24-hour Continuous Intravenous Infusion Research Articles

Phase I Study of Adozelesin Administered by 24-Hour Continuous Intravenous Infusion

Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations. We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed. Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 micrograms/m2 was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered. Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 micrograms/m2. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed. We recommend that the phase II dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 micrograms/m2, repeated every 6 weeks. Other potentially less myelosuppressive schedules could be pursued.

Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103.

To provide an investigational drug, paclitaxel, now commercially available, to women with refractory ovarian cancer and to evaluate response and toxicity in these patients. Patients with platinum-refractory ovarian cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3, at least three prior chemotherapy regimens, adequate hepatic and renal function, and no significant cardiac history were eligible. Patients were treated with paclitaxel 135 mg/m2 administered by 24-hour continuous intravenous infusion every 3 weeks. Leukopenia was the most frequent toxicity, with 78% of patients experiencing grade 3 or 4 toxicity. Other grade 3 and 4 toxicities were less common: fever (33%), infection (12%), thrombocytopenia (8%), vomiting (7%), cardiac (2%), neurologic (2%), and mucositis (1%). Fifteen treatment-related deaths (1.5%) were reported. The objective response rate was 22% (4% complete response [CR], 18% partial response; 95% confidence interval [CI] for overall response, 19% to 25%). The median time to progression from treatment initiation was 7.1 months in responding patients and 4.5 months for all patients. The median survival duration was 8.8 months. Paclitaxel has shown activity in women with platinum-refractory ovarian cancer, and it can be administered with an acceptable safety profile. Further research is needed to determine the optimal role of paclitaxel in the primary and salvage treatment of ovarian cancer.

Acute lung injury following treatment with high-dose cyclophosphamide, cisplatin, and carmustine: pharmacodynamic evaluation of carmustine.

Therapy with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury. The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy. We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 mg/m2 daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens. Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 (micrograms/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P < .03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (micrograms/mL) x minute developed lung injury. These results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen. Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect.

Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with Hodgkin's disease: a phase I/II study.

As bone marrow toxicity is the major limitation of the optimal administration of chemotherapy, we investigated whether recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) could prevent myelotoxicity or accelerate hematopoietic recovery after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy. Twenty-four previously untreated patients with Hodgkin's disease were included in a phase I/II study in which standard MOPP chemotherapy was followed by 5 days of GM-CSF at every other cycle. Patients were entered sequentially to receive one of four dosc levels (2, 4, 8, and 16 micrograms/kg of glycoprotein; 1.4, 2.8, 5.5, and 11.0 micrograms/kg of protein) and were randomly allocated to either 24-hour continuous intravenous (IV) infusion or twice daily subcutaneous (SC) injection of rhGM-CSF. WBC counts (mainly neutrophils, eosinophils, and monocytes) were significantly higher in cycles with rhGM-CSF than in cycles with MOPP alone. The total number of days of leukopenia (WBC count less than or equal to 2.0 x 10(9)/L) and neutropenia (absolute neutrophil count [ANC] less than or equal to 1.0 x 10(9)/L) was reduced in cycles with rhGM-CSF from 6.3 to 0.8 days and from 5.4 to 1.0 days, respectively. All dose levels of rhGM-CSF were effective in increasing the ANC, but only at the dose levels of 8 and 16 micrograms/kg did this significantly affect the scheduling of chemotherapy. Mild and reversible adverse reactions included low-grade fever, chest/bone pain, myalgias, erythemia, headache, fatigue, and periorbital edema. rhGM-CSF can be administered safely to patients with Hodgkin's disease and results in improved hematologic recovery after MOPP. Full-dose chemotherapy can be administered on time, resulting in an increase in the overall tolerated dose of myelosuppressive drugs when compared with historical controls. SC administration proved to be at least as effective as continuous IV infusion and should be preferred.

Interferon alfa-2a and fluorouracil in the treatment of patients with advanced esophageal cancer.

The trial was undertaken to determine the response rate to and toxicities from the combination of interferon alfa-2a (IFN) and fluorouracil (FU) in patients with advanced esophageal cancer. In this prospective phase II trial conducted at a large tertiary referral cancer center and university hospital, 40 patients with advanced locoregional, metastatic epidermoid, or adenocarcinoma of the esophagus were given FU 750 mg/m2 by 24-hour continuous intravenous infusion days 1 to 5, followed by weekly outpatient bolus FU 750 mg/m2 and IFN 9 x 10(6) U three times per week from day 1. Dose was attenuated for fatigue, neurotoxicity, gastrointestinal toxicity, and myelosuppression. Complete and partial responses were seen in 10 of 37 assessable patients with esophageal cancer (27%; 95% confidence interval, 0.13 to 0.41). Although substantial, toxicity was tolerable and primarily involved fatigue and mild myelosuppression. The median duration of response was 6.4 months (range, 2.8 to 14+ months). The combination of IFN and FU is an active regimen in the treatment of advanced esophageal cancer with a response rate similar to that reported for cisplatin-containing combinations in similar patient populations. Further studies based on this combination are indicated.

Concurrent preoperative chemotherapy and radiation therapy in localized esophageal adenocarcinoma

Twenty-four patients with localized, potentially resectable adenocarcinoma of the esophagus were enrolled in this study to evaluate the use of preoperative chemotherapy and radiation therapy, followed by transhiatal esophagectomy. The patients were newly diagnosed and had received no prior treatment. Radiation therapy consisted of 4900 cGy, administered as 350-cGy fractions 5 days a week for 14 fractions. The chemotherapy consisted of 5-fluorouracil 300 mg/m2/day administered as a continuous 24-hour intravenous infusion for 96 hours each week, concomitantly with the radiation therapy. After a 3-week rest, patients underwent transhiatal esophagectomy. Twenty-two patients could be observed for their responses to the chemotherapy and radiation regimen. Radiographically, 41% showed improvement, 36% had stable disease, and 23% had progression. Nineteen patients underwent surgery; all patients had total gross removal of disease, and two patients had a complete histologic response. All 24 patients could be examined for toxicity assessment. There were three deaths during the treatment period: one patient died of a perioperative complication, one of pneumonia, and one of a myocardial infarction. Eleven patients eventually had pleural and/or pericardial effusions, and six of these were symptomatic. All 24 patients could be examined for survival analysis. The median follow-up for all patients was 12.5 months, with 32.5 months for all surviving patients. Median survival was reached at 11 months. Disease-free survival was 9.5 months. It was concluded that the radiation-fractionation schedule in this preoperative regimen was associated with marked toxicity in the form of pleural and pericardial effusions. There was no improvement in survival compared with historic controls. The role of combined preoperative treatment in this patient population has yet to be determined.

Combination immunotherapy for non-small cell lung cancer: Results with interleukin-2 and tumor necrosis factor-α

Sixteen patients with advanced non-small cell lung cancer were treated with a combination of low-dose interleukin-2 and tumor necrosis factor-alpha. Patients received a continuous 24-hour intravenous infusion of interleukin-2 at 1 X 10(6) Cetus U/m2 and a simultaneous daily intramuscular dose of tumor necrosis factor-alpha (25 to 100 micrograms/m2) for 5 consecutive days. These doses did not have antitumor activity when administered alone in previous trials. Treatment was given at 3-week intervals. Common side effects included fever, local skin reaction at the injection site of tumor necrosis factor-alpha, pancytopenia, and general malaise, all of which were reversible within 48 hours of cessation of therapy. The maximum tolerated doses with this combination were 1 X 10(6) U/m2/day of interleukin-2 and 50 micrograms/m2/day of tumor necrosis factor-alpha, with thrombocytopenia (less than 50K) being the dose-limiting toxicity. Twelve patients received two cycles or more and were evaluable for response. Measurable tumor regression occurred in four patients. An additional seven patients had radiographic stabilization of disease (median = 12 weeks) before progression. All patients had augmented lymphokine-activated killer and natural killer activity during therapy. Enhanced lysis of autologous tumor in vitro was demonstrated in four of four patients during therapy. We conclude that combination immunotherapy with low-dose interleukin-2 and tumor necrosis factor-alpha can mediate tumor regression and can be given with acceptable toxicity.

Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma.

Taxol, a plant product, has significant activity against certain rodent and human xenograft tumors. It promotes microtubule assembly in vitro, in contrast to vinca alkaloids, which inhibit assembly. In this phase I study, taxol was administered as a 24-hour continuous intravenous (IV) infusion in 65 courses to 26 patients. A premedication regimen of dexamethasone, cimetidine, and diphenhydramine was used to prevent the acute hypersensitivity reactions observed in previous studies of taxol. Only one episode of mild stridor occurred in this study. Peripheral neuropathy was the dose-limiting toxicity and was observed in 40% of patients treated at a dose of 250 mg/m2. Significant neutropenia of brief duration was also common. Pharmacokinetic studies by a high-performance liquid chromatography (HPLC) method demonstrated that drug plasma concentrations increased during the 24-hour infusion and then declined rapidly. Peak plasma concentrations correlated with dose, and less than 5% of taxol was excreted in the urine. Most of the drug was bound to serum components. Partial responses of more than 3 months' duration were observed in four of 12 melanoma patients treated. The recommended phase II dose of taxol on this schedule is 250 mg/m2. Priority should be given to the study of taxol in melanoma.

Phase I study of cyclophosphamide (NSC 26271) by 72-hour continuous intravenous infusion.

A phase I clinical study of cyclophosphamide administered by 72-hour continuous intravenous infusion was conducted in 13 patients with various types of advanced solid tumors to evaluate the drug's toxicity and efficacy. The initial dosage of 300 mg/m2/day X 3 days repeated at 3-week intervals was progressively increased by 150 mg/m2/day-increments to a maximum dosage of 750 mg/m2/day. The dose-limiting toxicities were hematologic and gastrointestinal. Neutropenia was more severe than was thrombocytopenia. The lowest granulocyte count less than 500/mm3 occurred during more than half of the treatment courses at doses of 600 mg/m2 and higher. Severe nausea and vomiting were observed in patients during three of four treatment courses at the 750 mg/m2 dose level. None of the patients had microscopic hematuria or symptoms suggestive of cystitis. Partial response occurred in a patient with parotid cancer metastatic to the lung. Disease stabilization occurred in four patients, while six patients had progression of disease. The recommended starting dosage of cyclophosphamide by continuous intravenous infusion for phase II trials is 600 mg/m2/day X 3 every 3 weeks for patients with good bone marrow reserve.

VAB-6 combination chemotherapy without maintenance in treatment of disseminated cancer of the testis

Thirty-six men with Stage III or bulky Stage II malignant germ cell tumors of the testis who received no prior chemotherapy were treated with the VAB-6 protocol without maintenance and 34 were evaluable. The VAB-6 regimen is a 3-4 month program beginning with successive inductions at 3-4 week intervals: day 1, cyclophosphamide 600 mg/m2 of body surface, bleomycin 30 mg, vinblastine 4 mg/m2 and dactinomycin 1 mg/m2 intravenously; days 1-3, bleomycin 20 mg/m2/day X 3 by continuous 24-hour intravenous infusion; and day 4, cis-platinum 120 mg/m2 intravenously. Complete responders receive a fourth induction and are followed thereafter without further chemotherapy. Incomplete responders have resection of residual disease one month after the third induction. If the resected specimen contains malignant tissue, an additional two inductions are given. Thirty-one of 34 (91%) evaluable patients achieved complete remission and 28 remain in complete remission with median follow up of 24+ months. Chemotherapy alone was most effective in patients with minimal metastatic disease, with no teratoma in primary tumor, and with pure seminoma. Patients with advanced metastatic deposits or with teratoma in the primary tumor frequently required combined chemotherapy and surgery to achieve disease free status. Myelosuppression was the principal potentially serious toxicity. With effective induction, maintenance chemotherapy is not necessary.

VAB‐6 combination chemotherapy without maintenance in treatment of disseminated cancer of the testis

Thirty-six men with Stage III or bulky Stage II malignant germ cell tumors of the testis who received no prior chemotherapy were treated with the VAB-6 protocol without maintenance and 34 were evaluable. The VAB-6 regimen is a 3-4 month program beginning with successive inductions at 3-4 week intervals: day 1, cyclophosphamide 600 mg/m2 of body surface, bleomycin 30 mg, vinblastine 4 mg/m2 and dactinomycin 1 mg/m2 intravenously; days 1-3, bleomycin 20 mg/m2/day X 3 by continuous 24-hour intravenous infusion; and day 4, cis-platinum 120 mg/m2 intravenously. Complete responders receive a fourth induction and are followed thereafter without further chemotherapy. Incomplete responders have resection of residual disease one month after the third induction. If the resected specimen contains malignant tissue, an additional two inductions are given. Thirty-one of 34 (91%) evaluable patients achieved complete remission and 28 remain in complete remission with median follow up of 24+ months. Chemotherapy alone was most effective in patients with minimal metastatic disease, with no teratoma in primary tumor, and with pure seminoma. Patients with advanced metastatic deposits or with teratoma in the primary tumor frequently required combined chemotherapy and surgery to achieve disease free status. Myelosuppression was the principal potentially serious toxicity. With effective induction, maintenance chemotherapy is not necessary.

Chemotherapy of advanced gastric cancer with 72-hour continuous intravenous 5-fluorouracil infusion at 2-week intervals.

Twenty-nine patients with advanced gastric adenocarcinoma were treated with 72-hour continuous intravenous infusion of 5-fluorouracil (30 mg/kg/24 hr) at 2-week intervals. Six patients (21%) achieved partial response and four (14%) had stabilization of their disease. The median duration of partial response was 8 months, with a range of 5-19 months. The median survival time for all patients from the start of chemotherapy was 8 months. Various prognostic factors important in determining response and survival are analyzed.

Reassessment of the use of desferrioxamine B in iron overload.

Treatment of transfusion-induced iron overload by daily intramuscular injection of the chelator desferrioxamine has not produced impressive urinary iron excretion. We attempted to augment net iron excretion by altering both the route and quantity of chelator administered. Two ascorbic acid-replete patients excreted a mean of 14.5 mg of iron per 24 hours after a single intramuscular injection of 750 mg of desferrioxamine. Excretion increased to a mean of 44.9 mg when this dose was delivered by a continuous 24-hour intravenous infusion. When the intravenous dose of chelator was increased incrementally to as high as 16,000 mg per 24 hours, iron excretion increased up to 180 mg per day. At these high-dose levels, efficiency of binding of iron to chelator was compromised. Constant exposure of the labile iron pool to a chelating agent markedly enhances net iron excretion in splenectomized transfusion-dependent patients.