Roisin Eilish O'Cearbhaill

Treatment of advanced uterine leiomyosarcoma with aromatase inhibitors.

BACKGROUND Aromatase inhibitors are sometimes used in the treatment of selected patients with uterine leiomyosarcoma (LMS), but there are few data assessing the efficacy of aromatase inhibitors in this setting. METHODS We performed a retrospective electronic medical record review of patients with uterine LMS treated with an aromatase inhibitor at Memorial Sloan-Kettering Cancer Center between 1998 and 2008. We assessed progression-free survival (PFS) and objective response among patients with measurable disease and explored the correlation of hormone receptor status with outcome. RESULTS Forty patients with advanced or recurrent uterine LMS were treated with aromatase inhibitors. Thirty-four patients had measurable disease. Hormone receptor status for these patients was as follows: estrogen receptor (ER) positive-22, ER negative-9, ER unknown-3, progesterone receptor (PR) positive-10, PR negative-10, PR unknown-14. Aromatase inhibitors used were letrozole (in 74% of patients), anastrozole (21%), and exemestane (6%). Median PFS was 2.9 months (95% CI: 1.8-5.1). The 1-year PFS rate was 28% (95% CI: 11-48%) for ER and/or PR positive uterine LMS. Best objective response was partial response (PR) in 3/34 patients (9%) (all of whom were ER positive). CONCLUSIONS In this population of patients with mostly low-volume and ER positive uterine LMS, aromatase inhibitors achieved objective response in only 9%. Relatively prolonged PFS was observed among ER positive uterine LMS patients. In the absence of a no-treatment control group, the prolonged PFS cannot be attributed solely to the activity of the aromatase inhibitor treatment since it may reflect the underlying biology of low-volume, ER positive uterine LMS.

Neoadjuvant chemotherapy and primary debulking surgery utilization for advanced-stage ovarian cancer at a comprehensive cancer center

OBJECTIVE The aim of this study was to evaluate the use of neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) before and after results from a randomized trial were published and showed non-inferiority between NACT and PDS in the management of advanced-stage ovarian carcinoma. METHODS We evaluated consecutive patients with advanced-stage ovarian cancer treated at our institution from 1/1/08-5/1/13, which encompassed 32 months before and 32 months after the randomized trial results were published. We included all newly diagnosed patients with high-grade histology and stage III/IV disease. Associations between the use of NACT and clinical variables over time were evaluated. RESULTS Our study included 586 patients. Median age was 62 years (range, 30-90); 406 patients (69%) had stage III disease, and 570 (97%) had disease of serous histology. Twenty-six percent (154/586) were treated with NACT and 74% (432/586) with PDS. NACT use increased significantly from 22% (56/256) before 2010 (at which point the results of the randomized trial were published) to 30% (98/330) after 2010 (p=0.037). Although patients who underwent PDS were more likely to experience grade 3/4 surgical complications than those who underwent NACT, those selected for PDS had a median OS of 71.7 months (CI, 59.8-not reached) compared with 42.9 months (CI 37.1-56.3) for those selected for NACT. CONCLUSIONS In this single-institution analysis, the best survival outcomes were observed in patients who were deemed eligible for PDS followed by platinum-based chemotherapy. Selection criteria for NACT require further definition and should take institutional surgical strategy into account.

Surgical cytoreduction in patients with metastatic uterine leiomyosarcoma at the time of initial diagnosis

OBJECTIVE To determine whether cytoreduction is associated with improved outcome in patients newly diagnosed with metastatic uterine leiomyosarcoma (LMS). METHODS We retrospectively identified all patients treated at our institution for high-grade uterine LMS with extrauterine disease at the time of initial diagnosis from 7/1/82 to 7/31/07. Pattern of disease spread was classified as intraperitoneal (IP) or extraperitoneal (EP). Progression-free survival (PFS) and overall survival (OS) were determined from date of initial surgery using Kaplan-Meier estimates. RESULTS We identified 96 cases. Median age was 54 years (range, 23-81). IP disease was seen in 48 (50%) and EP in 48 (50%). A complete gross resection of all tumor was achieved in 41/84 (49%). Recurrence or progression was noted in 93 (97%); 81 (84%) have died. Median PFS and OS for the entire cohort was 9.7 months (range, 6.7-10.9) and 20.2 months (range, 15.5-24.8), respectively. All 8 non-surgical cases died within 30 months of diagnosis. Median PFS was 14.2 months (range, 11.4-16.9) for those with a complete gross resection versus 6.8 months (range, 4.1-9.5) for those with any residual disease (P=0.002). Median OS was 31.9 months (range, 3.3-60.4) versus 20.2 months (range, 11.8-28.6), respectively (P=0.04). On multivariate analysis, no residual disease was independently associated with PFS when adjusting for disease distribution (IP vs EP) and the use of chemotherapy but not OS. CONCLUSIONS Surgical cytoreduction of metastatic uterine LMS was independently associated with PFS but not OS in cases selected for surgery. The improvement in PFS must be weighed against the morbidity of surgery.

The prophylactic conversion to an extended infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian cancer patients during carboplatin retreatment

OBJECTIVE Repeated exposure to carboplatin can lead to hypersensitivity reactions during retreatment with carboplatin. This may prevent its further use in platinum-sensitive ovarian cancer patients. At our institution, an increasing proportion of patients are prophylactically converted to an extended schedule of infusion after 8 cycles of carboplatin. We sought to determine whether an incrementally increasing, extended 3-hour infusion of carboplatin with appropriate premedication was associated with a lower rate of hypersensitivity reactions compared to the standard 30-minute schedule in sequentially treated patients. METHODS We performed a retrospective electronic medical record review of patients with recurrent ovarian cancer retreated with carboplatin at our institution from January 1998 to December 2008. RESULTS Seven hundred and seventy-seven patients with relapsed ovarian, fallopian tube, or primary peritoneal cancer were retreated with carboplatin and met study inclusion criteria. Of these, 117 (17%) developed hypersensitivity reactions during second-line or greater carboplatin-based treatment for recurrent disease. Only 6 (3.4%) of the 174 patients who received the extended schedule developed hypersensitivity reactions (0% grade 4; 50% grade 3) compared to 111 (21%) of 533 patients in the standard schedule group (13% grade 4; 77% grade 3). The first hypersensitivity episode occurred after a median of 16 platinum (carboplatin and cisplatin) treatments in the extended group compared to 9 in the standard group. Using the Fisher exact test, there was an association with a reduced incidence of hypersensitivity reactions with the extended infusion schedule (P<0.001). CONCLUSION Our data suggest appropriate premedication and prophylactic conversion to an extended infusion during carboplatin retreatment may reduce hypersensitivity reactions.

Optimal primary management of bulky stage IIIC ovarian, fallopian tube and peritoneal carcinoma: Are the only options complete gross resection at primary debulking surgery or neoadjuvant chemotherapy?

OBJECTIVE To explore the impact of primary debulking surgery (PDS) to minimal but gross residual disease (RD) in women with bulky stage IIIC ovarian, fallopian tube, or primary peritoneal cancer. METHODS We retrospectively reviewed all patients with the aforementioned diagnosis who underwent PDS at our institution from 01/2001-12/2010. Those with disease of non-epithelial histology or borderline tumors were excluded. Clinicopathologic data were abstracted, and appropriate statistical tests were used. RESULTS We identified 496 eligible patients. Median age was 62years; 91% had disease of serous histology. Patients were grouped by RD status: no gross RD, 184 (37%); RD of 1-5mm, 127 (26%); RD of 6-10mm, 54 (11%); and RD >10mm, 131 (26%). With a median follow-up of 53months, the median progression-free survivals (PFS) were: 26.7, 20.7, 16.2, and 13.6months, respectively (p<0.001). The median overall survivals (OS) were 83.4, 54.5, 43.8, and 38.9months, respectively (p<0.001). Among patients with RD following PDS, those with RD of 1-10mm had improved PFS (p<0.001) and OS (p=0.001) compared with those with RD >10mm. Patients with RD 1-10mm who received intravenous/intraperitoneal (IV/IP) chemotherapy were younger and had prolonged OS compared with those solely exposed to IV chemotherapy (p<0.001 and p=0.002, respectively). CONCLUSIONS PDS to no gross RD was associated with the longest PFS and OS. However, cytoreduction to 1-10mm of RD was also associated with better survival outcomes compared with cytoreduction to >10mm of RD. We conclude that PDS remains an appropriate option for patients with a high likelihood of achieving RD 1-10mm, especially for younger patients who can receive IV/IP chemotherapy after PDS.

A phase II evaluation of pazopanib in the treatment of recurrent or persistent carcinosarcoma of the uterus: A Gynecologic Oncology Group study

OBJECTIVE Carcinosarcomas of the female genital tract, also called malignant mixed müllerian tumors, are aggressive biphasic tumors. Second-line treatment options in the recurrent/persistent setting have yielded marginal responses. Given the potential role of angiogenesis in the gynecological carcinomas, pazopanib, a VEGFR inhibitor, was investigated in the management of patients with recurrent carcinosarcoma of the uterus. METHODS Eligible patients had histologically confirmed carcinosarcoma of the uterus, a maximum of two prior lines of therapy, adequate renal, hepatic and hematologic function and a performance status of 0-2. Pazopanib was administered orally at 800mg. Two dose reductions were allowed. The primary objective was to ascertain the activity of pazopanib as measured by the proportion of patients who survive progression-free for at least six months and the proportion of patients that have objective tumor responses. Secondary objectives included the frequency and severity of adverse events as assessed by CTCAE v4.0. RESULTS Of the 22 enrolled patients, 19 were eligible and evaluable for toxicity and survival. No patients had a partial or complete response (90% confidence interval [CI]: 0%, 14.6%). Three patients (15.8%) had PFS ≥6months (90% CI: 4.4%, 35.9%). The median PFS was 2.0months (first and third quartiles were 1.6 and 4.0months, respectively). The median overall survival was 8.7months (first and third quartiles were 2.6 and 14.0months, respectively). CONCLUSION Pazopanib demonstrated minimal activity as a second or third line treatment for advanced uterine carcinosarcoma. Potential clinical trial participation should be discussed with the patients.

Quantifying the risk of recurrence and death in stage III (FIGO 2009) endometrial cancer

OBJECTIVE Advanced endometrial cancer patients comprise a heterogeneous group. This study assessed the association of clinicopathological factors with relapse and death from endometrial cancer. METHODS Eligible patients were treated for stage III (FIGO 2009) endometrial adenocarcinoma, had peritoneal cytology performed, and had no gross residual disease post-operatively. RESULTS Of 192 patients, 59% were ≥60 years old, 48% had ≥50% myometrial invasion, 71% lymphovascular invasion, 25% cervical stromal invasion, 37% adnexal involvement, and 23% positive peritoneal cytology. High-grade histology (serous, clear cell, undifferentiated, or grade 3 endometrioid) was present in 45%. Pelvic lymphadenectomy was performed in 93% and para-aortic lymphadenectomy in 73%. Adjuvant chemotherapy and/or radiation therapy was administered to 93%. At a median follow-up of 42 months, the 5-year rate of relapse was 37% and of death from endometrial cancer was 30%. On multivariate analysis, both outcomes were associated with high-grade histology, positive peritoneal cytology, and deep myometrial invasion (p≤0.04). The cohort was divided into subgroups of patients with 0 (n=46), 1 (n=83), or ≥2 (n=63) of these high-risk characteristics. The 5-year relapse rate for patients with 0 risk factors was 13%, 1 risk factor was 27%, and ≥2 risk factors was 62% (p<0.001). The corresponding 5-year rates of death from endometrial cancer were 11%, 20%, and 56%, respectively (p<0.001). CONCLUSIONS Stratification of stage III endometrial cancer according to high-grade histology, positive peritoneal cytology, and deep myometrial invasion is useful for prognostication and may grant insight into the optimal treatment for specific subgroups of patients.

Intraperitoneal chemotherapy after interval debulking surgery for advanced-stage ovarian cancer: Feasibility and outcomes at a comprehensive cancer center

OBJECTIVES Intraperitoneal (IP)-based chemotherapy following primary debulking surgery (PDS), although associated with substantial toxicity, is supported by a strong evidence base. We sought to determine feasibility and outcomes of IP chemotherapy after interval debulking surgery (IDS) among patients deemed ineligible for PDS. METHODS We identified all patients with high-grade, stage III/IV ovarian cancer treated at our institution with neoadjuvant chemotherapy (NACT) followed by IDS and postoperative chemotherapy from 1/2008-5/2013. IP and intravenous (IV) regimens were defined; demographic and clinical data were analyzed using appropriate statistics. RESULTS Of 128 evaluable patients, 118 (92%) achieved ≤1cm residual disease at IDS and 74 (58%) achieved a complete gross resection (CGR). An IP port was placed in 54/128 patients (42%), with 89% port utilization. Forty-eight (38%) of 128 patients received IP chemotherapy, 17 (13%) weekly IV paclitaxel/q3week carboplatin, and 63 (49%) q3week IV carboplatin/paclitaxel. Patients completed a median of 3 IP cycles (range, 2-6), with 3 (5.5%) of 54 ports removed due to complications. Overall survival (OS) for patients with a CGR treated with IP and weekly IV chemotherapy was 53.2months (range, 24.7-NE), and 44.2months (range, 30.2-NE) with any visible residual disease (p<0.001). Median OS was 53.2months (range, 44.5-NE) for IP-, not reached for weekly IV-, and 34.2months (range, 27.5-49.8) for q3week IV-treated patients (p=0.1). CONCLUSIONS Patients administered IP after IDS had a high rate of successful port utilization, with few regimen switches. Oncologic outcomes were optimal in patients with a CGR at IDS, regardless of chemotherapy used.

Primary osteosarcoma of the uterus with cardiac and pulmonary metastases

Highlights • This is the first reported case describing a female with primary uterine osteosarcoma that exhibited cardiac and pulmonary metastases.• Although extremely rare, uterine osteosarcomas, like leiomyosarcomas, do respond to doxorubicin and ifosfamide.• Uterine osteosarcoma behaves aggressively and is associated with a poor prognosis.

890PUNIMOLECULAR PENTAVALENT (GLOBO-H-GM2-STN-TF-TN) IMMUNIZATION OF PATIENTS (PTS) WITH EPITHELIAL OVARIAN(EOC), FALLOPIAN TUBE, OR PERITONEAL CANCER IN FIRST REMISSION.

ABSTRACT Aim: We conducted an IRB-approved phase I study to evaluate the safety and immunogenicity of a unimolecular pentavalent carbohydrate vaccine, bearing five antigens (AGs), Globo-H, GM2, STn, TF and Tn conjugated to keyhole limpet hemocyanin(KLH) and mixed with QS-21 adjuvant, in EOC pts in 1st remission. We previously demonstrated the safe induction of antibody (ab) responses to these individual AGs in a series of monovalent-KLH trials. Methods: Pts with stage III or IV OC in 1st remission were enrolled from 1/2011-09/2013. Three dose levels were planned (25, 50,100mcg) with 3 cohorts of 6 pts to be treated at each dose level (with an additional expansion cohort of 6 pts at the MTD). The schedule was 5 vaccines administered subcutaneously during weeks 1, 2, 3, 7 and 19. Serologic IgM and IgG responses were measured by ELISA against each AG. Serologic response per AG was defined as 1) Ab titer ≥1:80 for pts with no detectable baseline titer or 2) Ab titer ≥8-fold increase over baseline if detectable baseline titer. If ≥4 of 12 pts treated at the MTD were immune responders for ≥3AGs then the study would be considered positive. Results: n = 24 Median age 56yrs (36-79); 22 (92%) high grade serous; 21 (88%) stage III; 3 (12%) stage IV. No DLTs. Immune Results: IgG +/or IgM: ≥3 AGs 20/24 pts (83%). At MTD 100mcg n = 12: IgG +/or IgM: ≥3 AGs 9/12 pts (75%), ≥4 AGs 7/12 pts (58%), 5 AGs 3/12 pts (25%). IgM: ≥1 AG in pts, ≥3 AGs in pts. IgG: ≥1 AG in pts, ≥3 AGs in pts. With a median follow-up of 19mos (2-39), 8pts (33%) had recurred and 4 pts (17%) had died. Immune Response AG GM2 GM2 GloboH GloboH Tn Tn TF TF sTn sTn Ab IgM IgG IgM IgG IgM IgG IgM IgG IgM IgG n = 12 MTD responders 3 2 1 7 7 10 8 3 11 8 Conclusions: The unimolecular vaccine was shown to be safe and immunogenic. 9/12 (75%) pts at MTD (83% of all treated pts) responded to ≥3 AGs. This immune response was comparable to our previously reported immune response in a phase I trial of a heptavalent vaccine with individual antigens conjugated to KLH. The unimolecular construct warrants further investigation and permits multiple AG-targeting. The construct greatly simplifies manufacturing and allows easy scalability of the vaccine. Disclosure: S. Danishefsky: Dr Danifshesky has financial interest in the vaccine being studied. MSKCC holds the patent on this invention. All other authors have declared no conflicts of interest.