Leigh G. Seamon

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 Fishers 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.

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. LEVEL OF EVIDENCE: III

Robotic Hysterectomy and Pelvic-Aortic Lymphadenectomy for Endometrial Cancer

OBJECTIVE: To report the learning curve and outcomes after our first 105 patients underwent robotic hysterectomy and pelvic–aortic lymphadenectomy for the comprehensive staging of endometrial cancer. METHODS: We prospectively collected patient demographics, operative times, complications, pathologic results, and length of stay on all patients who underwent robotic hysterectomy pelvic–aortic lymphadenectomy for clinical stage I or occult stage II endometrial carcinoma. RESULTS: One hundred five patients at The Ohio State University between March 2006 and April 2008 underwent exploration with the intent of robotic hysterectomy pelvic–aortic lymphadenectomy. Ninety-two (87.6%) were completed robotically and 13 (12.4%) were converted. The probability of conversion was 15% (95% confidence interval [CI] 8.4–25.7), 24% (95% CI 12.4–39.9), 35% (95% CI 15.9–59.6), and 48% (95% CI 19.1–77.8) for a body mass index of 40, 45, 50, and 55 kg/m2, respectively. The median body mass index was 34 kg/m2 (range 19–58). In patients who underwent a robotic hysterectomy pelvic–aortic lymphadenectomy (n=79, 75%) or a robotic hysterectomy–pelvic lymphadenectomy (n=6, 5.7%), the average operating time from skin opening to closure was 242 minutes (±50 minutes). The median estimated blood loss was 99 mL (±83 mL). The median number of lymph nodes recovered was 29 (range 9–56), 21 (range 5–40) pelvic nodes and 9 (range 2–21) aortic nodes. The median length of stay was 1 night. After analysis of the data, we determined approximately 20 cases are needed to gain proficiency. CONCLUSION: Early experience demonstrates that robotic hysterectomy pelvic–aortic lymphadenectomy for endometrial cancer is feasible, with approximately 20 procedures needed to gain proficiency. LEVEL OF EVIDENCE: III

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. LEVEL OF EVIDENCE: III

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±13 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

Influence of intraoperative capsule rupture on outcomes in stage I epithelial ovarian cancer.

OBJECTIVE: To evaluate the effect of tumor capsule rupture on disease prognosis in stage I epithelial ovarian cancer. METHODS: All patients with International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer operated on at the Mayo Clinic and The Ohio State University between January 1991 and December 2007 were identified. Relevant tumor characteristics, procedures performed, adjuvant therapies, and follow-up were recorded and analyzed. Inclusion criteria included comprehensive staging. Cox proportional hazards, Kaplan-Meier estimation, log rank test, and &khgr;2 test were used for statistical analyses. RESULTS: There were 161 cases that met inclusion criteria. Seventy-four (46%) patients had intact capsules without positive cytology or surface involvement; 61 (38%) had capsule rupture; 33 (20%) had positive cytology; and 22 (14%) had surface involvement. Overall, 22 of 161 (14%) patients recurred and 12 of 161 (7%) patients died of their disease. In univariable analysis, both intraoperative capsule rupture and positive cytologic washings portended worse disease-free survival (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.5–8.9; P=.004 and HR 5.2, 95% CI 2.1–12.3; P<.001, respectively) and disease-specific survival (HR 4.1, 95% CI 1.3–15.4; P=.018 and HR 5.9, 95% CI 1.8–19.3; P=.005, respectively). In multivariable analysis, capsule rupture (HR 4.2, 95% CI 1.8–10.9; P=.001) and positive cytologic washings (HR 6.4, 95% CI 2.5–16.0; P<.001) remained independent predictors of worse disease-free survival. Disease-free survival and disease-specific survival were shortest for stage IC cases with positive cytology, surface involvement, or both, that also had intraoperative rupture. CONCLUSION: In stage I epithelial ovarian cancer, intraoperative capsule rupture portends a higher risk of disease recurrence and death from disease. Careful intraoperative removal of ovarian masses is important, and recognizing the higher-risk nature of such cases is imperative. LEVEL OF EVIDENCE: III

Lymphadenectomy for endometrial cancer: The controversy

Comprehensive surgical staging for endometrial cancer, including hysterectomy, bilateral salpingo-oophorectomy, pelvic washings, and pelvic–aortic lymphadenectomy, defines disease biology and facilitates triage of tailored adjuvant therapy. Recent publication of two randomized trials has cracked the foundation of the house lived in by those believing in the absolute value of endometrial cancer surgical staging—or has it? (Table 1) [1,2]. The first study (Panici trial) randomized clinical stage I endometrial carcinoma patients to systematic pelvic lymphadenectomy vs. no lymphadenectomy (control) [1]. Eligible patients included those with frozen sections demonstrating myometrial invasion (stage TIB grade 1 excluded) who were also ≤75 years old with a Karnofsky performance status ≥80 with no previous malignancy, chemotherapy, or radiation. A sample size of 524 patients was estimated to detect a 8% difference (80 to 88% 5-year overall survival, HR 0.52)with an alpha of 5% and beta of 80%. The study accrued 514 patients at 31 centers in 2 countries over 10 years (10 patients short of the trial design). While aortic dissection was left to surgeon discretion, systematic pelvic lymphadenectomy was required in the lymphadenectomy arm. Removal of bulky nodes (N1 cm) was allowed in the control arm. After 49 months median follow-up, the adjusted hazard ratio for relapse (HR=1.20, 95% CI=0.75–1.91) and death (HR=1.16, 95% CI=0.67–2.02) were similar; however, as noted above, the trial did not meet the requirements to detect a difference. There were no prespecified criteria for the application or standardization of postoperative adjuvant therapy and the Cox regression was not adjusted for postoperative therapy. More patients received adjuvant treatment in the control group compared to the lymphadenectomy arm (25.2% vs. 16.7%, p=0.033) and 16% and 11% in the control arm had N6 and 10 nodes removed, respectively. An exploratory analysis excluding lymphadenectomy protocol violations also noted no difference in outcomes; however, the protocol violation definition was 20 nodes. Thus, lymphadenectomy arm patients were excluded if b20 nodes were removed and control arm women excluded if ≥20 nodes were noted. While no standard definition of “adequate” lymphadenectomy exists, a pelvic node count ≥8–10 is an accepted surrogate for adequacy [3–7]. Perioperative complications were similar in both arms. While an increase in early and late postoperative complications was demonstrated in the lymphadenectomy arm, conclusions may be limited due to failure to adjust the rates for adjuvant therapy. Importantly, the trial did note an increase in the lymph node-positivity rate when systematic lymphadenectomy was performed (13.3% vs. 3.2%, pb0.001). The following month, the ASTEC (a study in the treatment of endometrial cancer) trial was published [2]. The objective was to determine if lymphadenectomy increases survival independent of adjuvant radiation. The primary outcome was overall survival. The trial included 85 centers in 4 different countries and accrued over

Combination gemcitabine, platinum, and bevacizumab for the treatment of recurrent ovarian cancer

OBJECTIVE To describe the response rate (RR), progression-free survival (PFS), and toxicity profile of combination gemcitabine, platinum, and bevacizumab (GPB) for the treatment of recurrent epithelial ovarian cancer (EOC). METHODS A chart review of all patients with recurrent EOC who were treated with D1, D15 GPB in a 28-day cycle at a single institution was performed. Standard doses were gemcitabine 1000 mg/m(2), cisplatin 30 mg/m(2) or carboplatin AUC 3, and bevacizumab 10 mg/kg. All patients were analyzed for toxicity. RR and PFS were assessed in all patients who received at least 2 cycles of GPB. RESULTS Thirty-five patients were identified, and 33 received at least 2 cycles of GPB. The majority of patients (80%) were platinum sensitive. Patients received a median of 6 cycles of GPB (range 1-24). Sixteen patients (48%) had a complete response (CR), and 10 patients (30%) had a partial response (PR), for a total RR of 78%. An additional 5 patients (15%) had stable disease, and only 2 (6%) patients had progressive disease. The median overall PFS was 12 months (95% CI 7-15), with a median follow-up time of 10 months (2-22). Two patients (6%) had bowel perforations, and both survived. Hematologic toxicities were most common, with 29% and 14% of patients experiencing grade 3 or 4 neutropenia and thrombocytopenia respectively. CONCLUSIONS The combination of GPB demonstrated excellent efficacy for the treatment of recurrent EOC. However, serious toxicities occurred, and the safety profile of this combination requires further study.

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.

Risk of malignancy in sonographically confirmed septated cystic ovarian tumors

OBJECTIVE To determine the risk of malignancy in septated cystic ovarian tumors. MATERIALS 1319 (4.4%) of 29,829 women were identified by transvaginal sonography (TVS) as having a complex cystic ovarian tumor with septations without solid areas or papillary projections and were placed on long-term ultrasound surveillance for ovarian malignancy. RESULTS These 1319 patients had a total of 2870 septated cystic ovarian tumors. 2288 tumors (79.7%) had a septal width <2 mm and 582 (20.3%) had a septal width >or=2 mm. 2286 tumors (79.6%) were <5 cm in diameter and 584 (20.4%) were>or=5 cm in diameter. 1114 septated cystic tumors (38.8%) resolved spontaneously (mean duration to resolution-12 months) and 1756 (61.2%) tumors persisted. 128 patients underwent surgical tumor removal within 3 months of ultrasound. Most common histopathology was: serous cystadenoma (75), mucinous cystadenoma (13), and endometrioma (10). One patient had an ovarian tumor of borderline malignancy (Stage IB). There were no cases of ovarian cancer. Patients were followed from 4 to 252 months (mean-77 months). One patient developed papillary morphology in the contralateral ovary 3.2 years after detection of a septated ovarian cyst and had epithelial ovarian cancer in that ovary and in the omentum (Stage IIIC disease). The remaining patients are all free of ovarian neoplasia after a total of 7642 follow-up years. CONCLUSIONS Septated cystic ovarian tumors without solid areas or papillary projections have a low risk of malignancy and can be followed sonographically without surgery.