pirarubicin and Uterine-Cervical-Neoplasms

Nine patients with locally recurrent carcinoma of the cervix were treated with balloon-occluded arterial infusion chemotherapy (BOAI) in order to secure high concentrations of antitumor agents. All the patients had previously received radiation therapy for squamous cell carcinoma of the cervix. Recurrence was diagnosed by cytology and/or biopsy, or CT. Either cisplatin 100 mg/body and doxorubicin hydrochloride 40 mg/body or cisplatin 50-100 mg/body and pirarubicin 40-60 mg/body were infused after the bilateral internal iliac arteries had been occluded using balloon catheters. As the largest diameter of the tumors on CT increased, the mean survival after BOAI decreased. The mean survival of 4 patients with no detectable masses on CT was 45 +/- 30.7 months. In 5 patients, neurological complications, subcutaneous and/ or skin reactions of the buttock, or necrosis of the uterus developed. The neurological complications were damage to the sciatic nerve at the level of S1 or S2. Our study suggests that BOAI therapy may lead to a high complication rate in patients with locally recurrent carcinoma of the cervix who previously received radiation therapy, although long-term survival can be expected in patients with no detectable masses on CT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Catheterization; Chemotherapy, Adjuvant; Cisplatin; Doxorubicin; Female; Humans; Infusions, Intra-Arterial; Middle Aged; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms

From 1986 to 1990, a multicentric phase II study was conducted with pirarubicin, a new semi-synthetic anthracyclin[4'-O-tetrahydropyranyl-adriamycin (THP)]. 87 patients with advanced gynaecological cancers were treated: epidermoid cervical carcinoma (n = 31), adenocarcinoma of the endometrium (n = 28) and ovarian adenocarcinoma (n = 28). THP was administered by short intravenous infusion, for 3 consecutive days, every 3 weeks. The initial dose of THP was 25 mg/m2 day (25% of patients) which was then reduced to 20 mg/m2 day. The average number of courses was 3.7 (range 1-10). The cumulative THP dose was 180 mg/m2 (range 56-594) in cervix and endometrial tumours and 121 mg/m2 (range 58-425) in ovarian tumours. Myelosuppression was the major observed toxicity with grade 3-4 leukopenia and thrombocytopenia in 62 and 19% of the patients, respectively. Severe general complications occurred in 6% of the patients with three fatalities due to infections. Gastro-intestinal side-effects were frequent and usually mild (7% of grade 3 vomiting). 48% of the patients showed alopecia, which was complete in 9 cases (10%). 3 patients experienced cardiac events. No significant antitumoral activity was observed in patients who had failed to respond to previous chemotherapy. Promising antitumoral activity was noticed in untreated cervico-uterine carcinomas with 19% partial responses and 12% complete responses (CR). THP activity was lower in endometrial carcinomas (9.5% CR). Results were found to be negligible in ovarian cancer patients, most of them being refractory to previous chemotherapy containing an anthracyclin compound. On the basis of these results, the definite role of THP in gynaecological cancers deserves to be studied in more favourable programmes (e.g. in combined protocols as first-line chemotherapy).

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Antineoplastic Agents; Doxorubicin; Endometrial Neoplasms; Female; Humans; Leukopenia; Middle Aged; Ovarian Neoplasms; Thrombocytopenia; Uterine Cervical Neoplasms; Vomiting

Pirarubicin (THP) is a newer generation anthracycline anticancer drug. In the clinic, THP and THP-based combination therapies have been demonstrated to be effective against various tumors without severe side effects. However, previous clinical studies have shown that most patients with cervical cancer are not sensitive to THP treatment, and the associated mechanisms are not clear. Consistent with the clinical study, we confirmed that cervical cancer cells were resistant to THP in vitro and in vivo. Our data demonstrated that THP induced a protective macroautophagy/autophagy response in cervical cancer cells, and suppression of this autophagy dramatically enhanced the cytotoxicity of THP. By scanning the mRNA level change of autophagy-related genes, we found that the upregulation of ATG4B (autophagy-related 4B cysteine peptidase) plays an important role in THP-induced autophagy. Moreover, THP increased the mRNA level of ATG4B in cervical cancer cells by promoting mRNA stability without influencing its transcription. Furthermore, THP triggered a downregulation of MIR34C-5p, which was associated with the upregulation of ATG4B and autophagy induction. Overexpression of MIR34C-5p significantly decreased the level of ATG4B and attenuated autophagy, accompanied by enhanced cell death and apoptosis in THP-treated cervical cancer cells. These results for the first time reveal the presence of a MIR34C-5p-ATG4B-autophagy signaling axis in THP-treated cervical cancer cells in vitro and in vivo, and the axis, at least partially, accounts for the THP nonsensitivity in cervical cancer patients. This study may provide a new insight for improving the chemotherapeutic effect of THP, which may be beneficial to the further clinical application of THP in cervical cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Proteins; Cell Line, Tumor; Cysteine Endopeptidases; Doxorubicin; Female; Humans; MicroRNAs; Signal Transduction; Uterine Cervical Neoplasms

Cervical clear cell carcinoma is one of the rare subtypes of cervical adenocarcinomas. Few cases of cervical clear cell carcinoma have been reported in adolescents.. We present here a case of a 14-year-old adolescent female diagnosed with a stage II cervical clear cell carcinoma. The patient had no sexual history or diethylstilbestrol-exposure in utero. Polymerase chain reaction identified in the tumor the presence of human papillomavirus type 18, a high-risk genotype for cervical cancer development. The ovaries were retained during surgery and the patient was still alive without recurrence after 9 years.. Positivity of HPV18 nucleic acids suggests an association between high risk HPV infection and cervical clear cell carcinoma in the case. Furthermore, in the treatment of young patients with cervical carcinoma, the risks associated with loss of ovarian function should be weighed against that of potential ovarian metastasis.

Topics: Adenocarcinoma, Clear Cell; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemoembolization, Therapeutic; Cyclophosphamide; Doxorubicin; Female; Human papillomavirus 18; Humans; Hysterectomy; Uterine Cervical Neoplasms

We report the therapeutic potential, longterm survival, and toxicity of neoadjuvant intraarterial chemotherapy (NAIC) using an original four-lumen double-balloon (4L-DB) catheter followed by radical hysterectomy and/or radiotherapy in patients with locally advanced cervical cancer.. Sixty patients with stage IIB-IVA cervical squamous cell cancer were treated with NAIC which included cisplatin (60-70 mg/m(2), day 1), mitomycin-C (10-20 mg/m(2), day 1), and pirarubicin hydrochloride (THP; 10-20 mg/m(2), day 1) for two courses every 21 days.. The median follow up among surviving patients was 93.7 months. Among 60 eligible patients, 22 had a complete response (CR; 36.7%) including 12 with a pathologic CR (20.0%). Thirty-six patients had a partial response (60.0%), and stable disease was observed in only 2 patients (3.3%). Moreover, we found that the platinum concentration in the cervix was correlated with the clinical response (P < 0.001). The 10-year progression-free survival (PFS) and 10-year survival were 90.9% and 90.9%, respectively, in patients with stage IIB disease and 66.0% and 70.7%, respectively, in patients with stage III disease. Leukopenia occurred in 86.7% of patients, but it was not very severe (grade 3, 4 in 13.3% of patients).. Our results with NAIC using the 4L-DB catheter in locally advanced cervical cancer demonstrate that a high platinum concentration has beneficial effects on primary lesions and improves long-term progression-free and overall survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Catheterization, Peripheral; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Equipment Design; Female; Follow-Up Studies; Humans; Hysterectomy; Infusions, Intra-Arterial; Kaplan-Meier Estimate; Middle Aged; Mitomycin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Radiotherapy, Adjuvant; Time Factors; Treatment Outcome; Uterine Cervical Neoplasms

To find an effective protocol for chemoradiotherapy with pirarubicin hydrochloride (THP) for advanced cervical cancer patients, effects of irradiation on THP sensitivity were examined using the radiosensitive human cervical squamous cell carcinoma cell line ME180. Concurrent irradiation significantly reduced THP sensitivity, and this was further reduced when cells were treated with THP 8 h after irradiation. However, the THP sensitivity of cells treated with THP 8 h before irradiation was significantly enhanced. Four months after the first irradiation, 4 subclones of ME180 cells that survived repetitive irradiation demonstrated significantly higher THP sensitivity than non-irradiated parent cells. These results indicate that THP injections, more than several hours before irradiation or after completion of radiotherapy, might be better therapies than concurrent chemoradiotherapy with THP for cervical cancer.

Topics: Carcinoma, Squamous Cell; Cell Survival; Combined Modality Therapy; Doxorubicin; Female; Humans; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Doxorubicin; Female; Humans; Hysterectomy; Lymph Node Excision; Middle Aged; Uterine Cervical 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

The patient was a 77-year-old woman who had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy following the diagnosis of uterine cervical cancer at the age of 57. A recurrent tumor was detected on the anterior surface of the right iliopsoas muscle and fine needle aspiration of the tumor revealed squamous cell carcinoma. A needle was inserted into the tumor under transabdominal ultrasound guidance, and anticancer agents, chiefly cis-diamminedichloroplatinum [II] (CDDP), were injected. The patient also received systemic chemotherapy (CAP therapy) and radiotherapy. Subsequently, computed tomography showed a 73% reduction in the size of the tumor. A mass 7 cm in diameter was still present on the anterior surface of the iliopsoas after treatment, but tumor markers fell to normal levels. The patient is presently receiving UFT (600 mg/day) as maintenance therapy. At 48 months after recurrence, there has been no increase in the tumor size or tumor marker levels, and the performance status is grade 0. In conclusion, a good outcome was achieved by local injection of anticancer agents combined with systemic chemotherapy and radiotherapy, and there were few side effects.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Doxorubicin; Drug Administration Schedule; Female; Humans; Injections, Intralesional; Muscle Neoplasms; Tegafur; Uracil; Uterine Cervical Neoplasms

Twenty-four patients with locally advanced cervical cancer were treated with radiation therapy (RT) and transcatheter arterial infusion (TAI) chemotherapy, while 22 patients were treated with RT alone. RT consisted of a combination of external irradiation and high-dose-rate intracavitary brachytherapy. TAI therapy consisted of two sessions using cisplatin and pirarubicin, performed concurrently during the periods of external irradiation. The local-regional control rates at 1 year for the patients treated with RT plus TAI and for those treated with RT alone were 87.5% and 58.3%, respectively (p < 0.05). The 3-year cause-specific survival (CSS) rates for RT plus TAI, and RT alone were 67.1% and 55.9%, respectively (p = n.s.). The 3-year CSS rate for the 14 patients treated with RT and TAI who had well- or moderately differentiated squamous cell carcinoma without pelvic lymph node swelling was 100%, while that for the 19 patients with the same background treated with RT alone was 49% (p < 0.01). Radiation therapy combined with TAI appears to be an effective and safe treatment modality for patients with locally advanced cervical cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Humans; Infusions, Intra-Arterial; Middle Aged; Radiotherapy Dosage; Survival Rate; Uterine Cervical Neoplasms

We hypothesized that postchemotherapeutic recurrent cancer cells consist of sensitive cells and resistant cells. To examine this hypothesis, the clonality of the postchemotherapeutic surviving cancer cells was characterized. The postchemotherapeutic surviving cancer cells was established using a human cervical carcinoma cell line, ME180, in which cells were treated with either SN38, VP16, or THP for more than 8 weeks. The surviving cells were subcloned by limiting dilutions yielding the following cloning efficiencies: 18% for SN38, 26% for VP16, and 57% for THP. Characterization of the established subclones proved that the postchemotherapeutic recurrent cancer cells consisted of both sensitive cancer cells and resistant cancer cells. This result supports the hypothesis and hence points toward improvement of chemotherapeutic effect through an understanding of the dual types of surviving cells.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Carcinoma, Squamous Cell; Cell Survival; Doxorubicin; Enzyme Inhibitors; Etoposide; Female; Humans; Irinotecan; Tumor Cells, Cultured; Uterine Cervical Neoplasms

A patient with neck lymph node metastasis from squamous carcinoma of the uterine cervix was treated by immunotherapy and neo-adjuvant intraarterial infusion chemotherapy (OK-432 ic, etoposide 25 mg/body x 7 days po, CDDP 100 mg/m2/5 hr iA, CPM 200 mg/body iv, THP 50 mg/m2/2 hr iA). Three courses of the neo-adjuvant chemotherapy were given. After the first course, the neck metastatic tumor appeared remarkably small. After the second, the neck tumor disappeared and the uterine tumor appeared small and to have good movement. Hysterectomy was performed one month after. Each tissue platina concentration (microgram/cm3) is 9.12 uterus cervix, 10.9 uterus corporis, 8.17 fallopian tube, 14.0 ovarium, 1.47-0.88 pelvic lymph node. This patient was treated with irradiation after operation, and is presently in a state of cytological complete remission. Now she continues maintenance immunochemotherapy with UFT and OK-432 with a home doctor.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Hysterectomy; Immunotherapy; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Lymph Node Excision; Picibanil; Remission Induction; Tegafur; Uracil; Uterine Cervical Neoplasms

The combined effects of pirarubicin (THP) and various antitumor drugs on HeLa S3 human uterine cervix carcinoma and K562 human myelocytic leukemia cells were determined by enhancement of their cytotoxic activities. The combination of 0.15 microgram/ml THP with cisplatin (CDDP), mitomycin C (MMC), peplomycin (PEP), 5-fluorouracil (5-FU), methotrexate (MTX), enocitabine (BH-AC) or etoposide showed synergistic effects on HeLa S3 cells. Also, the combination of 0.01 microgram/ml THP with CDDP, BH-AC or etoposide showed synergistic effects on K562 cells. Especially, the combined effects of THP with MMC or MTX were remarkable, and the combination under almost all concentrations of MMC or MTX showed synergistic effects on HeLa S3 cells. On the other hand, the combination of adriamycin (ADM) with MMC or MTX did not show such a remarkable effects on HeLa S3 cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Etoposide; Female; Humans; Leukemia, Myeloid; Methotrexate; Mitomycin; Mitomycins; Tumor Cells, Cultured; Uterine Cervical Neoplasms

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

THP-ADM is a new antitumor antibiotic which belongs to the anthracycline group. This agent was administered to 42 histology proven various malignant disease patients with a schedule of 60-80 mg per body (40-55 mg per m2) iv bolus, every three weeks. THP-ADM administration revealed mild upper GI toxicity (vomiting 19%, stomatitis 21%) and leukopenia (less than 2,000 per mm3) in 80% and thrombocytopenia (less than 60,000 per mm3) in 38% with good rebound. There was no signs or symptoms of cardiac failure including the patient who had received 740 mg per body (500 mg per m2). Definite response (CR, PR) was observed in ovarian carcinoma 4/11, cervix carcinoma 2/7, breast carcinoma 1/6, malignant lymphoma 5/5 and mesothelioma 1/2. Furthermore, some response (MR) was observed in lung metastasis from endometrial carcinoma 2/4, and stomach carcinoma 1/3. The above indicated usefulness of this agent and further study should be continued, especially a controlled study with adriamycin.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Doxorubicin; Drug Evaluation; Female; Humans; Lymphoma; Male; Mesothelioma; Middle Aged; Ovarian Neoplasms; Sarcoma; Stomach Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms