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Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC.An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%).The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Purpose: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. Patients and Methods: Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). Results: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. Conclusions: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.

PurposeTo compare patient/tumor characteristics and outcomes of Asians to Caucasian patients with epithelial ovarian cancer.MethodsAncillary data were pooled and analyzed from ten prospective randomized front-line Gynecologic Oncology Group clinical trials from 1996 to 2011. Demographic, clinicopathologic features, disease-specific and all-cause survival were analyzed.ResultsOf 7914 patients, 7641 were Caucasian and 273 Asian. When compared to Caucasians, Asians were younger at trial enrollment, had a better performance status, earlier-stage cancers (17.2% vs. 8.1% with stage I; p

The purpose of this study was to identify the prevalence of substance use disorder and its association with adherence to treatment and survival in locally advanced cervical cancer patients treated with primary radiation therapy. This is a retrospective case series of locally advanced cervical cancer patients with substance use disorder in a single academic institution treated with radiation therapy between 2005 and 2016. Substance use disorder was identified through chart review. Those with substance use disorder were compared to those without in regards to demographics, Charlson comorbidity index, treatment details and outcomes. Of the 129 patients with locally advanced cervical cancer, 16 (12.4%) were identified as having substance use disorder. Patients with substance use disorder were younger (42.1 years vs 51.5 years, p = .013) and more likely to be smokers (81.3% vs 42.5%, p = .004). The majority of patients with substance use disorder received concurrent chemotherapy (93.8%) and brachytherapy in addition to external beam radiation therapy (81.3%). There was no significant difference in days to completion of radiation therapy between patients with and without substance use disorder. Radiation dose received, toxicities and survival were similar between groups. Among cervical cancer patients receiving treatment with radiation therapy, substance use disorder was not associated with poorer adherence, longer radiation treatment times or a difference in total dose of radiation received. Our experience demonstrates that patients with substance use disorder are able to adhere to complex, multimodal treatment plans resulting in similar cancer specific outcomes compared to patients without substance use disorder., Highlights • Substance abuse disorder is common among locally advanced cervical cancer patients. • Treatment adherence is similar in patients with and without substance use disorder. • Treatment plan should not be altered based on a substance use disorder comorbidity.

ObjectiveThe purpose of this study is to identify incidence of and factors associated with severe late toxicity in women treated with radiation for cervical cancer.Materials and MethodsAll patients with cervical cancer treated with radiation as primary or adjuvant therapy from 2005 to 2017 in a single academic institution were included. Records were reviewed for demographic information, Charlson Comorbidity Index, treatment details, toxicities, and outcomes. Patients with and those without severe late gastrointestinal toxicity (SLGIT), severe late genitourinary toxicity (SLGUT), or any SLGIT or SLGUT, defined as any toxicity (AT), were compared. Overall survival and progression-free survival were also compared.ResultsOf 179 patients identified, 21.2% had AT, 17.3% had SLGIT, and 10% had SLGUT. Estimated AT rate at 3 years was 24.2%. The mean duration of follow-up was 37 months (range, 3–146 months). Most patients (84.1%) received 3-dimensional conformal therapy, and 15.9% received intensity-modulated radiation therapy. Factors associated with AT were lower body mass index (24.9 vs 28.3, P = 0.043), white race (63.2% vs 44%, P = 0.035), and active tobacco smoking during treatment (59.5% vs 40.2%, P = 0.036). Any toxicity was not associated with 3-dimensional versus intensity-modulated radiation therapy planning, low-dose versus high-dose–rate brachytherapy or time to complete radiation treatment. Higher total cumulative radiation dose to clinical target volume was associated with SLGIT. Progression-free survival and overall survival were similar among patients with AT compared to those without toxicity.ConclusionsIn patients with cervical cancer, radiation toxicity is correlated with lower body mass index, white race, and smoking. Despite technologic advances in radiotherapy planning and delivery, toxicity remains high and interventions to reduce the burden of treatment are needed.

Background: While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. Patients and methods: Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. Results: We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. Conclusions: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

Objectives This phase IB study assessed safety of Oregovomab (O) indirect immunization (monoclonal antibody for CA125) and TLR3 stimulation with H (polyICLC) in PROC. Secondary endpoints were RECIST response, immune response, response to subsequent therapies, and overall survival. Methods Patients with PROC (median 5 prior Rx) received 4 IV infusions with 2 mg O followed by 2 mg H IM 30 min & 48 hours post-O at weeks 0, 3, 6 and 9. Week 12, imaging was performed, and elective chemotherapy was allowed post-progression. A final O infusion was given at week-16 and patients were followed. Results 17 patients were enrolled at 2 centers; 15 were dosed and 13 completed the minimum 3 infusions. Treatment phase safety analysis is complete & post IT follow-up is ongoing. Local site reactions to H and mild fatigue/flulike symptoms were reported in 13(87%) patients. Serious adverse events were reported in 5 (33%) patients, attributed to underlying disease. No new safety signals were observed. Six (40%) had stable disease through the 12-week immunization period. Four patients with persistent/progressive disease stopped IT prior to infusion 4. Early humoral response by week-6 was observed in 7 of 9 (77%) patients with the available time points. 14 patients took additional cancer Rx, 5 died of disease and 5 with persistent/progressive disease are stable on Rx. Conclusions Safety, compatibility of combining O with H, and early humoral responsiveness to indirect immunization by week-6 have been established. The potential to enhance activity of chemotherapy using O indirect immunization is proposed.

Preclinical data suggest histone deacetylase inhibitors improve the therapeutic index of sorafenib. A phase I study was initiated to establish the recommended phase 2 dose of sorafenib combined with vorinostat in patients with unresectable hepatocellular carcinoma.Patients received vorinostat (200 to 400 mg by mouth once daily, 5 of 7 d) and sorafenib at standard or reduced doses (400 mg [cohort A] or 200 mg [cohort B] by mouth twice daily). Patients who received 14 days of vorinostat in cycle 1 were evaluable for dose-limiting toxicity (DLT).Sixteen patients were treated. Thirteen patients were evaluable for response. Three patients experienced DLTs, 2 in cohort A (grade [gr] 3 hypokalemia; gr 3 maculopapular rash) and 1 in cohort B (gr 3 hepatic failure; gr 3 hypophosphatemia; gr 4 thrombocytopenia). Eleven patients required dose reductions or omissions for non-DLTtoxicity. Ten patients (77%) had stable disease (SD). The median treatment duration was 4.7 months for response-evaluable patients. One patient with SD was on treatment for 29.9 months, and another patient, also with SD, was on treatment for 18.7 months. Another patient electively stopped therapy after 15 months and remains without evidence of progression 3 years later.Although some patients had durable disease control, the addition of vorinostat to sorafenib led to toxicities in most patients, requiring dose modifications that prevented determination of the recommended phase 2 dose. The combination is not recommended for further exploration with this vorinostat schedule in this patient population.

e17545 Background: Indirect immunization with tumor specific antibody is an approach to triggering therapeutic immunity to cancer through activated immune cells. O is a monoclonal IgG1 specific to CA125 (MUC16). O is currently in phase III evaluation of front-line chemoimmunotherapy (CIT), having shown benefit relative to chemotherapy alone in a randomized phase II study (Brewer, Gyn Onc 2020). H is a TLR3 agonist used as a stimulatory immune adjuvant. The dosing phase of the protocol established safety and compatibility of this combination. The primary safety and response outcomes were reported at IGCS-2019. Immune parameters and long-term outcome associations are the focus of this final update. Methods: Pts with heavily treated RECIST evaluable platinum resistant ovarian cancer (median of 5 prior Rx) received 4 IV infusions with 2 mg O followed by 2mg H IM 30 min & 48 hrs post O at wks 0, 3, 6, 9. At wk 12 imaging was performed and elective salvage Rx allowed. A fifth O+H was optional at wk 16. Study endpoints included immune associations after O+H, after second-line chemotherapy, and survival outcomes. Results: 17 pts were enrolled at 2 centers; 15 patients were dosed and 13 completed the specified minimum 3 infusions. The treatment was well tolerated with local reactions and mild flu like symptoms (13/15 pts) as the only reported adverse events. There was no treatment related serious adverse events. Median survival was 15.0 m [95% CI:10.8m-NE] and 4 patients remained alive at data lock (median 26.5 m). H stimulated an early humoral antibody response to O at wk 6 in 7 of 9 pts (78%). Interval administration of second-line Rx (bevacizumab, paclitaxel, carboplatin, &/or doxorubicin) and O were associated with further antibody spikes. Baseline neutrophil monocyte to lymphocyte ratio (NMLR), a measure of myeloid-derived immune suppression was inversely associated with survival. PROC patients with baseline NMLR ≤4x (n = 8) had median OS 19.6m [15.0 m -NE] vs median OS 10.8m [3.6m-NE] HR 2.44 [0.73-8.15], ( p= 0.13) for pts with NMLR > 4.0 (n = 7). Conclusions: H is a viable immune adjuvant for combination with O suitable for further study in immune resistant settings. Immune responsiveness was similar to that observed in a prior study of same day schedule of carboplatin-paclitaxel front-line immunotherapy (Braly, JIT 2009; Battaglia, Cll, 2020). Patterns of immune response to O in the setting of recurrent ovarian cancer are influenced by concomitant anti-neoplastic therapy. Clinical outcomes appear sensitive to myeloid burden (NMLR > 4) which may be more prevalent in patients with treatment resistant disease than in chemotherapy naïve patients, as previously observed in front-line CIT trials. A phase III study to further evaluate these associations in the front-line setting is currently underway NCT04498117. Clinical trial information: NCT03162562.

Importance: Screening for prostate cancer using PSA-testing can lead to problems of under- and over-diagnosis. A short, non-contrast MRI or transrectal ultrasound might overcome these limitations. Objective: To compare the performance of PSA, MRI and ultrasound as screening tests for prostate cancer. Design, Setting and Participants: This prospective, population-based, blinded cohort study was conducted at seven primary care practices and two imaging centres in the UK. 2034 community based men aged 50-69 years invited for prostate cancer screening and 408 were consented. Interventions: All participants underwent screening with a PSA test, MRI (T2-weighted and diffusion) and ultrasound (b-mode and shearwave elastography).-The tests were independently interpreted without knowledge of other results. Both imaging tests were reported on a validated 5-point scale of suspicion. If any test was screen-positive, a systematic 12-core biopsy was performed. Additional image-fusion targeted biopsies were taken if the MRI or ultrasound was positive. Main Outcomes and Measures: The proportion of men with screen-positive MRI or ultrasound (defined as either score 3-5 or 4-5) or screen-positive PSA (defined as PSA≥3g/L). Key secondary outcomes were the number of clinically-significant and clinically-insignificant cancers detected if each test was used exclusively. Clinically-significant cancer was defined as any Gleason score≥3+4. Results: The proportion with a screen-positive MRI (score 3-5) was higher than the proportion with a screen-positive PSA (72/406, 17.7%[95%CI 14.3-21.8] vs. 40/406,9.9%[95%CI 7.3-13.2]; p

// Andrew Poklepovic 1, 2 , Sarah Gordon 2 , Danielle A. Shafer 1, 2 , John D. Roberts 1, 2, 7 , Prithviraj Bose 1, 2, 8 , Charles E. Geyer Jr. 1, 2 , William P. McGuire 1, 2 , Mary Beth Tombes 1 , Ellen Shrader 1 , Katie Strickler 1 , Maria Quigley 1 , Wen Wan 1, 3 , Maciej Kmieciak 1 , H. Davis Massey 4 , Laurence Booth 5 , Richard G. Moran 1, 6 , Paul Dent 1, 5 1 Department of Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA 2 Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA 3 Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA 4 Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA 5 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, USA 6 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA 7 Current address: Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA 8 Current address: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Andrew Poklepovic, email: andrew.poklepovic@vcuhealth.org Keywords: clinical trial, pemetrexed, solid tumors, sorafenib Received: February 26, 2016 Accepted: April 16, 2016 Published: May 18, 2016 ABSTRACT Purpose: To determine if combination treatment with pemetrexed and sorafenib is safe and tolerable in patients with advanced solid tumors. Results: Thirty-seven patients were enrolled and 36 patients were treated (24 in cohort A; 12 in cohort B). The cohort A dose schedule resulted in problematic cumulative toxicity, while the cohort B dose schedule was found to be more tolerable. The maximum tolerated dose (MTD) was pemetrexed 750 mg/m 2 every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Because dosing delays and modifications were associated with the MTD, the recommended phase II dose was declared to be pemetrexed 500 mg/m 2 every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Thirty-three patients were evaluated for antitumor activity. One complete response and 4 partial responses were observed (15% overall response rate). Stable disease was seen in 15 patients (45%). Four patients had a continued response at 6 months, including 2 of 5 patients with triple-negative breast cancer. Experimental Design: A phase I trial employing a standard 3 + 3 design was conducted in patients with advanced solid tumors. Cohort A involved a novel dose escalation schema exploring doses of pemetrexed every 14 days with continuous sorafenib. Cohort B involved a modified schedule of sorafenib dosing on days 1–5 of each 14-day pemetrexed cycle. Radiographic assessments were conducted every 8 weeks. Conclusions: Pemetrexed and intermittent sorafenib therapy is a safe and tolerable combination for patients, with promising activity seen in patients with breast cancer.

Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40 mg/m2, intravenous infusion) administered every 4 weeks with or without olaratumab (20 mg/kg, IV infusion) every 2 weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2 months for olaratumab+liposomal doxorubicin and 4.0 months for liposomal doxorubicin (stratified hazard ratio [HR] = 1.043; 95% confidence interval [CI] 0.698–1.558; p = 0.837). Median OS was 16.6 months and 16.2 months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR = 1.098; 95% CI 0.71–1.71). In the platinum-refractory subgroup, median PFS was 5.5 months (95% CI 1.6–9.2) and 3.7 months (95% CI 1.9–9.2) in the olaratumab+liposomal doxorubicin (n = 15) and liposomal doxorubicin arms (n = 16), respectively (HR = 0.85; 95% CI 0.38–1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade ≥ 3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.

A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient. Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (q < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Furthermore, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methylation status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression-free and overall survival in SOC patients.

Ovarian cancer is the most lethal of the gynecologic cancers, with 5-year survival rates less than 50%. Most women present with advanced stage disease as the pattern of spread is typically with dissemination of malignancy throughout the peritoneal cavity prior to development of any symptoms. Prior to the advent of platinum-based chemotherapy, radiotherapy was used as adjuvant therapy to sterilize micrometastatic disease. The evolution of radiotherapy is detailed in this review, which establishes radiotherapy as an effective therapy for women with micrometastatic disease in the peritoneal cavity after surgery, ovarian clear cell carcinoma (OCCC), focal metastatic disease, and for palliation of advanced disease. However, with older techniques, the toxicity of whole abdominal radiotherapy (WAR) and the advancement of systemic therapies have limited the use of radiotherapy in this disease. With newer radiotherapy techniques, including intensity modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT) and low dose hyperfractionation in combination with targeted agents, radiotherapy could be reconsidered as part of the standard management for this deadly disease.

Platinum and taxane-based chemotherapy after surgical cytoreduction remains the mainstay of treatment for advanced ovarian malignancies, with median progression-free survival (PFS) ranging from 17 to 30 months and median overall survival (OS) ranging from 36 to 65 months depending on the volume of postcytoreductive disease. Furthermore, adding additional cytotoxic agents to first-line therapy has not had an impact on outcome. Given the therapeutic limitations of conventional chemotherapy, recent investigations have explored molecularly guided therapies to target pathways of oncogenesis. Angiogenesis is recognized as a hallmark of several types of tumors, including ovarian cancer. One of the most important cytokines responsible for tumor-mediated angiogenesis is vascular endothelial growth factor (VEGF), which is secreted by tumor cells and binds to the VEGF receptor (VEGFR) that is present on normal endothelial cells, stimulating new blood vessel formation. Thus, efforts to block this pathway, either by inhibiting VEGF or its receptor, have emerged as attractive strategies for cancer treatment. Approaches to manipulation of the VEGF pathway include extracellular interference with VEGF itself, as well as intracytoplasmic inhibition of the tyrosine kinase domain of the VEGFR. The most investigated antiangiogenic agent to date is the humanized monoclonal antibody to VEGF, bevacizumab, which prevents binding of VEGF to its receptor and thereby inhibits angiogenesis. More recently, small-molecule tyrosine kinase inhibitors, which interact with the cytoplasmic domains of VEGFR, have been investigated clinically. Pazopanib is a multitargeted tyrosine kinase inhibitor that inhibits several tyrosine kinase receptors including VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor, all of which modulate signaling through angiogenic, proliferative, or cell survival pathways. Early clinical trials have demonstrated promising single-agent activity of pazopanib in recurrent ovarian cancer. To date, four phase III randomized clinical trials testing bevacizumab in ovarian cancer have been published. The first, Gynecologic Oncology Group (GOG) protocol 218, was a three-arm placebo-controlled study investigating the addition of bevacizumab 15 mg/kg to standard carboplatin and paclitaxel chemotherapy in first-line, adjuvant treatment of advanced-stage epithelial ovarian carcinoma (EOC). The 1,873 enrolled patients were treated either with standard chemotherapy alone, standard chemotherapy with concurrent bevacizumab followed by placebo maintenance, or standard chemotherapy with concurrent and maintenance bevacizumab every 21 days for up to 16 doses. Patients who were treated with concurrent and maintenance bevacizumab experienced a significantly prolonged PFS when compared with chemotherapy alone (14.1 v 10.3 months; hazard ratio [HR], 0.717; 95% CI, 0.625 to 0.824; P .001). Although the PFS advantage was encouraging, this benefit did not translate into an OS or quality of life (QOL) advantage. A substantial crossover to bevacizumab ( 40%) occurred during this trial, thereby confounding OS analysis. The second trial of first-line bevacizumab, International Cooperative Group for Ovarian Neoplasia study 7 (ICON-7), compared standard carboplatin and paclitaxel chemotherapy alone or the same chemotherapy with concurrent bevacizumab followed by 12 cycles of maintenance bevacizumab at 7.5 mg/kg in 1,528 patients with early-stage, high-risk (clear cell histology or grade 3) and stages IIB to IV EOC. As was observed with GOG 218, a statistically significant improvement in PFS was reported in the bevacizumab arm compared with standard chemotherapy (19 v 17.3 months; HR, 0.81; 95% CI, 0.70 to 0.94; P .0041). Unfortunately, this PFS advantage again did not translate into an OS benefit. Post hoc subgroup analysis in patients at high risk for recurrence (patients with suboptimally cytoreduced stage III and stage IV disease) demonstrated an even larger 5.4-month improvement in PFS and a 9.4-month median OS advantage (30.3 v 39.7 months; P .0072), which seems somewhat counterintuitive. Final analysis of the ICON-7 data was presented at the 2013 European Cancer Congress. In the poor-prognosis group, 332 of 502 patients died (174 in the control arm; 158 in the bevacizumab arm), with an improvement of 4.8 months in restricted mean survival time from 34.5 to 39.3 months (log-rank P .03; proportional hazards test 0.007). Two additional phase III trials were undertaken to assess the effects of bevacizumab in platinum-sensitive and platinumresistant recurrent EOC, respectively. The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and AntiAngiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS), a phase III, randomized, placebo-controlled trial, evaluated bevacizumab in the treatment of 484 patients with platinum-sensitive recurrent disease, comparing gemcitabine and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 30 OCTOBER 2

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Treatment of recurrent ovarian cancer remains a challenge despite advances in surgical and chemotherapeutic options. A goal of many providers is to detect recurrences as early as possible and initiate treatment though there is controversy as to whether this impacts outcome. Elevations in CA125 and radiological findings may precede symptoms of recurrence by several months. While detection of recurrences by physical exam alone is unusual, a thorough exam in conjunction with reported symptoms and elevated CA125 is sufficient to detect 80-90% of recurrences. A spiral CT scan may be used to confirm recurrence in the setting of asymptomatic CA125 elevation and a PET/CT can yield additional insight if the CT is inconclusive. Initiating chemotherapy prior to the development of symptoms, even in the setting of elevated CA125, does not impact overall survival primarily because the efficacy of available treatments in the recurrent setting is poor. More information about tumor biology and ways to predict which patients will benefit from available treatment options is required. Consequently, the approach to post-treatment surveillance should be individualized taking into account the clinical benefit of the second-line therapy, versus the costs and morbidity of the surveillance method.

e22072Background: Studies describing patient factors associated with radiation toxicity in cervical cancer (CxCa) treatment predate advancements in the delivery of radiotherapy. This study identifi...

Purpose We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. Patients and Methods No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). Results Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. Conclusion Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

The present studies sought to determine whether the lethality of the drug combination [sorafenib + sildenafil] could be enhanced by the anti-inflammatory agent celecoxib, using ovarian cancer and other tumor cell lines as models. Also, in a dose dependent fashion celecoxib enhanced [sorafenib + sildenafil] lethality in multiple ovarian cancer cell lines. In a dose dependent fashion celecoxib enhanced the ability of [sorafenib + sildenafil] to reduce expression of multiple chaperone proteins in parallel with lower levels of the drug efflux pumps ABCB1 and ABCG2. Over-expression of GRP78 and HSP27 maintained pump expression in the presence of drugs. Cell killing by the 3 drug combination was mediated by mitochondrial / caspase 9 -dependent apoptotic signaling and by RIP-1 / caspases 2 and 4 / AIF -dependent necroptotic signaling. Pre-treatment of intrinsically resistant primary ovarian cancer cells with [celecoxib + sorafenib + sildenafil] significantly enhanced tumor cell killing by a subsequent cisplatin exposure. Similar data were obtained in some cancer cell lines, but not all, using the related platinum containing drugs, oxaliplatin and carboplatin. As our prior publications have also validated in vivo the combinations of [celecoxib + sildenafil] and [sorafenib + sildenafil] as cytotoxic to multiple tumor cell types, combined with the present findings, we would argue that the combination of celecoxib/sorafenib/sildenafil should be explored in a new phase I trial in ovarian cancer.

Purpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients Experimental Design: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6). Results: CYP3A activity (AUC0–40min) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by ∼50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, α-1 acid glycoprotein, explained ∼18% of overall variation in CYP3A activity (P < 0.001). Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.

Purpose: The purpose of this study was to determine whether amifostine (WR-2721) prevents or ameliorates clinically significant (grade 2 to 4) neurotoxicity associated with cisplatin and 3-hour paclitaxel chemotherapy. Materials and Methods: The chemotherapy program consisted of intravenous paclitaxel 175 mg/m2 over 3 hours followed by amifostine 740 mg/m2 and cisplatin 75 mg/m2 administered over 90 minutes beginning 15 minutes after amifostine administration. At baseline, before each treatment cycle, and for 3 months after completing chemotherapy, patients were evaluated for evidence of neurotoxicity and other treatment-related adverse effects using three methods: standard clinical evaluation (National Cancer Institute common toxicity criteria [CTC] grading), a neurotoxicity questionnaire to assess symptoms and limitations imposed by peripheral neuropathy, and vibration perception threshold (VPT) testing. Results: Four of 27 assessable patients developed grade 2 to 4 neurotoxicity based on clinical assessments and CTC grading. This number of neuropathic events exceeded the predetermined threshold level for a second stage of accrual and the study was closed. Conclusion: Amifostine’s level of activity in this trial was insufficient to warrant further study in a phase III trial. Based on the receiver operating characteristic analysis, it would appear that VPT measurements are less sensitive to the development of peripheral neuropathy than the neurotoxicity questionnaire. The questionnaire, referred to as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity, may be used instead of VPT measurements in future studies of chemotherapy-induced peripheral neuropathy.

In an effort to explore second-line therapy in ovarian, peritoneal, and tubal carcinoma, a phase I trial combining prolonged oral etoposide and liposomal doxorubicin was conducted by the Gynecologic Oncology Group.Liposomal doxorubicin (20 mg/m(2)) was administered intravenously over 1 h followed by oral etoposide at 50 mg/m(2)/day beginning on day 2. In the first phase of accrual, the number of days of oral etoposide was increased until its maximum tolerated dose (MTD) was determined based on hematologic toxicity. In the second phase, etoposide was given at the MTD while the dose of liposomal doxorubicin was escalated until its maximum tolerated dose was reached based on hematologic or nonhematologic toxicity. Cycles were repeated every 28 days for a maximum of 12 courses. Dose-limiting toxicity was defined as neutropenic sepsis, grade 4 thrombocytopenia, absolute neutrophil count1000/microl or platelets50,000 during treatment with etoposide, oror =grade 3 mucositis/stomatitis, palmar-plantar erythrodyesthesia, or rash.Fifteen patients were accrued to the study's first phase, and 3 were accrued to the second phase. Dose-limiting hematologic toxicity occurred with 14 days of oral etoposide in combination with liposomal doxorubicin at 20 mg/m(2). Efforts to escalate the dose of liposomal doxorubicin to 30 mg/m(2) in combination with 12 days of oral etoposide at 50 mg/m(2) resulted in dose-limiting hematologic toxicity. Five of 17 (29%; 95% CI: 13-53%) evaluable patients experienced a response.The regimen of oral etoposide at 50 mg/m(2)/day for 12 days in combination with liposomal doxorubicin at a dose of 20 mg/m(2) is tolerable without supportive therapy. While this dose of oral etoposide has demonstrated activity as a single agent in ovarian cancer, liposomal doxorubicin has only been effective in ovarian cancer at higher doses. There are no immediate plans to study this combination further.

5532 Background: Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib (paz) is a potent angiogenic small molecular inhibitor of the tyrosine kinases VEGRF-1, -2, -3, PDGFR, c-kit and has shown activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent, advanced ovarian cancer. Methods: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive ovarian cancer with up to 3 prior lines of chemotherapy, and measurable or evaluable disease. Patients were randomly assigned (1:1) to receive weekly gem 1000 mg/m2 with or without paz 800 mg QD and stratified according to platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. Intent-to-treat was defined as all eligible patients who receive any protocol treatment with analysis based on randomized arm. Results: As of 3/2017, we randomized 148 and treated 146 patients (target sample size 148 eligible patients who receive any protocol treatment). 75 (46 platinum resistant, 61%) were randomly assigned to receive gem/paz and 71 (41 platinum resistant, 58%) to receive gem only. 110 patients (75%) had received 2 or 3 prior lines. There were no unexpected toxicities or deaths. Adverse events were more common in the gem/paz group. The most common grade 3–4 AEs (gem/paz vs gem) were: neutropenia (25 [33%] vs 15 [21%]), fatigue (7 [10%] vs 1 [2%]), hypertension (11 [15%] vs 1 [1%]), elevated alanine aminotransferase (8 [11%] vs 0), thrombocytopenia (9 [12%] vs 12[3%]) and anemia (7 [9%] vs 2 [3%]). There were 2 GI perforations in the paz arm. Median time on therapy was 12 weeks (range 1-55 weeks). Of the 138 patients off study to date, 30 (22%) were for AE’s (23 on gem/paz arm). Conclusions: The gem/paz combination is tolerable in this population, with patients tolerating multiple cycles with manageable toxicity. Median follow-up and PFS data will be presented after 122 events (progression or death) have occurred per protocol (currently 117 events). Clinical trial information: NCT01610206.

Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR).Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks.Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27-80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7-37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2.Although antitumor activity was observed, the predetermined efficacy endpoints were not met.

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m2 and 45 mg/m2, whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m2. Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m2, doxorubicin 45 mg/m2, and paclitaxel 160 mg/m2 with G-CSF support is recommended for further testing.

A phase I study was performed to determine the maximum tolerated doses of intravenous etoposide and paclitaxel for women with previously treated persistent or recurrent ovarian cancer. Starting doses were paclitaxel 135 mg/m 2 during 24 hours and etoposide 50 mg/m 2 /day for 3 consecutive days. The study was designed to escalate first the dose of etoposide, and then the dose of paclitaxel, in successive cohorts of patients. In an attempt to determine whether toxicity was affected by sequence of the drugs, the order of administration of the two drugs was reversed on alternate cycles. The starting doses of paclitaxel (135 mg/m 2 /24 hours) and etoposide (50 mg/m 2 / day X 3) caused severe neutropenia even with the addition of granulocyte colony-stimulating factor, and the trial was amended to administer the paclitaxel during 3 hours. However, this also proved too myelosuppressive without growth factor support. Twenty-one women were treated. A complete response was observed in one of nine patients with measurable disease, and a major decrease in CA-125 was noted in two patients who did not have measurable disease. Because of the severe myelosuppression observed in most patients, dose reduction was often required after the first cycle. The power to detect sequence-dependent variation in toxicity was minimal; however, no large differences were observed. A combination of the usual doses of these drugs will be difficult to administer in patients who have received previous chemotherapy for ovarian cancer.

Trials performed in the past 15 years by the Gynecologic Oncology Group identified as optimal a platinum/taxane combination as the backbone to treat chemonaive ovarian cancer. Comparison to a triplet adding a third drug to the backbone is least likely to significantly improve outcome, however, of the drugs currently available for addition; doxil, etoposide, gemcitabine, and topotecan ; none appears to be any better or worse than was paclitaxel a decade ago. An approach more likely to improve outcome would be to incorporate as many of these new drugs as possible using sequential doublets. Some doublets have a better biochemical rationale such as cisplatin and gemcitabine (inhibition of DNA repair) or topotecan and either doxil or etoposide (upregulation of topoisomerase II levels by topotecan followed by a topoisomerase 11 inhibitor.

The authors report a case of a suspected pure pancreatic polypeptide-secreting neuroendocrine carcinoma of the gallbladder. The tumor was initially interpreted as an adenocarcinoma of the gallbladder, but was found to have a neuroendocrine component after review. The pathology supports the view that a primitive epithelial stem cell can express both epithelial and neuroendocrine characteristics and can differentiate into both an adenocarcinoma and a neuroendocrine carcinoma. Upon recurrence, the tumor produced symptoms due to local growth, but eventually metastasized and led to the death of the patient within 4 years. The patient was treated with chemoembolization followed by the long-acting somatostatin analog octreotide acetate. The high serum level of pancreatic polypeptide may have contributed to cholestasis and cholelithiasis. Earlier measurement of serum hormone levels and identification of high pancreatic polypeptide levels may have suggested the presence of residual tumor and led to closer follow-up, imaging studies, and therapy.

A case of metastatic adenocarcinoma of the endometrium following endometrial ablation is described. A discussion of the development and evolution of endometrial ablation procedures is presented. Recommendations for patient selection and postablation surveillance are suggested. The authors believe this case report to be the third described in the literature. (Background. A case of endometrial adenocarcinoma developing after transcervical endometrial ablation with a resectoscope was recently reported (A. B. Copperman, A. H. DeCherney, and D. L. Olive, Obstet. Gynecol. 82, 640-642 (1993)). It is recognized that functional residual islands of endometrial tissue remain in both symptomatic and asymptomatic patients following ablation. There is only limited experience using endometrial ablation in postmenopausal patients and in others at high risk for endometrial cancer. Case. A patient presented who developed metastatic adenocarcinoma of the endometrium after endometrial ablation for postmenopausal bleeding. Conclusion. With endometrial ablation procedures, the potential exists for missed areas or buried nests of functional endometrial tissue that may later undergo malignant transformation or have already become metaplastic and invaded the myometrium. Therefore, close postoperative surveillance, including thorough evaluation of postoperative bleeding, is indicated. Further studies with long-term follow-up are needed in order to define the safety and efficacy of endometrial ablation in the high-risk patient.

Histamine-2 receptor antagonists (H2RAs) are principal components of the premedication regimen used to prevent major hypersensitivity reactions in patients receiving paclitaxel. Several different H2RAs, including cimetidine, ranitidine and famotidine, have been used in clinical trials of paclitaxel, as well as by clinicians in different geographic regions and hospitals primarily because of differences in the availability of the various H2RAs. However, H2RAs have highly variable cytochrome P450-modulating capabilities, and the P450 system appears to play a major role in paclitaxel metabolism and disposition. Therefore, the use of different H2RAs may result in different pharmacologic, toxicologic and antitumor profiles due to differential effects on paclitaxel metabolism. This study evaluated whether cimetidine and famotidine, which possess disparate P450-modulating capabilities, differentially affect paclitaxel clearance rates and the agent's principal toxicity, neutropenia. Women with advanced, platinum-refractory ovarian carcinoma received two courses of treatment with 135 mg/m2 paclitaxel over 24 h while participating in the National Cancer Institute's Treatment Referral Center Protocol. A crossover design was employed in which consecutive patients received either 300 mg cimetidine i.v. or 20 mg famotidine i.v. before their first course of paclitaxel and the alternate H2RA before their second course. In order to evaluate the differential effects of cimetidine and famotidine on pertinent pharmacologic and toxicologic parameters in the same individual, paclitaxel concentrations at steady-state (Css), paclitaxel clearance rates, and absolute neutrophil counts (ANCs) were obtained during both courses. Paclitaxel Css values were not significantly different in individual patients when either cimetidine or famotidine preceded paclitaxel (p = 0.16). Mean paclitaxel clearance rates were 271 and 243 ml/min per m2 following cimetidine and famotidine, respectively. These clearance rates were not significantly different in paired analysis (p = 0.30). The likelihood of subsequently requiring granulocyte-colony stimulating factor (G-CSF) for severe neutropenia during course 1 did not differ significantly between the two H2RAs (p = 0.9). Among patients who did not require G-CSF, mean percentage decreases in ANC were 87.7% and 84.2% after paclitaxel cycles preceded by cimetidine and famotidine, respectively. These measures of neutropenia did not differ significantly in paired analysis (p = 0.13). These results show that the H2RAs cimetidine and famotidine do not differentially affect the pharmacologic and toxicity profiles of paclitaxel when used in the premediation regimen to prevent major hypersensitivity reactions, and may be interchanged.

Background. Medullary thyroid carcinoma (MTC) is a neoplasm of the parafollicular C cells of the thyroid gland, which belongs to the diffuse neuroendocrine system. This cancer usually behaves in a relatively indolent manner for most patients. However, approximately 20% of patients have a more aggressive course that requires effective management. There are few reported clinical trials of chemotherapy for MTC. From the literature, the most active agent appears to be doxorubicin, with response rates of 30% reported. On the basis of the activity of cyclophosphamide, vincristine, and dacarbazine (CVD) in other advanced neuroendocrine neoplasms, the authors tested the combination in patients with advanced MTC. Methods. Seven patients with advanced MTC were treated with cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2), and dacarbazine (600 mg/m2 daily for 2 days in each cycle) every 3 weeks. Assessments of measurable tumor and serum calcitonin and carcinoembryonic antigen were made before treatment and followed up until progressive disease was documented. Results. Two patients had partial tumor and biochemical responses for a duration of 14 and 29 months, respectively. One patient had a partial biochemical response and stable tumor measurements for 9 months, and another patient had stable tumor size and markers for 14 months. Three patients had progressive disease. Diarrhea and flushing improved in two patients who had partial biochemical responses. Conclusion. Our experience suggests that CVD chemotherapy has moderate activity and is well tolerated in patients with advanced MTC. Additional prospective studies of this regimen for MTC are required.

Taxol, a new and novel antimicrotubule agent, has shown clear activity as a salvage therapy in epithelial ovarian carcinoma. More importantly, it is active in tumors that have displayed resistance to platinum compounds. Its role as part of initial therapy in combination with cisplatin in advanced disease is currently being explored but data are too immature for any conclusions. Its major and dose-limiting toxicity is neutropenia which makes it an ideal drug to escalate with cytokines although, to date, no clear dose-response relationship has been identified. Taxol may well be the most important new antineoplastic agent to surface in the past decade as further studies suggest it has broad antitumor activity. Studies conducted over the next several years will more clearly place this drug in its proper role in the treatment of ovarian cancer as well as other tumors in which early trials suggest definite activity.

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.

Epithelial ovarian cancer is the leading cause of death from gynecological cancer in most of the Western world, and long-term survival remains poor despite good initial response to systemic therapy after debulking surgery. Even after complete pathological response, the risk of recurrence in the first few years is substantial. The peritoneum is the predominant site of failure and the disease remains confined to the peritoneal cavity for much of its course. Efforts to improve clinical outcomes in this group of patients included investigation of intraperitoneal administration of active agents to expose the low-volume postoperative residual disease in the peritoneum to high concentrations of these drugs. In spite of three National Cancer Institute-sponsored randomized trials demonstrating clinical benefit with intraperitoneal therapy in patients with advanced ovarian cancer, the fact remains that it is not uniformly accepted by the gynecologic oncology community in the USA and is rarely used by clinicians in Europe. Intraperitoneal regimens are perceived to be too toxic for administration, although most of the toxicity is reversible. In this article we discuss the available evidence for intraperitoneal chemotherapy, challenges facing the gynecologic oncology community to make this modality more widely acceptable, the selection of patients most likely to tolerate intraperitoneal therapy and ongoing research in this field.

Forty-four patients with advanced, measurable, epithelial carcinoma of the ovary were treated with 97 courses of N-methylformamide (N-MF) at doses ranging from 600-800 mg/m2, intravenously, daily for 5 days every 28 days. Forty-one patients had prior surgery and had received one prior chemotherapy regimen. Only seven patients had received any prior radiation therapy. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1, or 2. Three partial responses were seen. Hematologic adverse effects were extremely rare as predicted by early clinical trials. One major toxicity was a syndrome consisting of some combination of myalgias, arthralgias, pleuritic pain, abdominal pain, peripheral neuropathy, anorexia, lethargy, and declining performance status (pain-lethargy syndrome) that was reversible with discontinuation of the drug. This adverse effect was as common a reason as hepatic toxicity for discontinuation of N-MF. As reported in previous studies with this drug, hepatic toxicity was also common, usually reversible, and also a cause for discontinuation of the drug. The low level of clinical activity and the unpleasant adverse effects in this population of patients with previously treated ovarian cancer makes it unlikely that this drug will play any significant role in treatment of epithelial ovarian cancer.

PURPOSE To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.

Platinum/taxane regimens induce high response rates and prolong survival in women with ovarian cancer. After recurrence, however, response to second-line chemotherapy is limited. Pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), is the only liposomal anthracycline indicated for second-line treatment of platinum- and paclitaxel-refractory ovarian cancer. Response rates ranged from 14% to 20% in nonrandomized trials of this patient population. In a large phase 3 randomized trial, single-agent PLD and topotecan had similar efficacy overall in response rates, but PLD-treated patients had significantly improved overall survival compared with topotecan with a pronounced advantage in platinum-sensitive patients. Another randomized trial reported that PLD and paclitaxel were comparable with regards to response rate, progression-free survival, and overall survival, regardless of the degree of platinum sensitivity. Additional nonrandomized trials of PLD in combination with other active agents resulted in response rates ranging from 20% to 76%. PLD is generally well tolerated and its side-effect profile compares favorably with other commonly used chemotherapeutic agents in this clinical setting. Proper dosing and monitoring may further enhance tolerability while preserving the efficacy of this versatile agent for ovarian cancer.

Background. Ifosfamide has antitumor activity in previously treated ovarian epithelial tumors, squamous carcinomas of the cervix, trophoblastic disease, and untreated uterine sarcomas in Gynecologic Oncology Group (GOG) trials. Because cyclophosphamide and other alkylating agents are known to produce responses in adenocarcinoma of the endometrium, a Phase II trial of ifosfamide and the uroprotector, mesna, was undertaken. Methods. Fifty-two patients with advanced adenocarcinoma of the endometrium recurrent after surgery and/or radiation therapy and refractory to first-line chemotherapeutic agents were treated with ifosfamide, 1.2 g/m2 intravenous daily for 5 days every 4 weeks, and mesna, 300 mg/m2 intravenous every 4 hours for 3 doses daily for 5 days. Two patients were ineligible–-one due to prior therapy and one due to a second malignancy. Three patients had an inadequate trial, and 7 were inevaluable for response, leaving 47 patients evaluable for toxicity and 40 patients evaluable for response. Thirty-seven patients had undergone hysterectomy, 30 had received radiation therapy, and 32 had received prior cisplatin-based chemotherapy. All patients were GOG performance status 0, 1, or 2. Results. Complete responses were observed in three (7.5%) and partial responses in three patients (7.5%), for a response rate of 15% (95% confidence interval for the true response rate was 5.5%-29.8%). Severe (Grade 3 or 4) leukopenia and anemia were seen in 25 and 4 patients, respectively. Severe thrombocytopenia was observed in 7 patients. Five patients had Grade 3 or 4 neurotoxicity, and one had Grade 3 renal impairment. Reversible alopecia was universal. Conclusions. This dose and schedule of ifosfamide and mesna is active in patients with adenocarcinoma of the endometrium failing platinum-based therapy. Phase II testing in untreated patients is under way. Cancer 1994; 73:1453–5.

OBJECTIVE: Our objective was to determine the activity of ifosfamide and mesna in women with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy. STUDY DESIGN: This is a phase II drug study in which the starting dose of ifosfamide was 1.5 gm/m 2 daily intravenously for 5 days. The starting dose of ifosfamide was reduced to 1.2 gm/m 2 daily in patients who had received prior radiotherapy. The uroprotector mesna was given intravenously with, and at 4 and 8 hours after, the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. RESULTS: Fifty-six patients were placed in the study; 52 were evaluable for toxicity and 51 for response. Twenty-eight (54.9%) patients had previously undergone surgery and 46 (90.2%) had received radiotherapy before this trial. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in 7 (13.5%) patients, and 2 (3.9%) had grade 3 thrombocytopenia. Six (11.5%) patients had grade 3 or 4 neurotoxicity. Complete response was observed in 2 (3.9%) patients and partial responses in 6 (11.5%) patients, for a total response rate of 15.7% (95% confidence interval 7.02% to 28.59%). CONCLUSIONS: This response rate is higher than that reported by the Gynecologic Oncology Group in patients with previously treated squamous carcinoma of the cervix. Our findings fail to confirm that ifosfamide is a highly active agent in patients with squamous carcinoma of the cervix as reported by others; nonetheless, the observed activity of this drug deserves further study in combination therapy of squamous carcinoma of the cervix.

Meeting abstracts FBP (aka Folate Receptor-a) is an immunogenic protein that is over-expressed in breast, endometrial (EC) and ovarian cancer (OC). FBP expression in malignant cells is 20-80 fold higher compared to the limited distribution in normal cells. We have completed enrollment of a Phase

Aim: The inability to distinguish patient populations that are most likely to respond to different treatments is a continuing challenge for medical oncologists. Technologies that can be broadly applied to all patients, which enable multiple therapeutic regimens to be evaluated simultaneously to identify the ones most likely to be clinically beneficial, are needed. Drug sensitivity screening in patient-derived xenografts (PDXs) is a viable solution. In this study we examined the capacity of PDXs to replicate patient outcomes across a variety of solid tumors and treatments and report performance metrics highlighting the clinical utility of this tool. Methods: Tumor tissue from 495 cancer patients was engrafted into immunodeficient mice to generate PDX models. Of these, 65 were screened against the treatments received by the corresponding patient. Patient clinical responses and model drug responses were assessed and correlated using RECIST criteria, with parameters, including sensitivity, specificity, and predictive values, calculated to determine the capacity of PDX responses to capture patient responses. Results: Positive (complete and partial response as well as stable disease) and negative (progressive disease) patient outcomes to treatment were accurately replicated by PDXs, regardless of tumor type or treatment. Based on 96 correlations in 65 patients, we calculated a sensitivity of 99% (72/73 correlations) and specificity of 70% (16/23 correlations) for our PDX drug screens, as well as predictive values of 91% (72/79 correlations) and 94% (16/17 correlations). Despite patient exposure to first-line regimens, PDX models generated from the first resection retained the ability to reproduce outcomes to treatments used for recurrent disease. Conclusions: PDXs accurately reflect clinical responses and have strong potential to correctly guide an oncologist to treatments most likely to yield a favorable patient response, whilst avoiding those that would not. Integration of PDX technology into routine cancer care will re-shape clinical decision-making paradigms in oncology, generating better patient outcomes and eventually help cancer be managed as a chronic disease. Disclosure: M. Hidalgo: I am on the Scientific Advisory Board of Champions Oncology; A. Davies: I am an employee of Champions Oncology and I own stock in the company; D. Vasquez-Dunddel: I am an employee of Champions Oncology and I own stock in the company; D. Ciznadija: I am an employee of Champions Oncology and own shares in the company; A. Katz: I am an employee of Champions Oncology and I own stock in the company; D. Sidransky: I am on the Board of Directors for Champions Oncology and I own stock in the company; K. Paz: I am an employee of Champions Oncology and I own stock in the company. All other authors have declared no conflicts of interest.

5559 Background: Folate Receptor Alpha (FRa) (aka Folate Binding protein (FBP)) is an immunogenic protein that is over-expressed in breast, lung, endometrial (EC) and ovarian cancers (OC). In fact,...