Angeles Alvarez Secord

Retrospective Analysis of Selective Lymphadenectomy in Apparent Early-Stage Endometrial Cancer

PURPOSE Selective lymphadenectomy is widely accepted in the management of endometrial cancer. Purported benefits are individualization of adjuvant therapy based on extent of disease and resection of occult metastases. Our goal was to assess effects of the extent of selective lymphadenectomy on outcomes in women with apparent stage I endometrial cancer at laparotomy. PATIENTS AND METHODS Patients with endometrial cancer who received primary surgical treatment between 1973 and 2002 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/IIA disease and procedure including hysterectomy and selective lymphadenectomy (pelvic or pelvic + aortic). Exclusion criteria included presurgical radiation, grossly positive lymph nodes, or extrauterine metastases at laparotomy. Recurrence and survival were analyzed using Kaplan-Meier analysis and Cox proportional hazards model. RESULTS Among 509 patients, the median number of lymph nodes removed was 15 (median pelvic, 11; median aortic, three). Pelvic and aortic node metastases were found in 24 (5%) of 509 patients and 11 (3%) of 373 patients, respectively. Patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Number of nodes removed was not predictive of survival among patients with cancers of grade 1 to 2. Performance of aortic selective lymphadenectomy was not associated with survival. Three (27%) of 11 patients with microscopic aortic nodal metastasis are alive without recurrence. CONCLUSION These data add to the literature documenting the possible therapeutic benefit of selective lymphadenectomy in management of patients with apparent early-stage endometrial cancer.

Randomized Phase III Trial of Gemcitabine Compared With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer

PURPOSE Ovarian cancer (OC) patients experiencing progressive disease (PD) within 6 months of platinum-based therapy in the primary setting are considered platinum resistant (Pt-R). Currently, pegylated liposomal doxorubicin (PLD) is a standard of care for treatment of recurrent Pt-R disease. On the basis of promising phase II results, gemcitabine was compared with PLD for efficacy and safety in taxane-pretreated Pt-R OC patients. PATIENTS AND METHODS Patients (n = 195) with Pt-R OC were randomly assigned to either gemcitabine 1,000 mg/m2 (days 1 and 8; every 21 days) or PLD 50 mg/m2 (day 1; every 28 days) until PD or undue toxicity. Optional cross-over therapy was allowed at PD or at withdrawal because of toxicity. Primary end point was progression-free survival (PFS). Additional end points included tumor response, time to treatment failure, survival, and quality of life. RESULTS In the gemcitabine and PLD groups, median PFS was 3.6 v 3.1 months; median overall survival was 12.7 v 13.5 months; overall response rate (ORR) was 6.1% v 8.3%; and in the subset of patients with measurable disease, ORR was 9.2% v 11.7%, respectively. None of the efficacy end points showed a statistically significant difference between treatment groups. The PLD group experienced significantly more hand-foot syndrome and mucositis; the gemcitabine group experienced significantly more constipation, nausea/vomiting, fatigue, and neutropenia but not febrile neutropenia. CONCLUSION Although this was not designed as an equivalency study, gemcitabine and PLD seem to have a comparable therapeutic index in this population of Pt-R taxane-pretreated OC patients. Single-agent gemcitabine may be an acceptable alternative to PLD for patients with Pt-R OC.

The role of PET scanning in the detection of recurrent cervical cancer

OBJECTIVES [(18)F] Fluoro-2-deoxyglucose positron emission tomography (FDG PET) has recently been established as a sensitive and specific method of detecting lymph node metastases in newly diagnosed cervical cancer. Little is known about the efficacy of PET for detecting recurrent disease. We evaluated the potential role of FDG PET in the context of suspected recurrent cervical cancer. METHODS The records of patients undergoing PET scan to evaluate for cervical cancer recurrence between July 1998 and February 2002 were reviewed. Radiographic findings were classified as negative, suspicious, or equivocal. PET scan findings were compared to available clinical data to classify each PET result as a true positive, true negative, false positive, or false negative. Clinical proof of recurrence consisted of a tissue biopsy revealing recurrent cancer within 3 months of the PET scan. Clinical proof of no evidence of disease consisted of a negative tissue biopsy within 3 months or no clinical evidence of recurrence within 6 months after the PET scan. RESULTS Twenty-eight patients underwent 37 PET scans. Twenty-nine cases among 22 patients were clinically evaluable for recurrence status. Median age was 42, and stage distribution was IB 1 (n = 3), IB2 (n = 4), IIA (n = 1), IIB (n = 10), IIIB (n = 9), IVB (n = 1). Histologic types included squamous (n = 23) adenocarcinoma (n = 4) and unknown (n = 1). There were 12 true positive PET scans, 13 true negatives, 2 false positives, and 2 false negatives. The sensitivity and specificity of FDG PET for detecting recurrent cervical cancer were 85.7 and 86.7%, respectively. The positive and negative predictive values were 85.7 and 86.7%, respectively. CONCLUSIONS Whole-body FDG PET is a sensitive and specific tool for the detection of recurrent cervical cancer in patients who have clinical findings suspicious for recurrence. A larger prospective trial will determine whether this modality should be used routinely in conjunction with, or in lieu of, other imaging studies to detect recurrent disease in a broader population of cervical cancer patients.

Phase II Trial of Cetuximab and Carboplatin in Relapsed Platinum-Sensitive Ovarian Cancer and Evaluation of Epidermal Growth Factor Receptor Expression: A Gynecologic Oncology Group Study

PURPOSE This phase II trial assessed the activity and tolerability of cetuximab (C225, Erbitux) in combination with carboplatin in patients with relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. PATIENTS AND METHODS Patients were to receive combination therapy with cetuximab (initial dose of 400 mg/m2 intravenously on cycle 1, day 1, followed by weekly infusions of 250 mg/m2) and carboplatin (AUC of 6 on day 1 and every 3 weeks). The primary objectives of this trial were to estimate the anti-tumor activity and adverse events of this combination therapy. Immunohistochemical expression of EGFR was evaluated in tumor specimens from patients enrolled in this trial. RESULTS Of the 29 patients, 28 (97%) were eligible and evaluable for analysis of the efficacy and toxicity of cetuximab administered in combination with carboplatin. Of the evaluable entries, 26 had EGFR-positive tumors and the response rate in this group of patients was as follows: 9 demonstrated an objective response (3 CR; 6 PR) and 8 had stable disease. The response rate did not meet criteria for opening a second stage of accrual. The median time to progression was 9.4+ months (range: .9-22.2+). The most commonly observed adverse events were dermatologic toxicity (grade 3 in 32%), thrombocytopenia (grade 3 in 14%), and hypersensitivity reactions (grade 3 and 4 in 18%). CONCLUSIONS Cetuximab administered in combination with carboplatin had modest activity in screened patients with EGFR-positive, relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Cetuximab was associated with an acneiform rash in a majority of patients and occasional serious hypersensitivity reactions.

Metformin is associated with improved survival in endometrial cancer.

OBJECTIVE Preclinical evidence suggests that metformin exhibits anti-tumorigenic effects in endometrial cancer. We sought to investigate the association of metformin on endometrial cancer outcomes. METHODS A multi-institutional IRB-approved retrospective cohort analysis was conducted comparing endometrial cancer patients with diabetes mellitus who used metformin (based on medication review at the time of diagnosis) to those who did not use metformin from 2005 to 2010. Metformin use on treatment related outcomes (TTR: time to recurrence; RFS: recurrence free survival; OS: overall survival) were evaluated using univariate and multivariate modeling. RESULTS 24% (363/1495) endometrial cancer patients were diabetic, of whom 54% used metformin. Metformin users were younger and heavier than non-users, though nearly all were postmenopausal and obese. 75% of both groups had endometrioid histology. Stage, grade, and adjuvant therapy distributions were similar. Metformin users had improved RFS and OS. Non-metformin users had 1.8 times worse RFS (95% CI: 1.1-2.9, p = 0.02) and 2.3 times worse OS (95% CI: 1.3-4.2, p = 0.005) after adjusting for age, stage, grade, histology and adjuvant treatment. Metformin use was not associated with TTR. CONCLUSION Metformin use was associated with improved RFS and OS but not TTR, most likely due to improving all-cause mortality. Its role in modifying cancer recurrence remains unclear. Prospective studies that capture metformin exposure prior to, during and post endometrial cancer treatment may help define the role of metformin upon cancer specific and overall health outcomes.

An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC)

OBJECTIVES Stage I-II uterine papillary serous carcinoma (UPSC) patients have a significant risk for extrapelvic recurrence. However, clinicopathologic risk factors for recurrence are not well understood. This study was undertaken to define the prognostic factors for recurrence and survival in patients with early-stage UPSC. METHODS A retrospective, multi-institution analysis of surgically staged I-II UPSC patients was performed. Patients were treated by various adjuvant modalities. Age, race, sub-stage, percentage UPSC histology, lymphvascular space invasion (LVSI), tumor size and adjuvant treatment modality were evaluated for their effect on recurrence and survival outcomes. RESULTS We identified 206 patients. Forty patients (19.4%) had 5-49% UPSC, 55 (26.7%) had 50-99% and 111 patients (53.9%) had 100% UPSC in their respective uterine specimens. Twenty one percent of patients experienced a primary recurrence. On univariate analysis, age, increasing %UPSC, LVSI, and tumor size were not significantly associated with recurrence or progression-free survival (PFS). However, substage (p=0.005) and treatment with platinum/taxane-based chemotherapy (p=0.001) were associated with recurrence/PFS. On multivariate analysis, only chemotherapy (p=0.01) was a significant factor affecting PFS, whereas age (p=0.05), substage (p=0.05), and chemotherapy (p=0.02) were associated with overall survival. CONCLUSIONS Traditional risk factors for recurrence and survival in patients with early-stage endometrial cancer may not be relevant in patients with UPSC. Patients with any percentage UPSC in their uterine specimens are at a significant risk for recurrence and poor survival outcomes. Given that current clinicopathologic data does not accurately identify women most likely to benefit from adjuvant therapy, alternative prognostic markers based on novel techniques should be explored.

A multicenter evaluation of sequential multimodality therapy and clinical outcome for the treatment of advanced endometrial cancer.

OBJECTIVES The appropriate sequencing of chemotherapy and radiation for the treatment of advanced endometrial cancer has not yet been determined. We sought to evaluate the outcome and adverse effects in patients with advanced stage endometrial cancer treated with postoperative chemotherapy and radiation to determine whether there was an advantage to a particular sequencing modality. METHODS A multicenter retrospective analysis of patients with surgical stages III and IV endometrial cancer from 1993 to 2007 was conducted. Inclusion criteria were comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, +/- selective pelvic/aortic lymphadenectomy, and treatment with adjuvant chemotherapy and radiation. Differences in frequencies of adverse events were tested with Pearsons chi-square test for comparing proportions. OS and PFS rates were calculated using Kaplan-Meier estimates. Hazard Ratios (HR) were estimated from multivariate Cox proportional hazards models. RESULTS One hundred and nine patients with advanced stage endometrial cancer were identified who received postoperative adjuvant therapies; 41% (n=45) chemotherapy followed by radiation and then further chemotherapy (CRC), 17% (n=18) radiation followed by chemotherapy (RC), and 42% (n=46) chemotherapy followed by radiation (CR). The median age was 62 years (range: 35-83); 48% had endometrioid tumors; and 90% underwent optimal cytoreduction. There was no difference in the frequency of adverse effects due to either chemotherapy (p=0.35) or radiotherapy (p=0.14); dose modifications (p=0.055); or delays (p=0.80) between the various sequencing modalities. There was a significant difference between adjuvant treatment groups for both OS (log rank p=0.011) and PFS (log rank p=0.025), with those receiving CRC having a superior 3-year OS (88%) and PFS (69%) compared to RC (54% and 47%) or CR (57% and 52%). After adjusting for stage, age, grade, race, histology and cytoreduction status the OS HR for therapy was 5.74 (95% CI, 1.96 to 16.77) for RC and 2.60 (95% CI, 1.01 to 6.71) for CR, compared to CRC, p=0.003. When the analysis was restricted to optimally cytoreduced patients, those who were treated with RC were at higher risk for disease progression [HR=3.53 (95% CI, 1.29 to 9.71)], p=0.024, and death [HR=7.24 (95% CI, 2.25 to 23.37)], p=0.001, than patients who received sequential CRC. CONCLUSIONS Sequential CRC was associated with improved survival in women with advanced stage disease compared to other sequencing modalities with a similar adverse effect profile. Future clinical trials are needed to prospectively evaluate appropriate sequencing and types of adjuvant chemotherapy and radiotherapy for the treatment of advanced stage endometrial cancer.

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

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

Independent prognostic relevance of microvessel density in advanced epithelial ovarian cancer and associations between CD31, CD105, p53 status, and angiogenic marker expression: A Gynecologic Oncology Group study

OBJECTIVES The aims of this study were to examine prognostic significance of microvessel density (MVD) in previously-untreated, advanced epithelial ovarian cancer (EOC) and explore associations between MVD and factors that affect angiogenesis. METHODS MVD was determined by immunohistochemical expression of CD31 or CD105 in tumor sections from 106 women treated on GOG randomized phase III trials. Average MVD hotspots were quantified by light microscopy at high power (x400) and categorized as low (or=upper quartile). Immunoblot expression of MASPIN, THBS-1, bFGF, VEGF, VEGFR-1 and p53 status (mutation and overexpression) was previously determined. RESULTS Of 106 evaluable cases, 25% exhibited high CD31-MVD (>24.25 vessels/high power field [HPF]) or high CD105-MVD (>19.25 vessels/HPF). After adjusting for age and stratifying by GOG performance status, stage, cell type, grade, debulking status and treatment regimen, high versus low CD105-MVD was associated with increased risk of disease progression (hazard ratio [HR]=1.873; 95% confidence interval [CI]: 1.102-3.184; p=0.020), but not death (HR=1.125; 95% CI: 0.654-1.935; p=0.670) whereas CD31-MVD was not associated with risk of disease progression (HR=1.578; 95% CI=0.918-2.711; p=0.099) or death (HR=1.678; 95% CI=0.957-2.943; p=0.071). CD31-MVD was correlated with CD105-MVD (p=0.001) and MASPIN (p=0.016). Neither CD31-MVD nor CD105-MVD was associated with p53 status, THBS-1, bFGF, VEGF or VEGFR-1. CONCLUSIONS High MVD assessed using CD105, a marker of proliferating endothelial cells and neoangiogenesis, but not CD31 a pan-endothelial marker, appeared to be an independent prognostic factor for worse progression-free survival in women with advanced EOC after adjusting for prognostic clinical covariates.

Retrospective review of an intraoperative algorithm to predict lymph node metastasis in low-grade endometrial adenocarcinoma

OBJECTIVE To validate the Mayo algorithm to intraoperatively identify women with endometrial cancer in whom lymphadenectomy may be safely omitted. METHODS A multi-center retrospective chart review 1977-2010 was completed using two independent institutional endometrial cancer databases. Eligibility criteria were grade 1 or 2 endometrial carcinoma, low-risk histology, and myometrial invasion ≤ 50% on intraoperative pathology consultation; patients were considered to satisfy the Mayo criteria if, in addition to these, tumor diameter on the final pathology report was ≤ 2 cm. Analysis of nodal metastases, recurrent disease, and progression-free survival (PFS) using the Kaplan-Meier method was performed. RESULTS Six hundred and two patients met inclusion criteria for the study. Of 110 patients satisfying the Mayo algorithm with an adequate lymphadenectomy, 2 (1.8%) were diagnosed with lymph node metastasis and 4 (3.6%) subsequently developed recurrent disease. The Mayo algorithm identified with a 98.2% negative predictive value women who would not benefit from a lymphadenectomy. There was no significant difference in recurrence rate or PFS between women who underwent lymphadenectomy and those who did not when the Mayo algorithm was satisfied. CONCLUSIONS The Mayo algorithm intraoperatively identifies tumor characteristics of low-risk disease in endometrial carcinoma that predict a very low likelihood of nodal metastasis and recurrence. Although a small number of patients with advanced stage disease may be missed when applying the Mayo criteria, there is no apparent survival benefit to lymphadenectomy for patients satisfying this algorithm, and these data support its use at other institutions.