Phase 1/pharmacology study of intraperitoneal topotecan alone and with cisplatin: potential for consolidation in ovarian cancer.
OBJECTIVE
Most ovarian cancers recur after first-line treatment. We studied the pharmacology, tolerability, and therapeutic potential of intraperitoneal (IP) topotecan, alone and with IP cisplatin.


METHODS
Patients received IP topotecan 1.5 mg (flat dose) daily on days 1-5 (level 0) via IP catheter. Subsequent cohorts received IP cisplatin 50 mg/m(2) on day 1 added to topotecan 1.5 mg on days 1-3 (level I), topotecan 1.25 mg on days 1-3 (level II), or topotecan 1.25 mg on days 1-5 (level III). Plasma and IP concentrations of total and lactone (E-ring closed) topotecan were measured on days 1 and 2 in cycles 1 and 2.


RESULTS
Sixteen patients (15 tubo-ovarian, 1 gastric cancers) were entered at levels 0 (3), I (4), II (4), or III (5). Dose-limiting neutropenias occurred in seven patients at dose levels I and III; grade 3 thrombocytopenia occurred in two at level III. Other toxicities included grade 1 hives in two, serum creatinine elevations in two, and Staphylococcus epidermidis and chemical peritonitis (one each). A median progression-free survival of 13 months was recorded among ovarian cancer patients who had minimal (6) or no residuum (3) after platinum-based induction; 5 are alive at 4 years. Topotecan's AUC IP/AUC plasma ratios ranged from 13 to 119.


CONCLUSIONS
Topotecan IP for 3-5 days is tolerable; occasionally, myelosuppression is dose-limiting. Topotecan 1.25 mg (days 1-3) with IP cisplatin 50 mg/m(2) (day 1) is a regimen suitable for consolidation in phase 3 trials.
Department of Medical Oncology, Albert Einstein Cancer Center, Bronx, NY, USA.
Eleni
E
Andreopoulou
Thomas
T
Chen
Leonard
L
Liebes
John
J
Curtin
Stephanie
S
Blank
Robert
R
Wallach
Howard
H
Hochster
Franco
F
Muggia
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001202:Ascitic Fluid / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D005185:Fallopian Tube Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007783:Lactones / Q000097:blood / Q000378:metabolism; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012074:Remission Induction / Q000379:methods; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D016019:Survival Analysis; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007783:Lactones; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D002945:Cisplatin