Purpose/ObjectiveGiven the rarity of vulvar cancer, data on the incidence of acute and late severe toxicity and patients’ symptom burden from radiotherapy (RT) are lacking.Materials/MethodsThis multi-center, single-institution study included patients with vulvar squamous cell carcinoma treated with curative intent RT between 2009 and 2020. Treatment-related acute and late grade ≥ 3 toxicities and late patient subjective symptoms (PSS) were recorded.ResultsForty-two patients with predominantly stage III/IV disease (n = 25, 59.5 %) were treated with either definitive (n = 25, 59.5 %) or adjuvant (n = 17, 40.5 %) external beam RT to a median dose of 64 Gy and 59.4 Gy, respectively. Five patients received a brachytherapy boost with a median total dose of 84.3 Gy in 2 Gy-equivalent dose (EQD2). Intensity-modulated RT was used in 37 (88.1 %) of patients, and 25 patients (59.5 %) received concurrent chemotherapy. Median follow-up was 27 months. Acute grade ≥ 3 toxicity occurred in 17 patients (40.5 %), including 13 (31.0 %) acute grade 3 skin events. No factors, including total RT dose (p = 0.951), were associated with acute skin toxicity. Eleven (27.5 %) patients developed late grade ≥ 3 toxicity events, including 10 (23.8 %) late grade ≥ 3 skin toxicity events. Patients with late grade ≥ 3 skin toxicity had a higher mean body-mass index (33.0 vs 28.2 kg/m2; p = 0.009). Common late PSS included vaginal pain (n = 15, 35.7 %), skin fibrosis (n = 10, 23.8 %), and requirement of long-term opiates (n = 12, 28.6 %).ConclusionRT for vulvar cancer is associated with considerable rates of severe acute and late toxicity and PSS burden. Larger studies are needed to identify risk factors, explore toxicity mitigation strategies, and assess patient-reported outcomes.

Study Objective: To identify the incidence, type, and grade of postoperative adverse events in minimally invasive radical hysterectomy vs abdominal radical hysterectomy (ARH) for patients with early-stage cervical cancer and determine risk factors associated with these adverse events. Design: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was queried to identify patients with early-stage cervical cancer undergoing radical hysterectomy. Multivariable logistic regression was used to assess risk factors associated with adverse postoperative outcomes among patients undergoing radical hysterectomy. Setting: ACS NSQIP participating institutions within the United States. Patients: Patients were collected from the ACS NSQIP databases (2014-2017) undergoing radical hysterectomy for early-stage cervical cancer. Interventions: N/A Measurements and Main Results: ARH had a significantly increased incidence of any 30-day postoperative adverse event compared with minimally invasive radical hysterectomy (31.2% vs 19.9%, p < .001). There was a higher incidence of surgical site infection, both deep and superficial, and blood transfusions in ARH. On multivariable logistic regression, the abdominal surgical approach was the only risk factor significantly associated with any postoperative adverse event (odds ratio, 1.4; confidence interval, 1.1- 1.9; p = .018; 95% CIs). Conclusions: In this study, the abdominal surgical approach for radical hysterectomy in early-stage cervical cancer was associated with a higher incidence of postoperative adverse events than the minimally invasive approach. (C) 2022 AAGL. All rights reserved.

Carcinosarcomas (CSs) of the endometrium are biphasic malignancies, composed of high-grade carcinomatous and sarcomatous components. Surgical stage and pathologic characteristics are the most important prognostic findings, with a 5-yr survival of 15% to 30% in advance stage disease. Folate receptor alpha (FRA) overexpression has been observed in endometrial carcinomas and not yet studied in CSs. This study evaluates semiquantitative expression of FRA in both carcinomatous and sarcomatous components of CSs on whole tissue sections. Immunohistochemistry for FRA expression was performed and extent and intensity of staining were recorded for each case for both histologic components. A total of 46 cases were stained for FRA. The majority of these (40/46, 87%) showed FRA staining at variable intensity in the carcinomatous component, stronger in serous carcinomas and high-grade endometrioid, while only a small subset of tumors demonstrated weak staining in the sarcomatous component (2/46, 4.35%). CS is known to be associated with poor prognosis and adjuvant therapy is recommended even in low stage disease. Serous and high-grade endometrioid carcinomas are the most common carcinomatous components of CSs and are known to show consistently high FRA expression. Folate plays a role in tumor cell migration and loss of cellular adhesion, which are key steps in epithelial-mesenchymal transition, the process by which CS develops from carcinoma cells. Our study shows expression of FRA in the carcinomatous component of almost all CS cases (87%), further favoring FRA as a target for adjuvant treatment. While expression of FRA in the sarcomatous component was rarely observed, the carcinomatous component being associated with metastatic potential underscores the importance of anti-FRA therapy for systemic disease control.

Li-Fraumeni syndrome (LFS) is a rare highly penetrant cancer syndrome characterized by mutation in the TP53 tumor suppressor gene. Recent data suggest that this germline mutation is more frequent than once thought. While LFS has not been associated previously with pelvic serous carcinoma, gynecologic malignancies have been reported in this patient population. We present the case report of a 37-year-old patient with known LFS and a history of multiple cancers who underwent total abdominal hysterectomy for benign indications with incidental bilateral salpingo-oophorectomy. On final pathology, she was found to have serous tubal intraepithelial carcinoma of bilateral fallopian tubes. Our findings raise the question of the potential role of prophylactic gynecologic cancer-reducing surgery in this patient population.

Objective The aim of this study was to determine whether there is a survival or cost benefit dependent on detection strategy of recurrent ovarian cancer (ie, imaging, physical examination findings, report of symptoms, or rising cancer antigen 125 [CA-125] levels).Methods/Materials A retrospective chart review of 112 ovarian cancer patients was conducted, and method of detection of recurrent disease was determined from medical records. The following primary outcomes were determined using Cox proportional hazards regression model: progression-free survival (PFS) after diagnosis of recurrence and time to death after diagnosis of recurrence (overall survival [OS]). Several approaches to disease surveillance were proposed, and a cost model was applied.Results Median time to recurrence was 13.5 months. Overall, 6.3% presented with only physical examination findings; 24.1%, with elevating CA-125 levels; 34.8%, with imaging; and 32.1%, with symptoms. Most patients presenting with recurrent disease diagnosed by rising CA-125 were white (62.9%); those with imaging and symptomatic recurrences were blacks (56.4% and 57.1%, respectively). There was a small but not statistically significant OS benefit for recurrence detected via CA-125 (P = 0.85; OS per detection method: PE, 20.7 months; CA-125, 26.8 months; imaging, 17.8 months; and symptoms, 6.6 months). We modeled costs of surveillance in our patient cohort; up to 40.8% of cases of ovarian cancer recurrences would have been missed if no imaging were obtained during surveillance.Conclusions Results indicate minimal differences in PFS and statistically insignificant differences in OS, depending on detection method. Notably, black patients with Medicaid presented most often with symptomatic recurrences, which surprisingly did not affect patient OS and PFS; and interestingly, pr\ivate or self-pay insurance was associated with decreased OS among black patients. From our cost analysis, we estimate that the most cost-effective surveillance strategy for the first year costs $9.2 million annually and includes office visit biannually, biannual CA-125 levels, and annual asymptomatic imaging.

Objectives: To investigate the radiation dose received by patients undergoing routine plain x-ray and computed tomography scans for kidney stone studies. Methods: For x-ray scans two sets of experiments were performed. Thermo-Luminescence Dosimeters were used to determine the distribution of radiation dose across the abdominal surface and an acrylic water phantom equipped with a Farmer ionization chamber was used to measure the radiation dose as x-ray photons travel through the abdomen. For CT scans, the Dose Length Product (DLP) over 3 months for abdominal studies was recorded. Calculations were done to convert the DLP to effective dose using k factor values from the International Commission on Radiological Protection (ICRP) report 103. The results were then mapped and analysed using Microsoft excel and Wolfram Mathematical software. Results: Skin dose was greatest at the centre of the abdomen. Radiation equivalent dose to the skin for a plain abdominal x-ray ranged from 2.38mSv for patients with a sthenic body habitus to 5.45mSv for hypersthenic patients. For CT scans, effective dose was found to range between 6.72mSv and 24.27mSv. Conclusion: All radiation dose measured were found to be within recommended ICRP operational limits. The developed procedure could be implemented in other radiology departments in Jamaica as a part of their quality assurance program.

•Ovarian cancer presenting as a primary breast cancer two years prior•Ovarian cancer with metastases to breast is rare.•Metastases to the breast generally present as a recurrence.•Delay in diagnosis likely due to chemotherapy given for breast disease.

OBJECTIVE:To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. METHODS:In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). RESULTS:103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent. CONCLUSIONS:Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

5049 Background: AMG 386 is an investigational peptide-Fc fusion protein that inhibits angiogenesis by preventing angiopoietin 1/2 interaction with the Tie2 receptor. We report on an ongoing, open-label study of AMG 386 combined with PLD or T in advanced ovarian cancer. Methods: In part 1 of this 2-part dose de-escalation study, adult patients (pts) with recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer and GOG performance 0 or 1, and ≤ 3 prior chemotherapy regimens received, IV, AMG 386 at 10 mg/kg QW plus PLD at 50 mg/m2 Q4W (Arm A, n = 6 planned) or T at 4 mg/m2 QW (3 on/1 off; Arm B, n = 6 planned) until progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) in ≥ 3 pts in either arm triggers dose de-escalation of AMG 386 to 3 mg/kg; 6 pts to be enrolled at lower dose. Cohort expansion with 19 pts is planned for part 2 of the study if ≤ 1 pt in either arm has a DLT at either AMG 386 dose. The primary endpoint is DLT incidence; secondary endpoints are safety, PK and response per RECIST (ORR) or CA-125 (GCIG criteria). Results: 12 pts have been enrolled and received ≥ 1 dose of AMG 386 (Arm A/B, n = 6/6). With ≥ 4 weeks follow-up for each pt, there have been no DLTs and no AMG 386 dose de-escalations. 11 pts (Arm A/B, n = 6/5) had AMG 386-related adverse events (AEs): 5 had grade 3 AEs (n = 4/1). There were no grade 4 or 5 AEs. The most common AMG 386-related AEs were nausea (Arm A/B, n = 3/2; no grade 3), fatigue (n = 3/2; grade 3, n = 2/0), rash (n = 3/0; grade 3, n = 2/0), and anemia (n = 0/2; no grade 3). Other key AMG 386-related AEs included hypertension (n = 5/4, no grade 3) and peripheral edema (n = 0/1, grade 3). With median follow-up of 13/21 weeks (Arm A/B), 8 pts were progression-free (n = 5/3); 3 pts had progressed (n = 1/2) and 1 pt (Arm B) died from disease progression. ORR data are not mature. 6 pts had CA-125 responses (Arm A/B, n = 3/3); 1 pt in Arm A had CA-125 progression. Combining AMG 386 with PLD or T did not appear to affect the PK parameters of either agent. Planned cohort expansion to part 2 is underway. Conclusions: Based on these interim results with short follow-up, AMG 386 combined with PLD or T appears tolerable in pts with advanced ovarian cancer. Updated safety and efficacy data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Nuwan Nanayakkara via Quintiles Amgen, CTI Amgen Amgen, GlaxoSmithKline, Ortho Biotech Amgen

PURPOSE:To compare data on severe (grade 4) neutropenia duration and febrile neutropenia incidence in patients receiving chemotherapy with pegfilgrastim administered the same day or 24 hours after chemotherapy.PATIENTS AND METHODS:These were similar, randomized, double-blind phase II noninferiority studies of patients with lymphoma or non-small-cell lung (NSCLC), breast, or ovarian cancer. Each study was analyzed separately. The primary end point in each study was cycle-1 severe neutropenia duration. Approximately 90 patients per study were to be randomly assigned at a ratio of 1:1 to receive pegfilgrastim 6 mg once per cycle on the day of chemotherapy or the day after (with placebo on the alternate day).RESULTS:In four studies, 272 patients received chemotherapy and one or more doses of pegfilgrastim (133 same day, 139 next day). Three studies (breast, lymphoma, NSCLC) enrolled an adequate number of patients for analysis. However, in the NSCLC study, the neutropenic rate was lower than expected (only two patients per arm experienced grade 4 neutropenia). In the breast cancer study, the mean cycle-1 severe neutropenia duration was 1.2 days (95% confidence limit [CL], 0.7 to 1.6) longer in the same-day compared with the next-day group (mean, 2.6 v 1.4 days). In the lymphoma study, the mean cycle-1 severe neutropenia duration was 0.9 days (95% CL, 0.3 to 1.4) longer in the same-day compared with the next-day group (mean, 2.1 v 1.2 days). In the breast and lymphoma studies, the absolute neutrophil count profile for same-day patients was earlier, deeper, and longer compared with that for next-day patients, although the results indicate that same-day administration was statistically noninferior to next-day administration according to neutropenia duration.CONCLUSION:For patients receiving pegfilgrastim with chemotherapy, pegfilgrastim administered 24 hours after chemotherapy completion is recommended.

wnloade pose: This phase II trial evaluated bevacizumab plus erlotinib in platinum-resistant ovarian cancer; atory biomarker analyses, including that of tumor vascular endothelial growth factor A (VEGF-A), lso done. erimental Design: Forty heavily pretreated patients received erlotinib (150 mg/d orally) and bevab (10 mg/kg i.v.) every 2 weeks until disease progression. Primary end points were objective ree rate and response duration; secondary end points included progression-free survival (PFS), y, and correlations between angiogenic protein levels, toxicity, and efficacy. ults: Grade 3 toxicities included skin rash (n = 6), diarrhea (n = 5), fatigue (n = 4), and hypertenn = 3). Grade 4 toxicities were myocardial infarction (n = 1) and nasal septal perforation (n = 1). one grade 3 fistula and one grade 2 bowel perforation were observed. Nine (23.1%) of 39 evaluable ts had a response (median duration, 36.1+ weeks; one complete response), and 10 (25.6%) paachieved stable disease, for a disease control rate of 49%. Median PFS was 4 months, and 6-month as 30.8%. Biomarker analyses identified an association between tumor cell VEGF-A expression and ssion (P = 0.03); for every 100-unit increase in the VEGF-A score, there was a 3.7-fold increase in ds of progression (95% confidence interval, 1.1-16.6). clusions: Bevacizumab plus erlotinib in heavily pretreated ovarian cancer patients was clinically and well tolerated. Erlotinib did not seem to contribute to efficacy. Our study raises the intriguing ility that high levels of tumor cell VEGF-A, capable of both autocrine and paracrine interactions, are possib associated with resistance to bevacizumab, emphasizing the complexity of the tumor microenvironment. Clin Cancer Res; 16(21); 5320–8. ©2010 AACR.

We finished reading the recent report, Radical abdominal trachelectomy for (microscopic) stage IB1 cervical cancer at 15-week gestation by Abu-Rustum et al. [ [1] Abu-Rustum N.R. Tal M.N. DeLair D. Shih K. Sonoda Y. Radical abdominal trachelectomy for stage IB1 cervical cancer at 15-week gestation. Gynecol. Oncol. 2010; 116: 151-152 Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar ], and cannot understand why the authors elected to proceed with the procedure as described. There was a 1600 cc blood loss, the left uterine vessels were ligated and there was concern about a possible left ureteral injury. A gortex cerclage was placed and luckily held until fetal maturity. After all these risks that were taken, the patient then underwent hysterectomy at the time of caesarian delivery.

PURPOSE To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer. PATIENTS AND METHODS Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m(2), and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m(2) and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability. RESULTS With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC-and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC-treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions. CONCLUSION The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.

LBA5008 Background: Safety and efficacy of GC or TC induction followed by elective T consolidation (Tcon) were evaluated. Methods: Patients (pts) with stage IC-IV epithelial OC were randomized to GC: G 1,000 mg/m2 on days 1, 8 plus C AUC=5 on day 1; or TC: T 175 mg/m2 plus C AUC=6 on day 1 for a total of six 21-day cycles. Pts with a complete response (CR) could receive Tcon 135 mg/m2every 28 days for 12 cycles. Non-CR pts received single-agent crossover (CO) therapy (CO-T 175 mg/m2 on day 1 or CO-G 1,000 mg/m2 on days 1, 8) every 21 days until CR or progression of disease (PD). PD or death in 636 pts was required to compare GC and TC with 80% power for progression-free survival (PFS), the primary endpoint. Efficacy results were compared by log-rank test. Results: The trial was stopped in 8/2009 after an ad hoc futility analysis showed low probability of a positive PFS result. Of 919 pts enrolled, 88 pts were excluded (clerical errors); 831 pts were entered; 820 pts had induction; 352 pts had Tcon (GC-Tcon=169, TC-Tcon=183); 155 pts had crossover (CO-T=77, CO-G=78); 313 pts discontinued after induction (GC=165, TC=148). Baseline pt characteristics were balanced across arms. Overall response and adverse events for induction regimens were similar to interim results (Gordon, Clin Ovar Cancer, 2009). For GC and TC, median PFS were 20.0 and 22.2 months; median overall survival (OS) were 43.8 and 57.3 months, respectively. There was no significant difference in PFS (p=0.199) comparing GC and TC. Despite high censorship (GC: 52.8%, TC: 61.4%), OS was greater for TC (p=0.013) compared to GC, but there was no statistical difference after adjusting for significant covariates. For pts with CR, median OS was 65.6 months with Tcon versus 51.4 months without Tcon (p=0.041). Median OS was not reached for TC-Tcon and was 56.1 months for GC-Tcon (p=0.035). For pts not receiving Tcon or receiving either CO-T or CO-G crossover, there was no difference in OS. Conclusions: PFS was similar for GC and TC. Tcon improved OS. However, OS analysis was limited by study design and high censorship. GC does not offer an advantage over standard of care TC for first-line chemotherapy in advanced OC. No significant financial relationships to disclose.

Oregovomab is a monoclonal antibody that recognizes CA125 and forms circulating immune complexes that can elicit immunity against both tumor antigen and tumor. This study was designed to assess combining this immunotherapy at 2 dosing schedules with front-line chemotherapy in patients with advanced ovarian cancer. Forty patients with stage III/IV carcinomas were randomized to receive a 2 mg oregovomab infusion either the same day [simultaneous infusion (SIM)] or 1 week after [1-week delayed (OWD)] standard carboplatin-paclitaxel chemotherapy at cycles 1, 3, and 5, then quarterly for up to 11 antibody doses. The primary end point was antibody response to oregovomab. Secondary end points included cellular immune response, response rate to front-line treatment, and progression-free survival. A different immune response pattern was observed between the SIM arm and the OWD arm, baseline plasma cytokines were balanced. Humoral immunity occurred more rapidly (P=0.0033) and with greater magnitude in the SIM arm. Absolute lymphocyte counts decreased in the SIM arm at cycles 3 and 5 compared with baseline. Treatment emergent CA125-specific cellular immunity was measured more commonly with SIM (P=0.04) and clinical parameters directionally favored this schedule. The immune responses were stronger than those measured in a previous maintenance monoimmunotherapy protocol. Immunotherapy-associated toxicity was minimal in this study. Front-line chemotherapy with carboplatin-paclitaxel has immune adjuvant properties when combined with oregovomab immunotherapy; however, schedule is important. SIM strategies of carboplatin and paclitaxel should be further studied with oregovomab and other antigen-specific cancer immunotherapy approaches.

PURPOSETo examine early changes in CA125 relative to objective response in patients with recurrent ovarian cancer treated with pegylated liposomal doxorubicin (PLD) or topotecan and to compare the CA125 trends between the two chemotherapeutics.PATIENTS AND METHODSPatients with recurrent ovarian cancer, all of whom had measurable or evaluable disease, were randomized to receive 50 mg/m2 PLD every 28 days (n = 239) or 1.5 mg/m2 topotecan for 5 days every 21 days (n = 235) as part of a previously reported multicenter study. CA125 measurements were obtained prior to therapy and with each cycle of administration. Assessable patients underwent radiographic evaluation for response after two cycles of therapy. Objective responses were compared to trends in CA125 values at the end of cycles 1 and 2. CA125 changes were categorized as baseline (+/-10%), +/- 10%-25% variance, and > 25% variance.RESULTSAmong patients treated with PLD, 50% of complete responders (CR) and 41% of partial responders (PR) had increases in CA125 from baseline to cycle 1. Increases in CA125 were also seen in topotecan-treated patients; however, fewer patients had increases (20% and 8%, respectively). Overall, 15% of responding patients (CR + PR) receiving PLD and 6% receiving topotecan had elevated CA125 after two cycles of therapy. For those patients achieving a partial response, 19% of PLD-treated patients and 8% of topotecan-treated patients had CA125 levels above baseline at cycle 2.CONCLUSIONSConsiderable intrapatient variation in CA125 values is present among responding patients. Early increases in CA125 may not predict ultimate outcome, especially in PLD-treated patients.

3024 Background: Chemotherapy (C) induced bone marrow suppression has been assumed to inhibit the generation of augmented immune responses. This has limited investigation of front-line C-IT in OC. Temporal relationship of IT administration relative to C has not been established. Oregovomab is a CA125 specific MAb in development as an OC adjuvant treatment to induce tumor specific immunity. Methods: Patients (pts) awaiting staging laparotomy for presumptive OC were consented to the study and contributed primary tumor samples. Qualifying pts were subsequently randomized to concurrent C-IT with antibody administered at cycles 1, 3, and 5 (Arm A) or 8 ± 2 days following cycles 1, 3, and 5 (Arm B) of standard C-P. Both arms received additional infusions of oregovomab every 12 weeks until progression; response to C-IT was assessed at 36 weeks. Results: Forty stage III/IV pts (18 Arm A; 22 Arm B) were randomized and dosed. More pts in Arm A (39%) were stage IV vs Arm B (14%) however 27% of Arm B pts had >2cm residual disease vs. 11% in Arm A. Complete clinical response (CR) to surgery and C-IT was achieved in 15 pts (83%) in Arm A and 17 pts (77%) in Arm B. For pts with = 2 cm residual disease, 88% in Arm A had = 65 U/mL CA125 prior to/at cycle 3, normalized CA125 and a CR post C-IT compared to 75% of pts in Arm B. Robust Ab2 antibody response (>100 ng/mL) was achieved in 94% of Arm A and 68% of Arm B pts. The immune response developed earlier in Arm A. After one injection of oregovomab, 31% of pts in Arm A vs. 0% in Arm B generated HAMA > 3000 ng/mL and Ab2 > 100 ng/mL (P=0.016 Fisher’s Exact Test). Such an early and vigorous response pattern has not been seen in previous oregovomab studies which have not included concomitant front-line C. There were no IT related serious adverse events. Conclusions: Contrary to expectations, concurrent C-P resulted in enhanced immune stimulation with oregovomab. Interestingly, concurrent infusion of oregovomab was more immunogenic than delayed infusion. Clinical activity was favorable and safety profiles were similar to that expected for C alone. Further randomized evaluation of front-line CP-oregovomab vs CP is warranted. [Table: see text]

PURPOSEOvarian cancer (OC) patients experiencing progressive disease (PD) within 6 months of platinum-based therapy in the primary setting are considered platinum resistant (Pt-R). Currently, pegylated liposomal doxorubicin (PLD) is a standard of care for treatment of recurrent Pt-R disease. On the basis of promising phase II results, gemcitabine was compared with PLD for efficacy and safety in taxane-pretreated Pt-R OC patients.PATIENTS AND METHODSPatients (n = 195) with Pt-R OC were randomly assigned to either gemcitabine 1,000 mg/m2 (days 1 and 8; every 21 days) or PLD 50 mg/m2 (day 1; every 28 days) until PD or undue toxicity. Optional cross-over therapy was allowed at PD or at withdrawal because of toxicity. Primary end point was progression-free survival (PFS). Additional end points included tumor response, time to treatment failure, survival, and quality of life.RESULTSIn the gemcitabine and PLD groups, median PFS was 3.6 v 3.1 months; median overall survival was 12.7 v 13.5 months; overall response rate (ORR) was 6.1% v 8.3%; and in the subset of patients with measurable disease, ORR was 9.2% v 11.7%, respectively. None of the efficacy end points showed a statistically significant difference between treatment groups. The PLD group experienced significantly more hand-foot syndrome and mucositis; the gemcitabine group experienced significantly more constipation, nausea/vomiting, fatigue, and neutropenia but not febrile neutropenia.CONCLUSIONAlthough this was not designed as an equivalency study, gemcitabine and PLD seem to have a comparable therapeutic index in this population of Pt-R taxane-pretreated OC patients. Single-agent gemcitabine may be an acceptable alternative to PLD for patients with Pt-R OC.

Objective. To determine the safety and efficacy of a novel illudin S derivative, irofulven (MGI-114), in patients with recurrent ovarian cancer who had received extensive prior chemotherapy. Methods. The trial was an open label phase II study. Patients initially enrolled in this study were treated every 14 days with a dose of 24 mg/m2. Unexpected retinal toxicity associated with this dose and schedule lead to modification of the dosing to 0.55 mg/kg on the same schedule with a maximum individual dose of 50 mg. Dose reductions were permitted based on both hematologic and non-hematologic toxicities. Results. Seventy-four women were accrued and stratified into two cohorts including 58 women with platinum-resistant disease and 16 with platinum-sensitive disease. Non-hematologic toxicities included nausea, vomiting, and fatigue. Thirty-one women had between one and six visual symptoms, most were Grade 1 and 2 in nature. The majority of visual toxicities resolved either during treatment or post-treatment with irofulven. There was one partial response in each cohort with 19 (33%) and 8 (50%) of women having stable disease in the platinum-resistant and platinum-sensitive cohorts, respectively. Conclusions. Irofulven at 24 mg/m2 on every 14-day schedule is associated with significant retinal toxicity in this patient population. Dosing at 0.55 mg/kg has persistent retinal toxicity, yet demonstrated only limited anti-tumor activity in a population of women who had received extensive prior chemotherapy.