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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 administ...
Clinical settings evaluated
• Intraoperative at time of primary or
secondary surgery (+/- hyperthermia)
• Post-operative i...
Potential IP approaches
• Standard chemotherapeutic agents
• Radioactive agents (e.g, P32, AU198)
• Immunologic agents
– R...
Early findings
• IP chemotherapy not effective in bulky
disease; should be targeted at women with no
residual or minimal r...
Phase III clinical trials
• Adjuvant for early-stage disease (I,II)
– GOG, Norwegian Radium Hospital
• Post-operative in a...
Adjuvant IP therapy for early-
stage disease
• GOG, IP P32 vs. IV chemotherapy
– Young R, J Clin Oncol 2005
• NRH, XRT +/-...
SWOG 8501/GOG 104
• Control: Cisplatin/ cyclophosphamide IV
x 6
• Experimental: Cisplatin 100 mg/m2 IP +
cyclo IV x 6
• St...
GOG 114/ SWOG 9227
• Control: Cisplatin/ paclitaxel IV x 6
• Experimental: Carboplatin (AUC9) IV x
2-> cisplatin 100 mg/m2...
GOG 172
• Control Cisplatin/ paclitaxel IV x 6
• Experimental: Paclitaxel IV (day 1),
cisplatin 100 mg/m2 IP, paclitaxel 6...
EORTC 55875
• Control: surveillance
• Experimental: Cisplatin 100 mg/m2 IP x
4
• Stage IIB-III in PCR after platinum-
base...
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 ...
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 avail...
Toxicity with IP chemotherapy
• Presence of an IP catheter
– Infection, fever
• IP administration of chemotherapy
– Abdomi...
NCI Clinical Announcement
• Considered when a trial or trials have
identified an intervention which
substantially improves...
Previous NCI Clinical
Announcements
• Adjuvant therapy for node-negative breast
cancer, 1988
• Levamisole and 5FU for Duke...
Process for Clinical
Announcement
• Proposal from investigator or NCI staff
• Review of data by independent panel
nominate...
NCI Clinical Announcement
• Dissemination
• Education
– Physicians, nurses, lay audience
• Evaluation
– Impact upon clinic...
Dissemination
• Primary manuscript, NEJM, January 5,
2005
• Secondary manuscript, Gynecologic
Oncology, 1Q, 2006
• How to ...
Dissemination II
• National press release in US
• Local press releases from sites
participating in IP research
• Email, ne...
Education
• Primary surgeons:
– Gynecologic oncologists, gynecologists,
general surgeons, surgical oncologists
• Chemother...
Education II
• Websites
– Specific information on port placement,
chemotherapy administration, surveillance
and management...
Evaluation
• NCI-designanted Cancer Centers
• Health Maintenance Organizations
• SEER-Medicare linkage
• National Cancer D...
Impact upon clinical research
• GCIG 2004 consensus statement
• GCIG clinical trials
– GOG: randomized phase II evaluating...
Unanswered questions
• How to improve efficacy and decrease
toxicity
• How to integrate IP with new agents
• How to improv...
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IP Therapy in Ovarian Cancer

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IP Therapy in Ovarian Cancer

  1. 1. Intraperitoneal therapy in ovarian cancer Edward L. Trimble, MD, MPH National Cancer Institute, USA
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 18. NCI Clinical Announcement • Dissemination • Education – Physicians, nurses, lay audience • Evaluation – Impact upon clinical practice
  19. 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. 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. 21. Education • Primary surgeons: – Gynecologic oncologists, gynecologists, general surgeons, surgical oncologists • Chemotherapists – Gynecologic oncologists, medical oncologists, nurse oncologists • Patients
  22. 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. 23. Evaluation • NCI-designanted Cancer Centers • Health Maintenance Organizations • SEER-Medicare linkage • National Cancer Database
  24. 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. 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

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