Intraperitoneal chemotherapy for epithelial ovarian cancer

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Intraperitoneal chemotherapy for epithelial
ovarian cancer

• Hua-His Wu, MD
• OB/GYN, VGH-TPE

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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

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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

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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
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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

(?? ?? ???)
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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 gt vinblastine
• Cisplatin
• In mouse model (Los et al)
• Concentration
• in peripheral IP gt 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 subdiaphragmatic
  area ? directly absorbed into the lymphatic
  system
• Interstitium
• The supporting structure
• Distance varies

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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

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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 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
(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 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

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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 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)

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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 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, lt1cm 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
  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 95CI 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.

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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 (PC) to 38 months
  ( PT)

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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
  superior to IV cisplatin in small volume residual
  advanced ovarian cancer
• The 1st phase 3 trial in ovarian cancer to a
  median survival of gt5 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 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

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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 (lt1m).
• PEC or PAC regimens

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

• Progression-free survival
• HR0.79 (95CI 0.70-0.90)
• Overall survival
• HR0.79 (95CI 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 than the IV regimen

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Cross-trial comparison of GOG 172 and GOG 158
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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 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.

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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 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

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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
  line, 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
  catheter becomes infected or malfunction, will be
  unable to treated by this route of drug delivery
• Size of residual tumor masses
• lt0.5 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?
(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.

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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 docetaxel acceptable?
• 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?

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