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.

The use of fluoroscopy to guide needle placement in interstitial gynecological brachytherapy.

PURPOSE: Interstitial brachytherapy is generally performed for gynecological malignancies with extensive parametrial involvement, by inserting the needles through a transperineal template. Often, the implanted needles are not parallel, and the multiple sources can be difficult to identify on localization radiographs, especially if obtained with a portable X-ray unit. We have used fluoroscopy to guide the needles for interstitial brachytherapy to treat various gynecological malignancies. Because the resultant needles are parallel, dosimetry can be performed based on the template hole positions used, rather than identifying individual sources. This report focuses on the technique; the outcome of patients implanted with this technique will be reported separately. METHODS: Seventy-one patients were implanted transperineally with 192iridium using a Syed template under fluoroscopic guidance, from September 1989 to May 1995, for bulky parametrial disease, narrow vagina, extensive vaginal involvement, recurrent disease after previous course of pelvic radiation therapy, or in cases in which the patient had previously undergone hysterectomy. 137Cesium was added in a central tandem in cases with a cervical os. Thirty patients were treated for primary cervical or vaginal carcinoma; 41 patients were treated for recurrent disease from endometrial or cervical cancers. The brachytherapy dose (prescribed to the periphery of the implant) was 40 to 55 Gy when used alone (15 patients) and 22-40 Gy when used as a boost to 34.2 to 59.4 Gy of pelvic external-beam radiotherapy (56 patients). The patients were followed for 6 to 63 months. RESULTS: In all cases, some of the needles had to be repositioned to improve the alignment. Hence, the use of fluoroscopy aided in achieving parallel placement of the needles in all implants as seen on anterior-posterior radiographs. Because the 192iridium sources were ordered beforehand based on the preplan, and the dosimetry was based on idealized geometry of the template hole positions, all patients were loaded on the same day of implant. CONCLUSION: Fluoroscopically guided perineal interstitial brachytherapy is a feasible technique for use in various gynecological malignancies. The use of fluoroscopic guidance helped to achieve parallel needle placement in all of our implants, but it required repositioning of some of the needles in all cases. The parallel positioning allowed the use of preplanned dosimetry, minimizing the delay in loading of the patients. The outcome of the patients treated using this technique is currently undergoing analysis and will be reported separately.

Carcinoma of the vulva. Significance of surgical margin involvement in assessing prognosis.

Repeat pathologic analysis was completed in order to independently assign surgical margin status in a group of 61 patients from the Ohio State University gynecologic oncology tumor registry. Patients were entered into the study group after having undergone simple or radical vulvectomy for squamous carcinoma of the vulva. A statement regarding margin status was made following a detailed pathologic review, and parameters--including stage, grade and lymph node involvement--were assigned without regard to outcome. There was no statistically significant difference in the survival or recurrence rate with involved margins. Mean lesion size was significantly larger with involved margins (P less than .05). The survival and recurrence data support a primary surgical attempt at complete excision regardless of the microscopic margin status.

Adjuvant therapy for stage I uterine sarcoma.

A retrospective evaluation of adjuvant therapy in 64 patients with Stage I sarcoma was undertaken. A combination of operation and adjuvant radiation was compared with operation alone. A decreased recurrence of both pelvic and distant tumor was noted for endometrial sarcoma but not for leiomyosarcoma treated with adjuvant radiation. A Cox regression analysis showed a trend for improved survival, but the results were not statistically significant. Survival after vaginal cuff recurrence and treatment with radiation therapy (two patients) or combined radiation and chemotherapy (one patient) is reported. Seven patients received adjuvant chemotherapy with Adriamycin-based regimens. Chemotherapy alone did not statistically decrease recurrence in this small sample.

Primary invasive carcinoma of the vagina.

Carcinoma of the vagina remains a problem for the clinician. The experience of The Ohio State University Gynecologic Oncology section confirms that careful consideration of urinary complaints is important in patient evaluation. In our experience, a fourth of the patients in our series with primary carcinoma of the vagina presented with urinary complaints with or without associated pain or bleeding. Vaginal bleeding was the most common complaint. Radical surgery may result in equally successful therapy, as does radiation for early stage disease. The disease stage was the single most important prognostic factor. Finally, careful screening of the vagina for a neoplasm is important, especially in patients in the postmenopausal period with histories of other neoplasms.

Multiple primary gynecologic neoplasms.

Some patients may be predisposed to the development of more than one gynecologic neoplasm. We evaluated 130 cases of synchronous or metachronous tumors among 5967 patients followed up by The Ohio State University Gynecologic Tumor Registry for the past 44 years from 1939 to 1983. Based on primary tumor site and invasive behavior, expected incidences for a specific second malignancy were calculated by the person-years method. A second malignancy of the lower genital tract occurred in patients with cervical, vulvar, and vaginal cancers, 1.6%, 4.3%, and 9.6%, respectively, which supports the theory of multicentric cancer of the lower genital tract. Prior radiation therapy was rarely associated with increased second gynecologic malignancies (two of 41 patients, 4.9%). Four patients had three gynecologic tumors.

Endometrial carcinoma associated with pregnancy: A report of three cases and review of the literature.

Endometrial carcinoma associated with pregnancy is uncommon. In case 1, a 40-year-old gravida 2, para 2, was diagnosed with focal well-differentiated papillary adenocarcinoma 4 months postpartum. In case 2, a 35-year-old gravida 1, para 0, was diagnosed with a well-differentiated papillary adenocarcinoma of the endometrium after a D&C for an incomplete abortion at 7 weeks gestation. In case 3, a 32-year-old gravida 2, para 1, was diagnosed with a moderately differentiated adenocarcinoma with squamous metaplasia 4 months postpartum. All are without evidence of disease more than 2 years after therapy. A literature review shows 24 previous cases of pregnancy associated with endometrial cancer. These cases demonstrate the importance of endometrial sampling for abnormal postpartum bleeding despite the protective effects of pregnancy.

An improved human tumor stem cell assay in ovarian cancer.

To evaluate the effect of improved growth rates of ovarian cancers in the human tumor stem cell assay and its value in predicting clinical chemotherapy response, we studied 59 assays in 54 patients. A total of 81.6% of solid specimens and 85.7% of ascites specimens were successfully cultured and yielded an overall growth rate of 82.9%. Simultaneous primary and metastatic cultures were concordant for chemosensitivity in 80% (n = 16). The patients were evaluated for previous chemotherapy, residual volume of tumor, histologic type, and grade, and these were not statistically different between clinical responders and nonresponders. In vivo-in vitro correlations were made in 27 patients and yielded a predictive response of 13% and predictive resistance of 86% at 70% colony inhibition and 31% and 71% at 50% colony inhibition. Improved growth rates therefore did not result in better predictive correlations. The reported experience in ovarian cancer is summarized and the current status of the human tumor stem cell assay is reviewed.

Malignant peripheral primitive neuroectodermal tumor of the uterus.

Peripheral primitive neuroectodermal tumor (PPNET) is rare, occurring most often in young adults. Approximately 50 cases have been reported, with only four cases involving the female genital tract. We report the fifth patient. The term "PPNET" should be used only for tumors with neuroectodermal elements exclusively that occur at sites outside the central and sympathetic nervous system. The pathologic differential diagnoses include rhabdomyosarcoma, immature malignant teratoma, small cell carcinoma of the cervix, and ganglioneuroma. Therapy for this tumor has varied, and no effective regimen has been established.

An excess of uterine sarcomas after pelvic irradiation.

The Ohio State University Registry recorded 1208 uterine corpus malignancies between 1940 and 1983. Thirty cases occurred in women with a history of pelvic irradiation. Eight patients had previously been irradiated for pelvic malignancy, four of whom presented with advanced stage sarcomas and died of their disease within 14 months. This represents an increase over the expected sarcoma prevalence which is less than 5%. In contrast, the majority of women (20 of 22) previously irradiated for benign conditions were diagnosed with endometrial adenocarcinoma. In 18, the adenocarcinoma was diagnosed as Stage I, and the prognosis was only slightly less favorable than for nonirradiated women. No significant effect of age at the time of irradiation was apparent. This study of women with a history of pelvic irradiation who later developed uterine cancer demonstrates a tendency for patients previously irradiated for pelvic malignancy to present with advanced stage, extremely aggressive uterine tumors compared to those previously irradiated for benign conditions.

A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study.

Forty-one eligible patients with metastatic or recurrent carcinoma of the uterine cervix received 149 courses of carboplatin. The drug was administered at a starting dosage of 400 mg/m2 IV every 28 days. The overall response rate was 15% (two complete responses, four partial responses; 95% confidence interval 6-29%) and response durations were 2.0, 2.0, 2.5 +, 2.5+, 5.25 +, and 6.75 months. The major toxic effects included nausea and vomiting in 48% of courses, anemia in 47%, leukopenia in 38%, and thrombocytopenia in 22%. The activity of carboplatin against advanced cervical cancer is modest and similar to the activity of cisplatin alone. However, the toxicity profile of carboplatin is substantially better than that of cisplatin and warrants exploration of this agent against cervix cancer in more aggressive regimens or in combination with other agents.

A phase II trial of cisplatin and 5-fluorouracil with allopurinol for recurrent or metastatic carcinoma of the uterine cervix: a Southwest Oncology Group trial.

On the strength of recent evidence of the activity of the combination of cisplatin and 5-fluorouracil against squamous malignancies of the esophagus and head and neck, this regimen was evaluated in a phase II trial against metastatic or recurrent squamous carcinoma of the uterine cervix. Cisplatin was administered at a dosage of 100 mg/m2 iv bolus and 5-fluorouracil was continuously infused iv at a dosage of 1000 mg/m2/day for 4 days. In an effort to determine whether the toxicities of 5-fluorouracil could be ameliorated by coadministration of allopurinol, patients were randomized to receive allopurinol, 900 mg orally, an odd or even courses of therapy beginning 5 days before 5-fluorouracil administration and continuing until conclusion of the infusion. Fifty-two eligible patients received 177 evaluable courses of treatment. The overall response rate was 28% (8 complete responses and 6 partial responses). Toxicity was confined to nausea and vomiting (81% of courses), anemia (47%), leukopenia (37%), oral mucositis (15%), diarrhea (6%), and thrombocytopenia (4%). Allopurinol produced no improvement in treatment-related toxicities. Allopurinol did not permit substantial increases in 5-fluorouracil dosage.

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study.

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over 5 days at a starting dose of 1.7 mg/m2/day every 3 weeks. There were 44 fully evaluable and 6 partially evaluable patients. Forty-one of these patients had had only one prior treatment regimen. Grade 3 or 4 leukopenia occurred in 12 patients (24%), but Grade 3 or 4 thrombocytopenia occurred in only 2 patients. There were two clinical complete responses of 18- and 36-week durations and one partial response of 6 weeks for an overall response rate of 7%. We conclude that vinblastine, administered in optimal dose and schedule, has little clinical activity in previously treated patients with ovarian cancer.

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study.

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over five days at a starting dose of 1.7 mg/m2/day every 3 weeks. There were 44 fully evaluable and 6 partially evaluable patients. Forty-one of these patients had had only one prior treatment regimen. Grade 3 or 4 leukopenia occurred in 12 patients (24%), but Grade 3 or 4 thrombocytopenia occurred in only 2 patients. There were two clinical complete responses of 18 and 36 weeks duration and one partial response of 6 weeks for an overall response rate of 7%. We conclude that vinblastine, administered in optimal dose and schedule, has little clinical activity in previously treated patients with ovarian cancer.

Doxorubicin-cisplatin-vinblastine combination chemotherapy of advanced endometrial carcinoma: a Southwest Oncology Group Study.

A combination of doxorubicin (30 mg/m2 iv), cisplatin (50 mg/m2 iv), and vinblastine (5 mg/m2 iv) repeated every 3-4 weeks was used to treat 55 patients with advanced stage III or IV or recurrent disease. Of the 42 fully evaluable patients, there were 3 complete responders (7%) and 10 partial responders (24%). Responses were of short duration (median of 8 months, range 3-15 months) and the median survival of all evaluable patients was only 10 months from the start of therapy. Leukopenia was the major toxicity and was at least moderate in two-thirds of patients. We conclude that the addition of cisplatin and vinblastine to doxorubicin does not improve the clinical utility of doxorubicin in patients with advanced endometrial cancer.