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,

Slides:

Advertisements

Similar presentations

Palumbo A et al. Proc ASH 2013;Abstract 536.

Advertisements

Oncologic Drugs Advisory Committee

Delayed Neurotoxicity The cumulative risk at 5 years to develop overt dementia is 24-30% (1,2). For patients aged >60 year the risk of dementia at 7 years.

CARBON ION THERAPY FOR SACRAL CHORDOMAS

Brown JR et al. Proc ASH 2013;Abstract 523.

Treatment in Advanced Non-Small Cell Lung Cancer.

“ Handle with Care” A GP guide to cancer care for elderly patients.

Overview of Methotrexate Clinical Evaluations Malcolm Smith, MD, PhD Cancer Therapy Evaluation Program National Cancer Institute FDA Pediatric ODAC Meeting.

Introduction Discussion CT abdomen 3/3/06 lightheadedness and watery diarrhea. TSH was again less than 0.01, and ACTH less than 5. AST and ALT were 240.

JOURNAL CLUB  HIGH-DOSE RAPID AND STANDARD INDUCTION CHEMOTHERAPY FOR PATIENTS AGED OVER 1 YEAR WITH STAGE 4 NEUROBLASTOMA: A RANDOMISED TRIAL † Lancet.

Mary McCormack & Jonathan Ledermann NCRI Gynae Clinical Studies Group.

Hot topics in breast radiotherapy Mark Beresford.

PREOPERATIVE HYPOFRACTIONED RADIOTHERAPY IN LOCALIZED EXTREMITY/TRUNK WALL SOFT TISSUE SARCOMAS EARLY STUDY RESULTS Hanna Kosela; Milena Kolodziejczyk;

Pulmonary Metastasis From Osteosarcoma Multi-factorial analysis of survival at first lung involvement Ali Aljubran, Martin Blackstein for the University.

Hypofractionated Radiation Therapy for Early Stage Breast Cancer Patrick J. Gagnon, M.D. Resident, PGY-4 Radiation Medicine, OHSU Providence Hospital Breast.

1Stopeck A et al. Proc SABCS 2010;Abstract P

Renal Safety of Zoledronic Acid in Patients With Breast Cancer.

1 Phase II trial of sequential gemcitabine and carboplatin followed by paclitaxel as first-line treatment of advanced urothelial carcinoma Presented by.

Effect of Age on Efficacy and Safety Outcomes in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide and Low-Dose Dexamethasone.

Taxane-pretreated metastatic breast cancer (MBC): investigational agents TTP = median time to disease progression OS = median overall survival.

SPINDLE CELL SARCOMA OF BONE AN ASSESSMENT OF OUTCOME

State of the Art: Gestational Trophoblastic Lesions Treatment beyond single agents Barry Hancock (Sheffield, UK) International Gynecologic Society Meeting.

Taiwan 2000 Should all patients be treated with adjuvant and/or neoadjuvant treatment? Arnaud Roth MD Oncosurgery Geneva Switzerland Gastric Barcelona.

Arsenic Trioxide (ATO) in the Consolidation Treatment of Newly Diagnosed APL — First Interim Analysis of a Randomized Trial (APL 2006) by the French Belgian.

MANAGEMENT OF MANTLE CELL LYMPHOMA IN TUNISIA R BEN LAKHAL, L KAMMOUN, K ZAHRA, S KEFI Sousse 25 MAY 2012.

Results: In the presence of PD measurements, PK data provided little additional information. By a limited PD sampling the number of patients on target.

Prevention of Pegfilgrastim-induced Bone Pain (PIP): A URCC CCOP Randomized, Double-blind, Placebo-controlled Trial of 510 Cancer Patients Jeffrey J. Kirshner,

Quantitative Dosimetric Analysis Of Patterns Of Local Relapse After IMRT For Primary Extremity Soft Tissue Sarcomas Ryan M. Lanning, Sean L. Berry, Michael.

Results of Docetaxel Plus Oxaliplatin (DOCOX) +/- Cetuximab in Patients with Metastatic Gastric and/or Gastroesophageal Junction Adenocarcinoma: Results.

HOW CAN WE TAILOR DRUG DOSES IN EWING’S SARCOMA TO MAXIMISE BENEFIT AND MINIMISE SIDE EFFECTS?

K30 Case Presentation David Andorsky August 26, 2008.

The more it hurts, the better it works?

Axel Grothey, MD Professor of Oncology Mayo Clinic Rochester, Minnesota Strategies to Improve Patient Outcomes in Gastric and Gastroesophageal Junction.

Taiwan 2000 Comparative evaluation in tolerance of neoadjuvant versus adjuvant docetaxel based chemotherapy in resectable gastric cancer in a randomized.

L Johnetta Blakely, SR Patel, PF Thall,

A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of newly diagnosed diffuse large B cell lymphoma Results from a UK NCRI Lymphoma.

Introduction Osteosarcoma is the most common primary bone tumor diagnosed in childhood and adolescence, with peak incidence from ages 12-16; overall survival.

Preliminary Results from a Phase II study of FOLFIRI and Bevacizumab as First Line Treatment for Metastatic Colorectal Cancer (Abstract #3579) S. Kopetz,

Correlation of Hand-Foot Skin Reaction (HFS) with Treatment Efficacy in Pancreatic Cancer (PC) Patients (pts) Treated with Gemcitabine/Capecitabine plus.

. Background Paclitaxel and Irinotecan in Platinum Refractory or Resistant Small Cell Lung Cancer: a Galician Lung Cancer.

High Dose Rate Brachytherapy Boost for Prostate Cancer: Comparison of Two Different Fractionation Schemes Tania Kaprealian 1, Vivian Weinberg 3, Joycelyn.

Phase II trial of chemotherapy with high-dose FOLFIRI plus bevacizumab in the front-line treatment of patients with metastatic colorectal cancer (mCRC)

Inotuzumab Ozogamicin (IO; CMC544), a CD22 Monoclonal Antibody Attached to Calicheamycin, Produces Complete Response (CR) plus Complete Marrow Response.

Safety and Efficacy of Abbreviated Induction with Oral Fludarabine (F) and Cyclophosphamide (C) Combined with Dose-Dense IV Rituximab (R) in Previously.

Cooperative Clinical Trials with 13-Cis-Retinoic Acid in Neuroblastoma Katherine K. Matthay, M.D University of California, San Francisco Children’s Oncology.

Carboplatin and Creatinine Have we got it right?

Valerae O. Lewis HA Macapinlac Kevin Raymond Patrick Lin Alan Yasko

Low Dose Decitabine Versus Best Supportive Care in Elderly Patients with Intermediate or High Risk MDS Not Eligible for Intensive Chemotherapy: Final Results.

Journal Club Dr. Eyad Al-Saeed Radiation Oncology 12 January, 2008.

Brentuximab Vedotin in Combination with RCHOP as Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study Yasenchak CA et al. Proc.

Erlotinib Therapy in Non Small Cell Lung Cancer Patients - Survival of Patients on Reduced Erlotinib Doses M. Pesek 1, J. Krejci 1, J. Skrickova 2, P.

Mok TS, Wu SL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361: Gefitinib Superior.

Gemcitabine with Cisplatin or Paclitaxel in Metastatic Triple-negative Breast Cancer Xi-Chun Hu*, Binghe Xu, Li Cai, Zhong Hua Wang, Biyun Wang, Jian Zhang,

What Factors Predict Outcome At Relapse After Previous Esophagectomy And Adjuvant Therapy in High-Risk Esophageal Cancer? Edward Yu 1, Patricia Tai 5,

University of Auckland Nursing 785 Assignment 3. Marc McLaughlin

Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma: Final Results of the Phase Ib/II Ro-CHOP Study Dupuis J et al. Proc ASH.

Outcomes for Elderly, Advanced-Stage Non–Small-Cell Lung Cancer Patients Treated With Bevacizumab in Combination With Carboplatin and Paclitaxel: Analysis.

Phase I/II CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC

Results from the International, Randomized Phase 3 Study of Ibrutinib versus Chlorambucil in Patients 65 Years and Older with Treatment-Naïve CLL/SLL (RESONATE-2TM)1.

Abhishek Joshi1,2, Sabe Sabesan1,2, Suresh Varma1, Zulfiquer Otty1.

Comparative Toxicity Profiles of Two Platinum Doublets: Real Life Experience from a Cancer Unit Jessop S, Jeffs Y P, Thomas E, Azher M, Adu Poku K, Sa'D.

Outcomes of patients in the North Trent region with advanced non-small-cell lung cancer treated with maintenance pemetrexed following induction with platinum.

Treatment With Continuous, Hyperfractionated, Accelerated Radiotherapy (CHART) For Non-Small Cell Lung Cancer (NSCLC): The Weston Park Hospital Experience.

Causal inference with RCTs of chemotherapy

Niesvizky R et al. Proc ASH 2010;Abstract 619.

Nat. Rev. Clin. Oncol. doi: /nrclinonc

Predictive Performance of a Myelosuppression Model for Dose Individualization; Impact of Type and Amount of Information Provided Johan E. Wallin, Lena.

Published online Feb 7, 2019 Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling:

Proton Therapy for Thymic Malignancies: Multi-institutional Patterns-of-Care and Early Clinical Outcomes from the Proton Collaborative Group Registry &

Presentation transcript:

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

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

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)

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

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

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

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

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

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

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

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

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 HIGH-DOSE METHOTREXATE 16HIGH-DOSE METHOTREXATE 4 17ADRIAMYCIN + CISPLATIN HIGH-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)

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

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 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, 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

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

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

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

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

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

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

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

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

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

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) % 7 days (1-28) Regimen B (early adjustment) % 7 days (3-27) Both regimens % 7 days (1-28)

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) % 7 days (1-28) Regimen B (early adjustment) % 7 days (3-27) Both regimens % 7 days (1-28)

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) % 7 days (1-28) Regimen B (early adjustment) % 7 days (3-27) Both regimens % 7 days (1-28)

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

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

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

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

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

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) years (median: 20.5 yrs) years (median: 34 yrs) 9 >40 years (median: 45 years) 2

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%) years (median: 20.5 yrs) 26 43/70 (61.4%) 29/40 (72.5%)14/30 (46.6%) 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, 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%) years (median: 20.5 yrs) 26 43/70 (61.4%) 29/40 (72.5%)14/30 (46.6%) 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, 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

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 STOP 2cYES 201>7STOP 1cYES 322>7 STOP 1c, 2cYES 186>7n/a0001cNO 1763n/a5>7 4cNO n/aSTOPNOYES 216> cNO 1469>715072cNO 182>7 STOP 1c, 2cYES 166>7n/a0001cNO 1465>77n/a62cNO 21610>7310 2cNO STOP NOYES 234>701015STOP1cYES

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

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