Edward J. Tanner

A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer

OBJECTIVE The study objective was to compare the ability to detect sentinel lymph nodes (SLNs) in women with endometrial cancer (EC) or complex atypical hyperplasia (CAH) using fluorometric imaging with indocyanine green (ICG) versus colorimetric imaging with isosulfan blue (ISB). METHODS Women underwent SLN mapping, with either ISB or ICG, during robotic-assisted total laparoscopic hysterectomy (RA-TLH) from September 2012 to March 2014. SLNs were submitted for permanent pathologic analysis. Completion lymphadenectomy and ultrastaging were performed according to institutional protocols. RESULTS RA-TLH and SLN mapping was performed in 71 women; 64 had EC (64) and 7 had CAH. Age, body mass index (BMI), stage and tumor characteristics were similar in the ICG versus the ISB cohorts. Overall, SLNs were identified bilaterally (62.0%), unilaterally (21.1%), or neither (16.9%), and in 103 of 142 hemi-pelvises (72.5%). The mean number of SLNs retrieved per hemipelvis was 2.23(SD 1.7). SLNs were identified in the hypogastric (76.8%), external iliac (14.2%), common iliac (4.5%) and paraaortic (4.5%) regions. ICG mapped bilaterally in 78.9% of women compared with 42.4% of those injected with ISB (p=0.02). Five women (7%) had positive lymph nodes, all identified by the SLN protocol (false negative rate: 0%). On multivariate analysis, BMI was negatively correlated with bilateral mapping success (p=0.02). When stratified by dye type, the association with BMI was only significant for ISB (p=0.03). CONCLUSIONS Fluorescence imaging with ICG may be superior to colorimetric imaging with ISB in women undergoing SLN mapping for endometrial cancer. SLN mapping success is negatively associated with increasing patient BMI only when ISB is used.

Surveillance for the detection of recurrent ovarian cancer: Survival impact or lead-time bias?

OBJECTIVE To compare the survival impact of diagnosing recurrent disease by routine surveillance testing versus clinical symptomatology in patients with recurrent epithelial ovarian cancer (EOC) who have achieved a complete response following primary therapy. METHODS We identified all patients who underwent primary surgery for EOC at two institutions between 1/1997 and 12/2004 and were diagnosed with recurrent disease following a complete clinical response to primary chemotherapy. Survival and post-recurrence management were compared between asymptomatic patients in which recurrent disease was diagnosed at a scheduled visit by routine surveillance testing and symptomatic patients in which recurrent disease was diagnosed based on clinical symptomatology at an unscheduled office visit or hospitalization. RESULTS Of the 121 patients that met inclusion criteria, 22 (18.2%) were diagnosed with a symptomatic recurrence. Median primary PFS was similar for asymptomatic and symptomatic patients (24.8 versus 22.6 months, P = 0.36); however, post-recurrence survival was significantly greater in asymptomatic patients (45.0 versus 29.4 months, P = 0.006). Secondary cytoreductive surgery (SCRS) was attempted equally in both groups (41% versus 32%, P = NS); however, optimal residual disease (<or=5mm) was more often achieved in asymptomatic patients (90% versus 57%, P = 0.053). On multivariate analysis, detection of asymptomatic recurrence was a significant and independent predictor of improved overall survival (P = 0.001). Median OS was significantly greater for asymptomatic patients (71.9 versus 50.7 months, P = 0.004). CONCLUSIONS In patients with platinum-sensitive EOC, detection of asymptomatic recurrences by routine surveillance testing was associated with a high likelihood of optimal SCRS in operative candidates and extended overall survival.

Sentinel lymph node assessment in endometrial cancer: a systematic review and meta-analysis.

BACKGROUND: In the staging of endometrial cancer, controversy remains regarding the role of sentinel lymph node mapping compared with other nodal assessment strategies. OBJECTIVE: We conducted a systematic review to evaluate the diagnostic accuracy and clinical impact of sentinel lymph node mapping in the management of endometrial cancer. DATA SOURCES: We searched Medline, Embase, and the Cochrane Central Registry of Controlled trials for studies published in English before March 25, 2016 (PROSPERO CRD42016036503). STUDY ELIGIBILITY CRITERIA: Studies were included if they contained 10 or more women with endometrial cancer and reported on the detection rate, sensitivity, and/or impact on treatment or survival of sentinel lymph node mapping. STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors independently reviewed abstracts and full‐text articles for inclusion and assessed study quality. The detection rate, sensitivity, and factors associated with successful mapping (study size, body mass index, tumor histology and grade, injection site, dye type) were synthesized through random‐effects meta‐analyses and meta‐regression. RESULTS: We identified 55 eligible studies, which included 4915 women. The overall detection rate of sentinel lymph node mapping was 81% (95% confidence interval, 77–84) with a 50% (95% confidence interval, 44–56) bilateral pelvic node detection rate and 17% (95% confidence interval, 11–23) paraaortic detection rate. There was no difference in detection rates by patient body mass index or tumor histology and grade. Use of indocyanine green increased the bilateral detection rate compared with blue dye. Additionally, cervical injection increased the bilateral sentinel lymph node detection rate but decreased the paraaortic detection rate compared with alternative injection techniques. Intraoperative sentinel lymph node frozen section increased the overall and bilateral detection rates. The sensitivity of sentinel node mapping to detect metastases was 96% (95% confidence interval, 91–98); ultrastaging did not improve sensitivity. Compared with women staged with complete lymphadenectomy, women staged with sentinel lymph node mapping were more likely to receive adjuvant treatment. CONCLUSION: Sentinel lymph node mapping is feasible and accurately predicts nodal status in women with endometrial cancer. The current data favors the use of cervical injection techniques with indocyanine green. Sentinel lymph mapping may be considered an alternative standard of care in the staging of women with endometrial cancer.

Utilization of minimally invasive surgery in endometrial cancer care: A Quality and cost disparity

OBJECTIVE: To describe case mix-adjusted hospital level utilization of minimally invasive surgery for hysterectomy in the treatment of early-stage endometrial cancer. METHODS: In this retrospective cohort study, we analyzed the proportion of patients who had a minimally invasive compared with open hysterectomy for nonmetastatic endometrial cancer using the U.S. Nationwide Inpatient Sample database, 2007–2011. Hospitals were stratified by endometrial cancer case volumes (low=less than 10; medium=11–30; high=greater than 30 cases). Hierarchical logistic regression models were used to evaluate hospital and patient variables associated with minimally invasive utilization, complications, and costs. RESULTS: Overall, 32,560 patients were identified; 33.6% underwent a minimally invasive hysterectomy with an increase of 22.0–50.8% from 2007 to 2011. Low-volume cancer centers demonstrated the lowest minimally invasive utilization rate (23.6%; P<.001). After multivariable adjustment, minimally invasive surgery was less likely to be performed in patients with Medicaid compared with private insurance (adjusted odds ratio [OR] 0.67, 95% confidence interval [CI] 0.62–0.72), black and Hispanic compared with white patients (adjusted OR 0.43, 95% CI 0.41–0.46 for black and 0.77, 95% CI 0.72–0.82 for white patients), and more likely to be performed in high- compared with low-volume hospitals (adjusted OR 4.22, 95% CI 2.15–8.27). Open hysterectomy was associated with a higher risk of surgical site infection (adjusted OR 6.21, 95% CI 5.11–7.54) and venous thromboembolism (adjusted OR 3.65, 95% CI 3.12–4.27). Surgical cases with complications had higher mean hospitalization costs for all hysterectomy procedure types (P<.001). CONCLUSION: Hospital utilization of minimally invasive surgery for the treatment of endometrial cancer varies considerably in the United States, representing a disparity in the quality and cost of surgical care delivered nationwide.

Factors associated with successful bilateral sentinel lymph node mapping in endometrial cancer

OBJECTIVE As our understanding of sentinel lymph node (SLN) mapping for endometrial cancer (EC) evolves, tailoring the technique to individual patients at high risk for failed mapping may result in a higher rate of successful bilateral mapping (SBM). The study objective is to identify patient, tumor, and surgeon factors associated with successful SBM in patients with EC and complex atypical hyperplasia (CAH). METHODS From September 2012 to November 2014, women with EC or CAH underwent SLN mapping via cervical injection followed by robot-assisted total laparoscopic hysterectomy (RA-TLH) at a tertiary care academic center. Completion lymphadenectomy and ultrastaging were performed according to an institutional protocol. Patient demographics, tumor and surgeon/intraoperative variables were prospectively collected and analyzed. Univariate and multivariate analyses were performed evaluating factors known or hypothesized to impact the rate of successful lymphatic mapping. RESULTS RA-TLH and SLN mapping was performed in 111 women; 93 had EC and 18 had CAH. Eighty women had low grade and 31 had high grade disease. Overall, at least one SLN was identified in 85.6% of patients with SBM in 62.2% of patients. Dye choice (indocyanine green versus isosulfan blue), odds ratio (OR: 4.5), body mass index (OR: 0.95), and clinically enlarged lymph nodes (OR: 0.24) were associated with SBM rate on multivariate analyses. The use of indocyanine green dye was particularly beneficial in patients with a body mass index greater than 30. CONCLUSION Injection dye, BMI, and clinically enlarged lymph nodes are important considerations when performing sentinel lymph node mapping for EC.

Does adjuvant chemotherapy improve survival for women with early-stage uterine leiomyosarcoma?

OBJECTIVES To examine whether adjuvant therapy after primary surgery for treatment of early-stage uterine leiomyosarcoma (LMS) improves recurrence and survival rates. METHODS A multisite, retrospective study of women diagnosed with stage I-II high grade LMS from 1990-2010 was performed. All patients (pts) underwent primary surgery followed by observation (OBS), radiotherapy (RT), or chemotherapy (CT) postoperatively. RESULTS One hundred eight patients were identified with long-term follow-up; 94 pts (87.0%) had stage I and 14 (13.0%) had stage II disease. The mean patient age was 55.4 years and mean BMI was 28.0. Thirty-four (31.5%) patients underwent OBS, 35 (32.4%) received RT, and 39 (36.1%) received chemotherapy. After a median follow-up of 41.8 months, a recurrence was diagnosed in 70.8%. Recurrence was evident in 25/34 (73.5%) OBS, 23/35 (65.7%) RT, and 28/39 (71.8%) of CT cohorts and was not different based on treatment (p=0.413). However, extra-pelvic recurrences were significantly higher in the RT (95.2%) than in the OBS (60%) or CT (64.3%) cohorts (p=0.012). Additionally, recurrences were more likely to be successfully treated or palliated in those who initially received CT (p=0.031). On multivariate analysis, stage (p<0.001) and chemotherapy (p=0.045) were associated with overall survival. CONCLUSIONS Women with early-stage, high grade uterine LMS experience high recurrence rates and poor survival outcomes, irrespective of adjuvant therapy. These rates are higher than previously reported in the literature. Although women treated with CT had similar recurrence rates as those treated with OBS or RT, treatment with adjuvant chemotherapy may decrease the risk of extra-pelvic recurrence and improve survival.

The prognostic significance of pre- and post-treatment CA-125 in grade 1 serous ovarian carcinoma: A Gynecologic Oncology Group study

OBJECTIVES The study objective was to determine the prognostic significance of serum CA-125 levels in patients with grade 1 serous ovarian carcinoma (SOC) enrolled in a Phase III study. METHODS An ancillary analysis of a phase III study of women with advanced epithelial ovarian cancer treated with carboplatin/paclitaxel versus triplet or sequential doublet regimens. Grade 1 SOC was used as a surrogate for low-grade serous carcinoma. RESULTS Among 3686 enrolled patients, 184 (5%) had grade 1 disease and CA-125 levels available. For those with grade 1 SOC, the median patient age was 56.5; 87.3% had Stage III disease. Median follow-up was 102 months and there was no difference in pre-chemotherapy CA-125 by treatment arm (P=0.91). Median pretreatment CA-125 for those with grade 1 SOC was lower (119.1) than for patients with grade 2-3 SOC (246.7; P<0.001). In those with grade 1, pretreatment CA-125 was not prognostic of outcome. However, patients with CA-125 levels that normalized after cycle 1, 2 or 3 were 60-64% less likely to experience disease progression as compared to those who never normalized or normalized after 4 cycles (P ≤ 0.024). Normalization of CA-125 levels before the second cycle was negatively associated with death, with a HR of 0.45 (P=0.025). CONCLUSIONS Pretreatment CA-125 level was significantly lower in women with grade 1 SOC compared to those with high-grade SOC. While pretreatment CA-125 was not associated with survival, serial CA-125 measurements during chemotherapy treatment were prognostic, with normalization before the second chemotherapy cycle associated with a decreased risk of death.

Lymphopenia and its association with survival in patients with locally advanced cervical cancer

OBJECTIVE To evaluate the association between lymphopenia and survival in women with cervical cancer treated with primary chemoradiation. METHODS A single institution, retrospective analysis of patients with stage IB2-IVA cervical cancer who received upfront chemoradiation from 1998 to 2013 was performed. Complete blood counts from pre-treatment to 36 months post-treatment were analyzed. Lymphopenia and known prognostic factors were evaluated for an association with progression-free (PFS) and overall survival (OS). RESULTS Seventy-one patients met study criteria for whom 47 (66%) had a documented total lymphocyte count (TLC) two months after initiating chemoradiation. FIGO stage distribution was 6% Stage I, 46% Stage II, 45% Stage III and 3% Stage IV. Pre-treatment TLC was abnormal (<1000 cells/mm3) in 15% of patients. The mean reduction in TLC was 70% two months after initiating chemoradiation. Severe post-treatment lymphopenia (TLC <500 cells/mm3) was observed in 53% of patients; they experienced inferior median OS (21.2 vs. 45.0 months, P=0.03) and similar 25th percentile PFS (6.3 vs. 7.7 months, P=0.06) compared to patients without severe lymphopenia. Multivariate analysis demonstrated pre-treatment TLC ≥1000 cells/mm3 and post-treatment TLC >500 cells/mm3 had a 77% (HR: 0.23; 95% CI 0.05-1.03; P=0.053) and 58% decrease in hazards of death (HR: 0.42; 95%CI 0.12-1.46; P=0.17) respectively. CONCLUSION More than half of cervical cancer patients treated with chemoradiation experienced severe and prolonged lymphopenia. Although statistical significance was not reached, the findings suggest that pre- and post-treatment lymphopenia may be associated with decreased survival. Further research is warranted, given that lymphopenia could be a reversible prognostic factor.

Sentinel lymph node detection rates using indocyanine green in women with early-stage cervical cancer

OBJECTIVE Our study objective was to determine feasibility and mapping rates using indocyanine green (ICG) for sentinel lymph node (SLN) mapping in early-stage cervical cancer. METHODS We performed a retrospective review of all women who underwent SLN mapping with ICG during primary surgical management of early-stage cervical cancer by robotic-assisted radical hysterectomy (RA-RH) or fertility-sparing surgery. Patients were treated at two high-volume centers from 10/2012 to 02/2016. Completion pelvic lymphadenectomy was performed after SLN biopsy; additionally, removal of clinically enlarged/suspicious nodes was part of the SLN treatment algorithm. RESULTS Thirty women with a median age of 42.5 and BMI of 26.5 were included. Most (90%) had stage IB disease, and 67% had squamous histology. RA-RH was performed in 86.7% of cases. One patient underwent fertility-sparing surgery. Median cervical tumor size was 2.0cm. At least one SLN was detected in all cases (100%), with bilateral mapping achieved in 87%. SLN detection was not impacted by tumor size and was most commonly identified in the hypogastric (40.3%), obturator (26.0%), and external iliac (20.8%) regions. Five cases of lymphatic metastasis were identified (16.7%): three in clinically enlarged SLNs, one in a clinically enlarged non-SLN, and one case with cytokeratin positive cells in an SLN. All metastatic disease would have been detected even if full lymphadenectomy had been omitted from our treatment algorithm, CONCLUSIONS: SLN mapping with ICG is feasible and results in high detection rates in women with early-stage cervical cancer. Prospective studies are needed to determine if SLN mapping can replace lymphadenectomy in this setting.

Reducing overtreatment: A comparison of lymph node assessment strategies for endometrial cancer

OBJECTIVES To compare the utility of three lymph node (LN) assessment strategies to identify lymphatic metastases while minimizing complete lymphadenectomy rates in women with low-grade endometrial cancer (EC). METHODS Using our institutional standard protocol (SP), patients with complex atypical hyperplasia (CAH) or grade 1/2 EC underwent sentinel lymph node (SLN) mapping, hysterectomy, and intraoperative frozen section (FS). Lymphadenectomy was performed if high-risk uterine features were identified on FS. Utilizing SP data, two alternative strategies were applied: a Universal FS Strategy (UFS), omitting SLN mapping and performing lymphadenectomy based on FS results, and a SLN-Restrictive FS Strategy (SLN-RFS) in which FS and lymphadenectomy are performed only if bilateral SLN mapping fails. RESULTS Of 114 patients managed on the SP, SLNs were identified in 86%, with lymphatic metastases detected in eight patients. Six patients recurred after a median follow up of 15months. Most (83%) developed in those who had a negative systematic lymphadenectomy (n=4; mean LNs: 18) or no lymphadenectomy indication. When applying the alternative lymphatic assessment strategies, the SLN-RFS approach would theoretically result in lower lymphadenectomy rates compared to both the SP and the alternative UFS strategies (9.2% versus 36.8% and 36.8%, respectively; p=0.004), without a reduction in detection of LN metastases (8/8 versus 8/8 and 5/8, respectively). CONCLUSION In this modeling analysis, an operative strategy omitting universal frozen section and restricting its use to cases with failed SLN mapping may result in lower lymphadenectomy rates and reduce the risk of overtreatment without compromising oncologic outcome for patients with EC.