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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