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Keywords:

  • cancer;
  • moxifloxacin;
  • neutropenic fever;
  • outpatient

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Oral-based antibiotic therapy is the standard of care in the management of cancer patients with low-risk neutropenic fever. Nevertheless, to the authors' knowledge, the best antibiotic regimen and the feasibility of ambulatory treatment have not been clearly defined.

METHODS

The authors evaluated the efficacy and safety of moxifloxacin as outpatient treatment in cancer patients with febrile neutropenia who were selected according to the recently proposed Multinational Association for Supportive Care in Cancer (MASCC) risk assessment model. Moxifloxacin was given at a dose of 400 mg orally once daily.

RESULTS

Fifty-four patients with solid and hematologic malignancies, the majority of whom (84%) had advanced disease, were included in the current study. The median neutrophil count at the time of study entry was 340/mm3 (range, 20–950/mm3) and the median duration of neutropenia was 4 days (range, 3–14 days). Of 55 neutropenic episodes, 50 (91%) had a successful outcome with a median time to defervescence of 2 days (range, 1–5 days). A multivariate analysis indicated that severe neutropenia (an absolute neutrophil count of < 100 mm3) was the only independent factor associated with treatment failure (P < 0.04). Moxifloxacin was found to be well tolerated and there were no infectious deaths reported.

CONCLUSIONS

The results of the current study demonstrated that moxifloxacin was a highly effective and safe regimen in the outpatient treatment of cancer patients with febrile neutropenia. Cancer 2005. © 2005 American Cancer Society.

Neutropenic fever in patients receiving chemotherapy is a potentially serious event, with a significant risk of overwhelming infection.1 Urgent hospitalization, parenteral broad-spectrum antibiotics, and aggressive support are the standards of care that reportedly lead to a significant reduction in mortality and morbidity. However, febrile neutropenic patients represent a very heterogeneous population and the majority have a low risk for developing complications.2

Risk predictive models have been created to select low-risk patients and provide them with less aggressive and more convenient therapy.3–5 Recently, an international prospective study established an improved risk assessment model with which to identify low-risk patients based on clinical criteria—the Multinational Association for Supportive Care in Cancer (MASCC) index.6 Oral quinolone-based regimens are considered to be the optimal care in the management of hospitalized patients with uncomplicated febrile neutropenia.7, 8 In addition, outpatient treatment for carefully selected patients either with intravenous,9 oral,10, 11 or sequential parenteral and oral antibiotics12 has been shown to be an effective alternative strategy. The outpatient management of febrile neutropenia has apparent advantages in terms of quality of life and cost savings. However, there is debate regarding the safety of this practice because of several cases of (potentially preventable) deaths that reportedly occurred in a number of studies.11, 13 Furthermore, the spectrum of bacteria that cause infections in neutropenic cancer patients has changed over the years and gram-positive pathogens currently account for the majority of these bacteria (range, 60–70%), typically developing as severe breakthrough infections in patients receiving old-generation quinolones.2, 14, 15 In addition, the unexpected toxicity of combination quinolone-based regimens reported in some studies further emphasizes the need for alternative approaches.7, 8

Recently published guidelines have addressed the role of newer quinolones as promising agents in the care of low-risk cancer patients with febrile neutropenia, although to our knowledge studies with these agents currently are lacking.2, 16 Moxifloxacin, a new broad-spectrum quinolone, is reported to have increased potency against gram-positive pathogens and anaerobes compared with older quinolones, while it reportedly retains significant activity against the majority of gram-negative pathogens responsible for infections in cancer patients.17–19 In addition, moxifloxacin is administered once daily and has a favorable pharmacokinetic and pharmacodynamic profile, a lower incidence of adverse effects, fewer drug interactions, and lower mutation potency.17 The current study evaluated the efficacy and safety of oral moxifloxacin in low-risk neutropenic cancer patients who were selected with the recently proposed MASCC risk index.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients with histologically confirmed cancer and who received chemotherapy in the oncology unit of a teaching institution were included in the current study. To identify those cancer patients who were suitable for outpatient treatment, we used the MASCC Risk Index, with a value of 21 established as a threshold for entry into the study (Table 1). More specifically, patients were considered eligible when they were diagnosed with solid tumors or hematologic malignancies (excluding patients with acute leukemia and those who had undergone bone marrow transplantation), developed a fever > 38.3 °C, or > 38.0 °C as measured twice within the span of 1 hour, and had an absolute neutrophil count (ANC) < 500/mm3 or < 1000/mm3, with a predicted decrease to < 500/mm3 within the subsequent 48 hours. Additional criteria were a World Health Organization (WHO) performance status ≤ 2, the ability to ingest oral medicine and fluids, the absence of hypersensitivity to quinolones, a serum creatinine level < 2 mg/dL, a serum transaminase level < 4-fold that of normal, the absence of hypotension or any sign of dehydration, no clinical indications of serious illness, the absence of a history of chronic obstructive pulmonary disease, and the absence of documented pneumonia. Patients were excluded if they were age < 16 years, pregnant or lactating, had received antibiotics within the previous 7 days, and had developed fever while in the hospital. Each patient was required to be compliant to investigator instructions and could live no more than a 1-hour distance from the hospital. Informed consent was provided by all patients according to institutional guidelines.

Table 1. Scoring Index for the Identification of Low-Risk Febrile Neutropenic Patients at the Time of Presentation with Fever
Characteristic score 
  • a

    Choose one item only.

  • Note that the highest theoretic score is 26. The authors used a threshold of ≥; 21 to define “low-risk.” Adapted from Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18:3038–3051; and Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005;103:1103–1113.

Burden of illness: no or mild symptomsa5
No hypotension5
No chronic obstructive pulmonary disease4
Solid tumor or no previous fungal infection4
No dehydration3
Burden of illness: moderate symptomsa3
Outpatient status3
Age < 60 yrs2

Patients underwent a detailed history taking and complete physical examination. Detailed instructions and a contact phone number was given to each patient. The baseline evaluation included a complete blood count and differential; serum creatinine, urea, and electrolytes; liver function tests (alanine aminotransferase, aspartate aminotransferase, and bilirubin); urinalysis; clotting profile; chest X-ray; and blood and urine cultures. The follow-up visit was arranged on Days 3 and 7, and included any test or examination that was necessary after a complete reassessment. Moxifloxacin at a dose of 400 mg orally once daily was given to each patient for a minimum of 7 days, in case of response, with the first dose given in the physician's office along with granulocyte–colony-stimulating factor (G-CSF) support. Blood transfusions and intravenous fluid support in the ambulatory care unit also was permitted. Treatment success was considered to be the resolution of fever and any sign of infection within 5 days from the study entry, in the absence of disease recurrence during the following week. Failure was defined as the persistence of fever < 37.5 °C for more than 5 days from the time of study entry or any sign or symptom of clinical deterioration that required hospital admission. Toxicity was defined according to standard WHO criteria.

Statistical Analysis

For continuous variables the Mann–Whitney U test was used in analysis. Accordingly, quantitative parameters were transformed to binary categoric variables for statistical comparisons of factors predisposing patients to treatment failure. Statistical comparisons with regard to treatment outcome for categoric parameters were performed using the Fisher exact test or the chi-square test with Yates correction when appropriate. P values ≤ 0.05 were considered statistically significant for univariate analysis. Logistic regression analysis was performed, including selected risk factors found to have a P value of ≤ 0.1 on univariate analysis. Factors identified in logistic regression modeling were considered significant only if they had a P value of ≤ 0.05 without adjustment for multiple comparisons. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all the parameters in the resultant model. All analyses were performed using the Stata 8.0 software program (Stata Corporation, College Station, TX).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Between December 2002 and March 2004, 55 episodes of febrile neutropenia, which occurred in 54 patients, were treated with oral moxifloxacin. Patient characteristics are shown in Table 2. The majority of the patients were women (67%) and had solid tumors (78%), originating mainly in the ovary and breast. Among patients with hematologic malignancies (n = 12) the majority had multiple myeloma (n = 7). Approximately half of the patients were already receiving G-CSF at the time of study entry. The median ANC on study entry was 340/mm3 (range, 20–950/mm3), with 22% of patients having an ANC < 100/mm3; the median time to ANC recovery was 4 days (range, 3–14 days). Twelve patients had advanced cancer that was refractory to chemotherapy (22%) and were considered ineligible for treatment with oral antibiotics (Talcott Group III) according to a previous classification of low-risk febrile neutropenia4, 5 whereas the majority of patients (62%), had advanced cancer that was responsive to therapy. As shown in Table 3, the majority of patients (65%) had fever of unknown origin (FUO). In 19 cases of clinically documented infection, the lower respiratory tract (six patients) and the gastrointestinal tract (five patients) were the most common source of infection, whereas there were three cases of pyelonephritis, two cases of sinusitis, and one case each of tonsillitis and cellulitis, respectively. Only 3 patients (5%) had microbiologically defined infections as shown in Table 3. One of these patients had bacteremia with coagulase-negative Staphylococcus detected in two blood cultures whereas the other two patients had pyelonephritis.

Table 2. Patient Characteristics
 (%)
  1. CLL: chronic lymphocytic leukemia; MDS: myelodysplastic syndrome; ANC: absolute neutrophil count; G-CSF: granulocyte–;colony-stimulating factor; MASCC: Multinational Association for Supportive Care in Cancer index.

Assessable episodes55
Median age (yrs) (range)62 (20–80)
Male gender18/55 (32.7)
Hematologic malignancies12 (22)
Myeloma7 (13)
Lymphoma2 (4)
CLL2 (4)
MDS1 (2)
Solid tumors43 (78)
Ovarian carcinoma19 (35)
Breast carcinoma6 (11)
Lung carcinoma4 (7)
Other14 (25)
Median ANC at hospital admission (/mm3) (range)340 (20–950)
ANC < 100/mm312 (22)
Median duration of neutropenia (days)4 (3–14)
Patients already receiving G-CSF29 (53)
Table 3. Clinical Course and Outcome
Total episodes55
Successfully treated50 (91%)
Median no. of days febrile (range)2 (1–6)
Median no. of days neutropenic (range)4 (3–14)
Response rate 
Fever of unknown origin34/36 (94%)
Documented infection16/19 (84%)
Bacteremia1/1 (100%)
Urinary tract2/3 (67%)
Soft tissue/skin1/1 (100%)
Respiratory tract8/9 (89%)
Gastrointestinal tract4/5 (80%)
Hospitalization5/55
Reasons for hospitalization 
Fever lasting > 5 days2
Deteriorating condition1
Other2
Death0/55
Adverse effects 

Efficacy

Treatment was successful in 50 episodes of neutropenic fever (91%) whereas 5 patients required hospital admission and were considered treatment failures. As shown in Table 3, patients remained febrile for a median duration of 2 days (range, 1–6 days). There was a trend toward a better response in patients with FUO (34 of 36 patients [94%]) compared with those with clinically documented infections (16 of 19 patients [84%]) (P = 0.32). A sole case of coagulase-negative Staphylococcus bacteremia developed in a patient with early-stage colon carcinoma who was receiving irinotecan-based adjuvant chemotherapy. He responded promptly to treatment within 48 hours. The source of the infection remained obscure. Another patient with hormone-refractory and chemotherapy-refractory prostate carcinoma and a recent history of stent placement for urethral obstruction developed pyelonephritis with a high fever and severe neutropenia (ANC of 150/mm3) after docetaxel-based chemotherapy. Enterococcus faecalis, susceptible in vitro to moxifloxacin, was grown in urine cultures although the patient responded to therapy.

Among those patients who failed to respond, 2 required admission to the hospital because of the persistence of fever for greater than 5 days. One patient responded to intravenous piperacillin and tazobactam whereas in the other patient the fever resolved after discontinuation of intravenous ceftazidime and amikacin. Another patient was considered a treatment failure because of a recurrence of fever after 6 continuous days of initial defervescence. Also in this patient, the fever resolved without any intervention. Only one patient with advanced cervical carcinoma, indwelling ureteral stents, and bilateral obstructive nephropathy developed overwhelming infection and septic shock within the first 24 hours of study entry. During hospitalization, S. saprophyticus pyelonephritis was diagnosed based on urine cultures and the patient responded to combination treatment with piperacillin, tazobactam, and amikacin. It is interesting to note that the Staphylococcus isolate was susceptible in vitro to moxifloxacin. Finally, a woman with recurrent refractory ovarian carcinoma who was treated with a platinum-based regimen required hospitalization for persistent low-grade fever and abdominal pain although her disease was clinically stable. The patient responded to combination treatment with metronidazole and ceftriaxone. No patient died while on the study. Red blood cell and platelet transfusions were required in four patients whereas five patients received intravenous fluids in the ambulatory care unit to correct chemotherapy-induced electrolyte abnormalities. Finally, two patients received oral acyclovir and one patient received oral fluconazole for herpetic and Candida stomatitis, respectively; all outcomes were successful.

In univariate analysis (Table 4) severe neutropenia with an ANC ≤ 100 mm3 (P = 0.009) and fever ≥ 39 °C (P = 0.04) were found to be associated significantly with treatment failure. There also was a trend toward an inferior outcome for patients with a documented site of infection and the presence of a foreign body, although this trend did not achieve statistical significance (P = 0.16 and P = 0.17, respectively). On logistic regression analysis, the only factor found to be an independent predictor of treatment failure was severe neutropenia with an ANC ≤ 100 mm3 (P = 0.04). There was no significant association noted between response to moxifloxacin and patient age, type or stage of malignancy, hematocrit level at study entry, Talcott group, or duration of neutropenia.

Table 4. Factors Associated with Treatment Outcome by Univariate and Multivariate Analysis
Patients characteristicsTreatment failureSuccessful outcomeUV analysisMV analysis
P valueOR (95% CI)P valueOR (95% CI)
  • UV: univariate analysis; MV: multivariate analysis; OR: odds ratio; 95% CI: 95% confidence interval; ANC: absolute neutrophil count.

  • a, b

    On day of study entry.

  • b

    Patients with cancer who were unresponsive to chemotherapy.

Median age (yrs) (range)57 (20–60)62.5 (24–80)0.63   
Hematologic malignancy1/5 (20%)11/50 (22%)0.64   
Early-stage cancer0/5 (0%)11/50 (22%)0.57   
Determined site of infection3/5 (60%)14/50 (28%)0.16   
Presence of foreign body1/5 (20%)1/50 (2%)0.17   
Mucositis2/5 (40%)11/50 (22%)0.58   
Positive cultures1/5 (20%)2/21 (10%)0.52   
Median temperature (°C) (range)a39.0 (38.3–39.3)38.4 (38.0–39.5)0.07   
Fever > 39°Ca3/5 (60%)8/50 (16%)0.047.9 (1.13–55)  
ANC < 100/mm34/5 (80%)9/50 (18%)0.0098.2 (1.81–183)0.0417.9 (1.59–200)
Median no. of days with ANC < 1500/mm3 (range)4 (3–6)4 (3–14)0.40   
Median Ht level (range)a10.3 (8–11.3)10.65 (7.4–13.8)0.59   
Unfavorable Talcott group (III)b1/5 (20%)11/50 (22%)0.64   

Toxicity

The treatment was remarkably well tolerated. There was no case of renal function impairment reported, nor any other serious toxicity. Mild nausea (WHO Grade 1) developed in 10 patients and was controlled without the need to modify treatment and WHO Grade 1 diarrhea was reported to occur in 3 patients. A transient increase in liver enzymes (alanine aminotransferase and aspartate aminotransferase) resolved without the discontinuation of treatment in one patient.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Fever in cancer patients with chemotherapy-induced neutropenia remains a life-threatening complication despite progress in our understanding and treatment of this event.2 Over the last decade, it has become clear that morbidity and mortality vary greatly among neutropenic patients depending on several factors. Rubin et al.3 indicated that a short duration of neutropenia (< 7 days) is predictive of a favorable response to antibiotic therapy in 95% of patients, whereas Talcott et al.4 defined a low-risk population (Talcott Group IV), comprised of neutropenic patients with cancer who are responsive to chemotherapy and without significant comorbidities, that had a minimal risk (< 3%) of serious complications. Based on this classification, investigators at the M. D. Anderson Cancer Center in Houston were to our knowledge the first to examine the feasibility of the outpatient treatment of carefully selected low-risk cancer patients using oral quinolone-based regimens and reported excellent response rates (range, 88–90%).10 Further trials regarding the outpatient management of patients with febrile neutropenia used older quinolones as monotherapy or in combination with β-lactams and achieved response rates ranging from 77–95%.11, 12, 20, 21 Nevertheless, this approach remains an issue of debate because of deaths (4%) that occurred in the what to our knowledge was the largest randomized trial published to date, in which older quinolones were used.11, 13 Misclassification bias (e.g., the inclusion of patients with high-risk hematologic malignancies) may account for some of these deaths and treatment failures.

Recently, a large international collaborative study involving 1139 febrile neutropenic patients was conducted in the hopes of resolving the majority of these issues in the definition of low-risk cancer neutropenia.6 This consensus study developed a scoring system based on simple clinical criteria (as shown in Table 1), which enabled a more precise and uniform selection of patients with neutropenic fever for outpatient management. In contrast to previous models, cancer that was refractory to chemotherapy and a duration of neutropenia of more than 10 days were not included in the scoring system. In a recent study in which the MASCC risk index was validated prospectively, low-risk neutropenic patients were identified with an accuracy of 98.3% and there were no deaths reported in this group of patients.22 Furthermore, in the same study, the MASCC risk assessment index proved to be superior in terms of sensitivity, specificity, and predictive value when compared with the previous Talcott predictive model.

In the current study, 22% of the patients were considered to belong to Talcott Group III because their cancer was refractory to chemotherapy and they would have been excluded from an oral antibiotic study. We did not observe any inferior outcomes in this subset of patients. In addition, there were no deaths reported and only one patient required urgent admission to the hospital because of uncontrolled infection. Despite its small size, we believe the current study provides evidence that the MASCC risk assessment model can be used successfully to identify low-risk patients who may be eligible for outpatient management. This is in agreement with the preliminary results of a larger ongoing study in which low-risk neutropenic patients assessed by the MASCC score were reported to have a response rate of 96% to outpatient treatment with oral antibiotics.23

A new-generation quinolone, moxifloxacin, was used in the current study, although it has not been proposed in recently published guidelines.2, 24 To our knowledge, the current study is the first to assess the efficacy of moxifloxacin in the outpatient management of febrile neutropenia. We used moxifloxacin based on numerous in vitro data from bacterial isolates from cancer patients. Moxifloxacin is remarkably more potent (8–32-fold) than older quinolones against gram-positive bacteria while retaining significant activity for most gram-negative pathogens. Furthermore, moxifloxacin has improved potency against several multiresistant, gram-negative pathogens such as Stenotrophomonas maltophilia, Acinetobacter species, and other less common, still-emerging pathogens in cancer patients.17–19, 25, 26 Although the lack of significant activity of moxifloxacin against Pseudomonas aeruginosa is a cause for concern, the emergence of the multidrug resistant, gram-positive pathogens that now cause the majority of infections in cancer patients indicates the need for better gram-positive coverage in the empiric treatment of febrile neutropenia.2, 14, 15

Moxifloxacin was found to be highly effective, with a 91% success rate and the prompt resolution of fever reported to occur in a median time of 48 hours. Even serious infections such as a bacteremia due to coagulase-negative Staphylococcus and Enterococcus faecalis pyelonephritis were found to have favorable outcomes. Moxifloxacin proved to be safe with no deaths or serious adverse events reported in the current study. Among patients who failed to respond to treatment, only one was reported to have developed an overwhelming infection and septic shock. This patient was treated successfully with parenteral antibiotics. In keeping with previous reports, the results of the current study demonstrated that severe neutropenia (< 100/mm3) was the only parameter associated with a higher probability of treatment failure.1, 2

Because the current study was not randomized, it is difficult to draw firm conclusions. Nevertheless, we believe that moxifloxacin is a highly effective, convenient, safe, and well tolerated agent in the outpatient management of a properly selected population of cancer patients with low-risk febrile neutropenia. We believe that in the future, large prospective trials will better define the role of moxifloxacin in the management of febrile neutropenia. Considering the changes in the epidemiology of bacteria that cause infections in cancer patients, as well as the high rate of fulminant breakthrough infections with the use of older quinolones,14, 15 there is a clear need for such studies.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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    Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis. 1999; 29: 490494.
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