Total pelvic exenteration: the Albert Einstein College of Medicine/Montefiore Medical Center Experience (1987 to 2003).

OBJECTIVE: To review the trends, modifications and results of 103 consecutive total pelvic exenterations (TPE) performed at the Montefiore Medical Center and Albert Einstein College of Medicine from 1987 to 2003. METHODS: All patients who underwent TPE from January 1987 to December 2003 were included. The medical record, complications, follow-up, clinical status and demographic information were entered in a database. The procedure performed, the method of urinary diversion, colonic diversion, pelvic floor support and vaginal reconstruction were documented. Surviving patients were surveyed regarding their satisfaction with the urinary diversion, the vaginal reconstruction and their sexual function since the surgery. RESULTS: 103 pts were identified. Indications for TPE were recurrent cancers of the cervix (95), endometrium (2), colon and rectum (5), vulva (1). Overall 5-year survival was 47%. 5-year survival for pts with recurrent cervix cancer was 48%. Six pts (6%) recurred >5 years after the TPE. 14 pts (14%) had ureteral anastomotic leaks (no difference between ileal conduit 9/65 (14%) versus 5/38 (13%) continent conduit (P = 0.92). 34 pts (89%) with continent conduits were "continent." 14 pts (17%) had wound complications. 4 pts (4%) had parastomal hernias. 5/11 (46%) pts who had a low rectal reanastomosis developed recurrence in the pelvis. 21/39 (54%) of pts with continent conduits would choose an ileal conduit if they had the option again. Long-term renal function was similar in pts with ileal and continent conduits. Mesh of any type for pelvic floor reconstruction is associated with infection and bowel/urinary fistulas. VRAM flaps for neovagina fill the pelvic dead space, reduce the risk of fistulas and 20/36 pts (55%) are sexually active. CONCLUSIONS: Our overall 5-year survival is encouraging, and modifications in surgical technique have improved the reconstructive phase. Low rectal anastomoses at TPE adversely affects survival. Many of our pts with continent urinary diversions would not choose this method again. Mesh of any type is associated with sepsis and bowel/urinary fistulas. VRAM for neovagina reduces fistula rate and are functional in >55% of pts. TPE remains a potentially curative option for these pts.

Alpha-tocopherol and alpha-tocopheryl quinone levels in cervical intraepithelial neoplasia and cervical cancer.

OBJECTIVE: alpha-Tocopherol is a potent antioxidant that protects cell membranes against oxidative damage. Red blood cell alpha-tocopherol levels reflect membrane alpha-tocopherol concentrations, and altered levels may suggest membrane damage. The objective of this study was to determine the levels of alpha-tocopherol and alpha-tocopheryl quinone, the oxidized product of alpha-tocopherol, in plasma and red blood cells that were obtained from control subjects and patients with cervical intraepithelial neoplasia and cervical cancer. STUDY DESIGN: In this cross-sectional study, 72 women, (32 African American and 40 Hispanic) were recruited. Among these subjects, 37 women had cervical intraepithelial neoplasia; 14 women had cervical cancer, and 21 women were considered control subjects, who had normal Papanicolaou test results. alpha-Tocopherol and alpha-tocopheryl quinone levels were determined in red blood cell and plasma by high-pressure liquid chromatography. RESULTS: Plasma levels of alpha-tocopherol and alpha-tocopheryl quinone were decreased significantly (P=.012 and=.005, respectively, by Kruskal-Wallis test) in study groups compared with the control group; red blood cell levels of alpha-tocopherol and alpha-tocopheryl quinone were not altered significantly. CONCLUSION: The lower alpha-tocopherol level that was observed in this study is consistent with our previous reports of decreased antioxidant concentrations and increased oxidative stress in women with cervical intraepithelial neoplasia. Unaltered red blood cell alpha-tocopherol and alpha-tocopheryl quinone levels suggest undamaged cell membrane. Further studies are needed to investigate the potential role of oxidative stress in cervical intraepithelial neoplasia.

Evaluation of low-dose intraperitoneal interferon-alpha for palliation of ascites in patients with non-ovarian gynecologic malignancies.

OBJECTIVE: Intraperitoneal interferon-alpha (IP-IFNalpha) has shown some benefit in the treatment of patients with ovarian cancer. Our goal was to evaluate the use of low-dose IP-IFNalpha for the palliative control of ascites in non-ovarian gynecologic malignancies, including primary peritoneal and uterine papillary serous carcinomas. METHODS: Fifteen patients with non-ovarian gynecologic malignancies received one or two doses of 10 MU (10 x 10(6) U/m(2)) of IP-IFNalpha via single-use drum catheter for the symptomatic control of ascites. The median age for this patient group was 61 years (range 40-84). Histopathologic diagnoses were confirmed on all patients. Eleven of 15 (73%) patients had uterine cancers. Four of 15 (27%) patients had papillary serous primary peritoneal carcinomas. Thirteen of 15 (87%) patients had Stage III disease or more. All patients had been heavily pretreated with chemotherapy and all had progressive disease. RESULTS: Specific parameters used to evaluate IP-IFNalpha were (1) median survival; (2) number of days to recurrent ascites; (3) number of subsequent paracenteses required for symptomatic relief; and (4) symptomatology and side effects. Median overall survival was 3 months (range 0.5-13). Seven of 15 (47%) patients survived >3 months. Twelve of 15 (80%) patients had recurrent ascites within 30 days of treatment. However, 3/15 (20%) patients had a prolonged, >30-day period, without symptomatic ascites. One patient (6%) had a 270-day response with no ascites. Toxicity was minimal from IP-IFNalpha infusion. The most common side effect was fever in 6/15 (40%) patients. CONCLUSION: IP-IFNalpha was well tolerated and may have some benefit in a subset of patients. Although 80% of patients had recurrent ascites within 30 days, 20% had a prolonged, >30-day response. Further study is warranted to determine the role of immune modulators, such as IP-IFNalpha, in the palliative management of patients with non-ovarian gynecologic malignancies that cause ascites.

Extended-field radiotherapy and high-dose-rate brachytherapy in carcinoma of the uterine cervix: clinical experience with and without concomitant chemotherapy.

BACKGROUND: It has long been recognized that many patients with locally advanced carcinoma of the cervix harbor occult paraaortic metastases. A randomized study demonstrated that elective paraaortic irradiation improved survival and reduced distant metastases. More recently, concomitant chemotherapy with pelvic irradiation has improved survival among patients with locally advanced carcinoma of the cervix. This has led to a reexamination of the role of extended-field irradiation. An important issue is the toxicity of concomitant chemotherapy and extended-field radiotherapy. The authors report a retrospective analysis of their experience with extended-field radiotherapy and high-dose-rate brachytherapy with or without concomitant chemotherapy. METHODS: The authors treated 54 women with biopsy-confirmed carcinoma of the cervix using extended-field radiotherapy and high-dose-rate brachytherapy with or without concomitant chemotherapy. The histology was squamous cell carcinoma in 49 patients (91%) and nonsquamous cell carcinoma in 5 patients (9%). The median size of the primary tumor was 7 cm (range, 3-10 cm). Each patient received 45 grays (Gy) of external beam radiotherapy to the pelvis and the paraaortic region, followed by a parametrial boost (9 Gy) in the patients with disease extension to the parametrium or the pelvic side wall(s). Each patient also underwent two applications of high-dose-rate brachytherapy, 1 week apart. The median dose delivered to Point A from each application was 9 Gy. Forty-four of the 54 patients (81%) received concomitant chemotherapy (cisplatin, 20 mg/m(2)/day for 5 days) during the first and the fourth weeks of external beam radiotherapy, and once after the second high-dose rate application. Chemotherapy was not assigned randomly. RESULTS: One of the 10 patients (10%) treated without chemotherapy experienced acute toxicity, whereas 41 of 44 patients (93%) who received chemotherapy suffered from acute toxicity, including hematologic toxicity, gastrointestinal toxicity, and deep venous thrombosis. During a median follow-up period of 28 months (range, 12-70 months), 6 of the 54 patients have died (11%). The actuarial rate of local control at 3 years is 100% among the patients treated without chemotherapy, compared with 85% among those receiving chemotherapy. No one failed in the paraaortic region. The actuarial rates of freedom from distant metastases are 90% and 95% among the patients treated without and with chemotherapy, respectively. The actuarial incidence of late toxicity is 10% among the patients treated without chemotherapy and 6% among those receiving chemotherapy. CONCLUSIONS: The regimen of extended-field radiotherapy with concomitant cisplatin and high-dose-rate brachytherapy produced substantial acute toxicity, but its long-term toxicity is low and the preliminary tumor control excellent, albeit with limited follow-up. Only prospective, randomized trials can evaluate whether these results are truly better than those of pelvic radiotherapy with concomitant chemotherapy, or those of other regimens of extended-field radiotherapy with concomitant chemotherapy. Cancer 2003;97:1781-8.

Two fractions of high-dose-rate brachytherapy in the management of cervix cancer: clinical experience with and without chemotherapy.

PURPOSE: In recent years, high-dose-rate brachytherapy has become popular in the management of carcinoma of the uterine cervix, because it eliminates many of the problems associated with low-dose-rate brachytherapy. However, the optimum time-dose-fractionation remains controversial. Two fractions of high-dose-rate brachytherapy are convenient for patients, but most radiation oncologists in the United States do not use them, because of fear that they could lead to excessive rectal or bladder toxicity. Here we present our experience, which suggests that a two-fraction regimen is indeed safe and effective. METHODS: We treated 49 patients with Stages I-III biopsy-proven carcinoma of the uterine cervix by external beam radiation therapy (EBRT), plus two fractions of high-dose-rate brachytherapy. The histology was squamous cell carcinoma in 43 patients (88%) and nonsquamous in 6 (12%). The median size of the primary tumor was 6 cm (range: 3-10 cm). Each patient received EBRT to the pelvis to a median dose of 45 Gy (range: 41.4-50.4 Gy), followed by a parametrial boost when indicated. Thirty patients (61%) also received irradiation to the para-aortic lymph nodes to a dose of 45 Gy. After EBRT, each patient underwent two applications of high-dose-rate brachytherapy, 1 week apart. The dose delivered to point A was 9 Gy per application for 49 applications (50%) and 9.4 Gy for 43 applications (44%), and it varied from 7 to 11 Gy for the rest (6%). The total dose to the rectum from both high-dose-rate brachytherapy applications ranged from 4.7 to 11.7 Gy (median: 7.1 Gy), and the total dose to the bladder from 3.8 to 15.5 Gy (median: 10.5 Gy). Twenty-five of the 49 patients (51%) received concomitant chemotherapy (cisplatin 20 mg/m(2)/day for 5 days) during the first and fourth weeks of EBRT and once after the second high-dose-rate brachytherapy application. Chemotherapy was not assigned in a randomized fashion. The use of chemotherapy increased during the time period spanned by this study as increasing evidence supporting the use of chemotherapy began to appear. RESULTS: The observed survival rates after 2, 3, and 5 years were 83%, 78%, and 78%, respectively. The surviving patients have been followed up for a median of 3 years (range: 2-6 years). Eight of the 49 patients suffered local failures. Among patients treated without chemotherapy, the 3-year local control rate was 77%; it was 88% among those receiving chemotherapy. There have been no regional failures. Four patients developed distant metastases. At 3 years, 91% of the patients in each group were free of distant metastases. Ten of the 49 patients (20%) suffered Grade 3 acute toxicity; 11 (22%) had Grade 4. Among the 24 patients treated without chemotherapy, only 1 (4%) suffered Grade 3 toxicity. Among the 25 patients receiving chemotherapy, in contrast, 8 (32%) suffered Grade 3 and 12 (48%) Grade 4 acute toxicity. Only 2 patients suffered late toxicity: One suffered Grade 2 and the other Grade 3 late toxicity. The actuarial risk of Grade 2 or worse late toxicity was 5%, with or without chemotherapy. CONCLUSIONS: Our experience suggests that two fractions of high-dose-rate brachytherapy are safe and effective in the management of cervix cancer, even in conjunction with concomitant cisplatin. The fears that the use of two fractions would lead to excessive rectal or bladder toxicity proved unfounded. Guidelines for ensuring a low complication rate are discussed.

Expression of COX-2, Ki-67, cyclin D1, and P21 in endometrial endometrioid carcinomas.

COX-2, the isoform of cyclooxygenase inducible by cytokines, mitogens, and growth factors, appears to play an important role in inflammation and carcinogenesis. In the colon, COX-2 overexpression results in cell cycle alterations, and NSAIDs have proven effective in cancer chemoprevention. HNPCC (hereditary nonpolyposis colon cancer) is a clinically defined cancer susceptibility syndrome in which women are also at significantly increased risk for the development of endometrial carcinoma. The purpose of this study was to evaluate expression of COX-2 in benign and malignant endometrium in the context of other cell cycle and proliferation markers, including Ki-67, cyclin D1, and the cyclin-dependent kinase inhibitor, p21. Immunostains with COX-2, Ki-67, cyclin D1, and p21 antibodies were performed on formalin-fixed and paraffin-embedded tissue sections from 40 cases: 10 benign (5 atrophic and 5 proliferative) endometria, 6 hyperplasias (complex without atypia), and 24 endometrioid carcinomas (9 well, 4 moderately, and 11 poorly differentiated). Ki-67 was positive in all proliferative and neoplastic endometria. Cyclin D1 and p21 were both overexpressed in endometrial hyperplasia and endometrioid carcinomas. COX-2 was negative in the nonneoplastic endometrium, stained minimally in the well-differentiated endometrioid carcinomas, and stained most strongly in the moderately and poorly differentiated endometrioid carcinomas. Because cyclin D1 may function as an oncogene, its effects may dominate the usual inhibitory effect of a rising p21. Alternatively, it has been shown that p21 can promote cell cycle function by stabilizing cell cycle complexes. The overexpression of COX-2 in poorly differentiated endometrioid carcinoma and lack of expression in hyperplasia and well-differentiated carcinoma suggests that in this form of cancer, COX-2 may play a role in tumor progression rather than tumor initiation.