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İmmün Kontrol Noktası İnhibitörleri ile Tedavi Edilen Malign Melanom Hastalarında Antibiyotik ve Kortikosteroid Kullanımının Tedaviye Etkileri

Year 2021, Volume: 7 Issue: 1, 45 - 51, 01.01.2021

Abstract

Amaç: Son yıllarda malign melanom tedavisi tamamen değişmiş, özellikle immün kontrol noktası inhibitörlerinin kullanıma girmesiyle yaşam süresi belirgin olarak uzamıştır. Ancak bu ilaçlar hastaların sadece bir kısmında etkili olabilmektedir. Bu tedavilerden fayda gören hastaların belirlenebilmesi için biyobelirteçler ve tedaviye etki eden faktörler araştırılmaktadır. Çalışmamızda immün kontrol noktası inhibitörü kullanan ileri evre malign melanom hastalarında antibiyotik ve kortikosteroid kullanımının ve hastaların melanom için daha önce adjuvant olarak aldıkları tedavilerin tedavi sonuçları üzerine etkilerini araştırdık. Gereç ve Yöntemler: Çalışmamızda immün kontrol noktası inhibitörleri ile tedavi edilen ileri evre malign melanom hastaları retrospektif olarak tarandı. Yirmidokuz hastanın verilerine ulaşıldı. Hastane kayıtlarından antibiyotik ve kortikosteroid kullanımı ve hastaların daha önce aldıkları adjuvant tedavi verilerine ulaşılarak sağkalım analizleri yapıldı. Bulgular: Yirmidokuz hastanın 18 i %62 antibiyotik kullanımıştı, 16 sında %55 herhangi bir sebeple sistemik kortikosteroid kullanımı vardı. 17 %58,6 hastada adjuvant interferon kullanılmıştı. İstatistiki anlamlılığa ulaşmamasına rağmen tedavi sırasında antibiyotik kullananlarda progresyonsuz sağ kalım PFS ve genel sağ kalım OS daha kısaydı. PFS 9 ay ile 15,9 ay, p= 0,561, OS 18 ay ile 38 ay, p=0,404 . Progresyonsuz sağ kalım ve OS immün kontrol noktası inhibitörleri ile beraber kortikosteroid kullananlarda daha kısaydı PFS 27,2 ay ile 5,4 ay, p=0,007, OS 50 ay ile 14 ay, p=0,009 . Adjuvant dönemde interferon kullanmış olan hastaların metastatik evrede immün kontrol noktası inhibitörleri ile hem pfs hem os sürelerinin daha uzun olduğu görüldü PFS 23,2 ay ile 6.2 ay, p=0,019, OS 39,8 ay ile 12,9 ay, p=0,004 .Sonuç: İleri evre metastatik malign melanom hastalarında immün kontrol noktası inhibitörleri ile beraber antibiyotik ve kortikosteroid kullanımı tedavi sonuçlarını olumsuz etkileyebilmektedir

References

  • 1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711-23.
  • 2. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A. KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372(26):2521- 32.
  • 3. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, KalinkaWarzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B,Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4):320-30.
  • 4. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined Nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1):23-34.
  • 5. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Bérard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, lson CO, Doré J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013; 342(6161):971-6.
  • 6. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359(6371):104-8.
  • 7. Sivan A, Corrales L, Hubert N, Williams JB, AquinoMichaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264):1084-9.
  • 8. Francino MP. Antibiotics and the human gut microbiome: Dysbioses and accumulation of resistances. Front Microbiol 2016; 6:1543.
  • 9. Derosa L, Routy B, Enot D, Baciarello G, Massard C, Loriot Y, Fizazi K, Escudier BJ, Zitvogel L, Albiges L. Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Journal of Clinical Oncology 2017; (suppl 6):462.
  • 10. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, Long N, Plodkowski AJ, Arbour KC, Chaft JE, Rouche JA, Zitvogel L, Zalcman G, Albiges L, Escudier B, Routy B. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018; 29(6):1437-44.
  • 11. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Clémenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371):91-7.
  • 12. Kaderbhai C, Richard C, Fumet JD, Aarnink A, Foucher P, Coudert B, Favier L, Lagrange A, Limagne E, Boidot R, Ghiringhelli F. Antibiotic use does not appear to influence response to nivolumab. Anticancer Res 2017; 37(6):3195- 200.
  • 13. Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, Carvajal RD, Dickson MA, D’Angelo SP, Woo KM, Panageas KS, Wolchok JD, Chapman PB. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center. J Clin Oncol 2015; 33(28):3193-8.
  • 14. Garant A, Guilbault C, Ekmekjian T, Greenwald Z, Murgoi P, Vuong T. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: A systematic review. Crit Rev Oncol Hematol 2017; 120:86-92.
  • 15. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, Bernal GM, Chaft JE, Ferrara R, Lai WCV, Hendriks L, Sabari JK, Caramella C, Plodkowski AJ, Halpenny D, Planchard D, Riely GJ, Besse B, Hellmann MD. Deleterious effect of baseline steroids on efficacy of PD-(L) 1 blockade in patients with NSCLC. J Clin Oncol 2018; (Suppl 15): 9003.
  • 16. Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, Kammula US, Hughes MS, Allen TE, Levy CL, Yellin M, Nichol G, White DE, Steinberg SM, Rosenberg SA. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 2007; 13:6681-8.
  • 17. Rafique I, Kirkwood JM, Tarhini AA. Immune checkpoint blockade and interferon-α in melanoma. Semin Oncol 2015; 42(3):436-47.
  • 18. Gerner MY, Heltemes-Harris LM, Fife BT, Mescher MF. Cutting edge: IL-12 and type I IFN differentially program CD8 T cells for programmed death 1 re-expression levels and tumor control. J Immunol 2013;191(3):1011-5.

Impact of Antibiotics and Corticosteroids on The Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Melanoma

Year 2021, Volume: 7 Issue: 1, 45 - 51, 01.01.2021

Abstract

Objective: The treatment of malignant melanoma has changed a lot in recent years. The use of immune checkpoint inhibitors has prolonged survival in patients with advanced melanoma. Our study evaluates the impact of antibiotics, corticosteroids, and adjuvant treatment on the efficacy of immune checkpoint inhibitors in patients with advanced melanoma.Material and Methods: We conducted a retrospective analysis of metastatic melanoma patients treated with ipilimumab and nivolumab. Concomitant antibiotics, corticosteroids for any reason, and prior adjuvant treatment for melanoma were recorded. Progression free survival and overall survival were compared in each group. Results: We enrolled 29 patients with advanced melanoma treated with immune checkpoint inhibitors. Eighteen 62.1% patients had concomitant antibiotic therapy, and 16 55.2% patients had used corticosteroids for any reason. Seventeen patients 58.6% had adjuvant therapy with interferon alpha.Although not significant, PFS and OS were shorter in patients treated with concomitant antibiotics: PFS 15.9 months vs. 9 months, p=0.561; OS 38 months vs. 18 months, p=0.404.PFS and OS were shorter in patients who had used corticosteroids during immune checkpoint inhibitor treatment: PFS 27.2 months vs. 5.4 months p=0.007 and OS 50 months vs. 14 months p=0.009 . PFS was 23.2 months in the adjuvant interferon group vs. 6.2 months with no prior interferon, p=0.019. Overall survival was also longer in patients with prior adjuvant interferon treatment: 39.8 months vs. 12.9 months p=0.004 .Conclusion: Concomitant use of antibiotics and corticosteroids in patients with advanced melanoma may affect the efficacy of immune checkpoint inhibitors

References

  • 1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711-23.
  • 2. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A. KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372(26):2521- 32.
  • 3. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, KalinkaWarzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B,Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4):320-30.
  • 4. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined Nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1):23-34.
  • 5. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Bérard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, lson CO, Doré J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013; 342(6161):971-6.
  • 6. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359(6371):104-8.
  • 7. Sivan A, Corrales L, Hubert N, Williams JB, AquinoMichaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264):1084-9.
  • 8. Francino MP. Antibiotics and the human gut microbiome: Dysbioses and accumulation of resistances. Front Microbiol 2016; 6:1543.
  • 9. Derosa L, Routy B, Enot D, Baciarello G, Massard C, Loriot Y, Fizazi K, Escudier BJ, Zitvogel L, Albiges L. Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Journal of Clinical Oncology 2017; (suppl 6):462.
  • 10. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, Long N, Plodkowski AJ, Arbour KC, Chaft JE, Rouche JA, Zitvogel L, Zalcman G, Albiges L, Escudier B, Routy B. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018; 29(6):1437-44.
  • 11. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Clémenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371):91-7.
  • 12. Kaderbhai C, Richard C, Fumet JD, Aarnink A, Foucher P, Coudert B, Favier L, Lagrange A, Limagne E, Boidot R, Ghiringhelli F. Antibiotic use does not appear to influence response to nivolumab. Anticancer Res 2017; 37(6):3195- 200.
  • 13. Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, Carvajal RD, Dickson MA, D’Angelo SP, Woo KM, Panageas KS, Wolchok JD, Chapman PB. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center. J Clin Oncol 2015; 33(28):3193-8.
  • 14. Garant A, Guilbault C, Ekmekjian T, Greenwald Z, Murgoi P, Vuong T. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: A systematic review. Crit Rev Oncol Hematol 2017; 120:86-92.
  • 15. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, Bernal GM, Chaft JE, Ferrara R, Lai WCV, Hendriks L, Sabari JK, Caramella C, Plodkowski AJ, Halpenny D, Planchard D, Riely GJ, Besse B, Hellmann MD. Deleterious effect of baseline steroids on efficacy of PD-(L) 1 blockade in patients with NSCLC. J Clin Oncol 2018; (Suppl 15): 9003.
  • 16. Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, Kammula US, Hughes MS, Allen TE, Levy CL, Yellin M, Nichol G, White DE, Steinberg SM, Rosenberg SA. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 2007; 13:6681-8.
  • 17. Rafique I, Kirkwood JM, Tarhini AA. Immune checkpoint blockade and interferon-α in melanoma. Semin Oncol 2015; 42(3):436-47.
  • 18. Gerner MY, Heltemes-Harris LM, Fife BT, Mescher MF. Cutting edge: IL-12 and type I IFN differentially program CD8 T cells for programmed death 1 re-expression levels and tumor control. J Immunol 2013;191(3):1011-5.
There are 18 citations in total.

Details

Primary Language English
Journal Section Research Article
Authors

Sema Sezgin Göksu This is me

Ali Murat Tatlı This is me

Gökhan Karakaya This is me

Fatma Yalçın Musri This is me

Mustafa Serkan Alemdar This is me

Hasan Şenol Coşkun This is me

Publication Date January 1, 2021
Published in Issue Year 2021 Volume: 7 Issue: 1

Cite

Vancouver Sezgin Göksu S, Tatlı AM, Karakaya G, Yalçın Musri F, Alemdar MS, Coşkun HŞ. Impact of Antibiotics and Corticosteroids on The Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Melanoma. Akd Med J. 2021;7(1):45-51.