Mar 5th, 2007

Intraperitoneal chemotherapy for Intraperitoneal chemotherapy for epithelial ovarian cancerepithelial ovarian cancer

Hua-His Wu, MDHua-His Wu, MDOB/GYN, VGH-TPEOB/GYN, VGH-TPE

Mar 5th, 2007 H.H. Wu, MD

Epithelial ovarian cancer

Standard therapy A maximum cytoreductive surgery followed

by combination chemotherapy with paclitaxel and carboplatin

A chemo-sensitive tumor However, most recur Intraperitoneal spreading

Mar 5th, 2007 H.H. Wu, MD

History of IP C/T Weisberger 1955

Nitrogen mustard intraperitoneally for malignant ascites

Jones 1978 signicantly greater concentrations of certain chemot

herapeutic drugs in the peritoneal cavity than in the blood.

SWOG/GOG The first phase III trial since 1980s, presented in 1996 In favor of IP arm

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NCI announcement 2006

Encouraging the GO community to consider IP chemotherapy as the standard trestandard treatmentatment for optimally debulked advanced ovarian cancer patients

Based on a meta-analysis of three US trials and other phase III studies

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However, IP chemotherapy is still regarded as controversial issue.

Why

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IP Chemotherapy Principles

Pharmacology

Clinical aspects

Toxicities and QOL

Future directions

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Principles of IP C/T

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Basic pharmacologic concept of IP C/T

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What is the ideal anticancer agent for IP C/T?

Very effective systemically against ovarian cancer

Penetrate deep into the tumor Stays in the peritoneal cavity for

prolonged period Low incidence of systemic adverse

effect but providing satisfactory drug concentrations in the inner core of tumor

( 有效 夠深 留得久 )

Mar 5th, 2007 H.H. Wu, MD

Basic concept of IP C/T

Penetration Peritoneal dwelling Solute transport model Anatomy of the peritoneum and

capillary vessels Resistance to solute transport

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Penetration of anticancer agents Doxorubicin

4-6 layers (Ozols et al; Durand et al) Methotrexate

By osteosarcoma spheroids and autoradiographs (West et al) Limited ability in avascular tumor mass & ≧ 250 μm in dia.

Vinblastine & 5-FU In glioma spheroids (Nederman and Carlsson)) Penetration : 5-FU > vinblastine

Cisplatin In mouse model (Los et al) Concentration

in peripheral: IP > IV In center : IP = IV

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Peritoneal dwelling of anticancer drugs

Longer stay of anticancer agents Higher drug concentration in the inner

core

Is a contrary phenomenon

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Anatomy of the peritoneum Primary interface between abdominal cavity & vessels

Parietal peritoneum (10%) & visceral peritoneum (90%)

The area is approximately to the body surface area (1.0 -2.0 cm2)

Components Mesothelium Basement membrane Interstitium Microcirculation Visceral lymphatics

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Mesothelium, Interstitium

Mesothelium Monolayer of flattened cells about 0.5 mm thick Tight junction ; Gap junction Absence of tight junction in the subdiaphragmaticsubdiaphragmatic are

a directly absorbed into the lymphatic system

Interstitium The supporting structure Distance varies

Mar 5th, 2007 H.H. Wu, MD

Blood vessels

Visceral peritoneum Supplied by celiac and mesentary arteries with venous draina

ge via the portal vein Rapid firstpass metabolism by the liver

Parietal peritoneum Supplied by circumflex iliac, lumbar, intercostal, and epigastr

ic arteries with venous drainage via the systemic circulation.

Effective peritoneal surface area The density of the number of perfused capillaries The number and the size of pores within the capillaies

Mar 5th, 2007 H.H. Wu, MD

Peritoneal lymphatics

Extensive in the subdiaphragmatic area stoma exist, basement membrane absent Little resistance for the solute transport

Also present in parietal and visceral peritoneum

To maintain the relatively small volume of fluid (50-100 ml)

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Mechanism of solute transport between peritoneal cavity and capillary lumen

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Theoretical behaviors of anticancer agents Larger molecular weight or water-insoluble anticancer

drugs stay longer in the peritoneal cavity

Smaller molecular weight or water-soluble can go into the inner core but stay shorter in the cavity

Small molecular weight agents that are metabolized in the liver to become active form should not not be used for IP C/T.

Small molecular weight agents with already active form are suitable for IP C/T

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Pharmacologic advantage for IP C/T

Ratio of drug level, peritoneal cavity/plasma

Drug Molecular weight Water solubility Peak AUC

Cisplatin 300.05 + 20 12

Carboplatin 371.25 + 24 10-18

Topotecan 457.91 + 54

Mitomycin 334.33 +- 71 -

Melphalan 305.20 - 93 65

Methotrexate 454.44 - 92 100

Docetaxel 861.94 - 181

5-FU 130.08 +- 298 367

Doxorubicin 543.53 +- 474 -

Gemcitabine 299.66 + 759

Paclitaxel 853.92 - - 1000

mitoxantrone 517.40 - - 1400

(Modified from Markman M, Semin Oncol 1991)

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Choice of drugs

If the IP C/T is considered to be a regional therapy

paclitaxel, mitoxantrone

If the IP C/T is hypothesized as a route of systemic chemotherapy

platinum agents

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Pharmacology of IP drugs

Cisplatin

Carboplatin

Paclitaxel

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Cisplatin P/V ratio: peak 21; AUC 12 (Howell, 1982) The mode of administration did not affect systemic toxic

ity (Pretorius, 1981) The amount of drug recovered in the urine and the drug l

evels within the tissues were similar The peritoneal lining had 2.5-8 times higher levels of dru

g after IP administration

IP C/T might increase the therapeutic index for small tumors confined to the peritoneal cavity

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Carboplatin After 4 hrs dwelling, P/V ratio:

Peak: 24; AUC 10 (Elferink, 1998) Pharmacologic study after IP and IV (Miyagi, 2005)

24-hr free platinum AUC in the serum is identical 24-hr free platinum AUC in the peritoneal cavity was 17 times h

igher when which given via IP

IP infusion of carboplatin is feasible not only as an IP regioregional therapynal therapy but also as a more reasonable route for systemic chsystemic chemotherapyemotherapy

The recommended dose of IP carboplatin was 400 mg/m400 mg/m22

(Speyer and Sorich, 1992) (Speyer and Sorich, 1992)

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Paclitaxel

Dose-limiting toxicity: severe abdominal pain (when dose ≧175 mg/ ㎡ )

P/V ratio: peak & AUC : 1000-fold Paclitaxel persisted in peritoneum for more than

24-48 h24-48 h after a single IP instillation(Markman, 1992)

Very slow peritoneal clearance (at dose level ≧ 60 mg/ ㎡ , it can persist more than 1 wk

with significant level wkly IP Taxol ) Low plasma concentration

(Francis, 1995)

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IP agents and risk

(Makhija et al, 2001)

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Strengths of IP C/T

Achieve dose intensification (as ‘high-dose’)

Treats both intraperitoneal tumor bed and extraperitoneal tumor via systemic recirculation

Reaches IP sites that may not be reached by IV route, especially when up to 2L dialysate are administered

Onion skinning effect – IP cisplatin can penetrate as far as 4mm into surface of IP tumors(by definition, <1cm in size) and up to 6 repeated administrations

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Clinical aspects of IP C/T

Front-line chemotherapy

Consolidation

2nd-line chemotherapy

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Phase III trials of IP vs IV cisplatin-based chemotherapy

(Hamilton, 2006)

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Main results Eight randomized trials studied 1819 women receiv

ing primary treatment for ovarian cancer.

Women were less likely to dieless likely to die if they received an intraperitoneal (IP) component to the chemotherapy (hazard ratio (HR) =0.79; 95% confidence interval (CI): 0.70 to 0.90)and the disease free interval (HR =0.79; 95%CI: 0.69 to 0.90) was also significantly prolonged.

There may be greater serious toxicity with regard to gastrointestinal effectsgastrointestinal effects, painpain and feverfever but less ototoxicity with the intraperitoneal than the intravenous route.

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Hazard ratio for time to recurrence (IP vs IV C/.T)

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Hazard ratios for time to death (IP vs IV C/T)

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GOG 104(Alberts et al, 1996)

OS

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GOG 104: conclusions

As compared with IV cisplatin, IP cicplatin significantly improves survival and has significantly lower toxic effects in patients with stage III ovarian cancer and residual tumor mass of 2cm or less.

The only same “dose-intensity” in both arms phase 3 RCT

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Shorts of GOG 104

GOG 111 Median survival from 24 months (P+C) to

38 months ( P+T)

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GOG 114(Markman et al, 2001)

PFS

OS

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GOG 114: conclusions The 2nd phase 3 RCT to show IP cisplatin is sup

erior to IV cisplatin in small volume residual advanced ovarian cancer

The 1st phase 3 trial in ovarian cancer to a median survival of >5 years

Trial demonstrated that IP cisplatin favorably impacts survival, even through IV paclitaxel is a component of regimen

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Shorts of GOG 114

More complications in IP arm Neutropenia, thrombocytopenia G-I & metabolic toxicities

Carbopltin x 2 cycles ( AUC 9)

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GOG 172(Armstrong et al, 2006)

PFS

OS

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GOG 172residual tumor size & survival

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GOG 172: conclusions Significantly survival benefit in IP arm

The 65.6 months median survival is the longest survival reported to date from a randomized trial in advanced ovarian cancer

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Shorts of GOG 172 The IP regimen uses higher and more freque

nt dosing than the IV regimen

Toxicities were greater on the IP arm

Fewer patients on the IP arm were able to complete 6 cycles of therapy

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VGH-TPE: conclusions

Intravenous and intraperitoneal chemotherapy are associated with equivalent survival in patients with minimal residual stage III epithelial ovarian cancer after optimal cytoreductive surgery (<1m).

PEC or PAC regimens

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NCI Clinical Announcement, 1/5/06Pooled survival benefit of IP regimens

Progression-free survival HR=0.79 (95%CI: 0.70-0.90)

Overall survival HR=0.79 (95%CI: 0.70-0.89)

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New problems The role of carboplatin

GOG 158 (non-inferiority test) GOG 114 (moderately high dose IV Carboplatin before IP C/T) Cross-trial GOG172 vs GOG 158

How many courses of IP C/T is adequate?

Effect of Dose intensity? IP regimen uses higher and more frequent dosing schedule t

han the IV regimen

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Cross-trial comparison of GOG 172 and GOG 158

IP C/T arm Of GOG-172

Carbo-/Paclitaxel arm of GOG-158

No gross residual 38% 35%

Negative 2nd look 57% 53%

PFS 23.8 months 20.7 months

Overall survival 65.6 months 57.4 months

2-year survival 83% 83%

4-year survival 64-65% 61%

Complete 6 cycles

42% 87%

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GOG 172: eligible patients in IP arm

Although fewer than half the patients assignedto the IP group received six cycles of IP treatment, the group as a whole had a significant improvement in survival as compared with the intravenous group. It is possible that most of the benefit of IP therapy occurs early, during the initial cycles, or that the benefit of IP therapy may be greater if more patients can successfully complete six cycles of treatment.

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IP C/T as Consolidation

(Hamilton, 2006)

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Potential IP consolidation regimens

Cisplatin alone (50 mg/m2)

Cisplatin + topotecan

Cisplatin + FUDR

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IP C/T as 2nd-line C/T Phase I or II studies

IP C/T is safe, feasible, and pharmacokinetically advantageous, but responses varied widely.

Critical factors for response Tumor burden at initial treatment Paltinum sensitivity

Few candidates for 2nd-line IP C/T Those with stage IV, macroscopic, platinum-resistant, or extr

aperitoneal dz are less likely to be benefit Extensive adhesion 2nd-look op become rare recurrence is detected by palpabl

e or imageable lesions and symptoms.

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More Considerations

Catheter issues

Patient selection

Toxicity and QOL

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Complications of Catheter

Blockade Leakage Infection Diarrhea Bowel perforation Fistula formation

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Catheter issues

Timing of placement

34% discontinued IP C/T for catheter-specific complications (Walker et al, GO,2006)

Not associated with complication rate Pre-operative counseling, if possible Laparotomy, laparoscopy Close the vaginal cuff

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Catheter issues Types of Catheter

Tenckhoff peritoneal dialysis catheter Subcutaneous port implantation

Port-A-cath BardPort peritoneal catheter system

JP, CWV catheters Veress needles

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Tenckhoff tube

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Bardport catheter system

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Catheter issues Site of port placement

Goal To minimize patient discomfort, and Facilitate ease of access

Port site Superior and medial to the iliac crest, or On the inferior thorax, at the midclavicular li

ne, overlying the ribs.

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Common port sites

2

1

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Patient selection issues Patient characteristics

eg.: renal function ; neuropathy (DM –associated) Significant peritoneal adhesion Ongoing abdominal infection, or indwelling IP c

atheter becomes infected or malfunction, will be unable to treated by this route of drug delivery

Size of residual tumor masses <0.5 cm, 1cm, or 2 cm ? Onion skinning

Lt colon or rectosigmoid colon resection ?

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Toxicity and QOL In GOG172, in IP more

Bone marrow suppressions,

constitutional, G-I, neurologic symptoms, and infections

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Who said all IP cisplatin therapy is more toxic than IV cisplatin therapy?

Toxicity IP cisplatin(n=250)

IV cisplatin(n=276)

P-value

Granulocytopenia 56 69 0.002

Leukopenia 40 50 0.04

Tinnitus 7 14 0.01

Hearing loass 5 15 <0.001

Abdominal pain 18 2 <0.001

Hemoglobin 26 25 0.84

thrombocytopenia 9 8 0.64

(GOG 104)

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Quality of LifeGOG 172

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How to reduce the toxicities from IP C/T?

IP cisplatin-related toxicites Replacing cisplatin with carboplatin GOG phase I study:

IP carboplatin (AUC 6-7) + IV Taxol (175 mg/m2, 3hr)

IP Paclitaxel-related toxicities IV Docetaxel: less neurotoxic than Taxol

(SCOTROC trial) IP Docetaxel no dose-limiting toxicities

(Morgan et al)

IP catheter-related toxicities

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Conclusion IP cisplatin-based C/T has been shown to have

a survival benefit over IV cisplatin-based C/T for advance ovarian cancer patients with optimal debulking.

However, there are a number of unanswered questions that should be resolved before IP C/T becomes truly a standard care in the ovarian cancer.

Mar 5th, 2007 H.H. Wu, MD

Future Directions

1. Is IP administration of carboplatincarboplatin replacable to IP cisplatin as a less toxic alternative?

2. Is IP administration of paclitaxel necessary or IP administration of docetaxeldocetaxel acceptable?

3. What is the optimal numberoptimal number of IP treatment?

4. What is the optimal timing for the IP catheter placement and what is the optimal type and materialoptimal type and material??

5. Is IP C/T for ovarian cancer with bulky residual tumorbulky residual tumor as effective as those for small residual tumor?

6. How effective is IP C/T for retroperitoneal lymph node metastasislymph node metastasis?

Mar 5th, 2007 H.H. Wu, MD