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Annals of Surgical Oncology 8:179-186 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Treatment of Nosocomial Postoperative Pneumonia in Cancer Patients: A Prospective Randomized Study

I. Raad, MD, R. Hachem, MD, H. Hanna, MD, D. Abi-Said, PhD, C. Bivins, RN, G. Walsh, MD, J. Thornby, PhD, E. Whimbey, MD, A. Huaringa, MD and A. Sukumaran, MD

From the Department of Internal Medicine Specialties Section of Infection Control (IR) and Section of Infectious Diseases (RH, HH, DA-S, EW), the Department of Leukemia (CB), the Department of Cardio-Thoracic Surgery (GW), the Department of Internal Medicine Specialties, Section of Pulmonary Medicine (AH), and the Department of Anesthesiology and Critical Care (AS), The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and Department of Family and Community Medicine (JT), Baylor College of Medicine, Houston, Texas.

Correspondence: Address correspondence and reprint requests to: Issam Raad, MD, FACP, Section of Infection Control (Box 47), The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; Fax: 713-792-8233; E-mail: iraad{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Nosocomial pneumonia continues to be associated with high morbidity and mortality in cancer patients.

Methods: In an attempt to find an optimal treatment for this infection, nonneutropenic cancer patients with postoperative nosocomial pneumonia were randomized to receive either piperacillin/tazobactam (P/T) 4.5 g IV every 6 hours (30 patients) or clindamycin (Cl) 900 mg plus aztreonam (Az) 2 g IV every 8 hours (22 patients). Amikacin 500 mg IV every 12 hours was given to all patients for the first 48 hours.

Results: The two groups were comparable for the characteristics of pneumonia that included Gram-negative etiology and duration of intubation. Response rates were 83% for patients who received P/T and 86% for those who received Cl/Az (P > .99). There were no serious adverse events; however, at our center the cost of the P/T regimen was $73.86 compared with $99.15 for the Cl/Az regimen.

Conclusions: The two regimens had comparable high efficacy, and P/T had a slight cost advantage. Either of these antibiotic regimens combined with an aminoglycoside could lead to favorable outcome in cancer patients at high risk for nosocomial pneumonia.

Key Words: Nosocomial • Pneumonia • Antibiotics • Cancer • Postoperative


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nosocomial pneumonia is currently the second most commonly occurring nosocomial infection in the United States.1,2 Nosocomial pneumonia has been reported in up to 50 per 1000 admissions among patients with mechanical ventilation and those who have had surgery.3,4 In a study performed in an oncology center, nosocomial pneumonia was the most common nosocomial infection in cancer patients.5

Nosocomial pneumonia is also the leading cause of death due to nosocomial infection.6,7 The Centers for Disease Control and Prevention attributed 100,000 deaths in the United States in 1993 to nosocomial pneumonia, which is higher than the annual number of deaths attributed to accidents, homicide, human immunodeficiency virus, or sepsis.8 In two matched-pair cohort studies, a mortality rate of 27% to 33% was attributed to nosocomial pneumonia.9,10 The high mortality rate associated with this nosocomial infection could be due partly to the fact that the causative microbial agents for this disease (which include Gram-negative bacilli and Staphylococcus aureus) are highly virulent and often highly resistant organisms.7

Given its diverse microbial etiology, appropriate empirical antimicrobial therapy for nosocomial pneumonia should have broad-spectrum activity. Aztreonam (Az) is a monobactam antibiotic that often has been compared with aminoglycosides in its spectrum of antimicrobial activity against Gram-negative bacilli, which include Pseudomonas aeruginosa.11,12 The favorable penetration of Az into the respiratory tract along with its activity against Gram-negative organisms has prompted a number of clinical trials that evaluated the agent in the treatment of nosocomial pneumonia.11–13 The advantage of Az over aminoglycosides is that it does not cause nephrotoxicity. To cover for S. aureus and anaerobes, clindamycin has been suggested as an additional agent in the treatment of this infection. In two studies in which the combination of CI and Az was used to treat nosocomial pneumonia, a clinical response of 87% to 90% was reported.14,15

Piperacillin is an extended-spectrum penicillin that has been used to treat serious infections. It is active against most Gram-negative bacilli and has shown good activity against most anaerobic bacteria.16 Tazobactam is a ß-lactamase inhibitor of the penicillanic acid sulfase class that has activity against ß-lactamase enzymes produced by aerobic and anaerobic Gram-negative bacteria that are resistant to piperacillin sodium.17,18 In vitro studies show that piperacillin sodium plus tazobactam sodium (P/T) is one of the most active penicillin-inhibitor combinations with activity against resistant aerobic and anaerobic bacteria.19 Unlike piperacillin sodium alone, P/T results in activity against ß-lactamase-producing S. aureus. This antibiotic, however, has not been compared with Cl/Az in the treatment of nosocomial pneumonia.

The objective of this study was to compare P/T with Cl/Az in the treatment of postoperative nosocomial pneumonia in cancer patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From April 1994 to April 1996, a prospective, randomized study was conducted at our center. The study was approved by the Institutional Review Board, and signed informed consent was obtained from all patients before enrollment. The guidelines for human experimentation outlined by the U.S. Department of Health and Human Services and by our institution were followed in the conduct of this clinical research.

Patient Selection
Clinical eligibility criteria for enrollment included a recent onset of fever (> 38.3°C) and the presence of new pulmonary infiltrates, determined radiologically, that occurred postoperatively and more than 72 hours after admission and that developed in the absence of fever or pulmonary infiltrates at the time of admission in adult (minimum age 18 years), nonneutropenic (>= 1000 neutrophils/mm3) patients. Patients were excluded from the study if they were allergic to penicillin or if any of the following conditions existed: prior treatment with broad-spectrum antibiotics for more than 48 hours or response to antimicrobial therapy administered for nosocomial pneumonia; prior allergic reaction to any of the study drugs; pregnant or nursing an infant; a bacterial infection known to be resistant to the study antibiotics; a known mycobacterial, fungal, viral, rickettsial, or chlamydial infection; previous enrollment in the study for the same infection or during the preceding week; severe renal impairment as evidenced by an estimated creatinine clearance of > 15 ml/minute; postobstructive pneumonia secondary to a proven obstructed airway by a tumor; life expectancy of less than 48 hours.

Administration of Treatment
Eligible patients were randomized by the pharmacy to receive one of the following two antibiotic regimens: (1) P/T 4.5 g IV over 1 hour every 6 hours or (2) Cl 900 mg IV over 1 hour every 8 hours and Az 2 g IV over 1 hour every 8 hours. For patients with mild to moderate renal dysfunction, the doses of P/T and Cl/Az were adjusted according to the instructions on the package insert provided with each medication. Patients with penicillin allergy were placed on the Cl/Az arm. The randomization scheme was designed as 1.5 to 1.0 ratio for P/T vs. Cl/Az to balance the expected difference related to penicillin allergy. All patients in the two study arms received amikacin 500 mg IV every 12 hours. Patients were assessed after 48 hours of entry onto the study. For patients with nosocomial pneumonia caused by any organism other than P. aeruginosa, the amikacin was discontinued 48–72 hours after initiation. For pneumonias caused by P. aeruginosa, amikacin was continued for as long as the other study drugs were given.

Study Procedures
A complete medical history and physical examination with complete blood tests, which included white blood counts, differential, platelet counts, and cultures of blood and respiratory fluids (sputum or bronchoalveolar lavage [BAL]), were done before initiation of antibiotic therapy. As long as fever of >= 38.3°C persisted during study treatment, blood cultures were obtained daily, and respiratory cultures were obtained twice weekly. When the patient’s temperature normalized, blood and respiratory cultures were obtained at least once weekly during study treatment. All bacterial pathogens recovered were tested for their susceptibility to the study antibiotics by the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) tests previously described.20 All patients were followed for 2 weeks after discontinuation of antibiotic therapy. During follow-up, blood and respiratory fluid cultures were repeated within 48 hours of completion of antibiotic study treatment, and if abnormal laboratory results possibly attributable to study drugs were noted, the tests were repeated every 48 hours until results were normal. Indwelling central venous catheters that were removed during treatment or during posttreatment follow-up were cultured semiquantitatively by using the roll-plate culture technique.

Evaluation of Patients and Therapy
To be considered assessable, patients had to have evidence of new pulmonary infiltrate with new onset of fever (> 38.3°C) at least 48 hours after admission in the absence of any fever or pulmonary infiltrates at admission. In addition, the patient had to meet one of the following criteria according to the Centers for Disease Control and Prevention’s definition of nosocomial pneumonia: (1) new rales on examination of the chest, (2) new onset of purulent sputum or change in the character of sputum, or (3) leukocytosis.21 For assessability of clinical efficacy, the patient had to meet all of the previously mentioned criteria for nosocomial pneumonia in addition to having been treated with either study antibiotic regimen for at least 5 days and having at least one end of therapy or posttherapy clinical evaluation. Clinical and microbiological responses were assessed in accordance with the general guidelines for new anti-infective drugs for the treatment of respiratory tract infection as published by the Infectious Diseases Society of America and the U.S. Food and Drug Administration.22

Clinical response was defined as complete resolution of all signs and symptoms of pneumonia. Improvement was defined as the lack of progression of all abnormalities on chest radiograph. Clinical failure was defined as any of the following conditions: persistence or progression of all signs or symptoms after 96 hours of therapy, development of new pulmonary or extrapulmonary clinical findings consistent with active infection, persistence or progression of radiographic abnormalities, death due to pneumonia, or inability to complete the study because of adverse events. Microbiological eradication was defined as elimination of the original causative organism from the same site (such as expectorated sputum or BAL) during or on completion of therapy. Presumed microbiological eradication was defined as the absence of appropriate material for culture (such as sputum or pleural fluid or BAL) for evaluation because the patient improved clinically or did not produce sputum or because repeated aspiration of pleural fluid was not justified clinically. Microbiological persistence was defined as failure to eradicate the original causative organism from sites previously listed regardless of whether signs or symptoms of inflammation were present. Superinfection was defined as the appearance of one or more new pathogens and cultures taken on follow-up after the eradication of all baseline pathogens by the antibiotic study regimen.

Patients who responded were continued on intravenous antibiotic therapy for at least 5 days or for 3 days after becoming afebrile, provided all signs and symptoms of infection had resolved. At the end of parenteral therapy, provision was made to change the patient to an oral antibiotic regimen that consisted of amoxicillin/clauvulanic acid 500 mg every 8 hours with ciprofloxacin 500 mg every 8 hours to be given for at least 5 additional days.

Statistical Considerations
The primary analysis was a comparison of the response rate of the two therapeutic regimens for all patients. Differences between frequencies of categorical variables were determined by using the {chi}2 test or the Fisher’s exact test, as appropriate. Continuous variables with a normal distribution were compared by using the Student’s t-test. Continuous variables that were not normally distributed were compared by using the Mann-Whitney U-test. We considered P <= .05 to be significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
The characteristics of the patients in this study are outlined in Table 1 and are consistent with those of surgical cancer patients with a mean age of 60 years and an underlying thoracic, abdominal, or head and neck tumor that led to extensive surgery. The duration of treatment was comparable for the two groups.


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  		TABLE 1. Patient characteristics by treatment group
 
The distribution of patients was 30 in the P/T group and 22 in the Cl/Az group. Only two patients were allergic to penicillin and subsequently were placed on the P/T arm. The two study groups were comparable in terms of age, sex, underlying malignancy, duration of fever, and duration of intubation. The mean duration of hospitalization before the diagnosis of pneumonia was 5.3 days (95% confidence interval 4.0, 6.6 days) for patients who received Cl/Az and 5 days (95% confidence interval 2.7, 7.2 days) for patients who received P/T (P = .8) There was a higher frequency of severe pneumonia that resulted in intubation among patients entered onto the P/T arm compared with those onto the Cl/Az arm (40% vs. 23%, respectively; P > .15). None of the patients were neutropenic, and none developed neutropenia during treatment.

Bacteriological Results
Of the 29 cases of nosocomial postoperative pneumonia associated with an identified bacterial organism, 21 (72%) were caused by a Gram-negative bacillary organism (Table 2). The predominant Gram-negative organisms were Serratia marcescens, Enterobacter species, P. aeruginosa, and Klebsiella pneumoniae. The frequency of nosocomial Gram-negative pneumonias was higher in the Cl/Az regimen group than in the P/T group (55% vs. 30%, P = .08); however, there was a higher frequency of severe pneumonias that required intubation in the P/T group (Table 1). The nosocomial Gram-positive pneumonias were caused predominantly by beta-hemolytic streptococci followed by S. aureus (Table 2). In 44% of patients, polymicrobial flora or mixed respiratory flora without a particular pathogenic organism was considered to be the cause of the pneumonia. All of the Gram-negative bacillary pathogens isolated from patients in the Cl/Az group were susceptible to Az (MIC <= 2.0 µg/ml). In the P/T group, all Gram-negative bacilli were susceptible to Az except for two cases of resistant organisms (MIC >= 16 µg/ml). In one of these patients, the organism isolated was K. pneumoniae (MIC of P/T = 64 µg/ml and MBC = 128 µg/ml); however, P/T therapy plus amikacin induced a response (MIC of amikacin = 1 µg/ml and MBC = 2 µg/ml). The other patient had a polymicrobial pneumonia caused by Escherichia coli (MIC of P/T = 32 µg/ml and MBC = 128 µg/ml) and P. aeruginosa (MIC of P/T = 4 µg/ml and MBC > 128 µg/ml). In this patient, P/T plus amikacin therapy failed to induce a response. All Gram-positive organisms that caused pneumonias in the two groups were susceptible to the respective antibiotic regimens (Cl/Az or P/T) except one case of S. aureus in the P/T group. The S. aureus was resistant to P/T (MIC = 32 µg/ml and MBC > 128 µg/ml); however, the P/T therapy did induce a response. Hence, in general, there was little correlation between susceptibility and response to the antibiotic study regimen.


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  		TABLE 2. Response to therapy based on microbial etiology of pneumonia
 
Efficacy of Antibiotic Regimen and Outcome
A favorable clinical response associated with a definite or presumed microbiological eradication of the infection occurred in 86% of the patients in the Cl/Az group compared with 83% for those who received P/T (P > .99). However, patients who received Cl/Az tended to require a longer duration of treatment (mean, 8.1 days; SD, 3.0 days) than patients who received P/T (mean, 6.8 days; SD, 3.0 days, P = .1). Both antibiotic regimens induced a response rate of 100% in patients with Gram-positive infections. For patients with nosocomial Gram-negative pneumonia, the response rates for Cl/Az and P/T were 75% and 67%, respectively (P = .53). The morbidity rate associated with the infection, as determined by the number of days of hospitalization after entry onto the study, was comparable for the two groups (median 4 and 3.5 days for Cl/Az and P/T, respectively; P = .2). No deaths occurred while the patients received study drugs. The crude mortality rate for the two groups was comparable; however, there was a higher rate of death related to the nosocomial pulmonary infection in patients who received P/T (13%) compared with those who received Cl/Az (P = .1; Table 3). This difference was not significant and could be related to the fact that patients who received P/T had a higher frequency of severe pneumonias that resulted in intubation than those who received Cl/Az (40% vs. 18%; Table 1). Severe pneumonia that required intubation was the best predictor of poor response to the antibiotic regimens. Seven of the nine patients in whom the study regimen did not induce response were ventilator-dependent. Only one of the seven had an organism that was resistant to the study regimen (P/T).


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  		TABLE 3. Response and outcome by treatment group
 
Adverse Reactions and Superinfections
The two study regimens were well tolerated. No difference in the adverse effects to these drugs was noted, and the side effects that did occur were mostly related to rash, diarrhea, and occasional supraventricular arrhythmias (ventricular ectopic beats; Table 4). The increase in serum creatinine was attributed in both study groups to the amikacin, not to Cl/Az or P/T. This adverse reaction resolved when amikacin was discontinued. Most of the superinfections were caused by Candida infections (candidemia vs. candiduria) or by methicillin-resistant Staphylococcus epidermidis or S. aureus. A breakthrough Acinetobacter infection resistant to Az occurred in one patient who received Cl/AZ. There was no significant difference in the frequency of superinfections between the two groups.


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  		TABLE 4. Adverse events and superinfections by treatment group
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, early initiation of antimicrobial therapy with P/T or Cl/Az with aminoglycosides was highly efficacious in the treatment of postoperative nosocomial pneumonia in high-risk nonneutropenic cancer patients of whom one-third required intubation. The characteristics of the patients in the P/T and Cl/Az groups were comparable, particularly in terms of underlying disease and prior surgery. No difference in the efficacy of P/T and Cl/Az could be detected in the treatment of postoperative nosocomial pneumonia in a cancer patient population. The clinical and presumed microbiological efficacy of the two study regimens exceeded 80%, with a good safety profile noted for a low frequency of adverse reactions and superinfections associated with this therapy. The morbidity and mortality rates associated with nosocomial pneumonia in these two study groups were comparable and relatively low, with a median duration of hospitalization after the occurrence of pneumonia of 4 and 3.5 days and an attributable mortality rate of 0% and 13% for Cl/Az and P/T, respectively.

The combination of Cl and Az previously has been shown to be highly effective in treating nosocomial pneumonia according to two small randomized studies.14,15 In these studies, the clinical response rate to this combination regimen ranged from 87% to 90%; however, the patient population under treatment was a relatively low-risk group without underlying cancer or extensive surgery as in this study. In these referenced studies,14,15 Cl/Az was compared with Cl/Tobramycin. Data related to the use of P/T in nosocomial pneumonia are limited to either open trials or studies that compared it with ceftazidime without any other effective antimicrobial therapy to cover for Gram-positive or anaerobic organisms.23–25 Sifuentes-Osornio et al.23 treated 107 adult patients with lower respiratory tract infections with P/T in an open trial. The majority (77%) of the pneumonias were community acquired. In another open, noncomparative study, P/T was used to treat 133 patients with lower respiratory tract infection.24 Most (63%) of the clinically assessable patients had community-acquired pneumonias. More recently, two prospective randomized studies compared P/T plus an aminoglycoside with ceftazidime plus an aminoglycoside in the treatment of nosocomial pneumonia.25,26 P/T was superior to ceftazidime, and it showed a significant improvement in clinical outcome in one study and a trend toward improvement in the other.25,26 This current study is the first prospective randomized trial in which P/T as a single agent is shown to be as efficacious in the treatment of postoperative nosocomial pneumonia as the combination of Cl/Az. It is possible that the broad-spectrum activity of P/T against Gram-positive organisms, anaerobes, and Gram-negative bacilli might explain the inability to detect a difference between its efficacy and that of Cl/Az and its superior efficacy over ceftazidime.

Although the two regimens investigated in this study were comparable in terms of efficacy and outcome, there was a trend toward a higher mortality rate among patients who received P/T vs. Cl/Az (13% vs. 0, respectively; P = .1). This could be attributed to the fact that patients who received P/T had a higher rate of severe pneumonia that led to intubation (40% for the P/T group vs. 23% for the Cl/Az group; Table 1). However, a cost advantage was associated with P/T compared with Cl/Az. The daily cost of P/T (cost of drug plus cost of administration) at a dose of 4.5 g IV once every 6 hours was $73.86, whereas the daily cost of Cl/Az at a dose of 2 g IV once every 8 hours was $99.15. Az alone given at a dose of 2 g IV every 8 hours costs $82.05. The duration of therapy tended to be shorter in patients who received P/T, which gave this agent a further cost advantage.

As expected, in cases of nosocomial pneumonia, most (75% to 78%) of the identified organisms were Gram-negative bacilli. Nosocomial pneumonia secondary to Gram-negative pathogens has been associated with a relatively high mortality.9,27 In this study, 37% of the patients (P/T and Cl/Az) had a severe pneumonia that led to intubation, and almost all of the patients had cancer with extensive surgery before the occurrence of the pneumonia. In a comparable high-risk population, nosocomial pneumonia has been associated with a crude mortality rate as high as 70% and an attributable mortality rate of 27% to 33%.9,10,28 The antibiotic regimen used in our study resulted not only in a high efficacy of > 80% but in low attributable mortality rates of 0 (for the Cl/Az group) and 13% (for the P/T group).

In addition to comparing two broad-spectrum antibiotic regimens, this study provides a systematic approach to the treatment of postoperative nosocomial pneumonia in moderate- to high-risk cancer patients. Because this patient population is at a high risk for Gram-negative infections, especially P. aeruginosa,28 and has a relatively high mortality rate, we followed several steps in this protocol that resulted in good outcome associated with low morbidity and mortality rates. First, the treatments were broad-spectrum combination regimens that consisted of ß-lactam (a monobactam vs. an antipseudomonal penicillin with a ß-lactamase inhibitor, in this case tazobactam) plus an aminoglycoside with or without Cl. The use of an aminoglycoside is limited only to the first 48 hours until respiratory and blood cultures reveal the absence of P. aeruginosa in a clinically stable patient. Second, the therapy was modified after 48–72 hours based on clinical and microbiological evaluation. Patients with P. aeruginosa who responded were continued on aminoglycosides; however, aminoglycosides were discontinued for patients who improved after 72 hours. For patients who did not improve, alternative therapy was considered based on the culture results and the clinical status of the patient. For patients who improved, the intravenous antibiotic therapy was changed after 3–5 days of treatment to an oral regimen that consisted of amoxicillin/clauvulanic acid and a quinolone (ciprofloxacin).

In regard to the treatment of nosocomial pneumonia, controversy has emerged as to whether a combination therapy, which includes aminoglycosides, is always indicated vs. monotherapy with ß-lactam antibiotics.29 In this study, we have demonstrated that the successful treatment of postoperative nosocomial pneumonia in cancer patients at high risk for the infection should involve a systematic approach that lends itself to changes in the antibiotic regimen according to new clinical and microbiological findings on follow-up tests done every 48–72 hours. Hence, a successful approach in high-risk patients would be to start with a broad-spectrum combination of drugs and then change to a more directed and focused therapy after 48–72 hours and to ultimately change to a broad-spectrum oral regimen after 96–120 hours of successful intravenous therapy

The major limitation of this study is the fact that the microbiology of the infections was determined based on unprotected BAL or purulent sputum samples.29 However, in the clinical setting of these patients, particularly with emphasis on purulent sputum or change in the character of the sputum, culture data could be used to reflect the true microbiology of the infection. This is especially true given that the majority of the recovered organisms were Gram-negative bacilli. In addition, in 46% of the patients, the infection had a polymicrobial etiology or negative cultures that revealed only oral flora. This finding is comparable with other studies of nosocomial pneumonia, particularly in elderly patients, in which almost 50% of the patients had nosocomial pneumonia with only normal respiratory flora being cultured.30,31 However, in cancer patients with extensive thoraco-abdominal and head and neck surgery, anaerobes are highly suspected.28 In one study, anaerobes were implicated in up to 35% of patients who were cigarette smokers with nosocomial pneumonias.32 Hence, the broad-spectrum activity of the study regimen against Gram-negative bacilli and anaerobes resulted in a high efficacy in the two antibiotic study regimens and could explain the previously reported superiority of P/T over ceftazidime in the treatment of nosocomial pneumonia in high-risk patients. To detect, with significance, a small difference in response between the two treatment groups, an impractically large number of patients would need to be studied.

In conclusion, P/T or Cl/Az in combination with an aminoglycoside administered within the first 48 hours is highly efficacious as intravenous antibiotic treatment of postoperative nosocomial pneumonia in cancer patients. In our series, the two regimens had a high comparable efficacy, and P/T had a slight cost advantage. A systematic approach that starts with a combination therapy that includes aminoglycosides for the first 48 hours and then reevaluation every 48 hours, and that leads to a final change to oral antibiotics in patients in whom response is noted, could result in favorable outcome in this high-risk patient population.


   Acknowledgments
 
Supported by a grant from Bristol-Myers Squibb and Wyeth-Ayerst.

Received for publication March 21, 2000. Accepted for publication September 13, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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