Impact of tumour histology on survival in advanced cervical carcinoma: an NRG Oncology/Gynaecologic Oncology Group Study.

BACKGROUND: Based primarily on studies concerning early-stage tumours (treated surgically), and locally advanced disease (treated with chemoradiation), the prognosis for women with adenocarcinoma (AC) or adenosquamous (AS) carcinoma has been reported to be poorer than those with squamous cell carcinoma (SCCA) of the cervix. It is unclear whether differences in prognosis also persist in the setting of recurrent or metastatic disease treated using chemotherapy doublets with or without bevacizumab. METHODS: Cases were pooled from three Gynaecologic Oncology Group randomised phase III trials of chemotherapy doublets. Pearson's test was used to evaluate response rate (RR) of AC/AS vs SCCA, Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS), and Cox proportional hazards model to estimate the impact of histology on PFS and OS. RESULTS: Of 781 evaluable patients, 77% (N=599) had SCCA and 23% (N=182) AC/AS. There were no significant differences in RRs between histologic subgroups. The adjusted hazard ratio (HR) for death for SCCA vs AC/AS was 1.13 (95% CI 0.93, 1.38 P=0.23). When comparing SC/AS (N=661, 85%) to AC alone (N=120, 15%), the adjusted HR for death was 1.23 (95% CI 0.97, 1.57, P=0.09). CONCLUSIONS: AC/AS and SCCA have similar survival in recurrent or metastatic cervical carcinoma when treated with chemotherapy doublets.

Ten-year relative survival for epithelial ovarian cancer.

OBJECTIVE: Most patients with epithelial ovarian cancer who are alive at 5 years have active disease. Thus, 10-year survival rather than 5-year survival may be a more appropriate endpoint. Relative survival adjusts for the general survival of the United States population for that race, sex, age, and date at which the diagnosis was coded. Our objective was to estimate relative survival in epithelial ovarian cancer over the course of 10 years. METHODS: Using the Surveillance, Epidemiology and End Results 1995-2007 database, epithelial ovarian cancer cases were identified. Using the actuarial life table method, relative survival over the course of 10 years was calculated, stratified by stage, classification of residence, surgery as the first course of treatment, race, and age. RESULTS: There were 40,692 patients who met inclusion criteria. The overall relative survival was 65%, 44%, and 36% at 2, 5, and 10 years, respectively. The slope of decline in relative survival was reduced for years 5-10 as compared with years 1-5 after diagnosis. Relative survival at 5 years was 89%, 70%, 36%, and 17%, and at 10 years relative survival was 84%, 59%, 23%, and 8% for stages I, II III, and IV, respectively. At all stages, patients with nonsurgical primary treatment and those with advanced age had reduced relative survival. CONCLUSIONS: The 10-year relative survival for stage III is higher than expected. This information provides the physician and the patient with more accurate prognostic information.

Minimally invasive surgery versus laparotomy in women with high grade endometrial cancer: a multi-site study performed at high volume cancer centers.

OBJECTIVE: The study aim was to compare outcomes in women with high-grade endometrial cancer (EC) who underwent surgical staging via minimally invasive surgery (MIS) versus laparotomy. METHODS: This is a retrospective, multi-institutional cohort study of patients with high-grade EC who were comprehensively surgically staged by either MIS or laparotomy. Demographic, surgical variables, complications, and survival were analyzed. RESULTS: Three hundred and eighty-three patients met criteria: 191 underwent laparotomy and 192 MIS (65% robotic, 35% laparoscopy). Subgroups were well matched by age (mean 66 years), stage, body mass index, histology and adjuvant therapies. Median operative time was longer in the MIS group (191 vs. 135 min; p<.001). However, the MIS cohort had a higher mean lymph node count (39.0 vs. 34.0; p=.03), shorter hospital stay (1 vs. 4 days) and significantly fewer complications (8.4% vs. 31.3%; p<.001). There was no significant difference in lymph node count with laparoscopic versus robotic staging. With a median follow-up time of 44 months, progression-free (PFS) and overall survival were not significantly different between the surgical cohorts. On multivariable analysis, stage, treatment were associated with PFS. CONCLUSIONS: Women with high grade endometrial cancers staged by minimally invasive techniques experienced fewer complications and similar survival outcomes compared to those staged by laparotomy. As this population is elderly and most will receive adjuvant therapies, minimization of surgical morbidity is of interest. When managed by expert laparoscopists or robotic surgeons, a high-risk histologic subtype is not a contraindication to minimally invasive surgery in women with apparent early-stage disease.

Sexual function after intracavitary vaginal brachytherapy for early-stage endometrial carcinoma.

OBJECTIVE: To describe the effects of intracavitary brachytherapy (IVB) on sexual function and quality of life of women with early-stage endometrial cancer. METHODS: Women with International Federation of Gynecology and Obstetrics stage I to stage II endometrial cancer treated surgically with or without IVB were identified and mailed questionnaires. Quality of life and sexual function were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the cervical cancer disease-specific module. Pertinent data from prior surgery and radiation treatments were abstracted retrospectively. Linear transformation of the survey subscale scores was conducted per European Organization for Research and Treatment of Cancer guidelines. RESULTS: Sixteen women in the IVB arm and 53 in the surgery-alone group completed the survey. Of the sexually active patients, 33% of the IVB patients and 42% of the surgery-alone patients felt their vagina was dry during sexual activity (P = 0.804) and 17% versus 20% felt their vagina was short (P = 0.884). Seventeen percent of patients in the IVB group felt their vagina was tight compared to 29% in the surgery-alone group (P = 0.891) and 0% versus 14% of patients reported pain during intercourse (P = 0.808). There was no statistically significant difference in sexual/vaginal functioning, sexual worry, or sexual enjoyment between the 2 groups. CONCLUSIONS: Although both groups report vaginal changes that may affect sexual function, the patients treated with IVB reported similar outcomes on a sexual function questionnaire compared to patients treated with surgery alone.

Evolution of the Gynecologic Oncology Group protocols in the treatment of epithelial ovarian cancer.

This chapter reviews some of the sentinel Gynecologic Oncology Group (GOG) ovarian trials, describes their rationale, provides summary tables for reference, and is organized into early ovarian cancer (GOG 1, 7601, 7602, 95, 157, 175, 212), advanced ovarian cancer optimal (2, 25, 52, 104, 114, 158, 172, 182, 178, 212, 252), and suboptimal disease (3, 22, 47, 97, 111, 162, 182, 218, 252, 262).

Primary radiation therapy for medically inoperable patients with clinical stage I and II endometrial carcinoma.

OBJECTIVE: To determine the outcomes associated with primary radiation therapy for medically inoperable, clinical stage I and II, endometrial adenocarcinoma (EAC). METHODS: A multi-institution, retrospective chart review from January 1997 to January 2009 was performed. Overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS) and time to progression (TTP) were assessed using the Kaplan-Meier method. Disease-specific survival was analyzed using a competing risks approach. RESULTS: Seventy-four patients were evaluable. The median age and BMI were 65 years (range 36-92 years) and 46 kg/m(2) (range 23-111 kg/m(2)), respectively. 85.1% had severe systemic disease, most frequently cardiopulmonary risk and morbid obesity. With a mean follow-up of 31 months, 13 patients (17.6%) experienced a recurrence. The median PFS and OS were 43.5 months and 47.2 months, respectively. Overall, 35 women died, including 4 women who died of unknown cause. Of the remaining 31 women, 7 patients (9.5%) died of disease, while 24 died of other causes (32.4%). The hazard ratio comparing the risk of death due to other causes to the risk of death due to disease was 3.4 (95% CI 1.4-9.4, p=0.003). Among patients who are alive three years after diagnosis, 14% recurred and the conditional recurrence estimate did not exceed 16%. CONCLUSIONS: Primary radiation therapy for clinical stage I and II EAC is a feasible option for medically inoperable patients and provides disease control, with fewer than 16% of surviving patients experiencing recurrence.

Cervical cancer survival for patients referred to a tertiary care center in Kentucky.

OBJECTIVES: To identify prognostic factors influencing cervical cancer survival for patients referred to a tertiary care center in Kentucky. METHODS: A cohort study was performed to assess predictive survival factors of cervical cancer patients referred to the University of Kentucky from January 2001 to May 2010. Eligibility criteria included those at least 18 years-old, cervical cancer history, and no prior malignancy. Descriptive statistics were compiled and univariable and multivariable Cox proportional hazard analysis were performed. RESULTS: 381 patients met entry criteria. 95% were Caucasian (N=347) and 66% (N=243) lived in Appalachian Kentucky. The following covariates showed no evidence of a statistical association with survival: race, body mass index, residence, insurance status, months between last normal cervical cytology and diagnosis, histology, tumor grade, and location of primary radiation treatment. After controlling for identified significant variables, stage of disease was a significant predictor of overall survival, with estimated relative hazards comparing stages II, III, and IV to stage I of 3.09 (95% CI: 1.30, 7.33), 18.11 (95% CI: 7.44, 44.06), and 53.03(95% CI: 18.16, 154.87), respectively. The presence of more than two comorbid risk factors and unemployment was also correlated with overall survival [HR 4.25 (95% CI: 1.00, 18.13); HR 2.64 (95% CI 1.29, 5.42), respectively]. CONCLUSIONS: Residence and location of treatment center are not an important factor in cervical cancer survival when a tertiary cancer center can oversee and coordinate care; however, comorbid risk factors influence survival and further exploration of disease comorbidity related to cervical cancer survival is warranted.

A black raspberry extract inhibits proliferation and regulates apoptosis in cervical cancer cells.

OBJECTIVE: Cervical cancer is the second most common female cancer worldwide, and it remains a challenge to manage preinvasive and invasive lesions. Food-based cancer prevention entities, such as black raspberries and their derivatives, have demonstrated a marked ability to inhibit preclinical models of epithelial cancer cell growth and tumor formation. Here, we extend the role of black raspberry-mediated chemoprevention to that of cervical carcinogenesis. METHODS: Three human cervical cancer cell lines, HeLa (HPV16-/HPV18+, adenocarcinoma), SiHa (HPV16+/HPV18-, squamous cell carcinoma) and C-33A (HPV16-/HPV18-, squamous cell carcinoma), were treated with a lyophilized black raspberry ethanol extract (RO-ET) at 25, 50, 100 or 200µg/ml for 1, 3 and 5days, respectively. Cell proliferation was measured by WST1 (tetrazolium salt cleavage) assays. Flow cytometry (propidium iodide and Annexin V staining) and fluorescence microscopy analysis were used to measure apoptotic cell changes. RESULTS: We found that non-toxic levels of RO-ET significantly inhibited the growth of human cervical cancer cells, in a dose-dependent and time-dependent manner to a maximum of 54%, 52% and 67%, respectively (p<0.05). Furthermore, cell growth inhibition was persistent following short-term withdrawal of RO-ET from the culture medium. Flow cytometry and fluorescence microscopy demonstrated RO-ET-induced apoptosis in all cell lines. CONCLUSION: Black raspberries and their bioactive components represent promising candidates for future phytochemical-based mechanistic pathway-targeted cancer prevention strategies.

Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors.

OBJECTIVE: To compare the effectiveness of physician assessment with a new multivariate index assay in identifying high-risk ovarian tumors. METHODS: The multivariate index assay was evaluated in women scheduled for surgery for an ovarian tumor in a prospective, multi-institutional trial involving 27 primary- care and specialty sites throughout the United States. Preoperative serum was collected, and results for the multivariate index assay, physician assessment, and CA 125 were correlated with surgical pathology. Physician assessment was documented by each physician before surgery. CA 125 cutoffs were chosen in accordance with the referral guidelines of the American College of Obstetricians and Gynecologists. RESULTS: The study enrolled 590 women, with 524 evaluable for the multivariate index assay and CA 125, and 516 for physician assessment. Fifty-three percent were enrolled by nongynecologic oncologists. There were 161 malignancies and 363 benign ovarian tumors. Physician assessment plus the multivariate index assay correctly identified malignancies missed by physician assessment in 70% of nongynecologic oncologists, and 95% of gynecologic oncologists. The multivariate index assay also detected 76% of malignancies missed by CA 125. Physician assessment plus the multivariate index assay identified 86% of malignancies missed by CA 125, including all advanced cancers. The performance of the multivariate index assay was consistent in early- and late-stage cancers. CONCLUSION: The multivariate index assay demonstrated higher sensitivity and lower specificity compared with physician assessment and CA 125 in detecting ovarian malignancies.

Robotic pelvic and aortic lymphadenectomy for endometrial cancer: the console surgeon's perspectives on surgical technique and directing the assistant.

OBJECTIVE: Our purpose is to describe and demonstrate basic console dissection techniques in robotic hysterectomy, aortic and pelvic lymphadenectomy for endometrial carcinoma, and efficient methods to direct the assistant. METHODS: The operating room and patient are prepared as previously detailed. Adequate exposure is the key to a successful procedure, and a skilled bedside assistant is essential in developing the dissection. Clear communication between the console surgeon and assistant plays a critical role. In addition, proper use of the robotic fourth arm allows additional retraction and permits smooth case progression. RESULTS: We have completed more than 120 robotic hysterectomies, pelvic-aortic lymphadenectomies for endometrial cancer with these key steps. CONCLUSIONS: A systematic routine and effective use of the bedside assistant is essential for successfully completing robotic hysterectomy and aortic and pelvic lymphadenectomy. This manuscript and video illustrates our method emphasizing an efficient and comprehensive technique for this procedure.

Is there a high-risk subgroup of stage I epithelial ovarian cancer that is most likely to benefit from 6 versus 3 cycles of adjuvant chemotherapy?

OBJECTIVE: Despite results from Gynecologic Oncology Group (GOG) 157 showing no statistically significant survival differences in patients treated with 3 versus 6 cycles of carboplatin and paclitaxel, further analysis of GOG 157 data suggested that certain early-stage epithelial ovarian cancers (EOCs) might benefit from extended chemotherapy. We sought to determine those stage I EOC cases at highest risk of failing 3 cycles of therapy. METHODS: All patients with surgical International Federation of Gynecology and Obstetrics stage I EOC operated on at the Mayo Clinic and The Ohio State University between January 1991 and December 2007 were identified through retrospective chart review. A cohort of patients who received 6 cycles of adjuvant carboplatin and paclitaxel chemotherapy was compared with a cohort of patients who received 3 cycles. Disease-free survival and disease-specific survival were primary outcomes analyzed. RESULTS: There were 107 patients who received either 3 or 6 cycles of adjuvant carboplatin and paclitaxel. Among all stage I EOCs, the number of cycles did not influence disease-free survival or disease-specific survival. The highest recurrence rate (7 [46.7%] of 15 cases) was among stage IC cases with fixed tumors and positive cytology and/or surface involvement. Among this cohort, 6 (66.7%) of the 9 patients who received 3 cycles recurred, whereas only 1 (16.7%) of the 6 patients who received 6 cycles recurred (hazard ratio, 5.97; 95% confidence interval [CI], 0.98-114.46; P = 0.05, Cox proportional hazards regression model) for an odds ratio of 3.94. The absolute risk reduction for 6 cycles in this highest risk cohort was 50%. CONCLUSIONS: Patients with stage IC cancer and with fixed tumors and positive cytology and/or tumor surface involvement appear to have a higher risk of recurrence after 3 cycles (compared with 6) of platinum-based chemotherapy. The clinical behavior of this highest risk cohort implies a more aggressive tumor biology, and further understanding of such stage I EOCs is warranted.

Outpatient platinum-taxane intraperitoneal chemotherapy regimen for ovarian cancer.

INTRODUCTION: Intraperitoneal (IP) chemotherapy is associated with an improved survival at the expense of increased toxicity in optimally debulked ovarian cancer patients. We describe the toxicity profile of an outpatient regimen of an intravenous (IV) and IP taxane-platinum chemotherapy. METHODS: A chart review of all patients who received IP chemotherapy from December 2005 to May 2008 was performed. Optimally debulked patients after primary surgery for ovarian, primary peritoneal, or fallopian tubal cancer who received IV docetaxel 60 to 70 mg/m and IP cisplatin 80 to 85 mg/m on day 1 and IP paclitaxel 60 to 70 mg/m on day 8 every 21 days were included. Toxicities were recorded using the Common Terminology Criteria for Adverse Events v3.0. RESULTS: Thirty-three patients have completed chemotherapy. Of these, 19 patients (58%) completed all planned cycles of IP chemotherapy and 23 (70%) completed 75% or greater of the planned cycles. Four patients (12%) did not complete 50% or greater of the cycles. A total of 150.5 IP cycles were delivered, with a median number of 4 IP cycles (range, 0.5-7.5) completed. Grades 3 and 4 hematologic toxicities occurred in 21% of patients (n = 7), and 8 patients (24%) experienced grade 3 or 4 nonhematologic events. The overall response rate was 100% (complete response, 91%; partial response, 9.0%) with a progression-free survival of 19 months. CONCLUSIONS: This outpatient regimen of IV and IP platinum-taxane chemotherapy is well tolerated with acceptable toxicity. Importantly, most patients were able to complete all planned cycles of chemotherapy. These findings suggest that continued investigation of methods to decrease the toxicity of the treatment seen in the Gynecologic Oncology Group Protocol 172 is needed and should be studied in future phase 2 IP chemotherapy trials.

Reclassification of leiomyosarcoma as an extra-gastrointestinal stromal tumor of the gynecologic tract.

Extra-gastrointestinal stromal tumors (EGISTs) are rare, and may have similar histologic appearance to leiomyosarcomas. Thus, these tumors are often misdiagnosed when occurring in gynecologic organs. We present the fourth case of EGIST occurring in the rectovaginal septum and a review of the literature. A 56-year-old woman presented with a rectovaginal mass that was initially diagnosed as leiomyosarcoma and was treated with resection and adjuvant radiation. She presented with recurrence 4 years later and underwent a second resection. After a 5-year disease-free interval, she experienced a second recurrence and after resection was diagnosed with recurrent EGIST. EGISTs are rare but should be considered in the differential diagnosis of spindle-cell neoplasms located in or near the gynecologic tract.

Comprehensive surgical staging for endometrial cancer in obese patients: comparing robotics and laparotomy.

OBJECTIVE: To compare adequacy and outcomes of surgical staging for endometrial cancer in obese women by robotics or laparotomy. METHODS: Clinical stage I or occult stage II endometrial cancer patients with body mass indexes (BMIs) of at least 30 (BMI is calculated as weight (kg)/[height (m)]2) were identified undergoing robotic staging and matched 1:2 with laparotomy patients. Patient characteristics, operative times, complications, and pathologic factors were collected. An adequate lymphadenectomy was defined arbitrarily as at least 10 total nodes removed, and adequate pelvic and paraaortic lymphadenectomy was defined as at least six and at least four nodes removed, respectively. RESULTS: A total of 109 patients underwent surgery with the intent of robotic staging and were matched to 191 laparotomy patients. The mean BMI was 40 for each group. The robotic conversion rate was 15.6% (95% confidence interval [CI] 9.5-24.2%). Ninety-two completed robotic patients were compared with 162 matched laparotomy patients. The two groups were comparable regarding total lymph node count (25 +/- compared with 24 +/- 12, P =.45) and the percentage of patients undergoing adequate lymphadenectomy (85% compared with 91%, P=.16) and adequate pelvic (90% compared with 95%, P=.16) and aortic lymphadenectomy (76% compared with 79%, P=.70) for robotic and laparotomy patients, respectively, but there was limited power to detect this difference. The blood transfusion rate (2% compared with 9%, odds ratio [OR] 0.22, 95% CI 0.05-0.97, P=.046), the number of nights in the hospital (1 compared with 3, P<.001), complications (11% compared with 27%, OR 0.29, 95% CI 0.13-0.65 P=.003), and wound problems (2% compared with 17%, OR 0.10, 95% CI 0.02-0.43, P=.002) were reduced for robotic surgery. CONCLUSION: In obese women with endometrial cancer, robotic comprehensive surgical staging is feasible. Importantly, obesity may not compromise the ability to adequately stage patients robotically. LEVEL OF EVIDENCE: II

A detailed analysis of the learning curve: robotic hysterectomy and pelvic-aortic lymphadenectomy for endometrial cancer.

OBJECTIVE: To define the learning curve for robotic hysterectomy and pelvic-aortic lymphadenectomy for endometrial carcinoma. METHODS: Patient demographics and segmental operative times on all patients at one institution who underwent robotic comprehensive surgical staging (hysterectomy, pelvic and aortic lymphadenectomy) for endometrial cancer were prospectively collected. Patients were arranged in order based on surgery date and outcomes were compared between quartiles (cases 1-20, 21-40, 41-60, and 61-79). Proficiency was defined as the point at which the slope of the curve becomes less steep for operative times. Efficiency was defined as the point at which the slope is zero. ANOVA or Fisher's exact test was used to compare the procedure times. Locally weighted regression generated smoothed lines that represent operative time over the sequence of the operations. RESULTS: 79 patients were comprehensively staged robotically. While age, the percentage of patients with >/=2 co-morbidities, number of patients with previous laparotomy, EBL, LOS and lymph node counts do not differ between groups, the first 20 patients had a lower BMI compared to the next 20 (27 vs. 34 kg/m(2), P=0.009). Operative times decreased from the first 20 cases to next 20, but was not significantly changed over the next three quartiles. Each component of the procedure has a separate learning curve. CONCLUSIONS: Proficiency for robotic hysterectomy with pelvic-aortic lymphadenectomy for endometrial cancer is achieved after 20 cases; however, the number of procedures to gain efficiency varies for each portion of the case and continues to improve over time.

Paratubal borderline serous tumors.

BACKGROUND: While ovarian borderline tumors are common, their fallopian tube counterparts are extremely rare. We describe the first case of a serous borderline paratubal tumor with a review of the literature on paratubal and tubal low malignant potential tumors. CASE: A 26 year-old woman presented with acute onset of sharp right lower quadrant pain and nausea. Abdominal and pelvic CT revealed 12.5 cm cystic ovarian mass and she was admitted for pain control. On hospital day two, her pain escalated and torsion was suspected; thus, she underwent a diagnostic laparoscopy with right fallopian tube cystectomy and partial salpingectomy. Inspection of the cyst wall demonstrated multiple papillary excrescences and frozen section returned at least borderline fallopian tube neoplasm. After a fertility-sparing comprehensive surgical staging procedure was performed, she was diagnosed with stage IC fallopian tube serous borderline tumor and underwent no further therapy. Currently, she is without evidence of disease recurrence. CONCLUSION: Borderline fallopian tube or paratubal tumors are usually early stage at diagnosis and commonly present in the third decade with pain or are discovered on routine examination. Continued reporting of these tumors is essential to understanding the prognosis and treatment of this rare tumor.