Effect of recombinant human granulocyte colony stimulating factor (rhG-CSF) in patients receiving chemotherapy--phase I study

Seventeen patients with advanced malignancy were treated with recombinant human granulocyte colony stimulating factor rhG-CSF (KRN 8601) infused intravenously over a period of 30 minutes once daily at the dose level/25 micrograms, 50 micrograms, 100 micrograms, 200 micrograms, 400 micrograms, 800 micrograms/m2 for 14 consecutive days, and the effect was compared to the period without rhG-CSF treatment. The maximum numbers of peripheral leukocyte (granulocyte) showed a dose-related increase and the nadir of leukocyte counts escalated with shortening of the period. After stopping infusion, the neutrophil count dropped to the base line level within two or three days. RhG-CSF did not affect other components of peripheral blood such as monocyte, lymphocyte, eosinophil, and hemoglobin value and platelet counts. Transient bone pain occurred in two patients receiving a dose of 800 micrograms/m2. The biochemical changes detected were increased total alkaline phosphatase activity in serum, which appeared in parallel with the increase of neutrophil numbers, and less elevation of total uric acid values. We conclude that an optimal dose of rhG-CSF is 100 micrograms/m2 (average maximum peripheral granulocyte count, 10799/microliters; nadir granulocyte count, 3772/microliters; period of neutropenia, 2.6 days), and rhG-CSF is useful for acceleration of neutrophil recovery and prevention of infection from chemotherapy.     

Randomized phase II study of biweekly CHOP and dose-escalated CHOP with prophylactic use of lenograstim (glycosylated G-CSF) in aggressive non-Hodgkin's lymphoma: Japan Clinical Oncology Group Study 9505.

BACKGROUND: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is accepted as the best available standard treatment for first-line chemotherapy in aggressive non-Hodgkin's lymphoma (NHL). However, the therapeutic efficacy of CHOP remains unsatisfactory, particularly in high-intermediate risk and high risk patients, and a new strategy is warranted in this patient population. The aim of the present study was to explore a suitable therapeutic-intensified regimen for the treatment of aggressive NHL. PATIENTS AND METHODS: Between May 1995 and July 1998, a total of 70 patients with high-intermediate risk or high risk aggressive NHL, according to the International Prognostic Index, were enrolled and randomly assigned to receive either eight cycles of standard CHOP (cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.4 mg/m(2) and prednisolone 100 mg for 5 days) every 2 weeks, or six cycles of dose-escalated CHOP (cyclophosphamide 1500 mg/m(2), doxorubicin 70 mg/m(2), vincristine 1.4 mg/m(2) and prednisolone 100 mg for 5 days) every 3 weeks. Lenograstim (glycosylated rHuG-CSF), at a dose of 2 micro g/kg/day s.c., was administered daily from day 3 until day 13 with biweekly CHOP and until day 20 with the dose-escalated CHOP. The primary endpoint was complete response rate. RESULTS: The complete response rate was 60% [21 of 35; 95% confidence interval (CI) 42% to 76%] with biweekly CHOP and 51% (18 of 35; 95% CI 34% to 69%) with dose-escalated CHOP. The major toxicity was grade 4 neutropenia and was more frequent in the dose-escalated CHOP arm (86%) than in the biweekly CHOP arm (50%). Grade 4 thrombocytopenia was also more frequent in the dose-escalated CHOP arm (20%) than the biweekly CHOP arm (3%). Non-hematological toxicities were acceptable in both arms. One treatment-related death (due to cardiac arrhythmia) was observed in a dose-escalated CHOP patient. Progression-free survival at 3 years was 43% (95% CI 27% to 59%) in the biweekly CHOP arm and 31% (95% CI 16% to 47%) in the dose-escalated CHOP arm. Although seven patients were deemed ineligible by central review of the pathological diagnosis, the results for both eligible and all enrolled patients were similar. CONCLUSIONS: Similar complete response rates and progression-free survival rates, but lower toxicity, indicated that biweekly CHOP was superior to dose-escalated CHOP in the treatment of aggressive NHL. Based on these results, the Lymphoma Study Group of the Japan Clinical Oncology Group is conducting a randomized phase III study comparing biweekly CHOP with standard CHOP in newly diagnosed patients with advanced-stage aggressive NHL.     

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors

Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL).Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages.Results: The MTD in stage I was epirubicin 150 mg/m² and cyclophosphamide 1500 mg/m² with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m², cyclophosphamide 1500 mg/m², vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir <0.5 × 10⁹/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (<25 × 10⁹/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity.Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.     

Recombinant human granulocyte colony-stimulating factor (filgrastim) following high-dose chemotherapy and peripheral blood progenitor cell rescue in high-grade non-Hodgkin's lymphoma: clinical benefits at no extra cost.

In order to evaluate the potential clinical and economic benefits of granulocyte colony-stimulating factor (G-CSF, filgrastim) following peripheral blood progenitor cells (PBPC) rescue after high-dose chemotherapy (HDCT), 23 consecutive patients aged less than 60 years with poor-prognosis, high-grade non-Hodgkin''s lymphoma (NHL) were entered into a prospective randomized trial between May 1993 and September 1995. Patients were randomized to receive either PBPC alone (n = 12) or PBPC+G-CSF (n = 11) after HDCT with busulphan and cyclophosphamide. G-CSF (300 microg day[-1]) was given from day +5 until recovery of granulocyte count to greater than 1.0 x 10(9) l(-1) for 2 consecutive days. The mean time to achieve a granulocyte count > 0.5 x 10(9) l(-1) was significantly shorter in the G-CSF arm (9.7 vs 13.2 days; P<0.0001) as was the median duration of hospital stay (12 vs 15 days; P = 0.001). In addition the recovery periods (range 9-12 vs 11-17 days to achieve a count of 1.0 x 10(9) l[-1]) and hospital stays (range 11-14 vs 13-22 days) were significantly less variable in patients receiving G-CSF in whom the values clustered around the median. There were no statistically significant differences between the study arms in terms of days of fever, documented episodes of bacteraemia, antimicrobial drug usage and platelet/red cell transfusion requirements. Taking into account the costs of total occupied-bed days, drugs, growth factor usage and haematological support, the mean expenditure per inpatient stay was pound sterling 6500 (range pound sterling 5465-pound sterling 8101) in the G-CSF group compared with pound sterling 8316 (range pound sterling 5953-pound sterling 15,801) in the group not receiving G-CSF, with an observed mean saving of 1816 per patient (or 22% of the total cost) in the G-CSF group. This study suggests that after HDCT and PBPC rescue, the use of G-CSF leads to more rapid haematological recovery periods and is associated with a more predictable and shorter hospital stay. Furthermore, and despite the additional costs for G-CSF, these clinical benefits are not translated into increased health care expenditure.     

Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions--a phase I dose-toxicity study

Twenty patients with progressive metastatic solid tumours were entered into a study to evaluate the biological effects and toxicity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was given as half-hour intravenous infusions during two 10-day phases of daily treatments (separated by 10 days without GM-CSF) and over a final phase of 20 days of alternate day infusions. Doses were escalated in steps from 0.3 to 60 micrograms kg-1 day-1 between successive patient groups. Significant increases (P less than 0.005) of total leucocyte, neutrophil and eosinophil polymorph counts were seen over the periods of daily infusions (up to four-fold rises of total white count) at dose levels of 10 micrograms kg-1 and above. Counts produced at 30 micrograms kg-1 were significantly higher than at 10 micrograms kg-1 (P less than 0.025). Toxic side effects of GM-CSF included mild transient pyrexias, bone pain and pruritus. The maximum tolerated dose was 60 micrograms kg-1, which produced severe toxicity in 80% of patients. The toxicity at this dose included pericarditis and dyspnoea ascribed to a 'capillary-leak' syndrome. One patient receiving 60 micrograms kg-1 died as a result of a pulmonary embolus. Seven patients with previously rapidly progressive metastatic tumours experienced stabilisation of disease while receiving GM-CSF and one patient with a previously heavily pretreated metastatic soft tissue sarcoma underwent a greater than 50% reduction of tumour volume. Patients undergoing chemotherapy may benefit both from a reduction of the myelosuppressive effects of cytotoxic agents and from an antitumour effect if GM-CSF is incorporated into future regimens.     

Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma

The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.     

The safety of full-dose chemotherapy with secondary prophylactic granulocyte colony stimulating factor (G-CSF) following a prior cycle with febrile neutropenia

Secondary prophylactic administration of recombinant human granulocyte colony stimulating factor (G-CSF) following an episode of febrile neutropenia is recommended if maintenance of dose-intensity is desired. This policy was adopted in our center in patients treated with an intent for cure or durable complete response. The purpose of this study was to evaluate the safety and feasibility of this policy. Patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. Fifty-one patients who developed febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with the support of filgrastim (300 or 480 mg/d sc for at least 10 consecutive days). Diagnoses included lymphoma (n=19), breast cancer (n=15), germ cell tumor (n=7), small-cell lung cancer (n=5), and other solid tumors (n=5). The incidence of febrile neutropenia during the first cycle given with filgrastim support (N1) was 8/51 (16%). Intravenous antibiotics were required for 3–7 d (median, 4.5 d). During the following cycle (N2), febrile neutropenia developed in 4/41 (10%) patients. Intravenous antibiotics were given for 2, 4, 5, and 7 d. Other dose-limiting toxicities developed in 1/51 patients who received N1 and in 1/41 patients who received N2. There was no drug-related death associated with either cycle. In conclusion, a policy of full-dose chemotherapy with secondary G-CSF support in patients who develop febrile neutropenia following moderately myelotoxic chemotherapy is relatively safe and feasible.     

Routine prophylactic granulocyte colony stimulating factor (GCSF) is not necessary with accelerated (dose dense) paclitaxel for early breast cancer

Background Prophylactic granulocyte colony stimulating factor (GCSF) is recommended with accelerated adjuvant chemotherapy but is expensive and causes bone pain. We have reviewed a series of patients with early breast cancer treated with accelerated 2-weekly paclitaxel without routine GCSF to assess its need. Patients and methods Patients receiving accelerated (dose dense) paclitaxel 175 mg/m² 2 weekly for 4 courses as adjuvant/neoadjuvant treatment for early breast cancer were treated electively without prophylactic GCSF, and monitored for absolute neutrophil count (ANC) before each cycle, grade and duration of neutropenia, incidence of neutropenic sepsis, treatment delays and requirements for secondary GCSF. Results were compared with prior patients given prophylactic GCSF. Results Of the 61 patients, 42 (69%) did not require prophylactic GCSF. Mild/moderate neutropenia was more common than in the prior group given GCSF, but secondary GCSF was required in only 6 (10%) patients due to grade 3 neutropenia and in 12 (20%) with grade 2 neutropenia. There were no episodes of neutropenic sepsis and no dose reduction or treatment delay was required. Conclusions Accelerated paclitaxel in breast cancer patients without prophylactic GCSF is safe, avoids side effects, reduces costs and is not associated with an increase risk of neutropenic sepsis or treatment delays.     

基因重组人粒细胞/巨噬细胞集落刺激因子防治肿瘤化疗所致的白细胞减少

目的研究基因重组人粒细胞／巨噬细胞集落刺激因子（ｒｈＧＭ－ＣＳＦ，生白能）防治实体瘤化疗所致白细胞（ＷＢＣ）和中性粒细胞（ＡＮＣ）减少的临床效果及不良反应。方法采用多中心随机分组、自身交叉对照方法，对５７例肿瘤化疗患者随机分成ＡＢ组和ＢＡ组。ＡＢ组第１周期化疗加生白能治疗（治疗组），第２周期单用化疗（对照组）；ＢＡ组第１周期单用化疗，第２周期化疗加生白能治疗。有５５例可做临床疗效分析。结果生白能可明显减轻化疗所致ＷＢＣ和ＡＮＣ下降程度，缩短ＷＢＣ和ＡＮＣ降至正常值以下的持续时间，促进ＷＢＣ和ＡＮＣ早日恢复，有助于化疗按期进行。主要不良反应有轻、中度发热，注射部位疼痛，骨骼肌肉疼痛，乏力和皮疹，一般可以耐受。结论生白能是一种有价值的化疗辅助药物。     

Glycosylated and non-glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF)—what is the difference?

Two forms of recombinant human G-CSF (rhG-CSF) are available for clinical use: filgrastim is expressed inE coli and non-glycosylated, whereas lenograstim is derived from Chinese hamster ovary (CHO) cells and glycosylated. The function of the sugar chain, accounting for approximately 4% of the molecular weight of lenograstim (and native G-CSF), is not known. Glycosylation of the G-CSF molecule does not prolong its circulation half life. Lenograstim is more active than filgrastim (and research-use deglycosylated G-CSF) on a weight-by-weight basis inin vitro colony-forming and cell line assays. An international potency standard assigns a specific activity of 100 000 IU/μg to filgrastim and 127 760 IU/μg to lenograstim. Correspondingly, two randomised crossover studies in normal subjects, comparingmass equivalent doses of the two rhG-CSFs, have demonstrated a 25–30% higher concentration of blood stem cells (CD34⁺, CFU-GM) during lenograstim administration. No difference in side effects was observed. Results from a prospective, randomised, non-crossover trial in breast cancer patients suggest thatbioequivalent doses of filgrastim and lenograstim have a similar effect on mobilisation of CD34⁺ cells and immature CD34⁺ cell subsets, respectively. Although comparisons outside the setting of stem cell mobilisation are lacking, the clinical relevance of the greater specific activity of lenograstim may thus be limited. The difference in potency between μg identical doses of the two rhG-CSFs makes dosing in biological units (IU) rather than mass units (μg) more appropriate.     

Alternating chemotherapy regimen (P-VABEC) for intermediate and high-grade non-Hodgkin's lymphoma of the middle aged and elderly

An intensive third generation regimen (P-VABEC) including adriamycin, etoposide, cyclophosphamide, vincristine, bleomycin and prednisolone was administered to 43 unselected elderly patients with intermediate or high-grade non-Hodgkin's lymphomas (NHL). The median age was 67, 40 per cent were Ann Arbor stage IV, 73 per cent had‘B’ symptoms, 55 per cent had bulky disease, 48 per cent had serum lactate dehydrogenase greater than 450 U/1, 85 per cent had serum thymidine-kinase greater than 4 U/1. Thirty patients were previously untreated. The complete remission (CR) rate was 74 per cent, and the partial remission (PR) rate 23 per cent, with an overall response rate of 97 per cent. The regimen was carried out on an outpatient basis in all patients. No death occurred during therapy. The Kaplan-Meier actuarial survival of all patients at 3-years is 47 per cent, and 50 per cent (16/32) of all patients who attained CR remain alive and in remission at a median of 21+ months (range 6+ to 42+). These results confirm that high remission and failure-free survival rates can be achieved also in elderly unselected patients with aggressive NHL treated with curative intent.     

Superiority of second over first generation chemotherapy in a randomized trial for stage III-IV intermediate and high-grade non-Hodgkin's lymphoma (NHL): the 1980-1985 EORTC trial. The EORTC Lymphoma Group.

A first-generation CHOP-like cyclic combination chemotherapy (CT) regimen using cyclophosphamide 600 mg/m2 IV d1, hydroxorubicin (doxorubicin) 50 mg/m2 IV d1, VM26 60 mg/m2 IV d1, and prednisone 40 mg/m2 PO d1-5 (CHVmP) was compared to a second-generation combination wherein vincristine 1.4 mg/m2 IV and bleomycin 6 mg/m2 IM/IV were added at mid-interval (d15) to the former drugs (CHVmP + VB) in the treatment of intermediate- and high-grade malignant NHL. From April 1980 to January 1986, 141 eligible patients with stage III-IV unfavorable histologies (except T lymphoblastic NHL) entered this EORTC randomized trial. In both arms adjuvant radiotherapy (30 Gy) was given in instances of bulky or residual disease. In all patient subsets the outcome favored the second-generation regimen. The difference was even greater in patients with Diffuse Large Cell Lymphoma (DLCL). At 5 years, overall survival was 53% with CHVmP + VB versus 29% (p = 0.002). The advantage was due to a higher complete remission (CR) rate (80% versus 50%, p = 0.01). Indeed, once CR was achieved the relapse-free survival (RFS) was not significantly influenced (59% versus 49%). No significant additional toxicity could be attributed to vincristine and bleomycin. This study demonstrates a clear benefit for intermediate- and high-risk malignant NHL and particularly DLCL from intercalating non-myelotoxic drugs at mid-cycle intervals, without adverse effects.     

PEG-rhG-CSF初级预防同步放化疗后中性粒细胞减少的有效性观察

目的:评价聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)初级预防同步放化疗后中性粒细胞减少的有效性。方法:开放、单臂临床观察天津医科大学肿瘤医院2018—2019年行同步放化疗的58例患者采用PEG-rhG-CSF初级预防同步放化疗后中性粒细胞减少的有效性。结果:整个同步放化疗周期期间化疗延迟6例(10%...     

High dose cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) in the treatment of follicular, low grade non-Hodgkin's lymphoma: CALGB 9150

The main objectives of this study were to determine the feasibility of administering high doses of cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) every 14-21 days to patients with follicular small cleaved cell lymphoma. For each patient, the treatment was not considered feasible if fewer than four cycles of cyclophosphamide chemotherapy could be administered on schedule (i.e. at least every 29 days) or (1) hospitalization of the patient for longer than three days was necessary for neutropenic fever (38 degrees C) or bacteriologically documented infection in > 50% of the cycles, or (2) grade > or = 2 hemorrhage in association with thrombocytopenia of grade > or = 3 severity occurred in > 50% of the cycles or (3) non-hematologic toxicity (excluding nausea/vomiting and alopecia) of grade > or = 3 occurred in > 50% of cycles. The goal was to have a treatment program feasible in 75% or more of the treated patients. The secondary objectives were to determine the toxicities, the complete and partial response rates, and the time to treatment failure (TTF). The trial also attempted to assess the effectiveness of this treatment program in eradicating Bcl-2 rearrangements by PCR, and to assess complete remission duration in relationship to PCR results in patients who respond to this chemotherapy program. Patients were required to have histologically documented non-Hodgkin's lymphoma of the subtypes follicular, predominantly small cleaved cell (IWF-B) or follicular mixed, (IWF-C). Patients were required to have Stage IV disease including histologic evidence of bone marrow involvement. Measurable disease was required and patients were also required to have one of the following risk factors: > or = 2 extranodal sites, node or nodal group > or = 5 cm. Submission of fresh bone marrow for molecular genetic studies for the presence of Bcl-2-Ig fusion DNA was mandatory in previously untreated patients. Patients had to be between 18 and physiologic age 55 years (carefully selected patients over age 55 years were also eligible), expected survival > 2 years, performance status 0-1, and have adequate renal, hepatic and bone marrow function, and a cardiac ejection fraction > or = 50%. Cyclophosphamide 4.5 g/m2 i.v. was given with mesna every 14 days with rhG-CSF support. Twenty-nine patients were accrued to this trial. The median follow-up time is 5.0 years, with a range of 2.5-6.7 years. The overall response rate was 75% (9 CRs 37.5%, 9PRs 37.5%). The median duration of survival is 5.53 years. The 1-year estimated probability of freedom from treatment failure was 50% and of survival at 1 year was 92%. No strong association was observed between TTF and age, symptomatic stage, histology performance status, number of extranodal sites or baseline Bcl-2 status. At 3 years the survival of all patients was 78% and failure free survival was 17%. 15 (62%) of the 24 eligible previously untreated patients met the criteria for feasibility specified in the protocol. The 95% CI for the feasibility rate is (44 and 82%). Twenty-two of the 24 (92%) previously untreated patients had specimens submitted for testing for Bcl-2 rearrangements. Thirteen of the 22 (59%) were found to have rearrangements at baseline. Post-treatment specimens were submitted for seven of the 13 patients. Four of the seven converted to Bcl-2 negative following treatment. Eight of 13 Bcl-2 positive patients (62%) had a clinical response to treatment. The 95% exact binomial CI for the total response rate in this subgroup is (28 and 88%). This study demonstrates that repetitive doses of cyclophosphamide at 4.5 g/m2 every two weeks with rhG-CSF support can be administered to selected younger patients with advanced follicular lymphoma with morphologic involvement of the bone marrow with acceptable non-hematologic toxicity.     

An EORTC pilot study of filgrastim (recombinant human granulocyte colony stimulating factor) as support to a high dose-intensive epiadriamycin-cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or metastatic breast cancer

BACKGROUND: In an attempt to increase chemotherapy dose intensity by step-wisereduction of the time interval between treatment cycles, filgrastimwas administered to breast cancer patients receiving a three-monthcombination chemotherapy with epirubicin (E) and cyclophosphamide(C). PATIENTS AND METHODS: Chemotherapy-naïve patients with locally advanced or metastaticbreast cancer received fixed doses of E (120 mg/m²) and C (830mg/m²) by 15-min i.v. infusion on day 1 of each cycle and filgrastimat a dose of 4 µ/kg once daily by SC injection starting24 hours after chemotherapy. Cohorts of patients were treatedin successive schedules, each schedule corresponding to a specifiedtime interval between chemotherapy cycles. The toxicity observedin each schedule was evaluated before patients were accruedto the next schedule, which corresponded to a shorter time intervalbetween chemotherapy cycles. RESULTS: The maximum tolerated schedule was E (120 mg/m²) plus C (830mg/m²) given every 14 days with filgrastim support from day2 until day 13. On this schedule, 5 of 12 patients experienceddose-intensity-limiting toxicities (DLT) during the 3-monthstudy period. Non-hematological DLT occurred in 2/12 patients(mucositis, skin toxicity) while 3/12 experienced febrile neutropeniarequiring i.v. antibiotics. All patients achieved recovery ofANC to > 1.5 x 10⁹/l by the time of scheduled retreatment.The combination of filgrastim with this regimen did not seemto add major toxicities. The efficacy was high, with 87% ofpatients achieving an objective response and a median responseduration of 18 months (range: 4–;52 months). CONCLUSIONS: Filgrastim permits at 33% increase in ‘EC’ doseintensification over that of the conventional every-3-week administration.Randomized studies should now be initiated to evaluate the merit,if any, of ‘accelerated’ chemotherapy in advancedbreast cancer. chemotherapy dose-intensification, breast cancer, hematopoietic growth factor     

A humanized HLA-DR antibody (hu1D10, apolizumab) in combination with granulocyte colony-stimulating factor (filgrastim) for the treatment of non-Hodgkin's lymphoma: a pilot study

Apolizumab is a humanized monoclonal antibody against a polymorphic epitope on HLA DRbeta that demonstrated evidence for therapeutic activity in follicular lymphoma patients. In pre-clinical studies, we previously reported that granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced lymphoma cell killing by HLA class II antibodies, including apolizumab. These results suggested a combination trial of apolizumab and G-CSF (filgrastim). In this trial, we treated six patients with relapsed or refractory 1D10-positive non-Hodgkin's lymphoma with filgrastim and variable doses of apolizumab ranging from 0.15 to 1.5 mg/m2. The combination was clinically well tolerated, with only two patients experiencing grade III/IV hematological toxicity (thrombocytopenia and autoimmune hemolytic anemia). Another patient developed a pruritic skin rash, which was probably a treatment-related grade II skin toxicity. Interestingly, two patients with follicular lymphoma who received intensified apolizumab treatment on a three times weekly schedule experienced prolonged stabilization of their disease for 12 and more than 36 months. In conclusion, this small pilot study suggests that a combination of HLA class II antibodies and G-CSF is clinically feasible.     

A single-blind, randomised, vehicle-controlled dose-finding study of recombinant human granulocyte colony-stimulating factor (lenograstim) in patients undergoing chemotherapy for solid cancers and lymphoma

This study evaluated the effect of glycosylated recombinant human granulocyte colony-stimulating factor (rHuGCSF; lenograstim) on neutrophil granulocyte counts and on cells of other haematopoietic lineages in 66 patients with solid cancer or lymphoma who received myelosuppressive chemotherapy. Beginning 1 day after completion of chemotherapy, patients received lenograstim (at dosages of 0.5, 2, 5 or 10 μ/kg) or vehicle subcutaneously once daily for 14 consecutive days. Compared with vehicle, lenograstim significantly accelerated neutrophil recovery after chemotherapy in a dose-dependent manner. Mean neutrophil counts recovered to > 1.0 × 10⁹ cells/l by day 13 in the vehicle group compared with days 11, 10, 8 and 7 in the 0.5, 2, 5 and 10 μg/kg lenograstim groups, respectively. Doses of 0.5 and 2 μg/kg of lenograstim had a significant effect on the duration of neutropenia (< 1.0 × 10⁹ cells/l), the area under the absolute neutrophil count (ANC) curve and the time to ANC nadir. The dose of 5 μg/kg additionally decreased the total area of neutropenia and gave the narrowest range of values for all neutrophil parameters, while the 10 μg/kg dose brought no added benefit. A dose-response effect of lenograstim on time to neutrophil recovery was observed both for patients who received chemotherapy on a single day (n = 35) and for those who received chemotherapy over several days (n = 29). Based on these findings, a dose of 5 μg/kg/day was chosen for further trials.     

Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL).

INTRODUCTION: Sequential high dose (SHiDo) chemotherapy with stem cell support has been shown to prolong the event-free survival in patients with diffuse large B-cell lymphoma. METHODS: To confirm this result in a multicenter trial, we randomized patients with aggressive NHL, to receive either eight cycles of CHOP or SHiDo. The primary endpoint was overall survival. RESULTS: 129 evaluable patients were randomized to receive either CHOP or SHiDo: median age, 48 years; 62% male; stage III+IV: 73%; age adjusted International Prognostic Index 1/2/3: 21%/52%/27%. Toxicity grades 3+4 were more pronounced in the SHiDo-arm with 13% versus 3% of patients with fever; 34% versus 13% with infections; 13% versus 2% with esophagitis/dysphagia/gastric ulcer. The remission rates were similar in SHiDo and CHOP arms with 34%/37% complete remissions and 31%/31% partial remissions, respectively. After a median observation time of 48 months, there was no difference in overall survival at 3 years, with 46% for SHiDo and 53% for CHOP (P = 0.48). CONCLUSION: In this multicenter trial, early intensification with SHiDo did not confer any survival benefit in previously untreated patients with aggressive NHL and was associated with a higher incidence of grades 3/4 toxicity.     

A phase I trial of concomitant chemoradiotherapy with cisplatin dose intensification and granulocyte-colony stimulating factor support for advanced malignancies of the chest

Concomitant chemoradiotherapy with cisplatin and combination chemotherapy in the neoadjuvant setting have both shown promising results.Purpose: To identify a locally and systemically active concomitant chemoradiotherapy regimen incorporating high-dose cisplatin, interferon alfa-2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy.Methods: Phase I cohort design establishing the maximal tolerated dose (MTD) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of escalating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5-FU and HU (week 2) with single daily radiation fractions of 200 cGy during days 1–5 of weeks 1–3 and no treatment in week 4. When dose-limiting neutropenia was encountered, GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was altered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-week break (level 7).Results: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was cisplatin 50 mg/m² in weeks 1 and 2, IFN 5 million Units (MU)/m² per day on days 1–5 in week 1, 5-FU 800 mg/m² per day for 5 days by continuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m² during weeks 1 and 2, with a decreased dose of IFN at 2.5 MU/m² per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and esophagitis in 5 of 13 patients. Increased thrombocytopenia in patients receiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5-FU to 600 mg/m² per day. While severe esophagitis was reduced, grade 4 thrombocytopenia became more prevalent and was seen in 6 of 7 patients. In-field tumor responses were observed in 17 of 28 evaluated patients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients with all known disease confined to the radiotherapy field were considered the corresponding times were 6 and 15 months, respectively. Most treatment failures occurred outside of the irradiated field.Conclusions: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSF. The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m² week 1, and 100 mg/m² week 2, IFN 2.5 MU, HU 500 mg every 12 h×11 and 5-FU 800 mg/m² per day with single fraction radiotherapy during weeks 1–3 and GCSF during weeks 1, 3, and 4. (2) GCSF can be safely administered and provides effective support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal toxicity when high doses of IFN and cisplatin are given together. (4) Hyperfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encouraging and support its investigation in the phase II setting.Presented at the International Association for the Study of Lung Cancer Workshop on Non-Small Cell Lung Cancer, Bruges, Belgium, August, 1993     

A phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in the intensification of cisplatin and cyclophosphamide chemotherapy for advanced ovarian cancer.

A pilot study was undertaken in eight patients to assess the feasibility of recombinant human granulocyte-macrophage colony-stimulating factor (rH GM-CSF) support to intensify standard chemotherapy for advanced ovarian cancer using a shortened 15 day treatment interval. Only four patients completed the course of six cycles of cisplatin 75 mg m-2 and cyclophosphamide 750 mg m-2 with rH GM-CSF, 3-5 micrograms kg-1 day-1, days 3-14, but one of these suffered a toxic death on study. Another died of disease progression. There were two episodes of life-threatening infection (WHO grade 4), and three patients were withdrawn because of various rH GM-CSF-related problems. Although potentially affording some patients the hypothetical benefits of dose intensification, as well as the possible attraction of a shorter duration of chemotherapy, this regimen is not without problems.