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Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer
SOCIETY OF GYNECOLOGISTS There were no urinary fistulae. Clinically significant leg edema occurred in 1.4% of patients. Postoperative radiation was tailored to the histologic findings. Brachytherapy was routinely given; however, teletherapy was only rarely administered to patients with confirmed extrauterine spread. Survival and recurrence data will be discussed. This report suggests that extensive surgical staging of corpus cancer can be performed with low perioperative morbidity and mortality. Histologic findings can be used to rationally guide adjunctive therapy. 4. Overexpression of HER-Zjneu in Endometrial Carcinoma Is Associated with Poor Prognosis. A. BERCHUCK, G. RODRIGUEZ, R. B. KINNEY, J. T. SOPER,D. L. CLARKE-PEARSON,AND R. C. BAST, JR.,
Duke University, Durham, North Carolina 27710. HER-2/neu is a membrane-spanning glycoprotein that is thought to be a growth factor receptor due to its close homology to the epidermal growth factor receptor. Prior studies by our group and others have shown that HER-2/neu is overexpressed in approximately one-third of breast and ovarian cancers and that overexpression is associated with poor prognosis. We used a monoclonal antibody reactive with the extracellular domain of HER-2/neu to assessimmunohistochemically the level of HER-2/neu expression in frozen sections of normal and malignant endometrium. The intensity of staining was graded as light, moderate, or heavy. In 24 normal endometria. light to moderate staining for HER-2/neu was seen in the glands, and there was no variation in intensity of staining during the menstrual cycle. Among 95 primary endometrial adenocarcinomas, X6 (91%) had light to moderate staining for HER-2/neu, similar to normal endometrium, while Y (9%) had heavy staining for HER-Z/neu. Analysis of the relationship between known prognostic factors and HER-2/neu expression revealed that heavy staining for high HER-2/neu was associated with deep myometrial invasion (P < 0.05), extrauterine disease (P < O.Ol), and absence of estrogen receptor (P < 0.01). Only 3 of 73 patients (4%) with disease confined to the uterus had heavy staining for HER-2/neu compared to 6 of 22 patients (27%) with metastatic disease. All of the cancers that had heavy staining for HER-2/neu were estrogen receptor negative. The relationship between overexpression of HER-2/neu and the aggressive biologic behavior of a subset of endometrial cancers warrants further study. 5. Oncogenic Potential of Tamoxifen on the Endometrium of Patients with Breast Cancer-Preliminary Report. D. GAL, S. KOPEL, M. BASHEVKIN, .I. LEBOWICZ, R. LEV, AND M. L. TANCER, Maimonides
Medical Center and The Cancer Institute of Brooklyn, Brooklyn, New York 11219. Tamoxifen (T), a nonsteroidal antiestrogen, is in use for postmenopausal patients with early breast cancer. Recent reports suggest that T may cause endometrial neoplasia. This study is designed to evaluate the oncogenic potential of low dose T (20-40 mg daily) on the endometrium. Initially, endometrial screening of patients with breast cancer who received T therapy was conducted. Endometrial office biopsies, under local anesthesia, were obtained from 38 patients with breast cancer who were on T therapy for a period of l-6 years. Seven (18%) had hyperplastic changes, ranging from simple through complex hyperplasia with atypia. We proceeded with the following prospective study: after breast surgery and prior to initiation of T therapy, an office endometrial sampling was obtained for pre-T therapy control. Biopsies were studied by light and electron microscopy, as well as by flow cytometry. After initiation of T, therapy biopsies were repeated every 36 months providing that the patients were asymptomatic. To date, nine patients have entered the study. They have been followed from 3-15 months. In three (33%) patients who had normal endometria prior to T therapy there were no hyperplastic changes. These developed during T therapy. The preliminary results of this study, although with a small number of patients, indicate that T in low doses may have some oncogenic effect on the endometria of patients with breast cancer. This
ONCOLOGISTS-ABSTRACTS
169
study is still in progress. Additional prospective studies are warranted before a significant correlation between T and endometrial neoplasia is demonstrated. 6. Neoadjuvant Chemotherapy and Interval Deb&king for Advanced Epithelial Ovarian Cancer. J. JACOB, D. GERSHENSON,M. MORRIS, L. COPELAND,T. BURKE, AND J. WHARTON, University of Texas M. D.
Anderson Cancer Center, Houston. Texas 77030. A retrospective matched control study was conducted to review our experience with FIG0 stage III and IV epithelial ovarian cancer patients referred from 1977 to 1988 after an initial laparotomy and biopsy only. Twenty-two patients constituted the study group; they received two to four cycles of chemotherapy followed by interval debulking surgery after which six more cycles and second-look laparotomy were planned. Two control groups were used for comparison. The first control group consisted of 22 patients who underwent initial surgery and had >2 cm residual disease after which a minimum of six cycles of chemotherapy and second-look laparotomy were planned. The second control group consisted of 18 patients referred after initial laparotomy and biopsy only; they underwent immediate reexploration and debulking after which a minimum of six cycles of chemotherapy and second-look laparotomy were planned. Patients in all three groups were matched for FIG0 stage, histologic type and grade (2 or 3), and age ? 5 years. All received cisplatin-based chemotherapy. Optimal cytoreduction to s2 cm was achieved in 77% of the study group vs 39% of the immediate reexploration group (P = 0.02). There were no differences in median survival times among the three groups (16 vs 19.3 vs 18 months) (P = 0.58). Within the study group, patients who were optimally debulked had a significantly longer survival than those who were not (18.1 vs 7.5 months) (P = 0.02). Morbidity of the interval debulking procedures was acceptable. Within the immediate reexploration group, optimal cytoreduction had no effect on survival (17.3 vs 18.6 months) (P = 0.89). The findings of this study suggest that the prognosis for patients with bulky residual disease is uniformly poor regardless of the timing of further surgical intervention. 7. A Phase I Study of GM-CSF, Cyclophosphamide (CP), and Escalating Doses of Carboplatin (CBDCA) in Chemotherapy-Nake Patients with Ovarian Cancer. J. RUSTHOVEN, L. LEVIN, E. EISENHAUER. J. CARMICHAEL, J. MAZURKA, P. BRYSON, G. O’CONNELL, AND H. HIRIX, Ontario Cancer Foundation, Hamilton, Ontario LSV lC3,
and London, Ontario N6A 4G5, and National Cancer Institute of Canada (NCIC), Kingston, Ontario K7L 3N6. We attempted to increase the dose intensity of CBDCA-based therapy for ovarian cancer by conducting a Phase I trial to determine the maximum tolerated dose (MTD) of CBDCA with GM-CSF in previously untreated patients (pts). All pts received CP 600 mg/m’ iv and GMCSF 10 pg/kg SCdaily on Days 2-11. Groups of three or four pts were accrued at increasing dose levels of CBDCA starting at 400 mg/m’ iv. Doses for individual pts were not escalated. CBDCA was reduced the next cycle if either total granulocytes (PMN) fell below 0.25 x lO’/liter for >4 days or platelets fell below 25 x lO’/liter for >4 days. Hematological dose-limiting toxicity (HDLT) occurred if one of the above criteria for dose reduction were met during cycle 1 or 2. Among three pts treated at 400 mg/m’, full doses of chemotherapy could be given for 14/16 cycles. The median day to nadir was day 14 for both PMN (median 0.7 X log/liter) and platelets (median 1I1 x lO”/liter). Due to HDLT during cycle I in 3/4 pts at 600 mg/m’, 8 pts were treated at 500 mg/m’. Six pts received 19 cycles at full dose and five of these patients each received 3 or 4 cycles at full dose; no treatment delays occurred in 16/1Y cycles due in part to rapid platelet recovery by Day 22. Two patients were removed from study due to GM-CSF toxicity in cycle 1. ‘Median PMN and platelet nadirs at this dose level were 0.2 X lO’/Iiter and 38 X lO’/liter, respectively, and cumulative myelosuppression was evident. One pt developed febrile neutropenia; no
Duke University, Durham, North Carolina 27710. HER-2/neu is a membrane-spanning glycoprotein that is thought to be a growth factor receptor due to its close homology to the epidermal growth factor receptor. Prior studies by our group and others have shown that HER-2/neu is overexpressed in approximately one-third of breast and ovarian cancers and that overexpression is associated with poor prognosis. We used a monoclonal antibody reactive with the extracellular domain of HER-2/neu to assessimmunohistochemically the level of HER-2/neu expression in frozen sections of normal and malignant endometrium. The intensity of staining was graded as light, moderate, or heavy. In 24 normal endometria. light to moderate staining for HER-2/neu was seen in the glands, and there was no variation in intensity of staining during the menstrual cycle. Among 95 primary endometrial adenocarcinomas, X6 (91%) had light to moderate staining for HER-2/neu, similar to normal endometrium, while Y (9%) had heavy staining for HER-Z/neu. Analysis of the relationship between known prognostic factors and HER-2/neu expression revealed that heavy staining for high HER-2/neu was associated with deep myometrial invasion (P < 0.05), extrauterine disease (P < O.Ol), and absence of estrogen receptor (P < 0.01). Only 3 of 73 patients (4%) with disease confined to the uterus had heavy staining for HER-2/neu compared to 6 of 22 patients (27%) with metastatic disease. All of the cancers that had heavy staining for HER-2/neu were estrogen receptor negative. The relationship between overexpression of HER-2/neu and the aggressive biologic behavior of a subset of endometrial cancers warrants further study. 5. Oncogenic Potential of Tamoxifen on the Endometrium of Patients with Breast Cancer-Preliminary Report. D. GAL, S. KOPEL, M. BASHEVKIN, .I. LEBOWICZ, R. LEV, AND M. L. TANCER, Maimonides
Medical Center and The Cancer Institute of Brooklyn, Brooklyn, New York 11219. Tamoxifen (T), a nonsteroidal antiestrogen, is in use for postmenopausal patients with early breast cancer. Recent reports suggest that T may cause endometrial neoplasia. This study is designed to evaluate the oncogenic potential of low dose T (20-40 mg daily) on the endometrium. Initially, endometrial screening of patients with breast cancer who received T therapy was conducted. Endometrial office biopsies, under local anesthesia, were obtained from 38 patients with breast cancer who were on T therapy for a period of l-6 years. Seven (18%) had hyperplastic changes, ranging from simple through complex hyperplasia with atypia. We proceeded with the following prospective study: after breast surgery and prior to initiation of T therapy, an office endometrial sampling was obtained for pre-T therapy control. Biopsies were studied by light and electron microscopy, as well as by flow cytometry. After initiation of T, therapy biopsies were repeated every 36 months providing that the patients were asymptomatic. To date, nine patients have entered the study. They have been followed from 3-15 months. In three (33%) patients who had normal endometria prior to T therapy there were no hyperplastic changes. These developed during T therapy. The preliminary results of this study, although with a small number of patients, indicate that T in low doses may have some oncogenic effect on the endometria of patients with breast cancer. This
ONCOLOGISTS-ABSTRACTS
169
study is still in progress. Additional prospective studies are warranted before a significant correlation between T and endometrial neoplasia is demonstrated. 6. Neoadjuvant Chemotherapy and Interval Deb&king for Advanced Epithelial Ovarian Cancer. J. JACOB, D. GERSHENSON,M. MORRIS, L. COPELAND,T. BURKE, AND J. WHARTON, University of Texas M. D.
Anderson Cancer Center, Houston. Texas 77030. A retrospective matched control study was conducted to review our experience with FIG0 stage III and IV epithelial ovarian cancer patients referred from 1977 to 1988 after an initial laparotomy and biopsy only. Twenty-two patients constituted the study group; they received two to four cycles of chemotherapy followed by interval debulking surgery after which six more cycles and second-look laparotomy were planned. Two control groups were used for comparison. The first control group consisted of 22 patients who underwent initial surgery and had >2 cm residual disease after which a minimum of six cycles of chemotherapy and second-look laparotomy were planned. The second control group consisted of 18 patients referred after initial laparotomy and biopsy only; they underwent immediate reexploration and debulking after which a minimum of six cycles of chemotherapy and second-look laparotomy were planned. Patients in all three groups were matched for FIG0 stage, histologic type and grade (2 or 3), and age ? 5 years. All received cisplatin-based chemotherapy. Optimal cytoreduction to s2 cm was achieved in 77% of the study group vs 39% of the immediate reexploration group (P = 0.02). There were no differences in median survival times among the three groups (16 vs 19.3 vs 18 months) (P = 0.58). Within the study group, patients who were optimally debulked had a significantly longer survival than those who were not (18.1 vs 7.5 months) (P = 0.02). Morbidity of the interval debulking procedures was acceptable. Within the immediate reexploration group, optimal cytoreduction had no effect on survival (17.3 vs 18.6 months) (P = 0.89). The findings of this study suggest that the prognosis for patients with bulky residual disease is uniformly poor regardless of the timing of further surgical intervention. 7. A Phase I Study of GM-CSF, Cyclophosphamide (CP), and Escalating Doses of Carboplatin (CBDCA) in Chemotherapy-Nake Patients with Ovarian Cancer. J. RUSTHOVEN, L. LEVIN, E. EISENHAUER. J. CARMICHAEL, J. MAZURKA, P. BRYSON, G. O’CONNELL, AND H. HIRIX, Ontario Cancer Foundation, Hamilton, Ontario LSV lC3,
and London, Ontario N6A 4G5, and National Cancer Institute of Canada (NCIC), Kingston, Ontario K7L 3N6. We attempted to increase the dose intensity of CBDCA-based therapy for ovarian cancer by conducting a Phase I trial to determine the maximum tolerated dose (MTD) of CBDCA with GM-CSF in previously untreated patients (pts). All pts received CP 600 mg/m’ iv and GMCSF 10 pg/kg SCdaily on Days 2-11. Groups of three or four pts were accrued at increasing dose levels of CBDCA starting at 400 mg/m’ iv. Doses for individual pts were not escalated. CBDCA was reduced the next cycle if either total granulocytes (PMN) fell below 0.25 x lO’/liter for >4 days or platelets fell below 25 x lO’/liter for >4 days. Hematological dose-limiting toxicity (HDLT) occurred if one of the above criteria for dose reduction were met during cycle 1 or 2. Among three pts treated at 400 mg/m’, full doses of chemotherapy could be given for 14/16 cycles. The median day to nadir was day 14 for both PMN (median 0.7 X log/liter) and platelets (median 1I1 x lO”/liter). Due to HDLT during cycle I in 3/4 pts at 600 mg/m’, 8 pts were treated at 500 mg/m’. Six pts received 19 cycles at full dose and five of these patients each received 3 or 4 cycles at full dose; no treatment delays occurred in 16/1Y cycles due in part to rapid platelet recovery by Day 22. Two patients were removed from study due to GM-CSF toxicity in cycle 1. ‘Median PMN and platelet nadirs at this dose level were 0.2 X lO’/Iiter and 38 X lO’/liter, respectively, and cumulative myelosuppression was evident. One pt developed febrile neutropenia; no