Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study.

Cisplatin has proven to be the most active single agent in the treatment of metastatic and recurrent squamous cell cancer of the cervix. In a previous southwest Oncology Group (SWOG) pilot study, the addition of cisplatin to a mitomycin-C, vincristine, and bleomycin (MVB) regimen resulted in a relatively high percentage of durable complete responses. To gain more experience with cisplatin-based chemotherapy regimens, the SWOG initiated a phase II randomized trial of cisplatin, mitomycin-C plus cisplatin (MC), and MVB plus cisplatin (MVBC) in 119 patients with advanced squamous cell cancer of the cervix and no prior chemotherapy exposure. Because of slow patient accrual early in the trial, the cisplatin arm was discontinued. Five patients were declared ineligible according to protocol criteria. The three treatment groups were relatively well matched for age, prior radiation exposure, and sites of measurable disease. The overall objective response rates for cisplatin, MC, and MVBC treated patients were 33%, 25%, and 22%, respectively. Median response durations were greater than 6 months. Median survival durations associated with cisplatin, MC, and MVBC treatment were 17.0, 7.0, and 6.9 months, respectively. There were no drug-related deaths. Severe or life-threatening leukopenia and thrombocytopenia were observed in 18% to 24% of patients treated with MVBC and MC, but in none of those receiving cisplatin alone. We conclude that the low response rates and short durations of both response and survival observed in patients randomized to the two chemotherapy combinations suggest that only enhanced toxicity was gained through the addition of mitomycin-C or MVB to cisplatin in patients with advanced cervix cancer.

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.

Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer.

PURPOSE: To compare cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide as primary chemotherapy for stage III (suboptimal) and stage IV ovarian cancer. PATIENTS AND METHODS: Three hundred forty-two patients were randomly assigned to treatment with six courses of intravenous (i.v.) cisplatin 100 mg/m2 plus i.v. cyclophosphamide 600 mg/m2, or i.v. carboplatin 300 mg/m2 plus i.v. cyclophosphamide 600 mg/m2. RESULTS: The estimated median survivals were 17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively. The null hypothesis of a 30% survival superiority with the cisplatin arm was rejected at the P = .02 level. Clinical response rates were 52% for the cisplatin arm and 61% for the carboplatin arm. Pathologic complete response rates were similar for both study arms. There was less thrombocytopenia on the cisplatin arm (P less than .001); however, there was less nausea and emesis (P less than or equal to .001 for courses 1 to 5), renal toxicity (P less than .001), anemia (P = .01), hearing loss (P less than .001), tinnitus (P = .01), neuromuscular toxicities (P = .001), and alopecia (P less than .001) on the carboplatin arm. CONCLUSION: Carboplatin-cyclophosphamide proved to have a significantly better therapeutic index than cisplatin-cyclophosphamide in patients with stage III (suboptimal) and stage IV ovarian cancer.

Hyperinsulinemia and stromal luteinization of the ovaries in postmenopausal women with endometrial cancer.

Ovarian secretion of testosterone and androstenedione is increased in postmenopausal women with endometrial cancer, and insulin stimulates ovarian stromal androgen synthesis in vitro. We undertook this study to investigate whether women with endometrial cancer have increased serum immunoreactive insulin levels. Ten postmenopausal women with endometrial carcinoma and 10 postmenopausal women without cancer who matched the cancer patients in age, years since menopause, and percentage of ideal body weight were studied. The women with endometrial cancer had significantly higher fasting serum insulin levels than the normal women [mean, 187 +/- 26 (+/- SE) vs. 55 +/- 11 pmol/L; P less than 0.01]. The cancer patients had significantly higher insulin responses after glucose administration than normal women (sum of 1, 2, and 3 h postglucose values, 5545 +/- 1526 vs. 1444 +/- 156 pmol/L; P less than 0.02), even though their glucose responses were similar. Nests of luteinized cells, which were positive for testosterone by immunoperoxidase staining, were found in the ovarian stroma of 8 of the women with endometrial cancer, but in only 1 of those without cancer (P less than 0.01). Specific high affinity insulin receptors were demonstrable in the stroma of the postmenopausal ovaries. These results suggest that the frequency of stromal luteinization is increased in women with endometrial cancer and that insulin may play a role in the pathogenesis of this luteinization.

Ovarian steroid secretion in postmenopausal women with and without endometrial cancer.

The concentrations of testosterone (T), androstenedione (A), estradiol (E2), and estrone (E1) were measured in peripheral and ovarian venous serum obtained at the time of bilateral oophorectomy from 15 postmenopausal women with endometrial cancer and 9 without cancer. The cancer and noncancer (control) patients were matched for age, weight, and years since menopause. In women with endometrial cancer, significantly higher ovarian than peripheral venous concentrations were found for all hormones measured [T, 3781 +/- 1255 (+/- SE) vs. 213 +/- 43 pg/ml (P less than 0.01); A, 5352 +/- 1845 vs. 1299 +/- 187 pg/ml (P less than 0.04); E2, 52 +/- 11 vs. 23 +/- 3 pg/ml (P less than 0.02); E1, 81 +/- 12 vs. 32 +/- 2 pg/ml (P less than 0.001)], but in the control patients, only the concentration of T was significantly higher (623 +/- 108 vs. 156 +/- 21 pg/ml; P less than 0.001). Ovarian venous concentrations of T and A were significantly higher in thin women with cancer than in obese women with cancer. These results suggest that the ovaries of postmenopausal women with endometrial cancer secrete significantly more T and A than do the ovaries of women without cancer, while secreting only minimal amounts of E2 and E1. This increase in ovarian steroid secretion might play a role in the pathogenesis of endometrial cancer.

Serum levels of interleukins, growth factors and angiogenin in patients with endometrial cancer.

The purpose of this work was to study changes in serum levels of interleukins, growth factors and angiogenin during different stages of endometrial cancer progression. Serum levels were assayed by enzyme-linked immunosorbant assay in 59 women with stages I-IV of endometrial cancer (study subjects: stage I, n = 20; stage II, n = 8; stage III, n = 5; stage IV, n = 6) and compared to the serum levels in 20 women without cancer as control subjects. Patients with endometrial cancer had varied serum levels of interleukins and growth factors. There was a significant increase in serum levels of angiogenin in all stages of tumor progression. Levels of interleukin-8 (IL-8), IL-10 and transforming growth factor beta (TGF beta) were significantly elevated in patients with stages I and II carcinoma. The serum levels of tumor necrosis factor alpha (TNF alpha), granulocyte/macrophage-colony-stimulating factor, basic fibroblast growth factor (BFGF), IL-7 and IL-2 were significantly elevated in patients with stages II and III carcinoma and the serum level of tumor necrosis factor beta (TNF beta) was slightly elevated in patients with stage II carcinoma only. The serum levels of IL-1 alpha, IL-1 beta and IL-6 were not elevated in endometrial cancer patients in any of the clinical stages. The results showed that progression of endometrial cancer is associated with increased serum levels of cytokines, growth factors and angiogenin, which possibly amplify angiogenesis during different clinical stages.

Hyperthecosis of the ovaries in a woman with a placental site trophoblastic tumor.

Rapidly increasing testosterone levels were observed in a patient presenting with sudden onset of virilization. Exploratory laparotomy revealed a placental site trophoblastic tumor in the uterus. Wedge biopsies of the ovaries showed extensive luteinization of the ovarian stroma in both ovaries. Concentrations of testosterone, dihydrotestosterone, and androstenedione were markedly increased in the ovarian vein serum, indicating ovaries as the source of these steroids. The serum concentration of hCG was 69 mIU/mL. Pulsatile secretion of LH persisted in spite of elevated hCG levels. Follicle-stimulating hormone levels were low or undetectable. Elevated hCG levels and low FSH levels resulted in a hormonal environment similar to that seen in polycystic ovary disease (high LH to FSH ratio), resulting in extensive stromal luteinization. Decline in hCG levels after removal of the tumor resulted in the return of androgen levels to normal.

Tumor angiogenesis as a predictor of recurrence in stage Ib squamous cell carcinoma of the cervix.

OBJECTIVE: To explore the possibility of using histologic microvessel count of sections from the tumor to predict recurrence of stage Ib squamous cell carcinoma of the cervix. METHODS: Tumor sections from 22 patients (11 patients free of disease after 3 years and 11 patients with recurrence) were stained histoimmunochemically for factor VIII-related antigens. Vessel counting in the most active area of angiogenesis was performed by two pathologists on a x 200 microscopic field (0.739 mm2) without knowledge of the patient's' outcome. To predict recurrence, vessel count was compared with age, tumor size, tumor grade, lymph-vascular invasion, duration of follow-up, and type of therapy. RESULTS: Only high microvessel count (mean 19.9, range 7-43, versus mean 30.1, range 17-78; P < .05) and tumor size (mean 2.84 cm, range 1-4.2, versus mean 4.11 cm, range 2.2-6; P < .05) were independent factors predicting recurrence. CONCLUSION: High microvessel count in tumors may be used to predict recurrence in stage Ib squamous cell carcinoma of the cervix.

Cone biopsy during pregnancy.

Under a diagnostic schema that used cervical conization liberally for evaluating women with abnormal Papanicolaou smears, 82 pregnant patients underwent conization. Fifteen had significant morbidity related to cervical bleeding. The uncorrected perinatal mortality was 44.1/1000. Sixty-one cone biopsies, performed before colposcopy was introduced into the schema, uncovered 2 cases of previously undiagnosed invasive carcinoma. Among 21 patients who underwent colposcopy before conization, 1 case of microinvasive carcinoma was diagnosed. During the study, 15 patients with frankly invasive carcinoma were identified, 9 by punch biopsy of a gross lesion, 2 by cone biopsy without prior colposcopy, and 4 by colposcopically directed punch biopsy. As a result of the review, the diagnostic schema has been changed so that biopsy is used less often on pregnancy patients.

Clinical implications of tumor volume measurement in stage I adenocarcinoma of the cervix.

OBJECTIVE: To evaluate the prognostic significance of three-dimensional determination of tumor size in stage I cervical adenocarcinoma. METHODS: Tumor volume was measured using hematoxylin and eosin-stained sections of cone biopsy and hysterectomy specimens from 36 patients with stage I adenocarcinoma of the cervix. The volume was then correlated with pelvic lymphatic spread and clinical outcome. RESULTS: The subjects were followed for a mean (+/- SEM) of 63 +/- 8 months. No recurrence or lymphatic seeding was encountered in the 22 tumors measuring no more than 500 mm3. Two of 25 tumors (8%) having up to 5 mm depth of stromal invasion had lymph node metastasis, one of which was 1.5 mm, compared with four of 11 (36%) in the group with deeper than 5 mm invasion (P < .02). The depth of stromal invasion predicted recurrence less significantly. Among the 25 tumors with up to 5 mm stromal invasion, two recurred, compared with three of 11 with more than 5 mm invasion (P < .1). Two women who had tumor volumes below 500 mm3 and depths of stromal invasion up to 8.5 mm were disease-free at 52 and 96 months of follow-up. On the other hand, tumors with 2.6 and 3.8 mm stromal invasion, but with volumes exceeding 500 mm3, recurred. CONCLUSION: Tumor volume is a better predictor of pelvic lymph node metastasis and recurrence than is the depth of stromal invasion in stage I cervical adenocarcinoma.

Chronic plasma cell cervicitis simulating a cervical malignancy: a case report.

BACKGROUND: Only one case of plasma cell cervicitis, a rare variant of chronic cervicitis, has been reported. We report a second case and present data supporting the detection of human papillomavirus (HPV) outside of epithelial tissues. CASE: A 67-year-old woman was found to have a large cervical tumor. Extensive diagnostic evaluation failed to reveal a suspected cervical cancer; subsequently, a hysterectomy was performed. Light microscopic studies confirmed plasma cell cervicitis. Standard virologic tests were used to confirm the presence of HPV 16 in cervical sections. Retrospective study of the first reported case also demonstrated HPV. CONCLUSION: Fulminant cases of chronic cervicitis, presenting with clinical features similar to cervical cancer, are unusual. Even more interesting is the detection of HPV outside of the epithelium; this is the first case that clearly demonstrates HPV in plasma cells.

Mixed mesodermal tumors of the ovary: a clinicopathologic study of 14 cases.

Fourteen cases of mixed mesodermal tumor of the ovary are presented. The actuarial survival of patients with these tumors was 2.5 months. Eighty-six percent of patients were stage III or IV at the time of diagnosis. The stromal or carcinomatous component of the tumor could not be correlated with survival. Both our two longest survivors, 14 and 27 months, were treated with surgery and radiotherapy, one patient with and one without chemotherapy.

Management of patients with positive margins after cervical conization.

OBJECTIVE: To evaluate conservative management of patients undergoing cervical conization with cone margins positive for dysplasia. METHODS: The outcomes of 93 patients with cone biopsies that had margins positive for dysplasia were tabulated. RESULTS: Thirty of 47 patients (64%) undergoing conization only and followed by cytology had negative Papanicolaou smears for at least 2 years. Twenty-one of 37 women (57%) with conization and immediate hysterectomy had no residual disease in the cervix. Three of nine women (33%) with conization and delayed hysterectomy had no detectable dysplasia in the remaining cervix. There was no case of progression to invasive disease. The overall resolution rate was 58%. Persistence of disease was found most often at the endocervical margins associated with cervical intraepithelial neoplasia grade III. CONCLUSION: Patients with cone margins positive for dysplasia can be followed appropriately with cytology. In cases of recurrent abnormal Papanicolaou smears, colposcopy, biopsies, and endocervical curettage should be repeated.

Mixed müllerian tumors of the uterus: a clinicopathologic study.

Forty-seven cases of mixed müllerian tumors of the uterus were analyzed clinically and pathologically. All patients but one were postmenopausal. Vaginal bleeding was the most frequent presenting symptom, followed by abdominal mass and pelvic pain. Long-term survival was found only in those cases in which the tumor was localized to the uterus (surgical stage I), particularly if it arose from a benign endometrial polyp. No correlation could be established between survival and tumor size, depth of myometrial invasion, or histologic type of sarcoma. Tumors arising after previous irradiation had a poor prognosis. Treatment included surgery, radiation, and chemotherapy. The cumulative probability of 5-year survival was 35%.

Phase II study of fludarabine phosphate (NSC 312887) in patients with advanced cervical cancer. A Southwest Oncology Group study.

Twenty evaluable patients with advanced cervical cancer refractory to one prior chemotherapy regimen were treated with a 5-day schedule of fludarabine phosphate. No responses were noted. The major toxicities were anemia and leukopenia. Based on this study, fludarabine phosphate does not appear to be an active agent for patients with chemotherapy refractory cervical cancer.

Evaluation of amonafide in cervical cancer, phase II. A SWOG study.

The Southwest Oncology Group conducted a Phase II study of amonafide in patients with metastatic or recurrent squamous cell cervical cancer. Twelve of the 15 patients were fully evaluable for response and toxicity. There were no clinical responses seen; 2 patients had stable disease while 13 had progressive disease. The major complication of this therapy was myelosuppression. Four patients had life-threatening granulocytopenia (less than 500/microliters), 3 patients had life-threatening leukopenia (less than 1000/microliters), while 2 patients had life-threatening thrombocytopenia (less than 25,000/microliters). Amonafide has significant toxicity but appears to be an inactive drug in metastatic or recurrent squamous cell cancer of the cervix.

Three-dimensional endothelial-tumor epithelial cell interactions in human cervical cancers.

The purpose of this study is to understand the multicellular interaction between tumor epithelial (TEC) and human umbilical vein endothelial cells (HUVEC). The development of in vitro systems in which to coculture these cells as multicellular aggregates is very critical. Cell lines were established from cervical tumor cells (n = 6) and two from HUVEC (n = 2) and they were cultured as three-dimensional (3-D) multicellular-cultures using Cytodex-3 microcarrier beads in the rotating wall vessel (RWV). After a 240-h incubation, TEC and HUVEC proliferated exponentially to 4.2 x 10(7) and 2.2 x 10(7) cells/ml, respectively, without requiring a feeder layer; in contrast to the two-dimensional (2-D) cultures that average about 8 x 10(5) cells/ml. Phase contrast microscopy indicated formation of 3-D aggregates that varied in size from 0.5 to 5 mm. The size of the aggregates (1-5 mm, 6-14 microcarriers) increased over time; however, the number of aggregates (0.5-1 mm, 2-5 microcarriers) decreased over a long-term incubation (240 h) because the cells merged to form large clumps. Maximum aggregation was observed with TEC at 120 h and HUVEC at 96 h. The culture of TEC in the absence of HUVEC produced minimal differentiation in contrast to cocultures. The TEC and HUVEC as cocultures in RWV proliferated at an accelerated rate (1.3 x 10(7) cells/ml, 96 h). The TEC-HUVEC coculture presented tubular structures penetrating the tumor cell masses, forming aggregates larger in size than the monocultures and typically with greater cell mass and number. The cells were viable (trypan blue exclusion) and metabolically active (glucose utilization) until 240 h. These data suggest that RWV provides a new model that allows us to investigate the regulatory factors that govern tumor angiogenesis.

MRI of cervical carcinoma.

MRI is useful for demonstrating enlarged retroperitoneal lymph nodes and for demonstrating the carcinoma mass in patients with carcinoma of the cervix. MRI evaluation of the parametria appears promising, but further studies are necessary to elucidate the optimal imaging parameters and to better define the overall accuracy of MRI compared to the clinical evaluation of the parametria.

Bone metastasis in epithelial ovarian carcinoma.

Two cases of bone metastasis in patients with epithelial ovarian carcinoma and a review of the literature are presented. Bone metastases detected antemortem are rare and herald a poor prognosis.

Flow cytometry in cervical adenocarcinoma. Correlating DNA content analysis with the clinical picture.

OBJECTIVE: DNA quantitation by flow cytometry was used in this study to determine prognosis in stage I adenocarcinoma of the uterine cervix with negative pelvic lymph nodes. STUDY DESIGN: DNA content and proliferation index were determined by flow cytometry on formalin-fixed, paraffin-embedded tissue from 29 patients with stage I, pelvic lymph node-negative adenocarcinoma of the cervix. Using Student's t test, the results were correlated with tumor recurrence after 57 +/- 8 months. RESULTS: Diploid DNA content predominated (79%), whereas only 21% of the tumors were aneuploid. There was recurrence of the tumor in five cases (17%); two tumors were aneuploid, and three were euploid. The recurrence rate among the aneuploid population of 33% (2 of 6) was not statistically significant as compared to 13% (3 of 23) in the diploid population (P > .2). Similarly, the mean proliferation index (percentage in S plus G2/M phases) of the tumors in patients with recurrence was 13.7 +/- 3.68%, which was not significantly different from those that did not recur (mean 15.6 +/- 3.49%). CONCLUSION: DNA content analysis and proliferative activity do not predict recurrence in stage I, pelvic lymph node-negative adenocarcinoma of the uterine cervix.