Jo Ann Benda

Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study.

PURPOSE To compare whole-abdominal irradiation (WAI) and doxorubicin-cisplatin (AP) chemotherapy in women with stage III or IV endometrial carcinoma having a maximum of 2 cm of postoperative residual disease. PATIENTS AND METHODS Four hundred twenty-two patients were entered onto this trial. Of 396 assessable patients, 202 were randomly allocated to receive WAI, and 194 were allocated to receive AP. Irradiation dosage was 30 Gy in 20 fractions, with a 15-Gy boost. Chemotherapy consisted of doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 every 3 weeks for seven cycles, followed by one cycle of cisplatin. RESULTS Most patient and tumor characteristics were well balanced. The median patient age was 63 years; 50% had endometrioid tumors. Median follow-up time was 74 months. The hazard ratio for progression adjusted for stage was 0.71 favoring AP (95% CI, 0.55 to 0.91; P < .01). At 60 months, 50% of patients receiving AP were predicted to be alive and disease free when adjusting for stage compared with 38% of patients receiving WAI. The stage-adjusted death hazard ratio was 0.68 (95% CI, 0.52 to 0.89; P < .01) favoring AP. Moreover, at 60 months and adjusting for stage, 55% of AP patients were predicted to be alive compared with 42% of WAI patients. Greater acute toxicity was seen with AP. Treatment probably contributed to the deaths of eight patients (4%) on the AP arm and five patients (2%) on the WAI arm. CONCLUSION Chemotherapy with AP significantly improved progression-free and overall survival compared with WAI. Nevertheless, further advances in efficacy and reduction in toxicity are clearly needed.

Randomized Phase III Trial of Cisplatin With or Without Topotecan in Carcinoma of the Uterine Cervix: A Gynecologic Oncology Group Study

PURPOSE On the basis of reported activity of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or topotecan plus cisplatin in advanced cervix cancer, we undertook a randomized trial comparing these combinations versus cisplatin alone, to determine whether survival is improved with either combination compared with cisplatin alone, and to compare toxicities and quality of life (QOL) among the regimens. PATIENTS AND METHODS Eligible patients were randomly allocated to receive cisplatin 50 mg/m(2) every 3 weeks (CPT); cisplatin 50 mg/m(2) day 1 plus topotecan 0.75 mg/m(2) days 1 to 3 every 3 weeks (CT); or methotrexate 30 mg/m(2) days 1, 15, and 22, vinblastine 3 mg/m(2) days 2, 15, and 22, doxorubicin 30 mg/m(2) day 2, and cisplatin 70 mg/m(2) day 2 every 4 weeks (MVAC). Survival was the primary end point; response rate and progression-free survival (PFS) were secondary end points. QOL data are reported separately. RESULTS The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths occurred among 63 patients, and is not included in this analysis. Two hundred ninety-four patients enrolled onto the remaining regimens: 146 to CPT and 147 to CT. Grade 3 to 4 hematologic toxicity was more common with CT. Patients receiving CT had statistically superior outcomes to those receiving CPT, with median overall survival of 9.4 and 6.5 months (P = .017), median PFS of 4.6 and 2.9 months (P = .014), and response rates of 27% and 13%, respectively. CONCLUSION This is the first randomized phase III trial to demonstrate a survival advantage for combination chemotherapy over cisplatin alone in advanced cervix cancer.

Phase III Study of Cisplatin With or Without Paclitaxel in Stage IVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study

PURPOSE To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Eligible: patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. RESULTS Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n = 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. CONCLUSION C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.

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.

Randomized Trial of Cisplatin and Ifosfamide With or Without Bleomycin in Squamous Carcinoma of the Cervix: A Gynecologic Oncology Group Study

PURPOSE Phase II trial reports have suggested that the addition of bleomycin to the combination of cisplatin and ifosfamide may improve response rates and possible survival in squamous carcinoma of the cervix. This study prospectively evaluates the combination of bleomycin to this regimen in women with histologically proven advanced recurrent or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Eligible women were randomized to receive either cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CI) versus bleomycin 30 units over 24 hours on day 1 followed by cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CIB). Three hundred three women were enrolled onto this trial, of which 287 were assessable. RESULTS There were no significant differences between CI and CIB with regard to response rates (32% v 31.2%, respectively), progression-free survival (PFS), or overall survival. PFS and survival were associated with initial performance status (PS). Patients with a PS of 0 experienced a lower rate of failure (P =.013) and a lower risk of death (P =.009) compared with patients with PS of 2. The most frequent grade 3/4 toxicities were leukopenia, neutropenia, anemia, thrombocytopenia, and nausea and vomiting. Neither regimen was associated with a significant increase in incidence of these toxicities. CONCLUSION The CI regimen was virtually identical to CIB with regard to response rate, PFS, survival, and toxicity profile. Thus, the addition of bleomycin in the dose-schedule employed to cisplatin and ifosfamide did not improve outcome in patients with advanced cervical cancer.

Obesity and prognosis in endometrial cancer.

OBJECTIVE We tested the null hypothesis that morbid obesity as measured by the Quetelet index has no influence on survival in endometrial cancer. STUDY DESIGN A retrospective study of 492 women with endometrial carcinoma was performed. Age, height, weight, Quetelet index, stage, cell type, grade, node status, peritoneal cytologic findings, and depth of myometrial invasion were analyzed for influence on survival. RESULTS Mean Quetelet index was 34 (range 16 to 89). Quetelet index was < 30 in 45% of patients, 30 to 40 in 33%, and > 40 in 22%. Five percent of those with a Quetelet index > 40 had positive nodes, but 64% of patients with a Quetelet index > 40 did not have lymph node sampling done. Lack of sampling of lymph nodes in the entire group had no adverse effect on survival. In a proportional hazards regression model for time from diagnosis to death from disease, grade, node status, myometrial invasion, and stage had highly significant effects. When Quetelet index was analyzed as a continuous variable, as Quetelet index increased, time to recurrence was significantly increased (p = 0.0136), and significance was approached for survival (p = 0.0645). Quetelet index was strongly related to grade (p = 0.013), depth of myometrial invasion (p = 0.031), negative cytologic findings (p = 0.004), and stage (p = 0.011) with obese patients having better differentiated, less invasive tumors of lower stage with negative washings. CONCLUSIONS Morbid obesity positively affects survival in endometrial carcinoma. This effect is accounted for by the association of obesity with less aggressive disease. Morbid obesity is not associated with increased death from other causes. Lack of sampling of negative lymph nodes does not adversely affect survival.

Evaluation of commonly used adjuvants in the prevention of postoperative adhesions

The uterine horns of 30 rats were subjected to both division and microsurgical anastomosis of the proximal segment and division only of the distal segment. They were equally assigned to three groups, of which group 2 received dexamethasone and group 3 received ibuprofen preoperatively and postoperatively for a total of eight doses. During operation, five rats of each group were irrigated with normal saline and the other five, with 32% dextran 70 (Hyskon). The left uterine horn was anastomosed with 7-0 coated Vicryl, and the right horn, with 7-0 Dexon-S sutures. At repeat laparotomy 2 weeks later, the intraperitoneal adhesions were graded blindly according to their severity. Tissue blocks were obtained from the areas of anastomosis and division only for histologic assessment. Total adhesion scores were 104 for group 1, 53 for group 2 (p less than 0.05), and 90 for group 3 (p = 0.7). The histologic evaluation showed no difference between the three groups. The inflammatory tissue reaction was least around the areas of division only and greatest at the anastomotic sites, where it was most pronounced around the surgical knots. No difference in gross adhesions or histologic assessment was observed between the left horn and the right horn. Adhesions were significantly less in the Hyskon-treated animals (p less than 0.05) but the histologic evaluation showed similar inflammatory reactions. These results suggest that in this species there is no difference between Dexon-S and coated Vicryl sutures, that dexamethasone and Hyskon are effective in preventing postoperative adhesions, and that the inflammatory tissue reaction is not altered by these adjuvants but is significantly augmented by the presence and quantity of suture material.

Promotion of neovascularization around hollow fiber bioartificial organs using biologically active substances

A limiting factor of the long-term function of bioartificial organs is oxygen delivery to the encapsulated tissue. This study determined whether incorporation of endothelial cell growth factor (ECGF) into the alginate core of a hollow fiber bioartificial organ will induce neovascularization around the hollow fiber. Polyethersulfone (PES) and polyvinylidine difluoride (PVDF) hollow fibers were examined. Endothelial cell growth factor was incorporated into sodium alginate, extruded into the lumen of hollow fibers, and cured in calcium chloride. Samples without ECGF were fabricated and used as controls. Hollow fibers were implanted into 16 rats. For each rat, two implants were placed subcutaneously and two intraperitoneally, one with and one without ECGF at each site. Implants were placed on opposite sides of each animal. Implants were removed 65 days later and examined using immunohistochemical methods and light microscopy to determine the extent of neovascularization. A total of 64 implants were used. Most intraperitoneal implants were found free floating but were encased within a 100-microm thick avascular fibrotic reaction. This finding was independent from the presence of ECGF. Hollow fibers without ECGF, implanted subcutaneously, also had an avascular fibrotic reaction surrounding each implant. Subcutaneous implants with incorporation of ECGF within the alginate core had marked neovascularization within the fibrotic overgrowth that surrounded these implants. This was most prevalent in hollow fibers, with the thin separation layer facing the fiber lumen irrespective of limiting pore size. Potent angiogenic factors, such as ECGF, incorporated into diffusion chamber bioartificial organs can promote neovascularization around the subcutaneously implanted hollow fiber and may improve oxygen delivery to the tissue encapsulated within devices based on this technology.

Ploidy analysis by flow cytometry and fluorescence in situ hybridization in hydropic placentas and gestational trophoblastic disease

Placentas with hydropic change may be hydropic degeneration (HD) or gestational trophoblastic disease (GTD), partial (PM) or complete (CM) hydatidiform mole. The separation of HD from PM and PM from CM by histological findings may be problematic in some cases and can be clarified with ploidy analysis. Fluorescence in situ hybridization (FISH) using a probe to chromosome 7 (D7Z1) was applied to tissue cut from paraffin blocks from 10 histologically representative cases each of HD, PM, and CM on which ploidy had been previously confirmed by flow cytometry from paraffin embedded tissue. Villous stromal cells and nonproliferative trophoblast were examined for number of signals/cell and percentage of cells/placenta with three hybridization signals. The mean number of hybridization signals/cell was HD 1.14; PM 1.79; and CM 1.17, with statistical significance between HD and PM (P < .0001), and PM and CM (P < .0001). The mean percentage of cells/placenta with three hybridization signals was HD 1.10%, PM 23.1%, and CM 2.11%, with statistical significance between HD and PM (P < .0001), and PM and CM (P < .0001). In addition, there was no overlap in the mean percentage of cells with three hybridization signals between HD and PM, and PM and CM. Chromosome 2 probe (D2Z1) was applied to tissues that had three chromosome 7 signals to exclude trisomy, and in all cases three signals were present confirming triploidy in PM. FISH can identify diploid and triploid hydropic placentas in paraffin-embedded tissue to assist in differentiating HD from PM, and PM from CM.

Mucin production in defining mixed carcinoma of the uterine cervix: a clinicopathologic study.

SummaryEighty-seven Stage I cervical carcinomas treated by radical hysterectomy between 1970 and 1979 were reviewed for histotogic type, outcome, and factors predicting behavior. Initially, the cases were histologically classified by the Wentz and Reagan system and graded according to the Broders method. Stains for intracellular mucin were then examined in 69 cases and 39% were shown to contain intracellular mucin. Using intracellular mucin as an indicator of mixed carcinoma, this study showed a distribution of 35% keratinizing, 16% nonkeratinizing, 3% small cell, 16% adeno-, 3% undiffer-entiated, and 26% mixed carcinoma. The mixed carcinomas were derived from the traditional keratinizing, nonkeratinizing and small cell categories. Mixed carcinoma was the only histologic type that predicted lymph node metastasis (p = 0.009). The presence of lymph node metastasis predicted death due to disease or recurrence (p = 0.014} as did pure adenocarcinoma histology (p = 0.025). Overall 5 year survival was 92%. Survival at 5 years for adenocarcinoma was 85%, but one additional death occurred at 12 years and a first recurrence occurred at 7 years. An additional patient with a collision tumor (adenocarcinoma and squamous carcinoma) died at 8 years. Mixed carcinoma is relatively common and appears to be associated with a higher incidence of lymph node metastasis. Adenocarcinoma appears to have a poorer prognosis and a tendency for late recurrence in distant sites.