Intraperitoneal Chemotherapy in Advanced Ovarian Cancer At last recognition

1
Intraperitoneal Chemotherapy in Advanced Ovarian
CancerAt last recognition

• Jan B. Vermorken, MD, PhD
• University Hospital Antwerp
• Edegem, Belgium

2
Outline of Presentation

• Background on treatment of ADOVCA
• History of IP chemotherapy in OC
• Indications for IP chemothrapy
• Single agents and multi-agent IPCT
• Randomized trials with IPCT
• Conclusions

3
Prognostic Factors in Advanced-Stage Ovarian
CancerStages IIb-IV

• Postsurgery During Relapse
• Pre-chemotherapy Chemo
• Residual disease Type of chemo Time since last
  CT
• Performance status CA 125 fall Disease bulk
• Stage Interval debulking Histology
• Grade No. disease sites
• Age Perf. Status
• Ascites Time since DX
• Histology
• Proliferation markers
• Quantitative pathol. features
• Ploidy
• Molecular markers (unclear)

Eisenhauer et al, 1999 (modified)
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Management of Advanced-Stage Ovarian
CancerStages IIb-III (IV)

• Upfront radical cytoreductive surgery
• In case this is not possible, a second attempt
  should be made
• Platinum-based chemotherapy
• Six cycles
• No second-look

Consensus meeting, 1998 Bergen (the Netherlands)
/ 2004 Baden Baden (Germany)
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Treatment of Advanced Stage Ovarian
CancerCisplatin-based comparisons

• Paclitaxel (Taxol?) - platinum new standard
• McGuire et al (1996) N Engl J Med 334 1-6
• Piccart et al (2000) J Natl Cancer Inst 92
  699-708
• GOG-111 (n386 eligible) OV-10 (n680)
• Proportion alive TP 27 / CP 16 TP 34 / CP
  23
• Rel. Hazard of death O.70 0.75
• 95 CI 0.57-0.87 0.63-0.90
• 6.5 years follow-up results (Piccart et al,
  2003)

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Intergroup Ovarian Trial (OV10) Update with 6,5
years median follow-up Overall Survival
6.5 years follow-up results (Piccart et al, 2003)
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Randomized Trials of Paclitaxel-Cisplatin versus
Paclitaxel-Carboplatin
Study Stages Study No. of RR Median Group of
disease arms patients () PFS(wk) Dutch/ IIB-IV
TP (175-3h/75) 208 73 73 Danish TCb
(175-3h/AUC5) 71 75 AGO IIB-IV TP
(185-3h/75) 798 80 71 TCb (185-3h/AUC6) 68 69
GOG158 optimal TP (135-24h/75) 840 NA 94 stage
III TCb (175-3h/AUC7.5) NA 95
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Progressionfree Survival and Survival by
Treatment Group
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Median DFS (mos) 19.4 20.7
0.2
Median Survival (mos) 48.8
56.7
Treatment Cisplatin Paclitaxel Carboplatin
Paclitaxel
0.1
0.0
24
36
48
60
0
12
Months on Study
Ozols et al. J Clin Oncol 2003 21 3194-3200
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How to Improve Outcome in Advanced OCBeyond
PAC-CARBO

• Add
• New cytotoxics
• New non-cytotoxics
• Consolidate / Maintenance
• with cytotoxics or non-cytotoxics
• Substitute
• New agent for paclitaxel or platinum
• Modulate resistance
• Modulating agent
• Increase dose / exposure (systemic / regional)

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History of Intraperitoneal ChemotherapyOvarian
Cancer

• 1950s IPCT mainly for sclerosing properties
• High concentrations, small volumes
• 1970s IPCT used for its cytotoxic properties
• High concentrations, large volumes
• 1978 Landmark paper by Dedrick et al.
• A sound pharmacokinetic rationale
• 1996 First report of a survival benefit for
  IPCT in
• ADOVCA (Alberts et al)

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History of Intraperitoneal ChemotherapyOvarian
Cancer

• 1991 IP therapy times up (Ozols)
• Times not up (Muggia, Alberts)
• 2001 IP therapy a sacrifice bunt (McGuire)
• 2002 IP therapy a therapy whose time has come
• (Alberts et al)
• 2004 IP therapy interpretation of results
  remains
• controversial and therefore its use has not
• been widely adopted (GCIG-OCCC)

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Intraperitoneal Chemotherapy in OCBasis

• Higher concentrations in the peritoneal cavity
  than anywhere else
• Higher concentrations at the tumor site and less
  systemic toxicity
• Effects depend on tumor prenetration

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Intraperitoneal Chemotherapy in OCIdeal drug

• Large peritoneal/plasma concentration gradient
• Steep dose-response relationship over the
  concentration range used i.p.
• No local peritoneal toxicity
• No cross-resistance with agents used for systemic
  treatment

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Peritoneal Plasma Ratio in IPCT
Drug Peak AUC Cisplatin 31 26 Carboplatin 24
10 Doxorubicin 474 - Melphalan 93 65 Mitomyci
n C 71 - Mitoxantrone - 1400 Methotrexate 92
- 5-fluorouracil 298 367 Paclitaxel - 1000 E
lferink et al, 1988 Goel et al 1989 Markman 1991
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Platinum Distribution after IV or IP
CDDPPeritoneal tumors
Platinum conc. (ppm) Distance inward from 3 x
4 mg/kg 3 x 4 mg/kg the periphery (mm) IV
IP 0.1 11 3a 36 2 1.0 19 7 37
3 1.5 24 6 29 4 2.2 25 6 25 2 a
mean SD (Los et al, 1989)
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Platinum Distribution after IP CBDCA and
CDDPPeritoneal tumors
Platinum conc. (µg/g tumor tissue) Distance
inward from CBDCA (mg/kg) CDDP (mg/kg) the
periphery (mm) 2 x 4.9 24.6 2 x 4 0.1 4 2 8
2 29 4 0.5 3 2 - 26 4 1 ND 7 1 25
3 2 - 7 1 - 2.5 ND - 14 2 3 - 7
2 - Los et al, 1991
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Intraperitoneal Chemotherapy in OC

• Rationale
• Major route of spread within the peritoneal
  cavity
• Residual tumor (after debulking) exposed to
  increased concentrations of drugs for prolonged
  time
• Limitations
• Poor penetration of bulk tumor
• Less exposure of extra-peritoneal disease
• Complications
• Obstruction, inadequate distribution
• Infections peritonitis, abdominal wall or
  catheter
• Bowel perforation
• Armstrong, 2005

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Intraperitoneal Chemotherapy in OCIndications

• Early ovarian cancer
• Optimally debulked advanced ovarian cancer
• Response consolidation
• Liver metastases
• (therapeutic blood levels needed for bulky
  disease)

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Randomized Trials Comparing Intravenous vs
Intraperitoneal First-line Treatment of Ovarian
Cancer
Not completed
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GOG 104SWOG 8501
Second look Laparotomy
Cisplatin 100 mg/m2 IV Cyclophosphamide 600
mg/m2 IV q 21 days x 6
R A N D O M I Z E
Ovarian cancer Stage III Stratify lt 0.5 cm gt
0.5-2 cm
Cisplatin 100 mg/m2 IP Cyclophosphamide 600 mg/m2
IV q 21 days x 6
21
GOG 114SWOG 9227
Second look Laparotomy
X
Cisplatin 75 mg/m2 IV Cyclophosphamide 750mg/m2
IV q 21 days x 6
R A N D O M I Z E
Ovarian cancer Stage III lt 1.0 cm
Cisplatin 75 mg/m2 IV Paclitaxel 135 mg/m2 IV q
21 days x 6
Carboplatin AUC9 x 2 IV then Cisplatin 100 mg/m2
IP Paclitaxel 135 mg/m2 IV q 21 days x 6
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GOG 172
Second look Laparotomy (if chosen)
BRCA Analysis DNA Banking
R A N D O M I Z E
Paclitaxel 135 mg/m2/24h Cisplatin 75 mg/m2 q 21
days x 6
Ovarian cancer Optimal (lt1cm) Stage
III Stratify Gross residual Planned 2nd look
Paclitaxel 135 mg/m2/24h Cisplatin 100 mg/m2 IP
D2 Paclitaxel 60 mg/m2 IP D8 q 21 days x 6
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IPCT vs IVCT in Advanced Ovarian
CancerProgression-free survival
Investigators No. of Progression-free survival
(mo) year published pts Control arm Exp.
Arm Alberts et al, 1996 546 ND ND Polyzos et
al, 1999 90 19 18 Gadducci et al,
2000 113 25 42 Markman et al,
2001 462 22 281 Yen et al, 2001 118 ND ND Arms
trong et al, 2006 415 18 242 1 p 0.01 2 p
0.05
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IPCT vs IVCT in Advanced Ovarian CancerOverall
survival
Investigators No. of Overall survival
(mo) year published pts Control arm Exp.
Arm Alberts et al, 1996 546 41 491 Polyzos et
al, 1999 90 25 26 Gadducci et al,
2000 113 51 67 Markman et al,
2001 462 52 632 Yen et al, 2001 118 48 43 Arms
trong et al, 2006 415 50 663 1 p 0.02 2 p
0.05 3 p 0.03
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Armstrong et al, 2006
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Armstrong et al, 2006
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INTRAPERITONEAL CISPLATIN
VERSUS NO FURTHER TREATMENT A PHASE III
STUDY IN OVARIAN CANCER PATIENTS WITH A
PATHOLOGICALLY COMPLETE REMISSION AFTER
PLATINUM-BASED INDUCTION CHEMOTHERAPY AND
CYTOREDUCTIVE SURGERY EORTC 55875
EORTC Gynecologic Cancer Group
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55875 TRIAL DESIGN

• Institution
• Induction of CTX
• - DDP
• - CBDCA
• - both
• Grade
• Residual disease
• - ? 1 cm
• - gt 1 cm
• PS (0,1vs 2)

Cisplatin I.P. 90 mg/m2 q 3 weeks X 4
RADOMIZE
STRATIFY
PCR at second look
Observation
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55875 STUDY ACCRUAL AND MATURITY
Theoretical
Study
Median follow-up 8 years
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Hazard ratio 0.82 (95 CI) (0.5 1.3)
Piccart et al, 2003 (median survival 78 vs 91 mo)
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Pooled Data
HR 0.79 (95 CI 0.70, 0.89)
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GOG 172Hematologic Toxicities
Armstrong et al. Abs 803, ASCO 2002
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GOG 172Non-hematologic toxicities
Armstrong et al. Abs 803, ASCO 2002
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Completion Rate for Prescribed CT Courses ()
Investigators IV IV/IP year published regimen
() regimen () Alberts et al,
1996 58 58 Markman et al, 2001 86 71 Gadducci et
al, 2000 96 65 Piccart et al, 2003 NA 56 Armstrong
et al, 2006 90 42
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IP Chemotherapy in Optimal Stage III OCWhy did
it take so long?

• It was not a sexy drug
• The treatment was cumbersome
• There was always a reason why the results were
  interpreted differently
• GOG 104 not better than using paclitaxel
• GOG 114 because 8 cycles were used
• GOG 172 it is toxic, but

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It becomes difficult if you dont know what you
see
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Conclusions (1)

• Combined use of IV and IP chemotherapy leads to a
  significant survival benefit in women with
  optimally debulked EOC (median 12 mo).
• Based on the most recent trials, strong
  consideration should be given to a regimen with
  IP cisplatin (100 mg/m²) and a taxane (whether IV
  or IP).
• Toxicities, inconvenience and costs of IP therapy
  are justified by the improved survival.

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Conclusions (2)

• There is insufficient data to apply IP or
  combined IV/IP chemotherapy in the other
  suggested indications.
• Successful use of IP therapy requires training,
  skill, experience and dedication.
• New approaches to improve the toxicity profile
  need to be studied, such as different types of
  catheters, timing of catheter placement, timing
  of chemotherapy and the use of other agents.