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Originally published as JCO Early Release 10.1200/JCO.2003.10.082 on June 13 2003 © 2003 American Society for Clinical Oncology Phase III Trial of Paclitaxel at Two Dose Levels, the Higher Dose Accompanied by Filgrastim at Two Dose Levels in Platinum-Pretreated Epithelial Ovarian Cancer: An Intergroup Study
From the University of Alabama at Birmingham, Birmingham, AL; Gynecologic Oncology Group, Roswell Park Cancer Institute, and State University of New York at Buffalo, Buffalo, NY; Weill Medical College of Cornell University, New York, NY; Indiana University School of Medicine, Indianapolis, IN; Division of Gynecologic Oncology, Jackson Memorial Medical Center, University of Miami School of Medicine, Miami, FL; University of Kansas School of Medicine, Wichita, KS; Mayo Medical School, Mayo Clinic and Foundation, Rochester, MN; Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD. Address reprint requests to Gynecologic Oncology Group Administrative Office, 1600 John F. Kennedy Blvd, Suite 1020, Philadelphia, PA 19103.
Purpose: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. Patients and Methods: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 µg/kg of filgrastim per day subcutaneously. Results: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P = .027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P < .05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-µg/kg and 10-µg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim). Conclusion: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 µg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.
PACLITAXEL IS active in the treatment of advanced ovarian cancer and has become an important component of primary chemotherapy,1 but in the initial clinical development of this drug, it was uncertain whether there was a dose-response effect and whether that might translate into a survival benefit. Phase II studies indicated a higher probability of response with 250 mg/m2 of paclitaxel than with lower doses.2 Although recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim) 10 µg/kg was used as an adjunct to the 250-mg/m2 dose of paclitaxel, it was unclear whether this dose of filgrastim had an advantage over the recommended 5-µg/kg dose in reducing the incidence of neutropenic fever. In a large randomized trial,3 filgrastim demonstrated an ability to accelerate myeloid recovery after cyclophosphamide, doxorubicin, and etoposide chemotherapy for small-cell lung cancer. In regard to optimal dose, practical, pharmacologic, and economic issues generally limited outpatient dosing to a 10-µg/kg dose or less. The relatively large volume of administration of filgrastim makes the outpatient subcutaneous administration of larger doses impractical. The first objective of this study was to determine whether increasing the dose of paclitaxel increased the response rate, progression-free survival, and overall survival in women with platinum-pretreated ovarian cancer. The second objective was to assess whether increasing filgrastim from 5 to 10 µg/kg/d in conjunction with paclitaxel 250 mg/m2 reduced the incidence of febrile neutropenia.
Eligibility Eligible patients had histologically confirmed epithelial ovarian cancer that had been treated with no more than one prior platinum-based regimen and no prior taxane. According to the original study design, patients had to have platinum-resistant, clinically measurable disease. Platinum resistance was operationally defined as progression during first-line platinum treatment or within 6 months of completing therapy, a best response of stable disease after six courses of platinum, or stable disease with a rising CA-125 while on platinum. After the study was activated, however, because of declining enrollment, the eligibility criteria were expanded to include patients with platinum-sensitive disease and patients without clinically measurable disease (see Results). Platinum-sensitive patients were defined as patients who had an initial response to platinum therapy lasting at least 6 months, followed by progression or recurrence. Eligible patients had to have a performance status (PS) of 0, 1, or 2; have adequate marrow, renal, and hepatic function; and provide written informed consent. Ineligible patients included patients with borderline carcinoma (grade 0) or neoplasm termed probably malignant; patients who had received prior paclitaxel or irradiation or more than one prior chemotherapy regimen; patients with septicemia, other active infection, acute hepatitis, or severe gastrointestinal bleeding or other serious medical conditions likely to limit the patient’s ability to tolerate treatment; patients with any history of congestive heart failure or unstable angina or a myocardial infarction within the past 6 months or a history of cardiac arrhythmia requiring antiarrhythmic medication; patients whose circumstances did not permit completion of the study or the required follow-up; and patients with unclassified cases of ovarian cancer (cancers thought to be of ovarian origin but not explored, or patients in whom it was not possible to verify tumor arising from ovarian tissue). Patients with past or concomitant malignancy other than skin (excluding melanoma) and patients with known hypersensitivity to Escherichia coli–derived drug preparations were also ineligible.
Study Treatments and Randomization
Evaluation Criteria Clinical response was evaluated in those patients with measurable disease. Response was to be assessed before every other cycle of therapy. Neither pleural effusion nor elevated CA 125 was to be regarded as measurable disease. All eligible patients with measurable disease declared at registration form the sample in which treatments are compared, regardless of the amount of treatment actually received. A complete response was defined as disappearance of all gross evidence of disease for at least 4 weeks. A partial response required a 50% or greater reduction in the product of perpendicular measurements of each lesion for at least 4 weeks. The response evaluation did not include reassessment laparotomy. There were 10 women (three randomly assigned to the paclitaxel 175 mg/m2 regimen and seven to the 250 mg/m2 regimen) who were not assessed for response because of death, toxicity, or withdrawal, but they are classified as not responding for an intent-to-treat analysis among eligible patients. An individual’s time at risk of progression or death was measured from the date that she was registered onto the study. Progression-free survival was measured to the date of first progression or death from any cause. The time at risk was measured to the date of last contact for those individuals alive and progression-free at last contact. Survival was measured to the date of death or last contact if the date of death was unknown. The primary treatment comparisons of progression-free and overall survival include those patients deemed eligible for the study, regardless of the amount of treatment received, but both eligible and ineligible patients are included when an intent-to-treat analysis is specified in this article.
Statistical Considerations and Analyses A logistic model was used to estimate the adjusted relative odds of response, and the confidence intervals (CIs) for proportions are based on exact procedures. A proportional hazards model was used to estimate relative hazard rates. The P values in this article are all two-sided.
The study was activated in August 1992, before the commercial availability of paclitaxel, and completed enrollment in February 1995. The planned accrual was 540 patients. During the trial, however, there was a dramatic decrease in accrual rate coinciding with the marketing of paclitaxel, when patients began to be treated in a nonprotocol setting. Because it no longer seemed feasible to complete a three-arm trial in a reasonable period of time, accession to the lowest-dose paclitaxel regimen was stopped in October 1993 but was continued for the two higher-dose regimens. Eventually, 449 women were enrolled onto this study, of whom 77 were assigned to the lowest-dose regimen (88% eligible) before that arm was closed. There were 184 patients randomly assigned to the 175-mg/m2 dose of paclitaxel without filgrastim, of whom 164 (89%) were eligible, and 188 patients were assigned to the 250-mg/m2 dose of paclitaxel with filgrastim, of whom 166 (88%) were eligible. Reasons for ineligibility included inappropriate primary disease site (n = 34), improper prior treatment (n = 7), inadequately documented histology (n = 3), second primary cancer (n = 3), inadequate documentation of recurrence (n = 2), borderline tumor histology (n = 1), and wrong stage (n = 1).
This article focuses primarily on the comparison of the 175 and 250 mg/m2 regimens of paclitaxel and the comparison of the 5 versus 10 µg/kg of filgrastim within the 250-mg/m2 paclitaxel dose. Patient and disease characteristics are listed in Table 1
There was no significant difference between treatment groups in the number of cycles administered. Fifty-eight percent of the patients on the paclitaxel 175-mg/m2 arm and 55% of patients on the 250-mg/m2 arm received six or more cycles of therapy. Only one patient refused any of her randomly assigned therapy.
Figure 1
Among patients with measurable disease who were randomly assigned to the 175-mg/m2 regimen, 36 (27%) of 131 (95% CI, 20% to 36%) demonstrated an objective response (partial + complete response); whereas 49 (36%) of 134 (95% CI, 29% to 46%) of patients randomly assigned to the paclitaxel 250-mg/m2 regimen responded (Table 2  ). The overall odds ratio of responding to the high-dose regimen are 1.89 (95% CI, 1.07 to 3.31) times greater (P = .027) than the odds of responding to the low-dose regimen, after adjusting for histologic cell type (papillary serous v clear-cell or mucinous v other cell types), cooperative group, initial PS, and prior platinum response. However, the relative odds ratio of responding to the high-dose regimen is not consistent across the strata defined by the patient’s prior platinum response. There is a significant treatment-strata interaction (P = .041). Whereas the adjusted relative odds ratio of responding to the high-dose regimen is 2.59 (95% CI, 1.36 to 4.95) among the 213 patients who had platinum-resistant disease, it is only 0.630 (95% CI, 0.191 to 2.07) among the 52 who had platinum-sensitive disease.
Before the study amendment that terminated accrual to the paclitaxel 135-mg/m2 arm, there were 61, 64, and 57 eligible patients with platinum-resistant, measurable disease randomly assigned to the paclitaxel 135-mg/m2, 175-mg/m2, and 250-mg/m2 regimens, respectively. The percentage of patients responding on each regimen is 18%, 27%, and 37%, respectively. There is a significant linear trend between the dose-intensity of the regimen and the percentage of patients responding (P = .022). There is a strong association between response and the histology of the primary tumor. Although 66 (40%) of 165 patients (95% CI, 32% to 48%) with serous histology responded, only one (5%) of 21 patients (95% CI, 0.1% to 24%) with mucinous or clear-cell histology and measurable disease responded. The frequency of response among patients with other cell types was 18 (23%) of 79 patients (95% CI, 14% to 34%). Within the group of patients randomly assigned to the 250-mg/m2 dose, the proportion of patients responding was similar for the two filgrastim doses. Twenty-four (35%) of 68 patients (95% CI, 24% to 48%) with measurable disease and randomly assigned to 5 µg/kg of filgrastim responded, whereas 25 (37.9%) of 66 patients (95% CI, 26% to 51%) assigned to 10 µg/kg responded.
The Kaplan-Meier5 estimated cumulative distributions of the progression-free survival for the patients treated with either of the two more-intense paclitaxel regimens are plotted in Figure 2
The estimated cumulative distribution of the survival times for each treatment group is depicted in Figure 3 . The estimated median times to death for the 175-mg/m2 and the 250-mg/m2 paclitaxel regimens are 13.1 and 12.3 months, respectively. The estimated treatment HRs, from a proportional hazards model that included covariate adjustments for initial PS, cell type, response to prior platinum, cooperative group, and measurable disease status, are listed in Table 3. The adjusted death rate is only 3% lower (HR = 0.972; 95% CI, 0.774 to 1.22) on the highest dose regimen of paclitaxel. This difference is not statistically significant. An intent-to-treat analysis also indicates no significant benefit as a result of increasing the dose. Finally, when the multivariate survival analysis is restricted to patients who were platinum resistant, there was only an estimated 8% reduction (HR = 0.917; 95% CI, 0.709 to 1.19) in the death rate that could be attributed to the more-intense dose regimen.
The overall survival for patients who were deemed platinum sensitive and platinum resistant is displayed in Figure 4 . The median survival was 11.0 months for patients who were platinum resistant and 19.6 months for patients who were platinum sensitive. This difference in survival is significant (P < .001).
Before the study amendment that terminated accrual to the paclitaxel 135-mg/m2 arm, there were 68, 71, and 68 eligible patients (with measurable or nonmeasurable disease) randomly assigned to the 135-mg/m2, 175-mg/m2, and 250-mg/m2 regimens, respectively. Within these groups, the median time to death for each regimen was 11.4, 11.3, and 10.5 months, respectively. There are no apparent differences in survival among these groups. Neutropenic fever after the first course of therapy occurred in 22% of patients on the 175-mg/m2 dose of paclitaxel without filgrastim and in 19% of patients on the 250-mg/m2 paclitaxel regimen with filgrastim. This difference is not significant. Neutropenic fever after the first course of therapy occurred in 19% (16 of 83 patients) and 18% of patients (15 of 82 patients) on the 5-µg/kg and 10-µg/kg filgrastim regimens, respectively. The 95% confidence limits for the difference between the two filgrastim doses in incidence of neutropenia after the first course of therapy fever are -11% and 13%.
Other toxicities (Table 4
A phase II trial of second-line paclitaxel 250 mg/m2 over 24 hours every 21 days, with filgrastim 10 µg/kg/d beginning 24 hours after completing the paclitaxel infusion was reported by Kohn et al.2 Among the 44 platinum-pretreated women evaluated, there were six clinical complete responses (14%) and 15 partial responses (34%; overall probability of response, 48%; 95% CI, 32% to 63%). These results are consistent with the results from this trial, in which 13% of patients experienced a complete response, and 24% experienced a partial response on the high-dose paclitaxel regimen. There is a slight disparity in age between these two studies (median age, 55 years in Kohn et al study v 62 years in this study) that may favor the single-institution study. Nevertheless, what seems to be a therapeutic advance is severely tempered by significantly more toxicity and a failure of the higher dose in this trial to translate into an improvement in progression-free or overall survival. Other randomized trials in breast and lung cancer, as well as ovarian cancer, have addressed the dose of paclitaxel, generally with similar conclusions to those reported here. Eisenhauer et al6 compared, in a bifactorial design, 135 and 175 mg/m2 of paclitaxel over 3 or 24 hours in 382 assessable patients with platinum-pretreated ovarian cancer. The response rate was slightly higher for the 175-mg/m2 dose and for the longer infusion; the latter produced significantly more neutropenia. Progression-free survival was significantly longer in the high-dose group, but no survival differences were noted. In 563 women with advanced breast cancer, Smith et al7 compared the 3- and 24-hour infusions of paclitaxel 250 mg/m2; the longer infusion was routinely accompanied by G-CSF. The 24-hour infusion had a higher response rate (P = .025) but no significant improvement in event-free or overall survival. Winer et al8 randomly assigned 325 women with metastatic breast cancer to a 3-hour infusion of paclitaxel 175, 210, or 250 mg/m2 and found no significant difference in response rates or overall survival. There was a prolongation in time to treatment failure with the 250-mg/m2 dose (P = .03) but significantly more toxicity. Nabholtz et al9 randomly assigned 471 women with metastatic breast cancer to 135 or 175 mg/m2 of paclitaxel over 3 hours and found no significant difference in response rate or survival. In advanced non–small-cell lung cancer, Kosmidis et al10 studied the combination of carboplatin and paclitaxel, with the latter at either 175 or 225 mg/m2. In 178 assessable patients, there was no significant difference in response rate or survival. Time to progression favored the higher dose (P = .044) but with more toxicity. Also, in this type of lung cancer, in a total of 599 patients, Bonomi et al11 compared cisplatin plus etoposide with cisplatin plus paclitaxel, the latter given at 135 or 250 mg/m2 (with filgrastim) over 24 hours. For the two paclitaxel-containing arms, there was no significant difference in survival. Therefore, although there is some variation regarding other end points, the literature is consistent in reporting, as found in this study, no survival benefit for higher-dose paclitaxel. It is interesting to note that, in this study, the analysis of the relatively few patients treated at the 135-mg/m2 paclitaxel dose complements the primary analysis of the two more-intense paclitaxel regimens. That is, both the subgroup analysis and the primary analysis indicate that the probability of response increases with dose-intensity, but this does not translate into an increase in overall survival. In regard to a possible dose effect for filgrastim, a randomized trial in 86 lymphoma patients compared 5 µg/kg/d of filgrastim by subcutaneous bolus injection with 10 µg/kg/d by continuous infusion after high-dose chemotherapy and autologous marrow transplantation and found no significant difference in time to neutrophil recovery or related parameters.12 In contrast, for mobilization and harvesting of peripheral-blood progenitor cells, filgrastim at 24 µg/kg/d13 or 30 µg/kg/d14 significantly increased the numbers of CD34+ cells compared with 10 µg/kg/d, which, of course, addresses a different question from prophylaxis against neutropenic fever. With the advent of long-acting pegylated G-CSFs15,16 that use a single dose per cycle of chemotherapy rather than daily injections of filgrastim with at least equal safety and effectiveness, further assessment of high-dose filgrastim prophylaxis seems unattractive. One might assume that any benefit of higher-dose paclitaxel therapy would be more apparent among patients who had responded to their previous platinum treatment (because, for example, their tumors might be less likely to manifest multidrug resistance). Contrary to expectation, however, the small subset of patients in this trial who were considered platinum sensitive did not show the dose-response effect; the response rate for the 250-mg/m2 paclitaxel dose (36%) was actually slightly lower (not significantly) than that for the 175-mg/m2 dose (48%). Although this anomaly does not change any of the general conclusions of the study, it casts some doubt on the likelihood of a dose-response effect being achievable with first-line paclitaxel in ovarian cancer.
It was of interest that mucinous and clear-cell histologies were associated with a very low response rate (one of 21 patients) and higher death rate (Table 3 In summary, the addition of filgrastim in this trial facilitated the use of high-dose paclitaxel, but the high-dose paclitaxel was, as already discussed, of questionable benefit. Within the group of patients receiving 250 mg/m2 of paclitaxel, doubling the filgrastim dose did not change the frequency of neutropenic fever occurring after the first cycle. Whether higher or lower doses of filgrastim would give a different result is not addressed. Significant unfavorable prognostic factors for survival were resistance to prior platinum therapy, presence of clinically measurable disease, mucinous or clear-cell histology, and poor PS. Consideration of these factors is recommended for future trials of second-line therapy in ovarian cancer. With more nonneutrophil-associated toxicity and no survival benefit, the higher response rate achieved in this trial with a higher paclitaxel dose is of dubious clinical benefit.
The following institutions participated in this study: Gynecologic Oncology Group: University of Alabama at Birmingham, Birmingham, AL; Oregon Health Sciences Center, Portland, OR; Duke University Medical Center, Chapel Hill, NC; Temple University Health Science Center Hospital, Philadelphia, PA; University of Rochester Medical Center, Rochester, NY; Walter Reed Army Medical Center, Washington, DC; Wayne State University School of Medicine, Detroit, MI; University of Minnesota Medical School, Minneapolis, MN; University of Mississippi Medical Center, Jackson, MS; Colorado Foundation for Medical Care, Aurora, CO; University of Washington Medical Center, Seattle, WA; Hospital of the University of Pennsylvania, Philadelphia, PA; University of Miami School of Medicine, Miami, FL; The Milton S. Hershey School of Medicine of the Pennsylvania State University, Hershey, PA; Georgetown University Hospital, Washington, DC; University of Cincinnati College of Medicine, Cincinnati, OH; University of North Carolina School of Medicine, Chapel Hill, NC; University of Iowa Hospitals and Clinics, Iowa City, IA; University of Texas Health Science Center at Dallas, Dallas, TX; Indiana University Medical Center, Indianapolis, IN; Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC; The Albany Medical College of Union University, Albany, NY; University of California Medical Center at Irvine, Irvine, CA; Tufts New England Medical Center, Boston, MA; Illinois Cancer Council, Chicago, IL; Stanford University Medical Center, Stanford, CA; State University of New York Downstate Medical Center, Brooklyn, NY; University of Kentucky, Lexington, KY; Eastern Virginia Medical School, Norfolk, VA; Cleveland Clinic Foundation, Cleveland, OH; The Johns Hopkins Oncology Center, Baltimore, MD; Pennsylvania Hospital, Philadelphia, PA; Washington University School of Medicine, St. Louis, MO; Cooper Hospital University Medical Center, Camden, NJ; Columbus Cancer Council, Columbus, OH; University of Texas M.D. Anderson Cancer Center, Houston, TX; Fox Chase Cancer Center, Philadelphia, PA; Medical University of South Carolina, Charleston, SC; Women’s Cancer Center; University of Oklahoma Health Sciences Center, Oklahoma City, OK; University of Chicago, Chicago, IL; University of Arizona Health Science Center, Phoenix, AZ; Tacoma General Hospital, Tacoma, WA; Thomas Jefferson University Hospital, Philadelphia, PA; Case Western Reserve University, Cleveland, OH; Tampa Bay Cancer Consortium, Tampa Bay, FL; and the Southwest Oncology Group, the North Central Cancer Treatment Group, and the Eastern Cooperative Oncology Group.
This study was supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (grant no. CA 27469), the Gynecologic Oncology Group Statistical Office (grant no. CA 37517), the Southwest Oncology Group, the Eastern Cooperative Oncology Group, and the North Central Cancer Treatment Group.
1. McGuire WP III, Hoskins WJ, Brady M, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1–6, 1996
2. Kohn EC, Sorosy G, Bicher A, et al: Dose-intense Taxol: High response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 86:18–24, 1994 3. 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. N Engl J Med 325:164–170, 1991[Abstract] 4. Blessing JA: Design, analysis and interpretation of chemotherapy trials in gynecologic cancer, in Deppe G (ed): Chemotherapy of Gynecologic Cancer (ed 2). New York, NY, Alan R Liss, Inc, Scientific and Medical Publications, 1990, pp 63–97 5. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]
6. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654–2666, 1994
7. Smith RE, Brown AM, Mamounas EP, et al: Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol 17:3403–3411, 1999 8. Winer E, Berry D, Duggan D, et al: Failure of higher dose paclitaxel to improve outcome in patients with metastatic breast cancer: Results from CALGB 9342. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 388)
9. Nabholtz JM, Gelmon 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
10. Kosmidis P, Mylonakis N, Skarlos D, et al: Paclitaxel(175 mg/m2) plus carboplatin versus paclitaxel (225 mg/m2) plus carboplatin in advanced non-small-cell lung cancer (NSCLC): A multicenter randomized trial—Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 11:799–805, 2000
11. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18:623–631, 2000
12. Stahel RA, Jost LM, Honegger H, et al: Randomized trial showing equivalent efficacy of filgrastim 5 mcg/kg/d and 10 mcg/kg/d following high-dose chemotherapy and autologous bone marrow transplantation in high-risk lymphomas. J Clin Oncol 15:1730–1735, 1997
13. Engelhardt M, Bertz H, Afting M, et al: High- versus standard-dose filgrastim for mobilization of peripheral-blood progenitor cells from allogeneic donors and CD34+ immunoselection. J Clin Oncol 17:2160–2172, 1999 14. 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[CrossRef][Medline]
15. Viens P, Chabannon C, Pouillard P, et al: Randomized, controlled, dose-range study of Ro 25-8315 given before and after a high-dose combination chemotherapy regimen in patients with metastatic or recurrent breast cancer patients. J Clin Oncol 20:24–36, 2002
16. Holmes FA, O’Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 20:727–731, 2002 17. Omura GA, Brady MF, Homesley H, et al: Long follow-up and prognostic factor analysis in advanced ovarian carcinoma: The Gynecologic Oncology Group experience. J Clin Oncol 9:1138–1150, 1991[Abstract] Submitted October 16, 2002; accepted May 20, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
38.1°C) or more fever. 
