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Gynecol= ogic Oncology Group=
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<= /div>
<= /div>
<= /div>
‹h= eader›
<= /div>
<= /div>
<= /div>
‹date/time›
<= /div>
<= /div>
<= /div>
‹f= ooter›
<= /div>
<= /div>
<= /div>
‹#›
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Gynecologic Oncology Group
IP CHEMOTHERAPY WORKSHOP

 Ovarian Cancer:&n= bsp; The Role of Front-Line Intraperitoneal Chemotherapy

Thursday, January 19
6:30 – 8:30 pm
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Gynecologic Oncology Group
Workshop Outline
=
=
R= 26;
R= 26;A. Introduction (David Alberts, MD)
= 226; = ;
R= 26;B. IP Trials to date (40 min of presentations, followed by discussion)
R= 26; 1. David Alberts, MD (GOG-104)
R= 26; 2. Maurie Markman, MD (GOG-114)
R= 26; 3. Deborah Armstrong, MD (GOG-172)
R= 26; 4. Lori Wenzel, PhD (GOG-172 QOL Data)
R= 26; 5. Franco Muggia, MD (New IP Regimens)
R= 26; 6. Robert Ozols, MD (An Alternate Opinion)
R= 26; 7. Tate Thigpen, MD (Perspective of the GOG Protocol Committee)
R= 26; 8. Edward Trimble, MD (Perspective of NCI-DCTD)
= 226; = ;
R= 26;C. Logistics of IP therapy (40 minutes)
R= 26; 1. Patient selection – Maurie Markman, MD
R= 26; 2. IP catheter placement and management – Joan Walker, MD <= /div>
R= 26; 3. Toxicity management – Richard Barakat, MD
R= 26; 4. IP drug administration – Elisa Eldermire, RN
R= 26; 5. Supportive care issues – David Alberts, MD
= 226; = ;
R= 26;D. Panel Discussion (20 minutes= )
R= 26; = ;
= 226;Thank you MedImmu= ne for helping to sponsor this workshop!
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Gynecologic Oncology Group
Introduction to IP therapy
•David Alberts, MD
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Gynecologic Oncology Group
Intraperitoneal Perspectives
Historical Perspectives
=
Robert Dedrick i= s the chief pioneer
· At NIH (Bioengineering Branch) he and his colleagues described the pharmacokinetic and pharmacodynamic principles underlying IP chemotherapy in animal and human models in 1960s/early 1970s (Dedrick 1978; Cancer Treat Rep 62:1)
Steve Howell and Maurie Markman were the pioneers for the development of IP cisplatin in = the early 1980s
· Determined dose for phase III trials (100 mg/m<= /span>2) (Howell 1982; = Ann Int Med 97:845)
· Simplified administration guidelines (e.g. 2L salin= e; leave it in to achieve maximal IP and systemic exposure)
Markman and GOG established PK and potential efficacy <= span style=3D'font-size:108%;color:white;mso-color-index:0'>of IP paclitaxel= (Markman 1992; J Clin Oncol 10:1485)
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Gynecologic Oncology Group
IV CDDP 100 mg/m2
Plasma
= Peritoneal
= fluid
3D"Text
AUC=
IP CDDP 90 mg/m2
= Peritoneal
= fluid
Plasma
3D"Text
AUC=
Pharmacokinetics
* Adapted from Howell SB et al. Ann Intern Med 97:845-851, 1982 <= /div>
Intravenous versus Intraperitoneal Administration of Cisplatin*
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Gynecologic Oncology Group
Intraperitoneal Chemotherapy
Pharmacokinetic Principles
·= Inverse relationship between molecular weight of an IP drug and tumor penetration from its outer core (e.g. requires 10 times more IP carboplatin than IP cisplatin to achieve similar intratumoral concentrations of platinum) (Los 1989, Ca Res 49:3880; Los 1992, Ca Res)
·= The IP clearance rate is calculated as follows:
CLIP  =3D  Drug dose
IP Drug AUC =
·= Inverse relationship between= IP fluid volume of an IP drug and its clearance rate from the IP space (e.g. IP cisplatin is cleared from the <= /span>IP space 4 times more rapidly when administered in 500 ml than 2000 ml of saline)
<= span style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0'>·IP:&nbs= p; IV peak drug concentrations or drug AUCs*:
= Cisplatin =3D > 20 = (Howell 1982; Ann Int Med 97:845)
= Paclitaxel =3D > 800 = (Markman 1992; J Clin Oncol 10:1485)
•Dose escalation with “high dos= e IV chemotherapy”
 and BMT rarely > 4-5 fold standard IV doses
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Gynecologic Oncology Group
Intraperitoneal Chemotherapy
Concepts Defended
=
=
·= IP chemotherapy treats both intraperitoneal tumor bed and extraperitoneal tumor through systemic recirculation
·= IP chemotherapy achieves dose intensification of 5 to 250 fold that achiev= ed with “high-dose” intravenous chemotherapy regimens
·= IP chemotherapy reaches intraperitoneal sites that may not be reached by the intravenous route, especially when up to 2L of dialysate are administered
= ·= IP cisplatin can penetrate a= s far as 4 mm into surface of intraperitoneal tumors = (by definition, < 1 cm in size) and up to six repeat= ed administrations cause an onion skinning effect<= /span>
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Gynecologic Oncology Group
Intraperitoneal Chemotherapy
Seminal Publications
=
1978: Dedrick et al. Cancer Treat Rep 62:1
1982:  Howell et al.  Ann Int Med 97:845
1983: Casper et al.  Cancer Treat Rep= 67:325
1992: Markman et al.  JCO 10:1485
1996:  Alberts et al.  NEJM 335:1950
2001: Markman et al.  JCO 19:1001
2003: Rothenberg et al.  JCO 21:1313
2005: Armstrong et al.  NEJM, Jan 2006
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Gynecologic Oncology Group
NCI Clinical Announcement, 1/5/06
Summary of Findings=
=
=
= ·= <= b> Pooled overall survival bene= fit to IP regimens =3D HR 0.79 (95% CI: 0.70 ̵= 1; 0.89)
·= <= b> Pooled progression-free surv= ival benefit =3D HR 0.79 (95% CI: 0.70 = 211; 0.90)
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Gynecologic Oncology Group
GOG 104 / SWOG 8501
•David Alberts, MD
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Gynecologic Oncology Group
Cisplatin:  Intraperitoneal
vs Intravenous Administration
= •<= /span>Phase III study design =
•654 randomized patients (546 eligible) with stage III ovarian cancer, residual disease < 1 cm
•Treatment arms:  IP vs = IV administration of cisplatin 100 mg/m2
•Rationale:  reports of improved activity and reduced toxicity of IP cisplatin
Alberts DS et= al. N Engl J Med 335:1950-1955, 1996
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Gynecologic Oncology Group
=
=
• IP Cisplatin   IV Cisplatin p-value
•Negative second-l= ook rate (%)*   80       56 <0.05
•Median survival duration (months) 49        = ;             41    0.02        = ;            
•IP:IV death hazard ratio             = ;    0.76
• = ;
•* For patients who had microsco= pic disease after initial surgery
Alberts DS et al. N Engl J Med 335:1950-1955, 1996
The New England Journal of Medicine
INTRAPERITONEAL CISPLATIN PLUS INTRAVENOUS CYCLOPHOSPHAMIDE
VERSUS INTRAVENOUS CISPLATIN PLUS INTRAVENOUS CYCLOPHOSPHAMIDE
FOR STAGE III OVARIAN CANCER
DAVID S. ALBERTS, M.D., P.Y. LIU, PH.D., EDWARD V. HANNIGAN, M.D., ROBERT O’TOOLE, M.D.,
STEPHEN D. WILLIAMS, M.D., JAMES= A. YOUNG, M.D., ERNEST W. FRANKLIN, M.D., DANIEL L. CLARKE-PEARSON, M.D., = ;
VINAY K. MALVIYA, M.D., BRENT DUBESHTER, M.D., MARK D. ADELSON, M.D., AND WILLIAM J. HOSKINS, M.D.
  Background  Intravenous platinum-based chemo-therapy is the standard primary therapy for advanced ovarian cancer. We conducted a phase 3 trial to com-p= are the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated, stage III, epithelial ovarian cancer.=
Conclusions As compared with intravenous cisplatin, intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage = III ovarian cancer and residual tumor masses of 2 cm or less.
ABSTRACT <= /div>
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Gynecologic Oncology Group
=
=
• IP Cisplatin IV Cisplatin
•Toxicity (N =3D 250) (N =3D 276) p-value
• = ;
•Granulocytopenia = (%) 56 69 0.002
• (grade ≥ 3)
• = ;
•Leukopenia (%) 40 50    0.04
• (grade ≥ 3)
• = ;
•Tinnitus (%)     7= 14    0.01
• (moderate to severe)
• = ;
•Hearing loss (%)<= span style=3D'mso-tab-count:2;width:26.02%'>   5 15 < 0.001
• (moderate to severe)
• = ;
•Abdominal pain (%= ) 18     2 < 0.001
• (grade ≥ 2)
• = ;
•Hemoglobin (%) 26 25    0.84
• (grade > 3)
• = ;
•Thrombocytopenia = (%)   9   8    0.64
• (grade > 3)
Who Said All Intraperitoneal Cisplatin Therapy is = More Toxic than Intravenous Cisplatin Therapy?
Alberts DS et al. N Engl J Med 335:1950-1955, 1996
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Gynecologic Oncology Group
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