Phase I study of combination chemotherapy with irinotecan hydrochloride and nedaplatin for cervical squamous cell carcinoma: Japanese gynecologic oncology group study.

The aim of this study (JGOG1063) was to determine the recommended dose (RD) for combination chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin (NDP) for advanced cervical squamous cell carcinoma. CPT-11 was given intravenously in fixed doses of 60 mg/m2 on days 1 and 8 and NDP, in escalating doses, on day 1, every 4 weeks. A total of 15 patients were enrolled in the study. At level 1 (NDP: 50 mg/m2), one of the 3 patients developed grade 3 diarrhea, so 3 additional patients were enrolled at this level. As none of the 3 additional patients exhibited dose-limiting toxicity, level 1 was elevated to level 2 (NDP: 60 mg/m2). The maximum tolerated dose was not reached, even at the highest dose level (level 4; NDP: 80 mg/m2). No further dose escalation was carried out, and level 4 (CPT-11: 60 mg/m2, NDP: 80 mg/m2) was determined as the RD.

Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women.

PURPOSE: To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women. PATIENTS AND METHODS: This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points. RESULTS: CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months. CONCLUSION: The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.

Parathyroid hormone-related protein-secreting uterine endometrioid adenocarcinoma.

The diagnosis of parathyroid hormone-related protein (PTHrP)-secreting metastatic uterine endometrioid cancer was made in a 32-year-old Japanese woman with humoral hypercalcemia of malignancy. The primary endometrial cancer had been removed, and the tumor was diagnosed as Grade 1 endometrioid adenocarcinoma with shallow myometrial invasion. Salvage chemotherapy (paclitaxel and calboplatin) was started from 5 months after surgery when recurrent tumors were detected in the peritoneum and liver. Despite the salvage chemotherapy, the tumor progressed and hypercalcemia became evident with elevated PTHrP whereas no bone metastasis was identified. To the best of our knowledge, this is the first reported case of hypercalcemia due to PTHrP secretion in uterine endometrioid adenocarcinoma.

MR imaging evaluation of postmenopausal adnexal masses: correlation with final pathologic diagnosis.

OBJECTIVE: Adoption of transvaginal ultrasound in usual clinical settings allowed us to find asymptomatic adnexal masses more frequently in postmenopausal women. These masses were traditionally considered as the indication of surgical excision to determine histological diagnosis. Recently, if the appearance of that is simple cyst, conservative management may be acceptable because ultrasound benign diagnosis is proved to be reasonably reliable. We investigate here the reliability of benign diagnosis by MR imaging with gadolinium enhancement for both of simple and complex postmenopausal adnexal cystic masses. METHOD: We retrospectively examined the data of 121 postmenopausal patients who underwent surgery during a 3-years-period (from January, 2000 to December 2002) for adnexal mass under diagnosis of benign adnexal cysts based on MR imaging. RESULTS: Pathological examination identified two cases of malignancy among 121 cases diagnosed as benign by MR imaging. Among the cysts that revealed a simple pattern by MR imaging, 64/66 cases (97.0%) were benign histology and among the cysts that showed a complex pattern by MR imaging, 55/55 cases (100%) were benign histology. Among the cysts with diameter less than or equal to 10cm, 48/49 simple cysts and 32/32 complex cysts were benign histology. CONCLUSIONS: The diagnosis of benign adnexal mass in postmenopausal women by MR imaging was reliable. Conservative observation for postmenopausal patients of asymptomatic and small cysts under benign diagnosis based on MR imaging with gadolinium enhancement will be feasible even if the cysts appearances are complex, with careful follow-up program.

[A dose escalation study of concurrent chemoradiation therapy with nedaplatin for cervical cancer].

Doses of nedaplatin (CDGP) were established for concurrent chemoradiation therapy (CCRT) for cervical cancer, and a collaborative dose escalation study involving 8 hospitals was conducted to investigate the safety and efficacy of this therapy. Radiotherapy was performed according to the standard treatment described in the Regulations of Cervical Carcinoma Treatment. CDGP at 80 mg/m2 as Level 1 or at 90 mg/m2 as Level 2 was administered on Days 1 and 29 of treatment. Dose-limiting toxicity (DLT) was observed in 1 of 6.patients receiving 80 mg/m2 of CDGP and in all 2 patients receiving 90 mg/m2 of CDGP; therefore, Level 2 was regarded as the maximum tolerated dose (MTD), and Level 1 as the recommended dose. DLT signs consisted of delayed improvement in the leukocyte count in 2 patients and anorexia in 1 patient, suggesting that delayed improvement in the leukocyte count is the main DLT of this combination therapy. The main side effects were digestive disorders such as nausea and anorexia and bone marrow suppression, such as leukopenia, neutropenia, and thrombopenia. Side effects in the Level 1 group were more mild than in the Level 2 group. The efficacy was PR or better in all patients. The CR rates were 60% (6/10) in the Level 1 group and 50% (1/2) in the Level 2 group; there was no marked difference between the two groups. These results suggest that CCRT involving administration of CDGP at 80 mg/m2 on Days 1 and 29 is safe and effective.

Clinical over- and under-estimation in patients who underwent hysterectomy for atypical endometrial hyperplasia diagnosed by endometrial biopsy: the predictive value of clinical parameters and diagnostic imaging.

OBJECTIVE: The aim of this study was to analyze the clinical and imaging characteristics in patients diagnosed with atypical endometrial hyperplasia based on endometrial biopsy in comparison with the final diagnosis from resected uteri; i.e. to determine the rates of underestimation (endometrial cancer), equivalent diagnosis (atypical hyperplasia), and overestimation (hyperplasia without atypia or non-hyperplastic lesion). MATERIALS AND METHODS: We reviewed 33 patients who were diagnosed with atypical endometrial hyperplasia by endometrial biopsy using a small curette and then underwent total abdominal hysterectomy between September 1992 and May 2002. Clinical parameters obtained from patients' charts, and imaging analyses using transvaginal ultrasonography (TUS) and magnetic resonance (MR) imaging were retrospectively re-examined. RESULTS: Among 33 patients who underwent hysterectomy due to a diagnosis of atypical hyperplasia, nine cases (27.2%) were underestimated (cancer), nine cases (27.2%) were equivalent and 15 cases (45.6%) were overestimated as indicated by examination of the endometrium of the resected uterus. There was no difference among these groups in either clinical parameters or diagnostic images obtained by TUS or MR. CONCLUSION: Diagnosis of atypical endometrial hyperplasia by endometrial biopsy often resulted in under- or over-estimation, as shown by examination after hysterectomy. As there is neither a reliable clinical parameter nor imaging feature to distinguish between these groups, hysterectomy is still the best treatment for these patients if they are willing to give up their fertility.

Metastatic ovarian tumors: a review of 64 cases.

OBJECTIVE: The goal was to review cases of metastatic ovarian tumor with respect to their clinical features. METHODS: Sixty-four patients with pathologically confirmed metastatic ovarian carcinoma, who were treated between 1978 and 2002 at Osaka Medical Center for Cancer and Cardiovascular Diseases (OMCC), were reviewed and the clinical features examined. RESULTS: We found that metastatic tumors accounted for 21.1% (64/304) of malignant ovarian tumors. Of 64 metastatic ovarian tumors, 26 originated from gynecologic organs, and 38, from nongynecologic organs. Gynecologic primary sites were the uterine body (23%), uterine cervix (14%), and fallopian tube (3%). Eight of nine cervical cancers with ovarian metastases were adenocarcinomas. Adenocarcinoma of the uterine cervix metastasized to the ovaries more frequently than squamous cell carcinoma (5.6% vs 0.1%, respectively; P < 0.01). Among 38 cases of metastatic ovarian tumors from nongynecologic organs, Krukenberg tumors, pathologically characterized by the presence of typical signet-ring cells, were found in 11 patients (29%). Most (8/11) had originated in the stomach. Half (19/38) were preoperatively diagnosed as metastases. The 5-year survival rate after resection of metastatic ovarian tumors from gynecologic organs was significantly higher than the rate after resection of such tumors from nongynecologic organs (47% vs 19%, respectively; P = 0.026). CONCLUSIONS: Metastatic ovarian tumors are likely to be relatively common in Japan because of the high incidence of gastric cancer. In cases of pelvic tumor, metastatic ovarian tumor should always be included in the differential diagnoses. As the 5-year survival after resection of metastatic ovarian tumor is 19%, even for tumors from nongynecologic organs, it seems worthwhile to consider tumorectomy as the second cytoreduction.

Irinotecan (CPT-11) and cisplatin as first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of a combination of irinotecan (CPT-11) and cisplatin as first-line chemotherapy in advanced ovarian cancer. METHODS: Twenty-six patients with previously untreated advanced epithelial ovarian cancer were enrolled in this study. CPT-11 60 mg/m(2) was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m(2) on day 1. Cycles were repeated every 28 days for at least two cycles. The median patient age was 55 years (range, 37-75), and the median performance status was 1. RESULTS: Objective responses were recorded in 19 of 25 eligible patients (76%; 95% confidence interval, 55-91%). Complete responses were obtained in 2 patients (8%), and partial response in 17 patients (68%). Stable disease was recorded in 2 patients (8%) and progressive disease in 2 (8%). The median time to response was 62 days (range, 28-234 days). The median survival time for all 25 patients was 30.9+ months (range, 4.1-60.0+ months). The major toxic effects were leukopenia, neutropenia, and diarrhea. Grade 3 or 4 leukopenia, neutropenia, and diarrhea occurred in 17 (68%), 20 (83.3%), and 5 patients (20%), respectively. Thrombocytopenia was less common. No treatment-related deaths occurred. CONCLUSION: The combination of CPT-11 and cisplatin showed significant activity in chemotherapy-naive patients with advanced ovarian cancer. Neutropenia was the dose-limiting adverse effect, whereas diarrhea was mainly mild to moderate.

Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in cervical intraepithelial neoplasia.

Angiogenesis contributes to the growth and secondary spreading of solid tumors. Platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (TP) has been identified as such an angiogenic factor. In this study, the expression of PD-ECGF/TP and VEGF was evaluated by immunohistochemical staining of tumor specimens from 40 patients with cervical intraepithelial neoplasia (10 with moderate dysplasia; 10 with severe dysplasia; 10 with carcinoma in situ; 10 with invasive carcinoma). The microvessel density was assessed by immunostaining for factor VIII-related antigen in the most highly neovascularized area. In both the nucleus and cytoplasm, the intensity of PD-ECGF/TP expression in carcinoma in situ and invasive carcinoma was significantly stronger than that in moderate dysplasia. However, the intensity of VEGF expression was not significantly different in the various specimens. The microvessel density in mild dysplasia was significantly different from that in carcinoma in situ (p<0.05), and that in invasive carcinoma (p<0.05). There was no significant relationship between the microvessel density and the expression of PD-ECGF/TP or that of VEGF. These results show that the expression of PD-ECGF/TP appears to be involved in the promotion of angiogenesis in cervical intraepithelial neoplasia.