Intraperitoneal cisplatin and cytarabine in the treatment of refractory or recurrent ovarian carcinoma.

Preclinical evaluation has suggested impressive concentration-dependent cytotoxic synergy between cisplatin and cytarabine in ovarian carcinoma. To further evaluate the clinical relevance of these observations, 39 patients with refractory or recurrent ovarian carcinoma were entered onto a phase II trial of intraperitoneal (IP) cisplatin (100 to 105 mg/m2 per course) plus cytarabine (600 to 900 mg per course). Treatment was administered over 2 or 3 days for a maximum of five monthly courses, followed by surgical reevaluation in patients without clinical evidence of disease. The 3-day regimen was discontinued secondary to the development of severe thrombocytopenia (five of 12 courses platelets decreased to less than 50,000/mm3). Additional toxicities included abdominal pain (moderate to severe at some time during therapy in 46% of patients), fever without evidence of infection (44%), and bacterial peritonitis (10%). Three patients declined surgical reassessment. Fourteen of 36 (39%; 95% confidence interval [CI], 23% to 55%) assessable patients demonstrated surgically defined responses, including 12 of 23 (52%; 95% CI, 32% to 72%) patients with tumor nodules less than 1 cm in diameter and only two of 13 (15%; 95% CI, 0% to 34%) patients with any lesion greater than 1 cm. There were seven (30%; 95% CI, 11% to 49%) surgically defined complete responses (CRs) in patients with less than 1 cm disease and none in patients with larger tumor nodules. IP cisplatin/cytarabine results in a high surgically defined response rate in patients with minimal residual ovarian carcinoma, but activity is low in patients with bulky intraabdominal disease.

Results of radiotherapeutic management of primary carcinoma of the vagina.

Forty-five previously untreated patients with primary carcinoma of the vagina were treated with curative radiotherapy from 1965 through 1985. All patients were staged according to the FIGO system. One patient was classified as Stage 0, 15 as Stage I, 22 as Stage II, 6 as Stage III, and 1 as Stage IV. Treatment consisted of intracavitary irradiation alone in Stage 0 patients. Stage I patients received intracavitary/interstitial irradiation alone or in combination with external irradiation and an implant when feasible. When treated with an implant only, the total tumor dose delivered was between 65-70 Gy. External irradiation consisted of delivering a dose of 45-50 Gy over a period of 4 1/2-5 weeks to the whole pelvis to treat the regional lymph nodes. An additional dose of 20-25 Gy was delivered to the site of original involvement using an implant when feasible. If not technically feasible, as in advanced stages, the patient was treated with additional external irradiation to a total dose of 65-70 Gy by a shrinking field technique. All patients except one were followed either until death or for a minimum of 2 years. The actuarial 5-year survival rates were 100% for Stage 0, 78% for Stage I, and 71% for Stage II patients. None of the patients with Stage III or IV disease survived. Of the patients who recurred, all but two did so within 16 months after diagnosis. Pelvic recurrence as the first site of recurrence occurred in 86% of the patients who recurred. Distant recurrence as a component occurred in 20% of all failures. Complications as a consequence of therapy occurred in 18% of the patients. Vaginal necrosis that healed with conservative treatment was seen in four patients and the other four patients had rectal complications of varying severity. Thus, curative radiotherapy is an effective method of treatment, with acceptable morbidity, in patients with early stage primary carcinoma of the vagina.

Radiation therapy in the management of gestational choriocarcinoma metastatic to the central nervous system.

The Albert Mathieu Chorionepithelioma Registry's 1800 cases were screened, and 70 cases of trophoblastic disease involving the central nervous system were abstracted. In addition, eight patients with central nervous system trophoblastic disease from the Western Trophoblastic Disease Center, Department of Obstetrics and Gynecology, University of Southern California (USC) Medical Center, were reviewed. Eighteen patients received chemotherapy and whole-brain irradiation, 25 were treated with chemotherapy alone, and 35 received neither chemotherapy nor irradiation. In the no-treatment group (in which most patients died before therapy was begun), there were no survivors, and 74% of the deaths resulted from central nervous system causes. In the chemotherapy-alone group, 24% survived and 58% died of central nervous system causes. In the chemotherapy and irradiation group, 50% survived but none of the deaths were due to central nervous system involvement. This study suggests that radiation has a distinct therapeutic role in the treatment of central nervous system choriocarcinoma, and provides evidence that the irradiated brain tends to resist recurrent disease even in those patients for whom the outcome is fatal.

Salvage mitomycin/5-fluorouracil after platinum-based therapy for women with advanced ovarian cancer and related gynecologic malignancies.

PURPOSE: to determine response rates, survival, and toxicity of a regimen of mitomycin-C and 5-fluorouracil in patients previously treated with platinum-based combinations for ovarian cancer and related gynecologic malignancies. PATIENTS AND METHODS: retrospective chart review of all cases of persistent or recurrent ovarian, fallopian tube, and peritoneal carcinoma treated with mitomycin-C 7 mg/m2 followed by continuous infusion of 5-fluorouracil 600 mg/m2/day over 4 days. RESULTS: 26 patients were treated after a median of 2 prior platinum-based regimens, 22 with ovarian cancer, 3 with peritoneal cancer, and one with fallopian tube cancer. Only 2 patients completed 6 or more cycles. 2 patients had partial responses (8%); no complete responses were seen. 24 patients died a median of 3 months after the initiation of therapy, while 2 patients were alive 4 and 8 months after beginning therapy. All deaths were attributable to disease, not complications of treatment. 8 patients required dose modification or treatment delay for toxicity. Nine patients required a total of 11 unscheduled admissions. CONCLUSIONS: toxicity attributable to mitomycin-C/5-fluorouracil therapy of ovarian cancer is acceptable, but responses are few. More effective alternative should be sought.

A bleomycin/ifosfamide/cisplatin regimen exhibits poor activity against persistent or recurrent squamous gynecologic cancers.

Persistent or recurrent squamous malignancies of the female genital tract are usually incurable by conventional therapy, and results of single agent chemotherapy have been disappointing. We undertook this study to confirm a previously reported response rate of 69%, using a regimen of bleomycin 30U, ifosfamide 5g/m2 with mesna 6g/m2, and cisplatin 50 mg/m2 (BIP) for recurrent cervical cancer. This regimen was used to treat persistent or recurrent squamous cancers in women with cervical cancer (n = 11), vaginal cancer (n = 1) and vulvar cancer (n = 1). Results were reviewed retrospectively and toxicities graded according to the criteria of the Gynecologic Oncology Group. No complete responses were seen. One patient had a partial response (10%, 95% confidence interval 0-28%). Five patients (50%), exhibiting stable disease during therapy with BIP, progressed after cessation of therapy. Of 9 women with symptoms after one cycle. Significant toxicities included neutropenic fever (3 grade 3, 3 grade 4), emesis (1 grade 3), confusion (2 grade 4), vaginal bleeding (2 grade 3), and renal failure (1 grade 3). Eight patients were transfused with a total of 28 units of red cells. After 23 months of follow-up, all patients were dead of disease. Mean survival was 10 months. Toxicity associated with this regimen can be significant, and results appear no better than those reported with single agent therapy.

Smoking, obesity, and survival in squamous cell carcinoma of the vulva.

One hundred thirty-six patients with invasive squamous cell carcinoma of the vulva were studied retrospectively to determine prognostic factors for survival. In the regression analysis, three variables were statistically significantly related to survival: smoking history, tumor size, and node status. Smokers had a 6.3 times greater risk than nonsmokers, node positivity imparted an 8.3 times greater risk than node negativity, and for each 1-cm increase in the size of the tumor, the risk of death increased by 46%. A relative decrease in survival in smokers was observed, despite a younger age and fewer positive nodes at diagnosis compared to nonsmokers. Increased surveillance in these patients may be warranted.

Prognostic indicators of survival in advanced endometrial cancer.

Advanced endometrial cancer represents 14% of all stages but 54% of all deaths attributed to endometrial cancer. From 1973 to 1990, the charts of 137 patients with endometrial cancer (Stage III and IV) treated by the section of Gynecologic Oncology at Rush Medical College were retrospectively reviewed. The log rank method was used for univariate analysis and Cox proportional hazards regression was used for multivariate analysis. The patients were stratified as follows: Stage III, 92 (67.2%), Stage IV, 45 (32.8%); Grade 1, 15 (10.9%), Grade 2, 47 (34.3%), Grade 3, 67 (48.9%); adenocarcinoma, 93 (67.9%), adenosquamous, 18 (13.1%), adenoacanthoma, 2 (1.5%), clear cell, 1 (0.7%), papillary serous, 23 (16.8%). Using univariate analysis, median survival was 1.71 years for Stage III versus 0.68 years for Stage IV. Median survival based on treatment was as follows: radiotherapy (RT) only (n = 16), 0.89 years, surgery only (n = 36), 0.75 years, preoperative RT+surgery (n = 7), 2.5 years, surgery+postoperative RT (n = 56), 2.63 years, and other treatments (hormonal only n = 12, chemotherapy only n = 1, and no treatment n = 9), 0.6 years. Patients with vaginal extension survived a median of 0.82 years, versus 2.49 years without this factor (P = 0.002). Patients with clinically apparent parametrial involvement survived a median of 0.70 years versus 2.65 years without this factor (P = 0.0003). Multivariate analysis was possible via a surgical database (n = 99). Age > 60 (P = 0.01), parametrial involvement (P = 0.04), and abdominal metastases (P = 0.003) were significant prognostic indicators. Papillary or clear cell histology, advanced grade, and mode of treatment were not significant. Patients with abdominal metastases or parametrial extension of tumor have a significant decrease in mean survival.

Stage III ovarian tumors of low malignant potential treated with cisplatin combination therapy (a Gynecologic Oncology Group study).

By serendipity we have had the opportunity to evaluate cis-platin-based chemotherapy in ovarian tumors of low malignant potential (LMP). Optimal (less than 1 cm residual disease) FIGO stage III ovarian carcinomas were randomly assigned to treatment with cisplatin plus cyclophosphamide with or without doxorubicin on a prospective Gynecologic Oncology Group Study. On review by the Gynecologic Oncology Group Pathology Committee, 32 of these cases were determined to represent low malignant potential tumors. Mean age of patients with these lesions was 48 years (range, 25-75 years). After initial cytoreduction, 19 patients had residual disease less than 1 cm and 13 had no residual. Twenty (62.5%) received cisplatin plus cyclophosphamide and 12 cisplatin, cyclophosphamide, and doxorubicin chemotherapy; 75% of patients received six or more courses. Second-look surgery was done in 15 cases; only six were negative. However, with a median follow-up of 31.7 months (range, 1-75), only 1 patient has died; no cancer was found at autopsy. The remaining patients are alive without clinical evidence of disease at a median of 30 months. The need for adjunctive therapy in patients with advanced LMP tumors remains speculative.

Disseminated pelvic actinomycosis presenting as metastatic carcinoma: association with the progestasert intrauterine device.

Actinomycosis is caused by the anaerobic bacterium Actinomyces israelii. Asymptomatic colonization of the cervix with this organism has been noted in users of an intrauterine device (IUD), and its prevalence ranges between 1.6% and 36%. Rarely, symptomatic infection may occur, with the potential for extensive morbidity and even death. Herein we report a patient who survived severe disseminated actinomycosis yet presented with the clinical picture of a metastasized malignancy. This is the first report of disseminated pelvic actinomycosis presenting as an external lesion of the abdominal wall and in which a Progestasert IUD (Alza, Palo Alto, CA) was present. The common difficulty, and thus delay, in diagnosing this disease led to considerable morbidity due to an infection considered curable with penicillin. We recommend that all patients with an IUD or a history of IUD use have such information made known to those responsible for interpreting the Papanicolaou smear. Such knowledge may heighten suspicion and focus attention on the identification of these organisms before onset of clinical disease. It is important to consider this disease when caring for patients with an IUD or when counseling those contemplating its use as a contraceptive.

Phase II evaluation of dianhydrogalactitol in the treatment of advanced non-squamous cervical carcinoma. A Gynecologic Oncology Group study.

In an on-going Phase II evaluation, dianhydrogalactitol (NSC 132313) was administered intravenously to 28 patients with advanced or recurrent non-squamous cell carcinoma of the cervix. The initial dosage was 60 mg/m2/wk with escalation to 75 mg/m2/wk if there were no adverse effects. Twenty-seven patients were evaluable for toxicity and response. There was one complete response and one partial response. Adverse effects were not infrequent but tolerable.

Recurrence patterns and complications in endometrial adenocarcinoma with cervical involvement.

BACKGROUND: Cervical involvement in endometrial carcinoma is a diverse entity, and the optimal management of these patients is not well understood. METHODS: Recurrence patterns and complications in 202 patients with histologically confirmed endometrial carcinoma with cervical involvement were retrospectively studied. RESULTS: The 5-year actuarial survival rate for all patients was 65%. Recurrences were documented in 80 (40%) of the patients, and the overall long-term survival rate in this group was 4%. Patients treated with radical hysterectomy (n = 33) had a 6% isolated pelvic recurrence rate and the lowest serious complication rate among the five treatment groups despite having the highest frequency of risk factors for recurrence among any of the groups studied. Patients treated with extrafascial hysterectomy alone (n = 37) had a 14% pelvic recurrence rate and very few complications. When radiotherapy preceded extrafascial hysterectomy (n = 37), the frequency of pelvic recurrences was 30%, and 19% experienced serious gastrointestinal or genitourinary tract complications. When radiotherapy followed extrafascial hysterectomy (n = 68), the pelvic recurrence rate was 24%, and 13% experienced serious complications. Overall, 24% of patients (49 of 202) had isolated pelvic recurrences, whereas 10% (21 of 202) had isolated distant recurrences and 5% (10 of 202) were simultaneously diagnosed with both pelvic and distant recurrences. CONCLUSIONS: This large data base suggests that older conventional forms of therapy, particularly those using preoperative radiotherapy, subject the patient to significant morbidity over a 5- to 10-year period and, in terms of local control, are not necessarily superior to therapeutic modalities using primary surgical evaluation, such as radical hysterectomy. Consideration of primary surgery should be given in the appropriate situation, and radical hysterectomy should be considered when gross cervical involvement is encountered and intraoperative exploration does not show obvious extrauterine disease.

Intra-operative radiation therapy in the treatment of pelvic malignancies: a preliminary report.

Local control of advanced pelvic malignancies, particularly when complete surgical resection is not feasible, is often impeded by dosage limitations in radiation therapy and the intolerance to radiation of normal tissues. This is a preliminary report on the feasibility of improved local control in pelvic malignancies treated by intra-operative radiation therapy, as a radiation boost, in addition to conventional surgical resection and external beam radiation therapy. Fifteen gynaecological malignancies (five cervix, five uterus, four ovary, and one vulva) from Rush Medical College and the University of Navarre, as well as 36 other pelvic malignancies (32 colorectal, 4 genito-urinary) from Rush Medical College were reviewed. All tumours were advanced or recurrent, and all patients were felt to be at high risk of local failure. IORT was administered at a dose range of 10-26 Gy. Our data suggest that the probability of local control improves when IORT is used for primary and for microscopic disease, when the tumour is at least partially resectable, and when the total dose given in IORT and external beam radiation exceeds 70 Gy.

Radiation therapy in primary carcinoma of the vagina.

A retrospective analysis of 32 patients with carcinoma of the vagina treated with curative radiotherapy between 1965 and 1981 is presented. Squamous cell carcinoma was the most common histologic type, found in 78% of the patients. Patients were staged according to the FIGO system. Stage I and II disease was found in 8 and 18 patients, respectively. Six patients had either Stage III or IV disease. The absolute survival rate was 100% for Stage I and 72% for Stage II patients. The pattern of failure was analyzed. All patients who failed had done so within 14 months of completion of treatment. Treatment failure in the pelvis occurred only in 16% of the patients with early disease (Stages I and II) while 81% of the patients with late stage had failed in the pelvis.

Whole-abdomen radiation therapy in ovarian carcinoma: its role as a salvage therapeutic modality.

A significant proportion of patients with epithelial ovarian carcinoma eventually fail after initial responses to chemotherapy. Further treatment with chemotherapy consisting of either the same combination or second-line regimens has been ineffective in producing durable responses. Thus, between June 1983 and June 1987, thirty patients with epithelial ovarian carcinoma who failed one or more chemotherapeutic regimens were treated with whole-abdominopelvic-cavity radiation therapy. Prior to the radiation the amount of residual disease after debulking was noted to be microscopic in 16 patients and macroscopic in 14 patients. Radiation was delivered with an open-field technique that extended from the domes of the diaphragm to the obturator foramina. Doses of 2500 cGy were planned to the whole abdomen, with a boost of another 2500 cGy to the pelvic and or paraaortic nodes when indicated. Higher doses were delivered to the areas of gross disease in the pelvis. Only 2 patients were unable to complete the planned therapy. Another 26% of the patients required interruption of the therapy secondary to hematologic toxicity but eventually completed the treatment. With an overall median follow-up of 14 months, 56% of the patients remain alive. Two-year actuarial survival and recurrence-free survival rates are 47 and 32%, respectively. The survival and recurrence-free survival rates for the group with microscopic residual disease--61 and 33%, respectively--are better than those for the patients with macroscopic residual disease--36 and 18%. The abdominopelvic cavity was the first site of failure in all but one of the 17 patients who have failed. In spite of the higher doses, pelvic failure alone or as a component occurred in 54% of the patients. Small bowel obstruction necessitating surgical intervention as a complication of therapy was seen in 13% of the patients.

Angiogenesis factor in endometrial carcinoma: a new prognostic indicator?

OBJECTIVE: Tumor angiogenesis is believed to be a prognostic indicator associated with tumor growth and metastasis. Studies of angiogenesis in breast, prostate, and lung cancer, as well as melanoma, have shown that neovascularization correlates with the likelihood of metastasis and recurrences. The purpose of this study was to evaluate microvessel density as a prognostic factor in endometrial cancer. METHODS: Between 1980 and 1991 the tumor registry identified 25 patients with a diagnosis of recurrent endometrial cancer. These patients were matched with 25 patients with nonrecurrent disease for age, stage, grade, and treatment. The histologic slides of the 50 patients were reviewed. The paraffin blocks were obtained, and the area of the deepest myometrial invasion was selected for staining. The microvessels within the invasive cancer were highlighted by means of immunocytochemical staining to detect factor VIII-related antigen. Microvessels were counted by two investigators who were blinded to the patients' clinical status. Survival data were analyzed with Kaplan-Meier survival curves. RESULTS: Microvessel count was related to likelihood of recurrence, although this trend did not reach statistical significance. Patients with tumors of low capillary density had a mean survival time of 123 months. Patients with tumors of high capillary density had a mean survival time of 75 months (p = 0.02). Among patients with recurrent disease, those with a low capillary count survived a mean of 64 months. Patients with recurrent disease with tumors of high capillary density survived a mean of 45 months (p = 0.002). CONCLUSION: Angiogenesis factor correlates with survival in endometrial carcinoma.

Prognostic factors and long-term survival in endometrial adenocarcinoma with cervical involvement.

The clinical, surgical, and histopathologic data from 202 patients with endometrial adenocarcinoma with cervical involvement are presented. One hundred fifty-one (75%) had histopathologically confirmed cervical involvement at the time of their definitive surgery, while in 51 (25%) no cervical involvement was conclusively identified. The 5-year actuarial survival for patients with true surgical stage II endometrial carcinoma (N = 24) was 76%. Extrauterine disease was documented in 32% (27/84) of patients in which the primary treatment modality was surgical. The 5-year actuarial survival was 65% for all patients with clinical surgical stage II disease. There appeared to be a survival advantage for patients treated by radical surgery as compared with more conventional treatments, especially in patients with numerous high-risk factors. The subgroup of patients (N = 53) having tumor grossly involving the cervix had a 5-year survival of 48%. In this subgroup of patients, radical hysterectomy offered improved 5-year survival over more traditional forms of treatment, particularly compared with simple hysterectomy or combined treatment with radiation and surgery. Multivariate analysis positively correlated myometrial invasion, grade, uterine serosal involvement, lower uterine segment involvement, adnexal metastasis, pelvic metastasis, aortic node metastasis, and peritoneal cytology, with disease-free survival. Clinical and surgical findings correlated poorly; therefore, primary surgical evaluation is recommended when possible.