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Weekly or biweekly intraperitoneal (ip) mitoxantrone (M) as therapy (Rx) of refractory ovarian cancer (ROC)
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SOCIETY OF GYNECOLOGISTS
vomiting. Ototoxicity was mild. Among 10 pts evaluable for response, there were three PR’s with maximum duration of 3 months. Due to both the limited number and the short duration of responses seen, we conclude that C dose intensity does not enhance the response rate over that seen with conventional doses of C. 95. Single Agent Ifosfamide (IFOS) Therapy of Ovarian Cancer (OC) Previously Treated with Cisplatin (US). M. MARKMAN, T. HAKES, B. REICHMAN, W. HOSKINS, S. RUBIN, W. JONES, L. ALMADRONES, J. L. LEWIS, JR., Memorial Sloan-Kettering Cancer Center
(MSKCC), New York, New York 10021. In the management of OC, there is a critical need to identify antineoplastic agents which are active against US-resistant tumors. Reports of salvage therapy (Rx) in OC have often not distinguished activity in truly CIS-resistant tumors from responses in recurrent disease which may remain CIS-sensitive. To critically evaluate the activity of IFOS in CIS-resistant OC, 43 pts with prior CIS and cytoxan exposure were treated on a daily x 5 schedule of IFOS at an initial dose level of 1.0 g/m’/day (25 pts) (REG A) or 1.2 g/m’/day (18 pts) (REG B). Rx was repeated monthly. Toxicity included significant marrow suppression (two episodes nadir fever REG A, five in REG B), mild renal dysfunction (serum creatinine rise to 2.0-3.0 mg% in 4 pts), and neurological dysfunction (6 pts, 3 with severe symptoms of a reversible encephalopathy). Of the 36 pts evaluable for response (4 pts removed for toxicity, 3 pts remain on study), 5 (14%) demonstrated partial responses (PR). Response durations range from 2+ to 9+ months. To date, no responding patient has relapsed. In the 22 pts with (X-resistant OC (progression or no response to prior CIS), 3 PRs (14%) have been observed. We conclude that IFOS has moderate but unequivocal activity in (X-resistant OC, and the agent should be explored further as part of initial Rx of OC. 96. Weekly or Biweekly Intraperitoneal
(ip) Mitoxantrone (M) as Therapy (Rx) of Refractory Ovarian Cancer (ROC). M. MARKMAN, B. REICHMAN, T. HAKES, W. HOSKINS, S. RUBIN, W. JONES, L. ALMADRONES,AND J. L. LEWIS,JR., Memorial Sloan-Kettering Cancer
Center, New York, New York 10021. Previous evaluation has suggested that M is a potent agent against ROC at concentrations achievable in the peritoneal cavity following ip Rx. The utility of ip M when given on a monthly schedule of 20 mg/m’/dose for 6 months was limited by severe local effects (1. Clin. Oncol. 8, 146, 1990). In an effort to reduce toxicity, 28 pts with ROC received a lower concentration of ip M (10 mg/m*/dose) weekly for 12 courses. Rx was changed to every other week if excessive local/systemic toxicity was observed. Seventeen patients (61%) received >80% of the planned Rx (compared to 12/31 pts (39%) on the monthly Rx). Five patients required a change in schedule (local pain-l; marrow suppression-4). Ten patients (36%) needed narcotic analgesia at some point during Rx (compared to 74% with the monthly Rx). While 3 pts (11%) developed serious local toxicity of Rx (infection, catheter erosion into bowel), none could be directly attributed to M (compared to 6/31 pts who experienced M-related bowel dysfunction on the higher dose Rx). Among evaluable patients 3/17 (18%) (3 refused surgical reassessment, 6 catheter failure/removed for toxicity while in clinical CR, 2 awaiting surgery) experienced a surgically defined PR. Weekly ip Rx with M at a lower concentration reduces local toxicity, but without improvement in the surgically defined response rate compared to monthly Rx. 97. Survival and Patterns of Recurrence in Patients with Epithelial Ovarian Carcinoma (EOC) Who Have a Surgical Complete Response (SCR) following Salvage IntraperitoneaI Chemotherapy (IPC). W. HOSKINS, M. MARKMAN, S. RUBIN, T. HAKES, B. REICHMAN, W. JONES, L. ALMADRONES, D. CHAPMAN, AND J. L. LEWIS, JR., Mem-
orial Sloan-Kettering Cancer Center, New York, New York 10021.
ONCOLOGISTS-ABSTRACTS Twenty-seven of 177 evaluable patients (101 evaluated by surgery) with persistent (20) or recurrent (7) EOC had a SCR after IPC using Cisplatin + VP-16 (12), Cisplatin + ARA-C (7), Mitoxantrone (6), IV/IP 5Fu + Cisplatin (l), and Carboplatin + VP16 (1). Stage distribution was: Stage I (l), Stage II (2), Stage III (19), Stage IV (2), and unstaged (3). Grade distribution was: LMP (l), grade 1 (7), grade 2 (7), and grade 3 (12). At onset of IPC 12 patients had microscopic disease, 10 patients had macroscopic disease ~0.5 cm and 3 patients had disease 0.5 to 1 cm. Two patients had disease >I cm. At a median followup of 16 months (range 4 to 31 months), survival is 70.4% and disease-free survival is 48%. Thirteen of 27 patients (48%) have recurred. Recurrence by treatment is: Cisplatin + VP-16, 9/12; Cisplatin + ARA-C, 2/7; Mitoxantrone, 2/6; IV/IP 5Fu + Cisplatin, O/l; and Carboplatin + VP16, O/l. Recurrences occurred in the peritoneal cavity (S/13), liver (3/13), pericardium (l/13), and retroperitoneum (l/13). Although there is a substantial recurrence rate following SCR in patients treated with salvage IPC, the disease-free survival of 48% at a median of 16 months warrants continued clinical trials to evaluate this therapy. SCR is most likely to occur in patients with microscopic residual or residual <5 mm. The majority of patients recur in the peritoneal cavity. Supported in part by the Avon Program in Ovarian Cancer. 98. Phase II Study of 5-Fluorouracil and Leucovorin in Women with Advanced, Recurrent Ovarian Carcinoma. R. A. NELIMARK, H. J. LONG, AND H. S. WIEAND, North Central Cancer Treatment Group,
Rochester, Minnesota 55905. Forty-three women with advanced epithelial ovarian carcinoma who failed to achieve remission on platinum-based chemotherapy were treated with 5-fluorouracil425 mg/m* iv preceded by calcium leucovorin 20 mg/m’ iv daily for 5 consecutive days every 4 weeks. Seventeen patients had measurable disease, 15 evaluable disease, and 11 nonevaluable except for the presence of serous effusions or elevated CA 125 level. Nine had only minimal residual disease, 18 extensive disease, and 16 massive disease after secondary debulking surgery. Median age was 61 years (range 38-81). All patients were performance status (ECOG) O-3. Median time to progression was 3.25 months and median survival was 6.6 months. Overall response rate was 21.4% (95% CI: lo37). Individual response rates by evaluable status are: Measurable PR 3/17 (17.6%), evaluable regression 3/15 (20%), and nonevaluable regression (effusion or CA 125level) 3/11 (27.3%). No complete regressions were observed. Median WBC nadir was 2OOO/pl(range 300-4600) and median platelet nadir was 151,000/~1 (range 8-391 x 102). Other toxicities included stomatitis 76%, nausea 64%, vomiting 45%, diarrhea 52%, alopecia 45%, and cerebellar 24%. The above toxicities were grade 3 or less except for 5 patients with grade 4 stomatitis. There was 1 drug-related death. Conclusion: the combination of 5-fluorouracil and calcium leucovorin is an active salvage regimen for advanced recurrent ovarian carcinoma although the toxicity is moderate and survival advantage brief. [Supported in part by PHS Grants CA-25224 and CA37404 from NCI.] 99. The Prognostic Significance of Depth of Invasion in Early Stage IB Cervical Cancer. P. D. DEPRIEST, J. R. VAN NAGELL, JR., E. S. DONALDSON, H. H. GALLION, R. V. HIGGINS, D. DAVEY, AND R. J. KRYSCIO, University of Kentucky Medical Center, Lexington, Ken-
tucky 40536. Depth of stromal invasion was measured by calibrated optics in 71 patients (pts) undergoing radical hysterectomy and pelvic lymphadenectomy for Stage IB cervical cancers <3 cm diameter. Additional histomorphologic variables evaluated included cell type, lymph vascular space invasion, and lymph nodal metastasis. The mean age of the pts was 42 (range 26-71) and the mean gravidity was 3 (range O-7). Surgical margins were free of disease in all cases and three pts had lymph nodal metastases. Following treatment, pts were evaluated regularly from 1.2 to 13.4 years (mean 4.9 years). Seven pts developed recurrent cancer
SOCIETY OF GYNECOLOGISTS
vomiting. Ototoxicity was mild. Among 10 pts evaluable for response, there were three PR’s with maximum duration of 3 months. Due to both the limited number and the short duration of responses seen, we conclude that C dose intensity does not enhance the response rate over that seen with conventional doses of C. 95. Single Agent Ifosfamide (IFOS) Therapy of Ovarian Cancer (OC) Previously Treated with Cisplatin (US). M. MARKMAN, T. HAKES, B. REICHMAN, W. HOSKINS, S. RUBIN, W. JONES, L. ALMADRONES, J. L. LEWIS, JR., Memorial Sloan-Kettering Cancer Center
(MSKCC), New York, New York 10021. In the management of OC, there is a critical need to identify antineoplastic agents which are active against US-resistant tumors. Reports of salvage therapy (Rx) in OC have often not distinguished activity in truly CIS-resistant tumors from responses in recurrent disease which may remain CIS-sensitive. To critically evaluate the activity of IFOS in CIS-resistant OC, 43 pts with prior CIS and cytoxan exposure were treated on a daily x 5 schedule of IFOS at an initial dose level of 1.0 g/m’/day (25 pts) (REG A) or 1.2 g/m’/day (18 pts) (REG B). Rx was repeated monthly. Toxicity included significant marrow suppression (two episodes nadir fever REG A, five in REG B), mild renal dysfunction (serum creatinine rise to 2.0-3.0 mg% in 4 pts), and neurological dysfunction (6 pts, 3 with severe symptoms of a reversible encephalopathy). Of the 36 pts evaluable for response (4 pts removed for toxicity, 3 pts remain on study), 5 (14%) demonstrated partial responses (PR). Response durations range from 2+ to 9+ months. To date, no responding patient has relapsed. In the 22 pts with (X-resistant OC (progression or no response to prior CIS), 3 PRs (14%) have been observed. We conclude that IFOS has moderate but unequivocal activity in (X-resistant OC, and the agent should be explored further as part of initial Rx of OC. 96. Weekly or Biweekly Intraperitoneal
(ip) Mitoxantrone (M) as Therapy (Rx) of Refractory Ovarian Cancer (ROC). M. MARKMAN, B. REICHMAN, T. HAKES, W. HOSKINS, S. RUBIN, W. JONES, L. ALMADRONES,AND J. L. LEWIS,JR., Memorial Sloan-Kettering Cancer
Center, New York, New York 10021. Previous evaluation has suggested that M is a potent agent against ROC at concentrations achievable in the peritoneal cavity following ip Rx. The utility of ip M when given on a monthly schedule of 20 mg/m’/dose for 6 months was limited by severe local effects (1. Clin. Oncol. 8, 146, 1990). In an effort to reduce toxicity, 28 pts with ROC received a lower concentration of ip M (10 mg/m*/dose) weekly for 12 courses. Rx was changed to every other week if excessive local/systemic toxicity was observed. Seventeen patients (61%) received >80% of the planned Rx (compared to 12/31 pts (39%) on the monthly Rx). Five patients required a change in schedule (local pain-l; marrow suppression-4). Ten patients (36%) needed narcotic analgesia at some point during Rx (compared to 74% with the monthly Rx). While 3 pts (11%) developed serious local toxicity of Rx (infection, catheter erosion into bowel), none could be directly attributed to M (compared to 6/31 pts who experienced M-related bowel dysfunction on the higher dose Rx). Among evaluable patients 3/17 (18%) (3 refused surgical reassessment, 6 catheter failure/removed for toxicity while in clinical CR, 2 awaiting surgery) experienced a surgically defined PR. Weekly ip Rx with M at a lower concentration reduces local toxicity, but without improvement in the surgically defined response rate compared to monthly Rx. 97. Survival and Patterns of Recurrence in Patients with Epithelial Ovarian Carcinoma (EOC) Who Have a Surgical Complete Response (SCR) following Salvage IntraperitoneaI Chemotherapy (IPC). W. HOSKINS, M. MARKMAN, S. RUBIN, T. HAKES, B. REICHMAN, W. JONES, L. ALMADRONES, D. CHAPMAN, AND J. L. LEWIS, JR., Mem-
orial Sloan-Kettering Cancer Center, New York, New York 10021.
ONCOLOGISTS-ABSTRACTS Twenty-seven of 177 evaluable patients (101 evaluated by surgery) with persistent (20) or recurrent (7) EOC had a SCR after IPC using Cisplatin + VP-16 (12), Cisplatin + ARA-C (7), Mitoxantrone (6), IV/IP 5Fu + Cisplatin (l), and Carboplatin + VP16 (1). Stage distribution was: Stage I (l), Stage II (2), Stage III (19), Stage IV (2), and unstaged (3). Grade distribution was: LMP (l), grade 1 (7), grade 2 (7), and grade 3 (12). At onset of IPC 12 patients had microscopic disease, 10 patients had macroscopic disease ~0.5 cm and 3 patients had disease 0.5 to 1 cm. Two patients had disease >I cm. At a median followup of 16 months (range 4 to 31 months), survival is 70.4% and disease-free survival is 48%. Thirteen of 27 patients (48%) have recurred. Recurrence by treatment is: Cisplatin + VP-16, 9/12; Cisplatin + ARA-C, 2/7; Mitoxantrone, 2/6; IV/IP 5Fu + Cisplatin, O/l; and Carboplatin + VP16, O/l. Recurrences occurred in the peritoneal cavity (S/13), liver (3/13), pericardium (l/13), and retroperitoneum (l/13). Although there is a substantial recurrence rate following SCR in patients treated with salvage IPC, the disease-free survival of 48% at a median of 16 months warrants continued clinical trials to evaluate this therapy. SCR is most likely to occur in patients with microscopic residual or residual <5 mm. The majority of patients recur in the peritoneal cavity. Supported in part by the Avon Program in Ovarian Cancer. 98. Phase II Study of 5-Fluorouracil and Leucovorin in Women with Advanced, Recurrent Ovarian Carcinoma. R. A. NELIMARK, H. J. LONG, AND H. S. WIEAND, North Central Cancer Treatment Group,
Rochester, Minnesota 55905. Forty-three women with advanced epithelial ovarian carcinoma who failed to achieve remission on platinum-based chemotherapy were treated with 5-fluorouracil425 mg/m* iv preceded by calcium leucovorin 20 mg/m’ iv daily for 5 consecutive days every 4 weeks. Seventeen patients had measurable disease, 15 evaluable disease, and 11 nonevaluable except for the presence of serous effusions or elevated CA 125 level. Nine had only minimal residual disease, 18 extensive disease, and 16 massive disease after secondary debulking surgery. Median age was 61 years (range 38-81). All patients were performance status (ECOG) O-3. Median time to progression was 3.25 months and median survival was 6.6 months. Overall response rate was 21.4% (95% CI: lo37). Individual response rates by evaluable status are: Measurable PR 3/17 (17.6%), evaluable regression 3/15 (20%), and nonevaluable regression (effusion or CA 125level) 3/11 (27.3%). No complete regressions were observed. Median WBC nadir was 2OOO/pl(range 300-4600) and median platelet nadir was 151,000/~1 (range 8-391 x 102). Other toxicities included stomatitis 76%, nausea 64%, vomiting 45%, diarrhea 52%, alopecia 45%, and cerebellar 24%. The above toxicities were grade 3 or less except for 5 patients with grade 4 stomatitis. There was 1 drug-related death. Conclusion: the combination of 5-fluorouracil and calcium leucovorin is an active salvage regimen for advanced recurrent ovarian carcinoma although the toxicity is moderate and survival advantage brief. [Supported in part by PHS Grants CA-25224 and CA37404 from NCI.] 99. The Prognostic Significance of Depth of Invasion in Early Stage IB Cervical Cancer. P. D. DEPRIEST, J. R. VAN NAGELL, JR., E. S. DONALDSON, H. H. GALLION, R. V. HIGGINS, D. DAVEY, AND R. J. KRYSCIO, University of Kentucky Medical Center, Lexington, Ken-
tucky 40536. Depth of stromal invasion was measured by calibrated optics in 71 patients (pts) undergoing radical hysterectomy and pelvic lymphadenectomy for Stage IB cervical cancers <3 cm diameter. Additional histomorphologic variables evaluated included cell type, lymph vascular space invasion, and lymph nodal metastasis. The mean age of the pts was 42 (range 26-71) and the mean gravidity was 3 (range O-7). Surgical margins were free of disease in all cases and three pts had lymph nodal metastases. Following treatment, pts were evaluated regularly from 1.2 to 13.4 years (mean 4.9 years). Seven pts developed recurrent cancer