incidence of delays in chemotherapy due to methotrexate toxicity in treatment of osteosarcoma
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CTOS, 12th Annual Meeting, Venice 2-4 November 2006
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 toleranceThere 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
• Patient’s discomfort
• Increased morbidity
• Increased costs
• Potentially reduced treatment efficacy
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
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
CYCLE WEEK TREATMENT
1
1 ADRIAMYCIN + CISPLATIN
2
3
4 HIGH-DOSE METHOTREXATE
5 HIGH-DOSE METHOTREXATE
2
6 ADRIAMYCIN + CISPLATIN
7
8
9 HIGH-DOSE METHOTREXATE
10 HIGH-DOSE METHOTREXATE
11 SURGERY
3
12 ADRIAMYCIN + CISPLATIN
13
14
15 HIGH-DOSE METHOTREXATE
16 HIGH-DOSE METHOTREXATE
4
17 ADRIAMYCIN + CISPLATIN
18
19
20 HIGH-DOSE METHOTREXATE
21 HIGH-DOSE METHOTREXATE
5
22 ADRIAMYCIN
23
24 HIGH-DOSE METHOTREXATE
25 HIGH-DOSE METHOTREXATE
6
26 ADRIAMYCIN
27
28 HIGH-DOSE METHOTREXATE
29 HIGH-DOSE METHOTREXATE
MAP (Methotrexate + Adriamycin+ cisPlatin)
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
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
- 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
LATE
EARLY
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHODS
CYCLES COURSES ACTUAL DATE REASON FOR DELAY
1a
b
c
2a
b
c
3a
b
c
4a
b
c
5a
b
c
6a
b
c
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHODS
CYCLES COURSES ACTUAL DATE REASON FOR DELAY
1a 01/06/04
b 23/06/04
c 30/06/04
2a 08/07/04 1 day, no beds
b 30/07/04
c 06/08/04
3a 23/08/04 10 days, pancytopaenia
b 13/09/04
c 20/09/04
4a 27/09/04
b 18/10/04
c 25/10/04
5a 06/12/04 Surgery on 06/11/04
b 20/12/04
c OMITTED Due to severe mucositis post 5b
6a 08/01/05 >7 days, severe mucositis
b 22/01/05
c 29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHODS
CYCLES COURSES ACTUAL DATE REASON FOR DELAY
1a 01/06/04
b 23/06/04
c 30/06/04
2a 08/07/04 1 day, no beds
b 30/07/04
c 06/08/04
3a 23/08/04 10 days, pancytopaenia
b 13/09/04
c 20/09/04
4a 27/09/04
b 18/10/04
c 25/10/04
5a 06/12/04 Surgery on 06/11/04
b 20/12/04
c OMITTED Due to severe mucositis post 5b
6a 08/01/05 >7 days, severe mucositis
b 22/01/05
c 29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHODS
CYCLES COURSES ACTUAL DATE REASON FOR DELAY
1a 01/06/04
b 23/06/04
c 30/06/04
2a 08/07/04 1 day, no beds
b 30/07/04
c 06/08/04
3a 23/08/04 10 days, pancytopaenia
b 13/09/04
c 20/09/04
4a 27/09/04
b 18/10/04
c 25/10/04
5a 06/12/04 Surgery on 06/11/04
b 20/12/04
c OMITTED Due to severe mucositis post 5b
6a 08/01/05 >7 days, severe mucositis
b 22/01/05
c 29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHODS
CYCLES COURSES ACTUAL DATE REASON FOR DELAY
1a 01/06/04
b 23/06/04
c 30/06/04
2a 08/07/04 1 day, no beds
b 30/07/04
c 06/08/04
3a 23/08/04 10 days, pancytopaenia
b 13/09/04
c 20/09/04
4a 27/09/04
b 18/10/04
c 25/10/04
5a 06/12/04 Surgery on 06/11/04
b 20/12/04
c OMITTED Due to severe mucositis post 5b
6a 08/01/05 >7 days, severe mucositis
b 22/01/05
c 29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
METHODS
CYCLES COURSES ACTUAL DATE REASON FOR DELAY
1a 01/06/04
b 23/06/04
c 30/06/04
2a 08/07/04 1 day, no beds
b 30/07/04
c 06/08/04
3a 23/08/04 10 days, pancytopaenia
b 13/09/04
c 20/09/04
4a 27/09/04
b 18/10/04
c 25/10/04
5a 06/12/04 Surgery on 06/11/04
b 20/12/04
c OMITTED Due to severe mucositis post 5b
6a 08/01/05 >7 days, severe mucositis
b 22/01/05
c 29/01/05
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
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
Total number of cycles
Delayed cycles Incidence of delay
Median delay(range)
Regimen A(late adjustment)
98 5657%
7 days(1-28)
Regimen B(early adjustment)
77 3647%
7 days(3-27)
Both regimens 175 9252%
7 days(1-28)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES
Total number of cycles
Delayed cycles Incidence of delay
Median delay(range)
Regimen A(late adjustment)
98 5657%
7 days(1-28)
Regimen B(early adjustment)
77 3647%
7 days(3-27)
Both regimens 175 9252%
7 days(1-28)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES
Total number of cycles
Delayed cycles Incidence of delay
Median delay(range)
Regimen A(late adjustment)
98 5657%
7 days(1-28)
Regimen B(early adjustment)
77 3647%
7 days(3-27)
Both regimens 175 9252%
7 days(1-28)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES
52%57%
0%10%20%30%40%50%60%70%80%90%
100%
Reg A + B Reg A Reg B
total
delayed
47%
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
MTX-INDUCED DELAYS IN CHEMOTHERAPY
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
INCIDENCE OF DELAYS PER CYCLE
38%
67%
52%
70%
64%67%
31%
43%39%
68%
33%
55%
90%
44%
60%
0
10
20
30
40
50
60
70
80
90
100
Reg A + B Reg A Reg B
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
AGE AND DELAYED CYCLES
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
AGE AND DELAYED CYCLES
AGE GROUPS No patient
s
Reg A + B Reg A (late adjustment)
Reg B(early adjustment)
Delayed/ Applicable cycles
Delayed / Applicable cycles
Delayed / Applicable cycles
Up to 16 years (median: 12 yrs)
19
17-30 years(median: 20.5 yrs)
26
31-40 years(median: 34 yrs)
9
>40 years (median: 45 years)
2
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
AGE AND DELAYED CYCLES
AGE GROUPS No patient
s
Reg A + B Reg A (late adjustment)
Reg B(early adjustment)
Delayed/ Applicable cycles
Delayed / Applicable cycles
Delayed / Applicable cycles
Up to 16 years (median: 12 yrs)
19 35/68 (51.5%) 15/36 (41.6%) 20/32 (62.5%)
17-30 years(median: 20.5 yrs)
26 43/70 (61.4%) 29/40 (72.5%) 14/30 (46.6%)
31-40 years(median: 34 yrs)
9 12/24 (50%) 3/4 (75%) 9/20 (45%)
>40 years (median: 45 years)
2 4/5 (80%) 2/3 (66.6%) 2/2 (100%)
CTOS, 12th Annual Meeting, Venice 2-4 November 2006
AGE AND DELAYED CYCLES
AGE GROUPS No patient
s
Reg A + B Reg A (late adjustment)
Reg B(early adjustment)
Delayed/ Applicable cycles
Delayed / Applicable cycles
Delayed / Applicable cycles
Up to 16 years (median: 12 yrs)
19 35/68 (51.5%) 15/36 (41.6%) 20/32 (62.5%)
17-30 years(median: 20.5 yrs)
26 43/70 (61.4%) 29/40 (72.5%) 14/30 (46.6%)
31-40 years(median: 34 yrs)
9 12/24 (50%) 3/4 (75%) 9/20 (45%)
>40 years (median: 45 years)
2 4/5 (80%) 2/3 (66.6%) 2/2 (100%)
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
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