Journal of Clinical Oncology, Vol 17, Issue 3
(March), 1999: 846
© 1999 American Society for Clinical Oncology
Pamidronate Reduces Skeletal Morbidity in Women With Advanced Breast Cancer and Lytic Bone Lesions: A Randomized, Placebo-Controlled Trial
Richard L. Theriault,
Allan Lipton,
Gabriel N. Hortobagyi,
Richard Leff,
Stefan Glück,
John F. Stewart,
Sean Costello,
Ian Kennedy,
Joseph Simeone,
John J. Seaman,
Robert D. Knight,
Kathleen Mellars,
Maika Heffernan,
Dirk J. Reitsma,
for the Protocol 18 Aredia Breast Cancer Study Group
From the Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; the Milton S. Hershey Medical Center, Hershey, PA; Georgia Cancer Specialists, Decatur, GA; Northeastern Ontario Regional Centre, Sudbury, Ontario, Canada; Newcastle Mater Misericordiae Hospital, Waratah, New South Wales, Australia; Dunedin Hospital, Dunedin, New Zealand; Waikato Hospital, Hamilton, New Zealand; Massachusetts General Hospital, Boston, MA; and Novartis Pharmaceuticals, East Hanover, NJ.
Address reprint requests to Richard L. Theriault, DO, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 56, Houston, TX 77030; email rtheriau{at}mdanderson.org
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ABSTRACT
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PURPOSE: To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy.
PATIENTS AND METHODS: Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated.
RESULTS: One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skeletal morbidity rate was significantly reduced at 12, 18, and 24 cycles in patients treated with 90 mg of pamidronate (P = .028, .023, and .008, respectively). At 24 cycles, the proportion of patients having had any skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo (P = .049). There was no statistical difference in survival or in objective bone response rate. Pamidronate was well tolerated.
CONCLUSION: Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases.
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INTRODUCTION
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BONE METASTASES associated with breast cancer disease result in considerable morbidity, including bone pain, pathologic fractures, spinal cord compression, and hypercalcemia.1,2 Despite local therapy with radiation or surgery or systemic therapy with hormonal or chemotherapeutic agents, the majority of women continue to experience progressive osteolysis.3-8
Most complications of metastatic bone lesions result from excessive osteoclastic bone resorption stimulated by tumor-produced cytokines and other factors.9,10 Because of their ability to inhibit osteoclast-induced bone resorption, bisphosphonates have been studied for the prevention and treatment of lytic bone lesions for more than a decade.11-18 In an earlier open-label dose-ranging study, intravenous pamidronate, a second-generation bisphosphonate that does not inhibit bone mineralization at antiresorptive doses, significantly reduced bone pain in breast cancer patients.19-21 Radiographic changes consistent with healing of bone lesions were seen in 25% of patients. In a dose-ranging study in hypercalcemia of malignancy, 90 mg of intravenous pamidronate was the maximally effective dose.22 This double-blind, placebo-controlled 2-year trial was conducted to determine whether adjunctive therapy with intravenous pamidronate every 3 to 4 weeks could prevent skeletal complications in patients with advanced breast cancer and lytic bone lesions who were receiving hormonal therapy. Results of a trial evaluating pamidronate in a similar population receiving cytotoxic chemotherapy have been reported previously.23
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PATIENTS AND METHODS
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Ambulatory women 18 years of age or older with a confirmed diagnosis of breast cancer and two or more predominantly lytic metastatic bone lesions were enrolled. At least one lytic lesion had to have a diameter of 1 cm or more and no radiation therapy within the 3 months before study entry. Women with only one lytic lesion were enrolled if that lesion was at least 1 cm in diameter with no previous radiation and if extraskeletal metastases were also present. All women provided written informed consent, and the study protocol was approved by the institutional review board or ethics committee at each participating center.
Enrolled women were to be receiving a stable hormonal therapy regimen for breast cancer at the time of randomization into the trial. Changes in the therapeutic regimen were allowed at any time during the study. Treatment with cytotoxic chemotherapy within 3 months before randomization disqualified a patient from entering onto the study. Patients beginning such therapy during the study continued in the trial. Chronic treatment with corticosteroids was not permitted, but acute or subacute treatment for indications such as spinal cord compression was allowed. Calcitonin and mithramycin were not permitted within 14 days preceding the trial but were allowed for on-study treatment of episodes of hypercalcemia. Previous treatment with pamidronate at any time or treatment with other bisphosphonates 60 days before or at any time during the trial was not allowed.
Patients were not to have had a skeletal event in the 2 weeks before trial entry and were to have an estimated life expectancy of 9 months with no significant renal, hepatic, or cardiac impairment. They were stratified into two groups by Eastern Cooperative Oncology Group (ECOG) performance status24 of 0 and 1 (stratum 1) or 2 and 3 (stratum 2). Patients were enrolled at 85 sites constituting the Aredia Protocol 18 Breast Cancer Study Group in the United States, Canada, Australia, and New Zealand from December 21, 1990, to June 23, 1995.
Eligible patients within each stratum were randomly assigned in equal numbers to receive either 90 mg of pamidronate (Aredia; Novartis Pharmaceuticals Corp, East Hanover, NJ), administered in 250 mL of 5% dextrose in water, or placebo, 250 mL of 5% dextrose in water, given as a 2-hour intravenous infusion every 4 weeks for 24 cycles. To maintain blinding to treatment assignment, infusions of pamidronate or placebo were prepared by the study pharmacist at each site according to a site-specific, computer-generated randomization list. The infusions were identical in appearance after preparation. Other study personnel, as well as the patients and investigators, remained unaware of the treatment assigned.
A sample size of 330 patients was needed to permit 80% power at a .05 two-sided level of significance to detect a 15% difference in the proportion of patients reporting any skeletal complication. A total of 350 enrolled patients was planned to compensate for the anticipated number of dropouts.
The trial was divided into two phases, the efficacy and safety phase (first 12 cycles of treatment), also referred to as phase I, and the safety phase (treatment cycles 13 to 24), also referred to as phase II. Several patients required more than 12 or 24 cycles for the assessment of skeletal complications because of delays in infusion of the study drug.
The primary analysis of efficacy for the trial was performed at the end of phase I. The double-blind administration of the study drug continued during phase II. The purpose of phase I of the trial was to determine whether pamidronate could prevent skeleton-related complications, whereas phase II was conducted to continue to assess the long-term benefit of pamidronate treatment (if any was detected during phase I) and to assess survival rates. During the trial, data on the occurrence of any skeletal complication, defined as pathologic fractures, irradiation of or surgery on bone, spinal cord compression, or hypercalcemia (as defined by the presence of symptoms or a serum calcium concentration, corrected for the serum albumin concentration, of at least 12.0 mg/dL [3 mmol/L]) were recorded. These complications were recorded until the patient completed the 24 cycles of therapy, discontinued the study drug, or died.
The primary efficacy variables in the trial were the skeletal morbidity rate (SMR) at the end of phase I and the survival rate at the end of phase II. The SMR is defined as the ratio of the number of skeletal complications experienced by a patient divided by the time on the trial by the end of the specified time period. The analyses of the other variables and all other time points described in this paper were considered secondary. No adjustments were made to the P values for the secondary analyses on multiple end points or multiple time points. The significance results for secondary variables and time points may be inflated. The analysis was performed on the modified intent-to-treat data set. In this data set, two patients who were randomized to receive placebo received pamidronate and were included in the analysis as pamidronate patients. One patient randomized to placebo was excluded from the analysis, because she did not have bone metastases at baseline. This patient was included in the survival analysis.
Secondary outcome measures of bone pain, analgesic use, quality of life, and performance status were also evaluated at each visit. Bone pain was evaluated using a scoring system that quantified both severity and frequency of bone pain. Bone pain scores were calculated by multiplying the score for pain severity (graded from 0 to 3) by the score for pain frequency (graded from 0 to 3). A score of 0 indicates no bone pain, and a score of 9 indicates constant, severe bone pain. Analgesic use was assessed as a composite narcotic score obtained by multiplying a score for the type of medication administered by the frequency of administration of bone pain medication. A decrease in bone pain or analgesic scores represented an improvement. Quality of life was determined using the Spitzer quality-of-life index.25 The Spitzer index primarily reflects physical functioning. Performance status was evaluated according to standard ECOG criteria.
The radiologic bone surveys were reviewed by a central radiologist who was unaware of the treatment assignment of individual patients. A skeletal radiologic survey was to be performed within 1 month before the trial and at 3, 6, 12, 15, 18, and 24 cycles or at the last visit for patients who prematurely discontinued the study. Responses in bone were categorized as complete response (complete recalcification of all osteolytic lesions), partial response (partial recalcification of one or more osteolytic lesions, with no new or progressing lesions), no change, mixed progression, failure, or not assessable. Bone markers (urinary calcium, hydroxyproline, creatinine, and serum bone alkaline phosphatase) were obtained at baseline and again at 6, 12, 18, and 24 cycles. Safety parameters included adverse clinical experiences, laboratory studies, and survival.
The Wilcoxon rank-sum test was used for between-treatment comparison of the overall SMR and of each individual type of skeletal complication at 6, 12, 18, and 24 cycles. The  2 test for between-treatment comparison of the proportion of patients having any skeletal complication by 6, 12, 18, and 24 cycles was performed for all skeletal complications and for each individual type of skeletal complication. Kaplan-Meier estimates of the time from randomization to the first occurrence of any skeletal complication (and each type of complication) within each treatment group were calculated; the log-rank test was used for between-treatment comparisons. Kaplan-Meier estimates of the time from randomization until death within each treatment group were calculated for all randomized patients, and the log-rank test was performed for the between-treatment comparison. All tests were performed at an alpha level of .05 (two sided).
Other parameters were evaluated using the Wilcoxon signed rank test to examine within-treatment group changes, whereas the between-treatment comparisons of the changes from baseline in these variables were analyzed with the Wilcoxon rank-sum test. A 2 test was used to evaluate the between-treatment comparison of the objective response rate (complete or partial response) for radiologic results on osteolytic lesions.
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RESULTS
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Three hundred seventy-two women were enrolled onto the study (182 women to pamidronate and 189 to placebo) (Fig 1). One patient did not have documented bone metastasis and was not treated or included in efficacy analyses but was included in the survival analysis. Eighty-four percent of the patients were enrolled at 64 sites in the United States. The remaining patients were enrolled at sites in Canada (7%), Australia (5%), and New Zealand (3%). The baseline demographic and disease-specific characteristics of the 371 women included in all analyses were comparable between the two treatment groups (Table 1). The most common reasons for premature discontinuation were an adverse experience (20% pamidronate group, 16% placebo group), death (19% pamidronate group, 11% placebo group), and refusal to continue therapy (14% pamidronate group, 18% placebo group).
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Fig 1. Flow diagram of patient disposition. *Two patients randomized to placebo were included in the pamidronate group because the majority of infusions they received were pamidronate. **One patient in the placebo group was excluded from the efficacy analysis because she was determined not to have bone metastases.
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Table 1. Characteristics of the 371 Patients Included in the Intent-to-Treat Analysis, According to Treatment Group
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Skeletal complication data were collected only while patients were on study treatment. The median duration on study treatment was 17.4 months for the pamidronate group and 14.6 months for the placebo group. Survival information was collected at regular intervals for all patients until death or the prespecified analysis cutoff point (April 1, 1996). The median follow-up time (Kaplan-Meier estimate) for the survival analysis was 36.8 months for the pamidronate group and 37.1 months for the placebo group.
More than 95% of the women in each group had received tamoxifen, and half of the women in each group had received chemotherapy before entering onto the study. At baseline, tamoxifen and megestrol were each being prescribed for approximately 40% of the women in each group. During the study, both hormonal and antitumor therapies were prescribed in the two treatment groups. Megestrol acetate, the most commonly used hormonal agent, was administered to 52% and 61% percent of patients in the pamidronate and placebo groups, respectively. Fluorouracil, the most commonly prescribed chemotherapy agent, was used in 32% of women in the pamidronate group and 30% of women in the placebo group. One third of patients in both groups remained on the same anticancer regimen during the trial. In both groups, one third of the patients had one additional anticancer regimen added, and one third had two or more changes in their anticancer regimens. Other medications, including antibiotics, antiemetics, cytokines, and blood products, were also used in similar proportions of patients in each treatment group.
There were 475 skeletal complications in the pamidronate group and 648 in the placebo group. The overall SMR was significantly lower in the pamidronate group than in the placebo group at 12, 18, and 24 cycles (Table 2). For individual types of skeletal complications, the SMR for pathologic fractures was significantly lower in the pamidronate group than in the placebo group at 18 and 24 cycles, whereas the SMR for any radiation to bone and for radiation to bone for pain relief was significantly lower in the pamidronate group than in the placebo group at 6, 12, 18, and 24 months. A statistically significant difference in favor of pamidronate was also observed at 24 months for the SMR for hypercalcemia.
The proportion of patients having any skeletal complication (Table 3) was significantly lower in the pamidronate group than in the placebo group at 24 cycles (P = .027). By 24 cycles, the odds ratio of having an event on placebo to that on pamidronate was 1.6 (95% confidence interval [CI], 1.1 to 2.5). The most common type of skeletal complication was pathologic fracture, which occurred in 45% of patients in the pamidronate group and 55% of patients in the placebo group by 24 cycles (P = .054). The proportion of patients in the pamidronate group who had any radiation to bone was significantly lower than that in the placebo group at 6 and 12 cycles, whereas the proportion in the pamidronate group who had radiation to bone for pain relief was significantly lower than that in the placebo group at 6, 12, and 24 cycles. The proportion of patients in the pamidronate group with hypercalcemia was significantly lower than in the placebo group at 24 cycles. Only 4% of patients in the pamidronate group and 3% of patients in the placebo group had spinal cord compression.
The median time to the first skeletal complication was 10.4 months for patients receiving pamidronate versus 6.9 months for those receiving placebo (P = .049 by the log-rank test) (Fig 2). The times to the first radiation to bone (P = .016), first radiation to bone for pain relief (P = .010), and first episode of hypercalcemia (P = .018) were also longer in the pamidronate group than in the placebo group.
Eighty-eight percent of patients in the pamidronate group and 89% of patients in the placebo group had both a baseline and follow-up radiologic evaluation assessable for response. There were no complete responses. Thirty percent of patients in the pamidronate group and 24% of patients in the placebo group had a partial response by the 24th cycle (P = .202 by 2 test).
Bone pain scores improved from baseline during the first year of treatment in the pamidronate group but worsened in the placebo group, with a statistical difference between the two groups at 12 cycles (P = .002). At the final measurement, bone pain scores had increased (worsened) significantly more in the placebo group than in the pamidronate group (P = .007) (Fig 3). Mean analgesic use at 12 cycles and at the final measurement also increased significantly more from baseline in the placebo group than in the pamidronate group (P = .001 and P < .001, respectively). ECOG performance status and Spitzer quality-of-life scores worsened from baseline in both treatment groups, with no statistically significant difference between the two groups.
Urine hydroxyproline/creatinine and urine calcium/creatinine ratios showed median decreases of 18% and 42%, respectively, in the pamidronate group, and median increases of 13% and 25%, respectively, in the placebo group (P < .001) (Fig 4). Serum bone alkaline phosphatase levels showed a median decrease of 39% in the pamidronate group and a median increase of 2% in the placebo group (P < .001).
The only adverse experiences that occurred in at least 10% more patients in the pamidronate group than in the placebo group during the study were vomiting and fatigue. Toxicities commonly associated with chemotherapy were not more frequent or severe in the pamidronate group, except for leukopenia, which occurred slightly more frequently in the pamidronate group (9%) than in the placebo group (4%). Injection site reactions occurred in 6% of patients in the pamidronate group compared with 0.5% of patients in the placebo group. Hypocalcemia occurred in three patients in each group.
Three serious adverse experiences, two in the pamidronate group and one in the placebo group, were considered to be possibly related to the study drug. One patient in the pamidronate group was diagnosed with interstitial pulmonary infiltrates and dyspnea several days after the first treatment. Another patient in the pamidronate group discontinued the study owing to an allergic reaction in the left eye. A patient in the placebo group discontinued the study after developing cellulitis within 24 hours of study drug infusion.
The median estimate of survival was 23.2 months (95% CI, 19.3 to 25.8 months) for the pamidronate group and 23.5 months (95% CI, 18.7 to 27.4 months) for the placebo group (P = .685). An exploratory analysis was conducted to determine different subgroups of patients with respect to survival. These results showed that within the subgroup of women 50 years of age or younger, survival was longer with pamidronate (median estimate, 26 months) than with placebo (median estimate, 18 months; P = .029 by univariate log analysis). The significance of this finding may be inflated, as this was a subgroup analysis, and the overall survival rates are not significantly different.
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DISCUSSION
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We found that women with breast cancer and lytic bone disease who received intravenous pamidronate as adjunctive therapy to systemic hormonal treatment had fewer skeletal complications than women who received placebo and systemic hormonal treatment. The rate of skeletal complications was significantly lower at 1 year (12 cycles) for pamidronate-treated patients than for those receiving placebo and remained so after 2 years (24 cycles) of treatment. In addition, the proportion of patients treated with pamidronate who experienced skeletal complications was lower than the proportion of patients in the placebo group, and the time to the first skeletal complication was significantly longer for those treated with pamidronate than for those treated with placebo.
Because there were no constraints on the selection of anticancer treatment after enrollment, a significant proportion of patients in both groups received cytotoxic chemotherapy during the course of the trial. Thus, the results in this trial were obtained in a population of women with metastatic breast cancer who received the standard care prescribed by their physicians for the stage of their disease.
Our results in this study are consistent with those reported in two previous large randomized studies in patients with bone metastases in showing a decreased rate of skeletal complications and increased time to first skeletal complication in patients treated with intravenous pamidronate compared with those treated with placebo. In 380 metastatic breast cancer patients receiving cytotoxic chemotherapy at the start of the study, 43% of women in the pamidronate group compared with 56% of women in the placebo group had experienced a skeletal complication after 1 year (12 cycles) of treatment (P = .008), and the median time to the first complication was 13.1 versus 7.0 months (P = .005).23 In 392 patients with stage III multiple myeloma, a disease in which the clinical picture is often dominated by osteolysis, the proportion of patients with a skeletal complication after nine cycles (9 months) was 24% in the pamidronate group and 41% in the placebo group (P = .001), and the time to the first complication was again significantly shorter for the pamidronate group (P = .001).26 In all three studies, the most common complications were pathologic fractures and the need for radiation to bone, and in all three studies, the occurrence of these complications was significantly decreased by pamidronate. The pattern of response to pamidronate is therefore similar in osteolytic bone lesions of either solid tumor or hematologic tumor origin, consistent with the inhibition of osteoclastic bone resorption as the common mechanism of action.
The results of these large, randomized trials confirm and expand upon earlier reports of intravenous pamidronate treatment for osteolysis due to metastatic breast cancer.12-14,21 In the largest of these studies,21 60 women were randomized to one of four treatment groups to receive either 30 mg or 60 mg of pamidronate every 2 weeks or 60 mg or 90 mg every 4 weeks. All doses except the 30-mg dose resulted in significant improvement in bone pain and decreases in biochemical markers of bone resorption. In the only other published randomized trial evaluating intravenous pamidronate given in addition to endocrine treatment for bone metastases in advanced breast cancer, 82 postmenopausal women received aminoglutethimide with or without 30 mg of pamidronate given every 3 weeks. No difference in bone complications or radiologic response was observed during the 36-week study.16 The lower dose of pamidronate and shorter study duration may explain the difference from our results.
Several studies of oral clodronate and pamidronate in the treatment of bone metastases have also reported results favoring bisphosphonate therapy given in combination with conventional anticancer therapy, compared with conventional therapy alone.17,27,28 However, poor bioavailability and gastrointestinal side effects limit the use of oral bisphosphonates for extended clinical use.20,29,30
Patients treated with pamidronate in our study experienced a decrease in bone pain over the first year of the study. Although an increase in bone pain scores was reported at the second year time point for both groups in this study, the difference from placebo continued to be significant in favor of pamidronate. Unlike the trials in breast cancer patients receiving cytotoxic therapy and in multiple myeloma patients, performance status and quality-of-life evaluations in this study did not mirror the bone pain results in this trial. This may be attributable to the additional year of follow-up time, during which progression of the underlying disease continued in most patients.
Pamidronate induced a sustained reduction in biochemical markers of bone resorption and formation, whereas these parameters increased in the placebo group. These results are consistent with the known mechanism of action of pamidronate in inhibiting osteoclast function.19,20 With prolonged inhibition of resorption, bone formation may decrease, because the two processes are coupled in the bone remodeling cycle.31 Although bone histomorphometry was not part of our study, the clinical results showing fewer pathologic fractures in the pamidronate group indicate that there were no adverse clinical consequences of decreased bone formation in a setting of inhibited bone resorption.
The 90-mg infusions were well tolerated. Survival did not differ between the two treatment groups overall, nor was there any effect on the number of antineoplastic regimens used during the trial.
In summary, treatment with 90 mg of pamidronate as a 2-hour infusion every 4 weeks as a supplement to hormonal therapy in women with breast cancer and lytic bone lesions resulted in fewer skeletal complications and conferred meaningful clinical benefits for up to 2 years, compared with anticancer therapy alone.
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APPENDIX
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The following principal investigators of the Protocol 18 Aredia Breast Cancer Study Group participated in this study: United States: L. Baker, Ann Arbor, MI; T. Beck, Boise, ID; A. Benson, Chicago, IL; S. Berlin, Gloucester, MA; D. Blayney, Los Angeles, CA; B. Boston, Memphis, TN; E.L. Braud, Springfield, IL; R.J. Brooks, Tucson, AZ; J.T. Carpenter, Birmingham, AL; J.B. Craid, Shreveport, LA; K. Cryar, Temple, TX; F.J. Cummings, Providence, RI; D. Decker, Royal Oak, MI; A. Desai, Philadelphia, PA; T. Dobbs, Knoxville, TN; G. Edwards, Santa Barbara, CA; P. Eisenberg, Greenbrae, CA; J.E. Feldman, Mobile, AL; W. Fintel, Salem, VA; S. Flamm-Honig, Washington, DC; P.J. Flynn, Minneapolis, MN; S. George, Rancho Mirage, CA; D. Glover, Philadelphia, PA; F. Gonzalez, Columbia, SC; G. Gross, Tyler, TX; J. Harris, Fargo, ND; S. Jones, Dallas, TX; G. Justice, Fountain Valley, CA; C. Kardinal, New Orleans, LA; A. Kaufman, Sellersville, PA; A. Keller, Tulsa, OK; R. Kerr, Austin, TX; J. Kessler, Hampton, VA; W. Kincaid, Johnson City, TN; D.D. King, Phoenix, AZ; J. Lamon, Poway, CA; R. Leff, Atlanta, GA; I. Lerner, St. Paul, MN; A. Lipton, Hershey, PA; J.M. Long, Travis AFB, CA; J. Mailliard, Omaha, NE; R. Meyer, Cincinnati, OH, R. Navari, Birmingham, AL; B.M. Needles, St. Louis, MO; D. Osborn, Olympia, WA; C.K. Osborne, San Antonio, TX; T. Panella, Knoxville, TN; K. Pendergrass, Kansas City, MO; M. Perry, Columbia, MO; E. Pollard, Corpus Christi, TX; L. Porter, Nashville, TN; G. Rausch, Frederick, MD; S. Richman, Miami, FL; S. Rossman, Van Nuys, CA; J. Sandbach, Austin, TX; M. Sangosse, Newark, NJ; H. Sher, Jacksonville, FL; G. Smith, Santa Rosa, CA; J. Sparano, Bronx, NY; R. Stoltz, Evansville, IN; R. Theriault, Houston, TX; J. Trauscht, Missoula, MT; J.L. Wade, III, Decatur, IL; J. Ward, Salt Lake City, UT. Canada: S. Allan, Victoria, BC; S. Glück, Sudbury, ON; M. Lepine, Sherbrooke, QC; J. Skillings, Halifax, NS; S. Vass, Chicoutimi, QC; D. Vergidis, Thunder Bay, ON; J. Wilson, Weston, ON; L. Yelle, Montreal, QC. Australia: R. Basser, Melbourne, VIC; R. Bell, Ballaret, VIC; D. Dalley, Sydney, NSW; R. Murray, Melbourne, VIC; K. Phadke, Sydney, NSW; J. Stewart, Newcastle, NSW; H. Wheeler, Sydney, NSW. New Zealand: S. Allan, Palmerston North; W.J. Childs, Auckland; S.A. Costello, Dunedin; and I. Kennedy, Hamilton.
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NOTES
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This study was supported by a grant from Novartis Pharmaceuticals, East Hanover, NJ.
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Submitted June 4, 1998;
accepted November 20, 1998.
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TOP
ABSTRACT
INTRODUCTION
