1. Intraperitoneal therapy in ovarian cancer Edward L. Trimble, MD, MPH National Cancer Institute, USA

2. 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

3. 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

4. Potential IP approaches Standard chemotherapeutic agents Radioactive agents (e.g, P32, AU198) Immunologic agents –Radio-labeled antibodies –Cytokines (interferon, etc) –Tumor-infiltrating lymphocytes

5. 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

6. 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

7. Adjuvant IP therapy for early- stage 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

8. SWOG 8501/GOG 104 Control: Cisplatin/ cyclophosphamide IV x 6 Experimental: Cisplatin 100 mg/m2 IP + cyclo IV x 6 Stage III, <= 2 cm residual 546 patients Alberts et al, NEJM 1996

9. GOG 114/ SWOG 9227 Control: Cisplatin/ paclitaxel IV x 6 Experimental: Carboplatin (AUC9) IV x 2-> cisplatin 100 mg/m2 IP/ paclitaxel IV x 6 Stage III, <= 1 cm residual 462 patients Markman et al, JCO 2001

10. 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

11. EORTC 55875 Control: surveillance Experimental: Cisplatin 100 mg/m2 IP x 4 Stage IIB-III in PCR after platinum- based chemotherapy 153 patients Piccart et al, Int J Gynecol Oncol, 2003

12.  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.

13.  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.

14. 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

15. 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

16. 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

17. 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

18. NCI Clinical Announcement Dissemination Education –Physicians, nurses, lay audience Evaluation –Impact upon clinical practice

19. 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

20. 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

21. Education Primary surgeons: –Gynecologic oncologists, gynecologists, general surgeons, surgical oncologists Chemotherapists –Gynecologic oncologists, medical oncologists, nurse oncologists Patients

22. Education II Websites –Specific information on port placement, chemotherapy administration, surveillance and management of toxicity Workshops and conference calls Presentations at scientific meetings

23. Evaluation NCI-designanted Cancer Centers Health Maintenance Organizations SEER-Medicare linkage National Cancer Database

24. 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

25. 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