Pneumocystis jirovecii Pneumonia in Everolimus-Treated Renal Cell Carcinoma Introduction The prognosis of metastatic renal cell carcinoma (RCC) has been significantly improved in recent years with the introduction of mammalian target of rapamycin (mTOR) inhibitors. In this context, everolimus is increasingly used in first- and second-line therapies in patients with RCC. Pneumocystis jirovecii pneumonia (PCP) is a classic complication that is associated with mTOR inhibitors in solid organ transplantation. To our knowledge, PCP has been described in only one patient with RCC to date, and specific prophylactic measures were not recommended. Here, we report the first cases series, to our knowledge, of PCP associated with everolimus in patients with RCC, and we discuss potential implications of this underestimated condition in the management of mTOR inhibitor– treated RCC. Case Reports A 64-year-old man with papillary RCC was treated in 1989 by total nephrectomy. A nodal recurrence was diagnosed in 2009, and the patient received sunitinib followed by sorafenib because of disease progression. Everolimus (10 mg orally per day) was introduced in 2012, when a computed tomography (CT) scan revealed a mediastinal nodal recurrence. Two months later, the patient presented with cough and dyspnea. A CT scan showed a bilateral interstitial pneumonitis (Fig 1). Everolimus-associated pneumonitis was suspected. Everolimus was stopped and corticosteroids were prescribed. The clinical situation worsened, fever manifested, and a positive detection of P. jirovecii DNA

Fig 1. Journal of Clinical Oncology, Vol 33, No 8 (March 10), 2015: pp e45-e47




by polymerase chain reaction in induced sputum confirmed the diagnosis of PCP. The patient was hospitalized in the intensive care unit because of high oxygen needs. Cotrimoxazole with corticotherapy was started. The laboratory findings revealed lymphopenia (0.3 g/L) with a low CD4⫹ T-cell count (0.174 g/L) at diagnosis. The evolution was favorable, and everolimus was definitively stopped. A 56-year-old man with clear RCC was treated with a partial left nephrectomy in 2009. A local recurrence was diagnosed in October 2011 and was treated using sunitinib because of a contraindication to nephrectomy. In February 2012, sunitinib was replaced with everolimus (10 mg orally per day) because of digestive toxicity and a contraindication to nephrectomy. One month later, the patient developed mucosal inflammation and cough. A chest radiograph (Fig 2) and a CT scan showed an interstitial pneumonitis. mTOR inhibitor– associated pneumonitis was suspected, and everolimus was subsequently tapered by 5 mg orally per day, without clinical improvement. In April 2012, everolimus was stopped, and a bronchoalveolar lavage identified P. jirovecii trophozoites. A lymphopenia was associated (0.86 g/L) but the CD4⫹ T-cell count was normal (0.47 g/L). The outcome was favorable with cotrimoxazole. Everolimus was not reintroduced, particularly because of mTOR inhibitor–associated hypertriglyceridemia and cutaneous toxicity. A 72-year-old patient with clear RCC was treated with a total nephrectomy in 2001. Within the first year of follow-up, the patient developed nodal, pulmonary, adrenal, and contralateral kidney localizations. Five-year treatment with sorafenib began in 2007. In August 2012, a CT scan confirmed a pancreatic localization that was associated with the progression of nodal and renal localizations. Everolimus was introduced (10 mg orally per day) in September 2012. One month later, the patient developed dyspnea, cough, and fever. A CT scan

Fig 2.

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Loron et al

revealed a right pneumonitis. The patient was hospitalized in the intensive care unit and noninvasive ventilation was required. P. jirovecii DNA was positive in induced sputum. At that time, the medical history of the patient included a nontreated chronic lymphocytic leukemia with lymphocytosis (85 g/L), but the CD4⫹ T-cell count was low (0.267 g/L). The outcome was favorable with cotrimoxazole, and everolimus was stopped. Discussion mTOR is a serine/threonine kinase that regulates cell growth, proliferation, and angiogenesis.1,2 mTOR inhibitor drug therapies have been used as immunosuppressive agents in solid organ transplantation since the 1990s. More recently, everolimus was recommended as an anticancer agent in RCC with disease progression during treatment with a tyrosine kinase inhibitor.3-5 Everolimus has considerably improved the prognosis of RCC, with minimal impact on symptoms and quality of life.6,7 Motzer et al3 demonstrated that everolimus prolonged progression-free survival in patients with metastatic RCC who experienced progression while receiving other targeted therapies. However, in that study, patients receiving everolimus had higher rates of infection, noninfectious pneumonitis, and lymphopenia. The infections reported in the everolimus group were not specified, and potential cases of PCP were not identified.5 mTOR inhibitors have already been identified as a PCP risk factor in kidney transplantation. In 2009, Neff et al studied 32,757 Medicare primary transplantation recipients and found that sirolimus was associated with an increased risk of PCP.8 A case control study including 11 patients with PCP showed that mTOR inhibitors in kidney transplantation recipients were associated with PCP, with an odds ratio of 7.7.9 A low lymphocyte count (⬍ 0.5 g/L) and the use of corticosteroids were significantly associated with a higher risk of PCP at cotrimoxazole prophylaxis discontinuation. Kidney transplantation recipients generally present several risk factors that contribute to their immune deficiency, and are therefore at high risk to develop PCP. On the basis of several studies and expert opinion, low-dose cotrimoxazole is recommended for PCP prophylaxis in kidney transplantation recipients during the first 6 months after transplantation, and after the treatment of an acute allograft rejection.10-14 To date, PCP has never been described as an adverse event associated with mTOR inhibitors in patients with RCC on a large scale.3,15-18 One case report noted PCP that was associated with everolimus therapy.19 A safety study on everolimus in 1,367 patients with RCC found that 71 patients (5.2%) had pneumonia, but no PCP was reported.16 Over the last 4 years, in our center, 48 patients received first-line therapy with tyrosine kinase inhibitors and subsequently received everolimus. Twelve of these patients were diagnosed with everolimus-induced pneumonitis, and three with PCP. None of these three patients was diabetic or was exposed to specific environmental factors that were believed to contribute to PCP. Immune deficiency in patients with metastatic RCC is well established and is related both to the specific treatments and to the evolution of the disease itself.3,17 In RCC, everolimus is generally prescribed at higher doses than in solid organ transplantation and may therefore be a major contributor to the immunodepression that is responsible for PCP. The mechanisms whereby mTOR inhibitors may increase the risk of PCP remain uncertain. The immune response to Pneumocystis pathogens implicates humoral and cellular immunity, involving differentiated CD4⫹ and CD8⫹ T cells, natural killer cells, mononuclear e46

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phagocytes, and their secreted cytokines.20-23 Direct activation of pneumocytes of the alveolar epithelium by P. jirovecii leads to NF-␬B activation and the release of proinflammatory signals. It is also possible that P. jirovecii produces direct lung injury at this stage through an undetermined mechanism. mTOR plays a central role in directing T-cell fate.1,2,24 Accumulating evidence highlights a role for mTOR as a fundamental determinant of antigen-activated CD4⫹ and CD8⫹ T-cell activation and differentiation. Inhibition of mTOR promotes the generation of anergic and regulatory CD4⫹ T cells as well as the differentiation of memory CD8⫹ T cells.25 Therefore, modulation of T cells by mTOR inhibitors could be a major mechanism in increasing the susceptibility to PCP. Two of the three patients presented in this report had a low CD4⫹ T-cell count. The CD4⫹ count of the third patient was normal but was measured 1 month after everolimus was stopped. CD4⫹ T-cell count is an established risk factor for PCP in both HIV-positive and HIVnegative populations.26-28 On this basis, it may be hypothesized that in patients with RCC receiving everolimus, the risk of PCP could be increased if there is an associated lymphopenia. Noninfectious everolimus-associated pneumonitis is a frequent and potentially fatal adverse effect of the drug.3,15 In patients with metastatic RCC receiving everolimus, the overall incidence of pneumonitis of any grade was 6.1%.16 Similar to the adverse effects of tyrosine kinase inhibitors, it has been suggested that toxic pneumonitis may be a marker of stable RCC disease, and therefore may be associated with overall therapeutic benefit.29,30 When severe interstitial lung disease develops, withdrawal of the drug and short-term use of corticosteroids may result in rapid recovery.31 A major problem in the clinical management of PCP is that radiographic evaluation may be misleading and may be misinterpreted as drug-induced pneumonitis. Usually the diagnosis of noninfectious mTOR inhibitor–induced pneumonitis is performed with a CT scan.18,29,31-33 In a retrospective study by Kirby et al,34 28 lung biopsies performed in sirolimus-treated recipients of renal transplantation revealed one patient with granulomatous inflammation that was associated with P. jirovecii. In addition to bronchioalveolar lavage, biopsy may be a useful diagnostic tool in difficult cases, especially when differential diagnosis between drug-induced pneumonitis and PCP is not evident. Our series of patients shows that special care should be taken to differentiate between everolimus-induced pneumonitis and infectious pneumonitis. Particularly when no improvement is observed after everolimus discontinuation or dose reduction, PCP should be suspected and specific diagnostic evaluations should be performed. In this setting, the prescription of everolimus will presumably continue to increase because of the clinical benefit related to mTOR inhibitors in patients with RCC. Prevention, efficient recognition, and treatment of PCP in this population are therefore of major concern. Additional studies are needed to evaluate the incidence and clinical characteristics of mTOR inhibitor–induced PCP in patients with RCC. In conclusion, we suggest that specific recommendations concerning PCP prophylaxis in mTOR inhibitor–treated patients with RCC should be discussed.

Marie-Charlotte Loron and Steven Grange Rouen University Hospital, Rouen, France

Dominique Guerrot Rouen University Hospital; and Institut National de la Sante´ et de la Recherche Me´dicale Unit 1096, Rouen Medical University, Rouen, France JOURNAL OF CLINICAL ONCOLOGY

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Diagnosis in Oncology

Fre´de´ric Di Fiore, Caroline Freguin, Me´lanie Hanoy, Frank Le Roy, Gwenaelle Poussard, Isabelle Etienne, Bruno Legallicier, and Christian Pfister Rouen University Hospital, Rouen, France

Michel Godin Rouen University Hospital; and Institut National de la Sante´ et de la Recherche Me´dicale Unit 1096, Rouen Medical University, Rouen, France

Dominique Bertrand Rouen University Hospital, Rouen, France


Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Fre´de´ric Di Fiore, Roche, Novartis, Bayer, Merck, Amgen Research Funding: None Expert Testimony: None Patents: None Other Remuneration: None REFERENCES 1. LoPiccolo J, Blumenthal GM, Bernstein WB, et al: Targeting the P13K/Akt/ mTOR pathway: Effective combinations and clinical considerations. Drug Resist Updat 11:32-50, 2008 2. Wanner K, Hipp S, Oelsner M, et al: Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol 134:475-484, 2006 3. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449-456, 2008 4. Amato R: Everolimus for the treatment of advanced renal cell carcinoma. Expert Opin Pharmacother 12:1143-1155, 2011 5. Motzer RJ, Escudier B, Oudard S, et al: Phase 3 trial of everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. Cancer 116:4256-4265, 2010 6. Korhonen P, Zuber E, Branson M, et al: Correcting overall survival for the impact of crossover via a rank-preserving structural failure time (RPSFT) model in the RECORD-1 trial of everolimus in metastatic renal-cell carcinoma. J Biopharm Stat 22:1258-1271, 2012 7. Beaumont JL, Butt Z, Baladi J, et al: Patient-reported outcomes in a phase III study of everolimus versus placebo in patients with metastatic carcinoma of the kidney that has progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy. Oncologist 16:632-640, 2011 8. Neff RT, Jindal RM, Yoo DY, et al: Analysis of USRDS: Incidence and risk factors for Pneumocystis jiroveci pneumonia. Transplantation 88:135-141, 2009 9. De Castro N, Xu F, Porcher R, et al: Pneumocystis jirovecii pneumonia in renal transplant recipients occurring after discontinuation of prophylaxis: A case-control study. Clin Microbiol Infect 16:1375-1377, 2010 10. Di Cocco P, Orlando G, Bonanni L, et al: A systematic review of two different trimetoprim-sulfamethoxazole regimens used to prevent Pneumocystis jirovecii and no prophylaxis at all in transplant recipients: Appraising the evidence. Transplant Proc 41:1201-1203, 2009 11. Olsen SL, Renlund DG, O’Connell JB, et al: Prevention of Pneumocystis carinii pneumonia in cardiac transplant recipients by trimethoprim sulfamethoxazole. Transplantation 56:359-362, 1993 12. Elinder CG, Andersson J, Bolinder G, et al: Effectiveness of low-dose cotrimoxazole prophylaxis against Pneumocystis carinii pneumonia after renal and/or pancreas transplantation. Transpl Int 5:81-84, 1992

13. Kramer MR, Stoehr C, Lewiston NJ, et al: Trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii infections in heart-lung and lung transplantation: How effective and for how long? Transplantation 53:586-589, 1992 14. Torre-Cisneros J, de la Mata M, Lopez-Cillero P, et al: Effectiveness of daily low-dose cotrimoxazole prophylaxis for Pneumocystis carinii pneumonia in liver transplantation: An open clinical trial. Transplantation 62:1519-1521, 1996 15. Porta C, Calvo E, Climent MA, et al: Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: An exploratory analysis of the outcomes of elderly patients in the RECORD-1 trial. Eur Urol 61:826-833, 2012 16. Gru¨nwald V, Karakiewicz PI, Bavbek SE, et al: An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptortyrosine kinase inhibitor therapy. Eur J Cancer 48:324-332, 2012 17. Di Lorenzo G, Porta C, Bellmunt J, et al: Toxicities of targeted therapy and their management in kidney cancer. Eur Urol 59:526-540, 2011 18. White DA, Camus P, Endo M, et al: Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 182:396-403, 2012 19. Saito Y, Nagayama M, Miura Y, et al: A case of pneumocystis pneumonia associated with everolimus therapy for renal cell carcinoma. Jpn J Clin Oncol 43:559-562, 2013 20. Zheng M, Shellito JE, Marrero L, et al: CD4⫹ T-cell-independent vaccination against Pneumocystis carinii in mice. J Clin Invest 108:1469-1474, 2001 21. Kelly MN, Zheng M, Ruan S, et al: Memory CD4⫹ T cells are required for optimal NK cell effector functions against the opportunistic fungal pathogen Pneumocystis murina. J Immunol 190:285-295, 2013 22. Kolls JK, Habetz S, Shean MK, et al: IFN-gamma and CD8⫹ T cells restore host defenses against Pneumocystis carinii in mice depleted of CD4⫹ T cells. J Immunol 162:2890-2894, 1999 23. Gigliotti F, Wright TW: Immunopathogenesis of Pneumocystis carinii pneumonia. Expert Rev Mol Med 7:1-16, 2005 24. Delgoffe GM, Kole TP, Zheng Y, et al: The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832844, 2009 25. Chi H: Regulation and function of mTOR signalling in T cell fate decision. Nat Rev Immunol 12:325-338, 2012 26. Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE), Mocroft A, Reiss P, et al: Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count ⬍ 200 cells/microL?. Clin Infect Dis 51:611-619, 2010 27. Struijk GH, Gijsen AF, Yong SL, et al: Risk of Pneumocystis jiroveci pneumonia in patients long after renal transplantation. Nephrol Dial Transplant 26:3391-3398, 2011 28. Overgaard UM, Helweg-Larsen J: Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: A retrospective study 2002-2004. Scand J Infect Dis 39:589-595, 2007 29. Dabydeen DA, Jagannathan JP, Ramaiya N, et al: Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: Incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer 48:1519-1524, 2012 30. Di Fiore F, Rigal O, Me´nager C, et al: Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib. Br J Cancer 105:1811-1813, 2011 31. Mizuno R, Asano K, Mikami S, et al: Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma. Jpn J Clin Oncol 42:442-446, 2012 32. Lee HS, Huh KH, Kim YS, et al: Sirolimus-induced pneumonitis after renal transplantation: A single-center experience. Transplant Proc 44:161-163, 2012 33. Maroto JP, Hudes G, Dutcher JP, et al: Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol 29:1750-1756, 2011 34. Kirby S, Satoskar A, Brodsky S, et al: Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens. Diagn Pathol 7:25, 2012

DOI: 10.1200/JCO.2013.49.9277; published online ahead of print at www.jco.org on March 17, 2014

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Pneumocystis jirovecii pneumonia in everolimus-treated renal cell carcinoma.

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