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Consolidation with intraperitoneal cisplatin in first-line therapy of advanced ovarian cancer
Beller U; Speyer J; Colombo N; Sorich J; Wernz J; Hochster H; Zeleniuch-Jacquotte A; Porges R; Beckman EM
Seventy-five patients with advanced epithelial ovarian cancer were treated with a combined modality regimen of systemic, induction chemotherapy followed by intraperitoneal therapy (IPT). All patients underwent initial surgery for staging and/or cytoreduction followed by cisplatin 20 mg/m2 intravenously (IV) for 5 days and cyclophosphamide 600 mg/m2 on day 4 every 3 to 4 weeks for two to four cycles. Patients were then evaluated for IPT and, if eligible, had an intraperitoneal (IP) catheter placed. IPT consisted of cisplatin 60 mg/m2 in 2 L on day 1 and IV cyclophosphamide 600 mg/m2 on day 2 every 3 weeks for three to six cycles. Patients who demonstrated a clinical complete response (CCR) were then referred for second-look laparotomy (SLL). Of 71 patients who completed the induction phase, 53 (75%) were eligible for IPT, and 49 patients entered the therapy phase. Toxicity of the combined modality approach was acceptable and did not differ from our previous experience using the same drugs systemically. Thirty-two of the 49 patients who completed IPT achieved a CCR, which was confirmed by SLL in 20 patients. Twenty recurrences were documented in the 32 CCR patients, 13 occurred in patients after SLL. Projected median survival of all patients is 38 months. Median survival correlated with amount of residual disease following initial surgery (23 months for bulky v 45 months for minimal residual; P less than .001) and with performance status ([PS]; 24 months for PS 2, 3 v greater than 46 months for PS O; P less than .001). Patients who presented with bulky tumors were less likely to reach the consolidation IPT phase. Incorporation of IP cisplatin into the first-line regimen for treatment of ovarian cancer does not appear to have major impact on the survival of all treated patients when compared with our historical control series. Combined IV and IPT cisplatin and cyclophosphamide is feasible with acceptable toxicity. Its impact on response and survival may be limited to only 'good-prognosis' patients
PMID: 2016624
ISSN: 0732-183x
CID: 14031
Survival with regional and distant metastases from cutaneous malignant melanoma
Roses DF; Karp NS; Oratz R; Dubin N; Harris MN; Speyer J; Boyd A; Golomb FM; Ransohoff J; Dugan M; et al.
The clinical course of 312 consecutive patients after initial presentation with metastatic melanoma, 165 of whom presented with regional metastases at cutaneous or subcutaneous, or both, nodal sites and 147 with metastases at distant sites, was reviewed. The five year survival rate for regional metastases was 43.4 per cent compared with a five year survival rate for distant metastases of 4.9 per cent (p less than 0.0001). Favorable prognostic variables for survival from first regional metastases included primary melanoma sites on the extremities compared with the head, neck and trunk (p = 0.043) and a disease-free interval of more than one year from primary surgical treatment to regional metastases (p = 0.0058). Favorable prognostic variables for survival from the first distant metastasis included a disease-free interval of more than one year from primary surgical treatment to distant metastases (p = 0.0092), the type of resection of metastatic disease (p = 0.00027) and the addition of systemic immunotherapy (p = 0.0011). Forty-nine patients with totally resectable distant metastases had a five year survival rate from the treatment of the initial metastasis of 13.1 per cent, whereas 33 patients having palliative resections had a five year survival rate of 7.5 per cent. All 165 patients who did not have resection for distant metastases died within five years. The results of our experience support therapeutic efforts to ablate both regional and distant metastases of malignant melanoma when feasible
PMID: 2006449
ISSN: 0039-6087
CID: 25129
Cardioxane--ICRF-187 towards anticancer drug specificity through selective toxicity reduction
Koning J; Palmer P; Franks CR; Mulder DE; Speyer JL; Green MD; Hellmann K
PMID: 1933909
ISSN: 0305-7372
CID: 35092
Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2'-deoxyuridine
Muggia FM; Chan KK; Russell C; Colombo N; Speyer JL; Sehgal K; Jeffers S; Sorich J; Leichman L; Beller U; et al
Intraperitoneal (i.p.) 5-fluoro-2'-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32-78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at greater than 3,000 mg x 3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg x 3 days and leukopenia and thrombocytopenia at 5,000 mg x 3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2-4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2-4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage. (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 1 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 1831736
ISSN: 0344-5704
CID: 14203
ICRF-187 (ADR-529) cardioprotection against anthracycline-induced cardiotoxicity: clinical and preclinical studies
Green MD; Alderton P; Sobol MM; Gross J; Muggia FM; Speyer JL
PMID: 1683780
ISSN: 0927-3042
CID: 35093
A prospective randomized trial of ICRF-187 for prevention of cumulative doxorubicin-induced cardiac toxicity in women with breast cancer
Speyer JL; Green MD; Sanger J; Zeleniuch-Jacquotte A; Kramer E; Rey M; Wernz JC; Blum RH; Hochester H; Meyers M; et al
PMID: 2125531
ISSN: 0305-7372
CID: 15688
Antimelanoma monoclonal antibody-ricin A chain immunoconjugate (XMMME-001-RTA) plus cyclophosphamide in the treatment of metastatic malignant melanoma: results of a phase II trial
Oratz R; Speyer JL; Wernz JC; Hochster H; Meyers M; Mischak R; Spitler LE
Prior studies with the XMMME-001-RTA immunoconjugate composed of an antimelanoma monoclonal antibody and ricin A chain demonstrated some antitumor activity. However, almost all patients studied developed human antimurine antibodies and antiricin antibodies. In an effort to abrogate these host anti-immunotoxin immune responses and thus enhance antitumor activity, we treated 20 patients with the immunoconjugate plus a single dose of intravenous cyclophosphamide. An overall response rate of 20% was observed-predominantly in pulmonary and soft tissue nodules. There was no diminution in antibody responses against either the murine antibody or the ricin moiety. Further studies to elucidate the role of cyclophosphamide in monoclonal antibody therapy are planned
PMID: 2395000
ISSN: 0732-6580
CID: 15689
Phase II study of esorubicin (4'deoxydoxorubicin) in anthracycline naive patients with ovarian cancer
Green MD; Speyer JL; Wernz JC; Colombo N; Beller U; Muggia FM; Beckman EM
Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4'deoxydoxorubicin at a dose of 30 mg/m2 intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4'deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease
PMID: 2272774
ISSN: 0167-6997
CID: 15690
Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy
Speyer JL; Beller U; Colombo N; Sorich J; Wernz JC; Hochster H; Green M; Porges R; Muggia FM; Canetta R; et al
From August 1985 to November 1989 we conducted a trial of intraperitoneal (IP) carboplatin including a dose-escalation design in 25 women with advanced gynecologic malignancies. All had extensive prior therapy with cisplatin (median cumulative dose, 525 mg/m2). Carboplatin was administered IP in 2 L of 1.5% dextrose with a 4-hour dwell time every 4 weeks for six cycles at a starting dose of 200 mg/m2. Patients with reduced creatinine clearance (30 to 60 cc/min) were escalated more slowly than those with high (greater than 60 cc/min) clearance. Thrombocytopenia was dose-limiting and often more severe in patients with compromised renal function; there was no local drug toxicity. The median time of follow-up is 25 months. Complete responses (CRs) were documented in six of 23 assessable patients (26%) by repeat laparotomy, and an additional 11 patients (48%) had no disease evident by noninvasive restaging. Five of the CRs and six of the patients with no clinically evident disease have relapsed from 3 to 40 months after therapy. Six patients (26%) are alive and free of disease 8 to 47 (median, 20) months after therapy. IP carboplatin is effective against relapsed ovarian cancer, even after prior cisplatin therapy
PMID: 2199620
ISSN: 0732-183x
CID: 15691
Interferon alpha-2a and dacarbazine in melanoma
Kirkwood, J M; Ernstoff, M S; Giuliano, A; Gams, R; Robinson, W A; Costanzi, J; Pouillart, P; Speyer, J; Grimm, M; Spiegel, R
PMID: 2189999
ISSN: 0027-8874
CID: 162453