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CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 INCIDENCE OF DELAYS IN CHEMOTHERAPY DUE TO METHOTREXATE TOXICITY IN TREATMENT OF OSTEOSARCOMA M. Perisoglou,

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Presentation on theme: "CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 INCIDENCE OF DELAYS IN CHEMOTHERAPY DUE TO METHOTREXATE TOXICITY IN TREATMENT OF OSTEOSARCOMA M. Perisoglou,"— Presentation transcript:

1 CTOS, 12 th 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

2 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006

3 HIGH-DOSE METHOTREXATE IN TREATMENT OF OSTEOSARCOMA High-dose methotrexate (12 gr/m 2 ): essential component of osteosarcoma treatment

4 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 HIGH-DOSE METHOTREXATE IN TREATMENT OF OSTEOSARCOMA High-dose methotrexate (12 gr/m 2 ): essential component of osteosarcoma treatment Supportive measures - iv hydration - urinary alkalinisation - folinic acid rescue (pharmacokinetically guided)

5 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 HIGH-DOSE METHOTREXATE IN TREATMENT OF OSTEOSARCOMA High-dose methotrexate (12 gr/m 2 ): 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

6 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 METHOTREXATE TOXICITY → Mucositis / Stomatitis → Bone marrow suppression → Nephrotoxicity → Hepatotoxicity → Dermatitis → Encephalopathy

7 CTOS, 12 th 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

8 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 DELAYS IN CHEMOTHERAPY AND OUTCOME IN OSTEOSARCOMA

9 CTOS, 12 th 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

10 CTOS, 12 th 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

11 CTOS, 12 th 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

12 CTOS, 12 th 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

13 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 CYCLEWEEKTREATMENT 1 1ADRIAMYCIN + CISPLATIN 2 3 4HIGH-DOSE METHOTREXATE 5 2 6ADRIAMYCIN + CISPLATIN 7 8 9HIGH-DOSE METHOTREXATE 10HIGH-DOSE METHOTREXATE 11SURGERY 3 12ADRIAMYCIN + CISPLATIN 13 14 15HIGH-DOSE METHOTREXATE 16HIGH-DOSE METHOTREXATE 4 17ADRIAMYCIN + CISPLATIN 18 19 20HIGH-DOSE METHOTREXATE 21HIGH-DOSE METHOTREXATE 5 22ADRIAMYCIN 23 24HIGH-DOSE METHOTREXATE 25HIGH-DOSE METHOTREXATE 6 26ADRIAMYCIN 27 28HIGH-DOSE METHOTREXATE 29HIGH-DOSE METHOTREXATE MAP (Methotrexate + Adriamycin+ cisPlatin)

14 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 OBJECTIVES AND METHODS OBJECTIVE Incidence of delays in chemotherapy due to methotrexate toxicity in treatment of osteosarcoma

15 CTOS, 12 th 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

16 CTOS, 12 th 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

17 CTOS, 12 th 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

18 CTOS, 12 th 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

19 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 METHODS CYCLESCOURSESACTUAL DATEREASON FOR DELAY 1 a b c 2 a b c 3 a b c 4 a b c 5 a b c 6 a b c

20 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 METHODS CYCLESCOURSESACTUAL DATEREASON FOR DELAY 1 a01/06/04 b23/06/04 c30/06/04 2 a08/07/041 day, no beds b30/07/04 c06/08/04 3 a23/08/0410 days, pancytopaenia b13/09/04 c20/09/04 4 a27/09/04 b18/10/04 c25/10/04 5 a06/12/04Surgery on 06/11/04 b20/12/04 cOMITTEDDue to severe mucositis post 5b 6 a08/01/05>7 days, severe mucositis b22/01/05 c29/01/05

21 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 METHODS CYCLESCOURSESACTUAL DATEREASON FOR DELAY 1 a01/06/04 b23/06/04 c30/06/04 2 a08/07/041 day, no beds b30/07/04 c06/08/04 3 a23/08/0410 days, pancytopaenia b13/09/04 c20/09/04 4 a27/09/04 b18/10/04 c25/10/04 5 a06/12/04Surgery on 06/11/04 b20/12/04 cOMITTEDDue to severe mucositis post 5b 6 a08/01/05>7 days, severe mucositis b22/01/05 c29/01/05

22 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 METHODS CYCLESCOURSESACTUAL DATEREASON FOR DELAY 1 a01/06/04 b23/06/04 c30/06/04 2 a08/07/041 day, no beds b30/07/04 c06/08/04 3 a23/08/0410 days, pancytopaenia b13/09/04 c20/09/04 4 a27/09/04 b18/10/04 c25/10/04 5 a06/12/04Surgery on 06/11/04 b20/12/04 cOMITTEDDue to severe mucositis post 5b 6 a08/01/05>7 days, severe mucositis b22/01/05 c29/01/05

23 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 METHODS CYCLESCOURSESACTUAL DATEREASON FOR DELAY 1 a01/06/04 b23/06/04 c30/06/04 2 a08/07/041 day, no beds b30/07/04 c06/08/04 3 a23/08/0410 days, pancytopaenia b13/09/04 c20/09/04 4 a27/09/04 b18/10/04 c25/10/04 5 a06/12/04Surgery on 06/11/04 b20/12/04 cOMITTEDDue to severe mucositis post 5b 6 a08/01/05>7 days, severe mucositis b22/01/05 c29/01/05

24 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 METHODS CYCLESCOURSESACTUAL DATEREASON FOR DELAY 1 a01/06/04 b23/06/04 c30/06/04 2 a08/07/041 day, no beds b30/07/04 c06/08/04 3 a23/08/0410 days, pancytopaenia b13/09/04 c20/09/04 4 a27/09/04 b18/10/04 c25/10/04 5 a06/12/04Surgery on 06/11/04 b20/12/04 cOMITTEDDue to severe mucositis post 5b 6 a08/01/05>7 days, severe mucositis b22/01/05 c29/01/05

25 CTOS, 12 th 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

26 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES Total number of cycles Delayed cyclesIncidence of delay Median delay (range) Regimen A (late adjustment) 9856 57% 7 days (1-28) Regimen B (early adjustment) 7736 47% 7 days (3-27) Both regimens17592 52% 7 days (1-28)

27 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES Total number of cycles Delayed cyclesIncidence of delay Median delay (range) Regimen A (late adjustment) 9856 57% 7 days (1-28) Regimen B (early adjustment) 7736 47% 7 days (3-27) Both regimens17592 52% 7 days (1-28)

28 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES Total number of cycles Delayed cyclesIncidence of delay Median delay (range) Regimen A (late adjustment) 9856 57% 7 days (1-28) Regimen B (early adjustment) 7736 47% 7 days (3-27) Both regimens17592 52% 7 days (1-28)

29 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 INCIDENCE OF DELAYED CHEMOTHERAPY CYCLES

30 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 MTX-INDUCED DELAYS IN CHEMOTHERAPY

31 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 INCIDENCE OF DELAYS PER CYCLE

32 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 CyclesIncidence of delay Median delay (range) Cycle 266.6% (18/27) 7 (3-13) Cycle 363.6% (7/11) 7 (3-10) Cycle 443.5% (10/23) 7 (3-17) Cycle 568.5% (13/19) 9 (4-27) Cycle 644.5% (8/18) 7 (4-13) CyclesIncidence of delay Median delay (range) Cycle 238% (11/29) 7 (5-25) Cycle 370% (7/10) 7 (1-28) Cycle 431% (5/16) 9 (6-15) Cycle 533% (4/12) 6.5 (2-17) Cycle 690% (9/10) 7 (3-16) CyclesIncidence of delay Median delay (range) Cycle 252% (29/56) 7 (3-25) Cycle 366% (14/21) 7 (1-28) Cycle 438.5% (15/39) 7 (3-17) Cycle 555% (17/31) 8 (2-27) Cycle 660.7% (17/28) 7 (3-16) BOTH REGIMENSREGIMEN AREGIMEN B INCIDENCE OF DELAYS PER CYCLE

33 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 AGE AND DELAYED CYCLES

34 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 AGE AND DELAYED CYCLES AGE GROUPSNo patients Reg A + BReg A (late adjustment) Reg B (early adjustment) 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

35 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 AGE AND DELAYED CYCLES AGE GROUPSNo patients Reg A + BReg A (late adjustment) Reg B (early adjustment) 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%)

36 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 AGE AND DELAYED CYCLES AGE GROUPSNo patients Reg A + BReg A (late adjustment) Reg B (early adjustment) 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%)

37 CTOS, 12 th 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

38 CTOS, 12 th Annual Meeting, Venice 2-4 November 2006 EARLY DISCONTINUATION OF MAP AGE, GENDER RECEIVED CYCLES CYCLE 2 (number of days delayed by) CYCLE 3 (number of days delayed by) CYCLE 4 (number of days delayed by) CYCLE 5 (number of days delayed by) CYCLE 6 (number of days delayed by) OMITTED MTX COURSES MAP DISCONTINUA TION 12610n/a79>75cNO 66>7n/a0001cNO 472028STOP 2cYES 201>7STOP 1cYES 322>7 STOP 1c, 2cYES 186>7n/a0001cNO 1763n/a5>7 4cNO 4340107n/aSTOPNOYES 216>7301201cNO 1469>715072cNO 182>7 STOP 1c, 2cYES 166>7n/a0001cNO 1465>77n/a62cNO 21610>7310 2cNO 24301310STOP NOYES 234>701015STOP1cYES

39 CTOS, 12 th 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

40 CTOS, 12 th 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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