ARTICLE

A Double-Blind, Placebo-Controlled, Randomized Trial of Oral Sodium Clodronate for Metastatic Prostate Cancer (MRC PR05 Trial)

David P. Dearnaley, Matthew R. Sydes, Malcolm D. Mason, Mark Stott, Christopher S. Powell, Anne C. R. Robinson, Peter M. Thompson, Leslie E. Moffat, Sharon L. Naylor, Mahesh K. B. Parmar, The MRC PR05 Collaborators

Affiliations of authors: D. P. Dearnaley, Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK; M. R. Sydes, S. L. Naylor, M. K. B. Parmar, Cancer Division, Medical Research Council (MRC) Clinical Trials Unit, London, UK; M. D. Mason, Section of Oncology and Palliative Medicine, University of Wales College of Medicine, Velindre Hospital, Cardiff, UK; M. Stott, Department of Urology, Royal Devon and Exeter Hospital, Exeter, UK; C. S. Powell, Department of Urology, Countess of Chester Hospital, Chester, UK; A. C. R. Robinson, Department of Oncology, Southend General Hospital, Southend, UK; P. M. Thompson, Department of Urology, Dartford and Gravesham National Health Service Trust, Dartford, Kent, UK; L. E. Moffat, Department of Urology, Aberdeen Royal Infirmary, Aberdeen, UK.

Correspondence to: Matthew R. Sydes, MSc, Cancer Division, MRC Clinical Trials Unit, London, NW1 2DA, UK (e-mail: pr05{at}ctu.mrc.ac.uk).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Background: The most frequent site of metastases from prostate cancer is bone. Bisphosphonates reduce excessive bone turnover while preserving bone structure and mineralization in patients with other tumor types. We conducted a double-blind, placebo-controlled, randomized trial to determine whether the first-generation bisphosphonate sodium clodronate could improve bone progression–free survival (BPFS) times among men with bone metastases from prostate cancer. Methods: Between June 1994 and July 1998, 311 men who were starting or responding to first-line hormone therapy for bone metastases were randomly assigned to receive oral sodium clodronate (2080 mg/day) or placebo for a maximum of 3 years. The primary endpoint of the trial was symptomatic BPFS. Secondary endpoints included overall survival, treatment toxicity, and change in World Health Organization (WHO) performance status. Time-to-event data were analyzed using the log-rank chi-square test and Kaplan–Meier curves. All statistical tests were two-sided. Results: Baseline characteristics were balanced across the two groups. After a median follow-up of 59 months, the sodium clodronate group showed statistically nonsignificant better symptomatic BPFS (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.61 to 1.02; P = .066) and overall survival (HR = 0.80, 95% CI = 0.62 to 1.03; P = .082) than the control group. Patients in the clodronate group were less likely to have a worsened WHO performance status (HR = 0.71, 95% CI = 0.56 to 0.92; P = .008). However, the clodronate group reported more gastrointestinal problems and increased lactate dehydrogenase levels and required more frequent modification of the trial drug dose (HR for any adverse event = 1.71, 95% CI = 1.21 to 2.41; P = .002). Results of subgroup analyses suggested that clodronate might be more effective the sooner after diagnosis of metastatic bone disease it is started. Conclusion: These results suggest that further studies of the effect of newer generation bisphosphonates on BPFS in men with metastatic prostate cancer are warranted.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Prostate cancer is the most commonly diagnosed malignancy among men in the United States and, after lung cancer, the second most commonly diagnosed cancer in the U.K. and the European Union. In 2000, a global estimate of the number of prostate cancer deaths per annum was 204 000 (1). Prostate cancer is the second most common cause of cancer-related deaths among European and North American men (1–3). Prostate cancer spreads preferentially to the skeleton, and at least 85% of men with advanced prostate cancer will have bone metastases (4,5). Standard therapy for metastatic prostate cancer is chemical or surgical castration, which gives good palliation in approximately 80% of patients and is associated with an overall median survival time of 30–36 months (6–8). Additional hormone manipulations or chemotherapy after failure of first-line hormonal treatment provide only modest benefits (9). Skeletal complications from the disease are very common and include bone pain, pathologic fracture, spinal cord compression and, more rarely, hyper- or hypocalcemia. External beam or isotope radiotherapy frequently achieve palliation, although skilled attention to analgesia and supportive care are required (4,7–9).

Bisphosphonate compounds have a common phosphorus–carbon–phosphorus backbone, which has affinity for bone through binding to hydroxyapatite crystals that localize preferentially to areas of increased bone resorption and regeneration. Many aspects of the mechanism of action of bisphosphonates remain uncertain and may differ among different compounds. However, treatment with bisphosphonates is associated with a reduction in the number and activity of osteoclasts, probably because of direct effects on osteoclast action and recruitment as well as indirect effects on osteoblasts and macrophages. Thus, the overall effect of bisphosphonate treatment is the reduction of excessive bone turnover with preservation of bone structure and mineralization (10,11). Bisphosphonates have become the standard treatment for management of malignancy-related hypercalcemia (12–14); they also have a role in the management of bone pain in cancer patients with bone metastases (15–17) and have been associated with a statistically significant reduction in skeletal complications in myeloma and breast cancer patients when given in addition to standard chemotherapy or hormonal treatment for metastatic disease (15,16,18). Some studies suggest that bisphosphonates may also influence the rate of development of bone metastases and favorably modify the natural history of certain malignancies (10,19–24).

Prostate cancer bone metastases differ from bone metastases associated with most other cancers in that they are usually sclerotic or osteoblastic. However, biochemical and histomorphometric evidence suggests that prostate cancer bone metastases, like those of myeloma and breast cancer, have an osteolytic component and that osteoclast activation in prostate cancer patients can be inhibited by bisphosphonates (25–28). We hypothesized that because bisphosphonates have been shown to reduce osteolysis in prostate cancer, these agents might favorably modify the natural history of the disease. In the early 1990s, two multicenter, placebo-controlled, randomized phase III trials of bisphosphonates in prostate cancer were initiated by the U.K. Medical Research Council (MRC) with support from Boehringer Mannheim (Lothian, U.K.). One of these phase III trials (PR05-ISRCTN38477744) enrolled prostate cancer patients with bone metastases who were just commencing first-line hormone treatment or were already responding to such treatment; the other trial (PR04-ISRCTN61384873) enrolled men with locally advanced prostate cancer who had negative bone scans. This article presents the results of the PR05 trial.


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Trial Design

The PR05 trial was coordinated from the MRC Clinical Trials Unit (CTU), London (formerly MRC Cancer Trials Office, Cambridge). The trial was designed according to MRC Good Clinical Practice guidelines (29) and abided by the Declaration of Helsinki. Appropriate ethical approval (from local and multicenter research ethics committees in the U.K.) was obtained. All patients gave written informed consent before participating. The trial was conducted under a Clinical Trials Marketing Product number from the Medicines Control Agency (London, U.K.) because the active regimen (Loron 520 tablets) was being used for something other than for its licensed indication. All clinicians were required to register with the MRC CTU prior to participating. Patients were recruited from 34 centers (33 in the U.K. and one in New Zealand).

Eligibility Criteria

Patients had to meet the following 10 criteria prior to randomization: commencing or showing a positive response to initial hormone therapy with orchidectomy, luteinizing hormone–releasing hormone analogs, cyproterone acetate, flutamide, or maximal androgen blockade; normocalcemia; World Health Organization (WHO) performance status (30) less than or equal to 2; no concomitant or previous use of bisphosphonates; serum creatinine level less than twice the upper limit of the local normal range; no other active malignancy within the past 5 years; no acute, severe inflammatory conditions of the gastrointestinal tract; no serious concomitant physical or psychiatric disease; no use of any investigational drug within 12 months of the first dose of study tablets (an investigational drug was defined as any material, including a placebo or an active drug substance, dispensed under the provisions of a clinical trials protocol); and no previous use of long-term hormone therapy.

Randomization and Treatment Allocation

Randomization was performed centrally at the MRC CTU. Treatment was allocated in a 1 : 1 ratio using the method of minimization over four stratification factors: treatment center, time since starting long-term hormone therapy (<=6 weeks versus 6 weeks), type of hormone therapy (monotherapy versus maximal androgen blockade), and WHO performance status.

Patients were randomly assigned to receive either oral sodium clodronate (active regimen) or a matching placebo (control regimen) in addition to standard hormone therapy for metastatic prostate cancer. The active regimen consisted of a daily dose of four Loron 520 tablets (520 mg of clodronate per tablet). The control regimen consisted of a daily dose of four placebo tablets that were identical to the Loron 520 tablets in size, shape, and color. Patients were instructed to "take four tablets each evening at least one hour before or after food with a little fluid, not milk." All study tablets were ordered by the MRC CTU and were distributed initially by Boehringer Mannheim and subsequently by Quintiles (Lothian, U.K.) on behalf of Roche (Welwyn Garden City, U.K.). No patient information, other than their drug number and hospital, was revealed to the pharmaceutical companies.

Treatment Schedules

Patients were to start trial medication as soon as they received it after randomization and to remain on trial medication for a maximum of 3 years after randomization. Patients were to stop taking the trial medication before the 3-year period was reached if they developed symptomatic bone metastases or experienced unacceptable toxicities.

It was anticipated from the drug datasheet compendium (31) that the most common adverse reactions among patients receiving the active regimen would be gastrointestinal upsets and increased lactate dehydrogenase levels. The trial protocol advised physicians about how to modify the dose in the event of toxicities, including reducing trial medication dose and temporarily ceasing trial medication, with the possibility of progressing to permanent cessation of trial medication if unacceptable toxicities continued.

Follow-Up and Monitoring of Patients

Patients were to be followed up at 6 weeks after randomization (after approximately 4 weeks on trial medication) to ensure that they were tolerating the trial medication. Patients subsequently returned for assessment at 3 months after randomization, then every 3 months until 2 years after randomization, and then every 6 months. At each follow-up visit, serum prostate-specific antigen (PSA) and alkaline phosphatase (AP) levels were measured and toxicities monitored. Bone scans were performed as clinically indicated. Adverse events were defined as events leading to modification in the dose of trial medication, hospitalization, prolongation of hospitalization, or death and were reported on an Adverse Events Case Report Form. Source data verification was performed on a random sample of patients in each center (10 patients or 20% of patients, whichever was greater). During 2001, U.K. patients who were still alive were flagged with the Office for National Statistics to ensure the collection of long-term mortality data.

Statistical Design and Analysis

The primary outcome measure of the trial was symptomatic bone progression–free survival (BPFS), which was defined as the time from randomization to the development of symptomatic bone metastases (i.e., the need to initiate further treatment) or to death from prostate cancer. The BPFS endpoint is similar to the "skeletal-related events" endpoint that has been used in other studies of bisphosphonates, except that the definition of the latter endpoint includes evidence of asymptomatic disease progression, e.g., progression of disease on bone scans and asymptomatic vertebral fracture. We chose BPFS as the primary outcome measure because it directly affects the patient with regard to his symptoms, is an important biologic indicator of treatment efficacy, and is likely to be used by the clinician as the point at which to initiate a new treatment approach. Symptomatic bone progression was defined as osseous disease requiring an increase in regular analgesic use, treatment with radiotherapy, or change in hormone therapy, or that was associated with a pathological fracture or spinal cord compression. Therefore, the definition of symptomatic bone progression was chosen for both pragmatic and practical reasons. We included prostate cancer death in our definition of the primary endpoint to avoid under-reporting symptomatic bone progression, which would likely have occurred before death.

The secondary outcome measures were overall survival, toxicity, rate of events affecting bone during the trial, type of progressive disease (bone versus non–bone), analgesic consumption, WHO performance status, and PSA and AP levels.

The trial was designed with 80% power to detect an 11% improvement in symptomatic BPFS (i.e., from 50% to 61%, corresponding to a hazard ratio of 0.71) at 2 years at the {alpha} = .05 level. We anticipated that 300 patients would have to be recruited to the trial over 3 years to provide the 126 events necessary to meet these specifications.

Throughout the trial, time to the outcome measures was defined as the time from randomization to the first confirmed report of an event for each patient. The time on trial medication was calculated as the time from randomization to the date of the first follow-up form reporting cessation of trial medication. Hazard ratios and 95% confidence intervals (CIs) were calculated using the log-rank expected values. Hazard ratios of less than 1.0 denote an advantage to the patients receiving the active regimen. Time-to-event analyses of the primary outcome measure and of overall survival, deterioration in WHO performance status, and increases in analgesic consumption were performed. Time to these events was compared by the log-rank test and plotted using Kaplan–Meier curves. The effect of treatment on WHO performance status was investigated by using time from randomization to a sustained worsening of WHO performance status, which was defined as worsening of WHO performance status from that at randomization by at least one grade and confirmed on the next visit, or death. Patients who had a worsened WHO performance status only on their most recent follow-up visit could not have that change confirmed. Therefore, such patients were censored at the time of their previous visit, when their WHO performance status had not yet deteriorated. The impact of treatment on WHO performance status was further investigated by using time to performance status score of 3 or worse (all patients had performance status scores of 0, 1, or 2 at randomization) in a time-standardized area-under-the-curve approach (32).

We also performed several exploratory analyses. First, we defined subgroups of baseline characteristics for which we determined, using chi-square tests for interactions, whether the effect of the active regimen on the primary outcome measure was different across subgroups. Second, we measured the levels of two blood markers, PSA and AP, to determine whether there were detectable biochemical effects of clodronate on prostate cancer and bone metabolism. In both analyses, subgroups of patients were defined retrospectively by examining the overall trial data. Subgroups were defined by trying to make even-sized groups or groups with clinically relevant boundaries. We used a time-standardized area-under-the-curve approach (32) to examine the effect of treatments on PSA levels after randomization. Because PSA levels tend to increase exponentially, we used the logarithms of the PSA values in the analyses. The time-standardized approach to the area-under-the-curve analysis was performed to allow for different patterns of follow-up among patients, although there was in fact little difference in follow-up patterns, given the constrained time period used for this analysis. Results of pre-randomization PSA tests were not included in the analysis because of heterogeneity in the length of time on hormone therapy at randomization. AP levels were analyzed by using both difference in and ratio changes in levels, adjusted by the local upper limit of the normal range, between the baseline level and the levels at 6 months and 12 months after randomization in a pair-wise fashion among patients for whom data at both time points were available.

All analyses were performed on an intent-to-treat basis unless otherwise specified. The analyses were performed with the use of SPSS version 10.1 (SPSS, Chicago, IL), Stata version 7 (Stata Corporation, College Station, TX), and SCHARP 3.1 (MRC Clinical Trials Unit, London, U.K.) statistical software. All statistical tests were two-sided.

Overseeing Committees

The management and practicalities of the trial were routinely reviewed by the Trial Management Group. Starting in 1999, the trial was also scrutinized by an independent MRC Trial Steering Committee.

Full, blinded interim analyses, including those of the primary and secondary outcome measures, were produced for an independent Data Monitoring and Ethics Committee (DMEC) on three occasions (July 1996, July 1997, and September 1999). No formal stopping rules were prespecified. No formal adjustment of P values was performed. The DMEC was to consider recommending stopping the trial only if the results were sufficiently convincing to a broad range of clinicians. At the first two reviews, the DMEC recommended continuation of trial recruitment. At the third review (after recruitment was completed), the DMEC advised waiting until more than the protocol-specified number of events had been reported before analyzing the trial data. The delay was proposed to increase the statistical reliability of the results. The Appendix lists the full membership of all committees.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Trial Recruitment and Protocol Compliance

Between June 1994 and July 1998, 311 patients from 33 U.K. centers and one New Zealand center (listed in the Appendix) were randomly assigned to receive either the active regimen (155 patients) or the control regimen (156 patients) (Fig. 1Go). All patients stopped taking trial medication by August 2001. The median follow-up was 59 months (interquartile range = 50–70 months). Of those patients reported alive at the last follow-up, 99% had been followed up for at least 3 years and 32% had been followed up for at least 5 years. The two trial groups were well-balanced in terms of their disease-related baseline characteristics, general well-being, and use of primary hormone therapy (Table 1Go).



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Fig. 1. Trial flow diagram (CONSORT diagram). Other reasons patients discontinued taking trial drugs prior to 3 years on trial medication are presented in Table 2Go.

 

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Table 1. Patient characteristics at randomization by allocated treatment*
 
The median time on trial medication was 17.1 months (interquartile range = 6.6–34.4 months) for patients in the active group and 16.1 months (interquartile range = 6.9–34.4 months) for patients in the control group. There was no evidence of a difference between trial groups regarding time on trial medication (hazard ratio = 1.08, 95% CI = 0.86 to 1.35; log-rank {chi}2(1 df) = 0.41; P = .52).

The reasons patients stopped taking trial medications are listed in Table 2Go. Five patients in the active group and four patients in the control group never started trial medication, including two patients in the active group who had disease progression, one fatally, before trial medication arrived at the hospital. More patients in the control group than in the active group stopped taking trial medication because of symptomatic disease progression, whereas more patients in the active group than in the control group stopped taking trial medication because of gastrointestinal toxicity.


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Table 2. Reasons reported for stopping trial medication by allocated treatment*
 
Primary Outcome Measure: Symptomatic BPFS

The primary outcome measure, symptomatic BPFS, was observed in 236 patients (112 patients in the active group and 124 patients in the control group). Patients more commonly reached this outcome measure through symptomatic bone progression (197 patients) than prostate cancer death (39 patients).

Comparison of the Kaplan–Meier curves for BPFS gave a hazard ratio of 0.79 (95% CI = 0.61 to 1.02) in favor of the active regimen ({chi}2(1 df) = 3.39; P = .066) (Fig. 2Go). This hazard ratio represents a 21% reduction (95% CI = –2% to 39%) in the risk of symptomatic bone progression or prostate cancer death for patients receiving the active regimen. The median time to event was 23.6 months for patients in the active group and 19.3 months for patients in the control group, an increase of 4.3 months (95% CI = 0.8 to 11.5 months) for the active group. BPFS at 2 years on trial was 49.3% for patients in the active group and 41% for patients in the control group. Thus, the absolute increase in BPFS among patients in the active group was 8% (95% CI = –1% to 18%).



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Fig. 2. Kaplan–Meier curves for symptomatic bone progression-free survival time from randomization by allocated treatment.

 
Secondary Outcome Measures

Overall survival. A total of 235 deaths were reported, 111 among patients in the active group and 124 among patients in the control group. Comparison of the Kaplan–Meier curves for overall survival in both treatment groups gave a hazard ratio of 0.80 (95% CI = 0.62 to 1.03; {chi}2(1 df) = 3.03; P = .082) in favor of the active regimen (Fig. 3Go). This hazard ratio represents a 20% reduction (95% CI = 38% reduction to 3% increase) in the risk of death for patients in the active group. Median overall survival was 37.1 months for patients in the active group and 28.4 months for patients in the control group, an increase of 8.7 months (95% CI = 3.3 to 14.2 months) for patients in the active group. The proportion of patients alive at 2 years was 66.5% in the active group and 60% in the control group, an absolute increase of 6.5% (95% CI = 1% decrease to 14% increase) for the active group.



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Fig. 3. Kaplan–Meier curves for overall survival time from randomization by allocated treatment.

 
Prostate cancer alone was the most common main cause of death in both treatment groups, accounting for 87 deaths among patients in the active group and 93 deaths among patients in the control group. Prostate cancer in combination with other causes was the main cause of death in four additional patients in the active group and 12 additional patients in the control group, bringing the total number of prostate cancer deaths to 91 (82%) and 105 (85%), respectively. These 196 patients were all considered to have had prostate cancer deaths for the purposes of analysis (Table 3Go).


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Table 3. Number of events and hazard ratios for symptomatic bone progression and death (from all causes, from prostate cancer, and from prostate cancer–involved causes) for each study group alone*
 
Prostate cancer was reported as a major contributory factor in more than 90% of the deaths reported, of 99 patients in the active group and 114 in the control group. These 213 patients were all considered to have had prostate cancer–involved deaths for the purposes of these analyses. Cardiac failure, with or without prostate cancer, was the second most common cause of death, accounting for 10 deaths in the active arm and eight deaths in the control arm (data not shown).

Table 3Go presents the hazard ratios for symptomatic bone progression and for death from any cause, from prostate cancer, from prostate cancer–involved causes, and from combinations of these causes. Although the hazard ratios were consistently in favor of the active regimen, none of the comparisons achieved statistical significance. Nevertheless, the magnitude of the benefit observed was relatively robust across these measures.

Type of progression. A total of 266 (86%) patients reported at least one event on trial that affected the course of their disease. The first disease events reported on trial are listed in descending order of frequency in Table 4Go. The most common first disease event in both study groups was symptomatic bone progression.


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Table 4. First disease event reported by allocated treatment*
 
Non–bone progression was the first disease event on trial in 20 patients in the active group and 14 patients in the control group (Table 4Go). An additional 20 patients developed non–bone progression after reporting a different first disease event, bringing the number of patients who explicitly developed non–bone progression during the trial to 54 (27 patients in the active group and 27 patients in the control group). For 19 patients (6 in the active group and 13 in the control group), non–bone progression was reported within 5 weeks of a BPFS event. Comparison of the Kaplan–Meier curves for time to non–bone progression in the two treatment groups gave a hazard ratio of 0.92 (95% CI = 0.54 to 1.58). This hazard ratio represents an 8% reduction (95% CI = 46% reduction to 58% increase) in the risk of non–bone progression in favor of the active group ({chi}2(1 df) = 0.084; P = .772). Among the 54 patients with non–bone progression, 29 patients (15 patients [52%] in the active group and 14 patients [48%] in the control group) had hormone therapy changed within 5 weeks (before or after) non–bone progression. In addition, among these 54 patients, 45 patients (20 patients [74%] in the active group and 25 patients [93%] in the control group) subsequently or simultaneously developed a BPFS event.

Treatment at progression. The first reported BPFS event in 36 patients (17 active group patients and 19 control group patients) was prostate cancer death. Of those patients who had treatment at the time of the first reported BPFS event, 105 patients were treated with radiotherapy (50 active group patients and 55 control group patients), 112 patients required analgesics (49 active group patients and 63 control group patients), and 73 patients changed hormone therapy (33 active group patients and 40 control group patients). Treatments and symptoms at or beyond progression were reported as follows: 146 patients were treated with radiotherapy (71 active group patients and 75 control group patients), 19 patients had pathologic fractures (8 active group patients and 11 control group patients), 34 patients had spinal cord compression (15 active group patients and 19 control group patients), and 24 patients were treated with additional bisphosphonates (15 active group patients and 9 control group patients).

Toxicity and adverse events. Table 5Go presents the most commonly reported adverse events. More active group patients than control group patients reported at least one adverse event (78 active group patients versus 53 control group patients), and more adverse events overall were reported for patients in the active group than for patients in the control group (123 events versus 82 events). Comparison of Kaplan–Meier curves for time to first adverse event gave a hazard ratio of 1.71 (95% CI = 1.21 to 2.41). This hazard ratio represents a 71% increase (95% CI = 21% to 141%) in the risk of adverse events for patients in the active group (log-rank {chi}2 = 9.31; P = .002).


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Table 5. Adverse events reported by allocated treatment*
 
We gauged the severity of an adverse event by examining whether it led to a modification of the dose of the trial medication. More active group patients than control group patients experienced a dose-modifying adverse event (54 events versus 20 events). Comparison of Kaplan–Meier curves for time to the first dose-modifying adverse event gave a hazard ratio of 2.81 (95% CI = 1.78 to 4.44) (Fig. 4Go, A). This hazard ratio represents a 181% increase (95% CI = 78% to 344%) in the risk of dose-modifying adverse events for patients in the active group (log-rank {chi}2 = 19.63, P<.0001).



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Fig. 4. Kaplan–Meier curves for times from randomization to first dose-modifying adverse event (A) and to sustained deterioration in World Health Organization performance status (B) by allocated treatment. All patients from one center were excluded from this analysis due to the incomplete reporting of this variable.

 
Impact on WHO performance status. WHO performance status was recorded at randomization (when it was similarly distributed across the treatment groups; Table 1Go) and at all subsequent follow-up visits. Patients from one center were excluded from this analysis because the center did not collect this information during follow-up. Overall, 251 (85%) of the 296 patients included in this analysis had a sustained deterioration of their WHO performance status: 177 (60%) patients (79 active group patients and 98 control group patients) had a sustained worsening in WHO performance status compared with their status at randomization and 74 (25%) patients (39 active group patients and 35 control group patients) died without having a previously reported worsening in performance status. Comparison of the Kaplan–Meier curves for worsened WHO performance status gave a hazard ratio of 0.71 (95% CI = 0.56 to 0.92) (Fig. 4Go, B). This hazard ratio represents a 29% reduction (95% CI = 8% to 44%) in the risk of having a worsened WHO performance status for patients in the active group ({chi}2(1 df) = 6.99, P = .008). When we censored the 74 patients who died without having a previously reported deterioration in performance status, the hazard ratio was 0.66 (95% CI = 0.49 to 0.89). After randomization but before reaching the primary endpoint, 22 active group patients and 17 control group patients had an improved WHO performance status score compared with their pre-randomization scores. At trial entry, all patients had a WHO performance status score of 0, 1, or 2. Comparison of the Kaplan–Meier curves for the time to a WHO performance status score of 3 or worse gave a hazard ratio of 0.75 (95% CI = 0.57 to 0.97, {chi}2(1 df) = 4.70, P = .031) in favor of patients in the active group (data not shown). Using all the available data up to the overall median time to the primary event and a time-standardized area-under-the-curve approach, we found that WHO performance status was generally better in the active group than the control group (Mann–Whitney U test = 7731, P = .019).

Impact on analgesic consumption. Comparison of the Kaplan–Meier curves for time to first regular use of analgesics of any strength gave a hazard ratio of 1.12 (95% CI = 0.86 to 1.45), representing a 12% decrease (95% CI = 45% decrease to 14% increase) in the risk of regular analgesic use for patients in the active group ({chi}2(1 df) = 0.69, P = .41) (data not shown). The profiles of the first and strongest types of regular analgesics used were similar in both groups of patients.

Exploratory Analyses

Subgroup analyses. There was no evidence that the active regimen had differential effects with respect to age, WHO performance status, or baseline blood markers (i.e., hemoglobin, serum creatinine, and PSA), although there was a statistically nonsignificant improvement in BPFS for those patients in the active group who had higher baseline AP levels (Table 6Go). There was no evidence that the active regimen had differential effects among subgroups of patients defined by type of hormone therapy, time from diagnosis of bone metastases to randomization, time on long-term hormone therapy prior to randomization, or number of patients that were included in the trial from the clinical center.


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Table 6. Results of analyses comparing the effects of clodronate on symptomatic bone progression–free survival in patient subgroups, defined by clinical features at randomization*
 
There was a statistically significant trend in the association of the active regimen with the time from diagnosis to randomization, a surrogate measure of time spent with disease prior to randomization. The hazard ratios associated with the three categories of this measure—less than 6 weeks, 6 weeks to 6 months, and greater than 6 months—were 0.48 (95% CI = 0.26 to 0.91), 0.71 (95% CI = 0.46 to 1.08), and 0.99 (95% CI = 0.68 to 1.45), respectively. These hazard ratios represent a decrease of 52% (95% CI = 9% to 74%), a decrease of 29% (95% CI = 54% decrease to 8% increase), and a decrease of 1% (95% CI = 32% decrease to 45% increase), respectively, in the relative risk of BPFS in favor of the active group (trend {chi}2(1 df) = 3.937, P = .047). These results suggest a greater advantage to the patients in the active group with more recently diagnosed disease.

Biologic activity or analgesia. Bisphosphonates may lessen pain due to bone metastasis, and such analgesic activity could influence the time to development of bone pain or deterioration of performance status. We therefore examined whether clodronate treatment had any effects on levels of biochemical markers of cancer progression (PSA) and bone metabolism (AP). Using all available data up to the overall median time to the primary event and a time-standardized area-under-the-curve approach, we found that the PSA level after randomization was lower for the active group than the control group (Mann–Whitney U test = 6989, P = .053) (data not shown). The estimated median PSA level during the first 2 years on trial was 5.0 ng/mL for patients in the active group and 10.4 ng/mL for patients in the control group.

Baseline and 6-month post-randomization AP levels were available for 260 patients (132 active group patients and 128 control group patients). The two groups of patients had similar baseline distributions of upper limit of normal–adjusted AP levels (ULN–adj AP). In both groups of patients, AP levels decreased between the baseline and 6-month assessments. However, there was both an absolute change in AP level that was greater for patients in the active group than for patients in the control group (Mann–Whitney U test = 7139.5, P = .031) as well as a larger proportional change in the ULN–adj AP levels from baseline to 6 months in the active group compared with the control group change (Mann–Whitney U test = 6815, P = .007).

Baseline and 12-month post-randomization AP levels were available for 209 patients (108 active group patients and 101 control group patients). As with the baseline to 6 months comparison, the two groups of patients had similar baseline ULN–adj AP distributions and showed greater absolute (Mann–Whitney U test = 4195, P = .004) and proportional changes (Mann–Whitney U test = 4058, P = .001) in the ULN–adj AP levels in favor of the active arm.


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Our results suggest that men treated with the bisphosphonate sodium clodronate have longer symptomatic bone progression–free survival times than men treated with placebo. However, these findings were not statistically significant, perhaps because of the modest size of the randomized controlled trial. Our findings also raise the possibility that overall survival might be improved by clodronate treatment. Compared with patients in the control group, patients in the active group had a statistically significant increase in the time to deterioration of their WHO performance status and statistically significantly lower AP levels. PSA levels were also lower among active-group patients than among control-group patients, which is consistent with clodronate having a biologic effect on the progression of prostate cancer rather than merely an analgesic effect on the symptoms of bone metastases. Results of exploratory subgroup analyses suggested that there may be a benefit to starting clodronate earlier in the course of disease. This advantage might reflect a relatively longer exposure to clodronate or indicate the importance of commencing bisphosphonate therapy when hormone treatment is initiated, because androgen suppression is known to cause accelerated bone loss (33–36), which can be blocked by bisphosphonate drugs (35,37).

Limitations of our study include the small size of the trial (due to the limited availability of drug supplies) and our use of an oral rather than an intravenous route of drug administration. Intravenous bisphosphonates are considerably more bioavailable than oral preparations. However, because these patients were not receiving any other intravenous therapy for their disease, we chose to use an oral agent rather than an intravenous treatment. Clodronate was the most potent oral bisphosphonate available at the time and was given at 2080 mg/day using the Loron 520 preparation, which is bioequivalent to a higher dose of other clodronate preparations (38). Drug-related toxicity was tolerable (the most commonly reported toxicities were gastrointestinal problems or asymptomatic increases in lactate dehydrogenase), and all of these side effects abated when the dose of clodronate was reduced or the drug was stopped. However, approximately one-third of patients in the active group (54/155), compared with approximately one-eighth of patients in the control group (20/156), required dose modification. This side-effect profile suggests that higher doses of clodronate would have been impractical. Consequently, and because of the poor oral bioavailability of clodronate (approximately 2%) (39) and the marked effects of food intake on clodronate absorption (40), we believe there is a strong argument for further studies to be undertaken with a more potent or intravenous preparation of clodronate.

The evaluation of bisphosphonates in prostate cancer has lagged behind investigation of these agents in breast cancer and myeloma (10,15,16,19–21,23,24). For prostate cancer, both clinical and preclinical studies have shown that the effects of osteoclast activation can be inhibited by bisphosphonates (25–28,41–43). The results of initial phase II studies suggested that bisphosphonates provide benefits in terms of pain control (20,42,44–47). However, only one of five phase III trials has confirmed this finding (48–52), probably because the phase II studies were small, and the patients enrolled in them had advanced symptomatic, metastatic disease, which made compliance difficult (51). In these studies, measured markers of bone turnover were not reliably reduced, which may have been related to the potency and administration route of the bisphosphonate agents used (49,51). In a recently reported randomized controlled trial comparing two bisphosphonates in patients with a variety of malignancies (53), improvement in bone pain was related to suppression of bone resorption, and intravenous pamidronate was more effective at suppressing bone resorption than oral clodronate. The largest phase III trial of bisphosphonates in prostate cancer included 643 men with bone metastases and hormone-refractory disease who were randomly assigned to receive placebo or one of two doses of the third-generation nitrogen-containing bisphosphonate zoledronic acid, which is considerably more potent than either clodronate or pamidronate (54). Compared with men in the placebo group, men in the 4-mg/day zoledronic acid group had statistically significantly fewer skeletal-related events (33% versus 44%; P = .02); however, a lesser and statistically nonsignificant effect was seen for men in the higher-dose zoledronic acid group (39% for those receiving zoledronic acid at 8 mg/day—there was a toxicity-related dose modification to 4 mg in this arm in the latter part of the trial—versus 44% for men receiving placebo; P = .22) (54). Although there was an improvement in pain control for men in both zoledronic acid groups compared with men in the placebo group, there was no difference in clinical disease progression, quality-of-life indices, or performance status. Zoledronic acid treatment was associated with a statistically significant reduction in markers of bone resorption compared with placebo, and levels of bone AP stabilized rather than decreased in the zoledronic acid group but increased in the control group.

Our trial is the first to report the potential benefits of bisphosphonates when they are used as an adjunct therapy to initial androgen suppression. The parallel trial (MRC PR04) for men with advanced localized disease completed recruitment of more than 500 men in 1997 and should report preliminary results in 2004. Taken together, results of these studies should help guide future clinical research on the role of bisphosphonates in prostate cancer. However, at present, there is uncertainty about the role of these agents in this disease. Further data are needed that reflect the availability of the newer, more potent bisphosphonates as well as the changing patterns of care for men with prostate cancer.

These treatment changes have led to a reduction in the proportion of hormone-naive patients with bone metastases (55) and, thus, the PR05 Trial might be difficult to repeat. Instead, future studies may include men who have localized prostate cancer with a poor prognosis and who are likely to receive hormonal therapy as part of their initial treatment (7). PSA-led treatment of prostate cancer has led to the identification of men with biochemical failure that is unresponsive to hormone therapy but without demonstrable metastases; bisphosphonate trials would also be appropriate for this group of patients. Androgen suppression is being introduced into treatment at an earlier point in the natural history of prostate cancer (7,56), and the longer duration of androgen suppression is likely to increase risk of bone loss and osteoporosis. Although bisphosphonates may be useful in preventing or reducing bone loss (35,37), it is probable that the type of bisphosphonate, as well as the dose and duration of treatment required, may differ for prostate cancer progression and hormonally induced osteoporosis. Further impetus for evaluating bisphosphonates in prostate cancer comes from recent laboratory observations that suggest that bisphosphonates may have direct effects on prostate cancer cell lines by inhibiting cell growth and tumor cell invasion in a dose-dependent manner (57,58).

Although bisphosphonates appear to hold considerable promise for modifying the natural history of prostate cancer bone metastases, much work needs to be done to identify appropriate patient populations for treatment and to determine the appropriate type, dose, and duration of bisphosphonate therapy.


    APPENDIX
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Please note that all Writing Committee members and PR05 collaborators contributed to the trial and may be regarded as authors.

Writing Committee: D. P. Dearnaley, M. R. Sydes, M. D. Mason, M. Stott, C. S. Powell, A. C. R. Robinson, P. M. Thompson, L. E. Moffat, S. L. Naylor, M. K. B. Parmar.

Collaborating hospitals and consultants: (following the format: city, center name (total number of trial patients from center: participating clinicians at center) U.K.: Aberdeen Royal Infirmary (14: L. E. Moffat, D. Bissett); Bath, Royal United Hospital (4: H. Newman); Birmingham University and City Hospitals (15: J. Glaholm, N. D. James, D. Peake); Boston, Pilgrim Hospital (1: N. Dahar); Brighton General Hospital (1: P. Thomas); Bristol Oncology and Haematology Centre (4: J. Graham); Bristol, Southmead Hospital (6: J. C. Gingell); Burnley General Hospital (4: D. G. Barnes); Cambridge, Addenbrooke’s Hospital (1: A. Doble); Cardiff, Velindre Hospital (11: M. D. Mason, D. Mort); Carshalton, St. Heliers Hospital (7: P. J. R. Boyd); Chester, Countess of Chester Hospital (28: C. S. Powell); Chichester, St. Richard’s Hospital (9: P. G. Carter, P. Britton); Crewe, Leighton Hospital (13: S. J. S. Brough, P. Javle); Dartford, Dartford and Gravesham New Acute Hospital (19: P. M. Thompson, I. K. Dickinson); Edinburgh, Western General Hospital (3: J. W. Fowler); Exeter, Royal Devon and Exeter Hospital (30: M. Stott); Glasgow, Gartnavel General Hospital and Western Infirmary (12: D. Kirk, D. Dodds, M. Russell, M. Aitchison); Gosport, Royal Navy Hospital Haslar (2: D. N. Tulloch); Ipswich Hospital (2: J. LeVay); London, Charing Cross Hospital (1: R. J. Epstein), Middlesex Hospital (3: S. J. Harland), North Middlesex Hospital (1: S. Karp), and St. George’s Hospital (1: R. Eeles); Newcastle General Hospital (2: D. Ritchie, J. T. Roberts); Newcastle-upon-Tyne, Freeman Hospital (1: R. R. Hall); Reading, Royal Berkshire Hospital (4: J. M. Barrett); Southend General Hospital (27: A. C. R. Robinson, A. Lamont, C. W. L. Trask, J. Prejbisz); Stoke-on-Trent, North Staffordshire Royal Infirmary (9: F. A. R. Adab); Sutton/London, Royal Marsden NHS Trust (61: D. P. Dearnaley, R. A. Huddart, R. Shearer, R. Eeles); Torbay Hospital (4: J. P. MacDermott); Wolverhampton, New Cross Hospital (5: B. Waymont); Yeovil District Hospital (1: C. J. Parker); York District Hospital (3: M. J. Stower); New Zealand: Auckland Hospital (2: C. C. Jose).

Overseeing committees: Trial Management Group—D. P. Dearnaley (chair), A. Duffy (to 1995), P. M. Fayers (to 1995), J. Glaholm (to 1999), R. Jones, M. D. Mason, L. E. Moffat (from 1996), S. L. Naylor (from 2000), M. K. B. Parmar (from 1995), and M. R. Sydes (from 1995), plus a representative from the pharmaceutical company. Trial Steering Committee (from Nov. 1999)—H. Earl, D. Guthrie, and C. McArdle. Data Monitoring and Ethics Committee—J. Bliss, H. Earl, and P. Harper (chair).

Other participants and collaborators: Trials managers, MRC Clinical Trials Unit—A. Duffy (to 1995), M. R. Sydes (1995–2001), S. L. Naylor (from 2001). Statisticians, MRC Clinical Trials Unit— P. M. Fayers (to 1995), M. K. B. Parmar (from 1995), M. R. Sydes (from 1998). Analyses—all performed by M. R. Sydes and M. K. B. Parmar. Pharmaceutical company representatives, Boehringer Mannheim: F. Houghton (to 1997), B. Blaney (1997–1998), A.-M. Cairns (1998–1999); Roche: S. Kemp (from 2000), K. Mayne (from 2000). Research staff at participating centers—U.K.: Aberdeen Royal Infirmary (A. Hancock); Bath, Royal United Hospital (L. Morgan); Bristol Haematology and Oncology Centre (T. White, R. Hollister); Bristol, Southmead Hospital (P. Sage); Burnley General Hospital (M. Cade); Cambridge, Addenbrooke’s Hospital (J. Lynch); Cardiff, Velindre Hospital, (S. Broughton, K. Owen, B. Moore, L. Lane); Carshalton, St. Heliers Hospital (J. Pinfield); Chester, Countess of Chester Hospital (J. Stacey, J. Kirkham, B. King); Chichester, St. Richards Hospital (R. Speer, A. Simmonds); Crewe, Leighton Hospital (C. Hough); Dartford, Dartford and Gravesham New Acute Hospital (A. Elliott, P. Davies); Edinburgh, Western General Hospital, (N. Lyons); Glasgow, Gartnavel General Hospital and Western Infirmary (J. Graham, A. Griffen); Gosport, Royal Hospital Haslar (S. Hall); Ipswich Hospital (P. Taylor-Neale); Newcastle General Hospital (V. Turnball, J. Johnson, G. Bell); Reading, Royal Berkshire Hospital (C. Lewis); Stoke-on-Trent, North Staffordshire Royal Infirmary (S. Newman); Sutton/London, Royal Marsden NHS Trust (J. Gadd, J. McDonald-Clink); Torbay Hospital (F. Roberts); Wolverhampton, New Cross Hospital (C. Parr, M. Miletic); Yeovil District Hospital (S. Bulley); York District Hospital (J. Smith)—New Zealand: Auckland Hospital (K. Thompson, J. Ong)—and all supporting pharmacists at participating centers.

Sponsorship: This trial was sponsored by the U.K. Medical Research Council (MRC).

Pharmaceutical industry support: The trial was initiated with the support of Boehringer Mannheim. The company provided trial tablets (Loron 520 and matching placebo) free of charge, plus financial support (£250) on a per patient basis, which was sufficient to contribute toward the administrative costs of the trial. The financial support was distributed proportionately between the participating clinicians and the coordinating center. Patients received no payment for their participation. During the trial, Boehringer Mannheim was taken over by Roche Products Ltd., which honored all commitments regarding this trial.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Present address: P. M. Thompson, Kings College Hospital, London, U.K.

Present address: S. L. Naylor, Clinical Trials Centre, Cancer Research U.K., University College London, London, U.K.


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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 

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Manuscript received February 3, 2003; revised June 24, 2003; accepted July 8, 2003.


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