Randomized Phase III Trials of Intravenous vs. Intraperitoneal

Therapy in Optimal Ovarian Cancer

Deborah K. Armstrong, M.D.Deborah K. Armstrong, M.D.Associate Professor of Oncology,Associate Professor of Oncology,

Gynecology and ObstetricsGynecology and Obstetrics

Development of Development of Intraperitoneal ChemotherapyIntraperitoneal Chemotherapy

• 1950’s:1950’s: First use of intraperitoneal First use of intraperitoneal chemotherapy for malignant ascites chemotherapy for malignant ascites

• 1968: Long-term peritoneal access device1968: Long-term peritoneal access device• 1978: Demonstration of slow peritoneal 1978: Demonstration of slow peritoneal

clearance of some drugsclearance of some drugs• 1984: Feasibility of intermittent large 1984: Feasibility of intermittent large

volume intraperitoneal therapyvolume intraperitoneal therapy• 1996: First report of a survival benefit for IP 1996: First report of a survival benefit for IP

vs. IV chemotherapy in advanced ovarian vs. IV chemotherapy in advanced ovarian cancercancer

Peritoneal: Plasma RatioPeritoneal: Plasma Ratio Drug Peak AUC

Cisplatin 20 12

Carboplatin --- 18

Melphalan 93 65

Adriamycin 474 ---

5-FU 298 367

MTX 92 100

Paclitaxel ---1,000

Intraperitoneal Therapy:Intraperitoneal Therapy:Ovarian CancerOvarian Cancer

• Rationale:Rationale:– Major route of spread within the peritoneal cavity Major route of spread within the peritoneal cavity – Ability to reduce tumor volume with debulkingAbility to reduce tumor volume with debulking– Residual peritoneal tumor exposed to increased Residual peritoneal tumor exposed to increased

concentration of drug for prolonged period of timeconcentration of drug for prolonged period of time

• Limitations:Limitations:– Poor tumor penetration of bulk diseasePoor tumor penetration of bulk disease– Less exposure of extra-peritoneal disease to drugLess exposure of extra-peritoneal disease to drug

• Complications:Complications:– Obstruction to flow or inadequate distributionObstruction to flow or inadequate distribution– Infection: peritonitis, abdominal wall or catheterInfection: peritonitis, abdominal wall or catheter– Intestinal perforationIntestinal perforation

GOG #104GOG #104SWOG #8501SWOG #8501

Ovarian cancerOvarian cancerStage IIIStage IIIStratify:Stratify:<< 0.5 cm 0.5 cm> 0.5-2 cm> 0.5-2 cm

RRAANNDDOOMMIIZZEE

Cisplatin 100 mg/mCisplatin 100 mg/m22 IVIVCyclophosphamide Cyclophosphamide 600 mg/m600 mg/m22 IV IVq 21 days x 6q 21 days x 6

Cisplatin 100 mg/mCisplatin 100 mg/m22 IPIPCyclophosphamideCyclophosphamide600 mg/m600 mg/m22 IV IVq 21 days x 6q 21 days x 6

Second lookSecond lookLaparotomyLaparotomy

GOG #104GOG #104Alberts et.al. NEJM Dec 1996

CyclophosphamideCyclophosphamide

and Cisplatinand Cisplatin

INTRAPERITONEALINTRAPERITONEAL

CyclophosphamideCyclophosphamide

and Cisplatinand Cisplatin

INTRAVENOUSINTRAVENOUS

Path CR Path CR 47%47% 36%36%

SurvivalSurvival 49 mo49 mo 41 mo41 mo p=.02

Consensus: GOG 104Consensus: GOG 104The benefits of IP The benefits of IP

chemotherapy seen in GOG chemotherapy seen in GOG 104 are not greater than 104 are not greater than the benefits of the new the benefits of the new

agent, paclitaxelagent, paclitaxel

GOG #114GOG #114

Ovarian cancerOvarian cancerStage IIIStage III<< 1.0 cm 1.0 cm

RRAANNDDOOMMIIZZEE

Cisplatin 75 mg/mCisplatin 75 mg/m22 IV IVPaclitaxel 135 mg/mPaclitaxel 135 mg/m22 IV IV

q 21 days x 6q 21 days x 6

Carboplatin AUC=9 x 2 IVCarboplatin AUC=9 x 2 IVthenthen

Cisplatin 100 mg/mCisplatin 100 mg/m22 IPIPPaclitaxel 135 mg/mPaclitaxel 135 mg/m22 IV IV

q 21 days x 6q 21 days x 6

Second lookSecond lookLaparotomyLaparotomy

Cisplatin 75 mg/mCisplatin 75 mg/m22 IV IVCyclophosphamide Cyclophosphamide

750mg/m750mg/m22 IV IVq 21 days x 6q 21 days x 6

GOG #114GOG #114

Ovarian cancerOvarian cancerStage IIIStage III<< 1.0 cm 1.0 cm

RRAANNDDOOMMIIZZEE

Cisplatin 75 mg/mCisplatin 75 mg/m22 IV IVPaclitaxel 135 mg/mPaclitaxel 135 mg/m22 IV IV

q 21 days x 6q 21 days x 6

Carboplatin AUC=9 x 2 IVCarboplatin AUC=9 x 2 IVthenthen

Cisplatin 100 mg/mCisplatin 100 mg/m22 IPIPPaclitaxel 135 mg/mPaclitaxel 135 mg/m22 IV IV

q 21 days x 6q 21 days x 6

Second lookSecond lookLaparotomyLaparotomy

Cisplatin 75 mg/mCisplatin 75 mg/m22 IV IVCyclophosphamide Cyclophosphamide

750mg/m750mg/m22 IV IVq 21 days x 6q 21 days x 6X

GOG #114GOG #114 Markman et.el. JCO Feb 2001

IV CarboIV Carbo

IV TaxolIV Taxol

IP CisplatinIP Cisplatin

IV TaxolIV Taxol

IV CisplatinIV Cisplatin

PFSPFS 27.6 mos27.6 mos 22.5 mos22.5 mos P=.01P=.01

Overall Overall SurvivalSurvival 63.2 mos63.2 mos 52.5 mos52.5 mos P=.05P=.05

Consensus: GOG 114Consensus: GOG 114 The benefits of IP in GOG The benefits of IP in GOG

114 are likely explained by 114 are likely explained by the use of eight cycles of the use of eight cycles of

chemotherapy, not the use if chemotherapy, not the use if IP administration (see GOG IP administration (see GOG

182)182)

GOG #172GOG #172Armstrong et.al. Abs #803, ASCO 2002Armstrong et.al. Abs #803, ASCO 2002

Ovarian cancerOvarian cancerOptimal (<1cm) Optimal (<1cm) Stage IIIStage IIIStratify:Stratify:Gross residualGross residualPlanned 2Planned 2ndnd look look

RRAANNDDOOMMIIZZEE

BRCA AnalysisBRCA AnalysisDNA BankingDNA Banking

Paclitaxel 135 mg/mPaclitaxel 135 mg/m22/24h/24hCisplatin 75 mg/mCisplatin 75 mg/m22 q 21 days x 6q 21 days x 6

Paclitaxel 135 mg/mPaclitaxel 135 mg/m22/24h/24hCisplatin 100 mg/mCisplatin 100 mg/m22 IP D2 IP D2Paclitaxel 60 mg/mPaclitaxel 60 mg/m22 IP D8 IP D8q 21 days x 6q 21 days x 6

Second lookSecond lookLaparotomyLaparotomy(if chosen)(if chosen)

Treatment RegimensTreatment RegimensEvery 21 days x 6Every 21 days x 6

Regimen 1Intravenous

Regimen 2Intraperitoneal

D1: IV Paclitaxel (135mg/m2/24h)D2: IV Cisplatin (75mg/m2)

D1: IV Paclitaxel (135mg/m2/24h)D2: IP Cisplatin (100mg/m2)D8: IP Paclitaxel (60mg/m2)

D1IV

D2IV

D1IV

D2IP

D8IP

GOG #172:Non-hematologic toxicities

Armstrong et.al. Abs #803, ASCO 2002

IV IP

GI G3/4 24% 46%

Renal G3/4 1% 6%

Fatigue G3/4 5% 17%

Pain G3/4 1% 11%

Metabolic G3/4 7% 24%

Neuro G3/4 9% 19%

GOG #172:GOG #172:Hematologic ToxicitiesHematologic ToxicitiesArmstrong et.al. Abs #803, ASCO 2002

IV IP

Leukopenia G4 14% 31%

Infection G3/4 5% 16%

Plts G3/4 4% 12 %

Courses of Protocol Therapy by Regimen

# courses

Treatment Assignment

Intravenous Intraperitoneal

AssignedTreatment

(AT)

AT orCarboplatin*

Assigned Treatment

(AT)

AT or Crossover

to IV cisplatin

AT or Crossover toIV cisplatin

or carboplatin*

0 2 (1%) 0 (0%) 16 (8%) 5 (2%) 4 (2%)

1 8 (4%) 7 (3%) 38 (19%) 21 (10%) 10 (5%)

2 9 (4%) 4 (2%) 30 (15%) 20 (10%) 6 (3%)

3 11 (5%) 6 (3%) 14 (7%) 9 (4%) 4 (2%)

4 2 (1%) 0 (0%) 10 (5%) 5 (2%) 4 (2%)

5 4 (2%) 4 (2%) 11 (5%) 12 (6%) 7 (3%)

6 174 (83%) 189 (90%) 86 (42%) 133 (65%) 170 (83%)

* Carboplatin substituted for cisplatin

Second Look FindingSecond Look Finding IVIV IPIP

Negative 2Negative 2ndnd look look 35 (41%)35 (41%) 46 (57%)46 (57%)

Positive 2Positive 2ndnd look look 37 (44%)37 (44%) 23 (28%)23 (28%)

22ndnd look contraindicated look contraindicated 13 (15%)13 (15%) 12 (15%)12 (15%)

TotalTotal 85 (100%)85 (100%) 81 (100%)81 (100%)

GOG #172:GOG #172:Second Look ResultsSecond Look Results

GOG #172: Survival

Regimen 1

Intravenous

Regimen 2

Intraperitoneal

Progression-free 18.3 mos 23.8 mos

Overall Survival 49.5 mos 66.9 mos

Relative Risk:Relative Risk:IP vs. IV Therapy, GOG #172IP vs. IV Therapy, GOG #172

Relative Risk 95% CI p-value

PFS 0.79 0.63-0.99 0.027

OS 0.71 0.54-0.94 0.0076

Figure 1By Treatment Group

Pro

porti

on P

rogr

essi

on-F

ree

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months on Study0 12 24 36 48 60

Rx Group PF Failed Total IV 50 160 210

PF Failed Total

IP 63 142 205

Figure 2

By Treatment GroupP

ropo

rtion

Sur

vivi

ng

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months on Study0 12 24 36 48 60

Rx Group Alive Dead Total IV 93 117 210

Alive Dead Total

IP 117 88 205

Modulating Toxicity ofModulating Toxicity ofIP TherapyIP Therapy

• New approaches to improve toxicity profileNew approaches to improve toxicity profile– Type of catheter usedType of catheter used– Timing of catheter placementTiming of catheter placement– Timing of chemotherapy Timing of chemotherapy

• relative to surgery relative to surgery • relative to catheter placementrelative to catheter placement

– Agents usedAgents used• Successful use of IP therapy requires:Successful use of IP therapy requires:

– TrainingTraining– SkillSkill– ExperienceExperience– DedicationDedication

Consensus: 2005Consensus: 2005

• The toxicities, inconvenience and cost of The toxicities, inconvenience and cost of IP therapy are justified by the improved IP therapy are justified by the improved survival seen with this treatmentsurvival seen with this treatment

• New, targeted therapies are likely to be New, targeted therapies are likely to be more effective in patients who have an more effective in patients who have an excellent response to chemotherapyexcellent response to chemotherapy

• While we work to improve the While we work to improve the tolerability and toxicities of IP therapy, it tolerability and toxicities of IP therapy, it remains the most effective means of remains the most effective means of treating ovarian cancer todaytreating ovarian cancer today