while it was 15.3 mg/dl (range, 12.4–18.4) before the initial treatment in these eight patients. After re-treatment with a 4 mg dose, four patients achieved a CR by day 10, including the patient who did not achieve a CR to the initial treatment. These patients were not documented as relapsed until death or the end of study except for the patient with non-CR to the initial treatment, who had increased CSC at day 8 after re-treatment.
SAFETY
Safety was evaluated in all 26 treated patients. Zoledronic acid 4 mg was well tolerated. Adverse events with which a causal relationship with the study drug could not be ruled out are listed in Table 3. The most frequently observed adverse event was fever (38°C). Electrolyte abnormalities suspected to be drug related including grade 3 or 4 hypocalcemia, hypophosphatemia and hypokalemia were observed in 11 patients; however, all patients were asymptomatic. Grade 4 pulmonary edema, as a serious adverse event, was observed 2 days after the first administration of zoledronic acid in a patient with lung cancer who had lymphangitis, pleural effusion and pericardial effusion before the therapy. The pulmonary edema might have been related to the primary cancer and/or hydration, but a causal relationship to infusion of zoledronic acid could not be ruled out completely. No serious adverse events associated with renal toxicity were reported.
|
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
This study demonstrated the calcium-lowering effect and safety of zoledronic acid in the treatment of HCM in Japanese patients. The CSC level decreased in all patients after zoledronic acid treatment, and 84% of the patients became normocalcemic by day 10. The CR rate of our study was similar to that of large randomized studies of zoledronic acid in patients with HCM reported by Major et al. (84 versus 88%) (5) on the same eligibility and response criteria.
In the above studies by Major et al., subgroup analysis indicated zoledronic acid 4 mg to be equally effective with regard to the CR rate independent of a patient's demographics, such as baseline CSC, PTHrP, presence of bone metastases and cancer type. Although the subgroup analysis of CR rate in this Japanese trial showed some variation, our observation seemed to be comparable considering that the number of patients in each subgroup was small.
Our study demonstrated shorter time to relapse than reported by Major et al. (median, 23 versus 30 days). Duration of CR demonstrated the same tendency (median, 22 versus 32 days). The reason for the difference in duration of response might be due to a difference in patient demographics between these studies. Although the background of the patients including tumor type, sex, age and CSC at baseline were similar, the frequency of elevated (>2 pmol/l) PTHrP in our study was higher than that in the studies by Major et al. (80 versus 23%). Time to relapse was shorter in patients with high PTHrP levels than in patients with low levels. Considering PTHrP is accompanied by enhancement of kidney re-absorption of calcium and activation of osteoclasts, the higher proportion of patients with high PTHrP levels in our study may explain the shorter time to relapse and CR duration compared with the study by Major et al.
It is also noteworthy that the calcium-lowering effect of zoledronic acid 4 mg was retained even if patients had an elevated PTHrP level; nevertheless, it was reported that bisphosphonates such as pamidronate and ibandronate were less effective in reducing the serum calcium level in patients who had a higher PTHrP level (6–10). This important property is presumably due to the more potent pharmacological activity of zoledronic acid.
Currently, pamidronate, incadronate and alendronate are available for treatment of HCM in Japan. Although incadronate and alendronate have not been compared directly in clinical studies, available data indicate that zoledronic acid is more effective. For instance, a single recommended dose of incadronate 10 mg yielded normalization of calcium in 58% of patients with mean initial CSC of 14.2 mg/dl in a Japanese dose response study with HCM (11); and single doses of 5, 10 or 15 mg of alendronate resulted in an overall normalization rate of 74% and a time to relapse of 15 days with an initial CSC of 11.5 mg/dl (12).
The safety profile of zoledronic acid was similar to that of other bisphosphonates. The most frequent adverse events occurring in this study, i.e. transient fever and abnormality of electrolytes, were typical of bisphosphonates as a class. The incidence of these adverse events was generally within the expected range from the previous pamidronate trials (13). Although urinary laboratory abnormalities, such as urinary ß2 microglobulin and hematuria, were reported, no clinically relevant symptoms were observed. No patient developed grade 3 or 4 serum creatinine changes. Bisphosphonates, however, have been associated with impairment of renal function. The risk of renal dysfunction with zoledronic acid was also reported in cancer indications necessitating repeated dosing, but was similar to pamidronate (14). Monitoring of renal function therefore should be routine practice, particularly when patients have underlying or concomitant illnesses associated with renal function impairment. HCM constitutes a potentially life-threatening condition, thus serum creatinine levels of up to 4.5 mg/dl were accepted as baseline level at study entry.
In conclusion, zoledronic acid at a dose of 4 mg is well tolerated, and it effectively induces durable reduction in the corrected serum calcium level and improves the symptoms of HCM in Japanese patients.
|
Notes |
|---|
9 Present address: International University of Health and Welfare, 8-5-35 Akasaka, Minato, Tokyo, Japan
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
1 Ralston SH, Gallacher SJ, Patel U, Campbell J, Boyle IT. Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med 1990;112:499–504.
2 Russell RGG, Rogers MJ, Frith JC, Luckman SP, Coxon FP, Benford HL, et al. The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res 1999;14:53–65.
3 Green JR, Muller K, Jaeggi KA. Preclinical pharmacology of CGP42446 a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994;9:745–51.[Web of Science][Medline]
4 Saeki T, Sasaki Y, Itoh K, Igarashi T, Minami H, Fujii H, et al. Zoledronate: phase I and pharmacokinetics/pharmacodynamics study in cancer patients. Bone 2000;26:41S (abstract).
5 Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558–67.
6 Rizzoli R, Thiebaud D, Bundred N, Pecherstorfer M, Herrmann Z, Huss HJ, et al. Serum parathyroid hormone-related protein levels and response to bisphosphonate treatment in hypercalcemia of malignancy. J Clin Endcrinol Metab 1999;84:3545–50.
7 Body JJ, Dumon JC, Thirion M, Cleeren A. Circulating PTHrP concentrations in tumor-induced hypercalcemia: influence on the response to bisphosphonate and change after therapy. J Bone Miner Res 1993;8:701–6.[Web of Science][Medline]
8 Pecherstorfer M, Schilling T, Blind E, Zimmer-Roth I, Baumgartner G, Ziegler R, et al. Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients. J Clin Endcrinol Metab 1994;78:1268–70.[Abstract]
9 Wimalawansa SJ. Significance of plasma PTH-rP in patients with hypercalcemia of malignancy treated with bisphosphonate. Cancer 1994;73:2223–30.[CrossRef][Web of Science][Medline]
10 Blind E, Raue F, Meinel T, Wuster C, Ziegler R. Levels of parathyroid hormone-related protein (PTHrP) in hypercalcemia of malignancy are not lowered by treatment with bisphosphonate BM 21.0955. Horm Metab Res 1993;25:40–4.[Web of Science][Medline]
11 Matsumoto T, Takebe K, Ishii J, Nagata N, Onaya T, Tomita A, et al. Dose–response study of YM175 for treatment of malignancy-associated hypercalcemia. Rinsho to Kenkyu 1994;71:3263–80 (in Japanese).
12 Nussbaum S, Warrell P, Rude R, Glusman J, Bilezikian J, Stewart A, et al. Dose–response study of alendronate sodium for the treatment of cancer associated hypercalcemia of malignancy. J Clin Oncol 1993;11:1618–23.
13 Houston S and Rubens R. The tolerability and adverse event profile of pamidronate disodium. Rev Contemp Pharmacother 1998;9:213–24.
14 Ibrahim A, Scher N, Williams G, Sridhara R, Li N, Chen G, et al. Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases. Clin Cancer Res 2003;9:2394–9.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||