Prospective randomized comparison of morning versus night daily single subcutaneous administration of granulocyte-macrophage-colony stimulating factor in patients with soft tissue or bone sarcoma

BACKGROUND: Hematopoietic growth factors (HGFs) have been used to reduce the neutropenic complications of cytotoxic chemotherapy so that higher doses may be given. The authors have previously shown that endogenous serum granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) levels at night (p.m.) were significantly higher than those in the morning (a.m.). METHODS: Twenty-four patients with soft tissue or bone sarcoma who were treated with high dose ifosfamide-based chemotherapy were enrolled in this study. Patients were randomized to either a.m. or p.m. treatment. GM-CSF was administered at a dose of 5 microg/kg/day at 10 a.m. or 10 p.m., beginning 36-48 hours after the last chemotherapy dose. GM-CSF therapy was continued until the neutrophil count exceeded 1,000/mm3 for 2 consecutive days. Leukocyte, neutrophil, monocyte, and platelet counts were measured immediately before GM-CSF administration and exactly 12 hours after the first dose of GM-CSF, and every 24 hours until 3 days after the cessation of GM-CSF. RESULTS: The mean duration of Grade 3-4 neutropenia was 5.3 +/- 0.4 days for the a.m. treatment arm and 6.5 +/- 0.3 days for the p.m. treatment arm (P = 0.017). Although the duration of neutropenia in the a.m. arm was significantly shorter than in the p.m. arm, there were no differences related to the number of febrile neutropenic episodes or the duration of antibiotic administration. Also, there were no differences in the side effects observed in the a.m. and p.m. arms. CONCLUSIONS: The finding of 1.2 days' difference in the duration of Grade 3-4 neutropenia warrants further study of chronotherapy with HGFs.     

Placebo controlled phase I/II study of subcutaneous GM-CSF in patients with germ cell tumors undergoing chemotherapy.

Patients with metastatic germ cell tumors undergoing five-day chemotherapy with etoposide, vinblastin, bleomycin and cisplatinum were given recombinant GM-CSF (mammalian glycosylated, Sandoz/Schering-Plough) at increasing dose levels of 75, 150, 300 or 600 micrograms protein/day in a double blind placebo controlled study. The drug was administered SC twice a day for 5 days starting 24 hours after completion of chemotherapy. Fourteen treatment courses, 10 with GM-CSF and 4 with placebo in 11 patients were evaluable for assessment of toxicity and hematological recovery, and 2 were not evaluable due to complications of progressive germ cell tumor. One patient receiving the highest dose level developed a delayed skin reaction at the site of injection. Fever under 38.5 degrees C and a flu-like syndrome were observed in 4/5 patients receiving the higher two dose levels, but not with lower dose levels or placebo. Two patients experienced mild bone pain. The neutrophil nadir was similar in the two groups, but the duration of neutropenia was significantly shorter in the GM-CSF group. At day 21 of chemotherapy the neutrophil count was 2.57 +/- 1.37 10(9)/l with GM-CSF, and 1.01 +/- 0.56 10(9)/l with placebo (p less than 0.05). Patients receiving GM-CSF could be retreated on day 21, whereas in patients given placebo, retreatment was delayed for an average of 7 days (p less than 0.05). Thus, a 5-day treatment with GM-CSF given subcutaneously resulted in a significant shortening of neutropenia and allowed for the timely administration of the subsequent cycle of chemotherapy.     

Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia.

PURPOSE: Recombinant human thrombopoietin (rhTPO) increases platelets, and the peak response of rhTPO is delayed and is, therefore, not uniformly effective when administered after chemotherapy. The purpose of this study was to identify an effective schedule of rhTPO to best attenuate early thrombocytopenia. PATIENTS AND METHODS: Cohorts of six patients with sarcoma (66 assessable patients) were treated sequentially with doxorubicin and ifosfamide (AI), with rhTPO by a fixed dose and varying schedules being administered before and/or after chemotherapy in cycle 2 and subsequent cycles. Cycle 1 without rhTPO served as an internal control. RESULTS: AI causes cumulative thrombocytopenia. The platelet nadir in cycle 2 was higher than in cycle 1 (mean nadir +/- SEM, 119 +/- 12 x 10(3)/microL v 80 +/- 7 x 10(3)/microL, respectively; P <.001) in 24 (80%) of the 30 patients (P <.001) in whom rhTPO (1.2 microg/kg) was administered starting from 5 days before chemotherapy (pre/postdoses, three/one or one/one) compared with only four (17%) of 24 patients given rhTPO by other schedules (pre/postdoses, two/two, one/three, zero/four, or four/zero) and none of 15 historical control patients. The need for platelet transfusions in four cycles was significantly lower (13 [11%] of 114 cycles, P <.001) in patients who received rhTPO from day -5 (pre/post doses, three/one or one/one) compared with patients who received rhTPO at later time points (28 [47%] of 60 cycles). Bone marrow megakaryocytes increased markedly (four-fold) before chemotherapy with predosing rhTPO and remained elevated (two-fold) after chemotherapy, which may explain the possible mechanism for response. One patient developed subclavian vein thrombosis, and no patients developed neutralizing antibodies to rhTPO. CONCLUSION: These results demonstrate the importance of timing of rhTPO in relation to chemotherapy and indicate that, by optimizing the timing, only two doses of rhTPO (one before and one after chemotherapy) were required to significantly reduce the severity of chemotherapy-related early thrombocytopenia.     

Phase II study of iproplatin in advanced ovarian carcinoma

Iproplatin (cis-dichloro-trans dihydroxy-bis-isopropyl-amine platinum [IV]; CHIP) was administered intravenously (IV) at monthly intervals at doses of 300 mg/m2 and 240 mg/m2 to ten previously untreated and 97 previously treated patients with advanced ovarian carcinoma. The overall response rate was 78% among patients with no prior chemotherapy, 42% among patients with prior chemotherapy not including cisplatin, and 22% among patients with prior chemotherapy including cisplatin. Overall response rates to iproplatin were 6.4% and 54% in patients with/without clinical evidence of tumor resistance to cisplatin. Thrombocytopenia was the dose-limiting toxicity, median time to nadir and to recovery being 2 and 4 weeks, respectively. Patients who had received prior chemotherapy regimens for greater than 1 year showed a 10% greater reduction in platelet count (mean platelet nadir +/- SD, 57.5 +/- 49.96 X 10(3)/microL) and a higher incidence of grade 3 to 4 thrombocytopenia after the first cycle than patients who had received prior chemotherapy regimens for less than 1 year (94.7 +/- 65.99 X 10(3)/microL) Moderate to severe vomiting and diarrhea occurred in 84% and 16% of patients pretreated with chemotherapy. Neuropathy (6%) was reported only in patients with prior cisplatin treatment. Mild and reversible renal toxicity was observed in 6% of cases. Iproplatin is an active drug in ovarian cancer; the results achieved in patients previously treated with cisplatin strongly suggest that the two drugs are cross-resistant.     

Recombinant human interleukin-3 administered concomitantly with chemotherapy in patients with relapsed small cell lung cancer

Although recombinant human interleukin-3 (rhIL-3) shortens both the duration of chemotherapy-induced neutropenia and thrombocytopenia, its effect on nadir counts is limited. Concurrent administration of rhIL-3 and chemotherapy may enhance this effect. However, simultaneous administration of other hematopoietic growth factors and chemotherapy has resulted in enhanced myelosuppression. We investigated whether concomitant administration of rhIL-3 and chemotherapy would result in enhanced myelosuppression. Twelve patients with relapsed small cell lung cancer received vincristine, ifosfamide, mesna, and carboplatin on day 1 every four weeks. RhIL-3 was administered subcutaneously on days 1-14 during cycle 1 at doses of 4 (three patients) or 8 micrograms/kg/day (nine patients). During cycle 2 patients received only chemotherapy. No significant difference in leukocyte (1.4 +/- 1.0 vs. 0.9 +/- 0.4 x 10(9)/l (mean +/- SD), neutrophil (0.5 +/- 0.6 vs. 0.2 +/- 0.2 x 10(9)/l), and platelet (64 +/- 60 vs. 38 +/- 58 x 10(9)/l) nadir counts were demonstrated. The hemoglobin nadir level was significantly higher during cycle 1 (6.5 +/- 1.1 vs. 5.5 +/- 0.9 mmol/l, P = 0.05). Both leukocyte and platelet recovery were significantly enhanced in the rhIL-3 cycle. There was no significant difference in chemotherapy postponement or platelet transfusions. As a result of severe headaches, rhIL-3 administration was discontinued in one patient at 8 micrograms. RhIL-3 during this chemotherapy regimen for relapsed small cell lung cancer did not enhance myelotoxicity but did improve bone marrow recovery. This observation may increase the application of rhIL-3, for instance in combination with other hematopoietic growth factors.     

Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level.

PURPOSE: The purpose of this study was to optimize the dose, schedule, and timing of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administration that would best abrogate myelosuppression in patients with sarcoma. PATIENTS AND METHODS: Sarcoma patients who had experienced severe myelosuppression after chemotherapy with Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dacarbazine ([CyADIC], cycle 1) were eligible. GM-CSF was administered during a 14-day period until 1 week before cycle 2 of CyADIC and was resumed 2 days after cycle 2 completion. The schedule subsequently was modified to allow the earlier administration of GM-CSF in which CyADIC was compressed from 5 days to 3 days, and GM-CSF was administered immediately after the discontinuation of CyADIC in cycle 2. To understand better the impact of GM-CSF on bone marrow stem cells, the proliferative status of bone marrow progenitors was examined during treatment. To evaluate the effects of GM-CSF on effector cells, select functions of mature myeloid cells were also examined. RESULTS: In the seven patients who were treated on the initial schedule, GM-CSF enhanced the rate of neutrophil recovery; however, severe neutropenia was not abrogated, By using the modified schedule in 17 patients, GM-CSF significantly reduced both the degree and the duration of neutropenia and myeloid (neutrophils, eosinophils, and monocytes) leukopenia. The mean neutrophil and mature myeloid nadir counts were 100/mm3 and 280/mm3 in cycle 1 and 290/mm3 and 1,540/mm3 in cycle 2 (P less than .01 and P less than .001). The duration of severe neutropenia (neutrophil count less than 500/mm3) and myeloid leukopenia (myeloid leukocyte count less than 1,000/mm3) were reduced from 6.2 and 6.8 days in cycle 1 to 2.8 and 1.4 days in cycle 2 (P less than .001). While 16 of 17 patients experienced severe myeloid leukopenia (less than 500/mm3) in cycle 1, only two of 17 experienced severe myeloid leukopenia in cycle 2 (P less than .001). Overall, severe neutropenia was abrogated in seven patients, which made them eligible for dose-escalation of Adriamycin. The fraction of cycling progenitors increased threefold on GM-CSF and decreased dramatically below the baseline within 1 day of GM-CSF discontinuation. CONCLUSIONS: The modified schedule improved the beneficial effects of GM-CSF by enhancing myeloprotection and permitting dose-intensification of chemotherapy. The increased myeloid mass and quiescent progenitors at the initiation of chemotherapy suggest that GM-CSF might allow further chemotherapy dose-rate intensification by shortening the interval between courses.     

Combination chemotherapy with granulocyte-macrophage-colony stimulating factor in patients with locoregional and metastatic gastric adenocarcinoma.

BACKGROUND: A combination of etoposide, 5-fluorouracil, and folinic acid (ELF) remains popular for the treatment of patients with gastric carcinoma and has been reported to result in a response rate of up to 40% with good patient tolerance. The authors elected to add granulocyte-macrophage-colony stimulating factor (GM-CSF) to ELF to determine whether the response rate could be increased in patients with untreated advanced gastric carcinoma. METHODS: Previously untreated patients with measurable metastatic tumor were studied. Outpatient therapy was comprised of etoposide, 120 mg/m2 intravenously (i.v.), on Days 1-3; 5-fluorouracil, 500 mg/m2 i.v., on Days 1-3; and folinic acid, 300 mg/m2 i.v., on Days 1-3. Courses were repeated every 21 days. GM-CSF (at a dose of 250 microg/m2/day for 14 days from Day 4) was added after the first course of ELF if patients developed Grade 4 neutropenia in a previous course. RESULTS: Thirty patients were enrolled and 29 were evaluable for response. Four patients (14%) achieved a partial response (median duration of response, 6.5 months). The median duration of survival was 7.8 months. Grade 4 neutropenia occurred in 16 patients who then received GM-CSF. A similar rate of neutropenic fever was observed in courses both with or without GM-CSF (15% in courses without GM-CSF and 16% in courses with GM-CSF); however, a higher nadir absolute granulocyte count (1300 cells/microL) occurred in courses with GM-CSF compared with courses without GM-CSF (300 cells/microL). CONCLUSIONS: The ELF regimen resulted in a much lower response rate than reported in the literature. The attempt to improve the efficacy of this regimen by the addition of GM-CSF did not prove successful. The authors believe this regimen cannot be recommended for the treatment of patients with advanced gastric carcinoma outside of a protocol setting.     

Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors.

PURPOSE: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration. PATIENTS AND METHODS: On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m(2) without filgrastim and at 60, 70, and 80 mg/m(2) with filgrastim on day 1, and topotecan was administered at 0.75 mg/m(2) as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CL(DOC)) and topotecan (CL(TPT)) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CL(DOC) and CL(TPT) were calculated using compartmental methods. RESULTS: Mean +/- SD CL(DOC) in cycles 1 and 2 were 75.9 +/- 79.6 L/h/m(2) and 29.2 +/- 17.3 L/h/m(2), respectively (P: <.046). Mean +/- SD CL(TPT) in cycles 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectively (P: >. 05). Mean +/- SD neutrophil nadir in cycles 1 and 2 were 4,857 +/- 6, 738/microL and 2,808 +/- 4,518/microL, respectively (P: =.02). CONCLUSION: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.     

A double-blind placebo-controlled study with granulocyte-macrophage colony-stimulating factor during chemotherapy for ovarian carcinoma

In a placebo-controlled double-blind dose-finding trial, 15 patients with ovarian cancer stage III or IV received daily s.c. 1.5, 3, or 6 micrograms/kg recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). At each dose step three patients received recombinant human GM-CSF, and two received placebo. Chemotherapy comprised 6 cycles of carboplatin, 300 mg/m2, and cyclophosphamide, 750 mg/m2, by i.v. bolus on day 1 every 4 weeks. GM-CSF, given on days 6-12 on an outpatient basis, raised the mean leukocyte count on days 7, 10, and 15 and the mean neutrophil count on days 7 and 10 at all dose levels as compared with the control group. Neutrophil counts of less than 0.5 x 10(9)/liter occurred in 20 of 22 cycles in the control group and in 5 of 17 cycles at the 6-micrograms/kg/day GM-CSF dose level (P less than 0.0005). In comparison with the control group, the mean eosinophil count was higher on days 10 and 15 at all GM-CSF doses, as was the mean monocyte count on day 15. The mean platelet count was raised at the 3- and 6-micrograms GM-CSF doses on days 15 and 22. Chemotherapy dose reduction or postponement due to myelotoxicity occurred in 9 of 28 cycles in the placebo groups versus 5 of 44 cycles in the GM-CSF group (not significant). Local skin infiltrates at the GM-CSF injection sites occurred in 8/9 patients, leading to premature removal of two patients from the study. Capillary leakage of 131I-albumin was increased in all patients 5 days after the first chemotherapy course but was not significantly affected by 4 days of GM-CSF treatment. Tumor necrosis factor alpha and C-reactive protein serum levels increased during GM-CSF administration at the 6-micrograms dose level, but interleukin 6 serum levels were not affected. We conclude that a dose of 3 and 6 micrograms/kg/day GM-CSF reduces the severity of neutropenia and thrombocytopenia after carboplatin-cyclophosphamide. This GM-CSF dose does not induce additional capillary leakage.     

Pharmacodynamic model of topotecan-induced time course of neutropenia.

Pharmacodynamic measures of neutropenia, such as absolute neutrophil count at nadir and neutrophil survival fraction, may not reflect the overall time course of neutropenia. We developed a pharmacokinetic-pharmacodynamic model to describe and quantify the time course of neutropenia after administration of topotecan to children and to compare this with nonhuman primates (NHPs) as a potential preclinical model of neutropenia. Topotecan was administered as a 30-min infusion daily for 5 days, repeated every 21 days. As part of a Phase I Pediatric Oncology Group study, topotecan was administered at 1.4 and 1.7 mg/m(2)/day without filgrastim (POG), and at 1.7, 2, and 2.4 mg/m(2)/day with filgrastim (POG+G). In NHPs, topotecan was administered at 5, 10, and 20 mg/m(2)/day without filgrastim. A pharmacokinetic-pharmacodynamic model was fit to profiles of topotecan lactone plasma concentrations and neutrophil survival fraction from cycle 1 and used to calculate topotecan lactone area under the plasma concentration-versus-time curve from 0 to 120 h (AUC(LAC)) and the area between the baseline and treatment-related neutrophil survival fraction (ABC) from 0 to 700 h. The mean +/- SD neutrophil survival fraction at nadir for the POG, POG+G, and NHP groups was 0.12 +/- 0.09, 0.11 +/- 0.17, and 0.09 +/- 0.08, respectively (P > 0.05). The mean +/- SD for the ratio of ABC to AUC(LAC) for the POG and NHP groups was 1.02 +/- 0.38 and 0.16 +/- 0.09, respectively (P < 0.05). The model estimate of ABC and the ratio of ABC to AUC(LAC) in children and NHPs may better reflect sensitivity to chemotherapy-induced neutropenia.     

Early monocytopenia after chemotherapy as a risk factor for neutropenia

Neutropenia is a major adverse effect of cancer chemotherapy and sometimes causes life-threatening events. The present study was therefore conducted to identify risk factors for such neutropenia. Forty patients who had received chemotherapy at 3- or 4-week intervals for advanced lung cancer from May 1991 through February 1997 were analyzed retrospectively. Thirty-seven of the patients had received cisplatin-based chemotherapy. The mean neutrophil count on days 6 to 8 in 32 patients who developed grade 3 or 4 neutropenia during chemotherapy was not significantly different from that in eight patients who developed grade 1 or 2 neutropenia during chemotherapy. However, the mean leukocyte and monocyte counts on days 6 to 8 in the 32 patients with grade 3 or 4 neutropenia (5,181 +/- 1,830/microl and 87 +/- 84/microl, respectively) were significantly lower than those in the eight patients with grade 1 or 2 neutropenia (7175 +/- 1671/microl and 248 +/- 127/microl, respectively; p = 0.008 and p = 0.0001). Moreover, all 30 patients with a monocyte count of less than 150/microl on days 6 to 8 had grade 3 or 4 neutropenia and 8 of 10 patients with a monocyte count of 150/microl or higher on days 6 to 8 had grade 1 or 2 neutropenia, despite the absence of a correlation between the leukocyte count on days 6 to 8 and the neutrophil nadir. We conclude that a monocyte count of less than 150/microl on days 6 to 8 may be a predictor of grade 3 or 4 neutropenia during cancer chemotherapy at 3- or 4-week intervals (sensitivity 94%, specificity 100%).     

Granulocyte colony-stimulating factor in induction treatment of children with non-Hodgkin's lymphoma: a randomized study of the French Society of Pediatric Oncology.

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF; lenograstim) decreases the incidence of febrile neutropenia after induction courses in treatment of childhood non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients were randomized to receive (G-CSF+) or not receive (G-CSF-) prophylactic G-CSF, 5 microg/kg/d, from day 7 until an absolute neutrophil count > or = 500/microL was sustained over 48 hours, after two consecutive induction courses of cyclophosphamide 1.5 or 3 g/m(2), vincristine 2 mg/m(2), prednisone 60 mg/m(2)/d x 5, doxorubicin 60 mg/m(2), high-dose methotrexate 3 or 8 g/m(2), and intrathecal injections (COPAD[M]) on protocols LMB89, LMT89, and HM91 of the French Society of Pediatric Oncology. RESULTS: One hundred forty-eight patients were assessable, 75 G-CSF+ and 73 G-CSF-. Although duration of neutropenia less than 500/microL was 3 days shorter in G-CSF+ patients (P = 10(-4)), incidence of febrile neutropenia (89% v. 93% in the first course, 88% v. 88% in the second course), durations of hospitalization and antimicrobial therapy, percentages of infections, mucositis, and transfusions were not significantly different. Although the percentage of G-CSF+ patients commencing the following course on day 21 was significantly higher (84% v 68% after the first and 57% v. 38% after the second course; P <.05), the median delay between the two courses was only 1 day less in G-CSF+ patients (median delay after first COPAD(M), 19 v. 20 days, P =.01; after second, 21 v. 22 days, P = not significant). Remission and survival rates were similar in both arms. CONCLUSION: This study demonstrates that G-CSF did not decrease treatment-related morbidity, nor increase the dose-intensity in children undergoing COPAD(M) induction chemotherapy for NHL.     

Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: a randomized trial in very high-risk childhood acute lymphoblastic leukemia.

PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS: CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.     

Hematopoietic protection by dexamethasone or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients treated with carboplatin and ifosfamide

Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients (n = 28) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide. No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents.     

Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells.

PURPOSE: The purpose of this study was to compare the effects of filgrastim, sargramostim, or sequential sargramostim and filgrastim on CD34(+) cell yields and morbidity after myelosuppressive mobilization chemotherapy (MC). PATIENTS AND METHODS: One hundred fifty-six patients were randomized to receive filgrastim (n = 51), sargramostim (n = 52), or sargramostim for 5 days followed by filgrastim (n = 53) after MC with either cyclophosphamide and etoposide (n = 75) or paclitaxel and cyclophosphamide (n = 81). RESULTS: Compared with those who received sargramostim, patients who received filgrastim had faster recovery of an absolute neutrophil count of 0.5 x 10(9)/L or greater (a median of 11 v 14 days; P =. 0001), with fewer patients requiring RBC transfusions (P =.008), fewer patients with fever (18% v 52%; P = 0.001), fewer hospital admissions (20% v 42%; P =.013), and less intravenous antibiotic therapy (24% v 69%; P =.001). Patients who received filgrastim yielded more CD34(+) cells (median, 7.1 v 2.0 x 10(6)/kg/apheresis; P =.0001), and a higher fraction achieved 2.5 x 10(6) (94% v 78%; P =.021) and 5 x 10(6) (88% v 53%; P =.001) or more CD34(+) cells/kg with fewer aphereses (median, 2 v 3; P =.002) and fewer days of growth-factor treatment (median, 12 v 14; P =.0001). There were no major differences in outcomes between the filgrastim alone and the sequential regimens. After high-dose chemotherapy, patients who had peripheral-blood stem cells (PBSCs) mobilized with filgrastim or the sequential regimen received higher numbers of CD34(+) cells and had faster platelet recovery (P =.015), with fewer patients (P =.014) receiving fewer platelet transfusions (P =.001) than patients receiving sargramostim-mobilized PBSCs. CONCLUSION: It was concluded that filgrastim alone or sequential sargramostim and filgrastim were superior to sargramostim alone for the mobilization of CD34(+) cells and reduction of toxicities after MC.     

Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: a novel and effective method for delivering multiple courses of dose-intensive therapy.

PURPOSE: The trial was undertaken to study the effect of administering granulocyte-macrophage colony-stimulating factor (GM-CSF) with and without peripheral-blood progenitor cells (PBPC) on the hematologic and nonhematologic toxicity observed with multiple cycles of high-dose carboplatin chemotherapy. PATIENTS AND METHODS: Eighteen patients with a variety of solid tumors received a total of 40 cycles of carboplatin, 1,200 mg/m2 per cycle, administered by continuous infusion over 96 hours. All 40 courses were administered with a daily 4-hour intravenous (IV) infusion of either 5 or 10 micrograms/kg/d of recombinant human Escherichia coli-derived GM-CSF. The first 20 courses were administered without PBPC support (treatment A). Because of severe neutropenia and thrombocytopenia, the next 20 courses of therapy were administered with GM-CSF, PBPC, and oral antibiotic prophylaxis (treatment B). RESULTS: The addition of PBPC support led to a significant reduction in the duration of neutropenia (10.5 v 7.5 days; P = .027) and thrombocytopenia (12.4 v 5.2 days; P = .001), number of RBC transfusions (six v three; P = .01) and platelet transfusions (10.3 v 3.7; P = .013), number of hospital days (12.6 v 2.9; P = .01), and days of IV antibiotics (11.8 v 2.4; P = .007) per cycle. Significant increases in the weekly dose intensity (206 v 285 mg/m2/wk; P = .014) and total dose (2,287 v 3,600 mg/m2; P = .018) of carboplatin delivered were also observed with treatment B. The overall response rate in this study was 70%, with 11 of 16 assessable patients achieving either a complete (three patients) or partial (eight patients) remission. CONCLUSION: This combination of GM-CSF and PBPC infusion represents an effective method for delivering multiple cycles of high-dose carboplatin chemotherapy and may serve as a model for the administration of high-dose chemotherapy in future trials.     

Phase II study of combination therapy with paclitaxel and carboplatin against postoperative small residual disease in patients with stage I c-IV ovarian cancer--KCOG 989 trial

The tolerability and feasibility of combination therapy with paclitaxel (TXL) and carboplatin (CBDCA) against small residual disease following first-line optimal debulking of stage I c-IV ovarian cancer were evaluated in a multicenter dose-finding study. Eligibility criteria included histologically diagnosed stage I c-IV epithelial ovarian cancer with a postoperative residual lesion < or = 10 mm in diameter, no prior chemotherapy, and written informed consent of the patient and his/her family members to the chemotherapy. Twenty-two patients were enrolled and 20 of them were eligible. The patients were to receive 5 courses of TXL (175 mg/m2) and CBDCA (AUC 5) every 3 weeks. Hematological toxicities occurred in the form of grade 3 leukopenia during 25.7% of all courses, grade 3 neutropenia during 32.0% of all courses, and grade 4 neutropenia during 56.0% of all courses. No courses were associated with grade 4 leukopenia. G-CSF support was needed during 48 of 109 courses (44%) and caused normalization of the leukocyte count from a nadir of 1,921 +/- 434/mm3 after a mean time of 6 +/- 3.1 days, compared with 6 +/- 3.6 days needed for recovery from a nadir of 2, 357 +/- 360/mm3 without G-CSF support. This indicates similarly rapid recovery from severe leukopenia with the use of G-CSF. All eligible patients completed at least 5 courses of the chemotherapy. Some courses were given at a reduced dose or delayed due to toxicity but these dosage modifications were thought to be acceptable for both TXL and CBDCA. Five courses of TXL combined with CBDCA were tolerated well in this patient population.     

Single agent vincristine by infusion in refractory multiple myeloma

A phase 2 trial of vincristine infusion was conducted in a group of 21 patients with refractory multiple myeloma. Patients were generally heavily pretreated with radiotherapy and chemotherapy. Vincristine was given intravenously (IV) as a 0.5 mg bolus and followed immediately by infusion of 0.25 to 0.50 mg/m2/d for 5 days. Courses were repeated every 3 weeks in the absence of disease progression or prohibitive toxicity. Objective responses (partial) were noted in two patients (10%), both of whom were administered 0.5 mg/m2/d infusions. Response durations were brief (2.2 and 1.2 months). Toxicity consisted of neurotoxicity and myelosuppression. In addition to the occurrence of paresthesias and myalgias, ileus (two cases) and moderately severe loss of motor function (two cases) were observed. The mean lowest WBC count following treatment was 2.67 X 10(3)/microL v 3.96 X 10(3)/microL pretreatment (P = .008). The mean lowest platelet count was 75.0 X 10(3)/microL v 106.8 X 10(3)/microL pretreatment (P = .008). Vincristine infusion appears to have limited activity in the treatment of refractory multiple myeloma. Additionally, response durations were short lived and toxicity, both neurologic and hematologic, was appreciable.     

Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma.

PURPOSE: Interactions between the chemokine receptor CXCR4 and its ligand stromal derived factor-1 regulate hematopoietic stem-cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We performed a phase I study assessing the safety and clinical effects of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirteen patients (MM, n=7; NHL, n=6) received AMD3100 at a dose of either 160 microg/kg (n=6) or 240 microg/kg (n=7). WBC and peripheral blood (PB) CD34+ cell counts were analyzed at 4 and 6 hours following injection. RESULTS: AMD3100 caused a rapid and statistically significant increase in the total WBC and PB CD34+ counts at both 4 and 6 hours following a single injection. The absolute CD34+ cell count increased from a baseline of 2.6 +/- 0.7/microL (mean +/- SE) to 15.6 +/- 3.9/microL and 16.2 +/- 4.3/microL at 4 hours (P=.002) and 6 hours after injection (P =.003), respectively. The absolute CD34+ cell counts observed at 4 and 6 hours following AMD3100 were higher in the 240 microg/kg group (19.3 +/- 6.9/microL and 20.4 +/- 7.6/microL, respectively) compared with the 160 microg/kg group (11.3 +/- 2.7/microL and 11.3 +/- 2.5/microL, respectively). The drug was well tolerated and only grade 1 toxicities were encountered. CONCLUSION: AMD3100 appears to be a safe and effective agent for the rapid mobilization of CD34+ cells in patients who have received prior chemotherapy. Further studies in combination with granulocyte colony-stimulating factor in patients with lymphoid malignancies are warranted.     

The intramuscular administration of granulocyte colony-stimulating factor as an adjunct to chemotherapy in pretreated ovarian cancer patients: an Italian Trials in Medical Oncology (ITMO) Group pilot study.

No published data are available concerning the activity and tolerability of intramuscularly administered granulocyte colony-stimulating factor (G-CSF) in humans. To fill this gap, 19 patients with advanced ovarian cancer previously treated with at least one first-line chemotherapy cycle received the following myelosuppressive regimen: mitoxantrone (DHAD) 12 mg m-2 i.v. on day 1; ifosfamide (IFO) 4 g m-2 i.v. on days 1 and 2; mesna 800 mg m-2 i.v. t.i.d. on days 1 and 2. G-CSF (Filgrastim) was given at a dose of 5 micrograms/kg/day i.m. from day 6 to day 19, its pharmacokinetics being assessed in five patients. The neutrophil nadir was observed after a mean period of 8 days, and the neutrophil count was < 1.0 x 10(3) mm-3 for a mean of 6 days during the cycle of chemotherapy. The neutrophil count fell after the withdrawal of G-CSF on the 19th day of treatment. The difference in absolute neutrophil count between day 19 and day 21 was statistically significant (P = 0.0001); nevertheless, at day 21 no WHO grade 3-4 neutropenia was reported. DHAD and IFO were respectively given at 95% and 93% of the planned dose. The pharmacokinetics of G-CSF i.m. seems to be similar to that of the drug given subcutaneously. No evidence of cumulative myelosuppression was observed. G-CSF was well tolerated and no complications were observed at the injection sites. In conclusion, if the results obtained in this pilot study regarding the activity of i.m. G-CSF are confirmed by a randomised trial, the intramuscular administration of G-CSF could become a valid alternative for patients who dislike the subcutaneous route and who are being treated with chemotherapy that does not induce profound thrombocytopenia.