Ashley S. Case

Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer

OBJECTIVE We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix. METHODS Eligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50 mg/m(2) day 1, topotecan 0.75 mg/m(2) days 1, 2 and 3 and bevacizumab 15 mg/kgday 1 every 21 days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6 months. We explored PET/CT as a potential early indicator of response to therapy. RESULTS Twenty-seven eligible patients received a median of 3 treatment cycles (range, 1-19). Median follow-up was 10 months (range, 1.7-33.4). The 6-month PFS was 59% (80% CI: 46-70%). In 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4-14%) and 8 PR (31%; 80% CI: 19-45%) lasting a median of 4.4 months. Ten patients had SD (39%; 80% CI: 25-53%) with median duration of 2.2 months. Median PFS was 7.1 months (80% CI: 4.7-10.1) and median OS was 13.2 months (80% CI: 8.0-15.4). All patients were evaluated for toxicity. Grade 3-4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities. CONCLUSION The addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity.

Chemoradiation in locally advanced cervical carcinoma: An analysis of cisplatin dosing and other clinical prognostic factors

OBJECTIVES The aim of this study was to evaluate the effect of number of chemotherapy cycles and other clinical and pathologic factors on progression-free (PFS) and overall survival (OS) in patients with newly diagnosed cervical cancer. METHODS We identified 118 patients with locally advanced cervical cancer (stages IB2-IVA) treated with combination weekly cisplatin (40 mg/m(2)) and radiation therapy (RT) between 2003 and 2007. Kaplan-Meier and Cox proportional hazard models were utilized to evaluate PFS and OS for associations with number of chemotherapy cycles and other factors. RESULTS The majority of patients had stage IB2 or II disease (70%), squamous histology (91%), and size <6 cm (65%). Median RT duration was 50 days and 95% received brachytherapy. Thirty percent of patients completed <6 cycles of chemotherapy, and estimated PFS and OS were 63% and 75%, respectively. In multivariate analyses, the number of chemotherapy cycles was independently predictive of PFS and OS. Patients who received <6 cycles of cisplatin had a worse PFS (HR 2.65; 95% CI 1.35-5.17; p=0.0045) and OS (HR 4.47; 95% CI 1.83-10.9; p=0.001). Advanced stage, longer time to RT completion, and absence of brachytherapy were also associated with decreased OS and PFS (p<0.05). Similar results were found when analysis was conducted using a breakpoint of at least five but not less than five chemotherapy cycles. Higher grade was associated with decreased PFS (p=0.03) but not OS. Age, race, BMI, tumor size, smoking, histology, and IMRT were not statistically significant for OS or PFS. CONCLUSIONS Aggressive supportive care to minimize missed chemotherapy treatments may improve survival after chemoradiation.

Wound complications after gynecologic cancer surgery

OBJECTIVE To explore clinical correlates of wound complications in high-risk women undergoing abdominal gynecologic surgery in a tertiary referral center. METHODS Retrospective analysis of patient demographics, pre-operative and intra-operative information, and outcomes was performed in a cohort of patients who underwent abdominal surgery for suspected gynecologic malignancy between 1/2005 and 6/2008. The primary outcome was wound complication within 6 weeks of surgery. Univariate and multivariate logistic regression analyses were employed. A nomogram predicting post-operative wound complications was created and validated by receiver operating characteristic (ROC) curve analysis and 10-fold cross-validation. RESULTS Median age of 373 women analyzed was 57years (range 25-88), median body mass index (BMI) 32.3kg/m(2) (range 14.0-70.7). A total of 150 patients (40%) had prior abdominal surgery; 40 (11%) had a pre-operative serum albumin <3.5g/dl; and 78 (21%) had pulmonary disease. Wound complications occurred in 125 patients (34%). In multivariate analysis wound complications were correlated with BMI of 30-39.9kg/m(2) (OR=5.62, 95% CI 2.08-15.19, p<0.0001) and BMI≥40kg/m(2) (OR=10.27, 95% CI 3.66-28.88, p<0.0001), prior abdominal surgery (OR 3.28, 95%CI1.89-5.70, p<0.0001), serum albumin≤3.5g/dl (OR 4.24, 95%CI 1.87-9.61, p=0.0005), pulmonary disease (OR 2.22, 95%CI 1.09-4.51, p=0.03), lysis of adhesions (OR 3.57, 95%CI 1.04-12.26, p=0.04), and length of surgery (OR 2.42, 95%CI 1.35-4.35, p=0.003). Risk for wound complication was lower with pelvic drain placement (OR 0.26, 95%CI 0.11-0.64, p=0.003). CONCLUSIONS Wound complications are common in gynecologic oncology. Further studies should explore whether risk factor modification decreases complications.

The role of PET/CT in the management of patients with cervical cancer: practice patterns of the members of the Society of Gynecologic Oncologists.

OBJECTIVES Recent data has highlighted the role of PET/CT in the pretreatment evaluation and follow-up of patients with cervical cancer. The objective of our study was to assess the acceptance of PET/CT into the management of patients with cervical cancer. We also explored potential barriers to the use of these imaging modalities in patients with cervical cancer. METHODS A 14-item electronic questionnaire was initially sent to all working addresses of members of the SGO (n=1048). An opt-out option was offered. For members who did not respond within 3 weeks, a second electronic invitation was sent. A third request was finally sent to further improve response rates. Data were collected and analyzed using a commercially available on-line survey database. RESULTS A total of 305 responses were collected for an overall 30% response rate. PET/CT appears to be widely available (99%) and accessible (75%) in most practices. Although 83% of members order routine CT imaging for all newly diagnosed cervical cancer cases, only 28% routinely order a PET/CT. Conversely, 64% would order a PET/CT for newly diagnosed patients with advanced disease or those at high risk for distant metastatic disease. Most members (82%) do not routinely use PET/CT to assess response to treatment. Twenty percent of members believe that no useful prognostic information can be obtained from routine use of molecular imaging in patients with cervical cancer. The most common barriers for use of PET/CT cited by members were perceived lack of third-party payer coverage and lack of scientific evidence. CONCLUSIONS Despite clear scientific data supporting the use of PET/CT in patients with cervical cancer and apparent widespread availability, this imaging modality remains highly underutilized in clinical practice. Clarifying insurance coverage early in the evaluation process and replicating studies that have shown effectiveness of PET/CT in multiple roles may improve adoption of this potentially useful imaging modality.

The value of perioperative imaging in patients with uterine sarcomas.

OBJECTIVE To explore the yield and impact of perioperative imaging on management among patients undergoing surgical resection and treatment of uterine sarcomas. METHODS A retrospective chart review was done for women with histologically confirmed uterine sarcomas treated at Barnes Jewish Hospital/Washington University from 2001 to 2007. Descriptive statistics, Cox multivariate models, and Kaplan-Meier plots were used to evaluate associations and survival. RESULTS A total of 92 patients were identified and 55 (60%) were diagnosed with stage III-IV disease. Perioperative imaging was obtained in 84 (91%) cases, including chest X-ray in 66 (72%), computerized tomography (CT) of the abdomen and pelvis in 59 (64%), chest CT in 33 (36%), positron emission tomography (PET) in 8 (9%), and CT of the head, pelvic magnetic resonance imaging (MRI), or bone scan in a total of 2 (2.2%). Imaging identified abnormalities concerning for metastases in 30 (32%) studies. Thirty-four recurrences have been documented, and 21 (62%) of these treatment failures were extrapelvic. Multivariate analysis of this series noted that tomographic evidence of extrauterine disease predicted recurrence (p=0.028) and incomplete surgical resection (p=0.003, HR 6.0 95% CI 1.9-19.9) predicted disease-free survival. Imaging contributed to change in surgical and post-surgical treatment decisions in 8 (9%) patients. CONCLUSION Pretreatment imaging studies change management in a minority of patients with newly diagnosed uterine sarcomas.

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 &khgr;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.

técnica diagnóstica de extirpación electroquirúgica con asa para la resolución de discrepancias: predicen los factores preoperatorios la presencia de neoplasia cervical intraepitelial significativa?

Objetivo. Aunque las discrepancias anatomopatológicas entre los resultados del frotis de Papanicolaou y de la biopsia son un indicador aceptado de que se debe practicar una técnica diagnóstica de extirpación electroquirúrgica con asa (LEEP), dicha técnica no está exenta de complicaciones. Nuestro objetivo ha consistido en determinar la incidencia de la neoplasia cervical intraepitelial (CIN) 2 ó 3 y los factores de las pacientes que aumentan las posibilidades de detectar CIN 2 ó 3. Materiales y métodos. Realizamos una revisión retrospectiva de historias clínicas de pacientes a las que se había practicado una LEEP diagnóstica para resolver discrepancias anatomopatológicas en una clínica colposcópica de un centro universitario. La discrepancia anatomopatológica se define como un resultado de grado alto en un frotis de Papanicolaou y un resultado de CIN 1 o inferior en una biopsia dirigida colposcópicamente. Se recopiló información demográfica, citológica e histológica mediante una base de datos informatizada. Las pacientes se dividieron en dos grupos (por un lado, CIN 2 y 3 y, por otro, CIN 1 o inferior) según los datos anatomopatológicos de la muestra de la LEEP. Los factores de las pacientes se compararon con los resultados anatomopatológicos finales mediante la prueba χ2, la prueba de la t de Student, la prueba de sumas de rangos de Wilcoxon y un análisis multivariado según correspondiera. Resultados. Se identificó un total de 102 pacientes. Las muestras de siete pacientes fueron normales, en tres casos se detectaron alteraciones provocadas por el VPH, 25 mujeres presentaban CIN 1, 29 CIN 2 y 38 CIN 3. Un total de 35 pacientes (34%) presentaban CIN 1 o inferior, mientras que 67 pacientes (66%) presentaban CIN 2 ó 3. Los dos grupos fueron comparables en términos de edad (30,4 frente a 28,1 años), número de partos (2,2 frente a 1,9) y edad de la primera relación sexual (16,3 frente a 16,4 años). No existió ninguna diferencia estadística entre los grupos en cuanto a raza, hábito tabáquico, frotis de Papanicolaou, antecedentes de anomalías citológicas previas, método anticonceptivo, número de parejas sexuales anteriores y estado en cuanto al VIH. La mayoría de pacientes (75%) no se habían sometido a ningún tratamiento previo de la CIN. Las probabilidades de haberse sometido a un tratamiento previo o a una biopsia para detectar la presencia de CIN fueron superiores en el grupo de CIN 2 y 3 que en el grupo de CIN 1 o inferior (66% frente a 34%; p = 0,004). Los análisis univariado (p = 0,004) y multivariado (p < 0,001) pusieron de manifiesto un tratamiento previo de CIN como único predictor significativo de CIN 2 y 3. Conclusiones. Dos terceras partes de las mujeres a las que se había practicado una LEEP para resolver discrepancias anatomopatológicas entre los resultados del frotis de Papanicolaou y la biopsia de cérvix presentarán CIN 2 ó 3. Las mujeres que se han sometido a un tratamiento previo de CIN tienen más posibilidades de que se detecte CIN 2 ó 3 en su muestra obtenida mediante LEEP. ▪