Phase II trial of topotecan and cisplatin in persistent or recurrent squamous and nonsquamous carcinomas of the cervix.

OBJECTIVE: Cisplatin is a standard treatment in advanced, recurrent cervical cancer. Because topotecan is an established treatment in gynecologic malignancies such as ovarian cancer and exhibits nonoverlapping toxicity with cisplatin, a phase II trial was conducted to evaluate the tolerability and antitumor activity of a cisplatin/topotecan doublet in persistent or recurrent cervical cancer patients. METHODS: Patients with bidimensionally measurable persistent or recurrent squamous cell and non squamous cell cervical cancer and adequate bone marrow were enrolled. Patients received 50 mg/m(2) of cisplatin intravenously over 1 h on Day 1 and 0.75 mg/m(2) of topotecan intravenously over 30 min on Days 1, 2, and 3 of 21-day cycles for six cycles or until disease progression. Tumor response and regimen toxicity were assessed using established Gynecologic Oncology Group criteria. RESULTS: Thirty-two of 35 enrolled patients were evaluable for toxicity and tumor response. All but 2 evaluable patients had received previous radiotherapy. No patient received prior chemotherapy. The cisplatin/topotecan doublet was well tolerated, with 77 and 78% of courses given without interruption or delay and at full doses, respectively. As anticipated, the most common toxicity was hematologic, with grade 3/4 neutropenia and thrombocytopenia reported in 30 and 10% of cycles, respectively. The overall response rate was 28% (9/32), with 3 complete and 6 partial responses. The antitumor response in nonirradiated fields (30%) was similar to the response observed in previously irradiated fields (33%), suggesting good drug penetration. Median duration of response was 5 months (range, 2 to 15+ months). An additional 9 (28%) patients achieved stable disease. Median survival was 10 months, with 3 patients in lasting remission. CONCLUSIONS: These results demonstrate that the cisplatin/topotecan combination is safe, well tolerated, and active in persistent or recurrent cervical cancer patients. A phase III, multicenter trial is under way (cisplatin/topotecan versus cisplatin) based on these favorable results to confirm the safety and efficacy profile in this patient population.

Liquid-based cervical cytologic smear study and conventional Papanicolaou smears: a metaanalysis of prospective studies comparing cytologic diagnosis and sample adequacy.

OBJECTIVE: We sought to evaluate the cytologic diagnosis and sample adequacy of the liquid-based cervical cytologic smear (ThinPrep) compared with that of the conventional Papanicolaou smear. STUDY DESIGN: Prospective studies of ThinPrep and conventional Papanicolaou smears were analyzed for cytologic diagnosis and sample adequacy. Computerized databases, references in published studies, and index reviews published in English were used to identify direct-to-vial and split-sample clinical trials of cervical smears performed by conventional and liquid-based techniques. Only published studies that used the Bethesda system nomenclature with clearly documented outcome data were included. Each trial was assessed for the quality of its method, inclusion and exclusion criteria, adequacy of randomization, sampling protocols, definition of outcome, and statistical analyses. RESULTS: Twenty-five studies met inclusion criteria for this review. Odds ratios with 95% confidence intervals were calculated for each outcome. Estimates of odds ratios and risk differences for dichotomous outcomes were calculated by use of random and fixed-effects models. Homogeneity was tested across the studies. Results indicate that the ThinPrep test is as good as or superior to the conventional Papanicolaou smear in diagnosing uterine cervical premalignant abnormalities. Also the ThinPrep test provides improved sample adequacy when compared with the conventional Papanicolaou test. CONCLUSION: The ThinPrep test improved sample adequacy and led to improved diagnosis of low-grade and high-grade squamous intraepithelial lesions. However, there is no difference in the rate of atypical cells of undetermined significance diagnosis between ThinPrep and conventional smear groups. The added cost of ThinPrep cytologic screening and, hence, its cost-effectiveness are not evaluated in this study.

The prognostic value of HER-2/neu oncogene in cervical cancer.

BACKGROUND: Expression of the HER-2/neu oncogene has been suggested to confer added virulence or aggressive behavior in gynecologic malignancies. The aim of this study is to determine the frequency of HER-2/neu expression in invasive cervical cancer and its impact on survival in women with cervical cancer. DESIGN: Archival tissue from 150 patients with cervical carcinoma was evaluated immunohistochemically for HER-2/neu oncoprotein expression. Survival information was retrieved retrospectively from patients' medical records. RESULTS: The HER-2/neu expression was observed in 34 out of 150 tumors (22%). The HER-2/neu positive tumors exhibited considerable heterogeneity in the distribution of immunoreactive tumor cells. Tumor grade and histology did not influence the pattern or intensity of HER-2/neu expression. There was no statistically significant difference in survival of patients with HER-2/neu positive and those with HER-2/neu negative tumors (P = 0.50). Tumor stage at diagnosis was the only covariate with prognostic significance in patient survival (P < 0.001). CONCLUSION: Expression of HER-2/neu oncogene is a rare event in cervical cancer. Immunohistochemical detection of HER-2/neu expression is neither a predictor of survival of patients with cervical cancer nor does it identify subgroups of patients at higher risk for recurrence of disease.

Stage I squamous cell cervical carcinoma in pregnancy: planned delay in therapy awaiting fetal maturity.

PURPOSE: It is not known whether intentional delay to allow fetal maturity in patients with Stage I cervical carcinoma diagnosed during pregnancy will affect the survival of these patients. The purpose of this study is to report our experience with invasive squamous cervical carcinoma after planned delay in therapy for fetal indications, to assess maternal morbidity due to treatment delay, and to report maternal and fetal survival. METHODS: Between 1989 and 1994, eight pregnant women with Stage I squamous cervical carcinoma, who declined immediate therapy in order to improve fetal outcome, were prospectively followed until the late third trimester. Serial MRIs were used to follow the lesion in two patients. RESULTS: Stage IB cervical cancer was diagnosed in seven pregnant women. All lesions were less than 2.5 cm. The mean diagnosis-to-treatment interval was 109 days (range, 21-201; median, 112). One woman conceived in the cycle after diagnosis and had a diagnosis-to-treatment interval of 282 days. All were delivered by cesarean section-radical hysterectomy late in the third trimester. There was no clinical progression of disease detected during any of the pregnancies. Serial MRI examination confirmed stable disease in one patient and suggested an increase in tumor volume in one patient that was not pathologically confirmed. All are alive and disease free after a mean follow-up of 37 months (range, 13-68; median, 33). Neonatal morbidity was encountered in one infant (spontaneous pneumothorax). CONCLUSIONS: With a median follow-up of 33 months, patient-requested delays in therapy between 3 and 40 weeks (mean, 19) did not affect progression.

Staging and recurrence of disease in squamous cell carcinoma of the vulva.

In order to determine the prognostic significance of applying the revised FIGO staging system and identify factors contributing to survival after documentation of recurrent disease, a retrospective chart review of our vulvar cancer population was performed. Over a 17-year interval 135 patients were uniformly treated with primary surgical treatment consisting of radical vulvectomy and bilateral groin dissection. Factors contributing to disease-free survival were analyzed using a Cox proportional hazards model. Covariates of survival after recurrence of disease were analyzed using the log-rank method. Neither the clinical assessment of the groin nodes, nor the presence or absence of perineal involvement were related to outcome. Only lesion size and surgical status of the inguinal nodes were significant predictors of disease-free survival (P = 0.02 and P = 0.03, respectively). In addition, there was a statistically significant relationship between the extent of groin involvement (negative, unilateral positive, and bilateral positive nodes) and associated decrement in disease-free survival (P = 0.01). Thirty patients developed recurrence of disease from 2.0 to 47.3 months following surgery. The location of the recurrence, interval from primary therapy to recurrence, and status of the groin nodes at initial surgery were significant prognostic factors in subsequent survival. The revised staging system demonstrated an improvement in patient stratification compared to the criteria of the prior classification. The data are also consistent with the distinction made between Stage III and IV disease in the new classification. The status of the groin nodes at original surgery remained an important prognostic factor even in those patients who later demonstrated recurrence of disease.

Extended-field radiation therapy for carcinoma of the cervix.

The survival of cervical carcinoma patients with paraaortic/high common iliac nodal metastases was evaluated by retrospective chart review during a 13-year interval. Thirty-three patients with cervical carcinoma and surgically documented nodal metastases received primary, extended-field radiation therapy. Overall 2-year and 5-year actuarial survival rates after diagnosis were 37% and 31%, respectively. Survival was analyzed in terms of the variables patient age, clinical stage, tumor histologic type, the presence of enlarged paraaortic/high common iliac lymph nodes, the extent of nodal involvement (microscopic versus macroscopic), the presence of intraperitoneal disease, and whether intracavitary brachytherapy was administered. The use of intracavitary radiation therapy was associated with improved local control and survival (P = 0.017). None of the other variables were statistically related to patient survival. Twenty-two of the patients died of cervical cancer and five are surviving without evidence of cancer. Four patients died of intercurrent disease. Two patients developed bowel-related radiation complications; both patients received chemotherapy concurrent with the radiation therapy. One of the two patients died of radiation enteritis. The use of extended-field radiation therapy does benefit a small group of patients and may result in extended patient survival.

Sperm wash in three culture media: maximization of motile sperm recovery during swim-up incubation.

Three different culture media commonly used during in vitro gamete manipulations were studied for their efficacy in sperm wash procedure. Highest numbers of motile sperm were recovered at 6 hours following incubation in WT-6 and Ham's F-10 media. However, WT-6 yielded higher motile sperm numbers than Ham's F-10. Swim-up sperm number reached a peak at 3 hours following incubation in BWW. A period of 2 to 6 hours of incubation of sperm pellets overlayed with sperm wash media resulted in highly enriched motile sperm fractions free of dead spermatozoa and seminal debri.

Mouse embryo growth in different culture media: selection of a medium for quality control cross-testing of human in vitro fertilization conditions.

A total of 2070 two-cell mouse embryos were recovered from 89 superovulated female hybrid mice. Six different culture media were tested. The various media supported mouse embryo development as follows (percentage mean +/- SD, n = 10): Hopp and Pitts medium (H&P) 87 +/- 5 Dulbecco's modified; Eagle's medium supplemented with 10% (volume/volume, v/v) fetal bovine serum (DMEM) 80 +/- 4; Ham's F-10 +/- 15.0% (v/v) human fetal cord serum (hFCS) 79 +/- 3; Whittingham's T-6 medium (WT-6) 60 +/- 4; Ham's F-10 +/- 7.5% (v/v) hFCS 55 +/- 5; Krebs-Ringer low bicarbonate buffer (KRLBB) 42 +/- 6. In H&P, DMEM, WT-6, and Ham's F-10 medium supplemented with hFCS, the pH was maintained within a narrow range of 7.30-7.45 and adequate level of oxygenation was achieved during 72 h in culture. KRLBB had poor buffering capacity and attained ineffective levels of oxygenation during culture. Superior mouse embryo development from two-cells to morulae and hollow blastocysts occurred in H&P, Ham's F-10 + 15% hFCS, and DMEM. Ham's F-10 medium supplemented with hFCS is routinely checked for its ability to support mouse two-cell embryo development to morulae and blastocysts. This is done in conjunction with H&P medium as the control.

Quantitative ultramorphological evaluation of swim-up spermatozoa used in human in vitro fertilization and transcervical intrauterine insemination.

Ultramorphological changes that occur on the sperm head during in vitro incubation of human spermatozoa was investigated using transmission electron microscopy (TEM). Motile spermatozoa that swim-up were processed for TEM. Washed but unincubated sperm heads had all of the fine structural characteristics of normal spermatozoa: intact plasma membrane, acrosome, equatorial segment, postacrosomal sheath, subacrosomal space filled with fine granular material, dense nucleus containing conspicuous nuclear vacuoles of differing sizes and numbers, and faintly discernible nuclear membrane. The procedure of washing and centrifugation did not alter the structural integrity of spermatozoa. Any evidence of ultramorphological changes in the incubated spermatozoa appeared to be confined to the surface of the anterior two-thirds of the sperm head. These changes were characterized by detachment of plasma membrane, fusion of plasma and acrosomal membranes, vesiculation of membranes, and exposure of acrosomal contents. There was a significant (p less than 0.001) time-dependent increase in the proportion of spermatozoa with such changes. The anterior border of these denuded sperm heads were bound only by the acrosome that appeared as electron-dense granular material on the outer margin and attached on its inner border to the inner acrosomal membrane. Furthermore, in vitro incubation of washed spermatozoa did not lead to any time-dependent degenerative changes.