Neoadjuvant weekly carboplatin and paclitaxel followed by radical hysterectomy for locally advanced cervical cancer: long-term results.

INTRODUCTION: To determine the long-term effect of neoadjuvant chemotherapy with paclitaxel and carboplatin on a weekly schedule followed by radical surgery for patients with locally advanced cervical cancer. MATERIALS AND METHODS: Thirty patients with stage IB2 to IIIB uterine cervical cancer were treated with paclitaxel (60 mg/m) and carboplatin (area under the curve, 2-an area under the time-concentration curve of 2 mg x min/mL based on creatinine clearance) every week for 6 cycles. A radical hysterectomy was performed 6 days after the final administration of neoadjuvant chemotherapy. The patients were followed up, and 5-year progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Of 30 patients, 28 were followed up. The median follow-up period was 55.6 months (range, 26-83 months). An objective response (complete response + partial response) to the treatment was observed in 26 patients (87%; 95% confidence interval, 70%-95%). Two had complete response, 4 had stable disease, and the remaining patients had partial response; progressive disease was not seen in this study. A radical hysterectomy was performed in 28 patients without delay. Thirteen patients with high-risk factors received radiotherapy after surgery. The 5-year PFS and OS rates were 78.6% and 81.8%, respectively. The 5-year PFS and OS for patients with stage IB2 to IIB cervical cancer were 79.2% and 83.1%, respectively, which were comparable with those in the concurrent chemoradiation therapy study previously reported. There was no significant correlation in survival between preoperative staging and cell type, whereas larger initial tumor size and lymph node metastasis tended to be negatively correlated with survival. CONCLUSIONS: Neoadjuvant chemotherapy with paclitaxel and carboplatin on a weekly schedule followed by radical surgery for patients with locally advanced cervical cancer is a promising mode of therapy that may improve the prognosis. It would be worthwhile to conduct larger-scale trials for comparison with the results of the chemoradiation therapy study.

A phase I/II study of docetaxel and gemcitabine combination for chemotherapy-resistant ovarian cancer.

BACKGROUND: A phase I/II study of docetaxel (DOC) and gemcitabine (GEM) combination for treatment-resistant ovarian cancer (OC) was conducted. MATERIALS AND METHODS: Eligible patients exhibited recurrent OC within 12 months after initial treatment, or after more than 2 chemotherapy regimens. Planned dose levels (DL) were as follows: DOC 70 mg/m(2), GEM 800 mg/m(2) (DL1); DOC 70 mg/m(2), GEM 1000 mg/m(2) (DL2). DOC was administered on day 1 combined with GEM on days 1 and 8 every 3 weeks. Adverse events were assessed by NCI-CTC2.0J. Response was evaluated by RECIST or Rustin's criteria. RESULTS: The recommended dose was DL1. For all enrolled patients, the median interval from last chemotherapy was 2.5 (1-11) months and 32 patients were assessable for response. One complete response, 6 partial responses and 6 stable disease were noted. Median time to progression was 4.8 months. Toxicities were mainly hematological and manageable. CONCLUSION: This combination could be an acceptable treatment option before palliation.

Junctional adhesion molecule A [corrected] expression in human endometrial carcinoma.

Junctional adhesion molecule A (JAM-A) is involved in cell-cell contact and tight junction formation. Loss of cell adhesion molecules may be associated with high histologic grade and invasiveness of endometrial carcinoma. We attempted to determine JAM-A expression in human endometrial carcinoma and its correlations with pathologic features, stage, and survival. Junctional adhesion molecule A expression in human endometrial carcinoma was evaluated by immunohistochemistry. In addition, we cultured human well and poorly differentiated endometrial adenocarcinoma cell lines, Ishikawa cells, and KLE in 3-dimensional basement membrane preparation, and JAM-A expression in these cells was assessed by real-time reverse transcription-polymerase chain reaction and immunohistochemistry. Junctional adhesion molecule A immunostaining intensity was negatively correlated with histologic grade (tau = -0.420, P < 0.0001), myometrial invasion (tau = -0.306, P < 0.01), and stage (tau = -0.383, P < 0.0001). Low JAM-A immunostaining intensity was associated with positive vascular space involvement (P < 0.01). Moreover, low immunostain intensity was significantly (P < 0.0001) related to low overall survival rate and progression-free survival rate. Additionally, in our 3-dimensional epithelial cell culture, JAM-A expression in poorly differentiated adenocarcinoma was significantly lower than that in well-differentiated adenocarcinoma (P < 0.001). Junctional adhesion molecule A expression seems to be reduced in high-grade or advanced endometrial carcinoma and may be a prognostic factor.

Intravenous paclitaxel is specifically retained in human gynecologic carcinoma tissues in vivo.

Paclitaxel and carboplatin are commonly used and well-tolerated agents for gynecologic malignancies. The persistence of platinum in human tissues for 14 days and the long-term retention of platinum in tissues for up to 17 months have been reported. Paclitaxel remains in human uterine cervical cancer tissues for 6 days. These findings prompted us to determine the retention of paclitaxel and carboplatin in human uterine cervical carcinoma, endometrial carcinoma, ovarian carcinoma, and pelvic lymph nodes to establish baseline parameters and guide the development of more effective treatment interventions. Thirty patients with uterine or ovarian carcinomas were treated with intravenous weekly paclitaxel-carboplatin chemotherapy before surgery. The concentrations of these agents in carcinoma tissue, normal cervical, myometrial and ovarian tissues, and pelvic lymph nodes were measured 5 days after the final administration. Paclitaxel was specifically retained in cervical, endometrial, and ovarian carcinoma tissues but was not detected in lymph nodes. In contrast to paclitaxel, carboplatin was readily detectable with similar levels in all tumor-associated and normal host tissues. In addition, a low paclitaxel concentration in cervical carcinoma tissue was significantly associated with short progression-free survival and overall survival. Further studies are needed to clarify the tissue distribution of anticancer drugs in humans and promote optimal treatment strategies enhancing paclitaxel lymphatic targeting.

Function of estrogen-related receptor alpha in human endometrial cancer.

INTRODUCTION: The estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily that is closely related to estrogen receptor alpha (ERalpha). ERRalpha binds an estrogen response element (ERE), directly competes with ERalpha for binding ERE, and represses ERE-dependent transcription in MCF-7 cells, ER-positive breast cancer cells. OBJECTIVE: We investigated whether ERRalpha modulate some ER-dependent activities in endometrial cancer. METHOD: We investigated protein and mRNA expression of ERRalpha in endometrial cancer using immunohistochemistry and RT-PCR, respectively. After transient transfection using the ERRalpha expression vector (pCI-ERRalpha) or ERRalphaSi, which suppressed the expression of endogenous ERRalpha, Ishikawa cells were assayed for ERE-dependent luciferase activity. Cells stably overexpressing ERRalpha were generated and compared with estrogen-dependent and -independent cell growth. RESULT: ERRalpha was detected in human endometrial cancer tissues by immunohistochemistry. An RT-PCR study showed that mRNA of ERRalpha was expressed in four endometrial cancer cell lines (Ishikawa, Hec1a, KLE, and SNGII) and 11 human endometrial tissues. Overexpression of ERRalpha repressed estrogen-induced ERE-dependent transcriptional activity in Ishikawa cells. After transfection with ERRalphaSi1, the expression of endogenous ERRalpha decreased to 0.5-fold, and estrogen-induced ERE luciferase activity increased to 1.5-fold. The cells stably overexpressing ERRalpha grew up more slowly than control cells in the presence of 10 nm estradiol. CONCLUSION: ERRalpha is expressed in human endometrial cancer tissues and cell lines and suppresses ERE-dependent transcriptional activity in the presence of estrogen. ERRalpha modulates estrogen-induced activity in estrogen-dependent endometrial cancer.

Retention of paclitaxel in cancer cells for 1 week in vivo and in vitro.

PURPOSE: Clinically, the administration of paclitaxel for ovarian cancer on a dose-dense weekly schedule, rather than the conventional every-3-week schedule, might demonstrate greater tumor-cell death. Here, we investigate the pharmacokinetics and the pharmacodynamics of weekly paclitaxel in cancer cells in vivo and in vitro. EXPERIMENTAL DESIGN: Paclitaxel concentrations were measured by HPLC, and apoptotic cells were detected by TUNEL assay in paclitaxel-pretreated cervical cancer cells treated with paclitaxel (10 ng/ml) and in the tissues of cervical cancer patients treated with weekly paclitaxel (60 mg/m2/week). Polymerized tubulin was detected with a tubulin polymerization assay, and the BrdU cell proliferation assay was used to assess the effect of paclitaxel. RESULTS: Paclitaxel remained in the cancer tissues of six patients for 6 days after the last medication. In vitro, paclitaxel was retained in all cell lines for 24 h after its removal from the medium, and paclitaxel was still detectable in CaSki cells on day 7. Simultaneous treatment with depolymerizing drugs inhibited the retention of paclitaxel in cells and paclitaxel-induced polymerization of tubulin. After paclitaxel treatment, apoptotic cells were detected in cancer tissues and CaSki cells for 1 week. Under high magnification, apoptotic cells on day 7 after paclitaxel treatment showed multinucleation. CONCLUSIONS: Paclitaxel is unusual in that it accumulates especially in cancer cells and induces apoptosis for 1 week in vivo and in vitro. On the other hand, paclitaxel could not be detected in cancer tissues after 2 weeks. The administration of paclitaxel on a weekly schedule, rather than the standard every-3-week schedule, might produce greater tumor-cell death.

Management of postoperative follow-up and surgical treatment for Krukenberg tumor from colorectal cancers.

BACKGROUND/AIMS: The purpose of this retrospective study was to evaluate the clinical presentation as well as surgical intervention for ovarian metastasis from colorectal cancers identified during postoperative follow-up. METHODOLOGY: Nine cases of ovarian metastasis were observed among 452 female patients with colon cancers between 1990 and 2000. Initial symptoms were pain (67%), pelvic mass (50%), vaginal bleeding (33%), and uterine bleeding (17%). On pathological evaluation, six cases (67%) were found to be moderately differentiated, and three (33%) well differentiated adenocarcinomas. RESULTS: Early diagnosis is very difficult. The growth of metastatic ovarian tumors are slow in elder patients, its growth is rapid in younger patients, and frequently diagnosed as huge ovarian tumors. In some cases, as cystic ovarian lesions they were identified in their early stage but could not be diagnosed as ovarian metastases, later curative operation could not be performed. The consulting gynecologist could not reach the correct diagnosis. Regular postoperative pelvic CT or MRI should be helpful for diagnosis. Although serum CEA levels did not increase in most cases, tumor markers CA125 and SLX were elevated in several cases, and thus may be useful for the detection of ovarian metastases. Surgical treatment consisted of bilateral and unilateral salpingo-oophorectomy or pelvic exenteration and additional hysterectomy for one patient because of association with cervical cancer. The median survival time after the primary operation was 20.8 months, ranging from 3 to 96 months. Peritoneal dissemination and bone metastases were frequently observed as recurrence after these operations. Two cases (non-synchronous solitary metastasis or direct involvement, located in the pelvis) survived more than 5 years (85 and 96 months, respectively), and both patients were treated with pelvic exenteration. CONCLUSIONS: This suggests that in general most cases with ovarian metastasis have a poor prognosis and that radical operation such as pelvic exenteration can improve survival only in cases of recurrent solitary ovarian metastasis or local extended disease, i.e. when the lesion is located only in the pelvis.

[Phase II study of combination therapy with paclitaxel and carboplatin against postoperative small residual disease in patients with stage I c-IV ovarian cancer--KCOG 989 trial].

The tolerability and feasibility of combination therapy with paclitaxel (TXL) and carboplatin (CBDCA) against small residual disease following first-line optimal debulking of stage I c-IV ovarian cancer were evaluated in a multicenter dose-finding study. Eligibility criteria included histologically diagnosed stage I c-IV epithelial ovarian cancer with a postoperative residual lesion < or = 10 mm in diameter, no prior chemotherapy, and written informed consent of the patient and his/her family members to the chemotherapy. Twenty-two patients were enrolled and 20 of them were eligible. The patients were to receive 5 courses of TXL (175 mg/m2) and CBDCA (AUC 5) every 3 weeks. Hematological toxicities occurred in the form of grade 3 leukopenia during 25.7% of all courses, grade 3 neutropenia during 32.0% of all courses, and grade 4 neutropenia during 56.0% of all courses. No courses were associated with grade 4 leukopenia. G-CSF support was needed during 48 of 109 courses (44%) and caused normalization of the leukocyte count from a nadir of 1,921 +/- 434/mm3 after a mean time of 6 +/- 3.1 days, compared with 6 +/- 3.6 days needed for recovery from a nadir of 2, 357 +/- 360/mm3 without G-CSF support. This indicates similarly rapid recovery from severe leukopenia with the use of G-CSF. All eligible patients completed at least 5 courses of the chemotherapy. Some courses were given at a reduced dose or delayed due to toxicity but these dosage modifications were thought to be acceptable for both TXL and CBDCA. Five courses of TXL combined with CBDCA were tolerated well in this patient population.

A pilot study of docetaxel-carboplatin versus paclitaxel-carboplatin in Japanese patients with epithelial ovarian cancer.

BACKGROUND: It has been reported that a docetaxel-carboplatin combination as first-line chemotherapy for ovarian cancer showed a level of progression-free survival similar to that of paclitaxel-carboplatin while reducing neurotoxicity and improving quality of life. We investigated the recommended doses of docetaxel-carboplatin in Japanese patients with ovarian cancer and conducted a comparative study of docetaxel-carboplatin versus paclitaxel-carboplatin. METHODS: Thirty-nine patients with ovarian cancer were enrolled in this study and 38 patients were evaluated. We conducted a dose-escalation study using a docetaxel dose of 70 mg/m(2) and carboplatin AUC 5 and 6. In the comparative study, patients received either docetaxel 70 mg/m(2) and carboplatin AUC 5 or paclitaxel 175 mg/m(2) and carboplatin AUC 5. Progression-free survival, survival rate at 2 years, response rate, toxicity, and quality of life were investigated. RESULTS: In the dose-finding study, we determined the recommended doses as docetaxel 70 mg/m(2) and carboplatin AUC 5. In the comparative study, the two arms showed similar progression-free survival. Grade 4 neutropenia occurred more frequently in the docetaxel-carboplatin group (84.6%) than in the paclitaxel-carboplatin group (43.8%), while sensory neurotoxicity was less frequent in the docetaxel-carboplatin group (53.8%) than in the paclitaxel-carboplatin (68.8%) group. There were significant differences in the quality-of-life data in favor of docetaxel-carboplatin. CONCLUSION: We determined the recommended doses of docetaxel-carboplatin for Japanese patients with ovarian cancer to be docetaxel 70 mg/m(2) and carboplatin AUC 5. In the comparative study, we suggest that the docetaxel-carboplatin combination is effective and well tolerated as first-line chemotherapy for Japanese patients with ovarian cancer.