A Phase I Evaluation of Extended Field Radiation Therapy With Concomitant Cisplatin Chemotherapy Followed by Paclitaxel and Carboplatin Chemotherapy in Women With Cervical Carcinoma Metastatic to the Para-aortic Lymph Nodes: An NRG Oncology/Gynecologic Oncology Group Study.

BACKGROUND: Chemo-radiation (chemoRT) has improved the overall survival for locally advanced cervical cancer (LACC) though women whose disease involves the para-aortic nodes (PAN) experience recurrence rates and worse survival outcomes compared to those without PAN involvement. This Phase I study determined if additional cycles of systemic chemotherapy could be safely added to extended field chemoRT in this population of patients. METHODS: Women with LACC and documented positive PAN were eligible for treatment. All women were treated with extended field radiation and brachytherapy and concurrent cisplatin 40 mg/m2 weekly for six weeks. Four to six weeks after completion of chemoRT, patients were treated with four cycles of paclitaxel 135 mg/m2 and escalating doses of carboplatin (Dose Level (DL) 1 = AUC 4, DL2 = AUC 5). RESULTS: Eleven women were entered on study and 9 were evaluable for dose limiting toxicities (DLT). Two women (1 in each of 2 DLs) did not complete chemoRT and so were not evaluable for DLT. Three women completed all 10 cycles at DL 1 with no DLTs. Six women were then treated at DL 2. For the 10 patients evaluable for response, the ORR was 60% (CR + PR). PFS and OS at 12 months were 60% and 90%, respectively. The predominant grade 3 or 4 acute toxicities were hematologic. There were no grade 5 events. CONCLUSION: Extended field chemoRT followed by paclitaxel 135 mg/m2 and carboplatin AUC 5 is feasible in women with LACC and positive PAN.

Preferential human epidermal growth factor receptor 2 expression in myometrial and lymphovascular invasion of a uterine carcinosarcoma: A case report.

This case report describes a unique pattern of human epidermal growth factor receptor 2 expression in a patient with uterine carcinosarcoma. The endometrial tumor showed biphasic morphology composed of serous carcinoma and a heterologous high-grade sarcoma component. Human epidermal growth factor receptor 2 immunostaining showed positive (3+) expression in foci of myoinvasion, lymphovascular invasion, and lymph node metastasis but was negative in both the endometrial surface tumor and sarcomatous component. Fluorescent in situ hybridization testing for human epidermal growth factor receptor 2 confirmed no amplification within the endometrial surface carcinoma component and amplification of the lymphovascular invasion component. As the use of human epidermal growth factor receptor 2 immunohistochemical evaluation becomes more commonplace for therapeutic consideration in patients with uterine carcinosarcoma, interpretation of the immunohistochemical should be performed preferentially on large tissue sections including both a surface, myoinvasive portions, and suspected areas of lymphovascular invasion and lymph node metastasis.

Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

PURPOSE: The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix. PATIENTS AND METHODS: Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤2. Treatment consisted of cetuximab 400 mg/m(2) initial dose followed by 250 mg/m(2) weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design. RESULTS: Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n=25, 71.4%) or 2 (n=10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n=5), GI (n=4), anemia (n=2), constitutional (n=3), infection (n=2), vascular (n=2), pain (n=2), and pulmonary, neurological, vomiting and metabolic (n=1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology. CONCLUSION: Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology.

A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients.

BACKGROUND: We tested if magnesium would diminish bothersome hot flashes in breast cancer patients. METHODS: Breast cancer patients with at least 14 hot flashes a week received magnesium oxide 400 mg for 4 weeks, escalating to 800 mg if needed. Hot flash score (frequency × severity) at baseline was compared to the end of treatment. RESULTS: Of 29 who enrolled, 25 women completed treatment. The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 (standard error (SE), 13.7) to 27.7 (SE, 5.7), a 41.4% reduction, p = 0.02, two-sided paired t test. Hot flash score was reduced from 109.8 (SE, 40.9) to 47.8 (SE, 13.8), a 50.4% reduction, p = 0.04. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial. CONCLUSIONS: Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal. A randomized placebo-controlled trial is planned.

Health-related quality of life outcomes associated with four cisplatin-based doublet chemotherapy regimens for stage IVB recurrent or persistent cervical cancer: a Gynecologic Oncology Group study.

PURPOSE: To assess the differences in health-related quality of life (HRQL) of 4 cisplatin containing doublet chemotherapy combinations in women with advanced/recurrent cervical carcinoma. METHODS: Patients were randomized to three-week cycles of paclitaxel + cisplatin (PC); vinorelbine + C (VC); gemcitabine + C (GC); or topotecan + C (TC). We report HRQL results from data available on 434 eligible patients enrolled into this 513 patient trial. HRQL was assessed with the Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) the FACT/Gynecologic Oncology Group (FACT/GOG) four-item neurotoxicity scale, and the 0-10 "worst pain" item from the Brief Pain Inventory, at baseline (pre-treatment), prior to beginning cycle 2, prior to beginning cycle 5, and at 9 months after enrollment. As reported by Monk et al. (2009) [13] VC, GC and TC were found not to be superior to PC with regard to progression-free survival or overall survival. RESULTS: The trial was terminated early due to planned interim futility analysis, reducing power for HRQL analysis from 85% to 55%. Patients receiving VC, GC and TC doublets did not report significantly different HRQL, neuropathy, or pain from those who received the PC (control) doublet. Patients receiving PC tended to report worse neuropathy during treatment than patients who received other doublets (especially GC and TC), but the differences were not statistically significant. CONCLUSION: None of the 3 experimental doublets was different from PC in terms of HRQL during treatment. Long-term toxicity data are inconclusive. Except where patients may wish to reduce their risk of worsening pre-treatment neuropathy, PC remains the standard of care for this disease.

Biologic therapeutics and molecular profiling to optimize wound healing.

Non-healing wounds represent a significant cause of morbidity and mortality for a large portion of the adult population. Wounds that fail to heal are entrapped in a self-sustaining cycle of chronic inflammation leading to the destruction of the extracellular matrix. Among cancer patients, malnutrition, radiation, physical dehabilitation, chemotherapy, and the malignancy itself increase the likelihood of chronic wound formation, and these co-morbidity factors inhibit the normal wound healing process. Current wound treatments are aimed at some, but not all, of the underlying causes responsible for delayed healing of wounds. These impediments block the normal processes that allow normal progression through the specific stages of wound healing. This review summarizes the current information regarding the management and treatment of complex wounds that fail to heal normally and offers some insights into novel future therapies [Menke N, Ward KR, Diegelmann R. Non-healing wounds. Emerg Med Rep 2007; 28(4).,Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clin Dermatol 2007;25:19-25].

Soluble epidermal growth factor receptor (sEGFR) [corrected] and cancer antigen 125 (CA125) as screening and diagnostic tests for epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecologic cancers in the United States. Because women who are diagnosed with early stage disease have a better prognosis than women diagnosed with late stage disease, early detection represents a potentially practical approach to reduce the mortality associated with EOC. Unfortunately, no single screening test has proven to be effective for this purpose, and a valid and feasible screening program to detect early stage EOC in the general population has not yet been devised. Consequently, research has focused on coupling two or more screening modalities to improve program validity and feasibility. Serum cancer antigen 125 (CA125) and a soluble isoform of the epidermal growth factor receptor (p110 sEGFR) have been studied individually as biomarkers of ovarian cancer. In this study, we compare serum CA125 levels and sEGFR concentrations in women with EOC to women with benign gynecologic conditions of ovarian and non-ovarian origin. We show that serum sEGFR concentrations are lower in patients with EOC than in women with benign gynecologic conditions, whereas serum CA125 levels are higher in patients to EOC compared with women with benign gynecologic conditions. These data also reveal that age and serum sEGFR concentrations modify the association between CA125 levels and EOC versus benign gynecologic disease. Hence, age- and sEGFR-dependent CA125 cutoff thresholds improve the ability of CA125 to discern EOC patients from women with benign ovarian tumors and non-ovarian gynecologic conditions. Our analyses show that parallel testing with fixed sEGFR and CA125 cutoff thresholds optimizes sensitivity to detect EOC, whereas serial testing with age- and sEGFR-dependent CA125 cutoff thresholds optimizes test specificity, and overall accuracy to discern patients with EOC from women with benign ovarian and non-ovarian gynecologic conditions. The combined use of serologic sEGFR and CA125, thus, has improved utility for screening and diagnosing EOC, which may increase the positive predictive value of a multimodal screening program that incorporates these biomarkers to detect and subsequently differentiate benign from malignant ovarian tumors.

Soluble epidermal growth factor receptor (sEGFR/sErbB1) as a potential risk, screening, and diagnostic serum biomarker of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies in the United States, for which risk assessment, screening, and diagnostic tests are needed. We have shown previously that women with stage III/IV EOC have lower serum p110 sEGFR/sErbB1 (Soluble Epidermal Growth Factor Receptor) concentrations than healthy women. Here, we show that serum p110 sEGFR/sErbB1 is the product of a 3-kb EGFR/ERBB1 alternate transcript. We report that serum sEGFR concentrations in stage I/II and stage III/IV EOC patients are significantly lower than in healthy women, and that serum sEGFR concentrations are not associated with disease stage or tumor grade. Logistic regression models show that: (a) lower serum sEGFR concentrations are associated significantly with a greater risk of EOC; (b) the risk associated with lower serum sEGFR concentrations is reduced by older age or menopause; and (c) age- or menopausal status-specific cutoff values for sEGFR concentration are appropriate. Receiver operating characteristic curves indicate that: (a) serum sEGFR concentrations are more effective in discerning stage III/IV than stage I/II EOC cases from healthy women; and (b) sEGFR concentrations have an 89% probability of correctly discerning EOC patients from healthy women when accounting for effect modification by age. By maintaining a test specificity of approximately 95% across strata of age or menopausal status with appropriate cutoff values, we observe that sEGFR concentrations are most useful for detecting stage I/II (sensitivity: 64-67%) and stage III/IV (sensitivity: 75-81%) EOC in young, premenopausal women. We conclude that serum sEGFR concentrations warrant additional investigation in the risk assessment, early detection, and/or diagnosis of EOC.

Da Vinci robotic-assisted radical hysterectomy procedural guide.

The Da Vinci robotic surgical platform has rapidly been adopted by skilled surgeons for procedures in gynecologic oncology. The lack of specific procedural guides and surgical atlases for robotic surgery in gynecologic oncology produces challenges in the education of trainees in their role both as the assistant and as the console surgeon. This procedural guide was developed in order to facilitate trainee education in the technical aspects of radical hysterectomy for cervical cancer using the Da Vinci robotic surgical platform. Patient selection, preparation, and the technical aspects of robotic radical hysterectomy are described from both the standpoint of the console surgeon and the bedside assistant.

Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group.

PURPOSE: To estimate the antitumor activity of pemetrexed in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer and to determine the nature and degree of toxicities. PATIENTS AND METHODS: A phase II trial was conducted by the Gynecologic Oncology Group. Patients must have had cancer that had progressed on platinum-based primary chemotherapy or recurred within 6 months. Pemetrexed at a dose of 900 mg/m(2) was to be administered as an intravenous infusion over 10 minutes every 21 days. Dose delay and adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects. RESULTS: From July 6, 2004, to August 23, 2006, 51 patients were entered. A total of 259 cycles (median, four; range one to 19 cycles) of pemetrexed were administered, with 40% of patients receiving six or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15% of patients. No treatment-related deaths were reported. One patient (2%) had a complete and nine patients (19%) had partial responses, with a median duration response of 8.4 months. Seventeen patients (35%) had stable disease for a median of 4.1 months. Eighteen patients (38%) had increasing disease. Three patients (6%) were not assessable. Median progression-free survival was 2.9 months, and overall survival was 11.4 months. CONCLUSION: Pemetrexed has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation.

Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study.

PURPOSE: Assess toxicity and efficacy of cisplatin (Cis) doublet combinations in advanced and recurrent cervical carcinoma. PATIENTS AND METHODS: Patients were randomly assigned to paclitaxel 135 mg/m(2) over 24 hours plus Cis 50 mg/m(2) day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m(2) days 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (VC); gemcitabine 1,000 mg/m(2) day 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (GC); or topotecan 0.75 mg/m(2) days 1, 2, and 3 plus Cis 50 mg/m(2) day 1 every 3 weeks (TC). Survival was the primary end point with a 33% improvement relative to PC considered important (85% power, alpha = 5%). Quality-of-life data were prospectively collected. RESULTS: A total of 513 patients were enrolled when a planned interim analysis recommended early closure for futility. The experimental-to-PC hazard ratios of death were 1.15 (95% CI, 0.79 to 1.67) for VC, 1.32 (95% CI, 0.91 to 1.92) for GC, and 1.26 (95% CI, 0.86 to 1.82) for TC. The hazard ratios for progression-free survival (PFS) were 1.36 (95% CI, 0.97 to 1.90) for VC, 1.39 (95% CI, 0.99 to 1.96) for GC, and 1.27 (95% CI, 0.90 to 1.78) for TC. Response rates (RRs) for PC, VC, GC, and TC were 29.1%, 25.9%, 22.3%, and 23.4%, respectively. The arms were comparable with respect to toxicity except for leucopenia, neutropenia, infection, and alopecia. CONCLUSION: VC, GC, and TC are not superior to PC in terms of overall survival (OS). However, the trend in RR, PFS, and OS favors PC. Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.

Multimodal therapy including neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) for stage IIB to IV cervical cancer.

OBJECTIVE: The purpose of this study was to determine the survival rates and toxicity levels that are associated with multimodal therapy (including neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC]) in patients with stage IIB to IVB cervical cancer. STUDY DESIGN: We retrospectively reviewed the cases of 49 patients who were treated between 1989 and 1997 with neoadjuvant MVAC for advanced cervical cancer. RESULTS: The clinical response rate was 90% (27 partial responders, 17 complete responders). Grade 3 or greater toxicity was mostly limited to neutropenia; no deaths were attributed to MVAC. Combined therapy after MVAC included operation in 34 patients (69%) and radiation in 41 patients (84%). Twenty-one patients (43%) had <2 cm residual tumor at histologic evaluation. Pelvic control was achieved in 86% of patients. Five-year disease-specific survival for patients with stage III disease was 60%. CONCLUSION: For patients with advanced cervical cancer, neoadjuvant MVAC had a high response rate (90%) and an acceptable toxicity level. Compared with historic control subjects, multimodal treatment may be associated with improved rates of pelvic control.