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Purpose: Primary prophylactic colony-stimulating factors (PP-CSFs) are prescribed to reduce febrile neutropenia (FN) but their benefit for intermediate FN risk regimens is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) PP-CSF intervention, we conducted a substudy to evaluate the effectiveness of SOE for patients receiving intermediate-risk regimens., Methods: TrACER was a cluster randomized trial where practices were randomized to usual care or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to SOE of automated PP-CSF orders for high FN risk regimens and alerts against PP-CSF use for low-risk regimens versus usual care. A secondary 1:1 randomization assigned 24 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF for intermediate-risk regimens. Clinicians were allowed to over-ride the SOE. Patients with breast, colorectal, or non-small-cell lung cancer were enrolled. Mixed-effect logistic regression models were used to test differences between randomized sites., Results: Between January 2016 and April 2020, 846 eligible patients receiving intermediate-risk regimens were registered to either SOE to prescribe (12 sites: n = 542) or an alert to not prescribe PP-CSF (12 sites: n = 304). Rates of PP-CSF use were higher among sites randomized to SOE (37.1% v 9.9%, odds ratio, 5.91; 95% CI, 1.77 to 19.70; P = .0038). Rates of FN were low and identical between arms (3.7% v 3.7%)., Conclusion: Although implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving first-line intermediate-risk regimens, FN rates were low and did not differ between arms. Although this guideline-informed SOE influenced prescribing, the results suggest that neither SOE nor PP-CSF provides sufficient benefit to justify their use for all patients receiving first-line intermediate-risk regimens.

Purpose: This study evaluated the efficacy, safety, and immunogenicity of biosimilar pegfilgrastim (PegFilBS) and originator pegfilgrastim (PegFilOR) in patients with stage 2-4 breast cancer., Methods: This phase III randomized, multicenter, evaluator-blinded, noninferiority study recruited women with stage 2-4 breast cancer in Argentina who were scheduled to receive chemotherapy. Stratification was based on the breast cancer stage. The primary end point was the duration of severe neutropenia (DSN, noninferiority margin: 1 day) in the first chemotherapy cycle. Secondary end points assessed were incidence of severe neutropenia, grade 3 neutropenia, febrile neutropenia, infections, postchemotherapy hospitalization and duration, and the incidence of adverse drug reactions (ADRs)., Results: A total of 120 patients were randomly assigned to receive PegFilBS (58 patients) or PegFilOR (62 patients). Severe neutropenia occurred in 52 of 283 cycles (18.4%) for 27 patients who received PegFilBS and in 48 of 297 cycles (16.2%) for 20 patients who received PegFilOR ( P = .48). During the first cycle, severe neutropenia occurred in 16 patients who received PegFilBS (DSN: 0.78 ± 1.53 days) and in 11 patients who received PegFilOR (DSN: 0.53 ± 1.25 days; 95% CI, -0.26 to 0.76 days). In the intention-to-treat analysis, the mean DSN values were 0.90 ± 1.79 days for the PegFilBS group and 0.50 ± 1.21 for the PegFilOR group (95% CI, -0.15 to 0.95 days). No significant differences were observed for the secondary efficacy end points. Three patients experienced seven ADRs in the PegFilBS group while 10 patients experienced 31 ADRs in the PegFilOR group. The most common ADR was myalgia., Conclusion: Relative to PegFilOR, PegFilBS provided noninferior efficacy outcomes in Argentinian women with stage 2-4 breast cancer who were treated using myelosuppressive chemotherapy., Competing Interests: Ruben D. KowalyszynConsulting or Advisory Role: BMS Argentina, MSD Oncology, Astellas Pharma, Merck SeronoSpeakers' Bureau: BMS Argentina, NovartisResearch Funding: BMS, MSD Oncology, Novartis, Roche, Astellas Pharma, Lilly, Gemabiotech, Nektar, Poliphor, AstraZeneca Luis E. FeinConsulting or Advisory Role: Novartis, Pfizer, AstraZeneca/Merck Eduardo OrtizConsulting or Advisory Role: Boehringer Ingelheim, AstraZeneca, Pfizer, Roche, Bristol Myers SquibbSpeakers' Bureau: Bristol Myers SquibbResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Janssen, Amgen, Astellas Pharma, Roche, Novartis/PfizerTravel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer Juan J. ZarbaConsulting or Advisory Role: Pfizer/EMD Serono, Pfizer, Astellas PharmaResearch Funding: MSD Oncology, Lilly, Exelixis, Astellas PharmaExpert Testimony: LillyTravel, Accommodations, Expenses: Roche, Pfizer Ezequiel KlimovskyOther Relationship: Gema Biotech SAU, AbbVie, La Roche-Posay, Roemmers, Merz GmbH Nestor LagoEmployment: GemabiotechNo other potential conflicts of interest were reported.

Purpose: Curative chemotherapy for breast cancer is associated with significant toxicities including emergency room (ER) visits and hospital admissions (HAs), events that are underreported in clinical trials. This study examined the reasons for, and factors associated with, ER visits and HA after curative chemotherapy for breast cancer in a tertiary Ontario hospital., Patients and Methods: A retrospective study of all patients who completed at least one cycle of curative chemotherapy for breast cancer in 2011 and 2012 was conducted. We recorded ER visits and HAs within 30 days of any chemotherapy. We collected demographics, comorbidities, surgical data, tumor characteristics, chemotherapy type and cycles, and use of granulocyte colony-stimulating factors (G-CSF)., Results: A total of 149 patients underwent curative chemotherapy. Mean age was 58.6 years. Adjuvant chemotherapy was received by 85% of patients and G-CSF by 88.6%. At least one ER visit occurred in 53% of patients, and 13% required HA. The most common causes of ER visits were fever without neutropenia (23.3%), pain (12.8%), and febrile neutropenia (9%). Stage of breast cancer was the only factor statistically significantly associated with ER visits (P = .045); tumor size (P = .019), adjuvant chemotherapy (P = .045), and lower number of chemotherapy cycles (P = .005) were significantly associated with HA., Conclusion: Future research should focus on identifying the patient, provider, and health system factors associated with ER visits and HAs after chemotherapy for breast cancer, to minimize them and lessen the burden on the health care system., (Copyright © 2015 by American Society of Clinical Oncology.)

Purpose: Pegfilgrastim-induced bone pain is a significant clinical problem that may result in discontinuation of pegfilgrastim and lead to less effective chemotherapy dosing. Interventions for pegfilgrastim-induced bone pain are needed., Patients and Methods: The University of Rochester Cancer Center Clinical Community Oncology Program Research Base randomly assigned 510 patients at 17 sites to receive either naproxen (500 mg two times per day) or placebo on the day of pegfilgrastim administration, continuing for 5 to 8 days after pegfilgrastim. Patients recorded pain severity (using a scale of 0 to 10) and duration in daily diaries. The primary outcome measure was the area under the curve (AUC) for pain for days 1 through 5. Secondary outcome measures included the identification of risk factors for the development of pain and response to naproxen., Results: Patients' mean age was 55.6 years and 86% were female. Sixty-eight percent of patients had breast cancer and 10% had lung cancer. Pain reached its peak at 3 days for both groups. The mean AUC for pain was 7.71 for the placebo group and 6.04 for the naproxen group (P = .037). Naproxen reduced maximum pain from 3.40 to 2.59 (P = .005). Naproxen also reduced overall pain incidence from 71.3% to 61.1% (P = .020) and duration from 2.40 to 1.92 days (P = .009). The reduction in severe pain (> 5 on a scale of 1 to 10) from 27.0% to 19.2% was also significant (P = .048). Risk factors could not be identified to predict incidence, severity, or ability to prevent pegfilgrastim-induced bone pain., Conclusion: Our phase III randomized placebo-controlled clinical trial demonstrated that naproxen at a dose of 500 mg twice per day is effective in reducing the incidence and severity of pegfilgrastim-induced bone pain.

Purpose: To reduce the incidence of febrile neutropenia during rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) induction. In the High-Risk Neuroblastoma-1 (HR-NBL1) trial, the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) randomly assigned patients to primary prophylactic (PP) versus symptom-triggered granulocyte colony-stimulating factor (GCSF; filgrastim)., Patients and Methods: From May 2002 to November 2005, 239 patients in 16 countries were randomly assigned to receive or not receive PPGCSF. There were 144 boys with a median age of 3.1 years (range, 1 to 17 years) of whom 217 had International Neuroblastoma Staging System (INSS) stage 4 and 22 had stage 2 or 3 MYCN-amplified disease. The prophylactic arm received a single daily dose of 5 microg/kg GCSF, starting after each of the eight COJEC chemotherapy cycles and stopping 24 hours before the next cycle. Chemotherapy was administered every 10 days regardless of hematologic recovery, provided that infection was controlled., Results: The PPGCSF arm had significantly fewer febrile neutropenic episodes (P = .002), days with fever (P = .004), hospital days (P = .017), and antibiotic days (P = .001). Reported Common Toxicity Criteria (CTC) graded toxicity was also significantly reduced: infections per cycle (P = .002), fever (P < .001), severe leucopenia (P < .001), neutropenia (P < .001), mucositis (P = .002), nausea/vomiting (P = .045), and constipation (P = .008). Severe weight loss was reduced significantly by 50% (P = .013). Protocol compliance with the rapid induction schedule was also significantly better in the PPGCSF arm shown by shorter time to completion (P = .005). PPGCSF did not adversely affect response rates or success of peripheral-blood stem-cell harvest., Conclusion: Following these results, PPG-GSF was advised for all patients on rapid COJEC induction.

Purpose: This multicenter, randomized, open-label study evaluated the efficacy, safety, and pharmacokinetics of a single subcutaneous pegfilgrastim injection with daily subcutaneous filgrastim administration in pediatric patients receiving myelosuppressive chemotherapy for sarcoma. PATIENTS AND METHODS Forty-four patients with previously untreated, biopsy-proven sarcoma stratified into three age groups (0-5, 6-11, and 12-21 years) were randomly assigned in a 6:1 randomization ratio to receive a single pegfilgrastim dose of 100 microg/kg (n = 38) or daily filgrastim doses of 5 microg/kg (n = 6) after chemotherapy (cycles 1 and 3: vincristine-doxorubicin-cyclophosphamide; cycles 2 and 4: ifosfamide-etoposide). The duration of grade 4 neutropenia, time to neutrophil recovery, incidence of febrile neutropenia, and adverse events were recorded. Results Pegfilgrastim and filgrastim were similar for all efficacy and safety end points, and their pharmacokinetic profiles were consistent with those in adults. Younger children experienced more protracted neutropenia and had higher median pegfilgrastim exposure than older children. CONCLUSION A single dose of pegfilgrastim at 100 microg/kg administered once per chemotherapy cycle is comparable to daily injections of filgrastim at 5 microg/kg for pediatric sarcoma patients receiving myelosuppressive chemotherapy.

Purpose: Doxorubicin and cyclophosphamide (AC) every 3 weeks has been associated with frequent asymptomatic declines in left ventricular ejection fraction (LVEF). Dose-dense (dd) AC followed by paclitaxel (P) is superior to the same regimen given every third week. Herein, we report the early cardiac safety of three sequential studies of ddAC alone or with bevacizumab (B)., Patients and Methods: Patients with HER2-positive breast cancer were treated on two trials: ddAC followed by P and trastuzumab (T) and ddAC followed by PT and lapatinib. Patients with HER2-normal breast cancer were treated with B and ddAC followed by B and nanoparticle albumin-bound P. Prospective LVEF measurement by multigated radionuclide angiography scan before and after every 2 week AC for 4 cycles and at month 6 from all three trials were aggregated to determine the early risks of cardiac dysfunction., Results: From January 2005 to May 2008, 245 patients were enrolled. The median age was 47 years (range, 27 to 75 years). Median LVEF pre-ddAC was 68% (range, 52% to 82%). LVEF post-ddAC was available in 241 patients (98%) and the median was unchanged at 68% (range, 47% to 81%). Per protocol no patients were ineligible for subsequent targeted biologic therapy based on LVEF decline post-ddAC. In addition, LVEF was available in 222 patients (92%) at 6 months, at which time the median LVEF was similar at 65% (range, 24% to 80%). Within 6 months of initiating chemotherapy, three patients (1.2%; 95% CI, 0.25% to 3.54%) developed CHF, all of whom received T., Conclusion: Dose-dense AC with or without concurrent bevacizumab is not associated with frequent acute or short-term declines in LVEF.

Purpose: We report on the effects of granulocyte colony-stimulating factor (G-CSF) on hemoglobin (Hb) value in early breast cancer patients receiving high-dose epirubicin and cyclophosphamide (EC) adjuvant treatment., Methods: Five hundred and six stage I or stage II female breast cancer patients were treated with E 120 mg/m2 and C 600 mg/m2 with or without G-CSF and randomly assigned to receive in a factorial 2 x 2 design: EC; EC + lonidamine; EC + G-CSF; EC + lonidamine + G-CSF. Five consecutive G-CSF schedules tested 100 randomly assigned patients each: (1) 480 microg subcutaneously on days 8 to 14; (2) 480 microg on days 8, 10, 12, 14; (3) 300 microg on days 8 to 14; (4) 300 microg on days 8, 10, 12, and 14; and (5) 300 microg on days 8 and 12. The mean Hb level of 246 patients receiving EC plus G-CSF was compared with that of 240 patients receiving EC alone. The data presented are derived from an exploratory hypothesis-generating analysis., Results: The EC dose intensity did not statistically differ between the G-CSF and the control arm. From the third cycle onward, the mean Hb value resulted significantly lower in G-CSF arm compared with control at each time point of each cycle (P < .0001). No statistically significant difference in the mean Hb level was observed between schedule 5 and control. Of interest, from the second course onward, the mean Hb level tended to be lower in patients receiving seven or four G-CSF injections compared with those patients who received only two injections., Conclusion: Our data suggest that a G-CSF dose-related effect may play a role in worsening anemia in patients receiving adjuvant EC.

Purpose: We evaluated the efficacy of pegfilgrastim to reduce the incidence of febrile neutropenia associated with docetaxel in breast cancer patients., Patients and Methods: Patients were randomly assigned to either placebo or pegfilgrastim 6 mg subcutaneously on day 2 of each 21-day chemotherapy cycle of 100 mg/m(2) docetaxel. The primary end point was the percentage of patients developing febrile neutropenia (defined as body temperature >/= 38.2 degrees C and neutrophil count < 0.5 x 10(9)/L on the same day of the fever or the day after). Secondary end points were incidence of hospitalizations associated with a diagnosis of febrile neutropenia, intravenous (IV) anti-infectives required for febrile neutropenia, and the ability to maintain planned chemotherapy dose on time. Patients with febrile neutropenia were converted to open-label pegfilgrastim in subsequent cycles., Results: Nine hundred twenty-eight patients received placebo (n = 465) or pegfilgrastim (n = 463). Patients receiving pegfilgrastim, compared with patients receiving placebo, had a lower incidence of febrile neutropenia (1% v 17%, respectively; P < .001), febrile neutropenia-related hospitalization (1% v 14%, respectively; P < .001), and use of IV anti-infectives (2% v 10%, respectively; P < .001). The percentage of patients receiving the planned dose on time was similar between patients receiving pegfilgrastim and patients who initially received placebo (80% and 78%, respectively), as would be expected of the study design. Pegfilgrastim was generally well tolerated and safe, and the adverse events reported were typical of this patient population., Conclusion: First and subsequent cycle use of pegfilgrastim with a moderately myelosuppressive chemotherapy regimen markedly reduced febrile neutropenia, febrile neutropenia-related hospitalizations, and IV anti-infective use.

Purpose: Granulocyte colony-stimulating factor (G-CSF) is given after bone marrow transplantation (BMT) to shorten the neutropenic phase. Its effects have not been evaluated in a large patient population., Patients and Methods: We studied 1,789 patients with acute leukemia receiving BMT and 434 patients receiving peripheral-blood stem cells (PBSCs) from HLA-identical siblings from 1992 to 2002 and reported the findings to the European Group for Blood and Marrow Transplantation. Among the BMT and PBSC patients, 501 (28%) and 175 (40%), respectively, were treated with G-CSF during the first 14 days after the transplantation. The outcome variables were entered into a Cox proportional hazards model., Results: BMT and PBSC patients treated with G-CSF had a faster engraftment of absolute neutrophils greater than 0.5 x 10(9)/L (P <.01), but platelet engraftment ( > 50 x 10(9)/L) was slower (P <.001). In the BMT patients, acute graft-versus-host disease (GVHD) grades II to IV was 50% +/- 5% (+/- 95% CI) in the G-CSF group versus 39% +/- 3% in the controls (relative risk [RR], 1.33; P =.007, in the multivariate analysis). The incidence of chronic GVHD was also increased (RR, 1.29; P =.03). G-CSF was associated with an increase in transplantation-related mortality (TRM; RR, 1.73; P =.00016) and had no effect on relapse but reduced survival (RR, 0.59; P <.0001) and leukemia-free survival rates (LFS; RR, 0.64; P =.0003). No such effects of G-CSF were seen in patients receiving PBSC., Conclusion: After BMT, platelet engraftment was delayed, and GVHD and TRM were increased. Survival and LFS were reduced. This suggests that G-CSF should not be given shortly after BMT.

Purpose: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity., Patients and Methods: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients)., Results: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non-G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non-G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively)., Conclusion: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Purpose: This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of pegfilgrastim (SD/01, sustained-duration filgrastim; 100 microg/kg) is as safe and effective as daily filgrastim (5 microg/kg/d) for reducing neutropenia in patients who received four cycles of myelosuppressive chemotherapy., Patients and Methods: Sixty-two centers enrolled 310 patients who received chemotherapy with docetaxel 75 mg/m(2) and doxorubicin 60 mg/m(2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 2 either a single subcutaneous injection of pegfilgrastim 100 microg/kg per chemotherapy cycle (154 patients) or daily subcutaneous injections of filgrastim 5 microg/kg/d (156 patients). Absolute neutrophil count (ANC), duration of grade 4 neutropenia, and safety parameters were monitored., Results: One dose of pegfilgrastim per chemotherapy cycle was comparable to daily subcutaneous injections of filgrastim with regard to all efficacy end points, including the duration of severe neutropenia and the depth of ANC nadir in all cycles. Febrile neutropenia across all cycles occurred less often in patients who received pegfilgrastim. The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than 1 day. Pegfilgrastim was safe and well tolerated, and it was similar to filgrastim. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar., Conclusion: A single injection of pegfilgrastim 100 microg/kg per cycle was as safe and effective as daily injections of filgrastim 5 microg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m(2) and docetaxel 75 mg/m(2).

Purpose: To investigate the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response of primary operable breast cancer., Patients and Methods: Patients (tumor size > or = 3 cm, N0 to 2, M0) were prospectively randomized to receive every 14 days a total of four cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m(2), either with (ADocT) or without (ADoc) simultaneous tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment., Results: Within 14 months, 250 patients were included in the study at 56 centers. Of 992 planned cycles, 97.9% were administered. Pathologically complete remission (pCR) with no detectable viable tumor cells was achieved in 9.7%. There was a nonsignificant difference of -1.2% in favor of ADoc, with a 95% confidence interval of -8.6% to 6.2%. A further 2.4% had only noninvasive tumor residues, and 13.8% had focal invasive residues. Complete and partial responses detected by palpation were observed in 28.9% and 52.4%, respectively. The response rates (complete and partial) by best appropriate imaging methods were 77.5% and 67.5% for ADocT and ADoc, respectively. Breast conservation was possible in 68.8% of the patients. A tendency toward more frequent toxic events was observed with ADocT treatment. Significant predictors of pCR to chemotherapy were negative lymph node and negative estrogen receptor status., Conclusion: A dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and rapid efficacy as a form of preoperative chemotherapy in operable breast cancer. Concurrent treatment with tamoxifen for 8 weeks could not improve the pathologic response rate.

Purpose: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers., Patients and Methods: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not., Results: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma., Conclusion: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.

Purpose: To explore the use of SD/01 (a polyethylene glycol-conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia., Patients and Methods: Thirteen patients with non-small-cell lung cancer were randomized to receive daily filgrastim (5 microg/kg/d) or a single injection of SD/01 (30, 100, or 300 microg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed., Results: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 microg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 microg/kg. Dose-limiting toxicities were not noted. CD34(+) cells were mobilized in all cohorts., Conclusion: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34(+) cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.

Purpose: This study was designed to investigate the quality of life (QOL) of patients enrolled onto the High-Dose Chemotherapy for Breast Cancer Study Group trial (PEGASE 02), a French pilot multicenter trial of the treatment of inflammatory breast cancer (IBC) aimed at evaluating (1) toxicity and feasibility of sequential high-dose chemotherapy (HDC) with recombinant human granulocyte colony-stimulating factor (filgrastim) and stem-cell support and (2) response to HDC in terms of pathologic response and survival., Patients and Methods: QOL measures were performed at inclusion and four times subsequently up to 1 year using an ad hoc side-effect questionnaire (19 physical symptoms) and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30)., Results: Of the 95 patients entered, the overall QOL questionnaire completion compliance was 75.6%. During cycle 3 of HDC, the number of symptoms was high (mean +/- SD QOL score, 10 +/- 3), with fatigue, hair loss, appetite loss, nausea, change in taste, vomiting, fever, and weight loss reported by more than 60% of patients. Toxicity and distress associated with HDC were reflected in the decline of four EORTC QLQ-C30 scores: global QOL (P =.001), and physical, role, and social functioning (P <.001 for all statistics). However, QOL deterioration disappeared after treatment completion, except for physical functioning (P =.025). One year after inclusion, most QOL scores returned to baseline, and both emotional functioning and global QOL scores were even higher than baseline (P =.030 and P =.009, respectively)., Conclusion: If it is confirmed that improvements in pathologic response rates with HDC effectively translate into increased probabilities of survival for IBC patients, adoption of such treatment as PEGASE 02 will not involve crucial choices between length of life and QOL and should not be delayed for QOL arguments.

Purpose: Several groups have reported that the combination of doxorubicin plus paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles produces a high response rate (> 80%) and complete response rate (> 20%) in metastatic breast cancer, but is also complicated by a 20% incidence of congestive heart failure (CHF). The purpose of this phase II trial was to evaluate the antineoplastic activity of the regimen in a multi-institutional setting and to reduce the incidence of cardiotoxicity by limiting treatment to a maximum of six cycles., Patients and Methods: Fifty-two patients with advanced breast cancer received doxorubicin (60 mg/m(2) by IV injection) followed 15 minutes later by paclitaxel (200 mg/m(2) by IV infusion over 3 hours) every 3 weeks for four to six cycles., Results: Objective responses occurred in 25 of 48 assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including four complete responses (8%; 95% CI, 0% to 16%). The median cumulative doxorubicin dose given was 240 mg/m(2) (range, 132 to 360 mg/m(2)). Eleven patients (21%) were documented as having a decrease in the LVEF below normal, including three patients (6%; 95% CI, 0% to 12%) who developed CHF., Conclusion: The doxorubicin/paclitaxel regimen that we used is unlikely to produce an objective response rate of more than 70% and a complete response rate of more than 20% in patients with metastatic breast cancer, and proved to be excessively cardiotoxic for use in the adjuvant setting.

Purpose: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen., Patients and Methods: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days., Results: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths., Conclusion: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

Purpose: To investigate the efficacy and feasibility of concurrent chemoradiotherapy for locally advanced carcinoma of the esophagus., Patients and Methods: Fifty-four patients with clinically T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus were enrolled. Patients received protracted infusion of fluorouracil 400 mg/m(2)/24 hours on days 1 to 5 and 8 to 12, 2-hour infusion of cisplatin 40 mg/m(2) on days 1 and 8, and concurrent radiation therapy at a dose of 30 Gy in 15 fractions over 3 weeks. Filgrastim was prophylactically administered to 35 patients. This schedule was repeated twice every 5 weeks, for a total radiation dose of 60 Gy, followed by two courses of fluorouracil (800 mg/m(2)/24 hours for 5 days) and cisplatin (80 mg/m(2) on day 1)., Results: There were 21 patients with T4M0 disease, one with T2M1 LYM, 17 with T3M1 LYM, and 15 withT4M1 LYM. Forty-nine patients (91%) completed at least the chemoradiotherapy segment. The 18 patients (33%) who achieved a complete response included nine (25%) of the 36 with T4 disease and nine (50%) of the 18 with non-T4 disease. Major toxicities were leukocytopenia and esophagitis; there were four (7%) treatment-related deaths. Prophylactic filgrastim reduced the incidence of grade 3 or worse leukopenia without improving dose-intensity or response. With a median follow-up duration of 43 months, median survival time was 9 months. The 3-year survival rate was 23%., Conclusion: Despite its significant toxicity, this combined modality seemed to have curative potential even in cases of locally advanced carcinoma of the esophagus.

Purpose: To determine the efficacy and tolerance of single-agent docetaxel and granulocyte colony-stimulating factor in patients with advanced pancreatic cancer., Patients and Methods: Thirty-three chemotherapy-naive patients (median age, 65 years) with histologically confirmed pancreatic cancer were treated, after appropriate premedication, with docetaxel (100 mg/m(2)) and granulocyte colony-stimulating factor (150 microg/m(2)/d subcutaneously days 2 through 10) every 3 weeks. World Health Organization performance status was 0 to 1 in 28 patients (85%) and 2 in 5 patients (15%). Twenty-nine patients had stage III and IV disease., Results: One complete response (3%) and one partial response (3%) were observed for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had stable disease and 12 (36%) had progressive disease. The duration of the two objective responses was 10 and 28 weeks, and the median time to tumor progression was 20 weeks. The median overall survival was 36 weeks. The actuarial 1-year survival was 36.4%. The performance status improved in seven of 21 assessable patients (24%) and pain improved in 14 of 21 (67%) assessable patients; five patients (29%) experienced weight gain during treatment. Disease-related asthenia, anorexia, vomiting, and diarrhea improved in 29%, 15%, 67%, and 47% of the assessable patients, respectively. Serum concentrations of CA 19-9 were decreased by more than 50% in seven patients (35%). Grade 3 and 4 neutropenia occurred in four patients (12%) and eight patients (24%), respectively, with two episodes of febrile neutropenia. There were no treatment-related deaths. Grade 3/4 asthenia occurred in three patients., Conclusion: Although docetaxel has a marginal objective activity in pancreatic cancer, it seems to have an important effect on tumor growth control, conferring a clinical benefit.

Purpose: To compare the toxicity and effects on hematologic recovery and circulating progenitor cell mobilization of three cytokine regimens administered after high-dose cyclophosphamide (HD-CTX; 6 g/m(2)), given as the first step of a high-dose sequential chemotherapy., Patients and Methods: Forty-eight patients with breast cancer or non-Hodgkin's lymphoma were randomized to receive granulocyte colony-stimulating factor (G-CSF) alone (arm 1), granulocyte-macrophage colony-stimulating factor (GM-CSF) alone (arm 2), or sequential interleukin-3 (IL-3) and GM-CSF (arm 3). Cytokines were administered as a single daily subcutaneous injection at a dose of 5 to 6 microg/kg/d. Progenitor cells were evaluated in peripheral blood as well as in apheretic product as both CD34(+) cells and granulocyte-macrophage colony-forming units (CFU-GM)., Results: Neutrophil recovery was faster in arm 1 as compared with arms 2 and 3 (P <.0001); no significant differences were observed between arms 2 and 3. In arm 3, a moderate acceleration of platelet recovery was observed, but it was statistically significant only as compared with arm 1 (P =.028). The peak of CD34(+) cells was hastened in a median of 2 days in arm 1 compared with arms 2 and 3 (P =.0002), whereas the median peak value of CD34(+) cells and CFU-GM was similar in the three patient groups. Administration of IL-3 and GM-CSF resulted in more significant toxicity requiring pharmacologic treatment in 90% of patients., Conclusion: The three cytokine regimens administered after HD-CTX are comparably effective in reducing hematologic toxicity and mobilizing the hematopoietic progenitor cells. G-CSF accelerates leukocyte recovery and progenitor mobilization. Although G-CSF-treated patients have somewhat slower platelet recovery, they definitely have fewer side effects.

Purpose: This was the first randomized study to investigate the efficacy of peripheral-blood progenitor cell (PBPC) mobilization using stem-cell factor (SCF) in combination with filgrastim (G-CSF) following chemotherapy compared with filgrastim alone following chemotherapy., Patients and Methods: Forty-eight patients with ovarian cancer were treated with cyclophosphamide and randomized to receive filgrastim 5 microg/kg alone or filgrastim 5 microg/kg plus SCF. The dose of SCF was cohort-dependent (5, 10, 15, and 20 microg/kg), with 12 patients in each cohort, nine of whom received SCF plus filgrastim and the remaining three patients who received filgrastim alone. On recovery from the WBC nadir, patients underwent a single apheresis., Results: SCF in combination with filgrastim following chemotherapy enhanced the mobilization of progenitor cells compared with that produced by filgrastim alone following chemotherapy. This enhancement was dose-dependent for colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU-E), and CD34+ cells in both the peripheral blood and apheresis product. In the apheresis product, threefold to fivefold increases in median CD34+ and progenitor cell yields were obtained in patients treated with SCF 20 microg/kg plus filgrastim compared with yields obtained in patients treated with filgrastim alone. Peripheral blood values of CFU-GM, BFU-E, and CD34+ cells per milliliter remained above defined threshold levels longer with higher doses of SCF. The higher doses of SCF offer a greater window of opportunity in which to perform the apheresis to achieve high yields., Conclusion: SCF (15 or 20 microg/kg) in combination with filgrastim following chemotherapy is an effective way of increasing progenitor cell yields compared with filgrastim alone following chemotherapy.

Purpose: To evaluate the impact of granulocyte colony-stimulating factor (G-CSF) priming on peripheral-blood cell counts during standard-dose chemotherapy., Patients and Methods: Twelve patients with relapsed small-cell lung carcinoma (SCLC) were treated with two chemotherapy courses. Six patients received G-CSF priming only before the first course (group A) and the other six patients only before the second course (group B). Each patient served as his own control. Patients were treated with cyclophosphamide, epirubicin, and etoposide (CEE), or with vincristine, ifosfamide, mesna, and carboplatin (VIMP) every 4 weeks. G-CSF was administered subcutaneously 5 microg/kg/d for 6 days until 48 hours before the first or second chemotherapy course., Results: Priming caused a lowering of the WBC nadir, with a median value of 0.95 x 10(9)/L (P = .004), and of absolute neutrophil nadir, with a median value of 0.48 x 10(9)/L (P = .03). There was a trend for a lower platelet (PLT) nadir after G-CSF priming (P = .09). G-CSF priming resulted in a prolonged duration of WBC count less than 3.0 x 10(9)/L of +4.25 days (P = .04), and of WBC count less than 1.0 x 10(9)/L of +0.50 days (P = .03). The duration of neutropenia less than 0.5 x 10(9)/L seemed longer in primed courses (+3.75 days, P = .18). The duration of PLT counts less than 100 x 10(9)/L was prolonged by 1.5 days (P = .04). Hemoglobin (Hgb) levels were not influenced by G-CSF priming., Conclusion: G-CSF administration until 48 hours before the next chemotherapy course increases chemotherapy-associated leukocytopenia and thrombocytopenia. This may be of special concern when G-CSF is administered during dose-densified chemotherapy.

Purpose: The clinical indications and economic consequences of human granulocyte colony-stimulating factor (G-CSF) prescription during small-cell lung cancer (SCLC) chemotherapy remain controversial. The aim of this study, based on a Markov model, was to assess the impact of routine G-CSF use in the treatment of SCLC on costs and patient comfort. Markov models allow the modeling SCLC chemotherapy, in which the risk of febrile neutropenia (FN) is continuous over time and may occur more than once., Patients and Methods: We used a Markov model to compare three strategies: a chemotherapy dose reduction after FN and nonuse of G-CSF ("never" strategy), secondary use of G-CSF ("CSF if FN" strategy) and primary use of G-CSF ("systematic CSF" strategy). Model baseline probabilities were based on a review of medical records for all patients (n = 39) treated for SCLC in our unit during 1993 (when G-CSF was not used) and on published reductions in the incidence of FN obtained by using G-CSF. Two different types of rewards were used: a cost-utility scale that took into account the costs of FN (CFN) episodes and G-CSF (CCSF) courses; and a comfort-utility scale that took into account the discomfort of FN and G-CSF therapy. Costs were analyzed from the health care payer's perspective and utilities were assessed prospectively in standardized interviews with treated SCLC patients., Results: The never strategy was the least costly ($4,875 [United States] versus $5,816 and $7,690 for CSF if FN and systematic CSF) and gave the highest comfort value (378 U v 365 and 327 for CSF if FN and systematic CSF). Sensitivity analyses showed that the never strategy remains the less costly when the probability of a first FN episode was less than 49%, the probability of FN recurrence was less than 60%, or the CFN was less than $6,077, or the CCSF was greater than $863. In terms of patient comfort, the never strategy was the best choice, except for patients who considered that a course of G-CSF caused little or no discomfort, whether or not it prevented FN., Conclusion: Routine use of G-CSF during SCLC chemotherapy is not justified by clinical benefits, improved patient comfort, or economic considerations.

Purpose: We performed a pilot phase II study to evaluate the potential for delivery of rapidly sequenced high-dose chemotherapy treatments rescued with autologous peripheral-blood progenitor cells (PBP) in patients with previously untreated, advanced ovarian cancer., Patients and Methods: A single cycle of mobilization was used, primed with cyclophosphamide (CPA)/paclitaxel (Txl) and filgrastim (granulocyte colony-stimulating factor [G-CSF]), followed by three cycles of high-dose carboplatin (CBDCA)/Txl and one cycle of high-dose melphalan (MEL), each rescued by PBP. We then analyzed the outcome for a total of 56 consecutive patients treated with high-dose chemotherapy as part of this program., Results: In the phase II pilot, 21 patients were enrolled. There were no treatment-related deaths through 98 high-dose treatments, although 34 treatments were complicated by hospitalization, primarily for neutropenic fever. Seventy-six percent of patients experienced grade 3 to 4 gastrointestinal toxicity and 62% experienced grade 2 to 3 neuropathy. Five of 15 (33%) patients who underwent second-look surgery attained a pathologic complete response. In the overall analysis, 56 patients were reviewed. Forty-four patients were assessable for response by second-look surgery or clinical progression. Fifteen of 44 patients achieved a pathologic complete response (34%). The pathologic complete response rate in optimal-disease patients was 12 of 22 (55%), while only three of 22 (13%) suboptimal stage III and IV patients achieved a pathologic complete response., Conclusion: The Gynecologic Oncology Group has initiated a pilot phase II trial of this approach in patients with optimally debulked stage III ovarian cancer. There is no evidence to support the use of this or other aggressive regimens outside of a clinical trial.

Purpose: To define the maximum-tolerated dose (MTD) of liposome-encapsulated doxorubicin (LED) when used every 2 weeks with granulocyte colony-stimulating factor (G-CSF) in patients with advanced soft tissue sarcoma., Patients and Methods: Doxorubicin encapsulated in egg phosphatidylcholine/cholesterol liposomes was given to patients with sarcoma in a disease-specific phase I trial. The initial dose was 75 mg/m2 with G-CSF 5 micrograms/kg. The MTD was defined as the highest dose that could be given every 2 weeks., Results: Twenty-nine patients participated in this study. Major toxicities included myelosuppression, nausea and vomiting, fatigue, and mucositis. Eight patients were hospitalized for nadir fever. No cardiotoxicity was seen. The MTD was LED 105 mg/m2 with G-CSF 5 micrograms/kg. LED 120 mg/m2 resulted in tolerable, albeit prominent, acute toxicity, but did not permit recycling of therapy on day 15. Among 26 patients with soft tissue sarcoma, 23 had measurable disease, of whom three achieved a partial response (13%; 95% confidence interval, 2% to 34%)., Conclusion: LED can be administered every 2 weeks at a dose of 105 mg/m2 with G-CSF support, which provides a dose-intensity of 52.5 mg/m2/wk. To exceed this intensity, the dose of LED that would have to be administered every 3 weeks would be greater than 157.5 mg/m2. A formal phase II trial is needed to estimate better the true response rate.

Purpose: The optimal dose of granulocyte colony-stimulating factor (G-CSF) for mobilization of allogeneic-blood stem cells (AlloBSC) has yet to be determined. As part of a prospective trial, 41 related human leukocyte antigen (HLA)-matched donors had blood cells mobilized with G-CSF at 5 micrograms/kg/d by subcutaneous administration. The purpose of this trial was to monitor adverse effects during G-CSF administration and stem-cell collection, to determine the optimal timing for stem-cell collection, and to determine the cellular composition of stem-cell products following G-CSF administration., Patients and Methods: The median donor age was 42 years. Apheresis began on day 4 of G-CSF administration. At least three daily 12-L apheresis collections were performed on each donor. A minimum of 1.0 x 10(6) CD34+ cells/kg (recipient weight) and 8.0 x 10(8) mononuclear cells/kg were collected from each donor. All collections were cryopreserved in 5% dimethyl sulfoxide and 6% hydroxyethyl starch., Results: Toxicities associated with G-CSF administration and the apheresis process included myalgias/arthralgias (83%), headache (44%), fever (27%), and chills (22%). The median baseline platelet count of 242 x 10(4)/ mL decreased to 221, 155, and 119 x 10(6)/mL on days 4, 5, and 6 of G-CSF administration, respectively. Median numbers of CD34+ cells in collections 1, 2, and 3 were 1.99, 2.52, and 3.13 x 10(6)/kg, respectively. The percentage and total number of CD4+, CD8+, and CD56+/CD3- cells remained relatively constant during the three collections. Median total numbers of cells were as follows: CD34+, 7.73 x 10(6)/kg; and lymphocytes, 6.93 x 10(8)/kg., Conclusion: Relatively low doses of G-CSF can mobilize sufficient numbers of AlloBSC safely and efficiently.

Purpose: To assess the safety, tolerability, and hematopoietic efficacy of sequential and concomitant administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human interleukin-3 (rhIL-3), to accelerate reconstitution of hematopoiesis following myeloablative chemotherapy and autologous bone marrow transplantation (ABMT) for heavily pretreated lymphoma patients., Patients and Methods: Fifty-four consecutive patients with refractory or relapsed non-Hodgkin's lymphoma (NHL; n = 30) and Hodgkin's disease (HD; n = 24) were studied. Two different conditioning regimens were used for ABMT: carmustine, cyclophosphamide, etoposide, and cytarabine (BAVC) and carmustine, melphalan, etoposide, and cytarabine (BEAM) for NHL and HD, respectively. Patients were enrolled sequentially onto one of three treatment groups: group 1, G-CSF (5 micrograms/kg/d subcutaneously [SC]) from day +1 after reinfusion of autologous marrow (n = 23); group 2, G-CSF from day +1 combined with IL-3 (10 micrograms/kg/d SC) from day +6 (n = 22, overlapping schedule); and group 3, G-CSF treatment discontinued at day +6 before initiation of IL-3 administration (n = 9, sequential schedule). In the three groups, growth factor(s) was administered until the granulocyte count was greater than 0.5 x 10(9)/L for 3 consecutive days., Results: The study cytokines were generally well tolerated. No side effects were observed when G-CSF was given alone. Four of 31 patients (12.9%) who received SC IL-3 had one severe adverse event defined as World Health Organization (WHO) grade 3 to 4 toxicity (fever, n = 2; pulmonary toxicity, n = 2) and were withdrawn from the study. Groups 2 and 3 did not differ as for treatment tolerability, whereas we observed a trend toward a faster hematopoietic recovery when IL-3 was administered concomitant with G-CSF from day 6 (ie, group 2). Pooled together, patients who received IL-3 showed a median time to achieve a granulocyte count greater than 0.1 and greater than 0.5 x 10(9)/L of 8 and 11 days, respectively. The median time to an unsupported platelet count greater than 20 and 50 x 10(9)/L was 15 and 20 days, respectively, and only one patient did not reach a normal platelet count. The median number of days to hospital discharge was 16 after ABMT (range, 12 to 29). When the hematologic reconstitution of patients in groups 2 and 3 was compared with that of patients in group 1, the addition of IL-3 resulted in a significant improvement of multilineage hematopoietic recovery, lower transfusion requirements, a lower number of documented infections, and shorter hospitalizations., Conclusion: We conclude that the combination of G-CSF and IL-3 is safe and well tolerated in intensively pretreated lymphoma patients, undergoing ABMT and results in rapid hematopoietic recovery following myeloablative chemotherapy.

Purpose: To determine the maximum-tolerated dose (MTD) of mitoxantrone that could be safely used in combination with cyclophosphamide and filgrastim in patients with advanced breast carcinoma., Patients and Methods: Twenty-seven patients with metastatic (n = 24) or locally advanced (n = 3) breast carcinoma received escalating doses of mitoxantrone (16, 20, 24, 28, or 32 mg/m2) plus cyclophosphamide at one of three dose levels: group 1, 1,200 mg/m2; group 2, 2,400 mg/m2; and group 3,600 mg/m2. All patients also received filgrastim 5 micrograms/kg administered subcutaneously beginning on day 2 and continuing until the post-nadir absolute neutrophil count (ANC) was > or = 10,000/microL. Treatment was repeated every 3 weeks if the ANC was > or = 2,000/microL and platelet count > or = 90,000/microL for a maximum of six cycles. Dose escalation occurred within each group if zero of three or one of four patients had dose-limiting toxicity during the first cycle., Results: The MTD of mitoxantrone was 24 mg/m2 in group 1, less than 16 mg/m2 in group 2, and 28 mg/m2 in group 3. Neutropenia was dose-limiting, and cumulative neutropenia and thrombocytopenia occurred with continued therapy. Nonhematologic toxicity consisted predominantly of nausea, vomiting, alopecia, and fatigue. Three patients (11%) had a > or = 10% decrease in the left ventricular ejection fraction (LVEF), one patient (4%) had a decrease in the LVEF below normal, and none developed clinical congestive heart failure. Of patients with stage IV breast carcinoma who had not received prior chemotherapy for advanced disease, objective responses occurred in nine of 20 (45%), and the median response duration was 5 months., Conclusion: In combination with 600 mg/m2 of cyclophosphamide and filgrastim, the MTD of mitoxantrone is 28 mg/m2, a dose that is approximately twofold to 2.8-fold higher than the conventional dose used without a hematopoietic growth factor.

Purpose: To study the toxicity and efficacy of combined granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration for mobilization of hematopoietic progenitor cells (HPCs)., Materials and Methods: Cohorts of a minimum of five patients each were treated subcutaneously as follows: G-CSF 5 micrograms/kg on days 1 to 12 and GM-CSF at .5, 1, or 5 micrograms/kg on days 7 to 12 (cohorts 1, 2, and 3); GM-CSF 5 micrograms/kg on days 1 to 12 and G-CSF 5 micrograms/kg on days 7 to 12 (cohort 4); and G-CSF and GM-CSF 5 micrograms/kg each on days 1 to 12 (cohort 5). Ten-liter aphereses were performed on days 1 (baseline, pre-CSF), 5, 7, 11, and 13. Colony assays for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) were performed on each harvest., Results: The principal toxicities were myalgias, bone pain, fever, nausea, and mild thrombocytopenia, but none was dose-limiting. Four days of treatment with either G-CSF or GM-CSF resulted in dramatic and sustained increases in the numbers of CFU-GM per kilogram collected per harvest that represented 35.6 +/- 8.9- and 33.7 +/- 13.0-fold increases over baseline, respectively. This increment was attributable both to increased numbers of mononuclear cells collected per 10-L apheresis and to increased concentrations of progenitors within each collection. The administration of G-CSF to patients already receiving GM-CSF (cohort 4) caused the HPC content to surge to nearly 80-fold the baseline (P = .024); the reverse sequence, ie, the addition of GM-CSF to G-CSF, was less effective. The CFU-GM content of the baseline aphereses correlated with the maximal mobilization achieved (r = .74, P = .001)., Conclusion: Combined G-CSF and GM-CSF administration effectively and predictably mobilizes HPCs and facilitates apheresis.

Purpose: We previously demonstrated high locoregional control rates in patients with poor-prognosis head and neck cancer using fluorouracil (5-FU), hydroxyurea (HU), and concomitant radiotherapy (FHX). In two trials reported here, we added cisplatin with and without granulocyte colony-stimulating factor (G-CSF) to 5-FU, HU, and concomitant radiotherapy., Patients and Methods: Eligible patients had failed to respond to prior local therapy (group 1); previously untreated patients with unresectable and/or metastatic disease and a projected 2-year survival rate less than 10% were also eligible (group 2). Chemoradiotherapy consisted of 1.8 to 2.0 Gy on days 1 to 5 with simultaneous infusional 5-FU at 800 mg/m2/d and HU administered every 12 hours for 11 doses at escalating doses. Cisplatin was administered at 100 mg/m2 during every other cycle. Cycles were repeated every 14 days until completion of radiotherapy. In study 2, G-CSF was added on days 6 to 13 at 5 micrograms/kg/d., Results: Acute and cumulative myelosuppression limited the feasibility of adding cisplatin to FHX without G-CSF. G-CSF allowed for escalation of HU to 1 g orally every 12 hours without dose-limiting acute toxicity during cycles 1 and 2. Dose-limiting cumulative toxicity consisted of severe or life-threatening myelosuppression and mucositis. To decrease total treatment duration and, thus, cumulative toxicity, a hyperfractionated radiation therapy schedule was investigated using the established chemotherapy doses with 1.5 Gy twice daily on days 1 to 5 (75 Gy over five treatment cycles). No increase in acute toxicities was seen; cumulative toxicities remained frequently severe or life-threatening. Thirty-eight of 45 assessable patients responded. The median survival duration was 12 months for both groups. Median time to treatment failure was 8 months for group 1 and has not been reached for group 2. At 1 year, local control rates were 74% and 91% for groups 1 and 2, respectively., Conclusion: The addition of cisplatin to 5-FU, HU, and concomitant radiotherapy is feasible using G-CSF. The high locoregional control rate and failure-free interval justify further investigation of this regimen in previously untreated patients.

Purpose: Phase II trial in metastatic urothelial carcinoma using a novel combination chemotherapy regimen consisting of vinblastine, ifosfamide, and gallium nitrate (VIG)., Patients and Methods: Twenty-seven patients were entered onto this phase II study. Dosages were vinblastine 0.11 mg/kg days 1 and 2, ifosfamide 1.2 gm/m2 days 1 through 5 (with mesna), and gallium 300 mg/m2 as a 24-hour infusion days 1 through 5, with calcitriol (1,25-dihydroxycholecalciferol) 0.5 microgram/d orally starting 3 days before each course (except the first) and continuing throughout gallium administration, plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) (filgrastim) 5 micrograms/kg/d days 7 through 16. Courses were repeated every 21 days for a maximum of six cycles., Results: The major toxicity was granulocytopenia. Fifteen patients (55.6%) had grade 3 or 4 granulocytopenia, including eight patients with granulocytopenic fevers. Eleven patients had grade 3 or 4 anemia and four had grade 3 or 4 nephrotoxicity, which was reversible. Other grade 3 to 4 toxicities included hypocalcemia (three patients), thrombocytopenia (two), encephalopathy (one), and temporary blindness (one). There was one treatment-related mortality. Toxicity was more severe in patients older than 70 years and those with prior pelvic irradiation, prior cisplatin adjuvant therapy, or prior nephrectomy. We now decrease VIG by 20% in this patient population. Eighteen patients (67%) achieved an objective response, including 11 (41%) who attained a disease-free status (five with VIG alone and six with subsequent surgery). Median duration of remission was 20 weeks, with five patients still in remission at 22+ to 56+ weeks., Conclusion: VIG combination chemotherapy is very active in patients with metastatic urothelial carcinoma. Toxicity was significant but manageable.

Purpose: The aim of this prospective randomized trial was to examine the efficacy and safety of filgrastim after high-dose chemotherapy and autologous bone marrow transplantation (ABMT)., Patients and Methods: Patients with poor-risk non-Hodgkin's lymphoma or relapsed Hodgkin's disease were treated in a randomized, open-label trial to study the use of filgrastim as an adjunct to high-dose chemotherapy and ABMT. Of 43 assessable patients, 19 were randomized to receive filgrastim by continuous subcutaneous infusion at a dose of 10 micrograms/kg/d, 10 to filgrastim 20 micrograms/kg/d, and 14 to a parallel control group that received no filgrastim after ABMT., Results: For all filgrastim-treated patients analyzed together, the median time to neutrophil recovery > or = 0.5 x 10(9)/L after the day of ABMT was significantly accelerated to 10 days compared with 18 days in control patients (P = .0001). The median number of platelet transfusions was identical in both groups. Clinical parameters, including the median number of days with fever (1 v 4, P = .0418) and neutropenic fever (5 v 13.5, P = .0001) were significantly shorter in the filgrastim than in the control group. The number of days on intravenous antibiotics and duration of hospitalization were also shorter in the treated groups; however, the differences did not reach statistical significance. For patients treated with the two different dose levels of filgrastim, the neutrophil recovery and clinical results were similar. Filgrastim-associated toxicity appeared to be minimal, with five adverse events considered at least possibly related to filgrastim: two in the higher-dose group and three in the lower-dose group. All of these were rated moderate, except one case of severe bone pain that did not preclude continued filgrastim treatment at a lower dose. Survival and relapse-free survival were similar for control and filgrastim-treated patients., Conclusion: Taken together, the results of this first randomized study support the role of filgrastim given as an adjunct to ABMT in accelerating neutrophil recovery, as well as in reducing treatment-related morbidity and overall duration of the treatment procedure.

Purpose: To determine the feasibility and safety of a rapidly cycled sequence of high-dose myelosuppressive chemotherapy courses., Patients and Methods: Seventeen patients with metastatic breast cancer were treated with two courses of cyclophosphamide (CPA; 3.0 g/m2) supported by granulocyte colony-stimulating factor (G-CSF). Following the first CPA treatment, peripheral-blood leukaphereses commenced when the leukocyte count recovered to 1.0 x 10(9)/L. After hematologic recovery from the second dose of CPA, patients were treated with carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and CPA 5.0 g/m2 administered over 3 days. The peripheral-blood progenitors (PBPs) were reinfused 3 days later, and G-CSF was recommenced., Results: All patients received the three courses. The median interval between treatments was 14 days (range, 13 to 21). Sixteen of the 34 courses of CPA resulted in admissions for fever. Following the third course, neutrophil counts recovered to 0.5 x 10(9)/L at a median of 9 days (range, 8 to 18) after PBP reinfusion and platelets recovered to 50 x 10(9)/L at a median of 12 days (range, 9 to 102). There were no treatment-related deaths. Flow-cytometric analysis was performed on the leukapheresis collections of eight patients. Seven patients with at least 2.0 x 10(6) CD34+ CD33- cells per kilogram body weight exhibited prompt hematologic recovery. One patient with 0.03 x 10(6) CD34+ CD33- cells was still cytopenic on day 21, and required reinfusion of her back-up marrow. Among seven patients with measurable or assessable disease, there were two complete responses (CRs) and four partial responses (PRs)., Conclusion: These preliminary results suggest that multiple, rapidly cycled courses of high-dose myelosuppressive chemotherapy can be administered. PBPs, harvested during the G-CSF-augmented rebound from CPA-induced cytopenia, produce rapid hematologic recovery in patients undergoing high-dose chemotherapy (HDC). Further follow-up will be necessary to assess the efficacy of this specific regimen in the treatment of metastatic breast cancer.