Emma C. Rossi

A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study

BACKGROUND Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. METHODS In the FIRES multicentre, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardised cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 18 surgeons from ten centres (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by haematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov, number NCT01673022 and is completed and closed. FINDINGS Between Aug 1, 2012, and Oct 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and para-aortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97·2% (95% CI 85·0-100), and a negative predictive value of 99·6% (97·9-100). The most common grade 3-4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). 22 patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. INTERPRETATION Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. FUNDING Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology.

Perioperative Outcomes of Robotically Assisted Hysterectomy for Benign Cases With Complex Pathology

OBJECTIVE: To report on the perioperative outcomes after robotically assisted total hysterectomy for benign indications in a large patient population with predominantly complex pathology. METHODS: One hundred fifty-two patients underwent robotic hysterectomy for noncancer indications from May 2005 to May 2008. A systematic chart review of consecutive robotic cases was conducted based on preoperative and perioperative characteristics of each patient. Each case was evaluated for its complexity based on preoperative diagnosis, prior pelvic or abdominal surgery, patient’s body mass index, and uterine weight. RESULTS: The overall operative time was 122.9 minutes, estimated blood loss was 79.0 mL, and there were three (2.1%) intraoperative complications, with no perioperative blood transfusions or conversions. There were five (3.5%) patients with postoperative complications, and length of hospital stay was 1.0 days on average. Of the characteristics indicating complexity, only uterine weight greater than 250 g resulted in significantly increased operative times, attributable to increased morcellation time. CONCLUSION: Robotically assisted total hysterectomy for benign indications in patients with complex pathology is feasible, with low morbidity and a short hospital stay. This study suggests that robotic assistance facilitates the use of a minimally invasive approach in high-risk patient populations. LEVEL OF EVIDENCE: III

Detection of sentinel nodes for endometrial cancer with robotic assisted fluorescence imaging: cervical versus hysteroscopic injection.

Objective Sentinel lymph node (SLN) mapping with indocyanine green (ICG) detected by robotic near infrared (NIR) imaging is a feasible technique. The optimal site of injection (cervical or endometrial) for endometrial cancer has yet to be determined. We prospectively evaluated SLN mapping after cervical and endometrial injections of ICG to compare the detection rates and patterns of nodal distribution. Methods Twenty-nine subjects with endometrial cancer undergoing robotic hysterectomy with lymphadenectomy by a single surgeon received SLN mapping with robotic fluorescence imaging. Seventeen patients received cervical injections of 1 mg of ICG and 12 patients received hysteroscopic endometrial injections of 0.5-mg ICG. Detection rates between the 2 groups were compared using Fisher exact tests. Continuous variables such as operating room times and body mass index were compared using t tests. Results The SLN detection rate was 82% (14/17) for cervical and 33% (4/12) for hysteroscopic injection (P = 0.027). Sentinel lymph nodes were seen bilaterally in 57% (8/14) of the cervical injection group and 50% (2/4) of the hysteroscopic group. Para-aortic SLNs were seen in 71% (10/14) of patients who mapped after cervical injection and 75% (3/4) patients who mapped after hysteroscopic injection. There was 1 false-negative SLN in the cervical injection group. Conclusions Cervical ICG injection achieves a higher SLN detection rate and a similar anatomic nodal distribution as hysteroscopic endometrial injection for SLN mapping in patients with endometrial cancer.

A Novel Monoclonal Antibody to Secreted Frizzled-Related Protein 2 Inhibits Tumor Growth

Secreted frizzled-related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer and stimulates angiogenesis via activation of the calcineurin/NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of β-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling and to evaluate whether SFRP2 is a viable therapeutic target. The antiangiogenic and antitumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, tube formation assays, and in vivo angiosarcoma and triple-negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic and biodistribution data were generated in tumor-bearing and nontumor-bearing mice. SFRP2 mAb was shown to induce antitumor and antiangiogenic effects in vitro and inhibit activation of β-catenin and nuclear factor of activated T-cells c3 (NFATc3) in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared with control (P = 0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (P = 0.03) compared with control, whereas bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of β-catenin and NFATc3 in endothelial and tumor cells and is a novel therapeutic approach for inhibiting angiosarcoma and triple-negative breast cancer. Mol Cancer Ther; 12(5); 685–95. ©2013 AACR.

Variation in neoadjuvant chemotherapy utilization for epithelial ovarian cancer at high volume hospitals in the United States and associated survival

OBJECTIVE To estimate variation in the use of neoadjuvant chemotherapy by high volume hospitals and to determine the association between hospital utilization of neoadjuvant chemotherapy and survival. METHODS We identified incident cases of stage IIIC or IV epithelial ovarian cancer in the National Cancer Database from 2006 to 2012. Inclusion criteria were treatment at a high volume hospital (>20 cases/year) and treatment with both chemotherapy and surgery. A logistic regression model was used to predict receipt of neoadjuvant chemotherapy based on case-mix predictors (age, comorbidities, stage etc). Hospitals were categorized by the observed-to-expected ratio for neoadjuvant chemotherapy use as low, average, or high utilization hospitals. Survival analysis was performed. RESULTS We identified 11,574 patients treated at 55 high volume hospitals. Neoadjuvant chemotherapy was used for 21.6% (n=2494) of patients and use varied widely by hospital, from 5%-55%. High utilization hospitals (n=1910, 10 hospitals) had a median neoadjuvant chemotherapy rate of 39% (range 23-55%), while low utilization hospitals (n=2671, 14 hospitals) had a median rate of 10% (range 5-17%). For all ovarian cancer patients adjusting for clinical and socio-demographic factors, treatment at a hospital with average or high neoadjuvant chemotherapy utilization was associated with a decreased rate of death compared to treatment at a low utilization hospital (HR 0.90 95% CI 0.83-0.97 and HR 0.85 95% CI 0.75-0.95). CONCLUSIONS Wide variation exists in the utilization of neoadjuvant chemotherapy to treat stage IIIC and IV epithelial ovarian cancer even among high volume hospitals. Patients treated at hospitals with low rates of neoadjuvant chemotherapy utilization experience decreased survival.

Surgical readmission and survival in women with ovarian cancer: Are short term quality metrics incentivizing decreased long term survival?

OBJECTIVES To determine the association between treatment with neoadjuvant chemotherapy (NACT) or primary debulking surgery (PDS) and readmission after surgical hospitalization as well as overall survival among women with stage IIIC epithelial ovarian cancer (EOC). METHODS We identified incident cases of stage IIIC EOC treated with both chemotherapy and surgery in the National Cancer Database (NCDB) from 2006 to 2012. 30-day readmissions were categorized as planned or unplanned. Log binomial models were used to estimate risk ratios and 95% confidence intervals. Survival analysis was performed using cox proportional hazards models. RESULTS We identified 20,853 women with stage IIIC EOC. 15.6% (n=3242) were treated with NACT and 11.6% (n=2427) were readmitted within 30days of surgery, 59% (n=1421) were unplanned. NACT was associated with a 48% reduction in the risk of any readmission (aRR 0.52 95%CI 0.45-0.60) compared to PDS with adjustment for age, race, insurance, histology, year of diagnosis, and Charlson co-morbidity index score. However, in the same population, receipt of neoadjuvant chemotherapy was also associated with a 33% increase in the rate of death (HR 1.33 95%CI 1.29-1.40) with adjustment for the same factors. CONCLUSIONS Among women with stage IIIC EOC, NACT is associated with both decreased rates of readmission and decreased survival compared to PDS. While selection bias may account for some of the observed differences in survival, the current focus on short-term hospital-wide quality metrics, such as postoperative readmission, in the ovarian cancer population, may be creating incentives inconsistent with long-term goals.

Sentinel Lymph Node Technique in Endometrial Cancer

Importance Endometrial cancer (EMCA) is the most common gynecologic malignancy, with an estimated 54,000 new cases and 10,000 deaths in the United States in 2015. Lymph node metastasis is the most significant prognostic factor in EMCA. Sentinel lymph node (SLN) mapping has become a well-accepted procedure in surgical oncology and may strike a balance between the risks and benefits of lymphadenectomy. Objective The aim of this study was to review the current literature regarding the history, techniques, and clinical application of SLN mapping in EMCA. Evidence Acquisition Evidence was obtained through systematic literature review through PubMed and ClinicalTrials.gov. Conclusions Sentinel lymph node biopsy for EMCA is an accepted approach to the staging of this cancer; however, a consensus approach to the SLN biopsy technique and pathologic assessment is needed. Surgeons newly adopting the technique should proceed with caution and care to monitor outcomes.

Sentinel Lymph Node Biopsy in Endometrial Cancer: a New Standard of Care?

Opinion statementLymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment in endometrial cancer (EMCA). Unfortunately, full lymphadenectomy bears significant surgical and postoperative risks. The majority of patients with clinical stage I disease will not have metastatic disease; thus, a full lymphadenectomy only increases morbidity in this population of patients. The use of the sentinel lymph node (SLN) biopsy has emerged as an alternative to complete lymphadenectomy in EMCA. By removing the highest yield lymph nodes, the SLN biopsy has the same diagnostic ability as lymphadenectomy while minimizing morbidity. The sensitivity of sentinel lymph node identification with robotic fluorescence imaging for detecting metastatic endometrial and cervical cancer (FIRES) trial published this year is the largest prospective, multi-institution trial investigating the accuracy of the SLN biopsy for endometrial and cervical cancer. Results of this trial found an excellent sensitivity (97.2%) and false negative rate (3%) with the technique. The conclusions from the FIRES trial and those of a recent meta-analysis are that SLN biopsy has an acceptable diagnostic accuracy in detecting lymphatic metastases, and can replace lymphadenectomy for this diagnostic purpose. There remains controversy surrounding the SLN biopsy in high-risk disease and the use of adjuvant therapy in the setting of low volume disease detected with ultrastaging. Current data suggests that the technique is accurate in high-risk disease and that the increased detection of metastasis helps guide adjuvant therapy such that oncologic outcomes are likely not affected by forgoing a full lymphadenectomy. Further prospective study is needed to investigate the impact of low volume metastatic disease on oncologic outcomes and the need for adjuvant therapy in these patients.

Benign hysterectomy performed by gynecologic oncologists: Is selection bias altering our ability to measure surgical quality?

OBJECTIVE To compare the characteristics of women undergoing hysterectomy for benign disease with either a benign gynecologist or a gynecologic oncologist and to assess for differences in complication rates with and without risk adjustment. METHODS Patients undergoing benign hysterectomy recorded in the National Surgical Quality Improvement Program (NSQIP) targeted hysterectomy file in 2015 were identified. The primary outcome was any postoperative complication. Stratified analysis was performed by route of surgery. Bivariable tests and modified Poisson regression were used to adjust for confounding by procedure type and patient characteristics. RESULTS We identified 17,639 patients who underwent hysterectomy for benign pathology, primary surgeon was a benign gynecologist (82%) or gynecologic oncologist (18%). Patients who underwent surgery with gynecologic oncologists were older (51yo v 46yo), had a higher mean BMI (32 v 30), and a higher prevalence of prior abdominal surgery (29% v 25%, p < 0.001), diabetes (10.6% v 7.0%), hypertension (34% v 25%) and higher ASA and Charlson comorbidity scores (p < 0.001, for all). For laparoscopy, surgery with a gynecologic oncologist was associated with a decreased risk of complication (RR 0.80, 95% CI 0.66-0.98). For laparotomy, surgery with a gynecologic oncologist was associated with an increased risk of complication (RR 1.18 95% CI 1.01-1.38), however, this was no longer the case with risk adjustment (aRR 0.90, 95% CI 0.76-1.07). CONCLUSIONS Patients operated on by gynecologic oncologists have a higher prevalence of risk factors for complication compared to those operated on by benign gynecologists even with a benign indication for surgery. Quality measurement should account for this selection bias.

Sentinel-lymph-node mapping in endometrial cancer – Authors' reply

Authors’ reply Giorgio Bogani and colleagues articulate the dilemma of para-aortic node dissection in endometrial cancer staging, which is heightened with the development of the sentinel-lymphnode concept. The correspondents express concern for missed isolated para-aortic nodal metastases with a sentinel lymph node-only approach. This concern was challenged in the FIRES study in which we assigned high numbers of patients (196 [58%] of 340 total patients and 74 [74%] of 100 high-grade cases) to para-aortic lymphadenectomy as part of the gold standard lymphadenectomy. In this FIRES cohort, the sentinel lymph node biopsy did, in fact, identify two of the three patients with isolated para-aortic node metastases. Sentinel lymph nodes were not mapped successfully in the third patient, and her para-aortic nodal metastases would have been presumably identified by following the National Comprehensive Cancer Network (NCCN) recommended algorithm to complete lymphadenectomy in such a patient. Conventional wisdom suggests that cervical injection is inferior to myometrial or endometrial tracer injection of tracer because it will not map to the para-aortic regions. Although rates of para-aortic sentinel lymph node mapping are impressive following myometrial or endometrial tracer injection, this is an irrelevant observation if they do not replicate true patterns of disease spread. Most patients with fundal endometrial tumours have either pelvic-only nodal disease or para-aortic nodal disease coexisting with pelvic node metastases. The highest risk for isolated para-aortic node metastases occurs with deep myometrial invasion of high grade tumours. Therefore, one can argue that tumours of the endometrium, and inner myometrium (fundal or otherwise) predominantly drain to the pelvic lymph nodes, and a cervical injection capitalises on this lymphatic pathway. Perhaps rather than focusing on the potential for the rare missed isolated para-aortic node occurrence, we should focus more on the benefits that sentinel lymph node biopsy has in identifying the more commonly occurring aberrant lymphatic pathways that had been historically overlooked (eg, presacral, internal iliac, or medial common iliac). These anatomical regions represented 20% of positive sentinel lymph node’s found in the FIRES population, and represent a larger proportion of patients than those with isolated para-aortic nodal metastases. Conventional pelvic with para-aortic lymphadenectomy would have overlooked these metastases. This new staging technique creates a challenge for clinicians in prescribing adjuvant therapy, particularly radiotherapy, with partial information about the anatomic distribution and extent of nodal metastases. However, this is not unfamiliar territory. Currently not all patients with endometrial cancer receive comprehensive staging and therapeutic decisions are commonly made using incomplete data. As always, we will need to contemplate pre-operative or postoperative imaging to fill in the gaps of information. Ultimately, to determine whether the limitations of sentinel lymph node biopsy to characterise the extent of nodal metastases negatively affects outcomes for patients needs be determined in prospective studies: either a long term observational trial, or a trial in which women with high grade endometrial cancers are randomised to sentinel lymph node biopsy or lymphadenectomy. I declare no competing interests.