Guia Prático do Oncologista Clínico SBOC

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Sociedade Brasileira de Cancerologia

Guia Prático para o Oncologista Clínico

2011

Organização Dra. Aline Lauda Freitas Chaves Dra. Letícia Carvalho Neuenschwander

Revisão Dr. Amândio Soares Fernandes Júnior Dr. Enaldo Melo de Lima Dr. José Luiz Miranda Guimarães Srta. Paula Palmeira - Bibliotecária da SBOC

Editorial Caros Oncologistas Clínicos Associados da SBOC e da SBC; A SBOC, em conjunto com a SBC, elaborou esse compêndio com os principais protocolos de tumores onco-hematológicos, para facilitar a consulta no dia a dia dos esquemas de dose e frequência de tratamento. A confecção e compilação dos dados da literatura médica coube às Dras. Aline Lauda Freitas Chaves e Letícia Carvalho Neuenschwander e, após a elaboração do guia, foram realizadas diversas correções no conteúdo e diagramação, a fim de evitar informações incorretas, que pudessem gerar erros de prescrição e danos aos pacientes. Um esforço considerável foi dispendido para evitar erros e garantir a acurácia dos regimes apresentados. Esse guia prático incorpora os esquemas mais amplamente utilizados, tanto de monoterapia, como poliquimioterapia, além de hormonioterapia, bioterapia, anticorpos monoclonais e pequenas moléculas, que são utilizados na prática oncológica do dia a dia para tratamento de tumores sólidos e das neoplasias hematológicas. Ambas as entidades pretendem atualizar, anualmente esse trabalho, tendo em vista a rápida evolução da nossa especialidade e entendem esse trabalho como uma continuidade da prestação de serviço aos associados, com a incorporação de novos esquemas e programas de tratamento. Cordialmente,

Dr. Enaldo Melo de Lima Presidente da SBOC

Dr. Roberto Porto Fonseca Presidente da SBC

Apresentação Dentro da proposta das atuais diretorias da SBOC e SBC, temos uma maior aproximação entre essas entidades e seus associados, principalmente no que tange a facilitar a vida do Oncologista Clínico no Brasil. Foi dentro desta linha que surgiu este guia rápido de protocolos, com informações úteis para o dia a dia da prática do oncologista. Para montá-lo fizemos inicialmente a pergunta: “O que o oncologista tem que ter em mãos no momento de sua prática clínica junto ao paciente?” Seu intuito, portanto, é ser um guia de consulta prático, rápido e acessível. É importante ressaltar que não substitui o raciocínio clínico e nem pode ser considerado um manual de condutas de tratamento. Justamente por isso não foram separados subcapítulos de tratamento adjuvante, neoadjuvante, paliativo. Todos os dados aqui apresentados foram compilados na literatura médica disponível, com referências citadas no final de cada capítulo. Esperamos que seja útil a todos.

Dra. Aline Lauda Freitas Chaves Dra. Letícia Carvalho Neuenschwander Belo Horizonte - MG Agosto/2011

Sumário Protocolos de Tratamento Tumor de Sítio Primário Desconhecido Tumores do Sistema Nervoso Central Tumores Neuroendócrinos Câncer Anal Câncer Colo-retal Câncer de Intestino Delgado Câncer de Esôfago Câncer Gástrico e Junção Gastroesofágica Tumor do Estroma Gastrointestinal (GIST) Hepatocarcinoma Câncer de Vias Biliares Câncer de Pâncreas Câncer de Cabeça e Pescoço Linfoepitelioma – Nasofaringe Câncer de Tireóide Câncer de Glândula Salivar Câncer de Bexiga Câncer Renal Câncer de Próstata Câncer de Testículo Câncer de Pênis Câncer de Endométrio Câncer de Colo Uterino Câncer de Mama Metástases Ósseas e/ou Hipercalcemia Maligna Câncer de Ovário (Epitelial) Doença Trofoblástica Gestacional Câncer de Vulva Câncer de Pulmão Não Pequenas Células Câncer de Pulmão de Pequenas Células

.07 .09 .15 .20 .24 .26 .39 .41 .44 .50 .51 .53 .56 .61 .65 .72 .73 .75 .80 .83 .88 .92 .93 .98 .101 .121 .122 .128 .130 .131 .140

Mesotelioma Timoma Melanoma Maligno Linfoma de Hodgkin Linfoma Não-Hodgkin Linfoma de Grandes Células B Linfoma de Células do Manto Linfoma Primário do Sistema Nervoso Central Mieloma Múltiplo Síndrome Mielodisplásica Macroglobulinemia de Waldeströn Leucemia de Células Cabeludas (Tricoleucemia) Leucemias Agudas Leucemia Mielóide Crônica Leucemia Linfática Crônica Sarcomas de Partes Moles Sarcoma de Kaposi Sarcomas Ósseos Feocromocitoma

.144 .147 .149 .154 .160 .171 .172 .176 .179 .185 .187 .188 .190 .194 .195 .200 .206 .208 .212

Escala de Performance

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Fórmulas Úteis em Oncologia

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Determinação do Clearance de Creatinina Determinação da área sobre a curva (AUC) Cálculo da Superfície Corporal

.219 .219 .220

Correção de Dose para Pacientes em Hemodiálise

.221

Classificação Internacional de Doenças – CID – Oncologia

.227

Sites Úteis em Oncologia

.233

Protocolos de Tratamento

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Tumor de Sítio Primário Desconhecido PCE Paclitaxel: 200 mg/m2 IV D1 Carboplatina: AUC 6 IV D1 Etoposide: 50 mg alternando com 100 mg VO D1-10 a cada 21 dias Ref. (1) EP Etoposide: 80 a 120 mg/m2 IV D1–5 Cisplatina: 60 a 100 mg/m2 IV D1 a cada 21 dias

Ref. (2, 4)

PEB Cisplatina: 20 mg/m2 IV D1–5 Etoposide: 100 mg/m2 IV D1–5 Bleomicina: 30 unidades IV D1, 8 e 15 a cada 21 dias

Ref. (3)

GC Gencitabina 1250mg/m2 IV D1 e D8 Cisplatina 100mg/m2 IV D1 a cada 21 dias

Ref. (5)

IC Irinotecano 150 mg/m2 IV D1 Cisplatina 80mg/m2 IV D1 a cada 21 dias

Ref. (5)

PCF Paclitaxel 200mg/m2 IV em 1 hora D1 e D22 Guia Prático para o Oncologista Clínico •

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Carboplatina AUC 6 IV D1 e D22 5-Fluorouracil: 225mg/m2/dia IV em 24 horas, D1 a D35 a cada 6 semanas Ref. (6) GD Gencitabina: 1000mg/m2 IV D1 e D8 Docetaxel: 75 mg/m2 IV D8 em 1 hora a cada 21 dias

Ref. (7)

DC Docetaxel: 75mg/m2 IV D1 Cisplatina: 75mg/m2 IV D1 Ou

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Docetaxel: 60mg/m2 IV D1 Carboplatina: AUC 6 IV D1 a cada 21 dias

Ref. (8)

CP Paclitaxel: 200mg/m2 IV D1 em 3 horas D1 Carboplatina: AUC 6 IV D1 a cada 21 dias

Ref. (9)

GCP Gencitabina: 1000mg/m2 IV D1 e D8 Paclitaxel: 200mg/m2 IV D1 Carboplatina: AUC 6 IV D1 a cada 21 dias

Ref. (10)

CAE Carboplatina: 400mg/m2 IV D1 Adriamicina: 50mg/m2 IV D1 Etoposide: 100mg/m2 IV D1 a D3 a cada 21 dias

Ref. (11)

• Guia Prático para o Oncologista Clínico

GC Gencitabina: 1000mg/m2 IV D1 e D8 Carboplatina: AUC 5 IV D8 a cada 21 dias

Ref. (12)

GCC Carboplatina: AUC 5 IV D1 Gencitabina: 1000mg/m2 IV D1 e D8 Capecitabina: 1600mg/m2 VO D1 a D14 a cada 21 dias

Ref. (13)

IC Irinotecano: 60mg/m2 IV D1,8 e 15 Carboplatina: AUC 5 IV D1 a cada 28 dias

Ref. (14)

GEMZAR Gencitabina: 1000mg/m2 D1,D8 e D15 IV a cada 28 dias Ref. (15) GI Gencitabina: 1000mg/m2 IV D1 e D8 Irinotecano: 100mg/m2 IV D1 e D8 a cada 21 dias

Ref. (16)

OC Oxaliplatina: 130mg/m2 IV D1 Capecitabina: 1000mg/m2 duas vezes ao dia VO D1 a D14 a cada 21 dias Ref. (17) GCP Cisplatina: 35mg/m2 IV D1 e D8 Gencitabina: 1000mg/m2 IV D1 e D8 Paclitaxel: 70mg/m2 IV D1 e D8 a cada 21 dias

Ref. (18)

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GCV Cisplatina: 35mg/m2 IV D1 e D8 Gencitabina: 1000mg/m2 IV D1 e D8 Vinorelbina: 25mg/m2 IV D1 e D8 a cada 21 dias

Ref. (18)

1. Hainsworth JD, Erlance JB, Kalman LA, Schreeder MT, Greco FA. Carcinoma of unknown primary site: treatment with 1hour paclitaxel, carboplatin, extended-schedule etoposide. J Clin Oncol 1997;15:2385–2393. 2. Longeval E, et al. Combination chemotherapy with cisplatin and etoposide in bronchogenic squamous cell carcinoma adenocarcinoma.A study by the EORTC lung cancer working party. Cancer1982;50:2751–2756. 3. Hainsworth JD, et al. Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol 1992;10:912–922. 4. Sheperd FA. Treatment of advanced non-small cell lung cancer. Semin Oncol. 1994; 21(suppl 7): 7-18. 5. Culine S; Lortholary A; Voigt JJ; Bugat R; Theodore C; Priou F; Kaminsky MC; Lesimple T; Pivot X; Coudert B; Douillard JY; Merrouche Y; Allouache J; Goupil A; Negrier S; Viala J; Petrow P; Bouzy J; Laplanche A; Fizazi K. Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol 2003 Sep 15;21(18):3479-82. 6. Hainsworth JD, Burris HA 3rd, Meluch AA, Baker MN, Morrissey LH, Greco FA. Paclitaxel, carboplatin, and longterm continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial. Cancer. 2001 Aug 1;92(3):642-9.

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7. Pouessel D; Culine S; Becht C; Ychou M; Romieu G; Fabbro M; Cupissol D; Pinguet F. Gemcitabine and docetaxel as frontline chemotherapy in patients with carcinoma of an unknown primary site. Cancer 2004 Mar 15;100(6):1257-61. 8. Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin.Greco FA; Erland JB; Morrissey LH; Burris HA 3rd; Hermann RC; Steis R; Thompson D; Gray J; Hainsworth JD. Ann Oncol 2000 Feb;11(2):211-5. 9. Briasoulis E; Kalofonos H; Bafaloukos D; Samantas E; Fountzilas G; Xiros N; Skarlos D; Christodoulou C; Kosmidis P; Pavlidis Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study. J Clin Oncol 2000 Sep;18(17):3101- 7. 10. Greco FA; Burris HA 3rd; Litchy S; Barton JH; Bradof JE; Richards P; Scullin DC Jr; Erland JB; Morrissey LH; Hainsworth JD. Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study. J Clin Oncol 2002 Mar 15;20(6): 1651-6. 11. Piga A, Nortilli R, Cetto GL, Cardarelli N, Fedeli SL, Fiorentini G, D'Aprile M, Giorgi F, Parziale AP, Contu A, Montironi R, Gesuita R, Carle F, Cellerino R.Carboplatin, doxorubicin and etoposide in the treatment of tumours of unknown primary site. Br J Cancer. 2004 May 17;90(10):1898-904. 12. Pittman KB; Olver IN; Koczwara B; Kotasek D; Patterson WK; Keefe DM; Karapetis CS; Parnis FX; Moldovan S; Yeend SJ; Price TJ Gemcitabine and carboplatin in carcinoma of unknown primary site: a phase 2 Adelaide Cancer Trials and Education Collaborative study. Br J Cancer. 2006 Nov 20;95(10):1309-13. Epub 2006 Oct 31. 13. Schneider BJ; El-Rayes B; Muler JH; Philip PA; Kalemkerian GP; Griffith KA; Zalupski MM. Phase II trial of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site. Cancer. 2007 Aug 15;110(4):770-5. 14. Yonemori K; Ando M; Yunokawa M; Hirata T; Kouno T; Shimizu C; Tamura K; Katsumata N; Hirakawa A; Matsumoto Guia Prático para o Oncologista Clínico •

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K; Yamanaka Y; Arioka H; Fujiwara Y. Irinotecan plus carboplatin for patients with carcinoma of unknown primary site. Br J Cancer. 2009 Jan 13;100(1):50-5. Epub 2008 Dec 16. 156. Hainsworth JD; Burris HA 3rd; Calvert SW; Willcutt NT; Scullin DC Jr; Bramham J; Greco FA. Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: a phase II trial of the Minnie Pearl Cancer Research Network. Cancer Invest 2001;19(4):335-9. 16. Hainsworth JD; Spigel DR; Raefsky EL; Kuzur ME; Yost K; Kommor M; Litchy S; Greco FA. Combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site: a Minnie Pearl Cancer Research Network Phase II trial. Cancer 2005 Nov 1;104(9):1992-7. 17. Hainsworth JD; Spigel DR; Burris HA 3rd; Shipley D; Farley C; Macias-Perez IM; Barton J; Greco FA. Oxaliplatin and capecitabine in the treatment of patients with recurrent or refractory carcinoma of unknown primary site: a phase 2 trial of the Sarah Cannon Oncology Research Consortium. Cancer. 2010 May 15;116(10):2448-54. 18. Palmeri S; Lorusso V; Palmeri L; Vaglica M; Porta C; Nortilli R; Ferrau F; Comella G; Massidda B; Danova M Cisplatin and gemcitabine with either vinorelbine or paclitaxel in the treatment of carcinomas of unknown primary site : results of an Italian multicenter, randomized, phase II study. Cancer. 2006 Dec 15;107(12):2898-905.

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Tumores do Sistema Nervoso Central Temozolomida + Radioterapia Temozolomida: 75 mg/m2 VO ou IV por 6 semanas concomitante a radioterapia, seguido por 150 mg/m2 VO D1–5 a cada 28 dias Dose da Temozolomida após a radioterapia: 150 a 200 mg/m2 VO D 1-5 a cada 28 dias. Ref. (1) e Ref. (9) PCV Procarbazina: 60 mg/m2 VO D8–21 Lomustina: 110 mg/m2 VO D1 Vincristina: 1.4 mg/m2 IV D8 e 29 a cada 6 a 8 semanas por 6 a 7 ciclos (2). BCNu BCNU: 200 mg/m2 IV D1 a cada 6–8 semanas por um ano Ref. (3 ,4,10) Ou BCNU: 75–100 mg/m2 IV D1 e 2 a cada 6–8 semanas

Ref. (3)

Procarbazina Procarbazina: 150 mg/m2 VO diariamente dividido em 3 doses. Ref. (5) Temozolomida Temozolomida: 150 mg/m2 VO ou IV D1–5 a cada 28 dias

Ref. (6)

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Irinotecano Irinotecano: 350 mg/m2 IV em 90 min D1 a cada 3 semanas

Ref. (7)

Ou Irinotecano: 125 mg/m2 IV semanalmente por 4 semanas a cada 6 semanas Ref. (8) ACE Carboplatina: AUC 5 IV D1 Etoposide: 100mg/m2 IV D1 a D3 Bevacizumabe: 10mg/kg IV D2 a cada 3 semanas

Ref. (11)

BCE BCNU: 200mg/m2 IV D1 Cisplatina: 20mg/m2 IV D1 a D5 Etoposide: 100mg/m2 IV D1 a D5 a cada 5 semanas, seguido por radioterapia

Ref. (12)

Temozolamida + Cisplatina Temozolamida: 200 mg/m2/dia VO ou IV por 5 dias Cisplatina: 100mg/m2 IV D1

Ref. (13)

Cisplatina + Carmustina Cisplatina: 100mg/m2 IV D1 a cada 21 dias Carmustina: 160mg/m2 IV D2 a cada 42 dias

Ref. (14,15)

Temozolamida + Cisplatina Cisplatina: 75mg/m2 IV D1 Temozolamida: 150mg/m2 VO ou IV D1 a D5 a cada 21 dias Ref. (16)

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Bevacizumabe + Irinotecano Bevacizumabe: 10mg/kg IV Irinotecano: 125mg/m2 IV (se paciente não usando antiepiléptico) ou 340mg/m2 IV (se paciente usando antiepilético) a cada 15 dias Ref. (17, 18)

1. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–995. 2. Levin VA, et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, evincristine (PCV) over BCNU poranaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 1990; 18:321–324. 3. DeAngelis LM, et al. Malignant gliomas: who benefits from adjuvant chemotherapy? Ann Neurol 1998; 44:691–695. 4. Buckner JC, et al. Phase II trial of procarbazine, lomustine, andvincristine as initial therapy porpatients with low-grade oligodendrioglioma or oligoastrocytoma: efficacy eassociations with chromosomal abnormalities. J Clin Oncol 2003; 21: 251–255. 5. Yung A, et al. Randomized trial of temodal (TEM) vs. procarbazine (PCB) in glioblastoma multiforme (GBM) at first relapse. Proc Am Soc Clin Oncol 1999;18:139a. 6. Yung A, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 1999; 17: 2762–2771. 7. Raymond E, et al. Multicenter phase II study and pharmacokinetic analysis of irinotecan in chemotherapynaïve patients with glioblastoma. Ann Oncol 2003; 14: 603–614. 8. Friedman H, et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 1999; 17: 1516–1525. Guia Prático para o Oncologista Clínico •

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9. Stupp R; Hegi ME; Mason WP; van den Bent MJ; Taphoorn MJ; Janzer RC; Ludwin SK; Allgeier A; Fisher B; Belanger K; Hau P; Brandes AA; Gijtenbeek J; Marosi C; Vecht CJ; Mokhtari K; Wesseling P; Villa S; Eisenhauer E; Gorlia T; Weller M; Lacombe D; Cairncross JG; Mirimanoff. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTCNCIC trial. Lancet Oncol. 2009 Mar 6. 10. Stewart LA . Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002 Mar 23; 359(9311):1011-8. 11. Francesconi AB, Dupre S, Matos M, Martin D, Hughes BG, Wyld DK, Lickliter JD. .Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme. J Clin Neurosci. 2010 Aug; 17(8): 970-4. 12. Lassen U, Kristjansen PE, Wagner A, Kosteljanetz M, Poulsen HS. Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study. J Neurooncol. 1999 Jun; 43(2):161-6. 13. Balaña C, López-Pousa A, Berrocal A, Yaya-Tur R, Herrero A, García JL, Martín-Broto J, Benavides M, Cerdá-Nicolás M, Ballester R, Balart J, Capellades J.Phase II study of temozolomide and cisplatin as primary treatment prior to radiotherapy in newly diagnosed glioblastoma multiforme patients with measurable disease. A study of the Spanish Medical Neuro-Oncology Group (GENOM). J Neurooncol. 2004 Dec;70(3):359-69. 14. Buckner JC, Ballman KV, Michalak JC, Burton GV, Cascino TL, Schomberg PJ, Hawkins RB, Scheithauer BW, Sandler HM, Marks RS, O'Fallon JR; North Central Cancer Treatment Group 93-72-52; Southwest Oncology Group 9503 Trials Phase III trial of carmustine and cisplatin compared with

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carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-7252 and Southwest Oncology Group 9503 Trials. J Clin Oncol. 2006 Aug 20;24(24):3871-9. 15. Silvani A, Gaviani P, Lamperti EA, Eoli M, Falcone C, Dimeco F, Milanesi IM, Erbetta A, Boiardi A, Fariselli L, Salmaggi A. Cisplatinum and BCNU chemotherapy in primary glioblastoma patients. J Neurooncol. 2009 Aug;94(1): 57-62. Epub 2009 Feb 11. 16. Zustovich F, Lombardi G, Della Puppa A, Rotilio A, Scienza R, Pastorelli D. A phase II study of cisplatin and temozolomide in heavily pre-treated patients with temozolomiderefractory high-grade malignant glioma. Anticancer Res. 2009 Oct; 29(10): 4275-9. 17. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007 Oct 20; 25(30): 4722-9. 18. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):7405. Epub 2008 Dec 29.

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Tumores Neuroendócrinos Adriamicina + Estreptozotocina Adriamicina: 50 mg/m2 IV D1 e 22 Estreptozotocina: 500 mg/m2/dia IV D1–5 cada 6 semanas

Ref. (1)

EP Cisplatina: 45 mg/m2/dia IV por infusão contínua D2 e D3 Etoposide: 130 mg/m2/dia IV por infusão contínua nos D1-3 a cada 21 dias Ref. (2) EP Etoposide: 100 mg/m2 IV D1-3 Cisplatina: 25 mg/m2 IV D1-3 a cada 21 dias

Ref. (3)

Carboplatina + radioterapia Carboplatina: AUC 2, semanal, durante radioterapia Ref. (6) Octreotide Octreotide: 150–250 μg SC uma a três vezes por dia Ref. (4) Octreotide LAR: 20 a 40 mg IM 1x/mês Ref. (5)

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5-Fluorouracil + Octreotide 5-Fluorouracil: 200mg/m2 IV diariamente Octreotide LAR: 20mg IM mensalmente

Ref. (7)

Everolimo + Octreotide Everolimo: 5 a 10mg/dia VO Octreotide LAR: 30mg/mês IM

Ref. (8)

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PCE Paclitaxel: 200mg/m2 IV em 1 hora D1 Carboplatina: AUC 6 IV D1 Etoposide VO alternando 50mg e 100mg diariamente , D1 a D10 a cada 21 dias Ref. (10) Irinotecano + Cisplatina Irinotecano: 65mg/m2 IV D1 e D8 Cisplatina: 30mg/m2 IV D1 e D8 a cada 21 dias

Ref. (11)

Temozolamida + Talidomida Temozolamida: 150mg/m2 VO por 7 dias, a cada 15 dias Talidomida: 50 a 400mg VO diariamente. Ref. (12) Etoposide e Carboplatina associado a Radioterapia Etoposide: 80mg/m2 D1 a D3 IV Carboplatina: AUC 4.5 IV Semanas 1, 4, 7 e 10 Ref. (13) FDE Fluorouracil: 500mg/m2 IV D1 a D3 Dacarbazina: 200mg/m2 IV D1 a D3 Epirrubicina: 30mg/m2 IV D1 a D3 a cada 21 dias

Ref. (14)

Interferon alpha 2a Interferon 6 x 106 UI diariamente x 8 semanas, seguido por 6 x 106 UI , três vezes por semana Ref. (15) Everolimo 10 mg VO dia uso contínuo

Ref. (16)

1. Moertel CG, et al. Streptozocin-Adriamicina, streptozocinfluorouracil,or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:519–526. Guia Prático para o Oncologista Clínico •

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2. Moertel CG, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Cancer 1991; 68:227–232. 3. Longeval E, et al. Combination chemotherapy with cisplatin and etoposide in bronchogenic squamous cell carcinoma adenocarcinoma.A study by the EORTC lung cancer working party. Cancer. 1982; 50:2751–2756. 4. Saltz L, et al. Octreotide as an antineoplastic agent in the treatmentof functional and nonfunctional neuroendocrine tumors. Cancer 1993;72:244. 5. Rubin J. et al Octreotide Acetate Long-Acting Formulation Versus Open-Label Subcutaneous Octreotide Acetate in Malignant Carcinoid Syndrome. J Clin Oncol 17:600, 1999. 6. Poulsen M, Walpole E, Harvey J, Dickie G, O'Brien P, Keller J, Tripcony L, Rischin D. Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1070-4. 7. Brizzi MP, Berruti A, Ferrero A, Milanesi E, Volante M, Castiglione F, Birocco N, Bombaci S, Perroni D, Ferretti B, Alabiso O, Ciuffreda L, Bertetto O, Papotti M, Dogliotti L. Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte oncology network. BMC Cancer. 2009 Nov 3;9:388. 8. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study J Clin Oncol. 2008 Sep 10;26(26):4311-8. ERRATUM J Clin Oncol. 2008 Dec 1; 26 (34) 5660. 10. Hainsworth JD, Spigel DR, Litchy S, Greco FA. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol. 2006 Aug 1; 24(22):3548-54.

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11. Kulke MH, Wu B, Ryan DP, Enzinger PC, Zhu AX, Clark JW, Earle CC, Michelini A, Fuchs CS. A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors. Dig Dis Sci, 2006 Jun;51(6): 1033-8. 12. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. 13. Poulsen M, Rischin D, Walpole E, Harvey J, Mackintosh J, Ainslie J, Hamilton C, Keller J, Tripcony L; Trans-Tasman Radiation Oncology Group High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study--TROG 96:07. J Clin Oncol. 2003 Dec 1;21(23):4371-6. 14. Bajetta E, Rimassa L, Carnaghi C, Seregni E, Ferrari L, Di Bartolomeo M, Regalia E, Cassata A, Procopio G, Mariani L. 5Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer. 1998 Jul 15; 83(2):372-8. 15. Bajetta E, Zilembo N, Di Bartolomeo M, Di Leo A, Pilotti S, Bochicchio AM, Castellani R, Buzzoni R, Celio L, Dogliotti L, et al. Treatment of metastatic carcinoids and other neuroendocrine tumors with recombinant interferonalpha-2a. A study by the Italian Trials in Medical Oncology Group. Cancer. 1993 Nov 15;72(10):3099-105. 16. Yao, James C. M.D.; Shah, Manisha H. M.D.; Ito, Tetsuhide M.D. et. al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. N Engl J Med. 2011; 364 (6): 514523.

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Câncer Anal 5-Fluorouracil + Mitomicina C 5-Fluorouracil: 1,000 mg/m2/dia IV por infusão contínua D1–4 e D29–32 concomitante a radioterapia Mitomicina C: 15 mg/m2 IV no D1 Ref. (1) 5-Fluorouracil + Mitomicina C 5-Fluorouracil: 750 mg/m2/dia IV infusão contínua D1-5 e D29–33, concomitante a radioterapia Mitomicina C: 15 mg/m2 IV no D1 Ref. (2) 5-Fluorouracil + Cisplatina 5-Fluorouracil: 1,000 mg/m2/dia IV infusão contínua nos D1 a 5 Cisplatina: 75 mg/m2 IV D2 Ref. (3) Capecitabina + Mitomicina C Capecitabina: 825mg/m2 VO BID durante os dias da radioterapia Mitomicina C: 12mg/m2 IV D1 Ref. (4)

1. Nigro ND, et al. Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 1983;51:1826–1829. 2. Bartelink H, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization por Research e Treatment of

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Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 1997;15:2040–2049. 3. Hung A, et al. Cisplatin-based combined modality therapy for anal carcinoma: a wider therapeutic index. Cancer 2003; 97:1195–1202. 4. Glynne-Jones R; Meadows H; Wan S; Gollins S; Leslie M; Levine E; McDonald AC; Myint S; Samuel L; SebagMontefiore D. Multicenter Phase II Study of Chemoradiation Using a 5 Day per Week Oral Regimen of Capecitabine and Intravenous Mitomycin C in Anal Cancer. Int J Radiat Oncol Biol Phys. 2008 May 7.

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Câncer Colo-retal 5-Fluorouracil + Radioterapia 5-Fluorouracil: 1,000 mg/m2/dia IV infusão contínua D1 a 5 Repetir nas semanas 1 e 5 da radioterapia 5-Fluorouracil: 500 mg/m2 IV contínuo durante 5 dias a cada 28 dias por 4 ciclos Ref. (1) Capecitabina + Radioterapia Capecitabina: 825 mg/m2 VO BID durante toda a radioterapia Ou Capecitabina: 900–1,000 mg/m2 VO BID D1–5 de cada semana da radioterapia Ref. (2) 5-Fluorouracil + Leucovorin (Mayo Clinic) 5-Fluorouracil: 425 mg/m2 IV D–5 Leucovorin: 20 mg/m2 IV D1–5 (administrado antes do 5Fluorouracil) a cada 28 dias Ref. (3) 5-Fluorouracil + Leucovorin (Roswell Park) 5-Fluorouracil: 500 mg/m2 IV semanalmente por 6 semanas Leucovorin: 500 mg/m2 IV em 2 horas semanalmente por 6 semanas, administrado antes do 5-Fluorouracil a cada 8 semanas Ref. (4) 5-Fluorouracil + Leucovorin 5-Fluorouracil: 500 mg/m2 IV semanalmente por 6 semanas Leucovorin: 20 mg/m2 IV semanalmente por 6 semanas, Administrado antes do 5-Fluorouracil a cada 8 semanas Ref. (5)

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Quasar 5-Fluorouracil: 370mg/m2 IV Leucovorin: 25 ou 175mg IV (dose fixa) Uma vez por semana, por 30 semanas (29, 38) FOLFOX4 Oxaliplatina: 85 mg/m2 IV D1 5-Fluorouracil: 400 mg/m2 IV pulso, seguido por 600 mg/m2 IV infusão contínua por 22 horas D1 e 2 Leucovorin: 200 mg/m2 IV D1 e 2 em uma infusão de 2 horas, antes do 5-Fluorouracil. a cada 2 semanas Ref. (6) FLOX Nórdico Oxaliplatina: 85mg/m2 IV em 2 horas D1 5-Fluorouracil: 500mg/m2 IV pulso D1 e D2 Leucovorin: 60mg/m2 IV pulso D1 e D2 Intervalo a cada 14 dias

Ref. (30)

ROX Oxaliplatina: 85mg/m2 IV 2 horas D1 e D15 Leucovorin: 250mg/m2 IV 2horas D1, 8 e15 5-Fluorouracil: 500mg/m2 IV pulso, D1, 8 e 15 a cada 4 semanas (31) Capecitabina Capecitabina: 1,250 mg/m2 VO BID D1–14 a cada 21 dias

Ref. (7)

Irinotecano + 5-Fluorouracil + Leucovorin (IFL) Irinotecano: 125 mg/m2 IV em 90 minutos semanalmente por 4 semanas 5-Fluorouracil: 500 mg/m2 IV semanalmente por 4 semanas Leucovorin: 20 mg/m2 IV semanalmente por 4 semanas a cada 6 semanas Ref. (8)

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Irinotecano + 5-Fluorouracil + Leucovorin (IFL) + Bevacizumabe (BV) Irinotecano: 125 mg/m2 IV em 90 minutos semanalmente por 4 semanas (D1, 8, 15, 22) 5-Fluorouracil: 500 mg/m2 IV semanalmente por 4 semanas (D1, 8, 15, 22) Leucovorin: 20 mg/m2 IV semanalmente por 4 semanas (D1, 8,15, 22) Bevacizumabe: 5 mg/kg IV a cada 2 semanas D1,15 a cada 6 semanas Ref. (9) IFL (Regime de Douillard) Irinotecano: 180 mg/m2 IV D1 5-Fluorouracil: 400 mg/m2 IV pulso, seguido por 600 mg/m2 IV infusão contínua por 22 horas D1 e 2 Leucovorin: 200 mg/m2 IV D1 e 2 em 2 horas (infundir antes do 5-Fluorouracil) a cada 2 semanas Ref. (11) FOLFIRI Irinotecano: 180 mg/m2 IV D1 5-Fluorouracil: 400 mg/m2 IV pulso D1, seguido por 2.400 mg/m2 IV infusão contínua por 46 horas. Leucovorin: 200 mg/m2 IV D1 em 2 horas (infundir antes do 5Fluorouracil) a cada 2 semanas Ref. (12) FOLFOX6 Oxaliplatina: 100 mg/m2 IV D1 5-Fluorouracil: 400 mg/m2 IV pulso D1, seguido por 2.400 mg/m2 IV por infusão contínua em 46 horas. Leucovorin: 400 mg/m2 IV D1 em 2 horas (infundir antes do 5Fluorouracil) a cada 2 semanas Ref. (13)

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m FOLFOX6 Oxaliplatina: 85 mg/m2 IV em 2 horas D1 Leucovorin: 350 mg/m2 IV em 2 horas D1 5-Fluorouracil: 400 mg/m2 IV pulso D1, seguido por 2.400 mg/m2 IV em infusão contínua de 46 horas. a cada 2 semanas por 12 ciclos Ref. (39) FOLFOX7 Oxaliplatina: 130 mg/m2 IV D1 5-Fluorouracil: 2.400 mg/m2 IV infusão contínua D1 e 2 por 46 horas. Leucovorin: 400 mg/m2 IV D1 em 2 horas (infundir antes do 5Fluorouracil) a cada 2 semanas Ref. (13) FOLFOXIRI Irinotecano: 150mg/m2 IV D1 Oxaliplatina: 65mg/m2 IV D2 Leucovorin: 200mg/m2 IV D2 e D3 5-Fluorouracil: 400mg/m2 IV pulso D2 e D3 5-Fluorouracil: 600mg/m2 IV em infuão contínua D2 e D3 a cada 15 dias Ref. (32) Cetuximabe + Irinotecano Cetuximabe: 400 mg/m2 IV dose de ataque, seguido de 250 mg/m2 IV semanalmente Irinotecano: 350 mg/m2 IV D1 a cada 21 dias Ref. (14) XELOX Capecitabina + Oxaliplatina Capecitabina: 1,000 mg/m2 VO BID D1–14 Oxaliplatina: 130 mg/m2 IV D1 a cada 21 dias Guia Prático para o Oncologista Clínico •

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Capecitabina: 1.750 mg/m2 VO BID D1–7 Oxaliplatina: 85 mg/m2 IV D1 a cada 14 dias

Ref. (15)

XELIRI Capecitabina: 1.000 mg/m2 VO BID D1–14 Irinotecano: 250 mg/m2 IV D1 a cada 21 dias

Ref. (16)

IROX Oxaliplatina + Irinotecano Oxaliplatina: 85 mg/m2 IV D1 Irinotecano: 200 mg/m2 IV D1 a cada 3 semanas

Ref. (17)

Raltitrexede + Oxaliplatina Raltitrexede: 2,5mg/m2 IV em 15 minutos D1 Oxaliplatina: 100mg/m2 IV em 180 minutos D1 a cada 3 semanas

Ref. (33)

Raltitrexede: 3mg/m2 IV D1 Mitomicina C: 6mg/m2 IV D1 a cada 4 semanas

Ref. (34)

Ou Raltitrexede: 3mg/m2 IV D1 a cada 3 semanas Mitomicina C: 7mg/m2 IV D1 a cada 6 semanas

Ref. (35)

Ou Raltitrexede: 3mg/m2 IV D1 Mitomicina C: 7mg/m2 IV D1 a cada 3 a 4 semanas

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Ref. (28)

5-Fluorouracil + Leucovorin + Bevacizumabe 5-Fluorouracil: 500 mg/m2 IV semanalmente por 6 semanas Leucovorin: 500 mg/m2 IV semanalmente por 6 semanas, Administrado antes do 5-Fluorouracil Bevacizumabe: 5 mg/kg IV a cada 2 semanas a cada 8 semanas Ref. (18) “de Gramont Regimen” 5-Fluorouracil: 400 mg/m2 IV seguido de 600 mg/m2 IV por 22 horas D1 e D2 Leucovorin: 200 mg/m2 IV D1 e 2 em infusão de 2 horas a cada 2 semanas Ref. (19) FOLFOX4 + Bevacizumabe Oxaliplatina: 85 mg/m2 IV D1 5-Fluorouracil: 400 mg/m2 IV pulso, seguido por 600 mg/m2 IV por infusão contínua D1 e D2 Leucovorin: 200 mg/m2 IV D1 e 2 em infusão de 2 horas antes do 5-Fluorouracil Bevacizumabe: 10 mg/kg IV a cada 2 semanas a cada 2 semanas Ref. (20) Capecitabina + Oxaliplatina (XELOX) + Bevacizumabe Capecitabina: 850 mg/m2 VO BID D1–14 Oxaliplatina: 130 mg/m2 IV D1 Bevacizumabe: 7.5 mg/kg a cada 3 semanas a cada 21 dias Ref. (21) FLOX Oxaliplatina: 85mg/m2 IV em duas horas D1,15,29 Leucovorin: 500mg/m2 IV D1, 8, 15, 22, 29, 36 5-Fluorouracil: 500mg/m2 IV D1, 8, 15, 22, 29, 36 a cada 8 semanas por 3 ciclos

Ref. (27)

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Capecitabina Capecitabina: 1.250 mg/m2 VO BID D1–14 a cada 21 dias

Ref. (22)

Irinotecano (CPT11) (semanal) Irinotecano: 125 mg/m2 IV em 90 minutos semanalmente por 4 semanas. a cada 6 semanas Ref. (23) Irinotecano: 125 mg/m2 IV em 90 minutos semanalmente por 2 semanas. A cada 3 semanas. Irinotecano: 175 mg/m2 IV D1 e 10 a cada 3 semanas

Ref. (24)

Irinotecano: 350 mg/m2 IV D1 a cada 3 semanas

Ref. (25)

Cetuximabe Cetuximabe: 400 mg/m2 IV dose de ataque, seguido por 250 mg/m2 IV semanalmente Ref. (26) Cetuximabe + Irinotecano Irinotecano: 180mg/m2 IV D1 Cetuximabe: 500mg/m2 IV D1 a cada 15 dias b-Fol Oxaliplatina: 85mg/m2 D1 e 15 Leucovorin: 20mg/m2 D1, 8 e 15 5-Fluorouracil: 500mg/m2 D1, 8 e 15 a cada 28 dias Ref. (40)

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Ref. (36, 37)

uFT Leucovorin: 90 mg/dia VO D1 a D28 2 UFT: 100 mg/m três vezes ao dia VO D1 a D28 a cada 35 dias Ref. (41) FOLFIRI com bevacizumabe Irinotecano:180 mg/m2 IV D1 Leucovorin: 200 mg/m2 IV D1 2 5-Fluorouracil: 400 mg/m IV pulso D1 5-Fluorouracil: 2400 mg/m2 IV em infusão de 46 horas D1 Bevacizumabe: 5 mg/kg IV D1 a cada 14 dias Ref. (42)

1. Sauer R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–1740. 2. Minsky BD. Combined modality therapy of rectal cancer with oxaliplatin-based regimens. Clin Colorectal Cancer 2004; 4 Suppl 1:S29–36. 3. O’Connell MJ, et al. Controlled trial of fluorouracil and lowdose leucovorin given por6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997; 15: 246–250. 4. Wolmark N, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast eBowel Project Protocol C-03. J Clin Oncol 1993; 11: 1879–1887. 5. Benson AB, et al. NCCN practice guidelines for colorectal cancer. Oncology 2000;14:203–212. 6. de Gramont A, et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized mosaic trial. Proc Am Soc Clin Oncol 2003;22:253 (abstract 1015). Guia Prático para o Oncologista Clínico •

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7. Cassidy J, et al. Capecitabine (X) vs. bolus 5-FU/leucovorin (LV) as adjuvant therapy porcolon cancer (the X-ACT study): positive efficacy results of a phase III trial. Proc Am Soc Clin Oncol 2004;23:(abstract3509). 8. Saltz LB, et al. Irinotecan plus fluorouracil eleucovorin pormetastatic colorectal cancer. N Engl J Med 2000; 343: 905–914. 9. Hurwitz H, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin pormetastatic colorectal cancer. N Engl J Med 2004;350: 2335–2342. 10. Hwang JJ, et al. Capecitabine-based combination chemotherapy. Am J Oncol Rev 2003;2 (Suppl 5):15–25. 11. Douillard JY, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. Lancet 2000; 355: 1041–1047. 12. Andre T, et al. CPT-11 (irinotecan) addition to bimonthly, highdose leucovorin ebolus econtinuous-infusion 5fluorouracil (FOLFIRI) porpretreated metastatic colorectal cancer. GERCOR. Eur J Cancer 1999;35:1343–1347. 13. de Gramont A, et al. Leucovorin efluorouracil with ewithout oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947. 14. Cunningham D, et al. Cetuximab monotherapy ecetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345. 15. Scheithauer W, et al. Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2003;21: 1307–1312. 16. Kerr D. Capecitabine/irinotecan in colorectal cancer: European early-phase data eplanned trials. Oncology 2002;16 (Suppl 14):12–15. 17. Goldberg RM, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated

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metastatic colorectal cancer. J Clin Oncol 2004;22:23–30. 18. Kabbinavar F, et al. Results of a randomized phase II controlled trial of bevacizumab in combination with 5fluorouracil eleucovorin as first-line therapy in subjects with metastatic CRC. Proc Am Soc Clin Oncol 2004;23:Abstract 3516. 19. de Gramont A, et al. Randomized trial comparing monthly lowdose leucovorin efluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French Intergroup study. J Clin Oncol 1997;15:808–815. 20. Mitchell EP, et al. High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Presented at the 2005 American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 27–29, 2005 Hollywood, FL (abstract 169a). 21. Hochster HS, et al. Bevacizumab (B) with oxaliplatin (O)based chemotherapy in the first-line therapy of metastatic colorectal cancer (mCRC): Preliminary results of the randomized “TREE-2” trial. Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 27–29, 2005 Hollywood, FL (abstract 241). 22. Hoff P, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001;15:2282–2292. 23. Pitot HC, et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 1997; 15: 2910–2919. 24. Ulrich-Pur H, et al. Multicenter phase II trial of dosefractionated irinotecan in patients with advanced colorectal cancer failing oxaliplatin- based first-line combination chemotherapy. Ann Oncol 2001; 12:1269–1272. Guia Prático para o Oncologista Clínico •

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25. Rougier P, et al. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naïve patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997;15:251–260. 26. Saltz LB, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expressed the epidermal growth factor receptor. J Clin Oncol 2004;22:1201–1208. 27. Kuebler JP et al: Oxaliplatin combined with weekly bolus of fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C07. J Clin Oncol. 2007; 25:2198-2204. 28. Murad AM, Aragao BC, Guimarães RC. Phase II Trial of the Use of Raltitrexed and Mitomycin-C in the Treatment of Advanced Colorectal Cancer after 5FU Failure: Final Results. Proc Am Soc Clin Oncol, 2001 (20) abst 2188. 29. D. J. Kerr, R. Gray, C. McConkey & J. Barnwell for the QUASAR Colorectal Cancer Study Group. Adjuvant chemotherapy with 5-fluorouracil, L-folinic acid and levamisole for patients with colorectal cancer: Non-randomised comparison of weekly versus four-weekly schedules - less pain, same gain. Ann Oncol (2000) 11 (8): 947-955. 30. Sørbye H, Glimelius B, Berglund A, Fokstuen T, Tveit KM, Braendengen M, Øgreid D, Dahl O. Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2004 Jan 1; 22(1): 31-8. 31. Yamada Y, Ohtsu A, Boku N, Miyata Y, Shimada Y, Doi T, Muro K, Muto M, Hamaguchi T, Mera K, Yano T, Tanigawara Y, Shirao K. Phase I/II study of oxaliplatin with weekly bolus fluorouracil and high-dose leucovorin (ROX) as first-line therapy for patients with colorectal cancer. Jpn J Clin Oncol. 2006 Apr; 36(4):218-23. 32. Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D,

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Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27; 94(6):798-805. 33. Cortinovis D, Bajetta E, Di Bartolomeo M, Dognini G, Beretta E, Ferrario E, Ricotta R, Buzzoni R. Raltitrexed plus oxaliplatin in the treatment of metastatic colorectal cancer. Tumori. 2004 Mar-Apr; 90(2):186-91. 34. Rosati G, Rossi A, Germano D, Reggiardo G, Manzione L. Raltitrexed and mitomycin-C as third-line chemotherapy for colorectal cancer after combination regimens including 5fluorouracil, irinotecan and oxaliplatin: a phase II study. Anticancer Res. 2003 May-Jun; 23(3C):2981-5. 35. Michels J, Geldart T, Darby A, Craddock L, Iveson A, Richardson L, Iveson T. The combination of raltitrexed (Tomudex) and mitomycin-C in the treatment of advanced colorectal cancer - a phase II study. Clin Oncol (R Coll Radiol). 2006 Aug;18(6):431-5. 36. P Martı´n-Martorell1, S Rosello´ 1, E Rodrı´guez-Braun1, I Chirivella1, A Bosch1 and A Cervantes Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial British Journal of Cancer (2008) 99, 455–458. 37. Pfeiffer P., D. Nielsen, J. Bjerregaard, C. Qvortrup, M. Yilmaz & B. Jensen. Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil Annals of Oncology 19: 1141–1145, 2008 38. Gray R, Barnwell J, McConkey C et al. Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. Guia Prático para o Oncologista Clínico •

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39. Hochster HS, Hart LL, et al. Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab as First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study. J Clin Oncol; 2008:26:3523-3529. 40. H. S. Hochster, A. Chachoua, J. Speyer, et al. Oxaliplatin with weekly bolus 5FU and low-dose leucovorin (bFOL) as firstline therapy of colorectal cancer; a phase II study. 41. Lembersky BC, et al. Oral Uracil and Tegafur Plus Leucovorin Compared With Intravenous Fluorouracil and Leucovorin in Stage II and III Carcinoma of the Colon: Results From National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 2006;24:2059-64. 42. Kopetz SM, et al., Preliminary results from a phase II study of infusional 5-FU, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for metastatic colorectal cancer (mCRC), ASCO Annual Meeting Proceedings Part I, J Clin Oncol, 2006; 24, No 18S (Supplement): (Abstract 3579).

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Câncer de Intestino Delgado CAPOX Oxaliplatina: 130mg/m2 IV D1 Capecitabina: 750mg/m2 VO BID D1 a D14

Ref. (1)

FAM 5-Fluorouracil: 600mg/m2 IV D1,8,29 e 36. Doxorrubicina: 30mg/m2 IV D1 e D29 Mitomicina C: 10mg/m2 IV D1

Ref. (2)

Irinotecano + Cisplatina Irinotecano: 70mg/m2 IV D1 e D15 Cisplatina: 80mg/m2 IV D1 a cada 28 dias

Ref. (5)

FOLFOX Oxaliplatina: 85 ou 100 ou 135mg/m2 IV em 2 horas D1 Leucovorin: 400mg/m2 IV em 2 horas D1 5-Fluorouracil: 400mg/m2 IV em pulso D1 5-Fluorouracil: 2400mg/m2 IV em 48 horas, infusão contínua a cada 15 dias Ref. (3, 4) FOLFIRI Irinotecano: 180mg/m2 IV em 90 minutos D1 Leucovorin: 400mg/m2 IV em 2 horas D1 5-Fluorouracil: 400mg/m2 IV em pulso D1 5-Fluorouracil: 2400mg/m2 IV em 48 horas, infusão contínua a cada 15 dias Ref. (4, 5)

1. Overman MJ, Varadhachary GR, Kopetz S, Adinin R, Lin E, Morris JS, Eng C, Abbruzzese JL, Wolff RA. Phase II study of Guia Prático para o Oncologista Clínico •

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capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol. 2009 Jun 1;27(16):2598-603. 2. Gibson MK, Holcroft CA, Kvols LK, Haller D. Phase II study of 5-fluorouracil, doxorubicin, and mitomycin C for metastatic small bowel adenocarcinoma. Oncologist. 2005;10(2):132-7. 3. Overman MJ, Kopetz S, Wen S, Hoff PM, Fogelman D, Morris J, Abbruzzese JL, Ajani JA, Wolff RA. Chemotherapy with 5fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma. Cancer. 2008; 113(8):2038-45. 4. Kocher C, Malka D, Boige V, Lebray P, Elias D, Lasser P, Ducreux M. Combination chemotherapy in advanced small bowel adenocarcinoma. Oncology. 2005;69(4):290-4. 5. Fishman PN, Pond GR, Moore MJ, Oza A, Burkes RL, Siu LL, Feld R, Gallinger S, Greig P, Knox JJ. Natural history and chemotherapy effectiveness for advanced adenocarcinoma of the small bowel: a retrospective review of 113 cases. Am J Clin Oncol. 2006;29(3):225-31.

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Câncer de Esôfago 5-Fluorouracil + Cisplatina + Radioterapia 5-Fluorouracil: 1.000 mg/m2/dia IV infusão contínua D1 a D4 Cisplatina: 75 mg/m2 IV no D1 Repetir nas semanas 1, 5, 8, e 11 Ref. (1) 5-Fluorouracil + Cisplatina + Radioterapia (Esquema Hopkins/Yale) 5-Fluorouracil: 225 mg/m2/dia IV infusão contínua D1 a D30 Cisplatina: 20 mg/m2/dia IV D1–5 e 26–30 Paclitaxel: 135 mg/m2 IV em 24 horas D1 Cisplatina: 75 mg/m2 IV D2 a cada 21 dias por 3 ciclos

Ref. (2)

5-Fluorouracil + Cisplatina 5-Fluorouracil: 1.000 mg/m2/dia IV infusão contínua D1 a D5. Cisplatina: 100 mg/m2 IV D1 Semanas 1, 5, 8, e 11 Ref. (3) Irinotecano + Cisplatina Irinotecano: 65 mg/m2 IV semanalmente por 4 semanas Cisplatina: 30 mg/m2 IV semanalmente por 4 semanas a cada 6 semanas Ref. (4) Paclitaxel + Cisplatina Paclitaxel: 200 mg/m2 IV em 24 horas D1 Cisplatina: 75 mg/m2 IV D2 a cada 21 dias

Ref. (5)

Paclitaxel Paclitaxel: 250 mg/m2 IV em 24 horas D1 a cada 21 dias

Ref. (6)

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ECF Epirrubicina: 50mg/m2 IV D1 Cisplatina: 60mg/m2 IV D1 5-Fluorouracil: 225 mg/m2/dia IV D1 ao D21 a cada 21 dias Ref. (7) Oxaliplatina e Capecitabina Oxaliplatina: 30mg/m2 IV D1 Capecitabina: 1700mg/m2/dia VO D1 a D14 a cada 21 dias Ref. (8) EP Cisplatina: 30 mg/m2 IV D1 a D4 Etoposide: 120 mg/m2 IV D1 a D4 a cada 28 dias Ref. (9) Paclitaxel, Carboplatina e 5-Fluorouracíl Paclitaxel: 200 mg/m2 IV D1 e D22 Carboplatina: AUC6 IV D1 e D22 2 5-Fluorouracil: 225 mg/m /dia IV contínuo D1 a D42 * Regime aplicado junto com a radioterapia no pré-operatório. A cirurgia é realizada 4 a 5 semanas após o término do tratamento combinado. Ref. (10) Gencitabina, 5-Fluorouracil e Leucovorin Gencitabina: 1000 mg/m2 IV D1, D8 e D15 2 5-Fluorouracil: 600 mg/m IV D1, D8 e D15 Leucovorin: 25 mg/m2 IV D1, D8 e D15 a cada 28 dias Ref. (11)

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1. Herskovic A, et al. Combined chemotherapy eradiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593–1598. 2. Heath El, et al. Phase II evaluation of preoperative chemoradiation and postoperative adjuvant chemotherapy porsquamous cell and adenocarcinoma of the esophagus. J Clin Oncol 2000;18:868–876. 3. Kies MS, et al. Cisplatin e5-fluorouracil in the primary management of squamous esophageal cancer. Cancer 1987;60:2156–2160. 4. Ilson DH, et al. Phase II trial of semanalmente irinotecan plus cisplatin in first line advanced esophageal cancer. J Clin Oncol 1999;17: 3270–3275. 5. Ilson DH, et al. Phase II trial of paclitaxel, fluorouracil, ecisplatin in patients with advanced carcinoma of the esophagus. J Clin Oncol 1998;16:1826–1834. 6. Ajani JA, et al. Paclitaxel in the treatment of carcinoma of the esophagus. Semin Oncol 1995;22 (Suppl 6):35–40. 7. Cunningham D et al. Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer. N Engl J Med. 2006; 355:11-20. 8. Jatoi A et al. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Ann Oncol. 2006. 17; 29-34. 9. Hejna M, Kornek GV et al. Effective radiochemotherapy with cisplatin and etoposide for the management of patients with locally inoperable and metastatic esophageal carcinoma. Cancer 1996 15(78): 1646-50. 10. Melucti M,et al. Preoperative therapy with concurrent paclitaxel/ carboplatin/infusional 5-FU and radiation therapy in locoregional esophageal cancer: final results of a Minnie Pearl Cancer Research Network phase II trial. Canicer J 2003;9:251-60. 11. Morgan-Meadows, et al. A phase II trial of gemcitabine, 5fluorouracil and leucovorin in advanced esophageal carcinoma. Oncology 2005;69:130-4. Guia Prático para o Oncologista Clínico •

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Câncer Gástrico e Junção Gastroesofágica Quimioterapia concomitante a radioterapia (Esquema de MacDonald) 5-Fluorouracil: 425 mg/m2 IV D1 a D5 Leucovorin: 20 mg/m2 IV D1 a D5 Radioterapia iniciando no D28 do primeiro ciclo associada a 2 ciclos de quimioterapia conforme abaixo: 5-Fluorouracil: 400 mg/m2 IV D1-4 e D23-25 da radioterapia Leucovorin: 20 mg/m2 IV D1-4 e D23-25 da radioterapia Após término da radioterapia repetir mais dois ciclos de 5-Fluorouracil: 425 mg/m2 IV D1 a D5 Leucovorin: 20 mg/m2 IV D1 a D5 Ref. (1) DCF Docetaxel: 75 mg/m2 IV D1 Cisplatina: 75 mg/m2 IV em 3 horas D1 5-Fluorouracil: 750 mg/m2/dia IV infusão contínua D1 a D5 a cada 21 dias Ref. (2) CF Cisplatina: 100 mg/m2 IV em 3 horas D1 5-Fluorouracil: 1.000 mg/m2/dia IV por infusão contínua D1 a D5 a cada 28 dias Ref. (2) ECF Epirubicina: 50 mg/m2 IV D1 Cisplatina: 60 mg/m2 IV D1 5-Fluorouracil: 200 mg/m2/dia IV infusão contínua por 21 dias a cada 21 dias Ref. (4)

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ELF Etoposide: 120 mg/m2 IV D1 a 3 Leucovorin: 300 mg/m2 IV D1 a 3 5-Fluorouracil: 500 mg/m2 IV D1 a 3 a cada 28 dias

Ref. (5)

IP Irinotecano: 70 mg/m2 IV D1 e 15 Cisplatina: 80 mg/m2 IV D1 a cada 28 dias

Ref. (6)

FAM 5-Fluorouracil: 600 mg/m2 IV D1, 8, 29 e 36 Adriamicina: 30 mg/m2 IV D1 e 29 Mitomicina-C: 10 mg/m2 IV D1 a cada 8 semanas

Ref. (7)

FAMTX 5-Fluorouracil: 1.500 mg/m2 IV D1, iniciando 1 hora após o Methotrexate Leucovorin: 15 mg/m2 VO a cada 6 horas por 12 doses, iniciando 24 horas após início do Methotrexate Adriamicina: 30 mg/m2 IV D15 Methotrexate: 1.500 mg/m2 IV D1 a cada 28 dias Ref. (8) FAP 5-Fluorouracil: 300 mg/m2 IV D1 a 5 Adriamicina: 40 mg/m2 IV D1 Cisplatina: 60 mg/m2 IV D1 a cada 5 semanas

Ref. (9)

Docetaxel + Cisplatina Docetaxel: 85 mg/m2 IV D1 Cisplatina: 75 mg/m2 IV D1 a cada 21 dias

Ref. (10) Guia Prático para o Oncologista Clínico •

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5-Fluorouracil 5-Fluorouracil: 500 mg/m2 IV D1 a 5 a cada 28 dias

Ref. (11)

Docetaxel Docetaxel: 100 mg/m2 IV D1 a cada 21 dias

Ref. (12)

Ou Docetaxel: 35 mg/m2 IV semanalmente por 6 semanas a cada 8 semanas Ref. (12) Capecitabina Capecitabina: 2000mg/m2/dia VO D1 a D14, ciclos a cada 21 dias. Ref.(13) Cisplatina + Irinotecano Cisplatina: 30 mg/m2 IV Irinotecano: 60 mg/m2 IV Semanal x 3 semanas a cada 4 semanas

Ref. (14)

FOLFOXIRI Oxaliplatina: 85mg/m2 IV em 2 horas D1 Irinotecano: 165mg/m2 IV em 90 min D1 Leucovorin: 200mg/m2 IV em 2 horas D1 5-Fluorouracil 3200mg/m2 IV em 48 horas, infusão contínua a cada 15 dias Ref. (15) EOX Epirrubicina: 50mg/m2 IV D1 a cada 3 semanas Oxaliplatina: 130mg/m2 IV D1 a cada 3 semanas Capecitabina: 625mg/m2 VO, BID, durante todo o tratamento por 8 ciclos Ref. (16) ECX Epirrubicina: 50mg/m2 IV D1 Cisplatina: 75mg/m2 IV D1 Capecitabina: 1000mg/m2 VO, BID D1 a D14

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Ref. (17)

EXE Oxaliplatina: 130mg/m2 IV D1 a cada 3 semanas Capecitabina: 1000mg/m2 VO, BID, continuamente Epirrubicina: 50mg/m2 IV D1 a cada 3 semanas

Ref. (18)

PELF Cisplatina: 40mg/m2 IV D1 e D5 Epirrubicina: 30mg/m2 IV D1 e D5 Leucovorin: 100mg/m2 IV D1 a D4 Fluorouracil: 300mg/m2 IV D1 a D4 a cada 21 dias, total de 4 ciclos

Ref. (19)

DF Docetaxel: 75mg/m2 IV D1 5-Fluorouracil: 200mg/m2 IV D1 a D21 a cada 3 semanas

Ref. (20)

ECR Epirrubicina: 60 mg/m2 IV D1 Cisplatina: 60 mg/m2 IV D1 Raltitrexede: 1mg/m2 IV D1 e D8 a cada 3 semanas

Ref. (21)

Estudo ToGA Trastuzumabe: 8 mg/Kg dose inicial IV Dia 1 seguido por 6 mg/kg a cada 21 dias, até a progressão ou toxicidade intolerável, associado a: Cisplatina: 80 mg/m2 Dia 1 a cada 21 dias + 5-Fluorouracil: 800 mg/m2 Dias 1 a 5 em infusão contínua a cada 21 dias Ou Capecitabina: 1g/ m2 / VO 2 x ao dia Dias 1 a 14 a cada 21 dias por 6 ciclos. Ref. (22) 1. MacDonald JS, et al. Chemoradiotherapy after surgery compared with surgery alone poradenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–730. 2. Ajani JA, et al. Docetaxel (D), cisplatin, 5-fluorouracil compare Guia Prático para o Oncologista Clínico •

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to cisplatin (C) e5-fluorouracil (F) porchemotherapy-naïve patients with metastatic or locally recurrent, unresectable gastric carcinoma (MGC): interim results of a randomized phase III trial (V3325). Proc Am Soc Clin Oncol 2003;22:249 (abstract 999). 4. Findlay M, et al. A phase II study in advanced gastro-esophageal cancer using epirubicin ecisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol 1994; 5:609–616. 5. Wilke M, et al. Preliminary analysis of a randomized phase III trial of FAMTX versus ELF versus cisplatin/FU in advanced gastric cancer. A trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group ethe AIO. Proc Am Soc Clin Oncol 1995;14:206a. 6. Shirao K, et al. Phase I–II study of irintoecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 1997;15:921–927. 7. MacDonald JS, et al. 5-Fluorouracil, Adriamicina, emitomycin (FAM) combination chemotherapy poradvanced gastric cancer. Ann Intern Med 1980;93:533–536. 8. Kelsen D, et al. FAMTX versus etoposide, Adriamicina, and cisplatin: a random assignment trial in gastric cancer. J Clin Oncol 1992; 10:541–548. 9. Cullinan SA, et al. Controlled evaluation of three drug combination regimens versus fluorouracil alone porthe therapy of advanced gastric cancer. North Central Cancer Treatment Group. J Clin Oncol 1994;12:412–416. 10. Ajani JA, et al. Multinational randomized trial of docetaxel, cisplatin with or without 5-fluorouracil in patients with advanced gastric or GE junction adenocarcinoma. Proc Am Soc Clin Oncol 2000;20: 165a (abstract 657). 11. O’Connell MJ. Current status of chemotherapy poradvanced pancreatic egastric cancer. J Clin Oncol 1985;3:1032–1039. 12. Ajani JA. Docetaxel porgastric eesophageal carcinomas. Oncology 2002;16 (Suppl 6):89–96. 13. Hong S et al: A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol 15:1344,2004.

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14. Pozzo C et al: Irinotecan in combination with Fluorouracil and acid folinic or with cisplatin in patients with advanced gastric cancer , Ann Oncol 2004 Dec; 15 (12) : 1773-81.15. Cao W, Yang W, Lou G, Jiang J, Geng M, Xi W, Li H, Ma T, Jin Y.Phase II trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) as first-line treatment for advanced gastric cancer. Anticancer Drugs. 2009 Apr; 20(4): 287-93. 16. Cunninghan D, Starling N et al. Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer. N Engl J Med 2008; 358:36-46. 17. Yun J, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK. A randomised phase II study of combination chemotherapy with epirubicin, cisplatin and capecitabine (ECX) or cisplatin and capecitabine (CX) in advanced gastric cancer. Eur J Cancer. 2010 Mar; 46(5):885-91. 18. Schønnemann KR, Jensen HA, Yilmaz M et al. Phase II study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first-line therapy in patients with non-resectable gastric cancer. Br J Cancer. 2008 Sep 16;99(6):858-61. 19. Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, Cortesi E et al. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 2008 Mar 19;100(6):388-98. Epub 2008 Mar 11. 20. Thuss-Patience PC, Kretzschmar A, Repp M, Kingreen D, Hennesser D, Micheel S, Pink D, Scholz C, Dörken B, Reichardt P. Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. J Clin Oncol. 2005 Jan 20;23(3):494-501. 21. Ferrari VD, Amoroso V, Valcamonico F et al. Epirubicin, cisplatin, and raltitrexed in patients with advanced gastric and hepatobiliary carcinoma: a phase II study. Am J Clin Oncol. 2004 Oct;27(5):445-8. 22. Bang, YJ, Van Cutsem, E, Feyereislova, A, et. al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled Trial. Lancet. 2010;376:687-697.

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Tumor do Estroma Gastrointestinal (GIST) Imatinibe Imatinibe: 400 mg/dia VO Ref. (1) Imatinibe: 400 mg VO BID Ref. (2) Sunitinibe Sunitinibe: 50mg/dia VO por 4 semanas a cada 6 semanas Ref.(3) Nilotinibe Nilotinibe: 400mg VO BID Ref. (4)

1. Demetri GD, et al. Efficacy and safety of imatinib mesylate in advancedgastrointestinal stromal tumors. N Engl J Med 2002;347: 472–480. 2. Verweij J, Casali P et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial Lancet 364:1127,2004. 3. Demetri GD et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumors after failure of imatinib: a randomized controlled trial. Lancet 368:1329, 2006. 4. Montemurro M, Schöffski P, Reichardt P, Gelderblom H, Schütte J, Hartmann JT, et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib. Eur J Cancer. 2009 Sep; 45(13): 2293-7.

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Hepatocarcinoma Adriamicina Adriamicina: 20–30 mg/m2 IV semanalmente

Ref. (1)

Cisplatina Cisplatina: 80 mg/m2 IV D1, a cada 28 dias

Ref. (2)

Capecitabina Capecitabina: 1,000 mg/m2 VO BID D1–14 a cada 21 dias

Ref. (3)

Sorafenibe Sorafenibe: 400mg VO BID por dia

Ref. (4)

Capecitabina + Cisplatina Capecitabina: 2000mg/m2/dia, BID, VO, D1 a D14 Cisplatina: 60mg/m2 IV D1 a cada 3 semanas

Ref. (5)

PIAF Cisplatina: 20mg/m2 IV D1 a D4 Interferon alfa 2b 5MU/m2 SC D1 a D4 Doxorrubicina: 40mg/m2 IV D1 5-Fluorouracil: 400mg/m2 IV D1 a D4 a cada 3 semanas.

Ref. (6)

Tamoxifeno Tamoxifeno: 20mg VO por dia

Ref. (7)

1. Venook AP. Treatment of hepatocellular carcinoma: too many options? J Clin Oncol 1994;12:1323–1334. Guia Prático para o Oncologista Clínico •

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2. Okada S, et al. A phase 2 study of cisplatin in patients with hepatocellular carcinoma. Oncology 1993;50:22–26. 3. Aguayo A, et al. Nonsurgical treatment of hepatocellular carcinoma. Semin Oncol 2001;28:503–513. 4. llovet JM. Sorafenib in advanced hepatocellular Carcinoma. N Engl J Med 2008; 359:378-390. 5. Lee JO, Lee KW, Oh DY, Kim JH, Im SA, et al.Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma. Ann Oncol. 2009 Aug; 20(8):1402-7. 6. Yeo W, Mok TS, Zee B, Leung TW et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/ doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005 Oct 19;97(20):1532-8. 7. Barbare JC, Bouché O, Bonnetain F, Raoul JL, Rougier P, Abergel A, Boige V, Denis B, Blanchi A, Pariente A, Milan C, Bedenne L. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol. 2005 Jul 1; 23(19):4338-46.

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Câncer de Vias Biliares Gencitabina Gencitabina: 1000mg/m2 IV D1,8,15 , a cada 28 dias Ref.(1) Cisplatina + Gencitabina Cisplatina: 60mg/m2 IV D1 Gencitabina: 1250mg/m2 IV D1 e D8 a cada 21 dias

Ref.(2)

GEMOX Oxaliplatina: 100mg/m2 IV D1 Gencitabina: 1000mg/m2 IV D1 a cada 14 dias

Ref. (3)

GEMCAP Gencitabina: 1000mg/m2 IV D1 e D8 Capecitabina: 1300mg/m2/dia VO D1 a D14 a cada 21 dias

Ref. (4)

Capecitabina + Cisplatina Capecitabina: 1250mg/m2 VO BID por 14 dias Cisplatina: 60mg/m2 IV D1 a cada 3 semanas

Ref.(5)

Mitomicina + 5-Fluorouracil + Leucovorin Mitomicina C: 10mg/m2 IV D1 5-Fluorouracil: 350mg/m2 IV D1 a D4 Leucovorin: 350mg/m2 IV D1 a D4 a cada 4 semanas

Ref. (6)

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5-Fluorouracil + Radioterapia 5-Fluorouracil: 500mg/m² do D1 a D3 IV pulso na 1° e 5° semana da radioterapia Ou 5-Fluorouracil: 400mg/m² e Leucovorin: 20mg/m², ambos do D1 a D4 em pulso na 1° e 5° semana da radioterapia Radioterapia: concomitante ao 5-Fluorouracil na dose de 45 Gy em frações de 180cGy + boost de 5,4-9,0Gy (dose total 54Gy). Ref. (7) Capecitabina + Radioterapia (M. D. Anderson) Capecitabina: 1500mg/m²/dia VO duas vezes ao dia de segunda a sexta-feira durante todo o tratamento radioterápico. Radioterapia: concomitante a capecitabina na dose de 45 Gy com boost de 10Gy. Ref. (8) CAPOX Oxaliplatina: 130mg/m² IV em 2 horas no D1 Capecitabina: 1000mg/m² VO duas vezes ao dia do D1 ao D14 a cada 21 dias Ref. (9)

1. Gebbia V et al. Treatment of Inoperable and/or Metastatic Biliary Tree Carcinomas With Single-Agent Gemcitabine or in Combination With Levofolinic Acid and Infusional Fluorouracil: Results of a Multicenter Phase II Study. J Clin Oncol, 2001; 19: 4089-91. 2. Kim ST et al. A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer , 2006: 106:1339-46

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3. Andre T, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004; 15: 1339-43. 4. Knoxx JJ et al. Combining Gemcitabine and Capecitabine in Patients With Advanced Biliary Cancer: A Phase II Trial. J Clin Oncol. 2005; 23:2332-8. 5. Kim TW, Chang HM, Kang HJ, Lee JR, Ryu MH, Ahn JH, Kim JH, Lee JS, Kang YK. Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced biliary cancer. Ann Oncol. 2003 Jul;14(7):1115-20. 6. Polyzos A, Nikou G, Giannopoulos A et al. Chemotherapy of biliary tract cancer with mitomycin-C and 5-fluorouracil biologically modulated by folinic acid. A phase II study.Ann Oncol. 1996 Aug;7(6):644-5. 7. Kresl JJ, Schild SE, Henning GT, Gunderson LL, Donohue J, Pitot H, Haddock MG, Nagorney D. Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys 2002: 52: 167. 8. Borghero Y, Crane, CH, Szklaruk J, Oyarzo M, et al. Extrahepatic Bile Duct Adenocarcinoma: Patients at HighRisk for Local Recurrence Treated with Surgery and Adjuvant Chemoradiation Have an Equivalent Overall Survival to Patients with Standard-Risk Treated with Surgery Alone. Annals of Surgical Oncology. 2008: 15(11):3147–3156. 9. Capecitabine plus oxaliplatin as First-line treatment in patients with advanced biliary sysstem adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer 2008: 98: 309-315.

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Câncer de Pâncreas 5-Fluorouracil + Radioterapia 5-Fluorouracil: 500 mg/m2/dia IV D1 a 3 e D29 a 31 seguido de 5-Fluorouracil semanal iniciando no D71 Ref. (1) 5-Fluorouracil + Leucovorin 5-Fluorouracil: 425 mg/m2 IV D1 a 5 Leucovorin: 20 mg/m2 IV D1 a 5 a cada 28 dias

Ref. (2)

Gencitabina + Capecitabina Gencitabina: 1.000 mg/m2 IV D1 e 8 Capecitabina: 650 mg/m2 VO BID D1 a 14 a cada 21 dias

Ref. (3)

Gencitabina + Cisplatina Gencitabina: 1.000 mg/m2 IV D1, 8 e 15 Cisplatina: 50 mg/m2 IV D1 e15 a cada 28 dias

Ref. (4)

GEMOX Gencitabina: 1.000 mg/m2 IV a 10 mg/m2/min D1 Oxaliplatina: 100 mg/m2 IV em 2 horas D2 a cada 2 semanas

Ref. (5)

Gencitabina + Irinotecano Gencitabina: 1.000 mg/m2 IV em 30 minutos D1 e 8 Irinotecano: 100 mg/m2 IV em 90 minutos D1 e 8 a cada 21 dias Ref. (6) FAM 5-Fluorouracil: 600 mg/m2 IV D1, 8, 29 e 36

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Adriamicina: 30 mg/m2 IV D1 e 29 Mitomicina-C: 10 mg/m2 IV D1 a cada 56 dias

Ref. (7)

Gencitabina + Erlotinibe Gencitabina: 1.000 mg/m2 IV semanalmente por 7 semanas, seguida por uma semana de descanso e ciclos subsequentes com Gencitabina 1.000 mg/m2 IV semanalmente por 3 semanas com uma semana de descanso Erlotinibe: 100 mg VO diariamente Repetir o ciclo de 3 semanas a cada 28 dias Ref. (8) Gencitabina Gencitabina: 1,000 mg/m2 IV semanalmente por 7 semanas, seguido por uma semana de descanso Com ciclos subsequentes de 1.000mg/m2, IV semanalmente por 3 semanas com uma semana de descanso Repetir o ciclo de 3 semanas a cada 28 dias Ref. (9) Ou Gencitabina: 1.000 mg/m2 IV a 10 mg/m2/min D1, 8 e15 a cada 28 dias Ref. (10) Capecitabina Capecitabina: 1.250 mg/m2 VO BID D1 a 14 a cada 21 dias

Ref. (11)

FOLFOX6 Oxaliplatina: 100mg/m2 IV em 2 horas D1 Leucovorin: 400mg/m2 IV D1 5-Fluorouracil: 400mg/m2 IV pulso D1 5-Fluorouracil: 3000mg/m2 IV em 46 horas. a cada 15 dias

Ref. (12)

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Gencitabina + Docetaxel + Capecitabina (GTX) Gencitabina: 750 mg/m² IV no D4 e D11 Docetaxel: 30 mg/m² IV no D4 e D11 Capecitabina: 1000-1500 mg/m² VO duas vezes ao dia do D1 ao D14 a cada 2 semanas Ref. (13) FOLFIRINOX Oxaliplatina: 85mg/m² IV em 2h D1 Irinotecano: 180mg/ m² IV em 30 a 90 minutos D1 Leucovorin: 400mg/ m² IV D1 seguido de 5-Fluorouracil 400mg/ m² em pulso D1, seguido de 5Fluorouracil 2400 mg/m2 IV contínuo em 46 horas. a cada 2 semanas Ref. (14) Irinotecano Irinotecano: 350 mg/m2 Ref. (15)

IV

D1

21 dias

Docetaxel Docetaxel: 75 mg/m2 Ref. (16)

IV

D1

21 dias

1. Gastrointestinal Tumor Study Group. Comparative therapeutic trial of radiation with or without chemotherapy in pancreatic carcinoma. Int J Radiat Oncol Biol Phys 1979; 5: 1643–1647. 2. DeCaprio JA, et al. Fluorouracil ehigh-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II trial. J Clin Oncol 1991; 9: 2128–2133. 3. Hess V, et al. Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase I/II trial. J Clin Oncol 2003;21:66–68.

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4. Philip PA, et al. Phase II study of gemcitabine ecisplatin in the treatment of patients with advanced pancreatic carcinoma. J Clin Oncol 2001; 92:569–577. 5. Louvet C, et al. Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study. J Clin Oncol 2002; 20: 1512–1518. 6. Rocha-Lima C, et al. Irinotecan plus gemcitabine induces both radiographic and CA19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 2002;20:1182–1191. 7. Leonard RC, et al. Chemotherapy prolongs survival in inoperable pancreatic carcinoma. Br J Cancer 1994; 81: 882–885. 8. Moore MJ, et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the NCIC-CTG. J Clin Oncol 2005; 23:16S (abstract 1). 9. Burris HA, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy porpatients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–2413. 10. BreR, et al. A phase I trial of semanalmente gemcitabine administered as a prolonged infusion in patients with pancreatic cancer eother solid tumors. Invest New Drugs 1997;15:331–341. 11. Cartwright TH, et al. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 2002; 20:160–164. 12. Ghosn M, Farhat F, Kattan J, Younes F, Moukadem W, Nasr F, Chahine G. FOLFOX-6 combination as the first-line treatment of locally advanced and/or metastatic pancreatic cancer. Am J Clin Oncol. 2007 Feb;30(1):15-20. 13. Fine RL, et al. The GTX regimen: a biochemically synergistic combination for advanced pancreatic cancer (PC). Proc Am Soc Clin Oncol 2003;22:281 (abstract 1129). Guia Prático para o Oncologista Clínico •

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14. T. Conroy, F. Desseigne, et al. Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. J Clin Oncol 28:15s, 2010 (suppl; abstr 4010). 15. Wagener DJ, et al. Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study. Ann Oncol 1995:6:129-32. 16. Lenzi RL, et al. Phase II study of docetaxel in patients with pancreatic cancer previously untreated with cytotoxic chemotherapy. Cancer Invest 2002; 20: 464-72. Câncer Invest 2002;20:464-72.

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Câncer de Cabeça e Pescoço Cisplatina concomitante a radioterapia Cisplatina: 100mg/m2 IV em 2 horas nos D1,22, 43 Ref. (1) Cetuximabe concomitante a radioterapia Cetuximabe: 400mg/m2 (dose de ataque na primeira semana) seguido por 250mg/m2 por semana durante a radioterapia Ref. (2) TPF Docetaxel: 75 mg/m2 IV em 1 hora D1 Cisplatina: 75mg/m2 IV em 1 hora D1 5-Fluorouracil: 750 mg/m2 em 24 horas D1 a 5 a cada 21 dias

Ref. (3)

TIP Paclitaxel: 175 mg/m2 IV em 3 horas D1 Ifosfamida: 1.000 mg/m2 IV em 2 horas D1 a 3 Mesna: 400 mg/m2 IV antes da Ifosfamida e 200 mg/m2 IV, 4 horas após Ifosfamida Cisplatina: 60 mg/m2 IV D1 a cada 21–28 dias Ref. (4) TIC Paclitaxel: 175 mg/m2 IV em 3 horas D1 Ifosfamida: 1.000 mg/m2 IV em 2 horas D1–3 Mesna: 400 mg/m2 IV antes da Ifosfamida e 200 mg/m2 IV, 4 horas após Ifosfamida Carboplatina: AUC 6 IV D1 a cada 21–28 dias Ref. (5)

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Paclitaxel + Carboplatina Paclitaxel: 175 mg/m2 IV em 3 horas D1 Carboplatina: AUC 6 IV no dia 1 a cada 21 dias

Ref. (6)

Paclitaxel + Cisplatina Paclitaxel: 175 mg/m2 IV em 3 horas D1 Cisplatina: 75 mg/m2 IV D2 G-CSF: 5 μg/kg/dia SC D4–10 a cada 21 dias

Ref. (7)

PF Cisplatina: 100 mg/m2 IV D1 5-Fluorouracil: 1.000 mg/m2/dia IV infusão contínua D1 a D5 a cada 21–28 dias Ref. (8) PFL Cisplatina: 100 mg/m2 IV D1 5-Fluorouracil: 800 mg/m2/dia IV infusão contínua D1 a D5 Leucovorin: 50 mg/m2 VO a cada 6 horas D1–5 a cada 21 dias Ref. (9)

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Carboplatina + 5-Fluorouracil Carboplatina: 300–400 mg/m2 IV D1 5-Fluorouracil: 600 mg/m2 IV D1 a cada 21 dias

Ref. (13)

VP Vinorelbina: 25 mg/m2 IV D1 e 8 Cisplatina: 80 mg/m2 IV D1 a cada 21 dias

Ref. (14)

Docetaxel Docetaxel: 100 mg/m2 IV em 1 hora D1 a cada 21 dias

Ref. (15)

• Guia Prático para o Oncologista Clínico

Paclitaxel Paclitaxel: 250 mg/m2 IV em 24 horas D1 a cada 21 dias Ref. (16) Ou Paclitaxel: 137–175 mg/m2 IV em 3 horas D1 a cada 21 dias Ref. (16) Methotrexate Methotrexate: 40 mg/m2 IV or IM semanalmente

Ref. (17)

Vinorelbina Vinorelbina: 30 mg/m2 IV semanalmente

Ref. (18)

PF + Cetuximabe Cisplatina: 100mg/m2 IV em 1 hora D1 Fluorouracil: 1000mg/m2 IV em 24horas D1 a D4 Cetuximabe: 400mg/m2 (dose de ataque) seguido por 250mg/m2 IV por semana. A cada 21 dias, por 6 ciclos. Ref. (19) Gencitabina Gencitabina: 1250mg/m2, IV , D1 e D8, a cada 21 dias. Ref. (20) Capecitabina Capecitabina: 1250mg/m2 VO BID D1 a D14 a cada 21 dias

Ref. (21)

Ifosfamida Ifosfamida: 3g/m2 IV D1 a D3 Mesna: 1800mg/m2 IV D1 a D3 a cada 3 semanas

Ref. (22)

Cisplatina + 5-Fluorouracil + Radioterapia Cisplatina: 100 mg/m2 IV D1 5-Fluorouracil: 1000 mg/m2 D1 a 5 em infusão contínua Radioterapia concomitante. a cada 21 a 28 dias no total de 3 ciclos Ref. (32) Guia Prático para o Oncologista Clínico •

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Cisplatina + Radioterapia Cisplatina: 100 mg/m2 D1, 22 e 43 Radioterapia concomitante

Ref. (33)

Cisplatina + 5-Fluorouracil + Docetaxel Cisplatina: 75 mg/m2 IV D1 2 5-Fluorouracil: 750mg/m /dia IV D1 a D5 Infusão contínua Docetaxel: 75mq/m2 IV D1 a cada 21 dias por 3 ciclos O regime acima é administrado antes da cirugia e seguido por quimio-radioterapia, com o regime abaixo: Cisplatina: 100 mg/m2 IV D1 a cada 21 dias por 3 ciclos Ref. (34) Cisplatina + 5-Fluorouracil + Paclitaxel Cisplatina: 100 mg/m2 IV D2 5-Fluorouracil: 500 mg/m2/dia IV D2 a D6 Infusão contínua Paclitaxel: 175 mg/m2 IV D1 a cada 21 dias por 3 ciclos O regime acima é administrado antes da cirugia e seguido por quimio-radioterapia, com o regime abaixo: Cisplatina: 100 mg/m2 IV D1 a cada 21 dias por 3 ciclos Ref. (35) Paclixatel + Doxorrubicina peguilada Paclitaxel: 175 mg/m2 IV D1 21 dias 2 Doxorrubicina: 40 mg/m IV lipossomal peguilada D1 28 dias Ref. (40) Paclitaxel + Gencitabina Paclitaxel: 175 mg/m2 IV 2 Gencitabina: 1000 mg/m IV Ref. (41)

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D1 D1 e D8 a cada 21 dias

Linfoepitelioma – Nasofaringe Quimioterapia + Radioterapia Cisplatina: 100 mg/m2 IV D1, 22 e 43 durante radioterapia Após o término da quimio e radioterapia a quimioterapia segue com o seguinte protocolo: Cisplatina: 80 mg/m2 IV D1 5-Fluorouracil: 1,000 mg/m2/dia IV infusão contínua D1-4 a cada 28 dias por um total de 3 ciclos Ref. (12) PBF Cisplatina: 100mg/m2 IV D1 Bleomicina: 15 mg IV D1 Bleomicina: 16mg/m2/dia em infusão contínua D1 a D5 Fluorouracil 650mg/m2/dia IV D1 a D5 a cada 28 dias Ref. (23) Paclitaxel concomitante a radioterapia Paclitaxel: 35mg/m2 IV semanal por 6 semanas Após término da radioterapia: Paclitaxel: 135mg/m2 IV D1 Cisplatina: 30mg/m2 IV D1 a D3 a cada 4 semanas por 2 ciclos

Ref. (24)

Cisplatina + Epirrubicina Cisplatina: 100mg/m2 IV D1 Epirrubicina: 90mg/m2 IV D1 a cada 21 dias Repetir por 3 ciclos seguidos por radioterapia concomitante a Cisplatina: 100mg/m2 IV a cada 21 dias Ref. (25) Guia Prático para o Oncologista Clínico •

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Capecitabina + Cisplatina Capecitabina: 1000mg/m2 VO BID D1 a D14 Cisplatina: 80 mg/m2 IV D1 a cada 3 semanas Ref. (26) Gencitabina Gencitabina: 1000mg/m2 IV D1,8,15 a cada 4 semanas Ref. (27) Docetaxel + Cisplatina Docetaxel: 60mg/m2 IV D1 Cisplatina: 60mg/m2 IV D1 a cada 3 semanas Ref. (28) Gencitabina + Cisplatina Gencitabina: 1000mg/m2 IV D1,8,15 Cisplatina: 50mg/m2 IV D1 e D8 a cada 28 dias Ref. (29) Ifosfamida + 5-Fluorouracil + Leucovorin Ifosfamida: 1.200 mg/m2 (associado a Mesna) IV D1 a D5 5-Fluorouracil: 375mg/m2 IV D1 a D5 Leucovorin: 20mg/m2 IV D1 a D5 a cada 21 dias Ref. (30) BEC Bleomicina: 15mg IV D1 seguido por 12mg/m2/dia em infusão contínua D1 a D5 Epirrubicina: 70mg/m2 IV D1 Cisplatina: 100mg/m2 IV D1 a cada 3 semanas Ref. (31)

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Carboplatina + 5-Fluorouracil Carboplatina: 300 mg/m2 IV D1 5-Fluorouracil: 1000 mg/m2 IV D1 a D3 Infusão contínua a cada 21 dias por 3 ciclos Ref. (36) Carboplatina + Paclitaxel Carboplatina: AUC 6 IV pulso D1 2 Paclitaxel: 135 mg/m IV D1 a cada 21 dias por 6 ciclos Ref. (37) Cisplatina + Epirrubicina + Bleomicina (BEC) Cisplatina: 100 mg/m2 IV D1 Epirrubicina: 80 mg/m2 IV D1 Bleomicina: 15 mg IV pulso D1 Bleomicina: 16 mg/m2 IV D1 a D5 Infusão contínua a cada 28 dias por 3 ciclos Ref. (38) Docetaxel semanal Docetaxel: 40 mg/m2 Ref. (39)

IV

D1

Semanal

1. Forastiere AA. et al. Concurrent Chemotherapy and Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer. N Engl J Med 349:2091, 2003. 2. Bonner JA. et al Radiotherapy plus Cetuximab for SquamousCell Carcinoma of the Head and Neck. N Engl J Med 2006; 354:567-578. 3. Vermorken JB et al. Cisplatin, Fluorouracil, and Docetaxel in Unresectable Head and Neck Cancer. N Engl J Med 357: 1695,2007. 4. Shin DS, et al. Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head eneck squamous cell carcinoma. J Clin Oncol 1998;16:1325-1330. Guia Prático para o Oncologista Clínico •

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5. Shin DM, et al. Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head eneck squamous cell carcinoma of the head eneck (SCCHN). Cancer 1999; 91:1316-1323. 6. Fountzilas G, et al. Paclitaxel and carboplatin in recurrent or metastatic head and neck cancer: a phase II study. Semin Oncol 1997; 24 (Suppl 2):65-67. 7. Hitt R, et al. A phase I/II study of paclitaxel plus cisplatin as firstline therapy fo rhead and neck cancer. Semin Oncol 1995;22 (Suppl 15):50-54. 8. Kish JA, et al. Cisplatin and 5-fluorouracil infusion in patients with recurrent and disseminated epidermoid cancer of the head and neck. Cancer 1984;53:1819-1824. 9. Vokes EE, et al. Cisplatin, 5-fluorouracil, and high-dose oral leucovorin for advanced head and neck cancer. Cancer 1989;63 (Suppl 6):1048–1053. 10. Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324: 1685-1690. 11. Forastiere AA, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-2098. 12. Al-Sarraf M, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol 1998;16:1310-1317. 13. Forastiere AA, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head eneck: a Southwest Oncology Group study. J Clin Oncol 1992;10:1245–1251. 14. Gebbia V, et al. Vinorelbine plus cisplatin in recurrent or previously untreated unresectable squamous cell carcinoma of the head and neck. Am J Clin Oncol 1995;18:293–296.

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15. Dreyfuss A, et al. Taxotere for advanced, inoperable squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 1995;14:875a. 16. Forastiere AA. Current and future trials of Taxol (paclitaxel) in head and neck cancer. Ann Oncol 1994;5 (Suppl 6):51–54. 17. Hong WK, et al. Chemotherapy in head and neck cancer. N Engl J Med 1983;308:75-79. 18. Degardin M, et al. An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinomaof the head and neck. Ann Oncol 1998; 9:1103-1107. 19. Vermorken JB, et al. Platinum Based Chemotherapy plus cetuximab in Head and neck cancer. N Engl J Med 2008; 359.1116. 20. van Herpen CM, et al. Phase II study on gemcitabine in recurrent and/or metastatic adenoid cystic carcinoma of the head and neck (EORTC 24982). Eur J Cancer. 2008 Nov; 44(17):2542-5. 21. Martinez-Trufero J, Isla D, Adansa JC et al. Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment. Br J Cancer. 2010 Jun 8;102(12):1687-91. 22. Martín M, Diaz-Rubio E et al. Ifosfamide in advanced epidermoid head and neck cancer. Cancer Chemother Pharmacol. 1993;31(4):340-2. 23. Boussen H, Cvitkovic E, Wendling JL et al. Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol. 1991 Sep;9(9):1675-81 24. Hu W, Ding W, Yang H, Shao M. et al. Weekly paclitaxel with concurrent radiotherapy followed by adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma. Radiother Oncol. 2009 Dec; 93(3):488-91. 25. Airoldi M, Gabriele AM, Garzaro M et al. Induction chemotherapy with cisplatin and epirubicin followed by radiotherapy and concurrent cisplatin in locally advanced Guia Prático para o Oncologista Clínico •

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nasopharyngeal carcinoma observed in a non-endemic population.Radiother Oncol. 2009 Jul;92(1):105-10. 26. Li YH, Wang FH, Jiang WQ et al. Phase II study of capecitabine and cisplatin combination as first-line chemotherapy in Chinese patients with metastatic nasopharyngeal carcinoma. Cancer Chemother Pharmacol. 2008 Aug; 62(3): 539-44. 27. Zhang L, Zhang Y et al. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2008 Jan;61(1):33-8 28. Chua DT, Sham JS, Au GK.A phase II study of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic nasopharyngeal carcinoma. Oral Oncol. 2005 Jul;41(6):589-95. 29. Ngan RK, Yiu HH, Lau WH et al. Combination gemcitabine and cisplatin chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: report of a phase II study. Ann Oncol. 2002 Aug;13(8):1252-8. 30. Chua DT, Kwong DL, Sham JS, Au GK, Choy D.A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy. 2000 Apr;36(6):736-41. 31. No authors listed. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys. 1996 Jun 1;35(3):463-9. 32. Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685-90. 33. Forastiere AA et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-2098.

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34. Hitt R, et al. Randomized phase I/II clinical trial of induction chemotherapy with either cisplatin / 5-fluorouracil (PF) or docetaxel /cisplatin / 5-fluorouracil (TPF) followed by chemoradiotherapy (CRT) vs. CRT alone form in patients with unresectable locally advanced head and neck cancer (abst 5515). J Clin Oncol. 2006;24 Suppl 18: 283s. 35. Hitt R, et al. Phase III Study Comparing Cisplatin Plus Fluorouracil to Paclitaxel, Cisplatin, and Fluorouracil Induction Chemotherapy Followed by Chemoradiotherapy in Locally Advanced Head and Neck Cancer. J Clin Oncol 2005;23:8636-45. 36. Yeo W. et al. Phase II study of the combination of carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma. Cancer Chemother Pharmacol 1996;38:466-70. 37. Yeo W.et al. A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur J Cancer 1998;34:2027-31. 38. Fandi A, et al. Long-Term Disease-Free Survivors in Metastatic Undifferentiated Carcinoma of Nasopharyngeal Type. J Clin Oncol 2000;18:1324-30. 39. Guardiola E, et al. Results of a randomized phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer 2004;40:2071-6. 40. Fountzilas G, et al. Paclitaxel and gemcitabine vs. paclitaxel and pegylated liposomal doxorubicin in advanced nonnasopharyngeal head and neck cancer. An efficacy and cost analysis randomized study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 2006;17:1560-7. 41. Fountzilas G, et al. Paclitaxel and gemcitabine vs. paclitaxel and pegylated liposomal doxorubicin in advanced nonnasopharyngeal head and neck cancer. An efficacy and cost analysis randomized study conducted by the Hellenic Cooperative Oncology Group Ann Oncol 2006;17:1560-7.

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Câncer de Tireóide Adriamicina + Cisplatina Adriamicina: 60 mg/m2 IV D1 Cisplatina: 40 mg/m2 IV D1 a cada 21 dias Ref. (1) Sorafenibe Sorafenibe: 400mg VO BID Ref. (2) Paclitaxel Paclitaxel: 120 mg/m2 IV durante 96 horas a cada 21 dias Ref. (3)

1. Shimaoka K, et al. A randomized trial of Adriamicina versus Adriamicina plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985;56:2155–2160. 2. Lam ET, Ringel MD, Kloos RT, Prior TW et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010 May 10;28(14):2323-30. 3. Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Thyroid. 2000;10:587-94.

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Câncer de Glândula Salivar Adriamicina + Cisplatina Adriamicina: 50mg/m2 IV D1 Cisplatina: 20mg/m2/dia IV D1 a D5 a cada 3 semanas

Ref. (1)

Paclitaxel + Carboplatina Paclitaxel: 175mg/m2 IV D1 Carboplatina: AUC 5 IV D1 a cada 21 dias

Ref. (2)

Ciclofosfamida Ciclofosfamida: 1000mg/m2 IV D1 a cada 21 dias

Ref.(3)

CAP Ciclofosfamida: 500mg/m2 IV D1 Doxorrubicina: 50mg/m2 IV D1 Cisplatina: 50mg/m2 IV D1 a cada 28 dias

Ref. (4)

PAF Cisplatina: 50mg/m2 IV D1 e D8 Doxorrubicina: 30mg/m2 IV D1 e D8 5-Fluorouracil: 500mg/m2 IV D1 e D8 a cada 28 dias

Ref. (5)

Epirrubicina Epirrubicina: 90mg/m2 IV D1 a cada 21 dias

Ref. (6)

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Cisplatina + Vinorelbina Cisplatina: 80mg/m2 IV D1 Vinorelbina: 25mg/m2 IV D1 e D8 a cada 3 semanas

Ref. (7)

1. de Haan LD, De Mulder PH, Vermorken JB, Schornagel JH, Vermey A, Verweij J. Cisplatin-based chemotherapy in advanced adenoid cystic carcinoma of the head and neck. Head Neck. 1992 Jul-Aug;14(4):273-7. 2. Airoldi M, Fornari G, Pedani F, Marchionatti S, Gabriele P, Succo G, Bumma C. Paclitaxel and carboplatin for recurrent salivary gland malignancies. Anticancer Res. 2000 SepOct;20(5C):3781-3. 3. Spiers A, Esseltine DLW, et al. Metastatic Adenoid Cystic Carcinoma of Salivary Glands: Case Reports and Review of the Literature. Cancer Control Journal. Vol 3, No. 4 July/August 1996. 4. Dreyfuss AI, Clark JR et al. Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin. Cancer. 60:2869-2872, 1987. 5. Venook AP, Tseng A, et al. Cisplatin, Doxorubicin, and 5Fluorouracil Chemotherapy for Salivary Gland Malignancies: A Pilot Study of the Northern California Oncology Group. JCO June 1, 1987 vol. 5 no. 6 951-955 6. Vermorken JB, Verweij J et al. Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: A phase II study of the EORTC Head and Neck Cancer Cooperative Group . Annals of Oncology Volume4, Issue 9 Pp. 785-788. 7. Airoldi M,Pedani F, Succo G et al. Phase II Randomized Trial Comparing Vinorelbine versus Vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer 2001; 91: 541-7.

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Câncer de Bexiga Cisplatina + Gencitabina Cisplatina: 75mg/m2 IV Gencitabina: 1000mg/m2 IV a cada 28 dias

D1 D1, D8, D15

Carboplatina + Gencitabina Carboplatina: AUC 4 Gencitabina: 1000mg/m2 a cada 21 dias

IV IV

Gemcitabina + Paclitaxel Gencitabina: 1000mg/m2 Paclitaxel: 200mg/m2 a cada 21 dias

IV IV

D1, D8, D15 D1 Ref. (3)

MVAC Methotrexate: 30mg/m2 Vinblastina: 3mg/m2 Doxorrubicina: 30mg/m2 Cisplatina: 70mg/m2 a cada 28 dias

IV IV IV IV

D1, D15, D22 D2, D15, D22 D2 D2 Ref. (4)

CISCA Ciclofosfamida: 650mg/m2 Adriamicina: 50mg/m2 Cisplatina: 100mg/m2 a cada 21 dias

IV IV IV

D1 D1 D2

Ref. (1)

D1 D1, D8 Ref. (2)

Ref. (5)

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CMV Cisplatina: 100mg/m2 Methotrexate: 30mg/m2 Vinblastina: 4mg/m2 Ref. (6) Docetaxel + Cisplatina Docetaxel: 75mg/m2 Cisplatina: 75mg/m2

IV D2 IV D1, D8 IV D1, D8

a cada 21 dias

IV IV

D1 D1 a cada 21 dias

Paclitaxel + Carboplatina Paclitaxel: 225mg/m2 Carboplatina: AUC 6 Ref. (7)

IV IV

D1 D1 a cada 21 dias

CAP Ciclofosfamida: 400mg/m2 Doxorrubicina: 40mg/m2 Cisplatina: 75mg/m2 Ref. (8)

IV IV IV

D1 D1 D1 a cada 21 dias

IV

D1, D8, D15

Gencitabina Gencitabina: 1200mg/m2 a cada 28 dias Ref. (9) Paclitaxel Paclitaxel: 250mg/m2 24 horas a cada 21 dias

IV

D1 em infusão de Ref. (10)

Ou Paclitaxel: 80mg/m2 a cada 28 dias Ref. (11)

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IV

D1, D8, D15

Carboplatina + Paclitaxel + Gencitabina Paclitaxel: 80mg/m² IV D1 e D8 Carboplatina: AUC 5 IV D1 Gencitabina: 800mg/m² IV D1 e D8 a cada 21 dias Ref. (12) Cisplatina + Radioterapia Cisplatina: 100mg/m² IV em 2 aplicações, na 1° e 4° semana da Radioterapia. Radioterapia: dose total de 40 Gy em frações de 180 cGy . Ref. (13) Gencitabina + Paclitaxel + Cisplatina Gencitabina: 1000mg/m² IV D1 e D8 Paclitaxel: 80mg/m² IV D1 e D8 Cisplatina: 70 mg/m² IV D1 a cada 21 dias Ref. (14) Pemetrexede Pemetrexede: 500 mg/m² IV D1 a cada 21 dias Ref. (15) Vinflunina Vinflunina: para pacientes com ECOG PS (0) a dose recomendada é de 320mg/m² durante 20 minutos no D1. Para pacientes com ECOG PS (1) ou irradiação pélvica prévia iniciar com a dose de 280mg/m² e escalonar até a dose ideal de 320mg/m². Ref. (16)

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1. Kaufman, D., et al. Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol, 2000. 18(9): p. 1921-7. 2. Linardou, H., et al. Gemcitabine and carboplatin combination as first-line treatment in elderly patients and those unfit for cisplatin-based chemotherapy with advanced bladder carcinoma: Phase II study of the Hellenic Co-operative Oncology Group. Urology, 2004. 64(3): p. 479-84. 3. Meluch, A.A., et al. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol, 2001. 19(12): p. 3018-24. 4. Sternberg, C.N., et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer, 1989. 64(12): p. 2448-58. 5. Logothetis CJ, Dexeus FH, Chong C, et, al. Cisplatin, cyclophosphamide and doxorubicin chemotherapy for unresectable urothelial tumors: The M.D. Anderson Experience. J Urol. 1989; 141:33-37. 6. Harker, W.G., et al. Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study. J Clin Oncol, 1985. 3(11): p. 1463-70. 7. Vaughn, D.J., et al. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer, 2002. 95(5): p. 1022-7. 8. Okajima E, Ozono S, Hirao Y, et. al. Neoadjuvant therapy for locally invasive bladder cancer. Urol Int. 1989;44 (6):332-337. 9. Moore, M.J., et al. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol, 1997. 15(12): p. 3441-5.

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10. Roth, B.J., et al. Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol, 1994. 12(11): p. 2264-70. 11. Vaughn, D.J., et al. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol, 2002. 20(4): p. 937-40. 12. White RWV,,Lara P, Goldman B, Tangen C, Smith DC, et al. A Sequential Treatment Approach to Myoinvasive Urothelial Cancer: A Phase II Southwest Oncology Group Trial (S0219). The Journal of Urology: 2009; 181;2480-2481 13. Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1999;17(4):1327-8. 14. Bellmunt J, Von der Maase J, Mead GM, Heyer J, Houede N, et al. Randomized phase III study comparing paclitaxel/ cisplatin/ gemcitabine (PCG) and gemcitabine/cisplatin (GC) in patients with locally advanced (LA) or metastatic (M) urothelial cancer without prior systemic therapy; EORTC30987/Intergroup Study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: LBA5030. 15. Sweeney CJ, et al. Phase II Study of Pemetrexed for SecondLine Treatment of Transitional Cell Cancer of the Urothelium. J Clin Oncol 2006;24:3451-57 16. Bellmunt J, Theodore C, DemKov T, Komyakov B, Sengelov L, Daugaard G, Caty A, et al. Phase III Trial of Vinflunine Plus Best Suportive Care Compared with Best Supportive Care Alone After Platinum Containing Regimen in Patients With Advanced Transitional Cell Carcinoma of the Urothelial Tract (TCCU). J Clin Oncol 2009: 27: 4454-4461. Guia Prático para o Oncologista Clínico •

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Câncer Renal Bevacizumabe+ Interferon Alfa Bevacizumabe: 10mg/kg IV Interferon-alfa: 9 milhões UI SC Por 1 ano

D1, D14 3X/semana Ref. (1)

Interferon Alfa + Interleucina 2 Interferon alfa: 9 milhões U SC D1 a D4 Interleucina 2: 12 milhões U SC D1 a D4 em 4 semanas a cada 6 semanas Ref. (2)

80

Sunitinibe Sunitinibe: 50mg a cada 6 semanas

VO

Sorafenibe Sorafenibe: 400mg sem interrupção

VO (2X/dia)

Tensirolimo Tensirolimo: 25mg Ref. (5)

IV

D1 a D28 Ref. (3)

Contínuo Ref. (4)

D1

Semanal

Interferon Alfa Interferon alfa: 5-15milhões/UI Ref. (6)

SC

3-5X/semana

Interleucina 2 Interleucina 2: 720000UI/KG 8-12 semanas

IV

12/12H D1-5, 15-19 Ref. (7)

• Guia Prático para o Oncologista Clínico

Everolimo Everolimo: 10mg Ref. (8)

VO

dia

Contínuo

Pazopanibe Pazopanibe: 800mg Ref. (9)

VO

dia

Contínuo

1. Rini, B.I., Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for CALGB 90206 journal of clinical oncology, 2009. 27(18S): p. abstract 5020. 2. Atzpodien, J., et al. European studies of interleukin-2 in metastatic renal cell carcinoma. Semin Oncol, 1993. 20(6 Suppl 9): p. 22-6. 3. Motzer, R.J. and R.M. Bukowski, Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol, 2006. 24(35): p. 5601-8. 4. Ratain, M.J., et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol, 2006. 24(16): p. 2505-12. 5. Hudes, G., et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med, 2007. 356(22): p. 2271-81. 6. Minasian, L.M., et al. Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up. J Clin Oncol, 1993. 11(7): p. 1368-75. 7. Acquavella, N., et al. Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen in patients with metastatic melanoma and metastatic renal cell cancer. J Immunother, 2008. 31(6): p. 569-76. Guia Prático para o Oncologista Clínico •

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8. Motzer, R.J., et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet, 2008. 372(9637): p. 449-56. 9. Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28(6):1061-1068.

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• Guia Prático para o Oncologista Clínico

Câncer de Próstata Flutamida + Leuprorrelina Flutamida: 250mg VO TID Leuprorrelina: 7,5mg IM a cada 28 dias ou 22,5 mg IM a cada 12 semanas Ref. (01) Flutamida + Gosserrelina Flutamida: 250 mg VO TID Gosserrelina: 10,8 mg SC a cada 12 semanas

Ref. (02)

Docetaxel + Prednisona Docetaxel: 75 mg/m² IV D1 Prednisona: 5 mg VO BID a cada 21 dias no total de 10 ciclos

Ref. (03)

Docetaxel + Estramustina Docetaxel: 35 mg/m² IV D2 das semanas 1 e 2 Estramustina: 420 mg VO nas primeiras 4 doses e 280 mg VO nas próximas 5 doses D1 ao D3 das semanas 1 e 2 a cada 21 dias Ref. (04) Mitoxantrona + Prednisona Mitoxantrona: 12 mg/m² IV D1 Prednisona: 5 mg VO BID a cada 21 dias

Ref. (05)

Docetaxel Docetaxel: 20-40 mg/m² semanalmente por 3 semanas a cada 4 semanas Ref. (06) Gosserrelina Gosserrelina: 3,6 mg SC D1 a cada 28 dias Guia Prático para o Oncologista Clínico •

83

Ou Gosserrelina: 10,8 mg SC D1 a cada 12 semanas

Ref. (07)

Leuprorrelina Leuprorrelina: 7,5 mg IM D1 a cada 28 dias Ou Leuprorrelina: 22,5 mg IM D1 a cada 12 semanas

Ref. (08)

Bicalutamida Bicalutamida: 50 mg VO diariamente

Ref. (09)

Flutamida Flutamida: 250 mg VO TID

Ref. (10)

Nilutamida Nilutamida: 300 mg VO do D1 ao D30, e então 150 mg VO diariamente Ref. (11) Prednisona Prednisona: 5 mg VO BID

Ref. (12)

Cetoconazol Cetoconazol: 1200 mg VO diariamente

Ref. (13)

Paclitaxel Paclitaxel: 135-170 mg/m2 IV em 24 horas D1 a cada 21 dias

Ref. (14)

Ou

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• Guia Prático para o Oncologista Clínico

Paclitaxel: 150 mg/m2 IV D1 em infusão de 1 hora a cada 6 semanas. a cada 8 semanas Ref. (15) DES Dietilestilbestrol: 1 a 3 mg VO no dia

Ref. (16)

Cabazitaxel + Prednisona Cabazitaxel: 25 mg/ m2 IV a cada 21 dias Prednisona: 10 mg VO/dia

Ref. (17)

Vinorelbina + Hidrocortisona Vinorelbina: 30 mg/ m2 Dias 1 e 8 a cada 21 dias. + Hidrocortisona: 40 mg VO dia, uso contínuo.

Ref. (18)

Abiraterona + Prednisona Abiraterona: 1g VO dia + Prednisona: 5 mg VO 2 x dia, uso contínuo.

Ref. (19)

1. Eisenberger MA, et al. Prognostic factors in stage D2 prostate cancer: important implications for future trials; results of a cooperative intergroup study (INT.0036). The national cancer institute intergroup study #0036. Semin oncol 1994;21:613-619. 2. Jurincic CD, et al. Combined treatment (goserelin plis flutamide) versus monotherapy (goserelin alone) in advanced prostate cancer: a randomized study. Semin oncol 1991;18 (Suppl 6):21-25. 3. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004. 4. Copur MS, et al. Weekly docetaxel and estramustine in patients Guia Prático para o Oncologista Clínico •

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with hormone-refractory prostate cancer. Semin oncol 2001;28:16-21. 5. Tannock IF, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormoneresistant prostate cancer: a Canadian randomized trial with palliative end points. J clin oncol 1996:14:1756-1764. 6. Dreicer R. Chemotherapy for advanced prostate cancer: docetaxel and beyond. Hematol oncol clin north Am 2006;20:935-926. 7. Dijkman GA, et al. A randomized trial comparing the safety and efficacy oh the zoladex 10.8mg de pot, administered every twelve weeks, to that of the zoladex 3.6mg depot, administered every four weeks, in patients with advanced prostate cancer. The Dutch South East Cooperative Urological Group. Eur Urol 1995;27:43-46. 8. The Leuprolide Study Group. Leuporlide versus diethylstilbestrol for metastatic prostate cancer. N Engk J Med 1984;311:1281-1286. Sharifi R, et al. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. Clin Ther 1996;18:647-657. 9. Schellhammer PF, et al. Clinical benefits of bicalutamide compared with flutamide in combined androgen clockade for patients with advanced prostatic carcinoma: final report of a double blind, randomized, multicenter trial. Urology 1997;50:330-336. 10. Mc Leod DG, et al. The use of flutamide in hormone refractory metastatic prostate cancer. Cancer 1993;72:38703873. 11. Janknegt RA, et al. Orchiectomy and nilutamine or placebo as treatment of metastatic prostatic cancer in a multinational doubleblind randomized trial. J Urol 1993;149:77-82. 12. Tannock IF, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-

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• Guia Prático para o Oncologista Clínico

resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996:14:1756-1764. 13. Johnson DE, et al. Ketoconazole therapy for hormonally refractive metastatic prostate cancer Erology 1988;31:132134. 14. Roth BJ. et al. Taxol in advanced, hormone-refractory carcinoma of the rrw.ate. A phase II trial of the Eastern Cooperative Oncoiogy Group cancer 1993;2:245-2260. 15. Ahmed S, et al. Feasibility of weekly one hour paclitaxel in hormone refractory prostate cancer (HRPC): a preliminary report of a phase II trial. Proc Am Soe Clin Oncol 1998; 17:325a. 16. Smith DC, Redman BG, Flaherty LE, Li L, et al. phase II trial of oral diethylstilbesterol as a secondline hormonal agent in advanced prostate cancer. Urology.1998;52:257-60. 17. Bono J. S. de, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). J Clin Oncol. 2010. 28:15s (suppl; abstr 4508). 18. Abratt R. P , Brune D., Dimopoulos M. - A, et. Al. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormonerefractory prostate cancer. Ann Oncol. 2004;15(11): 16131621. 19. de Bono JS, Logothetis CJ, Molina A, et. al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 26;364(21):1995-2005.

Guia Prático para o Oncologista Clínico •

87

Câncer de Testículo PEB Bleomicina: 30 UI, IV D2, D9 e D16 Etoposide: 100 mg/m² IV D1 ao D5 Cisplatina: 20 mg/m² IV D1 ao D5 a cada 21 dias no total de 3 ou 4 ciclos Ref. (1) Carboplatina 1- 2 ciclos Carboplatina: AUC de 7 IV em 30 minutos a cada 3 semanas no total de 1 ou 2 ciclos Ref. (2) EP Etoposide: 100 mg/m² IV D1 ao D5 Cisplatina: 20 mg/m² IV D1 ao D5 a cada 21 dias no total de 4 ciclos Ref. (3) VeIP (regime de resgate) Vimblastina: 0,11 mg/kg IV D1 e D2 Ifosfamida: 1200 mg/m² IV D1 ao D5 Cisplatina: 20 mg/m² IV D1 ao D5 Mesna: 400 mg/m² IV, administrado 15 minutos antes da primeira dose de ifosfamida, e então 1200 mg/m²/dia IV infusão contínua por 5 dias a cada 21 dias Ref. (4)

88

• Guia Prático para o Oncologista Clínico

VIP (regime de resgate) Etoposide: 75 mg/m² IV D1 ao D5 Ifosfamida: 1200 mg/m² IV D1 ao D5 Cisplatina: 20 mg/m² IV D1 ao D5 Mesna: 400 mg/m² IV administrado 15 minutos antes na primeira dose de Ifosfamida, e então 1200 mg/m²/dia IV infusão contínua por 5 dias. Filgrastima: 300mcg SC por 5 dias a cada 21 dias Ref. (5) TIP (regime de resgate) Paclitaxel: 250 mg/m² IV infusão contínua D1 Ifosfamida: 1200 mg/m² IV durante 1 hora D2 ao D6 Cisplatina: 20 mg/m² IV durante 1 hora D2 ao D6 Mesna: 400 mg/m² IV 30 min antes, 4 e 8 horas após Ifosfamida Filgrastima: 300 mcg/dia SC por 5 dias. a cada 21 dias Ref. (6) BEP Cisplatina 50 mg/m2 IV D1 e D2 Bleomicina 30 mg IV D2, D9 e D16 Etoposide 165 mg/m2/dia IV D1, D2 e D3 Ref. (7) CBOP/BEP (regime de resgate) Ciclo 1 e 2 (C-BOP) Cisplatina 50 mg/m2 IV D1 e D2 Vincristina 2mg IV D1 e D8 Bleomicina 15 mg IV D1 e D8 Cisplatina 40 mg/m2 IV Carboplatina AUC3 IV D8 Bleomicina 15 mg IV em infusão contínua D8 a D12

Guia Prático para o Oncologista Clínico •

89

Ciclo 3 (BO) Vincristina 2mg IV D1 e D8 Bleomicina 15 mg IV D1 e D8 Ciclo 4, 5 e 6 (BEP modificado) Cisplatina 20 mg/m2/dia, D1 a D5 Etoposide 100mg/m2/dia, D1 a D5 Bleomicina 15 mg IV D1, D8 e D15 SEMANAS 1 a 4 → 2 ciclos de C-BOP SEMANAS 5 e 7 → 2 ciclos de BO SEMANAS 10, 13 e 17 → 3 ciclos de BEP modificado Ref. (8) 1. Williams SD, et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987;316:1465-1440. 2. Oliver RT, Mason MD, Mead GM, von der Maase H, Rustin GJ, Joffe JK, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 2005;366:293–300. 3. Bosl G, et al. A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with goodprognosis germ cell tumors. J Clin Oncol 1988;6:1231-1238. 4. Loehrer PJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988;109:540-546. 5. Loehrer PJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988;109:540-546. 6. Motzer R, Sheinfeld J, Mazumdar M et al. Paclitaxel, Ifosfamide, and Cisplatin Second-Line Therapy for Patients With Relapsed Testicular Germ Cell Cancer J Clin Oncol 2000:2413-2418.

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• Guia Prático para o Oncologista Clínico

7. De Wit R, Roberts JT, Wilkinson PM et al. Equivalence of Three or Four Cycles of Bleomycin, Etoposide, and Cisplatin Chemotherapy and of a 3- or 5-Day Schedule in GoodPrognosis Germ Cell Cancer: A Randomized Study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001;19:1629-40. 8. Christian JA, Huddart RA, Norman A et al. Intensive in duction chemotherapy with CBOP/BEP in patients with poor prognosis germ cell tumors. J Clin Oncol 2003;21: 871–77.

Guia Prático para o Oncologista Clínico •

91

Câncer de Pênis TIP Paclitaxel: 175 mg/m2 IV D1 Cisplatina: 25 mg/ m2 IV D1-D3 Ifosfamida: 1200 mg/ m2 IV D1-D3 Mesna : 400 mg/ m2 IV hora 0,4 e 8 da Ifosfamida a cada 21 dias Ref. (1) Cisplatina + 5-Fluorouracil Cisplatina: 100 mg/m2 IV 2 5-Fluorouracil: 1000 mg/m IV Ref. (2)

D1 D1-D4 a cada 21 dias

1. Pagliaro Lance C., Williams Dallas L., Daliani, Danai. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer:a phase II study. J Clin Oncol. 2010; 28: 3851-3857. 2. Shammas FV, Ous S, Fossa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol 1992;147:630-2.

92

• Guia Prático para o Oncologista Clínico

Câncer de Endométrio Carboplatina + Paclitaxel Carboplatina: AUC 5-7 Paclitaxel: 175mg/m2 a cada 21 dias Ref. (1) Adriamicina + Ciclofosfamida Doxorrubicina: 60mg/m2 Ciclofosfamida: 500mg/m2 a cada 21 dias Ref. (2) Adriamicina + Cisplatina Doxorrubicina: 50mg/m2 Cisplatina: 50mg/m2 a cada 21 dias Ref.(3) Adriamicina + Paclitaxel Doxorrubicina: 50mg/m2 Paclitaxel: 150mg/m2 a cada 21 dias Ref. (4)

IV IV

D1 D1

IV IV

D1 D1

IV IV

D1 D1

IV IV

D1 D1

Cisplatina + Doxorrubicina + Paclitaxel Cisplatina: 50mg/m2 IV Doxorrubicina: 45mg/m2 IV 2 Paclitaxel: 160mg/m IV Filgrastima: 5mcg/kg SC a cada 21 dias Ref. (5)

D1 D1 D2 D3-D12

Guia Prático para o Oncologista Clínico •

93

CAP Ciclofosfamida: 500mg/m2 Doxorrubicina: 50mg/m2 Cisplatina: 500mg/m2 Ref. (6)

IV IV IV

D1 D1 D1 a cada 21 dias

Carboplatina + Doxorrubicina Lipossomal Carboplatina: AUC 5 IV D1 2 Doxo lipossomal: 40mg/m IV D1 a cada 28 dias Ref. (7)

94

Doxorrubicina Doxorrubicina: 60mg/m2 IV Ref. (8)

D1 a cada 21 dias

Paclitaxel Paclitaxel: 200mg/m2 IV Se RXT prévia: 175mg/m2 IV Ref. (9)

D1 a cada 21 dias D1 a cada 21 dias

Topotecano Topotecano: 1mg/m2/dia Se RXT prévia 0,8mg/m2/dia Ref. (10)

IV D1-D5 a cada 21 dias IV D1-D5 a cada 21 dias

Acetato de Megestrol Acetato de megestrol: 160mg Ref.(11)

VO

Tamoxifeno Tamoxifeno: 20mg Ref.(12)

Contínuo

VO

• Guia Prático para o Oncologista Clínico

Contínuo

Anastrozol Anastrozol: 1 mg/dia VO contínuo Ref. (13) Letrozol Letrozol: 2,5 mg VO dia contínuo Ref. (14) Ifosfamida Ifosfamida: 1200mg/m2 IV Mesna: 300 mg/m2 IV D1 a D5 concomitante, 4 e 8hs após ifosfamida Ref. (15) Doxorrubicina lipossomal Doxorrubicina lipossomal: 40mg/m2 Ref. (16)

IV

a cada 28 dias

D1

28 dias

1. Hoskins, P.J., et al. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol, 2001. 19(20): p. 4048-53. 2. Thigpen, J.T., et al. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. J Clin Oncol, 1994. 12(7): p. 1408-14. 3. Deppe, G., et al. Treatment of recurrent and metastatic endometrial carcinoma with cisplatin and doxorubicin. Eur J Gynaecol Oncol, 1994. 15(4): p. 263-6. 4. Fleming G. F., Filiaci V. L., Bentley R. C, et. al.Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Guia Prático para o Oncologista Clínico •

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Gynecologic Oncology Group study. Ann Oncol. 2004; 15(8): 1173-1178. 5. Fleming, G.F., et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol, 2004. 22(11): p. 2159-66. 6. Burke, T.W., et al. Postoperative adjuvant cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy in women with high-risk endometrial carcinoma. Gynecol Oncol, 1994. 55(1): p. 47-50. 7. Pignata, S., et al. A multicentre phase II study of carboplatin plus pegylated liposomal doxorubicin as first-line chemotherapy for patients with advanced or recurrent endometrial carcinoma: the END-1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) group. Br J Cancer, 2007. 96(11): p. 1639-43. 8. Muss, H.B., Chemotherapy of metastatic endometrial cancer. Semin Oncol, 1994. 21(1): p. 107-13. 9. Ball, H.G., Do we know the best therapy for early endometrial cancer? Gynecol Oncol, 1996. 60(2): p. 173-5. 10. Wadler, S., et al. Topotecan is an active agent in the first-line treatment of metastatic or recurrent endometrial carcinoma: Eastern Cooperative Oncology Group Study E3E93. J Clin Oncol, 2003. 21(11): p. 2110-4. 11. Thigpen, J.T., et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol, 1999. 17(6): p. 1736-44. 12. Thigpen, T., et al. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol, 2001. 19(2): p. 364-7. 13. Rose PG, Brunetto, VL, et al. A Phase II trial of Anastrozolein advanced recurrent or persistent endometrial carcinoma: A Gynecologic Oncology Group Study. Gynecologic Oncology,2000; 78, 212-216.

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14. Ma B B.Y, Oza A, et al. The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers – a study of the National Cancer Institute of Canada Clinical Trials Group, Intern J Gynecol Cancer 2004. 14(4):650 - 658. 15. Sutton GP, et al. A Phase II Gynecologic Oncology Group Trial of Ifosfamide and Mesna in Advanced or Recurrent Adenocarcinoma of the Endometrium. Gynecol Oncol. Ginecol Oncol 1996;63:25-7. 16. Homesley, HD, et. al. Phase II trial of liposomal doxorubicin at 40 mg/m2 every 4 weeks in endometrial carcinoma: A Gynecologic Oncology Group Study Gynecol Oncol 2005; 98:294-8.

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Câncer de Colo Uterino Cisplatina + Radioterapia Cisplatina: 40mg/m2 IV término da radioterapia Paclitaxel + Cisplatina Paclitaxel: 135mg/m2 IV Cisplatina: 75mg/m2 IV Ref. (9)

D1

até Ref. (1)

D1 em infusão de 24 horas D1 a cada 21 dias

Cisplatina + Topotecano Cisplatina: 50mg/m2 Topotecano: 0,75mg/m2/dia Ref. (2)

IV D1 IV D1 a D3 a cada 21 dias

Cisplatina + 5-Fluorouracil Cisplatina: 75mg/m2 5-Fluorouracil: 1000mg/m2 Ref. (3)

IV D1 IV D1 a D5 a cada 21 dias

Cisplatina + Vinorelbina Cisplatina: 80mg/m2 IV D1 2 Vinorelbina: 25mg/m IV D1, D8 Ref. (4) Cisplatina + Irinotecano Cisplatina: 60mg/m2 IV Irinotecano: 60mg/m2 IV a cada 28 dias Docetaxel Docetaxel: 100mg/m2

98

Semanal

IV

• Guia Prático para o Oncologista Clínico

a cada 21 dias

D1 D1, D8, D15 Ref. (5)

D1 a cada 21 dias

Paclitaxel Paclitaxel: 175mg/m2 Ref. (6)

IV

D1 a cada 21 dias

Irinotecano Irinotecano: 125mg/m2 folga de 14 dias

IV

D1, D8, D15, D22 com Ref. (7)

Topotecano Topotecano: 1,5mg/m2/dia IV Ref. (8)

D1 a D5 a cada 21 dias

Vinorelbina Vinorelbina: 30 mg/m2 IV semanalmente

Ref. (10)

Ifosfamida Ifosfamida: 1.200 mg/m2 ( com Mesna) IV D1 a D5 a cada 21 dias Ref. (11) Gencitabina Gencitabina: 800 mg/m2 IV D1, D8 e D15 a cada 28 dias Ref. (12) 1. Rose, P.G., et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med, 1999. 340(15): p. 1144-53. 2. Long, H.J., 3rd, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol, 2005. 23(21): p. 4626-33. 3. Whitney, C.W., et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol, 1999. 17(5): p. 1339-48. Guia Prático para o Oncologista Clínico •

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4. Pignata, S., et al. Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix. J Clin Oncol, 1999. 17(3): p. 756-60. 5. Chitapanarux, I., et al. Phase II clinical study of irinotecan and cisplatin as first-line chemotherapy in metastatic or recurrent cervical cancer. Gynecol Oncol, 2003. 89(3): p. 402-7. 6. Thigpen, T., et al. The role of paclitaxel in the management of patients with carcinoma of the cervix. Semin Oncol, 1997. 24(1 Suppl 2): p. S2-41-S2-46. 7. Verschraegen, C.F., et al. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol, 1997. 15(2): p. 625-31. 8. Muderspach, L.I., et al. A Phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecol Oncol, 2001. 81(2): p. 213-5. 9. Piccart, M.J., et al. Randomized intergroup trial of cisplatinpaclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst, 2000. 92(9): p. 699-708. 10. Morris M, Brader KR, Levenback C, et al. Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix. J Clin Oncol. 1998; 16:1094-1098. 11. Sutton GP, Blessing JA, McGuire WP, et al. Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a gynecologic oncology group study. Am J Obstet Gynecol. 1993; 168:805-7. 12. Schilder RJ, Blessing JA, Morgan M, et al. Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: A phase II study of the Gynecologic Oncology Group. Gynecol Oncol 76:204–207, 2000.

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Câncer de Mama AC-D Adriamicina: 60 mg/m2 IV Ciclofosfamida: 600 mg/m2 IV Docetaxel: 100mg/m2 IV a cada 21 dias X 4 ciclos

D1 D1 a cada 21 dias X 4 ciclos D1 após 4 ciclos de AC Ref. (1-3)

Ou Doxorrubicina: 60 mg/m2 IV Ciclofosfamida: 600 mg/m2 IV Docetaxel: 35mg/m2 IV semanal X 12 semanas

D1 D1a cada 21 dias X 4 ciclos D1 após 4 ciclos de AC Ref. (2, 3)

AC-T Doxorrubicina: 60 mg/m2 IV Ciclofosfamida: 600 mg/m2 IV Paclitaxel: 175mg/m2 IV a cada 21 dias X 4 ciclos

D1 D1 a cada 21 dias X 4 ciclos D1 após 4 ciclos de AC Ref. (2)

Doxorrubicina: 60 mg/m2 IV Ciclofosfamida: 600 mg/m2 IV Paclitaxel: 80mg/m2 IV semanal X 12 semanas

D1 D1 a cada 21 dias X 4 ciclos D1 após 4 ciclos de AC Ref. (2, 3)

TAC Doxorrubicina: 50 mg/m2 Ciclofosfamida: 500 mg/m2 Docetaxel: 75 mg/m2 Ciprofloxacina: 500mg Filgrastima: 300mcg a cada 21 dias X 6 ciclos Ref. (4, 5)

IV IV IV VO BID SC

D1 D1 D1 D5-D14 D2-D14

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AC Doxorrubicina: 60 mg/m2 IV Ciclofosfamida: 600 mg/m2 IV Ref. (6-8)

D1 D1 a cada 21 dias X 4 ciclos

FAC 5-Fluorouracil: 500 mg/m2 IV Doxorrubicina: 50 mg/m2 IV Ciclofosfamida: 500 mg/m2 IV Ref. (9, 10)

D1 D1 D1 a cada 21 dias X 6 ciclos

CMF oral Ciclofosfamida: 100 mg/m2 VO D1 a D 14 Methotrexate: 40 mg/m2 IV D1 2 5-Fluorouracil: 600 mg/m IV D1 a cada 28 dias X 6 ciclos Ref. (11)

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CMF Ciclofosfamida: 600mg/m2 IV Methotrexate: 40 mg/m2 IV 5-Fluorouracil: 600 mg/m2 IV Ref. (12)

D1 D1 D1 a cada 21 dias X 6 ciclos

CMF Ciclofosfamida: 600mg/m2 IV Methotrexate: 40 mg/m2 IV 5-Fluorouracil: 600 mg/m2 IV ciclos

D1 e D8 D1 e D8 D1 e D8 a cada 28 dias X 6

TC Docetaxel: 75mg/m2 IV Ciclofosfamida: 600 mg/m2 IV Ref.(13)

D1 D1 a cada 21 dias X 4 ciclos

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FEC 100 5-Fluorouracil: 500mg/m2 IV Epirrubicina: 100 mg/m2 IV Ciclofosfamida: 500 mg/m2 IV Ref. (14-16)

D1 D1 D1 a cada 21 dias X 6 ciclos

FEC 100- Docetaxel 5-Fluorouracil: 500mg/m2 IV Epirrubicina: 100 mg/m2 IV Ciclofosfamida: 500 mg/m2 IV Docetaxel: 100mg/ m2 IV a cada 21 dias X 3 ciclos

D1 D1 D1 D1 após FEC Ref. (17)

TCH Docetaxel: 75mg/m2 Carboplatina: AUC 6 Trastuzumabe: 8mg/kg Trastuzumabe: 6mg/kg

D1 D1 a cada 21 dias X 6 ciclos D1 ATAQUE D1 a cada 21 dias por 1 ano

IV IV IV IV

AC-TH Doxorrubicina: 60mg/m2 IV Ciclofosfamida: 600mg/m2 IV Paclitaxel: 80mg/m2 IV semanal X 12 semanas Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV Ref.(18)

D1 D1 a cada 21 dias X 4 ciclos D1 após 4 ciclos de AC D1 D1

ATAQUE semanal por 1 ano

AC-TH Doxorrubicina: 60mg/m2 IV D1 2 Ciclofosfamida: 600mg/m IV D1 a cada 21 dias X 4 ciclos Paclitaxel: 175mg/m2 IV D1 após 4 ciclos de AC a cada 21 dias X 4 ciclos Trastuzumabe: 4mg/kg IV D1 ATAQUE Trastuzumabe: 2mg/kg IV D1 semanal por 1 ano Ref.(18) Guia Prático para o Oncologista Clínico •

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AC-TH Doxorrubicina: 60mg/m2 IV Ciclofosfamida: 600mg/m2 IV Paclitaxel: 80mg/m2 IV semanal X 12 semanas Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV DH-FEC Docetaxel: 100mg/m2 IV Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV 5-Fluourouracil: 600mg/m2IV Epirrubicina: 60mg/m2 IV 2 Ciclofosfamida: 600mg/m IV a cada 21 dias X 4 ciclos Ref. (19) VH-FEC Vinorelbina: 25g/m2 IV Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV 5-Fluourouracil: 600mg/m2IV Epirrubicina: 60mg/m2 IV 2 Ciclofosfamida: 600mg/m IV a cada 21 dias X 4 ciclos AD Doxorrubicina: 50mg/m2 IV Docetaxel: 75mg/m2 IV a cada 21 dias Ref. (8)

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D1 D1 a cada 21 dias X 4 ciclos D1 após 4 ciclos de AC D1 D1

ATAQUE semanal por 1 ano

D1 a cada 21 dias X 4 ciclos D1 ATAQUE D1 semanal por 9 semanas D1 D1 D1 após 4 ciclos de DH

D1 a cada 21 dias X 4 ciclos D1 ATAQUE D1 semanal por 9 semanas

D1 após 4 ciclos de DH Ref. (19)

D1 D1

AT Doxorrubicina: 60 mg/m2 IV Paclitaxel: 175 mg/m2 IV Ref. (20)

D1 D1

a cada 21 dias

Docetaxel + Capecitabina Docetaxel: 75 mg/m2 IV D1 a cada 21 dias Capecitabina: 1250mg/m2 VO BID D1 a D14 a cada 21 dias Ref. (21) Vinorelbina + Capecitabina Vinorelbina: 25 mg/m2 IV D1 e D8 a cada 21 dias Capecitabina: 1000 mg/m2 VO BID D1 a D 14 a cada 21 dias Ref. (22, 23) Gencitabina + Capecitabina Gencitabina: 2000 mg/m2 IV D1 a cada 21 dias 2 Capecitabina: 1250mg/m VO BID D1 a D 14 a cada 21 dias Ref. (24) Ou Gencitabina: 800mg/m2 Capecitabina 750mg/m2 Ref. (25)

IV D1 e D8 a cada 21 dias VO BID D1 a D14 a cada 21 dias

Vinorelbina + Gencitabina Vinorelbina 25mg/m2 IV Gencitabina: 1000mg/m2 IV Ref. (26)

D1 D1 a cada 14 dias

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Cisplatina + Gencitabina Cisplatina: 30 mg/m2 IV D1 e D8 2 Gencitabina: 750 mg/m IV D1 e D8 a cada 21 dias Ref. (27) Doxorrubicina Doxorrubicina: 60 mg/m2 IV D1 a cada 21 dias Ref. (28) Epirrubicina Epirrubicina: 75mg/m2 Ref. (29)

IV D1 a cada 21 dias

Paclitaxel Paclitaxel: 175mg/m2 Ref. (28, 30)

IV D1 a cada 21 dias

Ou Paclitaxel: 90mg/m2 Ref. (31) Docetaxel Docetaxel: 100mg/m2 Ref. (32)

IV D1 a cada 7 dias

IV D1 a cada 21 dias

Ou Docetaxel: 40mg/m2 IV D1, D8, D15, D22, D29, D36 Ref. (33)

com 14 dias de folga

Capecitabina Capecitabina: 1250mg/m2 VO BID D1 a D14 a cada 21 dias Ref. (34)

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Vinorelbina Vinorelbina: 30mg/m2 Ref. (35)

IV D1 e D8 a cada 21 dias

Doxorrubicina Lipossomal Doxo lipossomal: 40mg/m2 IV D1 a cada 28 dias

Ref. (36)

Gencitabina Gencitabina: 750mg/m2 Ref. (37)

IV

D1, D8, D15 a cada 28 dias

Trastuzumabe Trastuzumabe: 8mg/kg Trastuzumabe: 6mg/kg Ref. (38)

IV IV

D1 D1

ATAQUE a cada 21 dias

IV IV

D1 D1

ATAQUE a cada 7 dias

Paclitaxel + Trastuzumabe Paclitaxel: 175mg/m2 IV Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV subsequente

D1 D1 D1

a cada 21 dias ATAQUE a cada 7 dias Ref. (40)

D1 D1 D1

a cada 7 dias ATAQUE a cada 7 dias

Ou Trastuzumabe: 4mg/kg Trastuzumabe: 2mg/kg Ref. (39)

Ou Paclitaxel: 90mg/m2 Trastuzumabe: 4mg/kg Trastuzumabe: 2mg/kg subsequente Ref. (41)

IV IV IV

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Docetaxel + Trastuzumabe Docetaxel: 100mg/m2 IV Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV subsequente Ref. (42)

D1 a cada 21 dias D1 ATAQUE D1 a cada 7 dias

Ou Docetaxel: 35mg/m2 Trastuzumabe: 4mg/kg Trastuzumabe: 2mg/kg subsequente Ref. (43)

IV IV IV

Vinorelbina + Trastuzumabe Vinorelbina: 25mg/m2 IV Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV subsequente Ref. (44) Gencitabina + Trastuzumabe Gencitabina: 1200mg/m2 IV a cada 21 dias Trastuzumabe: 4mg/kg IV Trastuzumabe: 2mg/kg IV subsequente Ref. (45)

D1 a cada 7 dias D1 ATAQUE D1 a cada 7 dias

D1 a cada 7 dias D1 ATAQUE D1 a cada 7 dias

D1 e D8 D1 D1

ATAQUE a cada 7 dias

Vinorelbina Oral Vinorelbina: 80mg/m2 D1 semanal após 3 administrações com dose de 60mg/m2 semanal para testar mielossensibilidade Ref. (71)

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Gencitabina + Paclitaxel Gencitabina: 1250mg/m2 IV D1 e D8 Paclitaxel: 175mg/m2 IV D1 a cada 21 dias Ref. (46, 47) Gencitabina + Docetaxel Gencitabina: 1000mg/m2 IV Docetaxel: 75mg/m2 IV Ref. (48)

D1 e D8 D1 a cada 21 dias

Gencitabina + Vinorelbina Gencitabina: 1200mg/m2 IV Vinorelbina : 30mg/m2 IV Ref. (49)

D1 e D8 D1 e D8 a cada 21 dias

Lapatinibe + Capecitabina Lapatinibe: 1250mg Capecitabina : 2000mg/m2 a cada 21 dias Ref. (50)

VO/dia contínuo VO D1 a D14

Lapatinibe + Trastuzumabe Lapatinibe: 1250mg VO/dia contínuo Trastuzumabe: 4mg/kg IV D1 ATAQUE Trastuzumabe: 2mg/kg IV D1 a cada 7 dias Tamoxifeno Tamoxifeno: 20mg anos/indefinido Ref. (51, 52) Anastrozol Anastrozol: 1mg VO Ref. (53-55)

VO

Diariamente

Diariamente

5

5 anos/indefinido

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Letrozol Letrozol: 2,5mg VO Ref. (56, 57)

Diariamente

indefinido

Exemestano Exemestano: 25mg VO Diariamente Ref. (58, 59)

indefinido

Tamoxifeno + Letrozol Tamoxifeno: 20mg VO Letrozol: 2,5mg VO após término Tamoxifeno Ref. (60) Tamoxifeno + Exemestano Tamoxifeno: 20mg VO Exemestano: 25mg VO completar 5 anos Ref. (61)

5 anos 5 anos

Diariamente Diariamente

2-3 anos Até

Fulvestranto Fulvestranto: 250mg Ref. (62)

IM

Megestrol Megestrol: 160 mg VO Ref. (63)

Diariamente

indefinido

Toremifeno Toremifeno: 60mg VO Ref. (64)

Diariamente

indefinido

Análogo LHRH+ Tamoxifeno LHRH: -------- IM ou SCD1 Tamoxifeno: 20mg VO

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Diariamente Diariamente

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D1

a cada 28 dias

a cada 28 dias Contínuo

Ref. (65)

Analogo LHRH+ Anastrozol LHRH: -------- IM ou SCD1 Anastrozol 1mg VO

a cada 28 dias Contínuo

Dose densa AC ® T Doxorrubicina: 60 mg/m² IV no D1 Ciclofosfamida: 600 mg/m² IV no D1 Filgrastima: 300mcg SC do D2 ao D12 a cada 14 dias no total de 4 ciclos. seguido por Paclitaxel: 175 mg/m² IV no D1 a cada 14 dias por 4 ciclos Filgrastima: 300mcg SC do D2 ao D12 Ou Paclitaxel: 80 mg/m² IV semanalmente por 12 semanas Ref. (66) ATH ® TH ® CMFH (NOAH trial) Doxorrubicina: 60 mg/m² IV no D1 Paclitaxel: 175mg/m² IV D1 a cada 3 semanas X 3 ciclos Seguido de: Paclitaxel: 175 mg/m² IV D1 X 4 ciclos Seguido de: Ciclofosfamida: 600mg/m2 IV D1 e D8 Methotrexate: 40mg/m2 IV D1 e D8 5-Fluorouracil: 600mg/m2 D1 e D8 Repetir CMF a cada 28 dias por 3 ciclos. Trastuzumabe concomitante com toda a Quimioterapia (dose ataque 8mg/kg seguido de dose de manutenção de 6mg/kg a cada 3 semanas até completar 1 ano de terapia). Ref. (67) Guia Prático para o Oncologista Clínico •

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Paclitaxel + Bevacizumabe (ECOG 2100) Paclitaxel: 90 mg/m2 IV no D1, D8 e D15 a cada 4 semanas, associado a Bevacizumabe: 10mg/kg IV a cada 2 semanas. Ref. (68) Docetaxel + Bevacizumabe (AVADO) Docetaxel: 100mg/m2 IV no D1 a cada 3 semanas. Bevacizumabe: 15mg/kg IV no D1 a cada 3 semanas. Ref. (69) Capecitabina + Bevacizumabe (RIBBON 1) Capecitabina: 1000mg/m2 VO BID por 14 dias a cada 21 dias. Bevacizumabe: 15mg/kg IV no D1 a cada 3 semanas. Ref. (70) 1. Bear, H.D., et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol, 2003. 21(22): p. 4165-74. 2. Sparano, J.A., et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med, 2008. 358(16): p. 1663-71. 3. De Laurentiis, M., et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol, 2008. 26(1): p. 44-53. 4. Martin, M., et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med, 2005. 352(22): p. 2302-13. 5. Mackey, J., Proc.ASCO, 2002. 21(abstract137). 6. Fisher, B., et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National

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Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol, 1990. 8(9): p. 1483-96. 7. Fisher, B., et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol, 1998. 16(8): p. 2672-85. 8. Nabholtz, J.M., et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol, 2003. 21(6): p. 968-75. 9. Martin, M., et al. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol, 2003. 14(6): p. 833-42. 10. Stewart, D.J., et al. Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: superiority of doxorubicin. J Clin Oncol, 1997. 15(5): p. 1897-905. 11. Bonadonna, G., et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med, 1976. 294(8): p. 405-10. 12. Pritchard, K.I., et al. Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptorpositive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group. J Clin Oncol, 1997. 15(6): p. 2302-11. 13. Jones, S.E., et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol, 2006. 24(34): p. 5381-7. 14. Coombes, R.C., et al. Adjuvant cyclophosphamide, Guia Prático para o Oncologista Clínico •

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methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol, 1996. 14(1): p. 35-45. 15. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol, 2001. 19(3): p. 602-11. 16. Epirubicin-based chemotherapy in metastatic breast cancer patients: role of dose-intensity and duration of treatment. J Clin Oncol, 2000. 18(17): p. 3115-24. 17. Roche, H., et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol, 2006. 24(36): p. 5664-71. 18. Romond, E.H., et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med, 2005. 353(16): p. 1673-84. 19. Joensuu, H., et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med, 2006. 354(8): p. 809-20. 20. Biganzoli, L., et al. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol, 2002. 20(14): p. 3114-21. 21. O'Shaughnessy, J., et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracyclinepretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol, 2002. 20(12): p. 2812-23. 22. Biganzoli, L., M. Martin, and C. Twelves, Moving forward with capecitabine: a glimpse of the future. Oncologist, 2002. 7 Suppl 6: p. 29-35.

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23. Welt, A., et al. Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer. Ann Oncol, 2005. 16(1): p. 64-9. 24. Andres, R., et al. Gemcitabine/capecitabine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes. Clin Breast Cancer, 2005. 6(2): p. 158-62. 25. Abstracts of the 27th Annual San Antonio Breast Cancer Symposium. December 8-11, 2004, San Antonio, Texas, USA. Breast Cancer Res Treat, 2004. 88 Suppl 1: p. S1-265. 26. Stathopoulos, G.P., et al. Phase II trial of biweekly administration of vinorelbine and gemcitabine in pretreated advanced breast cancer. J Clin Oncol, 2002. 20(1): p. 37-41. 27. Nagourney, R.A., et al. Gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed breast cancer patients. J Clin Oncol, 2000. 18(11): p. 2245-9. 28. Sledge, G.W., et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as frontline chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol, 2003. 21(4): p. 588-92. 29. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. The French Epirubicin Study Group. J Clin Oncol, 1991. 9(2): p. 305-12. 30. Seidman, A.D., et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol, 1995. 13(10): p. 2575-81. 31. Seidman, A.D., et al. Dose-dense therapy with weekly 1hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol, 1998. 16(10): p. 3353-61. 32. Nabholtz, J.M., et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. J Clin Oncol, 1999. 17(5): p. 1413-24. Guia Prático para o Oncologista Clínico •

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33. Burstein, H.J., et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol, 2000. 18(6): p. 1212-9. 34. Blum, J.L., et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol, 1999. 17(2): p. 485-93. 35. Weber, B.L., et al. Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol, 1995. 13(11): p. 2722-30. 36. Al-Batran, S.E., et al. Reduced incidence of severe palmarplantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40 mg/m2 every 4 weeks in previously treated patients with metastatic breast cancer. Oncology, 2006. 70(2): p. 141-6. 37. Carmichael, J., et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol, 1995. 13(11): p. 2731-6. 38. Baselga, J., et al. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol, 2005. 23(10): p. 2162-71. 39. Baselga, J., et al. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neuoverexpressing metastatic breast cancer. Semin Oncol, 1999. 26(4 Suppl 12): p. 78-83. 40. Slamon, D.J., et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med, 2001. 344(11): p. 783-92. 41. Seidman, A.D., et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol, 2001. 19(10): p. 2587-95. 42. Marty, M., et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2positive metastatic breast cancer administered as first-line

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treatment: the M77001 study group. J Clin Oncol, 2005. 23(19): p. 4265-74. 43. Esteva, F.J., et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol, 2002. 20(7): p. 1800-8. 44. Burstein, H.J., et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol, 2001. 19(10): p. 2722-30. 45. O'Shaughnessy, J.A., et al. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin Breast Cancer, 2004. 5(2): p. 142-7. 46. O'Shaughnessy, J., Gemcitabine combination chemotherapy in metastatic breast cancer: phase II experience. Oncology (Williston Park), 2003. 17(12 Suppl 14): p. 15-21. 47. Albain, K.S., et al. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol, 2008. 26(24): p. 3950-7. 48. Chan, S., et al. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol, 2009. 27(11): p. 1753-60. 49. Martin, M., et al. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol, 2007. 8(3): p. 219-25. 50. Geyer, C.E., et al. Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med, 2006. 355(26): p. 2733-43. 51. Fisher, B., et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst, 1997. 89(22): p. 1673-82. 52. Jaiyesimi, I.A., et al. Use of tamoxifen for breast cancer: Guia Prático para o Oncologista Clínico •

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twenty-eight years later. J Clin Oncol, 1995. 13(2): p. 513-29. 53. Howell, A., Adjuvant aromatase inhibitors for breast cancer. Lancet, 2005. 366(9484): p. 431-3. 54. Buzdar, A.U., P.V. Plourde, and G.N. Hortobagyi, Aromatase inhibitors in metastatic breast cancer. Semin Oncol, 1996. 23(4 Suppl 9): p. 28-32. 55. Nabholtz, J.M., et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol, 2000. 18(22): p. 3758-67. 56. Dombernowsky, P., et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol, 1998. 16(2): p. 453-61. 57. Mouridsen, H., et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol, 2001. 19(10): p. 2596-606. 58. Lonning, P.E., Exemestane in breast cancer: current status and future directions. Clin Breast Cancer, 2000. 1 Suppl 1: p. S28-33. 59. Paridaens, R.J., et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol, 2008. 26(30): p. 4883-90. 60. Goss, P.E., et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptorpositive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst, 2005. 97(17): p. 1262-71. 61. Coombes, R.C., et al. A randomized trial of exemestane after

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two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med, 2004. 350(11): p. 1081-92. 62. Howell, A., Future use of selective estrogen receptor modulators and aromatase inhibitors. Clin Cancer Res, 2001. 7(12 Suppl): p. 4402s-4410s; discussion 4411s-4412s. 63. Kimmick, G.G. and H.B. Muss, Endocrine therapy in metastatic breast cancer. Cancer Treat Res, 1998. 94: p. 231-54. 64. Hayes, D.F., et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol, 1995. 13(10): p. 2556-66. 65. Klijn, J.G., et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol, 2001. 19(2): p. 343-53. 66. Citron ML et al. Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741 J Clin Oncol 2003;21(8):1481. 67. Gianni K, Ejermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed byadjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlledsuperiority trial with a parallel HER2-negative cohort. Lancet 2010: 375; 377-384. 68. Miller K, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat. 2005;94(suppl 1):S6. Abstract 3. Guia Prático para o Oncologista Clínico •

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69. Miles DW, Chan A, Romieu G, et al. Randomised, doubleblind, placebo controlled, phase III study of bevacizumab (BV) with docetaxel (D) or D with placebo (PL) as 1st line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol 2008: 26;18S. 70. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 2009: 27;15s (suppl; abstr 1005). 71. Freyer, T. Phase II Study of Oral Vinorelbine in First-Line Advanced Breast Cancer Chemotherapy. JCO Jan 1, 2003:35-40.

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Metástases Ósseas e/ou Hipercalcemia Maligna Denosumabe: 120 mg SC D1 a cada 30 dias Ref. (1) Ou Pamidronato: 90mg Ref. (2)

IV

D1 a cada 28 dias

IV

D1 a cada 21 a 28 dias

Ou Ácido zoledrônico: 4 mg Ref. (3)

1. Stopeck Alison T., Lipton Allan, Body Jean-Jacques, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clinc Oncol. 2010; 28: 5132-5139. 2. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol 2002 Sep 1;20(17): 3719-36. 3. Migliorati Cesar A, Siegel Michael A, Elting Linda S. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol. 2006; 7: 508-514.

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Câncer de Ovário (Epitelial) Ciclofosfamida + Carboplatina Ciclofosfamida: 600mg/m2 IV Carboplatina: 300mg/m2 IV Ref. (1)

D1 D1 a cada 28 dias X 6 ciclos

Ciclofosfamida + Cisplatina Ciclofosfamida: 600mg/m2 IV IV Cisplatina: 100mg/m2 Ref. (2)

D1 D1 a cada 28 dias X 6 ciclos

Cisplatina + Paclitaxel Cisplatina: 75mg/m2 Paclitaxel: 135mg/m2 a cada 21 dias X 6 ciclos Ref. (3)

IV IV

D1 D1 em 24 horas de infusão

IV

D1 a cada 21 dias X 6 ciclos

Ou Paclitaxel: 175mg/m2

Carboplatina + Paclitaxel Carboplatina: AUC 5 a 7 IV D1 Paclitaxel: 175mg/m2 IV D1 a cada 21 dias X 6 ciclos Ref. (4) Carboplatina + Docetaxel Carboplatina: AUC 6 IV D1 2 Docetaxel: 60mg/m IV D1 a cada 21 dias X 6 ciclos Ref. (5)

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Cisplatina + Gencitabina Cisplatina: 30mg/m2 IV D1 e D8 Gencitabina: 750mg/m2 IV D1 e D8 Ref. (6)

a cada 21 dias X 6 ciclos

Doxorrubicina Lipossomal Doxo Lipossomal: 40-50mg/m2 IV D1 a cada 28 dias Ref. (7-9) Gencitabina Gencitabina: 1000mg/m2 IV 21 dias Ref. (9)

D1, D8, D15

Paclitaxel Paclitaxel: 135-170mg/m2 IV Ref. (10)

a

cada

D1 a cada 21 dias

Ou Paclitaxel: 80mg/m2

IV

D1, D8 e D15 a cada 28 dias

Topotecano Topotecano: 1,5mg/m2 Ref. (11)

IV

D1 a D5 a cada 21 dias

Topotecano: 2,5 a 4mg/m2 Ref. (12) Etoposide Etoposide: 50mg/m2/dia VO 28 dias Ref. (13)

IV

D1, D8, D15 a cada 28 dias

D1 a D21

a

cada

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Carboplatina Carboplatina: AUC 6 Ref. (14)

IV

D1

Vinorelbina Vinorelbina: 25mg/m2 Ref. (15)

IV

D1, D8, D15 a cada 21 dias

Tamoxifeno Tamoxifeno: 20mg Ref. (16)

VO

Contínuo

a cada 21 dias

Quimioterapia intraperitonial (estágio III) Paclitaxel: 135 mg/m2 IV em 24h D1 2 Cisplatina: 100 mg/m IP D2 Paclitaxel: 60 mg/m2 IP D8 a cada 21 dias por 6 ciclos Ref. (18) Docetaxel Docetaxel: 100mg/m2 Ref. (19)

IV

D1

21 dias

Oxaliplatina Oxaliplatina: 100 mg/m2 IV Ref. (20)

D1

21 dias

TIP Paclitaxel: 250 mg/m2 em 24 horas IV D1 2 Ifosfamida: 1.200 mg/m IV D2 –D6 Mesna : 400 mg/m2 IV nas horas 0,4 e 8 da Ifosfamida D2-D6 Cisplatina: 20 mg/m2 IV D2-D6 a cada 21 dias. Ref. (21)

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VeIP Vinblastina: 0,1 mg/kg IV D1-D2 2 Ifosfamida: 1,200 mg/m IV D1 –D5 Mesna : 400 mg/m2 IV nas horas 0,4 e 8 da Ifosfamida D1-D5 Cisplatina: 20 mg/m2 IV D1-D5 Ref. (22)

Câncer de Ovário (Tumor de Células Germinativas) BEP Cisplatina: 20mg/m2 IV D1-D5 2 Etoposide: 100mg/m IV D1-D5 Bleomicina: 30UI IV D2, D9,D16 a cada 21 dias Ref. (17) 1. Swenerton, K., et al. Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 1992. 10(5): p. 718-26. 2. Alberts, D.S., et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol, 1992. 10(5): p. 706-17. 3. McGuire, W.P., et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med, 1996. 334(1): p. 1-6. 4. Ozols, R.F., Combination regimens of paclitaxel and the platinum drugs as first-line regimens for ovarian cancer. Semin Oncol, 1995. 22(6 Suppl 15): p. 1-6. 5. Markman, M., et al. Combination chemotherapy with carboplatin and docetaxel in the treatment of cancers of the ovary and fallopian tube and primary carcinoma of the peritoneum. J Clin Oncol, 2001. 19(7): p. 1901-5. Guia Prático para o Oncologista Clínico •

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6. Nagourney, R.A., et al. Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol, 2003. 88(1): p. 35-9. 7. Gordon, A.N., et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol, 2001. 19(14): p. 3312-22. 8. Rose, P.G., et al. Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages. Gynecol Oncol, 2001. 82(2): p. 323-8. 9. Ferrandina, G., et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol, 2008. 26(6): p. 890-6. 10. McGuire, W.P., et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med, 1989. 111(4): p. 273-9. 11. Kudelka, A.P., et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol, 1996. 14(5): p. 1552-7. 12. Bhoola, S.M., et al. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer. Gynecol Oncol, 2004. 95(3): p. 564-9. 13. Ozols, R.F., Oral etoposide for the treatment of recurrent ovarian cancer. Drugs, 1999. 58 Suppl 3: p. 43-9. 14. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet, 2002. 360(9332): p. 505-15. 15. Bajetta, E., et al. Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease. J Clin Oncol, 1996. 14(9): p. 2546-51. 16. Kristensen, g., Chemotherapy versus hormonal treatment in patients with platinum and taxane resistant ovarian cancer: A NSGO study journal of clinical oncology, 2008. 26(suplement): p. abst5508.

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17. Dimopoulos, M.A., et al. Treatment of ovarian germ cell tumors with a 3-day bleomycin, etoposide, and cisplatin regimen: a prospective multicenter study. Gynecol Oncol, 2004. 95(3): p. 695-700. 18. Armstrong Dk, et. al. Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer. New Engl Med 2006;354:34-43. 19. Kaye SS, et. al. Is cisplatin-taxol (PT) the standard treatment in advanced ovarian cancer. Eur J Cancer 1997:31-2167-70. 20. ChOllet P, et. al. Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer Ann Oncol 1996; 7: 1065-70. 21. Motzer RJ, Sheinfeld J, Mazumdar M, et al. Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol. 2000;18:2413-2418. 22. McCaffrey JA, Mazumdar M, Bajorin DF, et al. Ifosfamideand cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: Response and survival. J Clin Oncol . 1997; 15:2559-2563.

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Doença Trofoblástica Gestacional EP/EMA Etoposide: 150 mg/m2 IV D1 2 Cisplatina*: 75 mg/m IV D1 Etoposide:100 mg/m2 IV D8 2 Methotrexate: 300 mg/m IV(12hs) D8 Actinomicina: 0,5 mg IV D8 Leucovorin: 15 mg VO ou IV (4 doses; 12/1 2 hs) D9 (24hs após metotrexato) a cada 14 dias 2 * Aplicar em 3 doses de 25/mg/m por 4 horas cada, diluído em 1000ml de solução de Cloreto de Sódio a 0,9%. Ref. (1) Methotrexate Methotrexate: 1 mg/kg Leucovorin: 0,1 mg/kg Ref. (2)

IM D1, D3, D5 e D7 IM D2, D4, D6 e D8

Actinomicina Actinomicina: 1,25 mg/m2 IV Ref. (3)

D1

a cada14 dias

a cada 14 dias

EMA-CO Etoposide: 100 mg/m2 IV D1 e D2 Methotrexate: 300 mg/m2 IV (12hs)D1 Actinomicina: 0,5 mg IV D1 e D2 Leucovorin: 15 mg VO ou IV (4 doses; 12/1 2 hs) D2 (24 hs após Methotrexate) Vincristina: 0,8 mg/m2 (máx. 2mg) IV D8 2 Ciclofosfamida: 600 mg/m IV D8 a cada 14 dias Ref. (4)

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1. Newlands ES, et al. Etoposide and Cisplatin/Etoposide, Methotrexate, and Actinomycin D (EMA) Chemotherapy for Patients With High-Risk Gestational Trophoblastic Tumors Refractory to EMA/Cyclophosphamide and Vincristine Chemotherapy and Patients Presenting With Metastatic Placental Site Trophoblastic Tumors J Clin Oncol 200;18:854-9. 2. Berkowitz RS, et al. Ten years' experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986;23:111-8. 3. Chen LM, et al. Single-agent pulse dactinomycin has only modest activity for methotrexate-resistant gestational trophoblastic neoplasia. Gynecol Oncol 2004;94:204-7. 4. Bower M, et al. EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients [published erratum appears in J Clin Oncol 1997 Sep;15(9):3168]. J Clinc Oncol 1997;15:2636-43.

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Câncer de Vulva Cisplatina + 5-Fluorouracil Cisplatina: 50 mg/m2 IV D1 5-Fluorouracil: 1000 mg/m2 IV D1 – D4 a cada 21 dias Ref. (1) Paclitaxel Paclitaxel: 175 mg/m2 IV D1 – D4 a cada 21 dias Ref. (2) 1. Moore DH, Thomas GM, Montana GS, Saxer A, Gallup DG, Olt G. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 1998;42:79-85. 2. Witteveen P.O. Velden, I. J. Van Der Vergote, Oliveira C.F. de, et al. Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: A study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group). Ann of Oncol. 2009; 20: 1511- 1516.

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• Guia Prático para o Oncologista Clínico

Câncer de Pulmão Não Pequenas Células Carboplatina + Paclitaxel Paclitaxel: 200mg/m2 IV Carboplatina: AUC 6 IV Ref. (1) Vinorelbina + Cisplatina Vinorelbina: 25mg/m2 IV 2 Cisplatina: 50mg/m IV ciclos Carboplatina + Paclitaxel Carboplatina: AUC 6 IV Paclitaxel: 200 a 225mg/m2IV D1 Ref. (3)

D1 D1 a cada 21 dias X 4 ciclos

D1 semanal X 16 semanas D1 e D8 a cada 28 dias X 4 Ref. (2)

D1 a cada 21 dias

Ou Paclitaxel: 100mg/m2 Carboplatina: AUC 6 Ref. (4)

IV IV

D1 D1

SEMANAL a cada 28 dias

Carboplatina + Paclitaxel+ Bevacizumabe Paclitaxel: 200mg/m2 IV D1 Carboplatina: AUC 6 IV D1 Bevacizumabe: 15mg/kg IV D1 a cada 21 dias Ref. (3)

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Cisplatina + Paclitaxel Cisplatina: 80mg/m2 Paclitaxel: 175mg/m2 Ref. (5)

IV IV

D1 D1 a cada 21 dias

Docetaxel + Carboplatina Docetaxel: 75mg/m2 IV Carboplatina: AUC 6 IV Ref. (6)

D1 D1 a cada 21 dias

Docetaxel + Cisplatina Docetaxel: 75mg/m2 IV 2 Cisplatina: 75mg/m IV Ref. (6, 7)

D1 D1 a cada 21 dias

Docetaxel + Gencitabina Docetaxel: 100mg/m2 IV 2 Gencitabina: 1100mg/m IV G-CSF: 300mcg SC Ref. (8)

D8 D1 e D8 D9 a D15

Cisplatina + Gencitabina IV Cisplatina: 100mg/m2 Gencitabina: 1000mg/m2 IV 28 dias

132

a cada 21 dias

D1 D1, D8 e D15 Ref. (9)

a

cada

a

cada

Carboplatina + Gencitabina Carboplatina: AUC 5 IV 2 Gencitabina: 1000mg/m IV 28 dias Ref. (10)

D1 D1, D8 e D15

Gencitabina + Vinorelbina Gencitabina: 1200mg/m2 IV Vinorelbina: 30mg/m2 IV Ref. (11)

D1 e D8 D1 e D8 a cada 21 dias

• Guia Prático para o Oncologista Clínico

Vinorelbina + Carboplatina Vinorelbina: 25mg/m2 IV Carboplatina: AUC 6 IV Ref. (12)

D1 e D8 D1 a cada 28 dias

Pemetrexede + Cisplatina Pemetrexede: 500mg/m2 IV Cisplatina: 75mg/m2 IV Ref. (13)

D1 D1 a cada 21 dias

Pemetrexede + Carboplatina Pemetrexede: 500mg/m2 IV Carboplatina: AUC5 IV

D1 D1 a cada 21 dias Ref. (14)

EP Etoposide: 120mg/m2 Cisplatina: 60mg/m2 Ref. (15)

IV IV

D1-D3 D1 a cada 21 dias

Paclitaxel Paclitaxel: 225mg/m2 Ref. (16)

IV

D1 a cada 21 dias

Ou Paclitaxel: 80-100mg/m2 IV Ref. (17)

D1-D8-D15 a cada 21 dias

Docetaxel Docetaxel: 75mg/m2 Ref. (18)

IV

D1 a cada 21 dias

Ou Docetaxel: 35mg/m2 Ref. (19)

IV

D1, D8 e D15 a cada 28 dias

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133

Pemetrexede Pemetrexede: 500mg/m2 IV Ref. (20) Gencitabina Gencitabina: 1000mg/m2 IV 28 dias

D1 a cada 21 dias

D1, D8, D15 Ref. (21)

Vinorelbina Vinorelbina: 25mg/m2 Ref. (22)

IV

D1

Gefitinibe Gefitinibe: 250mg/m2 Ref. (23)

VO

Contínuo

VO

Contínuo

Erlotinibe Erlotinibe: 150mg/dia

a

cada

Semanal

Ref. (24)

Bevacizumabe+ Cisplatina+ Gencitabina Bevacizumabe: 7,5mg/kg IV D1 Cisplatina: 80mg/m2 IV D1 Gencitabina: 1200mg/m2 IV D1 e D8 a cada 21 dias Ref. (25) Cetuximabe+ Cisplatina + Vinorelbina Cetuximabe: 400mg/m2 IV D1 ATAQUE 2 Cetuximabe: 250mg/m IV Semanal Cisplatina: 80mg/m2 IV D1 2 Vinorelbina: 25mg/m IV D1 e D8 a cada 21 dias Ref. (26)

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Vinblastina + Cisplatina Vinblastina: 4mg/m² D1, D8, D15 e D28. Após o D43, repetir o ciclo a cada 2 semanas até a última administração de cisplatina. Cisplatina: 80mg/m² IV D1 Repetir a cisplatina cada 21 dias por 4 ciclos (D1, D22, D43 e D64). Ref. (27) Etoposide + Cisplatina Etoposide: 100mg/m² IV D1 ao D3 com cada administração de cisplatina. Cisplatina: 80mg/m² IV D1 a cada 28 dias no total de 4 ciclos Ref. (28) MIP Mitomicina: 6 mg/m2 Ifosfamida: 3000 mg/m2 Cisplatina: 50 mg/m2 Ref. (29)

IV IV IV

D1 D1 D1 a cada 21 dias por 3 ciclos

IV IV IV

D1 D1 a D3 D1 a D3 a cada 21 dias por

Cisplatina + Irinotecano Cisplatina: 80 mg/m2 IV 2 Irinotecano: 60 mg/m IV Ref. (31)

D1 D1, D8 e D15 a cada 28 dias

MIP(2) Mitomicina: 6 mg/m2 Ifosfamida: 1500 mg/m2 Cisplatina: 30 mg/m2 2 ciclos Ref. (30)

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Carboplatina + Paclitaxel Carboplatina: AUC:6 IV 2 Paclitaxel: 90 mg/m IV Ref. (32)

D1 D1, D8 e D15 a cada 28 dias

1. Strauss, G.M., et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol, 2008. 26(31): p. 5043-51. 2. Winton, T., et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med, 2005. 352(25): p. 2589-97. 3. Sandler, A., et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med, 2006. 355(24): p. 2542-50. 4. Belani, C.P., et al. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-smallcell lung cancer. J Clin Oncol, 2008. 26(3): p. 468-73. 5. Giaccone, G., et al. Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced nonsmall-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol, 1998. 16(6): p. 2133-41. 6. Fossella, F., et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol, 2003. 21(16): p. 3016-24. 7. Belani, C.P., et al. Docetaxel and cisplatin in patients with advanced non small-cell lung cancer (NSCLC): a multicenter phase II trial. Clin Lung Cancer, 1999. 1(2): p. 144-50. 8. Georgoulias, V., et al. Platinum-based and non-platinum-

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based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet, 2001. 357(9267): p. 1478-84. 9. Abratt, R.P., et al. Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol, 1997. 15(2): p. 744-9. 10. Langer, C.J., et al. Gemcitabine and carboplatin in combination: an update of phase I and phase II studies in nonsmall cell lung cancer. Semin Oncol, 1999. 26(1 Suppl 4): p. 12-8. 11. Frasci, G., et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced nonsmall-cell lung cancer. J Clin Oncol, 2000. 18(13): p. 2529-36. 12. Cremonesi, M., et al. Vinorelbine and carboplatin in inoperable non-small cell lung cancer: a monoinstitutional phase II study. Oncology, 2003. 64(2): p. 97-101. 13. Scagliotti, G.V., et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage nonsmall-cell lung cancer. J Clin Oncol, 2008. 26(21): p. 3543-51. 14. Scagliotti, G.V., Pemetrexed plus carboplatin or oxaliplatin in advanced non-small cell lung cancer. Semin Oncol, 2005. 32(2 Suppl 2): p. S5-8. 15. Longeval, E. and J. Klastersky, Combination chemotherapy with cisplatin and etoposide in bronchogenic squamous cell carcinoma and adenocarcinoma. A study by the EORTC lung cancer working party (Belgium). Cancer, 1982. 50(12): p. 2751-6. 16. Lilenbaum, R.C., et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol, 2005. 23(1): p. 190-6. 17. Tester, W.J., et al. Phase II study of patients with metastatic nonsmall cell carcinoma of the lung treated with paclitaxel by 3-hour infusion. Cancer, 1997. 79(4): p. 724-9. 18. Miller, V.A. and M.G. Kris, Docetaxel (Taxotere) as a single agent and in combination chemotherapy for the treatment Guia Prático para o Oncologista Clínico •

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of patients with advanced non-small cell lung cancer. Semin Oncol, 2000. 27(2 Suppl 3): p. 3-10. 19. Hainsworth, J.D., et al. Weekly docetaxel in the treatment of elderly patients with advanced nonsmall cell lung carcinoma. A Minnie Pearl Cancer Research Network Phase II Trial. Cancer, 2000. 89(2): p. 328-33. 20. Hanna, N., et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol, 2004. 22(9): p. 1589-97. 21. Manegold, C., et al. Single-agent gemcitabine versus cisplatin-etoposide: early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer. Ann Oncol, 1997. 8(6): p. 525-9. 22. Furuse, K., et al. Randomized study of vinorelbine (VRB) versus vindesine (VDS) in previously untreated stage IIIB or IV non-small-cell lung cancer (NSCLC). The Japan Vinorelbine Lung Cancer Cooperative Study Group. Ann Oncol, 1996. 7(8): p. 815-20. 23. Herbst, R.S., Dose-comparative monotherapy trials of ZD1839 in previously treated non-small cell lung cancer patients. Semin Oncol, 2003. 30(1 Suppl 1): p. 30-8. 24. Rosell, R., et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med, 2009. 361(10): p. 958-67. 25. Reck, M., et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol, 2009. 27(8): p. 1227-34. 26. Pirker, R., et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an openlabel randomised phase III trial. Lancet, 2009. 373(9674): p. 1525-31. 27. Arriagada R, Bergman B, Dunant A, et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-

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based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004;350:351-60. 28. Arriagada R, Bergman B, Dunant A, et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatinbased adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004;350:351-60. 29. Rosell R,et al. A Randomized Trial Comparing Preoperative Chemotherapy Plus Surgery With Surgery Alone In Patients With Non-Small-Cell Lung Cancer. N Engl Med 1994:330:153-8. 30. Depierre A., et al. Preoperative Chemotherapy Followed by Surgery Compared With Primary Surgery in Resectable Stage I (Except T1N0), II, and IIIa Non–Small-Cell Lung Cancer. J Clin Oncol 2002;20:247-251. 31. DeVore RF, et al. Phase II Study of Irinotecan Plus Cisplatin in Patients With Advanced Non–Small-Cell Lung Cancer. J CIin Oncoll 1999:17:2710-20. 32. Quoix E. A., Oster J., Westeel V., et al. Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 28:18s, 2010 (suppl; abstr 2).

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Câncer de Pulmão de Pequenas Células EP + Radioterapia Etoposide: 100mg/m² IV D1 ao D3 Cisplatina: 80mg/m² IV D1 a cada 28 dias no total de 4 ciclos, concomitante a radioterapia Ref. (1) CAV seguido de EP + Radioterapia Ciclofosfamida: 1000 mg/m² IV D1 Doxorrubicina: 50 mg/m² IV D1 Vincristina: 1mg/m² IV D1 (máximo 2mg) 3 semanas após CAV, administrar EP. Alternar CAV e EP a cada 3 semanas. Etoposide: 100mg/m² IV D22 ao D24 Cisplatina: 25mg/m² IV D22 Iniciar radioterapia torácica 20 a 30 Gy concomitante ao EP Ref. (2) EP Etoposide: 120 mg/m² IV D1 ao D3 ou etoposide 120mg/m² IV D1 e 240mg/m² VO D2 e D3 Cisplatina: 80 mg/m² IV D1 a cada 21 dias Ref. (3) EC Etoposide: 100 mg/m² IV D1 ao D3 Carboplatina: AUC de 6 IV D1 a cada 28 dias Ref. (4)

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Irinotecano + Cisplatina Irinotecano: 60 mg/m² IV D1, D8 e D15 Cisplatina: 60 mg/m² IV D1 a cada 28 dias Ref. (5) Carboplatina + Irinotecano Carboplatina: AUC de 4 IV D1 Irinotecano: 175mg/m² IV D1 a cada 21 dias Ref. (6) Carboplatina + Paclitaxel Paclitaxel: 200mg/m² IV D1 Carboplatina: AUC 6 IV D1 a cada 21 dias Ref. (7) Carboplatina + Paclitaxel + Etoposide Carboplatina: AUC 6 IV D1 Paclitaxel: 200 mg/m² IV durante 1 hora D1 Etoposide: 50 mg alternando com 100 mg VO D1 ao D10 a cada 21 dias Ref. (8) CAE Ciclofosfamida: 1000mg/m² IV D1 Doxorrubicina: 50mg/m² IV D1 Etoposide: 120mg/m² IV D1 e 240mg/m² VO D2 e D3 a cada 21 dias Ref. (9) Paclitaxel Paclitaxel: 80-100 mg/m² IV semanalmente por 3 semanas a cada 28 dias Ref. (10) Guia Prático para o Oncologista Clínico •

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Topotecano Topotecano: 4mg/m² IV semanalmente em 30 minutos Ou Topotecano: 2,3mg/m² VO D1 ao D5 a cada 21 dias Ref. (11)

1. Takada M. et al. Phase III Study of Concurrent Versus Sequential Thoracic Radiotherapy in Combination With Cisplatin and Etoposide for Limited-Stage Small-Cell Lung Cancer: Results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20:3054, 2002. 2. Murray N. et al. Abbreviated treatment for elderly, infirm or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16: 3323, 1998. 3. Ihde DC, et al. Prospective randomized comparison of highdose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive stage small cell lung cancer. J Clin Oncol 1994;12:2022-2034. Baka S. et al. Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung câncer. Br J Cancer99: 442, 2008 4. Viren M, et al. Carboplatin and etoposide in extensive small cell lung cancer. Acta Oncol 1994;33:921-924. 5. Noda K, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small cell lung cancer. N Engl J Med 2002;346:85-91. 6. Hermes A. et al. Irinotecan Plus Carboplatin Versus Oral Etoposide Plus Carboplatin in Extensive Small-Cell Lung Cancer: A Randomized Phase III Trial. J Clin Oncol 26: 4261, 2008. 7. Baka S. et al. Randomized phase III study of carboplatin and paclitaxel versus vincristine, doxorubicin and cyclophosphamide

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chemotherapy in intermediate and poor prognosis small cell lung cancer: Preliminary results. J Clin Oncol 24: abstr 7059, 2006. 8. Hainsworth JD, et al. Paclitaxel, carboplatin and extendedschedule etoposide in the treatment of small cell lung cancer comparison of sequential phase II trials using different dose-intensities. J Clin Oncol 1997;15:3464-3470. 9. Baka S. et al. Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung câncer. Br J Cancer99: 442, 2008. 10. Hainsworth JD, et al. The current role and future prospects of paclitaxelin in the treatment of small cell lung cancer. Semin Oncol 1999;26 (Suppl 2):60-66. 11. Shipley D. L. et al. Topotecan: Weekly intravenous (IV) schedule similar to standard 5-day IV schedule as secondline therapy for relapsed small cell lung cancer (SCLC)—A Minnie Pearl Cancer Research Network phase II trial . J Clin Oncol 24: abstr 7083, 2006. Mary E.R.et al. Phase III Trial Comparing Supportive Care Alone With Supportive Care With Oral Topotecan in Patients With Relapsed Small-Cell Lung Câncer. J Clin Oncol 24: 5441, 2006.

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Mesotelioma Cisplatina + Doxorrubicina Doxorrubicina: 60mg/m2 Cisplatina: 60mg/m2 Ref. (1)

IV IV

D1 D1 a cada 21 dias

CAP Ciclofosfamida: 500mg/m2 Doxorrubicina: 50mg/m2 Cisplatina: 80mg/m2 Ref. (2)

IV IV IV

D1 D1 D1 a cada 21 dias

Gencitabina + Cisplatina Gencitabina: 1000mg/m2 IV Cisplatina: 100mg/m2 IV Ref. (3)

D1, D8, D15 D1 a cada 28 dias

Gencitabina+ Carboplatina Gencitabina: 1000mg/m2 IV Carboplatina: AUC 5 IV Ref. (4)

D1, D8, D15 D1 a cada 28 dias

Pemetrexede + Cisplatina Pemetrexede: 500mg/m2 IV Cisplatina: 75mg/m2 IV Ref. (5)

D8 D1, D8

Pemetrexede Pemetrexede: 500mg/m2 IV em 10 min D1 a cada 21 dias Ref. (6)

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a cada 21 dias

Vinorelbina Vinorelbina: 30mg/m2 IV D1 semanalmente durante 6 ou 12 semanas (com intervalo de 2 semanas entre a 6a e 7a dose). Ref. (7) Pemetrexede + Carboplatina Pemetrexede: 500mg/m2 IV Carboplatina: AUC de 5 IV a cada 21 dias Ref. (8)

D1 D1

Cisplatina e Raltitrexede Cisplatina : 80 mg/m2 IV Raltitrexede: 3 mg/m2 IV Ref. (9)

D1 D1

a cada 21 dias

Raltitrexede Raltitrexede: 3 mg/m2 Ref. (10)

D1

a cada 21 dias

IV

1. Ardizzoni, A., et al. Activity of doxorubicin and cisplatin combination chemotherapy in patients with diffuse malignant pleural mesothelioma. An Italian Lung Cancer Task Force (FONICAP) Phase II study. Cancer, 1991. 67(12): p. 2984-7. 2. Shin, D.M., et al. Prospective study of combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin for unresectable or metastatic malignant pleural mesothelioma. Cancer, 1995. 76(11): p. 2230-6. 3. Nowak, A.K., et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer, 2002. 87(5): p. 491-6. 4. Favaretto, A.G., et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study. Cancer, 2003. 97(11): p. 2791-7. Guia Prático para o Oncologista Clínico •

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5. Vogelzang, N.J., et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol, 2003. 21(14): p. 2636-44. 6. Taylor, P et al. Single-Agent Pemetrexed for Chemonaive and Pretreated Patients with Malignant Pleural Mesothelioma: Results of an International Expanded Access Program. Journal of Thoracic Oncology, 2008;3:764-771. 7. Stebbing J, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009; 63:94-7. 8. Ceresoli GL, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006; 24:1443-1448. 9. van Meerbeeck JP, et al. Randomized Phase III Study of Cisplatin With or Without Raltitrexed in Patients With Malignant Pleural Mesothelioma: An Intergroup Study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 2005;23:6881-9. 10. Baas P, et al. The activity of raltitrexed (Tomudex®) in malignant pleural mesothelioma: an EORTC phase II study (08992). Eur J Cancer 2003;39:353-7.

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Timoma CAP Ciclofosfamida: 500 mg/m² IV D1 Doxorubicina: 50 mg/m² IV D1 Cisplatina: 50 mg/m² IV D1 a cada 21 dias Ref. (1) Cisplatina + Etoposide Cisplatina: 60 mg/m² IV D1 Etoposide: 120 mg/m² IV D1 ao D3 a cada 21 dias Ref. (2) CAPP Ciclofosfamida: 500 mg/m² IV D1 Doxorrubicina: 20 mg/m²/dia IV D1 ao D3 (total de 60 mg/m²) Cisplatina: 30 mg/m² IV D1 ao D3 Prednisona: 100 mg VO/dia D1 ao D5 a cada 21 dias Ref. (3) PEE Cisplatina: 75 mg/m² IV D1 Epirrubicina: 100 mg/m² IV D1 Etoposide: 120 mg/m² IV D1, D3 e D5 a cada 21 dias Ref. (4)

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ADOC Cisplatina: 50 mg/m² IV D1 Doxorubicina: 40 mg/m² IV D1 Vincristina: 0,6 mg/m² IV D3 Ciclofosfamida: 700 mg/m² IV D4 a cada 28 dias Ref. (5)

1. Loehrer PJ, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. J Clin Oncol 1994;12:11641168. 2. Giaccone G, et al. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phse II study of the European Organization for Research and Treatment of cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814-820. 3. Kim ES, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Câncer 44:369-379,2004. 4. Venuta F, et al. Multimodality Treatment of Thymoma: A Prospective Study. Ann Thorac Surg 1997;64:1585-1591. 5. Fornastero A, et al. Chemotherapy for invasive thymoma. Cancer 1991;68:30-33.

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Melanoma Maligno Alfainterferon 2b em altas doses Indução: 20 MUI/m²/dia IV durante 20 min, 5 vezes por semana, durante 4 semanas Consolidação/Manutenção: 10 MUI/m²/dia SC, 3 vezes por semana durante 48 semanas. Ref. (1) Dacarbazina (DTIC)* Dacarbazina: 250 mg/m²/dia IV durante 30-60 minutos D1 ao D5 a cada 21 ou 28 dias Ou Dacarbazina: 1000 mg/m²/dia IV durante 30 minutos D1 a cada 21 dias Ref. (2) Alfainterferon 2b Alfainterferon 2b: 20 MUI/m²/dia IM, 3 vezes por semana durante 12 semanas. Ref. (3) Interleucina-2 (IL-2) em altas doses Interleucina-2: 720.000 UI/kg IV durante 15 minutos a cada 8h máximo 12 a 15 doses por ciclo (do D1 ao D4 ou do D1 ao D5). A primeira dose do segundo curso de IL-2 deve ser administrada 14 dias após a primeira dose do primeiro curso. a cada 6 a 12 semanas Ref. (4)

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Temozolomida Temozolomida: 200 mg/m²/dia VO D1-5. a cada 28 dias

Ref. (5)

Fotemustina Indução: 100mg/m2 IV durante 60 min D1, D8 e D15, com intervalo de 05 semanas. Manutenção: 100mg/m2 IV durante 60 min D1 a cada 03 semanas. Ref. (6) Dacarbazina (DTIC) + Carmustina (BCNu) + Cisplatina Dacarbazina: 220 mg/m²/dia IV em 30-60 min D1 ao D3 a cada 21 dias Cisplatina: 25 mg/m²/dia IV em 30-45 min D1 ao D3 a cada 21 dias Carmustina: 150 mg/m² IV durante 2 a 3 horas D1 a cada 42 dias. Ref. (7) Paclitaxel + Carboplatina Paclitaxel: 100 mg/m2 IV durante 1 hora Carboplatina: AUC 2 IV em 30 min D1, D8 e D15 a cada 28 dias. Ou Paclitaxel: 175-200 mg/m2 IV durante 3 horas Carboplatina: AUC 5 IV em 60min D1 a cada 21 dias. Ref. (8)

Bioquimioterapia Cisplatina + Vinblastina + Dacarbazina + IL-2 + IFN α 2b Cisplatina: 20mg/m2/dia IV em 30 min D1 ao D4 Vinblastina: 1,2mg/m2/dia IV pulso D1 ao D4 Dacarbazina: 800 mg/m2/dia IV em 1 hora D1 (administrar 1 hora após Vinblastina)

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IL-2: 9 MUI/m2 IV em 24h infusão contínua D1-4 (total de 96h) Alfainterferon 2b: 5 MUI/m2 SC D1 ao D5, D8, D10 e D12 Filgrastima: 5mcg/Kg/d SC D7 ao D16 a cada 21 dias, com o máximo de 4 ciclos. Ref. (9) Paclitaxel Paclitaxel: 90 mg/m2 IV(80min) D1, D5 e D9 Ref. (10) CVD Cisplatina: 20mg/m2/dia IV Vinblastina: 1,6mg/m2/dia IV Dacarbazina: 800 mg/m2 IV Ref. (11)

a cada 21 dias

D2 a D5 D1 a D5 D1 a cada 21 dias

Regime Dartmouth* Carmustina: 150 mg/m2 IV D1 Cisplatina: 25 mg/m2 IV D1 a D3 2 Dacarbazina: 220 mg/m IV D1 a D3 a cada 21 dias *Além dos quimioterápicos, o regime inclui também tamoxifeno, 10 mg, 2 vezes ao dia, com início 1 semana antes da quimioterapia e tomado de forma contínua. Ref. (12) 1. Kirkwood JM, et al. Interferon alfa-2b adjuvant therapy of high risk resected cutaneous melanoma: the Eastern Cooperative Oncology Trial EST 1684. J Clin Oncol 1996;14:7-17. Kirkwood JM, et al. High-dose Interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of Intergroup Trial E1694/S9512/ C509801. J Clin Oncol 2001;19:2370-80. Kirkwood JM, et al. A pooled Analysis of Eastern Cooperative Oncology Group and Intergroup Trials of Adjuvant High – Dose Interferon for Melanoma. Clin Cancer Res 2004; 10:1670-1677. Guia Prático para o Oncologista Clínico •

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2. Middleton MR, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18: 158–66. Avril, MF et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004; 22:1118-25. Chapman PB, et al. Phase III multicentric randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17:2745-51. Eigentler, TK et al. Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol 2003;4:748-59. 3. Kirkwood JM, et al. Advances in the diagnosis and treatment of malignant melanoma. Semin Oncol 1997;24 (suppl 4): 1-48. 4. Smith, FO et al. Treatment of metastatic melanoma using Interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res 2008;14:5610-18. Atkins, MB et al. High-Dose recombinant Interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17: 2105-16. Schwartzentruber, DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother 2001; 24:287-93. 5. Middleton MR, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000;18:158-166. 6. Avril, MF et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004; 22:1118-1125. 7. Chapman PB, et al. Phase III multicentric randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17:2745-51. Creagen ET, et al. Phase III clinical trial of the combination of

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cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma. J Clin Oncol 1999;17:1884-1890. 8. Rao, RD et al. Combination of paclitaxel and carboplatin as second-Line therapy for patients with metastatic melanoma. Cancer 2006;106:375-82. 9. Atkins,MB et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2008; 26:5748-5754. 10. Bedikian AY, et al. Phase II evaluation of paclitaxel by short intravenous infusion in metastatic melanoma Melanoma Res 2004;14:63-6. 11. Legha SS, et al. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanomaCancer 1989;64:2024-9. 12. Chapman PS, et al. Phase III Multicenter Randomized Trial of the Dartmouth Regimen Versus Dacarbazine in Patients With Metastatic Melanoma. J Clin Oncol 1999; 17:2745-51.

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Linfoma de Hodgkin BEACOPP escalonado Bleomicina: 10 mg/m² IV D8 Etoposide: 200 mg/m² IV D1 ao D3 Doxorrubicina: 35 mg/m² IV D1 Ciclofosfamida: 1250 mg/m² IV D1 Vincristina: 1,4 mg/m² IV D8 (dose máxima 2 mg) Procarbazina: 100 mg/m² VO D1 ao D7 Prednisona: 40 mg/m² VO D1 ao D14 Filgrastima: 5 μg/kg/dia SC, iniciando no D8 até a recuperação dos neutrófilos. a cada 21 dias Ref. (01) DHAP Dexametasona: 40mg VO D1 ao D4 Cisplatina: 100mg/m² IV em infusão contínua por 24h D1 Citarabina: 2000 mg/m² IV em 2 horas 12/12h D2 Filgrastima: 300mcg SC D4 ao D13 Devem ser realizados 2-4 ciclos e no caso de resposta, coleta de células progenitoras e posterior TMO Profilaxia de conjuntivite por citarabina com colírio de dexametasona. Ref. (02) ICE Ifosfamida: 5mg/m² IV D2 Etoposide: 100mg/m² IV D1 ao D3 Carboplatina: AUC 5 IV D2 A Ifosfamida deve ser associada a Mesna na dose de 5000 mg/m². a cada 14 dias Filgrastima: 5 μg/kg D5 ao D12. Ref. (03)

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Gencitabina Gencitabina: 1250 mg/m² IV D1, D8 e D15 a cada 28 dias Ref. (04) Gencitabina + Vinorelbina + Doxorrubicina Lipossomal Peguilada Vinorelbina: 20mg/m² IV D1 e D8 em 10 min, sendo a 1º droga Gencitabina: 1000 mg/m² IV D1 e D8 em 30 min, sendo a 2º droga Doxorrubicina Lipossomal Peguilada: 15mg/m² IV D1 e D8 em 30-60 min a cada 21 dias Ref. (05) ABVD Doxorrubicina: 25mg/m² Bleomicina: 10UI/m² Vinblastina: 6mg/m² Dacarzabina: 375mg/m² a cada 28 dias Ref. (06)

IV IV IV IV

MOPP Mustarda Nitrogenada: 6mg/m² Vincristina: 1,4mg/m² Procarbazina: 100mg/m² Prednisona: 40mg/m² a cada 28 dias Ref. (07)

D1 e 15 D1 e 15 D1 e 15 D1 e 15

IV IV VO VO

D1 e 8 D1 e 8 D1 a 14 D1 a 14

MOPP/ABVD HÍBRIDO Mustarda Nitrogenada: 6mg/m² IV D1 e 8 Vincristina: 1,4mg/m² IV D1 ( Dose máxima de 2mg) Procarbazina: 100mg/m² VO D1 a 14 Prednisona: 40mg/m² IV D1 a 14 Guia Prático para o Oncologista Clínico •

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Doxorrubicina: 35mg/m² Bleomicina: 10UI/m² Hidrocortisona: 100mg Vinblastina: 6mg/m² a cada 28 dias Ref. (08)

IV D8 IV D8 IV dada antes da Bleomicina IV D8

EVA Etoposide: 200 mg/m2 IV D1-5 Vincristina: 2mg/m2 IV D1 Doxorrubicina: 50 mg/m2 IV D2 a cada 28 dias Ref. (09) EVAP Etoposide: 120 mg/m2 IV D1, 8 e 15 Vinblastina: 4 mg/m2 IV D1, 8 e 15 Citarabina: 30 mg/m2 IV D1, 8 e 15 Cisplatina: 40 mg/m2 IV D1, 8 e 15 a cada 28 dias Ref. (10) Mini- BEAM BCNU: 60 mg/m2 IV D1 Etoposide: 75 mg/m2 IV D2-5 Ara-C: 100 mg/m2 IV a cada 12 horas D2-5 Melfalano: 30 mg/m2 IV D6 a cada 4 a 6 semanas Ref. (11) BEACOPP Bleomicina: 10 mg/m2 IV D 8 Etoposide: 100 mg/m2 IV D1-3 Doxorrubicina: 25 mg/m2 IV D1 Ciclofosfamida: 650 mg/m2 IV D1

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Vincristina: 1.4 mg/m2 IV D (máximo 2 mg) Procarbazina: 100 mg/m2 VO D1-7 Prednisona: 40 mg/m2 VO D1-14 a cada 21 dias Ref. (12) Stanford V Doxorrubicina: 25 mg/m2 IV semanas 1, 3, 5, 7, 9 e 11 Vinblastina: 6 mg/m2 IV semanas 1, 3, 5, 7, 9 e 11 (dose é reduzida para 4 mg/m2 nas semanas 9 e 11 em paciente ≥ 50 anos). Mustarda Nitrogenada: 6 mg/m2 IV nas semanas 1, 5 e 9. Etoposide: 60mg/m2 IV por 2 dias nas semanas 3, 7 e 11. Vincristina: 1,4 mg/m2 IV nas semanas 2, 4, 6, 8,10 e 12. (A dose é reduzida para 1 mg/m2 nas semanas 10 e 12 em paciente ≥ 50 anos). Bleomicina: 5 UI/m2 IV nas semanas 2,4,6,8,10 e 12. Prednisona: 40 mg/ m2 VO em dias alternados por 10 semanas com desmame a cada 2 dias da semana 10 a 12. Ref .(13)

1. Diehl V; Franklin J; Pfreundschuh M; Lathan B; Paulus U; Hasenclever D; Tesch H; Herrmann R; Dorken B; MullerHermelink HK; Duhmke E; Loeffler M. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease.N Engl J Med 2003 Jun 12;348(24):2386-95. 2. Josting A. et al. Time-intensified dexamethasone/cisplatin/ cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Ann Oncol 13:1628, 2002. Guia Prático para o Oncologista Clínico •

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3. Abali H. et al. Comparison of ICE (Ifosfamide-CarboplatinEtoposide) Versus DHAP (Cytosine Arabinoside-CisplatinDexamethasone) as Salvage Chemotherapy in Patients with Relapsed or Refractory Lymphoma.Cancer investigation 2008, Vol. 26, No. 4, Pages 401-406. 4. Santoro A, et al. Gemcitabine in the treatment of refractory Hodgkin´s disease: results of a multicenter phase II study. J Clin Oncol 2000;18;2645-2619. 5. Barlet N. L. et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Annals of Oncology 18: 1071–1079, 2007. 6. Bonadonna G. et al. Combination Chemotherapy of Hodgkin’s disease With Adriamycin, bleomycin, Vinblastine, and Imidazole Carboxamide Versus Mopp. Cancer 1975; 36: 252259. 7. De Vita VT, Jr et al. Combination Chemotherapy in Tratamento of Advanced Hodgkin’s desease. Ann Intern Med 1970; 73; 881-895. 8. Klimo P. et al. Mopp/ABV hybrid program: Combination Chemotherapy baseol on Early introduction of seven effective drogs for advanced hodgkin’s disease. J Clin Oncol 1985; 3: 1174-1182. 9. Radford JÁ, et al. Results of a randomized trial comparing MVPP chemotherapy with a hybrid regimen, CHLVPP/EVA, in the initiai treatment of Hodginkin's disease J. Clin Oncol 1995;13:2379-2385. 10. Longo Dl, The use of chemotherapy in the treatment of Hodgkin's disease. Semin Oncol 1990;17:716-735. 11. Colwill R, et al. Mini-Beam as salvage therapy for relapsed or refractory Hodgkin's disease before intensive therapy and autologous boné marrow transplantation. J Clin Oncol 1995;13:396-402. 12. Diehl V. et al. BEACOPP, a new dose-escalated and accelerated regimen is at least as effective as COPP/ABVD in

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patients with advanced-stage hodgkin's lymphoma. J Clin Oncol 1998:16:3810-3821. 13. Hoskin PJ, Lowry L, Horwich A, Jack A, et al. Randomized comparison of the Stanford V Regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2009; 27:53905396.

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Linfoma Não-Hodgkin Rituximabe (LNH Folicular) Rituximabe: 375mg/m2 semanalmente por 4 semanas. Ref. (01) R – CVP (linfomas CD20 positivo) Ciclofosfamida: 750 mg/m² IV D1 Vincristina: 1,4 mg/m² IV D1 (dose máxima 2 mg) Prednisona: 40 mg/m² VO D1 ao D5 Rituximabe: 375mg/m² IV D1 a cada 21 dias no total de 8 ciclos Ref. (02) R – CHOP Rituximabe: 375mg/m2 D1 Ciclofosfamida: 750 mg/m² IV D1 Doxorrubicina: 50 mg/m² IV D1 Vincristina: 1,4 mg/m² IV D1 (dose máxima 2 mg) Prednisona: 100 mg/m² VO D1 ao D5 a cada 21 dias. Ref. (03) FND Fludarabina: 25 mg/m² IV D1 ao D3 Mitoxantrona: 10 mg/m² IV D1 Dexametasona: 20 mg VO D1 ao D5 a cada 21 dias Cuidados de Suporte Sulfametoxazol 800mg + Trimetoprima 160mg VO 1x/dia 3 dias por semana, até 3 meses após término do tratamento Ref. (04)

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R-FND Rituximabe: 375mg/m² IV D0 Fludarabina: 25 mg/m² IV D1 ao D3 Mitoxantrona: 10 mg/m² IV D1 Dexametasona: 20 mg VO D1 ao D5 a cada 21 dias Ref. (05) FC Fludarabina: 20 mg/m² IV D1 ao D5 Ciclofosfamida: 1000 mg/m² IV D1 a cada 21-28 dias Ref. (06) Fludarabina Fludarabina: 25 mg/m² IV D1 ao D5 a cada 28 dias Ref. (07) CVP Ciclofosfamida: 400 mg/m2 VO D1 -5 (ou 800 mg/m2 IV D1) Vincristina: 1.4 mg/m2 IV D1 (máximo 2 mg) Prednisona: 100 mg/m2 VO D1-5 a cada 21 dias Ref. (08) CHOP Ciclofosfamida: 750 mg/m2 IV D1 Doxorrubicina: 50 mg/m2 IV D1 Vincristina: 1.4 mg/m2 IV D1 (máximo 2 mg) Prednisona: 100 mg/m2 VO D1-5 a cada 21 dias Ref. (09)

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CNOP Ciclofosfamida: 750 mg/m2 IV D1 Mitoxantrona: 10 mg/m2 IV D1 Vincristina: 1.4 mg/m2 IV D1 (máximo 2 mg) Prednisona: 50 mg/m2 VO D1-5 a cada 21 dias Ref. (10) CHOP + Rituximabe (Nebraska regimen) Ciclofosfamida: 750 mg/m2 IV D3 Doxorrubicina: 5O mg/m2 IV D3 Vincristina: 1.4 mg/m2 IV D3 (máximo de 2 mg) Prednisona: 100 mg VO D3-7 Rituximabe: 375 mg/m2 IV no D1 a cada 21 dias Ref. (11) CNOP Ciclofosfamida: 750 mg/m2 D1 Mitoxantrona: 10 mg/m2 IV D1 Vincristina: 1.4 mg/m2 IV D1 (máximo de 2 mg) Prednisona: 100 mg VO D1-5 a cada 21 dias Ref. (12) EPOCH Etoposide: 50 mg/m2/dia IV em infusão contínua D1-4 Prednisona: 60 mg/m2 VO D1-5 Vincristina: 0.4 mg/m2/dia IV em infusão contínua D1-4 Ciclofosfamida: 750 mg/m2 IV D5, iniciar após infusão contínua Doxorrubicina: 10 mg/m2/dia IV em infusão contínua D1-4 a cada 21 dias Ref. (13)

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EPOCH + Rituximabe Etoposide: 50 mg/m2/dia IV em infusão contínua D1-4 Prednisona: 60 mg/m2 VO BID D1-5 Vincristina: 0.4 mg/m2/dia em infusão contínua D1-4 Ciclofosfamida: 750 mg/m2 IV D5, iniciar após infusão contínua Doxorrubicina: 10 mg/m2/dia IV em infusão contínua D1-4 Rituximabe: 375 mg/m2 IV no dia 1 a cada 21 dias Ref. (14) MACOP-B Methotrexate: 400mg/m2 IV nas semanas 2,6 e 10 Leucovorin: 15mg/m2 VO a cada 6 horas por 6 doses, iniciando 24 horas após o methotrexate Doxorrubicina: 50 mg/m2 IV nas semanas 1, 3, 5, 7, 9 e 11 Ciclofosfamida: 350 mg/m2 IV nas semanas 1, 3, 5, 7, 9 e 11 Vincristina: 1.4 mg/m2 IV nas semanas 2, 4, 6, 8, 10 e 12 Prednisona: 75mg/dia VO por 12 semanas com retirada nas 2 últimas semanas Bleomicina: 10 U/m2 IV nas semanas 4, 8 e12 Bactrim F: 1 comp. VO BID Cetoconazol: 200 mg/dia VO Administrar um ciclo. Ref. (15) m-BACOD Methotrexate: 200 mg/m2 IV D8 e 15 Leucovorin: 10 mg/m2 VO a cada 6 horas por 8 doses, iniciando 24 após o methotrexate Bleomicina: 4 U/m2 IV D1 Doxorubicina: 45 mg/m2 IV D1 Ciclofosfamida: 600 mg/m2 IV D1 Vincristina: 1 mg/m2 IV D1 (máximo de 2 mg) Dexametasona: 6 mg/m2 VO D1-5 a cada 21 dias Ref. (16) Guia Prático para o Oncologista Clínico •

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ProMACE/CytaBoM Prednisona: 60mg/m2 VO D1-14 Doxorrubicina: 25 mg/m2 IV D1 Ciclofosfamida: 650 mg/m2 IV D1 Etoposide: 120mg/m2 IV D1 Citarabina: 300mg/m2 IV D8 Bleomicina: 5 U/m2 IV D8 Vincristina: 1.4 mg/m2 IV D8 Methotrexate: 120 mg/m2 IV D8 Leucovorin resgate com: 25mg/m2 VO cada 6 horas por 6 doses, iniciando 24 horas após o methotrexate Bactrim F: 1 comp. VO BID D1-21 a cada 21 dias Ref. (17) ESHAP (Regime de salvamento) Etoposide: 40 mg/m2 IV D1-4 Metilprednisolona: 500 mg IV D1-4 Cisplatina: 25 mg/m2/dia IV infusão contínua D1-4 Citarabina: 2,000 mg/m2 IV D5 depois de completar a cisplatina e etoposide a cada 21 dias Ref. (18) DHAP (Regime de salvamento) Cisplatina: 100 mg/m2 IV infusão contínua de 24 horas D1 Citarabina: 2,000 mg/m2 IV em infusão de 3 horas a cada 12 horas por 2 doses D2 após término de infusão de cisplatina Dexametasona: 40 mg VO ou IV D1-4 a cada 3-4 semanas Ref. (19)

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ICE (Regime de salvamento) Ifosfamida: 5,000 mg/m2 IV infusão contínua de 24 horas D2 Etoposide: 100 mg/m2 IV D1-3 Carboplatina: AUC 5 IV D2 Mesna: 5,000 mg/m2 IV em combinação com a dose de Ifosfamida a cada 14 dias G-CSF é administrado na dose de 5 mg/kg D5-12. Ref. (20)

MINE (Regime de salvamento) Mesna: 1,330 mg/m2 IV administrar ao mesmo tempo de Ifosfamida D1 a 3, seguido por 500mg IV 4 horas depois da Ifosfamida D1 a 3 Ifosfamida: 1,330 mg/m2 IV D1-3 Mitoxantrona: 8 mg/m2 IV D1 Etoposide: 65 mg/m2 IV D1-3 a cada 21 dias Ref. (21)

Alto Grau Protocolo de Magrath (Linfoma de Burkitt) Ciclofosfamida: 1,200 mg/m2 IV D1 Doxorrubicina: 40 mg/m2 IV D1 Vincristina: 1.4 mg/m2 IV D1 (máximo de 2 mg) Prednisona: 40 mg/m2 VO D1 -5 Methotrexate: 300 mg/m2 IV D10, em 1 hora, seguido por 60 mg/m2 IV D10 e 11, em 41 horas Resgate com Leucovorin: 15 mg/m2 IV cada 6 horas por 8 doses, iniciando 24 horas após o methotrexate D12 Ara-C Intratecal: 30 mg/m2 IT D7, somente no ciclo 1 45 mg/m2 IT D7, em todos os ciclos subsequentes Guia Prático para o Oncologista Clínico •

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Methotrexate Intratecal em todos os ciclos: 12.5 mg IT D10 a cada 28 dias Ref. (22) Ou Regime A (CODOX-M) Ciclofosfamida: 800 mg/m2 IV D1 e 200 mg/m2 IV D2-5 Doxorrubicina: 40 mg/m2 IV D1 Vincristina: 1.5 mg/m2 IV D1 e 8 no ciclo 1 e D1, 8 e 15 no ciclo 3 Methotrexate: 1,200 mg/m2 IV durante 1 hora, seguido por 240 mg/m2/hora nas 23 horas seguintes D10 Leucovorin: 192mg/m2 IV iniciando na hora 36 após o início da infusão e 12 mg/m2 IV a cada 6 horas até os níveis de Methotrexate reduzirem abaixo de < 50 nMol/L Profilaxia do SNC Citarabina: 70 mg IT D1 e 3 Methotrexate: 12 mg IT D15 Regime B (IVAC) Ifosfamida: 1,500 mg/m2 D1-5 (com Mesna) Etoposide: 60mg/m2 IV D1-5 Citarabina: 2 g/m2 IV a cada 12 horas D1 e 2 no total de 4 doses Methotrexate: 12 mg IT D5 Sequência A/B/A/B - 4 ciclos Ref. (28) Regime de Stanford (Linfoma de Burkitt e pequenas células não-clivadas) Ciclofosfamida: 1,200 mg/m2 IV D1 Doxorrubicina: 40 mg/m2 IV D1 Vincristina: 1.4 mg/m2 IV D1 (máximo de 2 mg) Prednisona: 40 mg/m2 VO D1-5 Methotrexate: 3 g/m2 IV em infusão de 6 horas D10

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Resgate com Leucovorin: 25 mg/m2 IV ou VO a cada 6 horas por 12 doses, iniciando 24 horas após o Methotrexate Methotrexate Intratecal: 12 mg D1 e 10 a cada 21 dias Ref. (23) Stanford V Mustarda Nitrogenada: 6mg/m² Doxorrubicina: 25mg/m² Vinblastina: 6mg/m² Vincristina: 1,4mg/m² Bleomicina: 5UI/m² Etoposide: 60mg/m² Prednisona: 40mg a cada 28 dias

IV D1 IV D1 e 15 IV D1 e 15 IV D8 e 22 IV D8 e 22 IV D15 e 16 VO por dia

Em pacientes acima de 50 anos, a dose da Vinblastina deve ser reduzida para 4mg/m² e a dose da Vincristina para 1mg/m² nas semanas 9 e 12. Iniciar redução da dose da prednisona na semana 10. Usar Bactrin Profilático VO BID e Aciclovir 200mg VO TID. Ref. (24)

Regime de Monoterapia Rituximabe Rituximabe: 375 mg/m2 IV D1, 8, 15 e 22 Repetir um ciclo adicional. Ref. (25) Fludarabina Fludarabina: 25 mg/m2 IV D1-5 a cada 28 dias Ref. (26) Guia Prático para o Oncologista Clínico •

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Cladribina Cladribina: 0.5-0.7 mg/kg SC D1-5 or 0.1 mg/kg IV D1-7 a cada 28 dias Ref. (27) 1. Colombat P et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood 2001 Jan 1;97(1):101-6. 2. Marcus R. et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. BLOOD 105: 1417, 2005. 3. Hiddemann W; et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German LowGrade Lymphoma Study Group.Blood. 2005 Dec 1;106(12): 3725-32. Epub 2005 Aug 25. 4. MacLaughlin P, et al. Fludarabine, mitoxantrone and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol 1996;14:1262-1268. 5. McLaughlin P; et al. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma.Semin Oncol. 2000 Dec;27(6 Suppl 12):37-41. 6. Hochster H, et al. Eficacy of cyclophosphamide (CYC) and fludarabine (FAMP) as first-line therapy of low-grade nonHodgkin´s lymphoma (NHL). Clood 1994;84(Suppl 1):383a. 7. Falkson CI. A phase II trial in patients with previously trated low-grade lymphoma. Am J Clin Oncol 1996;19:268-270. 8. Bagley CM. Jr et al. Advanced lymphosarcoma: intensive cyclical Combination chemotherapy with cyclophosphamide,

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vincristine, and prednisone. Ann Intern Med 1972:76:227-234. 9. McKelvey EM, et al. Hydroxydaunomycin (Adriamycin) Combination chemotherapy in malignant lymphoma. Cancer 1976;38:1484-1493. 10. Sonnevald P. et al. Companson of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin's lymphoma using CHOP versus CNOP chemotherapy J Clin Oncol 1995;13;25302539. 11. Vose JM, et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non- Hodgkin's lymphoma. J clin Oncol 2001;19:389-397. 12. Vose JM, et al. CNOP for diffuse aggressive non-Hodgkin's lymphoma: the Nebraska lymphoma study group experience. Leuk Lymphoma 2002;43:799-804. 13. Wilson WH, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J clin Oncol 1993;11:1573-1582. 14. Wilson WH. Chemotherapy sensitization by rituximab: experimental and clinicai Evidence. Semin Oncol 2000;27 (Suppl 12):30-36. 15. 262. Klimo P, et al. MACOP-B Chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 1985;102:596-602. 16. Shipp MA, et al. Identification of major prognostic subgroups of patients with large-cell lymphoma treated with mBACOD or M- BACOD. Ann Intern Med 1986; 104:757-765. 17. Longo DL, et al. Superiority of proMACE- CytaBom over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J clin Oncol 1991;9:25-38. 18. Velasquez WS, et al. ESHAP-an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year tbllow-up study. J Clin Oncol 1994;12:1169-1176. Guia Prático para o Oncologista Clínico •

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19. Velasquez WS, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose ara-C and dexamethasone. Blood 1988:71:117-122. 20. Moskowitz C, et al. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral blood progenitor cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma. J Clin Oncol 1999;17:3776-3785. 21. Rodriguez MA, et al. a phase II trial of mesna/ifosfamide, mitoxantrone, and etoposide for refractory lymphoma. Ann Oncol 1995;6:609-611. 22. Magrath I, et al. An effective therapy for both undifferentiated lymphomas and lyrnphohlastic lymphomas in children and young adults. Blood 1984; 63:1102-1111. 23. Berstein JT. et al. Combined modality therapy for adults with small non-cleaved cell lymphoma(Burkitt's and nonBurkitt's types). J Clin Oncol 1986:4:847-858. 24. Bartlett NL, et. al. Brief Chemotherapy, Stanford V And Adjuvant Radiotherapy for Bulky 02 Advanced - Stage Hodgkin’s disease: A Preliminary Report. J Clin Oncol 1995; 13:1080-1088. 25. McLaughlin P, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy íbr relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J clin Oncol 1998;16:2825-2833. 26. Falkson Cl. A phase U trial in patients with previously trated low-grade lymphoma. Am J Clin Oncol 1996;19:268-270. 27. Betticher DC, et al. Fewer infections but maintained antitumor activity with lower-dose versus standard-dose cladribine in pretreated low-grade non-Hodgkin's lymphoma. J Clin Oncol 1998:16:850-858. 28. Magrath I, Adde M, Shad A, et al. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996; 14:925-34.

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Linfoma de Grandes Células B CHOP + Rituximabe Ciclofosfamida: 750 mg/m² IV D1 Doxorrubicina: 50 mg/m² IV D1 Vincristina: 1,4 mg/m² IV D1 (dose máxima 2 mg) Prednisona: 100 mg VO D1 ao D5 Rituximabe: 375 mg/m² IV D1 a cada 21 dias Ref. (01) R-ICE (regime de resgate) Rituximabe: 375mg/m² IV D1 Ifosfamida: 5000 mg/m² IV contínua por 24 horas D4 Etoposide: 100 mg/m² IV D3 ao D5 Carboplatina: AUC 5 IV D4 Mesna: 5000 mg/m² IV na mesma bolsa de infusão de Ifosfamida. a cada 14 dias Filgrastima: 5 μg/kg D7 ao D14. Ref. (02)

1. Coiffer B, et al. Rituximab plus CHOP in combination with CHOP chemotherapy in patients with diffuse large B-cell lymphoma; an update of the GELA study. N Engl J Med 2002; 346:235-242. 2. Kewalramani T et al.Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. BLOOD 2004; 103-10.

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Linfoma de Células do Manto Rituximabe + Hyper CVAD Ciclos 1, 3, 5 e 7 Rituximabe: 375mg/m² IV D1 Ciclofosfaminda: 300mg/m² IV por 3h D1 ao D4 de 12/12h ( total de 6 doses) Mesna: 600mg/m² IV em infusão contínua. Iniciar 1h pré ciclofosfamida até 12h após a última dose de ciclofosfamida. Doxorrubicina: 16,6mg/m²/dia IV em 24h contínuo D5 ao D7 (iniciar 12h após última dose de ciclofosfamida) Vincristina: 1,4mg/m² (máximo de 2mg) IV D5 e D12 Dexametasona: 40mg IV ou VO D2 ao D5 e D12 ao D15 Filgrastima: 5 mcg/kg/dia SC iniciar 24hs após término da quimioterapia Ciclos 2, 4, 6 e 8 Rituximabe: 375mg/m² IV D1 Methotrexate: 200mg/m² IV D2 por 2h, seguido por 800mg/m² IV por 22h Citarabina: 3000 mg/m2 IV por 2h a cada 12h D3 e D4 (total 4 doses) Resgate do MTX com Leucovorin: Iniciar 12hs após o término da infusão: Leucovorin 50mg, seguido de 15mg VO a cada 6h por 8 doses. Nível sérico de Methotrexate deve ser checado 24 e 48h após o fim da infusão e doses de Leucovorin devem ser aumentadas para 100mg IV a cada 3h se o nível sérico do MTX superar o valor de 1μmol/L ou 0,1μmol/L em 24 e 48h respectivamente. Ref. (01)

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CHOP + Rituximabe Ciclofosfamida: 750 mg/m² IV D1 Doxorrubicina: 50 mg/m² IV D1 Vincristina: 1,4 mg/m² IV D1 (dose máxima 2 mg) Prednisona: 100 mg VO D1 ao D15 Rituximabe: 375 mg/m² IV D1 a cada 21 dias no total de 6 ciclos Ref. (02) FCM + Rituximabe Fludarabina: 25 mg/m² IV por 30 min D2 ao D4 Ciclofosfamida: 200 mg/m² IV por 4h D2 ao D4 Mitoxantrona: 8mg/m² IV por 30 min D2 Rituximabe: 375mg/m² IV D1 a cada 28 dias para um total de 4 ciclos Ref. (03) Rituximabe + Hyper CVAD Ciclos 1,3, 5 e 7 Rituximabe: 375mg/m² IV D1 Ciclofosfamida: 300mg/m² IV por 3h de 12/12h D2 ao D4 Doxorrubicina: 12,7mg/m² IV em 24h contínuo D5 ao D7, iniciada 12h após última dose de Ciclofosfamida Vincristina: 1,4mg/m² (máximo de 2mg) IV 12h após a última dose de Ciclofosfamida e repetida D12 do ciclo Dexametasona: 40mg IV ou VO D2 ao D5 e D12 ao D15 Observação: 1h antes da admnistração de Ciclofosfamida deve ser iniciado mesna 600mg/m² IV por 24h D2 ao D4 e completada 12h após a última dose de Ciclofosfamida. Ciclos 2, 4, 6 e 8 Rituximabe: 375mg/m² IV D1 Methotrexate: 200mg/m² IV D2 por 2h, seguido por 800mg/m² IV por 22h Guia Prático para o Oncologista Clínico •

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Citarabina: 3000 mg/m2 IV por 2h a cada 12h D3 e D4 Terapia de Resgate: Leucovorin 50mg VO administrado como resgate do Methotrexate 12h após a infusão deste, seguido de 15mg VO a cada 6h por 8 doses. Ref. (04) Bortezomibe Bortezomibe: 1.3 mg/m2 IV D1, 4, 8 e 11 a cada 21 dias Ref. (5)

1. Romaguera J E et al. High Rate of Durable Remissions After Treatment of Newly Diagnosed Aggressive Mantle-Cell Lymphoma With Rituximab Plus Hyper-CVAD Alternating With Rituximab Plus High-Dose Methotrexate and Cytarabine. J Clin Oncol 23:7013, 2005. 2. Lenz G. et al. Immunochemotherapy With Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Significantly Improves Response and Time to Treatment Failure, But Not Long-Term Outcome in Patients With Previously Untreated Mantle CellLymphoma: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23:1984, 2005. 3. Forstpointner R et al.The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German LowGrade Lymphoma Study Group. Blood 2004 ; 104 : 3064 – 71. 4. Romaguera J E et al. Update of the M. D. Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma 8:S57, 2007.

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5. Goy AH, et al. Report of a phase II study of proteosome inhibitor bortezomib in patients with relapsed or refractory indolent and aggressive B-cell lytnphomas. Proc Am Soc Clin Oncol 2003;22:570 (abstract 2291).

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Linfoma Primário do Sistema Nervoso Central Protocolo de quimioterapia isolada para linfoma primário de SNC Methotrexate: 1000 mg/m2 IV D1, D10 e D20 Lomustina: 40 mg/m2 VO D1 Procarbazina: 60 mg/m2 VO D1 ao D7 Metilprednisolona: VO ou IV, 120 mg/m2 em dias alternados D1 ao D20 e 60 mg/m2 D21 ao D45 Methotrexate 15 mg e Citarabina 40 mg IT D1, D5, D10 e D15 Observação: Iniciar Methotrexate após alcalinização de urina e pH urinária >7,5. Resgate com leucovorin 25 mg iniciar 24 hs após o término da administração do Methotrexate IV a cada 6 horas por 3 dias e 10 mg a cada 6 horas por 2 dias após o Methotrexate IT ou conforme nível sérico de Methotrexate. Dia 45 – reavaliação Se doença estável ou progressiva, suspender protocolo Se resposta parcial ou completa, realizar mais 5 ciclos a cada 6 semanas Methotrexate: 1000 mg/m2 IV D1 Lomustina: 40 mg/m2 VO D1 Procarbazina 60mg/m2 VO D1 ao D7 Methotrexate IT 15 mg e citarabina 40 mg D1 Resgate com Leucovorin: iniciar 24 horas após o término da infusão do Methotrexate IV, Leucovorin 25 mg VO a cada 6 horas por 3 dias. Após o Methotrexate IT iniciar Leucovorin 10 mg a cada 6 horas por 2 dias. Ref. (01)

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Linfoma Primário do SNC Methotrexate: 3.5 gm/m2 IV durante 2 horas semanalmente por 5 doses Methotrexate Intratecal: 12 mg IT semanalmente depois do Methotrexate IV Leucovorin: 10 mg IV a cada 6 horas por 12 doses, iniciando 24 horas depois do MTX IV e 10mg IV a cada 12 horas por 8 doses, iniciando 24 horas depois do MTX IT Vincristina: 1.4 mg/m2 IV semanalmente durante o Methotrexate IV Procarbazina: 100 mg/m2/dia VO por 7 dias ciclos 1, 3 e 5 do Methotrexate IV Quando a quimioterapia é completada, a radioterapia holocraniana é realizada com dose total de 45 cGy. Ref. (02)

Tratamento de pacientes imunocompetentes Semanas 1, 5 e 9: Procarbazina: 100 mg/m2/dia VO, por 7 dias Vincristina: 1,4 mg/m2/dia IV (não exceder 2,8 mg) Methotrexate: 2,5 g/m2 IV, durante 2 h Leucovorin: 10 mg VO, de 6/6 h, por 12 doses; iniciar 24 h após o início do Methotrexate. Semanas 2, 4, 6, 8 e 10: Methotrexate intra-Ommaya: 12 mg/dose Leucovorin: 5 mg VO, de 12/12 h, por 8 doses; iniciar 24 horas após o Methotrexate. Semanas 3 e 7: Vincristina: 1,4 mg/m2 IV (não exceder 2,8 mg) Methotrexate: 2,5 g/m2 IV, durante 2 h Leucovorin®: 10 mg VO, de 6/6 h, por 12 doses; Guia Prático para o Oncologista Clínico •

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iniciar 24 h após o início do Methotrexate. Semana 11: - realizar RNM de cérebro. Se < 50 anos, prosseguir com RT: RT de cérebro total (45 Gy em 25 frações de 180 cGy/dia); 30 a 40 Gy em globo ocular acometido pelo linfoma. Para pacientes com RC, a RT de cérebro total é constituída de 36 Gy divididos em 2 frações diárias de 1,2 Gy (total de 15 dias). Se > 60 anos, administrar doses de Ara-C com as doses descritas para as semanas 16 e 19. Semana 16: realizar RNM de cérebro e administrar Ara-C: 2g/m2/dia IV, durante 3 horas, por 2 dias. Semana 19: Ara-C: 3 g/m2/dia IV, em 3 horas, por 2 dias. Ref. (03)

1. Hoang-Xuan et al. Chemotherapy alone as inicial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study of the european organization for research and treatmnet of câncer brain tumor group. JCO, 2003;21:2726-2731. 2. Abrey LÊ, et al. Treatment for primary CNS lymphoma; the next step. J Clin Oncol 2002;18:3144-3150. 3. De Angelis LM, Tong WP, Lin S, Fleisher M, et al. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 2002; 20: 4643-8.

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Mieloma Múltiplo Bortezomibe + Dexametasona (Vel/Dex) Bortezomibe: 1,3 mg/m2 IV pulso D1, D4, D8 e D11 Dexametasona: 40 mg/dia VO D1 ao D4 nos ciclos 1,2,3 e 4 Dexametasona 40 mg/dia VO D1-4 e D9-12 nos ciclos 1 e 2 a cada 21 dias no total de 4 ciclos Ref. (01) Bortezomibe + Doxorrubicina + Dexametasona (PAD) Bortezomibe: 1,3 mg/m² IV pulso D1, D4, D8 e D11 Doxorrubicina: 9 mg/m² IV em 1h D1 ao D4 Dexametasona: 40 mg VO D1 ao D4 para todos os ciclos; D8 ao D11 e D15 ao D18 somente para o ciclo 1. a cada 21 dias no total de 4 ciclos Ref. (02) VMP Bortezomibe: 1,3 mg/m2 IV D1, D4, D8, D11, D22, D25, D29 e D32 (ciclos 1-4) e D1, D8, D22 e D29 (ciclos 5-9) Melfalano: 9 mg/m2 e prednisona 60 mg/m2 VO D1 ao D4 a cada 6 semanas no total de 9 ciclos Total : 9 x ciclos de 6 semanas (54 sem) Ref. (03) CVD Bortezomibe: 1,3 mg/m2 IV em pulso D1, D4, D8 e D11 Dexametasona: 40mg/dia VO D1 e D2, D4 e D5, D8 e D9, D11 e D12 Ciclofosfamida: 500mg/dia VO D1, D8 e D15 a cada 21 dias no total máximo de 9 ciclos Ref. (04) Guia Prático para o Oncologista Clínico •

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Cybord 1ª cohort Bortezomibe: 1,3 mg/m2 IV em pulso D1, D4, D8 e D11 Dexametasona: 40mg VO D1 ao D4, do D9 ao D12 e D17 ao D20 Ciclofosfamida: 300mg/m2/dia VO D1, D8, D15 e D22 a cada 28 dias 2ª cohort Bortezomibe: 1,5 mg/m2 IV em pulso D1, D8, D15 e D22 Dexametasona: 40mg/dia VO D1 ao D4, D9 ao D12 e D17 ao D20 para os ciclos 1 e 2 e semanalmente nos ciclos 3 e 4. Ciclofosfamida: 300mg/m2/dia VO D1, D8, D15 e D22 a cada 28 dias Ref. (05)

Regimes Combinados MP Melfalano: 8-10 mg/m2 VO D1-4 Prednisona: 60 mg/m2 D1-4 a cada 42 dias Ref. (06) MPR Melfalano: 0.18 mg/kg por 4 dias Prednisona: 2 mg/kg/dia por 4 dias Revlimide: 10 mg/dia por 21 dias a cada 4-6 semanas Ref. (07) MPT Melfalano: 0.25 mg/kg D1 a 4 Prednisona: 1.5 mg/kg D1 a 4 a cada 4 a 6 semanas Talidomida: 50-100 mg/dia continuamente. Ref. (08)

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VAD Vincristina: 0.4 mg/dia IV em infusão contínua D1-4 Doxorrubicina: 9 mg/m2/dia IV em infusão contínua D1-4 Dexametasona: 40 mg VO D1-4, 9-12 e 17-20 a cada 28 dias Ref. (09) Talidomida + Dexametasona Talidomida: 200 mg/dia VO Dexametasona: 40 mg/dia VO D1-4, 9-12 e 17-20 a cada 28 dias (Celgene Talidomida PI.) Ref. (10) Bortezomibe + Doxorrubicina Lipossonal Peguilada Bortezomibe: 1.3 mg/m2 IV pulso D1, 4, 8 e 11 Doxorrubicina: 30 mg/m2 IV D4, depois do Bortezomibe a cada 21 dias Ref. (11) Lenalidomida + Dexametasona Lenalidomida: 25 mg/dia VO D1-21 Dexametasona: 40 mg/dia VO D1-4, 9-12 e 17-20 (nos primeiros 4 ciclos) seguido por 40 mg/dia VO D1-4 ou 40 mg/dia VO D1, 8, 15 e 22. a cada 28 dias (Celgene Revlimid PI) Ref. (12)

Regimes de Monoterapia Dexametasona Dexametasona: 40 mg IV ou VO D1-4, 9-12 e 17-20 a cada 21 dias Ref. (13) Guia Prático para o Oncologista Clínico •

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Lenalidomida Lenalidomida: 30 mg VO D1 a 21 a cada 28 dias Ref. (14) Melfalano Melfalano: 90-140 mg/m2 IV D1 a cada 28-42 dias Ref. (15) Talidomida Talidomida: 200-800 mg VO dia Continuar tratamento até progressão da doença ou toxicidade proibitiva. Ref. (16) Bortezomibe Bortezomibe: 1.3 mg/m2 IV D1, 4, 8 e 11 a cada 21 dias

Ref. (17)

Se ocorrer doença progressiva após 2 ciclos ou doença estável após 4 ciclos pode se acrescentar Dexametasona 20mg VO diariamente nos dias de descanso após o Bortezomibe. Interferon α-2b Interferon α -2b: 2 milhões IU SC ou IM. 3 vezes semanalmente Usar como terapia de manutenção em pacientes com resposta significativa com a quimioterapia de indução. Ref. (18) 1. Jean-Luc Harousseau et al. Bortezomib Plus Dexamethasone Is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial. JCO 2010. JCO October 20, 2010 vol. (28) : 4621-4629 2. Oakervee HR et al. BR J Haematol.2005;129:755-62 3. San Miguel, JF et al. Bortezomib plus Melphalan and

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Prednisone for Initial Treatment of Multiple Myeloma. N Engl J Med 2008; 359:906-917. 4. Davies, FE et al. The combination of cyclophosphamide, velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to velcade alone (V) and velcade plus dexamethasone (VD). Haematologica 2007;92:1149-1150. 5. Reeder et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia (2009) 23, 1337–1341. Craig B. Reeder, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood, Apr 2010; 115: 3416 – 3417. 6. Southwest Oncology Group study. Remission maintenance therapy for multiple myeloma. Arch Intern Med 1975:135:147-152. 7. Palumbo A, Falco P, Falcone A, Corradini P, Di Raimondo F, Giuliani N, Rossi G, Morabito F, Canepa L, Gozzetti A, Ambrosini MT, Zeldis J, Knight R, Foa R, Boccadoro M, Petrucci MT. Oral Revlimid plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma: Results of a multicenter phase I/II study(asbstract). Blood: ASH Annual Meeting Proceedings 2006: 108(11 Part l of2): 240a, abstract #0800. 8. Palumbo A. Bringhen S, Caravita T. Merla E, Capparella V, Callea V, Cangialosi C Grasso M, Rossini F, Galli M, Catalno L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M, Italian Multiple Myeloma Network GIMEMA. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 2006: 367(9513):825-31. 9. Barlogie B, et al. Effective treatment of advanced multiple mueloma refractory to alkylating agents. N Engl J Med 1984;310:1353-1356. 10. Rajkumar SV, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20:4319-4323. Guia Prático para o Oncologista Clínico •

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11. Orlowaki RX Peterson BI, Caligiuri MA, et al. Bortezomib and pegylated liposomal doxorubicin as initial therapy for adult patients with symptomatic multiple myeloma: CALGB study 10301 Póster presented at the 10th intemational myeloma Workshop, 2005, april 10-14, Sydney, Austrália. 12. Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Williams M. Abonour R, siegel D, Greipp P. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group (Abstract). Proceedings of the 43rd Annual Meeting of the American Society of clinicai oncology 2007b: june 1-5: Chicago. IL: Abstract #LBA8025. 13. Alexanian R, et al. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med 1986:105:8-11. 14. Richardson PG, blood E, MTsiades CS, Jagannath S, Zeldenrust S, Alsina M. Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T Munshi N, Kelly colson k, doss D, McKenney M, Gorelik S, Warren D, Freeman A, Rich R, Wu A Olesnyckj M, Wride K, Dalton W, Zeldis J, Knight R, Weller E. Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood :006;108(10):3458-64. 15. Cunningham D. et al. High-dose melphalan for multiple myeloma: long-tenn follow-up data. J Clin Oncol 1994;12:7&l-768. 16. Singhal S, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;34P1565-1571. 17. Richardson P. et al. A phase II study of botezomib in relapsed. refractory myeloma. N Engl J Med 2003;348:2609-2617. 18. Browman GP. et al. Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinicai Trials Group. J Clin Oncol 1995;13:2354-2360. 312.

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Síndrome Mielodisplásica Azacitidina Azacitidina: 75 mg/m2 SC diariamente por 7 dias a cada 6 semanas. Pacientes devem ser tratados por pelo menos 4 ciclos. Ref. (1) Decitabina Decitabina: 15 mg/m2 IV infusão contínua de 3 horas a cada 8 horas por 3 dias a cada 4 semanas. Pacientes devem ser tratados por pelo menos 4 ciclos. Ref. (2) Decitabina: 20 mg/m2 IV infusão contínua por 1h por 5 dias a cada 4 a 6 semanas. Pacientes devem ser tratados por pelo menos 4 ciclos. Ref. (3) Lenalidomida Lenalidomida: 10 mg VO dia A dose é continuada ou modificada baseada em achados clínicos e laboratoriais. Ref. (4)

1. Silverman LR, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome. studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006:324: 3895-3903. 2. Kantarjian H, et al. Decitabine improves patient outcomes in myelodysplastic syndromes. Cancer 2006; 106:1794-1780. Guia Prático para o Oncologista Clínico •

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3. Kantarjian H, et al. Decitabine dosíng schedules. sem in Hematolqly 2005;32 (suppl):sl7-522. 4. Galili N., et al. Immunomodulatory drugs in myelodysplastic syndromes Expert Opin Investig Drugs 2006;15:805-813.

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Macroglobulinemia de Waldeströn Bortezomibe e Rituximabe Bortezomibe: 1,6 mg/m2 IV semanalmente D1, D8, D15. Rituximabe: 375 mg/m2 IV semanalmente no ciclo 1 e 4. a cada 28 dias no total de 6 ciclos Ref. (01) Bendamustina e Rituximabe Rituximabe: 375 mg/m2/dia IV D1 Bendamustina: 90 mg/m2/dia IV durante 30 minutos D1 e D2 a cada 28 dias no total de 4 ciclos Ref. (02)

1. Irene M. Ghobrial et al. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia. American Journal of Hematology. 2010, 85: 670–674. 2. Mathias J. Rummel, Salah E. Al-Batran, Soo-Z. Kim, et al. Bendamustine Plus Rituximab Is Effective and Has a Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin's Lymphoma Journal of Clinical Oncology, Vol 23, No 15, 2005: pp. 3383-3389.

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Leucemia de Células Cabeludas (Tricoleucemia) Tratamento padrão: Cladribina: 0,1 mg/kg/dia IV infusão contínua por 7 dias (ciclo único). Opções do uso de cladribina: a. 0,14 mg/Kg/dia IV, infundir durante 2h por 5 dias b. 0,14 mg/Kg IV, infundir durante 2h uma vez por semana c. 0,14 mg/Kg SC, uma vez por semana Avaliar associação de rituximabe 375 mg/m2, IV na HCL variante Ref. (01)

1. Saven A, et al. Blood 1998;92:1918-26. Lauria F, Bocchia M, Marotta G, Raspadori D, Zinzani PL, Rondelli D. Weekly administration of 2-chlorodeoxyadenosine in patients with hairy-cell leukemia is effective and reduces infectious complications. Haematologica. 1999;84(1):22–25. Golomb HM. Hairy cell leukemia: treatment successes in the past 25 years. J Clin Oncol. 2008;26(16):2607–2609. Robak T, Jamroziak K, Gora-Tybor J, et al. Cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: final report from the Polish Adult Leukemia Group (PALG) of a prospective, randomized, multicenter trial. Blood. 2007;109(9):3672–3675. Juliusson G, Liliemark J. Purine analogues: rationale for development, mechanisms of action, and pharmacokinetics in hairy cell leukemia. Hematol Oncol Clin North Am. 2006;20(5):1087–1097. Zinzani PL, Tani M, Marchi E, et al. Long-term follow-up of frontline treatment of hairy cell leukemia with 2chlorodeoxyadenosine. Haematologica. 2004;89(3):309–313.

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Zenhausern R, Schmitz SF, Solenthaler M, et al. Randomized trial of daily versus weekly administration of 2-chlorodeoxyadenosine in patients with hairy cell leukemia: a multicenter phase III trial (SAKK 32/98). Leuk Lymphoma. 2009:1–11.

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Leucemias Agudas Quimioterapia de Indução Regime de Linker Daunorrubicina: 50 mg/m2 IV a cada 24 horas D1-3 Vincristina: 2 mg IV D1,8, 15 e 22 Prednisona: 60 mg/m2 VO dividido em 3 doses D1-28 L-Asparaginase: 6,000 U/m2 IM D17-28 Se a medula óssea foi positiva para leucemia residual, Daunorrubicina: 50 mg/m2 IV D15 Se a medula óssea no dia 28 for positiva para leucemia residual, Daunorrubicina: 50 mg/m2 IV D29 e 30 Vincristina: 2 mg IV D29 e 36 Prednisona: 60 mg/m2 VO D29-42 L-Asparaginase: 6,000 U/m2 IM D29-35 Ref. (1,2)

Terapia de Consolidação Regime de Linker Tratamento A (ciclo 1, 3, 5 e 7) Daunorubicina: 50 mg/m2 IV D1 e 2 Vincristina: 2mg IV D1 e 8 Prednisona: 60 mg/m2 VO D1-14 L-Asparaginase:12,000 U/m2 D2, 4, 7, 9, 11 e 14 Tratamento B (ciclo 2, 4, 6 e 8) Teniposide: 165 mg/m2 IV D1,4, 8 e 11 Citarrabina: 300 mg/m2 IV D1, 4, 8 e 11 Tratamento C (ciclo 9) Methotrexate: 690 mg/m2 IV durante 42 horas Leucovorin: 15 mg/m2 IV a cada 6 horas 12 doses iniciando na hora 42 Ref. (1,2)

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Terapia de Manutenção Regime de Linker Methotrexate: 20 mg/m2 VO semanalmente 6-Mercaptopurina: 75 mg/m2 VO contínuo por um total de 30 meses após a resposta completa. Profilaxia SNC Radioterapia craniana: 1,800 cGy em 10 reduções durante 12 a 14 dias Methotrexate: 12 mg IT semanalmente por 6 semanas Iniciar dentro de uma semana após resposta completa Em pacientes com envolvimento do SNC no diagnóstico a quimioterapia intratecal deve ser iniciada durante a quimioterapia de indução Methotrexate: 12 mg IT semanalmente por 10 doses Radioterapia craniana: 2,800 cGy Ref. (1,2)

Terapia de Indução Regime de Larson Indução (semana 1-4) Ciclofosfamida: 1,200 mg/m2 IV D1 Daunorrubicina: 45 mg/m2 IV D1-3 Vincristina: 2 mg IV D1, 8, 15 e 22 Prednisona: 60 mg/m2/dia VO D1-21 L-Asparaginase: 6,000 IU/m2 SC D5, 8, 11, 15, 18, 22 Intensificação precoce (semana 5-12) Methotrexate: 15 mg IT D1 Ciclofosfamida: 1,000 mg/m2 IV D1 6-Mercaptopurina: 60 mg/m2/dia VO D1-14 Citarabina: 75 mg/m2 IV D1-4 e D8-11 Vincristina: 2 mg IV D15 e 22 L-Asparaginase: 6,000 IU/m2 SC D15, 18, 22 e 25

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Profilaxia do SNC e manutenção interina (semana 13-25) Radioterapia craniana: 2,400 cGy D1-12 Methotrexate: 15 mg IT D1, 8, 15, 22 e29 6-Mercaptopurina: 60 mg/m2/dia VO D1-70 Methotrexate: 20 mg/m2 VO D36, 43, 50, 57 e 64 Intensificação Tardia (semana 26-33) Doxorrubicina: 30 mg/m2 IV D1, 8 e 15 Vincristina: 2 mg IV D1, 8 e15 Dexametasona: 10 mg/m2/dia VO D1-14 Ciclofosfamida: 1 ,000 mg/m2 IV D29 6-Tioguanina: 60 mg/m2/dia VO D29 - 42 Citarrabina: 75 mg/m2 D29, 32, 36-39 Manutenção Prolongada (continuar até 24 meses após o diagnóstico) Vincristina: 2mg IV D1 Prednisona: 60 mg/m2/dia VO D1-5 Methotrexate: 20 mg/m2 VO D1, 8, 15 e 22 6-Mercaptopurina: 80 mg/m2/dia VO D1-28 Repetir ciclo de manutenção a cada 28 dias. Ref. (3) Regime Hyper-CVAD Ciclofosfamida: 300 mg/m2 IV durante 3 horas a cada 12 horas por 6 doses D1-3 Mesna: 600 mg/m2 IV durante 24 horas D1-3, terminando 6 horas apos a última dose de Ciclofosfamida Vincristina: 2 mg IV D4 e 11 Doxorrubicina: 50 mg/m2 IV D4 Dexametasona: 40 mg VO ou IV D1-4 e 11-14 Alternando ciclos a cada 21 dias com: Methotrexate: 200 mg/m2 IV durante 2 horas, seguido por 800 mg/m2 IV durante 24 horas no D1 Leucovorin: 15 mg IV a cada 6 horas por 8 doses, iniciando 24

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horas após o término de infusão do Methotrexate Citarabina: 3,000 mg/m2 IV durante 2 horas a cada 12 horas por 4 doses D2-3 Metilprednisolona: 50 mg IV BID D1-3 Alternar 4 ciclos de hiper-CVAD com 4 ciclos de Methotrexate em dose alta Ref. (4). Profilaxia SNC Methotrexate: 12mg IT D2 Citarabina: 100 mg IT D8 Repetir a cada ciclo de quimioterapia, dependendo do risco de doença no SNC.

1. Linker CA, et al. Improved results of treatment of adult acute lymphoblastic leukemia. Blood 1987:69:1242-1248. 2. Linker CA, et al. treatmentof adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 1991;75:2814-2822. 3. Larson R, et al. A five-drug regimen remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer an Leukemia Group B study 8811, Blood 1995;85:2025-2037. 4. Kantarjian H, et al. Results of treatment with hyper- CVAD, a dose-intensive regimen in adult acute lymphoblastic leukemia. J Clin Oncol 2000;18:547-561.

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Leucemia Mielóide Crônica Imatinibe Imatinibe: 400 mg/dia VO Ref. (1) Dasatinibe Dasatinibe: 70mg VO BID Dasatinibe: 100mg VO MID Ref. (2) Nilotinibe Nilotinibe: 400mg VO BID Ref. (3) Hidroxiuréia Hidroxiuréia: 40 mg/kg/dia VO Ref. (4) 1. Kantarjian H, et al. Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia. NEJM.2002;346:645-52. 2. Shah NP; Kantarjian HM; Kim DW; et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and intolerant chronic-phase chronic myeloid leukemia.J Clin Oncol. 2008 Jul 1;26(19):3204-12. 3. Av a i l a b l e f r o m t h e U S F D A w e b s i t e a t :