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Intraperitoneal chemotherapy for epithelial ovarian cancer


Intraperitoneal chemotherapy for epithelial ovarian cancer. Hua-His Wu, MD OB/GYN, VGH-TPE. Epithelial ovarian cancer. Standard therapy A maximum cytoreductive surgery followed by combination chemotherapy with paclitaxel and carboplatin A chemo-sensitive tumor However, most recur

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Intraperitoneal chemotherapy for epithelial ovarian cancer

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Intraperitoneal chemotherapy for epithelial ovarian cancer

Intraperitoneal chemotherapy for epithelial ovarian cancer

Hua-His Wu, MD

OB/GYN, VGH-TPE


Epithelial ovarian cancer

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


History of ip c t

History of IP C/T

  • Weisberger 1955

    • Nitrogen mustard intraperitoneally for malignant ascites

  • Jones 1978

    • signicantly greater concentrations of certain chemotherapeutic 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


Nci announcement 2006

NCI announcement 2006

  • Encouraging the GO community to consider IP chemotherapy as the standard treatment 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


Ip chemotherapy

IP Chemotherapy

  • Principles

  • Pharmacology

  • Clinical aspects

  • Toxicities and QOL

  • Future directions


Principles of ip c t

Principles of IP C/T


Basic pharmacologic concept of ip c t

Basic pharmacologic concept of IP C/T


What is the ideal anticancer agent for ip c t

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)


Basic concept of ip c t

Basic concept of IP C/T

  • Penetration

  • Peritoneal dwelling

  • Solute transport model

  • Anatomy of the peritoneum and capillary vessels

  • Resistance to solute transport


Penetration of anticancer agents

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


Peritoneal dwelling of anticancer drugs

Peritoneal dwelling of anticancer drugs

  • Longer stay of anticancer agents

  • Higher drug concentration in the inner core

    Is a contrary phenomenon


Anatomy of the peritoneum

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


Mesothelium interstitium

Mesothelium, Interstitium

  • Mesothelium

    • Monolayer of flattened cells about 0.5 mm thick

    • Tight junction ; Gap junction

    • Absence of tight junction in the subdiaphragmatic area  directly absorbed into the lymphatic system

  • Interstitium

    • The supporting structure

    • Distance varies


Blood vessels

Blood vessels

  • Visceral peritoneum

    • Supplied by celiac and mesentary arteries with venous drainage via the portal vein

    • Rapid firstpass metabolism by the liver

  • Parietal peritoneum

    • Supplied by circumflex iliac, lumbar, intercostal, and epigastric 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


Peritoneal lymphatics

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)


Mechanism of solute transport between peritoneal cavity and capillary lumen

Mechanism of solute transport between peritoneal cavity and capillary lumen


Theoretical behaviors of anticancer agents

Theoretical behaviors of anticancer agents

  • Larger molecular weight or water-insolubleanticancer 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 be used for IP C/T.

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


Pharmacologic advantage for ip c t

Pharmacologic advantage for IP C/T

(Modified from Markman M, Semin Oncol 1991)


Choice of drugs

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


Pharmacology of ip drugs

Pharmacology of IP drugs

  • Cisplatin

  • Carboplatin

  • Paclitaxel


Cisplatin

Cisplatin

  • P/V ratio: peak 21; AUC 12 (Howell, 1982)

  • The mode of administration did not affect systemic toxicity(Pretorius, 1981)

  • The amount of drug recovered in the urine and the drug levels within the tissues were similar

  • The peritoneal lining had 2.5-8 times higher levels of drug after IP administration

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


Carboplatin

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 higher when which given via IP

       IP infusion of carboplatin is feasible not only as an IP regional therapy but also as a more reasonable route for systemic chemotherapy

  • The recommended dose of IP carboplatin was 400 mg/m2

    (Speyer and Sorich, 1992)


Paclitaxel

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 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)


Ip agents and risk

IP agents and risk

(Makhija et al, 2001)


Strengths of ip c t

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


Clinical aspects of ip c t

Clinical aspects of IP C/T

  • Front-line chemotherapy

  • Consolidation

  • 2nd-line chemotherapy


Phase iii trials of ip vs iv cisplatin based chemotherapy

Phase III trials of IP vs IV cisplatin-based chemotherapy

(Hamilton, 2006)


Main results

Main results

  • Eight randomized trials studied 1819 women receiving primary treatment for ovarian cancer.

  • Women were less 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 effects, pain and fever but less ototoxicity with the intraperitoneal than the intravenous route.


Hazard ratio for time to recurrence ip vs iv c t

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


Hazard ratios for time to death ip vs iv c t

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


Gog 104 alberts et al 1996

GOG 104(Alberts et al, 1996)

OS


Gog 104 conclusions

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


Shorts of gog 104

Shorts of GOG 104

  • GOG 111

    • Median survival from 24 months (P+C) to 38 months ( P+T)


Gog 114 markman et al 2001

GOG 114(Markman et al, 2001)

PFS

OS


Gog 114 conclusions

GOG 114: conclusions

  • The 2nd phase 3 RCT to show IP cisplatin is superior 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


Shorts of gog 114

Shorts of GOG 114

  • More complications in IP arm

    • Neutropenia, thrombocytopenia

    • G-I & metabolic toxicities

  • Carbopltin x 2 cycles ( AUC 9)


Gog 172 armstrong et al 2006

GOG 172(Armstrong et al, 2006)

PFS

OS


Gog 172 residual tumor size survival

GOG 172residual tumor size & survival


Gog 172 conclusions

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


Shorts of gog 172

Shorts of GOG 172

  • The IP regimen uses higher and more frequent 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


Vgh tpe conclusions

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


Nci clinical announcement 1 5 06 pooled survival benefit of ip regimens

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)


New problems

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 coursesof IP C/T is adequate?

  • Effect of Dose intensity?

    • IP regimen uses higher and more frequent dosing schedule than the IV regimen


Cross trial comparison of gog 172 and gog 158

Cross-trial comparison of GOG 172 and GOG 158


Gog 172 eligible patients in ip arm

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.


Ip c t as consolidation

IP C/T as Consolidation

(Hamilton, 2006)


Potential ip consolidation regimens

Potential IP consolidation regimens

  • Cisplatin alone (50 mg/m2)

  • Cisplatin + topotecan

  • Cisplatin + FUDR


Ip c t as 2nd line c t

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 extraperitoneal dz are less likely to be benefit

    • Extensive adhesion

    • 2nd-look op become rare recurrence is detected by palpable or imageable lesions and symptoms.


More considerations

More Considerations

  • Catheter issues

  • Patient selection

  • Toxicity and QOL


Complications of catheter

Complications of Catheter

  • Blockade

  • Leakage

  • Infection

  • Diarrhea

  • Bowel perforation

  • Fistula formation


Catheter issues timing of placement

Catheter issuesTiming 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


Catheter issues types of catheter

Catheter issuesTypes of Catheter

  • Tenckhoff peritoneal dialysis catheter

  • Subcutaneous port implantation

    • Port-A-cath

    • BardPort peritoneal catheter system

  • JP, CWV catheters

  • Veress needles


Tenckhoff tube

Tenckhoff tube


Bardport catheter system

Bardport catheter system


Catheter issues site of port placement

Catheter issuesSite 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 line, overlying the ribs.


Common port sites

Common port sites

2

1


Patient selection issues

Patient selection issues

  • Patient characteristics

    • eg.: renal function ; neuropathy (DM –associated)

  • Significant peritoneal adhesion

  • Ongoing abdominal infection, or indwelling IP catheter 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 ?


Toxicity and qol

Toxicity and QOL

  • In GOG172, in IP more

    • Bone marrow suppressions,

    • constitutional,

    • G-I,

    • neurologic symptoms,

    • and infections


Who said all ip cisplatin therapy is more toxic than iv cisplatin therapy

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

(GOG 104)


Quality of life gog 172

Quality of LifeGOG 172


How to reduce the toxicities from ip c t

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


Conclusion

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.


Future directions

Future Directions

Is IP administration of carboplatin replacable to IP cisplatin as a less toxic alternative?

Is IP administration of paclitaxel necessary or IP administration of docetaxelacceptable?

What is the optimal number of IP treatment?

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

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

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