Cost benefit of intermittent pneumatic compression for venous thromboembolism prophylaxis in general surgery.

AIM: In moderate to high-risk general surgical patients, the cost effectiveness of mechanical prophylaxis for venous thromboembolism (VTE) is uncertain. Therefore, we determined the costs and savings of intermittent pneumatic compression (IPC) plus graduated compression stockings (GCS). METHODS: Postoperative VTE events in the absence of prophylaxis, efficacy of prophylaxis and costs of prophylaxis have been obtained from the English literature and Medicare 2004 reimbursement schedule. RESULTS: In 1000 moderate to high risk general surgical patients, in the absence of prophylaxis, the cost of investigating and treating 72 patients with clinical suspicion of DVT and 32 with PE is calculated to be $263,779. This corresponds to a cost of $263 per surgical patient. The cost of IPC combined with TED stockings in 1000 similar patients would be $66 760, and the cost of diagnosis and treatment of the reduced numbers (69% reduction) of clinical VTE is $ 83,574 making a total of $150 344. This means a saving of $133,435 ($263,779 - $150,344) per 1000 patients. This corresponds to a saving of $113 per surgical patient. Sensitivity analysis demonstrates that despite variation in costs or efficacy for IPC plus GCS, marked savings persist. CONCLUSIONS: Prophylaxis with IPC not only prevents VTE but also saves money.

Defining practice patterns in gynecologic oncology to prevent pulmonary embolism and deep venous thrombosis.

OBJECTIVE: The goal of venous thromboembolism (VTE) prophylaxis is to reduce the morbidity and mortality associated with the development of a deep venous thrombosis (DVT) or pulmonary embolism (PE). Because women with gynecologic cancers are at high risk to develop VTE, we sought to determine the present practice patterns of gynecologic oncologists regarding their use of VTE prophylaxis. METHODS: 1073 members of the Society of Gynecologic Oncologists (SGO) were mailed surveys that asked about preferred methods to prevent the development of VTE after gynecologic oncology surgery. Data were collected by online member entry and return mail. Frequency distributions were calculated and nonparametric test used for comparisons. RESULTS: 343/1073 (34%) of SGO members and fellows responded. 142/343 (42%) preferred double prophylaxis consisting of external pneumatic compression (EPC) and an anticoagulant while 41% (n=141) preferred EPC with no additional anticoagulation. Of respondents choosing any anticoagulant, 40% preferred Enoxaparin pre- and/or postoperatively. Ovarian cancer patients were perceived by respondents to have the highest risk of developing a postoperative PE. CONCLUSIONS: Most respondents agree that women with gynecologic cancers undergoing major surgery should receive VTE prophylaxis, though there is not agreement as to which method is optimal. While 42% of members preferred double prophylaxis, 41% chose no additional measures other than EPC. Randomized studies in gynecologic oncology should be initiated in the United States to determine the optimal practice pattern.

Comparison of gracilis and rectus abdominis myocutaneous flap neovaginal reconstruction performed during radical pelvic surgery: flap-specific morbidity.

To compare flap-specific complications of gracilis myocutaneous (GM) and rectus abdominis myocutaneous (RAM) flap neovaginal reconstructions after radical pelvic surgery. The study was a single-institution retrospective review of patients undergoing concurrent radical pelvic surgery with GM or RAM neovaginal reconstructions performed on a gynecological oncology service, 1978-2003. Flap-specific complications were compared between the techniques. Forty-four GM and 32 RAM neovaginal reconstructions were analyzed: plastic surgeons developed 12 (27%) GM and 4 (13%) RAM flaps, with all other flaps performed by gynecological oncologists. Primary procedures included 54 (71%) total pelvic exenterations, with partial exenterations or radical vulvovaginectomies in 16 (21%) and 6 (8%) patients, respectively. Forty (53%) patients had received radiation and 28 (36%) received chemoradiation before radical surgery. There were no significant differences in patient characteristics, other than more frequent use of continent urinary conduits (P < 0.001) and a trend for more frequent sidewall radiation (P < 0.1) in the RAM group, reflecting use in more recent patients (P < 0.001). Median follow-up is 28 months (range: 2 weeks to 216 months), with 5% acute operative mortality. Flap-specific complications were significantly increased in GM patients (P < 0.03). Overall flap loss was significantly increased in GM patients (P < 0.02). Thirty (59%) of 51 patients surviving for more than 12 months reported coitus, with no significant difference between the groups. Because of lower overall incidence of flap-specific complications and significantly lower incidence of flap loss compared with GM flap, RAM flap has become our technique of choice for neovaginal reconstruction concurrent with radical pelvic surgery.

High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients.

PURPOSE: To report our recent experience managing four patients with brain metastases of gestational trophoblastic neoplasia (GTN), coordinating systemic chemotherapy with early neurosurgical intervention or stereotactic radiosurgery and intensive supportive care during initial therapy to prevent early mortality. MATERIALS AND METHODS: A series of four consecutive patients with brain metastases from high-risk Stage IV GTN managed at our institution in 2003 and 2005. Patients were assigned FIGO stage and risk score prospectively. Because of concern for chronic toxicity resulting from concurrent moderate dose methotrexate and whole brain radiation, an individualized multidisciplinary approach was used to manage patients. RESULTS: All four women presented with brain and pulmonary metastases; one had multiple liver metastases. Neurological symptoms at presentation included grand mal seizures in 2 patients, left upper extremity hemiparesis and headache each in 1 patient, while 1 patient was asymptomatic. Index pregnancies were term pregnancies in all patients with interval from prior delivery ranging from 2 weeks to 4 years. Two had received prior chemotherapy for postmolar GTN prior to the index pregnancy with incomplete follow-up. Initial hCG values ranged from 26,400 to 137,751 mIU/ml; FIGO risk scores were > or =16 for all patients. Systemic combination chemotherapy was initiated with etoposide and cisplatin followed by moderate/high-dose (500-1000 mg/m(2)) methotrexate combinations. Craniotomy was used before or during the first chemotherapy cycle to extirpate solitary lesions in 3 patients, while stereotactic radiosurgery was administered after the first cycle to treat two brain lesions in the remaining patient. None received whole brain radiation or intrathecal methotrexate. In one patient, selective angiographic embolization was used to control hemorrhage from multiple liver metastases. Two patients required ventilator support early in treatment to allow stabilization from intrathoracic hemorrhage and neutropenic sepsis with respiratory distress syndrome, respectively. Hysterectomy was performed in one patient after completion of salvage chemotherapy. All have completed maintenance chemotherapy and are in prolonged remission (12-24 months). Neurologic sequelae include persistent left upper extremity dyskinesia and weakness in one patient, and episodic grand mal seizures and pseudoseizures in a second patient with a pre-existing seizure disorder. CONCLUSION: This case series documents the utility for a multidisciplinary approach to the treatment of brain metastases from GTN. Using early craniotomy or stereotactic radiosurgery combined with etoposide-cisplatin and moderate/high-dose methotrexate combination chemotherapy, we were able to stabilize patients early in their treatment and avoid whole brain radiation therapy or intrathecal chemotherapy.

Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer.

OBJECTIVE: A phase I/II study of Doxil combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects. PATIENTS AND METHODS: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil at a dose of 40 mg m-2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle. RESULTS: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60 min after either average vaginal and rectal temperatures of 40 degrees C had been achieved or after 30 min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2-8) and six patients had been previously treated with Doxil. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3-4 PPE toxicity. Doxil systemic exposure was higher in those with grade 3-4 PPE compared to those with no PPE. None of the patients had grade 3-4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy. CONCLUSIONS: Therapy with intravenous Doxil and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.

Rectus abdominis myocutaneous flaps for neovaginal reconstruction after radical pelvic surgery.

The objective of this article is to compare the flap-specific complications associated with vertical (VRAM) and transverse (TRAM) rectus abdominis myocutaneous flap vaginal reconstructions performed during radical pelvic procedures. A retrospective chart review was performed to identify all patients who underwent VRAM and TRAM neovaginal reconstructions performed on the Gynecologic Oncology Service at Duke University Medical Center. Flap-specific complications were compared between the two techniques. From 1988 to 2003, 14 VRAM and 18 TRAM flap neovaginal reconstructions were performed on 32 women during the course of 22 (68%) total pelvic exenterations, 8 (25%) partial exenterations, and 2 (6%) radical vulvovaginectomies. Twenty-eight (88%) patients had been previously treated with radiation therapy or concurrent chemoradiation. Associated procedures included continent urinary conduit in 21 (66%), rectosigmoid reanastomosis in 8 (25%), and intraoperative or postoperative sidewall radiation therapy in 7 (22%) of patients. Overall median survival was 14 months (range: 2-week postoperative death to 65 months), with two (6%) acute postoperative mortalities. Fifteen flap-specific complications occurred in 12 (38%) patients, with no significant differences in flap type. Abdominal wound complications included four (12%) superficial wound separations, while one (3%) patient had a fascial dehiscence associated with complex fistulas that contributed to her death, but no patient developed incisional hernia. One patient each developed > 50% flap loss after TRAM and < 50% flap loss after VRAM flap, respectively. Four (12%) patients developed vaginal stricture or stenosis, two (6%) required percutaneous drainage of pelvic abscess or hematoma, and two (6%) developed rectovaginal fistula. Univariate analysis revealed a trend for increasing flap loss with body mass index > 35 (P = 0.056, Fisher exact two-tailed test), but there were no significant associations with other patient characteristics or flap-specific complications. Thirteen (62%) of 21 patients who survived >12 months reported coitus. Both VRAM and TRAM are reliable techniques for neovaginal reconstructions after radical pelvic surgery and have a similar distribution of flap-specific complications involving the donor and recipient sites.

Cost-effectiveness of combination thromboembolism prophylaxis in gynecologic oncology surgery.

OBJECTIVE: To compare the cost-effectiveness of external pneumatic compression devices with and without the addition of low-molecular-weight heparin for the prevention of deep vein thrombosis in high-risk surgical patients with gynecologic cancer. METHODS: A Markov decision analytic model was used to estimate the costs and outcomes associated with the prophylactic use of external pneumatic compression with and without low-molecular-weight heparin in patients undergoing gynecologic surgery. We estimated cost per fatal pulmonary embolus prevented, cost per deep vein thrombus prevented, and cost per life-year saved. Probability estimates for various outcomes and efficacies were obtained from the literature, using data specific for gynecologic surgery patients when available. RESULTS: In the base case scenario, cost-effectiveness estimates for combination prophylaxis varied from 10,091 dollars per life-year saved for a 35-year-old patient with IB cervix cancer patient to 50,181 dollars for a 65-year-old patient with stage IIIC ovarian cancer, costs within the 50,000-65,000 dollars per life-year saved threshold considered to be cost-effective. Combination prophylaxis appeared to be cost-effective in gynecologic oncology patients as long as the risk of perioperative thromboembolism using this method of prevention was less than or equal to 4%. Sensitivity analysis indicated that variation of the marginal cost of low-molecular-weight heparin and the marginal effectiveness to extremes did not change the conclusions of the statistical model. CONCLUSION: The use of combination therapy external pneumatic compression is estimated to be cost-effective for high-risk gynecologic oncology patients undergoing surgery. Clinical trials to determine the efficacy of perioperative combination therapy in gynecologic surgery are justified.

Oral topotecan as single-agent second-line chemotherapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age > or = 18 years, performance status < or = 2, and life expectancy > or = 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial.

OBJECTIVE: To compare the efficacy and treatment-related complications of low molecular weight heparin and external pneumatic compression in the prevention of venous thromboembolism of postoperative gynecologic oncology patients. METHODS: A total of 211 patients over age 40 years, undergoing a major operative procedure for gynecologic malignancy, were randomized to receive perioperative thromboembolism prophylaxis with either low molecular weight heparin (n = 105) or external pneumatic compression (n = 106). Demographic data and clinical outcome were recorded for each patient. All patients underwent bilateral Doppler ultrasound of the lower extremities on postoperative days 3-5 to evaluate for the presence of occult deep vein thrombosis. A follow-up interview 30 days after surgery sought to detect patients who developed deep vein thrombosis or pulmonary embolism after hospital discharge. RESULTS: Venous thrombosis was diagnosed in two patients receiving low molecular weight heparin and in one patient receiving external pneumatic compression. The frequency of bleeding complications, measured by the number of required perioperative transfusions, and estimated intraoperative blood loss was similar between the two groups. CONCLUSION: Low molecular weight heparin and external pneumatic compression are similarly effective in the postoperative prophylaxis of thromboembolism. The use of low molecular weight heparin is not associated with an increased risk of bleeding complications when compared with external pneumatic compression. We believe that both modalities are reasonable choices for prophylaxis in this high-risk group of patients.

The outcome of stage I-II clinically and surgically staged papillary serous and clear cell endometrial cancers when compared with endometrioid carcinoma.

PURPOSE: The aim of this study was to compare survival and recurrence in clinical and surgical stage I-II papillary serous (PS), clear cell (CC), and endometrioid (EM) cancers of the endometrium and examine the prognostic utility of myometrial invasion. METHODS: Clinical, surgicopathologic, and survival data were retrospectively collected on 574 clinical stage I-II endometrial cancer patients, including 53 PS and 18 CC (based on postoperative histology), undergoing hysterectomy at Duke University Medical Center between 1967 and 1990. All staging material was available and reexamined prior to this analysis, and FIGO surgical staging was retrospectively assigned. Prognostic variables examined included age, stage, grade, myometrial invasion, lymph-vascular space invasion (LVSI), and histology. PS and CC histologic subtypes were compared as both common category and discrete categories versus EM, EM grade 1 (EM1), EM grade 2 (EM2), and EM grade 3 (EM3). Statistical analyses were performed using chi(2), Fisher's exact, and Wilcoxon rank sum tests, Cox regression analysis, and Kaplan-Meier survival analysis. RESULTS: PS tumors accounted for 9%, CC for 3%, and EM for 88% of cases. Recurrences were more frequent among PS (38%) and CC (22%) compared with EM (9%) (P < 0.001 and 0.08, respectively), and PS recurred more frequently than EM3 alone (20%) (P = 0.06). Among PS, CC, and EM3 patients with recurrences there were no statistical differences in the proportion that received preoperative or postoperative radiotherapy or chemotherapy. Prognostic factors for shorter survival included age >=60, surgical stage III+IV, presence of LVSI, histology (PS, CC, or EM3), and >=50% myometrial invasion. The estimated 5-year survival of PS+CC patients with <2 mm myometrial invasion is 0.56 compared to 0.93 for EM patients (P < 0. 001). PS + CC tumors confined to the endometrium had a 5-year survival of 0.60 compared to 0.98 and 1.00 for EM and EM3, respectively. The 5-year survival for surgically staged IA patients (0.57) was not different from stages IB and IC combined (0.53) (P = 0.72). The 5-year survival for surgical stage I + II PS + CC patients (0.56) was comparable to that for clinical stage I + II PS + CC patients (0.46) and remained significantly smaller than that for EM patients (0.86) (P < 0.001). CONCLUSION: Recurrences are more frequent among PS and CC tumors compared with EM and among PS compared with EM3. When controlled for surgical stage I-II tumors, 5-year survival for PS + CC patients remains comparable to that of clinical stage I-II patients and below that of EM. Prognostic factors for survival in PS and CC patients include age, stage, and LVSI. PS, CC, and EM3 subtypes together are predictors of poor survival. Thorough extended surgical staging is indicated in PS and CC tumors, and prospective trials of aggressive adjuvant therapies for surgical stage I-II tumors are needed to improve outcome in PS and CC patients.

Cost-effectiveness of deep venous thrombosis prophylaxis in gynecologic oncology surgery.

OBJECTIVE: To estimate the cost-effectiveness of preventive strategies for deep vein thrombosis (DVT) in patients undergoing surgery for gynecologic cancer. METHODS: A model was constructed to estimate the costs and outcomes associated with the use of external pneumatic compression, unfractionated heparin, and low molecular weight heparin in women with cervical, endometrial, and ovarian cancer. We estimated cost per DVT prevented, per fatal pulmonary embolus (PE) prevented, and per life-year saved. Probability estimates for various outcomes and efficacies were obtained from the literature, using data specific for gynecologic patients when available. RESULTS: Cost-effectiveness estimates ranged from $27 per life-year saved for a 55-year-old endometrial cancer patient to $5132 per life-year saved for a 65-year-old with ovarian cancer. Although low molecular weight heparin and unfractionated heparin were cost-effective compared with no prophylaxis, each was less effective than external pneumatic compression in the base case. The results of the analysis were sensitive to assumptions about the relative risk of DVT, the life expectancy of the patient, the costs of future treatment, and the relative effectiveness of the different strategies: If unfractionated heparin or low molecular weight heparin is at least 2-3% more effective than external pneumatic compression, then the incremental cost per life-year of either would be less than $50,000 compared with external pneumatic compression. CONCLUSION: Prophylaxis of DVT is cost-effective in terms of life-years gained even for patients with relatively short life expectancies, such as ovarian cancer patients. External pneumatic compression appears to be the most cost-effective strategy under our baseline assumptions, but further studies in gynecologic cancer are needed to validate our conclusions.

Epidemiologic and surgicopathologic findings of papillary serous and clear cell endometrial cancers when compared to endometrioid carcinoma.

PURPOSE: The aim of this study was to identify similarities and differences in epidemiologic and surgicopathologic staging results for papillary serous (PS) and clear cell (CC) endometrial cancers compared with endometrioid (EM) carcinoma of the endometrium. METHODS: Clinical and surgicopathologic data were retrospectively collected on 574 clinical stage I-II endometrial cancer patients, including 53 PS and 18 CC (based on postoperative histology), undergoing hysterectomy at Duke University Medical Center between 1967 and 1990. All staging material was available and reexamined prior to this analysis, and FIGO surgical staging was retrospectively assigned. PS and CC histologic subtypes were compared both as a common category and as discrete categories versus EM, EM grade 1 (EM1), EM grade 2 (EM2), and EM grade 3 (EM3). Fisher's exact test was used to compare proportions with unordered categories (2x2 tables), while the chi(2) test for trend was used to compare proportions in 3x2 tables with ordered categories. Differences in medians were compared with the Wilcoxon rank-sum test. RESULTS: PS tumors accounted for 8%, CC for 2%, and EM for 90% of cases. Overall, 14% of tumors were changed to a different postoperative histology including 64% of PS, 50% of CC, and 8% of EM. Postoperative histology changes were 4% for EM1 and 21% for EM3. PS, CC, and EM3 had more surgical sampling performed than for other EM. Rates for lymph node dissections were similar for EM3 (81%), PS (72%), and CC (67%) tumors, although metastases were more frequent for PS and CC compared with EM3. When PS tumors were confined to the endometrium, paraaortic metastases occurred in 13%. LVSI increased with EM grade and was highest for PS and CC. Upstaging to surgical stage III-IV occurred in 47% of PS, 39% of CC, and 12% of EM. The majority of PS and CC tumors were confined to the inner one-third of the myometrium, compared with EM tumors, where grade correlated with depth of myometrial invasion. Extrauterine metastases occurred in 55% of PS and 45% of CC tumors confined to the inner one-half, compared with 17% of EM3. CONCLUSION: Frequent changes from preoperative to postoperative histology and grade may contribute to misassignment of preoperative and intraoperative risk as determined by depth of myometrial invasion for PS and CC patients. The higher frequency of extrauterine metastases in PS and CC tumors compared with EM3, despite similar surgical sampling rates, supports a more virulent behavior. The poor correlation between depth of myometrial invasion and risk for extrauterine metastases helps to explain poorer survival in PS and CC patients, in addition to more frequent upstaging. These results support routine extended surgical staging for women with preoperative or intraoperative diagnosis of PS and CC tumors. Intraoperative assessment of tumor grade and histology may be indicated and warrants further investigation.

Cost-effectiveness of treatment of early stage endometrial cancer.

OBJECTIVE: The purpose of this study was to determine the average life-years gained and cost per life-year gained in treatment of early endometrial cancer. METHODS: We performed a decision analysis using statistical models for survival after treatment for Stage I endometrial cancer. Estimates for survival probabilities without treatment, with surgery alone, and with surgery and radiation were derived from the literature. Charges and costs of treatment were estimated based on data from our institution. We calculated the average number of life-years gained and the cost per life-year gained of various treatment options based on these estimates. Sensitivity analyses were performed to determine the effect of uncertainty about parameter estimates on the results derived from our model. RESULTS: Based on the assumptions of our model, most of the life-years gained in treatment of early endometrial cancer are attributable to hysterectomy, with a very low associated cost. For the "average" woman with endometrial cancer, about 10 life-years are gained from hysterectomy at a cost of $1000 per life-year gained, whereas adjuvant radiation yields on average 1 year of life gained at $4000 per life-year gained. Both life-years gained and cost are dramatically affected by age at diagnosis and to a lesser extent by histologic grade and comorbid medical conditions. CONCLUSIONS: This analysis suggests that the use of hysterectomy and adjuvant radiation in treatment of early endometrial cancer is a worthwhile use of health care resources. More sophisticated models may help determine the cost-effectiveness of various treatment strategies in specific subgroups of patients.

Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study.

PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer.

BACKGROUND AND METHODS: On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens -- cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone -- in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 micromol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3). RESULTS: The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively. CONCLUSIONS: Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.

Suppression of diacylglycerol levels by antibodies reactive with the c-erbB-2 (HER-2/neu) gene product p185c-erbB-2 in breast and ovarian cancer cell lines.

Seven of 10 murine monoclonal antibodies reactive with the extracellular domain of p185c-erbB-2 inhibited the anchorage independent growth of the SKBr3 breast cancer cell line that overexpressed p185c-erbB-2. Significant inhibition (56-72%) of diacylglycerol (DAG) levels (P < 0.0001) was observed with the 10 antibodies that inhibited SKBr3 growth (RC1, NB3, RC6, PB3, 741F8, DB5, ID5), whereas the 3 antibodies (TA1, 520C9, 454C11) that failed to inhibit SKBr3 growth also failed to affect DAG levels. Thus, DAG levels correlated with antibody-mediated growth regulation for each of the 10 monoclonal reagents. Antibody-induced inhibition of anchorage-independent growth of SKBr3 could be reversed by incubation with phorbol myristate acetate. The ID5 antibody inhibited growth of the SKBr3, SKOv3, and OVCA 432 tumor cell lines, but not of OVCA 420, OVCA 429, and OVCA 433. DAG levels were significantly decreased after ID5 treatment of the SKBr3 and SKOv3 cell lines, but not the OVCA 420, OVCA 429, and OVCA 433 lines. In the 432 line, there was a decrease which did not reach significance. Consequently, changes in DAG levels correlated with growth regulation in 5 of 6 breast and ovarian carcinoma cell lines tested with a trend toward correlation in the sixth. Decreases in DAG may be one mediator of the growth regulatory signals produced by anti-p185c-erbB-2 antibodies.

Racial disparity in overexpression of the p53 tumor suppressor gene in stage I endometrial cancer.

OBJECTIVE: This study was conducted to determine whether overexpression of the p53 tumor suppressor gene is associated with poor outcome in early-stage endometrial cancers and whether a racial difference in the frequency of p53 overexpression contributes to the observed racial disparity in survival rates. STUDY DESIGN: Immunostaining for the p53 gene was performed in 164 women with stage I endometrial adenocarcinomas. RESULTS: Overexpression of mutant p53 protein was seen in 28 out of 164 (17%) cases and was associated with a poor histologic grade (p = 0.003) and a nonendometrioid histologic appearance (p = 0.06). Overexpression also was three times more frequent in blacks (15 out of 44, 34%) than in whites (13 out of 117, 11%) (p = 0.003). Recurrent disease developed in 15 out of 164 (9%) cases and was more than twice as frequent in cases when the p53 gene was overexpressed (5 out of 28, 18%) than in cases with normal expression (10 out of 136, 7%). Recurrent disease was seen in 6 out of 44 (14%) blacks compared to 9 out of 117 (8%) whites. CONCLUSIONS: These data support the hypothesis that differences in the frequency of alteration of the p53 tumor suppressor gene contribute to the racial disparity in endometrial cancer survival.

Comparison of combination therapy with paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with suboptimal stage III and stage IV ovarian cancer: a Gynecologic Oncology Group study.

This prospective study compared the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin with the standard therapy of cyclophosphamide/cisplatin in women with suboptimal stage III and stage IV ovarian cancer. Of the initial 410 women who presented with advanced disease and greater than 1 cm residual masses after initial surgery, 386 met all eligibility criteria and were randomly assigned to receive a regimen of cisplatin 75 mg/m2 and cyclophosphamide 750 mg/m2 or cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 delivered over 24 hours. Dosage reductions were permitted in the event of significant toxicity. Among 216 patients with measurable disease, responses were reported in 73% of those receiving cisplatin/paclitaxel and in 60% of those receiving cisplatin/cyclophosphamide. Median progression-free survival was significantly longer (P < .001) in the group treated with cisplatin/paclitaxel, compared with those receiving cisplatin/cyclophosphamide (17.9 v 12.9 months, respectively).

Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study.

PURPOSE: Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone. PATIENTS AND METHODS: Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival. RESULTS: CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05). CONCLUSION: CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.