REVIEW URRENT C OPINION
Procalcitonin as a biomarker for infection-related mortality in cancer patients Ali M. Sedef, Fatih Kose, Huseyin Mertsoylu, and Ozgur Ozyilkan
Purpose of review Infectious diseases are the second leading cause of death following direct cancer-related complications in the field of oncology. Clinical studies using the classic inflammatory biomarkers, C-reactive protein, erythrocyte sedimentation rate, leukocytosis, and thrombocytosis fail to show a significant correlation between these biomarkers and infection-related mortality. It is therefore crucial to define new biomarkers that are not affected by the primary cancer and precisely show the severity of the infection to help in the decision-making process. Recent findings A significant increase in the number of cancer patients in the past decades has created an exponential increase in the number of immunocompromised patients. Preemptive and typically unnecessary usage of broad-spectrum antibiotics is common during the treatment of these patients and may result in an increase in multidrug-resistant microbial strains. Recent clinical studies suggest that a significant reduction in antibiotic consumption may be achieved by procalcitonin-guided algorithms without sacrificing the outcome of patients with severe infection. Summary In this article, we focus on procalcitonin and its potential role in differentiating cancer and infectioninduced inflammation. Using this strategy may significantly reduce the usage of empirical broad-spectrum antibiotics and result in earlier discharge of patients. Keywords biomarker, cancer, infection-related mortality, procalcitonin
INTRODUCTION Cancer is the second leading cause of death after the cardiovascular disease throughout the world. Although, most cancer patients eventually die of their primary disease, infection-related complications rank second for mortality in cancer patients. Early diagnosis and true assessment of the infections are crucial for the optimal management of these patients. Although the advent of antibiotic therapy led to a dramatic reduction in rates of infectionrelated mortality and morbidity in chronic diseases, as well as cancer patients, the global spread of microbial resistance overshadows this successful history of antibiotics in the past decade [1,2]. Methods to control unnecessary use of antibiotics like using pathogen-specific agents, decrease the rate of empirical usage of antibiotics during long hospital staying periods, and stopping the antibiotic treatment at earlier period should be encouraged. There is a limited number of effective antibiotics that are effective against resistant microorganisms. www.supportiveandpalliativecare.com
The number of these antibiotics decreases with a fast pace. So, this limited ‘antibiotic effectiveness’ should be maintained and restored [3]. Ironically, further advances in oncological treatment created an enormous population of immunocompromised hosts with infections that caused by multidrugresistant microbes [2]. Unfortunately, we are now further away from solving infectious complications than three decades ago which, despite the availability of broad-spectrum antibiotics, means that infections are third leading cause of death in worldwide and second leading cause of death in cancer patients Department of Medical Oncology, Faculty of Medicine, Baskent University, Adana, Turkey Correspondence to Ali M. Sedef, MD, Department of Medical Oncology, Faculty of Medicine, Baskent University, Adana kısla saglik yerleskesi, Yuregir, Adana 01130, Turkey. Tel: +90507 7019297; fax: +90322 344 4445; e-mail: [email protected] Curr Opin Support Palliat Care 2015, 9:168–173 DOI:10.1097/SPC.0000000000000142 Volume 9 Number 2 June 2015
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PCT as a biomarker for cancer patients Sedef et al.
KEY POINTS Infections are responsible for a significant number of deaths in cancer patients particularly during the active treatment phase with chemotherapeutics, and many of these deaths are related to multidrug-resistant pathogens. Classic inflammatory biomarkers failed to discriminate between tumor-induced and infectionrelated inflammation. Clinical studies have failed to show a significant relation between classic inflammatory biomarkers (CRP, ESR, leukocytosis, and thrombocytosis) or even positive bacterial culture results and infection-related mortality. However, studies do demonstrate a significant relation between PCT and infection-related mortality. PCT algorithms might be used on the initial evaluation of cancer patients who exhibit signs and symptoms of systemic inflammatory response and also to narrow antibiotic spectrum without sacrificing patient safety. Implementing PCT algorithms into the field of oncology with high-quality prospective trials is warranted.
apart from in those with primary disease [4]. Therefore, maintaining and restoring the ‘antibiotic effectiveness’ is particularly important and necessary for the development of advances in myeloablative therapies for cancer. As a result, the evaluation of severity of the infection is crucial for the optimal management. However, there is no single proven clinical or laboratory prognostic marker for infection-related mortality and optimal management of these patients remains a continual challenge for oncologists [5]. Cancer itself stimulates a strong immune response and a continuous ‘smoldering’ inflammatory state that are associated with elevation of classic inflammatory biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leukocyte, and thrombocyte count [2,5]. These biomarkers are not specific to infection but the result of response to cytokines released during inflammation that are formed against the assaulting organism, certain type of cell in autoimmune condition, or cancer cells. The purpose of this article is to emphasize the increasing rate of infectious complications in cancer patients, discuss the superiority of new infection specific biomarker, procalcitonin (PCT), and review the potential usage of this new biomarker in the field of oncology.
CANCER AND INFECTION The malignancy itself and cancer treatment can predispose patients to severe and/or recurrent
infections [5]. Although, neutropenia is the most considered factor, there are other factors that are immunodeficiency-related, with primary malignancy, disruption of mucosal barriers, corticosteroids, and chemotherapy, which affect the immune system at different stages. Latter factors are major concerns for the solid tumors compared with neutropenia in the hematological malignancies. Combination therapy of chemotherapy and radiotherapy even further disrupt the mucosal barrier of the alimentary tract and cause severe infection. Most of the pathogens are bacteria, whereas fungi and viruses are also common but usually at the late phase of infection [5]. Coagulase-negative staphylococci, Staphylococcus aureus, viridians group streptococci, and enterococci are the major Grampositive pathogens. Coliforms and Pseudomonas aeruginosa are common causative pathogens for infectious complications [5–7].
Why are infection-related complications so important in cancer? For most cancer patients, the optimal oncologic treatment plan includes major surgical operation and/or catheter placement that potentially cause organ dysfunction such as gastrectomy, hepatectomy, lobectomy, and deployment of biliary drainage catheter. Anatomical properties of the tumors such as endobronchial obstruction and necrosis of primary tumors also serve as a focus for local abscess and recurrent infection. Chemotherapeutics when accompanied by catabolic state of body, decrease in serum albumin and gamma globulin levels, significantly increase the mortality rate of infection. As a result, most deaths in cancer patients are because of their disease. However, risk of the death from infection in cancer remains high and even higher than in any other chronic diseases.
Are current guidelines enough for the management of infectious complications in cancer patients? ESMO clinical recommendations and NCCN guidelines are two major tools actively used by oncologists to optimize the cancer patient care. But, there are no detailed recommendations for the management of nonneutropenic cancer-related infection cases in the ESMO and NCCN guidelines [8,9]. Algorithms proposed by these guidelines have been mostly formed for high-risk hematological malignancies or transplant patients and focused on vaccination, prophylactic antimicrobial usage [5]. Therefore, these guidelines cannot be used for low-risk (expected neutropenia time after chemotherapy below 7 days) solid
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tumor cancer patients [6]. Thus, these patients were managed according to guidelines of infectious disease communities, which accepted malignancy as a risk factor for multidrug-resistant pathogens without any specific recommendation for cancer patients [10]. Cancer diagnosis and its common consequences can complicate the decision-making process for infectious complications in these specific group of patients. For example, a nonsmall cell lung cancer patient with central mass treated with radiotherapy and chemotherapy who lost 4 kg during 3-week chemoradiotherapy period has postural hypotension with signs of dehydration, and laboratory evaluation revealed a mild increase in urea level with moderate anemia following admission to the emergency department. Further evaluation revealed increase in amount of sputum, rales at the physical examination, and increase in CRP levels, leukocytosis, and thrombocytosis at the laboratory examination. All these mentioned signs and symptoms may be a result of superposed lung infection or toxicities of current therapy. None of the current oncologic or nononcological guidelines suggested any further biomarker to differentiate infectious or tumor-induced inflammation for these conditions. However, these patients were accepted as high-risk patients treated with broad-spectrum antibiotics for long periods in oncology in-ward clinics.
CANCER AND IMMUNE SYSTEM Cumulative genetic mutations cause development of cancer cells [11]. According to the best of our knowledge, cancer is a clonal disorder and the progression of one cell to cancer tissue requires dysregulation of effective immune system. Cancer cells express different glycopepeptides that cause a strong immune response [12]. Studies of the cancerimmune system relation have shown that both innate and adaptive immune mechanisms contribute to recognition and destruction of cancer cells [12]. Animal studies have shown that interaction between cancer cells and the immune system starts on the second day of a xenograft model [13]. Interaction between the immune system and cancer can be resulted with elimination, equilibrium, and escape phase of cancer [14]. At the escape phase of cancer, although the growth rate of the tumor is high, there is a strong but dysregulated inflammatory response to cancer tissue [15]. At this phase, the presence of a systemic inflammatory response can be detected by measuring CRP and IL-6 levels, and the strength of this response has prognostic value [16 ]. The stronger the inflammatory response the worse the prognosis. Conversely, inflammation can support tumorigenesis by &&
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supplying a tumor microenvironment via molecules including proangiogenic, growth and survival factors that increase the capacity of cancer cells for invasion, angiogenesis, and metastasis [17 ,18]. &
Pitfalls of differentiating cancer-induced inflammation from infection, failure of classic inflammatory biomarkers Can we differentiate the inflammation induced by infection from the tumor by itself? The exact answer to this question is absent, ‘too big’ to answer and beyond the scope of this article. During tissue injury associated with infectious causes, a multiple network of chemical signals starts and maintains a continuous response to assaulting organisms [19]. This multiphasic process involves activation of leukocytes (monocytes, neutrophils, and eosinophils) and accumulation to the site of inflammation. Recruitment of leukocytes requires activation of selectin and integrin family members then induction of angiogenesis and proliferation of fibroblast and endothelial cells to form a nidus for reconstitution of the normal microenvironment [20]. During this process, different types of chemokines/cytokines such as tumor necrosis factor-a and tumor growth factor b1 are expressed and excreted from the inflammatory site [21,22]. High ESR, CRP, leukocytosis, and thrombocytosis are the end result of these cytokines. During routine clinical practice, we use these biomarkers as they are correlated with severity of the infectious process. The key concept in infectioninduced inflammation is usually a self-limiting process. However, after the ‘initiation’ and ‘promotion’ phase of cancer development, cancer cells produce distinct types of cytokine/chemokine products to form a unique chronic inflammatory state. Tumorassociated macrophages, tumor-associated lymphocytes with tumor-associated fibroblasts are major contributors of this tumor microenvironment. These cells contribute to tumor growth by releasing extracellular proteases, proangiogenic factors, growth factors, and chemokines. High concentrations of these factors also induce angiogenesis and help the tumor to gain metastatic potential [10]. Also, several studies showed that long-term use of acetyl salicylic acid and nonsteroidal antiinflammatory drugs effectively reduces the development of cancer risk by 50% for colon cancer, and to a lesser extent for esophagus, stomach, and lung cancers [23,24]. However, to the best of our knowledge, we do not know whether inflammatory cells fight against or make strong association with tumors to support their development and what is the net effect of this relation? What we know is that chronic and underlying inflammation is associated with most tumors and cannot Volume 9 Number 2 June 2015
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PCT as a biomarker for cancer patients Sedef et al.
be differentiated from infection-related inflammation with classic inflammatory biomarkers.
PROCALCITONIN PCT is a peptide composed of 116 amino acids, also known as the prohormone of calcitonin, but PCT and calcitonin are distinct proteins. Calcitonin is exclusively produced by C-cells of the thyroid gland in response to hormonal stimuli, whereas PCT can be produced from several sites including liver, kidney, adipocytes, and muscle cells particularly in response to bacterial toxins [25,26]. Abnormally raised PCT levels were first reported by Assicot et al. [27] in children with bacterial infections. To the best of our knowledge, there is no difference between Gram-positive and Gram-negative bacteriarelated sepsis induced and increase levels of PCT. High PCT levels are detectable 2–3 h after endotoxin injection in healthy volunteers and the half-life of PCT in serum is 25–30 h [28]. However, the biological half-life of PCT of 22–26 h is shorter when compared with CRP and ESR half-lives [29]. PCT analysis is simple to perform and results are rapidly available. The quantitative estimation of PCT using cryptate emission technology can be performed in less than half an hour.
especially in advanced cancer patients, and differential diagnosis may not be possible with the history, physical examination, and using classic inflammatory biomarkers. PCT is a promising biomarker. Significant elevation in blood occurs at an early time point in sepsis, even in the first 2–3 h. This distinct property of PCT combining with half-life of 22–26 h may make it a useful marker as compared with CRP and ESR which increase only after 24 h of infection and have halflives of 2–3 days [31]. A meta-analysis including 3244 patients in 30 clinical studies showed that PCT can differentiate effectively between sepsis and SIRS of noninfectious origin, with an area under the ROC curve of 0.85 [95% confidence interval (CI) 0.81–0.88] [30 ,32]. The results were found significant for medical, surgical, or pediatric patients. These studies suggested that PCT can be used at initial admission or during hospitalization when severe sepsis is suspected. PCT has high accuracy in establishing or refusing a sepsis diagnosis when value PCT is below the level of 0.5 mg/l or over the level of 2.0 mg/l [30 ]. One recent study in cancer patients showed that PCT was able to differentiate tumor-and infection-induced fever [33]. Thus, the PCT is not only a more sensitive biomarker, but also a more specific marker (with high-negative predictive value for infection) compared with CRP and ESR [31]. &&
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Procalcitonin and infection PCT synthesis and secretion are induced by microbial toxins specifically, proinflammatory cytokines like interleukin-1b, tumor necrosis factor-a, and interleukin-6 are produced [30 ]. In healthy people, serum PCT concentrations are found to be below 0.05 mg/l. A PCT concentration over 0.5 mg/l is interpreted as an abnormal value suggestive of bacterial infection. PCT values in the range of 0.5–2 mg/l represent a ‘gray’ zone with uncertainty when the diagnosis of sepsis is concerned. PCT level above 2 mg/l is highly specific for severe sepsis [31]. Traditionally, diagnosis of sepsis is made by the isolation of an offending organism in blood culture. However, detection rate of microorganism has been reported to be as low as 20–30% in literature [30 ]. Furthermore, the required time for positive culture results can be as long as 7 days and most of the positive cases require more than one sample, and it comes with the risk of significant rate of false-positive results [30 ]. Waiting for the result of blood cultures is impractical and may potentially increase mortality rate of infection-related complication in cancer patients. What we need is to differentiate severe sepsis from cancer-induced clinical systemic complications at an early stage. However, signs and symptoms of severe infection may be similar to cancer-induced inflammatory response &&
Procalcitonin and cancer A ‘smoldering’ inflammatory environment is found at different rates in distinct type of tumors. Cancer itself stimulates and modulates this environment by the secretion of soluble factors and chemokines, and interaction between cancer and immune system is usually associated with the elevation of inflammatory markers such as CRP, ESR, and leukocyte count [34,35,36 ]. Remarkably, studies showed that tumor-induced inflammation does not alter PCT levels [37,38]. As a result, PCT is a promising biomarker for evaluating severity of infection and making a precise decision about spectrum of antibiotics. &&
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DISCUSSION PCT-guided algorithms for antibiotic therapy decisions were developed mostly for respiratory tract infections, including pneumonia, bronchitis, and related sepsis and in a systematic review of 14 randomized controlled trials (4467 patients), Schuetz et al. [40] showed that using PCT in clinical practice was effective in reducing misuse of antibiotics without sacrificing patient safety [39,40]. Most of these studies draw benefit not from the high sensitivity of PCT but from the high specificity
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of PCT. Indeed, in high-risk patient PCT levels were not used to determine whether antibiotic therapy should be initiated but when to discontinue it [40]. Decreasing the level of PCT during clinical course shows a strong correlation with resolution of bacteremia, so we could well tolerate discontinuation of antibiotic treatment and in low-risk patient PCT values can be used to decide whether starting antibiotic treatment could be omitted totally [40]. These algorithms also decrease emergence of multidrugresistant pathogens. These antibiotic-resistant infections increase hospital length of stay, mortality, and hospital costs [41]. A meta-analysis published in 2011 with eight studies (3431 patients) showed a significant reduction in antibiotic prescription in the PCTguided antibiotic treatment groups [42]. However, one should keep in mind that all patients should be carefully and frequently reassessed to ensure that their clinical condition improves spontaneously in a clinically appropriate time. Therefore, PCT is a sensitive and specific biomarker for bacterial sepsis, and the level of PCT increase is correlated with the severity of the infection and not affected from primary malignancy as CRP, ESR did [43,44]. Using PCT levels as a prognostic biomarker has been shown to reduce the duration of hospital stay in pediatric and ICU patients [45,46]. Higher PCT levels have been associated with increased mortality rates and correlated with severity scores (APACHE, SOFA, and SAPS) [47 ]. A study that presented MASCC 2014 symposium showed that single value PCT is found to be significantly related with in-patient mortality for cancer patients. Although statistical analysis failed to show significant relation between mortality, serum and CRP, LDH, sedimentation albumin, serum calcium levels, and positive culture results. There was no relation between PCT and the aforementioned inflammatory markers [48]. Other clinical studies also failed to show significant relation between classical inflammatory biomarkers and even culture positivity with infection-related mortality. In cancer patients, cancer induced increases in inflammatory biomarkers in blood and in cancer-related factors, that severely disturb patients’ general condition, make it even harder to answer these questions. Who truly benefits from antibiotic therapy? If treated, what is the optimal treatment duration? There is no single proven clinical or laboratory prognostic biomarker for infection-related mortality. Thus, managing these patients remains a continual challenge for oncologists. It is remains difficult to determine with clinical data and current classic inflammatory biomarkers which of the patients who present with signs and symptoms of sepsis on initial evaluation will actually go on to develop a severe septic illness &&
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resulting in organ dysfunction and/or mortality [49,50]. Several potential bloodstream biomarkers have been investigated for their ability to diagnose sepsis, estimate its severity, and provide a prognosis. Although PCT is well known, other promising biomarkers appear to be on the horizon including the soluble triggering receptor expressed on myeloid cells-1, soluble urokinase-type plasminogen receptor, proadrenomedullin, and presepsin [51 ]. Certain new biomarkers including PCT have recently been investigated in severe infection. In this article, we provide a review of the recent advancements regarding the usage PCT in infectious complications of cancer patients. It is envisioned that the usage of PCT may be implanted within the routine clinical practice in the near future, reducing the hospitalization duration and maintaining the antibiotic effectiveness. &
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest The authors declare that they have full control of all primary data and we agree to allow the journal to review our data if requested by the journal editorial system, and we also state that we did not enter any financial relationship with any organization or company.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Yealy DM, Fine MJ. Measurement of serum procalcitonin: a step closer to tailored care for respiratory infections? JAMA 2009; 302:1115–1116. 2. Spellberg B, Guidos R, Gilbert D, et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:155–164. 3. Laxminarayan R, Malani A, Howard D, Smith DL. Extending the cure: policy responses to the growing threat of antibiotic resistance. Antibiotic effectiveness as a natural resource. Resour future 2007; 19–21. 4. Pinner RW, Teutsch SM, Simonsen L, et al. Trends in infectious diseases mortality in the United States. JAMA 1996; 275:189–193. 5. Baden LR, Bensinger W, Angarone M, et al. Prevention and Treatment of Infections. J Natl Compr Canc Netw 2012; 10:1412–1445. 6. 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; 52:e56–e93. 7. Rolston KV. The Infectious Diseases Society of America 2002 guidelines for the use of antimicrobial agents in patients with cancer and neutropenia: salient features and comments. Clin Infect Dis 2004; 39 (Suppl 1):S44–S48. 8. de Naurois J, Novitzky-Basso2 I, Gill MJ, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol 2010; 21 (Suppl 5):252–256. 9. National Comprehensive Cancer Network (NCCN) (Version 2. 2014) Myeloid Growth Factors. http://www.nccn.org/professionals/physician_gls/pdf/ myeloid_growth.pdf. Accessed 15 June 2014.
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PCT as a biomarker for cancer patients Sedef et al. 10. Pneumonia H. Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416. 11. Mills KD, Ferguson DO, Alt FW. The role of DNA breaks in genomic instability and tumorigenesis. Immunol Rev 2003; 194:77–95. 12. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol 2012; 23 (Suppl 8):6–9. 13. Simeoni M, Magni P, et al. Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents. Cancer Res 2004; 64:1094–1101. 14. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331:1565– 1570. 15. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6:295–307. 16. Liu Z-Q, Chu L, Fang J-M, et al. Prognostic role of C-reactive protein in && prostate cancer: a systematic review and meta-analysis. Asian J Androl 2014; 16:467–471. This study demonstrates that CRP may have a critical prognostic value in patients with prostatic cancer. 17. Misra UK, Pizzo SV. Evidence for a pro-proliferative feedback loop in prostate & cancer: the role of Epac1 and COX-2-dependent pathways. PLoS One 2013; 8:e63150. This trial shows that Epac1, a downstream effector of cAMP, functions as a proinflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling. 18. Hoyt MA, Stanton AL, Bower JE, et al. Inflammatory biomarkers and emotional approach coping in men with prostate cancer. Brain Behav Immun 2013; 32: 173–179. 19. Coussens Lisa M, Zena Werb. Inflammation and cancer. Nature 2002; 420:860–867. 20. Chettibi S, Ferguson MWJ. Inflammation: basic principles and clinical correlates. Gallin JI, Snyderman R, editors. Philadelphia: Lippincott, Williams and Wilkinson; 1999, pp. 865–881. 21. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000; 18:217–242. 22. Homey B, Muller A, Zlotnik A. Chemokines: agents for the immunotherapy of cancer? Nature Rev Immunol 2002; 2:175–184. 23. Baron JA, Sandler RS. Nonsteroidal anti-inflammatory drugs and cancer prevention. Annu Rev Med 2000; 51:511–523. 24. Garcia-Rodriguez LA, Huerta-Alvarez C. Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. Epidemiology 2001; 12:88–93. 25. Donadona P, Nix D, Wilson MF, et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab 1994; 79:1605–1608. 26. Maruna P, Nedelnikova K, Gurlich R. Physiology and genetics of procalcitonin. Physiol Res 2000; 49 (Suppl 1):57–61. 27. Assicot M, Gendrel D, Carsin H, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993; 341:515–518. 28. Dandona P, Nix D, Wilson MF, et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab 1994; 79:1605–1608. 29. Limper M, deKruif MD, Duits AJ, et al. The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from noninfectious fever. J Infect 2010; 60:409–416. 30. Philipp Schuetza, Issam Raadb, Amin Devendra N. Using procalcitonin&& guided algorithms to improve antimicrobial therapy in ICU patients with respiratory infections and sepsis. Curr Opin Crit Care 2013; 19:453–460. PCT data in clinical algorithms improve individualized decision making regarding antibiotic treatment in patients in critical care for respiratory infections or sepsis. 31. Bernard Uzzan, Re´gis Cohen, et al. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 2006; 34:; DOI: 10.1097/ 01.CCM.0000226413.54364.36.
32. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010; 375:463–474. 33. Shomali W, Hachem R, Chaftari AM, et al. Can procalcitonin distinguish infectious fever from tumor-related fever in nonneutropenic cancer patients? Cancer 2012; 118:5823–5829. 34. Povoa P. C-reactive protein: a valuable marker of sepsis. Intensive Care Med 2002; 28:235–243. 35. Du Clos TW, Mold C. The role of C-reactive protein in the resolution of bacterial infection. Curr Opin Infect Dis 2001; 14:289–293. 36. Elinav E, Nowarski R, Thaiss CA, et al. Inflammation-induced cancer: crosstalk && between tumours, immune cells and microorganisms. Nat Rev Cancer 2013; 13:759–771. This article suggested a role for commensal microorganisms in inflammationinduced cancer. 37. Schuttrumpf S, Binder L, Hagemann T, et al. Utility of procalcitonin concentration in the evaluation of patients with malignant diseases and elevated C-reactive protein plasma concentrations. Clin Infect Dis 2006; 43:468– 473. 38. Jimeno A, Garcia-Velasco A, del Val O, et al. Assessment of procalcitonin as a diagnostic and prognostic marker in patients with solid tumors and febrile neutropenia. Cancer 2004; 100:2462–2469. 39. Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis 2009; 49:1175–1184. 40. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011; 171:1322–1331. 41. Ohl CA, Luther VP. Antimicrobial stewardship for inpatient facilities. J Hosp Med 2011; 6 (Suppl 1):S4–S15. 42. Li H, Luo YF, Blackwell TS, Xie CM. Meta-analysis and systematic review of procalcitonin-guided therapy in respiratory tract infections. Antimicrob Agents Chemother 2011; 55:5900–5906. 43. Assicot M, Gendrel D, Carsin H, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993; 341:. 44. Chirouze C, Schuhmacher H, Rabaud C, et al. Low serum procalcitonin level accurately predicts the absence of bacteremia in adult patients with acute fever. Clin Infect Dis 2002; 35:. 45. Barnes C, Ignjatovic V, Newall F. Change in serum procalcitonin (delta PCT) predicts the clinical outcome of children admitted with febrile neutropenia. Br J Haematol 2002; 118:1197–1198. 46. Vandack Nobre, Stephan Harbarth, et al. Use of procalcitonin to shorten antibiotic treatment duration in septic patients. Am J Respir Crit Care Med 2008; 177:498–505. 47. Vincent J, Beumier M. Diagnostic and prognostic markers in sepsis. Expert && Rev Anti Infect Ther 2013; 11:265–275. This article discussed changing approaches to sepsis diagnosis and discuss some of the markers that seem most relevant at the present time. 48. Sedef AM, Kose F, et al. Procalcitonin is the first biomarker that is significantly correlated with the infection related mortality in cancer patients independent from C-reactive protein, sedimentation rate, performance scale, and leukocyte count. Presented at MASCC 2014 symposium. 49. Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353:1332– 1341. 50. Shapiro N, Howell MD, Bates DW, et al. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med 2006; 48:583–590; 590 e581. 51. Henriquez-Camacho C, Losa J. Biomarkers for sepsis. Biomed Res Int 2014; & 2014:547818. New biomarkers such as those in this article are discussed as the major types of biomarkers of bloodstream infections/sepsis.
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Procalcitonin as a biomarker for infection-related mortality in cancer patients Ali M. Sedef, Fatih Kose, Huseyin Mertsoylu, and Ozgur Ozyilkan
Purpose of review Infectious diseases are the second leading cause of death following direct cancer-related complications in the field of oncology. Clinical studies using the classic inflammatory biomarkers, C-reactive protein, erythrocyte sedimentation rate, leukocytosis, and thrombocytosis fail to show a significant correlation between these biomarkers and infection-related mortality. It is therefore crucial to define new biomarkers that are not affected by the primary cancer and precisely show the severity of the infection to help in the decision-making process. Recent findings A significant increase in the number of cancer patients in the past decades has created an exponential increase in the number of immunocompromised patients. Preemptive and typically unnecessary usage of broad-spectrum antibiotics is common during the treatment of these patients and may result in an increase in multidrug-resistant microbial strains. Recent clinical studies suggest that a significant reduction in antibiotic consumption may be achieved by procalcitonin-guided algorithms without sacrificing the outcome of patients with severe infection. Summary In this article, we focus on procalcitonin and its potential role in differentiating cancer and infectioninduced inflammation. Using this strategy may significantly reduce the usage of empirical broad-spectrum antibiotics and result in earlier discharge of patients. Keywords biomarker, cancer, infection-related mortality, procalcitonin
INTRODUCTION Cancer is the second leading cause of death after the cardiovascular disease throughout the world. Although, most cancer patients eventually die of their primary disease, infection-related complications rank second for mortality in cancer patients. Early diagnosis and true assessment of the infections are crucial for the optimal management of these patients. Although the advent of antibiotic therapy led to a dramatic reduction in rates of infectionrelated mortality and morbidity in chronic diseases, as well as cancer patients, the global spread of microbial resistance overshadows this successful history of antibiotics in the past decade [1,2]. Methods to control unnecessary use of antibiotics like using pathogen-specific agents, decrease the rate of empirical usage of antibiotics during long hospital staying periods, and stopping the antibiotic treatment at earlier period should be encouraged. There is a limited number of effective antibiotics that are effective against resistant microorganisms. www.supportiveandpalliativecare.com
The number of these antibiotics decreases with a fast pace. So, this limited ‘antibiotic effectiveness’ should be maintained and restored [3]. Ironically, further advances in oncological treatment created an enormous population of immunocompromised hosts with infections that caused by multidrugresistant microbes [2]. Unfortunately, we are now further away from solving infectious complications than three decades ago which, despite the availability of broad-spectrum antibiotics, means that infections are third leading cause of death in worldwide and second leading cause of death in cancer patients Department of Medical Oncology, Faculty of Medicine, Baskent University, Adana, Turkey Correspondence to Ali M. Sedef, MD, Department of Medical Oncology, Faculty of Medicine, Baskent University, Adana kısla saglik yerleskesi, Yuregir, Adana 01130, Turkey. Tel: +90507 7019297; fax: +90322 344 4445; e-mail: [email protected] Curr Opin Support Palliat Care 2015, 9:168–173 DOI:10.1097/SPC.0000000000000142 Volume 9 Number 2 June 2015
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PCT as a biomarker for cancer patients Sedef et al.
KEY POINTS Infections are responsible for a significant number of deaths in cancer patients particularly during the active treatment phase with chemotherapeutics, and many of these deaths are related to multidrug-resistant pathogens. Classic inflammatory biomarkers failed to discriminate between tumor-induced and infectionrelated inflammation. Clinical studies have failed to show a significant relation between classic inflammatory biomarkers (CRP, ESR, leukocytosis, and thrombocytosis) or even positive bacterial culture results and infection-related mortality. However, studies do demonstrate a significant relation between PCT and infection-related mortality. PCT algorithms might be used on the initial evaluation of cancer patients who exhibit signs and symptoms of systemic inflammatory response and also to narrow antibiotic spectrum without sacrificing patient safety. Implementing PCT algorithms into the field of oncology with high-quality prospective trials is warranted.
apart from in those with primary disease [4]. Therefore, maintaining and restoring the ‘antibiotic effectiveness’ is particularly important and necessary for the development of advances in myeloablative therapies for cancer. As a result, the evaluation of severity of the infection is crucial for the optimal management. However, there is no single proven clinical or laboratory prognostic marker for infection-related mortality and optimal management of these patients remains a continual challenge for oncologists [5]. Cancer itself stimulates a strong immune response and a continuous ‘smoldering’ inflammatory state that are associated with elevation of classic inflammatory biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leukocyte, and thrombocyte count [2,5]. These biomarkers are not specific to infection but the result of response to cytokines released during inflammation that are formed against the assaulting organism, certain type of cell in autoimmune condition, or cancer cells. The purpose of this article is to emphasize the increasing rate of infectious complications in cancer patients, discuss the superiority of new infection specific biomarker, procalcitonin (PCT), and review the potential usage of this new biomarker in the field of oncology.
CANCER AND INFECTION The malignancy itself and cancer treatment can predispose patients to severe and/or recurrent
infections [5]. Although, neutropenia is the most considered factor, there are other factors that are immunodeficiency-related, with primary malignancy, disruption of mucosal barriers, corticosteroids, and chemotherapy, which affect the immune system at different stages. Latter factors are major concerns for the solid tumors compared with neutropenia in the hematological malignancies. Combination therapy of chemotherapy and radiotherapy even further disrupt the mucosal barrier of the alimentary tract and cause severe infection. Most of the pathogens are bacteria, whereas fungi and viruses are also common but usually at the late phase of infection [5]. Coagulase-negative staphylococci, Staphylococcus aureus, viridians group streptococci, and enterococci are the major Grampositive pathogens. Coliforms and Pseudomonas aeruginosa are common causative pathogens for infectious complications [5–7].
Why are infection-related complications so important in cancer? For most cancer patients, the optimal oncologic treatment plan includes major surgical operation and/or catheter placement that potentially cause organ dysfunction such as gastrectomy, hepatectomy, lobectomy, and deployment of biliary drainage catheter. Anatomical properties of the tumors such as endobronchial obstruction and necrosis of primary tumors also serve as a focus for local abscess and recurrent infection. Chemotherapeutics when accompanied by catabolic state of body, decrease in serum albumin and gamma globulin levels, significantly increase the mortality rate of infection. As a result, most deaths in cancer patients are because of their disease. However, risk of the death from infection in cancer remains high and even higher than in any other chronic diseases.
Are current guidelines enough for the management of infectious complications in cancer patients? ESMO clinical recommendations and NCCN guidelines are two major tools actively used by oncologists to optimize the cancer patient care. But, there are no detailed recommendations for the management of nonneutropenic cancer-related infection cases in the ESMO and NCCN guidelines [8,9]. Algorithms proposed by these guidelines have been mostly formed for high-risk hematological malignancies or transplant patients and focused on vaccination, prophylactic antimicrobial usage [5]. Therefore, these guidelines cannot be used for low-risk (expected neutropenia time after chemotherapy below 7 days) solid
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tumor cancer patients [6]. Thus, these patients were managed according to guidelines of infectious disease communities, which accepted malignancy as a risk factor for multidrug-resistant pathogens without any specific recommendation for cancer patients [10]. Cancer diagnosis and its common consequences can complicate the decision-making process for infectious complications in these specific group of patients. For example, a nonsmall cell lung cancer patient with central mass treated with radiotherapy and chemotherapy who lost 4 kg during 3-week chemoradiotherapy period has postural hypotension with signs of dehydration, and laboratory evaluation revealed a mild increase in urea level with moderate anemia following admission to the emergency department. Further evaluation revealed increase in amount of sputum, rales at the physical examination, and increase in CRP levels, leukocytosis, and thrombocytosis at the laboratory examination. All these mentioned signs and symptoms may be a result of superposed lung infection or toxicities of current therapy. None of the current oncologic or nononcological guidelines suggested any further biomarker to differentiate infectious or tumor-induced inflammation for these conditions. However, these patients were accepted as high-risk patients treated with broad-spectrum antibiotics for long periods in oncology in-ward clinics.
CANCER AND IMMUNE SYSTEM Cumulative genetic mutations cause development of cancer cells [11]. According to the best of our knowledge, cancer is a clonal disorder and the progression of one cell to cancer tissue requires dysregulation of effective immune system. Cancer cells express different glycopepeptides that cause a strong immune response [12]. Studies of the cancerimmune system relation have shown that both innate and adaptive immune mechanisms contribute to recognition and destruction of cancer cells [12]. Animal studies have shown that interaction between cancer cells and the immune system starts on the second day of a xenograft model [13]. Interaction between the immune system and cancer can be resulted with elimination, equilibrium, and escape phase of cancer [14]. At the escape phase of cancer, although the growth rate of the tumor is high, there is a strong but dysregulated inflammatory response to cancer tissue [15]. At this phase, the presence of a systemic inflammatory response can be detected by measuring CRP and IL-6 levels, and the strength of this response has prognostic value [16 ]. The stronger the inflammatory response the worse the prognosis. Conversely, inflammation can support tumorigenesis by &&
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supplying a tumor microenvironment via molecules including proangiogenic, growth and survival factors that increase the capacity of cancer cells for invasion, angiogenesis, and metastasis [17 ,18]. &
Pitfalls of differentiating cancer-induced inflammation from infection, failure of classic inflammatory biomarkers Can we differentiate the inflammation induced by infection from the tumor by itself? The exact answer to this question is absent, ‘too big’ to answer and beyond the scope of this article. During tissue injury associated with infectious causes, a multiple network of chemical signals starts and maintains a continuous response to assaulting organisms [19]. This multiphasic process involves activation of leukocytes (monocytes, neutrophils, and eosinophils) and accumulation to the site of inflammation. Recruitment of leukocytes requires activation of selectin and integrin family members then induction of angiogenesis and proliferation of fibroblast and endothelial cells to form a nidus for reconstitution of the normal microenvironment [20]. During this process, different types of chemokines/cytokines such as tumor necrosis factor-a and tumor growth factor b1 are expressed and excreted from the inflammatory site [21,22]. High ESR, CRP, leukocytosis, and thrombocytosis are the end result of these cytokines. During routine clinical practice, we use these biomarkers as they are correlated with severity of the infectious process. The key concept in infectioninduced inflammation is usually a self-limiting process. However, after the ‘initiation’ and ‘promotion’ phase of cancer development, cancer cells produce distinct types of cytokine/chemokine products to form a unique chronic inflammatory state. Tumorassociated macrophages, tumor-associated lymphocytes with tumor-associated fibroblasts are major contributors of this tumor microenvironment. These cells contribute to tumor growth by releasing extracellular proteases, proangiogenic factors, growth factors, and chemokines. High concentrations of these factors also induce angiogenesis and help the tumor to gain metastatic potential [10]. Also, several studies showed that long-term use of acetyl salicylic acid and nonsteroidal antiinflammatory drugs effectively reduces the development of cancer risk by 50% for colon cancer, and to a lesser extent for esophagus, stomach, and lung cancers [23,24]. However, to the best of our knowledge, we do not know whether inflammatory cells fight against or make strong association with tumors to support their development and what is the net effect of this relation? What we know is that chronic and underlying inflammation is associated with most tumors and cannot Volume 9 Number 2 June 2015
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PCT as a biomarker for cancer patients Sedef et al.
be differentiated from infection-related inflammation with classic inflammatory biomarkers.
PROCALCITONIN PCT is a peptide composed of 116 amino acids, also known as the prohormone of calcitonin, but PCT and calcitonin are distinct proteins. Calcitonin is exclusively produced by C-cells of the thyroid gland in response to hormonal stimuli, whereas PCT can be produced from several sites including liver, kidney, adipocytes, and muscle cells particularly in response to bacterial toxins [25,26]. Abnormally raised PCT levels were first reported by Assicot et al. [27] in children with bacterial infections. To the best of our knowledge, there is no difference between Gram-positive and Gram-negative bacteriarelated sepsis induced and increase levels of PCT. High PCT levels are detectable 2–3 h after endotoxin injection in healthy volunteers and the half-life of PCT in serum is 25–30 h [28]. However, the biological half-life of PCT of 22–26 h is shorter when compared with CRP and ESR half-lives [29]. PCT analysis is simple to perform and results are rapidly available. The quantitative estimation of PCT using cryptate emission technology can be performed in less than half an hour.
especially in advanced cancer patients, and differential diagnosis may not be possible with the history, physical examination, and using classic inflammatory biomarkers. PCT is a promising biomarker. Significant elevation in blood occurs at an early time point in sepsis, even in the first 2–3 h. This distinct property of PCT combining with half-life of 22–26 h may make it a useful marker as compared with CRP and ESR which increase only after 24 h of infection and have halflives of 2–3 days [31]. A meta-analysis including 3244 patients in 30 clinical studies showed that PCT can differentiate effectively between sepsis and SIRS of noninfectious origin, with an area under the ROC curve of 0.85 [95% confidence interval (CI) 0.81–0.88] [30 ,32]. The results were found significant for medical, surgical, or pediatric patients. These studies suggested that PCT can be used at initial admission or during hospitalization when severe sepsis is suspected. PCT has high accuracy in establishing or refusing a sepsis diagnosis when value PCT is below the level of 0.5 mg/l or over the level of 2.0 mg/l [30 ]. One recent study in cancer patients showed that PCT was able to differentiate tumor-and infection-induced fever [33]. Thus, the PCT is not only a more sensitive biomarker, but also a more specific marker (with high-negative predictive value for infection) compared with CRP and ESR [31]. &&
&&
Procalcitonin and infection PCT synthesis and secretion are induced by microbial toxins specifically, proinflammatory cytokines like interleukin-1b, tumor necrosis factor-a, and interleukin-6 are produced [30 ]. In healthy people, serum PCT concentrations are found to be below 0.05 mg/l. A PCT concentration over 0.5 mg/l is interpreted as an abnormal value suggestive of bacterial infection. PCT values in the range of 0.5–2 mg/l represent a ‘gray’ zone with uncertainty when the diagnosis of sepsis is concerned. PCT level above 2 mg/l is highly specific for severe sepsis [31]. Traditionally, diagnosis of sepsis is made by the isolation of an offending organism in blood culture. However, detection rate of microorganism has been reported to be as low as 20–30% in literature [30 ]. Furthermore, the required time for positive culture results can be as long as 7 days and most of the positive cases require more than one sample, and it comes with the risk of significant rate of false-positive results [30 ]. Waiting for the result of blood cultures is impractical and may potentially increase mortality rate of infection-related complication in cancer patients. What we need is to differentiate severe sepsis from cancer-induced clinical systemic complications at an early stage. However, signs and symptoms of severe infection may be similar to cancer-induced inflammatory response &&
Procalcitonin and cancer A ‘smoldering’ inflammatory environment is found at different rates in distinct type of tumors. Cancer itself stimulates and modulates this environment by the secretion of soluble factors and chemokines, and interaction between cancer and immune system is usually associated with the elevation of inflammatory markers such as CRP, ESR, and leukocyte count [34,35,36 ]. Remarkably, studies showed that tumor-induced inflammation does not alter PCT levels [37,38]. As a result, PCT is a promising biomarker for evaluating severity of infection and making a precise decision about spectrum of antibiotics. &&
&&
&&
DISCUSSION PCT-guided algorithms for antibiotic therapy decisions were developed mostly for respiratory tract infections, including pneumonia, bronchitis, and related sepsis and in a systematic review of 14 randomized controlled trials (4467 patients), Schuetz et al. [40] showed that using PCT in clinical practice was effective in reducing misuse of antibiotics without sacrificing patient safety [39,40]. Most of these studies draw benefit not from the high sensitivity of PCT but from the high specificity
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of PCT. Indeed, in high-risk patient PCT levels were not used to determine whether antibiotic therapy should be initiated but when to discontinue it [40]. Decreasing the level of PCT during clinical course shows a strong correlation with resolution of bacteremia, so we could well tolerate discontinuation of antibiotic treatment and in low-risk patient PCT values can be used to decide whether starting antibiotic treatment could be omitted totally [40]. These algorithms also decrease emergence of multidrugresistant pathogens. These antibiotic-resistant infections increase hospital length of stay, mortality, and hospital costs [41]. A meta-analysis published in 2011 with eight studies (3431 patients) showed a significant reduction in antibiotic prescription in the PCTguided antibiotic treatment groups [42]. However, one should keep in mind that all patients should be carefully and frequently reassessed to ensure that their clinical condition improves spontaneously in a clinically appropriate time. Therefore, PCT is a sensitive and specific biomarker for bacterial sepsis, and the level of PCT increase is correlated with the severity of the infection and not affected from primary malignancy as CRP, ESR did [43,44]. Using PCT levels as a prognostic biomarker has been shown to reduce the duration of hospital stay in pediatric and ICU patients [45,46]. Higher PCT levels have been associated with increased mortality rates and correlated with severity scores (APACHE, SOFA, and SAPS) [47 ]. A study that presented MASCC 2014 symposium showed that single value PCT is found to be significantly related with in-patient mortality for cancer patients. Although statistical analysis failed to show significant relation between mortality, serum and CRP, LDH, sedimentation albumin, serum calcium levels, and positive culture results. There was no relation between PCT and the aforementioned inflammatory markers [48]. Other clinical studies also failed to show significant relation between classical inflammatory biomarkers and even culture positivity with infection-related mortality. In cancer patients, cancer induced increases in inflammatory biomarkers in blood and in cancer-related factors, that severely disturb patients’ general condition, make it even harder to answer these questions. Who truly benefits from antibiotic therapy? If treated, what is the optimal treatment duration? There is no single proven clinical or laboratory prognostic biomarker for infection-related mortality. Thus, managing these patients remains a continual challenge for oncologists. It is remains difficult to determine with clinical data and current classic inflammatory biomarkers which of the patients who present with signs and symptoms of sepsis on initial evaluation will actually go on to develop a severe septic illness &&
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resulting in organ dysfunction and/or mortality [49,50]. Several potential bloodstream biomarkers have been investigated for their ability to diagnose sepsis, estimate its severity, and provide a prognosis. Although PCT is well known, other promising biomarkers appear to be on the horizon including the soluble triggering receptor expressed on myeloid cells-1, soluble urokinase-type plasminogen receptor, proadrenomedullin, and presepsin [51 ]. Certain new biomarkers including PCT have recently been investigated in severe infection. In this article, we provide a review of the recent advancements regarding the usage PCT in infectious complications of cancer patients. It is envisioned that the usage of PCT may be implanted within the routine clinical practice in the near future, reducing the hospitalization duration and maintaining the antibiotic effectiveness. &
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest The authors declare that they have full control of all primary data and we agree to allow the journal to review our data if requested by the journal editorial system, and we also state that we did not enter any financial relationship with any organization or company.
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