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