Transcript Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer

Intraperitoneal
Cisplatin and Paclitaxel
in Ovarian Cancer
부산백병원 산부인과
R2 서영진
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
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
Intraperitoneal(IP) chemoTx
- high cost, toxicity, cilnicians’ lack of familiarity
with peritoneal administration, cathrter-placement
technique
Development of IP CTx
1950’s: 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
IV paclitaxel + IV cisplatin
(6 cycle)
VS.
IV paclitaxel + IP cisplatin / IP paclitaxel
(6 cycle)
METHODS (patient)
Stage III epithelial ovarian or peritoneal carcinoma
- no residual mass (<1.0cm) 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)
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
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
DAY 0
- Dexamethasone 20 mg PO
DAY 1
- Paclitaxel 135 mg/m2 IV (3 hours)
: 6시간 전 Dexamethasone 20 mg PO
(or 30분 전 Dexamethasone 10~20 mg IV)
: 30~60분 전 Ranitidine 50 mg IV
Diphenhydramine 50 mg IV
DAY 2
- Palonosetron 250 mcg IV
Dexamethasone 12 mg IV/PO
Aprepitant 135 mg PO
- hydration before cisplatin
: N/S 1000ml (350ml/hr)
: output > 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
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
30분전 Dexamethasone 10mg IV
30~60분 전 Ranitidine 50mg IV
Diphenhydramine 50mg IV
Before the treatment
- ANC > 1,500 PLT > 100,000 Cr < 2.0 Ccr < 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
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
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
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 > III
second primary cancer
nonepithelial cell type
other primary cancer
inadequate surgery
low malignant potential
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
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
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
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
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
Toxic events
- IP group > 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
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
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
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