Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients.

OBJECTIVE: To estimate the cost-effectiveness of screening strategies for Lynch syndrome among newly diagnosed endometrial cancer patients. METHODS: A decision analysis compared four strategies to screen women with newly diagnosed endometrial cancer for Lynch syndrome: 1) Amsterdam criteria strategy, where full gene sequencing was performed for women who meet Amsterdam criteria; 2) Sequence-all strategy, where full gene sequencing was performed for all women with endometrial cancer; 3) Sequence aged younger than 60 years strategy, where full gene sequencing was performed for women aged younger than 60 years with endometrial cancer; and 4) immunohistochemistry/single gene strategy, where immunohistochemistry was performed for the DNA mismatch repair genes for all women after single gene sequencing for specific women lacking protein expression. Prevalence rates, probabilities of immunohistochemistry staining loss, and gene mutation rates were calculated from published data. Costs were estimated from Medicare reimbursement rates. Cost-effectiveness ratios and incremental cost-effectiveness ratios were estimated for each strategy. RESULTS: For the estimated 40,000 women diagnosed annually with endometrial cancer, the sequence-all strategy detects 920 patients with Lynch syndrome at a cost of $105 million. The Amsterdam criteria give the least-expensive strategy ($7 million), but detect the fewest patients (n=83) with Lynch syndrome. The immunohistochemistry/single gene sequencing strategy detects 858 patients at a cost of $17 million; this strategy has an incremental cost-effectiveness ratio of $13,812. The sequence aged younger than 60 years strategy was less effective and more costly than other strategies. CONCLUSION: Of the strategies studied, immunohistochemical evaluation of tumor specimens for mismatch repair protein expression after single gene sequencing for patients with endometrial cancer is a cost-effective strategy for detecting Lynch syndrome. LEVEL OF EVIDENCE: : III.

The management of cervical intraepithelial neoplasia during pregnancy: is colposcopy necessary?

OBJECTIVE: The 2006 American Society for Colposcopy and Cervical Pathology Consensus guidelines state that it is acceptable to defer colposcopy until 6 weeks postpartum in pregnant patients with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cytology. Therefore, we sought to determine the incidence of cervical intraepithelial neoplasia (CIN) 2,3 in pregnant patients referred to a university colposcopy clinic. MATERIALS AND METHODS: A retrospective study identified all pregnant women with abnormal cytology referred to the University of Alabama at Birmingham colposcopy clinic between May 2005 and September 2007. After an institutional review board approval was obtained, demographic information, referral cytology, and histologic data were collected. The colposcopic impression was also obtained from the records. RESULTS: Six hundred twenty-five pregnant patients were identified. The mean age was 23 years (range, 14-44 years), the mean parity was 1 (range, 0-7), and the mean gestational age was 24 weeks (range, 4-39 weeks). The most common referral cytology was LSIL (41.0%), followed by ASC-US (34.1%), and high-grade squamous intraepithelial lesion (13.6%). One hundred thirty-eight patients (22%) underwent cervical biopsy at the time of initial colposcopy. Forty-three patients had CIN 1, 28 patients had CIN 2, and 23 patients had CIN 3. Forty-four patients (32%) had no evidence of CIN on biopsy. There were no cases of invasive cervical cancer identified. Of the 469 patients with ASC-US and LSIL cytology, 20 of 78 patients who had a cervical biopsy were diagnosed with CIN 2,3. Of the 128 patients with high-grade intraepithelial lesion or high-grade squamous intraepithelial lesion cytology, 31 of 60 patients who had a cervical biopsy were diagnosed with CIN 2,3. Repeat colposcopy in the third trimester was performed on 47 patients. Only 3 of 13 patients with a repeat biopsy had CIN 2,3. CONCLUSIONS: Pregnant patients with ASC-US or LSIL cytology rarely have colposcopically suspected CIN 2,3 at their initial colposcopy that warrants a cervical biopsy; therefore, it is reasonable to defer the initial colposcopy in patients with ASC-US and LSIL until at least 6 weeks postpartum.

Advancements in adenoviral based virotherapy for ovarian cancer.

Ovarian cancer is a leading gynecologic malignancy with relatively grim survival statistics. There is a significant need for the development of new treatment options for this malignancy. The development of virotherapy as a treatment option for ovarian cancer has the potential to improve patient survival. Adenoviruses have multiple advantages as vectors for virotherapy including a well-understood structure and the ability to infect cells easily. We will outline the advances in virotherapy in the treatment of ovarian cancer, with particular attention directed toward adenoviral vectors.

The timing of normalization of CA-125 levels during primary chemotherapy is predictive of survival in patients with epithelial ovarian cancer.

OBJECTIVE: To determine if the timing of normalization of CA-125 levels during primary chemotherapy for epithelial ovarian cancer (EOC) could predict survival. METHODS: Patients who reached a complete clinical response for EOC with primary taxane/platinum-based chemotherapy were eligible. Patient demographics, chemotherapy administration, CA-125 levels, and survival outcomes were abstracted. Progression free survival (PFS), overall survival (OS), and platinum sensitivity (>6 months from chemotherapy completion) were compared to CA-125 levels during primary therapy. RESULTS: 262 patients who achieved a complete clinical response were identified. Patients who achieved normalization of CA-125 by 3rd cycle of chemotherapy were compared to patients who failed to achieve normalization by the 3rd cycle. Patients with early normalization demonstrated improved PFS (19 vs. 6 months; p<0.001), OS (48 vs. 27 months; p<0.001) and platinum sensitivity (78 vs. 22%; p<0.001). This survival advantage was maintained when patients were evaluated by debulking status. Additionally, when stratified by the specific cycle patients' achieved normalization, PFS ranged from 25 months after surgery to 2 months after 6th cycle (p<0.001). OS demonstrated a similar trend from 74 months to 22 months (p<0.001), while platinum sensitivity decreased from 72% to 24% (p<0.001). An average of 3.8 months in PFS and 8.6 months of OS was gained for each one-cycle improvement in CA-125 normalization. CONCLUSION: Earlier normalization of CA-125 levels during primary chemotherapy for EOC predicts improvement in platinum sensitivity, PFS, and OS. This data provides prognostic information that may influence future decisions regarding chemotherapy and potentially earlier enrollment in treatment protocols.

An outpatient intraperitoneal chemotherapy regimen for advanced ovarian cancer.

OBJECTIVES: To assess the feasibility, associated toxicities, and reasons for early cessation of an outpatient intraperitoneal (IP) chemotherapy regimen for treatment of advanced ovarian cancer following optimal cytoreductive surgery. METHODS: Between January 2006 and December 2007, 42 patients with stages IIC-IV epithelial ovarian, tubal, or primary peritoneal cancer who had residual disease <1 cm after cytoreductive surgery were treated with an outpatient IP chemotherapy protocol. Patients received intravenous (IV) docetaxel 75 mg/m(2) and IP cisplatin 75-100 mg/m(2) on day 1, followed by IP paclitaxel 60 mg/m(2) on day 8, with the intent to treat patients every 21 days for 6 cycles of chemotherapy. Charts were abstracted for demographic, chemotherapy, and toxicity-related data. RESULTS: The median age of the 42 patients was 59 years (range 33-70) and the majority of patients had epithelial ovarian cancer (80%), FIGO stage IIIC (83%), and papillary serous histology (74%). Of an intended 252 IP chemotherapy cycles, 172 (68%) were administered. Twenty-nine patients (69%) completed >or=4 cycles and 12 (29%) received all 6 IP cycles. Common grade 3/4 toxicities by patient included neutropenia (43%), infection (21.5%), and gastrointestinal effects (14%). There was one treatment-related death. Reasons for discontinuation were largely chemotherapy (43%) or port (37%) related. CONCLUSIONS: With supportive measures, such as scheduled hydration and granulocyte colony-stimulating factors, outpatient administration of IP chemotherapy was feasible. This regimen resulted in few hospitalizations or treatment delays and demonstrated less toxicity than previously reported IP chemotherapy regimens. Port-related complications were a leading cause of IP chemotherapy discontinuation.

The effect of obesity on survival in patients with ovarian cancer.

OBJECTIVE: Data has suggested obesity as an independent prognostic factor for lower survival in patients with epithelial ovarian cancer (EOC). We sought to determine if obesity portends a disadvantage to surgical outcomes at the time of initial surgery affecting survival. METHODS: A retrospective chart review of patients diagnosed with EOC was performed. All patients underwent primary cytoreductive surgery followed by taxane/platinum-based chemotherapy. Patient demographics, surgicopathologic and survival data were evaluated. Patients were compared based on body mass index (BMI) (<30 vs. > or =30) and BMI strata (underweight, normal weight, overweight, obese and morbidly obese). Survival analyses were performed with the Kaplan Meier method and compared using the log rank test, chi(2) test, and Fischer's exact test. RESULTS: 304 patients were identified. 71 patients (23%) were obese (BMI>30). The groups were similar in regard to stage, grade, histology, and chemotherapy administered. In regard to surgical outcomes, no difference was seen in estimated blood loss (EBL), operating room (OR) time, or operative complications excluding wound complications. Optimal debulking rates were similar in obese and non-obese patients (52% vs. 51% respectively, p=0.88). There was no statistical difference in progression free survival (17 vs. 11 months) or overall survival (48 vs. 40 months) between the two groups or across BMI strata. CONCLUSION: Although obesity has been reported as an independent prognostic factor for survival, this data demonstrates that survival rates are similar between obese and non-obese patients when optimal debulking statuses are the same. Therefore, maximal effort should be directed towards optimal debulking obese patients with EOC.

The safety and efficacy of day 1 versus day 2 administration of pegfilgrastim in patients receiving myelosuppressive chemotherapy for gynecologic malignancies.

OBJECTIVE: Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with gynecologic malignancies who are receiving myelosuppressive chemotherapy. We sought to compare the safety and efficacy of day 1 pegfilgrastim administration to day 2 administration in patients with gynecologic malignancies. METHODS: We retrospectively evaluated patients receiving both chemotherapy and pegfilgrastim from June 1, 2006 to August 31, 2007 for a gynecologic malignancy. Abstracted data included patient demographics, pathology, blood counts, toxicity, and chemotherapy. After administration of chemotherapy, all patients either received 6 mg of pegfilgrastim subcutaneously on day 1 or day 2. RESULTS: 1226 administrations of pegfilgrastim in 230 patients were identified. 490 administrations of pegfilgrastim were given on day 1 compared to 736 on day 2. 70% of patients had ovarian cancer with a median age of 64 years (range 15-88). 79% of patients had stage III, IV, or recurrent disease and 67% were undergoing primary chemotherapy. The most common chemotherapy was docetaxel/carboplatin (53%) followed by paclitaxel/carboplatin (19%). The mean absolute neutrophil count (ANC) nadir was 4810/mm(3) in the day 1 cohort compared to 4212/mm(3) in the day 2 cohort (p=.004). The incidence of Grade 3/4 neutropenia was similar in both groups (4.9% in day 1 vs. 5.7% in day 2; p=.63). Grade 3/4 febrile neutropenia was uncommon in both cohorts (0 episodes vs. 3 episodes; p=.41). Treatment delays were similar in both cohorts (5.9% vs. 7.5%; p=.35). Dose modifications were also similar in both cohorts (2.8% vs. 5.3%; p=.06). CONCLUSION: Day 1 administration of pegfilgrastim is as effective as day 2 administration in the prevention of neutropenia in patients with gynecologic malignancies. Treatment delays and dose modifications were not increased after day 1 administration of pegfilgrastim. Administering pegfilgrastim on day 1 appears to be safe, effective, and convenient in selected patients receiving myelopsuppressive chemotherapy for gynecologic malignancies.

Expression of c-kit and platelet-derived growth factor receptors in ovarian granulosa cell tumors.

OBJECTIVE: This study aimed at evaluating the expression of tyrosine kinase receptors c-kit, (platelet-derived growth factor receptor-alpha (PDGFR-alpha), and PDGFR-beta in ovarian granulosa cell tumors (GCTs). STUDY DESIGN: Primary ovarian GCT specimens were obtained for immunohistochemical staining.The expressions of c-kit, PDGFR-alpha, and PDGFR-beta were analyzed and scored by a semiquantitative (SQ) method. Normal ovarian tissue from the same patients' specimens served as internal controls. RESULTS: A total of 21 specimens were available for evaluation. C-kit was expressed in only 2 samples, whereas both PDGFR-alpha and PDGFR-beta stained positive in 100% of tumors. PDGFR targets demonstrated strong positive expression in intensity and amount of tissue stained. Normal ovarian tissue demonstrated complete absence of staining for all 3 antibodies evaluated. CONCLUSIONS: The data demonstrated significant expression of PDGFR targets of imatinib mesylate in GCTs, whereas normal ovarian tissues had a complete absence of staining.This expression profile provides the rationale to investigate the role of imatinib mesylate in PDGFR-positive GCTs.

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.

Chemotherapy-related myelosuppression as a marker of survival in epithelial ovarian cancer patients.

OBJECTIVE: Authors have suggested that chemotherapy-induced neutropenia could represent a surrogate parameter of cancer stem cell response to treatment. Thus, the aim of this study was to evaluate the association of relative chemotherapy-induced neutropenia with survival in advanced epithelial ovarian cancer (EOC). METHODS: A computerized database identified patients for primary advanced EOC with 6 cycles of platinum-taxane-based chemotherapy. Data collected included demographics, chemotherapy administration, laboratory evaluation, and survival outcomes. Relative neutropenia, defined as an absolute neutrophil count (ANC) <1000/mm3 at chemotherapy cycle nadir, was evaluated and correlated to PFS, OS, and platinum sensitivity (recurrence >6 months from completion of chemotherapy). RESULTS: 255 patients were identified. Patients with neutropenia (n=203) during treatment were similar to patients who never had neutropenia (n=52) in regards to age, race, body mass index (BMI), stage, histology, grade, and debulking status. Neutropenic patients demonstrated improvements in PFS (14 vs. 6 months; p=0.01), OS (45 vs. 29 months; p=0.03) and platinum sensitivity rates (69% vs. 44%; p=0.001). As the number of neutropenic episodes increased, improvements in PFS (range 6 to 17 months; p=0.07) and platinum sensitivity (range 44% to 90%; p=0.002) was demonstrated. When stratified by debulking status, neutropenia conferred a survival advantage in suboptimally debulked patients, but only demonstrated marginal improvements in optimally debulked patients. CONCLUSIONS: Our data demonstrates that patients with chemotherapy-induced neutropenia is associated with a survival advantage in ovarian cancer, especially in suboptimally debulked patients.

Looks can be deceiving.

BACKGROUND: A thorough history, physical examination, and comprehensive work-up is important to differentiate the etiology of a cervical mass in unusual cases. CASE: A 36-year-old white female presented with heavy vaginal bleeding, pelvic pain, and an exophytic cervical mass extending to the anterior vaginal wall. She underwent cold knife cone with biopsies of the vagina. Pathology revealed dysgerminoma. Computed tomography of the abdomen and pelvis demonstrated pelvic lymphadenopathy, an enlarged uterus, and a 4 cm complex ovarian mass. The final pathology helped establish the true diagnosis. CONCLUSION: The accurate diagnosis of rare tumors requires a broad differential diagnosis and careful review of the pathologic findings and clinical scenario.

Complete uterine necrosis following chemoradiation for advanced cervical cancer: a case report.

BACKGROUND: Radiation therapy is an effective therapy for advanced cervical cancer. Although generally transient, complications of radiation therapy can become severe and require further intervention. Uterine necrosis is uncommon and the management can be complex. CASE: A 46-year-old African American female with stage IB2 squamous cell carcinoma of the cervix was treated with chemoradiation after an aborted radical hysterectomy. Five months after completion, the patient developed severe pelvic pain and persistent vaginal bleeding. Several biopsies confirmed radiation necrosis without evidence of tumor. Due to the severity of symptoms, the patient underwent a total abdominal hysterectomy. CONCLUSION: Uterine necrosis is a rare, late complication after chemoradiation for cervical cancer. Although several treatment options exist for radiation necrosis, surgical intervention may be necessary in severe cases.

Fertility-sparing radical abdominal trachelectomy for clear cell adenocarcinoma of the upper vagina: a case report.

BACKGROUND: Clear cell adenocarcinoma (CCA) of the vagina is traditionally treated with radical surgical resection with tailored postoperative radiation when indicated. Due to a bimodal distribution, women of reproductive age are frequently affected and could benefit from radical trachelectomy to preserve fertility. CASE: A 22 year old female was diagnosed with clinical stage I vaginal clear cell adenocarcinoma in the left fornix abutting the cervix. The patient desired future fertility; therefore, she underwent radical abdominal trachelectomy and upper vaginectomy. Twenty-eight months after initial surgery, she has no evidence of recurrence with regular menstrual cycles. CONCLUSION: For patients with CCA of the upper vagina, where removal of the cervix is necessary, a radical trachelectomy with upper vaginectomy should be considered to conserve fertility.

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.