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Objective: The purpose of this phase II study was to evaluate on an intent-to-treat basis the activity and toxicity of single-agent vinorelbine (VRL) as second-line chemotherapy of patients with platinum-resistant ovarian cancer. Platinum-resistant disease was defined as disease refractory to or relapsing within 12 months after finishing platinum-containing chemotherapy., Methods: VRL (30 mg/m(2)) was administered intravenously as a bolus injection days 1 and 8 every 21 days. Initially, four courses of VRL were given. Patients with responding or stable disease received four more courses of VRL to a maximum of eight courses., Results: Twenty-eight of 33 eligible patients were considered evaluable for response. The overall response rate was 21% (7/33) (95% CI: 7--35). Median time to progression was 3.1 months and median survival was 10.1 months. Toxicity was generally mild. Leukopenia was the dose-limiting toxicity. CALGB grade III/IV infection was observed in 15/0% of patients. The most important nonhematologic toxicities were nausea and constipation. Grade III/IV nausea was observed in 6/0% and grade III/IV constipation in 3/3% of patients. Peripheral neurotoxicity was only a minor problem with no grade III/IV toxicity. No patients stopped treatment because of toxicity and no toxic death was reported., Conclusion: VRL was generally well tolerated, but the activity in platinum-resistant ovarian cancer was only modest, although fully comparable to other second-line treatments. Further studies are required to define the role of VRL in combination chemotherapy for ovarian cancer., (Copyright 2001 Academic Press.)

Aim: The authors analyzed in a retrospective manner the prognostic significance of p53 and mdm-2 expression, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathological prognostic factors in patients with uterine leiomyosarcomas., Material: Forty-nine patients were diagnosed with uterine leiomyosarcoma (25 stage I, 4 stage II, 8 stage III, and 12 stage IV). DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors., Results: Of the 49 patients, 35 (71%) died of disease and 2 died of intercurrent disease. The 5-year survival rate was 33%. FIGO surgical stage, DNA ploidy, SPF, mitotic index, cellular atypia, and tumor grade obtained significance (P < 0.05) in a univariate survival analysis of the leiomyosarcomas. In a multivariate analysis with survival as the end point, stage was found to be the most important factor (P = 0.007); DNA ploidy (P = 0. 045) and SPF (P = 0.041) also had independent prognostic significance. For FIGO stage I tumors, DNA ploidy (P = 0.04) and tumor grade (P = 0.01) were statistically significant in a univariate analysis, while only grade had independent prognostic significance (P = 0.01) in a multivariate analysis. In a univariate analysis including only FIGO stage I and II tumors with disease-free survival as the end point, p53 overexpression (P = 0.0016), DNA ploidy (P = 0.042), and tumor grade (P = 0.008) obtained significance. In a multivariate analysis, only p53 had independent statistical significance (P = 0.01). All p53 immunopositive stage I-II tumors recurred within 28 months from diagnosis., Conclusion: This study found that stage represents the most important prognostic factor for uterine leiomyosarcomas. DNA ploidy and SPF had independent prognostic value. DNA flow cytometry is useful in gaining additional prognostic information. In stage I patients, tumor grade gives significant information regarding clinical outcome. In addition, p53 overexpression may predict a higher risk of recurrence in early stage leiomyosarcomas., (Copyright 1998 Academic Press.)

Aim: The authors retrospectively analyzed the prognostic significance of p53, mdm-2, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathologic factors in patients with malignant mixed Müllerian tumors (MMMT) of the uterus., Methods: Between 1970 and 1995, 44 uterine tumors were diagnosed as MMMT (21 stage I, 2 stage II, 10 stage III, and 11 stage IV). Thirty-two were homologous type and 12 were heterologous type. DNA flow cytometry and immunohistochemical analysis for p53 and mdm-2 overexpression were performed on paraffin-embedded archival tissue., Results: 68% of the tumors were nondiploid and 61% had an SPF greater than 10%. Sixty-one percent overexpressed p53 and 25% were mdm-2-positive. Furthermore, 91% of the tumors had a mitotic count greater than 10/10 hpf and 95% had high-grade cytologic atypia. Twenty-seven (61%) patients died of tumor and 6 (14%) died of intercurrent disease. Eleven (25%) patients are alive with no evidence of disease. The median follow-up for patients still alive was 59 months (range, 28-178 months). The overall 5-year survival rate was 38%. In a univariate analysis that included stage, histologic type, DNA ploidy, SPF, p53, mdm-2, mitotic index, and age, and with survival as the end point, only stage reached statistically prognostic significance., Conclusion: The majority of the tumors had obvious signs of aggressiveness such as high grade, high mitotic count, nondiploid pattern, high SPF, and overexpression of p53. This study found that stage is the most important prognostic factor for survival in MMMTs of the uterus., (Copyright 1998 Academic Press.)

This study comprised 328 patients with histologically confirmed primary invasive vulvar cancer, treated between 1948 and 1994. It retrospectively analyzes survival rates in relation to various prognostic factors. Mean and median age at diagnosis was 69 years (n = 328). The patients had experienced various symptoms on an average of 16.3 months prior to diagnosis (median, 6 months). Common presenting symptoms were pruritus, smarting pain, and vulvar tumor. Three hundred patients (91.5%) had squamous cell carcinomas and they were classified according to stage and tumor differentiation as follows: Stage I, 106 (35%); Stage II, 111 (37%); Stage III, 44 (15%); and Stage IV, 39 (13%); well differentiated, 107 (36%); moderately differentiated, 129 (43%); poorly or undifferentiated, 45 (15%); and in 19 cases (6%), tumor differentiation was not available. In 277 (92%) patients the primary treatment was surgical; 189 (63%) patients additionally received radiotherapy and 13 (4%) patients were also given chemotherapy. In 18 patients (6%), the primary treatment was radiotherapy and 5 of these also received chemotherapy. Two patients were given primary chemotherapy and three patients received no treatment. Median survival rate was not reached during the observation time for Stage I. At 10 years observation time survival rate was 85% in this stage. Median survival times for Stages II, III, and IV were reached at 128, 20, and 8 months observation time, respectively. The median survival time in patients with well-differentiated tumors was 152 months; corresponding figures for moderately differentiated and poorly differentiated tumors were 114 and 74 months, respectively. The most important prognostic factors in this study were tumor stage (P < 0.00001), patient age (P < 0.01), and tumor differentiation (P = 0.02).

Fine-needle aspiration (FNA) cytology for the diagnosis of malignant lesions has been used in gynecologic oncology for a long time. Core biopsies have also been used for the same purpose for many years but there are, to my knowledge, no reports in the literature of the use of core biopsies in the diagnosis of gynecologic lesions. The purpose of this study was to evaluate the accuracy of these two methods in gynecologic cancer. This study comprises 85 patients examined from 1986 through 1995. The histology and cytology of gynecologic lesions were investigated by the use of an automatic biopsy instrument (Biopty) with a specially designed needle guide. Concomitantly all patients underwent FNA for cytology. Three hundred thirty-nine FNA and 141 biopsies using the Biopty core instrument (BCI) were obtained from patients with persistent, recurrent, or metastatic disease. Correct diagnosis was made with FNA cytology in 67/85 (79%) and with BCI in 62/85 (73%) of the cases (P = 0.08). Insufficient material for evaluation was recorded for FNA in 12/85 (14%) compared to 10/85 (12%) for the BCI (P = 0.29). False-negative diagnoses occurred in 5% of the cases with FNA compared to 15% with BCI (NS). The sensitivity of FNA was 92% and that of BCI 73% (P = 0.01) and the specificities 92 and 100% (NS), respectively. The predictive values of positive results for the two methods were 96 and 100%, respectively. The complication rate was negligible. In conclusion, FNA in combination with BCI in gynecologic lesions is a simple and safe operation using needle guides. In comparison with FNA cytology the sensitivity for BCI is lower but the specificity is higher. No significant differences were found in accuracy between the two methods. BCI biopsy should be considered in the subset of patients where additional information about the tumor is desired for planning the treatment of recurrent disease.

Peritoneal access devices (port-catheters) were subcutaneously implanted in 125 patients for intraperitoneal chemotherapy of ovarian cancer. In 98% of patients Pharmacia's Port-A-Cath was used. Four hundred sixty-five intraperitoneal courses were given to these patients, with a median of 4 courses per patient (range 0-8). The first course was given 0-60 days (median 11 days) after Port-A-Cath implantation. In 125 patients, 27 (21.6%) complications of severe or moderate degree during the treatment were registered. In 81% of the patients, the treatment was given according to chemotherapy protocol as outlined. In 7% of the patients, early termination was related to the use of Port-A-Cath and in 12% related to chemotherapy. The probability for proper functioning of Port-A-Cath was 0.74 at 6 months and 0.69 at 1 year after implantation. The mean observation time was 13.6 months, median 10.5 (range 0.3-59.6 months). Total patient access time was 141.9 years. In conclusion, the complication rate after implantation of intraperitoneal access devices is acceptable. The rate of infections associated with the system is lower than that associated with open catheter systems.

In a previously reported phase I study of carboplatin administered ip to patients with ovarian cancer at our clinic, it was determined that the recommended dose for phase II was 500 mg/m2. In this study, this dose was given to 47 patients with the purpose of determining the relapse-free interval and toxicity. Four courses were given with a 28-day interval in an escalated fashion. Median age of patients was 55 years. Karnofsky index was 100 in 98% of the patients. Thirty-one patients had FIGO stage I and 16 patients had FIGO stage II ovarian cancer. Median time to recurrence has not yet been reached among 43 evaluable patients after a median (range) follow-up time of 26.2 (5.5-45.9) months. Recurrent disease was documented in 10 patients (23%). The relapse site was intraabdominal in 7 and extraabdominal in 1 patient. Two patients had combined intra- and extraabdominal relapse sites. Thirty-six of 43 patients went through second-look surgery. The total number of treatment cycles given to evaluable patients was 154. In the patient group with relapsed tumor, > or = 3 courses were administered to 60%, whereas nonrelapsed patients had > or = 3 courses in 94% (P = 0.019). The reason for this distribution was higher toxicity and more frequent catheter-related problems in patients with relapsed tumor. Median (range) disease-free interval for relapsed patients was 11.5 (5.5-26.6) months. Myelosuppression, especially thrombocytopenia, was the dose-limiting systemic toxicity. The overall hematologic toxicity (all courses) was median (range) WBC 3.9(0.3-25.0) x 10(9)/liter, PLTC 212(7-961) x 10(9)/liter, and Hb 109(75-153) g/liter. WHO grade 4 toxicity for WBC was observed in 6.7%, for PLTC in 17.8%, and for Hb in 0% of the patients. Day to nadir values for WBC, PLTC, and HB were in median (cycle 1-4) 18, 16, and 18 days, respectively. Subjective toxicity was mild. In conclusion, ip carboplatin as a single-agent drug in first-line adjuvant chemotherapy of early-stage ovarian cancer has shown moderate activity. The administered dose in this study was safe, with acceptable toxicity.

Granulosa and theca cell tumors of the ovary account for 2-3% of ovarian malignancies. This study includes 54 patients with the diagnosis of granulosa cell tumors of the ovary treated between 1953 and 1987. Median age at diagnosis was 57 (27-83) years. The lesions were staged according to FIGO. The number of patients in various stages was IA, 41; IB, 3; IC, 3; IIB, 6; and III, 1. Median tumor size, 11 cm; range, 0.5-30 cm. Post-menopausal bleeding was diagnosed in 48%, MHC in 37%, proliferative endometrium in 32%, and atypia of endometrial cells in 13% of the cases. Fifty patients were treated with primary surgery, 48 patients were treated with adjuvant external radiotherapy, and 3 patients received complementary chemotherapy. The survival rates in stage I were 94 and 88% after 5 and 10 years, respectively, and in stages II-III were 44% after 5 and 10 years. Overall survival was 90% at 5 years. The frequency of observed mitosis influenced the survival rate: with less or equal 4/10 HPF the survival was 100% in 5 years, with 5-9/10 HPF the survival was 80% in 5 years with a median survival time of 9 years, and with more or equal 10/10 HPF the longest survival was 4 years. At the end of the study, 45 patients (83%) are alive with no evidence of disease, 1 patient is alive with disease, 4 patients are dead of recurrent disease, and 4 patients are dead from intercurrent disease. Endometrial carcinoma was detected in 5 patients. The total survival is better than that with epithelial ovarian cancer as the hormonal symptoms make an early diagnosis possible. Stage for stage the survival is equal. There is an increased incidence of endometrial carcinoma and concomitant other malignancies. The mitotic rate is a well-defined parameter and influences the survival significantly and should be considered the most important prognostic factor at treatment planning.

Several randomized trials of various malignancies treated with cisplatin indicate a dose-response relationship with higher MST and longer survival achieved with high-dose compared to standard dose cisplatin regimens. Thirty-five patients with stages II-IV ovarian cancer with refractory cancer at second look or recurrent disease were treated second line with intraperitoneal (ip) combination chemotherapy of high-dose cisplatin (100-200 mg/m2) plus etoposide (350 mg/m2) in 1-6 cycles. Sodium thiosulfate was given as an intravenous antidote to cisplatin. A WBC nadir < 2.0 x 10(9)/liter was registered in 39 courses and a platelet nadir < 50 x 10(9)/liter in 3 courses. Severe nephrotoxicity was observed in 2 patients. Nonhematologic and nonrenal toxicity was mild except for vomiting and nausea and alopecia. No severe neurotoxicity was observed. A total of 127 courses were administered. Total median administered dose was 960 mg and 49 mg/m2/week. Treatment was changed in 5 (14%) patients due to severe nausea and vomiting, in 4 (11%) patients due to PAC problems, and in 2 (6%) patients due to nephrotoxicity. In 4 (11%) patients the dose was reduced due to hematologic toxicity. No toxic death was recorded. Median survival time from date of diagnosis was 21.8 (mean 37.9) months and the median progression-free survival from start of ip chemotherapy was 13.7 months. For patients with MRD < or = 2 cm the MST was 18.1 months. At the closing point of this study after a median follow-up time of 16.1 (range, 4.6-55.6) months, 7 (20%) patients were alive without evidence of progression, 4 (11%) were alive with cancer, and 23 (66%) were dead of cancer and 1 (3%) was dead of intercurrent disease.

Flow cytometry of various gynecological tumors has shown that aneuploid tumors and a high S-phase rate carry a prognosis worse than that of diploid tumors or tumors with a low S-phase. The aim of this study is to investigate the prognostic importance of DNA ploidy and S-phase rate in relation to mitotic count, tumor stage, tumor grade, and histology in 37 patients with uterine sarcoma stages I-IV (FIGO). Flow cytometry was performed on archival paraffin-embedded tumor tissue and the histologic specimens were reviewed by a single pathologist. Nineteen (51%) of the tumors were classified as DNA aneuploid. The S-phase fraction (SPF) was determined in 33 cases. The mean SPF (+/- SD) was 15.0% (+/- 9.5%). The mean SPF was three times higher in aneuploid tumors than in diploid cases. Both the proportion of aneuploid tumors and the mean SPF were significantly higher in later stage tumors, more poorly differentiated tumors, and tumors with a higher mitotic index. No significant differences were seen between histologic types with respect to the two cytometric variables. The 5-year cancer survival rate was only 11% in aneuploid cases compared with 59% in diploid cases (log rank, P = 0.0002). There was a significantly worse prognosis in cases with a higher SPF (P = 0.0009) and in case with a higher mitotic index (P = 0.0016). In the multivariate survival analysis using the Cox proportional hazards model, DNA ploidy showed a significant prognostic value (P = 0.046) even when adjusted for stage, grade, and mitotic index. When adjusted for stage and grade only, SPF showed significant additional prognostic value.

Early stage poor-risk ovarian cancer patients are at considerable risk for recurrent disease. Adjuvant radio- or chemotherapy has been found to improve disease-free and overall survival. Carboplatin, a second generation platinum, is documented comparable in efficacy to cisplatin in patients with advanced ovarian cancer. The toxicity profile is different from that of cisplatin. Dose-limiting toxicity is myelosuppression. The incidence and grade of renal and neurological toxicity is much lower compared with cisplatin, as is nausea and vomiting. Carboplatin given intraperitoneally (ip) is shown to have a favorable theoretical therapeutic advantage compared with iv administration since the peak peritoneal cavity/peak plasma concentration ratio is 18. Patients with early stage ovarian cancer seem suitable for carboplatin ip treatment. The study was designed to find the maximal tolerated dose (MTD). Three new patients were given two courses at each dose level. The MTD found was confirmed with further patients. Carboplatin was given in 2 liters of glucose via a subcutaneous implantable port without removal of fluid from the cavity. The starting dose was 300 mg/m2. Dose-limiting toxicity was thrombocytopenia and leukopenia. Leukocyte and platelet counts were reconstituted within 28 days in all cases. One case of severe but transient nephrotoxicity was observed. MTD was determined to 500 mg/m2.