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Intraperitoneal therapy in ovarian cancer Edward L. Trimble, MD, MPH National Cancer Institute, USA Theory of IP approach • High IP concentration of drug • Longer half-life of drug in abdominal cavity than with IV administration • Prolonged systemic exposure • Dedrick R et al, Cancer Treat Rep 1978 Clinical settings evaluated • Intraoperative at time of primary or secondary surgery (+/- hyperthermia) • Post-operative in advanced disease – Optimally & suboptimally debulked • Adjuvant for early-stage disease • Consolidation • After neo-adjuvant chemo + surgery Potential IP approaches • Standard chemotherapeutic agents • Radioactive agents (e.g, P32, AU198) • Immunologic agents – Radio-labeled antibodies – Cytokines (interferon, etc) – Tumor-infiltrating lymphocytes Early findings • IP chemotherapy not effective in bulky disease; should be targeted at women with no residual or minimal residual disease • Chemotherapeutic agents with higher molecular weight had longer half-lives • Platinums/ taxanes have 10-20 times greater concentration IP than when given IV Phase III clinical trials • Adjuvant for early-stage disease (I,II) – GOG, Norwegian Radium Hospital • Post-operative in advanced disease – SWOG, GOG, etc. • Consolidation: EORTC GCG Adjuvant IP therapy for earlystage disease • GOG, IP P32 vs. IV chemotherapy – Young R, J Clin Oncol 2005 • NRH, XRT +/-IP P32, IP P32 +/- thiotepa, IP P32 vs. IV platinum – Vergote I, Cancer 1992; Trope C, Gynecol Oncol 1993 • Endpoints: Unable to prove survival benefit of adjuvant therapy; IP P32 more toxic than IV chemotherapy SWOG 8501/GOG 104 • Control: Cisplatin/ cyclophosphamide IV x6 • Experimental: Cisplatin 100 mg/m2 IP + cyclo IV x 6 • Stage III, <= 2 cm residual • 546 patients • Alberts et al, NEJM 1996 GOG 114/ SWOG 9227 • Control: Cisplatin/ paclitaxel IV x 6 • Experimental: Carboplatin (AUC9) IV x 2-> cisplatin 100 mg/m2 IP/ paclitaxel IV x6 • Stage III, <= 1 cm residual • 462 patients • Markman et al, JCO 2001 GOG 172 • Control Cisplatin/ paclitaxel IV x 6 • Experimental: Paclitaxel IV (day 1), cisplatin 100 mg/m2 IP, paclitaxel 60 mg IP (day 8) x 6 • Stage III, <= 1 cm residual • 415 patients • Armstrong et al, NEJM 2006 EORTC 55875 • Control: surveillance • Experimental: Cisplatin 100 mg/m2 IP x 4 • Stage IIB-III in PCR after platinumbased chemotherapy • 153 patients • Piccart et al, Int J Gynecol Oncol, 2003 2 heterogeneity (3 d.f.)= 1.0, p=0.80 PFS hazard ratios are not available from the published report on SWOG-8501 and the Taiwan study. PFS hazard ratio is not reported for the Italian study but it is calculated from the available data reported. 2 heterogeneity (5 d.f.)= 3.1, p=0.68 Hazard ratio is not reported for the GONO study but it is calculated from the available data reported. Hazard ratio is not reported for the Greek study. Toxicity with IP chemotherapy • Presence of an IP catheter – Infection, fever • IP administration of chemotherapy – Abdominal pain, nausea, vomiting • Chemotherapy – Greater hematologic, metabolic, and neurologic toxicity NCI Clinical Announcement • Considered when a trial or trials have identified an intervention which substantially improves survival or reduces morbidity and when that intervention is available to the general public • Not a directive but an educational document Previous NCI Clinical Announcements • Adjuvant therapy for node-negative breast cancer, 1988 • Levamisole and 5FU for Dukes C colon cancer, 1989 • Adjuvant therapy for rectal cancer, 1991 • Update on tamoxifen as adjuvant for breast cancer, 1995 • Chemoradiation for cervical cancer, 1999 Process for Clinical Announcement • Proposal from investigator or NCI staff • Review of data by independent panel nominated by investigator/ Cooperative Group and NCI; recommendation by panel to NCI Director • Draft reviewed by FDA, relevant companies, NIH • Release when data is available to public NCI Clinical Announcement • Dissemination • Education – Physicians, nurses, lay audience • Evaluation – Impact upon clinical practice Dissemination • Primary manuscript, NEJM, January 5, 2005 • Secondary manuscript, Gynecologic Oncology, 1Q, 2006 • How to give IP chemotherapy, JCO, 1Q, 2006 • Review article, IJGC, 1Q, 2006 • Meta-analysis, in submission, 1Q, 2006 Dissemination II • National press release in US • Local press releases from sites participating in IP research • Email, newsletters, websites: NCI, Cooperative Groups, profesional societies, Cancer Centers, advocacy groups Education • Primary surgeons: – Gynecologic oncologists, gynecologists, general surgeons, surgical oncologists • Chemotherapists – Gynecologic oncologists, medical oncologists, nurse oncologists • Patients Education II • Websites – Specific information on port placement, chemotherapy administration, surveillance and management of toxicity • Workshops and conference calls • Presentations at scientific meetings Evaluation • • • • NCI-designanted Cancer Centers Health Maintenance Organizations SEER-Medicare linkage National Cancer Database Impact upon clinical research • GCIG 2004 consensus statement • GCIG clinical trials – GOG: randomized phase II evaluating different IP regimens in development – JGOG, NCIC CTG, NCRI/MRC: considering IP trials – EORTC, AGO-Germany: unconvinced by available data Unanswered questions • How to improve efficacy and decrease toxicity • How to integrate IP with new agents • How to improve catheters • Role of IP with optimally debulked stage IV, neoadjuvant, consolidation, recurrence, hyperthermia