Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer

1
Intraperitoneal Cisplatin and Paclitaxel in
Ovarian Cancer

• ????? ????
• R2 ???

2
BACKGROUND

• Ovarian cancer
• - leading cause of the death in USA
• Standard chemotherapy for the initial Tx
• - combination of a platinum analogue with
  paclitaxel
• - with modern surgical intervention
• attain clinical remission
• ? however, relapse and die of the disease
• The rationale for intraperitoneal CTx
• - the peritoneum receives sustained exposure
  to
• high concentrations of antitumor agents
  while
• normal tissues are relatively spared

3
Theory of IP approach

• High IP concentration of drug
• Longer half-life of drug in abdominal
• cavity than with IV administration
• Prolonged systemic exposure
• IP chemotherapy not effective in bulky disease
• should be targeted at women with no residual
  or
• minimal residual disease
• Chemotherapeutic agents with higher molecular
• weight had longer half-lives
• Platinums/ taxanes have 10-20 times greater
• concentration IP than when given IV

4

• Intraperitoneal(IP) chemoTx
• - high cost, toxicity, cilnicians lack of
  familiarity
• with peritoneal administration,
  cathrter-placement
• technique

5
Development of IP CTx

• 1950s First use of intraperitoneal chemotherapy
  
• for malignant ascites
• 1968 Long-term peritoneal access device
• 1978 Demonstration of slow peritoneal clearance
• of some drugs
• 1984 Feasibility of intermittent large volume
• intraperitoneal therapy
• 1996 First report of a survival benefit for IP
  vs. IV
• chemotherapy in advanced ovarian
  cancer

6

• IV paclitaxel IV cisplatin
• (6 cycle)
• VS.
• IV paclitaxel IP cisplatin / IP paclitaxel
• (6 cycle)

7
METHODS (patient)

• Stage III epithelial ovarian or peritoneal
  carcinoma
• - no residual mass (lt1.0cm) after surgery
• - GOG performance status of 0 to 2
• - normal CBC, adequate renal hepatic
  function
• At registration
• - decide the 2nd-look laparotomy at the
  completion
• of chemotherapy
• Before each Tx
• - PEx, Hx, CBC, chemistry, CA125
• (every 3 months for 24 months and then
  every 6
• months)

8

• Quality-of-life assessment (FACT-O)
• - at registration
• before cycle 4
• 3 to 6 weeks after cycle 6
• 12 months after the completion of therapy

9
METHODS (treatment plan)

• IV group
• - day 1 IV paclitaxel 135 mg/m2
• day 2 IV cisplatin 75 mg/m2
• IP group
• - day 1 IV paclitaxel 135 mg/m2
• day 2 IP cisplatin 100 mg/m2
• day 8 IP paclitaxel 60 mg/m2
• Standard premedication
• - hydration antiemetics before cisplatin
• - reconstituted IP agent with 2 liter warmed
  N/S

10

• DAY 0
• - Dexamethasone 20 mg PO
• DAY 1
• - Paclitaxel 135 mg/m2 IV (3 hours)
• 6?? ? Dexamethasone 20 mg PO
• (or 30? ? Dexamethasone 1020 mg IV)
• 3060? ? Ranitidine 50 mg IV
• Diphenhydramine 50 mg IV
  

11

• DAY 2
• - Palonosetron 250 mcg IV
• Dexamethasone 12 mg IV/PO
• Aprepitant 135 mg PO
• - hydration before cisplatin
• N/S 1000ml (350ml/hr)
• output gt 100mg/hr
• - cisplatin 75mg/m2 IP in 2L saline
• need a bed,lie flat, slight head
  elevation
• ascites should be drained
• - hydration after cisplatin
• N/S 350ml/hr x 5 hrs

12

• DAY 3
• - Dexamethasone 12 mg PO
• Aprepiant 80 mg PO in AM
• DAY 4
• - Dexamethasone 12 mg PO
• Aprepiant 80 mg PO in AM
• DAY 8
• - Paclitaxel 60mg/m2 IP in 2L saline
• 30?? Dexamethasone 10mg IV
• 3060? ? Ranitidine 50mg IV
• Diphenhydramine 50mg IV

13

• Before the treatment
• - ANC gt 1,500 PLT gt 100,000 Cr lt 2.0 Ccr lt
  50
• hepatic toxicity, peripheral neuropathy
• ? if not, cycle delay, dose reduction, G-CSF
• 2nd-look laparotomy
• - 8 weeks after the last cycle
• negative complete response
• positive microscopic or grossly visible

14

• Dose of IP CTx
• - grade 2 abd. pain, neuropathy
• If grade 3 abd. pain , recurrent grade 2 abd.
  pain
• complication s involving the IP catheter
• - IV CTx for the remaining cycle
• Cisplatin-related complication
• - carboplatin substituted for cisplatin

15
METHODS (statistical analysis)

• Overall survival
• - survival was measured up to the date of
  death
• or, for living patients, the date of last
  contact
• Progression-free survival
• - until progression, death, or the date of
  last contact

16
RESULTS (patients)

• March 1998 January 2001
• IV group 215 patients
• IP group 214 patients
• Ineligible patients (14 patients)
• - IV group (5), IP group (9)
• - stage gt III
• second primary cancer
• nonepithelial cell type
• other primary cancer
• inadequate surgery
• low malignant potential

17
(No Transcript)
18
RESULTS (toxicity)

• Intolerable toxic effects related cisplatin
• - drug was switched to IV carboplatin
• Primary reason for discontinuation of IP CTx
• - catheter-related complications
• All treatment-related deaths were attributed
  infection

19
(No Transcript)
20
RESULTS (pathologic responses at
second-look laparotomy)

• Laparotomy was not mandatory
• IV group
• - 102 patients
• 41 complete pathological responses
• IP group
• - 100 patients
• 57 complete pathological responses

21
RESULTS (survival)

• The median duration of follow-up
• - IV group 48.2 months
• IP group 52.6 months
• Median progression-free survival
• - IV group 18.3 months
• IP group 23.8 months
• Median overall survival
• - IV group 49.7 months
• IP group 65.6 months

22
(No Transcript)
23

• Mean FACT-O quality-of-life score
• - IP group reported lower scores than IV group
• - but, no significant differences between the
• groups 1 year after tretment

24
(No Transcript)
25
DISCUSSION

• IP CTx significantly improved progression-free
• survival and overall survival
• - IP CTx had a 25 reduction in the risk of
  death
• In a previous GOG study
• - doubling dose of IV cisplatin
  cyclophosphamide
• - increasing dose density or intensity
• ? limitation

26

• Toxic events
• - IP group gt IV group
• - may be attributed to the higher cisplatin
• Paclitaxel
• - persists in the peritoneum for 1 week
• - peritoneal clearance is very slow
• - peritoneal clearance is altered when drug is
  given
• after IP cisplatin
• - increase toxicity

27

• IP CTx toxic effects
• - catheter-related substantial portion
• - catheter type the timing of catheter
  replacement
• were not specified
• - standardization of the device
• improve the success of IP CT

28

• Conclusion
• - IP CTX has a clinical advantage in the
  ovarian ca
• - but, toxicity ? quality of life ?
• - Use of IP CTx in patients with advanced
  ovarian
• cancer

29
CONSENSUS 2005

• The toxicities, inconvenience and cost of IP
• therapy are justified by the improved
  survival seen
• with this treatment
• New, targeted therapies are likely to be more
• effective in patients who have an excellent
• response to chemotherapy
• While we work to improve the tolerability and
• toxicities of IP therapy, it remains the most
• effective means of treating ovarian cancer
  today