Transcript Safety profile of biweekly schedule of liposomal

Safety profile of biweekly schedule of
liposomal Doxorubicin (Caelyx) in
salvage therapy of adult solid tumors.
Greige Yolla, Sr. Salloum Warde, Adaimy Ina,
Serhal Mira, Kattan Joseph
Department of Hematology-Oncology, Saint Joseph Hospital, Beirut, Lebanon
LSMO 7, 13-14 Nov. 2008, Beyrouth, Lebanon
Reducing Anthracycline-Induced
Cardiotoxicity
1. Anthracycline analogs
2. Weekly low-dose and prolonged continuous
infusion
3. ICRF-187 (dexrazoxane) = Cardioxane
4. Liposomal drug delivery : CAELYX
Structure of
™
CAELYX /
PEG
®
Doxil
(PLD)
Evades immune system
Significantly prolongs t½
Remains encapsulated until
it reaches tumor1
Concentrates in tumor
Doxorubici
n
1 Gabizon,
et al. Cancer Res. 1994;54:987-992.
Cardiac Safety of CAELYX™/Doxil® (PLD)
in animal models
• PLD (0.25-1 mg/kg) was less cardiotoxic than conventional
doxorubicin (1 mg/kg) in rats1
• The incidence of cardiotoxicity in rabbits treated with PLD (1
mg/kg) was 16% vs 67% with conventional doxorubicin (1
mg/kg)2
• There was no evidence of cardiotoxicity in dogs treated with
PLD (0.25-1 mg/kg) 1-5 weeks after treatment1, while mild
to moderate cardiomyopathy occurred in all dogs
treated with conventional doxorubicin (1 mg/kg)1
1Schering-Plough,
2Working
data on file.
PK, et al. J Pharm Exp Ther. 1999;289:1128-1133.
CAELYX™/ Doxil® (PLD)
Effect on LVEF
• A median CAELYX™/ Doxil® (PLD) dose of 660 mg/m2
(500 to 1500 mg/m2) was administered
• Median LVEF change by MUGA scan of –2% (–15% to +9%), no clinical
cardiac symptoms
• Five patients had LVEF decreases of more than 10%
• No correlation was found between cumulative dose
of PLD and change in LVEF
• Billingham scores ( semiquantitative histologic scoring system)
of cardiac biopsies were 0 to 1.5 with no cardiac symptoms
Safra T, et al. Ann Oncol. 2000;11:1029-1033.
Rationale
• CAELYX : classical dosage
50 mg/m2/4 w
• CAELYX : less cardiotoxicity
But cutaneous toxicity = PPE
( Palmar-Plantar Erythro-dysesthesia )
• CAELYX : PPE = 49%
grade 3-4 = 23%
• Prevention : cold application on hands and foots
time and work consuming
Toxicities evaluation
Les criteres NCI de toxicites :
Grade
PPE
1
Reaction
moderee:
dermatite ou
erytheme;
sans douleur
2
Reaction
importante:des
quamation,
oedeme,
saignement;
Avec douleur
3
Dermatite
ulcerative ou
douleur
interferant
avec les
activites
4
Risque vital
Recent Literature
• Reduce dosage to 40 mg/m2/4w
PPE grade 3-4 decreases to 8,3 - 1,1%
Ref : Campus SM. Gynecol.Oncol. 2001;81:206-212
Rose PG. Gynecol.Oncol. 2001;82:323-328
Recent Literature
• Split dosage to 20 mg/m2/2w
PPE = 47%
grade 3-4 = 4,7%
PPE = 34%
grade 3-4 = 0,02%
Ref : Sehouli J. Ann Oncol 2006;17:957-961
Strauss HG. Anti-cancer drugs 2008;19:541-545
Included patients
•
-
Since 1/1/2008 :
Age from 18 to 75 ans
Metastatic solid tumors
Resistant to at least one line of chemotherapy
Good cardiac, renal and hepatic functions
Medications
• CAELYX : 20 mg / m2 / 2 weeks
• Dilute in 250 cc 5% Dextrose in 30 minutes
• Premedications : Anti-emetic
Solumedrol
Zantac
• No cold application
Resultats
• 15 patients are included
• 6 M et 9 F
• Cancer types:
Ovary
6
Breast
2
Sarcoma
2
NSCLC
2
HN
1
CUP
2
Resultats
• Mean age : 53 ( extremes 20 to 73 )
• Total number of cycles : 78
• Mean number of cycles per patient : 5,2
( extremes 1 to 11 )
• Dose in mg : 30 ---- 8 patients
35 ---- 3 patients
40 ---- 3 patients
Resultats
• Tolerability :
- Hematologic : Anemia :
grade 2 : 1 patient
grade 3 : 1 patient
Neutropenia grade 3 : 1 pt
- Mucositis : grade 2 : 1 patient
- Biologic : 0
- PPE grade 1-2 : 2 patients = 0,13%
PPE grade 3-4 : 0
Conclusions
• The new schedule 20 mg/m2/2w is well
tolerated
• 0,13% PPE
0 toxicity PPE grade 3-4
• Reponse and survival are ongoing