Transcript Intraperitoneal therapy in ovarian cancer

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