Allan Covens

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.

Pregnancy outcomes in patients after radical trachelectomy.

OBJECTIVES This study was undertaken to review and analyze the fertility and pregnancy outcomes in patients who have undergone radical trachelectomy as the method of management of invasive carcinoma of the cervix. STUDY DESIGN All preoperative, operative, and follow-up data were collected prospectively. Perinatal information was completed by chart reviews and patient questionnaires. RESULTS Of 80 patients having undergone the above procedure, 39 have attempted to conceive for a median of 11 months (range 1-85). There have been a total of 22 pregnancies in 18 patients (4 patients pregnant twice). Of the 22 pregnancies, 18 were viable, with 12 progressing to term and delivering by caesarean section. Preterm premature rupture of membranes was the primary cause of preterm delivery. CONCLUSION This series confirms that pregnancy is a safe and realistic outcome for women undergoing radical trachelectomy for invasive carcinoma of the cervix. Given the apparently high incidence of preterm premature rupture of membranes, these pregnancies should be managed as high risk.

Surgery Insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer

Over the past decade, the treatment of cervical cancer has evolved with an increased emphasis on preservation of fertility. There has been a gradual abandonment of radical surgical procedures in favor of more conservative techniques in an effort to decrease morbidity and preserve fertility without compromising overall survival. Radical vaginal trachelectomy (RVT) with laparoscopic pelvic lymphadenectomy is a fertility-preserving procedure that has recently gained worldwide acceptance as a method of surgically treating small invasive cancers of the cervix. Since the original description of RVT by Daniel Dargent in 1994, over 500 cases of utilization of this technique have been reported in the literature, with over 100 live births reported following this procedure. The morbidity associated with RVT is low, with a tumor recurrence rate of 5% and a mortality rate of 3%. The current literature indicates no difference in the rate of recurrence with this technique compared with radical hysterectomy when proper selection criteria are used. Combining RVT with laparoscopic sentinel lymph-node biopsy can further reduce the duration, extent, and complications of surgery.

Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systematic review with metaanalyses.

Because women with advanced ovarian cancer have poor outcomes, it is imperative to continue exploring for novel therapies. The opportunity for intraperitoneal treatment, especially in the subgroup of patients with minimal residual disease, in which the intraperitoneal approach may have a biologic rationale for benefit over and above the standard intravenous route, needs to be explored to the fullest extent. The MEDLINE, EMBASE, and Cochrane Library databases were searched up to January 2006 for randomized trials that compared first‐line intraperitoneal‐containing chemotherapy with first‐line intravenous chemotherapy in the treatment of women with stage III epithelial ovarian cancer. Seven randomized, controlled trials were identified, including 3 large Phase III trials and 4 smaller randomized trials. The 3 large Phase III trials detected statistically significant overall survival benefits with intraperitoneal cisplatin‐containing chemotherapy compared with intravenous chemotherapy alone. The improvements in survival were 8 months, 11 months, and 16 months, respectively. Pooled analysis from 6 of the 7 randomized trials confirmed the survival effect with intraperitoneal chemotherapy compared with intravenous chemotherapy alone (relative risk, 0.88; 95% confidence interval, 0.81–0.95). Severe adverse events and catheter‐related complications with intraperitoneal chemotherapy were significantly more common and often were dose‐limiting. The results from this review indicated that cisplatin‐containing intraperitoneal chemotherapy should be offered to patients on the basis of significant improvements in overall survival. The appropriate clinical and institutional multidisciplinary facilities are needed for the safe delivery of this treatment in optimally debulked patients. Further research is needed concerning specific aspects of the treatment, such as optimal agent, dose, and scheduling. Cancer 2007;109:692–702.

Sentinel lymph node biopsy vs. pelvic lymphadenectomy in early stage cervical cancer: Is it time to change the gold standard?

OBJECTIVE To compare the incidence of pelvic lymph node metastases in early stage cervical cancer patients undergoing sentinel lymph node biopsy (SLN) to a matched cohort undergoing pelvic lymphadenectomy. METHODS All patient data were entered prospectively into an ongoing cervical cancer database. Since April 2004, 87 patients with FIGO stage IA/B1 cervical cancer underwent SLN detection with identification of bilateral SLN. This cohort (cases) was compared to a matched group of patients who underwent complete pelvic lymphadenectomy (controls). The groups were matched 3:1 for tumour size (+/-5 mm), histology, depth of invasion (+/-2 mm), and presence of capillary lymphatic space invasion (CLS). Descriptive statistics were calculated for all variables of interest. The association between cases and controls and lymph node metastases was carried out using a conditional logistic regression analysis. RESULTS 81 women in the SLN cohort were matched with 1 control, 72 cases with 2 controls, and 65 cases with 3 controls. Among cases, 14 (17%) had pelvic lymph nodes metastases vs. 15 (7%) in the controls (p=0.0059, odds ratio= 2.8, 95% CI=1.3-5.9). Among the 14 cases of SLN metastases, 11 were detected by frozen section and 3 were detected on final paraffin sectioning. All were detected by H and E stains. The size of the SLN metastases ranged from less than 1 mm to 8 mm. CONCLUSIONS Sentinel lymph node biopsy in early cervical cancer is a more sensitive procedure in detecting pelvic lymph node metastases compared to complete lymphadenectomy.

Phase III Trial of Weekly Methotrexate or Pulsed Dactinomycin for Low-Risk Gestational Trophoblastic Neoplasia: A Gynecologic Oncology Group Study

PURPOSE There is no consensus on the best regimen for the primary treatment of low-risk gestational trophoblastic neoplasia (GTN). PATIENTS AND METHODS Two commonly used single-drug regimens were compared with respect to the proportion of patients meeting the criteria for a complete response (CR) in a randomized phase III trial conducted by the Gynecologic Oncology Group. Eligibility was purposefully broad to maximize the generalizability of the results and included patients with a WHO risk score of 0 to 6 and patients with metastatic disease (limited to lung lesions < 2 cm, adnexa, or vagina) or choriocarcinoma. RESULTS Two hundred forty women were enrolled, and 216 were deemed eligible. Biweekly intravenous dactinomycin 1.25 mg/m² was statistically superior to weekly intramuscular (IM) methotrexate 30 mg/m² (CR: 70% v 53%; P = .01). Similarly, in patients with low-risk GTN as defined before the 2002 WHO risk score revisions (risk score of 0 to 4 and excluding choriocarcinoma), response was 58% and 73% in the methotrexate and dactinomycin arms, respectively (P = .03). Both regimens were less effective if the WHO risk score was 5 or 6 or if the diagnosis was choriocarcinoma (CR: 9% and 42%, respectively). There were two potential recurrences; one at 4 months (dactinomycin) and one at 22 months (methotrexate). Not all patients completed follow-up. Both regimens were well tolerated. CONCLUSION The biweekly dactinomycin regimen has a higher CR rate than the weekly IM methotrexate regimen in low-risk GTN, a generally curable disease.

Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: A matched case-control study

OBJECTIVE To determine the efficacy and outcome from radical vaginal trachelectomy (RVT) compared to a matched group of patients undergoing radical hysterectomy for small early stage cervical cancer. METHODS All patient data were entered prospectively. Patients wishing preservation of fertility with cervical cancer, tumor <2 cm, and not meeting the definition of microinvasive cancer were offered RVT. The outcomes were compared to a matched group of patients who underwent radical hysterectomy for stage IA/IB cervical cancer. Groups were matched 1:1 for age (+/-5 years), tumor size (+/-1 mm), histology, grade, depth of invasion (+/-1 mm), presence of capillary lymphatic space invasion, pelvic lymph node metastasis, and adjuvant radiotherapy. RESULTS A total of 137 patients underwent RVT between 1994 and 2007. Of them, 90 patients were successfully matched. Median tumor size was microscopic. Moreover, 43% and 49% were squamous and had adeno/adenosquamous histology. Median depth of invasion was 3.1 mm. Capillary lymphatic space invasion was present in 68% of cases. Of the tumors, 60% were grade 1, 29% were grade 2, and 11% were grade 3. After a median follow-up of 51 and 58 months, 5 and 1 recurrences were diagnosed in the RVT and radical hysterectomy groups, respectively. Five-year recurrence-free survival rates were present in 95% and 100% of the groups, respectively (p=0.17). In addition, 3 and 1 deaths occurred in the RVT and radical hysterectomy groups, resulting in 5-year survival rates of 99% and 100%, respectively (p=0.55). CONCLUSIONS RVT seems to be the procedure of choice for women with small early stage cervical cancers wishing to preserve fertility.

Sentinel lymph node in vulvar cancer

The aim of the study was to assess the feasibility, efficacy, and accuracy of the sentinel lymph node (SLN) procedure in vulvar cancer.

Adenomyosis is associated with myometrial invasion by FIGO 1 endometrial adenocarcinoma

Summary: Adenomyosis is commonly seen in hysterectomy specimens for endometrial adenocarcinoma where it could be involved with the tumor. When adenocarcinoma involves adenomyosis, the tumor may remain limited to the adenomyosis or proceeds to invade the adjacent myometrium. The purpose of this study was to investigate whether the risk of myometrial invasion by grade 1 endometrioid adenocarcinoma in cases with cancer-positive adenomyosis is different from that of cases where cancer occurs in the absence of adenomyosis. Forty-six consecutive hysterectomy specimens with International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrial endometrioid adenocarcinoma involving adenomyosis and 49 consecutive specimens with the same tumor occurring in the absence of adenomyosis were retrospectively studied by 4 experienced gynecologic pathologists. In cases with adenomyosis, myometrial invasion was confirmed by CD10-negative staining around glands with irregular outline surrounded by inflamed desmoplastic stroma. Myometrial invasion was found in significantly more adenomyosis cases (n = 42, 91.3%) than in cases without adenomyosis (n = 38, 77.5%) (&khgr;2 = 4.79, P = 0.03). In 16 cases of the former group, the invasion only occurred from the foci of adenomyosis. Although myometrial invasion in the outer half was more common in the adenomyosis group (n = 16, 34.8%) than in cases without adenomyosis (n = 9, 18.4%), the difference was not statistically significant (&khgr;2 = 3.29, P = 0.07). By involving coexistent adenomyosis, FIGO grade 1 endometrial endometrioid adenocarcinoma is associated with myometrial invasion, probably through increasing the surface area of its interface with the adjacent myometrium. When compared with their counterparts that occur in the absence of adenomyosis, these tumors are significantly more likely to invade the myometrium.

Histopathologic score predicts recurrence free survival after radical surgery in patients with stage IA2–IB1–2 cervical carcinoma

The authors evaluated clinical and pathologic factors that predicted for recurrence after patients underwent radical surgery for International Federation of Gynecology and Obstetrics (FIGO) Stage IA2–IB1–2 cervical carcinoma and developed a simple method of scoring those predictive factors to quantify outcome.