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Urinary gonadotropin fragments (UGF): A new gynecologic cancer marker
SOCIETY
OF GYNECOLOGIC
ONCOLOGISTS-ABSTRACTS
133
The recognition of these two prognostic groups brings the therapeutic challenges in vulvar cancer into clearer focus. In the low-risk group, the need is to reduce surgical morbidity without compromising cure rates. In the high-risk group, locoregional control rates must be improved in order to improve cure rates. Since 27 of the 30 relapses were in the vulva or groin, and only 3 were beyond that, adjunctive radiotherapy might improve cure rates if applied in high-risk patients. 16. Recurrent Gestational Neoplasia: Experience of the Southeastern Trophohlastic Disease Center. DAVID G. MUTCH, M.D., JOHNT. SOPER,M.D., CRISTINJ. BABCOCK,M.D., CARLW. CHRISTENSEN, M.D., PH.D., DANIELL. CLARKE-PEARSON, M.D., ANDCHARLES B. HAMMOND,M.D., Duke University, Durham, North Carolina 27710. Between 1968 and 1985, 28 patients with recurrent gestational trophoblastic disease were treated at the Southeastern Regional Trophoblastic Disease Center (SRTDC). Sixteen patients received primary therapy at this center and had recurrence diagnosed by reevaluation of human chorionic gonadotropin (hCG) levels after three consecutive negative levels: 5 (2.5%) of 204 patients with nonmetastatic gestational trophoblastic disease, and 8 (13%) of 61 with poor prognosis disease. The remaining 12 patients were referred for therapy after receiving primary therapy elsewhere. All episodes of recurrence were observed within 36 months of remission with 50 and 86% before 3 and 18 months, respectively. Fourteen (56%) of 25 patients who achieved secondary remission developed a second recurrence and 5 (45%) of 11 surviving a second recurrence developed one or more further episodes of recurrent gestational trophoblastic disease. Nineteen patients (68%) have sustained remission 18 months following therapy for recurrent gestational trophoblastic disease. Factors relating to development and survival of recurrent disease include poor prognosis metastatic disease, inadequate initial staging and therapy, lack of adequate maintenance chemotherapy beyond the first negative hCG level, and prolonged intervals between cycles of chemotherapy. Recent regimens introduced have contributed to an increasing salvage rate: 15 of 18 patients treated since 1978 are without evidence of disease whereas only 4 of 9 treated prior to 1978 are currently in remission (P = 0.03). 17. Clinical Experience with Placental Site Trophoblastic Tumors (PSTT) at the New England Trophoblastic Disease Center (NETDC). NEIL J. FINKLER,Ross S. BERKOWITZ,SHIRLEYG. DRISCOLL..
DONALDP. GOLDSTEIN,AND MARILYNR. BERNSTEIN,Departments of Obstetrics and Gynecology and Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115. From 1982 to 1986, seven patients with pathologically confirmed PSTT underwent treatment at the NETDC. All seven patients presented with nonmetastatic disease. Mean patient’s age was 26.7 years and gravidity ranged from one to six (mean = 3). Mean pretreatment hCG was only 97 mIU/ml. Six patients presented with vaginal bleeding and one presented with amenorrhea. Three patients were treated by dilatation and curettage and all have achieved remission. Four patients were treated by total abdominal hysterectomy and adjuvant chemotherapy and three have remained in gonadotropin remission. Mitotic counts ranged from 1 to 3 mitoses/lOHPF in endometrial curettings from the seven patients. One patient developed recurrent PSTT following hysterectomy and adjuvant chemotherapy. While the uterine tumor contained 2 mitoses/lOHPF, recurrent nodal metastases had as many as 10 mitoses/lOHPF. Recurrent PSTT in this patient was resistant to various chemotherapy combinations including methotrexate, actinomycin D, VP-16, bleomycin, cisplatin, vinblastine. vincristine, and cyclophosphamide. Twelve months following pelvic radiation therapy, this patient remains in clinical and gonadotropin remission. Treatment recommendations for PSTT are made based on the evolving knowledge of this uncommon tumor. 18. Urinary Gonadotropin Fragments (UGF): A New Gynecologic Cancer Marker. L. A. COLE, Y. WANG,J. CHAMBERS, S. CHAMBERS, ANDP. SCHWARTZ, Yale University, New Haven, Connecticut 06510. Fragments of hCG, free P-subunit, desialylated free P-subunit, and the core peptide of desialylated P-subunit (residues 6-40 disulfide-linked to 55-91) are produced by gynecologic cancers and can be detected in urines. Using an immunoradiometric assay that equally detects free p-subunit and fragments
134
SOCIETY
OF GYNECOLOGIC
ONCOLOGISTS-ABSTRACTS
(UGF), but not hCG, we demonstrated their presence in 50 of 68 (74%) urines from patients with active cervical, ovarian, or endometrial cancer (sensitivity 70,73, and 77%, respectively) and showed correlation between stage of disease (1 to 4) and UGF sensitivity (50 to 83%) and also stage of disease and mean UGF titers (0.63 to 2.4 rig/ml). Three of 50 control urines were positive for this marker, suggesting a specificity of 92% (Cole et al., Cancer Res., 1987, in press). We report the first studies on UGF monitoring gynecologic cancer therapy. Serial urine samples were examined from 10 patients with ovarian, 5 with endometrial, 2 with cervical, and 1 with uterine cancer (18 total). In 3 patients with progressive disease and increasing serum CA125 levels UGF was detected (>0.2 rig/ml) but at levels not correlating with changes in clinical status. In a further 9 patients treated with chemotherapy, however, UGF levels correlated with changes in clinical observations and paralleled changes in CA125 or squamous cell carcinoma antigen (SCC) levels. UGF levels also correlated with disease status in 6 patients (3 at first sign of recurrence) with active malignancy (4 ovarian, 2 other) and negative serum CA125 (<35 U/ml) or SCC (c2.5 rig/ml) values. This shows that UGF can be used for subjects negative for CA125 in monitoring therapy and screening for recurrent disease. UGF levels alone (in I5 of 18 patients) or with serum CA125 (in I8 of 18 patients) are a means for monitoring therapy in a wide spectrum of gynecologic cancers. 19. Cell Kinetic Measurements
in in Vivo Human Cancers-The
Effect of Surgical
Debulking
and
R. KLEVECZ, Department of Gynecologic Oncology, City of Hope National Medical Center, Duarte, California 91010; Department of Obstetrics and Gynecology, University of California, Irvine, California 92668;and Cell Biology, Beckman Research Institute at the City of Hope National Medical Center, Durate, California 91010. Chemotherapy.
PATRICIA S. BRALY AND ROBERT
Several intraperitoneal chemotherapy protocols at our institution require the surgical implantation and frequent postoperative irrigations of peritoneal dialysis catheters. Tumor and normal host cells from these washings have been analyzed by flow cytometry for DNA content, tumor-associated antigens, and percentage of cells in S phase. When analyzed over time, proliferation dynamics including the period and amplitude of S-phase waves and the time of day when peak proliferation occurs can be determined. Patients were divided into three separate subgroups depending on tumor ploidy and the presence or absence of free tumor cells in the peritoneal cavity and these findings were compared to clinical outcome. A total of 97 patients with abdominal carcinomatosis were analyzed with at least one DNA histogram for S-phase fraction and 31 patients were extensively studied with serial measurements. In 28 of 31 around-the-clock analyses, rhythmic changes in the fraction of cells in S phase were detected. Most showed a significant 24-hr rhythm in proliferation. The S-phase fraction varied from less than I% to more 35%. Peak tumor cell proliferation appears to occur in the early afternoon while normal diploid cells show maximum proliferation in the late evening. In many instances of surgical debulking there appears a superimposed increase in the absolute value of S-phase cells 5-7 days postoperatively. We hope to be able to use this information to modify the timing of administration of chemotherapy to maximize the antitumor effect and minimize systemtic toxicity. 20. Therapy of Ovarian Carcinoma: The Relationship of Dose Level (DL) and Treatment Intensity ([) to Survival. G. S. SOMMERS, A. J. JACOBS, H. M. CAMEL, J. H. AXELROD, M.-S. KAO, A. E.
J. PARHAM, AND L. LIPPMANN, Departments of Obstetrics and Gynecology, Washington University, St. Louis, Missouri 63110, and St. Louis University, St. Louis, Missouri 63104.
GALAKATOS,
Following primary maximal cytoreduction, 71 previously untreated patients with stage III or IV epithelial ovarian carcinoma received combination chemotherapy consisting of cisplatin (P), doxorubicin (A), and cyclophosphamide (C). Treatment began within I2 weeks of surgery in all patients, and within 6 weeks in all but 9. All received at least six courses of chemotherapy. Forty-nine patients either survived 2 years or were followed until death; all patients were followed at least 9 months. Treatment modification during chemotherapy and management of recurrent or persistent disease were at the discretion of the individual physician. DL2 and DL, were defined for each drug as the quantity of drug received through the third and sixth course of chemotherapy. DL-P and DL-A of 1.0 were defined as 50 mg of A or P per course, while a DL-C consisted of 500 mg of C per course. The combined DL (DL-TOT) was the mean of DL-P, DL-A, and DL-C. I, and I, were calculated
OF GYNECOLOGIC
ONCOLOGISTS-ABSTRACTS
133
The recognition of these two prognostic groups brings the therapeutic challenges in vulvar cancer into clearer focus. In the low-risk group, the need is to reduce surgical morbidity without compromising cure rates. In the high-risk group, locoregional control rates must be improved in order to improve cure rates. Since 27 of the 30 relapses were in the vulva or groin, and only 3 were beyond that, adjunctive radiotherapy might improve cure rates if applied in high-risk patients. 16. Recurrent Gestational Neoplasia: Experience of the Southeastern Trophohlastic Disease Center. DAVID G. MUTCH, M.D., JOHNT. SOPER,M.D., CRISTINJ. BABCOCK,M.D., CARLW. CHRISTENSEN, M.D., PH.D., DANIELL. CLARKE-PEARSON, M.D., ANDCHARLES B. HAMMOND,M.D., Duke University, Durham, North Carolina 27710. Between 1968 and 1985, 28 patients with recurrent gestational trophoblastic disease were treated at the Southeastern Regional Trophoblastic Disease Center (SRTDC). Sixteen patients received primary therapy at this center and had recurrence diagnosed by reevaluation of human chorionic gonadotropin (hCG) levels after three consecutive negative levels: 5 (2.5%) of 204 patients with nonmetastatic gestational trophoblastic disease, and 8 (13%) of 61 with poor prognosis disease. The remaining 12 patients were referred for therapy after receiving primary therapy elsewhere. All episodes of recurrence were observed within 36 months of remission with 50 and 86% before 3 and 18 months, respectively. Fourteen (56%) of 25 patients who achieved secondary remission developed a second recurrence and 5 (45%) of 11 surviving a second recurrence developed one or more further episodes of recurrent gestational trophoblastic disease. Nineteen patients (68%) have sustained remission 18 months following therapy for recurrent gestational trophoblastic disease. Factors relating to development and survival of recurrent disease include poor prognosis metastatic disease, inadequate initial staging and therapy, lack of adequate maintenance chemotherapy beyond the first negative hCG level, and prolonged intervals between cycles of chemotherapy. Recent regimens introduced have contributed to an increasing salvage rate: 15 of 18 patients treated since 1978 are without evidence of disease whereas only 4 of 9 treated prior to 1978 are currently in remission (P = 0.03). 17. Clinical Experience with Placental Site Trophoblastic Tumors (PSTT) at the New England Trophoblastic Disease Center (NETDC). NEIL J. FINKLER,Ross S. BERKOWITZ,SHIRLEYG. DRISCOLL..
DONALDP. GOLDSTEIN,AND MARILYNR. BERNSTEIN,Departments of Obstetrics and Gynecology and Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115. From 1982 to 1986, seven patients with pathologically confirmed PSTT underwent treatment at the NETDC. All seven patients presented with nonmetastatic disease. Mean patient’s age was 26.7 years and gravidity ranged from one to six (mean = 3). Mean pretreatment hCG was only 97 mIU/ml. Six patients presented with vaginal bleeding and one presented with amenorrhea. Three patients were treated by dilatation and curettage and all have achieved remission. Four patients were treated by total abdominal hysterectomy and adjuvant chemotherapy and three have remained in gonadotropin remission. Mitotic counts ranged from 1 to 3 mitoses/lOHPF in endometrial curettings from the seven patients. One patient developed recurrent PSTT following hysterectomy and adjuvant chemotherapy. While the uterine tumor contained 2 mitoses/lOHPF, recurrent nodal metastases had as many as 10 mitoses/lOHPF. Recurrent PSTT in this patient was resistant to various chemotherapy combinations including methotrexate, actinomycin D, VP-16, bleomycin, cisplatin, vinblastine. vincristine, and cyclophosphamide. Twelve months following pelvic radiation therapy, this patient remains in clinical and gonadotropin remission. Treatment recommendations for PSTT are made based on the evolving knowledge of this uncommon tumor. 18. Urinary Gonadotropin Fragments (UGF): A New Gynecologic Cancer Marker. L. A. COLE, Y. WANG,J. CHAMBERS, S. CHAMBERS, ANDP. SCHWARTZ, Yale University, New Haven, Connecticut 06510. Fragments of hCG, free P-subunit, desialylated free P-subunit, and the core peptide of desialylated P-subunit (residues 6-40 disulfide-linked to 55-91) are produced by gynecologic cancers and can be detected in urines. Using an immunoradiometric assay that equally detects free p-subunit and fragments
134
SOCIETY
OF GYNECOLOGIC
ONCOLOGISTS-ABSTRACTS
(UGF), but not hCG, we demonstrated their presence in 50 of 68 (74%) urines from patients with active cervical, ovarian, or endometrial cancer (sensitivity 70,73, and 77%, respectively) and showed correlation between stage of disease (1 to 4) and UGF sensitivity (50 to 83%) and also stage of disease and mean UGF titers (0.63 to 2.4 rig/ml). Three of 50 control urines were positive for this marker, suggesting a specificity of 92% (Cole et al., Cancer Res., 1987, in press). We report the first studies on UGF monitoring gynecologic cancer therapy. Serial urine samples were examined from 10 patients with ovarian, 5 with endometrial, 2 with cervical, and 1 with uterine cancer (18 total). In 3 patients with progressive disease and increasing serum CA125 levels UGF was detected (>0.2 rig/ml) but at levels not correlating with changes in clinical status. In a further 9 patients treated with chemotherapy, however, UGF levels correlated with changes in clinical observations and paralleled changes in CA125 or squamous cell carcinoma antigen (SCC) levels. UGF levels also correlated with disease status in 6 patients (3 at first sign of recurrence) with active malignancy (4 ovarian, 2 other) and negative serum CA125 (<35 U/ml) or SCC (c2.5 rig/ml) values. This shows that UGF can be used for subjects negative for CA125 in monitoring therapy and screening for recurrent disease. UGF levels alone (in I5 of 18 patients) or with serum CA125 (in I8 of 18 patients) are a means for monitoring therapy in a wide spectrum of gynecologic cancers. 19. Cell Kinetic Measurements
in in Vivo Human Cancers-The
Effect of Surgical
Debulking
and
R. KLEVECZ, Department of Gynecologic Oncology, City of Hope National Medical Center, Duarte, California 91010; Department of Obstetrics and Gynecology, University of California, Irvine, California 92668;and Cell Biology, Beckman Research Institute at the City of Hope National Medical Center, Durate, California 91010. Chemotherapy.
PATRICIA S. BRALY AND ROBERT
Several intraperitoneal chemotherapy protocols at our institution require the surgical implantation and frequent postoperative irrigations of peritoneal dialysis catheters. Tumor and normal host cells from these washings have been analyzed by flow cytometry for DNA content, tumor-associated antigens, and percentage of cells in S phase. When analyzed over time, proliferation dynamics including the period and amplitude of S-phase waves and the time of day when peak proliferation occurs can be determined. Patients were divided into three separate subgroups depending on tumor ploidy and the presence or absence of free tumor cells in the peritoneal cavity and these findings were compared to clinical outcome. A total of 97 patients with abdominal carcinomatosis were analyzed with at least one DNA histogram for S-phase fraction and 31 patients were extensively studied with serial measurements. In 28 of 31 around-the-clock analyses, rhythmic changes in the fraction of cells in S phase were detected. Most showed a significant 24-hr rhythm in proliferation. The S-phase fraction varied from less than I% to more 35%. Peak tumor cell proliferation appears to occur in the early afternoon while normal diploid cells show maximum proliferation in the late evening. In many instances of surgical debulking there appears a superimposed increase in the absolute value of S-phase cells 5-7 days postoperatively. We hope to be able to use this information to modify the timing of administration of chemotherapy to maximize the antitumor effect and minimize systemtic toxicity. 20. Therapy of Ovarian Carcinoma: The Relationship of Dose Level (DL) and Treatment Intensity ([) to Survival. G. S. SOMMERS, A. J. JACOBS, H. M. CAMEL, J. H. AXELROD, M.-S. KAO, A. E.
J. PARHAM, AND L. LIPPMANN, Departments of Obstetrics and Gynecology, Washington University, St. Louis, Missouri 63110, and St. Louis University, St. Louis, Missouri 63104.
GALAKATOS,
Following primary maximal cytoreduction, 71 previously untreated patients with stage III or IV epithelial ovarian carcinoma received combination chemotherapy consisting of cisplatin (P), doxorubicin (A), and cyclophosphamide (C). Treatment began within I2 weeks of surgery in all patients, and within 6 weeks in all but 9. All received at least six courses of chemotherapy. Forty-nine patients either survived 2 years or were followed until death; all patients were followed at least 9 months. Treatment modification during chemotherapy and management of recurrent or persistent disease were at the discretion of the individual physician. DL2 and DL, were defined for each drug as the quantity of drug received through the third and sixth course of chemotherapy. DL-P and DL-A of 1.0 were defined as 50 mg of A or P per course, while a DL-C consisted of 500 mg of C per course. The combined DL (DL-TOT) was the mean of DL-P, DL-A, and DL-C. I, and I, were calculated