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Journal of Clinical Oncology, Vol 18, Issue 20 (October), 2000: 3558-3585
© 2000 American Society for Clinical Oncology


ASCO SPECIAL ARTICLE

2000 Update of Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-Based, Clinical Practice Guidelines*

By, Howard Ozer, James O. Armitage, Charles L. Bennett, Jeffrey Crawford, George D. Demetri, Philip A. Pizzo, Charles A. Schiffer, Thomas J. Smith, George Somlo, James C. Wade, James L. Wade, III, Rodger J. Winn, Antoinette J. Wozniak, Mark R. Somerfield, for the American Society of Clinical Oncology Growth Factors Expert Panel

From the American Society of Clinical Oncology.

Address reprint requests to American Society of Clinical Oncology, 1900 Duke St, Suite 200, Alexandria, VA 22314; email guidelines{at}asco.org


    INTRODUCTION
 TOP
 INTRODUCTION
 SUMMARY OF RELEVANT BACKGROUND...
 SPECIFIC GUIDELINES
 REFERENCES
 
THE AMERICAN Society of Clinical Oncology (ASCO) published evidence-based clinical practice guidelines for the use of hematopoietic colony-stimulating factors (CSFs) in 1994. ASCO guidelines are updated on a regular basis by a Review Committee of the original expert panel. The CSF guidelines were updated by the full expert panel in 2000.

For the 2000 update, an update committee, composed of members from the full panel and selected ad hoc members, was formed to complete the review and analysis of data published since 1994. Computerized literature searches of MEDLINE and CancerLit were performed. The key phrases granulocyte-macrophage colony-stimulating factors, granulocyte colony-stimulating factors, and clinical trials were used in searches of the published English-language literature from 1994 to 1999.

The Update Committee had two face-to-face meetings to consider the evidence for each of the 1996 recommendations. The guideline was circulated in draft form to the update committee and to the full expert panel for review and approval. Each guideline from the 1996 update is listed below, followed by the 2000 update, and the 2000 recommendation.


    SUMMARY OF RELEVANT BACKGROUND DATA
 TOP
 INTRODUCTION
 SUMMARY OF RELEVANT BACKGROUND...
 SPECIFIC GUIDELINES
 REFERENCES
 
Myelotoxicity of Standard Chemotherapy Regimens
To determine the need for primary administration of colony-stimulating factors (CSFs), one must decide whether the risk of neutropenia associated with a particular chemotherapy regimen warrants CSF use. Table 1 lists a number of the commonly used chemotherapies usually given without CSF support (except when indicated) and the reported rates of neutropenia, fever, and sepsis. Table 1 Go is an updated version of Table 3 Go Go Go of the original CSF guidelines published in 1994. Many new chemotherapeutic agents, including the taxanes, topoisomerase-1 inhibitors, and vinorelbine, have been used as part of regimens in the 1990s. Whenever possible, large clinical trials are referenced as well as studies that represent current trends in treatment (eg, 3-hour instead of 24-hour paclitaxel administration).


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Incidence of Hematologic and Infectious Toxicities Associated With Selected Chemotherapy Regimens
 

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(Continued)
 

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Summary of Guideline Updates
 

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Summary of Guideline Updates (continued, 1 of 3)
 

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Summary of Guideline Updates (continued, 2 of 3)
 

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Summary of Guideline Updates (continued, 3 of 3)
 
As before, these trials focus on the results of overall treatment rather than on hematologic and infectious side effects. As a consequence, these data suffer from differences in the definition of infectious complications as well as from underreporting of febrile episodes. Despite these limitations, few of these common chemotherapy regimens produce significant complications related to neutropenia. It should be noted that when chemotherapy is given for treatment of relapsed or refractory disease, it is more likely to produce neutropenia (eg, topotecan in relapsed small-cell carcinoma of the lung).

Impact of CSFs on Economics of Febrile Neutropenia
The routine use of CSFs for primary prophylaxis cannot be justified on the basis of cost savings with any routine chemotherapy. Cost analyses have shown that CSFs save money when the risk of febrile neutropenia (FN) is greater than 40%,35,36 but no routine regimens have rates greater than 15%. This analysis was sometimes confused with the initial CSF guideline that used a 40% rate of FN as a clinical threshold for use of CSFs, based on the observed rate of neutropenia seen in the initial randomized trials used for Food and Drug Administration licensing in the United States.

The economic models used costs of hospitalization for FN of $10,000; if the costs were much lower, as with early-discharge models or outpatient treatment models, the rate of FN would have to be much higher to offset the costs of using CSFs. Alternatively, CSFs could be justified if they cost substantially less. The use of CSFs at a much lower dose (eg, 2 µg/kg instead of 5 µg/kg), which is promising but needs confirmation,37 would lower the cost.

For secondary prophylaxis, the rate of FN could be 40% and could justify use of CSF, but dose modification would be a medically acceptable alternative because no major clinical benefit of maintaining delivery of previously toxic levels of chemotherapy with CSF use has been shown. A recent decision analysis model showed acceptable cost-effectiveness of CSFs to maintain dose-intensity in adjuvant therapy for breast cancer,38 but CSFs are rarely needed for four cycles of doxorubicin and cyclophosphamide, and no benefit has been found to date even for escalated doses of doxorubicin39 with CSF support.

A major advance would be a model to predict who will develop FN, so that CSF use could be restricted to that group. At present, it is not possible to predict who will develop FN and who would therefore benefit from prophylaxis with CSFs. Current models are promising but need prospective validation. Some possible predictors include a high risk of FN of 49% (23 of 47 patients) if the absolute lymphocyte count is less than 700/mm3, compared with 11% (seven of 65 patients) if the absolute lymphocyte count is greater than 700/mm3.40 Similarly, others have proposed that the risk of FN is higher in adjuvant breast cancer chemotherapy if the hemoglobin or absolute neutrophil count (ANC) falls during the first cycle of chemotherapy.36


    SPECIFIC GUIDELINES
 TOP
 INTRODUCTION
 SUMMARY OF RELEVANT BACKGROUND...
 SPECIFIC GUIDELINES
 REFERENCES
 
1. Guidelines for Primary Prophylactic CSF Administration
Definition of the Problem Neutropenia and infection are major dose-limiting side effects of chemotherapy. The risk of initial infection and subsequent complications are directly related to the depth and duration of neutropenia.41 The magnitude of neutropenia depends on the intensity of the chemotherapy regimen. In addition, a number of host- and disease-related factors that are only partially characterized may also influence the risks of neutropenia in the patient receiving chemotherapy.42-44 Because fever may be the first and only manifestation of infection, it has been standard practice for all patients who present with fever in the setting of neutropenia to receive broad-spectrum antibiotics.42 Usually this has been accompanied by hospitalization, although certain favorable subgroups of patients may possibly be treated as outpatients.45 Traditionally, patients have remained hospitalized, on antibiotic therapy, until fever and any sign of active infection have resolved and the ANC has recovered.

Clinical Outcomes In current practice, infectious mortality resulting from FN is low, and the incidence of FN with common chemotherapy regimens (with the exception of AIDS-related malignancies) seldom exceeds 25% to 40% in chemotherapy-naïve patients (Table 1Go). However, the average length of hospitalization for FN can exceed 1 week,21,43,46,47 during which time patients undergo numerous diagnostic procedures and intravenous (IV) antibiotic support with the attendant potential complications of such therapy. In addition to the impact on quality of life for the patient, episodes of FN may result in subsequent chemotherapy delays or dose reductions. Avoiding the occurrence of FN by use of a CSF might therefore be expected to enhance patient quality of life, reduce hospital costs, and improve chemotherapy delivery. Nonetheless, the incidence of FN depends entirely on the dose-intensity of the chemotherapy regimen, on the prior history of the patient population, and on the presence or absence of other comorbid conditions. Although it is now well established that primary prophylaxis with a CSF can reduce the incidence of FN by as much as 50%,48-53 in the absence of benefits in survival or response, such reductions can only have a significant impact on patient outcomes when improved clinical outcomes justify the costs of CSF administration. By design, primary prophylaxis results in unnecessary treatment of at least 50% of patients who would not have experienced FN on standard chemotherapy regimens, thus further hampering any cost benefit of CSF prophylaxis.

Alternative Approaches Alternative approaches for avoiding an initial episode of FN remain limited. Prophylactic antibiotics continue to be used, particularly with high-dose chemotherapy regimens in hematologic malignancies,48 but a positive clinical impact has not been universally documented.49 Moreover, there is serious concern regarding the emergence of resistant microorganisms when prophylactic antibiotics are administered. Accordingly, the Infectious Disease Society of America does not recommend routine antibiotic prophylaxis, especially with fluoroquinolones.54 Other strategies have involved initial chemotherapy dose reduction or the use of an alternative, less myelosuppressive chemotherapy regimen in the high-risk patient. The introduction of novel chemotherapy and biologic agents or combinations in the 6-year period since the American Society of Clinical Oncology (ASCO) guidelines were first published has not resulted in an increase in the incidence of FN for initial therapy of any malignancy.

General Circumstances 1996 Recommendation. Primary administration of CSFs was shown to reduce the incidence of FN by approximately 50% in the three major randomized trials in adults in which the incidence of FN was greater than 40% in the control group. The value of primary CSF administration has not been clearly established in less myelosuppressive regimens, and the cost benefit of primary versus secondary administration for the majority of initial chemotherapy regimens is unproven. It is recommended that primary administration of CSFs be reserved for patients expected to experience levels of FN that are at least comparable to or greater than those seen in control patients in these randomized trials, ie, an expected incidence ≥ 40%. Thus, for previously untreated patients receiving most chemotherapy regimens, primary administration of CSFs cannot be recommended.

2000 Update. Routine use of CSFs for primary prophylaxis of FN for any common disease in previously untreated patients is not justified by the existing data. CSFs have had a disappointingly small impact to date on disease-free and overall survival.50,51 It was anticipated that CSF use might result in an improved cure rate, particularly for chemosensitive tumors such as non-Hodgkin’s lymphoma (NHL), small-cell lung cancer, testicular cancer, and breast cancer. For the most part, either this has not been tested adequately or no impact has been found.

In several of the trials that initially described a reduction in the incidence of FN (with no impact on survival), the regimens created excess FN and are considered too toxic without significantly improved anticancer efficacy to justify current routine clinical use.52,53 For example, in the largest trial of CSFs in metastatic small-cell lung cancer, the rate of FN was 40% for the control arm45; a rate of 10% or less would be expected with current regimens. This topic has recently been reviewed in detail.50,51

Similar initial data in NHL also suggested the potential for lessened FN despite increased dose-intensity.55 However, the increase of approximately 10% in dose-intensity has not resulted in an increase of either disease-free or overall survival, either because the benefit is too small (< 5%) or because this degree of increased dose-intensity does not convey a survival advantage, even in this very chemosensitive tumor. As indicated in Table 1 Go, however, CSFs may permit completion of chemotherapy in patients with special circumstances, such as those with AIDS-related NHL or the elderly, but they still do not provide a benefit in clinical outcome, such as improved survival. Similar comments apply to patients undergoing treatment for Hodgkin’s disease.50,51 Although CSFs may allow completion of therapy in patients with special circumstances and may reduce the duration and severity of neutropenia in this setting, significant differences in delivered dose-intensity, hospitalizations, infections, and survival have not been determined in this population.

Phase II and III data in testicular and nonseminomatous germ cell tumors also demonstrate no difference in overall or disease-free survival.52 CSF use allowed completion of a full six cycles of chemotherapy, with fewer toxic deaths among the high-risk group of patients, but again with no impact on overall survival.53 This suggests that those patients may be considered under the heading of "Special Circumstances" and may thus benefit from CSF use by exception.

In the setting of breast cancer, there are, to date, no prospective, multicenter randomized data demonstrating an improvement in disease-free or overall survival by increasing the dose of doxorubicin beyond 60 mg/m2 x 455 or by applying dose-intensive chemotherapy.56-59 One must await further maturation of data from already-completed and ongoing randomized trials in order to better assess the effect of high-dose chemotherapy on outcome. There are no direct data supporting a benefit for maintaining dose-intensity.

The available data indicate that, with a sufficiently high incidence of FN (≥ 40%), there is strong evidence for the primary administration of CSFs to reduce hospitalization for antibiotic administration. Cost-effectiveness modeling also suggests that, depending on local cost factors, CSF administration may provide therapeutic savings if the expected incidence of FN is at least 40%, but only in high-risk patients or those requiring prolonged hospitalizations sufficient to exceed 10 to 14 days of CSF administration. In patients receiving more typical routine initial chemotherapy (the vast majority of newly diagnosed patients), CSF use for primary treatment cannot be recommended on either clinical or economic grounds. Primary administration of CSFs should be reserved for only those patients who are considered at high risk for FN due to special circumstances. Even in this patient population, the treating physician should be aware that the data are primarily modest for improved clinical outcomes (complications of FN) or economic benefit and that, because there are no data demonstrating an improvement in response or survival, dose reduction and schedule modification remain acceptable alternatives to the increased cost incurred by use of CSFs.

2000 Recommendation. No change.

Special Circumstances 1996 Recommendation. Clinicians may occasionally be faced with patients who might benefit from relatively nonmyelosuppressive chemotherapy but who have potential risk factors for FN or infection because of bone marrow compromise or comorbidity. It is possible that primary CSF administration may be exceptionally warranted in patients at higher risk for chemotherapy-induced infectious complications, even though the data supporting such use are not conclusive. Such risk factors might include the following: pre-existing neutropenia due to disease, extensive prior chemotherapy, or previous irradiation to the pelvis or other areas containing large amounts of bone marrow; a history of recurrent FN while receiving earlier chemotherapy of similar or lesser dose-intensity; or conditions potentially enhancing the risk of serious infection, eg, poor performance status and more advanced cancer, decreased immune function, open wounds, or already-active tissue infections. This is not meant to be an all-inclusive list; it is anticipated that, depending on the unique features of the clinical situation, there will be instances when the administration of a CSF will be appropriate outside of uses recommended in other guidelines.

2000 Recommendation. No change.

2. Guidelines for Secondary Prophylactic CSF Administration
Definition of Problem The rationale for secondary CSF administration in patients with a prior episode of FN is two-fold. It may direct the use of the CSF to a more restricted subset of patients who are most likely to benefit from CSF support. In addition, such a strategy can prevent the use of a CSF in many patients who might not need CSF support at all but who would nevertheless experience the inconvenience and cost of CSF support.

Clinical Outcomes In providing secondary administration of a CSF, there is the expectation that subsequent neutropenic complication of chemotherapy may be circumvented. In addition, secondary administration may allow chemotherapy dose maintenance, which is important if it improves overall survival, disease-free survival, quality of life, toxicity, or cost-effectiveness.

Alternative Approaches The principle alternative to intervention with a CSF has been chemotherapy dose modifications.

1996 Recommendation. There is evidence that CSF administration can decrease the probability of FN in subsequent cycles of chemotherapy after a documented occurrence in an earlier cycle. Even if FN has not occurred, the use of CSFs may be considered if prolonged neutropenia is causing excessive dose reduction or a delay in chemotherapy. However, in the absence of clinical data supporting maintenance of chemotherapy dose-intensity, physicians should consider chemotherapy dose reduction as an alternative to the use of CSFs.

2000 Update. The data supporting the use of CSFs for secondary prophylaxis are derived from the small-cell lung cancer trial by Crawford et al.21 This trial enrolled 199 patients with metastatic small-cell lung cancer, 102 of whom were treated with cyclophosphamide, doxorubicin, and etoposide and 97 of whom were treated with cyclophosphamide, doxorubicin, and etoposide followed by CSFs. Those patients in the control arm who developed neutropenic fever were allowed to receive open-label CSF as prophylaxis against infection for subsequent cycles of chemotherapy. Those patients who were treated with open-label CSF in this part of the study had a shorter duration of neutropenia (6 days in cycle 1 and 2.5 days in cycle 2 with CSF) and a reduction in the rate of fever with neutropenia (100% during cycle 1 and 23% during cycle 2), despite receiving the same doses of chemotherapy for both cycles. For patients on the placebo arm who did not develop neutropenic fever on cycle 1, and who continued on placebo, the duration of neutropenia was similar to that in cycle 1. Patients who remained on placebo had a continuing low rate of FN (5%) that was even lower than that of patients who crossed over and were receiving CSF. Thus, the results of this one study provide some evidence of improved incidence of FN in patients with a prior episode of FN.

2000 Recommendation. In the setting of many tumors exclusive of curable tumors (eg, germ cell tumors), dose reduction after an episode of severe neutropenia should be considered as a primary therapeutic option. No published regimens have demonstrated disease-free or overall survival benefits when the dose of chemotherapy was maintained and secondary prophylaxis was instituted. In the absence of clinical data or other compelling reasons to maintain chemotherapy dose-intensity, physicians should consider chemotherapy dose reduction after neutropenic fever or severe or prolonged neutropenia after the previous cycle of treatment.

3. Guidelines for CSF Therapy
Definition of the Problem Patients with neutropenia are predisposed to infection because of the absence of granulocytes, the disruption of the integumentary, mucosal, and mucociliary barriers, and because of the inherent microbial flora shifts that accompany severe illness and antimicrobial usage.42,60 CSFs were licensed to reduce the likelihood of patients developing fever and neutropenia. A 1994 survey of CSF use found that 34% of physicians surveyed would administer a CSF to afebrile patients diagnosed with neutropenia.61 Seventy-three percent of surveyed physicians would use CSFs in conjunction with IV antimicrobial agents after the onset of fever and neutropenia. Some physicians have initiated a CSF later in the infection course when the patient has failed to show clinical improvement or when the cause of the infection is associated with a poor outcome (ie, invasive fungal infection, antibiotic-resistant bacteria).

Clinical Outcomes The goals of therapeutic intervention with the CSFs are to reduce the incidence of infectious episodes and infection-related morbidity and mortality. This improvement in supportive care could potentially enhance a patient’s quality of life by reducing the incidence and duration of hospitalization and antibiotic use, but the cost and toxicity of CSF therapy should be considered in all treatment decisions.

Alternative Approaches The traditional alternative to prophylactic or therapeutic CSF administration has been to manage patients with neutropenia by monitoring temperature and ANC and by initiating empiric, broad-spectrum antibiotics if fever develops.54,62 Patients with neutropenia and fever have often been hospitalized for empiric antibiotic therapy until infection and neutropenia have resolved completely. This approach has been very successful, with a low incidence of infection-related mortality. Recent studies of infection risk have now defined lower-risk patients who may be suitable for outpatient or home antibiotic therapy.44,45,63

A. Afebrile Patients 1996 Recommendation. Data are inadequate in regard to whether patients with neutropenia but no fever will benefit clinically from the initiation of a CSF at the time neutropenia is diagnosed; intervention with a CSF in afebrile neutropenic patients is not recommended.

2000 Update. Two small studies using CSFs in patients who were afebrile but neutropenic were reviewed in the 1994 version of the ASCO recommendations for the use of hematopoietic CSFs.64,65 These studies failed to show clinical benefit, and despite being randomized, both included significant study design defects. A large randomized study has subsequently been reported.66 This trial assessed the effect of granulocyte CSF (G-CSF) treatment on severe, chemotherapy-induced neutropenia in afebrile adults with cancer. All 138 patients had solid tumors or lymphoma and were randomized to receive CSF or placebo. The time to neutrophil recovery of more than 500/µL was 2 days shorter for G-CSF–treated patients (2 v 4 days), but this statistical difference was not accompanied by any apparent clinical benefit. The need for hospitalization, the number of days in the hospital, the number of days of parenteral antibiotic treatment, and the number of culture-positive infections were not reduced. The neutropenia in these patients was profound but short. Recent clinical data do not show clinical benefit for the routine uses of CSFs in afebrile patients at the time that neutropenia is diagnosed.

2000 Recommendation. Current evidence supports the recommendation that CSFs should not be routinely used for patients with neutropenia who are afebrile. The strength of this recommendation has increased with the trial reported in 1997.66

B. Febrile Patients 1996 Recommendation. For the majority of patients with FN, the available data do not clearly support the routine initiation of CSFs as adjuncts to antibiotic therapy. However, certain FN patients may have prognostic factors that are predictive of clinical deterioration, such as pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or fungal infection. The use of CSFs together with antibiotics may be reasonable in such high-risk patients, even though the benefits of administration under these circumstances have not been definitively proven.

2000 Update. Eight prospective, randomized, controlled trials have been completed evaluating G-CSF, granulocyte-macrophage CSF (GM-CSF), or both as adjunct therapy for patients with chemotherapy-induced fever and neutropenia.67-74 Six of these trials were placebo-controlled, four were double blind, and six provide strong evidence regarding clinical benefit (Table 2).


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CSF Therapy of Fever and Neutropenia: Results of Randomized Trials
 
The largest trial was a study conducted in Australia and evaluated patients with fever and neutropenia who had received chemotherapy for treatment of solid tumors, lymphoma, or acute lymphoblastic leukemia (ALL).67 Study participants were treated with IV antibiotics and then randomized to receive G-CSF 12 µg/kg/d or placebo. The results of this trial were reviewed as part of the evidence included in the 1994 ASCO CSFs guideline.75 The duration of neutropenia (ANC < 500/µL) was 1 day shorter for G-CSF recipients, but there was no clinical improvement in days of fever, duration of antibiotic therapy, or hospitalization. The beneficial effect of G-CSF on neutrophil recovery was most evident among patients with solid tumors who were more than 10 days from completion of chemotherapy when they became febrile. There was a suggestion that there were fewer protracted hospital admissions among G-CSF–treated patients.

Similar clinical results have been reported by four other studies conducted among adult patients.69-71,74 The largest of these studies evaluated 134 patients with solid tumors and hematologic malignancies.69 Patients were randomly assigned to receive GM-CSF at a dose of 5µg/kg/d or placebo. GM-CSF administration was not associated with a statistically significant decrease in the duration of hospitalization. Quality-of-life indicators, including limitation of mobility, emotional distress, and decreased energy, were reported more frequently among GM-CSF recipients than among those who received placebo. The trial from Spain enrolled 121 patients and used a three-arm design with both G-CSF and GM-CSF.71 CSF-treated patients had a statistically significant decrease in the duration of neutropenia (ANC < 500/µL) and the duration of hospitalization. There was a slight trend toward increased infection-related mortality among G-CSF recipients. The trial conducted in Houston enrolled 100 patients and compared GM-CSF recipients to untreated control subjects.70 This trial included a subset analysis, which reported that those patients with pneumonia, cellulitis, abscess, or sinusitis had improved response rates (100% v 59%) when antibiotic therapy was combined with GM-CSF.

The group from France performed a randomized, unblinded trial of 68 adult patients with fever and neutropenia.72 GM-CSF treatment reduced the median duration of neutropenia (ANC < 500/µL), days of antibiotic therapy, and duration of hospitalization by 1 to 1.5 days. The greatest benefit for GM-CSF therapy was seen for patients who had received chemotherapy that was considered to have less than a 15% risk of inducing fever during the neutropenic period.

Studies among pediatric patients have shown some clinical benefit. The largest pediatric trial enrolled 186 patients with leukemia, lymphoma, and solid tumors.68 Patients were randomized to receive G-CSF at 5 µg/kg/d or placebo. G-CSF therapy reduced the median hospital stay by 2 days (5 v 7 days) and the duration of antibiotic therapy by 1 day. G-CSF therapy seemed to benefit three subgroups: (1) patients with ALL or those not receiving dose-intensive, alkylating agent–based regimens; (2) patients with early onset of fever (< 10 days) after chemotherapy completion; and (3) those without documented septicemia or focal infection.

A second pediatric trial failed to show a decrease in the duration of neutropenia, but the duration of hospitalization was shorter for GM-CSF recipients.73 In all eight adjuvant studies, the infection-associated mortality was low and unaffected by CSF therapy.

Cost analysis was performed for three of the randomized trials.68,69,71 The pediatric trial was a prospective analysis that included costs of hospital bed days, antimicrobial agents, blood products, parenteral nutrition, and G-CSF. The median total cost per episode of fever and neutropenia was more expensive for placebo-treated patients than for G-CSF–treated patients ($5,169 v $4,147), but this difference was not statistically significant. The relative hospital room costs and antimicrobial charges were significantly lower for the CSF recipients.68 In contrast, the cost analysis performed for the other two trials reported trends toward decreased cost for placebo recipients rather than for CSF-treated patients.69,71

A group from the Netherlands has developed a "Markov-type" economic model that calculates all relevant direct costs and savings of CSF therapy.36 Savings associated with CSFs in this study were highly dependent on the probability of the occurrence of fever and neutropenia. This probability differs among malignancies, treatment modalities, health conditions of the patients, disease status at time of therapy, and institutional policies regarding antibiotic discontinuation and hospitalization. This model found savings only with the administration of CSFs to patients with a high risk of complicated infections.

There is some variability in outcomes among the eight published trials. These discrepancies are likely secondary to differences in patient characteristics, study design, sample size, and data analysis, as well as possible clinical differences between G-CSF and GM-CSF in this therapeutic setting. Institutional policies regarding the timing of antibiotic discontinuation or need for hospitalization may also have hampered the ability of a CSF to influence these clinical parameters. The timing of antibiotic discontinuation remains controversial. The Infectious Diseases Society of America clinical guideline recommends that antibiotics be continued for at least 7 days and until all clinical and microbiologic signs of infection have resolved and the ANC is more than 500/µL.54 The National Comprehensive Cancer Network (NCCN) clinical guideline recommends that the duration of antibiotic treatment be individualized but be based on neutrophil recovery, specific site of infection and pathogen, and the status of the patient’s underlying disease. The NCCN guideline recommends as little as 4 days of antibiotic therapy for some patients with an uncomplicated infection and a sustained neutrophil recovery (ANC > 1,000/µL). Recommendations that support shorter duration of antibiotic treatment, or that report success with outpatient therapy of uncomplicated episodes of fever and neutropenia, suggest a lesser chance that CSFs will be beneficial when used in low-risk patients.

Conversely, subset analysis in several of the adjunctive therapy studies suggested that certain groups of patients could benefit from adjunctive CSF therapy, but these conclusions are inconsistent. The pediatric trial reported enhanced benefit for patients with ALL or those patients who did not receive dose-intensive alkylating treatment regimens, for patients with early-onset fever (< 10 days from chemotherapy), and for patients without a documented infection site.68 The Australian study reported benefit only for patients with solid tumors who developed fever more than 10 days after completing their chemotherapy.67 The study from Houston reported that CSFs improved outcomes primarily for patients with documented pneumonia, cellulitis, abscess, or sinusitis.70 The group from France reported maximum benefit from CSFs for patients receiving chemotherapy associated with a low risk of fever and neutropenia. These reported differences cannot be reconciled; they likely represent the difficulties inherent in subset analysis of small patient groups and would need to be confirmed in larger patient trials.

The risk of serious infection and poor outcome depends on the duration of profound (ANC < 100/µL) neutropenia, the degree of the therapy-induced mucosal and mucociliary barrier damage, and the specific infection pathogen (ie, invasive yeast and molds, antibiotic-resistant bacteria).42 Patients with these higher-risk characteristics are those who theoretically could benefit from adjunct CSF therapy, as indicated by data published in abstract form only.76 Continued study is required to determine whether such high-risk patients can be prospectively identified and whether CSF therapy will reduce mortality, hospitalization time, and infection-associated morbidity and treatment expense.

2000 Recommendation. The collective results of the eight trials67-74 provide strong and consistent support for the recommendation that CSFs should not be routinely used as adjunct therapy for the treatment of uncomplicated fever and neutropenia. Uncomplicated fever and neutropenia are defined as follows: fever of ≤ 10 days in duration; no evidence of pneumonia, cellulitis, abscess, sinusitis, hypotension, multiorgan dysfunction, or invasive fungal infection; and no uncontrolled malignancies. The eight trials have consistently shown a decrease in the duration of neutropenia of less than 500/µL, but clinical benefit has not consistently accompanied the decreased duration of neutropenia.

Certain patients with fever and neutropenia are at higher risk for infection-associated complications and have prognostic factors that are predictive of poor clinical outcome. The use of a CSF for such high-risk patients may be considered, but the benefits of a CSF in these circumstances have not been proven. These factors include profound (ANC < 100/µL) neutropenia, uncontrolled primary disease, pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), and invasive fungal infection. Age greater than 65 years and posttreatment lymphopenia may also be high-risk factors but have not been consistently confirmed by multicenter trials.

4. Guidelines for Use of CSFs to Increase Chemotherapy Dose-Intensity
Definition of Problem In preclinical systems, there is substantial evidence for a steep dose-response curve for many antineoplastic agents. However, clinical evidence for a dose response beyond those doses used in standard chemotherapy regimens has been variable and limited. Most clinical evidence for the importance of chemotherapy dose has been of two types. The first of these is derived from retrospective analyses of delivered dose or dose-intensity, usually as a fraction of that specified by the protocol. While intriguing, these analyses cannot definitively prove that drug dose is directly related to therapeutic effect; the alternative possibility is that toxicity leading to dose reduction acts as a marker of patients with poor prognoses and that higher doses of chemotherapy over and above that which can be delivered under normal circumstances are of no benefit. The second type of evidence comes from the retrospective analysis of published data in which regimens are allocated a dose-intensity score compared with some standard regimen. These analyses are prone to bias because of differences between protocols with respect to patient characteristics or supportive care.

In addition to the retrospective reviews of dose-intensity, there have been examples of prospective studies in which patients have been intentionally assigned lower-than-standard chemotherapy doses; the results suggest decreased disease control and worsened survival compared with those achieved with conventional doses. A few randomized clinical trials also indicate that dose-intensity greater than that of conventional therapy but less than that requiring progenitor-cell support improves disease control. One of these randomized trials in small-cell lung cancer demonstrated that dose intensification of ifosfamide/carboplatin/etoposide/vincristine to a 3-week rather than a 4-week regimen was not associated with increased FN or sepsis but did improve survival significantly.77 In this trial with a 2 x 2 factorial design, no benefit was achieved in reduction of myelosuppressive complications by the addition of GM-CSF. Collectively, both the randomized and retrospective analyses have generated interest in using the CSFs to support increased chemotherapy delivery rather than to reduce the toxicity of standard regimens.

Clinical Outcomes It has been hoped that administration of a CSF in support of chemotherapy can result in improved chemotherapy dose-intensity and consequent increases in response rates and duration of response.

Alternative Approaches The principal alternative to providing higher chemotherapy dose-intensity with CSF support has been the administration of standard-dose chemotherapy with dose modification for neutropenic and other toxicities.

1996 Recommendation.. Outside of clinical research trials, there is little justification for the use of CSFs to increase chemotherapy dose-intensity. In settings in which clinical research demonstrates that dose-intensity therapy not requiring progenitor-cell support produces improvement in disease control, CSFs should be used when these therapies are expected to produce significant rates of FN (eg, in ≥ 40% of patients).

2000 Update. Several studies have demonstrated the possibility of achieving a modest to moderate increase in dose-intensity using CSFs as an adjunct to higher-dose chemotherapy.76,78-84 Unfortunately, the number of randomized, multicenter clinical trials in nonhematologic malignancies that have demonstrated a survival benefit for patients receiving higher-dose therapy remains extremely limited,85 and increased toxicity is frequent. In the absence of a greater number of positive randomized trials in specific settings, this treatment approach must be approached cautiously. In the vast majority of trials to date, increased dose-intensity has not been demonstrated to improve overall survival.

2000 Recommendation. In the absence of more trials demonstrating a favorable effect on overall survival, disease-free survival, quality of life, or toxicity, there is no justification for the use of CSFs to increase chemotherapy dose-intensity or schedule or both outside of a clinical trial. This application of CSF use remains the domain of appropriately designed clinical investigation.

5. Guidelines for Use of CSFs as Adjuncts to Progenitor-Cell Transplantation
Definition of Problem The major complications of high-dose chemotherapy supported by autologous bone marrow transplantation (BMT) or peripheral-blood progenitor cell (PBPC) transplantation are disease recurrence, infection, the need for RBC and platelet transfusions, delayed or incomplete engraftment, organ damage from the ablative regimen, prolonged hospitalization, and the high cost of treatment. These same problems, plus graft-versus-host disease (GvHD) and graft rejection, are also present in patients undergoing allogeneic BMT.

Clinical Outcomes CSFs have been administered after both autologous and allogeneic BMT in anticipation of reducing the severity of infectious complications and thereby decreasing hospitalization time, reducing costs, and improving quality of life. Use of the CSFs to mobilize PBPCs into the circulation for collection is expected to enhance progenitor numbers, lessen the frequency, duration, and cost of leukopheresis procedures, and potentially speed hematologic recovery after transplantation of the CSF-mobilized cells.

Alternative Approaches The primary alternatives to administration of CSFs after cytoreduction and PBPC transplantation have been monitoring of temperature and ANC, initiation of antibiotic therapy if a fever develops, and continuation of hospitalization until satisfactory resolution of infection and neutropenia. Before CSFs were used to increase PBPC numbers, these cells were collected without CSF-assisted mobilization, either by performing multiple leukophereses in steady state or by using high doses of chemotherapy alone to force progenitor cells into the blood for collection.

1996 Recommendation. CSFs can successfully shorten the period of neutropenia and reduce infectious complications in patients undergoing high-dose cytotoxic therapy with autologous BMT. CSFs are effective in mobilizing autologous PBPCs for transplantation, and autologous PBPC transplantation has been shown to lead to earlier hematopoietic recovery than autologous BMT.86,87 Trials have demonstrated the value of CSF administration after high-dose chemotherapy and PBPC transplantation.88-90 Available data suggest clinical benefits after allogeneic BMT, and routine primary CSF administration in this setting seems warranted.91 CSFs can also be used to mobilize donor PBPC for allogeneic transplantation.92-95 There also may be a role for the CSFs in assisting in the recovery of patients who experience delayed or inadequate neutrophil engraftment after PBPC transplantation. CSFs can be routinely recommended as adjuncts to allogeneic and autologous PBPC transplantation, both for mobilization of PBPCs and as a means to speed hematopoietic reconstitution after BMT or PBPC transplantation. Administration of a CSF in cases of engraftment failure is warranted.

2000 Update. PBPCs may be less contaminated than bone marrow collections with tumor cells, although the mobilization process may lead to migration of tumor contaminants into the peripheral circulation; the clinical significance of such phenomena is controversial.96-98 Increasingly, CSF-mobilized PBPCs procured from healthy donors are used in the setting of allogeneic transplantation, providing faster hematopoietic recovery, similar to the autologous setting.99 One major concern regarding the use of donor-derived, mobilized PBPCs is the theoretical potential for an increased incidence and/or severity of GvHD. Preliminary data suggest no such adverse effect regarding acute GvHD and the possible increase in the incidence/severity of chronic GvHD; an ongoing multi-institutional, randomized, prospective study is currently assessing GvHD-related complications after donor-derived, CSF-mobilized PBPC transplantation versus BMT.100-102 CSFs, when administered shortly after reinfusion of PBPCs and at least within 5 days after autologous PBPC reinfusion, shorten the duration of neutropenia. The optimal timing is still under investigation.103,104 CSFs, when administered after PBPC reinfusion, accelerate neutrophil recovery and lower costs after allogeneic BMT and after reinfusion of autologous PBPCs.105,106 The therapeutic role of G-CSF in the treatment of relapsed acute and chronic leukemias after allogeneic BMT requires confirmation.107

2000 Recommendation. CSFs are recommended to help mobilize PBPCs and after PBPC infusion. Mobilized PBPCs have largely replaced bone marrow–derived cells for use in autologous transplantation. Side effects associated with mobilization and subsequent apheresis are usually limited and include constitutional symptoms and a decrease in platelets and other hematopoietic elements, especially after mobilization with combinations of chemotherapeutic agents and a CSF. The optimal dose of CSFs and chemotherapeutic agents is the subject of ongoing investigations, but a higher (10 µg/kg/d) dose of G-CSF in the setting of mobilization may yield greater content of CD34+ progenitor cells in the PBPC product, as documented in patients with hematologic malignancies and in patients with rheumatoid arthritis.88,108 Although the optimal method of mobilization needs further investigation, especially in heavily pretreated patients, administration of G-CSF, either alone or in combination with GM-CSF, or after the use of chemotherapeutic agents, generates PBPCs, leading to rapid hematopoietic recovery, shorter hospitalization, and possibly reduced costs.87,109-111 Further investigations are necessary to assess the potential risks, especially that of secondary hematologic malignancies associated with the use of combining chemotherapeutic agents and CSFs.112 The role of CSF-mobilized donor bone marrow in the autologous transplant setting is also under assessment.113

6. Guidelines for Use of CSFs in Patients With Acute Leukemia and Myelodysplastic Syndromes
Definition of Problem Essentially all patients with acute leukemia receiving induction therapy, and most such patients receiving intensive, postremission consolidation therapy, develop fevers that require hospitalization and IV antibiotics until neutrophil recovery occurs. Although morbidity and death from hemorrhage can occur in patients with associated coagulopathy or those with alloimmunization and refractoriness to platelet transfusion, infectious complications remain the major supportive care problem in the treatment of patients with acute leukemia. This is particularly true in older patients, in whom infectious deaths represent a major cause of failure to achieve complete remission. In patients who survive, complications of infections can compromise the ability to safely deliver postremission or subsequent therapy. In particular, fungal infections, which frequently occur later in the course of treatment, are difficult to treat and result in greater morbidity and mortality. Pulmonary and hepatic fungal infections and renal damage associated with amphotericin-B therapy can preclude administration of potentially curative postremission consolidation with chemotherapy or BMT. In patients with myelodysplastic syndromes (MDS) and chronic neutropenia, infection remains a major cause of morbidity and mortality, with the rate of infection directly related to the degree of neutropenia.

Data have been generated showing that the CSFs have the potential to alter cell-cycle kinetics in patients with acute myeloid leukemia (AML) such that drug sensitivity to S-phase–specific agents such as cytarabine could be enhanced. These in vitro data suggest that the CSFs have the potential to increase the effectiveness of treatment if administered before and/or concurrently with chemotherapy as leukemic cell "priming" agents.

Clinical Outcomes Because of the underlying disease and the intensity of the chemotherapy administered for AML, CSF use will not eliminate severe neutropenia, but it may shorten the duration of neutropenia. Theoretically, CSF administration could decrease the incidence of serious bacterial infections and fungal infections, minimize time spent on empiric therapy with amphotericin-B, reduce hospitalization time, increase the likelihood of achieving an initial complete remission, and promote delivery of subsequent therapy more safely and cheaply. Although reduced infectious mortality remains the most important potential consequence of postchemotherapy CSF administration, this is a difficult end point to evaluate with statistical confidence because of the effectiveness of current antibiotic and antifungal therapies. It is important to place such comparisons in clinical perspective, as results that are statistically significant but clinically insignificant do not help decision makers. Use of CSFs as primers for chemotherapy might enhance response rates and disease-free survival. In patients with MDS, a reduction in the number and severity of neutropenic infections and improvements in quality of life would be envisioned.

The potential for adverse effects with CSF administration in patients with myeloid malignancies also exists. Because most myeloid leukemia cells express receptors for the CSFs, postchemotherapy stimulation of leukemia growth has been a concern. Similar anxiety has arisen regarding CSF administration in patients with MDS, in whom conversion to overt leukemia is a natural feature of the disease. In patients undergoing CSF priming, it is conceivable that the CSF might prevent chemotherapy-induced apoptosis of leukemia cells. Therefore, randomized comparisons of complete response rate must be performed, with particular emphasis on differences in treatment failure caused by persistence of drug-resistant leukemia. Because CSF-primed patients receive chemotherapy and CSFs concurrently, stimulation of normal hematopoietic precursors with increased cytotoxicity against these elements might actually result in more prolonged marrow aplasia. Lastly, it is current practice to administer amphotericin-B to neutropenic patients receiving antibiotics who have persistent fever or other constitutional symptoms. If such side effects occur after CSF administration, it is possible that more, rather than fewer, patients will receive amphotericin-B or other changes in antibiotics, not because of infectious problems, but because of CSF-induced toxicity. In view of all these issues, it is essential that randomized trials be double-blinded with a placebo administered in the control arm.

Alternative Approaches At this time, standard support after induction chemotherapy for leukemia consists of careful monitoring for infection and empiric institutions of antibiotics and antifungal agents in febrile patients. There is still controversy about the value of prophylaxis with oral antibiotics and antifungal agents. Neutropenic patients with MDS are conventionally provided antibiotic support in response to fever or infection.

A. AML 1996 Recommendation. Primary administration of a CSF can be used after completion of induction chemotherapy in patients 55 years of age or older. Although there are fewer data, it is likely that the results showing shortening of the duration of neutropenia may apply to younger patients as well. CSFs given either before and/or concurrently with chemotherapy for priming effects still cannot be recommended outside of a clinical trial.

2000 Update. PRIMARY CSF ADMINISTRATION AFTER INDUCTION CHEMOTHERAPY FOR AML. Multiple, placebo-controlled, randomized studies114-122 have been conducted to evaluate the use of either GM-CSF or G-CSF begun after completion of induction therapy in newly diagnosed adult patients with AML. Most, but not all, of the trials enrolled predominantly older patients with AML. Although there are modest differences in design among the studies, the overall conclusions are remarkably similar and are as follows: (1) The addition of the CSFs decreased the time to recovery to 500 neutrophils/mm3 by 2 to 6 days. These studies did not use standard definitions of the duration of neutropenia, which perhaps accounts for the differences in magnitude of the effect. (2) Except for one study whose findings were discrepant from the others,114 there was no benefit from the use of CSFs in terms of improvement of complete response rates. Alternatively, there was no evidence of stimulation of leukemia growth and enhanced drug resistance after the use of CSFs, except in one small study in which a lower complete response rate in the group of patients receiving GM-CSF may have been related to maldistribution of other prognostic factors.121 (3) Most, but not all, studies showed statistically significant reductions in the duration of hospitalization and antibiotic use in patients receiving CSFs. The CSFs did not significantly prolong hospitalization in any of the studies.123 (4) Except for one small study, CSF use had no effect on patient survival.115 Further analysis of this study suggested that clinical benefits were restricted to a subpopulation of patients who required two courses of induction therapy.124 (5) In some studies, the CSF was not begun until marrow aplasia was demonstrated on bone marrow biopsy after the completion of chemotherapy115,118; functionally, this resulted in a 2- to 3-day gap between the end of chemotherapy and the initiation of the CSF. In other studies, however, the CSF was begun the day after completion of chemotherapy with no requirement for marrow biopsy assessment.116,117,120 The results seem to be identical using these two approaches, and it would seem that it is not necessary to routinely perform bone marrow biopsies before initiation of the CSF. However, since the results were similar using the two approaches, one could infer that delaying the start of the CSF for 2 to 3 days does not reduce the effect and could result in some cost savings. It should be emphasized that these different schedules have not been directly compared in randomized trials. (6) CSF use had no effect on platelet or RBC transfusion requirements. (7) Comparative studies have not been done, but the overall results suggest similar effects for G-CSF and GM-CSF. (8) Overall, during intensive chemotherapy for adult AML patients, clinical benefits included a shortening of hospital stays and cost savings of $2,230 and $2,310 in two studies and an increase in costs of $120 in a third study.123,125,126

CSF PRIMING OF LEUKEMIA CELLS IN PATIENTS WITH AML. In vitro studies have suggested that the CSFs have the potential to alter cell-cycle kinetics such that cytotoxicity from cell-cycle–specific agents, such as cytarabine, could be enhanced.127 Four prospective randomized trials have evaluated this approach by using GM-CSF begun before the initiation of chemotherapy: three trials included patients receiving initial induction therapy,119-121,127 and the other included patients receiving high-dose cytarabine therapy for AML in first relapse.128 An additional small trial evaluated the effect of G-CSF begun 2 days before induction chemotherapy in patients with relapsed or refractory AML.129 There was no improvement in any study in response rate, response duration, or overall survival in patients receiving a CSF before and during their induction chemotherapy.

CONSOLIDATION THERAPY FOR PATIENTS WITH AML IN COMPLETE REMISSION. Postremission chemotherapy is routinely administered to patients with AML in an attempt to increase the fraction of long-term, disease-free survival in younger patients. In most centers, this chemotherapy is administered either in the outpatient setting or during a brief hospital admission after which the patient is discharged to the outpatient setting. Two large randomized trials evaluated the role of G-CSF given after completion of relatively standard consolidation therapy117,130 to such patients. Both demonstrated marked decreases in the duration of severe neutropenia, with elimination of severe neutropenia in a subfraction of patients. This was associated with a decreased rate of infection requiring antibiotic therapy. There was no effect on complete response duration or overall patient survival. Similarly, shortening of the duration of neutropenia compared with a prior cohort treated without G-CSF was noted in a study evaluating intensive consolidation chemotherapy with a less standard, investigational regimen.130

2000 Recommendation. CSF use can be considered in this setting if benefits in terms of possible shortening of hospitalization outweigh the costs of CSF use. Several studies have shown that CSF administration can produce modest decreases in the duration of neutropenia when begun shortly after completion of the initial days of chemotherapy of the initial or repeat induction. Beneficial effects on end points such as duration of hospitalization and incidence of severe infections have been variable and modest, although patients 55 years of age or older are most likely to benefit from CSF use. No study has yet demonstrated significant improvement in complete response rates or long-term outcome. Thus, while there seems to be minimal risk associated with the use of CSFs in this situation, the choice of whether or not to use the CSF is likely to be determined by cost considerations. In a nutshell, the cost of the cytokine must be balanced against any possible shortening of hospitalization associated with the slightly more rapid marrow recovery, as, for example, in patients 55 years of age or older. It is not known from the published data whether the CSFs significantly accelerate recovery to ANCs of 100 to 200/mm3. In most patients, regenerating counts of this level are sufficient to protect against infection so as to permit safe discharge of patients from hospital.

There is no evidence that CSFs given either before or concurrently with chemotherapy for priming effects are of benefit, and their use in this fashion cannot be recommended outside the setting of the clinical trial.

There seems to be more profound shortening of the duration of neutropenia after consolidation chemotherapy for patients with AML in remission. Although the randomized studies did not address this issue, it is likely that this will be associated with decreased rates of hospitalization and possibly shorter durations of hospitalization in such patients. No benefit has been demonstrated in terms of prolongation of complete response duration or overall survival; however, the available evidence indicates that the CSFs can be recommended after the completion of consolidation chemotherapy.

B. MDS 1996 Recommendation. CSFs can increase the ANC in neutropenic patients with MDS. Data supporting the routine, long-term, continuous use of CSFs in these patients are lacking. Intermittent administration of CSFs may be considered in a subset of patients with severe neutropenia and recurrent infection.

2000 Update. Morbidity and death from infection as a consequence of chronic, severe neutropenia are common in patients with MDS. CSFs can increase the level of circulating neutrophils in patients with MDS, with clinical improvement of infections in some such patients.131,132 The ANC declines when the CSF is discontinued. These observations were confirmed in a randomized trial comparing G-CSF and a policy of best supportive care in patients with MDS.133 Although the overall rate of transformation to frank AML was similar in the two groups, overall survival was shorter in the G-CSF recipients with refractory anemia and excess blasts. There is no clear-cut explanation for this observation, but prolonged or continuous treatment with G-CSF cannot be recommended in patients with MDS. Ongoing trials are evaluating whether the addition of G-CSF to erythropoietin increases the response rate compared with erythropoietin alone.

2000 Recommendation. No change.

C. ALL (Note. This topic is new to the guideline.) Evidence-Based Review. Using study designs similar to those for patients with AML, six studies,134-139 of which five were prospectively randomized trials,134-138 evaluated the effect of G-CSF in both adults and children receiving initial induction and postremission therapy for ALL. A major difference from AML, however, is that after multidrug therapy given for the first 3 to 6 days of each treatment course, most protocols for patients with ALL have additional therapy, usually corticosteroid/antimetabolite–based, given either intermittently or continuously. Thus, in contrast to AML studies, some of the ALL studies administered G-CSF concurrently with some chemotherapeutic drugs. In addition, the regimens used in these studies were more heterogeneous than those in the AML studies, and although most of the studies started the G-CSF shortly after the completion of the first few days of chemotherapy, the largest study in children135 and a smaller study in adults136 did not begin G-CSF/placebo until day 30 of initial induction therapy.

Nonetheless, most of the findings were similar. Although three of the trials were relatively small (< 40 patients/arm)136-138 and not all trials were double-blinded and placebo-controlled, they all demonstrated shortening of the duration of neutropenia (generally defined as recovery to > 1,000 neutrophils/mm3) after both the first and second courses of induction chemotherapy. The largest studies in adults134 and children135,140 showed reductions in the duration of neutropenia of 6, 8, and 5 days. The effect on other clinical parameters, such as the incidence of severe infections or FN, the frequency and duration of hospitalization, and the ability to deliver the regimens on time, were variable. In the large (198 patients) trial in adults conducted by Cancer and Leukemia Group B, there was a trend toward a higher complete response rate in patients receiving G-CSF, particularly in patients more than 60 years old.134 Given the very high complete response rate in children with ALL, the trials were not designed to detect further improvements in this parameter. The largest pediatric trial (164 patients), conducted at St Jude’s Children’s Research Hospital (Memphis, TN), did demonstrate shorter median hospital stays and fewer documented infections, although the overall requirement for hospitalization was not decreased and the overall costs were $2,497 higher.135 There was no improvement in disease-free or overall survival associated with the use of G-CSF in any of the five randomized trials.

2000 Recommendation. The data are sufficient to recommend G-CSF administration begun after completion of the first few days of chemotherapy of the initial induction or first postremission course, thus shortening the duration of neutropenia of less than 1,000/mm3 by approximately 1 week. Effects on the incidence and duration of hospitalization and the acquisition of serious infections are less consistent. Although there was a trend for improved complete response rates in one large study,134 particularly in older adults, there was no prolongation of disease-free or overall survival in any of the trials. G-CSF can be given together with the continued corticosteroid/antimetabolite therapy, which is a feature of many ALL regimens, without evidence that such concurrent therapy prolongs the myelosuppressive effects of the chemotherapy. As in AML, it is not known from the published data whether the CSFs significantly accelerate recovery to ANCs of 100 to 200/mm3. In most patients, regenerating counts of this level are sufficient to protect against infection so as to permit safe discharge of patients from the hospital. The use of G-CSF for children with ALL was associated with small benefits in days of antibiotic use or in-hospital days, although a small amount of additional costs was incurred, after the costs of the CSFs were taken into consideration. Cost estimates of CSFs for adults with ALL have not been reported.

D. Leukemia in Relapse (Note. This topic is new to the guideline.) Evidence-Based Review. There have been few randomized studies in patients treated in relapse for AML or ALL. One of the earliest studies of CSFs evaluated a heterogeneous group of patients with relapsed leukemia and demonstrated faster neutrophil recovery in patients receiving G-CSF after completion of chemotherapy.141 In patients with relapsed ALL, a small study suggested more rapid neutrophil recovery compared with historical controls, with no effect on infectious morbidity or response rate.142

2000 Recommendation. The available data are not sufficient to recommend either for or against the use of CSFs in patients with refractory or relapsed ALL. Few controlled studies have evaluated CSFs in patients with relapsed or refractory acute leukemia. The available data suggest shortening of the duration of neutropenia but are inadequate to comment on any effects on infectious complications and, in particular, on whether there may be an adverse effect on response rates in some patients with myeloid malignancies because of a stimulatory effect on leukemia growth in a situation in which there is less of a guarantee that chemotherapy will produce sufficient cytoreduction. Therefore, there is no evidence that CSFs are of important benefit in patients with refractory or relapsed myeloid leukemia, and they should be used judiciously or not at all in such patients.

7. Guidelines for Use of CSFs in Patients Receiving Concurrent Chemotherapy and Irradiation
Definition of Problem In theory, adding chemotherapeutic agents such as cisplatin and fluorouracil to high-dose radiation therapy can kill tumor cells outside a radiation field, and these agents can also act as radiation sensitizers within the field.143,144 In clinical practice, concurrent chemotherapy and radiation therapy may be important in the treatment of some malignancies; the clinical evidence has been most persuasive in patients with esophageal cancer, demonstrating better local control and survival with combined chemoradiotherapy.145-147 In patients with lung cancer, randomized studies have suggested that combination chemotherapy in addition to high-dose radiation results in improved survival compared with irradiation alone.148,149 Although mucositis and pneumonitis have been the primary dose-limiting toxicities with radiation, the addition of chemotherapy has provoked sufficient hematologic toxicity to spur interest in administration of CSFs.

Clinical Outcomes CSF support of chemoradiotherapy might be expected to decrease the incidence and severity of neutropenic complications. In addition, based on preliminary observations,150 there has been the prospect that mucositis associated with combined-modality cytotoxic treatment might also be reduced by CSF use.

Alternative Approaches The principal alternative to intervention with a CSF has been chemotherapy dose modification or interruption in administration of radiotherapy. Antibiotics, pain relief, nutritional support, corticosteroids, and other similar measures have been provided to blunt the toxicities of combined-modality therapy.

1996 Recommendation. CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy.

2000 Update. CSFs have been shown in several studies to reverse the effect of radiation therapy, with or without chemotherapy, on neutrophil counts. The clinical benefit of this effect may facilitate the administration of radiation according to schedule, but an impact on outcomes has not been demonstrated. The major concern about the use of CSFs as supportive therapy for combined chemoradiation lies with findings that suggest a possible deleterious effect on platelet count. The principal study demonstrating this finding is the Southwestern Oncology Group study of the role of CSFs in patients treated with concurrent chemoradiation.151 This randomized trial treated 215 assessable small-cell lung cancer patients with a regimen of cisplatin, etoposide, and thoracic irradiation; 108 received GM-CSF and 107 did not. Although grade 4 neutropenia occurred, the study also found a significant increase in thrombocytopenia in the GM-CSF arm: the incidences of grade 3 and grade 4 platelet toxicity were 54% and 35%, respectively, in the treated group and only 12% and 6% in the control population. Most of the toxicity occurred in the second course of treatment, although the effect persisted in subsequent courses. In addition, there were more toxic deaths (nine v one, P < .01) in the GM-CSF arm, with the majority being related to pulmonary toxicity. Studies of lesser strength demonstrating the deleterious effect on platelets include a nonrandomized comparison of non–small-cell lung cancer patients treated with cisplatin, etoposide, mitomycin, and chest irradiation, in which the mean nadir platelet count was 131 x 103 in seven patients who received the growth factor.

Several small studies of CSFs in patients undergoing large-field irradiation have demonstrated that CSFs may help ameliorate the effect of radiation on neutropenia. These possible benefits have been seen in studies using CSFs after WBC count depression in craniospinal radiotherapy and a variety of large-field applications, and prophylactically in Hodgkin’s disease and multiple myeloma. A possible mechanism for the impact on platelets may be the demonstration that blood colony-forming units–megakaryocytes induced by CSFs may be more radiosensitive to radiation than nonrecruited marrow progenitors. There is evidence indicating the potential for an adverse interaction between mediastinal radiotherapy and CSF administration. However, it should be noted that the thrombocytopenia observed might be unique to this site of irradiation and only in the setting of combined chemoradiation. At present, the routine use of CSF in this setting should be avoided unless studied as part of a clinical trial with appropriate monitoring of thrombocytopenia and pulmonary toxicity. CSF use to support large-field irradiation may have benefits, but further studies are required to recommend this usage. CSF use in conjunction with radiation has not been studied extensively, and further studies are required to ascertain the optimal sequencing.

2000 Recommendation. CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum. In the absence of chemotherapy, in patients receiving radiation therapy involving large fields, therapeutic use of CSFs may be considered if prolonged delays secondary to neutropenia are expected.

8. Guidelines for Use of CSFs in the Pediatric Population
Definition of Problem In contrast to adults with cancer, the majority of pediatric patients are treated on clinical research protocols. Chemotherapy for pediatric cancers is generally more intensive, and myelosuppression is thus more frequent and severe. Infants receiving chemotherapy are at a particular risk for neutropenic morbidity because of the immaturity of the hematopoietic and immune systems. These factors can increase the incidence of FN and the potential for life-threatening infections. However, there is an acceptable risk-to-benefit ratio because of the greater curability of most pediatric cancers.

Clinical Outcomes The same end points used in the previous guidelines should be considered in determining CSF benefit in pediatric patients, eg, incidence of FN, length of hospital stay, antibiotic use, therapeutic costs, and quality of life.

Alternative Approaches Alternative approaches for pediatric patients receiving chemotherapy would be to treat without CSFs, modifying chemotherapy doses and providing antibiotic support as necessary.

1996 Recommendation. In the absence of conclusive pediatric data, the guidelines recommended for adults are generally applicable to the pediatric age group. However, optimal CSF doses have yet to be determined. Further clinical research into the use of these factors in support of chemotherapy and PBPC transplantation in the pediatric age group should be given high priority.

2000 Update. Although the pediatric community is well aware of the ASCO guidelines on growth factor use, a number of important differences in the care of children with cancer impact the application of the ASCO guidelines. Perhaps most important is the fact that the vast majority of children with cancer are enrolled in clinical protocols directed by National Cancer Institute–sponsored national cooperative group efforts. Accordingly, the use of growth factors is largely determined by the requirements delineated in these protocols. A recent review of the practices within the Pediatric Oncology Group152 indicates that primary prophylaxis with growth factors occurs more commonly in children than in adults and is guided by the anticipated duration of neutropenia (> 7 days) in the pediatric population. At the same time, use of growth factors in primary prophylaxis is not uniform across all protocols and diseases and is influenced by physician preference as well as by available data. The use of growth factors for secondary prophylaxis seems more similar in children and adults, although a reduction in chemotherapy dosage is rarely selected by pediatric oncologists as an alternative to use of a growth factor. Although a near majority of pediatric oncologists surveyed reported using growth factors in children presenting with fever and neutropenia, this was less commonly done in uncomplicated fever and neutropenia but was more frequently used in patients who had perceived complicated illness with fever and neutropenia. Overall, pediatric oncologists seem to use growth factors more commonly than their adult colleagues for primary and secondary prophylaxis than the current ASCO guidelines would indicate but less often for uncomplicated fever and neutropenia. It seems that differences in utilization are guided by treatment strategies in adult and pediatric patients and, in particular, by the perceived toxicity of high–dose-intensity regimens in children.

2000 Recommendation. No change.

9. Guidelines for CSF Dosing and Route of Administration
Definition of Problem A variety of CSF doses have been tested. Phase I studies have examined escalating doses; however, toxicity, not efficacy, has been the major end point, and small cohort sizes have hindered dose-response assessments. Phase II and III trials often used a single, arbitrarily chosen dose of CSFs. Only a few trials have evaluated a dose range of CSFs in a randomized fashion. Additionally, differences in the biologic activities and toxicities of G-CSF and the two types of GM-CSF, sargramostim and molgramostim, have potential implications for dosing.

Clinical Outcomes The primary end points of benefit assessed by the panel included rates of FN, hospitalization, and antibiotic use, convenience, and cost. A review of CSF dose and route effects on ANC was also necessary because many studies have been inadequately sized to detect differences in other clinical outcomes. Relative toxicity was also evaluated across CSF dose levels (see Impact of CSFs on Economics of Febrile Neutropenia, under Summary of Relevant Background Data).

1996 Recommendation In adults, the recommended CSF doses are 5 µg/kg/d for G-CSF (filgrastim) and 250 µg/m2/d for GM-CSF (sargramostim). These agents can be administered subcutaneously or intravenously as clinically indicated. CSF dose escalation is not advised. The available data suggest that rounding the dose to the nearest vial size may enhance patient convenience and reduce costs without clinical detriment.

2000 Update Higher doses of either G-CSF or GM-CSF have not been associated with improved clinical benefits.153,154 One exception may be in the setting of PBPC mobilization, where a dose of 10 µg/kg/d resulted in an improved leukapheresis product compared with lower doses.155-158 The schedule of administration of G-CSF (5 µg/kg bid v 10 µg/kg as single injection) may also result in improved mobilization.159 No randomized trials of doses below those recommended for G-CSF and GM-CSF have been reported. Clinical and clinical trial experience continue to support rounding of dose to the nearest vial size. Pharmacokinetic analysis favors subcutaneous administration compared with IV use for both agents.160-162

2000 Recommendation. In adults, the recommended CSF doses are 5 µg/kg/d for G-CSF (filgrastim) and 250 µg/m2/d for GM-CSF (sargramostim) for all clinical settings other than PBPC mobilization. In the setting of PBPC mobilization, if G-CSF is used, a dose of 10 µg/kg/d seems preferable. Outside of this indication, CSF dose escalation is not advised. Rounding the dose to the nearest vial size is an appropriate strategy to maximize cost benefit. The preferred route of CSF administration is subcutaneous.

10. Guidelines for Initiation and Duration of CSF Administration
Definition of Problem Appropriate timing of CSF administration relative to chemotherapy and the duration of CSF use are important concerns in trying to achieve the greatest degree of clinical benefit with the least possible cost.35 The package insert recommends that G-CSF be initiated no earlier than 24 hours after the administration of chemotherapy and that daily dosing with the drug be continued until the ANC has reached at least 10,000/µL after the neutrophil nadir. It has also been advised that G-CSF not be given in the period 24 hours before treatment with the next cycle of chemotherapy. In patients undergoing BMT, the manufacturer recommends tapering the G-CSF dose from 10 µg/kg/d to 5 µg/kg/d once the ANC has recovered to 1,000/µL for at least 3 days and then discontinuing the G-CSF once the ANC has been greater than 1,000/µL for 3 additional days. Because GM-CSF (sargramostim) has been licensed specifically for use after autologous or allogeneic BMT and for AML, the manufacturer’s instructions for administration have been limited to those clinical settings. Current recommendations for BMT are to initiate GM-CSF beginning on the day of bone marrow infusion and not less than 24 hours from the last chemotherapy and 12 hours from the most recent radiotherapy. GM-CSF should be continued until an ANC greater than 1,500 cells/mm3 for 3 consecutive days is obtained. It is also advised that the drug be discontinued early or the dose be reduced by 50% should the ANC increase to greater than 20,000/µL. However, based on recent publications, the optimal timing of CSF administration is still under investigation: CSFs, when administered within 1 to 5 days after PBPC reinfusion, shorten the duration of neutropenia.96,97 In the setting of graft failure or engraftment delay, the recommended dose of GM-CSF is 250 µg/m2/d for 14 days followed by a 7-day break. Up to three such courses, with dose escalation to 500 µg/m2/d in the third course, are advised.

Clinical Outcomes In assessing the impact of schedule on the benefits of CSF administration, the duration of neutropenia has most often been used as a surrogate marker of benefit. Correlations also need to be made with clinical measures of benefit, eg, incidence of hospitalization, reduced cost, increased convenience, or enhanced maintenance of chemotherapy delivery.

1996 Recommendation. Existing clinical data suggest that starting G-CSF or GM-CSF between 24 and 72 hours subsequent to chemotherapy may provide optimal neutrophil recovery. Continuing the CSF until the occurrence of an ANC of 10,000/µL after the neutrophil nadir, as specified in the G-CSF package insert, is known to be safe and effective. However, a shorter duration of administration that is sufficient to achieve clinically adequate neutrophil recovery is a reasonable alternative, considering issues of patient convenience and cost.

2000 Recommendation. The optimal timing and duration of CSF administration are still under investigation. Starting CSFs up to 5 days after PBPC reinfusion is reasonable based on available clinical data.

11. Special Commentary on Comparative Clinical Activity of G-CSF and GM-CSF
1996 Recommendation. Guidelines about equivalency of the available recombinant preparations of G-CSF and GM-CSF cannot be proposed because there have been no large-scale, prospective, comparative trials evaluating relative CSF efficacy. The strength of evidence to support the use of G-CSF or GM-CSF varies based on the specific indication for CSF administration, eg, support after BMT or use with nontransplantation chemotherapy regimens. The panel strongly encourages additional clinical investigation that will guide clinical application of these biologically distinct molecules by addressing issues of comparative clinical activity, toxicity, and cost-effectiveness.

2000 Update. Guidelines about the equivalency of the available recombinant preparations of G-CSF and GM-CSF cannot be proposed because there have been no large-scale, comparative trials evaluating relative CSF efficacy in primary or secondary prophylaxis. Since the last update of the ASCO CSF guidelines was published in 1996,163 a comparison study was published in 1998.164 This randomized, double-blind study was performed in patients who had received chemotherapy and were neutropenic at the time of study entry, with a mean ANC of 277/µL for the GM-CSF group and 282/µL for the G-CSF group. Entry criteria required chemotherapy within 4 weeks of registration, age over 17, ANC less than 500/µL, and absence of fever. Patients were excluded if they met any of the following exclusion criteria: use of long-acting chemotherapeutic agents within 6 weeks of study entry; concurrent thoracic radiation or history of pelvic radiation; use of growth factors within 6 weeks of study entry; concurrent use of oral or IV antibiotics or systemic antifungal agents; pregnancy or lactation; allergy to either growth factor; and infection with the human immunodeficiency virus. End points of the study were time to ANC recovery, incidence of fever, infection, and hospitalization, and duration of hospitalization. One hundred eighty-one patients were assessable for safety and 170 patients were assessable for efficacy of the two study arms. There was no significant difference in the time needed for patients to reach an ANC of 500/µL, but there was a statistically significant, but not clinically important, measurably shorter time to an ANC of 1,000/µL and an ANC of 1,500/µL for G-CSF over GM-CSF. There was no difference in the reported incidence of fever or hospitalization. This study has many design flaws that make comparative analysis of the relative efficacy of G-CSF versus GM-CSF impossible. It does provide an opportunity to compare the relative toxicity of these two agents. There were no significant differences in adverse events between the two groups. The G-CSF group did have a 10.7% incidence of grade 2 fever 4 hours after injection, compared with a 3.8% incidence for the GM-CSF group, but no conclusions can be drawn from this difference because of the study design. From this study, one can probably conclude that the two agents probably have fairly similar toxicities; otherwise, a greater disparity would have been observed in adverse events.

In the setting of progenitor-cell transplantation, a second, more recently published randomized trial compared G-CSF with GM-CSF or the sequential combination of both cytokines in mobilization of CD34+ progenitor cells in patients with myeloma, lymphoma, or breast cancer.165 All patients in this trial then received G-CSF after CD34+-cell infusion and chemotherapy. During the mobilization period after chemotherapy (median duration, 12 to 13.5 days), patients demonstrated faster recovery of neutrophils and an increased incidence of sargramostim-related fever. In addition, there was an unexpected and unexplained increase in the incidence of anemia and RBC transfusions in the sargramostin group. There were no differences in platelet nadirs and only nonsignificant differences in platelet transfusions. Compared with those who received GM-CSF mobilization, patients who received either G-CSF alone or the combination demonstrated significant improvement in days to ANC of 500/mm3, as well as in incidence of fever, hospitalization, antibiotic therapy, and RBC and platelet transfusions. Improved outcomes after peripheral stem-cell infusions were a direct result of the improvement in CD34+-cell yield with each apheresis in those patients receiving either the G-CSF or combination G-CSF plus GM-CSF mobilization regimens in comparison to GM-CSF alone.

2000 Recommendation. No change.


    ACKNOWLEDGMENT
 
ACKNOWLEDGMENT

ASCO sincerely appreciates the contributions of the following members of the ASCO Hematopoietic Colony-Stimulating Factors Expert Panel: James Anderson, Paul Anderson, Gerald Bodey, Nancy Davidson, John Hamm, Bruce Hillner, Carl Kardinal, Mark Levine, John Miller, Judith Ochs, Victor Santana, Thomas Shea, Saroj Vadhan-Raj, and Jane Weeks.

APPENDIX


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APPENDIX Hematopoietic Growth Factors Update Subcommittee
 


    NOTES
 
Adopted on July 21, 2000, by the American Society of Clinical Oncology.

Manuscript editing was completed by H. Ozer and M. Somerfield.

*The American Society of Clinical Oncology considers adherence to these guidelines to be voluntary. The ultimate determination regarding their application is to be made by the physician in light of each patient’s individual circumstances. In addition, these guidelines describe administration of therapies in clinical practice; they cannot be assumed to apply to interventions performed in the context of clinical trials, given that such clinical studies are designed to test innovative and novel therapies for this symptom in which better treatment is of paramount importance. In that guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions for further research and those settings in which investigational therapy should be considered. Back


    REFERENCES
 TOP
 INTRODUCTION
 SUMMARY OF RELEVANT BACKGROUND...
 SPECIFIC GUIDELINES
 REFERENCES
 
1. Dillman RO, Davis RB, Green MR, et al: A comparative study of two different doses of cytarabine for acute myeloid leukemia: A phase III trial of Cancer and Leukemia Group B. Blood 78: 2520-2526, 1991[Abstract/Free Full Text]

2. Laubenstein LV, Krigel RL, Odajnyk CM, et al: Treatment of epidemic Kaposi’s sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol 2: 1115-1120, 1984[Abstract]

3. Harrison M, Tomlinson D, Stewart S: Liposomal-entrapped doxorubicin: An active agent in AIDS-related Kaposi’s sarcoma. J Clin Oncol 13: 914-919, 1985

4. Kaplan LD, Lakin JO, Crowe S, et al: Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma: Results of a randomized trial. J Clin Oncol 9: 929-940, 1991[Abstract]

5. Kaplan LD, Straus DJ, Testa MA, et al: Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus infection: National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group [see comments]. N Engl J Med 336: 1641-1648, 1997[Abstract/Free Full Text]

6. Loehrer PJS, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative study. J Clin Oncol 10: 1066-1073, 1992[Abstract]

7. Redman BG, Smith DC, Flaherty L, et al: Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol 16: 1844-1848, 1998[Abstract]

8. Bajorin DF, McCaffrey JA, Hilton S, et al: Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: A phase II trial. J Clin Oncol 16: 2722-2727, 1998[Abstract]

9. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330: 1253-1259, 1994[Abstract/Free Full Text]

10. Fisher B, Brown A, Dimitrov N, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8: 1483-1496, 1990[Abstract]

11. Nabholtz JM, Gelman K, Bontenbal M, et al: Multicenter randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14: 1858-1867, 1996[Abstract/Free Full Text]

12. Hudis CA, Serdman AD, Crown JPA, et al: Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer. J Clin Oncol 14: 58-65, 1996[Abstract]

13. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13: 2688-2699, 1995[Abstract]

14. O’Connell MJ, Laurie JA, Kahn M, et al: Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 16: 295-300, 1998[Abstract/Free Full Text]

15. Poon MA, O’Connell MJ, Wieand HS, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9: 1967-1972, 1991[Abstract/Free Full Text]

16. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 353: 1412-1418, 1998

17. Nichols CR, Williams SD, Loehrer PJ, et al: Randomized study of cisplatin dose-intensity in poor-risk germ cell tumors: A Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9: 1163-1172, 1991[Abstract]

18. Nichols CR, Saxman S: Primary salvage treatment of recurrent germ cell tumors: Experience at Indiana University. Semin Oncol 25: 210-214, 1998[Medline]

19. Forastiere AA, Metch B, Schullerr DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 10: 1245-1251, 1992[Abstract/Free Full Text]

20. Fountzilas G, Athanassiadis A, Samantas E, et al: Paclitaxel and carboplatin in recurrent or metastatic head and neck cancer: A phase II study. Semin Oncol 24: 65-67, 1997 (suppl 2)

21. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer (r-medHuG-CSF). N Engl J Med 325: 164-170, 1991[Abstract]

22. Roth BJ, Johnson DH, Einhorn LH, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10: 282-291, 1992[Abstract]

23. Schiller J, von Pawel J, Shepherd F, et al: Topotecan (T) versus (vs) cyclophosphamide (C), doxorubicin (A) and vincristine (V) for the treatment (tx) of patients (pts) with recurrent small cell lung cancer (SCLC): A phase III study. Proc Am Soc Clin Oncol 17: 456a, 1998 (abstr 1755)

24. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 16: 2459-2465, 1998[Abstract]

25. Natale RB: Preliminary results of a phase I/II clinical trial of paclitaxel and carboplatin in non-small cell lung cancer. Semin Oncol 23: 51-54, 1996 (suppl 16)[Medline]

26. Crino L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 15: 297-303, 1997[Abstract/Free Full Text]

27. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327: 1478-1484, 1992[Abstract]

28. Fisher RI, Gayner ER, Dahlberg S, et al: Comparison of standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328: 1002-1006, 1993[Abstract/Free Full Text]

29. Salmon SE, Crowley JJ, Grogan TM, et al: Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: A Southwest Oncology Group study. J Clin Oncol 12: 2405-14, 1994[Abstract/Free Full Text]

30. Barlogie B, Smith L, Alexanian R: Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310: 1353-1356, 1984[Abstract]

31. McGuire WP, Hoskins WJ, Brady MF, et al: Comparison of combination therapy with paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with suboptimal stage III and stage IV ovarian cancer: A Gynecologic Oncology Group study. Semin Oncol 24: 13-16, 1997 (suppl 2)

32. Bookman MA, McGuire WP, Kilpatrick D, et al: Carboplatin and paclitaxel in ovarian carcinoma: A phase I study of the Gynecologic Oncology Group. J Clin Oncol 14: 1895-1902, 1996[Abstract/Free Full Text]

33. Saltz L, Janik JE: Topotecan and the treatment of recurrent ovarian cancer: Is there a role for granulocyte colony-stimulating factor? Semin Oncol 24: 26–30, 1997 (suppl 5)

34. Antman K, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcoma. J Clin Oncol 11: 1276-1285, 1993[Abstract/Free Full Text]

35. Lyman GH, Lyman CG, Sanderson RA, et al: Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 85: 488-493, 1993[Abstract/Free Full Text]

36. Uyl-de Groot CA, Vellenga E, Rutten FF: An economic model to assess the savings from a clinical application of haematopoietic growth factors. Eur J Cancer 32A:57-62, 1996

37. Toner GC, Shapiro JD, Laidlaw CR, et al: Low-dose versus standard-dose lenograstim prophylaxis after chemotherapy: A randomized, crossover comparison. J Clin Oncol 16: 3874-3879, 1998[Abstract/Free Full Text]

38. Silber JH, Fridman M, Shpilsky A, et al: Modeling the cost-effectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer. J Clin Oncol 16: 2435-2444, 1998[Abstract]

39. Anonymous: Drugs of choice for chemotherapy. Med Letter 35:43-50, 1993

40. Blay JY, Chauvin F, Le Cesne A, et al: Early lymphopenia after cytotoxic chemotherapy as a risk factor for febrile neutropenia. J Clin Oncol 14: 636-643, 1996[Abstract/Free Full Text]

41. Bodey GP, Buckley M, Sathe YS, et al: Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64: 328-340, 1966

42. Pizzo PA: Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 328: 1323-1332, 1993[Free Full Text]

43. Talcott JA, Finberg R, Mayer RJ, et al: The medical course of cancer patients with fever and neutropenia. Arch Intern Med 148: 2561-2568, 1988[Abstract/Free Full Text]

44. Talcott JA, Siegel RD, Finberg T, et al: Risk assessment in cancer patients with fever and neutropenia: A prospective, two-center validation of a prediction rule. J Clin Oncol 10: 316-322, 1992[Abstract]

45. Rubenstein EB, Rolston K, Benjamin RS, et al: Outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer. Cancer 71: 3640-3646, 1993[Medline]

46. Riikonen P, Saarinen UM, Makipernaa A, et al: Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: A double-blind placebo-controlled study in children [see comments]. Pediatr Infect Dis 13: 197-202, 1994

47. Mayordomo JI, Ribera F, Diaz-Puente MT, et al: Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors [see comments]. J Natl Cancer Inst 87: 803–808, 1995[Abstract/Free Full Text]

48. Lew MA, Kehoe K, Ritz J, et al: Prophylaxis of bacterial infections with ciprofloxacin in patients undergoing bone marrow transplantation. Transplantation 51: 630-636, 1991[Medline]

49. Donnelly JP: Selective decontamination of the digestive tract and its role in antimicrobial prophylaxis. J Antimicrob Chemother 31: 813-829, 1993[Abstract/Free Full Text]

50. Savarese DM, Hsieh C, Stewart FM: Clinical impact of chemotherapy dose escalation in patients with hematological malignancies and solid tumors. J Clin Oncol 15: 2981-2995, 1997[Abstract]

51. Phillips K, Tannock IF: Design and interpretation of clinicals trials that evaluate agents that may offer protection from the toxic effects of cancer chemotherapy. J Clin Oncol 16: 3179-3190, 1998[Abstract/Free Full Text]

52. Bokemeyer C, Kuczyk MA, Kohne H, et al: Hematopoietic growth factors and treatment of testicular cancer: Biological interactions, routine use and dose-intensive chemotherapy. Ann Hematol 72: 1-9, 1996[Medline]

53. Fossa SD, Kaye SB, Mead GM, et al: Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell. J Clin Oncol 16: 716-724, 1998[Abstract]

54. Hughes WT, Armstrong D, Bodey GP, et al: 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 25: 551-573, 1997[Medline]

55. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17: 101a, 1998 (abstr 390A)

56. Rodenhuis S, Richel DJ, van der Wall E, et al: Randomized trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 352: 515-521, 1998[Medline]

57. Hortobagyi GN, Buzdar AU, Theriault RL, et al: Randomized trial of high-dose chemotherapy for high-risk primary breast carcinoma. J Natl Cancer Inst 92: 225-233, 2000[Abstract/Free Full Text]

58. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer: Philadelphia Bone Marrow Transplantation Group [see comments]. N Engl J Med 342: 1069-1076, 2000[Abstract/Free Full Text]

59. Peters W, Rosner G, Vredenburg J, et al: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): Preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proc Am Soc Clin Oncol 18: 1a, 1999 (abstr 2)

60. Wade JC: Management of infection in patients with acute leukemia. Hematol Oncol Clin North Am 7: 293-315, 1993[Medline]

61. Bennett CL, Smith TJ, Weeks JC, et al: Use of hematopoietic colony-stimulating factors: The American Society of Clinical Oncology survey. J Clin Oncol 14: 2511-2520, 1996[Abstract]

62. NCCN practice guidelines for fever and neutropenia: National Comprehensive Cancer Network. Oncology (Huntingt) 13: 197-257, 1999

63. Talcott JA, Whalen A, Clark J, et al: Home antibiotic therapy for low-risk cancer patients with fever and neutropenia: A pilot study of 30 patients based on a validated prediction rule. J Clin Oncol 12: 107-114, 1994[Abstract]

64. Fukuda M, Nakano A, Kinoshita A, et al: Optimal timing of G-CSF administration in patients receiving chemotherapy for non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 12: 447, 1993 (abstr 1549)

65. Gerhartz HH, Stern AC, Wolf-Hornung B, et al: Intervention treatment of established neutropenia with human recombinant granulocyte-macrophage colony-simulating factor (rhGM-CSF) in patients undergoing cancer chemotherapy. Leuk Res 17: 175-185, 1993[Medline]

66. Hartmann LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia. N Engl J Med 336: 1776-1780, 1997[Abstract/Free Full Text]

67. Maher DW, Lieschki GJ, Green M, et al: Filgrastim in patient with chemotherapy-induced febrile neutropenia: A double-blind, placebo-controlled trial. Ann Intern Med 121: 492-501, 1994[Abstract/Free Full Text]

68. Mitchell PLR, Morland B, Stevens MCG, et al: Granulocyte colony-stimulating factor in established febrile neutropenia: A randomized study of pediatric patients. 1 5: 1163-1170, 1997

69. Vellenga E, Uyl-de Groot CA, de Wit R, et al: Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia. J Clin Oncol 14: 619-627, 1996[Abstract/Free Full Text]

70. Anaissie E, Vartivarian S, Bodey GP, et al: Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-simulating factor (Escherichia coli-derived) in cancer patients with fever and neutropenia. Am J Med 100: 17-23, 1996[Medline]

71. Mayordomo JI, Rivera F, Diaz-Puente MT, et al: Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors. J Natl Cancer Inst 87: 803–808, 1995

72. Ravaud A, Chevreau C, Cany L, et al: Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: Results of a randomized phase III trial. J Clin Oncol 16: 2930-2936, 1998[Abstract/Free Full Text]

73. Riikonen P, Saarinen UM, Makipernaa A, et al: Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: A double-blind placebo-controlled study in children. Pediatr Infect Dis J 13: 197-202, 1994[Medline]

74. Biesma B, de Vries EG, Willemse PH, et al: Efficacy and tolerability of recombinant human granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related leukopenia and fever. Eur J Cancer 26: 932-936, 1990

75. American Society of Clinical Oncology: American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 12: 2471-2508, 1994[Abstract/Free Full Text]

76. Garcia-Carbonera R, Mayordomo JI, Tornamira MV, et al: Filgrastim in the treatment of high-risk febrile neutropenia: Results of a multicenter randomized phase III trial. Proc Am Soc Clin Oncol 18: 583a, 1999 (abstr 2253)

77. Steward WP, von Pawel J, Gatzemeier U, et al: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: A prospective randomized study of 300 patients. J Clin Oncol 16: 642-650, 1998[Abstract]

78. Gordon LI, Young M, Weller E, et al: A phase II trial of 200% ProMACE-CytaBOM in patients with previously untreated aggressive lymphomas: Analysis of response, toxicity, and dose intensity. Blood 94: 3307-3314, 1999[Abstract/Free Full Text]

79. Shipp MA, Neuberg D, Janicek M, et al: High-dose CHOP as initial therapy for patients with poor-prognosis aggressive non-Hodgkin’s lymphoma: A dose-finding pilot study. J Clin Oncol 13: 2916-2923, 1995[Abstract]

80. Santoro A, Balzarotti M, Tondini C, et al: Dose-escalation of CHOP in non-Hodgkin’s lymphoma. Ann Oncol 10: 519-525, 1999[Abstract/Free Full Text]

81. Talbot SM, Westerman DA, Grigg AP, et al: Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin’s lymphoma and advanced solid tumors. Ann Oncol 10: 907-914, 1999[Abstract/Free Full Text]

82. Tanosaki R, Okamoto S, Akatsuka N, et al: Dose escalation of biweekly cyclophosphamide, doxorubicin, vincristine, and prednisolone using recombinant human granulocyte colony stimulating factor in non-Hodgkin’s lymphoma. Cancer 74: 1939-1944, 1994[Medline]

83. Laporte JP, Fouillard L, Douay L, et al: GM-CSF instead of autologous bone-marrow transplantation after the BEAM regimen. Lancet 338: 601-602, 1991[Medline]

84. Bronchud MH, Howell A, Crowther D, et al: The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer 60: 121-125, 1989[Medline]

85. Thatcher N, Girling DJ, Hopwood P, et al: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: Results of a British Medical Research Council multicenter randomized trial. J Clin Oncol 18: 395-404, 2000[Abstract/Free Full Text]

86. Beyer J, Schwella N, Zingsem J, et al: Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: A randomized comparison. J Clin Oncol 13: 1328-1335, 1995[Abstract]

87. Schmitz N, Linch DC, Dreger P, et al: Randomized trial of filgrastim-mobilized peripheral blood progenitor cell transplantation versus autologous bone marrow transplantation in lymphoma patients. Lancet 347: 353-357, 1996[Medline]

88. Nademanee A, Sniecinski I, Schmidt GM, et al: High-dose chemotherapy followed by autologous peripheral-blood stem-cell transplantation for patients with Hodgkin’s disease and non-Hodgkin’s lymphoma using unprimed and granulocyte colony-stimulating factor mobilized peripheral blood stem cells. J Clin Oncol 12: 2176-2186, 1994[Abstract/Free Full Text]

89. Schmitz N, Dreger P, Zander AR, et al: Results of a randomized controlled multicenter study of recombinant human granulocyte colony stimulating factor (filgrastim) in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma undergoing autologous bone marrow transplantation. Bone Marrow Transplant 15: 261-266, 1995[Medline]

90. Klumpp TR, Mangan KF, Goldberg SL, et al: Granulocyte colony-stimulating factor accelerates neutrophil engraftment following peripheral-blood stem-cell transplantation: A prospective, randomized trial. J Clin Oncol 13: 1323-1327, 1995[Abstract]

91. Nemunaitis J, Rosenfeld CS, Ash R, et al: Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplant 15: 949-954, 1995[Medline]

92. Korbling M, Przepiorka D, Huh YO, et al: Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: Potential advantage of blood over marrow allografts. Blood 85: 1659-1665, 1995[Abstract/Free Full Text]

93. Dreger P, Haferlach T, Eckstein V, et al: G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: Safety, kinetics of mobilization, and composition of the graft. Br J Haematol 87: 609-613, 1994[Medline]

94. Schmitz N, Dreger P, Suttorp M, et al: Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood 85: 1666-1672, 1995[Abstract/Free Full Text]

95. Bensinger WI, Weaver CH, Appelbaum FR, et al: Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood 85: 1655-1658, 1995[Abstract/Free Full Text]

96. Brugger W, Bross KJ, Glatt M, et al: Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 83: 636-640, 1994[Abstract/Free Full Text]

97. Pedrazzoli P, Battaglia M, Da Prada GA, et al: Role of tumor cells contaminating the graft in breast cancer recurrence after high-dose chemotherapy. Bone Marrow Transplant 20: 167-169, 1997[Medline]

98. Cooper BW, Moss TJ, Ross AA, et al: Occult tumor contamination of hematopoietic stem-cell products does not affect clinical outcome of autologous transplantation in patients with metastatic breast cancer. J Clin Oncol 16: 3509-3517, 1998[Abstract]

99. Pavlevic S, Bishop M, Tarantolo S, et al: Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies. J Clin Oncol 15: 1608-1616, 1997[Abstract]

100. Schmitz N, Bacigalupo A, Hasenclever D, et al: Allogeneic bone marrow transplantation vs filgrastim-mobilized peripheral blood progenitor cell transplantation in patients with early leukemia: First results of a randomized multicentre trial of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 21: 995-1003, 1998[Medline]

101. Storek J, Gooley T, Siadak M, et al: Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease. Blood 90: 4705-4709, 1997[Abstract/Free Full Text]

102. Bensinger W, Martin P, Clift R, et al: A prospective randomised trial of peripheral blood stem cells (PBSC) or marrow (BM) for patients undergoing allogeneic transplantation for hematologic malignancies. Proc Am Soc Hematol 94: 368A, 1999 (abstr 1637)

103. Bolwell BJ, Pohlman B, Andersen S, et al: Delayed G-CSF after autologous progenitor cell transplantation: A prospective randomized trial. Bone Marrow Transplant 21: 369-373, 1998[Medline]

104. Colby C, McAfee S, Finkelstein D, et al: Early vs delayed addition of G-CSF following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 21: 1005-1010, 1998[Medline]

105. Linch DC, Milligan DW, Winfield DA, et al: G-CSF after peripheral blood stem cell transplantation in lymphoma patients significantly accelerated neutrophil recovery and shortened time in hospital: Results of a randomized BNLI trial. Br J Haematol 99: 933-938, 1997[Medline]

106. Lee S, Weller E, Alyea E, et al: Efficacy and costs of granulocyte colony-stimulating factor in allogeneic T-cell depleted bone marrow transplantation. Blood 92: 2725-2729, 1998[Abstract/Free Full Text]

107. Giralt S, Escudier S, Kantarjian H, et al: Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation. N Engl J Med 329: 757-761, 1993[Abstract/Free Full Text]

108. Snowden JA, Biggs JC, Milliken ST, et al: A randomized, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for hematopoietic stem cell mobilization in patients with severe rheumatoid arthritis. Bone Marrow Transplant 22: 1035-1041, 1998[Medline]

109. Ho AD, Young D, Maruyama M, et al: Pluripotent and lineage-committed CD34+ subsets in leukapheresis products mobilized by G-CSF, GM-CSF vs. a combination of both. Exp Hematol 24: 1460-1468, 1996[Medline]

110. Meisenberg B, Brehm T, Schmeckel A, et al: A combination of low-dose cyclophosphamide and colony-stimulating factors is more cost-effective than granulocyte-colony-stimulating factors alone in mobilizing peripheral blood stem and progenitor cells. Transfusion 38: 209-215, 1998[Medline]

111. Cesana C, Carlo-Stella C, Regazzi E, et al: CD34+ cells mobilized by cyclophosphamide and granulocyte colony stimulating factor (G-CSF) are functionally different from CD34+ cells mobilized by G-CSF. Bone Marrow Transplant 21: 561-568, 1998[Medline]

112. Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95: 1588-1593, 2000[Abstract/Free Full Text]

113. Weisdorf D, Miller J, Verfaillie C, et al: Cytokine-primed bone marrow stem cells vs. peripheral blood stem cells for autologous transplantation: A randomized comparison of GM-CSF vs. G-CSF. Biol Blood Marrow Transplant 3: 217-223, 1997[Medline]

114. Dombret H, Chastang C, Fenaux P, et al: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myeloid leukemia: AML Cooperative Study Group. N Engl J Med 332: 1678-1683, 1995[Abstract/Free Full Text]

115. Rowe JM, Andersen JW, Mazza JJ, et al: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: A study of the Eastern Cooperative Oncology Group (E1490). Blood 86: 457-462, 1995[Abstract/Free Full Text]

116. Stone RM, Berg DT, George SL, et al: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia: Cancer and Leukemia Group B. N Engl J Med 332: 1671-1677, 1995[Abstract/Free Full Text]

117. Heil G, Hoelzer D, Sanz MA, et al: The International Acute Myeloid Leukemia Study Group: A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 90: 4710-4718, 1997[Abstract/Free Full Text]

118. Godwin JE, Kopecky KJ, Head DR, et al: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: A Southwest Oncology Group study (9031). Blood 91: 3607-3615, 1998[Abstract/Free Full Text]

119. Lowenberg B, Boogaerts MA, Daenen SMGJ, et al: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15: 3496-3506, 1997[Abstract/Free Full Text]

120. Lowenberg B, Suciu S, Archimbaud E, et al: Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: Final report of AML-111, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Group. Blood 90: 2952-2961, 1997[Abstract/Free Full Text]

121. Zittoun R, Suciu S, Mandelli F, et al: Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: A randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. J Clin Oncol 14: 2150-2159, 1996[Abstract/Free Full Text]

122. Witz F, Sadoun A, Perrin M-C, et al: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Blood 91: 2722-2730, 1998[Abstract/Free Full Text]

123. Bennett CL, Stinson TJ, Laver JH, et al: Cost analyses of adjunct colony stimulating factors for acute leukemia: Can they improve clinical decision making. Leuk Lymphoma 37: 65-70, 2000[Medline]

124. Bennett CL, Golub R, Waters TM, et al: Economic analyses of phase III cooperative cancer group clinical trials: Are they feasible? Cancer Invest 15: 227-236, 1997[Medline]

125. Bennett DL, Hynes D, Godwin J, et al: Economic analysis of granulocyte colony-stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): Estimates from a Southwest Oncology Group clinical trial. Cancer Invest (in press)

126. Luo R, Erder H, Heil G, et al: Cost impact of filgrastim as an adjunct to chemotherapy for patients with acute myeloid leukemia. Proc Am Soc Hematol 88: 209a, 1996 (abstr 826)

127. Bhalla K, Birkhofer M, Arlin A, et al: Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. Leukemia 2: 810-813, 1988[Medline]

128. Peterson BA, George SL, Bhalla K, et al: A phase III trial with or without GM-CSF administered before and during high dose cytarabine in patients with relapsed or refractory acute myelogenous leukemia: CALGB 9021. Proc Am Soc Clin Oncol 14: 1749, 1996 (abstr 2016)

129. Ohno R, Naoe T, Kanamaru A, et al: A double-blind controlled study of granulocyte-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia: Kohseisho Leukemia Study Group. Blood 83: 2086-2092, 1994[Abstract/Free Full Text]

130. Harousseau JL, Witz B, Lioure B, et al: G-CSF after intensive consolidation chemotherapy in acute myeloid leukemia: Results of a randomized trial of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques. J Clin Oncol 18: 780-787, 2000[Abstract/Free Full Text]

131. Vadhan-Raj S, Keating M, LeMaistre A, et al: Effects of human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med 317: 1545-1552, 1987[Abstract]

132. Negrin RS, Nagler A, Kobayashi Y, et al: Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony stimulating factor. Blood 78: 36-43, 1990

133. Greenberg P, Taylor K, Larson R, et al: Phase III randomized multicenter trial of G-CSF vs. observation for myelodysplastic syndromes (MDS). Proc Am Soc Hematol 82: 196a, 1993 (abstr 768)

134. Larson RA, Dodge RK, Linker CA, et al: A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia. Blood 92: 1556-1564, 1998[Abstract/Free Full Text]

135. Pui C, Boyett JM, Hughes WT, et al: Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 336: 1781-1787, 1997[Abstract/Free Full Text]

136. Ottmann OG, Hoelzer D, Gracien E, et al: Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: A randomized Phase III Trial. Blood 86: 444-450, 1995[Abstract/Free Full Text]

137. Welte K, Reiter A, Mempel K, et al: A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia: Berlin-Frankfurt-Munster Study Group. Blood 87: 3143-3150, 1996[Abstract/Free Full Text]

138. Geissler K, Koller E, Hubmann E, et al: Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia: A randomized phase-III study. Blood 90: 590-596, 1997[Abstract/Free Full Text]

139. Scherrer R, Geissler K, Kyrle PA, et al: Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL). Ann Hematol 66: 283-289, 1993[Medline]

140. Laver J, Amylon M, Desai S, et al: Effects of r-metHuG-CSF in an intensive treatment for T-cell leukemia and advanced stage lymphoblastic lymphoma of childhood: A Pediatric Oncology Group pilot study. J Clin Oncol 16: 522-526, 1998[Abstract]

141. Ohno R, Tomonaga M, Kobayashi T, et al: Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia. N Engl J Med 323: 871-877, 1990[Abstract]

142. Kantarjian HM, Estey EH, O’Brien S, et al: Intensive chemotherapy with mitoxantrone and high dose cytosine arabinoside followed by granulocyte-macrophage colony-stimulating factor in the treatment of patients with acute lymphocytic leukemia. Blood 79: 876-881, 1992[Abstract/Free Full Text]

143. Douple E: Platinum-radiation interactions. NCI Monogr 6: 315-319, 1988

144. Leipzig R, Weismore S, Putzeys R, et al: Cisplatin potentiation or radiotherapy. Arch Otolaryngol Head Neck Surg 11: 114-118, 1985

145. Coia L, Engstrom P, Paul A: Nonsurgical management of esophageal cancer: Report of a study of combined radiotherapy and chemotherapy. J Clin Oncol 5: 1783-1790, 1987[Abstract/Free Full Text]

146. Kean T, Harwood A, Tahany E, et al: Radical radiation therapy with 5-fluorouracil infusion and mitomycin C for esophageal squamous carcinoma. Radiother Oncol 4: 205-210, 1985[Medline]

147. Herskovic A, Martz K, Al-Sarrat M, et al: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326: 1593-1598, 1992[Abstract]

148. Johnson E, Salem C, Nesbitt J, et al: Limited stage small cell lung cancer treated with concurrent hyperfractionated chest radiotherapy and etoposide/cisplatin. Lung Cancer 9: 521-526, 1993 (suppl 1)

149. Bonomi P: Treatment of locally advanced non-small cell lung cancer. Lung Cancer 9: 549-560, 1993 (suppl 2)

150. Gabrilove J, Kakubowski A, Scher H, et al: Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 318: 1414-1422, 1988[Abstract]

151. Bunn PA Jr, Crowley J, Kelly K, et al: Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: A prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 13: 1632-1641, 1995[Abstract/Free Full Text]

152. Parsons SK, Mayer DK, Alexander SW, et al: Growth factor practice patterns among pediatric oncologists: Results of a 1998 Pediatric Oncology Group survey—Economic Evaluation Working Group the Pediatric Oncology Group. J Pediatr Hematol Oncol 22: 227-241, 2000[Medline]

153. Hamm J, Schiller JH, Cuffie C, et al: Dose-ranging study of recombinant human granulocyte-macrophage colony-stimulating factor in small-cell lung carcinoma. J Clin Oncol 12: 2667-2676, 1994[Abstract/Free Full Text]

154. Stahel RA, Jost LM, Honegger H, et al: Randomized trial showing equivalent efficacy of filgrastim 5 mg/kg/d and 10 mg/kg/d following high-dose chemotherapy and autologous bone marrow transplantation in high-risk lymphomas. J Clin Oncol 15: 1730-1735, 1997[Abstract/Free Full Text]

155. Grigg AP, Roberts AW, Raunow H, et al: Optimizing dose and scheduling of filgrastim (granulocyte colony-stimulating factor) for mobilization and collection of peripheral blood progenitor cells in normal volunteers. Blood 86: 4437-4445, 1995[Abstract/Free Full Text]

156. Weaver CH, Birch R, Greco FA, et al: Mobilization and harvesting of peripheral blood stem cells: Randomized evaluations of different doses of filgrastim. Br J Haematol 100: 338-347, 1998[Medline]

157. Somlo G, Sniecinski I, Ahn C, et al: Priming with G-CSF 10 mg/kg is more effective than 5 mg/kg in patients receiving high-dose chemotherapy followed by peripheral stem cell rescue. Proc Am Soc Hematol 82: 642a, 1993 (abstr 2551)

158. Erban J, Miler K, Berkman E, et al: Filgrastim priming of PBSC and hematopoietic reconstitution following high-dose chemotherapy for breast cancer: Effect of dose on PBSC yield and engraftment. Proc Am Soc Clin Oncol 14: 316, 1995 (abstr 929)

159. Somlo G, Sniecinski I, Odom-Maryon T, et al: Effect of CD34+ selection and various schedules of stem cell reinfusion and granulocyte colony stimulating factor priming on hematopoietic recovery after high-dose chemotherapy for breast cancer. Blood 89: 1521-1528, 1997[Abstract/Free Full Text]

160. Stute N, Furman WL, Schell M, et al: Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in children after intravenous and subcutaneous administration. J Pharm Sci 84: 824-828, 1995[Medline]

161. Honkoop AH, Hoekman K, Wagstaff J, et al: Continuous infusion or subcutaneous injection of granulocyte-macrophage colony-stimulating factor: Increased efficacy and reduced toxicity when given subcutaneously. Br J Cancer 74: 1132-1136, 1996[Medline]

162. Roskos LK, Cheung EN, Vincent M, et al: Pharmacology of filgrastim (r-metHuG-CSF), in Morstyn G, Dexter TM, Foote MA (eds): Filgrastim (r-metHuG-CSF) in Clinical Practice ( ed 2). New York, NY, Marcel Dekker, Inc, 1998, pp 51–71

163. Ozer H, Miller LL, Schiffer CA, et al: Update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based clinical practice guidelines. J Clin Oncol 14: 1957-1960, 1996[Free Full Text]

164. Beveridge RA, Miller JA, Kales AN, et al: A comparison of the efficacy of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in the therapeutic setting of chemotherapy-induced myelosuppression. Cancer Invest 16: 366-373, 1998[Medline]

165. Weaver CH, Schulman KA, Wilson-Relyea B, et al: Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells. J Clin Oncol 18: 43-53, 2000[Abstract/Free Full Text]

Submitted August 4, 2000; accepted August 7, 2000.


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Risk Models for Predicting Chemotherapy-Induced Neutropenia
Oncologist, June 1, 2005; 10(6): 427 - 437.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
G. Marcucci, W. Stock, G. Dai, R. B. Klisovic, S. Liu, M. I. Klisovic, W. Blum, C. Kefauver, D. A. Sher, M. Green, et al.
Phase I Study of Oblimersen Sodium, an Antisense to Bcl-2, in Untreated Older Patients With Acute Myeloid Leukemia: Pharmacokinetics, Pharmacodynamics, and Clinical Activity
J. Clin. Oncol., May 20, 2005; 23(15): 3404 - 3411.
[Abstract] [Full Text] [PDF]


Home page
JAMAHome page
E. G. C. Brain, T. Bachelot, D. Serin, S. Kirscher, Y. Graic, J.-C. Eymard, J.-M. Extra, M. Combe, E. Fourme, C. Nogues, et al.
Life-Threatening Sepsis Associated With Adjuvant Doxorubicin Plus Docetaxel for Intermediate-Risk Breast Cancer
JAMA, May 18, 2005; 293(19): 2367 - 2371.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
C. L. Vogel, M. Z. Wojtukiewicz, R. R. Carroll, S. A. Tjulandin, L. J. Barajas-Figueroa, B. L. Wiens, T. A. Neumann, and L. S. Schwartzberg
First and Subsequent Cycle Use of Pegfilgrastim Prevents Febrile Neutropenia in Patients With Breast Cancer: A Multicenter, Double-Blind, Placebo-Controlled Phase III Study
J. Clin. Oncol., February 20, 2005; 23(6): 1178 - 1184.
[Abstract] [Full Text] [PDF]


Home page
The OncologistHome page
D. W. Blayney, B. W. McGuire, S. E. Cruickshank, and D. H. Johnson
Increasing Chemotherapy Dose Density and Intensity: Phase I Trials in Non-Small Cell Lung Cancer and Non-Hodgkin's Lymphoma
Oncologist, February 1, 2005; 10(2): 138 - 149.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
A. Ardizzoni, A. Favaretto, L. Boni, E. Baldini, F. Castiglioni, P. Antonelli, F. Pari, C. Tibaldi, A. M. Altieri, S. Barbera, et al.
Platinum-Etoposide Chemotherapy in Elderly Patients With Small-Cell Lung Cancer: Results of a Randomized Multicenter Phase II Study Assessing Attenuated-Dose or Full-Dose With Lenograstim Prophylaxis--A Forza Operativa Nazionale Italiana Carcinoma Polmonare and Gruppo Studio Tumori Polmonari Veneto (FONICAP-GSTPV) Study
J. Clin. Oncol., January 20, 2005; 23(3): 569 - 575.
[Abstract] [Full Text] [PDF]


Home page
Am J Health Syst PharmHome page
D. M. Stull, R. Bilmes, H. Kim, and R. Fichtl
Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia
Am. J. Health Syst. Pharm., January 1, 2005; 62(1): 83 - 87.
[Full Text] [PDF]


Home page
JCOHome page
F. Andre, K. Slimane, T. Bachelot, A. Dunant, M. Namer, A. Barrelier, O. Kabbaj, J. P. Spano, H. Marsiglia, R. Rouzier, et al.
Breast Cancer With Synchronous Metastases: Trends in Survival During a 14-Year Period
J. Clin. Oncol., August 15, 2004; 22(16): 3302 - 3308.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
L. Sung, P. C. Nathan, B. Lange, J. Beyene, and G. R. Buchanan
Prophylactic Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Decrease Febrile Neutropenia After Chemotherapy in Children With Cancer: A Meta-Analysis of Randomized Controlled Trials
J. Clin. Oncol., August 15, 2004; 22(16): 3350 - 3356.
[Abstract] [Full Text] [PDF]


Home page
Ann OncolHome page
C. Eng, H. L. Kindler, S. Nattam, R. H. Ansari, K. Kasza, K. Wade-Oliver, and E. E. Vokes
A phase II trial of the epothilone B analog, BMS-247550, in patients with previously treated advanced colorectal cancer
Ann. Onc., June 1, 2004; 15(6): 928 - 932.
[Abstract] [Full Text] [PDF]


Home page
Jpn J Clin OncolHome page
S. Niho, Y. Ohe, K. Goto, H. Ohmatsu, T. Matsumoto, K. Kubota, R. Kakinuma, and Y. Nishiwaki
Randomized Trial of Oral Versus Intravenous Antibiotics in Low-risk Febrile Neutropenic Patients with Lung Cancer
Jpn. J. Clin. Oncol., February 1, 2004; 34(2): 69 - 73.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
G. H. Lyman, D. C. Dale, and J. Crawford
Incidence and Predictors of Low Dose-Intensity in Adjuvant Breast Cancer Chemotherapy: A Nationwide Study of Community Practices
J. Clin. Oncol., December 15, 2003; 21(24): 4524 - 4531.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
J.K. Doorduijn, B. van der Holt, G.W. van Imhoff, K.G. van der Hem, M.H.H. Kramer, M.H.J. van Oers, G.J. Ossenkoppele, M.R. Schaafsma, L.F. Verdonck, G.E.G. Verhoef, et al.
CHOP Compared With CHOP Plus Granulocyte Colony-Stimulating Factor in Elderly Patients With Aggressive Non-Hodgkin's Lymphoma
J. Clin. Oncol., August 15, 2003; 21(16): 3041 - 3050.
[Abstract] [Full Text] [PDF]


Home page
CA Cancer J ClinHome page
C. E. Holmes and H. B. Muss
Diagnosis and Treatment of Breast Cancer in the Elderly
CA Cancer J Clin, July 1, 2003; 53(4): 227 - 244.
[Abstract] [Full Text]


Home page
Clin. Cancer Res.Home page
J. C. Trent, V. Valero, D. J. Booser, L. T. Esparza-Guerra, N. Ibrahim, Z. Rahman, L. Vernillet, S. Patel, C. L. David, J. L. Murray, et al.
A Phase I Study of Docetaxel Plus Cyclophosphamide in Solid Tumors followed by a Phase II Study as First-Line Therapy in Metastatic Breast Cancer
Clin. Cancer Res., July 1, 2003; 9(7): 2426 - 2434.
[Abstract] [Full Text] [PDF]


Home page
J Oncol Pharm PractHome page
B. L Stanford, S. D Zondor, and E. Cobos
Is pegfilgrastim appropriate for the treatment of established febrile neutropenia?
Journal of Oncology Pharmacy Practice, June 1, 2003; 9(2-3): 113 - 119.
[Abstract] [PDF]


Home page
BloodHome page
M. V. Relling, J. M. Boyett, J. G. Blanco, S. Raimondi, F. G. Behm, J. T. Sandlund, G. K. Rivera, L. E. Kun, W. E. Evans, and C.-H. Pui
Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment
Blood, May 15, 2003; 101(10): 3862 - 3867.
[Abstract] [Full Text] [PDF]


Home page
Ann OncolHome page
V. C. G. Tjan-Heijnen, S. Caleo, P. E. Postmus, A. Ardizzoni, J. T. M. Burghouts, E. Buccholz, B. Biesma, T. Gorlia, R. Crott, G. Giaccone, et al.
Economic evaluation of antibiotic prophylaxis in small-cell lung cancer patients receiving chemotherapy: an EORTC double-blind placebo-controlled phase III study (08923)
Ann. Onc., February 1, 2003; 14(2): 248 - 257.
[Abstract] [Full Text] [PDF]


Home page
Ann OncolHome page
J. Crawford
Pegfilgrastim: the promise of pegylation fulfilled
Ann. Onc., January 1, 2003; 14(1): 6 - 7.
[Full Text] [PDF]


Home page
NEJMHome page
C. L. Shapiro and A. Recht
Side Effects of Adjuvant Treatment of Breast Cancer
N. Engl. J. Med., June 28, 2001; 344(26): 1997 - 2008.
[Full Text] [PDF]


Home page
JCOHome page
L. Balducci, G. H. Lyman, and H. Ozer
Patients Aged {>=} 70 Are at High Risk for Neutropenic Infection and Should Receive Hemopoietic Growth Factors When Treated With Moderately Toxic Chemotherapy
J. Clin. Oncol., March 1, 2001; 19(5): 1583 - 1585.
[Full Text] [PDF]


Home page
JNCI J Natl Cancer InstHome page
B. E. Johnson
Is More Better? Chemotherapy for Patients With Extensive-Stage Small-Cell Lung Cancer
J Natl Cancer Inst, February 21, 2001; 93(4): 254 - 255.
[Full Text] [PDF]


Home page
ASH Education BookHome page
G. R. Donowitz, D. G. Maki, C. J. Crnich, P. G. Pappas, and K. V.I. Rolston
Infections in the Neutropenic Patient-- New Views of an Old Problem
Hematology, January 1, 2001; 2001(1): 113 - 139.
[Abstract] [Full Text] [PDF]


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