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Journal of Clinical Oncology, Vol 18, Issue 13 (July), 2000: 2545-2552
© 2000 American Society for Clinical Oncology

Gemcitabine in Combination With Doxorubicin in Advanced Breast Cancer: Final Results of a Phase II Pharmacokinetic Trial

By G. Pérez-Manga, A. Lluch, E. Alba, J. A. Moreno-Nogueira, M. Palomero, J. García-Conde, D. Khayat, N. Rivelles

From the Hospital Gregorio Mara-ñ-ón, Madrid, Hospital Clínico Universitario, Valencia, Hospital Clínico de la Virgen Victoria, Málaga, and Hospital Virgen del Rocío, Seville, Spain, and Hôpital de la Pitié-Salpêtrière, Paris, France.

Address reprint requests to G. Pérez-Manga, MD, Medical Oncology Department, Institute of Oncology, Hospital Gregorio Mara-ñ-ón, c/Maiquez, 7.28007 Madrid, Spain.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Gemcitabine has promising single-agent activity in advanced breast disease. The aim of this phase II study was to determine the efficacy, toxicity, and pharmacokinetic profile of gemcitabine administered with doxorubicin as first-line treatment in patients with metastatic breast cancer.

PATIENTS AND METHODS: Of the 42 women with metastatic breast cancer (age 33 to 74 years; mean age, 55 years), 13 were chemotherapy-naive and 29 had received adjuvant chemotherapy. Gemcitabine (800 or 1,000 mg/m2) and doxorubicin (25 mg/m2) were administered intravenously on days 1, 8, and 15 of each 28-day cycle. Blood samples were drawn on day 8 of cycles 1, 2, and 3 and of subsequent odd cycles for gemcitabine pharmacokinetic determinations and before and after the first dose of cycle 1 or 2 for doxorubicin determinations.

RESULTS: There were three complete and 20 partial responses, for an overall response rate of 55% (95% confidence interval [CI], 40% to 70%) and a complete response rate of 7%. The median survival time for all 42 patients was 27 months (95% CI, 13.4 to 30.0 months) and the 1-year survival rate was 80%. Toxicity was mainly hematologic. The disposition of both drugs was unchanged when they were administered on the same day compared with when they were given singly.

CONCLUSION: The combination of gemcitabine (800 mg/m2) and doxorubicin (25 mg/m2) can be safely administered using a weekly schedule. The disposition of both drugs is unchanged when they are administered on the same day. This combination shows promising activity with acceptable toxicity compared with other combination therapies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
DESPITE THE AVAILABILITY of a wide variety of chemotherapeutic agents with known activity against advanced breast cancer, either singly or in combination, fewer than one in five patients is alive 5 years after the diagnosis of metastatic disease.1 In such advanced disease, the principal goal of the therapist is palliation of symptoms, with maximum benefit being achieved with minimal toxicity. It may also be useful to combine drugs with different resistance patterns, although toxicity is a primary concern to the therapist. For example, the main adverse effects of anthracycline therapy are acute myelosuppression, mucositis, and cumulative cardiac toxicity. The novel nucleoside analog gemcitabine offers proven activity against a range of solid tumors2-9 and combines therapeutic efficacy with low systemic toxicity and high patient tolerability.10,11 To date, the efficacy data for single-agent gemcitabine in the treatment of advanced breast cancer range from no objective response, in the first phase II study that took place in the United States,9,12 to response rates of 25% to 46%,8,13,14 depending on the starting dose and whether the patients had received previous chemotherapy for metastatic disease and/or adjuvant chemotherapy.

Thus, gemcitabine plus doxorubicin is a logical combination for the treatment of patients with metastatic breast cancer. An aim of the present study was to determine the efficacy and toxicity profile of gemcitabine plus doxorubicin, drugs that are considered efficacious when administered singly but that could be given in combination in a schedule that has been used in many other gemcitabine studies. The pharmacokinetic objective of the study was to determine whether the disposition of gemcitabine and/or doxorubicin was altered when both compounds were administered on the same day.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This multicenter phase II study of gemcitabine and doxorubicin therapy, administered to patients with metastatic breast carcinoma, was conducted according to the guidelines for good clinical practice and was approved by the ethical committees of all of the referring hospitals. Signed informed consent was obtained from all patients before enrollment.

Patient Eligibility
Patients were enrolled onto the study only if they met all of the following criteria: histologic or cytologic diagnosis of stage IV disease, initially diagnosed as stage IV or distant recurrence from any other stage (according to the American Joint Committee on Cancer classification), which was not amenable to surgery or radiotherapy with curative intent; age >= 18 years; Karnofsky performance status >= 60; bidimensionally measurable disease; estimated life expectancy >= 12 weeks; no previous chemotherapy except adjuvant chemotherapy administered >= 1 year before enrollment; normal left ventricular ejection fraction (LVEF), determined by scintigraphy or echocardiography; adequate bone marrow reserve (WBC count >= 3.5 x 109/L, platelet count >= 100 x 109/L, hemoglobin level >= 100 g/L, hematocrit >= 30%); adequate liver function (bilirubin level <= 1.5 mg/dL, ALT and AST levels <= three times normal values; ALT and AST levels <= five times normal limits allowed in patients with known liver metastases); adequate renal function (plasma creatinine level <= 1.5 times normal value); normal serum calcium level; and doxorubicin dose less than 300 mg/m2 or epirubicin dose less than 540 mg/m2, if these drugs were given in the adjuvant setting. Prior radiation therapy was allowed if it had been administered at least 4 weeks before enrollment and if the irradiated field was not the only site of measurable disease. Previous endocrine treatment in the 4 weeks before enrollment was not allowed. Patients were excluded if they were pregnant or possibly pregnant, had CNS metastases, had active infection or serious concomitant systemic disorders, or had second primary malignancies (except cervical carcinoma-in-situ or adequately treated basal cell carcinoma of the skin). Mediastinum irradiation plus anthracycline-based adjuvant chemotherapy was also an exclusion criterion, as was the use of other investigational agents in the month before enrollment onto the study.

The clinical status of each patient was assessed not more than 1 week before enrollment. Assessments included taking of medical history, physical examination, height and weight measurements, evaluation of performance status, measurement of palpable or visible lesions, and chest radiography. Not more than 3 weeks before enrollment, patients were assessed (if necessary for tumor measurement or if clinical or laboratory data suggested the presence of disease in a site or sites in which tumor measurement was not possible by the methods just described) by computed tomography, magnetic resonance imaging, nuclear medicine, or ultrasound. Not more than 2 weeks before enrollment, blood pressure and heart rate were measured and routine blood chemical analysis, blood cell counts, coagulation analysis, urinalysis, and electrocardiographic measurements were performed.

Hematologic analysis was repeated weekly. Biochemical analysis, urinalysis, and electrocardiographic measurements were performed on day 1 of each 28-day cycle, before gemcitabine and doxorubicin administration. Blood pressure and heart rate measurements were obtained before and after every infusion. Before every other therapy cycle, the LVEF was determined by scintigraphy or echocardiography, and chest radiography and radiologic imaging were performed to assess disease status.

Treatment
Both gemcitabine and doxorubicin were administered intravenously on an outpatient basis. Gemcitabine 800 mg/m2 was given as a 30-minute infusion on days 1, 8, and 15 of each 28-day cycle to the first six patients, who were considered a pilot group for the study. This dose was increased to 1,000 mg/m2 for patients no. 7 through 12, but because of toxicity the dose was reduced to 800 mg/m2 for patients no. 13 through 42, according to the protocol design. Doxorubicin was administered at a dose of 25 mg/m2 after the gemcitabine infusion on days 1, 8, and 15 of each cycle. Treatment was continued for a maximum of eight cycles after the best response was achieved, or until disease progression. The maximum cumulative dose of doxorubicin was 550 mg/m2, or 400 mg/m2 for patients who had undergone prior mediastinum irradiation.

Pharmacokinetic Evaluation
The study was prospectively designed to include a sparse sampling strategy to support pharmacokinetic analysis. Pharmacokinetic evaluation was conducted to verify that the plasma concentrations of gemcitabine were similar to those in female members of a reference population, and to investigate whether the concentrations were affected by doxorubicin cotherapy. The pilot group of six patients provided blood samples for determination of concentrations of gemcitabine; its deaminated metabolite, difluoro-deoxyuridine (dFdU); and doxorubicin. In the case of the first three patients, multiple samples were taken at predetermined times over a 72-hour period during the first dose of cycles 1 and 3. A single sample was taken from each of these patients during the first dose of cycle 2 and subsequent odd cycles. In the case of the second set of three patients, multiple blood samples were collected at predetermined times over a 72-hour period during the first dose of cycle 2, and a single sample was taken from each of the three patients during cycles 1 and 3 and subsequent odd cycles. These sampling schedules were used so that the gemcitabine data would be comparable with data generated from the reference population using sparse sampling, whereas the pharmacokinetics of doxorubicin were generated using a conventional noncompartmental analysis.

The reference population comprised 228 patients, of whom 61 were women and 167 were men. Approximately 70% of these patients had non–small-cell lung cancer. A wide range of gemcitabine doses (500 to 3,600 mg/m2) was administered to this reference population.

Data were analyzed by population pharmacostatistical modeling and noncompartmental pharmacokinetic analysis. The population analysis used a two-compartment model expressed in terms of the parameters systemic clearance, central and peripheral volumes of distribution, and intercompartmental flow rate. This model included previously identified covariates such as age and body-surface area. Estimates of parameters and variances were obtained by fitting the model to the data using the nonlinear mixed-effects model (NONMEM, version V) program.

Noncompartmental pharmacokinetic analysis was applied to plasma doxorubicin concentration–time data obtained during cotherapy with gemcitabine. The elimination rate constant (8z) was determined as the slope of the linear regression for the terminal log–linear portion of the concentration-time curve. A terminal half-life value was calculated as ln(2)/8z. Area under the plasma concentration versus time curve and area under the first moment curve were calculated by the trapezoidal method and extrapolated to infinite time using the predicted concentration () at the last measurable sampling time. Mean residence time, plasma clearance, and volume of distribution at steady-state were also calculated using standard methods.

Gemcitabine and Doxorubicin Dose Modifications
Dose adjustments were made as follows during the cycle in which toxicity was experienced: In the case of hematologic toxicity, gemcitabine and doxorubicin doses were reduced by 25% (when granulocyte counts were between 1,000 and 1,500 x 106/L and/or platelet counts were between 50,000 and 100,000 x 106/L) or were reduced by 50% or withheld, depending on clinical judgment (when granulocyte counts were less than 999 x 106/L and/or platelet counts were less than 50,000 x 106/L). In the case of World Health Organization (WHO) grade 3 nonhematologic toxicity, with the exception of nausea and vomiting and alopecia, doses of both gemcitabine and doxorubicin were reduced by 50% or withheld, depending on clinical judgment. Patients with WHO grade 4 nonhematologic toxicity had their doses withheld, at the discretion of the investigator.

The dose of doxorubicin was reduced by 50% if bilirubin concentrations increased to 1.5 to 3 mg/dL. If bilirubin concentrations increased to more than 3 mg/dL, doxorubicin was administered at 25% of the starting dose or not given, depending on the judgment of the clinician. With regard to cardiac toxicity, doxorubicin was withheld if the height of the QRS complex as determined by electrocardiography decreased by >= 30% during therapy, the LVEF was less than 45%, the total decrease was >= 10% of the LEVF, or clinical cardiac failure was evident.

Response Criteria
WHO response criteria were used throughout. Disease was measured using the product of the perpendicular bidimensional diameters of disease determined by physical examination, chest radiography, computed tomography, or magnetic resonance imaging. Complete responders had no evidence of disease and were free of symptoms. Partial responders had more than a 50% reduction in their carcinomas and no new lesions. Responses were objectively assessed after every other cycle (ie, every 8 weeks) using appropriate radiologic techniques, and they had to be maintained for a minimum of 4 weeks to qualify as partial or complete responses. Durations of response were measured from the first infusion. Responses and survival were calculated on an intent-to-treat basis. All responses were reviewed and validated by an independent, external oncology review board.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Forty-two patients from one French and four Spanish hospitals were entered onto the study between April 1994 and July 1996. All 42 patients were eligible for safety analysis and response assessment. The basic characteristics of all eligible patients are listed in Table 1. The sites of secondary disease are listed in Table 2.


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  		Table 1. Patient Characteristics
 

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  		Table 2. Sites of Disease
 
Two hundred twenty-eight cycles were administered (median, seven per patient; range, one to nine). Thirty cycles were given at a gemcitabine dose of 1,000 mg/m2. The median numbers of doses per infusion were 832 mg/m2 for the six patients treated with gemcitabine 1,000 mg/m2, and 600 mg/m2 for those treated with gemcitabine 800 mg/m2. The median dose per infusion of doxorubicin was 20.0 mg/m2. In the case of patients given gemcitabine 800 mg/m2 in combination with doxorubicin, 15% of the scheduled doses were omitted, 35% were reduced, and 2% were delayed. In the case of the six patients administered gemcitabine 1,000 mg/m2 with doxorubicin, 8% of the scheduled doses were omitted, 40% were reduced, and 1% were delayed. Given that only 30 cycles were administered at the higher dose of gemcitabine, no significant conclusions can be drawn from these differences. Dose omissions and reductions were more frequent on day 15 (66% of doses were omitted and 81% were reduced) than on either day 1 (21% were omitted and 27% were reduced) or day 8 (36% were omitted and 48% were reduced). The main reasons for dose modifications were neutropenia and thrombocytopenia.

Toxicity
All of the toxicities were calculated for each patient, and those reported are the worst recorded for each patient. Toxicity was primarily hematologic (Table 3). Nine patients (21%) had grade 4 neutropenia. Febrile neutropenia was seen in only two patients, one of whom died. That patient was a 73-year-old woman with skin, soft tissue, lymphatic, and bone disease and cord compression. After receiving radiotherapy from day 5 to day 10, she started chemotherapy. After three doses of gemcitabine 1,000 mg/m2 and doxorubicin, the patient was found to have bilateral lung infiltrate, severe dyspnea, and mild (grade 2) neutropenia. The patient died after treatment with broad spectrum antibiotics. An autopsy was not performed, but further review of her earlier x-rays revealed that she had had bilateral undiagnosed pneumonia at the time of enrollment.


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  		Table 3. Hematologic Toxicity
 
There were three non–treatment-related deaths during the study. One patient who died was a 54-year-old woman with liver, lung (lymphangitis), and bone involvement. At the beginning of the study, the patient was receiving concomitant medication, including an anticoagulant (low molecular weight heparin), and oxygen at home and had a performance status of 60. After two infusions of both gemcitabine and doxorubicin, she was found to have severe myelosuppression with neutropenia and grade 4 thrombocytopenia. She received platelet transfusions and her platelet count increased to more than 100,000 x 106/L. While being transferred to another hospital, however, she died with hemoptysis and melena. The day before her death, her prothrombin time (12.4 seconds) and partial thromboplastin time (36.4 seconds) were almost normal (normal times, 12.1 and 33.0 seconds, respectively). However, the fact that low molecular weight heparin was used means that a coagulation disorder induced by the heparin cannot be completely ruled out. Her previous bone scan showed no disease, but it is not known whether there was bone marrow involvement. This death therefore was not considered to be related to the treatment. The other two deaths on study were a death as a result of disease progression in the lung and a sudden death after a hypertensive crisis.

Other toxicities that occurred included alopecia, transient increases in transaminase levels (grade 3: three patients), mucositis (grade 3: three patients), and nausea and vomiting, which were usually well controlled (Table 4). There did not seem to be any significant differences in toxicity between patients who received the lower dose of gemcitabine (800 mg/m2) and those who received the higher dose (1,000 mg/m2). There was a higher incidence of grade 4 neutropenia in the low-dose group (25% [nine patients]) than in the high-dose group (0%). However, given the small number of patients in the latter group (six), no outcome assessments can be made. Six patients had abnormal electrocardiographic readings, but five of these had normal echocardiographic or scintigraphic findings; the remaining patient had decreasing cardiac ejection, but this was without clinical consequence.


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  		Table 4. Nonhematologic Toxicity
 
Response to Therapy
Among 42 assessable patients, there were three complete responses (7% complete response rate) and 20 partial responses to gemcitabine and doxorubicin (Table 5). The overall response rate was 55% (95% confidence interval [CI], 40% to 70%). Of the remaining 19 patients, 13 had stable disease, four had progressive disease, and two died early (one from septic shock, the other suddenly) without re-evaluation. Two of the 13 patients classified as having stable disease had unconfirmed partial responses, and there was one patient who had an unconfirmed complete response. These three patients had survival times of 13.0, 12.8, and 24.3 months, respectively. In total, seven patients with stable disease remained alive. As a result, the median survival time for patients with stable disease has not yet been reached, but it is expected to be more than 24 months.


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  		Table 5. Response to Treatment With Gemcitabine and Doxorubicin
 
Responses were seen in 14 patients with soft tissue disease (breast and lymph nodes), eight patients with liver metastases, and nine with pulmonary disease. One of the 33 patients who responded to treatment had a well-differentiated tumor, seven had moderately differentiated tumors, two had poorly differentiated tumors, one had an undifferentiated tumor, and 12 had tumors of unknown histology.

Three responders were estrogen receptor–negative, two were estrogen receptor–positive, and estrogen receptor status was unknown in 18 responders. Seven of the 23 responders had received hormonal treatment. Eleven of the 23 had received previous adjuvant chemotherapy, five with anthracyclines. One had received previous chemotherapy for metastatic disease. This patient was treated in one hospital and then transferred to another hospital and entered onto the study before her records were transferred. Although this was a protocol violation, the patient fulfilled all criteria for evaluation of efficacy and was therefore allowed to remain on study for ethical reasons.

The median duration of response was 12 months (range, 8.4 to 17.5 months). The Kaplan-Meier duration of response curve for all patients is shown in Fig 1. Median time to response was 2 months (range, 1.7 to 2.5 months), and median time to progressive disease was 11.5 months (range, 7.2 to 18.1 months).



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  		Fig 1. Kaplan-Meier response duration curve.

 
The median duration of survival for all 42 patients was 27 months (95% CI, 13.4 to 30.0 months), and the 1-year survival rate was 80%. The Kaplan-Meier survival curve for all patients is shown in Fig 2. Eighteen patients (42%) were alive after 2 years.



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  		Fig 2. Kaplan-Meier survival curve for all patients.

 
Pharmacokinetic Data
The results of the population analysis of gemcitabine pharmacokinetics are presented in Table 6. Plasma concentrations of gemcitabine and dFdU varied with respect to dose, sampling time, duration of infusion, and patient age. Plasma gemcitabine concentrations as a function of time are shown in Fig 3. Concentrations achieved were similar to those previously noted in the reference female population (Table 7)15,16 and to data held on file by Eli Lilly & Co, Indianapolis, IN. This confirmed that cotherapy with doxorubicin did not significantly affect gemcitabine disposition.


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  		Table 6. Population Pharmacokinetic Model for Gemcitabine in Combination With Doxorubicin
 


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  		Fig 3. Plasma gemcitabine concentrations as a function of time.

 

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  		Table 7. Population Estimates for Gemcitabine for the Present Study and the Reference Study
 
The results of the noncompartmental analysis of doxorubicin pharmacokinetics are presented in Table 8. There was considerable variation in the plasma doxorubicin concentrations of the six patients tested, but this variation was principally due to the data from one patient and was not inconsistent with the between-patient variability reported in other studies.17-19


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  		Table 8. Mean Doxorubicin Parameter Estimates for the Present Study and Published Values17,19
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Reported rates of response to single-agent treatment by patients with advanced metastatic breast cancer include the following: 25% for carboplatin,20 47% for doxorubicin,21 43% for epirubicin,22,23 and 41% for vinorelbine24 therapies. Also reported were response rates of 26% and 56% in two separate nonrandomized studies in which single-agent paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ) was used to treat patients who had received prior chemotherapy.25,26 All of these response rates were achieved with high levels of toxicity. In one study of paclitaxel therapy (200 to 250 mg/m2 in a 24-hour infusion), 47% of patients experienced grade 4 neutropenia.27 Cumulative peripheral neurotoxicity with severe paresthesias has been a clinical issue. In randomized trials, initially observed promising response rates associated with single-agent paclitaxel therapy have not been maintained.28,29 The combination of doxorubicin and paclitaxel, though having a response rate of 94%, was associated with cumulative cardiac toxicity and short response duration.30 The main adverse events of anthracycline therapy are acute myelosuppression, mucositis, and cumulative cardiac toxicity, whereas the dose-limiting toxicities of paclitaxel are mucositis and neutropenia. Paclitaxel therapy is also associated with cardiovascular complications, including asymptomatic bradycardia, atrioventricular block, and ventricular tachycardia. Paclitaxel use has also been associated with signs of cardiac ischemia.31 In contrast, gemcitabine has no apparent multidrug resistance and has activity in patients previously treated with anthracyclines.8 Gemcitabine has a mild hematologic toxicity profile and is generally well tolerated by patients. Thus, it was logical to combine doxorubicin with gemcitabine, given gemcitabine’s novel mechanism of action, mild toxicity profile, and known single-agent activity in advanced breast cancer.

The findings of the present study are encouraging. The response rate of 55% is consistent with the responses obtained with standard combination therapies.32 This activity was achieved without any significant increase in high-grade toxicity as a consequence of combining the two drugs. In particular, cardiac toxicity was uncommon. There was a low incidence of patient hospitalization and a reduced need for supportive intervention (eg, blood product transfusions). Time-to-event data are encouraging: the overall survival time was 27 months (95% CI, 13.4 to 30.0 months), the 1-year survival rate was 80%, and 18 patients remained alive at 2 years. There was only one death on study that was thought to be related to the study therapy and the patient’s disease. Given the small number of study patients, this is within normal limits. There was no indication that the combination used in this study results in unexpected mortality.

The combination of gemcitabine and doxorubicin did not significantly affect the pharmacokinetics of either drug. Although this was the expected outcome (given the different metabolic pathways of the two drugs), ours was the first study of the combination in this patient population and therefore a pharmacokinetic analysis was believed necessary. The range of gemcitabine concentrations in the study patients receiving combination therapy was similar to that in the reference female population treated with gemcitabine alone. Doxorubicin is rapidly metabolized by the liver and is excreted, with its metabolites, principally in the bile. Gemcitabine, on the other hand, is metabolized to dFdU and is mainly excreted in urine.

In conclusion, the combination of gemcitabine and doxorubicin is active in women with metastatic breast cancer. The response rate of 55%, median duration of response of 12 months, and median duration of survival of 27 months compare favorably with results from other studies. Toxicities were generally manageable and well tolerated, and pharmacokinetic studies confirmed that the disposition of both drugs was unchanged when they were given on the same day compared with when they were given singly. Results from this study suggest that the combination of gemcitabine and doxorubicin warrants further investigation in larger, randomized clinical trials.


   ACKNOWLEDGMENTS
 
Supported by Eli Lilly & Co, Indianapolis, IN.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Parker SL, Tong T, Bolden S, et al: Cancer statistics, 1996. CA Cancer J Clin 46:5-27, 1996[Abstract]

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3. Cormier Y, Eisenhauer E, Muldal A, et al: Gemcitabine is an active agent in previously untreated extensive small cell lung cancer (SCLC): A study of the National Cancer Institute of Canada Clinical Trial Group. Ann Oncol 5:283-285, 1994[Abstract/Free Full Text]

4. Anderson H, Lund B, Bach F, et al: Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 12:1821-1826, 1994[Abstract/Free Full Text]

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21. Andersson M, Daugaard S, Von der Masse H, et al: Doxorubicin versus mitomycin versus doxorubicin plus mitomycin in advanced breast cancer: A randomised study. Cancer Treat Rev 70:1181-1186, 1986

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Submitted January 25, 1999; accepted January 24, 2000.


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