Clinical analysis of pathologic complete responders in advanced-stage ovarian cancer.

OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI: 1.14-11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.

Surgical complexity score and role of laparoscopy in women with advanced ovarian cancer treated with neoadjuvant chemotherapy.

OBJECTIVES: To evaluate surgical complexity scores (SCS) and minimally invasive surgery (MIS) at interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT). METHODS: A multi-institutional study of NACT with IDS for advanced EOC was conducted. Demographic data were abstracted and SCS assigned based on IDS findings. Disease-specific overall survival (DSS) was defined as the time from completion of adjuvant chemotherapy to death due to disease. Cox proportional hazards regression models were used for univariate and multivariate survival analyses. RESULTS: 282 patients were identified; 80.5% had high-grade serous histology and 54.6% were <75 (median 63.9; range 34.1-84.8). Approximately 84% were optimally cytoreduced (61% R0; 23% <1 cm). In multivariate analyses, age 75+ (p ≤ 0.001), residual disease (>1 cm; p = 0.03), and SCS ≥ 3 (p = 0.04) were significantly predictive of worse DSS when morbidity and ASA score were also in the model. When optimally debulked was defined as R0, only age 75+ (<0.001) was significantly associated with decreased DSS. In the R0 cohort, SCS did not significantly predict DSS. However, subset analysis defining optimal ≤1 cm, revealed higher SCS was associated with a 1.6-fold increased risk of death (p = 0.02). Fifty-one patients underwent laparoscopic IDS. Twenty-four (47%) were converted to laparotomy to achieve optimal debulking in 21 patients (87.5%); while 25 had laparoscopic optimal cytoreduction (19/25 [76%] R0). CONCLUSIONS: In women with advanced EOC treated with NACT, older age, SCS ≥ 3, and residual disease >1 cm at IDS were predictors of worse survival. MIS appears safe and feasible with acceptable optimal cytoreduction rates.

Factors influencing clinical trial enrollment among ovarian cancer patients.

OBJECTIVE: To characterize patients who did not enroll on a clinical trial and identify barriers that may limit enrollment among patients with advanced epithelial ovarian cancer (EOC) presenting for first-line chemotherapy. METHODS: We conducted a retrospective review of patients diagnosed with stage II-IV EOC from 10/2009-4/2013, a time period during which multiple trials were available to all EOC patients, including optimally debulked, suboptimally debulked, or undergoing neoadjuvant chemotherapy. Enrollment status, demographics, tumor characteristics, and treatment details were recorded. SAS version 9.3 was used for all analyses. RESULTS: 144 patients met study criteria; 67% were enrolled on a trial. Enrolled patients were significantly younger (median 61 vs 68years, p=0.002). Stage (p=0.30), race (p=0.75), and performance status (p=0.38) were similar between enrolled and non-enrolled patients. Distance did not impact enrollment, as nearly half of patients in both groups lived >50miles from the treatment center (39.0% vs 47.8%, p=0.36). Mode of chemotherapy administration significantly differed based on participation (all p<0.05). Despite similar residual disease status (p=1.00) and number of chemotherapy regimens received (p=0.59), patients treated on trial had a higher 3-year survival rate (70.7% vs 51.7%, p=0.031). The difference in median progression-free survival approached significance (20.2 vs 9.2months, p=0.091). CONCLUSION: In an institution where the culture is to offer clinical trials to all eligible patients, 33% of front-line EOC patients did not participate. Increasing age was associated with non-participation. Modifiable barriers must be overcome so that trial enrollment can better reflect true EOC demographics.

Contribution of age to clinical trial enrollment and tolerance with ovarian cancer.

INTRODUCTION: Increasing age has been correlated with shorter survival in ovarian cancer patients, a finding attributed to diminished tolerance of standard therapy. Elderly patients, however, are less likely to enroll on clinical trials; thus, limited data exists to evaluate their response to front line treatment. This study describes how elderly patients on trial fared, with respect to toxicity and response, compared to younger women. METHODS: A retrospective cohort study was performed of ovarian cancer patients enrolled in front line chemotherapy trials at our institution between 2000 and 2013. Patients were dichotomized by age: <70 and ≥70years. Clinical, pathologic, and treatment characteristics were recorded and analyzed using SAS version 9.3. RESULTS: 336 patients were enrolled. Of these, 79 (23.5%) were ≥70yrs. Demographics were similar between the two groups. Compared to patients <70, those ≥70 completed a comparable number of chemotherapy cycles (p=0.16) and had similar numbers of dose modifications (p=0.40) and delays (p=0.26). Both hematologic and non-hematologic toxicities occurred at similar rates as well. Age≥70 (HR 1.8, 95% CI 1.27-2.54, p=0.0009), stage III/IV (HR 3.44, 95% CI 1.08-10.95, p=0.036), and residual disease (HR 2.63, 95% CI 1.82-3.78, p<0.0001) were independently predictive of shorter overall survival. CONCLUSION: Our data continues to support reports of shorter survival for older women with ovarian cancer. With physician bias removed and similar chemotherapy tolerance noted, our study suggests that inherent tumor biology may be a significant contributor. Further research is needed to identify the mechanisms which contribute to the inequality that age imposes on outcomes.

Evaluation of the Hematologic Safety of Same Day Versus Standard Administration (24- to 72-Hour Delay) of Pegfilgrastim in Gynecology Oncology Patients Undergoing Cytotoxic Chemotherapy.

OBJECTIVE: We assessed the safety and efficacy of administration of pegfilgrastim on the same day compared with standard administration 24 to 72 hours after chemotherapy in patients with gynecologic malignancies. METHODS: A retrospective review was conducted on patients undergoing pegfilgrastim to mitigate the myelosuppressive consequences of chemotherapy. The primary outcome was incidence of grade 3 to 4 neutropenia following pegfilgrastim for same-day administration (D1) versus standard administration (D2+). Secondary outcomes included dose delay, regimen change, hospitalization due to neutropenia, and incidence of febrile neutropenia. RESULTS: Four hundred twenty-one patients with 2071 administrations of pegfilgrastim were included. Five hundred six administrations of pegfilgrastim were given on D1 compared with 1565 administrations on D2+. The most common malignancy was ovarian cancer (79.1%), followed by endometrial (14.5%). Comparing the D1 and D2+ cohorts, noninferiority was not established for the incidence of grade 3 to 4 neutropenia (2.6% vs 1.8%, adjusted relative risk [aRR], 1.6; 90% confidence interval [CI], 0.87-3.2) or dose modification (6.5% vs 4.9%; aRR, 1.3; 90% CI, 0.9-1.8). However, the rate of treatment delays (7.3% vs 9.4%; aRR, 0.8; 90% CI, 0.6-1.1) in the D1 and D2+ groups suggested that delays in the D1 group were not more common than in the D2+ group. CONCLUSIONS: The incidence of hematologic toxicities and dose modification in patients receiving same-day pegfilgrastim were not as low as in those undergoing standard administration. However, treatment delays were found to be no more frequent in those receiving same-day pegfilgrastim versus standard administration. Same-day administration of pegfilgrastim is a reasonable option.

Endometriosis-associated colorectal carcinosarcoma: A case report and review of the literature.

•Endometriosis associated intestinal tumors are rare, with 5 cases documented.•Endometriosis associated intestinal tumors might present like colorectal carcinoma.•Endometriosis associated intestinal Carcinoma is associated with poor prognosis.

Is it reasonable to administer pegfilgrastim on day 1 of a myelosuppressive chemotherapy regimen? A cost-utility analysis.

BACKGROUND: There is recent evidence supporting the safety and efficacy of same-day dosing of pegfilgrastim in patients undergoing chemotherapy. OBJECTIVE: To determine the cost-effectiveness of pegfilgrastim on day 1 (D1) versus day 2 (D2) for primary prevention of neutropenia in women receiving chemotherapy. MATERIALS AND METHODS: A cost-utility model was designed comparing standard D2 versus D1 administration of pegfilgrastim to ovarian cancer patients receiving chemotherapy with an intermediate risk (10-15%) of febrile neutropenia (FN). Rates of FN despite prophylaxis were modeled as 10% for D1 and 5% for D2. Societal costs associated with D2 injection ($175.71) were incorporated. Quality of life (QOL) was modeled from published data; we assumed a small decrement in QOL on treatment days. Sensitivity analyses were performed. RESULTS: D1 administration was less costly ($17,195 versus $17,681) and resulted in higher QOL (0.2298 quality adjusted life years (QALYs) versus 0.2288 QALYs) than D2. Results were sensitive to the risk of FN. D1 remained dominant or cost-effective (ICER less than $50,000/QALY) compared to D2 if the FN rate with D1 was assumed less than 14.5% (baseline estimate 10%). If the FN rate with D1 was assumed greater than or equal to 15%, D1 was not cost-effective compared to D2, with an ICER greater than $100,000/QALY. Findings are insensitive to variations in the modeled cost of treating FN, the additional cost of D2 injection, and the reduced QOL associated with treatment visits. CONCLUSION: Administration of D1 pegfilgrastim is cost-effective in women with ovarian cancer who are treated with intermediate risk chemotherapy.

Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer.

BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathologic significance of BMI-1, small-molecule inhibitors against BMI-1 are recently being developed. In this study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by posttranslational modification. We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays, whereas normal cells remain unaffected. Mechanistically, hyperphosphorylation-mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis. In vivo, orally administered PTC-028, as a single agent, exhibits significant antitumor activity comparable with the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian cancer, where treatment options are limited. Mol Cancer Ther; 17(1); 39-49. ©2017 AACR.

Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer.

With rising incidence rates, endometrial cancer is one of the most common gynecologic malignancies in the United States. Although surgery provides significant survival benefit to early-stage patients, those with advanced or recurrent metastatic disease have a dismal prognosis. Limited treatment options include chemotherapy and radiotherapy. Hence, there is a compelling need for developing molecularly targeted therapy. Here, we show that the polycomb ring finger protein BMI1, also known as a stem cell factor, is significantly overexpressed in endometrial cancer cell lines, endometrial cancer patient tissues as well as in nonendometrioid histologies and associated with poor overall survival. PTC-028, a second-generation inhibitor of BMI1 function, decreases invasion of endometrial cancer cells and potentiates caspase-dependent apoptosis, while normal cells with minimal expression of BMI1 remain unaffected. In an aggressive uterine carcinosarcoma xenograft model, single-agent PTC-028 significantly delayed tumor growth and increased tumor doubling time compared with the standard carboplatin/paclitaxel therapy. Therefore, anti-BMI1 strategies may represent a promising targeted approach in patients with advanced or recurrent endometrial cancer, a population where treatment options are limited. Mol Cancer Ther; 17(10); 2136-43. ©2018 AACR.