John V. Brown

Randomized, Double-Blind, Placebo-Controlled Phase II Study of AMG 386 Combined With Weekly Paclitaxel in Patients With Recurrent Ovarian Cancer

PURPOSE To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. PATIENTS AND METHODS Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. RESULTS One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarones test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. CONCLUSION AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

Phase II study of CT-2103 in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

PURPOSE To evaluate the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-L-glutamic acid, in heavily pretreated patients with recurrent ovarian, fallopian tube, or peritoneal cancer. PATIENTS AND METHODS Ninety-nine patients with measurable disease received intravenous CT-2103 at 175 mg/m2 of conjugated paclitaxel over 10 minutes every 3 weeks without routine premedications. Platinum-sensitive (n = 42) and platinum-refractory or platinum-resistant patients (n = 57) were enrolled. Thirty-nine patients (39%) had received one or two prior regimens, and 60 patients (61%) had received between three and 12 regimens. RESULTS In 99 patients, the median number of cycles was three (range, one to 14 cycles). The response rate (RR) for all patients was 10% (10 of 99 patients), with median time to disease progression (TTP) of 2 months. The RR (partial response) in platinum-sensitive and platinum-resistant patients was 14% (six of 42 patients) and 7% (four of 57 patients), respectively. In patients with only one or two prior regimens, the RR in platinum-sensitive and platinum-resistant patients was 28% (five of 18 patients) and 10% (two of 21 patients), with a median TTP of 4 and 2 months, respectively. Grade 2 (15 patients) or 3 (15 patients) neuropathy was reported in 30 patients (30%). Grade 2 hypersensitivity occurred in eight patients (8%) who were subsequently treated with premedications; one patient had grade 3 hypersensitivity and was removed. Grade 2 alopecia was absent. CONCLUSION CT-2103 is active in patients with recurrent ovarian cancer. Neurotoxicity in these heavily pretreated patients was more frequent than predicted from phase I trials. Further study to define toxicity and efficacy in patients with less prior therapy is ongoing.

Three-consecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer☆

OBJECTIVE The aim was to determine the response rate and toxicity of topotecan administered Days 1-3 every 21 days for recurrent epithelial cancers of the ovary, peritoneum, or fallopian tube. A 3-day regimen may be more convenient and less expensive than a 5-day schedule. METHODS Patients with recurrent epithelial cancer of the ovary, peritoneum, or fallopian tube who had adequate hepatic, renal, and hematologic function were eligible for participation. Topotecan (2 mg/m(2)) was administered for 3 consecutive days every 21 days. Response was measured clinically and serologically. Granulocyte colony stimulating factors (GCSF) were not utilized prophylactically, but could be added under specific conditions. RESULTS Thirty-one patients with recurrent ovarian cancer whose median age was 63 (range 32-84) received 165 cycles of topotecan (median = 6; range 2-8) and are evaluable for toxicity. The median number of prior regimens was 1. Topotecan was administered on schedule in 96.6% of cycles. Grade 3/4 neutropenia was seen in 29.1 and 23.6% of courses, respectively; but only 3.4% of cycles required GCSF support (6 cycles for 2 patients). Grade 4 thrombocytopenia was rare (1% of cycles). Nonhematologic toxicity was mild. The response rate for 28 evaluable patients was 32.1% (10.7% complete response (CR) and 21.4% partial response (PR)); stable disease was seen in 17.9% of patients. The median progression-free interval (PFI) for all patients was 15.5 weeks (range 5-40). Eighteen platinum-sensitive patients demonstrated a 43.4% response rate (12.5% CR and 31.3% PR); stable disease was documented in 18.8%. The median PFI for platinum-sensitive patients was 18.5 weeks (range 5-40). CONCLUSION Topotecan is an effective regimen with acceptable toxicity for recurrent ovarian cancer when administered for 3 consecutive days (2 mg/m(2)) every 21 days. It can be delivered on schedule without GCSF support in the vast majority of patients.

Survival rate comparisons amongst cervical cancer patients treated with an open, robotic-assisted or laparoscopic radical hysterectomy: A five year experience.

BACKGROUND The purpose of this retrospective study was to assess the 5-year survival outcomes of cervical cancer patients who underwent an, open radical hysterectomy (ORH), robotic-assisted radical hysterectomy (RRH) or laparoscopic radical hysterectomy (LRH) for the treatment of their disease. METHOD We conducted a review of all cervical cancer patients who were managed with an ORH, RRH or LRH. RESULT Forty-nine patients were treated with LRH, 58 were managed via RRH and 39 patients underwent an ORH. The LRH (1.78 h) patients had a significantly shorter operative duration than the RRH (2.88 h) and ORH (2.39 h) subjects (p < 0.001). Blood loss was the highest in the ORH (475 cc) group (RRH = 207 cc and LRH = 312 cc) (P < 0.001). Moreover, the ORH (5.04 days) patients had a significantly longer hospital stay than the LRH (2.95 days) and RRH (2.50 day) subjects (P < 0.001). Kaplan-Meier survival analysis revealed a progression free survival (PFS) rate of 84.6% for the ORH group, 89.8% for the LRH group and 89.7% for the RRH patients (P = 0.271) at 60 months; overall survival was 92.3% for the ORH group, 95.9% for the LRH group and 96.6% for the RRH patients (P = 0.80). CONCLUSION The results from this study suggest that, irrespective of operative approach, patients who underwent a radical hysterectomy for early stage cervical cancer attained similar 5-year disease free and overall survival outcomes.

Contemporary diagnosis and management of a uterine arteriovenous malformation.

BACKGROUND: Uterine arteriovenous malformations (AVMs) are extremely rare and can result in severe complications. Experience with diagnosis and management of these vascular malformations is very limited. CASE: We report on a patient with a history of nonmetastatic gestational trophoblastic disease. The patient developed a concomitant 4.4-cm intrauterine mass, suggestive of a molar pregnancy, during her second pregnancy. Despite suction and sharp curettage, the mass and menorrhagia persisted. After complex diagnostic imaging, the diagnosis of a uterine AVM was made. Subsequently, the patient underwent uterine arterial embolization and laparoscopic surgery to resect the mass. CONCLUSION: Because uterine AVMs are infrequently encountered, they initially may not be included in the differential diagnosis. The use of contemporary imaging, interventional radiology, and surgery can optimize patient outcome.

A Retrospective Review of the GelPort System in Single-Port Access Pelvic Surgery

STUDY OBJECTIVE Since the advent of single-port access surgery, novel instruments have been developed to facilitate this laparoscopic approach. The GelPort system is an innovative sealing device that permits abdominal access and frequent instrument exchange during surgery while preserving the pneumoperitoneum. The GelPort system has been previously reported in gastric, colorectal, and urologic single-port access procedures but has yet to be described during pelvic surgery. DESIGN A retrospective pilot study reviewing 19 single-port access pelvic surgeries that involved the GelPort system was undertaken. Patient and operative statistics, including diagnosis, surgery and anesthesia times, complications and length of hospital stay were evaluated (Canadian Task Force Classification II-2). RESULTS Operative time exhibited a direct association with anesthesia time (p=.001). Additionally, patient blood loss (p=.043) and anesthesia time (p=.003) were significant prognostic indicators for length of hospital stay. There were no significant patient complications or subsequent port site hernias. CONCLUSIONS The GelPort system appears to contribute favorably to single-port access surgery because the device permits circumferential access and retraction during instrumentation. Furthermore, the specialized design augments a surgeons versatility and access to complicated anatomic regions without compromising the peritoneum.

Same-Day Discharge in Clinical Stage I Endometrial Cancer Patients Treated with Total Laparoscopic Hysterectomy, Bilateral Salpingo-Oophorectomy and Bilateral Pelvic Lymphadenectomy

Objectives: The purpose of this retrospective study was to evaluate the capacity for same-day discharge in clinical stage I endometrial cancer (EC) patients treated with total laparoscopic hysterectomy (TLH), bilateral salpingo-oophorectomy (BSO) and bilateral pelvic lymph node dissection (BPLND). Methods: We retrospectively reviewed the charts of stage I EC patients who were treated with TLH, BSO and BPLND and discharged on the same day. The intra- and postoperative clinical variables (e.g., age, complications, surgery time, patient hospital stay) were evaluated in an attempt to discern which factors may predispose a patient to same-day discharge. Results: Twenty-one patients were successfully discharged on the same day of surgery. Mean operative time was 1.48 h and length of hospital stay was 6.35 h. There were no intraoperative complications or hospital readmissions. Conclusions: We present a single, institutional experience solely assessing the capacity for same-day discharge in clinical stage I EC patients treated with TLH, BSO and BPLND. Since the postoperative complication rate was minimal with no hospital readmissions, we suggest that particularly selected stage I EC patients are amenable to outpatient management.

Perivascular Epithelioid Cell Neoplasms: A Systematic Review of Prognostic Factors

Perivascular epithelioid cell tumors (PEComas) are rare, soft tissue tumors characterized by epithelioid cells with clear or eosinophilic cytoplasm and a perivascular disbursement. We compiled the treatment and follow-up results from an extensive collection of reported gynecologic PEComa cases and statistically analyzed their respective therapy modalities and corresponding patient outcomes. In the group of patients with PEComa who received surgical management alone, there was a tendency for them to exhibit a lower disease recurrence rate. Conversely, patients with PEComa who initially received surgery and chemotherapy or radiation therapy were associated with a higher disease recurrence rate (P =.024). Metastatic involvement was related to higher patient mortality rates (P =.0001), although this finding was unrelated to treatment type. Surgical management alone may suffice for nonaggressive lesions, but chemotherapy and radiotherapy appear necessary for patients who present with high-risk histologic condition or metastatic disease. Because PEComas exhibit varying biologic behavior and an ill-defined presentation, the treatment for these lesions necessitates further evaluation.

Increased incidence of severe gastrointestinal events with first-line paclitaxel, carboplatin, and vorinostat chemotherapy for advanced-stage epithelial ovarian, primary peritoneal, and fallopian tube cancer.

Objectives We sought to assess the response rate and toxicity of paclitaxel, carboplatin, andvorinostat primary induction therapy for the treatment of advanced-stage ovarian carcinoma. Methods Patients were treated with 6 cycles of weekly paclitaxel (80 mg/m2), carboplatin (6 times area under the curve), and vorinostat (200 mg) every 28 days according to an institutional review board–approved protocol. The subjects were eligible for response evaluation; in patients who achieved stable disease or better following the conclusion of primary induction chemotherapy, they were subsequently treated with a planned 12 cycles of paclitaxel (135 mg/m2) and vorinostat (400 mg) maintenance chemotherapy every 28 days. Results Eighteen patients received a combined 90 cycles (median, 6 cycles; range, 1–6 cycles) of primary induction chemotherapy. Of the 18 subjects, 7 demonstrated a complete response, and 2 subjects exhibited a partial response (a total response rate of 50.0%). Eight patients also received a combined total of 50 cycles (median, 5 cycles; range, 1–12 cycles) of consolidation therapy. Grade 3/4 neutropenia and thrombocytopenia were observed in 9 (56.3%) and 2 (12.5%) patients. One patient (6.3%) developed grade 3 anemia, and another (6.3%) manifested a grade 3 neuropathy. Remarkably, we observed a significant gastrointestinal event (eg, bowel anastomotic perforation) in 3 patients, which effectuated the study’s closure. Conclusions Because the current study was prematurely terminated, we cannot derive a conclusive assessment regarding the efficacy of this treatment. Nevertheless, the high incidence of severe gastrointestinal toxicity warrants further consideration when using vorinostat in the adjuvant setting for patients who have undergone a bowel resection as part of their initial tumor debulking.

Sequential chemotherapy and radiotherapy as sandwich therapy for the treatment of high risk endometrial cancer

Objective The purpose of this retrospective study was to assess the tolerability and efficacy of sequential chemotherapy and radiotherapy for the treatment of high risk endometrial cancer. Methods We conducted a retrospective study of previously untreated high risk endometrial cancer patients who received sequential chemotherapy and radiotherapy in accordance with the sandwich approach from June 2008 until June 2011. High risk endometrial cancer patients underwent complete surgical staging followed by adjuvant therapy encompassing sequential chemotherapy, radiation therapy and consolidation chemotherapy. Results The study analysis comprised 32 endometrial cancer patients. All subjects were treated with carboplatin and paclitaxel chemotherapy; currently, 186 cycles have been administered and 94% of patients have completed the planned number of cycles. Grade 3 neutropenia developed in 1 (3.1%) patient; there was no incidence of grade 4 neutropenia. Moreover, we observed grade 3 anemia in four (12.5%) patients and grade 4 anemia in one (3.1%) patient. One (3.1%) patient developed grade 3 thrombocytopenia; grade 4 thrombocytopenia was not observed. Five patients exhibited progressive disease, three of whom have since expired; mean progression free survival and follow-up were 17.4 months and 18.9 months, respectively. Conclusion The preliminary results from our study suggest that the sandwich approach to treating high risk endometrial cancer patients is feasible. Hematologic toxicity was well tolerated and non-hematologic toxicity was mild and easily managed. Further study of this novel regimen in a larger patient population with extended follow-up is necessary.