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Use of ablation and ultrasonic aspiration at primary debulking surgery in advanced stage ovarian, fallopian tube, and primary peritoneal cancer

Li, Sue; Manning-Geist, Beryl; Gockley, Allison; Ramos, Amanda; Sisodia, Rachel C; Del Carmen, Marcela; Growdon, Whitfield B; Horowitz, Neil; Berkowitz, Ross; Worley, Michael
OBJECTIVES:Ovarian cancer patients with miliary disease have the lowest rates of complete surgical resection and poorest survival. Adjunct surgical techniques may potentially increase rates of complete surgical resection. No studies have evaluated the use of these techniques in primary debulking surgery for ovarian cancer patients with miliary disease. The aim of this study was to examine the use of adjunct surgical techniques during primary debulking surgery for patients with advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer with miliary disease. METHODS:Medical records of patients with International Federation of Gynecology and Obstetrics (FIGO) stages IIIC-IVB epithelial ovarian, fallopian tube, or primary peritoneal cancer with miliary disease undergoing primary debulking surgery from January 2010 to December 2014 were reviewed. Adjunct surgical techniques were defined as ultrasonic surgical aspiration, argon enhanced electrocautery, thermal plasma energy, and traditional electrocautery ablation. Patients undergoing surgery with and without these devices were compared with respect to demographics, operative characteristics, postoperative complications, residual disease, progression free survival and overall survival. RESULTS:A total of 135 patients with miliary disease underwent primary debulking surgery, of which 30 (22.2%) patients used adjunct surgical techniques. The most common devices were ultrasonic surgical aspiration (40%) and argon enhanced electrocautery (36.7%). The most common sites of use were diaphragm (63.3%), pelvic peritoneum (30%), bowel mesentery (20%), and large bowel serosa (20%). There were no differences in age, stage, primary site, histology, operative time, surgical complexity, or postoperative complications for patients operated on with or without these devices. Volume of residual disease was similar (0.1-1 cm: 60% with adjunct techniques versus 68.6% without; complete surgical resection: 16.7% with adjunct techniques versus 13.3% without; p=0.67). For patients with ≤1 cm residual disease, median progression free survival (15 versus 15 months, p=0.65) and median overall survival (40 versus 55 months, p=0.38) were also similar. CONCLUSION:Adjunct surgical techniques may be incorporated during primary debulking surgery for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer with miliary disease; however, these do not improve the rate of optimal cytoreduction.
PMID: 32487686
ISSN: 1525-1438
CID: 5029272

Clinical trial participation and aggressive care at the end of life in patients with ovarian cancer

Nitecki, Roni; Bercow, Alexandra S; Gockley, Allison A; Lee, Hang; Penson, Richard T; Growdon, Whitfield B
OBJECTIVES:In non-gynecologic cancers, clinical trial participation has been associated with aggressive care at the end of life. The objective of this investigation was to examine how trial participation affects end of life outcomes in patients with ovarian cancer. METHODS:In a retrospective review of women diagnosed with ovarian cancer at our institution between January 2010 and December 2015, we collected variables identified by the National Quality Forum as measures of aggressive end of life care including chemotherapy in the last 14 days of life, intensive care unit (ICU) admission in the last 30 days of life, or death in the acute care setting. Trials investigating medications but not surgical interventions were included. The primary outcome of this study was the association between trial participation and the National Quality Forum measures of aggressive end of life care in ovarian cancer decedents. Data were analyzed with univariable and multivariable parametric and non-parametric testing, and time to event outcomes were analyzed using the Kaplan-Meier method and Cox's proportional hazard models. RESULTS:Among 391 women treated for ovarian cancer, 62 patients (16%) participated in a clinical trial. Patients enrolled in clinical trials were more likely to have chemotherapy administered within 14 days of death; however, no association was found with other metrics of aggressive care at the end of life including the initiation of a new chemotherapy regimen in the last 30 days of life, ICU admissions, and death in an acute care setting. Among patients with recurrent ovarian cancer, median overall survival for trial participants was 57 months compared with only 31 months in non-trial participants (p<0.001). CONCLUSIONS:In patients with ovarian cancer, clinical trial enrollment is associated with chemotherapy administration within 14 days of death, but not other measures of aggressive care at the end of life. Given the importance of clinical trial participation in improving care for women with ovarian cancer, this study suggests that concerns regarding aggressive care prior to death should not limit clinical trial participation.
PMID: 31911533
ISSN: 1525-1438
CID: 5029252

The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells

Bellio, Chiara; DiGloria, Celeste; Spriggs, David R; Foster, Rosemary; Growdon, Whitfield B; Rueda, Bo R
One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa.
PMID: 31671803
ISSN: 2072-6694
CID: 5029242

Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer

Konstantinopoulos, Panagiotis A; Luo, Weixiu; Liu, Joyce F; Gulhan, Doga C; Krasner, Carolyn; Ishizuka, Jeffrey J; Gockley, Allison A; Buss, Mary; Growdon, Whitfield B; Crowe, Heather; Campos, Susana; Lindeman, Neal I; Hill, Sarah; Stover, Elizabeth; Schumer, Susan; Wright, Alexi A; Curtis, Jennifer; Quinn, Roxanne; Whalen, Christin; Gray, Kathryn P; Penson, Richard T; Cannistra, Stephen A; Fleming, Gini F; Matulonis, Ursula A
PURPOSE:Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC). METHODS:; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity. RESULTS:-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing. CONCLUSION:mutated ECs was low.
PMID: 31461377
ISSN: 1527-7755
CID: 5029232

Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer

Matsuo, Koji; Cripe, James C; Kurnit, Katherine C; Kaneda, Michiko; Garneau, Audrey S; Glaser, Gretchen E; Nizam, Aaron; Schillinger, Rachel M; Kuznicki, Michelle L; Yabuno, Akira; Yanai, Shiori; Garofalo, Denise M; Suzuki, Jiro; St Laurent, Jessica D; Yen, Ting-Tai; Liu, Annie Y; Shida, Masako; Kakuda, Mamoru; Oishi, Tetsuro; Nishio, Shin; Marcus, Jenna Z; Adachi, Sosuke; Kurokawa, Tetsuji; Ross, Malcolm S; Horowitz, Max P; Johnson, Marian S; Kim, Min K; Melamed, Alexander; Machado, Karime K; Yoshihara, Kosuke; Yoshida, Yoshio; Enomoto, Takayuki; Ushijima, Kimio; Satoh, Shinya; Ueda, Yutaka; Mikami, Mikio; Rimel, Bobbie J; Stone, Rebecca L; Growdon, Whitfield B; Okamoto, Aikou; Guntupalli, Saketh R; Hasegawa, Kosei; Shahzad, Mian M K; Im, Dwight D; Frimer, Marina; Gostout, Bobbie S; Ueland, Frederick R; Nagao, Shoji; Soliman, Pamela T; Thaker, Premal H; Wright, Jason D; Roman, Lynda D
OBJECTIVE:To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS:This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS:During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION:Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.
PMID: 31427143
ISSN: 1095-6859
CID: 5029222

A novel classification of residual disease after interval debulking surgery for advanced-stage ovarian cancer to better distinguish oncologic outcome

Manning-Geist, Beryl L; Hicks-Courant, Katherine; Gockley, Allison A; Clark, Rachel M; Del Carmen, Marcela G; Growdon, Whitfield B; Horowitz, Neil S; Berkowitz, Ross S; Muto, Michael G; Worley, Michael J
BACKGROUND:Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease. OBJECTIVE:To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes. STUDY DESIGN:Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated. RESULTS:Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P<.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P<.001). CONCLUSION:Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients.
PMID: 31082382
ISSN: 1097-6868
CID: 5029212

Infection, thrombosis, and oncologic outcome after interval debulking surgery: Does perioperative blood transfusion matter?

Manning-Geist, Beryl L; Alimena, Stephanie; Del Carmen, Marcela G; Goodman, Annekathryn; Clark, Rachel M; Growdon, Whitfield B; Horowitz, Neil S; Berkowitz, Ross S; Muto, Michael G; Worley, Michael J
OBJECTIVES:To determine whether perioperative red blood cell transfusion (PRBCT) affects infection, thrombosis, or survival rates in epithelial ovarian cancer (EOC) patients undergoing neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS). METHODS:Demographics, operative characteristics, and outcome data were abstracted from records of stage IIIC-IV EOC patients managed with NACT-IDS from 01/2010-07/2015. Associations of PRBCT with morbidity and oncologic outcomes were evaluated. RESULTS:Of 270 patients, 136 (50.4%) received PRBCT. Patients with preoperative anemia and higher estimated blood loss (EBL) were more likely to undergo PRBCT (OR,95%CI 1.80, 1.02-3.17) and (OR,95%CI 1.00, 1.002-1.004), respectively. There were no significant differences in PRBCT based on patient age, Charlson Comorbidity Index, or stage. When compared to low complexity operations, patients with moderate and high complexity surgeries were more likely to receive PRBCT (OR,95%CI 1.81, 1.05-3.09) and (OR,95%CI 2.25, 1.13-4.50), respectively. On univariate analysis, PRBCT was associated with intraabdominal infection (OR,95%CI 8.31, 1.03-67.41), but not wound complications (OR,95%CI 1.57, 0.76-3.23) or venous thromboembolism/pulmonary embolism (VTE/PE) (OR,95%CI 2.02, 0.49-8.23). After adjusting for surgical complexity and preoperative anemia, PRBCT was not independently associated with intraabdominal infection (OR,95%CI 7.66, 0.92-63.66), wound complications (OR,95%CI 1.70, 0.80-3.64), or VTE/PE (OR,95%CI 2.15, 0.51-9.09). When comparing patients undergoing PRBCT versus those who did not, there were no significant differences in median progression-free survival (PFS) or median overall survival (OS) on univariate analysis after adjusting for age, stage and residual disease. CONCLUSIONS:Among patients undergoing NACT-IDS, intraabdominal infection, wound complication and VTE/PE rates are similar, regardless of PRBCT. PRBCT does not impact PFS or OS.
PMID: 30635213
ISSN: 1095-6859
CID: 5029192

CT prediction of surgical outcome in patients with advanced epithelial ovarian carcinoma undergoing neoadjuvant chemotherapy

Bregar, Amy; Mojtahed, Amirkasra; Kilcoyne, Aoife; Kurra, Vikram; Melamed, Alexander; Growdon, Whitfield; Alejandro Rauh-Hain, J; Del Carmen, Marcela; Lee, Susanna I
OBJECTIVE:A scoring system has been proposed to predict gross residual disease at primary debulking surgery (PDS) for advanced epithelial ovarian cancer. This scoring system has not been assessed in patients undergoing neoadjuvant chemotherapy (NACT). The aim of this study is to assess the reproducibility and prognostic significance of the scoring system when applied to women undergoing NACT followed by interval debulking surgery (IDS). METHODS:A retrospective cohort study was conducted of patients with advanced ovarian cancer who underwent NACT and IDS between 2005 and 2014. Change in tumor burden using computed tomography (CT) at diagnosis (T0) and after initiation of NACT but before IDS (T1) was independently assessed by two radiologists blinded to outcomes using two read criteria: a scoring system utilizing clinical and radiologic criteria and RECIST 1.1. Relationship between CT assessments to surgical outcome, progression free survival (PFS) and overall survival (OS) were evaluated. Reader agreement was measured using Fleiss's kappa (ĸ). RESULTS:76 patients were analyzed. Optimal surgical outcome was achieved in 69 (91%) of patients. Median progression free survival was 13.2 months and overall survival was 32.6 months, respectively. Predictive score change from T0 to T1 of >1 (denoting an improvement in disease burden) was associated with optimal cytoreduction (p = 0.02 and 0.01 for readers 1 and 2, respectively). Neither predictive score nor RECIST 1.1 assessment was predictive of OS or PFS. Reader agreement was substantial for predictive score (κ = 0.77) and moderate for RECIST (κ = 0.51) assessments. CONCLUSIONS:A change in score before and after neoadjuvant chemotherapy minimizes reader variability and predicts surgical outcome.
PMID: 30642626
ISSN: 1095-6859
CID: 5029202

PARP Inhibition Induces Enrichment of DNA Repair-Proficient CD133 and CD117 Positive Ovarian Cancer Stem Cells

Bellio, Chiara; DiGloria, Celeste; Foster, Rosemary; James, Kaitlyn; Konstantinopoulos, Panagiotis A; Growdon, Whitfield B; Rueda, Bo R
PARP inhibitors (PARPi) are FDA-approved monotherapy agents for the treatment of recurrent ovarian cancer in patients with and without a BRCA mutation. Despite promising response rates, not all patients derive benefit, and the majority develop resistance. PARPi treatment in vitro and in vivo induced an enrichment of CD133+ and CD117+ ovarian cancer stem cells (CSC). This effect was not affected by BRCA mutation status. In the CSC fractions, PARPi induced cell-cycle arrest in G2-M with a consequent accumulation of γH2AX, RAD51, and uniquely DMC1 foci. DNA damage and repair monitoring assays demonstrated that CSCs display more efficient DNA repair due, in part, to activation of embryonic repair mechanisms which involved the RAD51 homologue, DMC1 recombinase. Preserved and induced homologous repair (HR) could be a mechanism of an inherent resistance of CSCs to the synthetic lethality of PARPi that likely promotes disease recurrence. IMPLICATIONS: Treatment with PARPi fails to significantly affect ovarian cancer CSC populations, likely contributing to recurrent disease. Ovarian cancer CSCs stabilize genomic integrity after PARPi treatment, due to a more efficient inherent DNA repair capacity. PARPi-induced DMC1 recombinase and HR proficiency provide CSCs the opportunity to repair DNA damage more efficiently.Visual Overview:
PMID: 30401718
ISSN: 1557-3125
CID: 5029182

Assessment of treatment factors and clinical outcomes in cervical cancer in older women compared to women under 65 years old

Diver, Elisabeth J; Hinchcliff, Emily M; Gockley, Allison A; Melamed, Alexander; Contrino, Leah; Feldman, Sarah; Growdon, Whitfield B
OBJECTIVE:This study aims to understand the treatment patterns and clinical outcomes of older women with cervical cancer compared to younger women. METHODS:Women undergoing care for cervical cancer between 2000 and 2013 at two academic institutions were identified. The cohort of older patients was defined as >65 years old at diagnosis. Patient charts were retrospectively reviewed, and clinical variables were extracted. Fisher's exact tests, logistic regression, and Kaplan-Meier analyses were performed. RESULTS:From 2000 to 2013 1119 women with cervical cancer were identified. Of these, 191 (17.0%) were >65 years old at the time of diagnosis. Older women were more likely to present with higher stage disease (p < 0.001). Controlling for stage, older women were less likely to undergo surgery during their treatment course (38% versus 70%, p < 0.001) and more likely to undergo radiation (77% versus 52%, p < 0.001), but no more likely to receive chemotherapy (p = 0.34). If they did undergo surgery, older women were less likely to have a pelvic lymph node dissection performed (41% versus 61%, p = 0.04), though the rate of positive pelvic lymph nodes was not different (p = 0.80). Overall survival was decreased in the older cohort (p < 0.001). A multivariate model identified age > 65 (HR 1.76, 95%CI 1.30-2.40), stage (HR 2.77, 95%CI 2.40-3.21), and ever undergoing surgery (HR 0.60, 95%CI 0.44-0.82) as independently associated with overall survival. CONCLUSIONS:Women over age 65 with cervical cancer are less likely to undergo surgical management and were observed to have a decreased overall survival, even when controlling for use of surgery and stage of disease.
PMID: 29503115
ISSN: 1879-4076
CID: 5029152