Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells.

The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and platinum treatments (both singly and combined) on the growth inhibition of MCF-7 cells, an epithelial cell line shown to possess specific receptors for 1,25(OH)2D3, were evaluated. The inhibitory effects of 1,25(OH)2D3 and platinum on MCF-7 cell proliferation in vitro were time and dose related. The data showed that 10 nM and 100 nM 1,25(OH)2D3 inhibited MCF-7 cell growth by 10.8 +/- 2.4% and 34.9 +/- 0.5% (mean +/- SE), respectively. The degrees of growth inhibition induced by 0.2 to 200 micrograms/ml of cis-diammine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin) were slightly less than those induced by 0.02 to 20 micrograms/ml of cis-diamminedichloroplatinum(II) (cisplatin). The combined administration of 10 nM and 100 nM 1,25(OH)2D3 with either carboplatin (200 to 0.2 micrograms/ml) or cisplatin (20 to 0.02 micrograms/ml) was evaluated. Addition of 1,25(OH)2D3 to the platinum resulted in marginal to marked enhancement of growth inhibition over that observed with either platinum alone. The strength of these interactions varied inversely with the dose of the platinum drugs. Evaluation of drug interactions with isobolograms showed that at near-serum levels, carboplatin or cisplatin interacted synergistically with 1,25(OH)2D3 to inhibit MCF-7 cell growth. Our findings suggest potential usefulness in combining 1,25(OH)2D3, a biological modifier, with cytotoxic agents for the treatment of malignant disease.

Phase I trial of carboplatin-cyclophosphamide and iproplatin-cyclophosphamide in advanced ovarian cancer: a Southwest Oncology Group study.

The Southwest Oncology Group has carried out a phase I clinical trial of carboplatin plus cyclophosphamide and iproplatin plus cyclophosphamide in 20 patients with stages III and IV ovarian cancer prior to initiating a phase III trial to compare these platinum analog-cyclophosphamide combinations with standard cisplatin-cyclophosphamide therapy. Myelosuppression proved the dose-limiting toxicity of both the carboplatin (300 mg/m2) plus cyclophosphamide (600 mg/m2) and iproplatin (180 mg/m2) plus cyclophosphamide (600 mg/m2) regimens. Evaluating up to six courses of therapy (repeated at 4-week intervals), the median nadir WBC and platelet counts associated with carboplatin-cyclophosphamide therapy were 1800 (range, 900-4000) and 69 000 per microliter, respectively, and those associated with iproplatin-cyclophosphamide therapy were 1400 (1100-1600) and 140 000 per microliter, respectively. Although the starting doses of carboplatin and iproplatin required a median decrease of 25%, the median doses of each administered through six courses of therapy were 300 and 180 mg/m2, respectively. Neither nephrotoxicity nor neuropathy were experienced by the patients, but mild to moderate nausea and vomiting occurred in more than 75% of those treated with either drug combination. Alopecia of mild to severe degree was observed in 40% of patients. Although the results of this phase I trial are still preliminary, we can recommend for future phase III trials 300 mg/m2 carboplatin and 180 mg/m2 iproplatin when combined with 600 mg/m2 cyclophosphamide repeated a 4-week intervals for six treatment courses.

Postoperative radiation for cervical cancer with pathologic risk factors.

PURPOSE: To examine the efficacy of postoperative radiation therapy for early-stage cervical cancer with pathologic risk factors. METHODS AND MATERIALS: We reviewed the charts of 83 patients who received postoperative radiation therapy at our facility from March 1980 to November 1993 for early stage cervix cancer with positive surgical margins, positive pelvic or periaortic lymph nodes, lymphovascular space invasion, deep invasion, or for disease discovered incidently at simple hysterectomy. Twenty-eight patients received low dose rate (LDR) intracavitary radiation with or without external beam pelvic irradiation and 55 patients received external beam pelvic irradiation with high dose rate (HDR) intracavitary implants. Of these 83 patients, 66 were evaluable--20 LDR and 46 HDR patients. All patients received 45-50 Gy external beam irradiation and 20 Gy LDR equivalent intracavitary irradiation prescribed to 0.5 cm below the mucosa. Ninety percent of the LDR group and 92% of the HDR group completed treatment within < 56 days. Treatment-related toxicities were scored according to the GOG toxicity scale. Mean and median follow-up times were 101 months and 111 months (3-172 months) for the LDR group and 42 and 40 months (3-98 months) for the HDR group. RESULTS: The 5-year disease-free survival was 89% for the LDR group and 72% for the HDR group. Local control was observed in 90% (18 out of 20) of the LDR patients and 89% (41 out of 46) of the HDR patients for an overall local control rate of 89.5%. Two of 20 LDR patients (10%) experienced recurrence (two pelvic with distant metastasis). Nine of 46 HDR patients (22%) had recurrence of disease (three pelvic, four distant metastasis, and two pelvic with distant metastasis). In the HDR group, 6 out of 16 (38%) with positive lymph nodes died of disease whereas, 27 out of 30 (90%) of the patients with negative lymph nodes remain free of disease. Three of 20 (15%) LDR patients and 4 out of 46 (9%) HDR patients experienced Grade 2 or 3 late treatment- related complications. No patient in either group had Grade 4 or 5 complications. Pathologic risk factors were analyzed. Lymph node positivity and lymphovascular space invasion were found to be significant (p = 0.01 and p = 0.02). Positive margins, deep invasion, and age were not significant. CONCLUSION: Our results demonstrate the efficacy of postoperative irradiation for cervical cancer with pathologic risk factors. Overall, the local control rate was 89.5% The HDR results demonstrate that this method can be delivered safely and effectively.

Radiation therapy for endometrial cancer in patients treated for postoperative recurrence.

PURPOSE: To retrospectively evaluate the outcome and risk factors in patients treated with radiation for endometrial cancer at time of recurrence. MATERIALS AND METHODS: Three hundred ninety-nine women were treated with radiation therapy for endometrial cancer at KCI/WSU from January 1980 to December 1994. Of these, 26 patients treated primarily with surgery received radiation therapy at the time of recurrence. Median time to recurrence after surgery was 8 months, with all recurrences occurring within 24 months. Twenty-four patients had recurrences in the vaginal cuff, vagina, or pelvis. These patients received external-beam radiation to the pelvis (45.00-50.40 Gy) and periaortic lymph nodes (45.00-50.00 Gy), along with a boost given by external-beam radiation or brachytherapy (16.00-30.00 Gy). Mean follow-up was 15 months (range 1-85 months). RESULTS: The 2-year survival was 50% and median survival was 16 months (survival range 1-85 months). Of 26 patients, 54% (14) failed locally following radiation therapy. Factors indicative of poor survival included histology (sarcoma, poorly differentiated adenocarcinoma), grade, and lymph node positivity. Histological differentiation influenced local control; lymphovascular space invasion was of borderline significance with regard to local control. CONCLUSION: Local control and survival for surgically treated endometrial cancer patients who receive radiation at the time of recurrence are poor, with the exception of those patients with recurrent disease limited to the vagina. Early detection of recurrence may improve outcome. Pathologic risk factors may identify those patients at risk for extrapelvic recurrence. Alternative treatment modalities need to be developed for this high-risk group of patients.

Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study.

PURPOSE: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.

Detoxifying enzymes in human ovarian tissues: comparison of normal and tumor tissues and effects of chemotherapy.

Many anticancer drugs exert their cytotoxic effects via formation of oxygen free radicals. Cellular thiols, glutathione (GSH)-dependent enzymes and other redox enzymes are involved in the metabolism of these anticancer drugs and of the oxygen free radicals that may be generated during their metabolism. We quantified these biochemical parameters in cytosol from human ovarian tissues. We compared non-protein thiol levels, GSH transferase, GSH peroxidase, superoxide dismutase, catalase, DT diaphorase and aldehyde dehydrogenase activity in serous ovarian tumors (n = 15), other malignant ovarian tumors (n = 12), benign ovarian tissue (n = 10) and histologically normal ovarian tissue (n = 12). Mean GSH transferase and DT diaphorase activities were similar in serous and other malignant ovarian tumors. GSH transferase activity was decreased in malignant tissues relative to normal and benign tissues. Mean DT diaphorase and superoxide dismutase activities were increased in the malignant tissues, although this was not statistically significant. The mean levels of all enzymes except superoxide dismutase and aldehyde dehydrogenase in benign tissues were fairly similar to the mean levels found in normal tissue samples. Tissues from patients with serous ovarian tumors, who had received cyclophosphamide and cisplatin prior to surgery, also were analyzed (n = 7). Except for aldehyde dehydrogenase, all the parameters measured were decreased in these samples relative to serous tissue from untreated patients. These biochemical analyses may be useful in understanding the mechanisms involved in the response to chemotherapy.

Control of intraoperative hemorrhage in gynecology with the use of fibrin glue.

Fibrin glue, a biodegradable tissue adhesive, is a valuable topical hemostatic agent and an effective tissue sealant. We describe the use of fibrin glue in controlling life-threatening hemorrhage in three gynecology patients. Simultaneous injection of equal amounts of cryoprecipitate and bovine thrombin at bleeding sites results in formation of the glue, which effectively controls the bleeding. When used in conjunction with good surgical technique, fibrin glue may decrease the need for blood transfusions and may shorten operating room time.

Endometrial carcinoma and oral contraceptive agents.

Six patients who took oral contraceptive agents for 5 to 18 years developed endometrial neoplasia. Endometrial adenocarcinoma occurred in 4 of these patients and severe adenomatous hyperplasia occured in 2. Five of the 6 patients took sequential agents; 1 patient used a combined agent. An additional patient who took Premarin and Provera sequentially developed adenocarcinoma of the endometrium. Eighteen cases of endometrial adenocarcinoma and 7 cases of adenomatous hyperplasia in patients with long-term sequential oral contraceptive use have previously been reported by others. Progestogens may not be completely protective against the endometrial cancer-causing potential of the estrogens, especially in the sequential regimens.

Combination chemotherapy of advanced endometrial adenocarcinoma with adriamycin, cyclophosphamide, 5-fluorouracil, and medroxyprogesterone acetate.

Seven patients with advanced endometrial adenocarcinoma achieved objective tumor regression following chemotherapy with cyclophosphamide, Adriamycin, 5-fluorouracil, and medroxyprogesterone acetate. Combination chemotherapy has a favorable risk/benefit ratio for patients with advanced endometrial adenocarcinoma, including patients with severe debilitation, if supportive care such as hospitalization, parenteral antibiotics, and platelet transfusions are available. New Adriamycin-based drug combinations have sufficient antitumor activity to warrant major prospective evaluation by oncology cooperative groups.

Combination chemotherapy for advanced carcinoma of the fallopian tube.

Two patients with advanced adenocarcinoma of the fallopian tube were treated with cis-diamminedichloroplatinum, adriamycin, and progestins. Cyclophosphamide was added to the treatment of 1 patient. Both regimens achieved surgically proved complete remission. No severe drug-related toxicity occurred.

Adriamycin treatment of advanced vulvar carcinoma.

Four consecutive patients with measurable recurrent squamous cell carcinoma of the vulva were treated with Adriamycin, in small doses approximately 45 mg/square meter of body surface area every 3 weeks. Three patients achieved objective regression of nodal metastases and residual tumor with clinical subjective benefit. Tumor control was maintained for 32, 31+, and 28+ weeks.

Treatment of advanced adenocarcinoma of the endometrium with melphalan, 5-fluorouracil, and medroxyprogesterone acetate: a preliminary study.

Combination chemotherapy can produce a rapid and frequent therapeutic effect against advanced endometrial adenocarcinoma regardless of the tumor distribution. A new treatment program is described. Melphalan, 5-fluorouracil, and medroxyprogesterone acetate achieved 6 of 7 objective responses in patients. This result with combination chemotherapy is substantially better than results with single agents or hormones alone and justifies further evaluation of combinations of cytotoxic chemotherapy as part of the initial treatment of choice for patients with advanced endometrial adenocarcinoma.

Common aspects of immunologic tolerance in pregnancy and malignancy.

The fetoplacental allograft and the malignant neoplasm represent the only 2 biologic conditions in which antigenic tissue is tolerated by a seemingly intact immune system. Recent investigations in the fields of tumor and pregnancy immunology have resulted in the recognition of a variety of immunologic mechanisms which are common to both systems. These common denominators are reviewed and a thesis suggesting a common mechanism in the nonrejection of pregnancy and malignancy, based on the presence of embryonic antigens in both systems, is presented.

Debulking of pelvic and para-aortic lymph node metastases in ovarian cancer with the cavitron ultrasonic surgical aspirator.

Six patients with metastatic ovarian cancer with extensive involvement of the pelvic and/or para-aortic lymph nodes underwent surgical debulking with the Cavitron Ultrasonic Surgical Aspirator. Intraoperative and postoperative morbidity was minimal. It is suggested that this technique may be used for cytoreductive surgery in combination with standard surgical techniques.

Trichloroacetic acid in the treatment of human papillomavirus infection of the cervix without associated dysplasia.

Human papillomavirus-induced cytologic changes were found in 379 (10.9%) of 3461 Papanicolaou smears done at the Gynecology Clinic at Wayne State University. Of these 379 patients, 98 (25.8%) had no cytologic evidence of dysplasia. Forty-six of the 98 patients, who had colposcopic and histologic evidence of human papillomavirus without dysplasia, agreed to participate in this study. All patients underwent a Q-Tip application of 85% trichloroacetic acid to the entire cervix, including the endocervical canal and the transformation zone, until the mucosa turned white. Coexistent vaginal and vulvar condyloma were treated simultaneously in six patients. The patients were reexamined at two-week intervals to ascertain the need for reapplication of trichloroacetic acid. No colposcopic evidence of human papillomavirus was found in 18 patients at the first visit, whereas 28 patients required reapplication of trichloroacetic acid. Three months after treatment, a follow-up Papanicolaou smear and colposcopic examination revealed no human papillomavirus infection in 31 patients. Seven patients had persistent infection and eight patients were lost to follow-up. Our preliminary data from this study suggest that 85% trichloroacetic acid is effective treatment of human papillomavirus infection of the cervix without dysplasia.

Direct diagnosis of unruptured ectopic pregnancy by real-time ultrasonography.

Real-time sonography was used in a prospective study of 32 patients as the sole diagnostic parameter for ectopic pregnancy. The minimal finding for diagnosis was an identifiable gestational sac with a circular pattern of echoes. Neither the presence or absence of an intrauterine sac nor the knowledge of either a positive or negative pregnancy test was used in the diagnosis. Among the 32 study patients, the diagnosis of ectopic pregnancy was made by sonography in nine (28.4%). Follow-up surgery confirmed the diagnosis in eight (89%). Among 23 patients with negative findings on sonography, only one was found on follow-up to have an ectopic pregnancy, for a 96% diagnostic accuracy for the negative group. Thus, of 32 patients with the potential diagnosis of ectopic pregnancy, 30 (94%) were correctly diagnosed using real-time sonography alone.

Chemotherapy of recurrent ovarian carcinoma with cis-dichlorodiammine platinum II and adriamycin.

Forty-six patients with recurrent disseminated ovarian carcinoma were treated with a combination of cis-dichlorodiammine platinum II (DDP) 50 mg/m2 and adriamycin 50 mg/m2 given intravenously every 3 weeks. All patients had failed prior chemotherapy. The combination of adriamycin and DDP produced objective responses in 14 of 46 patients. Severe side effects were frequent, but no patient died as a result of treatment. Disease in 4 of 7 complete responders is currently in remission up to 4 years.

Treatment of recurrent and persistent germ cell tumors with cisplatin, vinblastine, and bleomycin.

Four patients were treated with vinblastine, cisplatin, and bleomycin for recurrent or persistent germ cell tumors. In all patients a clinical response was achieved. In 2 patients complete response was attained and they are free of disease following second-look laparotomy. One had a mixed germ cell tumor that persisted as dysgerminoma following primary chemotherapy. The other was a true hermaphrodite with pure dysgerminoma. In patients with endodermal sinus tumor transient response was achieved, but the tumors recurred and the patients died within 6 months.

Cerebral blindness in association with cis-platinum chemotherapy for advanced carcinoma of the fallopian tube.

A 62-year-old woman with a diagnosis of metastatic fallopian tube carcinoma was treated with cis-platinum and doxorubicin (Adriamycin) at a dosage of 50 mg/m2 intravenously every 3 weeks. After the 10th course of cis-platinum and doxorubicin, she complained of headache and inability to see. Physical examination was compatible with cortical blindness. The brain scan and computed tomographic scan were normal. Visual evoked potentials showed a delay in latency. Visual acuity completely returned over the next months, but right homonymous hemianopia persists. The temporal relationship between the findings and the treatment with platinum implicates this drug as the possible causative agent in the cortical blindness.

Multidrug treatment of advanced and recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

Patients (358) with advanced (FIGO stages III and IV) or recurrent endometrial cancer were treated with one of two regimens: 1) melphalan and 5-fluorouracil daily for four days, repeated every four weeks with megace daily for eight weeks and 2) adriamycin, 5-fluorouracil, and cyclophosphamide, intravenous bolus every 21 days with megace daily for eight weeks. All patients were randomized except for 63 with known cardiac disease who were assigned to regimen 1 (to avoid adriamycin) and studied separately. Stratification was effected for performance status, history of previous progestational therapy, presence or absence of measurable disease, and stage of disease. The objective response rate in those with measurable disease was 36.8% in both groups; 36.8% of each group had stable disease, and only 26.4% progressed on treatment. Response was unaffected by site of recurrence, time to first recurrence, presence or absence of previous treatment by progestational or radiation therapy, or age. Grade of tumor and performance status did affect response, although 44 of 57 objective responders had undifferentiated tumors. The two combinations achieved response rapidly, required careful supervision, and were especially useful in treating patients with usually poor prognostic features.