Investigator

Carrie L. Langstraat

Mayo Clinic

CLLCarrie L. Langstr…
Papers(12)
Fertility Preservatio…Measuring the impact …A Phase I Trial of Na…Rewinding the clock o…Impact of comorbiditi…Prognostic factors in…Artificial intelligen…How deep is too deep?…Endometrial cancer wi…Incidence of sentinel…Comparison of the Con…Secondary Cytoreducti…
Collaborators(10)
Gretchen GlaserAndrea MarianiAmanika KumarIlaria CapassoGiovanni ScambiaFrancesco MultinuGiuseppe CucinellaLuigi Antonio De VitisDiletta FumagalliGiorgia Dinoi
Institutions(4)
Mayo ClinicAgostino Gemelli Univ…European Institute Of…Fondazione Isal

Papers

Measuring the impact of specific surgical complications after ovarian cancer cytoreductive surgery on short-term outcomes

Objective We sought to measure the impact of specific peri-operative complications after primary cytoreductive surgery on relevant patient outcomes and use of resources. Methods A cohort of patients with advanced ovarian cancer who underwent primary cytoreductive surgery at two institutions (2006–2016) were studied. Specific known complications (‘exposures’) within 30 days of surgery were evaluated to determine the impact on outcomes. Exposures included bowel leak, superficial surgical site infection, deep surgical site infection, venous thromboembolic event, and cardiac event. Outcomes were prolonged lengths of stay, readmission or non-home discharge, reoperation, organ failure, delay to adjuvant chemotherapy, and 90-day mortality. Population attributable risk (PAR) was used to estimate the proportion of adverse outcomes that could be prevented by elimination of a causal exposure and considers both the strength of the association and the prevalence of the complication; adjusted PARs (aPAR) were calculated using adjusted relative risks (aRR) adjusted for stage (IIIC vs IV) and American Society of Anesthesiology score (<3 vs ≥3). Results A cohort of 892 patients was included. Each of the evaluated exposures had an impact on readmission/non-home discharge (aPAR range 5.3 to 13.5). A venous thromboembolic event was significantly associated with 90-day mortality (aRR=2.9 (95% CI 1.3 to 6.7); aPAR=8.6 (95% CI −1.8 to 19.1)) and organ failure (aRR=4.7 (95% CI 2.3 to 9.5); aPAR=13.9 (95% CI 2.8 to 25.1)). Similarly, a cardiac event was most strongly associated with organ failure and was very impactful (aPAR=19.0 (95% CI 6.8 to 31.1)). Bowel leak was a major contributor to poor outcome, including reoperation (aPAR=45.5 (95% CI 34.3 to 56.6)), organ failure (aPAR=13.6 (95% CI 2.6 to 24.6)), readmission/non-home discharge (aPAR=5.3 (95% CI 1.6 to 9.0)), delay to adjuvant chemotherapy (aPAR=5.9 (95% CI 2.3 to 9.4)), and prolonged lengths of stay (aPAR=13.0 (95% CI 9.1 to 16.9)). Conclusion Going beyond reporting complications using common scales to measure their genuine impact provides important information for providers, patients, and payers. We report that less frequent exposures, including a venous thromboembolic event, cardiac events, and bowel leaks, have a high impact on patients and use of resources.

A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies

Abstract Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75–175 mg/m2, BEV 30–70 mg/m2). Pharmacokinetic analyses were performed. Results: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. Conclusions: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

Rewinding the clock on positive peritoneal cytology in endometrial cancer: does it predict prognosis in low-risk disease?

Positive peritoneal cytology in endometrial cancer is a known risk factor for worse oncologic outcomes but is not used for staging purposes or to guide adjuvant treatment. Additionally, its prognostic impact on low-risk patients remains unclear. Therefore, we investigated the role of positive peritoneal cytology in patients with endometrial cancer and focused on low-risk disease. This is a retrospective cohort study including all consecutive patients undergoing primary surgery for endometrial cancer at Mayo Clinic from 1999 to 2021. The role of positive peritoneal cytology was investigated in the entire cohort and in 2 subgroups: the National Comprehensive Cancer Network (NCCN) low-risk group, including low-risk patients according to NCCN guidelines (endometrioid, grade 1-2, stage IA) and the European Society of Gynecologic Oncology/European Society of Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) low-risk group, including low-risk patients according to ESGO/ESTRO/ESP guidelines (as NCCN, plus no lymphovascular space invasion). Univariate and multivariable analyses were used to evaluate the association of positive peritoneal cytology with recurrence within 5 years after surgery, and Kaplan-Meier survival analyses were performed in all groups. A total of 3517 patients were included, 1911 in the NCCN low-risk group and 1832 in the ESGO/ESTRO/ESP low-risk group. Positive peritoneal cytology was found in 15.9% of the entire cohort (559/3517), 8.1% of the NCCN low-risk group (154/1911), and 7.9% of the ESGO/ESTRO/ESP low-risk group (145/1832). In both low-risk groups, 5-year recurrence-free survival was worse in patients with positive peritoneal cytology (p < .01 and p = .03, respectively), but there was no difference in overall survival. On univariate analysis, age, tumor grade, and positive peritoneal cytology were significant predictors of recurrence in both subgroups. After multivariable analysis, positive peritoneal cytology remained independently associated with recurrence (p < .01 and p = .03, respectively). Positive peritoneal cytology was an independent predictor of recurrence and was associated with worse recurrence-free survival in patients with low-risk endometrial cancer. However, overall survival was not impacted.

Impact of comorbidities and extent of lymphadenectomy on quality of life in endometrial cancer patients treated with minimally invasive surgery in the era of sentinel lymph nodes

To identify predictors of quality of life (QoL) among patients who undergo surgical staging with sentinel lymph node (SLN) biopsy or lymphadenectomy for endometrial cancer. Patients who underwent minimally invasive surgery for primary endometrial cancer at the Mayo Clinic from October 2013 to June 2016 were mailed a 30-item QoL in Cancer survey (QLQ-C30) and a validated 13-item lower extremity lymphedema screening questionnaire. Patients who answered <50% of the items or had a pre-operative history of lymphedema were excluded. Multivariable linear regression models were fit to evaluate predictors of QoL using inverse-probability of treatment weighting to adjust for differences at the time of the surgery between the lymphadenectomy and SLN groups. The 221 patients included in the analysis were stratified into two groups: patients who underwent (1) bilateral lymphadenectomy as 'backup' after SLN mapping (lymphadenectomy group; n=101) or (2) SLN removal with or without side-specific lymphadenectomy (SLN group; n=120). On multivariable analysis, obesity, lower extremity lymphedema, and kidney disease had significant (p<0.05) and clinically meaningful negative impacts on global QoL. Declines in average adjusted global QoL scores were marked (19.7 points lower) in patients with BMI ≥40 kg/m Lower extremity lymphedema coupled with obesity predicts poorer QoL in patients who undergo surgical staging for endometrial cancer. In this population, reduction of lower extremity lymphedema by performing SLN instead of lymphadenectomy and earlier targeted interventions may improve patients' QoL. Future research focusing on targeted interventions is needed.

Prognostic factors in patients with endometrial cancer with isolated lymphatic recurrence

To analyze the clinicopathological features and outcomes in patients with endometrial cancer with isolated lymphatic recurrence after lymphadenectomy, stratified by different isolated lymphatic recurrence sites and treatment approaches. We retrospectively reviewed all surgically treated patients with endometrial cancer, identifying those with recurrence. We defined primary isolated lymphatic recurrence as the first and unique evidence of recurrence in lymph node-bearing areas, without concomitant vaginal, hematogenous, or peritoneal recurrence. Isolated lymphatic recurrences were classified as pelvic, para-aortic, distant, or multiple sites. Our primary outcome was cause-specific survival after diagnosis of the recurrence. Among 4216 patients with surgically staged endometrial cancer, we identified 66 (1.6%) women with isolated lymphatic recurrence. The overall median cause-specific survival for patients with isolated lymphatic recurrence was 24 months. Although cause-specific survival was not significantly different between the four isolated lymphatic recurrence groups (p=0.21), 7 of 15 (47%) patients with isolated lymphatic recurrence in the para-aortic area were long-term survivors. At multivariate Cox regression, the absence of lymphovascular space invasion and grade 1 histology in the primary tumor were significantly associated with improved cause-specific survival. In addition, patients with isolated lymphatic recurrence who underwent surgery for recurrence (with/without other associated therapies) had improved cause-specific survival compared with patients who did not undergo surgery, also after adjusting for age. Low-grade histology and absence of lymphovascular space invasion in the primary tumor were predictors of improved prognosis in patients with endometrial cancer with isolated lymphatic recurrence. In addition, in this retrospective cohort, patients with isolated lymphatic recurrence who were selected for eradicative surgical treatment had improved cause-specific survival.

Artificial intelligence model for enhancing the accuracy of transvaginal ultrasound in detecting endometrial cancer and endometrial atypical hyperplasia

Transvaginal ultrasound is typically the initial diagnostic approach in patients with postmenopausal bleeding for detecting endometrial atypical hyperplasia/cancer. Although transvaginal ultrasound demonstrates notable sensitivity, its specificity remains limited. The objective of this study was to enhance the diagnostic accuracy of transvaginal ultrasound through the integration of artificial intelligence. By using transvaginal ultrasound images, we aimed to develop an artificial intelligence based automated segmentation model and an artificial intelligence based classifier model. Patients with postmenopausal bleeding undergoing transvaginal ultrasound and endometrial sampling at Mayo Clinic between 2016 and 2021 were retrospectively included. Manual segmentation of images was performed by four physicians (readers). Patients were classified into cohort A (atypical hyperplasia/cancer) and cohort B (benign) based on the pathologic report of endometrial sampling. A fully automated segmentation model was developed, and the performance of the model in correctly identifying the endometrium was compared with physician made segmentation using similarity metrics. To develop the classifier model, radiomic features were calculated from the manually segmented regions-of-interest. These features were used to train a wide range of machine learning based classifiers. The top performing machine learning classifier was evaluated using a threefold approach, and diagnostic accuracy was assessed through the F1 score and area under the receiver operating characteristic curve (AUC-ROC). 302 patients were included. Automated segmentation-reader agreement was 0.79±0.21 using the Dice coefficient. For the classification task, 92 radiomic features related to pixel texture/shape/intensity were found to be significantly different between cohort A and B. The threefold evaluation of the top performing classifier model showed an AUC-ROC of 0.90 (range 0.88-0.92) on the validation set and 0.88 (range 0.86-0.91) on the hold-out test set. Sensitivity and specificity were 0.87 (range 0.77-0.94) and 0.86 (range 0.81-0.94), respectively. We trained an artificial intelligence based algorithm to differentiate endometrial atypical hyperplasia/cancer from benign conditions on transvaginal ultrasound images in a population of patients with postmenopausal bleeding.

How deep is too deep? Assessing myometrial invasion as a predictor of distant recurrence in stage I endometrioid endometrial cancer

The goal of this study was to evaluate the depth of myometrial invasion as a predictor of distant recurrence in patients with node-negative stage IB endometrioid endometrial cancer. A retrospective multicenter study, including surgically staged endometrial cancer patients at Mayo Clinic, Rochester (MN, USA) between January 1999 and December 2017, and Fondazione Policlinico Universitario A. Gemelli (Rome, Italy) between March 2002 and March 2017, was conducted. Patients without lymph node assessment were excluded. The follow-up was restricted to the first 5 years following surgery. Recurrence-free survival was estimated using the Kaplan-Meier method. Cox proportional hazards models were fit to evaluate the association of clinical and pathologic characteristics with the risk of recurrence. Of 386 patients, the mean (SD) depth of myometrial invasion was 70.4 (13.2)%. We identified 51 recurrences (14 isolated vaginal, 37 non-vaginal); the median follow-up of the remaining patients was 4.5 (IQR 2.3-7.0) years. At univariate analysis, the risk of non-vaginal recurrence increased by 64% (95% CI 1.28 to 2.12) for every 10-unit increase in the depth of myometrial invasion. International Federation of Gynecology and Obstetrics (FIGO) grade and myometrial invasion were independent predictors of non-vaginal recurrence. The 5-year non-vaginal recurrence-free survival was 95.2% (95% CI 92.0% to 98.6%), 84.0% (95% CI 76.6% to 92.1%), and 67.1% (95% CI 54.2% to 83.0%) for subsets of patients with myometrial invasion <71% (n=207), myometrial invasion ≥71% and grade 1-2 (n=132), and myometrial invasion ≥71% and grade 3 (n=47), respectively. A total of 256 (66.3%) patients received either vaginal brachytherapy only or no adjuvant therapy. Patients who received adjuvant chemotherapy, regardless of receipt of external beam radiotherapy or vaginal brachytherapy, had an approximately 70% lower risk of any recurrence (HR adjusted for age, grade, myometrial invasion 0.31, 95% CI 0.12 to 0.85) and of non-vaginal recurrence (adjusted HR 0.32, 95% CI 0.10 to 0.99). The invasion of the outer third of the myometrium and histologic grade were found to be independent predictors of distant recurrence among patients with endometrioid, node-negative stage IB endometrial cancer. Future studies should investigate if systemic adjuvant therapy for patients with myometrial invasion of the outer third would improve outcomes.

Endometrial cancer with positive sentinel lymph nodes: pathologic characteristics of metastases as predictors of extent of lymphatic dissemination and prognosis

To assess predictors of extensive lymph node dissemination and non-vaginal recurrence in patients with endometrial cancer with positive sentinel lymph nodes (SLNs). Patients with endometrial cancer who underwent primary surgery with SLN mapping and had at least one positive node between October 2013 and May 2019 were included. Positive SLNs were reviewed, and cases were classified according to the location of the metastasis (extracapsular vs intracapsular), and the size of the largest SLN metastasis (isolated tumor cells, micrometastasis, macrometastasis). Associations were assessed based on fitting logistic regression models and Cox proportional hazards models. A total of 103 patients met the inclusion criteria: including 36 (34.9%) with isolated tumor cells, 27 (26.2%) with micrometastasis, and 40 (38.8%) with macrometastasis. Notably, 71.4% of patients exhibiting extracapsular SLN metastases had multiple positive SLNs (p=0.008). Extracapsular invasion (adjusted odds ratio (aOR) 5.81, 95% CI 1.4 to 23.6) and age (aOR=1.8, 95% CI 1.1 to 3.0) emerged as independent predictors of multiple positive SLNs. Among the 38 patients who underwent a backup pelvic lymphadenectomy, 18 (47.4%) presented with positive pelvic non-SLNs, a phenomenon more prevalent in patients with macrometastasis (p=0.004).Independent predictors of non-vaginal recurrence included SLN macrometastasis (adjusted hazard ratio (aHR) 3.3, 95% CI 1.3 to 8.3), non-endometrioid histology (aHR=3.7, 95% CI 1.5 to 9.3), and cervical stromal invasion (aHR=5.5, 95% CI 2.0 to 14.9). Among the 34 patients with isolated tumor cells and endometrioid histology, 3 (9%) experienced a recurrence, all of whom had not received any adjuvant chemotherapy or external beam radiotherapy. Patients with positive SLN macrometastasis are independently associated with extensive lymphatic dissemination and distant recurrences. The risk of multiple positive SLNs increases with the extracapsular location of the SLN metastasis and with age. Independent uterine pathologic predictors of non-vaginal recurrence are non-endometrioid histology and cervical stromal invasion.

Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study

Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted. We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3). Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%. Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified.

Comparison of the Contracted Accordion, Expanded Accordion, and Clavien-Dindo complication grading scales after ovarian cancer cytoreduction

To compare the ability of current complication reporting scales (Contracted Accordion Scale, Expanded Accordion Scale, Clavien-Dindo Scale) to reflect the severity of patient outcomes after cytoreductive surgery for ovarian cancer. We included all patients undergoing primary debulking surgery for stage IIIC/IV ovarian cancer from 2006 to 2016 at two expert centers for ovarian cancer. Complications within 30 days of surgery were graded according to three scales. Outcomes included length of stay, mortality (90-day), and delayed initiation of chemotherapy (>42 days after surgery). Correlations were assessed using the Spearman rank correlation, and comparisons between groups were evaluated using the Wilcoxon rank-sum test and the χ Among the 892 patients, 185 (20.7%) patients had a grade 3 or higher complication per all scales. Patients with grade 3 or higher complications (compared with those with none, grade 1 or grade 2) had longer length of stay, higher 90-day mortality, and delayed initiation of chemotherapy. The expanded scales (Expanded Accordion Scale and Clavien Dindo Scale) provided a more refined characterization of outcome compared with the Contracted Accordion Scale. However, mortality was actually found to be as high as 25.0% for grade 5 complications using the Expanded Accordion Scale. Patients with organ failure or requiring an invasive procedure had significantly worse outcomes than those without either complication, highlighting the importance of separating these events. All three scales demonstrated general correlation with important outcomes after ovarian cancer surgery. However, the expanded scales (Clavien Dindo Scale and Expanded Accordion Scale) used important events commonly encountered after cytoreductive surgery, provided a more refined view of the severity of complications, and should be used in reporting outcomes in ovarian cancer.

Secondary Cytoreduction and Carboplatin Hyperthermic Intraperitoneal Chemotherapy for Platinum-Sensitive Recurrent Ovarian Cancer: An MSK Team Ovary Phase II Study

PURPOSEThe purpose of this phase II study was to evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin for recurrent ovarian cancer during secondary cytoreductive surgery.MATERIALS AND METHODSPatients were intraoperatively randomly assigned to carboplatin HIPEC (800 mg/m2for 90 minutes) or no HIPEC, followed by five or six cycles of postoperative IV carboplatin-based chemotherapy, respectively. Based on a binomial single-stage pick-the-winner design, an arm was considered winner if ≥ 17 of 49 patients were without disease progression at 24 months post-surgery. Secondary objectives included postoperative toxicity and HIPEC pharmacokinetics.RESULTSOf 98 patients, 49 (50%) received HIPEC. Complete gross resection was achieved in 82% of the HIPEC patients and 94% of the standard-arm patients. Bowel resection was performed in 37% of patients in the HIPEC arm compared with 65% in the standard ( P = .008). There was no perioperative mortality and no difference in use of ostomies, length of stay, or postoperative toxicity. At 24 months, eight patients (16.3%; 1-sided 90% CI, 9.7 to 100) were without progression or death in the HIPEC arm and 12 (24.5%; 1-sided 90% CI, 16.5 to 100) in the standard arm. With a medium follow-up of 39.5 months, 82 patients progressed and 37 died. The median progression-free survival in the HIPEC and standard arms were 12.3 and 15.7 months, respectively (hazard ratio, 1.54; 95% CI, 1 to 2.37; P = .05). There was no significant difference in median overall survival (52.5 v 59.7 months, respectively; hazard ratio, 1.39; 95% CI, 0.73 to 2.67; P = .31). These analyses were exploratory.CONCLUSIONHIPEC with carboplatin was well tolerated but did not result in superior clinical outcomes. This study does not support the use of HIPEC with carboplatin during secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer.

A Phase III Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor–Positive Ovarian Cancer (Study 006)

PURPOSE The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor–positive ovarian cancer. METHODS This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light. RESULTS From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor–positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7; P &lt; .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4; P &lt; .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported. CONCLUSION This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.

12Works
13Papers
64Collaborators
2Trials
Endometrial NeoplasmsNeoplasm StagingOvarian NeoplasmsNeoplasm Recurrence, LocalCarcinoma, Ovarian EpithelialGenital Neoplasms, FemalePrognosisNeoplasm Micrometastasis