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Conrad Notes
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F. Levi, MD, PhD, The P. Brouse Hospital, Villejuif, France, studied 90 colorectal cancer patients infused with chronotherapeutic oxaliplatin (OXA), 5-fluorouracil (5-FU), and folinic acid (FA) by an ambulatory programmable pump. Dose-ranging for safety began with OXA at 25, 5-FU at 700, and FA at 300 mg/m sq. Survival at at 24 months was 38%.

Introduction Circadian rhythms (CRs) are biological rhythms which repeat about every 24 hours. In mammals, the suprachiasmatic nucleus serves as the primary pacemaker for CRs. Cell functions including replication and responsiveness to chronotherapy cycle daily. Such cycling allows timing the administration of medication(s) to achieve enhanced therapeutic activity and diminished adverse effects. Optimal drug delivery schedules have been obtained for more than 20 anticancer agents from animal studies. Levi coauthored a report on the circadian variation of vinorelbine toxicity in mice (Chronobiol International 1995;12:195-198).
Patients The 90 untreated metastatic colorectal patients ranged in age from 54 to 66 years. Other demographic data included male/female, 53/37; WHO performance status of 0 in 55/90, 1 in 28/90 and and 2 in 7/90; cancer of colon/rectum, 69/21; number of metastatic organs, one in 42/90 and two or more in 48/90; liver metastases in 79/90; prior adjuvant therapy in 16/90; and carcinoembryonic antigen (CEA) >10 ng/ml in 37/90. Clinical signs included diarrhea in 10/90 and hepatomegaly in 30/90. Patients were classified using the Duke stages as A/B, 10%; C, 20%; D, 69%; and unknown, 1%.
Treatment schedule Each course included 4 days on treatment and 10 days off. A multichannel ambulatory pump allowed iv infusion of 5-FU and folinic acid (FA) beginning at 10 PM, peak delivery at 4 AM, and ending at 10 AM. In like manner, the oxaliplatin (OXA) infusion was adjusted to deliver the highest dose at 4 PM after starting at 10 AM and stopping at 10 PM. Upward and downward dose adjustments of 5-FU depended on the observed toxicity.
Safety in 90 patients Levi views the following percentages of grade 3/4 toxicities in the 90 patients as clinically acceptable:

 Per PatientPer Course
Diarrhea 41 8.2
Nausea or Vomiting 38 7.6
Neutropenia 15 1.8
Leukopenia 9 2.0
Mucositis 8 1.7
Thrombocytopenia 3 0.4
Anemia 2 0.3

In addition, 25% of the study patients developed peripheral sensitive neuropathy after cumulative doses of OXA, up to 1300 mg/m sq. This symptom was usually reversible.

Efficacy in CRC According to CT scans, 59 of 90 patients (66%) achieved a greater than 50% response. The remaining 31 colorectal patients were judged to have stable (19) or progressive (8) disease, with four unevaluable. Median survival was 18.6 months.
Comments Chronotherapy merits higher use in treating cancer. This technique, based on the innate rhythms of host tolerance and possibly tumor cell replication, represents another science-based strategy for treatment delivery.

For professional correspondence, please contact Dr.Levi at: francis.levi@hol.fr

Eugene A. Conrad

Presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) on May 17-20, 1997
CONRAD NOTES, © 1997 All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078 / June 1997

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