Genetics and the Gynecologic Patient.

Background: The field of hereditary cancer syndromes and genetic testing for patients and families is a rapidly evolving discipline, with an emphasis on cancer prevention. Methods: We review the literature regarding the most common genetic syndromes associated with gynecologic malignancies and discuss the management of these conditions. We also examine the logistic process surrounding cancer genetic testing and identify some perceived barriers. Results: Five genetic syndromes are known to be associated with gynecologic malignancies: hereditary breast and ovarian cancer, Lynch, Cowden, Peutz-Jeghers, and Li-Fraumeni. Each is associated with varying risks of breast, ovarian, and uterine malignancies. The National Comprehensive Cancer Network guidelines regarding the management of these syndromes are focused primarily on reducing the risk of developing gynecologic malignancies. However, great complexity is involved with genetic testing for patients and their families, and barriers exist for the widespread use and implementation of such testing. Conclusion: Genetic testing is fundamental to primary cancer prevention and to oncologic care. Physicians, payers, and institutions must work collaboratively to maximize genetic testing with the goals of primary cancer prevention and treatment.

Characteristics of African American women at high-risk for ovarian cancer in the southeast: Results from a Gynecologic Cancer Risk Assessment Clinic.

OBJECTIVES: Describe patient characteristics in African American (AA) women seen for gynecologic cancer related genetic counseling at a large southeastern comprehensive cancer center. METHODS: We reviewed an IRB approved, prospective observational cohort of patients from a Gynecologic Cancer Risk Assessment Clinic. Data evaluated included personal cancer history, family history, frequency of genetic testing, frequency/type of genetic mutations, and frequency of surgical intervention. Standard statistical statistics were utilized. RESULTS: 1227 patients were evaluated from 2003 to 2015, of which 95 (7.7%) were AA. Sixteen patients had a personal history of ovarian cancer. 21 women (22%) underwent genetic counseling only; subsequent genetic testing was not recommended based on absence of risk factors. Of the seventy-four AA patients in whom genetic testing was recommended, sixty-six (69.5%) completed testing. Of women tested, 37 (56%) had abnormal results. Eight and 14 patients had pathogenic variants in BRCA1 and BRCA2, respectively. Two were found to have pathogenic PALB2 variants; one had a pathogenic ATM variant and one constitutional MLH1 epimutation case was identified. Eleven had BRCA variants of uncertain significance. Of the patients with abnormal testing, six of 22 women with pathogenic BRCA variants underwent risk-reducing salpingo-oophorectomy (RRSO). CONCLUSIONS: Our study demonstrates that in a region where AAs represent 27% of the population, the proportion of AA patients referred to a Gynecologic Cancer Risk Assessment Clinic remains low. Pathogenic variant and variant of uncertain significance rates were high in patients tested, likely representing a selection bias of high-risk patients. Endeavors should continue to identify minorities at risk for ovarian cancer and institute measures to provide thorough genetic counseling and testing.

Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma.

While high-grade serous ovarian carcinoma (HGSOC) is the most common histologic subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants [by DNA next-generation sequencing (NGS) using a 50 gene Ion Torrent panel] and gene expression (using the NanoString PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT). NGS was performed on plasma cell free DNA (cfDNA) on a select group of patients (n = 14) to assess the utility of using cfDNA to monitor these changes. A total of 86 genes had significant changes in RNA expression after NACT. Thirty-eight genetic variants (including SNPs) from 6 genes were identified in tumors pre-NACT, while 59 variants from 19 genes were detected in the cfDNA. The number of DNA variants were similar after NACT. Of the 59 variants in the plasma pre-NACT, only 6 persisted, whereas 33 of 38 specific variants in the tumor DNA remained unchanged. Pathway analysis showed the most significant alterations in the cell cycle and DNA damage pathways.Implications: Gene expression profiles at the time of interval debulking provide additional genetic information that could help impact treatment decisions after NACT; although, continued collection and analysis of matched tumor and cfDNA from multiple time points are needed to determine the role of cfDNA in the management of HGSOC. Mol Cancer Res; 16(5); 813-24. ©2018 AACR.

Does a standardized preoperative algorithm of clinical data improve outcomes in patients with ovarian cancer? A quality improvement project.

OBJECTIVE: To evaluate the potential impact of a standardized preoperative algorithm on outcomes of patients with suspected ovarian cancer. METHODS: From January 1 to December 31, 2013, patients with suspected ovarian cancer were triaged to primary debulking surgery or neoadjuvant chemotherapy/interval debulking surgery (NACT/IDS) based on a comprehensive review of preoperative clinical data as part of a quality improvement project. Demographics, surgical, and postoperative data were collected. RESULTS: A total of 110 patients with newly diagnosed ovarian cancer were identified: 68 (62%) underwent PDS with an 85% optimal debulking rate. The 30-day readmission rate was 14.7% with a 2.9% 60-day mortality rate. Forty-two patients (38%) underwent NACT. Two patients (4.8%) died before receiving NACT. Thirty-five patients have undergone IDS with an 89% optimal debulking rate. The 30-day readmission rate was 8.5% with a 5.7% 60-day mortality rate after IDS. CONCLUSIONS: Although it is difficult to predict which patients will undergo optimal debulking at the time of PDS, surgical morbidity and mortality can be decreased by using NACT in select patients. The initiation of a quality improvement project has contributed to an improvement in patient outcomes at our institution.

Incidence of port site hernias and/or dehiscence in robotic-assisted procedures in gynecologic oncology patients.

OBJECTIVES: The incidence of port site hernia and/or dehiscence using bladeless trocars is 0-1.2%. Robotic surgery uses additional port sites and increases manipulation of instruments, raising the concern for more complications. We sought to characterize the incidence of port site complications following robotic surgery when fascia was not routinely closed. METHODS: Robotically-assisted (RA) procedures performed for suspected gynecologic malignancy between 1/2006 and 12/2011 were retrospectively reviewed. Bladeless 12 mm and 8mm robotic trocars were used. Fascial closure was not routinely performed except after specimen removal through the port site. The decision to close the fascia remained at the discretion of the surgeon. RESULTS: Data from 842 procedures were included. Mean patient age was 55.6 years. Mean Body Mass Index was 33.6 kg/m(2). RA-total laparoscopic hysterectomy (TLH)± unilateral or bilateral salpingo-oophorectomy (BSO)± lymphadenectomy (LND) accounted for 91.6% of procedures. Final pathology confirmed malignancy in 58.6% of cases, primarily endometrial cancer. In 35 cases, the specimen was removed through the port site; fascia was closed in 54.3% of them and no port site hernias or dehiscences occurred. Only one patient underwent a RA-TLH/BSO/LND for endometrial adenocarcinoma and had a port site dehiscence of the 8mm trocar site. No port site hernias occurred. CONCLUSION: Port site hernias and dehiscences are rare in RA gynecologic oncology procedures. When bladeless dilating trocars are used, routine closure of even up to a 12 mm port site is unnecessary, even in cases requiring removal of the specimen through the trocar sites.

Treatment of chemotherapy-induced anemia in ovarian cancer patients: does the use of erythropoiesis-stimulating agents worsen survival?

OBJECTIVE: Considering the paucity of data relating erythropoiesis-stimulating agent (ESA) use to ovarian cancer survival, our objective was to evaluate the effect of ESA as used for the treatment of chemotherapy-induced anemia (CIA) on survival in ovarian cancer patients. MATERIALS AND METHODS: A multi-institution retrospective chart review was performed on ovarian cancer patients. Data collection included patient demographic, surgicopathologic, chemotherapy, ESA, and survival data. Patients were stratified by ever-use of ESA and were compared using appropriate statistical methods. RESULTS: A total of 581 patients were eligible for analysis with 39% (n = 229) patients with ever-use of ESA (ESA-YES) and 61% (n = 352) never-use ESA (ESA-NO). Mean age was 60.4 years with most patients having stage IIIC (60%) of papillary serous histological diagnosis (64%) with an optimal cytoreduction (67%). Median follow-up for the cohort was 27 months. Both ESA-YES and ESA-NO groups were similar regarding age, body mass index, race, stage, histological diagnosis, and debulking status. Compared with the ESA-NO group, ESA-YES patients were significantly more likely to experience recurrence (56% vs 80%, P < 0.001) and death (46% vs 59%, P = 0.002). Kaplan-Meier curves demonstrated a significant reduction in progression-free survival for ESA-YES patients (16 vs 24 months, P < 0.001); however, overall survival was statistically similar between the 2 groups (38 vs 46 months, P = 0.10). When stratifying by ever experiencing a CIA, ESA-YES patients demonstrated a significantly worse progression-free survival (17 vs 24 months, P = 0.02) and overall survival (37 vs 146 months, P < 0.001). CONCLUSIONS: Our data evaluating the use of ESA as a treatment of CIA in ovarian cancer patients are similar to reports in other tumor sites. Considering that patients who used ESA were more likely to experience recurrence and death and to have decreased survival, the use of ESA in ovarian cancer patients should be limited.

Incidence of mechanical malfunction in low-profile subcutaneous implantable venous access devices in patients receiving chemotherapy for gynecologic malignancies.

OBJECTIVE: The purpose of this study was to investigate the incidence of mechanical complications associated with low-profile subcutaneous implantable venous access devices in gynecologic oncology patients. METHODS: Gynecologic oncology patients with low-profile Port-a-Caths implanted between March 2005 and July 2006 were identified into a computerized database. Patient demographics, operative complications, number of chemotherapy cycles, duration of implantation, and mechanical complications were collected. Primary outcomes included port leakage, catheter fracture, and catheter embolization. RESULTS: 112 patients underwent 115 Port-a-Cath placements with low profile single-lumen plastic ports with Groshong-valved catheters. Mean Port-a-Cath indwelling duration was 197 days (range: 4-395) with a mean number of 12 chemotherapy cycles (range 0-64). The cumulative complication rate necessitating removal or replacement was 15%. Of the 14 Port-a-Caths removed, ten (8.7%) were secondary to mechanical malfunction: one for leakage at the port site, two for catheter fracture, and seven for fracture with catheter embolization to the heart or pulmonary vasculature-most commonly the right ventricle. Patients with embolization were asymptomatic and all embolized catheters were successfully retrieved by interventional radiology without complications. CONCLUSIONS: The rates of catheter fracture and embolization have previously been reported to be low in patients with subcutaneous Port-a-Caths, and have not been studied in patients receiving low-profile subcutaneous Port-a-Caths. This study suggests that catheter fracture may be more common (8.7%) and must be considered in patients with malfunctioning low-profile Port-a-Caths. Embolized catheters can be removed by interventional radiology without significant adverse affects.

Conservative management of postoperative Fever in gynecologic patients undergoing major abdominal or vaginal operations.

BACKGROUND: To develop a standardized protocol for management of postoperative fever in gynecology patients to decrease unnecessary diagnostic workups and empiric use of antibiotics. STUDY DESIGN: A prospective analysis of postoperative gynecology patients identified those who experienced fever (maximum temperature [T(max)] > 100.4 degrees F). Patients were triaged into low- and high-risk groups. High-risk patients were managed independent of the protocol. High-risk criteria included bowel operation, preoperative infection, immunodeficiency, indwelling vascular access, mechanical heart valves, and intensive care unit admissions. Low-risk patients were treated with observation and antipyretics. Patients with persistent or high fever, defined as T(max) > 101 degrees F for > 48 hours, were evaluated and treated based on physical examination findings. RESULTS: We evaluated 292 postoperative patients. Forty-seven percent of patients had a final diagnosis of malignancy. Sixty-four patients were high-risk and 33% of these patients experienced fever. Using the standardized protocol, 228 low-risk patients were managed. Thirty-seven of the 228 patients (16%) had fever postoperatively. Nineteen patients had low-grade fever (100.4 to 101 degrees F); none of these patients required antibiotics. Seventeen patients had fever (101.1 to 102 degrees F) and one patient had fever > 102 degrees F. Using the protocol, 6 of 37 patients (16%) were treated with antibiotics for an infectious diagnosis. CONCLUSIONS: Although postoperative fever is common in gynecologic patients, the incidence of infection is low (3%). A standardized postoperative fever protocol in low-risk gynecology patients decreases use of empiric antibiotics without compromising morbidity.

A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma.

OBJECTIVES: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. METHODS: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. RESULTS: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n=1), and non-dose limiting G3 neutropenia (n=3). Of the 11 patients who received >or=1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. CONCLUSIONS: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.

Lynch syndrome in women less than 50 years of age with endometrial cancer.

OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6-19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its therapeutic potential in breast and gynecologic cancers.

OBJECTIVE: The relationship between the apoptotic pathway and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising area of scientific interest for cancer researchers. TRAIL-receptor-activating agents have demonstrated favorable in vitro and in vivo activity for the treatment of several malignancies including breast and gynecologic cancers. METHODS: This article reviews the available peer-reviewed literature and our own institution's experience with specific TRAIL-receptor-activating agents. Emphasis was placed on the apoptotic/TRAIL mechanism, preclinical evaluation, and phase I studies in various malignancies. RESULTS: Preclinical and early phase I studies indicate that these novel agents are safe with enhanced target specificity for malignancy. When these targeted agents are combined with conventional chemotherapy drugs or radiation therapy, they appear to increase cell death over single-agent modalities. CONCLUSIONS: TRAIL-receptor-activating agents represent an exciting new class of targeted therapies that hold promise to improve the treatment of women with breast and gynecologic malignancies.

Diagnostic loop electrosurgical excisional procedure for discrepancy: do preoperative factors predict presence of significant cervical intraepithelial neoplasia?

OBJECTIVE: Although pathological discrepancy between Pap smear and biopsy is an accepted indication to perform a diagnostic loop electrosurgical excision procedure (LEEP), this procedure is not without complications. Our objective was to determine the incidence of cervical intraepithelial neoplasia (CIN) 2,3 and patient factors that increase the likelihood of detecting CIN 2,3. MATERIALS AND METHODS: We performed a retrospective chart review of patients who underwent a diagnostic LEEP for pathological discrepancy at a university-based colposcopy clinic. Pathological discrepancy is defined as a high-grade Pap smear with a colposcopically directed biopsy of CIN 1 or less. Demographic, cytological, and histological information were collected using a computerized database. The patients were divided into 2 groups (CIN 2,3 and CIN 1 or less) based on the pathology from the LEEP specimen. Patient factors were compared with final pathological results using chi(2) test, Student t test, Wilcoxon rank sum test, and multivariate analysis as indicated. RESULTS: A total of 102 patients were identified. Seven patients had normal specimens, 3 had HPV changes, 25 had CIN 1, 29 had CIN 2, and 38 had CIN 3. Thirty-five patients (34%) had CIN 1 or less, whereas 67 patients (66%) had CIN 2,3. The 2 groups were comparable in terms of age (30.4 vs 28.1 years), parity (2.2 vs 1.9), and age of coitarche (16.3 vs 16.4 years). No statistical difference existed between the groups regarding race, smoking status, Pap smear, history of previous cytological abnormality, contraception method, number of previous sexual partners, and HIV status. The majority of patients (75%) had not undergone previous treatment of CIN. The CIN 2,3 group were more likely than the CIN 1 or less group to have had previous treatment or biopsy for CIN (66% vs 34%; p = .004). Univariate (p = .004) and multivariate (p < .001) analysis demonstrated previous treatment of CIN as the only significant factor predicting CIN 2,3. CONCLUSION: Two thirds of women undergoing a LEEP for pathological discrepancy between Pap smear and cervical biopsy will have CIN 2,3. Women that have had previous treatment of CIN are more likely to have CIN 2,3 detected on their LEEP specimen.

Efficacy of anti-death receptor 5 (DR5) antibody (TRA-8) against primary human ovarian carcinoma using a novel ex vivo tissue slice model.

OBJECTIVES: The purpose of this study was to evaluate the cytotoxicity of a death receptor 5 (DR5) targeting monoclonal antibody (TRA-8) in primary ovarian cancer specimens utilizing a tissue slice technique that allows for assessment of anti-tumor activity in a three-dimensional ex vivo model. METHODS: Nineteen primary ovarian tumor specimens were obtained at the time of cytoreductive surgery and tumor slices were prepared with the Krumdieck tissue slicer. Tumor slices were incubated with TRA-8 for 24 h and a dose-response curve was established for each specimen using non-linear modeling, with IC50 values used as the parameter of TRA-8 sensitivity. In parallel with ATP viability assays, TRA-8 treated and untreated tumor slices were assessed by immunohistochemistry (IHC) and western blot analysis to confirm apoptosis induction. RESULTS: Incubation with 0-1000 ng/ml TRA-8 resulted in a dose response with maximum killing observed at 1000 ng/ml compared to untreated control slices. IC50 values of 6.0 to >1000 ng/ml were calculated for individual tumor specimens. H&E, IHC, and western blot specimens demonstrated TRA-8-induced cellular death in a dose-dependent fashion via apoptosis and activation of caspases 3, 8, and 9. The apoptosis produced by varying concentrations of TRA-8 was confirmed using the TUNEL technique. Treatment with TRA-8 markedly reduced proliferation in the ovarian cancer cells as measured by expression of Ki-67/SP6. CONCLUSIONS: This study demonstrates that targeting DR5 with TRA-8 decreases cellular proliferation, increases caspase activation, and induces apoptosis in this novel three-dimensional ex vivo model of primary ovarian cancer.

Autoclave sterilization of instruments used on women with cervical neoplasia is an effective method of eradicating residual human papillomavirus DNA: a polymerase chain reaction-based evaluation.

OBJECTIVE: To determine whether autoclave sterilization eradicates human papillomavirus (HPV) DNA on specula and instruments used to treat women with cervical neoplasia. METHODS: Specula and instruments used in two referral colposcopy clinics were evaluated to determine the PGMY9/11 primer system's ability to amplify residual HPV DNA. Each speculum and instrument was sampled with a Dacron swab and stored in PreservCyt solution (Cytyc Corporation, Marlborough, MA) at 4 degrees C. DNA amplification was performed under standard conditions with appropriate controls followed by HPV typing using the reverse line blot test (Roche Molecular Systems, Alameda, CA). Once validated, the same polymerase chain reaction method was used on autoclave-sterilized specula and biopsy instruments and heated glass bead- and Cidex bath (Johnson & Johnson, New Brunswick, NJ)-sterilized instruments. All results, with appropriate positive and negative controls, were confirmed in triplicate. RESULTS: A total of 140 instruments (70 used and 70 autoclaved) were sampled for residual HPV DNA. Five samples in the contaminated specula arm were excluded from analysis secondary to insufficient sampling. Of the remaining samples, 52.3% (34/65) of contaminated instruments-both specula and biopsy instruments-had detectable HPV DNA. Fifty-five percent of contaminated biopsy instruments (11/20) were positive and 51.1% of contaminated specula (23/45) were positive. All 70 autoclaved samples (50 specula and 20 biopsy instruments) were negative for residual HPV DNA or beta-globin. One instrument in the glass bead and Cidex group that was presumed sterile was positive for HPV 16 DNA. CONCLUSIONS: The PGMY9/11 primer system is an effective method to detect residual HPV DNA. Autoclave sterilization appears to eradicate HPV DNA to levels undetectable with this sensitive assay, whereas heated glass beads followed by Cidex bath appears to be inadequate methods. These results suggest that autoclave sterilization is effective when using nondisposable instruments and should be the method of choice in studies using polymerase chain reaction-based amplification of HPV DNA.

The honeymoon is over.

BACKGROUND: The importance of a broad differential diagnosis is highlighted by a complex patient case. CASE: A young woman returned from her honeymoon complaining of activity-limiting pain. The evaluation revealed multiple constitutional symptoms, a breast mass, a large pelvic mass, pulmonary abnormalities, an external iliac venous thrombosis, and lytic bone lesions. Biopsies from several sites revealed no evidence of neoplasia. CONCLUSION: Consideration of potential etiologies outside of one's practice specialty may be necessary to make a correct diagnosis.

Bowel resection at the time of primary debulking for epithelial ovarian carcinoma: outcomes in patients treated with platinum and taxane-based chemotherapy.

BACKGROUND: Our goal was to determine the morbidity, disease-free survival, and overall survival of patients with bowel resection at primary cytoreductive surgery for advanced epithelial ovarian carcinoma in the era of platinum and taxane chemotherapy. STUDY DESIGN: We performed a retrospective study of patients undergoing bowel resection at the time of primary cytoreduction for advanced epithelial ovarian carcinoma, who subsequently received platinum and taxane chemotherapy, from 1996 to 2001. Data collected included demographics, stage, histology, debulking status, surgical morbidity, recurrence, and survival. Survival analysis and comparisons were performed using the Kaplan-Meier method and log-rank test. RESULTS: Of 48 patients (45 stage III; 3 stage IV), 25 patients (52%) were optimally debulked to < 1 cm of residual disease; the remaining 23 patients had residual disease > 1 cm. Four-year disease-free survival in the optimally debulked group was 24% versus 12% in the suboptimally debulked group (p=0.009). Four-year overall survival was 81% in the optimally debulked group versus 54% in the suboptimally debulked group (p=0.162). Five patients (10%) experienced a major postoperative complication including stroke, small bowel obstruction, anastomotic leak, entercutaneous fistula, and pelvic abscess. Two perioperative deaths occurred in the suboptimally debulked group. CONCLUSIONS: Patients with advanced epithelial ovarian carcinoma who undergo bowel resection as part of optimal cytoreduction and receive platinum and taxane chemotherapy have improved disease-free survival and a trend toward improved overall survival. Bowel resection at the time of primary cytoreductive surgery is associated with acceptable perioperative morbidity.

Role of chemotherapy for patients with recurrent platinum-resistant advanced epithelial ovarian cancer: A cost-effectiveness analysis.

BACKGROUND: Current chemotherapy in platinum-resistant ovarian cancer patients has demonstrated minimal to no improvements in survival. Despite the lack of benefit, significant resources are utilized with such therapies. Therefore, the objective in the current study was to assess the cost-effectiveness of salvage chemotherapy for patients with platinum-resistant epithelial ovarian cancer (EOC). METHODS: A decision analysis model evaluated a hypothetical cohort of 4000 platinum-resistant patients with recurrent EOC. Several chemotherapy strategies were analyzed: 1) best supportive care (BSC); 2) second-line chemotherapy-monotherapy; 3) second-line chemotherapy-combination therapy; 4) third-line chemotherapy after disease progression on second-line monotherapy; and 5) third-line chemotherapy after disease progression on second-line combination therapy. Sensitivity analyses were performed on all pertinent uncertainties. RESULTS: Using costs alone, BSC was the only definitive cost-effective treatment for platinum-resistant recurrent ovarian cancer patients, and second-line monotherapy was a reasonable cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of 64,104 dollars. The cost-effectiveness ranged from 4,065 dollars per month of overall survival (OS) for BSC to 12,927 dollars for third-line previous combination therapy. Compared with BSC, second-line monotherapy gained an additional 3 months of OS, with a cost-effectiveness of 4,703 dollars per month of OS. Second-line combination therapy and third-line therapies exhibited unfavorable ICER. CONCLUSIONS: The current decision analysis was intended to be thought-provoking and bring awareness to the high costs of subsequent chemotherapy with limited effectiveness in patients with recurrent platinum-resistant EOC. Although actual patients may receive multiple lines of chemotherapy, from the perspective of costs alone this model using a hypothetical cohort demonstrated that best supportive care was the only cost-effective strategy, with second-line monotherapy appearing to be a reasonable cost-effective strategy given current chemotherapeutic options.

Efficacy and toxicity of the novel chemotherapeutic agent KW-2170 in recurrent epithelial ovarian cancer.

OBJECTIVES: KW-2170 is a novel DNA intercalating agent whose mechanism of action is similar to doxorubicin HCl, yet is associated with less cardiac toxicity. The objective of this study was to evaluate the activity and toxicity of this novel chemotherapeutic agent in patients with recurrent ovarian carcinoma. METHODS: A prospective phase II trial was performed in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma and measurable disease. Patients could have platinum-sensitive or refractory disease and could have received any number of prior treatments. One treatment cycle consisted of KW-2170 administered at a dose of 18 mg/m(2) weekly for 3 weeks followed by a 21-day rest period. Toxicity was assessed using the NCI Common Toxicity Criteria (Version 2.0), and dose reduction was allowed for significant toxicity. Response to therapy was assessed in patients who completed at least 2 cycles using RECIST criteria. RESULTS: A total of 28 patients were enrolled in this phase II trial at 5 separate centers. Of the 28 patients evaluated, all had stage III/IV disease at initial diagnosis. The median number of prior therapeutic regimens in these patients was 4 (range 1-8). The median number of KW-2170 cycles administered was 2 (range 1-5). Treatment-related toxicity in this heavily pretreated population was acceptable as only 6 patients (21%) had grade 3-4 neutropenia. Dose reductions occurred in 6 patients (21%) for grades 1-4 neutropenia, and no patient had febrile neutropenia. Four patients completed less than 1 cycle; 3 secondary to progressive disease, and one due to Gram-positive sepsis. Of patients receiving at least 2 full cycles, 10 patients (55%) had stable disease with a median of 4.5 months (range 3-10) to disease progression. All other patients were removed from the study after 1-2 cycles of therapy with no significant clinical effect noted. CONCLUSIONS: Although associated with relatively little toxicity, KW-2170 at the dose and schedule evaluated demonstrated little clinical activity in this heavily pretreated population of recurrent ovarian cancer patients. Whether KW-2170 would have greater clinical activity in a more treatment naive group of patients at an increased dose awaits clinical trial evaluation.

Traumatic diaphragmatic rupture: a rare cause of postoperative shortness of breath.

BACKGROUND: Shortness of breath is a common symptom reported by patients after gynecologic procedures. Delayed traumatic diaphragmatic rupture is a rare cause of shortness of breath. CASE: This report describes the diagnosis and management of a patient with a delayed presentation of a ruptured right hemidiaphragm after a laparotomy for a pelvic mass. CONCLUSION: Although rare, delayed presentation of traumatic diaphragmatic rupture should be considered in patients with a history of blunt chest or abdominal trauma as a possible cause of shortness of breath in the postoperative setting.

Management strategies for stage IB2 cervical cancer: a cost-effectiveness analysis.

OBJECTIVE: To assess the potential effectiveness and medical costs of three common strategies to manage Stage IB2 squamous cell carcinoma of the cervix (CXCA). METHODS: A decision analysis model compared three strategies to manage Stage IB2 CXCA: (1) radical hysterectomy with pelvic and para-aortic lymphadenectomy followed by tailored chemoradiation therapy for high-risk patients (RHYST); (2) primary chemoradiation therapy for all patients (CTRT); and (3) neoadjuvant chemotherapy followed by radical hysterectomy and tailored chemoradiation therapy for high-risk patients (NAC). RESULTS: RHYST was the least expensive strategy with a cost of 284 Million (M) per 10,000 women and a 5-year disease free survival (5-DFS) of 69%. Both NAC and CTRT had similar 5-DFS (69.3% and 70%, respectively); however, both NAC and CTRT were more expensive than RHYST at 299 M and 508 M, respectively. This translated into a higher cost-effectiveness ratio for NAC and CTRT ($43,197 and $72,613, respectively) when compared to RHYST ($41,212). NAC yielded 30 additional survivors compared to RHYST but at a cost of $499,783 per survivor. CTRT was more effective than RHYST with 100 additional survivors but at a substantial cost of $2,240,000 per survivor. CONCLUSIONS: RHYST is the most cost-effective strategy to manage Stage IB2 CXCA and would be favored in settings where resources are limited. Although NAC and CTRT are reasonable treatment strategies, policymakers must be willing to spend approximately $500,000 per additional survivor (NAC) or $2.2 M per additional survivor (CTRT).