A profilaxia com fatores estimuladores de colônias de granulócitos (G-CSFs) reduz a incidência de neutropenia febril em adultos submetidos a quimioterapia para tumores sólidos e linfoma.[33]Wang L, Baser O, Kutikova L, et al. The impact of primary prophylaxis with granulocyte colony-stimulating factors on febrile neutropenia during chemotherapy: a systematic review and meta-analysis of randomized controlled trials. Support Care Cancer. 2015 Nov;23(11):3131-40.
https://link.springer.com/article/10.1007/s00520-015-2686-9
http://www.ncbi.nlm.nih.gov/pubmed/25821144?tool=bestpractice.com
[34]Renner P, Milazzo S, Liu JP, et al. Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients. Cochrane Database Syst Rev. 2012 Oct 17;(10):CD007913.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007913.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/23076939?tool=bestpractice.com
[35]Kuderer NMD. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007 Jul 20;25(21):3158-67.
http://www.ncbi.nlm.nih.gov/pubmed/17634496?tool=bestpractice.com
[36]Cooper KL, Madan J, Whyte S, et al. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer. 2011 Sep 23;11:404.
https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-404
http://www.ncbi.nlm.nih.gov/pubmed/21943360?tool=bestpractice.com
O uso profilático de G-CSF é recomendado em pacientes:[23]Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: a systematic review. Crit Rev Oncol Hematol. 2014 Jun;90(3):190-9.
http://www.ncbi.nlm.nih.gov/pubmed/24434034?tool=bestpractice.com
[37]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].
https://www.nccn.org/guidelines/category_3
[38]Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015 Oct 1;33(28):3199-212.
http://ascopubs.org/doi/full/10.1200/JCO.2015.62.3488
http://www.ncbi.nlm.nih.gov/pubmed/26169616?tool=bestpractice.com
[39]Aapro MS, Bohlius J, Cameron DA, et al; European Organisation for Research and Treatment of Cancer. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011 Jan;47(1):8-32.
http://www.ncbi.nlm.nih.gov/pubmed/21095116?tool=bestpractice.com
com alto risco (>20%) para neutropenia febril, ou
com risco intermediário (10% a 20%) de neutropenia febril que apresentam ≥1 fator de risco (isto é, >65 anos de idade; quimioterapia prévia; neutropenia persistente; radioterapia prévia; cirurgia recente; comprometimento da medula óssea [por tumor]; disfunção hepática; disfunção renal).
Os G-CSFs não são rotineiramente recomendados nos pacientes com baixo risco (<10%) de neutropenia febril, mas podem ser considerados (com base em critérios clínicos) naqueles que têm dois ou mais fatores de risco (isto é, idade >65 anos; quimioterapia prévia; neutropenia persistente; radioterapia prévia; cirurgia recente; comprometimento da medula óssea [por tumor]; disfunção hepática; disfunção renal).[23]Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: a systematic review. Crit Rev Oncol Hematol. 2014 Jun;90(3):190-9.
http://www.ncbi.nlm.nih.gov/pubmed/24434034?tool=bestpractice.com
[37]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].
https://www.nccn.org/guidelines/category_3
Se um paciente tiver desenvolvido neutropenia febril durante um ciclo anterior de quimioterapia e a profilaxia com G-CSF não tiver sido usada, então a profilaxia com G-CSF deve ser considerada para uso nos ciclos subsequentes de quimioterapia.[37]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].
https://www.nccn.org/guidelines/category_3
[38]Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015 Oct 1;33(28):3199-212.
http://ascopubs.org/doi/full/10.1200/JCO.2015.62.3488
http://www.ncbi.nlm.nih.gov/pubmed/26169616?tool=bestpractice.com
[39]Aapro MS, Bohlius J, Cameron DA, et al; European Organisation for Research and Treatment of Cancer. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011 Jan;47(1):8-32.
http://www.ncbi.nlm.nih.gov/pubmed/21095116?tool=bestpractice.com
A avaliação do risco de neutropenia febril deve ser realizada após cada ciclo de quimioterapia.
Formulações biossimilares de G-CSF e formulações de ação prolongada (como lipegfilgrastim, eflapegrastim e alfaefbemalenograstim) estão aprovadas em alguns países para a profilaxia da neutropenia febril induzida por quimioterapia. As formulações de ação prolongada podem oferecer benefícios clínicos em comparação com os G-CSFs de ação curta, como o filgrastim.[40]Bond TC, Szabo E, Gabriel S, et al. Meta-analysis and indirect treatment comparison of lipegfilgrastim with pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia-related events. J Oncol Pharm Pract. 2018 Sep;24(6):412-23.
https://journals.sagepub.com/doi/full/10.1177/1078155217714859
http://www.ncbi.nlm.nih.gov/pubmed/28614980?tool=bestpractice.com
[41]Pfeil AM, Allcott K, Pettengell R, et al. Efficacy, effectiveness and safety of long-acting granulocyte colony-stimulating factors for prophylaxis of chemotherapy-induced neutropenia in patients with cancer: a systematic review. Support Care Cancer. 2015 Feb;23(2):525-45.
http://www.ncbi.nlm.nih.gov/pubmed/25284721?tool=bestpractice.com
[42]Schwartzberg LS, Bhat G, Peguero J, et al. Eflapegrastim, a long-acting granulocyte-colony stimulating factor for the management of chemotherapy-induced neutropenia: results of a phase III trial. Oncologist. 2020 Aug;25(8):e1233-41.
https://academic.oup.com/oncolo/article/25/8/e1233/6443672
http://www.ncbi.nlm.nih.gov/pubmed/32476162?tool=bestpractice.com
[43]Cobb PW, Moon YW, Mezei K, et al. A comparison of eflapegrastim to pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early-stage breast cancer undergoing cytotoxic chemotherapy (RECOVER): a phase 3 study. Cancer Med. 2020 Sep;9(17):6234-43.
https://onlinelibrary.wiley.com/doi/10.1002/cam4.3227
http://www.ncbi.nlm.nih.gov/pubmed/32687266?tool=bestpractice.com
Uma revisão sistemática concluiu que são necessários mais ensaios clínicos para avaliar os benefícios e malefícios dos CSFs em comparação com antibióticos para a prevenção de infecção em pacientes com câncer de todas as idades recebendo quimioterapia.[44]Skoetz N, Bohlius J, Engert A, et al. Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy. Cochrane Database Syst Rev. 2015 Dec 21;(12):CD007107.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007107.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/26687844?tool=bestpractice.com
Profilaxia antibacteriana
As diretrizes conjuntas da ASCO e da Infectious Diseases Society of America (IDSA) recomendam profilaxia antibiótica com fluoroquinolona para pacientes com alto risco de neutropenia febril ou neutropenia profunda e prolongada (>7 dias), como pacientes com leucemia mieloide aguda, síndromes mielodisplásicas ou tratamento com transplante de células-tronco hematopoiéticas com regimes de condicionamento mieloablativo.[45]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com
A profilaxia com fluoroquinolona em pacientes de alto risco requer uma avaliação cuidadosa dos riscos e benefícios em longo prazo, levando em consideração as taxas locais e regionais de resistência a fluoroquinolonas e outras consequências do uso profilático de antibióticos de amplo espectro.[46]Mikulska M, Averbuch D, Tissot F, et al. Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines. J Infect. 2018 Jan;76(1):20-37.
http://www.ncbi.nlm.nih.gov/pubmed/29079323?tool=bestpractice.com
Os pacientes que recebem profilaxia devem ser monitorados de perto quanto ao surgimento de organismos resistentes.[1]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
A profilaxia com antibióticos não é recomendada rotineiramente para pacientes com tumores sólidos.[45]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com
Profilaxia antifúngica
A profilaxia usando um azol oral ou uma equinocandina parenteral é recomendada para pacientes com risco de neutropenia profunda e prolongada; por exemplo, aqueles com leucemia mieloide aguda, síndromes mielodisplásicas ou pacientes submetidos ao transplante de células-tronco hematopoiéticas.[45]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com
Um antifúngico azólico ativo contra bolor (por exemplo, voriconazol, posaconazol, isavuconazol) é recomendado para profilaxia quando o risco de aspergilose invasiva for >6%, como ocorre em pacientes com leucemia mieloide aguda ou síndromes mielodisplásicas durante o período neutropênico associado com a quimioterapia.[45]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com
Para receptores de transplante autólogo e alogênico de células-tronco hematopoéticas com risco padrão, o uso da profilaxia com fluconazol durante a neutropenia é a abordagem convencional, sendo o uso de profilaxia com azol ativo contra bolor normalmente reservado para pacientes com aumento do risco de infecção por bolor ou história prévia de infecção por bolor (ou seja, profilaxia secundária).[1]Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56-93.
https://academic.oup.com/cid/article/52/4/e56/382256
http://www.ncbi.nlm.nih.gov/pubmed/21258094?tool=bestpractice.com
[45]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com
[47]Groll AH, Pana D, Lanternier F, et al. 8th European Conference on Infections in Leukaemia: 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation. Lancet Oncol. 2021 Jun;22(6):e254-69.
http://www.ncbi.nlm.nih.gov/pubmed/33811813?tool=bestpractice.com
O risco de infecção por bolor invasiva é maior nos pacientes com doença do enxerto contra o hospedeiro que exige uso de corticosteroide, após um transplante alogênico de células-tronco hematopoiéticas, e um azol ativo para bolor (por exemplo, posaconazol) deve ser fortemente considerado neste contexto.[45]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com
Os agentes azólicos ativos contra bolor estão associados com efeitos adversos, toxicidade e interação medicamentosa que merecem uma consideração cuidadosa.
A profilaxia com antifúngicos não é recomendada rotineiramente para pacientes com tumores sólidos.[45]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018 Oct;36(30):3043-54.
http://ascopubs.org/doi/full/10.1200/JCO.18.00374
http://www.ncbi.nlm.nih.gov/pubmed/30179565?tool=bestpractice.com