Mario M. Leitao

Improved Survival with Bevacizumab in Advanced Cervical Cancer

BACKGROUND Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).

Endometrial cancer: A review and current management strategies: Part I

Endometrial carcinoma is the most common gynecologic malignancy. A thorough understanding of the epidemiology, pathophysiology, and management strategies for this cancer allows the obstetrician-gynecologist to identify women at increased risk, contribute toward risk reduction, and facilitate early diagnosis. The Society of Gynecologic Oncologys Clinical Practice Committee has reviewed the literature and created evidence-based practice recommendations for diagnosis and treatment. This article examines: • Risk factors, including genetic predisposition • Diagnostic and metastatic evaluation • Surgical management of early and advanced cancer, including lymphadenectomy in early cancer.

An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy (NACT)

OBJECTIVE The recent EORTC-NCIC randomized trial comparing primary debulking surgery (PDS) to neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian carcinoma (EOC) reported a median progression-free survival (PFS) of 12 months and overall survival (OS) of 30 months for both arms. Due to the equivalent survival and decreased morbidity with NACT, many now consider it the preferred approach. We analyzed the outcomes of patients treated with PDS at our institution during the same time period in which the EORTC-NCIC trial was conducted, using identical inclusion criteria. METHODS We identified all patients undergoing primary treatment for advanced EOC at our institution from 9/98-12/06. Study inclusion and exclusion criteria were identical to those of the EORTC-NCIC trial. Standard statistical tests were used. RESULTS Of 316 eligible patients, 285 (90%) underwent PDS and 31 (10%) received NACT due to extra-abdominal disease, medical comorbidities, and/or advanced age (>85 years). Of the 285 patients who underwent PDS, most had carcinoma of ovarian origin (248, 87%); stage IIIC disease (249, 87%); grade 3 tumors (237, 83%); and serous histology (249, 87%). Optimal cytoreduction (≤1 cm residual) was achieved in 203 patients (71%). Postoperative platinum-based chemotherapy was given to 281 of 285 patients (99%). The median PFS and OS were 17 and 50 months, respectively. CONCLUSION PDS should continue to be the preferred initial management for patients with bulky stages IIIC-IV ovarian carcinoma. NACT should be reserved for those who cannot tolerate PDS and/or for whom optimal cytoreduction is not feasible.

Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women With Squamous Cell Carcinoma of the Vulva: A Gynecologic Oncology Group Study

PURPOSE To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer. PATIENTS AND METHODS Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed. RESULTS In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%). CONCLUSION Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.

Oncologic outcome of fertility-sparing radical trachelectomy versus radical hysterectomy for stage IB1 cervical carcinoma.

OBJECTIVE To compare the oncologic outcomes of women who underwent a fertility-sparing radical trachelectomy (RT) to those who underwent a radical hysterectomy (RH) for stage IB1 cervical carcinoma. METHODS We performed a case-control study of all patients with stage IB1 cervical carcinoma who underwent a vaginal or abdominal RT between 11/01 and 6/07. The control group consisted of patients with stage IB1 disease who underwent an RH between 11/91 and 6/07 and who would be considered candidates for fertility-sparing surgery. Information was extracted from a prospectively acquired database. Recurrence-free and disease-specific survival (RFS and DSS) were estimated using Kaplan-Meier estimates and compared with the log-rank test where indicated. Multivariate analysis was performed using the Cox regression method. RESULTS Forty stage IB1 patients underwent an RT and 110 patients underwent an RH. There were no statistical differences between the two groups for the following prognostic variables: histology, median number of lymph nodes removed, node positive rate, lymph-vascular space involvement (LVSI), or deep stromal invasion (DSI). The median follow-up for the entire group was 44 months. The 5-year RFS rate was 96% (for the RT group compared to 86% for the RH group (P=NS). On multivariate analysis in this group of stage IB1 lesions, tumor size <2 cm was not an independent predictor of outcome, but both LVSI and DSI retained independent predictive value (P=0.033 and 0.005, respectively). CONCLUSION For selected patients with stage IB1 cervical cancer, fertility-sparing radical trachelectomy appears to have a similar oncologic outcome to radical hysterectomy. LVSI and DSI appear to be more valuable predictors of outcome than tumor diameter in this subgroup of patients.

Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities.

Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a high risk for endometrial cancer (EC) and frequently present with a gynecologic cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumors. The revised Bethesda Guidelines provide screening criteria for HNPCC in colorectal cancers. However, there are currently no such screening recommendations for women with endometrial carcinoma. We applied some of the colorectal cancer screening criteria, including age and tumor morphology, to endometrial endometrioid carcinoma. The purpose of this study was to describe patient and tumor characteristics and to assess the ability of these criteria to enhance detection of mismatch repair (MMR) deficiency, and hence HNPCC in EC. Immunohistochemistry (IHC) for DNA mismatch repair (IHC-MMR) proteins was performed in a defined subset of patients with EC. This included women younger than 50 years of age and women ≥50 years whose tumors showed morphologic features suggestive of MMR deficiency (TM-MMR). The extent of IHC-MMR in the older patient group was compared with that in a comparison group of EC ≥50 years that was previously analyzed for microsatellite instability status. Seventy-one patients met the selection criteria for IHC testing; 32 (45%) showed abnormal results. The rate of IHC abnormality in the younger group was approximately 30% with a nearly equal distribution of MLH1/PMS2 and MSH2/MSH6 abnormalities. In the older age group, TM-MMR triggered IHC analysis in 31 of 34 cases. Of these, 18 cases showed loss of IHC-MMR (58% of cases), 7 with loss of MSH2/MSH6. In contrast, the rate of microsatellite instability in the comparison group was only 21%. The IHC abnormal group showed more frequent tumor infiltrating lymphocytes, dedifferentiated EC, more tumors centered in the lower uterine segment, and more frequent synchronous clear cell carcinomas of the ovary than tumors with a normal immunophenotype. Although many of the patients with loss of IHC-MMR showed personal and/or family history (13 of 32) of HNPCC-associated tumors, most did not. Tumor morphology (TM-MMR) along with IHC-MMR enhances the detection of EC patients at risk of HNPCC.

Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus

OBJECTIVE The purpose of this study was to determine the incidence of lymph node and ovarian metastases in newly diagnosed uterine leiomyosarcoma (LMS), and to describe possible predictive factors. METHODS We used our prospectively acquired databases to identify 275 consecutive patients with uterine LMS treated from 7/82 to 12/01. Patients were included if there was clear documentation of lymph nodes and/or ovarian tissue in the pathologic reports. Clinical data were extracted from electronic medical records. Statistical analysis using the Fisher exact test was used to determine prognostic factors. RESULTS There were 108 patients (39.2%) identified in whom an oophorectomy and 37 patients (13.5%) in whom lymph node sampling was performed as part of the initial surgical management of uterine LMS. Bilateral oophorectomy was performed in 102 (94.4%) of the 108 patients. The median numbers of pelvic, para-aortic, and total lymph nodes acquired were 5 (range, 1-27), 3 (range, 1-9), and 6 (range, 1-34), respectively. Ovarian metastases were found in 4 (3.9%) out of 108 patients. Two (2.8%) of the 71 patients with disease confined to the uterus and/or cervix (stage I/II) and 2 (5.4%) of the 37 patients with gross extrauterine disease had ovarian metastases (P = 0.43). Positive lymph nodes were seen in 3 (8.1%) of 37 patients. No patients with stage I/II disease had positive lymph nodes (P = 0.015). None of the factors analyzed predicted for metastases to the ovary. Only the presence or absence of gross extrauterine disease correlated with lymph node metastasis. In addition, all three of these cases had clinically suspicious (enlarged) lymph nodes. CONCLUSIONS The incidence of ovarian and lymph node metastases in uterine LMS is very low and is most commonly associated with extrauterine disease. Lymph node dissection for uterine LMS should be reserved for patients with clinically suspicious nodes.

Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes

OBJECTIVE To compare the incidence of metastatic cancer cells in sentinel lymph nodes (SLN) vs. non-sentinel nodes in patients who had lymphatic mapping for endometrial cancer and to determine the contribution of metastases detected on ultrastaging to the overall nodal metastasis rate. METHODS All patients who underwent lymphatic mapping for endometrial cancer were reviewed. Cervical injection of blue dye was used in all cases. Sentinel nodes were examined by routine hematoxylin and eosin (H&E), and if negative, by standardized institutional pathology protocol that included additional sections and immunohistochemistry (IHC). RESULTS Between 09/2005 and 03/2010, 266 patients with endometrial cancer underwent lymphatic mapping. Sentinel node identification was successful in 223 (84%) cases. Positive nodes were diagnosed in 32/266 (12%) patients. Of those, 8/266 patients (3%) had the metastasis detected only by additional section or IHC as part of SLN ultrastaging. Excluding the 8 cases with positive SLN on ultrastaging only, 24/801 (2.99%) SLN and 30/2698 (1.11%) non-SLN were positive for metastatic disease (p=0.0003). CONCLUSION Using a cervical injection for mapping, metastatic cells from endometrial cancer are three times as likely to be detected in SLN than in the non-sentinel nodes. This finding strongly supports the concept of lymphatic mapping in endometrial cancer to fine tune the nodal dissection topography. By adding SLN mapping to our current surgical staging procedures we may increase the likelihood of detecting metastatic cancer cells in regional lymph nodes. An additional benefit of incorporating pathologic ultrastaging of SLN is the detection of micrometastasis, which may be the only evidence of extrauterine spread.

The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes

OBJECTIVE To describe the incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes. METHODS Using a prospectively maintained database we identified all cases of endometrial cancer that had both pelvic and aortic nodal dissection and determined the rate of isolated paraaortic nodal metastasis in the setting of negative pelvic nodes. For this report a satisfactory pelvic node dissection meant the identification of 8 or more pelvic nodes on final pathology. RESULTS 1942 endometrial cancer patients were surgically treated at our institution from 1/93 to 1/08. 847 had both pelvic and paraaortic nodes removed during surgery and identified by pathology. 734 had negative pelvic nodes with at least one paraaortic node identified. Only 12 (1.6%) had positive paraaortic nodes with negative pelvic nodes. Seven (1%) of 640 cases with 8 or more negative pelvic nodes had positive paraaortic nodes. Final grade for these cases included: G1 (2), G2 (2), G3 (1), papillary serous (1), and undifferentiated (1). Of the 570 cases with a final diagnosis of grade 1 endometrial cancer, 187 had both pelvic and aortic node dissection during the same operation, and 2/187 (1%) had a positive paraaortic node with negative pelvic nodes. CONCLUSIONS Isolated paraaortic nodal metastasis in the setting of negative pelvic nodes occurs in approximately 1% of surgically staged endometrial cancer cases. This low rate seems consistent for low- and high-grade lesions. Future studies looking at the incidence of isolated paraaortic nodal metastasis in the setting of negative sentinel pelvic nodes are warranted.

Stage-Specific Outcomes of Patients With Uterine Leiomyosarcoma: A Comparison of the International Federation of Gynecology and Obstetrics and American Joint Committee on Cancer Staging Systems

PURPOSE Uterine leiomyosarcoma (LMS) is staged by the modified International Federation of Gynecology and Obstetrics (FIGO) staging system for uterine cancer. We aimed to determine whether the American Joint Committee on Cancer (AJCC) soft tissue sarcoma (STS) staging system is more accurate in predicting progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS Patients with uterine LMS who presented at our institution from 1982 to 2005 were staged retrospectively according to a modified FIGO staging system and the AJCC STS staging system. The predictive accuracy of the two staging systems was compared using concordance estimation. RESULTS Two hundred nineteen patients had sufficient clinical and pathologic information to be staged under both systems; 132 patients were upstaged using the AJCC staging system, whereas only four were downstaged. Stage-specific PFS and OS rates for stages I, II, and III differed substantially between the two staging systems. In both systems, there was prognostic overlap between stages II and III. Thus, despite the marked stage-specific differences in 5-year PFS and OS rates for stages I, II, and III, both systems had similar concordance indices. CONCLUSION Estimates of stage-specific PFS and OS for uterine LMS were altered substantially when using the AJCC versus FIGO staging system. Adjuvant treatment strategies should be tested in patients at substantial risk for disease progression and death. Neither the FIGO nor AJCC staging system is ideal for identifying such patients, suggesting a need for a uterine LMS-specific staging system to better target patients for trials of adjuvant therapies.