Continuous Ambulatory Infusion Research Articles

Temperature variation in the home setting: implications for continuous ambulatory infusions

AbstractBackgroundHome infusion therapy is being increasingly utilised. Little is known about variation in the temperature of the infusion solution in the home and its effect on drug stability.AimTo investigate temperature changes over a 24‐h period during usual daily activities and assess the effect of ice packs on infusion solution temperature during storage at 25°C or 32°C.MethodSix healthy volunteers (without intravenous access) wore a waist pouch containing an elastomeric infuser for 24 h during autumn and recorded their daily activities. Infusion solution temperature and ambient temperature were measured every 10 min. In a separate experiment, an infuser was placed inside a waist pouch containing ice packs and ambient temperature was maintained at 25°C or 32°C for 24 h. Ice packs were replaced eight‐hourly. The procedure was repeated twice at each temperature.ResultsThe mean temperature of the infusion solutions worn by volunteers ranged from 22.7°C (±3.5) to 27.9°C (±5.6), and the cumulative time exceeding 25°C ranged 6–20 h. The infusers stored in waist pouches with ice packs usually maintained a solution temperature below 20°C when stored at 25°C. Infusers stored at 32°C maintained a solution temperature greater than 20°C for up to 11 h.ConclusionInfusion solutions may reach temperatures above 30°C in the home which should be considered when assessing patient suitability for home therapy. There is a need to assess drug stability at high temperatures and determine if exposure to high temperatures has a negative impact on therapeutic outcomes.

Bimonthly Regimen of High-Dose Leucovorin, Infusional 5-Fluorouracil, Epirubicin and Cisplatin (Modified ECF) as Adjuvant Chemotherapy in Resected Gastric Adenocarcinoma

Background: The administration of the de Gramont regimen in combination with cisplatin and epirubicin (modified ECF) has previously been reported as a treatment for advanced gastric cancer, but here we report this regimen combination in an adjuvant setting for the first time. Methods: Forty-eight patients with curatively resected gastric cancer were treated. Each 2-week cycle consisted of epirubicin (50 mg/m²), cisplatin (50 mg/m²), 5-fluorouracil (5-FU) IV bolus (400 mg/m²) and 5-FU IV (2,400 mg/m²) over 46 h plus leucovorin IV (400 mg/m²) over 2 h. Postoperative chemoradiotherapy was also administered to the patients when indicated. We retrospectively reviewed the patients who were treated with modified ECF. Results: The median disease-free survival (DFS) was 40.7 months and the 1-, 3- and 5-year DFS rates were 78.5, 55.7 and 44.6%, respectively. The most common grade 3–4 toxicities were hematological and gastrointestinal. Conclusion: A modified ECF regimen may be an effective and convenient treatment with tolerable toxicities for the adjuvant treatment of gastric cancer. It may provide an alternative regimen to the standard ECF when a continuous ambulatory infusion pump is not feasible or not preferred by the patient.

A phase I and II trial of epirubicin, cisplatin, 24‐hour infusion 5 fluorouracil and sodium folinate in patients with advanced esophagogastric carcinomas

Advanced esophagogastric carcinoma has a poor prognosis. Palliative chemotherapy provides a survival advantage and improved quality of life. Epirubicin, cisplatin and continuous infusional 5-fluorouracil (5-FU) (ECF) is a well-established chemotherapy regimen but a continuous chemotherapy infusion is not always feasible or acceptable. We conducted a phase I and II trial of a modified version of ECF, utilizing 5-FU as a 24-h infusion on day 1 and day 8 of a 21-day cycle, administered with sodium folinate as a modulator of 5-FU (ECSF). In the phase I study the dose of 5-FU was increased in successive cohorts from 1250 mg/m(2) , 1500 mg/m(2) , and 1750 mg/m(2) to 2000 mg/m(2) per 24 h. Dose limiting toxicity of febrile neutropenia was encountered at 2000 mg/m. The recommended dose for 5-FU was 1750 mg/m(2) . Overall 29 patients were treated with ECSF of whom 27 were evaluable for toxicity. The response rate was 45% on an intention-to-treat analysis with a complete response rate of 3%. The median response rate was 4.1 months and the median survival was 10.7 months. A total of 23 patients (72%) obtained clinical benefit with improvement in dysphagia or weight gain. central venous catheter (CVC) complications were observed in 12 (41%) patients. ECSF was associated with a response rate and survival similar to that reported with standard ECF. ECSF may provide an alternative regimen to standard ECF when a continuous ambulatory infusion pump is not feasible or not preferred by the patient. CVC complications are a limitation.

Phase II study of prolonged ambulatory infusion carboplatin and oral etoposide for patients progressing through hormonal therapy for prostate cancer

To develop a well-tolerated outpatient chemotherapy regimen for hormone-insensitive prostate cancer. Forty patients received carboplatin 20 mg/m2 by continuous ambulatory infusion with oral etoposide 50 mg/day for 21 days repeated every 6 weeks. Four patients had a partial response and 16 patients had stable disease. Two of the partial responders and three additional patients recorded falls in prostate specific antigen of 50% or more. The median freedom from progression was 24 weeks and median survival 32 weeks. Twenty-four of 31 patients had decreasing pain scores and 20 of 34 patients recorded improved quality of life with at least one cycle of treatment. The main toxicity occurred in seven patients with World Health Organization (WHO) grade 4 neutropenia and in four patients with WHO grade 3 neutropenia. Only one patient developed febrile neutropenia. Six patients had grade 3 anaemia and three patients had grade 3 thrombocytopenia. Two patients reported grade 3 lethargy whereas 11 patients had grade 2 lethargy. This was a well-tolerated regimen that improved symptomatic control of hormone-insensitive prostate cancer.

A Phase I Study of Prolonged Ambulatory Infusion of Ifosfamide with Oral Mesna

Background: Oral mesna allows investigation of ifosfamide as a prolonged ambulatory infusion for dose-intense out-patient use. Methods: Cohorts of 3 patients received escalating doses of ifosfamide from 200 to 1,000 mg/m²/day as continuous ambulatory infusion with oral mesna at 30% of the ifosfamide dose every 6 h commencing 2 h prior to ifosfamide infusion as uroprotection on a 14-day schedule with cycles repeated every 28 days. Results: Fifteen patients received a median of three cycles.Dose-limiting toxicities with cycle 1 were lethargy and hepatotoxicity at 1,000 mg/m²/14 days. Transient transaminase elevation was seen at all dose levels. The other grade 3 toxicities were single episodes of anaemia, granulocytopenia, nausea and hypotension. The best response was stable disease in a patient with thyroid cancer. Conclusion: Ambulatory infusion of 600 mg/m² ifosfamide with 180 mg/m² oral mesna was considered suitable for phase II trials and delivers dose-intense out-patient therapy without urotoxicity.

Pharmacokinetic properties and stability of continuous-infusion meropenem in adults with cystic fibrosis

Background: Meropenem is commonly used to treat lung infections in adults with cystic fibrosis (CF). Although continuous infusion is the ideal method to maximize the pharmacodynamic properties of this betalactam antibiotic, meropenem is stable for only ∼4 to 6 hours at room temperature, and its pharmacokinetic (PK) properties, when administered by continuous infusion to patients with CF, are largely unknown. Objective: This study was undertaken to determine the PK properties and stability of meropenem when administered to adults with CF by a continuous ambulatory drug-delivery infusion pump stored in a cold pouch between 2 freezer packs. Methods: This open-label, multidose, randomized, crossover PK study was conducted at the Clinical Research Center at Hartford Hospital (Harford, Connecticut). Adults aged ≥ 18 years with CF were eligible. Study participants were randomized to receive meropenem 125 mg/h or 250 mg/h (equivalent to 3 g and 6 g, respectively, over 24 hours) by continuous IV infusion for 12 hours. Serum samples were collected throughout the infusion and then for 6 hours after infusion to determine the PK properties (volume of distribution [V d], elimination rate constant, total body clearance [CL], terminal half-life [ t 1 2 ], and steady-state concentration [C ss]). Serum meropenem concentrations were assayed using high-performance liquid chromatography, and PK profiles were determined using compartmental analysis. Meropenem stability was ascertained by sampling the drug directly from the infusion pump at prespecified time points. Meropenem tolerability was assessed throughout the study by questioning subjects on how they felt. In addition, laboratory values of serum chemistries and liver enzymes were compared with baseline values. Results: Seven adult volunteers with CF (4 women, 3 men; mean [SD] age, 27 [10] years [range, 19–46 years]) participated in the study. Mean (SD) C ss values were 8.31 (0.68) mg/L and 18.50 (3.31) mg/L for the 125-mg/h and 250-mg/h infusion rates, respectively. V d, CL, and t 1 2 were dose independent and similar between the 2 infusion rates. Meropenem stability was maintained over 12 and 24 hours. Meropenem by continuous infusion was well tolerated. One patient complained of a headache during the study. Conclusions: In this study of adults with CF, meropenem infusion rates of 125 mg/h and 250 mg/h provided serum drug concentrations greater than the minimum inhibitory concentration for pathogens considered meropenem susceptible (≤ 4 μg/mL) and intermediately resistant (8 μg/mL), respectively.

Establishing a programme for continuous ambulatory infusion chemotherapy.

The development of venous access devices (VADs) and portable infusion pumps has enabled chemotherapy to be administered continuously within the home environment. The objective of this study was to describe the experience of establishing an ambulatory chemotherapy programme for patients receiving protracted infusions (PVIs) of 5-fluorouracil (5-FU). The files of all patients receiving PVI 5-FU as a component of their treatment for gastrointestinal malignancy were reviewed. The types of VADs, infusion pump systems and their management were documented. Information packages and education programmes were developed for patients. Seventy-four patients with gastrointestinal cancer were studies. At the end of the period the Portacath was the preferred VAD, while both pumps used were found to have advantages and disadvantages. The choice of pump was decided more by patient preference than systematic differences in performance of the pumps. The findings in this review confirm that, with close attention to the potential pitfalls of ambulatory chemotherapy, an acceptable service can be provided.

Stability and compatibility study of a carboplatin solution in syringes for continuous ambulatory infusion in syringes for continuous ambulatory infusion

The aim of this study was to verify the physico-chemical stability and compatibility between a 10 mg/ml carboplatin parenteral solution and the portable pump Intelliject® when stored at 25°C over an 8-day period. During this study, the pH was determined and carboplatin degradation products were assayed by a validated HPLC method. The compatibility study consisted of the titration of reducing substances, TLC of extracted additives, assay of extracted ions by AAS, resistivity measure, dynamometric test and UV, visible and IR absorption spectrophotometry. Stability and compatibility studies showed that a 10 mg/ml carboplatin parenteral solution remained chemically stable in the Intelliject® pump over a period of 8 days under the tested conditions.

Concurrent radiotherapy and continuous ambulatory infusion 5-fluorouracil in advanced head and neck cancer

Patients with locally advanced stage 3 or 4 recurrent squamous cell carcinoma of the head and neck received 5-fluorouracil (5-FU) 200 or 300 mg/m 2/day by prolonged ambulatory infusion concomitantly with radiotherapy (60–66 Gy) to the primary site and neck nodes in 30–33 fractions at five fractions per week, boosting to smaller volumes after 60 Gy. Of 39 patients, the complete response rate was 82% (95% CI: 67–93%). The estimated percentage without failure at 2 years was 59% (S.E. 8%) and at 4 years was 50% (S.E. 8%). Estimated head and neck cancer specific survival was 64% (S.E. 8%) at 2 years and 52% (S.E. 8%) at 4 years. Acute toxicities included moist desquamation in 49% and dry desquamation in 28%, confluent mucositis in 56% and patchy mucositis in 44%. Late effects, more than 6 months after completing treatment, assessed in 35 patients, included severe salivary dysfunction in 3 patients and moderate in 21, severe osteonecrosis in 4 patients and moderate toxicity in subcutaneous tissues in 13, skin in 3 and mucosa in 2 patients. It is feasible to give continuous 5-FU concurrently with radiotherapy in locally advanced or recurrent head and neck cancer, albeit with increased toxicity. The response rate and survival obtained in this trial justify further investigation of the combined treatment in a randomised trial. Key words: 5-fluorouracil (5-FU), radiotherapy, continuous infusion, head and neck cancer

575 Epirubicin (E), cisplatin (C) and continuous infusional 5-fluorouracil (F) (ECF) active combination chemotherapy for non-resectable gastric adenocarcinoma (AC)

45 patients (pts), 26 male & 19 female with gastric AC, with non-resectable adenocarcinoma were treated with E (50 mg/m2) and C (60 mg/m2) given every 3 weeks, with a continuous ambulatory infusion of F (200 mg/m2 per day). A cohort of 19 pts presenting from April 1993 to Sept 1994 were added to 26 previously reported cases. ECOG score 0-1, median age 61 (29-81), 258 cycles were given (1–12, median 6). All pts had a degree of alopecia no greater than Grade III. A single case of grade IV toxicity was seen (diarrhea). Grade III toxicity was seen as follows: vomiting 2 pts, diarrhea 2 pts, stomatitis 2 pts, infection 5 pts. Nine pts had mild foot & mouth syndrome. Five pts were not evaluable for response (3 early deaths and 2 stopped early due to toxicity). Of 40 evaluable pts, reassessed at 9 weeks, 57% responded- 2 (5%) CR, 21 (52%) PR, 13 stable disease & 4 progressed. Median survival was 9 months (1.4- 41+). We conclude that ECF has a high response rate in non-resectable gastric AC. Response rates in this cohort were similar to our previous report. A randomised phase III trial of ECF versus FAMTX, is open for accrual to assess the true value of this innovative regimen. 45 patients (pts), 26 male & 19 female with gastric AC, with non-resectable adenocarcinoma were treated with E (50 mg/m2) and C (60 mg/m2) given every 3 weeks, with a continuous ambulatory infusion of F (200 mg/m2 per day). A cohort of 19 pts presenting from April 1993 to Sept 1994 were added to 26 previously reported cases. ECOG score 0-1, median age 61 (29-81), 258 cycles were given (1–12, median 6). All pts had a degree of alopecia no greater than Grade III. A single case of grade IV toxicity was seen (diarrhea). Grade III toxicity was seen as follows: vomiting 2 pts, diarrhea 2 pts, stomatitis 2 pts, infection 5 pts. Nine pts had mild foot & mouth syndrome. Five pts were not evaluable for response (3 early deaths and 2 stopped early due to toxicity). Of 40 evaluable pts, reassessed at 9 weeks, 57% responded- 2 (5%) CR, 21 (52%) PR, 13 stable disease & 4 progressed. Median survival was 9 months (1.4- 41+). We conclude that ECF has a high response rate in non-resectable gastric AC. Response rates in this cohort were similar to our previous report. A randomised phase III trial of ECF versus FAMTX, is open for accrual to assess the true value of this innovative regimen.

A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF)

A phase II study was performed in patients with unresectable or metastatic gastric cancer evaluating the efficacy of a new chemotherapy schedule combining epirubicin and cisplatin with a continuous ambulatory infusion of 5-fluorouracil (ECF). One hundred thirty-nine consecutive, previously untreated patients were given ECF. Of these, 128 had measurable disease. Epirubicin (50 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v.) were administered every three weeks for 8 cycles during a 21 week continuous i.v. infusion of 5-fluorouracil (200 mg/m2/day). In total 773 cycles of chemotherapy were given. Objective tumour responses was seen in 91 (71%) of the 128 patients with measurable disease, of which 15 (12%) had a complete response. Twenty patients with locally advanced disease responding to ECF had attempted resection of the primary--11 (55%) were completely removed, 4 of these had no residual tumour in the resected specimen. The overall median survival was 8.2 months with 1 and 2 year survivals of 30% and 10% respectively. Grade 3 or 4 emesis occurred in 13%, stomatitis in 7%, diarrhoea in 4%, infection in 6%, leucopenia in 21% and thrombocytopenia in 8% of patients. Myelosuppression delayed treatment in 39 (5%) of the 773 cycles. Six of the 139 patients (4.3%) had treatment related deaths. There was no measurable reduction in quality of life during chemotherapy, while 67% of the 66 patients with dysphagia had complete resolution of this symptom. The ECF regimen displays high anti-tumour activity with moderate toxicity in patients with gastric cancer and in some cases enabled resection of previously inoperable tumours.

Administration of Buprenorphine by Continuous Subcutaneous Infusion

Due to the risks associated with permanent central venous access, and disadvantages of repetitious intramuscular injections. continuous subcutaneous infusion of buprenophine was attempted in three patients with chronic pain not responsive to more traditional medication regimens. Buprenorphine is a highly lipophilic opioid analgesic which exhibits opioid antagonist activity. It is indicated for moderate to severe pain by intramuscular or intravenous injections administered every four to six hours. Three chronic pain patients who were unresponsive to pure opioid analgesics, administered either orally or parenterally, but who responded favorably to intramuscular injections of buprenorphine, were evaluated for administration of buprenorphine via continuous ambulatory infusion pump. Potential serious side effects were avoided without the complexities of chronic central venous access. Adequate pain control was achieved in patients previously unresponsive to conventional therapies. Quality of life was improved. ...

Evaluation of an implantable venous access system in a general oncology population.

Venous access has been a problem for the practicing oncologist. Previous approaches, such as arteriovenous fistulas, grafts, or percutaneous catheters, have not gained widespread acceptability. We report our experiences with 230 Port-a-Cath devices, a totally implantable venous access system. The catheters were placed in 218 general oncology patients for the administration of chemotherapy. One patient had three catheters placed and 10 patients had two catheters each. Most patients received standard bolus chemotherapy, while 25 patients were treated with continuous ambulatory infusions. The catheters were in place for an average of 271 days (range 2-1,427 days) for a total of 62,330 catheter days, representing the largest published experience with devices of this type in cancer patients. A total of 24 complications occurred in 22 patients. Catheter insertion was associated with four pneumothoraces, two of which required chest tube drainage. Five catheters were removed because of infection. There were 6 cases of venous thrombosis, but none resulted in pulmonary embolism. Other complications were manageable and included catheter occlusion, migration, and extravasation of chemotherapy agents. The Port-a-Cath is safe and is associated with a low rate of complications. Implantable venous access systems represent a significant advantage in the management of oncology patients with poor venous access.

Cyclophosphamide, methotrexate, and 5-fluorouracil in a three-drug admixture. Phase I trial of 14-day continuous ambulatory infusion.

The compatibility and stability at room temperature for up to 7 days of a three-drug admixture of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) was established permitting the practical delivery of the combination as an infusion in an ambulatory setting. Fourteen patients received 20 courses of CMF administered on a continuous infusion schedule for 14 days of a 28-day cycle. The dose rates were fixed for 5-FU (300 mg/M2/day) and methotrexate (0.75 mg/M2/day). The cyclophosphamide dose was escalated from 25 to 50, 75, and 100 mg/M2/d. Leukopenia and thrombocytopenia were observed in two of five patients receiving the maximal dose of cyclophosphamide. No other toxicities were observed including alopecia, stomatitis or liver function abnormalities. This Phase I trial suggests that the cumulative doses of cyclophosphamide, methotrexate, and 5-FU are comparable to the maximum doses delivered as single agent infusions. Furthermore, when the infusion CMF is compared to the "standard" bolus schedule for CMF, the infusion schedule delivers 116%, 8%, and 350% of the respective three component drugs (cyclophosphamide, methotrexate, and 5-FU).

Cis platine (CDDP) in continuous intravenous ambulatory infusion: a new method of administration.

Twenty-three patients with metastatic tumors received multiple chemotherapy regimens which included CIS platine (CDDP) by continuous ambulatory infusion for 4 successive days at a rate of 25 mg/m2/day repeated every 4 weeks. Continuous infusion was provided by an external disposable pump, the "Infusor," which delivers the drug in a volume of 48 ml at a constant rate of 2 ml/hour, in conjunction with oral hydration and antiemetics. No incident detrimental to the patient was recorded. The average duration of the infusions was 23 hr. Only 22% of the patients had minor nausea and vomiting, and 1 case of functional renal insufficiency (4%) was easily corrected by simple intravenous hydration. A randomized study is ongoing to compare continuous perfusion with standard infusion for efficiency, side effects and response rate. Patients with "Infusor" are treated at home under Minitel supervision.