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 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

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

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

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 platinum-based chemotherapy

• 153 patients

• Piccart et al, Int J Gynecol Oncol, 2003

2 heterogeneity (3 d.f.)= 1.0, p=0.80PFS 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=0.68Hazard 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