Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326).

OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response.

Reduction of tumor necrosis factor-alpha bioactivity by a human ovarian epithelial cancer cell line in vitro.

OBJECTIVE: Our purpose was to determine the ability of an ovarian epithelial carcinoma cell line, Caov-3, to alter the bioactivity of exogenously added tumor necrosis factor-alpha. STUDY DESIGN: Caov-3 cells were cultured for up to 6 days in Dulbecco's modified Eagle's medium containing 10% fetal calf serum. The control and tumor necrosis factor-alpha-treated cells were analyzed for proliferation, distribution throughout the cell cycle by flow cytometry, their ability to release bioactive tumor necrosis factor-alpha by L929 bioassay, and their ability to release immunoreactive tumor necrosis factor-alpha by a specific double sandwich enzyme-linked immunosorbent assay. RESULTS: Tumor necrosis factor-alpha induced a dose- and time-dependent inhibition of cell proliferation accompanied by accumulation of cells in late S and G2/M phases of the cell cycle. Tumor necrosis factor-alpha bioactivity was undetectable in the media of control Caov-3 cell cultures, but these cells exhibited TNF-alpha messenger ribonucleic acid. After culture of the cells for 2 days in the presence of various doses of TNF-alpha (0.1, 1.0, 10, or 100 ng/ml), a significant decline (p < 0.01) in bioactivity was observed in all groups with the exception of 100 ng of TNF-alpha. Further declines in bioactivity were observed 2 and 4 days later. Addition of TNF-alpha to Caov-3 cells did not affect its immunoactivity, and Western blots of media revealed major bands of immunoactivity at approximately 17 kd, the expected molecular size of TNF-alpha. CONCLUSION: These results indicate that Caov-3 ovarian carcinoma cells reduce the bioactivity of TNF-alpha, an important growth regulator, by a novel yet unknown mechanism to escape the modulatory effects of the normal immune response during cancer cell growth.

Tumor necrosis factor-alpha in the female reproductive tract.

Tumor necrosis factor-alpha (TNF), originally identified as an inflammation-associated cytokine, is synthesized throughout the female reproductive tract as well as in placentas and embryos. Development, female sex steroid hormones, and lipopolysaccharide influence expression of this gene. The functions of TNF may be determined in part by differential expression of the two species of TNF receptors, both of which seem to be regulated by female sex steroid hormones. Evidence has accumulated that supports a role for this potent, pleiotropic cytokine in autocrine and paracrine processes central to reproduction, including gamete and follicle development, steroidogenesis, uterine cyclicity, placental differentiation, development of the embryo, and parturition.

Local anesthesia for cryosurgery on the cervix.

Forty-five patients were evaluated in a prospective, randomized study to determine the effectiveness of a local injection of lidocaine in reducing pain during cervical cryosurgery. Study patients received a submucosal cervical injection of 1% lidocaine with a 1:100,000 dilution of epinephrine. Control patients did not receive an injection. Both groups received a single dose of naproxen sodium or ketoprofen prior to the procedure. The patient and the observing nurse recorded the pain experienced with a visual analog scale (VAS). Nurse and patient response for the control and study groups showed a high correlation (r = .573 and P < .01, r = .673 and P < .001, respectively). The mean VAS score recorded for the 26 control patients was 4.27, significantly greater than the mean score for the 19 study patients, 1.16 (P < .001). These findings indicate that a submucosal local injection of lidocaine with epinephrine is effective in reducing pain during cervical cryosurgery.

Epithelial ovarian tumors of low malignant potential.

The records of 31 women with ovarian tumors of low malignant potential were retrospectively reviewed to identify factors that determine the prognosis. Median follow-up was 51 months. Eighteen women had stage I disease. Twenty-three women (74%) had serous tumors, of which 46% were bilateral. Nine patients (29%) had concomitant endometriosis or endosalpingiosis. Two patients died of disease; both had mucinous tumors with extraovarian metastases at initial operation and inadequate pathologic sampling of their tumors. These results were combined with those of 970 women identified in previous reports to show that the rate of recurrence or persistence of ovarian tumors rises from 2% for women with stage I disease to 14% for those with stage III or IV disease, while mortality rises from 2 to 5%. Careful staging and pathologic sampling are important for establishing the prognosis. Testing of adjuvant therapy should be limited to patients with extraovarian disease.

Diagnosis and management of brain metastasis from gestational trophoblastic disease.

Significant advances have been made since the introduction of methotrexate towards the improvement of long-term survival in patients with brain metastases from gestational trophoblastic disease. Early diagnosis via computed tomography of the head and beta-hCG serum testing along with aggressive, multiagent intervention have greatly improved patient prognosis from this once highly fatal condition. Although toxicity is commonly associated with this treatment, death from sepsis or drug reactions is unusual. Surgery has been found useful only to relieve intracranial pressure and is discouraged as part of diagnosis.

The prognostic significance of CA 125 half-life in patients with ovarian cancer who have received primary chemotherapy after surgical cytoreduction.

Fifty-four patients with advanced epithelial ovarian cancer were monitored with serial serum CA 125 levels after surgical cytoreduction and during multi-agent chemotherapy with cisplatin-containing regimens. CA 125 half-life of less than 20 days was associated with prolonged overall survival (p less than 0.015). In those patients who eventually were found to be disease-free at surgical surveillance procedures, normalization of serum CA 125 levels to less than 35 U/ml within 65 days of primary operation also suggested an improved survival (p less than 0.059).

Preoperative serum tumor-associated antigen levels in women with pelvic masses.

Preoperative sera were assayed for tumor-associated antigens CA 125, TAG 72, and CA 15-3 in 100 women with pelvic masses. Serum CA 125 levels were elevated above 65 U/mL in 83% of 42 patients with ovarian malignancies, in 58% of 12 patients with nonovarian malignancies, and in 17% of 46 patients with benign pelvic masses. Elevations of TAG 72 and CA 15-3 levels occurred less frequently in all groups of patients. Serum CA 125 levels distinguished most effectively between patients with malignant pelvic masses and those with benign pelvic masses, having a sensitivity of 78% and a specificity of 83% at a threshold level of 65 U/mL. When comparing 33 patients with epithelial ovarian carcinomas to 46 patients with benign masses, the CA 125 level alone yielded a sensitivity of 88% with a specificity of 83%. Coordinate elevations of CA 125 (above 65 U/mL) and TAG 72 (above 10 U/mL) or CA 15-3 (above 30 U/mL) distinguished ovarian epithelial carcinomas from benign masses with a sensitivity of 73% and a specificity of 98%, which improved to 81 and 100%, respectively, among patients over 50 years of age. Given the marked increase in specificity observed with this panel of three serum tumor-associated antigens, use of multiple markers might facilitate screening for ovarian carcinoma and appropriate referral of patients with pelvic masses for cytoreductive operations.

CA 125 in peritoneal fluid and serum from patients with benign gynecologic conditions and ovarian cancer.

CA 125 was measured in peritoneal fluid from 200 patients with primary ovarian malignancies (35) and benign gynecologic conditions (165). In 86 patients CA 125 was measured both in peritoneal fluid and in serum. Patients with ovarian cancer had markedly greater serum CA 125 levels compared to patients with benign disease. CA 125 levels in peritoneal fluid were usually higher than serum levels. Twenty-six (93%) of 28 patients with ovarian cancer had peritoneal fluid levels which exceeded serum levels in paired samples. peritoneal fluid CA 125 values greater than 200 U/ml identified ovarian cancer patients with 96% sensitivity and 99% specificity. Serum CA 125 values greater than 35 U/ml identified ovarian cancer patients bearing ascites with a sensitivity of 99% and specificity of 94%. Only 2 of 165 patients with benign gynecological conditions had peritoneal fluid values above 200 U/ml. By contrast, only two values below 200 U/ml were found in ascitic fluids from 35 patients with ovarian cancer. CA 125 levels in peritoneal fluid deserve further evaluation for follow-up of patients with ovarian cancer.

Short gracilis myocutaneous flaps for vulvovaginal reconstruction after radical pelvic surgery.

The short gracilis myocutaneous flap derives its blood supply from terminal branches of the obturator artery, and the vascular pedicle derived from the medial femoral circumflex artery is sacrificed. Twenty-one short gracilis myocutaneous flaps were used for vulvovaginal reconstructions in 11 patients undergoing radical pelvic surgery: bilateral flaps in nine patients for neovaginal construction after pelvic exenterations, bilateral flaps in one patient for vulvovaginal reconstruction after radical vulvovaginectomy, and a unilateral flap in one patient for vulvovaginal reconstruction after radical vulvectomy with partial vaginectomy. Major complications consisted of bilateral flap necrosis occurring in one patient who had received preoperative irradiation to the vulva and groin combined with chemotherapy. Minor degrees of necrosis (less than 5%) and/or separation of vaginal suture lines occurred in five patients without marked loss of the flaps. Vaginal caliber and depth are excellent in ten patients (91%) after follow-up of 1-22 months. The short gracilis flap is an excellent alternative to the more bulky gracilis flap, which derives its blood supply from perforating branches of the femoral artery. Based on our experience, the short gracilis flap provides adequately vascularized tissue for vulvovaginal reconstruction in patients after radical pelvic surgery, but should not be used in patients who have received extensive groin irradiation.