A randomized phase II trial of bevacizumab vs. bevacizumab and erlotinib as first-line consolidation after carboplatin, paclitaxel, and bevacizumab in newly diagnosed patients with mullerian tumors.

BACKGROUND: The combination of paclitaxel to platinum remains the backbone of therapy in patients with advanced Mullerian tumors. In patients with newly diagnosed Mullerian tumors, we investigated the progression-free survival benefit of bevacizumab and bevacizumab and erlotinib as consolidation therapy post-induction therapy. METHODS: Sixty patients were enrolled in a phase II trial of carboplatin, paclitaxel, and bevacizumab (induction therapy). After the completion induction therapy, patients were stratified by response (≥ SD) and then randomized (1:1) to either bevacizumab (A) or bevacizumab and erlotinib (AE.) The primary endpoint was PFS. Secondary endpoints included the response rate of induction and consolidation therapy and toxicity profile of each consolidative arm. Each consolidative arm was compared to the historical control GOG 111. RESULTS: Forty-eight patients advanced to the consolidative phase of the trial. Twelve patients were removed in the induction phase, the majority for toxicity. The most common toxicity (grade ≥ 3) was diarrhea (20%: arm AE; 0%: arm A). One patient in the AE arm had a fatal cardiac arrest deemed unrelated to the study treatment. No gastrointestinal perforations were reported. The median PFS in the AE and A arm was 18.9 months (p < 0.0001) and 13.3 months (p: ns), respectively. The overall rate of grade 3/4 toxicities in the AE arm was 72% and in the A arm 30%. Six patients remain free of disease 10 years after enrollment. CONCLUSION: Combinatorial consolidation therapy with AE was associated with an improved progression-free survival in patients with Mullerian tumors.

Ofranergene obadenovec (VB-111) in platinum-resistant ovarian cancer; favorable response rates in a phase I/II study are associated with an immunotherapeutic effect.

OBJECTIVE: Report final results of a phase I/II study of VB-111, a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response, in combination with paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Study NCT01711970 was a prospective, open label, dose escalation study assessing combination treatment of VB-111 and weekly paclitaxel. In the Phase I part of the study, patients were treated with escalating doses of intravenous VB-111 and paclitaxel. In Phase 2, patients were treated with therapeutic doses of VB-111 and paclitaxel 80 mg/m2. Assessments included safety, overall survival (OS), progression free survival (PFS), and tumor response (CA-125 and RECIST). RESULTS: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled. 17/21 received the therapeutic dose. Patients had a median of 3 prior lines of therapy. Half of the subjects were platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and associated with mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients. The median OS was 16.6 months in patients treated with therapeutic dose compared to 5.8 months in sub-therapeutic dose (p = 0.028). Tumor specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells in regions of apoptotic cancer cells. CONCLUSIONS: Treatment with VB-111 in combination with paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect.

Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions.

BACKGROUND: The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE: We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS: Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS: Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS: Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

A prospective feasibility study of radiation and concurrent bevacizumab for recurrent endometrial cancer.

OBJECTIVES: To determine the toxicity and survival rates in a trial of concurrent bevacizumab and external beam radiation (EB) for patients with recurrent endometrial or ovarian cancer. METHODS: Nineteen women with recurrent endometrial (n = 15) or ovarian (n = 4) cancer with gross disease involving the vaginal cuff, and/or pelvic nodes and/or para-aortic nodes, cancer were enrolled between 2008 and 2010. All patients received bevacizumab during radiation. Toxicity was assessed at baseline, weekly during treatment and every 3 months for at least 1 year after treatment. RESULTS: All patients completed EB on schedule. For the 15 patients with recurrent endometrial cancer, the 1- and 3-year progression-free survival (PFS was) 80%/67% and overall survival (OS) was 93%/80%. Patients that had a vaginal cuff recurrence alone had a 1- and 3-year PFS of 75%/63% and OS of 100%/75%. Two patients with pelvic node involvement did not recur throughout the entire follow-up period. The 5 patients with para-aortic node involvement had a 1- and 3-year PFS of 80%/60% and OS of 80%/80%. Of the 4 ovarian cancer patients 3 relapsed with 1- and 3-year PFS of 80%/40% and OS of 100%/60%. Toxicities included thrombosis and 1 embolic event in the setting of metastatic disease. No gastrointestinal perforations were noted. CONCLUSIONS: Delivering bevacizumab with concurrent radiation provides excellent local tumor control and survival for women with recurrent endometrioid endometrial cancer, particularly those with unresectable nodes. Caution must be used in those at highest risk of developing metastatic disease given the increased risk of thromboembolic events. This regimen may be considered for recurrent gynecologic malignancies in future trials.

A phase II trial of Sunitinib malate in recurrent and refractory ovarian, fallopian tube and peritoneal carcinoma.

OBJECTIVE: Ovarian cancer is a highly angiogenic tumor and a model for antiangiogenic research. The tyrosine kinase receptor inhibitors target several receptors allowing for the pharmacological disruption of several independent pathways. Sunitinib malate is a multitargeted tyrosine kinase inhibitor. A phase II study utilizing a modified dosing schedule was conducted to assess the efficacy and safety of Sunitinib in recurrent ovarian, fallopian tube and peritoneal carcinoma. METHODS: A nonrandomized phase II study was modeled as a two-stage Simon design initially enrolling 17 evaluable participants in stage one and 18 patients in stage two. Patients received the study drug at 37.5mg every day over a 28 day treatment cycle until clinical or radiological evidence of progressive disease. Disease was evaluated radiographically and best overall response was defined using the RECIST 1.0 criteria. The primary objective of this study was to define the response rate (defined as complete response and partial response) while the secondary objectives included both the progression free rate as well as the safety of this agent in this patient population. RESULTS: The response rate (PR+CR) was 8.3% (95% confidence interval: 1.8%, 22.5%). The 16-week and 24 week progression-free survival estimate was 36% (95% confidence interval and 19.2%), respectively. The median progression-free survival estimate was 9.9 weeks. Hypertension and gastrointestional events were the most common toxicities noted. CONCLUSIONS: A modest response rate of 8.3% was achieved with Sunitinib malate. This phase II study adds to the body of literature of VEGFR inhibitors and further underscores the need of defining a genetic angiogenic signature.

Eribulin mesylate (halichondrin B analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer: a 2-cohort, phase 2 study.

BACKGROUND: Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. In this study, the authors assessed the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer. METHODS: Patients with recurrent, measurable epithelial ovarian cancer who had received ≤2 prior cytotoxic regimens and who had adequate organ function were enrolled into 2 separate cohorts: 1) platinum-resistant patients (who had a progression-free interval <6 months after their last platinum-based therapy) and 2) platinum-sensitive patients (who had a progression-free interval ≥6 months after their last platinum-based therapy). Eribulin 1.4 mg/m(2) was administered over 15 minutes intravenously on days 1 and 8 every 21 days. Efficacy was determined by objective response on computed tomography studies. RESULTS: In the platinum-resistant cohort, 37 patients enrolled, and 36 patients were evaluable for response and toxicity. Two patients achieved a partial response (5.5%), and 16 patients (44%) had stable disease as their best response. The median progression-free survival was 1.8 months (95% confidence interval, 1.4-2.8 months). In the platinum-sensitive cohort, 37 patients enrolled, and all were evaluable for response. Seven patients achieved a partial response (19%). The median progression-free survival was 4.1 months (95% confidence interval, 2.8-5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% of platinum-resistant patients; 54% of platinum-sensitive patients). CONCLUSIONS: Eribulin produced an objective response in 5.5% of women with platinum-resistant, recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. The median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group.

Sequential bevacizumab and oral cyclophosphamide for recurrent ovarian cancer.

OBJECTIVE: Test the safety and efficacy of sequentially blocking angiogenesis by adding oral cyclophosphamide to bevacizumab following cancer progression on bevacizumab in patients with recurrent ovarian cancer. METHODS: Eligibility included ≤ 2 lines of treatment for recurrence and measurable cancer by RECIST 1.0. Patients received bevacizumab (15 mg/kg every 3 weeks IV) and upon RECIST progression, oral cyclophosphamide (50mg orally daily) was added. Objectives included safety, toxicities, 3- and 6-month PFS rates, response rate, PFS, and OS. RESULTS: 20 patients were enrolled. Overall response rate was 10%, and 65% of patients had confirmed stable disease (SD). Thirteen of 20 patients received oral cyclophosphamide added to bevacizumab upon bevacizumab progression. Of these 13 patients, 1 patient subsequently achieved a PR (this patient had SD as best response during bevacizumab) and 3 patients had a confirmed SD. For all patients, median PFS was 8.41 months, 6 month PFS rate was 65%, duration of response (DOR) was 7.3 months, and median OS was 22.72 months. Median DOR for patients receiving both bevacizumab and cyclophosphamide was 8.4 months. Most toxicities were grades 1 and 2 and manageable. Grades 3 and grade 4 toxicities included 1 myocardial infarction, 1 gastrointestinal perforation (GIP), and 12/20 patients (60%) developed grade 3 HTN. CONCLUSIONS: Addition of oral cyclophosphamide to bevacizumab at the time of cancer progression on bevacizumab appears to have continued anti-cancer effects in a subgroup of patients and appears to be safe. Randomized trials testing combination versus sequential anti-angiogenic therapy for recurrent ovarian cancer are warranted.

Young women diagnosed with early-stage ovarian cancer or borderline malignancy of the ovary: a focus on fertility and sexual function.

Malignant ovarian neoplasms represent the leading cause of death in gynecological malignancies. Although the majority of ovarian neoplasms occur in women of advanced years, ovarian neoplasms can occur in women of the reproductive age group. Preservation of fertility balanced with treatment of disease is the goal of young patients diagnosed with ovarian neoplasms. A new discipline termed "oncofertility" has emerged; however, several informational gaps exist. Concern has centered on the safety of conservative treatment, the uncertain efficacy of fertility options, the detrimental effects of chemotherapy to remaining reproductive organs, and the timing and execution of fertility workup relative to disease requiring treatment. This study involved an evaluation of young premenopausal women who underwent fertility-sparing surgery for an ovarian neoplasm. Given the rarity of this disease in premenopausal women the objective was to assess the feasibility of this study as defined by the completion rate of the survey. The aim was to broaden our knowledge of patient needs to partner with our survivorship clinic thereby ensuring that patients may facilitate their options. Patients were asked to complete a questionnaire titled Ovarian Cancer or Borderline Malignancy of the Ovary: Fertility Sparing Survey and a previously published instrument termed The Sexual Activity Questionnaire, a 21-item scale that assessed the impact of treatment on sexual functioning. All participants completed the survey illustrating the feasibility of the study. The study revealed that the majority of patients (91%) discussed fertility options with their clinicians, yet only 16% engaged in measures to preserve fertility. Patient's sexual interest and activity was maintained in this cohort of patients. This underscores the importance of continued studies in this unique population to ensure optimal fertility counseling and to better delineate the sexual well-being of young women diagnosed with ovarian neoplasms.

A phase I study of AZD2171 and Temsirolimus in patients with advanced gynecological malignancies.

PURPOSE: Temsirolimus, a mTOR inhibitor, and AZD2171, a VEGFR inhibitor, have independently shown activity in patients with gynecological malignancies. Understanding the pivotal role of the PI3K/PTEN/AKT/mTOR pathway in regulating angiogenesis, a phase I study utilizing Temsirolimus and AZD2171 was initiated to study the safety of targeting the mTOR and VEGF pathway in patients with recurrent or refractory gynecological malignancies. METHODS: Patients with advanced gynecological cancers were enrolled in this phase 1 study with Temsirolimus and AZD2171. A traditional 3 + 3 design was followed. The primary objective was to determine the MTD of the combination. Secondary objectives included efficacy, progression free survival (PFS) and toxicity profile. An expansion phase was planned after the MTD was determined. RESULTS: The study enrolled 11 patients over 16 months. All patients were enrolled in dose level 1. Due to toxicity, the trial was halted at dose level 1. No MTD was determined. The most common grade 3/4 toxicities included hypertension, thrombocytopenia, thromboembolic events, and hypertriglyceridemia. Five patients were evaluable for best overall clinical response. The best overall clinical response was stable disease. Two patients died without documented progression of disease. The median PFS was 7.2 months. CONCLUSIONS: Despite a conservative dose escalation, the toxicity data demonstrated that the combination of AZD2171 and Temsirolimus was not tolerable. Increased awareness of novel toxicities, pharmacological interactions, coupled with strict patient selection and early mitigation of side effects may enhance phase I clinical trial development.

Phase II trial of GM-CSF in women with asymptomatic recurrent müllerian tumors.

OBJECTIVE: GM-CSF is a recombinant human cytokine, which promotes the proliferation and differentiation of granulocytes and monocytes, and is associated with anti-tumor activity. The primary objective was to define the median time to treatment termination (TTT) with women with relapsed ovarian cancer treated with single agent GM-CSF delivered subcutaneously (SC). PATIENTS AND METHODS: Open label phase II study in asymptomatic patients with recurrent müllerian malignancy without an indication for immediate systemic chemotherapy. In the first cohort of 35 women, GM-CSF 250 microg/m(2) was administered SC on days 1-14 of a 28-day cycle, the second cohort received continuous GM-CSF 150 microg/m(2) given with dose escalation. RESULTS: Seventy-two women were enrolled. Best overall response included one complete response, and 20 patients with stable disease (23%), 4 of whom had stable disease for >6 months. Median TTT was 78 days. Toxicity in both cohorts was generally mild; however, four patients experienced excessive toxicity and withdrew consent. In the first cohort, CA-125 dropped in 70% of women from their baseline on study value (median change -23%, range -48 to +116%) after 14 days of GM-CSF. The magnitude of CA-125 drop during the first 2 weeks of therapy also showed a positive inverse correlation with day 15 white cell count for the whole group (p=0.038). CONCLUSION: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT is modest, a subset of women had prolonged stable disease.

Phase I trial of liposomal doxorubicin and ZD1839 in patients with refractory gynecological malignancies or metastatic breast cancer.

BACKGROUND: Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer. METHODS: Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed. RESULTS: Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease. CONCLUSIONS: Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.

Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.

BACKGROUND: Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. OBJECTIVE: We have developed a standardized rapid desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. METHODS: Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. RESULTS: Of the 413 desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. CONCLUSIONS: Our standardized 12-step protocol for rapid drug desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.

Molecular Characterization of an Endometrial Endometrioid Adenocarcinoma Metastatic to a Thyroid Hürthle Cell Adenoma Showing Cancerization of Follicles.

Tumor-to-tumor metastasis is rare. Herein, we present a unique case of endometrial endometrioid adenocarcinoma metastatic to a thyroid Hürthle cell adenoma 9 years after initial diagnosis. On histologic examination of the thyroid, the malignant endometrioid glands and single cells (donor tumor) were dispersed within the Hürthle cell adenoma (recipient tumor). In several sections of the adenoma with still preserved microfollicular architecture, malignant endometrial adenocarcinoma cells were admixed within oncocytic adenomatous epithelium (so-called "cancerization of the follicles"). This unusual phenomenon, to our knowledge, is a novel finding in the thyroid gland. Immunohistochemistry, subsequently elicited clinical history, and morphologic comparison of the tumor in the thyroid to the primary endometrial tumor confirmed the origin of the donor tumor cells. Molecular analysis of both the metastatic and primary endometrial tumors demonstrated PIK3CA and PTEN mutations in both tumors, as is characteristic of well-differentiated endometrioid tumors of the endometrium. Amplification of chromosome 1q was detected in both sites; however, only the metastatic tumor showed loss of chromosomes 2, 9, and 22. The morphologic differential diagnosis of metastatic endometrioid adenocarcinoma in the thyroid includes columnar cell variant of papillary thyroid carcinoma (CCVPTC) arising in a preexisting adenoma, endocrine glandular atypia within an adenoma, and metastasis from other anatomic sites. Histomorphologic differences among these entities may be subtle; therefore, knowledge of and morphologic comparison with prior malignancies and immunohistochemistry can be helpful in rendering the correct diagnosis.

Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies.

BACKGROUND: Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patient's reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined. OBJECTIVE: We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD. METHODS: We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group. RESULTS: RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls. CONCLUSIONS: RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy.

Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer.

OBJECTIVES: Combining histone deacetylase inhibitors and chemotherapy is synergistic. This phase I study combined escalating vorinostat doses with constant doses of carboplatin and gemcitabine for the treatment of recurrent platinum-sensitive ovarian cancer. The objectives of this study were to determine the maximally tolerated dose of this combination; secondary objectives included preliminary response rate of this regimen and toxicity profile. METHODS: Fifteen patients with relapsed ovarian cancer were enrolled into this phase I study. Doses of carboplatin and gemcitabine were AUC 4 on day 1 and 1000 mg/m(2) on days 1 and 8, respectively; cycles were administered every 21 days. Vorinostat was tested using four different schedules. The first dose level (DL A) tested vorinostat as daily oral dosing from days 1 to 14. DL B tested twice daily (BID) vorinostat dosing on days 1-3 and 8-10. DL C tested BID vorinostat dosing on days 1, 2, 8, and 9, starting vorinostat 1 day prior to initiation of carboplatin and gemcitabine, and DL D tested vorinostat on days 1 and 2 with chemotherapy starting on day 2. RESULTS: All four DLs tested resulted in dose-limiting toxicities, and no MTD was determined. Toxicities were mostly hematologic. Seven patients were evaluable for RECIST assessment, and six of them had partial responses (PR) via RECIST. CONCLUSIONS: Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early.

Radiation dose escalation using intensity modulated radiation therapy for gross unresected node-positive endometrial cancer.

PURPOSE: To determine rates of nodal control and survival in patients with endometrial cancer treated with intensity modulated radiation therapy (IMRT) with dose escalation to unresected nodal disease. METHODS AND MATERIALS: Between November 2005 and April 2011, 22 endometrial-cancer patients received IMRT with dose escalation to gross nodal disease with curative intent. Twelve were treated for recurrent disease (RD) and 10 in the primary setting, of whom 5 had a hysterectomy. The boost area included pelvic nodes in 9 patients (41%), paraaortic nodes (PAN) in 6 (27%) and both pelvic and PAN in 7 (32%). The median gross nodal dose was 63 Gy (range, 55-65). Rates of local control, disease-free survival (DFS) and overall survival (OS) were determined using the Kaplan-Meier method. RESULTS: Median follow-up time was 37.6 months (range, 10-88). Median nodal size was 2.25 cm (range, 1-6.9). The median time to first relapse after IMRT was 12 months (range, 6-49). Relapses occurred in 5/12 RD (42%), 1/5 hysterectomy (20%), and 5/5 inoperable cases. Nodal relapses occurred in-field in 3/12 RD and 1/5 hysterectomy patients. At 3 years, nodal control was 86%, DFS was 58% and OS was 68%. Three patients experienced grade 3 late hematologic toxicity (anemia). No late grade ≥3 gastrointestinal or genitourinary toxicity occurred. CONCLUSIONS: In endometrial cancer, the use of IMRT for dose escalation to gross nodal disease is feasible with acceptable rates of toxicity. Patients with nodal recurrence or unresectable nodal disease after a hysterectomy may benefit from radiation dose escalation.

Typical and atypical metastatic sites of recurrent endometrial carcinoma.

The purpose of this article is to illustrate the imaging findings of typical and atypical metastatic sites of recurrent endometrial carcinoma. Typical sites include local pelvic recurrence, pelvic and para-aortic nodes, peritoneum, and lungs. Atypical sites include extra-abdominal lymph nodes, liver, adrenals, brain, bones and soft tissue. It is important for radiologists to recognize the typical and atypical sites of metastases in patients with recurrent endometrial carcinoma to facilitate earlier diagnosis and treatment.

Safety, Efficacy, and Biomarker Exploration in a Phase II Study of Bevacizumab, Oxaliplatin, and Gemcitabine in Recurrent Müllerian Carcinoma.

OBJECTIVE: To explore the safety, efficacy, and biomarkers of bevacizumab with gemcitabine and oxaliplatin in women with recurrent platinum-sensitive ovarian carcinoma. METHODS: The patients received bevacizumab (10 mg/kg), gemcitabine (1000 mg/m(2)), and oxaliplatin (65 mg/m(2)) on days 1 and 15 in 28-day cycles. The patients with safely accessible tumor underwent intratumoral fluid pressure (IFP) measurements and positron-emission tomographies immediately and 2 weeks after treatment. Blood biomarkers were evaluated at 5 time points. RESULTS: The trial was closed after enrolling 19 of the 53 projected patient accrual. Thirteen (68.5%) of 19 patients showed a response (1 complete response, 12 partial responses), and 6 patients showed stable disease (31.6%). Median progressive-free survival was 36.9 weeks (258.3 days), and the median overall survival was 112.3 weeks (633 days, not reached). Toxicity was acceptable, and there were no arterial thromboses, serious bleeding, gastrointestinal perforations, or complications from the invasive procedures. Bevacizumab with chemotherapy induced a substantial drop in tumor IFP after treatment. The regimen induced sustained elevation in circulating plasma vascular endothelial growth factor (VEGF), placental growth factor (PlGF), basic fibroblast growth factor (bFGF), soluable vascular endothelial growth factor receptor 2 (sVEGFR2), and circulating progenitor cells. Plasma PlGF, VEGFR2(+) monocytes, and urinary matrix metalloproteinase 2 activity showed differential associations with treatment outcome when evaluated at baseline and after 14 days of treatment. CONCLUSIONS: Despite early termination of the study, the results indicate that the regimen was well tolerated and demonstrated activity in platinum-sensitive ovarian cancer. Biomarker evaluations showed that bevacizumab with chemotherapy significantly changed the levels of several circulating cellular and molecular biomarkers. The increases in plasma PlGF and VEGFR2(+) monocytes showed correlations with outcome. These exploratory data should be further evaluated in future studies of bevacizumab in ovarian cancer.

Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor.

BACKGROUND AND OBJECTIVES: Hypertension and proteinuria are common but poorly understood renal toxicities of vascular endothelial growth factor (VEGF) receptor signaling pathway inhibitors. In this phase II study of cediranib (AZD2171) for recurrent epithelial ovarian cancer, the time course and severity of BP changes and proteinuria were characterized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 46 women ages 41 to 77 years were treated with cediranib. 26% had baseline hypertension. Twice-daily BP was recorded. Urinalyses were performed every 2 weeks, and in some patients proteinuria was further quantified. RESULTS: 31 women (67%) developed hypertension by day 3; 87% by the end of the study. 43% developed grade > or =3 hypertension. Mean systolic BP increase over 3 days was 18 mmHg. Women above the mean age (> or =57 years) had a larger rise in systolic BP by day 3 (15.9 versus 7.0 mmHg). 14 women developed proteinuria. There was a dose response (45 versus 30 mg daily). Proteinuria also developed rapidly, with 7 of 14 women developing proteinuria within 2 weeks. Only 7 of 20 women who developed grade 3 hypertension developed proteinuria. CONCLUSIONS: Cediranib induced a rapid but variable rise in BP within 3 days of initiation in most patients. Proteinuria was common and also developed rapidly. The rapid development of hypertension suggests that acute inhibition of VEGF-dependent vasodilation might explain the BP rise with VEGF inhibitors. Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients.