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PURPOSE We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

The NCCN Guidelines for Uterine Neoplasms provide interdisciplinary recommendations for treating endometrial carcinoma and uterine sarcomas. These NCCN Guidelines Insights summarize the NCCN Uterine Neoplasms Panel's 2016 discussions and major guideline updates for treating uterine sarcomas. During this most recent update, the panel updated the mesenchymal tumor classification to correspond with recent updates to the WHO tumor classification system. Additionally, the panel revised its systemic therapy recommendations to reflect new data and collective clinical experience. These NCCN Guidelines Insights elaborate on the rationale behind these recent changes.

Purpose To evaluate risk factors for GI adverse events (AEs) within a phase III trial of bevacizumab in first-line ovarian cancer therapy. Patients and Methods Women with previously untreated advanced disease after surgery were randomly allocated to six cycles of platinum-taxane chemotherapy plus placebo cycles (C)2 to C22 (R1); chemotherapy plus bevacizumab C2 to C6 plus placebo C7 to C22 (R2); or chemotherapy plus bevacizumab C2 to C22 (R3). Patients were evaluated for history or on-study development of potential risk factors for GI AEs defined as grade ≥ 2 perforation, fistula, necrosis, or hemorrhage. Results Of 1,873 patients enrolled, 1,759 (94%) were evaluable, and 2.8% (50 of 1,759) experienced a GI AE: 10 of 587 (1.7%, R1), 20 of 587 (3.4%, R2), and 20 of 585 (3.4%, R3). Univariable analyses indicated that previous treatment of inflammatory bowel disease (IBD; P = .005) and small bowel resection (SBR; P = .032) or large bowel resection (LBR; P = .012) at primary surgery were significantly associated with a GI AE. The multivariable estimated relative odds of a GI AE were 13.4 (95% CI, 3.44 to 52.3; P < .001) for IBD; 2.05 (95% CI, 1.09 to 3.88; P = .026) for LBR; 1.95 (95% CI, 0.894 to 4.25; P = .093) for SBR; and 2.15 for bevacizumab exposure (aggregated 95% CI, 1.05 to 4.40; P = .036). Conclusion History of treatment for IBD, and bowel resection at primary surgery, increase the odds of GI AEs in patients receiving first-line platinum-taxane chemotherapy for advanced ovarian cancer. After accounting for these risk factors, concurrent bevacizumab doubles the odds of a GI AE, but is not appreciably increased by continuation beyond chemotherapy.

For the first time, NCCN Guidelines are available for vulvar cancer, a rare gynecologic cancer. Early-stage cancers can be managed by surgery and observation, and many of these patients can be cured. Lymph node status drives treatment and correlates with survival. Positive groinal nodes require additional therapy, including radiation plus chemotherapy, depending on stage. Sentinel lymph node biopsy is recommended in selected patients.

More than 14 million new cancer cases and 8.2 million cancer deaths are estimated to occur worldwide on an annual basis. Of these, 57% of new cancer cases and 65% of cancer deaths occur in low- and middle-income countries. Disparities in available resources for health care are enormous and staggering. The WHO estimates that the United States and Canada have 10% of the global burden of disease, 37% of the world's health workers, and more than 50% of the world's financial resources for health; by contrast, the African region has 24% of the global burden of disease, 3% of health workers, and less than 1% of the world's financial resources for health. This disparity is even more extreme with cancer. NCCN has developed a framework for stratifying the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to help health care systems in providing optimal care for patients with cancer with varying available resources. This framework is modified from a method developed by the Breast Health Global Initiative. The NCCN Framework for Resource Stratification (NCCN Framework) identifies 4 resource environments: basic resources, core resources, enhanced resources, and NCCN Guidelines, and presents the recommendations in a graphic format that always maintains the context of the NCCN Guidelines. This article describes the rationale for resource-stratified guidelines and the methodology for developing the NCCN Framework, using a portion of the NCCN Cervical Cancer Guideline as an example.

BACKGROUND: A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum-resistant ovarian, peritoneal, or fallopian tube cancer (OC). METHODS: Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m2 on days 1, 8, and 15 of a 28-day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression-free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity. RESULTS: Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment-related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0-9.4) and 16.6 months (95% CI, 12.8-22.9), with 22 (55%) patients progression-free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02). CONCLUSIONS: A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum-resistant OC; further study is warranted. Cancer 2011;. © 2011 American Cancer Society.

Primary mucinous adenocarcinomas of the ovary are uncommon, and their biological behavior is uncertain. Retrospective studies have suggested that many mucinous carcinomas initially diagnosed as primary to the ovary have in fact metastasized from another site. A prospective randomized trial provided an opportunity to estimate the frequency of mucinous tumors, diagnostic reproducibility, and clinical outcomes.A phase 3 trial enrolled 4000 women with stage III or IV ovarian carcinoma, treated by surgical staging and debulking, with randomization to one of five chemotherapeutic arms. Slides and pathology reports classified as primary mucinous carcinoma were reviewed independently by three pathologists. Cases were reclassified as primary or metastatic to the ovary according to two methods. Overall survival (OS) of reclassified groups was compared within the groups and with that of patients with serous carcinomas.Forty-four cases were classified as mucinous adenocarcinoma upon review. Using either method, only about one third were interpreted by the three reviewers as primary mucinous carcinomas. Reproducibility of interpretations among the reviewers was high, with unanimity of opinion in 30 (68%) cases. The median survival (MS) did not differ significantly between the groups interpreted as primary or metastatic, but the OS was significantly less than that for women with serous carcinoma (14 vs 42 months, P0.001).Advanced stage mucinous carcinoma of the ovary is very rare and is associated with poor OS. Many mucinous adenocarcinomas that are diagnosed as primary ovarian neoplasms appear to be metastatic to the ovary.

Purpose Vascular endothelial growth factor (VEGF) seems to be a promoter of tumor progression for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC). We conducted a phase II trial to assess the efficacy and tolerability of single-agent bevacizumab, an anti-VEGF monoclonal antibody. Patients and Methods Eligible patients had persistent or recurrent EOC/PPC after one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of at least 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 21 days until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. Results The study consisted of 62 eligible and assessable patients, median age 57 years, 41 (66.1%) having received two prior regimens and 36 (58.1%) considered platinum resistant. Grade 3 adverse events at least possibly related to bevacizumab were hematologic (1), GI (3), hypertension (6), thromboembolism (1), allergy (2), hepatic (1), pain (3), coagulation (1), constitutional (1), and dyspnea (1). Grade 4 adverse events included pulmonary embolus (1), vomiting and constipation (1), and proteinuria (1). Thirteen patients (21.0%) experienced clinical responses (two complete, 11 partial; median response duration, 10 months), and 25 (40.3%) survived progression free for at least 6 months. Median PFS and overall survival were 4.7 and 17 months, respectively. There was no significant association of prior platinum sensitivity, age, number of prior chemotherapeutic regimens, or performance status with the hazard of progression or death. Conclusion Bevacizumab seems to be well tolerated and active in the second- and third-line treatment of patients with EOC/PPC and merits phase III investigation.

Predictive factors for efficacy of bevacizumab in advanced ovarian cancer have remained elusive. We investigated ascites both as a prognostic factor and as a predictor of efficacy for bevacizumab.Using data from GOG 0218, patients receiving cytotoxic therapy plus concurrent and maintenance bevacizumab were compared to those receiving cytotoxic therapy plus placebo. The presence of ascites was determined prospectively. Chi-square and Wilcoxon-Mann-Whitney tests compared baseline variables between subgroups. Survival was estimated by Kaplan-Meier method, and Cox proportional hazard models were used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on survival.Treatment arms were balanced with respect to ascites and other prognostic factors. Overall, 886 (80%) women had ascites, 221 (20%) did not. Those with ascites were more likely to have: poorer performance status (p0.001); serous histology (p=0.012); higher baseline CA125 (p0.001); and suboptimal cytoreduction (p=0.004). In multivariate survival analysis, ascites was prognostic of poor OS (Adjusted HR 1.22, 95% CI 1.00-1.48, p=0.045), but not PFS. In predictive analysis, patients without ascites treated with bevacizumab had no significant improvement in either PFS (AHR 0.81, 95% CI 0.59-1.10, p=0.18) or OS (AHR 0.94, 95% CI 0.65-1.36, p=0.76). Patients with ascites treated with bevacizumab had significantly improved PFS (AHR 0.71, 95% CI 0.62-0.81, p0.001) and OS (AHR 0.82, 95% CI 0.70-0.96, p=0.014).Ascites in women with advanced ovarian cancer is prognostic of poor overall survival. Ascites may predict the population of women more likely to derive long-term benefit from bevacizumab.

The NCCN Guidelines for Cervical Cancer provide interdisciplinary recommendations for treating cervical cancer. These NCCN Guidelines Insights summarize the NCCN Cervical Cancer Panel's discussion and major guideline updates from 2014 and 2015. The recommended systemic therapy options for recurrent and metastatic cervical cancer were amended upon panel review of new survival data and the FDA's approval of bevacizumab for treating late-stage cervical cancer. This article outlines relevant data and provides insight into panel decisions regarding various combination regimens. Additionally, a new section was added to provide additional guidance on key principles of evaluation and surgical staging in cervical cancer. This article highlights 2 areas of active investigation and debate from this new section: sentinel lymph node mapping and fertility-sparing treatment approaches.

Objective. To determine whether tumor size or morphology is predictive of extrauterine disease and/or recurrence risk in endometrial cancer and therefore guide decisions about the necessity of complete surgical staging and adjuvant therapy. Methods. All women with surgically treated endometrial carcinoma between 1 January 1990 and 1 January 2000 were eligible. 345 patients were eligible for retrospective chart review. Univariate and multivariate logistic regression models were used to determine the predictors of nodal metastasis and recurrence. Results. As tumor size increased, the risk of nodal metastasis increased. However, a risk of nodal metastasis remained even with small lesions less than or equal to 2 cm (6.3% risk). Patients with tumor size greater than 2 cm had a 26.3% incidence of nodal metastasis. In univariate analysis, the odds ratio (OR) for tumor size as a predictor of extrauterine disease was 1.4 (95% CI 1.2–1.6). In multivariate analysis, tumor size was not statistically significant. Only the lesions greater than or equal to 8 cm confer a risk that approaches previously identified well-known predictors. Tumor size was not found to be a statistically significant predictor of recurrence OR 1.3 (1.0–1.8). Conclusions. Tumor size correlates with extrauterine disease, but it is not an independent prognostic variable. Although the risk of extrauterine disease increases with tumor size, the risk of nodal metastases remains even for those patients with very small tumors, underscoring the need for routine complete surgical staging. Tumor size does not appear to be an independent predictor of recurrence.

Objective. A non-randomized comparison of outcome in women undergoing second-look laparotomy (SLL) or clinical follow-up, after receiving six cycles of combination chemotherapy with paclitaxel plus either cisplatin or carboplatin, for optimally resected stage III ovarian cancer. Methods. Prior to chemotherapy randomization, patients chose whether or not to undergo SLL; this was a stratification factor to insure balance of treatment assignment. Any subsequent therapy was physician-directed. Explanatory analysis replaced intent-to-treat because of a higher likelihood of detecting SLL effect in the presence of noncompliance. Results. There were 393 patients (median age: 54) who Elected SLL and 399 (median age: 59) who Elected No SLL. The former group was more likely to have gross residual disease at initial surgery than the latter group (69% versus 60%, respectively). In the Elected SLL group, 59 (15%) patients subsequently refused surgery, in nine (2%) surgery was contraindicated, and 31 (8%) relapsed or died prior to the procedure. Cancer was found in 46% of 294 (75%) patients undergoing SLL. Since early failures (prior to SLL) do not address benefit, such patients (SLL: 32; No SLL: 33), defined as progression-free survival (PFS) < 6 months, were excluded from analysis. The adjusted relative risk of progression is 0.89 (95% confidence interval: 0.75, 1.07); the difference in median PFS is 1.0 month (SLL: 23.9 months; No SLL: 22.9 months). The survival rate curves are superimposable. Conclusion. In the context of a non-randomized comparison, the performance of a SLL was not associated with longer survival.

Ovarian cancer is the second most common gynecologic cancer in women and the leading cause of death caused by gynecologic malignancy. Surgery plays a fundamental role in treating this challenging disease. Goals of primary surgery for ovarian cancer are to establish diagnosis, proper staging, determination of prognosis, and optimal cytoreduction of gross disease before chemotherapy for improved outcome. In addition to standard removal of the ovaries, uterus, omentum, and pelvic and para-aortic lymph nodes for early disease, extended surgical techniques used to debulk advanced disease include bowel resection, splenectomy, partial liver resection, peritoneal or diaphragmatic stripping, and use of laser or ultrasound (CUSA). Secondary surgery is used in a variety of situations. Second-look procedures were performed historically to determine response to chemotherapy to delineate duration of treatment, but now are best used in a research setting with the advent of improved chemotherapeutic agents. As a high percentage of patients have a gynecologic malignancy recurrence after primary treatment, many practitioners perform secondary cytoreductive procedures for recurrent disease. Additionally, in the recurrent setting, surgery may be necessary for relief of bowel obstruction and palliation of symptoms. Surgical management of ovarian cancer must be performed by surgeons, such as gynecologic oncologists, who have a firm understanding of the disease process, display good clinical judgment, and are adequately trained to perform the complex surgery that commonly is required for appropriate care.

Objective The survival of cervix cancer patients is associated with their hemoglobin (Hgb) level during radiotherapy. The Southwest Oncology Group (SWOG) conducted a phase II trial to determine whether recombinant human erythropoietin (rHuEPO) safely corrects anemia during chemoradiotherapy for cervix cancer. Methods Patients had stage IIB–IVA cervix cancer and a Hgb between 8.0 and 12.5 g/dl. All patients received rHuEPO thrice weekly and oral iron starting 10–15 days before their 5-week course of whole pelvic irradiation and weekly cisplatin followed by intracavitary brachytherapy. Results Fifty-three patients from 26 institutions received the protocol treatment. The mean Hgb was 10.4 ± 1.3 g/dl on the first day of rHuEPO administration (baseline), 11.0 ± 1.6 g/dl on the first day of chemoradiotherapy, 11.6 ± 1.9 g/dl at the midpoint of chemoradiotherapy, and 11.8 ± 2.2 g/dl at the end of chemoradiotherapy. The target Hgb level of 12.5 g/dl was achieved in 40% of patients (95% CI 26–56%) by the midpoint of Chemoradiotheraphy. Change in Hgb was associated with baseline serum iron ( P = 0.008) and transferrin saturation ( P = 0.05) levels, but not with baseline Hgb or serum ferritin, or patient age. Seven patients developed deep vein thrombosis. Two-year progression-free survival (PFS) was 43% and overall survival (OS) was 51%. Survival was significantly associated with Hgb level at the end of chemoradiotherapy, but not with the baseline Hgb level. Conclusions rHuEPO and iron gradually increased Hgb levels in anemic women with local advanced cervix cancer during chemoradiotherapy. There was a higher than expected incidence of deep vein thrombosis. The progression-free and overall survival rates were lower than reported for women with normal Hgb levels.

Purpose: In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population. Patients and Methods: Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II). Results: Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02). Conclusion: In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.

Objective. Glassy cell carcinoma (GCC) of the cervix has traditionally been characterized as an aggressive histologic subtype with poor outcomes. An earlier series from our institution supported a grim prognostic outlook, demonstrating a survival rate of only 55% in women with stage I disease. We present a comparison of a contemporary series of patients with GCC. Methods. All cases of GCC treated from 1993 to 1999 identified by our tumor registry were reviewed for a variety of clinicopathologic features, treatment strategies, and outcome. Results. A total of 403 cases of invasive cancer of the cervix were identified. There were 22 patients with histologically confirmed GCC, representing only 5.4% of all cervical cancer diagnoses. Patients with GCC had an overall survival of 73% (16/22) and a disease-free survival of 64% (14/22). The incidence of stage I lesions was 64% (14/22). Overall survival of patients with stage I disease was 86% (12/14), with a disease-free survival of 71% (10/14) at a median follow-up of 28.5 months. Seven stage IB lesions were treated with surgery alone, whereas six received adjuvant radiation or chemoradiation following surgery. Two patients in each treatment group recurred, yielding an overall recurrence rate of 29% (4/14). However, of those who recurred with stage I disease, all 4 patients had two or more intermediate risk factors (lymph–vascular space invasion [LVSI], deep tumor invasion, or tumor size greater than 3 cm). Conclusions. Glassy cell carcinoma of the cervix appears to have a better prognosis than previously reported. We observed that intermediate risk histopathologic features identified in squamous cell cohorts are also predictive of a poorer outcome in patients with GCC. Thus, patients with LVSI, deep stromal invasion, and large tumor size are at the highest risk for pelvic relapse and should be candidates for adjuvant treatment.

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.

Adenocarcinoma of the endometrium (also known as endometrial cancer or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. An estimated 49,560 new uterine cancer cases will occur in 2013, with 8190 deaths resulting from the disease. Uterine sarcomas (stromal/mesenchymal tumors) are uncommon malignancies, accounting for approximately 3% of all uterine cancers. The NCCN Guidelines for Uterine Neoplasms describe malignant epithelial carcinomas and uterine sarcomas; each of these major categories contains specific histologic groups that require different management. This excerpt of these guidelines focuses on early-stage disease.

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.

The aim of this study was to evaluate the impact of total radiation dose on residual tumor and the prognostic significance of persistent disease in women with bulky, barrel-shaped cervical carcinoma who received definitive radiation followed by adjuvant hysterectomy.The medical records of 57 patients with bulky endophytic cervical carcinoma treated at the University of Washington between 1976 and 1997 were reviewed. All patients received external beam pelvic radiotherapy supplemented by intracavitary brachytherapy, followed by extrafascial hysterectomy 6 to 8 weeks later.The mean pretreatment tumor diameter was 5.9 cm, with a range of 4-9 cm. Total radiation dose to point A ranged from 5040 to 9700 cGy, and the mean for the group was 7966 cGy. Residual disease was present in 35 (61%) of the hysterectomy specimens. The frequency of cervical tumor sterilization correlated significantly with the mean radiation dose to point A (P = 0.016). Patients without histologic residual disease had a significantly improved outcome, with 95% of patients remaining clinically free of disease at last follow-up, versus 31% of those with residual disease (P0.001). As expected, the pelvic control rate was excellent (100%) in patients with complete tumor eradication compared to the group with residual tumor (44%). Those with no residual disease enjoyed a significantly improved survival compared to those with residual tumor (P0.001). Furthermore, a statistically significant higher survival was realized in patients harboring only microscopic residual compared to those with either macroscopically evident tumor residuum and/or positive surgical margins (P = 0.036).Higher radiation doses are associated with an improved likelihood of tumor eradication in the treatment of bulky, endophytic cervical cancer and complete tumor sterilization at adjuvant hysterectomy is predictive of significantly enhanced survival and pelvic control. The high rate of histologic tumor persistence in our series emphasizes the need for more efficacious therapies in patients with bulky endophytic cervical cancer and argues for escalation of radiation dose even when adjuvant hysterectomy is planned.

Objectives. Surgicopathologic evaluation of the scalene fat pad is considered a critical step in the pretreatment evaluation of patients at our institution with cervical or corpus carcinoma when the periaortic lymph nodes (PAN) are involved. However, enthusiasm for this procedure at other centers has waned, largely due to a wide discrepancy in the reported rates of occult scalene node involvement. In an attempt to clarify the benefit of pretreatment scalene node sampling in gynecologic malignancies, we present our experience over the past 18 years. Materials and methods. We identified 57 patients who underwent scalene node sampling between 1980 and 1998. In 39 of 49 (80%), the decision to proceed with scalene node sampling was based entirely on histologically documented PAN metastases. In the remainder, scalene node sampling was prompted by the presence of suspicious clinical findings. Results. Of the 49 patients included in the study, 33 had carcinoma of the cervix, while 16 had corpus carcinoma. Ninety percent of scalene node sampling was performed at the time of primary diagnosis. Overall, 9 patients (18%) had scalene node metastases. Notably, not a single patient with corpus cancer was found to have scalene node metastases in the absence of clinically evident scalene node enlargement independent of PAN status. In cervix cancer cases, the presence of grossly involved PAN was predictive of a high likelihood of scalene node metastases (44%), while no patient with occult PAN metastases had involvement of the scalene node. Only 1 minor complication was encountered following scalene node sampling. The 40 scalene node-negative patients were treated with either extended field radiation or whole abdominal radiation therapy, and 20% developed a major, RTOG grade ≥3 complication such as fistula formation, bowel obstruction, or ureteral stenosis. Only 1 case of mild radiation enteritis and cellulitis occurred during palliative radiation in the group of patients with scalene node metastases. Conclusions. Scalene node sampling may be of benefit in the pretreatment evaluation of patients with cervical carcinoma when PAN are grossly involved. Given that scalene node involvement satisfies the criteria for distant metastases, identification of such allows the clinician to avoid the morbidity of extended field radiotherapy in a setting without the chance for cure.

Objective: To determine if oncogene overexpression in patients with advanced epithelial ovarian cancer correlates with survival. Methods: Twenty-two women with stage III ovarian cancer, observed for a median of 66 (range 48–204) months were compared with 30 with a median survival of 18 (range 2–28) months. Using immunocytochemistry, tumors were immunostained for overexpression of p53, c-erb-B-2, and epidermal growth factor receptor and were evaluated quantitatively for expression of estrogen receptor, progesterone receptor, and Ki-67 antigen, a marker of cellular proliferation. Results: The median age of long-term survivors was 52 (range 30–76) years compared with 55 (range 36–80) years for short-term survivors. Optimal cytoreduction was achieved in 11 of the 22 long-term survivors compared with seven of the 30 short-term survivors, a significant difference (P = .05). The average level of Ki-67 expression was 43% in long-term survivors and 64% in short-term survivors (P = .007). Overexpression of p53 was seen in 54% of long-term survivors and 80% of short-term survivors (P = .05). A combination of Ki-67 level of 50% or greater plus p53 overexpression was seen in 22% of long-term survivors compared with 68% of short-term survivors (P = .005). Epidermal growth factor receptor, c-erb-B-2, estrogen receptor, and progesterone receptor statuses did not differ significantly between the two groups. Conclusion: Markers that did not correlate with survival included the hormone receptors, estrogen receptor and progesterone receptor, and the oncogenes, c-erb-B-2 and epidermal growth factor receptor. Long-term survivors with advanced ovarian cancer were more likely to have had an optimal cytoreduction and lower levels of Ki-67 antigen expression and were less likely to overexpress p53 than were short-term survivors.

OBJECTIVE: We set out to evaluate the prognostic factors in cervical adenocarcinoma metastatic to lymph nodes. STUDY DESIGN: We performed a retrospective review of 40 patients with cervical adenocarcinoma and lymph node metastasis from 1976 to 1996. RESULTS: Thirty-four patients had adenocarcinoma, and six had adenosquamous carcinoma. Median survival was 50 months. The median survival for patients with stage I disease was 69 months. Stage at diagnosis, treatment with radical hysterectomy, and receiving adjuvant therapy were associated with prolonged survival. A trend toward improved survival was noted with the use of concurrent radiation and chemotherapy as an adjuvant therapy. CONCLUSIONS: Adenocarcinoma metastatic to the lymph nodes does not have a uniformly poor prognosis, especially with early-stage disease. Improved survival was observed with the use of adjuvant therapy, specifically the use of combined chemotherapy and radiation after radical hysterectomy. The optimal therapy in this setting is yet to be determined. (Am J Obstet Gynecol 1998;178:1131-7.)

Objective. Earlier studies have demonstrated that the uterine papillary serous carcinoma (UPSC) variant of endometrial carcinoma has a high recurrence rate, even when disease is apparently confined to the uterus. The current study evaluated survival in patients with surgically staged UPSC. Methods. Patients with UPSC were identified from surgical pathology files and charts were retrospectively reviewed. Only patients who had undergone a TAH–BSO, lymph node dissection, and peritoneal cytology were included. Results. The FIGO stages of the 36 patients were 12 Stage I (4 IA, 4 IB, 4 IC), 2 Stage IIB, 13 Stage III (5 IIIA, 8 IIIC), and 9 Stage IV. Of the 14 Stage I/II patients, 6 did not receive adjuvant therapy, 5 received whole pelvic radiation (WPXRT), and 3 received whole abdominal radiation therapy (WART); after a median follow-up interval of 50 months only 2 (14%) of these Stage I/II patients have developed a recurrence. Both of the recurrences were in Stage IC patients who received radiation; 1 recurred in the radiation field. Of the 5 Stage IIIA patients, 3 patients declined therapy and 2 were treated with WART; 3 patients, including the 2 who received radiation therapy, are alive without disease. Of the 8 Stage IIIC patients, 2 declined postoperative therapy, 2 received WART, and 4 received WPXRT with an extended field to include paraaortic nodes. Four of the 6 Stage IIIC patients treated with curative intent are without evidence of disease and 1 died of unrelated causes after a median follow-up interval of 48 months. Both of the Stage IIIC patients who declined treatment recurred. Of the 9 patients with Stage IV disease, 8 have died of disease. Conclusion. Women with UPSC have a good prognosis when surgical staging confirms that disease is confined to the uterus (Stage I/II). Surgical findings can also be used to tailor adjuvant radiation treatments. Further study is required to define the optimal treatment for women with metastatic UPSC.

These NCCN Clinical Practice Guidelines in Oncology for Cervical Cancer focus on early-stage disease, because it occurs more frequently in the United States. After careful clinical evaluation and staging, the primary treatment of early-stage cervical cancer is either surgery or radiotherapy. These guidelines include fertility-sparing and non-fertility-sparing treatment for those with early-stage disease, which is disease confined to the uterus. A new fertility-sparing algorithm was added for select patients with stage IA and IB1 disease..

Recent anatomic and radiographic studies have indicated that standard external beam radiation portals may not adequately treat the volume at risk in patients with local-regionally advanced cervical cancer. A feasibility study was undertaken to evaluate toxicity, outcome, and patterns of failure in patients with advanced cervical cancer treated by expanded pelvic radiation fields.Thirty-eight women with stages IIB and III cancers of the cervix confined to the pelvis were irradiated with curative intent with expanded pelvic radiation portals. Anteriorly and posteriorly, the median field length and width were 20 and 17.5 cm, respectively. Lateral fields had a median width of 16.5 cm, and the posterior border encompassed the entire sacral silhouette. The median external beam whole-pelvis dose was 4140 cGy, with overall point A dose boosted by brachytherapy to 8315 cGy.Stage IIB patients (n = 22) had a 4-year actuarial local control rate of 70%, freedom from distant metastases rate of 62%, and disease-specific survival rate of 76%. In stage III disease (n = 16), the 4-year actuarial local control, freedom from distant metastases, and disease-specific survival rates were 80%, 48%, and 53%, respectively. Radiographically determined nodal status was an important predictor of disease-specific survival and distant metastases but not local control. The 4-year disease-specific survival rate was 40% in 11 patients with nodal disease compared with 71% in 27 node-negative patients (p0.01). The rate of freedom from distant metastases was 36% in node-positive patients versus 67% in node-negative cases (p0.01). The actuarial overall 4-year severe late complication rate was 14.8%.This study has demonstrated that expanded fields for pelvic radiotherapy is feasible, well tolerated, and therapeutic. The pelvic field design concepts presented should be integrated into radiation oncology practice.

Uterine malignant mixed mesodermal tumors (MMMT) are highly malignant tumors containing both malignant glands and stroma, while adenosarcomas (AS) are less aggressive tumors composed of malignant stroma and benign glands. Immunohistochemistry was used to grade overexpression of p53 protein, HER-2/neu protein, epidermal growth factor receptor (EGFR), and Ki-67 antigen in both the glands and stroma of tissue from 20 women with MMMT and 6 women with AS. EGFR was overexpressed in 2 AS and 9 MMMT, and was more commonly found in the sarcomatous component than the carcinomatous component in MMMT (P = 0.03). p53 was not found in any AS samples and was strongly present in 6 MMMT samples with a random distribution between the malignant components. HER-2/neu protein was not overexpressed in any AS or primary MMMT. Ki-67 antigen, a marker of cell proliferation, was found at higher levels in MMMT than AS samples (P = 0.03) and high Ki-67 antigen expression correlated with a decreased survival in patients with MMMT (P = 0.004). Independent characterization of oncogene proteins in the malignant components of these heterogeneous tumors may provide insight into the histogenesis and behavior of these malignancies.

Objective: Our purpose was to evaluate the contribution of intraoperative radiation therapy in the management of recurrent cervical cancer. Study design: Twenty-two patients were treated with electron beam intraoperative radiation therapy for recurrent cervical cancers that were confined to the pelvis but were too extensive to be adequately treated by radical surgery alone. All patients underwent extensive surgical dissection for exposure and maximal tumor resection. Doses of intraoperative radiation therapy ranged from 14 to 27.8 Gy (median 22 Gy). Twelve patients received intraoperative radiation therapy to address gross residual disease, and 10 patients were treated for microscopically positive or close surgical margins. Results: The five-year disease-specific survival and local control rates were 43% and 48%, respectively. There were trends toward better local control and disease-specific survival in patients with microscopic residual disease compared with those with gross residual disease. Seven patients had peripheral neuropathy related to treatment, and four of these cases resolved. Conclusion: In carefully selected cases intraoperative radiation therapy contributes to radical salvage of patients with recurrent cervical cancer involving the pelvic wall.

196 Background: Natural language processing (NLP) has the potential to significantly ease the burden of manual abstraction of unstructured electronic text when measuring adherence to national guidelines. We incorporated NLP into standard data processing techniques such as manual abstraction and database queries in order to more efficiently evaluate a regional oncology clinic’s adherence to ASCO’s Choosing Wisely colony stimulating factor (CSF) recommendation using clinical, billing, and cancer registry data. Methods: Database queries on the clinic’s cancer registry yielded the study population of patients with stage II-IV breast, non-small cell lung (NSCL), and colorectal cancer. We manually abstracted chemotherapy regimens from paper prescription records. CSF orders were collected through queries on the clinic’s facility billing data, when available; otherwise through a custom NLP program and manual abstraction of the electronic medical record. The NLP program was designed to identify clinical note text containing CSF information, which was then manually abstracted. Results: Out of 31,725 clinical notes for the eligible population, the NLP program identified 1,487 clinical notes with CSF-related language, effectively reducing the number of notes requiring abstraction by up to 95%. Between 1/1/2012-12/31/2014, adherence to the ASCO CW CSF recommendation at the regional oncology clinic was 89% for a population of 322 patients. Conclusions: NLP significantly reduced the burden of manual abstraction by singling out relevant clinical text for abstractors. Abstraction is often necessary due to the complexity of data collection tasks or the use of paper records. However, NLP is a valuable addition to the suite of data processing techniques traditionally used to measure adherence to national guidelines.

To analyze quality of life (QOL) in a randomized, placebo-controlled phase III trial concluding that the addition of concurrent and maintenance bevacizumab (Arm 3) to carboplatin and paclitaxel prolongs progression-free survival in front-line treatment of advanced ovarian cancer compared to chemotherapy alone (Arm 1) or chemotherapy with bevacizumab in cycles 2-6 only (Arm 2).The Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary (FACT-O TOI) was used to assess QOL before cycles 1, 4, 7, 13, and 21; and 6months after completing study therapy. Differences in QOL scores were assessed using a linear mixed model, adjusting for baseline score, and age. The significance level was set at 0.0167 to account for multiple comparisons.1693 patients were queried. Arm 2 (p0.001) and Arm 3 (p0.001) reported lower QOL scores than those in Arm 1. The treatment differences were observed mainly at cycle 4, when the patients receiving bevacizumab (Arm 2 and Arm 3) reported 2.72 points (98.3% CI: 0.88-4.57; effect size=0.18) and 2.96 points (98.3% CI: 1.13-4.78; effect size=0.20) lower QOL respectively, than those in Arm 1. The difference in QOL scores between Arm 1 and Arm 3 remained statistically significant up to cycle 7. The percentage of patients who reported abdominal discomfort dropped over time, without significant differences among study arms.The small QOL difference observed during chemotherapy did not persist during maintenance bevacizumab.

The Seattle Cancer Care Alliance (SCCA) is a Pacific Northwest regional network that enables patients from community cancer centers to participate in multicenter oncology clinical trials where patients can receive some trial-related procedures at their local center. Results of positron emission tomography (PET) scans performed at community cancer centers are not currently used in SCCA Network trials since clinical trials customarily accept results from only trial-accredited PET imaging centers located at academic and large hospitals. Oncologists would prefer the option of using standard clinical PET scans from Network sites in multicenter clinical trials to increase accrual of patients for whom additional travel requirements for imaging are a barrier to recruitment. In an effort to increase accrual of rural and other underserved populations to Network trials, researchers and clinicians at the University of Washington, SCCA and its Network are assessing the feasibility of using PET scans from all Network sites in their oncology clinical trials. A feasibility study is required because the reproducibility of multicenter PET measurements ranges from approximately 3% to 40% at national academic centers. Early experiences from both national and local PET phantom imaging trials are discussed, and next steps are proposed for including patient PET scans from the emerging regional quantitative imaging network in clinical trials. There are feasible methods to determine and characterize PET quantitation errors and improve data quality by either prospective scanner calibration or retrospective post hoc corrections. These methods should be developed and implemented in multicenter clinical trials employing quantitative PET imaging of patients.

Purpose: Recent studies have suggested that pentoxifylline, a methylxanthine, can prevent or ameliorate late radiation injury in animals and humans. Caffeine is a commonly consumed methylxanthine that provides a model for evaluating the impact of this category of drugs on radiation injury. A retrospective study was undertaken to determine if there is an association between caffeine consumption and a lower incidence of late radiation toxicity. Methods and Materials: From 1984 through 1990, 82 patients with cervical cancer and 53 patients with endometrial cancer were treated with primary or adjuvant radiation therapy at the University of Washington. Patients were interviewed regarding ingestion of caffeine-containing beverages, and average daily caffeine consumption during the time of radiotherapy was estimated. The evaluable patients (42 cervical, 31 endometrial) were stratified by quantity of caffeine consumption for correlation with the incidence of radiation toxicity. Results: Acute radiation toxicity was not associated with caffeine consumption for cervical or endometrial cancer. There was a nonstatistically significant trend toward a decrease in overall late radiation toxicity with increased caffeine intake for cervical cancer patients. Subgroup analysis revealed this trend to be attributable to a decreased incidence of severe late radiation injury in cervical cancer patients who consumed higher levels of caffeine at the time of their radiotherapy ( p = 0.02). This relationship was not observable for late toxicity in the endometrial cancer patients due to the low incidence of severe late injury following radiation for that disease. Conclusions: This investigation is supportive of previous studies showing a radioprotective effect for pentoxifylline, and suggests that the mechanisms of radioprotection may be common to methylxanthines as a drug class.

Uterine papillary serous carcinoma (UPSC) is a distinct histologic type of endometrial cancer which is associated with a high relapse rate and poor prognosis. Between 1983 and 1993, 50 patients with UPSC of the endometrium were surgically staged. Thirty-three patients had pure UPSC and 17 had UPSC admixed with other histologies. Extrauterine disease was found in 36 women (72%). Lymph node metastases were present in 36% of women without myometrial invasion, 50% with inner one-half invasion, and 40% with outer one-half invasion. Similarly, the presence of intraperitoneal disease or positive washings did not correlate with increasing myometrial invasion. Grade and histology (mixed vs pure) were also not predictive of extrauterine disease. Patients with lymphatic/vascular space invasion (LVSI) were more likely to have extrauterine disease (85%); however, even without LVSI the incidence of extrauterine disease was 58% (P = 0.05). Unlike endometrioid adenocarcinomas, grade and depth of myometrial invasion were not significant predictors for extrauterine disease. This study reinforces the need for complete surgical staging in all patients with UPSC regardless of depth of invasion.

Objective : Our aim was to determine the efficacy and toxicity of paclitaxel in the treatment of refractory and platinum-resistant epithelial ovarian cancer. Study Design : Eligibility required three prior failed chemotherapy regimens and documented platinum resistance. One hundred patients with advanced ovarian cancer received paclitaxel 135 mg/m 2 over 24 hours every 21 days with optional granulocyte colony-stimulating factor support. Results : Paclitaxel was generally well tolerated. In four patients bowel perforation or fistula developed. After three cycles 34% of patients had stable disease and 25% of patients demonstrated a response, either partial or complete. After six cycles 24% of patients continued to respond. To date six patients have achieved a complete response. Conclusion : A 25% response rate in patients with refractory ovarian cancer was observed which was durable to six cycles.

Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has shown single-agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy.In our double-blind, placebo-controlled, phase 3 trial, we randomly assigned eligible patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive one of three treatments. All three included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg per square meter of body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks' duration. The control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg per kilogram of body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. The primary end point was progression-free survival.Overall, 1873 women were enrolled. The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% confidence interval [CI], 0.795 to 1.040; P=0.16) with bevacizumab initiation and 0.717 (95% CI, 0.625 to 0.824; P0.001) with bevacizumab throughout. At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups. The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively.The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer. (Funded by the National Cancer Institute and Genentech; ClinicalTrials.gov number, NCT00262847.).

Purpose : To quantify, based on pretreatment computer tomographic measurements, potential groin node depths, which will aid in optimal treatment planning for patients requiring groin node radiation. Methods and Materials : The pretreatment computer tomographic scans of 50 gynecologic cancer patients were reviewed to determine the distance of each femoral vessel beneath the overlying skin surface, as an indicator of potential groin node depth. Correlative data regarding height and weight were obtained from patient medical records, and were used to calculate the Quetelet index, defined as (weight in kg)/(height in m)2. Treatment parameters of 5 patients who failed prophylactic groin radiation in a recently published study were assessed to determine if underdosage represented a possible cause of failure. Results : Individual femoral vessel depths ranged from 2.0 to 18.5 cm. When the depths of all four femoral vessels were averaged in each patient, the mean “4-vessel average” depth for this patient population was 6.1 cm. The median Quetelet index for the group was 25.6, and there was a strong correlation between femoral vessel depth and patient Quetelet index. Recalculation of doses provided to the 5 patients failing prophylactic groin radiation in the Gynecologic Oncology Group study showed that all had received potential tumor doses 30%. Conclusion : While surgery is often indicated in the management of patients with potential groin node metastases, the role of prophylactic groin radiation should not be rejected. Data from this study may aid in the optimal design and implementation of groin node radiotherapy.

Purpose : To determine, in a retrospective single institutional study, the role of concurrent radiotherapy and chemotherapy in the treatment of local-regionally advanced vulvar cancer. Methods and Materials : From 1984 to 1991, 20 patients with locally extensive primary or recurrent carcinoma of the vulva were treated with initial combined radiotherapy and chemotherapy. Seven patients had Federation Internationale de Gynecologie et d'Obstretrique Stage III disease, 10 had Stage IV disease, and three were treated for recurrent disease. None of these patients were considered candidates for primary radical vulvectomy and groin node dissection. Median radiation doses to regions of microscopic disease and gross tumor were 40 Gy (range 30–54 Gy) and 54 Gy (34–70.4 Gy), respectively. All patients received 2 or 3 cycles of 5-Fluorouracil concurrently with radiotherapy. In addition, five patients received Cis-platinum, and one Mitomycin-C. Median at-risk follow-up interval was 37 months. Results : Ten patients had complete resolution of tumor to initial chemoradiotherapy, and eight of these have remained free of tumor relapse. Eight other patients had partial responses, with tumor bulk reduced by > 50%, while the remaining two patients had local-regionally progressive disease. Six of the patients with partial responses had residual tumor successfully resected, although four subsequently recurred. For the entire group of 20 patients, the actuarial 3- and 5-year local control rates were 48% each, and the corresponding disease-specific survival rates were 59% and 49%. There was a suggestion that better local control was obtained in patients who received gross tumor radiation doses ≥ 50 Gy. Skin reaction was the major acute toxicity and responded well to conservative management. Long-term sequalae were limited to skin and subcutaneous atrophy. Conclusion : These results indicate that initial combined radiotherapy and chemotherapy is effective in the management of advanced vulvar cancer.

Objective This study aimed to determine the first-cycle maximum tolerated dose (MTD) of intraperitoneal carboplatin in combination with intravenous paclitaxel and then assess the feasibility of this dose over multiple cycles. Methods Beginning at an intraperitoneal (IP) carboplatin dose area under the curve (AUC) of 5 and a fixed intravenous dose of 175mg/m 2 paclitaxel, patients were entered on a dose-escalating phase evaluating first-cycle dose-limiting toxicity (DLT). After estimating the MTD, cohorts of 20 patients were then entered in an expanded phase to evaluate DLT over four cycles. Results Twenty-one patients were entered on the dose-escalating phase. A first-cycle MTD of carboplatin at AUC 8 was tolerated although thrombocytopenia was dose-limiting over multiple cycles. An additional 69 patients were treated in expanded cohorts. Only 5/90 (5.6%) patients discontinued treatment because of a port problem. Four-cycle DLT required de-escalation to a carboplatin AUC of 6, and even at that dose, there were 14 dose-limiting toxic effects in 40 patients (35%). Seven dose-limiting toxicities were due to neutropenia, and 6 were due to grade 3/4 thrombocytopenia. Six cycles of therapy were completed in 75% of eligible patients, but dose adjustments were required. Conclusions The first-cycle MTD did not predict the tolerability of this regimen over multiple cycles. Using an IP carboplatin dose of AUC 6 in combination with paclitaxel, the regimen can be administered with a high completion rate over multiple cycles. Because neutropenia is a frequent DLT, the addition of hematopoietic growth factors may permit a high completion rate while maintaining this dose.

The ability of a panel of monoclonal antibodies generated in this laboratory to identify "pagetoid" melanoma cells and distinguish them from true Paget's adenocarcinoma cells in a retrospective analysis of vulvar neoplasms was investigated. Paraffin blocks of formalin and Carnoy's fixed tissue from 15 cases of vulvar Paget's disease and 11 cases of primary vulvar melanoma were retrieved and sections were incubated with the following panel of monoclonal antibodies: HMB45, a melanoma-specific monoclonal antibody; and 35 beta H11 and 34 beta E12, two different anti-cytokeratin monoclonal antibodies, to low molecular and high molecular weight cytokeratins, respectively. The anti-melanoma monoclonal antibody (HMB45) positively identified the melanoma cells, distinguishing them from normal melanocytes, in all 11 cases of melanoma. In contrast, the HMB45 antibody failed to react with the intraepithelial neoplastic cells in all cases of Paget's disease. These latter malignant cells were strongly positive only with the monoclonal anti-low molecular weight cytokeratin antibody 35 beta H11. This latter antibody absolutely distinguished tumor cells from neighboring uninvolved squamous epithelium, which was positive only with the monoclonal antibody 34 beta E12. Using this panel of monoclonal antibodies, the surgical margins could also be better evaluated; in at least one case the surgical margin thought by histological evaluation to be free of tumor was demonstrated by immunocytochemistry to be positive for tumor. In the vulvectomy specimens obtained in both diseases, Paget's or melanoma cells were identified in sections histologically interpreted as free of tumor. Thus, a panel of monoclonal antibodies is able to identify, with high sensitivity and specificity, vulvar melanoma cells and absolutely distinguish them from vulvar Paget's cells and can help in evaluating surgical margins in a more accurate manner.

Objective(s) The Gynecologic Oncology Group (GOG) examined the association between ERBB2 amplification and clinical covariates, tumor response, disease status post-chemotherapy, progression-free survival (PFS), and overall survival (OS) in epithelial ovarian cancer (EOC). Methods Women with suboptimally-resected, advanced stage EOC who participated in GOG-111, a multi-center randomized phase III trial of cyclophosphamide+cisplatin versus paclitaxel+cisplatin, and provided a tumor block through the companion protocol GOG-9404 were eligible. ERBB2 amplification was examined using fluorescence in situ hybridization (FISH) with probes for ERBB2 and the centromere of chromosome 17 (CEP17). Results ERBB2 amplification, defined as >2 copies of ERBB2 /CEP17, was a rare event in EOC with 7% (9/133) of women exhibiting between 2.2 and 33.7 copies of ERBB2 /CEP17, and was not associated with patient age, race, GOG performance status, stage, cell type, grade, measurable disease status, volume of ascites, tumor response or disease status post-chemotherapy. Women with >2 verses ≤2 copies of ERBB2 /CEP17 did not have a reduced risk of disease progression (hazard ratio [HR]=0.56; 95% confidence interval [CI]=0.27–1.16; p =0.120) or death (HR=0.57; 95% CI=0.26–1.23; p =0.152), and ERBB2 amplification was not an independent prognostic factor for PFS or OS. ERBB2 amplification, defined as >4 copies of ERBB2 /nuclei, was observed in 9% (12/133) of women with levels ranging from 4.2 to 49.2 copies of ERBB2 /nuclei, and was associated with older age and volume of ascites, but not with the other clinical covariates or outcome. Conclusion(s) ERBB2 amplification is a rare event and has no predictive or prognostic value in suboptimally-resected, advanced stage EOC treated with platinum-based combination chemotherapy.

Cervical carcinoma remains a health issue for women worldwide. Cervical cytology screening is the current method for early detection, and the NCCN Cervical Cancer Screening Clinical Practice Guidelines in Oncology provide direction for evaluating and managing this process, including clarified and revised recommendations on screening techniques and intervals and follow-up of abnormal screening results, including colposcopy. Human papillomavirus (HPV) DNA testing for primary cervical cancer has been approved by the FDA, and HPV DNA testing for high-risk virus types can also be used as a component of both primary screening and workup of abnormal cytology results. Colposcopy, along with colposcopically directed biopsies, has become the primary method for evaluating women with abnormal cervical cytologies. Special considerations for colposcopy performed during pregnancy are also discussed. For the most recent version of the guidelines, please visit NCCN.org