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Disease Distribution at Presentation Impacts Benefit of IP Chemotherapy Among Patients with Advanced-Stage Ovarian Cancer

Manning-Geist, Beryl L; Sullivan, Mackenzie W; Sarda, Vishnudas; Gockley, Allison A; Del Carmen, Marcela G; Matulonis, Ursula; Growdon, Whitfield B; Horowitz, Neil S; Berkowitz, Ross S; Clark, Rachel M; Worley, Michael J
BACKGROUND:Ovarian cancer with miliary disease spread is an aggressive phenotype lacking targeted management strategies. We sought to determine whether adjuvant intravenous/intraperitoneal (IV/IP) chemotherapy is beneficial in this disease setting. METHODS:Patient/tumor characteristics and survival data of patients with stage IIIC epithelial ovarian cancer who underwent optimal primary debulking surgery from 01/2010 to 11/2014 were abstracted from records. Chi-square and Mann-Whitney U tests were used to compare categorical and continuous variables. The Kaplan-Meier method was used to estimate survival curves, and outcomes were compared using log-rank tests. Factors significant on univariate analysis were combined into multivariate logistic regression survival models. RESULTS:Among 90 patients with miliary disease spread, 41 (46%) received IV/IP chemotherapy and 49 (54%) received IV chemotherapy. IV/IP chemotherapy, compared with IV chemotherapy, resulted in improved progression-free survival (PFS; 23.0 versus 12.0 months; p = 0.0002) and overall survival (OS; 52 versus 36 months; p = 0.002) in patients with miliary disease. Among 78 patients with nonmiliary disease spread, 23 (29%) underwent IV/IP chemotherapy and 55 (71%) underwent IV chemotherapy. There was no PFS or OS benefit associated with IV/IP chemotherapy over IV chemotherapy in these patients. On multivariate analysis, IV/IP chemotherapy was associated with improved PFS (HR, 0.28; 95% CI 0.15-0.53) and OS (HR, 0.33; 95% CI 0.18-0.61) in patients with miliary disease compared with those with nonmiliary disease (PFS [HR, 1.53; 95% CI 0.74-3.19]; OS [HR, 1.47; 95% CI 0.70-3.09]). CONCLUSIONS:Adjuvant IV/IP chemotherapy was associated with oncologic benefit in miliary disease spread. This survival benefit was not observed in nonmiliary disease.
PMID: 33683525
ISSN: 1534-4681
CID: 5029322

Predictive validity of American College of Surgeons: National Surgical Quality Improvement Project risk calculator in patients with ovarian cancer undergoing interval debulking surgery

Manning-Geist, Beryl; Cathcart, Ann M; Sullivan, Mackenzie W; Pelletier, Andrea; Cham, Stephanie; Muto, Michael G; Del Carmen, Marcela; Growdon, Whitfield B; Sisodia, Rachel Clark; Berkowitz, Ross; Worley, Michael
INTRODUCTION/BACKGROUND:In gynecologic patients, few studies describe the accuracy of the American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) pre-operative risk calculator for women undergoing surgery for ovarian cancer. OBJECTIVE:To determine whether the ACS-NSQIP risk calculator accurately predicts post-operative complications and length of stay in patients undergoing interval debulking surgery for advanced stage epithelial ovarian cancer. METHODS:For this multi-institutional retrospective cohort study, pre-operative risk factors, post-operative complication rates, and Current Procedural Terminology codes were abstracted from records of patients with ovarian cancer managed with open interval debulking surgery from January 2010 to July 2015. A power calculation was done to estimate the minimum number of complications needed to evaluate the accuracy of the ACS-NSQIP risk calculator. Predicted risk compared with observed risk was calculated using logistic regression. The predictive accuracy of the ACS-NSQIP risk calculator in estimating post-operative complications or length of stay was assessed using c-statistics and Briar scores. Complications with a c-statistic of >0.70 and Brier score of <0.01 were considered to have high discriminative ability. RESULTS:A total of 261 patients underwent interval debulking surgery, encompassing 21 unique Current Procedural Terminology codes. Readmission (n=25), surgical site infection (n=35), urinary tract infection (n=12), and serious post-operative complications (n=57) met the minimum event threshold (n>10). All predicted complication rates fell within the IQR of the observed incidence rates. However, the ACS-NSQIP calculator demonstrated neither discriminative ability nor accuracy for any post-operative complications based on c-statistics and Brier scores. The calculator accurately predicted length of stay within 1 day for only 32% of patients and could not accurately predict which patients were likely to have a prolonged length of stay (c-statistic=0.65). CONCLUSION/CONCLUSIONS:Among patients undergoing interval debulking surgery, the ACS-NSQIP did not accurately discriminate which patients were at increased risk of complications or extended length of stay. The risk calculator should be considered to have limited utility in informing pre-operative counseling or surgical planning.
PMID: 34518239
ISSN: 1525-1438
CID: 5029362

Impact of residual disease at interval debulking surgery on platinum resistance and patterns of recurrence for advanced-stage ovarian cancer

Greer, Anna; Gockley, Allison; Manning-Geist, Beryl; Melamed, Alexander; Sisodia, Rachel Clark; Berkowitz, Ross; Horowitz, Neil; Del Carmen, Marcela; Growdon, Whitfield B; Worley, Michael
OBJECTIVE:To evaluate the impact of size and distribution of residual disease after interval debulking surgery on the timing and patterns of recurrence for patients with advanced-stage epithelial ovarian cancer. METHODS:Patient demographics and data on disease treatment/recurrence were collected from medical records of patients with stage IIIC/IV epithelial ovarian cancer who were managed with neoadjuvant chemotherapy/interval debulking surgery between January 2010 and December 2014. Among patients without complete surgical resection but with ≤1 cm of residual disease, the number of anatomic sites (<1 cm single anatomic location vs <1 cm multiple anatomic locations) was used to describe the size and distribution of residual disease.  RESULTS: A total of 224 patients were included. Of these, 70.5% (n=158) had a complete surgical resection, 12.5% (n=28) had <1 cm single anatomic location, and 17.0% (n=38) had <1 cm multiple anatomic locations. Two-year progression-free survival for complete surgical resection, <1 cm single anatomic location, and <1 cm multiple anatomic locations was 22.2%, 17.9% and 7%, respectively (p=0.007). Size and distribution of residual disease after interval debulking surgery did not affect location of recurrence and most patients had recurrence at multiple sites (complete surgical resection: 64.7%, <1 cm single anatomic location: 55.6%, and <1 cm multiple anatomic locations: 71.4%). Controlling for additional factors that may influence platinum resistance and surgical complexity, the rate of platinum-resistant recurrence was similar for patients with complete surgical resection and <1 cm single anatomic location (OR=1.07, 95% CI 0.40 to 2.86; p=0.888), but women with <1 cm multiple anatomic locations had an increased risk of platinum resistance (OR=3.09, 95% CI 1.41 to 6.78 p=0.005). CONCLUSIONS:Despite current classification as 'optimal,' <1 cm multiple anatomic location at the time of interval debulking surgery is associated with a shorter progression-free survival and increased risk of platinum resistance.
PMID: 34429355
ISSN: 1525-1438
CID: 5029352

Lymph node assessment at the time of hysterectomy has limited clinical utility for patients with pre-cancerous endometrial lesions

Sullivan, Mackenzie W; Philp, Lauren; Kanbergs, Alexa N; Safdar, Nida; Oliva, Esther; Bregar, Amy; Del Carmen, Marcela G; Eisenhauer, Eric L; Goodman, Annekathryn; Muto, Michael; Sisodia, Rachel C; Growdon, Whitfield B
OBJECTIVE:The objective of this study was to determine the proportion of patients with a pre-invasive endometrial lesion who meet Mayo criteria for lymph node dissection on final pathology to determine if the use of sentinel lymph node biopsy in patients with pre-invasive lesions would be warranted. METHODS:All women who underwent hysterectomy for a pre-invasive endometrial lesion (atypical hyperplasia or endometrial intra-epithelial neoplasia) between 2009 and 2019 were included for analysis. Relevant statistical tests were utilized to test the associations between patient, operative, and pathologic characteristics. RESULTS:141 patients met inclusion criteria. 51 patients (36%) had a final diagnosis of cancer, the majority (96%) of which were Stage IA grade 1 endometrioid carcinomas. Seven patients (5%) met Mayo criteria on final pathology (one grade 3, seven size >2 cm, one >50% myoinvasive). Three of these seven patients had lymph nodes assessed of which 0% had metastases. Six of these patients had frozen section performed, and 2 met (33%) Mayo criteria intraoperatively. Of the seven patients in the overall cohort that had lymph node sampling, six had a final diagnosis of cancer and none had positive lymph nodes. Of the 51 patients with cancer, only 10 had cancer diagnosed using frozen section, and only two met intra-operative Mayo criteria. Age > 55 was predictive of meeting Mayo criteria on final pathology (p = 0.007). No patients experienced a cancer recurrence across a median follow up of 24.3 months. CONCLUSIONS:Atypical hyperplasia and endometrial intra-epithelial neoplasia portend low risk disease and universal nodal assessment is of limited value.
PMID: 34247769
ISSN: 1095-6859
CID: 5029342

Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions

Lynch, Katherine N; Liu, Joyce F; Kesten, Nikolas; Chow, Kin-Hoe; Shetty, Aniket; He, Ruiyang; Afreen, Mosammat Faria; Yuan, Liping; Matulonis, Ursula A; Growdon, Whitfield B; Muto, Michael G; Horowitz, Neil S; Feltmate, Colleen M; Worley, Michael J; Berkowitz, Ross S; Crum, Christopher P; Rueda, Bo R; Hill, Sarah J
Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.
PMCID:8125555
PMID: 34063609
ISSN: 2072-6694
CID: 5029332

Palliative care referral patterns and measures of aggressive care at the end of life in patients with cervical cancer

Bercow, Alexandra S; Nitecki, Roni; Haber, Hilary; Gockley, Allison A; Hinchcliff, Emily; James, Kaitlyn; Melamed, Alexander; Diver, Elisabeth; Kamdar, Mihir M; Feldman, Sarah; Growdon, Whitfield B
INTRODUCTION:Fifteen per cent of women with cervical cancer are diagnosed with advanced disease and carry a 5 year survival rate of only 17%. Cervical cancer may lead to particularly severe symptoms that interfere with quality of life, yet few studies have examined the rate of palliative care referral in this population. This study aims to examine the impact of palliative care referral on women who have died from cervical cancer in two tertiary care centers. METHODS:We conducted a retrospective review of cervical cancer decedents at two tertiary institutions from January 2000 to February 2017. We examined how aggressive measures of care at the end of life, metrics defined by the National Quality Forum, interacted with clinical variables to understand if end-of-life care was affected. Univariate and multivariate parametric and non-parametric testing was used, and linear regression models were generated to determine unadjusted and adjusted associations between aggressive measures of care at the end of life with receipt of palliative care as the main exposure. RESULTS:Of 153 cervical cancer decedents, 73 (47%) received a palliative care referral and the majority (57%) of referrals occurred during an inpatient admission. The median time from palliative care consultation to death was 2.3 months and 34% were referred to palliative care in the last 30 days of life. Palliative care referral was associated with fewer emergency department visits (OR 0.18, 95% CI 0.05 to 0.56), inpatient stays (OR 0.21, 95% CI 0.07 to 0.61), and intensive care unit admissions (OR 0.24, 95% CI 0.06 to 0.93) in the last 30 days of life. Palliative care did not affect chemotherapy or radiation administration within 14 days of death (p=0.36). Women evaluated by palliative care providers were less likely to die in the acute care setting (OR 0.19, 95% CI 0.07 to 0.51). DISCUSSION:In two tertiary care centers, less than half of cervical cancer decedents received palliative care consultations, and those referred to palliative care were often evaluated late in their disease course. Palliative care utilization was also associated with a lower incidence of poor-quality end-of-life care.
PMID: 33046575
ISSN: 1525-1438
CID: 5029302

Patient reported outcome measures among patients with vulvar cancer at various stages of treatment, recurrence, and survivorship

Alimena, Stephanie; Sullivan, Mackenzie W; Philp, Lauren; Dorney, Katelyn; Hubbell, Harrison; Del Carmen, Marcela G; Goodman, Annekathryn; Bregar, Amy; Growdon, Whitfield B; Eisenhauer, Eric L; Sisodia, Rachel Clark
OBJECTIVE:Our goal was to pragmatically describe patient reported outcomes (PROs) in a typical clinic population of vulvar cancer patients, as prior studies of vulvar cancer PROs have examined clinical trial participants. METHODS:A prospective PRO program was implemented in the Gynecologic Oncology clinic of a tertiary academic institution in January 2018. Vulvar cancer patients through September 2019 were administered the European Organization for the Research and Treatment of Cancer Quality of life Questionnaire, the Patient Reported Outcome Measurement Information System Instrumental and Emotional Support Scales, and the Functional Assessment of Cancer Therapy-Vulvar questionnaire. Binary logistic regressions were performed to determine adjusted odds ratios for adverse responses to individual questions by insurance, stage, age, time since diagnosis, recurrence, radiation, and surgical radicality. RESULTS:Seventy vulvar cancer patients responded to PROs (85.4% response rate). Seventy-one percent were > 1 year since diagnosis, 61.4% had stage I disease, and 28.6% recurred. Publicly insured women had less support and worse quality of life (QOL, aOR 4.15, 95% CI 1.00-17.32, p = 0.05). Women who recurred noted more interference with social activities (aOR 4.45, 95% CI 1.28-15.41, p = 0.019) and poorer QOL (aOR 5.22 95% CI 1.51-18.10, p = 0.009). There were no major differences by surgical radicality. Those >1 year since diagnosis experienced less worry (aOR 0.17, 95% CI 0.04-0.63, p = 0.008). CONCLUSIONS:Surgical radicality does not affect symptoms or QOL in vulvar cancer patients, whereas insurance, recurrence, and time since diagnosis do. This data can improve counseling and awareness of patient characteristics that would benefit from social services referral.
PMID: 33139040
ISSN: 1095-6859
CID: 5029312

Neoadjuvant chemotherapy does not disproportionately influence post-operative complication rates or time to chemotherapy in obese patients with advanced-stage ovarian cancer

Kanbergs, Alexa N; Manning-Geist, Beryl L; Pelletier, Andrea; Sullivan, Mackenzie W; Del Carmen, Marcela G; Horowitz, Neil S; Growdon, Whitfield B; Clark, Rachel M; Muto, Michael G; Worley, Michael J
OBJECTIVES:To determine whether neoadjuvant chemotherapy (NACT) disproportionately benefits obese patients. METHODS:Data were collected from stage IIIC-IV ovarian cancer patients treated between 01/2010-07/2015. We performed univariate/multivariate logistic regression analyses with post-operative infection, readmission, any postoperative complication, and time to chemotherapy as outcomes. An interaction term was included in models, to determine if the effect of NACT on post-operative complications was influenced by obesity status. RESULTS:Of 507 patients, 115 (22.6%) were obese and 392 (77.3%) were non-obese (obese defined as BMI ≥30). Among obese patients undergoing primary debulking surgery (PDS) vs. NACT, rates of postoperative infection were 42.9% vs. 30.8% (p = 0.12), 30-day readmission 30.2% vs. 11.5% (p < 0.02), and any post-operative complication were 44.4% vs 30.8% (p = 0.133). Among non-obese patients undergoing PDS vs. NACT, rates of post-operative infection were 20.0% vs. 12.9% (p = 0.057), 30-day readmission 16.9% vs. 9.2% (p = 0.02), and any post-operative complication were 19.4% vs 28% (p = 0.044). Obesity was associated with post-operative infection (OR 2.3; 95%CI 1.22-4.33), 30-day readmission/reoperation (OR 2.27; 95%CI 1.08-3.21) and the development of any post-operative complication (OR 2.1; CI 1.13-3.74). However, there was not a significant interaction between obesity and NACT in any of the models predicting post-operative complications. CONCLUSIONS:The decision to use NACT should not be predicated on obesity alone, as the reduction in post-operative complications in obese patients is similar to non-obese patients.
PMID: 32951891
ISSN: 1095-6859
CID: 5029292

Prognostic Value of Preoperative Imaging: Comparing 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography to Computed Tomography Alone for Preoperative Planning in High-risk Histology Endometrial Carcinoma

St Laurent, Jessica D; Davis, Michelle R; Feltmate, Colleen M; Goodman, Annekathryn; Del Carmen, Marcella G; Horowitz, Neil E; Lee, Susanna I; Growdon, Whitfield B
OBJECTIVE:18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) increases the sensitivity for preoperative detection of lymph nodes and distant metastases in endometrial cancer. The objective of this investigation was to determine the prognostic value of preoperative PET-CT compared with computed tomography (CT) alone for high-risk endometrial carcinoma. MATERIALS AND METHODS:We performed a retrospective review of high-risk histology endometrial cancer from 2008 to 2015. Clinical variables including surgical procedure, preoperative imaging modality, and outcome were collected. Survival analysis was performed utilizing the Kaplan-Meier and Cox proportional hazards methodologies. RESULTS:Of the 555 women treated for high-risk histology endometrial cancer, 88 (16%) had preoperative PET-CT, and 97 (17%) CT without PET available. PET-CT demonstrated positive findings in 37 women (42%) compared with 33 (30%) with preoperative CT alone. PET-CT had a positive predictive value of 96% for nodal metastasis compared with 60% for CT alone. The median follow-up time for the entire cohort was 59 months (range, 12 to 96 mo). Patients with a negative preoperative PET-CT (n=54) had a median progression-free survival (PFS) that was not reached, whereas the median PFS in the PET-CT positive group was 13 months (n=34). Women with a negative PET-CT had a longer median overall survival (OS) not yet reached compared with 34 months in the PET-CT positive cohort (hazard ratio, 2.4; P<0.001). CT findings did not associate with PFS or OS. CONCLUSIONS:PET-CT demonstrated superior sensitivity for lymph node metastasis and detecting distant disease compared with CT. Preoperative PET-CT, whether positive or negative, offered OS and PFS prognostic value not observed with CT alone.
PMID: 32804777
ISSN: 1537-453x
CID: 5029282

Factors associated with referral and completion of genetic counseling in women with epithelial ovarian cancer

Alimena, Stephanie; Scarpetti, Lauren; Blouch, Erica L; Rodgers, Linda; Shannon, Kristen; Del Carmen, Marcela; Goodman, Annekathryn; Growdon, Whitfield B; Eisenhauer, Eric; Sisodia, Rachel Clark
OBJECTIVE:The National Comprehensive Cancer Network recommends that all women diagnosed with epithelial ovarian cancer undergo genetic testing, as the diagnosis of pathogenic variants may inform cancer survival and impact treatment options. The objective of this study was to assess factors associated with referral to genetic counseling in women with epithelial ovarian cancer. METHODS:A retrospective cohort study identified women with epithelial ovarian cancer from 2012 to 2017 at Massachusetts General Hospital and North Shore Medical Center, a community hospital affiliated with Massachusetts General Hospital. Multivariate logistic regression evaluated how race, age, stage, year of diagnosis, insurance status, family history of breast or ovarian cancer, and language relates to the receipt of genetic counseling. RESULTS:Of the total 276 women included, 73.9% were referred for genetic screening, of which 90.7% attended a genetic counseling visit. Older women were less likely to undergo genetic counseling (age ≥70 years: OR 0.26, 95% CI 0.07-0.94, p=0.04). Women who died within 365 days of initial oncology consult rarely reached a genetic counselor (OR 0.05, 95% CI 0.01-0.24, p<0.001). Women with a family history of breast or ovarian cancer were more likely to undergo counseling (OR 3.27, 95% CI 1.74-6.15, p<0.001). There was no difference in receipt of genetic counseling by race, stage, year of diagnosis, insurance status, or language. CONCLUSION:Older women with epithelial ovarian cancer and those who died within 1 year of initiation of care were less likely to undergo recommended genetic counseling. Race, insurance status, and language were not identified as predictive factors, although we were limited in this assessment by small sample size.
PMID: 32447294
ISSN: 1525-1438
CID: 5029262