Chemotherapy of advanced ovarian cancer with 4'-O-tetrahydropyranyl doxorubicin and cisplatin: a randomized phase II trial with an evaluation of circadian timing and dose-intensity.

Abstract

The efficacy and toxicity of the new anthracycline, 4'-0-tetrahydropyranyl doxorubicin (THP) (50 mg/m2 intravenous [IV] bolus) in association with cisplatin (100 mg/m2 IV as a 4-hour infusion) was assessed in 31 patients with advanced ovarian carcinoma. Twenty-eight patients were assessable for toxicity among whom 25 were assessable for response (International Federation of Gynecology and Obstetrics [FIGO] stage IIIa, four patients; IIIb, 15 patients; IV, six patients). Nine patients had received prior treatment. Patients were randomized to receive schedule (sch) A (THP at 6 hours, then cisplatin from 16 to 20 hours) or sch B (THP at 18 hours, then cisplatin from 4 to 8 hours). Sch A was hypothesized as less toxic since THP was best tolerated in the late rest span and cisplatin near the middle of the activity span in experimental studies. The rate of clinical complete response (CR) was 52%, that of partial response (PR) was 12%, and the overall clinical response rate (CR plus PR) was 64% (sch A, 73%; sch B, 57%). Median progression-free survival and survival times were, respectively, 10 and 19 months. Of 12 patients in clinical CR evaluated at second-look laparotomy, four had a pathological CR (33%), and three had microscopic residual disease (MD). The overall rate of pathological CR was 16%. Sch A was associated with less neutropenia (P = .10), thrombocytopenia (P less than .01), anemia (P less than .01), and renal toxicity (P less than .05) than sch B. Of four patients withdrawn for toxicity, three were on sch B (one death). Mean dose intensities (DIs) of THP and cisplatin, respectively, decreased by 30% and 47% over the five initial courses. Such decrease was significantly more pronounced for sch B than for sch A in previously untreated patients (P from 2-way analysis of variance [ANOVA] less than .01). THP-cisplatin is active against advanced ovarian cancer, and its toxicities can be significantly decreased by dosing THP in the early morning and cisplatin in the late afternoon as compared with THP in the evening and cisplatin the next morning.

In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

“…(22)(23)(24)(25)(26) It exhibits faster intracellular uptake and more potent antitumor activity than doxorubicin in vivo due to its pyranyl group and lipophilic properties. (26)(27)(28)(29)(30)(31) However, it exerts poor tumor targeting properties as is common to other low molecular weight anticancer agents. (26)(27)(28)(29)(30)(31)(32) The rationale for the choice of pirarubicin for the SMA-micelle is that once SMA-pirarubicin micelles reach the target tumor tissue, the micelles will release free pirarubicin slowly in a sustained manner in the vicinity of tumor cells by virtue of the EPR effect.…”

“…(26)(27)(28)(29)(30)(31) However, it exerts poor tumor targeting properties as is common to other low molecular weight anticancer agents. (26)(27)(28)(29)(30)(31)(32) The rationale for the choice of pirarubicin for the SMA-micelle is that once SMA-pirarubicin micelles reach the target tumor tissue, the micelles will release free pirarubicin slowly in a sustained manner in the vicinity of tumor cells by virtue of the EPR effect. Pirarubicin will be more effectively transported into tumor cells than doxorubicin.…”

DNA cell cycle distribution and glutathione (GSH) content according to circadian stage in bone marrow of cancer patients

“…There are less dose reductions, less treatment related complications and less postponements of drug courses when drugs have been administered at certain times of the day (Hrushesky, 1985;Kerr et al, 1990;Levi et al, 1990). …”

Los ritmos circadianos en cáncer y la cronoterapia

“…En 1990 el grupo del Hospital Paul Brousse en Francia llevó a cabo un ensayo clínico fase II con 28 pacientes con diagnóstico de carcinoma epitelial de ovario comparando el uso de doxorrubicina a las 6 a. m. y a las 6 p. m. y el de cisplatino en intervalos desde las 4 a. m. a las 8 a. m. y desde las 4 p. m. a las 8 p. m. Este ensayo mostró que el grupo que recibió la doxorrubicina en la mañana y el cisplatino en la noche tuvo menos alteraciones hematológicas y renales, además de una mayor respuesta clínica que el otro grupo (52).…”