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© 2003 American Society for Clinical Oncology Randomized, Double-Blind, Controlled Trial of Mitoxantrone/Prednisone and Clodronate Versus Mitoxantrone/Prednisone and Placebo in Patients With Hormone-Refractory Prostate Cancer and Pain
From the Tom Baker Cancer Centre, Calgary; Cross Cancer Institute, Edmonton, Alberta; Princess Margaret Hospital, Toronto; London Regional Cancer Centre, London; National Cancer Institute of Canada, Kingston, Ontario; Nova Scotia Cancer Centre, Halifax, Nova Scotia; and Vancouver Cancer Centre, Vancouver, British Columbia, Canada. Address reprint requests to D.S. Ernst, MD, London Regional Cancer Centre, 790 Commissioners Rd E, London, Ontario N6A 4L6, Canada; e-mail: scott.ernst{at}lrcc.on.ca.
Purpose: To compare the incidence of palliative response in patients with hormone-resistant prostate cancer (HRPC) treated with mitoxantrone and prednisone (MP) plus clodronate with that of patients treated with MP plus placebo. Materials and Methods: Men with HRPC, bone metastases, and bone pain were randomly assigned to receive clodronate 1,500 mg administered intravenously (IV) or placebo every 3 weeks, in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid. Patients completed the present pain intensity (PPI) index and Prostate Cancer–Specific Quality-of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis. The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50% in analgesic intake, without increase in either. Results: The study accrued 209 eligible patients over 44 months. One hundred sixty patients (77%) had mild PPI scores (1 or 2), and 49 (24%) had moderate PPI scores (3 or 4). The primary end point of palliative response was achieved in 46 (46%) of 104 patients on the clodronate arm and in 41 (39%) of 105 patients on the placebo arm (P = .54). The median duration of response, symptomatic disease progression-free survival, overall survival, and overall quality of life were similar between the arms. Subgroup analysis suggested possible benefit in patients with more severe pain. Conclusion: MP provides useful palliation in symptomatic men with HRPC. Clodronate does not increase the rate of palliative response or overall quality of life. Clodronate may be beneficial to patients who have moderate pain, but this requires further confirmation.
IN PATIENTS with advanced prostate cancer, the development of hormone resistance is an unfortunate final common pathway.1 Progressive disease occurs despite adequate androgen suppression, usually after a median time of 2 years of hormone sensitivity.2 For the clinician, the number of potential therapeutic options narrows. For symptomatic patients, irrespective of the interventions, the median survival is usually approximately 10 to 12 months.3 When patients with symptomatic hormone-resistant prostate cancer (HRPC) are treated with chemotherapy, the goals of treatment are improvement in the duration or quality of survival. Tumor response is not an end point of patient benefit, and its determination has been hampered by the relative infrequency of measurable disease to which standard assessments of response can be applied.4 Clinical response has been increasingly accepted as an alternate means of assessing activity in HRPC. In 1996, Tannock et al5 reported the results of a randomized controlled study of the anthracenedione and mitoxantrone in combination with low-dose prednisone versus prednisone alone. The primary end point of the trial was palliative response, defined as changes in patient symptom scores and analgesic requirements. Using the same criteria as in the current trial, the palliative response rate was 38% for the mitoxantrone plus prednisone (MP) arm and 21% for the prednisone arm, with a longer duration of response for patients randomly assigned to receive chemotherapy. The Cancer and Leukemia Group B (CALGB 9132) conducted a similar randomized trial, comparing mitoxantrone plus hydrocortisone with hydrocortisone alone.6 Although no difference was seen in the primary end point of survival, quality-of-life (QOL) assessments demonstrated an improvement in pain in the patients treated with chemotherapy. On the basis of these two studies, the United States Food and Drug Administration approved mitoxantrone for use in HRPC.7 The MP combination remains a standard to which newer combinations are often compared. Another class of drugs, the bisphosphonates, have been evaluated in patients with HRPC. The bisphosphonates represent a family of pyrophosphate analogs, and each member differs from another by the composition of two side-chain elements.8 The agents are avidly taken up by bone and impair osteoclast function. Studies in patients with prostate cancer who are receiving hormone therapy suggest that these agents may have a role in reducing time to symptomatic progression and skeletal events in both hormone-sensitive prostate cancer and HRPC.9–11 In the present study, we have evaluated whether clodronate enhances the frequency and duration of the palliative response obtained with MP in patients with symptomatic HRPC. We have also explored the impact on QOL and determined whether biochemical markers of bone resorption can be useful in predicting those patients with bone metastases who may respond to the bisphosphonate.
Study Design From Oct 1997 to May 2001, 17 Canadian sites affiliated with the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) enrolled 227 patients with HRPC and symptomatic bone involvement onto the study. Patients were randomly assigned to receive either clodronate or placebo in conjunction with MP. The institutional review board approved the study protocol at each site, and all patients provided informed, written consent before entering the study. Before randomization, patients completed the six-point present pain intensity (PPI) scale of the McGill-Melzack Pain Questionnaire.12,13 The pain scale consists of a series of verbal descriptors: 0 = no pain, 1 = mild pain, 2 = discomforting pain, 3 = distressing pain, 4 = horrible pain, and 5 = excruciating pain. Patients were explicitly asked to identify the average pain level during the previous 24 hours. A minimum PPI score of 1 was required for study entry. Patients were stratified according to pain level (mild = PPI 1 or 2, moderate = PPI 3 or 4) and on the basis of previous corticosteroid use (yes or no). Patients were also required to have stable analgesic intake as measured by use of an analgesic diary. The daily analgesic score was determined by the total number of analgesics units defined as follows: one unit was used for standard doses of nonopioids (eg, acetaminophen 325 mg, indomethacin 25 mg, and so on) and two units for opioid doses of morphine 10-mg equivalents (eg, hydromorphone 2 mg, oxycodone 20 mg, and so on). Stable analgesia was defined as no greater than 25% variance in analgesic scores during the week before randomization.
All patients had radiologically confirmed, progressive bone disease, which was defined as the presence of new lesions on bone scan, increased isotope uptake at previous sites of disease, or increasing bone pain. Patients were required to have castrate levels of testosterone (< 3 nmol/L) achieved by bilateral orchidectomy or administration of a luteinizing-hormone releasing hormone agonist. Nonsteroidal antiandrogens were withdrawn a minimum of 4 weeks (flutamide, nilutamide) or 6 weeks (bicalutamide) before randomization. Additional inclusion criteria included Eastern Cooperative Oncology Group performance status less than 3, baseline measurement of left ventricular ejection fraction (LVEF) greater than 50%, ability to complete pain and QOL scores, and adequate hematologic and biochemical function as defined by WBC Exclusion criteria were as follows: prior malignancy excluding nonmelanoma skin cancer, more than one previous chemotherapy regimen or a previous regimen containing mitoxantrone or an anthracycline, previous bisphosphonate therapy, treatment with radiotherapy within the previous 4 weeks or radioisotopes within the previous 8 weeks, radicular or back pain suggestive of epidural metastases, potential spinal cord or nerve root compression, impending pathologic fracture, and uncontrolled cardiac failure or active infection. In addition to the above, baseline assessment included physical examination, completion of a health related QOL questionnaire (HRQOL), serum testosterone and prostate-specific antigen (PSA), bone scans, chest radiographs (including other diagnostic imaging as clinically indicated), and a 24-hour urine collection for measurement of calcium, creatinine, and pyridinium cross-links.
Treatment Mitoxantrone was administered at 3-weekly intervals providing that the pretreatment granulocyte count was greater than 1.5 x 109/L and platelets were greater than 100 x 109/L. Mitoxantrone was discontinued permanently if two consecutive delays of 1 week for neutropenia or thrombocytopenia occurred. If there was neutropenic fever or bleeding associated with a platelet count less than 100 x 109/L, the dose of mitoxantrone was reduced to 9 mg/m2 for subsequent cycles. The study drug (clodronate or placebo) was withheld if the serum calcium was less than 2.01 mmol/L or if the serum creatinine was greater than 200 µmol/L. Mitoxantrone was discontinued after a cumulative dose of 140 mg/m2. In responding patients, prednisone and study drug were continued until disease progression.
Assessment of Outcome The primary end point for the study was the palliative response, previously defined by Moore et al14 as either (1) a two-point reduction in the six-point PPI (or complete loss of pain if initial PPI was 1 or 2) without an increase in analgesic score or evidence of disease progression, or (2) a greater than 50% decrease in analgesic score without an increase in PPI. These criteria had to be maintained on two consecutive evaluations at least 3 weeks apart. Disease progression was defined as one of more of the following: a one-point or more increase in the PPI, 25% increase in analgesic consumption (both compared with baseline), need for palliative radiotherapy, or unequivocal evidence of radiologic progression. Secondary end points included time to symptomatic progression, duration of palliative response, PSA response (50% or more decrease in serum PSA compared with baseline and sustained for at least two visits), incidence of morbid skeletal events (ie, episodes of hypercalcemia, number of pathologic fractures, and number of palliative radiotherapy interventions), toxicity, and HRQOL. Urine pyridinium cross-links and calcium/creatinine ratios were also measured as indicators of biochemical markers of bone resorption. HRQOL was assessed by the Prostate Cancer–Specific Quality-of-Life Instrument (PROSQOLI).15 The instrument, completed by the patients at each visit, used a series of nine linear analog scales related to pain, physical activity, fatigue, appetite, constipation, passing urine, family/marriage relationships, mood, and overall well-being. HRQOL response was defined as a 1-cm improvement from baseline on the 10-cm visual analog scale for overall well-being maintained on two successive visits no less than 3 weeks apart.
Statistical Considerations
No interim analysis was planned for the study. Patient accrual ceased when the required number of eligible patients had been assigned. Analyses of pretreatment characteristics, response rates, survival, time to progression, and HRQOL were undertaken on an intent-to-treat basis for all eligible patients. Safety and drug exposure analyses were based on the actual drug received, whereas all other analyses were performed on the treatment arm as randomly assigned. The following variables were used to adjust the regression analyses of the palliative response rate, overall survival, time to symptomatic progression, and the duration of palliative response: age (<70 v > 70 years), baseline hemoglobin (<100 g/L v > 100 g/L), and performance status (0, 1 v 2, 3). The proportion of palliative response between the two treatment arms was compared using a Pearson’s HRQOL from randomization to date of symptomatic progression was assessed using the PROSQOLI. The proportion of patients satisfying criteria for HRQOL response and the median and maximum improvement from baseline for the duration of the treatment was measured for the two treatment arms. Differences in these summary scores were assessed using the Wilcoxon rank sum test.18 No correction was applied for multiple significance testing.
Patient Characteristics A total of 227 patients were accrued in 17 Canadian centers; 115 were randomly assigned to the clodronate arm, and 112 were randomly assigned to the placebo arm. Eleven patients on the clodronate arm and seven patients on the placebo arm were found to be ineligible for the following reasons: insufficient baseline analgesic data (seven patients), unstable or no baseline analgesia (four patients), preceding or concurrent therapy (two patients), concurrent malignancy, no baseline bone scan, LVEF less than 50%, PSA less than upper limit of normal (one patient each), or therapeutic radiation within 4 weeks of randomization (one patient). One patient who was randomly assigned to the clodronate arm received placebo, while all other patients received the assigned therapy. No difference in outcomes, including palliative response, overall survival, and symptomatic progression-free survival (SPFS), were observed, whether all randomized patients or eligible patients were included in the analyses. Results below are given for the 209 fully eligible patients.
The characteristics of patients at randomization are listed in Table 1
Response to Therapy The primary criterion of palliative response was met in 46 (45%) of 104 patients in the clodronate arm and 41 (39%) of 105 patients receiving placebo. This difference was not statistically significant (P = .54 from Pearson’s  2 test with Yate’s correction). Using the Cochran-Mantel-Haenszel test19 controlling for stratification variables, the difference remained nonsignificant (P = .37). The patients receiving clodronate were 1.16 times (95% confidence interval [CI], 0.84 to 1.61) more likely to achieve a palliative response than those receiving placebo. Similar results were obtained with all randomized patients included in the analysis. Forty-nine of the 115 patients in the clodronate arm and 42 of 112 patients in the placebo arm met the criteria of palliative response (P = .52, Pearson’s 2 test with Yates correction). The palliative response had two components: the PPI and analgesic scores. For the patients receiving the clodronate, 34 (33%) of 104 patients had a two or more reduction in the PPI score in comparison with baseline irrespective of analgesic response. Similarly, for the placebo arm, 27 (26%) of 105 patients achieved a pain response (P = .34). Analgesic response, as defined as a 50% decrease in analgesic score from the baseline with no increase in pain, occurred in 34 (33%) of 104 patients on the clodronate arm and 32 (30%) of 105 patients on the placebo arm (P = .84). The numbers of patients who no longer required any analgesics for two consecutive cycles for the clodronate and placebo arms were 33 patients (31%) and 27 patients (25%), respectively, and were not statistically different (P = .42). In an exploratory analysis, logistical regression was used to adjust for the baseline stratification variables. This analysis suggested that the likelihood of a palliative response was dependant on the baseline PPI score. Of the 209 eligible patients, 49 (23%) had moderate pain (PPI of 3 or 4) at baseline. For this group, the odds ratio for palliative response for the clodronate arm as compared with the placebo arm was 4.6 (95% CI, 1.3 to 15.5). The response rate for patients with moderate pain on the clodronate arm was 58% (95% CI, 41% to 77%) in contrast with 26% (95% CI, 13% to 48%) in the placebo arm (P = .04 using Fisher’s exact test). In contrast, for the remaining 75% of patients who had mild pain at baseline (PPI of 1 or 2), the odds ratio for palliative response was 0.9 (95% CI, 0.5 to 1.7) for patients treated with clodronate compared with those treated with placebo. The duration of response was defined as the time from the first date at which palliative response criteria were fulfilled to the first date at which disease progression was noted. The median duration was 6.2 months (95% CI, 5.0 to 9.2) for the clodronate arm versus 6.4 months (95% CI, 4.0 to 9.6) for the placebo group (P = .79).
SPFS was defined as the time from the date of randomization to the date of progression from pain or other symptoms. For patients who died without progression, their date of death was used as the progression date. A total of 196 patients developed symptomatic progression (95 on clodronate and 101 on placebo). The median SPFS was 5.0 months (95% CI, 4.1 to 6.8) for the clodronate arm and 4.0 months (95% CI, 2.9 to 4.9) for the placebo arm. The Kaplan-Meier curves for SPFS are shown in Figure 1
Overall survival was measured from the date of randomization to the date of death. For living patients, this was censored at the last known date when the patient was alive. A total of 176 deaths (87 on clodronate and 89 on placebo) were observed. One hundred seventy-five of the 176 deaths were caused by progressive disease. One patient committed suicide. The Kaplan-Meier curves for survival are shown in Figure 2  . The median survival was 10.8 months (95% CI, 8.2 to 13.0) for the clodronate arm and 11.5 months (95% CI, 8.8 to 14.4) for the placebo arm. The hazard ratio (placebo to clodronate) was 0.95 (95% CI, 0.71 to 1.28).
PSA response, as defined as a greater than 50% decrease from baseline, was recorded in 30 (29.7%) of 104 patients on the clodronate arm compared with 30 (28.6%) of 105 patients on the placebo arm and was not statistically different.
Table 2
Fifty percent of the clodronate patients and 44% of the placebo patients received at least seven cycles of therapy. The reasons for discontinuation of protocol therapy are listed in Table 3 . Disease progression was defined more specifically as unequivocal evidence of new lesions, radiologic progression, or the need for local palliative radiotherapy. There was no significant differences between the arms. The site of progression was predominantly osseous (82%), and measurable soft tissue disease was present in 14% of patients. The most common determinant for discontinuation of therapy was disease progression and was similar in both the clodronate and placebo arms (51% and 54%, respectively). Local investigators stopped the mitoxantrone and study agent after 10 cycles in 24 patients (14 on the clodronate arm and 10 on the placebo arm) even though provision was made in the study protocol to continue therapy on responding patients with LVEF greater than 50% to a maximum cumulative dose of 140 mg/m2. Twenty-one patients (11 on clodronate arm and 10 on placebo arm) requested treatment discontinuation. Only five patients stopped because of treatment-related toxicity. Serious adverse events were infrequent and similar in both treatment arms (Table 4). There were no treatment-related deaths.
QOL Compliance with the QOL portion of the study was high. The PPI and PROSQOLI scales were obtained in 100% of initial clinic visits and did not differ between the study arms over subsequent cycles of therapy. The incidence rates of QOL responses from all patients with a baseline assessment were 39 (37.5%) of 104 patients on the clodronate arm and 44 (42%) of 105 patients on placebo (P = .61). Median changes from baseline in the PROSQOLI scores for all patients who had completed a minimum of two assessments are illustrated in Figure 3 . The distribution favored the clodronate arm for the pain domain (P = .022 by Wilcoxon rank sum test). There were no significant differences in median changes between the arms in the other domains. Similarly, on analysis of the maximum changes in PROSQOLI scores, the distribution favored the clodronate arm (P = .042, by Wilcoxon rank sum test), with no significant differences seen in the other domains.
Biochemical Markers of Bone Resorption Urinary calcium, creatinine, and pyridinium cross-links were assessed at 12 and 24 weeks after randomization. A logistical regression model was used to explore changes from baseline as potential predictors of palliative response. For each marker, change from baseline of the biochemical marker as fixed effect was fitted to the longitudinal data. A model with changes of all three markers was also fitted to the data. For the pyridinium cross-links, 73 patients provided useful samples at both time points. On regression analysis, with one unit of increase from baseline in pyridinium cross-links, the chance of a palliative response decreased by 0.1% (P = .097; 95% confidence limit, -0.02%, 0.23%). In the 55 patients with at least two evaluations of the calcium/creatinine ratio, there was also a trend for the change in calcium/creatinine ratio to be predictive of a palliative response. With each unit increase in the change of calcium/creatinine ratio, the chance or achieving a palliative response increased by 37.7% (P = .056; 95% confidence limit, -0.08%, 91.3%). An exploratory analysis using general mixed linear models was conducted to determine whether changes of the markers were predictive of changes in the PSA. On univariate and multivariate analysis, none of the markers, including urine pyridium cross-links, calcium, and calcium/creatinine ratios, were significant predictive factors in changes from baseline of PSA.
The overall palliative response rate for the study population was 42%, all of whom received MP. In the previous study of Tannock et al, 5 which compared MP with prednisone alone in patients with symptomatic HRPC, the palliative response rate was 38% for the MP group, using the same criteria of response. Similarly, we found that MP was well tolerated, and the addition of clodronate did not impact on the toxicity profile of MP. This regimen is readily manageable in an outpatient setting. The current study provides further evidence supporting the role of chemotherapy in HRPC. In both arms, the PSA response rate was 29.5%, which is consistent with the PSA response rates of 33% and 37.5% reported in previous randomized trials.5,6 The present study indicates that the addition of clodronate to MP does not improve the palliative response rate or duration of response in symptomatic men with HRPC. Because this study was powered to identify a 20% increase in the response rate, the negative result may have been due to a true lack of impact of clodronate or to the existence of a smaller effect than initially postulated. Another possible explanation relates to the type of patients entered onto the trial. Subgroup analysis suggested that patients with moderate pain were more likely to benefit from the addition of clodronate compared with chemotherapy alone. The majority of patients (76%) had mild pain in which a palliative response might be more difficult to demonstrate. In the mild pain cohort, relatively small increases in analgesic consumption could result in the declaration of disease progression. Conversely, patients with mild pain were required to have complete resolution of pain to be scored as a palliative response. Furthermore, in these patients, distinguishing bone pain from other sources of somatic pain, such as arthritis or muscular spasm, may not be easily achieved clinically and could influence potential benefit of bisphosphonate therapy.20,21 Impact on QOL is an important consideration in the evaluation of new palliative treatments. This study demonstrated that clodronate might improve pain scores but had little impact on other domains either in a positive or negative direction. Improvements in all domains of QOL were evident in both arms of the study. Maximum changes and median changes from baseline were similar in direction and magnitude as those observed using the same PROSQOLI assessment tool in the MP arm of our previous study.5,22 Biochemical markers of bone turn-over have shown some promise in objectively measuring response to therapy.23,24 The baseline rate of bone resorption can be measured by relatively high levels of pyridinium cross-links or by reductions in ratios of urinary calcium to creatinine.25 We found that changes in calcium/creatinine ratios were more predictive of the palliative response than pyridinium cross-links. However, the small number of measurements included in our analysis may have contributed to the lack of a statistically significant association between these markers of bone turnover and palliative response. This potential strategy requires further confirmation in prospective studies. Several recent reports have suggested that bisphosphonate therapy may prevent or delay the onset of skeletal-related events (SRE), such as fractures or pain requiring local radiotherapy.9,10 Zoledronic acid is much more potent than clodronate and can be given safely as a 15-minute intravenous infusion. In a recent randomized, placebo-controlled trial of zoledronic acid, Saad et al10 found that 38% of patients who were treated with zoledronic acid 4 mg administered intravenously experienced an SRE, compared with 49% of patients who received placebo. In the zoledronic acid group, the time to the first SRE was significantly delayed by 5.5 months, and mean annual skeletal morbidity rate was reduced by almost 50%. In our study, pain control constituted the primary end point, and all patients had bone pain on study entry. In the Saad study, 75% of patients had pain at baseline, and subsequent pain scores were observed to decrease slightly during the initial 3 months. However, after 15 months, those remaining patients who received zoledronic acid had pain scores that were significantly lower than those who had received placebo. Although these two studies differ in objectives and methodologies, the observed trend towards pain improvement is consistent. A variety of bisphosphonates are currently available for clinical use. They differ in potency, toxicity, and mode of administration. The potential remains for more pronounced effect on bone pain using alternate agents at different doses and schedules. Given the results of our study, routine use of clodronate cannot be recommended for palliation of symptomatic bone disease in patients with HRPC. A palliative role may exist for patients with moderate to severe pain, but this remains to be confirmed in a prospective clinical trial. Selection of the appropriate patient population for treatment with bisphosphonates based on indicators of bone turnover may be feasible, but further studies are needed before adoption of this practice. In the meantime, chemotherapy with MP remains a reasonable option for palliation of patients with symptomatic HRPC.
Supported by a grant from Immunex Corporation, Seattle, WA, and Aventis Pharma, Laval, Quebec, Canada. Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18–21, 2002, Orlando, FL.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3.0 x 109/L, absolute granulocyte count 
54 µmol/L, serum calcium 
