Correlation between extreme drug resistance assay and response to primary paclitaxel and cisplatin in patients with epithelial ovarian cancer.

OBJECTIVE: The extreme drug resistance (EDR) assay has been correlated with failure of response to chemotherapy in greater than 99% of patients. The goal of this study is to correlate the results of the EDR assay to response to first-line paclitaxel/cisplatin among patients with epithelial ovarian cancer. METHODS: Seventy-five of 100 patients with epithelial ovarian cancer for whom EDR assay was performed were treated with weekly induction cisplatin (1 mg/kg body wt) x 4, followed by monthly paclitaxel (135 mg/m2) and cisplatin (75 mg/m2) x 6 and were evaluable for correlation of response to chemotherapy and EDR assay. Specimens for EDR assay were obtained at primary surgery and the EDR assay was performed by Oncotech, Inc. Response to chemotherapy was correlated to EDR assay results regarding paclitaxel and cisplatin. RESULTS: Among 75 evaluable patients, the prevalence of EDR to paclitaxel was 20.0% (n = 15) and to cisplatin it was 2.7% (n = 2). Only 1 patient (1.3%) exhibited EDR to both paclitaxel and cisplatin. Surgical assessment of response was performed in 42 patients; 33 patients were clinically evaluable. The overall response rate was 85.3%. The overall response rate for patients whose tumors demonstrated no EDR to either paclitaxel or cisplatin did not differ significantly from that for patients whose tumors demonstrated EDR to at least one of these two drugs (86.4% versus 81.3%, respectively, P = 0.692). Similarly, the complete surgical response rate for both groups did not differ significantly (25.4% versus 12.5%, respectively, P = 0. 34). A single patient whose tumor exhibited EDR to both paclitaxel and cisplatin had tumor progression. The sensitivity, specificity, positive predictive value, and negative predictive value of the EDR assay were 79.6, 27.0, 86.0, and 19.0%, respectively. CONCLUSIONS: EDR to paclitaxel does not preclude response to the combination of paclitaxel and cisplatin as primary therapy for patients with epithelial ovarian cancer. The role of the EDR assay in the primary management of patients with epithelial ovarian cancer remains to be determined.

Treatment of advanced ovarian carcinoma in the elderly.

This study retrospectively analyzes the treatment of advanced ovarian cancer (Stages III and IV) in elderly patients (> or = 65) compared to that in younger patients (< 65). The purpose of this study was to identify possible treatment bias toward the elderly and to statistically analyze the nature of these differences. Seventy patients were evaluated of which 29 were identified as elderly and 41 as young. All patients were treated with platinum-based chemotherapy. Chi 2, log rank, Kaplan-Meier, and Cox model analyses were performed for multiple variables including age, grade of tumor, adequacy of surgery, and dose intensity. The elderly significantly differed from the young in the following analyses: median length of hospitalization, 20 days vs 11 days (P < 0.001); optimum surgery, 79.3% vs 97.5% (P = 0.02); initial chemotherapeutic dose reduction, 15.4% vs 0% (P = 0.02); median survival compared to age, 19.2 months vs 36.7 months (P < 0.03). When survival analysis was performed comparing 17 elderly patients and 40 younger patients who had optimum surgery and optimum initial chemotherapy, the median survival remained essentially unchanged, 22.0 months vs 36.7 months. There were differences in treatment intensity between young and old, however, the indications generally were valid and when analyzed by the Kaplan-Meier and Cox model, these differences became insignificant. It was concluded that when elderly patients can undergo aggressive surgical and chemotherapeutic management, survival remained significantly decreased for aged compared to younger patients. Physician bias was not a major factor accounting for the poorer survival observed in elderly patients. Age was the most significant variable related to survival and could not be accounted for by differences in adequacy of surgery or dose intensity.

Ovarian endodermal sinus tumor associated with pregnancy: review of the literature.

Endodermal sinus tumor is the second most common malignant germ cell tumor of the ovary and its reported concurrence with pregnancy is extremely rare. This report is the 10th case of endodermal sinus tumor associated with pregnancy and also reviews the previous literature regarding the subject.

Pelvic radiation in stage I endometrial adenocarcinoma with high-risk attributes.

From 1977 to 1987, 45 patients with FIGO stage I endometrial adenocarcinoma with high-risk attributes and disease confined to the pelvis were prospectively treated with postoperative pelvic radiation. By study design, all patients underwent staging laparotomy with pelvic and paraaortic lymphadenectomy. All patients had either grade 1 or 2 adenocarcinoma and greater than 50% myometrial invasion or grade 3 adenocarcinoma with less than or greater than 50% myometrial invasion. The estimated 5-year survival for all 45 patients was 77% and the 5-year disease-free interval was 82%. Regional control was achieved in 89% of all patients, with 4% recurring at distant sites. When patients were stratified according to surgical-pathologic findings, 33 patients with disease confined to the uterus or uterus and pelvic nodes (surgical stage I) had estimated 5-year survival and disease-free interval of 88%. Of these 33 patients, 10 with grade 1 or 2 adenocarcinoma and deep myometrial invasion had 5-year disease-free intervals of 100%, while 23 patients with grade 3 adenocarcinoma with less than or greater than 50% myometrial invasion had disease-free intervals of 79 and 91%, respectively. From these results, it was concluded that patients with high-risk attributes demonstrated to have disease confined to the uterus or uterus and pelvic nodes can achieve excellent survival following surgical staging and postoperative pelvic radiation.

Adjuvant cisplatin-based chemotherapy for stage I ovarian adenocarcinoma: a preliminary report.

Thirty stage I patients with invasive ovarian adenocarcinoma were treated with 6 months of adjuvant induction cisplatin and monthly cisplatin, adriamycin, and cyclophosphamide. To date, 97% (29) are alive with no evidence of disease and normal CA-125 levels and 93% (28) are alive progression free with a median follow-up of 34 months (13-56).

Surgically documented response to intraperitoneal cisplatin, cytarabine, and bleomycin after intravenous cisplatin-based chemotherapy in advanced ovarian adenocarcinoma.

Thirty-one evaluable patients with stages III and IV invasive ovarian adenocarcinoma were treated on a phase II protocol of second-line intraperitoneal cisplatin, cytarabine, and bleomycin. All 31 patients received first-line intravenous (IV) cisplatin-based chemotherapy; the size of the residual cancer was documented surgically before intraperitoneal chemotherapy in all patients. Response to intraperitoneal chemotherapy was documented by a third-look laparotomy in all patients not evidencing progression of disease clinically. There were eight responses (26%): five surgical complete responses and three surgical partial responses. Responders were patients with stage III ovarian cancer, small residual disease of less than or equal to 1 cm (primarily less than or equal to 5 mm), and patients who previously had responded to cisplatin-based IV chemotherapy. Of the 15 patients with stage III ovarian cancer, residual disease less than or equal to 1 cm, and those who had responded to first-line IV cisplatin-based chemotherapy, 53% (eight) responded to second-line intraperitoneal chemotherapy. Intraperitoneal chemotherapy as used in this phase II protocol would appear to be an effective second-line treatment in advanced ovarian cancer in this specific subset of patients.

Effect of adjuvant chemotherapy on time to recurrence and survival of stage I uterine sarcomas.

We have evaluated the effect of adjuvant chemotherapy on time to recurrence and survival in two prospective trials of women with stage I uterine sarcomas. The first trial compared surgery only to surgery plus Adriamycin. The 5-year estimated survival rate was 36% for surgery alone and 63% for surgery plus Adriamycin. The 5-year recurrence free rate for surgery alone was 46% as compared to 75% for surgery plus Adriamycin. The second trial, without a concurrent control group, included patients with stage I uterine sarcoma and adjuvant cyclaphosphamide, vincristine, Adriamycin, and dacarbazine (CYVADIC) chemotherapy. The 5-year survival rate was 89% and the recurrence-free rate was 80%. In all of these trials, as well as in the report of Van Nagell et al (Cancer 57:1451-1454, 1986) of adjuvant vincristine, actinomycin-D, and cyclophosphamide (VAC) chemotherapy, there are too few patients to make any formal statistical comparison of the groups, although the surgery plus CYVADIC group appears to be the most promising.

The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma.

Forty consecutive patients with stage III and IV invasive ovarian carcinoma were treated on a phase II protocol consisting of optimal debulking surgery, induction cisplatin, cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy, 6-month interval laparoscopy, reinduction cisplatin, PAC chemotherapy, and second-look procedure. All 40 patients have either disease progression or have completed the 12-month protocol. Eighty-seven percent of the patients (35) underwent optimal (less than or equal to 2 cm residual) debulking surgery before chemotherapy, in spite of the fact that 50% (20) were referred to Roswell Park Memorial Institute (RPMI) as inoperable after initial surgery elsewhere. There were no postoperative deaths and chemotherapy was started in less than or equal to 14 days in 97% of the patients. Of the 40 patients, 30% (12) achieved a pathologic complete remission (11) or a clinical complete remission (one patient refused second-look surgery). The estimated 3-year survival rate was 62%, but the 3-year progression-free survival rate was only 29%. The median survival time was 48 months. The estimated 3-year progression-free survival rate was 31% for residual disease less than or equal to 2 cm. For the five patients with residual disease greater than 2 cm, four died within 3 years. The median survival time of patients with less than or equal to 2 cm residual disease was 48 months, as compared with 21 months for those with greater than 2 cm residual disease. Although the estimated 3-year survival rate of 62% is noteworthy, the 3-year progression-free survival rate of only 29% is probably indicative that in spite of extensive debulking surgery and cisplatin-based chemotherapy as used in this protocol, the long range proportion of patients "cured" will remain small.

Radical hysterectomy and pelvic lymphadenectomy versus radiation therapy for small (less than or equal to 3 cm) stage IB cervical carcinoma.

One hundred and three women with FIGO stage IB cervical carcinoma were treated either by radical hysterectomy and bilateral pelvic lymphadenectomy, or external pelvic radiation and intracavitary brachytherapy to deliver greater than or equal to 6000 rads to point A. Surgical therapy was to be limited to stage IB tumors measuring less than or equal to 3 cm in greatest diameter, Patients with lesions greater than 3 cm, medical contraindications to surgery, or advanced age were to be treated by radiation therapy. Of the 55 women treated surgically, 3 (5.6%) were found on final histologic evaluation to have tumors greater than 3 cm. The 5-year estimated disease-free interval was 92.3% for patients treated by surgery and 91.1% for patients treated by radiation therapy. Similar rates were achieved for the 5-year disease-free interval for lesions greater than 1 cm, 1-3 cm, and less than 3 cm in diameter by either surgery or radiation. It is tentatively concluded that radical hysterectomy and pelvic lymphadenectomy or radiation therapy as outlined above provide equally good disease-free intervals for stage IB cervical tumors measuring less than or equal to 3 cm in diameter. Because of a bias against patients treated with radiation, it is possible that radiation could lead to better results than surgery in comparable (younger, healthier, thinner) population. The advantage of surgical treatment in the younger patient is preservation of ovarian function.

Mixed mesodermal tumor of the uterus (RJ-984): case report and in vitro study.

This report describes the establishment of a cell line of a human uterine mixed mesodermal tumor. The tumor of origin derived from a hysterectomy specimen, has been maintained for 14 months in vitro and continues to grow as an established cell line. The original tumor as well as the cell line exhibited no estrogen receptors. alpha-Fetoprotein was not detected in the cultured cells or in the spent culture medium. Karyotyping revealed 46 XX chromosome complement with a balanced 11-16 translocation. This is the first documentation of such a chromosome abnormality in a genital tract carcinoma. Steroids inhibited cell growth at high (10.0 micrograms/ml) concentrations. This cell line continues to be studied and further characterized. The cell line is readily available for study of this aggressive human neoplasm.

Potential for cure in ovarian cancer.

There has been steady progress in improving the survival stage by stage for women with ovarian carcinoma. Part of this is the "Will Rogers" phenomenon: the improvement in results among two groups by movement of a subset of patients from one stage to the other stage. For those stage I patients at low risk (stage I-A1, I-B1, well or moderately differentiated) for recurrence, the exceeding of 90% survival rates in these carefully staged patients without postoperative radiation or chemotherapy represents significant progress in comparison to results a decade ago. Moreover, those patients thought to be stage I or II but found to have upper abdominal metastasis by careful surgical staging will now receive the best therapy for stage III ovarian cancer. The combination of the small volume of upper abdominal tumor discovered in these latter patients and the effects of receiving the best therapy for stage III disease should result in improved survival for this subset of patients. The impact of cisplatin-based chemotherapy has already impacted positively on improved survival for women with stage III and IV ovarian carcinoma. With more surgeons now trained in the techniques of debulking surgery in advanced ovarian carcinoma, the recent survival rates for patients receiving cisplatin-based chemotherapy should improve significantly in the next decade.

Prevention of vaginal recurrence of stage I endometrial adenocarcinoma with postoperative vaginal radiation.

From 1975 to 1982 a prospective study was conducted at Roswell Park in 68 patients (group 1) for surgical stage I endometrial cancer, grade 1 or 2, and less than 50% myometrial invasion. These patients were treated by total abdominal hysterectomy, bilateral salpingo-oophorectomy, and postoperative vaginal radium. With median follow-up of 4.8 years, there has not been a single vaginal recurrence. This treatment plan was based on a prospective study at the same institute from 1958 to 1967, which compared patients with stage I endometrial cancer treated by hysterectomy alone, preoperative radium followed by hysterectomy, and hysterectomy followed by postoperative radium. In addition, 19 patients (group 2) were evaluated as to their initial treatment after their referral to Roswell Park with vaginal recurrence after surgical treatment for stage I endometrial cancer. None of these patients were treated initially with postoperative vaginal radium after hysterectomy. Based on the zero incidence of vaginal recurrence in 117 patients with FIGO stage I endometrial cancer, the estimated five-year survival rate of 97.2% for the group 1 patients, and the actuarial five-year survival of 95% in the 1958 to 1967 prospective study, it is concluded that primary surgery should be followed by postoperative vaginal radium (cesium) in those patients with stage I endometrial cancer, grade 1 or 2, with less than 50% myometrial invasion.

Doxorubicin hydrochloride (Adriamycin) cardiotoxicity evaluated by sequential radionuclide angiocardiography.

A prospective study was carried out to evaluate the role of radionuclide angiocardiography (CEF) in accessing subclinical cardiotoxicity secondary to Adriamycin (doxorubicin) therapy in 73 women with gynecologic malignancies. Based on the findings of this study, the authors conclude that all patients should have an initial CEF before Adriamycin therapy. In patients with an initial CEF of greater than or equal to 55, frequent determinations are not necessary unless there is a significant decrease from the initial CEF. Patients with low normal initial CEF or significant difference between the initial CEF and minimum CEF should have CEF studies performed at more frequent intervals. Patients who develop below normal CEF should have Adriamycin withheld and CEF should be repeated at more frequent intervals. If the CEF returns to normal Adriamycin therapy can be reinstated. Patients requiring continuation of Adriamycin past 550 mg/m2, can safely do so as long as the CEF values remain normal.

Adenocarcinoma in an isolated sigmoid urinary conduit.

In recent years the colon urinary conduit has been used more frequently as an isolated urinary conduit at the time of total pelvic exenteration for recurrent carcinoma of the uterine cervix. This avoids an intestinal anastomosis and allows for the colon ureteral anastomosis to be outside of the previous irradiation field. Presented is the third case report of adenocarcinoma occurring in an isolated colonic urinary conduit, suggesting that careful surveillance for such malignancies may be required until the potential of neoplastic change is determined.

Erythropoiesis in the X-irradiated, bled rat.

Exposure to low levels of x-irradiation (50R) followed by phlebotomy (50% blood volume) one month post-irradiation, resulted in identifiable alterations of the erythropoietic status of the rat. The red cell indices revealed a decrease in mean corpuscular volume and an increase in mean corpuscular hemoglobin concentration. The half-life of 51Cr-labeled erythrocytes was 16.7 days versus 14.4 days for the untreated controls. These subjects also demonstrated hyperplastic marrows with an approximate 60% mean increase in marrow cellularity. A reproducible mortality of 25% was seen at 17 weeks post-irradiation; the one group of animals followed for an extended period exhibited an 86% cumulative mortality at 23 weeks. The observations supported the concept that x-irradiated rats exposed to a relatively low dose of X-rays (less than 10% LD/50) maintain a latent or residual injury of the bone marrow. These animals, when subsequently challenged by phlebotomy, are placed at greater risk with respect to their ability to survive.