Use of Prophylactic Growth Factors and Antimicrobials in Elderly Patients with Cancer: A

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1 Supportive Care in Cancer Use of Prophylactic Growth Factors and Antimicrobials in Elderly Patients with Cancer: A Systematic Review of the Medicare Database Romina Sosa, Shuling Li, Julia T. Molony, Jiannong Liu, Scott Stryker, Allan J. Collins Corresponding Author Allan J Collins, MD, FACP Chronic Disease Research Group, Minneapolis Medical Research Foundation ACollins@cdrg.org

2 Supplementary Table S1. Administrative codes used to identify chemotherapy Type of Codes Codes ICD-9-CM procedure codes for administration CPT codes for administration excluding HCPCS codes for administration C8953-C8955, G0355-G0362 excluding G0356, G3001, Q0083-Q0085 ICD-9-CM diagnosis code V58.1, V66.2, V67.2 Revenue codes 0331, 0332, 0335 DRG codes 410 and 492 on inpatient claims with discharge date before October 1, 2007; and on inpatient claims with discharge date on or after October 1, 2007 HCPCS codes for chemotherapeutic A9522, A9523, A9534, A9542-A9545, C1081, C1083, agents * C1166, C1167, C1178, C9017, C9110, C9117, C9118, C9127, C9205, C9213-C9215, C9253, C9257, C9259, C9260, C9265, C9414, C9415, C9417-C9429, C9431- C9433, C9437, C9439, C9440, J0594, J7527,, J8510, J8520, J8521, J8530, J8560-J8562, J8565, J8600, J8610, J8700, J8705, J9000-J9999 (excluding J9155, J9202, J9212, J9215-J9219, J9225, J9226, J9395), Q2017, Q2024, Q2025, Q2049, S0116, S0172, S0178, S0182 CPT, Current Procedural Terminology; DRG, diagnosis-related group; HCPCS, Healthcare Common Procedure Coding System; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification. * Includes Aldesleukin, Alemtuzumab, Arsenic trioxide, Asparaginase (erwinaze), Azacitidine, BCG (intravesical) per instillation, Bendamustine, Bevacizumab (Avastin), Bleomycin, Bortezomib, Brentuximab vedotin, Busulfan, Cabazitaxel, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil (Leukeran), Cisplatin, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine liposome, Dacarbazine, Dactinomycin, Daunorubicin, Denileukin diftitox, Diethylstilbestrol diphosphate, Docetaxel, Doxorubicin, Elliotts b solution, Epirubicin, Eribulin mesylate, Etoposide, Everolimus, Floxuridine, Fludarabine, Fluorouracil, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, Ibritumomab tiuxetan (Zevalin), Idarubicin,

3 Ifosfamide, Interferon alfa-2a and alfa-2b, Ipilimumab, Irinotecan, Ixabepilone, Lomustine, Mechlorethamine, Melphalan, Mesna, Methotrexate, Mitomycin, Mitoxantrone, Nelarabine, Ofatumumab, Oxaliplatin, Paclitaxel, Panitumumab, Pegaspargase, Pemetrexed, Pentostatin, Plicamycin, Porfimer sodium, Pralatrexate, Procarbazine hydrochloride, Rituximab, Romidepsin, Streptozocin, Temozolomide, Temsirolimus, Teniposide, Thiotepa, Topotecan, Tositumomab (Bexxar), Trastuzumab, Valrubicin, Vinblastine, Vincristine, and Vinorelbine.

4 Supplementary Table S2. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes used to define comorbid conditions Comorbid Conditions ICD-9-CM Diagnosis Codes Chronic kidney disease 016.0, 095.4, 189.0, 189.9, 223.0, , 250.4, 271.4, 274.1, , 403.X1, 404.X2, 404.X3, 440.1, 442.1, 447.3, 572.4, , 591, 642.1, 646.2, , , 753.2, and Atherosclerotic heart disease , V45.18, and V45.82 Cerebrovascular accidents/transient ischemic attacks Chronic obstructive pulmonary disease 491.xx-494.xx, 496.xx, 510.xx Congestive heart failure , 422.xx, 425.xx, 428.xx, 402.x1, 404.x1, 404.x3, V42.1 Diabetes mellitus 250.xx, 357.2, 362.0x, Dysrhythmia 426.xx-427.xx, V45.0, and V53.3 Gastrointestinal disorders , 530.7, 531.xx-534.xx, , , 578 Liver disease 570.xx, 571.xx, 572.1, 572.4, , V42.7, Other cardiovascular disease 420.xx-421.xx, 423.xx-424.xx, 429.xx, , V42.2, and V43.3 Peripheral vascular disease ; 447; ; 557 Anemia HIV infection 042, Thyroid disease 240.x-246.x Peptic ulcer disease 531.x-539.x Rheumatoid disease (rheumatoid arthritis) 714.x Osteoarthritis 715.x Other cancer ; ; (excluding for breast cancer, for lung cancer, and 200 and 202 for non-hodgkin lymphoma)

5 Supplementary Table S3. List of oral antimicrobial agents Antimicrobial Class Antibacterials Penicillins Cephalosporins Macrolides Tetracyclines Fluoroquinolones Aminoglycosides Sulfonamides Other Antifungals Antivirals Drug Name Amoxicillin, Dicloxacillin sodium, Amoxicillin and Clavulanate, Ampicillin Cefadroxil, Cephalexin, Cefaclor, Cefprozil, Cefuroxime Axetil, Cefdinir, Cefditoren, Cefixime, Cefpodoxime, Ceftibuten Erythromycin, Azithromycin, Clarithromycin, Fidaxomicin Demeclocycline, Doxycycline, Minocycline, Tetracycline Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Gemifloxacin Neomycin, Paromomycin Sulfadiazine, Sulfamethoxazole-Trimethoprim Vancomycin, Telithromycin, Clindamycin, Linezolid Terbinafine, Flucytosine, Griseofulvin, Ketoconazole, Nystatin, Fluconazole, Itraconazole, Posaconazole, Voriconzaole Adefovir dipivoxil, Amantadine HCl, Acyclovir, Famciclovir, Valacyclovir, Boceprevir, Entecavir, Oseltamivir, Ribavirin, Rimantadine HCl, Telaprevir, Valganciclovir

6 Supplementary Table S4. Distribution of chemotherapy regimens or top five most frequently used agents, by cancer type and febrile neutropenia risk category of chemotherapy regimen Cancer Type, Risk Category, or Agents n % Breast cancer (n = 9110) High risk (n = 923) Dose dense AC + sequential T (doxorubicin, cyclophosphamide, paclitaxel) TAC (docetaxel, doxorubicin, cyclophosphamide) Docetaxel + trastuzumab AT (doxorubicin, paclitaxel) AT (doxorubicin, docetaxel) ^ ^ Docetaxel every 14 days * * Intermediate risk (n = 908) Paclitaxel every 21 days CMF classic (cyclophosphamide, methotrexate, fluorouracil) Paclitaxel, Trastuzumab Docetaxel every 21 days FEC (fluorouracil/epirubicin/cyclophosphamide) Other risk (n = 7279) Top five agents by number of patients received during the course Cyclophosphamide/docetaxel Bevacizumab Capacitabine Trastuzumab/docetaxel/carboplatin Trastuzumab Lung cancer (n = 12,032) High risk (n = 37) Topotecan Intermediate risk (n = 5130) Carboplatin/paclitaxel Etoposide/carboplatin Cisplatin/etoposide Cisplatin/vinorelbine Docetaxel Cisplatin/docetaxel Cisplatin/paclitaxel Cisplatin/irinotecan Other risk (n = 6865) Top five agents by number of patients received during the course Docetaxel/carboplatin Pemetrexed Carboplatin/pemetrexed Gemcitabine/carboplatin Paclitaxel/carboplatin/bevacizumab

7 Non-Hodgkin lymphoma (n = 6306) High risk (n = 1035) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) + rituximab RICE (rituximab, ifosfamide, carboplatin, etoposide) * * MINE (mesna, ifosfamide, novantrone, etoposide) * * CHOP-14 (cyclophosphamide, doxorubicin, vincristine, prednisone) * * ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine) * * Intermediate risk (n = 24) FM (fludarabine, mitoxantrone) GDP (gemcitabine, dexamethasone, cisplatin) * * EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) * * GDP (gemcitabine, dexamethasone, cisplatin)+rituximab * * Other risk (n = 5247) Top five agents by number of patients received during the course n % Rituximab Cyclophosphamide/rituximab/vincristine Rituximab/bendamustine Bevacizumab Rituximab/fludarabine * Values for cells with ten or fewer patients are suppressed. ^ Value is suppressed to avoid deriving another cell with ten or fewer patients.

Primary malignant neoplasms, not lymphatic or hematopoietic. Secondary malignant neoplasms (i.e.metastatic) Malignant neoplasm, unknown site

Supplementary Table 1. ICD-9-CM codes used to define cancer ICD-9 Diagnosis code 140.xx-172.xx 174.xx-195.xx 196.xx 198.xx 199.xx 200.xx-208.xx Description Primary malignant neoplasms, not lymphatic or