pirarubicin and Genital-Neoplasms--Female

The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00h and 21:00h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Cycle; Chronotherapy; Circadian Rhythm; Cisplatin; Doxorubicin; Endometrial Neoplasms; Female; Floxuridine; Genital Neoplasms, Female; Humans; Kidney Neoplasms; Male; Ovarian Neoplasms; Prostatic Neoplasms; Rats; Urinary Bladder Neoplasms; Urogenital Neoplasms

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Doxorubicin; Drug Administration Schedule; Endometrial Neoplasms; Female; Genital Neoplasms, Female; Humans; Leukopenia; Middle Aged; Neutropenia; Ovarian Neoplasms; Paclitaxel; Retrospective Studies; Taxoids; Thrombocytopenia; Uterine Cervical Neoplasms

Pirarubicin (PIRA) has been shown to have improved potency with less cardiac toxicity in several phase I and II clinical trials in Japan and Europe. Since Adriamycin (DXR) remains one of the most potent drugs in treatment of gynecologic cancers, this derivative has the potential to become an important chemotherapeutic agent. In this study, we compared the performance of these two drugs against a panel of 10 gynecologic cancer cell lines. The ATP chemosensitivity assays were used to determine dose-response curves. Flow cytometry was used to study cell kinetic response to both drugs. Using an IC50 value of 0.2 micrograms/ml as a cutoff for drug sensitivity, 4 cell lines, ECC1, HEC1B, BG1, and SKOV3, were considered resistant to DXR. By comparing IC50s, PIRA was 3.4 +/- 0.4 times more potent than DXR (P = 0.05). The other 6 cell lines, AN3, AE7, HEC1A, CAOV3, SKUT1B, and ME180, were considered sensitive to DXR. In this group of cell lines, PIRA was 1.6 +/- 0.3 times more potent than DXR (P = 0.5). Both PIRA and DXR elicited a spectrum of cell kinetics. By comparing the magnitude of G2 blocks at 0.1 micrograms/ml, PIRA was approximately 2-5 times more potent than DXR in SKUT1B, HEC1A, and BG1 cell lines. PIRA also displayed a reverse dose-response pattern of G2 block so that at high dose, cell cycle kinetics would mirror those of untreated controls. This observation supports the presence of a resistant tumor subpopulation and the concept of tumor heterogeneity.

Topics: Antibiotics, Antineoplastic; Cell Cycle; Doxorubicin; Female; Genital Neoplasms, Female; Humans; Kinetics; Tumor Cells, Cultured

We treated 14 patients with cyclophosphamide, adriamycin and cisplatin (CAP), and 16 patients with cyclophosphamide, Pirarubicin and cisplatin (CTP). Hematological changes in the peripheral blood were compared in the two groups to determine whether there was any difference in bone marrow suppression. 1) The lowest leukocyte counts were similar in the two groups. The leukocyte count reached its nadir at 11.6 +/- 2.1 days in the CTP group and at 15.1 +/- 2.8 days in the CAP group, a significant difference (p less than 0.01). 2) The leukocyte count recovered rapidly in the CTP group and was significantly higher (p less than 0.01) at 3 to 4 weeks than in the CAP group, and it returned to the pretreatment level in the CTP group in the fourth week. 3) The platelet count reached its lowest level in the second week in both groups. In the CTP group, it was significantly higher (p less than 0.01) than in the CAP group. 4) Reticulocyte count reached its lowest level in the first week in both groups, and then started increasing. 5) In the CTP group, a course of treatment was 28.0 +/- 2.3 days and it was 29.5 +/- 2.3 days in the CAP group. In 28% of the CPA group, it took 30 days or more for the leukocyte count to return to normal after one course, while none of the CTP group did the leukocyte count remain low for 30 days. These results show that CTP causes more rapid bone marrow suppression (particularly leukocytopenia) than CAP, does but that a recovery is more rapid with CTP. These CTP may be a better form of treatment than CAP.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Genital Neoplasms, Female; Humans; Leukocyte Count; Platelet Count

We conducted a joint phase II study in 76 patients with gynecological cancer (42 patients with ovarian cancer, 22 patients with cervical cancer, 10 patients with endometrial cancer and 2 patients with vaginal cancer). The response rate was 25.0% in the patients with ovarian cancer, 13.3% in those with cervical cancer, and 28.6% in those with endometrial cancer. The overall response rate was 23.1%. When the patients were classified according to dose schedules, the highest response rate was obtained in the group administered THP-ADM at a dose of 60 mg per body by single i.v. injection at 3-week intervals. Such side effects as myelosuppression and gastrointestinal disturbances were observed, but alopecia, a marked side-effect of ADM administration, was mild, and no cardiac toxicity was seen in any of the patients.

Topics: Adult; Aged; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Genital Neoplasms, Female; Humans; Middle Aged; Ovarian Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms; Vaginal Neoplasms