Transcript Protherics

INCIDENCE OF DELAYS IN CHEMOTHERAPY
DUE TO METHOTREXATE TOXICITY
IN TREATMENT OF OSTEOSARCOMA
M. Perisoglou, B. Seddon, S. Daniels, N. Mayne, J. Whelan
Department of Oncology
University College Hospital, London, UK
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
HIGH-DOSE METHOTREXATE
IN TREATMENT OF OSTEOSARCOMA
•
High-dose methotrexate (12 gr/m2): essential component of osteosarcoma treatment
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
HIGH-DOSE METHOTREXATE
IN TREATMENT OF OSTEOSARCOMA
•
High-dose methotrexate (12 gr/m2): essential component of osteosarcoma treatment
•
Supportive measures
- iv hydration
- urinary alkalinisation
- folinic acid rescue (pharmacokinetically guided)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
HIGH-DOSE METHOTREXATE
IN TREATMENT OF OSTEOSARCOMA
•
High-dose methotrexate (12 gr/m2): essential component of osteosarcoma treatment
•
Supportive measures
- iv hydration
- urinary alkalinisation
- folinic acid rescue (pharmacokinetically guided)
•
Methotrexate tolerance
There is wide intra- and inter-patient variation to MTX tolerance, primary
determinant of which appears to be variation in the pharmacokinetics of the drug
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHOTREXATE TOXICITY
→
Mucositis / Stomatitis
→
Bone marrow suppression
→
Nephrotoxicity
→
Hepatotoxicity
→
Dermatitis
→
Encephalopathy
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHOTREXATE TOXICITY
→
Mucositis / Stomatitis
→
Bone marrow suppression
→
Nephrotoxicity
→
Hepatotoxicity
→
Dermatitis
→
Encephalopathy
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
• Patient’s discomfort
• Increased morbidity
• Increased costs
• Potentially reduced treatment efficacy
DELAYS IN CHEMOTHERAPY
AND OUTCOME IN OSTEOSARCOMA
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
DELAYS IN CHEMOTHERAPY
AND OUTCOME IN OSTEOSARCOMA
•
Frei at al. Am J Med, 1980
Chemotherapy response in osteosarcoma improves by increasing MTX dose and
worsens by increasing the time between MTX administrations
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
DELAYS IN CHEMOTHERAPY
AND OUTCOME IN OSTEOSARCOMA
•
Frei at al. Am J Med, 1980
Chemotherapy response in osteosarcoma improves by increasing MTX dose and
worsens by increasing the time between MTX administrations
•
Delepine et al. Cancer, 1996
Dose intensity of MTX seems to be a major factor in predicting the outcome of
patients with localised high grade osteosarcoma
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
DELAYS IN CHEMOTHERAPY
AND OUTCOME IN OSTEOSARCOMA
•
Frei at al. Am J Med, 1980
Chemotherapy response in osteosarcoma improves by increasing MTX dose and
worsens by increasing the time between MTX administrations
•
Delepine et al. Cancer, 1996
Dose intensity of MTX seems to be a major factor in predicting the outcome of
patients with localised high grade osteosarcoma
•
French Tumour Study Group, Cancer, 1998
Delay in MTX course administration is a negative prognostic factor in osteosarcoma
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
DELAYS IN CHEMOTHERAPY
AND OUTCOME IN OSTEOSARCOMA
•
Frei at al. Am J Med, 1980
Chemotherapy response in osteosarcoma improves by increasing MTX dose and
worsens by increasing the time between MTX administrations
•
Delepine et al. Cancer, 1996
Dose intensity of MTX seems to be a major factor in predicting the outcome of
patients with localised high grade osteosarcoma
•
French Tumour Study Group, Cancer, 1998
Delay in MTX course administration is a negative prognostic factor in osteosarcoma
•
Bacci et al. Oncol Rep, 2001
Avoiding reductions in MTX doses and /or delays in chemotherapy is crucial in
osteosarcoma outcome
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
MAP (Methotrexate + Adriamycin+ cisPlatin)
CYCLE
WEEK
TREATMENT
12
1
ADRIAMYCIN + CISPLATIN
13
3
2
1
3
4
HIGH-DOSE METHOTREXATE
5
HIGH-DOSE METHOTREXATE
6
ADRIAMYCIN + CISPLATIN
4
8
9
HIGH-DOSE METHOTREXATE
10
HIGH-DOSE METHOTREXATE
11
SURGERY
5
6
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
14
15
HIGH-DOSE METHOTREXATE
16
HIGH-DOSE METHOTREXATE
17
ADRIAMYCIN + CISPLATIN
18
7
2
ADRIAMYCIN + CISPLATIN
19
20
HIGH-DOSE METHOTREXATE
21
HIGH-DOSE METHOTREXATE
22
ADRIAMYCIN
23
24
HIGH-DOSE METHOTREXATE
25
HIGH-DOSE METHOTREXATE
26
ADRIAMYCIN
27
28
HIGH-DOSE METHOTREXATE
29
HIGH-DOSE METHOTREXATE
OBJECTIVES AND METHODS
• OBJECTIVE
Incidence of delays in chemotherapy due to methotrexate toxicity in treatment of
osteosarcoma
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
OBJECTIVES AND METHODS
• OBJECTIVE
Incidence of delays in chemotherapy due to methotrexate toxicity in treatment of
osteosarcoma
• METHODS
- Patients treated with MAP between 2003 and January 2006
- Notes of 56 patients retrieved
- Data collected on age, gender, chemotherapy dates, surgery dates, folinic acid rescue
- Delayed courses identified, information collected on delays due to MTX toxicity
- Applicable and non-applicable cycles
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
FOLINIC ACID RESCUE (FAR) REGIMENS
• FAR regimen A
- FAR starts at 24 hours and continues until MTX serum levels <0.2 µmol/L
- FAR is adjusted according to MTX levels, 48 hours onwards
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
FOLINIC ACID RESCUE (FAR) REGIMENS
• FAR regimen A
- FAR starts at 24 hours and continues until MTX serum levels <0.2 µmol/L
- FAR is adjusted according to MTX levels, 48 hours onwards
• FAR regimen B
- FAR starts at 24 hours and continues until MTX serum levels <0.2 µmol/L
- FAR is adjusted according to MTX levels, 24 hours onwards
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
FOLINIC ACID RESCUE (FAR) REGIMENS
• FAR regimen A
LATE
- FAR starts at 24 hours and continues until MTX serum levels <0.2 µmol/L
- FAR is adjusted according to MTX levels, 48 hours onwards
• FAR regimen B
EARLY
- FAR starts at 24 hours and continues until MTX serum levels <0.2 µmol/L
- FAR is adjusted according to MTX levels, 24 hours onwards
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHODS
CYCLES
COURSES
ACTUAL DATE
a
1
b
c
a
2
b
c
a
3
b
c
a
4
b
c
a
5
b
c
a
6
b
c
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
REASON FOR DELAY
METHODS
CYCLES
1
2
3
4
5
6
COURSES
ACTUAL DATE
a
01/06/04
b
23/06/04
c
30/06/04
a
08/07/04
b
30/07/04
c
06/08/04
a
23/08/04
b
13/09/04
c
20/09/04
a
27/09/04
b
18/10/04
c
25/10/04
a
06/12/04
b
20/12/04
c
OMITTED
Due to severe mucositis post 5b
a
08/01/05
>7 days, severe mucositis
b
22/01/05
c
29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
REASON FOR DELAY
1 day, no beds
10 days, pancytopaenia
Surgery on 06/11/04
METHODS
CYCLES
1
2
3
4
5
6
COURSES
ACTUAL DATE
a
01/06/04
b
23/06/04
c
30/06/04
a
08/07/04
b
30/07/04
c
06/08/04
a
23/08/04
b
13/09/04
c
20/09/04
a
27/09/04
b
18/10/04
c
25/10/04
a
06/12/04
b
20/12/04
c
OMITTED
Due to severe mucositis post 5b
a
08/01/05
>7 days, severe mucositis
b
22/01/05
c
29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
REASON FOR DELAY
1 day, no beds
10 days, pancytopaenia
Surgery on 06/11/04
METHODS
CYCLES
1
2
3
4
5
6
COURSES
ACTUAL DATE
a
01/06/04
b
23/06/04
c
30/06/04
a
08/07/04
b
30/07/04
c
06/08/04
a
23/08/04
b
13/09/04
c
20/09/04
a
27/09/04
b
18/10/04
c
25/10/04
a
06/12/04
b
20/12/04
c
OMITTED
Due to severe mucositis post 5b
a
08/01/05
>7 days, severe mucositis
b
22/01/05
c
29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
REASON FOR DELAY
1 day, no beds
10 days, pancytopaenia
Surgery on 06/11/04
METHODS
CYCLES
1
2
3
4
5
6
COURSES
ACTUAL DATE
a
01/06/04
b
23/06/04
c
30/06/04
a
08/07/04
b
30/07/04
c
06/08/04
a
23/08/04
b
13/09/04
c
20/09/04
a
27/09/04
b
18/10/04
c
25/10/04
a
06/12/04
b
20/12/04
c
OMITTED
Due to severe mucositis post 5b
a
08/01/05
>7 days, severe mucositis
b
22/01/05
c
29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
REASON FOR DELAY
1 day, no beds
10 days, pancytopaenia
Surgery on 06/11/04
METHODS
CYCLES
1
2
3
4
5
6
COURSES
ACTUAL DATE
a
01/06/04
b
23/06/04
c
30/06/04
a
08/07/04
b
30/07/04
c
06/08/04
a
23/08/04
b
13/09/04
c
20/09/04
a
27/09/04
b
18/10/04
c
25/10/04
a
06/12/04
b
20/12/04
c
OMITTED
Due to severe mucositis post 5b
a
08/01/05
>7 days, severe mucositis
b
22/01/05
c
29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
REASON FOR DELAY
1 day, no beds
10 days, pancytopaenia
Surgery on 06/11/04
RESULTS
• Total number of patients: 56
• Median age: 20 years
• M:F
1.6:1
• Total number of cycles received: 235
• Median number of cycles received per patient: 5
• Applicable cycles: 175
FAR regimen A: 98/175 (56%)
FAR regimen B: 77/175 (44%)
• Median number of applicable cycles received per patient: 4
• Median number of delayed cycles per patient: 1.5
• No deaths due to MTX toxicity
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES
Regimen A
Total number
of cycles
Delayed cycles
98
56
77
36
175
92
Incidence of
delay
57%
(late adjustment)
Regimen B
47%
(early adjustment)
Both regimens
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
52%
Median delay
(range)
7 days
(1-28)
7 days
(3-27)
7 days
(1-28)
INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES
Regimen A
Total number
of cycles
Delayed cycles
98
56
77
36
175
92
Incidence of
delay
57%
(late adjustment)
Regimen B
47%
(early adjustment)
Both regimens
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
52%
Median delay
(range)
7 days
(1-28)
7 days
(3-27)
7 days
(1-28)
INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES
Regimen A
Total number
of cycles
Delayed cycles
98
56
77
36
175
92
Incidence of
delay
57%
(late adjustment)
Regimen B
47%
(early adjustment)
Both regimens
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
52%
Median delay
(range)
7 days
(1-28)
7 days
(3-27)
7 days
(1-28)
INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
57%
52%
47%
total
delayed
Reg A + B
Reg A
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
Reg B
MTX-INDUCED DELAYS IN CHEMOTHERAPY
nephrotoxicity
7.6%
infection 12%
BM suppression
28.5%
mucositis 50.5%
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
INCIDENCE OF DELAYS PER CYCLE
100
90%
90
80
70
60
67%
67%
60%
52%
70%
55%
50
40
64%
68%
39%
43%
44%
38%
33%
31%
30
20
10
0
Reg A + B
Reg A
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
Reg B
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
AGE AND DELAYED CYCLES
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
AGE AND DELAYED CYCLES
AGE GROUPS
Up to 16 years
No
patients
Reg A + B
Reg A
(late adjustment)
Reg B
(early adjustment)
Delayed/ Applicable
cycles
Delayed / Applicable
cycles
Delayed / Applicable
cycles
19
(median: 12 yrs)
17-30 years
26
(median: 20.5 yrs)
31-40 years
9
(median: 34 yrs)
>40 years
2
(median: 45 years)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
AGE AND DELAYED CYCLES
AGE GROUPS
Up to 16 years
Reg A + B
Reg A
(late adjustment)
Reg B
(early adjustment)
Delayed/ Applicable
cycles
Delayed / Applicable
cycles
Delayed / Applicable
cycles
19
35/68 (51.5%)
15/36 (41.6%)
20/32 (62.5%)
26
43/70 (61.4%)
29/40 (72.5%)
14/30 (46.6%)
9
12/24 (50%)
3/4 (75%)
9/20 (45%)
2
4/5 (80%)
2/3 (66.6%)
2/2 (100%)
No
patients
(median: 12 yrs)
17-30 years
(median: 20.5 yrs)
31-40 years
(median: 34 yrs)
>40 years
(median: 45 years)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
AGE AND DELAYED CYCLES
AGE GROUPS
Up to 16 years
Reg A + B
Reg A
(late adjustment)
Reg B
(early adjustment)
Delayed/ Applicable
cycles
Delayed / Applicable
cycles
Delayed / Applicable
cycles
19
35/68 (51.5%)
15/36 (41.6%)
20/32 (62.5%)
26
43/70 (61.4%)
29/40 (72.5%)
14/30 (46.6%)
9
12/24 (50%)
3/4 (75%)
9/20 (45%)
2
4/5 (80%)
2/3 (66.6%)
2/2 (100%)
No
patients
(median: 12 yrs)
17-30 years
(median: 20.5 yrs)
31-40 years
(median: 34 yrs)
>40 years
(median: 45 years)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
OMITTED MTX COURSES
AND EARLY DISCONTINUATION OF MAP
• OMITTED MTX COURSES
- of 350 planned MTX courses, 5% (16/350) were omitted due to MTX toxicity
• MAP EARLY DISCONTINUATION
- in 10% (6/56) of the patients MAP treatment was discontinued early due to MTX
toxicity
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
CONCLUSIONS
•
MTX-induced chemotherapy delays have decreased by ~20% with early FAR
adjustment (57% vs 47%)
•
Median number of delayed chemotherapy cycles per patient: 1.5/4
•
Incidence of MTX-induced chemotherapy delays is still high
•
Improving rescue from MTX-toxicity is a worthwhile goal
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
CONCLUSIONS
•
MTX-induced chemotherapy delays have decreased by ~20% with early FAR
adjustment (57% vs 47%)
•
Median number of delayed chemotherapy cycles per patient: 1.5/4
•
Incidence of MTX-induced chemotherapy delays is still high
•
Improving rescue from MTX-toxicity is a worthwhile goal
CTOS, 12th Annual Meeting, Venice 2-4 November 2006