Supplementary webappendix

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1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009; 373:

2 Webappendix Patient Flow Diagram Total received: n=14206 patients, 53 studies n=14042 patients, 53 studies n=13944 patients, 53 studies N=13936 patients, 53 studies Exclusion of patients without allocated study arm Study (n=162) Study (n=1) Study (n=1) Exclusion of ineligible study stratum: study 80515, 3 children with Acute Lymphatic Leukemia (ALL), Non Hodgkin Lymphoma (NHL) in stratum 1 (n=98); patients with Hodgkin s Disease (HD) and solid tumors in stratum 2; stratum 1 was excluded. For studies where the data of randomization was missing for all patients (study ), the date of randomization was replaced with the date of first study drug as provided by the company. For studies where only single patients had no date of randomization the patients were excluded from the analysis. Study (n=1) Study (n=4) Study (n=3) If both date of randomization and date of first study drug were missing (see above) patients were excluded; study (n=3) Total included: N=13933 patients, 53 studies References 1. Osterborg A, Brandberg Y, Molostova V et al. Randomized, double-blind, placebocontrolled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 2002;20(10): Osterborg A, Boogaerts MA, Cimino R et al. Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-hodgkin s lymphoma - a randomized multicenter study. Blood 1996;87(7):

3 3. Razzouk BI, Hord JD, Hockenberry M et al. Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy. J Clin Oncol 2006;24(22): Boogaerts M, Coiffier B, Kainz C, and the Epoetin beta QOL Working Group. Impact of epoetin beta on quality of life in patients with malignant disease. Br J Cancer 2003;88(7): Luksenburg H, Weir, A, and Wager R. INT-3 in: Safety concerns associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the treatment of anemia associated with cancer chemotherapy Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Oncologic Drugs Advisory Committee. 6. Untch M, Fasching PA, Bauerfeind I et al. PREPARE trial. A randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF with a standard dosed epirubicin/cyclophosphamide followed by paclitaxel +/- darbepoetin alfa in primary breast cancer: A preplanned interim analysis of efficacy at surgery. J Clin Oncol 2008;26(Suppl.):Abstract Cazzola M, Messinger D, Battistel V et al. Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-hodgkin s lymphoma: dose finding and identification of predictors of response. Blood 1995;86(12):

4 Table 1: Study characteristics Study author Study number n Drug Dosage Chemotherapy trials Leyland-Jones 2003 & 2005 [full text] 1, Epoetin Untch 2008 [abstract] 3 Moebus 2007 [abstract] 4 Pirker 2008 [full text] 5 Aapro 2008 [full text] 6 Milroy 2003 [abstract] 7 Taylor 2005 [abstract] Darbepoetin Epoetin Darbepoetin Epoetin beta Epoetin Darbepoetin 1 x 40,000 IU qw sc 1 x 4.5 µg/kg/ q2w sc 3 x 150 IU/kg qw sc 1 x 300 µg QW sc weeks 1-4 then 300 µg q3w starting week 5 onwards 1 x 30,000 IU qw sc if body weight > 45 kg 3 x 10,000 IU qw sc, if body weight < 45 kg 3 x 5,000 IU qw sc 1 x 300 µg q3w sc Hb ceiling Hb Hb 13 Hb Hb Hb Hb (women), Hb g/dl (men) Hb Planned ESA treatment duration Cancer details 52 weeks Breast cancer (stage IV, M1) during chemotherapy during chemotherapy Breast cancer (M0) Breast cancer (high risk, stage II/IIIA; M0) 19 weeks SCLC (untreated, extensive stage) 24 weeks Breast cancer (M1) during chemotherapy NSCLC (stage IIIb or IV, advanced) 15 weeks Non myeloid cancers, breast, lung, haematological, gastrointestinal, genitourinary, Primary and secondary outcomes of the study Primary: overall survival; secondary : Hb, transfusion, tumour control, QoL, time to progression Primary: relapse free survival time, overall survival; secondary: tumour control, safety and tolerability, transfusion, Hb level, QoL Primary: transfusion, Hb; secondary: recurrence free survival, overall survival, relapse, QoL Primary: Hb change, survival; secondary: QoL, progressionfree-survival, tumour response, time to progression, transfusion Primary: overall survival; secondary: progression free survival, tumour response rate, QoL Primary: QoL; secondary: Hb, tumour response, survival, transfusion Primary: transfusion; secondary: Hb target achieved, number of transfusions, safety, QoL 3

5 gynecological, other, (stage I- IV) Littlewood 2001 [full text] 9 Chang 2005 [full text] 10 Hedenus 2003 [full text] 11 Osterborg 2002 [full text] 12 Witzig 2005 [ full text] 13 Vansteenkiste 2002 [full text] 14 Savonije 2005 [full text] 15 Boogaerts 2003 [full text] Epoetin Epoetin Darbepoetin Epoetin beta Epoetin Darbepoetin Epoetin Epoetin beta 3 x 150 IU/kg qw sc 1 x 40,000 IU qw sc 1 x 2.25 µg/kg/ qw sc 3 x 150 IU/kg qw sc 1 x 40,000 IU qw sc 1 x 2.25 mg/kg qw sc 3 x 10,000 IU qw sc 3 x 150 IU/kg/wk sc Hb Hb Hb (women), Hb g/dl (men) Hb Hb Hb (women), Hb (men) Hb Hb during chemotherapy during chemotherapy Breast cancer, NHL, MM, HD, CLL, GI, other Breast cancer (stage I-IV) 12 weeks HD, NHL, MM, CLL, Waldenstrom s disease Primary: transfusion; secondary: Hb, Hct, reticulocytes, predictors for response, QoL, after protocol amendment also survival Primary: QoL; secondary: maintain Hb above 12, tumour response, overall survival Primary: Hb response; secondary: transfusion, Hb change, QoL, safety 16 weeks MM, NHL, CLL Primary: transfusion free survival; secondary: Hb response, time to response, number of blood transfusions, QoL, safety 16 weeks Lung cancer, breast cancer, other cancers, active incurable advanced stage 12 weeks SCLC (limited and extensive), and non-sclc (stage I-IV) during chemotherapy NSCLC, gastrointestinal, gynecological, colorectal, SCLC, other 12 weeks MM, NHL, CLL, HD, ovarian, bone, gastrointestinal, respiratory, Primary: transfusion; secondary: Hb change, hemoglobin over time, predictors for response, incidence of nephrotoxicity, overall survial, tumour response, QoL Primary: transfusion; secondary: Hb response, Hb, transfusion timing and quantity, QoL Primary: transfusion; secondary: Hb, tumour response, QoL, survival Primary: QoL; secondary: direct and indirect costs 4

6 other Kotasek 2003 [full text] 17 Unpublished [ODAC] 18 Oberhoff 1998 [full text] 19 Grote 2005 [full text] 20 Prozanto 2002 [abstract] 21 Ray-Coquard 2006 [abstract] Darbepoetin Epoetin Epoetin beta Epoetin Epoetin Epoetin a: 1 x 4.5 g/kg Q3W, b: 1 x 6.75 g/kg Q3W, c: 1 x 9 g/kg Q3W, d: 1 x 12 g/kg Q3W, e: 1 x 13.5 g/kg Q3W, f:1 x 15 g/kg Q3W sc a: 3 x 150 IU/kg qw sc; b: 3 x 300 IU/kg qw sc 7 x 5,000 IU qw sc 3 x 150 IU/kg qw sc if body weight > 45 kg 3 x 10,000 IU if body weight < 45 kg 2 x 10,000 IU qw sc, if body weight 45 kg to < 89 kg 3 x 10,000 IU qw sc, if bodyweight > 89 kg 4 x 10,000 IU qw sc Hb 13-14, Hb Hb 12.5 to 14 Hb 14 Hb Hb 14 Hb weeks Solid cancers: breast, gynecological, gastrointestinal, lung, genitourinary, other (stages I- IV, most patients advanced) during chemotherapy Ovarian cancer (FIGO stage I- IV) 12 weeks Solid tumours; ovarian, breast, lung, genitourinary, gastrointestinal, other during chemotherapy during chemotherapy SCLC, limited and extensive disease Breast cancer (stage I-IV) 12 weeks Breast, sarcoma, lung, ovarian, and other solid and haematological malignancies Primary: safety; secondary: determine effective dose, effect of ESA, QoL feasibilty Primary: transfusion; secondary: Hb change, Hct, QoL Primary: transfusion ; secondary: Hb response, safety Primary: assess possible stimulatory effects of ESA on solid tumour growth, tumour response, secondary: overall survival, Hb, transfusion, safety Primary: QoL, secondary: Hb change, tumour response Primary: transfusion dependent anaemia, secondary: QoL, Hb response predictors, Hb, toxicity, survival, costs 5

7 Unpublished [ODAC] 23 Wilkinson 2006 [full text] 24 Kotasek 2002 [abstract] 25 Case 1993 [full text] 26 Osterborg 1996 [full text] 27 Dammacco 2001 [full text] 28 Cazzola 1995 [full text] 29 Henry 1995 [ full text] Epoetin Epoetin Darbepoetin Epoetin Epoetin beta Epoetin Epoetin beta Epoetin 3 x 150 IU/kg qw sc if body weight > 45 kg patients received 3 x 10,000 IU or 150 IU/kg qw a: 1 x 9 g/kg Q4W, b: 1 x 12 g/kg Q4W, c: 1 x 15 g/kg Q4W, d: 1 x 18 g/kg Q4W sc 3 x 150 IU/kg qw sc a: 7 x 10,000 IU/wk sc, b: titration 3 x 150 IU/kg qw sc a: 7 x 1,000 IU qw, b:7 x 2,000 IU/wk sc; c: 7 x 5,000 IU/wk sc; d: 7 x 10,000 IU/wk sc 3 x 150 IU/kg qw sc Hb (women), Hb g/dl (men) Hb Hb (women), Hb g/dl (men) Hct 38%- 40% Hb Hb Hb 13 (MM), Hb 15 (NHL) Hct 38%- 40% 12 weeks Breast cancer, NHL, MM, ovarian cancer, SCLC, other during chemotherapy Ovarian cancer (FIGO stage I- IV) 12 weeks Solid tumours including lung, breast, gastrointestinal, genitourinary, gynecological, other (stage I- IV) 12 weeks Solid and haematological tumours Primary: Transfusion; secondary: Hb, QoL Primary: Hb response; secondary: QoL, transfusion, tumour reponse Primary: safety; secondary: determine effective dose, effect of ESA, QoL feasibility transfusion, Hct; QoL, safety 24 weeks MM, NHL, CLL Primary: transfusion; secondary: safety, Hb 12 weeks Multiple myeloma Primary: Transfusion; secondary: Hb, Hct, reticulocytes, serum erythropoietin levels, QoL 8 weeks MM, NHL Primary: Hb response; secondary: Hb, Hct, reticulocytes, iron, ferritin, safety 12 weeks Solid and haematological tumours Primary: Hct, transfusion;; secondary: correction of anaemia, response to therapy, QoL, safety 6

8 Thatcher 1999 [full text] 31 Thomas 2002 [abstract] 41 Razzouk 2006 [full text] 32 Ten Bokkel 1998 [full text] 33 O'Shaughnessy 2005 [full text] Epoetin Epoetin Epoetin Epoetin beta Epoetin a: 3 x 150 IU/kg qw, b: 3 x 300 IU/kg qw sc if body weight > 45 kg 3 x 10,000 IU qw sc, if body weight < 45 kg 3 x 5,000 IU qw sc 1 x 600 IU/kg qw iv a: 3 x 150 IU/kg qw, b: 3 x 300 IU/kg qw sc 1 x 40,000 IU qw sc Hb Hb Hb (age > 12 years), Hb (age <12 years) Hb Hb weeks SCLC efficacy, safety, QoL 12 weeks "cancer patients receiving platinum and non platinum chemotherapy" 16 weeks Solid tumours, Hodgkin's disease, non- Hodgkin's disease, ALL during chemotherapy during chemotherapy Ovarian cancer (stage II-IV) Neoadjuvant breast cancer (stage I, II, IIIB) Primary: Hb response; secondary: QoL,, tumour response, survival, safety Primary: QoL; secondary: Hb, transfusion Primary: transfusion; secondary: Hb, reticulocytes, Hct, safety Primary: cognitive function, fatigue; secondary: QoL, Huddart 2002 [abstract] Epoetin Unpublished Epoetin Unpublished Epoetin 3 x 10,000 IU qw sc 3 x 10,000 IU qw sc 1x 40,000 IU qw sc Hb Hb Hb during chemotherapy during chemotherapy during chemotherapy "cancer patients receiving non platinum chemotherapy" SCLC, extensive stage Multiple myeloma Hb response, reticulocyte, survival, QoL, safety Primary: rate of patients with anaemia; secondary: QoL, tolerability of ESA, transfusion, effectiveness of chemotherapy, antibodies Primary: Hb change; secondary: QoL, Hb response, transfusion, safety Quirt 1996 [abstract] 39 Radiochemotherapy trials Epoetin 3 x 150 IU/kg qw sc Hb weeks Lymphoma, solid tumours Primary: transfusion: secondary: QoL, costs from societal perspective, tumour response 7

9 Debus 2006 [abstract] 40 Thomas 2008 [full text] 34 Goss 2005 [abstract] 42 Strauss 2007 [full text] 43 Vadhan-Raj 2004 [abstract] Epoetin Epoetin Epoetin Epoetin beta Epoetin 1 x 40,000 IU qw sc 1 x 40,000 IU qw sc 1 x 40,000 IU qw sc 3 x 150 IU/kg qw sc 1 x 40,000 IU qw sc Hb Hb Hb 14-16, in 10/2002 reduced to Hb Hb Hb during chemotherapy and radiotherapy during chemotherapy during chemotherapy NSCLC (stage III, primarily inoperable) Cervix carcinoma (stage IIB to IV A, M0) SCLC, limited disease 12 weeks Cervical cancer (stage IIB-IVA) 16 weeks Gastric or rectal cancer (stage I-III) Primary: 2-yearsurvival rate; secondary: tumour response, QoL, tolerance to epoetin, Hb change, transfusion, safety Primary: progression-free survival; secondary: overall survival, local control, distant recurrences, TVEs Disease progression free survival, tumour response, overall survival, local disease progression, Hb, transfusion, QoL Primary: tumour control failures; secondary: progression-free survival, overall response rate, frequency and localisation of relapses/metastases, overall survival, Hb change, QoL, safety Primary: transfusions; secondary: maintain Hb levels, QoL, tumour response, safety Radiotherapy trials Henke 2003 [full text] Epoetin beta Unpublished [ODAC] Epoetin 3 x 300 IU/kg qw sc if hb < 12.5 then 3 x 10,000 IU qw sc; if hb > 12.5 then 3 x 4,000 IU qw sc Hb >14 (women), Hb > 15 (men) Hb during radiotherapy during chemotherapy Head and neck cancer (advanced, stage III, IV) Head and neck cancer (stage I- IV) Primary: efficacy of radiotherapy, measured as local progression free survival; secondary: survival, progression free survival, Hb, safety and tolerability Primary: local disease free survival; secondary: overall survival, QoL,, safety 8

10 Machtay 2007 [full text] Epoetin No anticancer therapy Smith 2008 [full text] Darbepoetin Charu 2007 [full text] 49 Gordon 2006 [abstract] 50 Abels 1993 [full text] Darbepoetin Darbepoetin Epoetin 1x 40,000 IU qw sc 1 x 6.75 µg/kg/ q4w sc 1 x 3.0 µg/kg/ q2w sc 1 x 6.75 µg/kg/ q4w sc 3 x 100 IU/kg qw sc Hb (female), Hb (male) Hb Hb (women), Hb (men) Hb not reported 8 weeks Head and neck cancer (stage I- IV) 16 weeks Various different solid and haematological malignancies (stage III- IV) 12 weeks Lymphoma, breast, lung, gastrointestinal, genitourinary, gynecologic, other 16 weeks Non myeloid cancers, breast, haematologic, GI, genitourinary, lung, gynecological, other (stage I- IV) 8 weeks Solid and haematological tumours Primary: local regional control tumour response; secondary: overall survival, patterns of failure, local-regional progression-free survival, Hb, toxicity, QoL Primary: transfusion; secondary: Hb, QoL, safety Primary: hospitalization days; secondary: costs, QoL, transfusion, Hb, safety Primary: Hb response; secondary: transfusion, Hb change, QoL, safety Primary: transfusion, Hct; secondary: QoL, safety Wright 2007 [full text] Epoetin 1 x 40,000 IU qw sc Hb weeks NSCLC (advanced stages IIIA, B and IV, recurrent disease) Primary: QoL; secondary: hb, Hct, transfusion, safety Other Rose 1994 [abstract] 53 Unpublished [ODAC] Epoetin Epoetin 3 x 150 IU/kg qw sc 3 x 150 IU/kg qw sc Hct 38%- 40% Hct 38%- 40% 12 weeks CLL (stage III, IV) 12 weeks CLL (any RAI stage) Primary: Hct; secondary: transfusion, QoL, safety Primary: Hct: secondary: Hb, transfusion, QoL, safety References 9

11 1 Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003;4: Leyland-Jones B, Semiglazov V, Pawlicki M et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly non anemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 2005;23(25): Untch M, Fasching PA, Bauerfeind I et al. PREPARE trial. A randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF with a standard dosed epirubicin/cyclophsophamide followed by paclitaxel +/- darbepoetin alfa in primary breast cancer: A preplanned interim analysis of efficacy at surgery. J Clin Oncol 2008;26(Suppl.):Abstract Moebus V, Lueck H, Thomssen C et al. The impact of epoetin- on anemia, red blood cell (RBC) transfusions, and survival in breast cancer patients (pts) treated with dose-dense sequential chemotherapy: Mature results of an AGO phase III study (ETC trial). J Clin Oncol 2007;25(18S):Abstract Pirker R, Ramlau RA, Schuette W et al. Safety and efficacy of darbepoetin in previously untreated extensive-stage small-cell lung cancer treated with platinum plus etoposide. J Clin Oncol 2008;26(14): Aapro M, Leonard RC, Barnadas A et al. Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy: results of the Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study. J Clin Oncol 2008;26(4): Milroy R, Scagliotti G, van den Berg PM et al. Early intervention with epoetin alfa maintains hemoglobin (Hb) in advanced non-small cell lung cancer (NSCLC) patients. Lung Cancer 2003;41. 8 Taylor K, Ganly P, Charu V, DiBenedetto J, Kracht K, Rossi G. Randomized, doubleblind, placebo-controlled study of darbepoetin alfa every 3 weeks for the treatment of chemotherapy-induced anemia. Blood 2005;106(11):Abstract Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19(11): Chang J, Couture F, Young S, McWatters KL, Lau CY. Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 2005;23(12): Hedenus M, Adriansson M, San Miguel J et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 2003;122(3):

12 12 Osterborg A, Brandberg Y, Molostova V et al. Randomized, double-blind, placebocontrolled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 2002;20(10): Witzig TE, Silberstein PT, Loprinzi CL et al. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 2005;23(12): Vansteenkiste J, Pirker R, Massuti B et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002;94(16): Savonije JH, van Groeningen CJ, Van Bochove A et al. Effects of early intervention with epoetin alfa on transfusion requirement, hemoglobin level and survival during platinum-based chemotherapy: Results of a multicenter randomised controlled trial. Eur J Cancer 2005;41(11): Boogaerts M, Coiffier B, Kainz C, and the Epoetin beta QOL Working Group. Impact of epoetin beta on quality of life in patients with malignant disease. Br J Cancer 2003;88(7): Kotasek D, Steger G, Faught W et al. Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study. Eur J Cancer 2003;39(14): Luksenburg H, Weir A, Wager R. INT-1 in: Safety Concerns Associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the Treatment of Anemia Associated with Cancer Chemotherapy Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Oncologic Drugs Advisory Committee. 19 Oberhoff C, Neri B, Amadori D et al. Recombinant human erythropoietin in the treatment of chemotherapy- induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study. Ann Oncol 1998;9(3): Grote T, Yeilding AL, Castillo R et al. Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2005;23(36): Prozanto P, Cortesi E, van der Rijt K et al. Early intervention with epoetin alfa in breast cancer (BC) patients (pts) undergoing chemotherapy (CT): results of a randomized, multicenter, phase IIIb study (EPO-INT-47 Study Group). Ann Oncol 2002;13(Suppl. 5):

13 22 Ray-Coquard I, Perol D, Debourdeau P et al. ELYPSE 4: A prospective randomized trial comparing Epo A in primary prophylaxis of severe anemia requiring red cells transfusion in high risk patients. Ann Oncol 2006;17(Suppl. 9):ix Luksenburg H, Weir A, Wager R. INT-3 in: Safety Concerns Associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the Treatment of Anemia Associated with Cancer Chemotherapy Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Oncologic Drugs Advisory Committee. 24 Wilkinson PM, Antonopoulos M, Lahousen M, Lind M, Kosmidis P. Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomised trial. Br J Cancer 2006;94(7): Kotasek D, Albertsson M, Mackey J. Randomized, double-blind, placebo-controlled, dose-finding study of darbepoetin alfa administered once every 3 (Q3W) or 4 (Q4W) weeks in patients with solid tumors. Proc Am Soc Clin Oncol 2002;21:Abstract Case DC, Bukowski RM, Carey RW et al. Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. J Natl Cancer Inst 1993;85(10): Osterborg A, Boogaerts MA, Cimino R et al. Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-hodgkin s lymphoma - a randomized multicenter study. Blood 1996;87(7): Dammacco F, Castoldi G, Rodjer S. Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma. Br J Haematol 2001;113(1): Cazzola M, Messinger D, Battistel V et al. Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-hodgkin s lymphoma: dose finding and identification of predictors of response. Blood 1995;86(12): Henry DH, Brooks BJ, Case DC et al. Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy. Cancer Sci Am 1995;1: Thatcher N, De Campos ES, Bell DR et al. Epoetin prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999;80(3-4): Razzouk BI, Hord JD, Hockenberry M et al. Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy. J Clin Oncol 2006;24(22): Ten Bokkel Huinink WW, De Swart CA, Van Toorn DW et al. Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin 12

14 on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy. Med Oncol 1998;15(3): Thomas G, Ali S, Hoebers FJ et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 120 with erythropoietin vs above 100 without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 2008;108(2): O'Shaugnessy J, Vukelja SJ, Holmes FA et al. Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. Clin Breast Cancer 2005;5(6): Huddart RA, Welch RS, Chan S, Perren T, Atkinson R. A prospective randomised comparative-group evaluation of epoetin alfa for the treatment of anaemia in UK cancer patients receiving platinum-based chemotherapy. Ann Oncol 2002;13(Suppl. 5): unpublished. EPO-GER-20. Prospective, randomized, controlled, open phase-iv study on the treatment of small cell lung cancer (SCLC) in the extensive disease (ED) stage per VALGB classification with doxorubicin, cyclophosphamide, etoposide (ACE Regimen) 38 unpublished. A randomised comparison of the effect of maintaining haemoglobin levels with weekly epoetin alfa or with conventional anaemia management in subjects with Multiple Myeloma undergoing chemotherapy (EMMY); Protocol No: OBE/EPO-INT Quirt I, Couture F, Pichette R, Olweny C, White D, King M. The role of recombinant human erythropoietin (EPO) in reducing red blood cell transfusions and maintaining quality of life (QOL) in patients with lymphoma and solid tumors receiving cytotoxic chemotherapy. Results of a randomized, double-blind, placebo-controlled clinical trial. Blood 1996;88(10 Suppl. 1):347a. 40 Debus J, Hindermann S, Morr H et al. Epoetin alfa (EPO) and survival in patients with non-resectable NSCLC-Interim results. 27th Congress of the German Cancer Society Thomas H, McAdam KF, Thomas RJ et al. Early intervention with epoetin alfa for treatment of anaemia and improvement of quality of life in cancer patients undergoing myelotoxic chemotherapy. Ann Oncol 2002;13(Suppl. 5): Goss G, Feld R, Bezjak A et al. Impact of maintaining Hb with epoetin alfa on time to progression (TTP), overall survival (OS), quality of life (QoL), and transfusion reduction in limited disease SCLC patients. Lung Cancer 2005;49(Suppl. 2):S Strauss HG, Haensgen G, Dunst J et al. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer. Int J Gynecol Cancer

15 44. Vadhan-Raj S, Skibber JM, Crane C et al. Randomized, double-blind, placebocontrolled trial of epoetin alfa (Procrit) in patients with rectal and gastric cancer undergoing chemo-radiotherapy (CT/RT) followed by surgery: early termination of the trial due to increased incidence of thrombo-embolic events (TEE). Blood 2004;104(11):2915a. 45 Henke M, Laszig R, Ruebe C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebocontrolled trial. Lancet 2003;362: Luksenburg H, Weir A, Wager R. EPO GBR-07 in: Safety concerns associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the treatment of anemia associated with cancer chemotherapy Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Oncologic Drugs Advisory Committee. 47 Machtay M, Pajak TF, Suntharalingam M et al. Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: A randomized trial of the Radiation Therapy Oncology Group (RTOG 99-03). Int J Radiat Oncol Biol Phys Smith RE, Jr., Aapro MS, Ludwig H et al. Darbepoetin for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol 2008;26(7): Charu V, Belani CP, Gill AN et al. Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: a controlled, randomized, open-label phase II trial. Oncologist. 2007;12(6): Gordon DH, Nichols G, Ben-Jacob A, Lam H, Lillie T, Miller C. Treating anemia of cancer with darbepoetin alfa administered every 4 weeks: Final results from a phase 2, randomized, double-blind, placebo-controlled study in cancer patients not receiving chemotherapy and/or radiotherapy. Blood 2006;108(11):Abstract Abels R. Erythropoietin for anemia in cancer patients. Eur J Cancer 1993;29a(Suppl. 2): Wright JR, Ung YC, Julian JA et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25(9): Rose E, Rai K, Revicki D, et al. Clinical and health status assessments in anemic chronic lymphocytic leukemia (CLL) patients treated with epoetin alfa (EPO). Blood 1994;84(10 Suppl. 1):526a. 54 Luksenburg, H., Weir, A., Wager, R. P-174 in: Safety concerns associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, 14

16 L.P., for the treatment of anemia associated with cancer chemotherapy Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Oncologic Drugs Advisory Committee. 15

17 Table 2: Assessment of interaction for on study mortality in all cancer patients On study mortality all cancer patients ESA arm Control arm ESA versus control Patients events sample % events sample % HR 95% CI p-value* Patient level characteristics Hb at baseline (continuous) 0.82 Hb at baseline (cat. 1) 0.75 Hb % % Hb , ,222 13% 239 1,708 14% Hb , ,851 11% 220 2,153 10% Hb , ,433 10% 114 1,410 8% Hb > % % Unknown % % Hb at baseline (cat. 2) 0.79 Hb % % Hb 8-9 1, % % Hb , ,480 12% 138 1,131 12% Hb , ,699 11% 121 1,228 10% Hb , ,152 10% % Hb , % % Hb , % % Hb > % % Unknown % % Malignancy type Tumor (cat. 1) 0.16 Haematological malignancies 2, ,400 9% 79 1,003 8% Solid tumours 10, ,848 12% 532 4,947 11% Other % % Missing / unknown % %

18 Tumor (cat. 2) 0.47 Haematological malignancies 2, ,400 9% 79 1,003 8% Breast cancer 4, ,245 10% 164 2,057 8% Head and neck cancer % % Lung cancer 3, ,618 18% 243 1,458 17% Gastrointestinal cancer % % Gynecological cancer 1, % % Genitourinay cancer % % Other % % Missing / unknown % % Sex Male 5, ,854 15% 309 2,282 14% Female 8, ,780 9% 356 4,017 9% Age Age continuous 0.87 Age categorical 0.50 < 18 years % % Not estimable Not estimable years % % years 1, % % years 3, ,614 10% 111 1,396 8% years 4, ,237 11% 222 1,956 11% years 3, ,970 14% 210 1,547 14% years 1, % % Missing % % Not estimable Not estimable Hct levels at baseline Hct continuous 0.57 Hct categorical % % % % 2, ,567 13% 191 1,221 16% % 4, ,692 12% 223 1,923 12% % 2, ,258 14% 130 1,200 11% >41.2% % % Missing 2, ,493 4% 57 1,404 4%

19 Serum Epo at baseline Serum Epo continuous 0.21 Serum Epo categorical 0.54 <25 mu/ml 1, % % <100 mu/ml 2, ,643 12% 171 1,265 14% <200 mu/ml % % <500 mu/ml % % > 500 mu/ml % % Unknown 8, ,371 10% 360 3,911 9% Performance score ECOG categorical 0.63 ECOG 0 3, ,808 5% 76 1,584 5% ECOG 1 4, ,779 12% 250 2,121 12% ECOG 2 1, % % ECOG % % ECOG % 0 1 0% Not estimable Not estimable ECOG missing 3, ,035 9% 143 1,786 8% ECOG dichotomous 0.56 ECOG 0, 1, 2 10, ,578 12% 505 4,505 11% ECOG 3, % % ECOG missing 3, ,977 9% 142 1,731 8% Body mass index 19 kg/m² % % kg/m² 5, ,964 13% 277 2,523 11% kg/m² 3, ,864 10% 144 1,579 9% > 30 kg/m² 1, % % Missing 2, ,515 10% % History of thromboembolic events Yes % % No 9, ,044 13% 474 4,015 12% Missing / not reported 4, ,272 8% 149 2,041 7% History of cardiovascular events Yes 3, ,002 14% 197 1,591 12% No 6, ,700 11% 319 3,029 11%

20 Missing / not reported 3, ,932 10% 149 1,679 9% History of hypertension Yes 2, ,219 11% % No 7, ,143 13% 409 3,384 12% Missing / not reported 4, ,272 8% 149 2,041 7% History of diabetes mellitus Yes % % No 7, ,927 14% 427 3,389 13% Missing / not reported 5, ,335 7% 182 2,573 7% Geographical region Northern America 3, ,004 9% 159 1,565 10% Northern, Western & Southern Europe 7, ,030 10% 320 3,410 9% Eastern Europe 1, ,030 23% % Australia & New Zealand % % Other % % Missing / not reported % % Tumor stage Metastatic / advanced 8, ,482 15% 527 3,631 15% Not metastatic / not advanced 4, ,116 3% 45 1,923 2% Missing / not reported 1, ,036 11% % Planned Hb ceiling Planned Hb ceiling (cat. 1) 0.98 <Hb , ,624 13% 157 1,419 11% Hb , ,631 11% 468 4,562 10% Hb % % Other % % Planned Hb ceiling (cat. 2) 0.88 <Hb , ,624 13% 157 1,419 11% Hb , ,733 10% 322 3,083 10% Hb , ,898 11% 146 1,479 10% Hb % % Other % % Study level characteristics Treatment population 19

21 Treatment population (cat. 1) Chemotherapy 10, ,676 11% 490 4,765 10% Radiochemotherapy % % Radiotherapy % % Mixed % % None 1, ,007 19% % Treatment population (cat. 2) Chemotherapy 10, ,676 11% 490 4,765 10% Radiotherapy / radiochemotherapy 1, % % Mixed % % None 1, ,007 19% % Iron supplementation Fixed iron supplementation 2, ,293 5% 60 1,296 5% Iron supplementation as needed 11, ,232 12% 584 4,888 12% Other % % Planned ESA treatment duration Up to 8 weeks % % weeks 4, ,738 9% 204 2,062 10% > 17 weeks 3, ,701 23% 286 1,568 18% Until end of chemo- or radiotherapy 5, ,939 7% 158 2,510 6% Planned weekly ESA dosage < 100 µg Darb or < 40,000 IU EPO 4, ,297 10% 193 1,900 10% = 100 µg Darb or = 40,000 IU EPO 3, ,545 16% 190 1,536 12% > 100 µg Darb or > 40,000 IU EPO 3, ,076 12% 184 1,769 10% Other 2, ,716 8% 98 1,094 9% Planned frequency of ESA application Three times per week or more frequent 6, ,458 9% 238 2,673 9% Once per week 3, ,972 15% 231 1,976 12% Every second week or less frequent 3, ,795 10% 122 1,241 10% Other % % 0.93 Placebo controlled trial Yes 7, ,211 14% 456 3,446 13% No 6, ,423 8% 209 2,853 7%

22 Randomization Adequate 3, ,047 15% 245 1,835 13% Unclear 10, ,587 10% 420 4,464 9% Concealment of allocation Adequate 10, ,839 13% 559 4,756 12% Unclear 3, ,795 7% 106 1,543 7% Endpoint survival Primary endpoint 3, ,547 16% 195 1,569 12% Secondary endpoint 4, ,282 9% 161 2,031 8% Safety /adverse events 6, ,805 11% 309 2,699 11% Year of last patient randomized , % % , ,001 9% % , ,105 10% 337 3,515 10% , ,638 15% 191 1,503 13% Source of data Manufacturer 12, ,789 12% 641 5,440 12% Clinical study group 1, % % *p-value for likelihood-ratio test, patients with missing data are excluded from the test, analysis based on one-stage Cox fixed-effects model stratified by study 21

23 Table 3: Assessment of interaction for on study mortality in chemotherapy patients On study mortality chemotherapy patients ESA arm Control arm ESA versus control Subgroups Patients events sample % events sample % HR 95% CI p-value* Patient level characteristics Hb at baseline (continuous) 0.87 Hb at baseline (cat 1) 0.90 Hb % % Hb , ,606 12% 156 1,282 12% Hb , ,121 10% 171 1,627 11% Hb , ,108 11% 100 1,077 9% Hb > % % Unknown % % Hb at baseline (cat 2) 0.99 Hb % % Hb % % Hb , ,057 11% % Hb , ,179 10% % Hb , % % Hb , % % Hb % % Hb > % % Unknown % % Malignancy type Tumor (cat. 1) 0.18 Haematological malignancies 1, ,034 10% % Solid tumours 7, ,311 11% 379 3,656 10% Other % % Missing / unknown % % Tumor (cat. 2)

24 Haematological malignancies 1, ,034 10% % Breast cancer 4, ,076 10% 152 1,962 8% Head and neck cancer % % Lung cancer 2, ,172 16% 173 1,065 16% Gastrointestinal cancer % % Gynecological cancer 1, % % Genitourinay cancer % % Other % % Missing / unknown % % Sex Male 3, ,720 14% 209 1,405 15% Female 7, ,956 9% 281 3,360 8% Age Age continuous 0.57 Age categorical 0.34 < 18 years % % Not estimable Not estimable years % % years 1, % % years 2, ,311 9% 93 1,114 8% years 3, ,724 10% 172 1,509 11% years 2, ,359 14% 146 1,085 13% years % % Missing / unknown % % Not estimable Not estimable Hct levels at baseline Hct continuous 0.57 Hct categorical % % % % 2, ,135 10% % % 3, ,882 11% 163 1,399 12% % 1, % % > 41.2% % % Missing / unknown 2, ,335 4% 53 1,257 4%

25 Serum Epo at baseline Serum Epo continuous 0.91 Serum Epo categorical 0.20 < 25 mu/ml 1, % % <100 mu/ml 2, ,162 9% % <200 mu/ml % % <500 mu/ml % % mu/ml % % Missing / unknown 6, ,401 10% 292 3,081 9% Performance score ECOG categorical 0.58 ECOG 0 3, ,582 5% 66 1,443 5% ECOG 1 3, ,105 11% 185 1,679 11% ECOG 2 1, % % ECOG % % ECOG % 0 1 0% Not estimable Not estimable ECOG missing / unknown 2, ,307 11% 112 1,077 10% ECOG dichotomous 1.00 ECOG 0, 1, 2 7, ,310 10% 365 3,639 10% ECOG 3, % % ECOG missing 2, ,307 11% 112 1,077 10% Body mass index 19 kg/m² % % kg/m² 4, ,318 11% 208 1,965 11% kg/m² 2, ,468 10% 116 1,230 9% > 30 kg/m² 1, % % Missing / not reported 1, % % History of thromboembolic events Yes % % No 6, ,469 12% 320 2,823 11% Missing / not reported 3, ,000 9% 141 1,774 8%

26 History of cardiovascular events Yes 2, ,295 12% 126 1,024 12% No 5, ,721 10% 223 2,329 10% Missing / not reported 3, ,660 11% 141 1,412 10% History of hypertension Yes 1, % % No 5, ,878 11% 268 2,393 11% Missing / not reported 3, ,000 9% 141 1,774 8% History of diabetes mellitus Yes % % No 5, ,786 13% 286 2,363 12% Missing / not reported 4, ,671 8% 167 2,191 8% Geographical region Northern America 2, ,088 8% % Northern, Western & Southern Europe 6, ,342 10% 267 2,740 10% Eastern Europe 1, % % Australia & New Zealand % % Other % % Missing / not reported % % Tumor stage Metastatic / advanced 6, ,325 15% 388 2,729 14% Not metastatic / not advanced 2, ,491 2% 24 1,411 2% Missing / not reported 1, % % Planned Hb ceiling Planned Hb ceiling (cat 1) 0.28 <Hb , % % Hb , ,630 11% 415 3,821 11% Hb % % Other % %

27 Planned Hb ceiling (cat 2) 0.38 <Hb , % % Hb , ,200 10% 277 2,730 10% Hb , ,430 14% 138 1,091 13% Hb % % Other % % Study level characteristics Iron supplementation Fixed iron supplementation 1, % % Iron supplementation as needed 8, ,620 12% 429 3,693 12% Other % % Planned ESA treatment duration up to 8 weeks % % weeks 3, ,075 9% 167 1,748 10% > 17 weeks 2, ,184 21% 192 1,096 18% Until end of chemo- or radiotherapy 4, ,303 7% 129 1,892 7% Planned weekly ESA dosage < 100 µg Darb or < 40,000 IU EPO 3, ,023 10% 174 1,710 10% <= 100 µg Darb or = 40,000 IU EPO 2, ,101 16% 144 1,099 13% > 100 µg Darb or > 40,000 IU EPO 1, % 76 1,011 8% Other 2, ,565 8% % Planned frequency of ESA application Three times per week or more frequent 5, ,853 9% 210 2,163 10% Once per week 3, ,528 16% 185 1,539 12% Every second week or less frequent 1, % % Other % % Placebo controlled trial Yes 5, ,996 13% 307 2,477 12% No 4, ,680 8% 183 2,288 8% Randomization Adequate 3, ,693 14% 202 1,565 13% Unclear 7, ,983 9% 288 3,200 9%

28 Concealment of allocation Adequate 8, ,501 12% 423 3,751 11% Unclear 2, ,175 5% 67 1,014 7% Endpoint survival Primary endpoint 2, ,352 16% 177 1,379 13% Secondary endpoint 3, ,730 11% 147 1,492 10% Safety /adverse events 4, ,594 8% 166 1,894 9% Year of last patient randomized , % % , ,001 9% % , ,263 11% 298 2,849 10% , % % Source of data Manufacturer 8, ,889 12% 467 3,962 12% Clinical study group 1, % % *p-value for likelihood-ratio test, patients with missing data are excluded from the test, analysis based on one-stage Cox fixed-effects model stratified by study 27

29 Table 4: Assessment of interaction for overall survival in all cancer patients Overall survival in all cancer patients ESA arm Control arm ESA versus control Patients events sample % events sample % HR 95% CI Subgroups p- value* Patient level characteristics Hb at baseline Hb at baseline (continuous) 0.75 Hb at baseline (cat 1) 0.63 Hb % % Hb , ,222 33% 672 1,708 39% Hb , ,851 34% 777 2,153 36% Hb , ,433 39% 553 1,410 39% Hb > % % Unknown % % Hb at baseline (cat 2) 0.83 Hb % % Hb 8-9 1, % % Hb , ,480 32% 420 1,131 37% Hb , ,699 32% 414 1,228 34% Hb , ,152 37% % Hb , % % Hb , % % Hb > % % Unknown % % Malignancy type Tumour (cat. 1) 0.23 Haematological malignancies 2, ,400 27% 286 1,003 29% Solid tumours 10,795 2,103 5,848 36% 1,916 4,947 39% Other % % Missing / unknown % % Tumor (cat. 2)

30 Haematological malignancies 2, ,400 27% 286 1,003 29% Breast cancer 4, ,245 25% 481 2,057 23% Head and neck cancer % % Lung cancer 3, ,618 61% 975 1,458 67% Gastrointestinal cancer % % Gynaecological cancer 1, % % Genitourinal cancer % % Other % % Missing / unknown % % Sex Male 5, ,854 46% 1,193 2,282 52% Female 8, ,780 28% 1,157 4,017 29% Age Age continuous 0.38 Age categorical 0.26 Not < 18 years % % estimable Not estimable years % % years 1, % % years 3, ,614 33% 439 1,396 31% years 4, ,237 37% 793 1,956 41% years 3, ,970 40% 711 1,547 46% years 1, % % Not Missing % % estimable Not estimable Hct levels at baseline Hct continuous 0.90 Hct categorical % % % % 2, ,567 30% 479 1,221 39% % 4, ,692 35% 732 1,923 38% % 2, ,258 46% 558 1,200 47% >41.2% % % Missing / unknown 2, ,493 26% 361 1,404 26%