Originally published as JCO Early Release 10.1200/JCO.2003.05.147 on October 27 2003

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Combined Analysis of Two Multicenter, Randomized, Placebo-Controlled Studies of Pamidronate Disodium for the Palliation of Bone Pain in Men With Metastatic Prostate Cancer

Eric J. Small, Matthew R. Smith, John J. Seaman, Stephanie Petrone, Mildred Ortu Kowalski

From the University of California, San Francisco, San Francisco, CA; Massachusetts General Hospital, Boston, MA; and Novartis Pharmaceuticals, East Hanover, NJ.

Address reprint requests to Eric J. Small, MD, UCSF Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero St, A718, San Francisco, CA 94115; e-mail: smalle{at}medicine.ucsf.edu.

	ABSTRACT

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Purpose: Bone metastases occur in approximately 80% of patients with advanced prostate cancer. Pain is common in these patients. The purpose of this study was to evaluate the effect of an intravenous bisphosphonate, pamidronate disodium, on pain control in metastatic prostate cancer patients.

Patients and Methods: Two multicenter, double-blind, randomized, placebo-controlled trials were conducted in patients with bone pain due to metastatic prostate cancer, with disease progression after first-line hormonal therapy. Intravenous pamidronate disodium (90 mg) or placebo was administered every 3 weeks for 27 weeks. Efficacy was measured via self-reported pain score (Brief Pain Inventory), analgesic use, the proportion of patients with a skeletal-related event (SRE; defined as pathologic fracture, radiation or surgery to bone, spinal cord compression, or hypercalcemia), and a pilot quantitative measurement of mobility. Laboratory evaluations included serum prostate-specific antigen, interleukin-6, bone alkaline phosphatase, and urinary bone resorption markers.

Results: Results of the two trials were pooled. There were no sustained significant differences between the pamidronate and placebo groups in self-reported pain measurements, analgesic use, proportion of patients with an SRE, or mobility at week 9 or 27. Urinary bone resorption markers were suppressed in the pamidronate group compared with placebo.

Conclusion: Pamidronate disodium failed to demonstrate a significant overall treatment benefit compared with placebo in palliation of bone pain or reduction of SREs. Evaluation of more potent bisphosphonates in patients with prostate cancer is warranted.

	INTRODUCTION

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THE AMERICAN Cancer Society estimates that 189,000 new cases of prostate cancer will be diagnosed in the United States in 2002.¹ Prostate cancer remains the second most common cause of cancer mortality in US men, with an estimate that 30,200 deaths will be attributed to this disease in 2002.¹ Metastases to bone occur in approximately 80% of men with advanced disease,^2–4 and the majority of these patients experience bone pain.⁵ Therefore, controlling the pain associated with end-stage prostate cancer is a problem of major clinical importance. Narcotic analgesics, radiation therapy, and radiopharmaceuticals are mainstays of pain management in this population.^6,7 However, even with these modalities, pain management is often suboptimal. In addition, patients with advanced prostate cancer are at risk of vertebral instability and collapse, spinal cord compression, and pathologic fractures, all of which result in significant morbidity and decreased quality of life.

Bisphosphonates are effective inhibitors of osteoclast-mediated bone resorption and have demonstrated efficacy in the treatment of hypercalcemia of malignancy, osteoporosis, Paget’s disease of bone, and osteolytic bone metastases from breast cancer and multiple myeloma.^8–18 Osteoblastic bone metastases associated with prostate cancer are characterized by increased bone formation around tumor cell deposits, presumably as a result of bone growth factors produced by prostate tumors, such as transforming growth factor beta-2 and basic fibroblast growth factor, that cause increased bone formation.^19–22 However, a body of histomorphometric and biochemical evidence has shown that osteoblastic lesions are also associated with increased osteolysis and marked increases in bone turnover and that bone resorption markers are significantly elevated in patients with advanced prostate cancer.^23–28 These data provide a biologic rationale for the use of bisphosphonates in prostate cancer. Indeed, studies have shown that bisphosphonates can effectively decrease or normalize bone resorption markers in patients with advanced prostate cancer.^25,26,28,29

A number of studies have investigated the activity of bisphosphonates in the treatment of bone metastases associated with prostate cancer, with control of bone pain as the primary end point in most of these studies. Several small, open-label studies with clodronate, pamidronate disodium, and alendronate have suggested that bisphosphonates may effectively relieve bone pain in patients with advanced prostate cancer,^29–35 although the effects were transient in some patients.

Stabilization or regression of bone lesions has also been reported in some patients treated with bisphosphonates.^29,30 However, the results of these studies have not been confirmed in randomized, placebo-controlled trials. In randomized trials with etidronate and clodronate, no significant clinical benefit was demonstrated with respect to palliation of bone pain.^36–40

Pamidronate disodium (Aredia; Novartis Pharmaceuticals AG, Basel, Switzerland) is a second-generation nitrogen-containing bisphosphonate that has demonstrated efficacy in three large, international, phase III trials in patients with bone metastases from breast cancer and multiple myeloma.^{8,9,12–14,18} In uncontrolled studies, pamidronate disodium has been shown to reduce bone pain in patients with prostate cancer. In a small, single-arm trial (n = 25), Clarke et al²⁹ reported that pamidronate disodium (30 mg intravenously [IV] weekly for 4 weeks, then twice per month for 5 months) relieved bone pain in 11 (65%) of 17 patients with pain at baseline. Similar results were also obtained in a dose-ranging, phase II trial conducted in 58 patients with advanced (stage D2) prostate cancer. Patients received varying doses of pamidronate disodium (30, 60, or 90 mg) every 2 or 4 weeks for 3 months. Treatment was well tolerated and resulted in a reduction from baseline pain scores in all dose groups.⁴¹ Based on these preliminary trials, two randomized, phase III trials of similar design were carried out to further explore the efficacy of pamidronate disodium for the reduction of bone pain and analgesic use in patients with advanced prostate cancer.

	PATIENTS AND METHODS

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Two separate multicenter, randomized, double-blind, placebo-controlled trials (trials INT-05 and CGP 032) were conducted concurrently to evaluate the efficacy and safety of pamidronate disodium for the treatment of bone metastases in patients with advanced-stage prostate cancer. INT-05 was an international trial; CGP 032 was conducted in the United States.

Patients
Inclusion and exclusion criteria in these two trials were nearly identical. Men age 18 years, with prostate cancer, skeletal or bone metastases confirmed by central radiology review, and bone pain secondary to bone metastases were eligible. All patients had a life expectancy of 6 months and had developed progressive systemic disease despite androgen deprivation, as evidenced by progression of metastatic disease in bone or extraskeletal sites (an increase in serum prostate-specific antigen [PSA] was not considered a sufficient indication of disease progression). Patients with WBC count 3 x 10⁹ cells/L, platelet count less than 50 x 10⁹/L, serum creatinine 5.0 mg/dL, corrected serum calcium 11.0 mg/dL or 8.4 mg/dL, magnesium 0.9 mg/dL, or total bilirubin more than 2.5 mg/dL were excluded. Similarly, patients with untreated brain metastases, prior bisphosphonate therapy (> 3 doses or treatment within 90 days of randomization), clinically significant abnormal ECG, ascites, impending spinal cord compression or spinal orthosis, or a skeletal event (pathologic fracture, radiation or surgery to bone) within 1 month before randomization, were not eligible. Patients were also not eligible if they changed their chemotherapy or hormone therapy regimen within 6 weeks before randomization (protocol 032 only). Drugs or therapies that affected osteoclast activity (eg, calcitonin, gallium nitrate, or other bisphosphonates) were not allowed. Standard radiation therapy to treat extraskeletal and/or skeletal tumor sites, including strontium-89 and samarium-153, was allowed during the trial. After randomization, patients were permitted to receive subsequent hormonal therapy or chemotherapy, as clinically indicated. Drugs not expected to affect osteoclast activity were allowed. Corticosteroids to treat spinal cord compression or for other recognized indications, such as prevention of treatment-related nausea and vomiting, were also allowed. All patients provided informed written consent.

Treatment
Patients were randomly assigned to receive pamidronate disodium (90 mg admixed in 250 mL 5% dextrose) or placebo (250 mL 5% dextrose) via 2-hour IV infusion every 3 weeks for 27 weeks (9 visits). Before infusion, the IV line was flushed with 10 mL normal saline, and separate lines were used to prevent mixture with other drugs or with calcium-containing solutions, such as Ringer’s lactate. Consenting patients were provided open-label treatment after week 27.

Efficacy Assessments
The primary objective of the two studies was to determine if there was a reduction in pain or analgesic use associated with 90 mg pamidronate disodium compared with placebo. Pain was measured via a self-administered numeric rating scale (part of the Brief Pain Inventory [BPI]).⁴² The BPI pain assessment is based on an 11-point scale (0 to 10) on which 0 represents no pain and 10 represents pain as severe as can be imagined. The "least," "average," and "worst" pain since the last visit were recorded at visits 1 through 11. Analgesic use was self-recorded daily and assigned oral morphine equivalents (OME)^43,44 before analysis. The primary assessment of efficacy for the combined studies was the difference in worst pain score from baseline (visit 2) to week 9 (visit 5). A secondary preplanned analysis of pain in a subset of patients with decreasing or stable analgesic use was conducted at the completion of the trial at 27 weeks.

Secondary efficacy assessments included the proportion of patients with a skeletal related event (SRE) at weeks 9 and 27, skeletal morbidity rate (SMR), defined as the ratio of the number of SREs divided by the time on trial (at 9 and 27 weeks), and a pilot quantitative measurement of mobility. An SRE was defined as hypercalcemia (corrected serum calcium 12.0 mg/dL), a pathologic fracture (vertebral or nonvertebral), requirement of radiation therapy to bone for pain relief or to treat or prevent fractures or spinal cord compression, surgery to treat or prevent fractures, spinal cord compression, or need for a spinal orthotic brace (trial INT-05 only). Radionuclide bone scans using technetium-99 and skeletal surveys were performed at baseline and final visit. The quantitative measurement of mobility included the number of seconds required to walk 10 feet and the number of steps required to make a 360 degree turn to the left.⁴⁵ Laboratory evaluations included serum PSA, interleukin-6 (IL-6), and markers of bone resorption including serum bone alkaline phosphatase and excretion of hydroxyproline, calcium, pyridinoline, deoxypyridinoline, and N-telopeptide. Disease progression was assessed by disease stage, clinical manifestations, and pain. All patients were monitored for safety purposes throughout the duration of the trial.

Statistical Analysis and End Points
The primary efficacy variable was change from baseline pain scores and was summarized by frequencies and percentages. An analysis of covariance for the change in pain was used with baseline pain score as covariate and with treatment and centers as factors; 95% CIs for the difference between the two treatments were also determined. The primary analysis was performed at 9 weeks or with the last nonmissing postbaseline assessment (ie, last observation carried forward).

Secondary efficacy assessments were performed at visit 5 (9 weeks) and at 27 weeks (final visit) and also using the last nonmissing postbaseline assessment (ie, last observation carried forward). The SMR was described and summarized by frequency and percentages. An analysis of covariance was used with baseline assessment as a covariate and treatment and centers as factors. The 95% CI for the difference between the two treatments was also reported.

The sample size for the primary and secondary efficacy analyses at 9 weeks was calculated based on the primary efficacy variable (change from baseline average pain score). The sample size was determined based on 90% power to detect an expected treatment difference of 3 points and a standard deviation of 4 points on the BPI scale, using a two-sided t-test with a significance level of 0.05 and a dropout rate of 20%. A total sample size of 92 randomly assigned patients (46 per treatment group per study) was necessary for the primary analysis. The sample size calculated based on the secondary efficacy variable (SMR for any SRE at 27 weeks) was determined based on 80% power to detect an expected treatment difference of 1.38 ± 4.5, with a two-sided significance level of 0.05 and allowing for a dropout rate of 20%. A sample size of 398 randomly assigned patients (199 per group per study) was deemed necessary. However, because full enrollment was not achieved in either trial and because extending the enrollment would have delayed completion and analysis of the results, a decision was made to pool the data from the two trials.

Treatment groups in each individual trial and the pooled database were compared for baseline prognostic factors using an analysis of variance model with treatment and center as factors for continuous variables and the Cochran-Mantel-Haenszel test controlling for center for categoric variables.

All analyses are based on the pooled data set. The design of the trials and case report forms were nearly identical. In those few instances where the case report forms differed in nonefficacy variables, the data were categorized to the less discrete variable reported for both trials.

	RESULTS

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Patients
A total of 378 patients were randomly assigned in both studies between February 3, 1998, and November 9, 1999. International trial INT-05 enrolled 138 patients at 30 sites, and US trial CGP 032 enrolled 240 patients at 46 sites. Of the total 378 patients, 374 patients received study drug and were included in the safety analysis (180 patients in the pamidronate group and 194 patients in the placebo group). Because of protocol violations, 350 patients were included in the intent-to-treat efficacy analysis (169 patients in the pamidronate group and 181 patients in the placebo group). For assessment of pain and analgesic use, 147 patients in the pamidronate group and 154 patients in the placebo group were assessable at 9 weeks; 110 and 108 patients were assessable in the respective treatment groups at 27 weeks. A summary of patient disposition is presented in Table 1. The majority of patients received all scheduled infusions of study drug; 166 patients(92%) in the pamidronate group and 164 patients (85%) in the placebo group completed three infusions of study drug over 9 weeks. Furthermore, 104 patients (57%) in the pamidronate group and 97 patients (50%) in the placebo group received all nine infusions of study drug during 27 weeks. However, the most common reasons for discontinuation (death, adverse events, and unsatisfactory therapeutic effect) were the same for both treatment groups (Table 1). The treatment groups in each individual study and the pooled data set were well balanced for age, baseline pain score, past history of SREs, baseline OME score, baseline mobility, time from diagnosis of cancer to bone metastasis, time since diagnosis of bone metastasis, number of anticancer therapies, and level of study-drug exposure. Of the 374 patients included in the safety analysis, 373 had undergone prior androgen deprivation. The use of prior androgen deprivation could not be confirmed in one patient on INT-05. Data on prior chemotherapy was available from the US trial (CGP 032): 46 (40%) of 114 patients on the pamidronate arm and 53 (43%) of 122 patients on the placebo arm had received prior chemotherapy. Demographic and baseline disease characteristics by treatment group are summarized in Table 2. While similar eligibility criteria were used for the two studies, comparability of the two patient groups cannot be assumed. However, the characteristics cited in Table 2 were similar in both studies.

To explore the effect of pamidronate on patients with varying degrees of pain at baseline, separate analyses of change from baseline worst pain score were performed on patients with mild (BPI 0 to 3), moderate (BPI 4 to 7), and severe (worst; BPI 8 to 10) pain at baseline. These retrospective analyses were performed on data at 9 and 27 weeks. Overall, no consistent treatment effects, regardless of OME use, were found in any of these subgroups. Patients with mild pain at baseline showed only a minor change from baseline pain score at 9 and 27 weeks, and the difference between treatment groups was not statistically significant. Among patients with moderate pain at baseline and stable analgesic use, pamidronate-treated patients had a statistically significant reduction in pain compared with placebo (P = .004) at week 9, but this difference was not maintained at 27 weeks. Only a small number of patients had severe pain at baseline and maintained stable analgesic use throughout the trial; therefore, these results are not reported.

There was also no difference between treatment groups in the proportion of patients with an SRE. At week 9, 12% of patients in the pamidronate group and 11% of patients in the placebo group had an SRE. At week 27, 25% of patients in each treatment group had an SRE. The most common SREs were radiation to bone for pain relief, radiation to treat or prevent fractures, and pathologic fractures (Table 4). The SMR was also similar between treatment groups. Moreover, there were no significant differences in change from baseline in mobility measurements for either treatment group to week 9 or week 27.

Mean serum levels of PSA and IL-6 increased from baseline in both treatment groups, whereas mean bone alkaline phosphatase levels decreased slightly in the pamidronate group and remained fairly stable in the placebo group (data not shown). All urinary markers of bone resorption decreased from baseline in the pamidronate group but increased or remained the same over time in the placebo group. N-telopeptide, the most sensitive and bone-specific marker of bone resorption, decreased by nearly 50% from baseline values in the pamidronate group (mean N-telopeptide/creatinine ratio was reduced from 188 nmol bone collagen equivalents [BCE]/mmol at baseline to 97 nmol BCE/mmol at 9 weeks) and remained suppressed throughout the duration of the trial.

Safety
Overall, pamidronate disodium was well tolerated. The percentages of patients who reported 1 adverse event, any serious adverse event, or treatment discontinuation due to an adverse event were similar for the pamidronate and placebo groups. The most frequently reported adverse events in both treatment groups were bone pain, nausea, anorexia, and fatigue (Table 5), and the majority of adverse events were mild to moderate in severity. The most common grade 3 or 4 adverse events were bone pain, nausea, vomiting, anemia, and dyspnea. No change from mean baseline serum creatinine was observed in either treatment group. There were 22 deaths in the pamidronate group and 26 deaths in the placebo group, primarily due to progressive disease.

View this table: [in this window] [in a new window]   Table 5. Adverse Events Occurring in 10% of Patients in Any Treatment Group

	DISCUSSION

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Before these trials, the largest randomized study of a bisphosphonate in patients with prostate cancer was reported by Elomaa et al.³⁶ That trial randomly assigned 75 patients receiving estramustine therapy to receive either oral clodronate (n = 36) or placebo (n = 39). The investigators reported that one third of patients treated with oral clodronate (3200 mg/d for 1 month followed by 1600 mg/d maintenance) were pain free and that 38% of clodronate-treated patients discontinued analgesics compared with 18% of placebo-treated patients, but this difference did not reach statistical significance because of the small sample size. Although several uncontrolled trials have shown that first- and second-generation bisphosphonates, including etidronate, clodronate, and pamidronate disodium, reduced bone pain in patients with advanced prostate cancer, no randomized, placebo-controlled trial has demonstrated a statistically significant clinical benefit associated with these agents.^{29,30,32–35} Perhaps the failure of those trials stems, in part, from the choice of end points. Pain is a subjective end point that may be confounded by the placebo effect, thereby compromising the power of these trials to detect a statistically significant difference. There are also various causes of pain. To what extent a patient’s pain is due to tumor-induced osteolysis, proinflammatory cytokines, or mechanical forces, such as spinal instability or nerve entrapment, is difficult to assess. Although bisphosphonates inhibit bone resorption and may inhibit the release of cytokines,⁴⁷ it is not known to what extent bisphosphonates may affect pain associated with inflammatory mechanisms. Of note, levels of IL-6 were not reduced by pamidronate disodium in the present trials.

Pamidronate disodium also showed no clinical benefit relative to placebo with respect to secondary efficacy end points, such as the proportion of patients with an SRE. This objective end point has been shown to be statistically conservative⁴⁸ and is supported by the American Society of Clinical Oncology guidelines on the role of bisphosphonates in breast cancer.⁴⁹ Despite biochemical evidence that bone resorption was inhibited by pamidronate disodium, in this pooled data set, this did not appear to correspond to a reduction in the proportion of patients with a pathologic fracture or with the need for radiation therapy.

By contrast, a recently completed trial of a third-generation bisphosphonate demonstrated a significant reduction in skeletal morbidity in patients with advanced prostate cancer.⁵⁰ Zoledronic acid, a new, highly potent, nitrogen-containing bisphosphonate, was investigated in a randomized, placebo-controlled trial in patients with advanced hormone-refractory prostate cancer. Zoledronic acid has been shown to be several orders of magnitude more potent than pamidronate disodium in preclinical models of bone resorption.⁵¹ In the zoledronic acid trial, patients had a mean baseline PSA less than 300 ng/mL and mean baseline BPI pain score of approximately 2. (Notably, approximately 25% of patients had no bone pain at study entry). In contrast to the results presented here for pamidronate disodium, treatment with 4 mg zoledronic acid resulted in a 25% relative reduction in the proportion of patients with an SRE at 15 months and delayed the median time to first SRE by more than 4 months compared with placebo.⁵⁰ Zoledronic acid also consistently reduced bone pain compared with placebo throughout the trial.

These findings suggest either that pamidronate disodium does not have sufficient activity in prostate cancer patients with bone metastases or that the patients enrolled had such advanced skeletal disease that bisphosphonate therapy was ineffective. (Of note, patients enrolled in this trial had a mean baseline PSA > 400 ng/mL and an average BPI pain score > 4). In general, it appears that first- and second-generation bisphosphonates have limited activity in prostate cancer patients with osteoblastic bone metastases. It is possible that a more potent agent or perhaps earlier intervention would have greater efficacy in this setting.

In summary, pamidronate disodium has not demonstrated an overall treatment benefit compared with placebo in patients with advanced prostate cancer and painful bone metastases. Treatment with 90 mg pamidronate disodium did not lower pain scores in the intent-to-treat patient population compared with placebo at either 9 weeks or 27 weeks. Moreover, no reduction in SREs was observed in the pamidronate disodium group compared with placebo. Because of the substantial morbidity and erosion of quality of life associated with bone metastases, effective bisphosphonate therapy has long been pursued for patients with advanced prostate cancer. It appears, however, based on the available evidence, that first- and second-generation bisphosphonates have limited activity in this setting.

	APPENDIX

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	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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	ACKNOWLEDGMENTS

 
We acknowledge the contributions of all the investigators who are members of the Aredia Prostate Cancer Group (see Appendix), as well as Ming Zheng, PhD, who conducted the exploratory analyses and supported completion of this article.

	NOTES

 
Supported by Novartis Oncology, East Hanover, NJ.

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Submitted May 21, 2002; accepted May 28, 2003.

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