Amanika Kumar

Tumorgrafts as In Vivo Surrogates for Women with Ovarian Cancer

Purpose: Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design: Clinically relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results: Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models is annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions: Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment. Clin Cancer Res; 20(5); 1288–97. ©2014 AACR.

Impact of obesity on surgical and oncologic outcomes in ovarian cancer

OBJECTIVES The aim of this study is to determine the impact of obesity on surgical and oncologic outcomes after primary debulking surgery (PDS) in advanced epithelial ovarian cancer (EOC). METHODS Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/2/2003 and 12/30/2011 were included. Patient characteristics, intraoperative and postoperative outcomes, recurrence and status were abstracted. Complications were graded according to the 4-point Accordion classification. For analyses, patients were divided into three groups according to body mass index (BMI): group 1-BMI <25.0 kg/m(2); group 2-BMI 25.0-39.9 kg/m(2); and group 3-BMI ≥40.0 kg/m(2). RESULTS Of the 620 patients included in the study, 36.6%, 56.9%, and 6.5% were in weight groups 1, 2, and 3, respectively. Weight group 3 was an independent predictor of severe complications after adjusting for confounders (adjusted odds ratio (95% CI): 2.93 (1.38, 6.20) for group 3 vs. group 2). Weight group was not associated with differences in residual disease (p=0.80). The 90-day mortality rates were 11.9%, 6.7%, and 15.7%, respectively, in weight group 1, 2, and 3 (p=0.049 unadjusted, p=0.01 adjusted). There was no difference in OS (p=0.52) or PFS (p=0.23) between weight groups. CONCLUSIONS BMI ≥40.0 kg/m(2) is an independent predictor of severe 30-day postoperative morbidity and 90-day mortality after PDS for EOC-information useful in preoperative counseling. BMI does not appear to impact long-term oncologic outcomes including residual disease at PDS, although we had limited power at the extremes of BMI. BMI may be an important factor to consider in risk-adjustment models and reimbursement strategies.

Muscle composition measured by CT scan is a measurable predictor of overall survival in advanced ovarian cancer

OBJECTIVES To assess the impact of muscle composition and sarcopenia on overall survival in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). METHODS Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/1/2006 and 12/31/2012 were included. Patient variables and vital status were abstracted. Body composition was evaluated in a semi-automated process using Slice-O-Matic software v4.3 (TomoVision). Skeletal muscle area and mean skeletal muscle attenuation were recorded. Associations with overall survival were evaluated using Cox proportional hazards models and recursive partitioning. RESULTS We identified 296 patients and 132 (44.6%) were classified as sarcopenic. The average mean skeletal muscle attenuation of the entire cohort was 33.4 Hounsfield units (HU). A multivariate model of overall risk of death included histology, residual disease, and mean skeletal attenuation. Among patients without residual disease, overall survival, but not progression free survival was significantly different between patients with low versus high mean skeletal attenuation (median survival, 2.8 vs. 3.3years). Among patients with residual disease, overall survival was significantly different between patients with low versus high mean skeletal attenuation ≥36.40 vs. <36.40 HU (median survival, 2.0 vs. 3.3years). CONCLUSIONS Sarcopenia and low mean skeletal muscle attenuation are common in women undergoing PDS for advanced EOC. These factors are associated with poorer outcomes, and can be used in preoperative risk stratification and patient counseling. Further research into body composition and whether this risk factor can be altered via nutrition or fitness in this population is warranted.

Performance of AGO score for secondary cytoreduction in a high-volume U.S. center.

OBJECTIVES Determine the predictive value of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score, and prognostic factors for survival, in patients undergoing secondary cytoreductive surgery (SCS) for recurrent ovarian cancer in a high-volume U.S. center. METHODS Medical records of women undergoing SCS between 12/1/1998 and 12/31/2013 were reviewed. Women with no gross residual disease (RD0) at primary surgery, ECOG performance status (PS) ≤1 at recurrence, and no ascites on CT at recurrence were classified as AGO score positive. Women with incomplete information to determine the AGO score were excluded. Overall survival (OS) and progression-free survival (PFS) following SCS, respectively, were estimated from multivariable Cox proportional hazards models. RESULTS 192 women met inclusion criteria. Median disease-free interval (DFI) was 1.9years (IQR, 1.0-3.5). Of the 102 (53.1%) AGO score positive cases, 84.3% (95% CI, 77.3-91.4%) achieved RD0 at SCS. However, 64.4% of AGO score negative cases also reached RD0. Patients with RD0 after SCS survived longer (median OS, 5.4years) vs. RD ≤1cm (2.4years) vs. RD >1cm (1.3years) (p<0.001). Median PFS was also longer in patients with RD0 (1.5years) vs. RD ≤1cm (0.9years) vs. RD >1cm (1.0years) (p=0.001). Among those with RD0 at SCS, AGO score was not associated with survival benefit, however, number of disease sites at recurrence, ECOG PS at recurrence, and DFI were associated with OS and PFS. CONCLUSIONS AGO score can identify patients with a high likelihood of complete secondary cytoreduction and improved survival. However, most AGO score negative cases were also completed resected at SCS. Additional refinement of the score is needed to exclude women from SCS.

Risk-prediction model of severe postoperative complications after primary debulking surgery for advanced ovarian cancer

OBJECTIVES To refine models to predict surgical morbidity and 90-day mortality after primary debulking surgery (PDS) for advanced epithelial ovarian cancer (EOC). METHODS Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/2/2003 and 12/30/2011 were included. Patient characteristics, intraoperative and postoperative outcomes, and vital status were abstracted. Complications were graded using the Accordion classification. Nomograms were generated based on multivariate modeling. RESULTS 138 (22.3%) of the 620 patients who underwent PDS experienced a grade≥3 complication. Age (OR 1.21 per 10 years increase in age), BMI (OR 1.35 for BMI<25 kg/m2 versus reference, OR 2.83 for BMI≥40 kg/m2 versus reference), ASA score≥3 (OR 1.49), stage (OR 1.69 stage IV) and surgical complexity (OR 2.32 high complexity versus intermediate) were predictive of an accordion grade≥3 complication Within 90 days of surgery, 55 (8.9%) patients died. A multivariable model included age (OR 1.76 per 10 year increase in age), ASA score≥3 (OR 3.28), preoperative albumin<3.5 (OR 4.31), and BMI (OR 2.04 for BMI<25 kg/m2 versus reference, OR 3.64 for BMI≥ 40 kg/m2 versus reference) was predictive of 90-day mortality. CONCLUSION Using an independent cohort we report the importance of age, ASA score, preoperative albumin, FIGO stage, and surgical complexity, and BMI, to refine a prediction model for complications after PDS for advanced EOC. This information is useful in preoperative counseling and can be utilized to aid in patient-centered decision making and risk stratification.

Efforts at maximal cytoreduction improve survival in ovarian cancer patients, even when complete gross resection is not feasible

OBJECTIVE We sought to determine survival associated with residual disease (RD) after primary debulking surgery (PDS) for advanced ovarian cancer (OC), and evaluate impact on complications and survival after practice changes to improve PDS. METHODS Outcome variables were collected for patients undergoing PDS for FIGO (2009) stage IIIC OC from 2003 to 2011. The cohort was divided into time periods (2003-2006 vs. 2007-2011), before and after cytoreduction standardization. RD categories were: RD0, RD 0.1-0.5cm, RD 0.6-1.0cm, and RD>1cm. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS 447 patients (mean age, 65.3years) met inclusion criteria. RD for the entire cohort: RD0=44.5%; RD 0.1-0.5cm=30.9%; RD 0.6-1.0cm=11.4%; and RD>1cm=13.2%, with median OS of 58months, 35months, 29months, and 22months, respectively. OS was significantly better for RD0 vs. all other RD categories (p≤0.001), and for RD 0.1-1.0cm vs. RD>1cm (p=0.01). RD0 improved from 32.7% to 54.3% (p<0.001), and RD>1cm decreased from 20.3% to 7.3% (p<0.001) when comparing the 2003-2006 (n=202) vs. 2007-2011 (n=245) cohorts. Surgical complexity increased in the latter time period (24.3% vs. 41.2%). 30-day Accordion grade 3-4 morbidity remained consistent (18.8% vs. 20.8%, p=0.60), 30-day mortality decreased (4.5% to 1.2%, p=0.035), and median OS improved from 36 to 40months after cytoreduction standardization. CONCLUSION Patients with RD0 had longest OS, with survival advantage for RD1 when compared to RD>1cm. These data support PDS to lowest RD even when RD0 cannot be obtained. Practice improvement efforts can increase RD0 rates, improving OS without compromising morbidity.

Functional not chronologic age: Frailty index predicts outcomes in advanced ovarian cancer☆

OBJECTIVES To assess the impact of frailty as measured by a frailty deficit index (FI) on outcomes in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). METHODS Women with Stage IIIC/IV EOC who underwent PDS between 1/1/2003-12/31/2011 were included. Medical records were reviewed for patient characteristics and outcomes. The FI includes 30 items scored at 0, 0.5 or 1 and is calculated by summing across all the item scores and dividing by the total. Frailty was defined as a FI ≥0.15. Associations were assessed using logistic regression and Cox proportional hazards regression. RESULTS Of the 535 studied, 78% had stage IIIC disease and mean (SD) age was 64.3 (11.3) years. Median FI was 0.08, and 131 patients (24.5%) were considered frail with FI ≥0.15. Compared to non-frail patients, frail patients were more likely to have an Accordion grade 3+ complication (28.2 vs. 18.8%; odds ratio (OR): 1.70, 95% CI: 1.08-2.68) and more likely to die within 90days of surgery (16.0 vs. 5.2%; OR: 3.48, 95% CI: 1.83-6.61). After adjusting for known risk factors, these associations remained significant, adjusted OR (aOR): 1.62, 95% CI: 1.00-2.62; aOR: 2.60, 95% CI 1.32-5.10; and aOR: 0.57, 95% CI 0.34-0.97, respectively. Overall survival (OS) for the entire cohort was 39.6months (m). OS was shorter in the frail versus non-frail (median 26.5 vs 44.9m, p<0.001). Frailty was independently associated with death (adjusted hazard ratio: 1.52, 95% CI: 1.21-1.92) after adjusting for known risk factors. CONCLUSIONS Frailty is a common finding in patients with EOC and is independently associated with worse surgical outcomes and poorer OS. Routine assessments of frailty can be incorporated into patient counseling and decision-making for the EOC patient beyond simple reliance on single factors such as age.

Intraperitoneal disease dissemination patterns are associated with residual disease, extent of surgery, and molecular subtypes in advanced ovarian cancer

OBJECTIVE To investigate the association between intraperitoneal (IP) disease dissemination patterns, residual disease (RD), surgical complexity, and molecular subtypes in advanced high-grade serous ovarian cancer (HGSOC). METHODS 741 patients with operable stage III-IV HGSOC undergoing primary debulking surgery at Mayo Clinic from 1994 to 2011 were categorized into four mutually exclusive IP disease dissemination patterns: upper abdominal (60%), miliary (16%), lower abdominal (15%), and pelvic (9%). Surgical complexity was classified as high, intermediate, or low; RD status was defined as 0, 0.1-0.5, 0.6-1.0, or >1cm; molecular subtype assignments were derived from expression profiling of tumors from 334 patients. RESULTS Patients with either miliary or upper abdominal dissemination patterns were less likely to achieve RD0 compared to patients with pelvic and lower abdominal dissemination patterns (25% vs. 9% and 62%, each P<0.001) despite higher surgical complexity (39% vs. 6% and 20%, each P<0.001). Among the subset with molecular subtype data, patients with mesenchymal subtype of tumors were more likely to have upper abdominal or miliary dissemination patterns compared to patients with differentiated, proliferative, or immunoreactive subtypes (90% vs. 77%, 70%, 69%, respectively, P<0.05). CONCLUSIONS IP disease dissemination patterns are associated with RD, surgical complexity, and tumor molecular subtypes. Patients with upper abdominal or miliary dissemination patterns are more likely to have mesenchymal HGSOC and in turn achieve lower rates of complete resection. This provides a plausible model for how the biologic behavior of molecular subtypes is manifest in disease and oncologic outcomes.

Primary Gastric Choriocarcinoma Presenting as a Pregnancy of Unknown Location.

BACKGROUND Pregnancy of unknown location presents a diagnostic challenge, in rare occasions leading to the diagnosis of malignancy. We describe a case of β-hCG-secreting nongestational primary gastric choriocarcinoma presenting as a pregnancy of unknown location. CASE A 37-year-old woman, gravida 4 para 3013, presented with several days of vaginal bleeding and rising β-hCG level without ultrasound localization of pregnancy. The diagnosis of pregnancy of unknown location was made and methotrexate administered at a β-hCG level of 7,779 milli-international units/mL. A 40% decrease in β-hCG level was noted between days 4 and 7. One week later, an inappropriate β-hCG level rise to 10,937 milli-international units/mL was noted, prompting a second dose of methotrexate and computed tomography imaging, leading to the discovery of gastric and liver lesions. Pathology from gastric biopsies revealed nongestational choriocarcinoma. The patient was treated with chemotherapy, with death from cardiac arrest 7 months after diagnosis. CONCLUSION Malignancies that can secrete β-hCG include gestational trophoblastic disease, gonadal and extragonadal germ cell tumors, and malignancies with choriocarcinoma differentiation. Although ectopic pregnancy compromises approximately 2% of first-trimester pregnancy, gestational trophoblastic neoplasia and gestational choriocarcinoma can be seen in 1 of 1,500 and 1 of 20,000 pregnancies, respectively. When β-hCG levels do not fall appropriately in women undergoing medical management for pregnancy of unknown location, ectopic β-hCG secretion by a malignancy must be considered.

Impact of Obesity on Surgical Approaches to Gynecologic Malignancies

As already described in previous chapters, the obesity epidemic in America is on the rise, with approximately 36% of Americans being obese, and more than 6% having Class III obesity (8% in women) defined as a BMI ≥40 kg/m2. The rising obesity rate in women has profound effects on gynecologic malignancy occurrence and treatment. As surgery is a part of treating the majority of gynecologic malignancies, understanding the nuances of intra-operative and peri-operative management of the obese patient is an essential skill of the gynecologic oncologist. This chapter will briefly review the medical and anesthetic considerations for surgery in the obese woman with a gynecologic malignancy. It will focus on the impact of obesity in surgery in both endometrial cancer and in ovarian cancer as well as mention the impact on other gynecologic cancers. The chapter concludes with a mention of techniques that can be employed to facilitate surgery in obese women.