Constant infusion schedule for adriamycin: a phase I-II clinical trial of a 30-day schedule by ambulatory pump delivery system

Our plain-English summary of Constant infusion schedule for adriamycin: a phase I-II clinical trial of a 30-day schedule by ambulatory pump delivery system, by J. Lokich, A. Bothe, T. Zipoli, et al (Journal of Clinical Oncology, 1983).

The study

• Authors: J. Lokich, A. Bothe, T. Zipoli, R. Green, H. Sonneborn, S. Paul, D. Philips
• Journal: Journal of Clinical Oncology
• Published: 1983;1(1):24-8
• Cited by: 65 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Eighteen patients received a continuous intravenous infusion of adriamycin for 14-60 days in a phase I study in which the dose rates were escalated from 2 mg/sq m/day to 5 mg/sq m/day to establish the optimal dose to be delivered over a 30-day period. The drug was delivered via a tunneled subclavian catheter by a portable infusion pump (Cormed model ML-6) primed to provide a volume of diluted drug of 10 cc/day. Leukopenia and stomatitis were observed at 4 mg/sq m/day doses or greater in 50% of courses. At doses less than 4 mg/sq m/day, only 3/17 courses (18%) were associated with stomatitis. Partial alopecia developed in all patients, but less than 50% of scalp hair was affected. The cumulative dose of continuous infusion adriamycin at 30 days is comparable to the dose delivered by standard bolus intermittent schedules (60-90 mg/sq m g 21 days), but the adverse drug effects are eliminated or substantially reduced. Cardiac toxicity was assessed in selected patients treated to 450 mg/sq m or greater by cardiac biopsy and/or gated pool studies. No histopathologic lesions were noted in 3 patients receiving 450 mg/sq m or greater. The recommended daily dose rate of adriamycin in this protracted infusion regimen is 3 mg/sq m/day. The phase II study of this schedule and dose rate in 38 additional patients (a total of 52 evaluable patients) demonstrated objective responses in 1/9 soft tissue sarcoma, 1/3 mesothelioma, 1/3 hepatoma, and 2/13 breast cancer. Phase III studies of the protracted continuous infusion schedule for adriamycin are indicated in that clinical activity is demonstrated at a substantial reduction in toxicity. Pharmacologic studies expanding the existing data base are also necessary.

In plain English

This article is a cancer drug trial, not a study of asbestos exposure. It is relevant here only because 3 of the patients treated had mesothelioma, and it does not describe asbestos exposure in any patient. At the New England Deaconess Hospital in Boston, the authors gave the drug adriamycin as a continuous intravenous infusion, through a catheter and a portable pump, to 56 patients with advanced cancer. In the phase I part, 18 patients received 23 courses at dose rates from 2 to 5 mg/sq m/day. At 4 mg/sq m/day or more, 3 of 6 patients (50%) developed both leukopenia and stomatitis. At 3.5 mg/sq m/day or less, toxicity occurred in 3 of 17 courses. None of the 18 phase I patients had total hair loss, and nausea, vomiting or diarrhea were not seen in any patient. Heart biopsies in three patients who reached 450 mg/sq m showed no drug-related changes. At the chosen rate of 3 mg/sq m/day, 7 responses were seen among 52 evaluable patients, including 1 of 3 patients with mesothelioma. The authors recommended 3 mg/sq m/day and concluded that phase III studies were indicated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I-II clinical trial: a phase I dose-escalation study followed by a phase II study of tumor response at the chosen dose rate
• Who was studied: 56 patients with advanced, histologically confirmed cancer and no standard alternative treatment, treated at the New England Deaconess Hospital and Harvard Medical School, Boston. Ages ranged from 19 to 79 years (median 60). Tumors included breast cancer (13 patients), soft tissue sarcoma (9), mesothelioma (3) and others. 18 patients were in phase I and 38 more in phase II; 52 were evaluable for response. The treatment dates are not given.
• Exposure: No asbestos exposure was studied. The treatment studied was adriamycin given as a continuous intravenous infusion through a tunneled subclavian catheter with a Cormed ML-6 ambulatory pump. Dose rates were 2 to 5 mg/sq m/day in phase I and 3 mg/sq m/day in phase II.
• Main results:
  • Among phase I patients receiving 4 mg/sq m/day or more, 3 of 6 (50%) developed both leukopenia and stomatitis.
  • At 3.5 mg/sq m/day or less, 3 of 17 courses (17%) were associated with toxicity, and marrow suppression was evident in only 1 of those 3.
  • None of the 18 phase I patients had total hair loss. All hair loss was estimated at less than 50% of pretreatment scalp coverage.
  • Nausea, vomiting, diarrhea or anorexia were not observed in any patient.
  • In three patients without prior adriamycin who reached 450 mg/sq m, heart biopsy showed no adriamycin-induced changes. One patient previously treated with bolus adriamycin to a maximum cumulative dose showed a progressive decrease in ejection fraction.
  • 7 patients developed subclavian vein thrombosis, one with superior vena cava syndrome.
  • In the phase II study at 3 mg/sq m/day, 7 responses were seen in 52 evaluable patients: 2 of 13 breast cancer, 1 of 9 soft tissue sarcoma, 1 of 3 mesothelioma, 1 of 3 hepatoma, 1 prostate tumor and 1 tumor of unknown origin.
• The authors' conclusion: The authors recommended a daily dose rate of 3 mg/sq m/day for this protracted infusion. They concluded that phase III studies were indicated because clinical activity was shown with substantially reduced toxicity, and that further pharmacologic studies were needed.
• Limitations the authors state:
  • The authors noted that the cumulative dose in individual patients was limited when assessing hair loss.
  • The authors noted that the study population had adverse features, such as prior chemotherapy and prior bolus adriamycin, that might prevent tumor regression.

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, Cumulative Dose, Biopsy, Sarcoma, Mesothelioma.

Related studies

• Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion — I. Rassmann, R. Thödtmann, et al. (1998)
• A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma — V. Kovac, M. Zwitter, et al. (2012)
• Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors — R. Bahleda, M.C. Le Deley, et al. (2018)
• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors — T. Shimizu, K. Fukuoka, et al. (2016)
• The value of adriamycin in the treatment of diffuse malignant pleural mesothelioma — B.S. Yap, R.S. Benjamin, et al. (1978)
• Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors — C.A. Johnson, D. Kilpatrick, et al. (1997)

Browse more research in Journal of Clinical Oncology, or return to medical research.