Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).

BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.

Phase III Randomized Trial of Maintenance Taxanes Versus Surveillance in Women With Advanced Ovarian/Tubal/Peritoneal Cancer: A Gynecologic Oncology Group 0212:NRG Oncology Study.

PURPOSE: To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube (O/PC/FT) cancer who attained clinical complete response after first-line platinum-taxane therapy. METHODS: Women diagnosed with O/PC/FT cancer who attained clinical complete response after first-line platinum-taxane-based chemotherapy were randomly allocated 1:1:1 to S or maintenance, P 135 mg/m2 once every 28 days for 12 cycles, or PP at the same dose and schedule. Overall survival (OS) was the primary efficacy end point. RESULTS: Between March 2005 and January 2014, 1,157 individuals were enrolled. Grade 2 or worse GI adverse events were more frequent among those treated with taxane (PP: 20%, P: 27% v S: 11%). Grade 2 or worse neurologic adverse events occurred more often with taxane treatment (PP: 46%, P: 36% v S: 14%). At the fourth scheduled interim analysis, both taxane regimens passed the OS futility boundary and the Data Monitoring Committee approved an early release of results. With a median follow-up of 8.1 years, 653 deaths were reported; none were attributed to the study treatment. Median survival durations were 58.3, 56.8, and 60.0 months for S, P, and PP, respectively. Relative to S, the hazard of death for P was 1.091 (95% CI, 0.911 to 1.31; P = .343) and for PP, it was 1.033 (95% CI, 0.862 to 1.24; P = .725). The median times to first progression or death (PFS) were 13.4, 18.9, and 16.3 months for S, P, and PP, respectively. Hazard ratio = 0.801; 95% CI, 0.684 to 0.938; P = .006 for P and hazard ratio = 0.854; 95% CI, 0.729 to 1.00; P = .055 for PP. CONCLUSION: Maintenance therapy with P and PP did not improve OS among patients with newly diagnosed O/tubal/peritoneal cancer, but may modestly increase PFS. GI and neurologic toxicities were more frequent in the taxane treatment arms.

Fertility preserving options in patients with gynecologic malignancies.

A proportion of reproductive age women are affected by gynecologic malignancies. This patient population is faced with difficult decisions, related to their cancer care and treatment, as well as future childbearing potential. Therefore, it is important for gynecologists to be familiar with fertility sparing management options in patients with cervical, ovarian, and endometrial cancer. In addition to understanding the surgical approaches available, providers should be able to counsel patients regarding their eligibility for and the indications and limitations of fertility sparing therapy for gynecologic cancer, allowing for appropriate referrals. A comprehensive PUBMED literature search was conducted using the key words "fertility preservation," "cervical cancer," "endometrial cancer," "ovarian cancer," "borderline tumor of the ovary," "germ cell tumor," "obstetrical outcomes," "chemotherapy," and "radiation." The following review summarizes fertility sparing options for patients with cervical, ovarian and endometrial cancer, with an emphasis on appropriate patient selection, oncologic, and obstetric outcomes.

Node count and groin recurrence in early vulvar cancer: A Gynecologic Oncology Group study.

OBJECTIVE: To determine if low node count from superficial groin dissection correlated with first recurrence in the groin for patients with early vulvar cancer. METHODS: The Gynecologic Oncology Group (GOG) conducted a trial for patients with early stage squamous vulvar cancer, lesions <2 cm in size and <5 mm in depth. All fatty tissue below the inguinal ligament, medial to the sartorious and lateral to the adductor longus was removed. Incision of the fascia and skeletonizing the femoral vessels were not required. For this secondary analysis, we reviewed the records of all patients to assess node counts. RESULTS: Of the 113 patients eligible for the study, 104 patients (with 117 dissected groins) did not have a first recurrence in the groin. The median number of negative nodes was 9 (range: 1-26). Nine patients (with 9 dissected groins) suffered a first recurrence in the groin. The median number of negative nodes removed per groin was 7 (range: 4-22). There were no significant differences between patients with first recurrence in the groin and those without (p value=0.7475). There was a broad overlap of the confidence intervals. CONCLUSIONS: We were unable to show that groin failure after superficial lymphadenectomy was a result of low lymph node count. The small number of recurrences made firm conclusions impossible. Variations in anatomy and other factors may make node counting an unreliable measure of surgical quality.

Colposcopy to evaluate abnormal cervical cytology in 2008.

The rates of cervical cancer in the United States are low in comparison with developing nations. Whereas the Papanicolaou smear has performed well in terms of detecting both precursors of squamous cell carcinoma and squamous cell carcinoma of the cervix, this test has been less successful at identifying those women with the highest-risk premalignant disease. The use of human papillomavirus testing has also contributed to the improved sensitivity of screening for cervical cancer. In light of this, the colposcopy clinic retains high referral rates yet has poor diagnostic accuracy. Unfortunately, patients are triaged to follow-up for abnormal Papanicolaou smears based on algorithms that rely on the less evidence-based techniques of colposcopy. Therefore, the need to improve the specificity of colposcopic-guided biopsy remains. The colposcopic procedure is highlighted in this review and evaluated in terms of current literature on technique, the colposcopic impression, cervical biopsy, and methods proposed to enhance appreciation of the highest-risk lesions. By outlining certain flaws in technique and discussing the proposal of new tests to supplement the current standard of care, this review aimed to highlight the need for future research to maintain sensitivity but improve the specificity of colposcopy.

Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.

PURPOSE: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model.

The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.

Differences in prognostic molecular markers between women over and under 45 years of age with advanced ovarian cancer.

PURPOSE: The purpose of this study was to determine whether differences in molecular markers might explain the better prognosis of women < or =45 years of age versus women >45 years of age diagnosed with ovarian cancers. EXPERIMENTAL DESIGN: Tissue sections from women with stage III-IV ovarian cancers were examined for expression of CD34, p53, and HER2. The Kaplan-Meier method and Cox Proportional Hazard analyses were used to identify predictors for outcome. RESULTS: Fifty-two women < or =45 years of age were matched with 52 women who were >45 years old. Of the 46 available tissue sections, 24 were from the younger age group (mean age, 41 years), and 22 were from the older age group (mean age, 61 years). Based on CD34 expression, tumors from women >45 years of age had lower microvessel density (MVD) compared with tumors of younger women (10.3 versus 16.1 microvessels per x400 field; P = 0.03). Lower MVD (< or =11 microvessels per x400 field) predicted for a worse prognosis than higher MVD (>11 microvessels per x400 field) in the overall study group (P = 0.001) and within the older subgroup (P = 0.03). The expressions of p53 (P = 0.13) and HER2 (P = 0.49) did not vary between the two age groups. The median survivals of those with tumors that overexpressed p53 and HER2 were 28.6 and 23.9 months compared with 51.7 and 38.6 months in those with cancers that underexpressed these markers, respectively (P = 0.09 for p53, P = 0.15 for HER2). CONCLUSIONS: Ovarian cancers in women >45 years of age had lower MVD compared with those in women < or =45 years of age. Lower MVD was an independent prognostic factor for decreased survival. Lower frequency of neovascularization in these cancers may contribute to the decreased survival observed in women >45 years of age.

Stages III and IV invasive epithelial ovarian carcinoma in younger versus older women: what prognostic factors are important?

UNLABELLED: OBJECTIVE; To compare the survival rates in younger (45 years or younger) and older women (over 45) diagnosed with advanced-stage invasive epithelial ovarian cancer. Clinical and pathologic factors responsible for survival differences between the two groups were also determined. METHODS: All younger women with advanced-stage epithelial ovarian carcinoma diagnosed between 1984 and 2001 were identified from tumor registry databases at two hospitals. Patients with borderline tumors were excluded. An older group of comparable controls was selected for comparison. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors for survival. RESULTS: Of 104 women with advanced-stage epithelial ovarian carcinoma, 52 were 45 or younger and the rest were over 45. The 5-year survival rate and median survival in younger patients were 48% and 54 months, compared with 22% and 34 months in the older women (P =.003). Younger women had significantly better performance status than older patients, and survival remained significantly better in younger women based on Kaplan-Meier analysis stratified by performance status (0 versus 1 to 2, P =.02). Furthermore, overall survival was significantly better in younger women after stratification by stage (III versus IV, P =.002) and by cytoreductive surgery (optimal versus suboptimal, P =.003). Multivariable analysis demonstrated that all these factors remained as significant independent prognostic factors for survival. CONCLUSION: Younger women with advanced-stage invasive epithelial ovarian cancer have significantly improved survival rates relative to older patients. Age, performance status, stage of disease, and extent of cytoreductive surgery are important independent prognostic factors for survival.

Borderline ovarian tumors in reproductive-age women. Fertility-sparing surgery and outcome.

OBJECTIVE: To evaluate the fertility and survival outcomes in young women with borderline ovarian tumors treated with fertility-sparing surgery. STUDY DESIGN: From 1985 to 2002, 25 women with borderline ovarian cancers surgically managed with preservation of the uterus and at least a portion of 1 ovary were identified from tumor registry databases at 2 southern California hospitals. Data for analysis were collected from hospital charts, office records and tumor registry files. RESULTS: Twenty-five patients (median age, 29 years) with borderline ovarian tumors, including 10 with stage IA, 3 with stage IC, 1 with stage IIIA and 11 with unstaged disease, underwent fertility-sparing surgery, consisting of unilateral adnexectomy in 19, unilateral adnexectomy with contralateral cystectomy in 5 and unilateral cystectomy in 1. No disease recurred, providing an overall survival of 100%. Fertility status was available on 15 patients 4-157 months after surgery; 6 of them attempted to become pregnant. Five women had successful pregnancies, with a total of 5 live births. One woman underwent assisted reproductive techniques, became pregnant but aborted. The median follow-up was 80 months (range, 4-157). CONCLUSION: Conservative surgery for borderline ovarian tumors should be considered for women in the reproductive age group who desire preservation of fertility.

Margin distance and other clinico-pathologic prognostic factors in vulvar carcinoma: a multivariate analysis.

OBJECTIVES: To determine the importance of margin status and other prognostic factors associated with the recurrence and survival of patients with squamous cell vulvar carcinoma. METHODS: Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. All slides were re-reviewed by two gynecologic pathologists. RESULTS: Ninety patients (median age: 69) were treated for vulvar carcinoma from 1984 to 2002, including 28 FIGO stage I, 20 stage II, 26 stage III and 16 with stage IV disease. Sixty-three (70%) patients underwent complete radical vulvectomies and 27 (30%) had modified radical vulvectomies. Nineteen (20%) patients received adjuvant radiotherapy. Five-year disease-specific survival rates were 100%, 100%, 86% and 29% for stages I-IV, respectively. None of the 30 patients with a pathologic margin distance >8 mm had local recurrence. Of the 53 women with tumor-free pathologic margin of <8 mm, 12 (23%) had a local recurrence. Moreover, women with >2 positive groin nodes had significantly higher recurrence risk compared to those with <2 metastatic groin nodes (p<0.001). On multivariate analysis, positive groin nodes and margin distance were important prognostic factors for recurrence. Moreover, stage, tumor size, margin distance, and depth of invasion were significant independent predictors for disease-specific survival. The median follow-up was 58 months (range: 2-188). CONCLUSIONS: Pathologic margin distance is an important predictor of local vulvar recurrence. Our data suggest that a > or =8-mm pathologic margin clearance leads to a high rate of loco-regional control.

Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer.

OBJECTIVE: To determine clinical or biological associations between mast cell density, blood clotting, angiogenesis, and survival of patients with advanced ovarian cancer. METHODS: Tumor tissue sections were assessed for mast cell density by staining for mast cell tryptase, blood clotting by staining of thrombosed blood vessels, and angiogenesis by CD34 expression. Chi-square, Kaplan-Meier, and Cox proportional hazard statistical analyses were used. RESULTS: 44 women with stage III-IV ovarian cancers had tumor blocks available for immunohistochemical analysis. Higher mean vessel density (MVD) (>11 vessels/400x field) predicted for better survival than lower MVD (< or =11 vessels/400x field) (P = 0.004). Women whose tumors had low levels of peri-tumoral mast cell infiltration had a mean survival of 40.6 months compared to 50.6 months in those whose tumors had high levels (P = 0.47). Tumors with higher MVD and high peri-tumoral mast cell infiltration had a mean survival of 80.3 months compared to 37.8 months in those with low mast cell density or low MVD (P = 0.015). Patients with tumors showing a low degree of blood clotting had a mean survival of 45.5 compared to 45.1 months in those with tumors showing a high degree of blood clotting (P = 0.91). There was no significant association between angiogenesis and mast cell density (P = 0.123). In multivariate analysis, higher MVD remained as a significant prognostic factor for improved survival after adjusting for clotting and mast cell density. CONCLUSIONS: Our data suggest that peri-tumoral mast cell infiltration in tumors with high MVD predicts for improved survival in women with advanced epithelial ovarian cancer.

Clinicopathologic features of six cases of primary cervical lymphoma.

OBJECTIVE: Primary lymphoma of the uterine cervix is rare, with less than 60 cases reported. We present a series of 6 patients with cervical lymphoma and review the literature. STUDY DESIGN: Between 1988 and 2003, we identified 6 women with primary lymphoma of the uterine cervix treated at our institutions. Data for analysis were obtained from hospital charts, office records, and tumor registry files. We also reviewed 20 published reports on cervical lymphoma, providing information on 58 additional patients. RESULTS: The median age at diagnosis was 52 years (range 40-76). Three patients had an abnormal Papanicolaou test within 6 months of the diagnosis. Mean tumor size was 8.3 cm (range 3-14 cm). On the basis of the Ann Arbor system of staging where "E" denotes extranodal tumor origin, 2 patients had stage IE, 1 had stage IIIE, and 3 had stage IVE disease. The median follow-up for these 6 women was 33 months (range 12-120). Adding the 6 patients in our series to the 58 patients obtained from published reports, 43 had stage IE, 14 had stage IIE, 2 had stage IIIE, and 5 had stage IVE disease. There was no consistent pattern of treatment identified from our literature review. CONCLUSION: Primary lymphoma of the uterine cervix is a rare malignancy. Most patients present with stage IE disease. Women with localized disease typically respond to various combinations of surgery, chemotherapy, and radiotherapy. Combination chemotherapy with tailored radiotherapy appears to be the preferred treatment option in women with advanced disease.

Prognostic factors responsible for survival in sex cord stromal tumors of the ovary--a multivariate analysis.

OBJECTIVE: To evaluate prognostic factors that impacts the survival of women with sex cord stromal tumors of the ovary (SCST). METHODS: Cases were identified from tumor registry databases at three academic institutions between 1975 and 2003. Patient characteristics, surgical treatment, adjuvant therapy, pathologic and follow-up information were collected from hospital charts and clinic records. Kaplan-Meier and Cox proportional hazards analyses were used to identify predictors of outcome. RESULTS: Eighty-three women (median age: 49 years) with SCST of the ovary, including 73 with granulosa and 10 with Sertoli-Leydig cell tumors were identified. Fifty-one were stage I, 8 stage II, 10 stage III, 3 stage IV, and 11 patients were unstaged. The median and 5-year disease-specific survival of women with stage I-II vs. III-IV was 180 months and 85% compared to 58 months and 48%, respectively (P = 0.012). Furthermore, age <50 (P = 0.003), premenopausal status (P = 0.013), tumor size < 10 cm (P = 0.003), lack of lymph node invasion (P < 0.0005), and absence of residual disease (P = 0.002) were all significant predictors for improved survival. Of the patients who received adjuvant treatment, chemotherapy did not impact survival (P = 0.11). Twelve of 51 stage I patients underwent fertility-sparing surgery with three recurrences. In multivariate analysis, age <50, smaller tumor size, and absence of residual disease remained as independent prognostic factors. The median follow up was 58 months (range: 1-310). CONCLUSIONS: Age <50, smaller tumor size, and absence of residual disease are important predictors for improved survival in patients with SCST of the ovary.

Conservation of in vitro drug resistance patterns in epithelial ovarian carcinoma.

PURPOSE: To compare the in vitro drug resistance profiles of advanced stage primary and recurrent epithelial ovarian cancer specimens using the tritiated thymidine uptake assay. METHODS: Extreme drug resistance (EDR) to cisplatin, paclitaxel, 4-hydroxycyclophosphamide, and topotecan was determined for an unselected population of primary and metastatic malignant ovarian tissues, synchronous tumors (primary and metastatic tissues obtained from the same patient at diagnosis), and metachronous lesions (specimens from the same patient before and after chemotherapy). RESULTS: For the large unselected population of malignant tissues (total, N = 6990; primary ovarian, N = 2031; metastatic ovarian, N = 4959), no statistically significant differences were discovered between primary tissues and metastatic lesions when a comparison was made between the percentage of tumors from each group that exhibited extreme drug resistance to the agents assayed. From the library of 6990 specimens, 119 synchronous pairings were identified. These synchronous lesions did not differ significantly in the %EDR between primary and metastatic sites in the same patient; approximately 10% shifted between low drug resistance and EDR. A total of 334 metachronous pairings were identified and the percentage of tissues that exhibited EDR also failed to show a significant difference when primary tumors were compared with matched recurrences in the same patient. CONCLUSIONS: For the agents studied, acquired resistance was not a function of disease site. In vitro drug resistance observed at recurrence was not influenced significantly by intervening therapy. It is possible that assay results at diagnosis could be used to guide subsequent therapy at relapse, especially when recurrent tissue is not available for analysis.

Treatment of ovarian cancer: new strategies.

OBJECTIVES: The objective was to review the progress made in gene- and molecular-based management of ovarian cancer over the past decade and the future direction of targeted therapies. METHODS: Research studies, review articles, and scientific meeting abstracts published between 1994 and 2002 were reviewed and analyzed. RESULTS: Significant progress has been made in understanding the molecular biology of ovarian cancer and the role that single-nucleotide polymorphisms, tumor suppressor genes, and oncogenes play in promoting tumor cell growth and proliferation. Strategies have been developed to correct gene defects or single out ovarian cancer cells for destruction. Molecular-based therapies are now under development to specifically target receptors and signal transduction pathways that control cell proliferation and apoptosis, angiogenesis, cellular adhesion, and cell motility in ovarian tumors. CONCLUSIONS: The end product of this intense investigation will be new targeted therapies that offer the hope of improving the medical management of ovarian cancer while being significantly less toxic to normal cells.

Hormone replacement therapy for survivors of breast and endometrial cancer.

Indirect evidence suggests that endogenous and exogenous estrogen does not influence the outcome of patients treated for breast or endometrial cancer. However, many reports have affirmed beneficial effects of hormone replacement therapy (HRT) in preventing multiple disease states and improving the quality of life of individual patients. Every practitioner of urogynecology understands the benefits of local and systemic therapy to women who suffer from urinary incontinence and/or loss of pelvic floor support. Thus, it seems appropriate to suggest that survivors of breast or endometrial cancer who request information on HRT for relief of their menopausal symptoms and for other benefits, of which patients are becoming increasingly aware, deserve a comprehensive explanation.