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Intraperitoneal therapy in ovarian cancer

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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 ... – PowerPoint PPT presentation

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Title: Intraperitoneal therapy in ovarian cancer


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, lt 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-gt
    cisplatin 100 mg/m2 IP/ paclitaxel IV x 6
  • Stage III, lt 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, lt 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, p0.80 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, p0.68 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
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