Chemotherapy Sequencing Guide – For therapies given on …

1 BevacizumabBleomycinCarboplatinCisplatin CyclophosphamideCytarabineDacarbazineDoc etaxelDoxorubicinEpirubicinEtoposideFlud arabineFluorouracilGemcitabineIfosfamide IrinotecanLeucovorinLiposomalDoxorubicin OxaliplatinMethotrexateMitomycinPaclitax elPemetrexedPralatrexateTopotecanVincris tineVinorelbineBevacizumabI1,B2 BleomycinB1, P2 CarboplatinNo EffectF1, C2No EffectNo EffectT1, C2TT1, C2 TCisplatinNo EffectF1, C2G1, C2TC1, I2EP1, C2 TCyclophosphamideTCytarabineF1, C2 EDacarbazineD1, G2 DocetaxelNo EffectNo EffectNo EffectD1, F2G1, D2I1, D2TI1, D2LD1, D2TD1, O2P1, D2D1, T2 DoxorubicinNo EffectG1, D2No EffectD1, P2 EpirubicinNo EffectG1, E2E1, P2 EtoposideE1, M2No EffectT1, E2E1, V2 FludarabineF1, C2 EFluorouracilF1, C2F1, C2D1, F2No EffectG1, F2I1, F2TL1, F2EO1, D2F1, M2EP1, F2 GemcitabineNo EffectG1, C2D1, G2G1, D2G1, D2G1,E2G1, F2G1, I2G1, O2P1, G2E, TP1, G2E, TV1, G2 IfosfamideI1, D2TI1, P2 IrinotecanI1, B2C1, I2EI1, D2I1, F2TG1, I2No EffectP1, I2 LeucovorinL1, F2EM1, L2 TLiposomalDoxorubicinLD1, D2 TNo EffectLD1, V2 OxaliplatinD1, O2O1, D2G1, O2No EffectP1, O2 MethotrexateNo EffectF1, M2EM1, L2 TMitomycinE1,M2 PaclitaxelB1, P2No EffectP1, C2TC1, P2TD1, P2T, PKE1, P2PK, TNo EffectP1, F2I1, P2P1, I2P1, O2 PemetrexedP1, D2P1, G2E, TPEM1,PralatrexateP1, G2 TopotecanT1, C2T1, C2TD1, T2T, PKT1,E2No EffectVincristineE1,V2 VinorelbineD1, V2TV1, G2LD1, V2No EffectX1, Y2EX1, Y2 See OPTIMAL SEQUENCE directions on how to read the sequence order and Interaction letters.

2 The literature noted no clinical effect from sequence literature supported no difference in order Sequencing with respect to outcome or toxicity. P1, G2E, TDoxo1,Doce2 TDoxo1,Doce2 TTT OPTIMAL SEQUENCE DIRECTIONS FOR USE (valid only for therapies given on the same day)1. Match Chemotherapy agents from either the top or side First initial(s) of each agent used to explain sequence > Example: M + methotrexate, 1 = administer first3. Determine the order of optimal sequence as demonstrated in the following example: > G1, F2 = gemcitabine given first, followed by Fluorouracil given Letter(s) under optimal sequence, T, E, or PK refers to an interaction. Refer to INTERACTION LEGEND at LETTERSIf a letter is present under the optimal sequence symbols, an interaction has been noted in published data.

3 Data is limited to a human, in-vivo interaction with a clear benefit for the optimal sequence administration order. The letter and sequence benefit interaction are summarized at right:T = a TOXICITY related interaction can be avoidedE = EFFICACY related interaction happensPK = a PHARMACOKINETIC related interactionEmpty Box = denotes a lack of evidence in the literature. October 2011 McKesson Specialty Health. All rights , TC1, P2PK, TT, PKPAC2 PEM1,PAC2T, PKD1, V2 TPK, TChemotherapy Sequencing Guide For therapies given on the same day October 2011 McKesson Specialty Health. All rights reserved. Adjei AAReferences:Clinical studies of pemetrexed and gemcitabine combinations Ann Oncol 2006;15(supp 5):v29-v32 Adjei AA, Klein CE, Kastrissios H, et alPhase I and pharmacokinetic study of irinotecan and docetaxel in patients with advanced solid tumors: preliminary evidence of clinical activity JCO 2000;18:1116-1123 Airoldi M, Cattel L, Passera R, et alGemcitabine and oxaliplatin in patients with pancreatic adenocarcinoma: clinical and pharmacokinetic data Pancreas 2006;32:44-50 Airoldi M, Cattel L, Pedani F, et alClinical data and pharmacokinetics of a docetaxel vinorelbine combination in anthracycline resistant/relapsed metastatic breast cancer Acta Oncologica 2003.

4 42:186-194 Airoldi M, Cattel L, Pedani F, et alClinical and pharmacokinetic data of a docetaxel epirubicin combination in metastatic breast cancer Breast Cancer Res Treat 2001;70:185-195 Airoldi M, Cattell L, Marchionatti S, et alDocetaxel and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results Am J Clin Oncology 2003;26:378-381 Alarcon GS, Morgan SLFolinic acid to prevent side effects of methotrexate in juvenile rheumatoid arthritis J Rheumatol 1996;23:2184-2185 Ando M, Saka H, Ando Y, et alSequence effect of docetaxel and carboplatin on toxicity, tumor response and pharmacokinetics in non-small-cell lung cancerpatients: a phase I study of two sequences Cancer Chemother Pharmacol 2005; 55:552-558 Belani CP, Kearns CM, Zuhowski EG, et alPhase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer JCO 1999;17:676-684 Bhargava P, Marshall JL, Fried K, et alPhase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer Cancer Chemother Pharmacol 2001;48:95-103 Bonner JA, Kozelsky TFThe significance of the sequence of administration of topotecan and etoposide Cancer Chemother Pharmacol 1996;39:109-112 Phase 1 pharmacokinetic and pharmacodynamic study of carboplatin and topotecan administered intravenously every 28 days to patients with malignant solid tumors Clin Cancer Res 2009.

5 15:4475-4483 Cattel L, Airoldi M, Passera R, et al gemcitabine plus vinorelbine chemother-apy regimens: a pharmacokinetic study of alternate administration sequences Pharm World Sci 2004;26:238-241 Cattell L, Passera R, Katsaros D, et alegylated liposomal doxorubicin and vinorelbine in recurrent ovarian carcinoma: a pharmacokinetic study on alternate administration sequences Anticancer Res 2006;26:745-750 Cho H, Imada T, Oshima T, et alIn-vitro effect of a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) on human gastric cancer cell lines: timing ofcisplatin treatment Gastric Cancer 2002;5:43-46 Coates AS, Tattersall MH, Swanson C, et alCombination therapy with methotrexate and 5-fluorouracil: a prospective randomized clinical trial of order of administration JCO 1984;2:756-761 Correale P, Cerretani D, Marsili S, et alGemcitabine increases systemic 5-fluorouracil exposure in advanced cancer patients Eur J Cancer 2003;39:1547-1551 Danesi R, Conte PF, Del Tacca MPharmacokinetic optimisation of treatment schedules for anthracyclines and paclitaxel in patients with cancer Clin Pharmacokinet 1999;37:195-211de Jonge MJ, Verweij J, de Bruijn P, et alPharmacokinetic, metabolic, and pharmacodynamic profiles in a dose escalating study of irinotecan and cisplatin JCO 2000;18:195-203de Jonge MJ, Verweij J, Plating AS, et alDrug administration sequence does not change pharmacodynamic and kinetics of irinotecan and cisplatin Clin Cancer Res 1999.

6 5:2012-2017 Denlinger CS, Blanchard R, Xu L, et alPharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors Cancer Chemother Pharmacol May 5, 2009 DiPaola RS, Rubin E, Toppmeyer D, et alGemcitabine combined with sequential paclitaxel and carboplatin in patients with urothelial cancers and other advanced malignancies Med Sci Monit 2003;9:PI5-PI11 Dumez H, Louwerens M, Pawinsky A, et alThe impact of drug administration sequence and pharmacokinetic interaction in a phase I study of the combination of docetaxel and gemcitabine in patients with advanced solid tumors Anticancer Drugs 2002;13:583-593 Dupont J, Aghajanian C, Andrea G, et alTopotecan and liposomal doxorubicin in recurrent ovarian cancer: is sequence important? Int J Gynecologic Cancer 2006;16(suppl 1):68-73 Edelman MJ, Quam H, Mullins BInteractions of gemcitabine , carboplatin and paclitaxel in molecularly defined non-small-cell lung cancer cell lines Cancer Chemother Pharmacol 2001;48:141-144 Esaki T, Nakano S, Tatsumoto T, et alInhibition by 5-fluorouracil of cis-diammine-dichloroplatinum(II)-induce d DNA interstrand cross-link removal in a HST-1 human squamous carcinoma cell line Cancer Res 1992;52:6501-6506 Falcone A, Allegrini G, Masi G, et al5-Fluorouracil administered as a 48-hour chronomodulated infusion in combination with leucovorin and cisplatin: a random-ized phase II study in metastatic colorectal cancer Oncology 2001.

7 61:28-35 Falcone A, Di Paolo A, Masi G, et alSequence effect of irinotecan and fluo-rouracil treatment on pharmacokinetics and toxicity in Chemotherapy na ve metastatic colorectal cancer patients JCO 2001;19:3456-3462 Felip E, Massuti B, Camps C, et alSuperiority of sequential versus concurrent administration of paclitaxel with etoposide in advanced non-small cell lung cancer: comparison of two phase II trials Clin Cancer Res 1998;4:2723-2728 Fleming GF, Roth BJ, Baker SD, et alPhase I trial of paclitaxel and etoposide for recurrent ovarian carcinoma: a Gynecologic Oncology Group Study Am J Clin Oncology 2000;23:609-613 Focan C, Graas MP, Beauduin M, et alSequential administration of epirubicin and paclitaxel for advanced breast cancer, A phase I randomized trial Anticancer Res 2005;25:1211-1217 Forastiere AA, Urba SGSingle agent paclitaxel and paclitaxel plus ifosfamide in the treatment of head and neck cancer Semin Oncol 1995;22:24-27 Fracasso PM, Rodriguez LC, Herzog TJ, et alPhase 1 dose and Sequencing study of pegylated liposomal doxorubicin and docetaxel in patients with advanced malignancies Cancer 2003;98:610-617 Frassineti GL, Zoli W, Tienghi A, et alThe sequential administration of com-bined doxorubicin and paclitaxel in the treatment of advanced breast cancer Semin Oncol 1996;23:22-28 Gandhi V, Kemena A, Keating MJ, et alFludarabine infusion potentiates arabi-nosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia Cancer Res 1992.

8 52:897-903 Giaccone G, Huizing M, Postmus PE, et alDose finding and Sequencing study of paclitaxel and carboplatin in non-small cell lung cancer Semin Oncol 1995;22:78-82 Gianni L, Munzone E, Capri G, et alPaclitaxel by 3-hour infusion in combina-tion with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study JCO 1995;13:2688-2699 Gil-Delgado MA, Bastian G, Guinet F, et alOxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients Am J Clin Oncology 2004;27:294-298 Goel A, Grossbard ML, Malamud S, et alPooled efficacy analysis from a phase I-II study of biweekly irinotecan in combination with gemcitabine , 5-fluorouracil, leuco-vorin and cisplatin in patients with metastatic pancreatic cancer Anticancer Drugs 2007;18:263-271 Han JY, Lim HS, Lee DH, et alRandomized phase II study of two opposite administration sequences of irinotecan and cisplatin in patients with advanced non-small cell lung carcinoma Cancer 2006;106:873-880 Harita S, Watanabe Y, Kiura K, et alInfluence of altering administration sequence of docetaxel, gemcitabine and cisplatin in patients with advanced non-small cell lung cancer Anticancer Res 2006.

9 26:1637-1641 Hervonen P, Jekunen A, Lefebvre P, et alDocetaxel-ifosfamide combination Chemotherapy in patients with metastatic hormone refractory prostate cancer: a phase I pharmacokinetic study Int J Clin Pharmacol Res 2003;23:1-7 Holmes FA, Madden T, Newman RA, et alSequence dependent alteration of dox-orubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxoru-bicin in patients with metastatic breast cancer JCO 1996;14:2713-2721 Hotta K, Ueoka H, Kiura K, et alA phase I study and pharmacokinetics of irinotecan (CPT-11) and paclitaxel in patients with advanced non-small cell lung cancer Lung Cancer 2004;45:77-84 Huisman C, Postmus PE, Giaccone G, et alA phase I study of sequential intravenous topotecan and etoposide in lung cancer patients Ann Oncol 2001;12:1567-1573 Huizing MT, Giaccone G, van Warmerdam LJ, et alPharmacokinetics of paclitaxel and carboplatin in a dose escalating and dose Sequencing study in The European Cancer Centrepatients with non-small-cell lung cancer JCO 1997;15:317-329 Itoh K, Sasak Y, Fujii H, et alStudy of dose escalation and sequence switching of administration of the combination of docetaxel and doxorubicin inadvanced breast cancer Clin Cancer Res 2000;6:4082-4090 Jolivet JRole of leucovorin dosing and administration schedule Eur J Cancer 1995;31A:1311-1315 Joyce DA, Will RK, Hoffman DM, et alExacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid Ann Rheum Dis 1991;50:913-914 Juergens R, Brahmer J, Ettinger DGemcitabine and vinorelbine in recurrent advanced