Resuscitation of critically ill patients in shock from cardiogenic, hypovolemic, obstructive, distributive, or neurogenic etiology is a cornerstone of the care delivered by emergency physicians (EPs).¹ Regardless of the etiology, it is essential that the treating EP initiate resuscitative measures in a timely manner and closely trend the patient’s response to these interventions.

The early goal-directed therapy (EGDT) initially proposed by Rivers et al² in 2001 demonstrated a bundled approach to fluid resuscitation by targeting end points for volume resuscitation, mean arterial blood pressure (MAP), oxygen (O₂) delivery/extraction (mixed venous O₂ saturation, [S_vO₂]), hemoglobin (Hgb) concentration, and cardiac contractility. Since then, advancements in laboratory testing and hemodynamic monitoring (HDM) devices further aid and guide resuscitative efforts, and are applicable to any etiology of shock.

In addition to these advancements, the growing evidence of the potential harm from improper fluid resuscitation, such as the administration of excessive intravascular fluid (IVF),³ underscores the importance of a precise, targeted, and individualized approach to care. This article reviews the background, benefits, and limitations of some of the common and readily available tools in the ED that the EP can employ to guide fluid resuscitation in critically ill patients.

Physical Examination

Background

The rapid recognition and treatment of septic shock in the ED is associated with lower rates of in-hospital morbidity and mortality.⁴ The physical examination by the EP begins immediately upon examining the patient. The acquisition of vital signs and recognition of physical examination findings suggestive of intravascular volume depletion allows the EP to initiate treatment immediately.

In this discussion, hypotension is defined as systolic blood pressure (SBP) of less than 95 mm Hg, MAP of less than 65 mm Hg, or a decrease in SBP of more than 40 mm Hg from baseline measurements. Subsequently, shock is defined as hypotension with evidence of tissue hypoperfusion-induced dysfunction.^5,6 Although the use of findings from the physical examination to guide resuscitation allows for rapid patient assessment and treatment, the predictive value of the physical examination to assess hemodynamic status is limited.

Benefits

The major benefit of the physical examination as a tool to evaluate hemodynamic status is its ease and rapid acquisition. The patient’s vital signs and physical examination can be obtained in the matter of moments upon presentation, without the need to wait on results of laboratory evaluation or additional equipment. Additionally, serial examinations by the same physician can be helpful to monitor a patient’s response to resuscitative efforts. The negative predictive value (NPV) of the physical examination in evaluating for hypovolemia may be helpful, but only when it is taken in the appropriate clinical context and is used in conjunction with other diagnostic tools. The physical examination can exclude hypovolemic volume status with an NPV of approximately 70%.⁷

A constellation of findings from the physical examination may include altered mentation, hypotension, tachycardia, and decreased urinary output by 30% to 40% intravascular volume loss.^8,9Findings from the physical examination to assess fluid status should be used with caution as interobserver reliability has proven to be poor and the prognostic value is limited.

Limitations

The literature shows the limited prognostic value of the physical examination in determining a patient’s volume status and whether fluid resuscitation is indicated. For example, in one meta-analysis,¹⁰ supine hypotension and tachycardia were frequently absent on examination—even in patients who underwent large volume phlebotomy.⁸ This study also showed postural dizziness to be of no prognostic value.

Another study by Saugel et al⁷ that compared the physical examination (skin assessment, lung auscultation, and percussion) to transpulmonary thermodilution measurements of the cardiac index, global end-diastolic volume index, and extravascular lung water index, found poor interobserver correlation and agreement among physicians.

The physical examination is also associated with weak predictive capabilities for the estimation of volume status compared to the device measurements. Another contemporary study by Saugel et al⁹ evaluated the predictive value of the physical examination to accurately identify volume responsiveness replicated these results, and reported poor interobserver correlation (κ coefficient 0.01; 95% caval index [CI] -0.39-0.42) among physical examination findings, with a sensitivity of only 71%, specificity of 23.5%, positive predictive value of 27.8%, and negative predictive value of 66.7%.⁹

Serum Lactate Levels

Background

In the 1843 book titled, Investigations of Pathological Substances Obtained During the Epidemic of Puerperal Fever, Johann Joseph Scherer described the cases of seven young peripartum female patients who died from a clinical picture of what is now understood to be septic shock.¹¹ In his study of these cases, Scherer demonstrated the presence of lactic acid in patients with pathological conditions. Prior to this discovery, lactic acid had never been isolated in a healthy individual. These results were recreated in 1851 by Scherer and Virchow,¹¹ who demonstrated the presence of lactic acid in the blood of a patient who died from leukemia. The inference based on Scherer and Virchow’s work correlated the presence of excessive lactic acid with bodily deterioration and severe disease. Since this finding, there has been a great deal of interest in measuring serum lactic acid as a means to identify and manage critical illness.

In a 2001 groundbreaking study of EGDT for severe sepsis and septic shock, Rivers et al² studied lactic acid levels as a marker for severe disease. Likewise, years later, the 2014 Protocol-Based Care for Early Septic Shock (PROCESS), Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials used lactate levels in a similar manner to identify patients appropriate for randomization.^12-14 While the purpose of measuring lactic acid was only employed in these studies to identify patients at risk for critical illness, the 2012 Surviving Sepsis Campaign Guidelines recommended serial measurement of lactate, based on the assumption that improved lactate levels signified better tissue perfusion.¹⁵

Although much of the studies on lactate levels appear to be based on the treatment and management of septic patients, findings can be applied to any etiology of shock. For example, a serum lactate level greater than 2 mmol/L is considered abnormal, and a serum lactate greater than 4 mmol/L indicates a significantly increased risk for in-hospital mortality.¹⁶

Benefits

It is now a widely accepted belief that the rapid identification, triage, and treatment of critically ill patients has a dramatic effect on morbidity and mortality.⁴ As previously noted, lactate has been extensively studied and identified as a marker of severe illness.^17,18 A serum lactate level, which can be rapidly processed in the ED, can be easily obtained from a minimally invasive venous, arterial, or capillary blood draw.¹⁸ The only risk associated with serum lactate testing is that of any routine venipuncture; the test causes minimal, if any, patient discomfort.

Thanks to advances in point-of-care (POC) technology, the result of serum lactate assessment can be available within 10 minutes from blood draw. This technology is inexpensive and can be easily deployed in the prehospital setting or during the initial triage assessment of patients arriving at the ED.¹⁹ These POC instruments have been well correlated with whole blood measurements and permit for the rapid identification and treatment of at risk patients.

Limitations

The presence of elevated serum lactate levels is believed to represent the presence of cellular anaerobic metabolism due to impaired O₂ delivery in the shock state. Abnormal measurements therefore prompt aggressive interventions aimed at maximizing O₂ delivery to the tissues, such as intravenous fluid boluses, vasopressor therapy, or even blood product administration.

A return to a normalized serum lactate level is assumed to represent a transition back to aerobic metabolism. Lactate elevations, however, are not solely an indication of anaerobic metabolism and may only represent a small degree of lactate production.²⁰ While the specific cellular mechanics are out of the scope of this article, it has been postulated that the increase in plasma lactate concentration is primarily driven by β-2 receptor stimulation from increased circulating catecholamines leading to increased aerobic glycolysis. Increased lactate levels could therefore be an adaptive mechanism of energy production—aggressive treatment and rapid clearance may, in fact, be harmful. Type A lactic acidosis is categorized as elevated serum levels due to tissue hypoperfusion.²¹

However, lactate elevations do not exclusively occur in severe illness. The use of β-2 receptor agonists such as continuous albuterol treatments or epinephrine may cause abnormal lactate levels.²² Other medications have also been associated with elevated serum lactate levels, including, but not limited to linezolid, metformin, and propofol.^23-25 Additionally, lactate levels may be elevated after strenuous exercise, seizure activity, or in liver and kidney disease.²⁶ These “secondary” causes of lactic acidosis that are not due to tissue hypoperfusion are referred to as type B lactic acidosis. Given these multiple etiologies and lack of specificity for this serum measurement, a failure to understand these limitations may result in over aggressive or unnecessary medical treatments.

Central Venous Pressure

Background

Central venous pressure (CVP) measurements can be obtained through a catheter, the distal tip of which transduces pressure of the superior vena cava at the entrance of the right atrium (RA). Thus, CVP is often used as a representation of RA pressure (RAP) and therefore an estimate of right ventricular (RV) preload. While CVP is used to diagnose and determine the etiology of shock, evidence and controversy regarding the use of CVP as a marker for resuscitation comes largely from sepsis-focused literature.⁵ Central venous pressure is meant to represent preload, which is essential for stroke volume as described by the Frank-Starling mechanism; however, its use as a target in distributive shock, a state in which it is difficult to determine a patient’s volume status, has been popularized by EGDT since 2001.²

Since the publication of the 2004 Surviving Sepsis Guidelines, CVP monitoring has been in the spotlight of sepsis resuscitation, albeit with some controversy.²⁷ Included as the result of two studies, this recommendation has been removed in the most recent guidelines after 12 years of further study and scrutiny.^2,27,28

Hypovolemic and hemorrhagic shock are usually diagnosed clinically and while a low CVP can be helpful in the diagnosis, the guidelines do not support CVP as a resuscitation endpoint. Obstructive and cardiogenic shock will both result in elevated CVP; however, treatment of obstructive shock is generally targeted at the underlying cause. While cardiogenic shock can be preload responsive, the mainstay of therapy in the ED is identification of patients for revascularization and inotropic support.²⁹

Benefits

The CVP has been used as a surrogate for RV preload volume. If a patient’s preload volume is low, the treating physician can administer fluids to improve stroke volume and cardiac output (CO). Clinically, CVP measurements are easy to obtain provided a central venous line has been placed with the distal tip at the entrance to the RA. Central venous pressure is measured by transducing the pressure via manometry and connecting it to the patient’s bedside monitor. This provides an advantage of being able to provide serial or even continuous measurements. The “normal” RAP should be a low value (1-5 mm Hg, mean of 3 mm Hg), as this aids in the pressure gradient to drive blood from the higher pressures of the left ventricle (LV) and aorta through the circulation back to the low-pressure of the RA.³⁰ The value of the CVP is meant to correspond to the physical examination findings of jugular venous distension.^31,32 Thus, a low CVP may be “normal” and seen in patients with hypovolemic shock, whereas an elevated CVP can suggest volume overload or obstructive shock. However, this is of questionable value in distributive shock cases.

Aside from the two early studies on CVP monitoring during treatment of septic patients, there are few data to support the use of CVP measurement in the early resuscitation of patients with shock.^2,28 More recent trials (PROMISE, ARISE, PROCESS) that compared protocolized sepsis care to standard care showed no benefit to bundles including CVP measurements.^12-14 However, a subsequent, large observational trial spanning 7.5 years demonstrated improvements in sepsis-related mortality in patients who received a central venous catheter (CVC) and CVP-targeted therapy.³³ Thus, it is possible that protocols including CVP are still beneficial in combination with other therapies even though CVP in isolation is not.

Limitations

The traditional two assumptions in CVP monitoring are CVP value represents the overall volume status of the patient, and the LV is able to utilize additional preload volume. The latter assumption, however, may be hampered by the presence of sepsis-induced myocardial dysfunction, which may be present in up to 40% of critically ill patients.³⁴ The former assumption does not always hold true due to processes that change filling pressures independent of intravascular volume—eg, acute or chronic pulmonary hypertension, cardiac tamponade, intra-abdominal hypertension, or LV failure. Even before the landmark EGDT study, available data suggested that CVP was not a reliable marker for resuscitation management.³⁵ A recent systematic review by Gottlieb and Hunter³⁶ showed that the area under the receiver-operator curve for low, mid-range, or high CVPs was equivocal at best. In addition to its unreliability and lack of specificity, another significant drawback to using CVP to guide resuscitation therapy in the ED is that it necessitates placement of a CVC, which can be time-consuming and, if not otherwise indicated, lead to complications of infection, pneumothorax, and/or thrombosis.³⁷

Mixed Venous Oxygen

Background

Most EPs are familiar with the use of S_cvO₂ in EGDT protocols to guide volume resuscitation of septic patients.² A patient’s S_cvO₂ represents the O₂ saturation of venous blood obtained via a CVC at the confluence of the superior vena cava and the RA, and thus it reflects tissue O₂ consumption as a surrogate for tissue perfusion. The measurement parallels the S_vO₂ obtained from the pulmonary artery. In a healthy patient, S_vO₂ is around 65% to 70% and includes blood returning from both the superior and inferior vena cava (IVC). As such, S_cvO₂ values are typically 3% to 5% lower than S_vO₂ owing to the lower O₂ extracted by tissues draining into the IVC compared to the mixed venous blood sampled from the pulmonary artery.³⁸

Though a debate over the benefit of EGDT in treating sepsis continues, understanding the physiology of S_cvO₂ measurements is another potential tool the EP can use to guide the resuscitation of critically ill patients.³⁹ A patient’s S_vO₂ and, by extension, S_cvO₂ represents the residual O₂ saturation after the tissues have extracted the amount of O₂ necessary to meet metabolic demands (Figure 2).

Benefits

A critically ill patient’s S_cvO₂ can potentially provide EPs with insight into the patient’s global tissue perfusion and the source of any mismatch between O₂ delivery and consumption. Using additional tools and measurements (physical examination, serum Hgb levels, and pulse oximetry) in conjunction with an S_cvO₂ measurement, assists EPs in identifying targets for therapeutic intervention. The effectiveness of this intervention can then be assessed using serial S_cvO₂ measurements, as described in Rivers et al² EGDT protocol. Importantly, EPs should take care to measure serial S_cvO₂ values to maximize its utility.³⁸ Similar to a CVP measurement, S_cvO₂is easily obtained from blood samples for serial laboratory measurements, assuming the patient already has a CVC with the distal tip at the entrance to the RA (S_cvO₂) or a pulmonary artery catheter (PAC) (S_vO₂).

Limitations

Serial measurements provide the most reliable information, which may be more useful in patients who spend extended periods of their resuscitation in the ED. In comparison to other measures of global tissue hypoxia, work by Jones et al⁴¹ suggests non-inferiority of peripherally sampled, serial lactate measurements as an alternative to S_cvO₂. This, in conjunction with the requirement for an internal jugular CVC, subclavian CVC, or PAC with their associated risks, may make S_cvO₂ a less attractive guide for the resuscitation of critically ill patients in the ED.

Monitoring Devices

Background

As noted throughout this review, it is important not only to identify and rapidly treat shock, but to also correctly identify the type of shock, such that treatment can be appropriately directed at its underlying cause. However, prior work suggests that EPs are unable to grossly estimate CO or systemic vascular resistance when compared to objective measurements of these parameters.⁴² This is in agreement with the overall poor performance of physical examination and clinical evaluation as a means of predicting volume responsiveness or guiding resuscitation, as discussed previously. Fortunately, a wide variety of devices to objectively monitor hemodynamics are now available to the EP.

In 1970, Swan et al⁴³ published their initial experience with pulmonary artery catheterization at the bedside, using a balloon-tipped, flow-guided PAC in lieu of fluoroscopy, which had been mandated by earlier techniques. The ability to measure CO, right heart pressures, pulmonary arterial pressures, and estimate LV end diastolic pressure ushered in an era of widespread PAC use, despite an absence of evidence for causation of improved patient outcomes. The utilization of PACs has fallen, as the literature suggests that the empiric placement of PACs in critically ill patients does not improve mortality, length of stay, or cost, and significant complication rates have been reported in large trials.^44,45Subsequently, a number of non-invasive or less-invasive HDM devices have been developed. Amongst the more commonly encountered modern devices, the techniques utilized for providing hemodynamic assessments include thermodilution and pulse contour analysis (PiCCO^TM), pulse contour analysis (FloTrac/Vigileo^TM), and lithium chemodilution with pulse power analysis (LiDCOplus^TM).⁴⁶ The primary utility of these devices for the EP lies in the ability to quantify CO, stroke volume, and stroke volume or pulse pressure variation (PPV) to predict or assess response to resuscitative interventions (volume administration, vasopressors, inotropes, etc).

Benefits

Many of these devices require placement of an arterial catheter. Some require the addition of a CVC. Both of these procedures are well within the clinical scope of the EP, and are performed with fair frequency on critically ill patients. This is a distinct advantage when compared to pulmonary artery catheterization, a higher risk procedure that is rarely performed outside of the intensive care unit or cardiac catheterization laboratory. In addition, all of the devices below present hemodynamic data in a graphical, easy-to-read format, in real time. All of the devices discussed report stroke volume variation (SVV) or PPV continuously.

Limitations

Though these measures have validated threshold values that predict volume responsiveness, they require the patient to be intubated with a set tidal volume of greater than or equal to 8 mL/kg without spontaneous respirations and cardiac arrhythmias, in order to accurately do so. All of the HDM devices that rely on pulse contour analysis as the primary means of CO measurement cannot be used in the presence of significant cardiac arrhythmias (ie, atrial fibrillation), or mechanical circulatory assistance devices (ie, intra-aortic balloon counterpulsation). None of these devices are capable of monitoring microcirculatory changes, felt to be of increasing clinical importance in the critically ill.

The use of HDM devices to monitor CO with a reasonable degree of accuracy, trend CO, and assess for volume responsiveness using a number of previously validated parameters such as SVV is now in little doubt. However, these devices are still invasive, if less so than a pulmonary artery. The crux of the discussion of HDM devices for use in ED resuscitation revolves around whether or not the use of such devices to drive previously validated, protocolized care results in better outcomes for patients. The EP can now have continuous knowledge of a large number of hemodynamic parameters at their fingertips with relatively minimal additional efforts. At the time of this writing, though, this is both untested and unproven, with respect to the ED population.

Point-of-Care Ultrasound

Background

Over the past two decades, ultrasound (US) has become an integral part of the practice of emergency medicine (EM), and is now included in all United States Accreditation Council for Graduate Medical Education Emergency Medicine Residency Programs.^47,48 It has emerged as a very important bedside tool performed by the clinician to identify type of shock and guide resuscitation, and has been endorsed by both EM and critical care societies.^49-51 This section reviews the utility of US as a modality in identifying shock and guiding resuscitation, in addition to the pitfalls and limitations of this important tool.

In 2010, Perera et al⁴⁷ described in their landmark article the Rapid Ultrasound in SHock (RUSH) examination, which describes a stepwise (the pump, tank, pipes) approach to identify the type of shock (cardiogenic, hypovolemic, obstructive, or distributive) in the crashing, hypotensive ED patient. We do not describe the full RUSH examination in this review, but discuss key elements of it as examples of how POCUS can assist the EP to make a rapid diagnosis and aid in the management of patients in shock. The “pump” is the heart, which is assessed in four different views to identify a pericardial effusion and possible tamponade, assess contractility or ejection fraction of the LV (severely decreased, decreased, normal, or hyperdynamic), and right heart strain which is identified by an RV that is larger than the LV, indicative of a potential pulmonary embolus.

The “tank” is then assessed by visualizing the IVC in the subxiphoid plane, and is evaluated for respiratory collapsibility (CI) and maximum size. This has been quite the debated topic over the last two decades. In 1988, Simonson and Schiller⁵² were the first to describe a correlation in spontaneously breathing patients between IVC caliber (measured 2 cm from the cavoatrial junction) and variation and RAP, where a larger IVC diameter and less respiratory variation correlated with a high RAP. Kircher et al⁵³ later went on to describe that a CI greater than 50% correlated with an RAP of less than 10 mm Hg and vice versa in spontaneously breathing patients. Since then there have been more studies attempting to verify these findings in both spontaneously breathing and mechanically ventilated patients.^54-56 The purpose of performing these measurements is not to estimate CVP, but to assess fluid responsiveness (ie, a blood pressure response to a fluid challenge). It can be assumed in states of shock that a small IVC, or one with a high CI, in the presence of a hyperdynamic heart is indicative of an underfilled ventricle and fluid responsiveness, especially if the IVC size increases with fluid.^55,57 However, there are several caveats to this. First, in mechanically ventilated patients, the IVC is already plethoric due to positive pressure ventilation, and increases in diameter with inspiration and decreases with expiration as compared to spontaneously breathing patients. Second, the CI value to predict volume responsiveness in ventilated patients is set at 15% instead of 50%.⁵⁵ Third, it is important to always take the clinical scenario in context; a dilated IVC with small CI is not necessarily only due to volume overload and congestive heart failure, but can be due to elevated RAP from obstructive shock due to cardiac tamponade or massive pulmonary embolus, which is why it is important to assess the “pump” first.^47,58 It is also crucial to not forget to assess the abdominal and thoracic cavities, as intraperitoneal or pleural fluid with a collapsed IVC can potentially make a diagnosis of hemorrhagic or hypovolemic shock depending on the clinical scenario.⁴⁷ The final part of the RUSH protocol is to evaluate the “pipes,” inclusive of the lower extremity deep venous system for evaluation of potential thrombosis that could increase suspicion for a pulmonary embolism causing obstructive shock, and the aorta with the common iliac arteries if there is concern for aortic dissection or aneurysmal rupture.

Benefits

Some of the most significant advantages to the use of POCUS to guide resuscitation is that it is quick, non-invasive, does not use ionizing radiation, and can be easily repeated. As noted above, it is a requirement for EM residencies to teach its use, so that contemporary graduates are entering the specialty competent in applying it to the care of their patients. Furthermore, POCUS is done at the bedside, limiting the need to potentially transport unstable patients.

In the most basic applications, POCUS provides direct visualization of a patient’s cardiac function, presence or absence of lung sliding to suggest a pneumothorax, presence of pulmonary edema, assessment of CVP pressures or potential for fluid responsiveness, as well as identification of potential thoracic, peritoneal, or pelvic cavity fluid accumulation that may suggest hemorrhage. There is literature to support that these assessments performed by the EP have been shown to be comparable to those of cardiologists.^59,60 With continued practice and additional training, it is possible for EPs to even perform more “advanced” hemodynamic assessments to both diagnose and guide therapy to patients in shock (Figures 3 and 4).⁶¹

Limitations

Although POCUS has been shown as a remarkable tool to help assist the EP in making rapid decisions regarding resuscitation, it is always important to remember its limitations. Most of the studies regarding its use are of very small sample sizes, and further prospective studies have to be performed in order for this modality to be fully relied on.⁶²Compared to some of the previously mentioned HDM devices that may provide continuous data, POCUS needs to be performed by the treating physician, thereby occurring intermittently. Emergency physicians need to be aware of their own experience and limitations with this modality, as errors in misdiagnosis can lead to unnecessary procedures, with resulting significant morbidity and mortality. Blanco and Volpicelli⁶³ describe several common errors that include misdiagnosing the stomach as a peritoneal effusion, assuming adequate volume resuscitation when the IVC is seen to be plethoric in the setting of cardiac tamponade, or mistaking IVC movement as indicative of collapsibility, amongst other described misinterpretations. Several other studies have shown that, despite adequate performance of EPs in POCUS, diagnostic sensitivities remained higher when performed by radiologists.^64-67 Thus it remains important for the EPs to be vigilant and not anchor on a diagnosis when in doubt, and to consult early with radiology, particularly if there is any question, to avoid potential adverse patient outcomes.

Summary

There are several ways to diagnose and track resuscitation in the ED, which include physical examination, assessment of serum laboratory values, monitoring of hemodynamic status, and use of POCUS. Unfortunately, none of these methods provides a perfect assessment, and no method has been proven superior and effective over the others. Therefore, it is important for EPs treating patients in shock to be aware of the strengths and limitations of each assessment method (Table).

Resuscitation of critically ill patients in shock from cardiogenic, hypovolemic, obstructive, distributive, or neurogenic etiology is a cornerstone of the care delivered by emergency physicians (EPs).¹ Regardless of the etiology, it is essential that the treating EP initiate resuscitative measures in a timely manner and closely trend the patient’s response to these interventions.

The early goal-directed therapy (EGDT) initially proposed by Rivers et al² in 2001 demonstrated a bundled approach to fluid resuscitation by targeting end points for volume resuscitation, mean arterial blood pressure (MAP), oxygen (O₂) delivery/extraction (mixed venous O₂ saturation, [S_vO₂]), hemoglobin (Hgb) concentration, and cardiac contractility. Since then, advancements in laboratory testing and hemodynamic monitoring (HDM) devices further aid and guide resuscitative efforts, and are applicable to any etiology of shock.

In addition to these advancements, the growing evidence of the potential harm from improper fluid resuscitation, such as the administration of excessive intravascular fluid (IVF),³ underscores the importance of a precise, targeted, and individualized approach to care. This article reviews the background, benefits, and limitations of some of the common and readily available tools in the ED that the EP can employ to guide fluid resuscitation in critically ill patients.

Physical Examination

Background

The rapid recognition and treatment of septic shock in the ED is associated with lower rates of in-hospital morbidity and mortality.⁴ The physical examination by the EP begins immediately upon examining the patient. The acquisition of vital signs and recognition of physical examination findings suggestive of intravascular volume depletion allows the EP to initiate treatment immediately.

In this discussion, hypotension is defined as systolic blood pressure (SBP) of less than 95 mm Hg, MAP of less than 65 mm Hg, or a decrease in SBP of more than 40 mm Hg from baseline measurements. Subsequently, shock is defined as hypotension with evidence of tissue hypoperfusion-induced dysfunction.^5,6 Although the use of findings from the physical examination to guide resuscitation allows for rapid patient assessment and treatment, the predictive value of the physical examination to assess hemodynamic status is limited.

Benefits

The major benefit of the physical examination as a tool to evaluate hemodynamic status is its ease and rapid acquisition. The patient’s vital signs and physical examination can be obtained in the matter of moments upon presentation, without the need to wait on results of laboratory evaluation or additional equipment. Additionally, serial examinations by the same physician can be helpful to monitor a patient’s response to resuscitative efforts. The negative predictive value (NPV) of the physical examination in evaluating for hypovolemia may be helpful, but only when it is taken in the appropriate clinical context and is used in conjunction with other diagnostic tools. The physical examination can exclude hypovolemic volume status with an NPV of approximately 70%.⁷

A constellation of findings from the physical examination may include altered mentation, hypotension, tachycardia, and decreased urinary output by 30% to 40% intravascular volume loss.^8,9Findings from the physical examination to assess fluid status should be used with caution as interobserver reliability has proven to be poor and the prognostic value is limited.

Limitations

The literature shows the limited prognostic value of the physical examination in determining a patient’s volume status and whether fluid resuscitation is indicated. For example, in one meta-analysis,¹⁰ supine hypotension and tachycardia were frequently absent on examination—even in patients who underwent large volume phlebotomy.⁸ This study also showed postural dizziness to be of no prognostic value.

Another study by Saugel et al⁷ that compared the physical examination (skin assessment, lung auscultation, and percussion) to transpulmonary thermodilution measurements of the cardiac index, global end-diastolic volume index, and extravascular lung water index, found poor interobserver correlation and agreement among physicians.

The physical examination is also associated with weak predictive capabilities for the estimation of volume status compared to the device measurements. Another contemporary study by Saugel et al⁹ evaluated the predictive value of the physical examination to accurately identify volume responsiveness replicated these results, and reported poor interobserver correlation (κ coefficient 0.01; 95% caval index [CI] -0.39-0.42) among physical examination findings, with a sensitivity of only 71%, specificity of 23.5%, positive predictive value of 27.8%, and negative predictive value of 66.7%.⁹

Serum Lactate Levels

Background

In the 1843 book titled, Investigations of Pathological Substances Obtained During the Epidemic of Puerperal Fever, Johann Joseph Scherer described the cases of seven young peripartum female patients who died from a clinical picture of what is now understood to be septic shock.¹¹ In his study of these cases, Scherer demonstrated the presence of lactic acid in patients with pathological conditions. Prior to this discovery, lactic acid had never been isolated in a healthy individual. These results were recreated in 1851 by Scherer and Virchow,¹¹ who demonstrated the presence of lactic acid in the blood of a patient who died from leukemia. The inference based on Scherer and Virchow’s work correlated the presence of excessive lactic acid with bodily deterioration and severe disease. Since this finding, there has been a great deal of interest in measuring serum lactic acid as a means to identify and manage critical illness.

In a 2001 groundbreaking study of EGDT for severe sepsis and septic shock, Rivers et al² studied lactic acid levels as a marker for severe disease. Likewise, years later, the 2014 Protocol-Based Care for Early Septic Shock (PROCESS), Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials used lactate levels in a similar manner to identify patients appropriate for randomization.^12-14 While the purpose of measuring lactic acid was only employed in these studies to identify patients at risk for critical illness, the 2012 Surviving Sepsis Campaign Guidelines recommended serial measurement of lactate, based on the assumption that improved lactate levels signified better tissue perfusion.¹⁵

Although much of the studies on lactate levels appear to be based on the treatment and management of septic patients, findings can be applied to any etiology of shock. For example, a serum lactate level greater than 2 mmol/L is considered abnormal, and a serum lactate greater than 4 mmol/L indicates a significantly increased risk for in-hospital mortality.¹⁶

Benefits

It is now a widely accepted belief that the rapid identification, triage, and treatment of critically ill patients has a dramatic effect on morbidity and mortality.⁴ As previously noted, lactate has been extensively studied and identified as a marker of severe illness.^17,18 A serum lactate level, which can be rapidly processed in the ED, can be easily obtained from a minimally invasive venous, arterial, or capillary blood draw.¹⁸ The only risk associated with serum lactate testing is that of any routine venipuncture; the test causes minimal, if any, patient discomfort.

Thanks to advances in point-of-care (POC) technology, the result of serum lactate assessment can be available within 10 minutes from blood draw. This technology is inexpensive and can be easily deployed in the prehospital setting or during the initial triage assessment of patients arriving at the ED.¹⁹ These POC instruments have been well correlated with whole blood measurements and permit for the rapid identification and treatment of at risk patients.

Limitations

The presence of elevated serum lactate levels is believed to represent the presence of cellular anaerobic metabolism due to impaired O₂ delivery in the shock state. Abnormal measurements therefore prompt aggressive interventions aimed at maximizing O₂ delivery to the tissues, such as intravenous fluid boluses, vasopressor therapy, or even blood product administration.

A return to a normalized serum lactate level is assumed to represent a transition back to aerobic metabolism. Lactate elevations, however, are not solely an indication of anaerobic metabolism and may only represent a small degree of lactate production.²⁰ While the specific cellular mechanics are out of the scope of this article, it has been postulated that the increase in plasma lactate concentration is primarily driven by β-2 receptor stimulation from increased circulating catecholamines leading to increased aerobic glycolysis. Increased lactate levels could therefore be an adaptive mechanism of energy production—aggressive treatment and rapid clearance may, in fact, be harmful. Type A lactic acidosis is categorized as elevated serum levels due to tissue hypoperfusion.²¹

However, lactate elevations do not exclusively occur in severe illness. The use of β-2 receptor agonists such as continuous albuterol treatments or epinephrine may cause abnormal lactate levels.²² Other medications have also been associated with elevated serum lactate levels, including, but not limited to linezolid, metformin, and propofol.^23-25 Additionally, lactate levels may be elevated after strenuous exercise, seizure activity, or in liver and kidney disease.²⁶ These “secondary” causes of lactic acidosis that are not due to tissue hypoperfusion are referred to as type B lactic acidosis. Given these multiple etiologies and lack of specificity for this serum measurement, a failure to understand these limitations may result in over aggressive or unnecessary medical treatments.

Central Venous Pressure

Background

Central venous pressure (CVP) measurements can be obtained through a catheter, the distal tip of which transduces pressure of the superior vena cava at the entrance of the right atrium (RA). Thus, CVP is often used as a representation of RA pressure (RAP) and therefore an estimate of right ventricular (RV) preload. While CVP is used to diagnose and determine the etiology of shock, evidence and controversy regarding the use of CVP as a marker for resuscitation comes largely from sepsis-focused literature.⁵ Central venous pressure is meant to represent preload, which is essential for stroke volume as described by the Frank-Starling mechanism; however, its use as a target in distributive shock, a state in which it is difficult to determine a patient’s volume status, has been popularized by EGDT since 2001.²

Since the publication of the 2004 Surviving Sepsis Guidelines, CVP monitoring has been in the spotlight of sepsis resuscitation, albeit with some controversy.²⁷ Included as the result of two studies, this recommendation has been removed in the most recent guidelines after 12 years of further study and scrutiny.^2,27,28

Hypovolemic and hemorrhagic shock are usually diagnosed clinically and while a low CVP can be helpful in the diagnosis, the guidelines do not support CVP as a resuscitation endpoint. Obstructive and cardiogenic shock will both result in elevated CVP; however, treatment of obstructive shock is generally targeted at the underlying cause. While cardiogenic shock can be preload responsive, the mainstay of therapy in the ED is identification of patients for revascularization and inotropic support.²⁹

Benefits

The CVP has been used as a surrogate for RV preload volume. If a patient’s preload volume is low, the treating physician can administer fluids to improve stroke volume and cardiac output (CO). Clinically, CVP measurements are easy to obtain provided a central venous line has been placed with the distal tip at the entrance to the RA. Central venous pressure is measured by transducing the pressure via manometry and connecting it to the patient’s bedside monitor. This provides an advantage of being able to provide serial or even continuous measurements. The “normal” RAP should be a low value (1-5 mm Hg, mean of 3 mm Hg), as this aids in the pressure gradient to drive blood from the higher pressures of the left ventricle (LV) and aorta through the circulation back to the low-pressure of the RA.³⁰ The value of the CVP is meant to correspond to the physical examination findings of jugular venous distension.^31,32 Thus, a low CVP may be “normal” and seen in patients with hypovolemic shock, whereas an elevated CVP can suggest volume overload or obstructive shock. However, this is of questionable value in distributive shock cases.

Aside from the two early studies on CVP monitoring during treatment of septic patients, there are few data to support the use of CVP measurement in the early resuscitation of patients with shock.^2,28 More recent trials (PROMISE, ARISE, PROCESS) that compared protocolized sepsis care to standard care showed no benefit to bundles including CVP measurements.^12-14 However, a subsequent, large observational trial spanning 7.5 years demonstrated improvements in sepsis-related mortality in patients who received a central venous catheter (CVC) and CVP-targeted therapy.³³ Thus, it is possible that protocols including CVP are still beneficial in combination with other therapies even though CVP in isolation is not.

Limitations

The traditional two assumptions in CVP monitoring are CVP value represents the overall volume status of the patient, and the LV is able to utilize additional preload volume. The latter assumption, however, may be hampered by the presence of sepsis-induced myocardial dysfunction, which may be present in up to 40% of critically ill patients.³⁴ The former assumption does not always hold true due to processes that change filling pressures independent of intravascular volume—eg, acute or chronic pulmonary hypertension, cardiac tamponade, intra-abdominal hypertension, or LV failure. Even before the landmark EGDT study, available data suggested that CVP was not a reliable marker for resuscitation management.³⁵ A recent systematic review by Gottlieb and Hunter³⁶ showed that the area under the receiver-operator curve for low, mid-range, or high CVPs was equivocal at best. In addition to its unreliability and lack of specificity, another significant drawback to using CVP to guide resuscitation therapy in the ED is that it necessitates placement of a CVC, which can be time-consuming and, if not otherwise indicated, lead to complications of infection, pneumothorax, and/or thrombosis.³⁷

Mixed Venous Oxygen

Background

Most EPs are familiar with the use of S_cvO₂ in EGDT protocols to guide volume resuscitation of septic patients.² A patient’s S_cvO₂ represents the O₂ saturation of venous blood obtained via a CVC at the confluence of the superior vena cava and the RA, and thus it reflects tissue O₂ consumption as a surrogate for tissue perfusion. The measurement parallels the S_vO₂ obtained from the pulmonary artery. In a healthy patient, S_vO₂ is around 65% to 70% and includes blood returning from both the superior and inferior vena cava (IVC). As such, S_cvO₂ values are typically 3% to 5% lower than S_vO₂ owing to the lower O₂ extracted by tissues draining into the IVC compared to the mixed venous blood sampled from the pulmonary artery.³⁸

Though a debate over the benefit of EGDT in treating sepsis continues, understanding the physiology of S_cvO₂ measurements is another potential tool the EP can use to guide the resuscitation of critically ill patients.³⁹ A patient’s S_vO₂ and, by extension, S_cvO₂ represents the residual O₂ saturation after the tissues have extracted the amount of O₂ necessary to meet metabolic demands (Figure 2).

Benefits

A critically ill patient’s S_cvO₂ can potentially provide EPs with insight into the patient’s global tissue perfusion and the source of any mismatch between O₂ delivery and consumption. Using additional tools and measurements (physical examination, serum Hgb levels, and pulse oximetry) in conjunction with an S_cvO₂ measurement, assists EPs in identifying targets for therapeutic intervention. The effectiveness of this intervention can then be assessed using serial S_cvO₂ measurements, as described in Rivers et al² EGDT protocol. Importantly, EPs should take care to measure serial S_cvO₂ values to maximize its utility.³⁸ Similar to a CVP measurement, S_cvO₂is easily obtained from blood samples for serial laboratory measurements, assuming the patient already has a CVC with the distal tip at the entrance to the RA (S_cvO₂) or a pulmonary artery catheter (PAC) (S_vO₂).

Limitations

Serial measurements provide the most reliable information, which may be more useful in patients who spend extended periods of their resuscitation in the ED. In comparison to other measures of global tissue hypoxia, work by Jones et al⁴¹ suggests non-inferiority of peripherally sampled, serial lactate measurements as an alternative to S_cvO₂. This, in conjunction with the requirement for an internal jugular CVC, subclavian CVC, or PAC with their associated risks, may make S_cvO₂ a less attractive guide for the resuscitation of critically ill patients in the ED.

Monitoring Devices

Background

As noted throughout this review, it is important not only to identify and rapidly treat shock, but to also correctly identify the type of shock, such that treatment can be appropriately directed at its underlying cause. However, prior work suggests that EPs are unable to grossly estimate CO or systemic vascular resistance when compared to objective measurements of these parameters.⁴² This is in agreement with the overall poor performance of physical examination and clinical evaluation as a means of predicting volume responsiveness or guiding resuscitation, as discussed previously. Fortunately, a wide variety of devices to objectively monitor hemodynamics are now available to the EP.

In 1970, Swan et al⁴³ published their initial experience with pulmonary artery catheterization at the bedside, using a balloon-tipped, flow-guided PAC in lieu of fluoroscopy, which had been mandated by earlier techniques. The ability to measure CO, right heart pressures, pulmonary arterial pressures, and estimate LV end diastolic pressure ushered in an era of widespread PAC use, despite an absence of evidence for causation of improved patient outcomes. The utilization of PACs has fallen, as the literature suggests that the empiric placement of PACs in critically ill patients does not improve mortality, length of stay, or cost, and significant complication rates have been reported in large trials.^44,45Subsequently, a number of non-invasive or less-invasive HDM devices have been developed. Amongst the more commonly encountered modern devices, the techniques utilized for providing hemodynamic assessments include thermodilution and pulse contour analysis (PiCCO^TM), pulse contour analysis (FloTrac/Vigileo^TM), and lithium chemodilution with pulse power analysis (LiDCOplus^TM).⁴⁶ The primary utility of these devices for the EP lies in the ability to quantify CO, stroke volume, and stroke volume or pulse pressure variation (PPV) to predict or assess response to resuscitative interventions (volume administration, vasopressors, inotropes, etc).

Benefits

Many of these devices require placement of an arterial catheter. Some require the addition of a CVC. Both of these procedures are well within the clinical scope of the EP, and are performed with fair frequency on critically ill patients. This is a distinct advantage when compared to pulmonary artery catheterization, a higher risk procedure that is rarely performed outside of the intensive care unit or cardiac catheterization laboratory. In addition, all of the devices below present hemodynamic data in a graphical, easy-to-read format, in real time. All of the devices discussed report stroke volume variation (SVV) or PPV continuously.

Limitations

Though these measures have validated threshold values that predict volume responsiveness, they require the patient to be intubated with a set tidal volume of greater than or equal to 8 mL/kg without spontaneous respirations and cardiac arrhythmias, in order to accurately do so. All of the HDM devices that rely on pulse contour analysis as the primary means of CO measurement cannot be used in the presence of significant cardiac arrhythmias (ie, atrial fibrillation), or mechanical circulatory assistance devices (ie, intra-aortic balloon counterpulsation). None of these devices are capable of monitoring microcirculatory changes, felt to be of increasing clinical importance in the critically ill.

The use of HDM devices to monitor CO with a reasonable degree of accuracy, trend CO, and assess for volume responsiveness using a number of previously validated parameters such as SVV is now in little doubt. However, these devices are still invasive, if less so than a pulmonary artery. The crux of the discussion of HDM devices for use in ED resuscitation revolves around whether or not the use of such devices to drive previously validated, protocolized care results in better outcomes for patients. The EP can now have continuous knowledge of a large number of hemodynamic parameters at their fingertips with relatively minimal additional efforts. At the time of this writing, though, this is both untested and unproven, with respect to the ED population.

Point-of-Care Ultrasound

Background

Over the past two decades, ultrasound (US) has become an integral part of the practice of emergency medicine (EM), and is now included in all United States Accreditation Council for Graduate Medical Education Emergency Medicine Residency Programs.^47,48 It has emerged as a very important bedside tool performed by the clinician to identify type of shock and guide resuscitation, and has been endorsed by both EM and critical care societies.^49-51 This section reviews the utility of US as a modality in identifying shock and guiding resuscitation, in addition to the pitfalls and limitations of this important tool.

In 2010, Perera et al⁴⁷ described in their landmark article the Rapid Ultrasound in SHock (RUSH) examination, which describes a stepwise (the pump, tank, pipes) approach to identify the type of shock (cardiogenic, hypovolemic, obstructive, or distributive) in the crashing, hypotensive ED patient. We do not describe the full RUSH examination in this review, but discuss key elements of it as examples of how POCUS can assist the EP to make a rapid diagnosis and aid in the management of patients in shock. The “pump” is the heart, which is assessed in four different views to identify a pericardial effusion and possible tamponade, assess contractility or ejection fraction of the LV (severely decreased, decreased, normal, or hyperdynamic), and right heart strain which is identified by an RV that is larger than the LV, indicative of a potential pulmonary embolus.

The “tank” is then assessed by visualizing the IVC in the subxiphoid plane, and is evaluated for respiratory collapsibility (CI) and maximum size. This has been quite the debated topic over the last two decades. In 1988, Simonson and Schiller⁵² were the first to describe a correlation in spontaneously breathing patients between IVC caliber (measured 2 cm from the cavoatrial junction) and variation and RAP, where a larger IVC diameter and less respiratory variation correlated with a high RAP. Kircher et al⁵³ later went on to describe that a CI greater than 50% correlated with an RAP of less than 10 mm Hg and vice versa in spontaneously breathing patients. Since then there have been more studies attempting to verify these findings in both spontaneously breathing and mechanically ventilated patients.^54-56 The purpose of performing these measurements is not to estimate CVP, but to assess fluid responsiveness (ie, a blood pressure response to a fluid challenge). It can be assumed in states of shock that a small IVC, or one with a high CI, in the presence of a hyperdynamic heart is indicative of an underfilled ventricle and fluid responsiveness, especially if the IVC size increases with fluid.^55,57 However, there are several caveats to this. First, in mechanically ventilated patients, the IVC is already plethoric due to positive pressure ventilation, and increases in diameter with inspiration and decreases with expiration as compared to spontaneously breathing patients. Second, the CI value to predict volume responsiveness in ventilated patients is set at 15% instead of 50%.⁵⁵ Third, it is important to always take the clinical scenario in context; a dilated IVC with small CI is not necessarily only due to volume overload and congestive heart failure, but can be due to elevated RAP from obstructive shock due to cardiac tamponade or massive pulmonary embolus, which is why it is important to assess the “pump” first.^47,58 It is also crucial to not forget to assess the abdominal and thoracic cavities, as intraperitoneal or pleural fluid with a collapsed IVC can potentially make a diagnosis of hemorrhagic or hypovolemic shock depending on the clinical scenario.⁴⁷ The final part of the RUSH protocol is to evaluate the “pipes,” inclusive of the lower extremity deep venous system for evaluation of potential thrombosis that could increase suspicion for a pulmonary embolism causing obstructive shock, and the aorta with the common iliac arteries if there is concern for aortic dissection or aneurysmal rupture.

Benefits

Some of the most significant advantages to the use of POCUS to guide resuscitation is that it is quick, non-invasive, does not use ionizing radiation, and can be easily repeated. As noted above, it is a requirement for EM residencies to teach its use, so that contemporary graduates are entering the specialty competent in applying it to the care of their patients. Furthermore, POCUS is done at the bedside, limiting the need to potentially transport unstable patients.

In the most basic applications, POCUS provides direct visualization of a patient’s cardiac function, presence or absence of lung sliding to suggest a pneumothorax, presence of pulmonary edema, assessment of CVP pressures or potential for fluid responsiveness, as well as identification of potential thoracic, peritoneal, or pelvic cavity fluid accumulation that may suggest hemorrhage. There is literature to support that these assessments performed by the EP have been shown to be comparable to those of cardiologists.^59,60 With continued practice and additional training, it is possible for EPs to even perform more “advanced” hemodynamic assessments to both diagnose and guide therapy to patients in shock (Figures 3 and 4).⁶¹

Limitations

Although POCUS has been shown as a remarkable tool to help assist the EP in making rapid decisions regarding resuscitation, it is always important to remember its limitations. Most of the studies regarding its use are of very small sample sizes, and further prospective studies have to be performed in order for this modality to be fully relied on.⁶²Compared to some of the previously mentioned HDM devices that may provide continuous data, POCUS needs to be performed by the treating physician, thereby occurring intermittently. Emergency physicians need to be aware of their own experience and limitations with this modality, as errors in misdiagnosis can lead to unnecessary procedures, with resulting significant morbidity and mortality. Blanco and Volpicelli⁶³ describe several common errors that include misdiagnosing the stomach as a peritoneal effusion, assuming adequate volume resuscitation when the IVC is seen to be plethoric in the setting of cardiac tamponade, or mistaking IVC movement as indicative of collapsibility, amongst other described misinterpretations. Several other studies have shown that, despite adequate performance of EPs in POCUS, diagnostic sensitivities remained higher when performed by radiologists.^64-67 Thus it remains important for the EPs to be vigilant and not anchor on a diagnosis when in doubt, and to consult early with radiology, particularly if there is any question, to avoid potential adverse patient outcomes.

Summary

There are several ways to diagnose and track resuscitation in the ED, which include physical examination, assessment of serum laboratory values, monitoring of hemodynamic status, and use of POCUS. Unfortunately, none of these methods provides a perfect assessment, and no method has been proven superior and effective over the others. Therefore, it is important for EPs treating patients in shock to be aware of the strengths and limitations of each assessment method (Table).

Resuscitation of critically ill patients in shock from cardiogenic, hypovolemic, obstructive, distributive, or neurogenic etiology is a cornerstone of the care delivered by emergency physicians (EPs).¹ Regardless of the etiology, it is essential that the treating EP initiate resuscitative measures in a timely manner and closely trend the patient’s response to these interventions.

The early goal-directed therapy (EGDT) initially proposed by Rivers et al² in 2001 demonstrated a bundled approach to fluid resuscitation by targeting end points for volume resuscitation, mean arterial blood pressure (MAP), oxygen (O₂) delivery/extraction (mixed venous O₂ saturation, [S_vO₂]), hemoglobin (Hgb) concentration, and cardiac contractility. Since then, advancements in laboratory testing and hemodynamic monitoring (HDM) devices further aid and guide resuscitative efforts, and are applicable to any etiology of shock.

In addition to these advancements, the growing evidence of the potential harm from improper fluid resuscitation, such as the administration of excessive intravascular fluid (IVF),³ underscores the importance of a precise, targeted, and individualized approach to care. This article reviews the background, benefits, and limitations of some of the common and readily available tools in the ED that the EP can employ to guide fluid resuscitation in critically ill patients.

Physical Examination

Background

The rapid recognition and treatment of septic shock in the ED is associated with lower rates of in-hospital morbidity and mortality.⁴ The physical examination by the EP begins immediately upon examining the patient. The acquisition of vital signs and recognition of physical examination findings suggestive of intravascular volume depletion allows the EP to initiate treatment immediately.

In this discussion, hypotension is defined as systolic blood pressure (SBP) of less than 95 mm Hg, MAP of less than 65 mm Hg, or a decrease in SBP of more than 40 mm Hg from baseline measurements. Subsequently, shock is defined as hypotension with evidence of tissue hypoperfusion-induced dysfunction.^5,6 Although the use of findings from the physical examination to guide resuscitation allows for rapid patient assessment and treatment, the predictive value of the physical examination to assess hemodynamic status is limited.

Benefits

The major benefit of the physical examination as a tool to evaluate hemodynamic status is its ease and rapid acquisition. The patient’s vital signs and physical examination can be obtained in the matter of moments upon presentation, without the need to wait on results of laboratory evaluation or additional equipment. Additionally, serial examinations by the same physician can be helpful to monitor a patient’s response to resuscitative efforts. The negative predictive value (NPV) of the physical examination in evaluating for hypovolemia may be helpful, but only when it is taken in the appropriate clinical context and is used in conjunction with other diagnostic tools. The physical examination can exclude hypovolemic volume status with an NPV of approximately 70%.⁷

A constellation of findings from the physical examination may include altered mentation, hypotension, tachycardia, and decreased urinary output by 30% to 40% intravascular volume loss.^8,9Findings from the physical examination to assess fluid status should be used with caution as interobserver reliability has proven to be poor and the prognostic value is limited.

Limitations

The literature shows the limited prognostic value of the physical examination in determining a patient’s volume status and whether fluid resuscitation is indicated. For example, in one meta-analysis,¹⁰ supine hypotension and tachycardia were frequently absent on examination—even in patients who underwent large volume phlebotomy.⁸ This study also showed postural dizziness to be of no prognostic value.

Another study by Saugel et al⁷ that compared the physical examination (skin assessment, lung auscultation, and percussion) to transpulmonary thermodilution measurements of the cardiac index, global end-diastolic volume index, and extravascular lung water index, found poor interobserver correlation and agreement among physicians.

The physical examination is also associated with weak predictive capabilities for the estimation of volume status compared to the device measurements. Another contemporary study by Saugel et al⁹ evaluated the predictive value of the physical examination to accurately identify volume responsiveness replicated these results, and reported poor interobserver correlation (κ coefficient 0.01; 95% caval index [CI] -0.39-0.42) among physical examination findings, with a sensitivity of only 71%, specificity of 23.5%, positive predictive value of 27.8%, and negative predictive value of 66.7%.⁹

Serum Lactate Levels

Background

In the 1843 book titled, Investigations of Pathological Substances Obtained During the Epidemic of Puerperal Fever, Johann Joseph Scherer described the cases of seven young peripartum female patients who died from a clinical picture of what is now understood to be septic shock.¹¹ In his study of these cases, Scherer demonstrated the presence of lactic acid in patients with pathological conditions. Prior to this discovery, lactic acid had never been isolated in a healthy individual. These results were recreated in 1851 by Scherer and Virchow,¹¹ who demonstrated the presence of lactic acid in the blood of a patient who died from leukemia. The inference based on Scherer and Virchow’s work correlated the presence of excessive lactic acid with bodily deterioration and severe disease. Since this finding, there has been a great deal of interest in measuring serum lactic acid as a means to identify and manage critical illness.

In a 2001 groundbreaking study of EGDT for severe sepsis and septic shock, Rivers et al² studied lactic acid levels as a marker for severe disease. Likewise, years later, the 2014 Protocol-Based Care for Early Septic Shock (PROCESS), Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials used lactate levels in a similar manner to identify patients appropriate for randomization.^12-14 While the purpose of measuring lactic acid was only employed in these studies to identify patients at risk for critical illness, the 2012 Surviving Sepsis Campaign Guidelines recommended serial measurement of lactate, based on the assumption that improved lactate levels signified better tissue perfusion.¹⁵

Although much of the studies on lactate levels appear to be based on the treatment and management of septic patients, findings can be applied to any etiology of shock. For example, a serum lactate level greater than 2 mmol/L is considered abnormal, and a serum lactate greater than 4 mmol/L indicates a significantly increased risk for in-hospital mortality.¹⁶

Benefits

It is now a widely accepted belief that the rapid identification, triage, and treatment of critically ill patients has a dramatic effect on morbidity and mortality.⁴ As previously noted, lactate has been extensively studied and identified as a marker of severe illness.^17,18 A serum lactate level, which can be rapidly processed in the ED, can be easily obtained from a minimally invasive venous, arterial, or capillary blood draw.¹⁸ The only risk associated with serum lactate testing is that of any routine venipuncture; the test causes minimal, if any, patient discomfort.

Thanks to advances in point-of-care (POC) technology, the result of serum lactate assessment can be available within 10 minutes from blood draw. This technology is inexpensive and can be easily deployed in the prehospital setting or during the initial triage assessment of patients arriving at the ED.¹⁹ These POC instruments have been well correlated with whole blood measurements and permit for the rapid identification and treatment of at risk patients.

Limitations

The presence of elevated serum lactate levels is believed to represent the presence of cellular anaerobic metabolism due to impaired O₂ delivery in the shock state. Abnormal measurements therefore prompt aggressive interventions aimed at maximizing O₂ delivery to the tissues, such as intravenous fluid boluses, vasopressor therapy, or even blood product administration.

A return to a normalized serum lactate level is assumed to represent a transition back to aerobic metabolism. Lactate elevations, however, are not solely an indication of anaerobic metabolism and may only represent a small degree of lactate production.²⁰ While the specific cellular mechanics are out of the scope of this article, it has been postulated that the increase in plasma lactate concentration is primarily driven by β-2 receptor stimulation from increased circulating catecholamines leading to increased aerobic glycolysis. Increased lactate levels could therefore be an adaptive mechanism of energy production—aggressive treatment and rapid clearance may, in fact, be harmful. Type A lactic acidosis is categorized as elevated serum levels due to tissue hypoperfusion.²¹

However, lactate elevations do not exclusively occur in severe illness. The use of β-2 receptor agonists such as continuous albuterol treatments or epinephrine may cause abnormal lactate levels.²² Other medications have also been associated with elevated serum lactate levels, including, but not limited to linezolid, metformin, and propofol.^23-25 Additionally, lactate levels may be elevated after strenuous exercise, seizure activity, or in liver and kidney disease.²⁶ These “secondary” causes of lactic acidosis that are not due to tissue hypoperfusion are referred to as type B lactic acidosis. Given these multiple etiologies and lack of specificity for this serum measurement, a failure to understand these limitations may result in over aggressive or unnecessary medical treatments.

Central Venous Pressure

Background

Central venous pressure (CVP) measurements can be obtained through a catheter, the distal tip of which transduces pressure of the superior vena cava at the entrance of the right atrium (RA). Thus, CVP is often used as a representation of RA pressure (RAP) and therefore an estimate of right ventricular (RV) preload. While CVP is used to diagnose and determine the etiology of shock, evidence and controversy regarding the use of CVP as a marker for resuscitation comes largely from sepsis-focused literature.⁵ Central venous pressure is meant to represent preload, which is essential for stroke volume as described by the Frank-Starling mechanism; however, its use as a target in distributive shock, a state in which it is difficult to determine a patient’s volume status, has been popularized by EGDT since 2001.²

Since the publication of the 2004 Surviving Sepsis Guidelines, CVP monitoring has been in the spotlight of sepsis resuscitation, albeit with some controversy.²⁷ Included as the result of two studies, this recommendation has been removed in the most recent guidelines after 12 years of further study and scrutiny.^2,27,28

Hypovolemic and hemorrhagic shock are usually diagnosed clinically and while a low CVP can be helpful in the diagnosis, the guidelines do not support CVP as a resuscitation endpoint. Obstructive and cardiogenic shock will both result in elevated CVP; however, treatment of obstructive shock is generally targeted at the underlying cause. While cardiogenic shock can be preload responsive, the mainstay of therapy in the ED is identification of patients for revascularization and inotropic support.²⁹

Benefits

The CVP has been used as a surrogate for RV preload volume. If a patient’s preload volume is low, the treating physician can administer fluids to improve stroke volume and cardiac output (CO). Clinically, CVP measurements are easy to obtain provided a central venous line has been placed with the distal tip at the entrance to the RA. Central venous pressure is measured by transducing the pressure via manometry and connecting it to the patient’s bedside monitor. This provides an advantage of being able to provide serial or even continuous measurements. The “normal” RAP should be a low value (1-5 mm Hg, mean of 3 mm Hg), as this aids in the pressure gradient to drive blood from the higher pressures of the left ventricle (LV) and aorta through the circulation back to the low-pressure of the RA.³⁰ The value of the CVP is meant to correspond to the physical examination findings of jugular venous distension.^31,32 Thus, a low CVP may be “normal” and seen in patients with hypovolemic shock, whereas an elevated CVP can suggest volume overload or obstructive shock. However, this is of questionable value in distributive shock cases.

Aside from the two early studies on CVP monitoring during treatment of septic patients, there are few data to support the use of CVP measurement in the early resuscitation of patients with shock.^2,28 More recent trials (PROMISE, ARISE, PROCESS) that compared protocolized sepsis care to standard care showed no benefit to bundles including CVP measurements.^12-14 However, a subsequent, large observational trial spanning 7.5 years demonstrated improvements in sepsis-related mortality in patients who received a central venous catheter (CVC) and CVP-targeted therapy.³³ Thus, it is possible that protocols including CVP are still beneficial in combination with other therapies even though CVP in isolation is not.

Limitations

The traditional two assumptions in CVP monitoring are CVP value represents the overall volume status of the patient, and the LV is able to utilize additional preload volume. The latter assumption, however, may be hampered by the presence of sepsis-induced myocardial dysfunction, which may be present in up to 40% of critically ill patients.³⁴ The former assumption does not always hold true due to processes that change filling pressures independent of intravascular volume—eg, acute or chronic pulmonary hypertension, cardiac tamponade, intra-abdominal hypertension, or LV failure. Even before the landmark EGDT study, available data suggested that CVP was not a reliable marker for resuscitation management.³⁵ A recent systematic review by Gottlieb and Hunter³⁶ showed that the area under the receiver-operator curve for low, mid-range, or high CVPs was equivocal at best. In addition to its unreliability and lack of specificity, another significant drawback to using CVP to guide resuscitation therapy in the ED is that it necessitates placement of a CVC, which can be time-consuming and, if not otherwise indicated, lead to complications of infection, pneumothorax, and/or thrombosis.³⁷

Mixed Venous Oxygen

Background

Most EPs are familiar with the use of S_cvO₂ in EGDT protocols to guide volume resuscitation of septic patients.² A patient’s S_cvO₂ represents the O₂ saturation of venous blood obtained via a CVC at the confluence of the superior vena cava and the RA, and thus it reflects tissue O₂ consumption as a surrogate for tissue perfusion. The measurement parallels the S_vO₂ obtained from the pulmonary artery. In a healthy patient, S_vO₂ is around 65% to 70% and includes blood returning from both the superior and inferior vena cava (IVC). As such, S_cvO₂ values are typically 3% to 5% lower than S_vO₂ owing to the lower O₂ extracted by tissues draining into the IVC compared to the mixed venous blood sampled from the pulmonary artery.³⁸

Though a debate over the benefit of EGDT in treating sepsis continues, understanding the physiology of S_cvO₂ measurements is another potential tool the EP can use to guide the resuscitation of critically ill patients.³⁹ A patient’s S_vO₂ and, by extension, S_cvO₂ represents the residual O₂ saturation after the tissues have extracted the amount of O₂ necessary to meet metabolic demands (Figure 2).

Benefits

A critically ill patient’s S_cvO₂ can potentially provide EPs with insight into the patient’s global tissue perfusion and the source of any mismatch between O₂ delivery and consumption. Using additional tools and measurements (physical examination, serum Hgb levels, and pulse oximetry) in conjunction with an S_cvO₂ measurement, assists EPs in identifying targets for therapeutic intervention. The effectiveness of this intervention can then be assessed using serial S_cvO₂ measurements, as described in Rivers et al² EGDT protocol. Importantly, EPs should take care to measure serial S_cvO₂ values to maximize its utility.³⁸ Similar to a CVP measurement, S_cvO₂is easily obtained from blood samples for serial laboratory measurements, assuming the patient already has a CVC with the distal tip at the entrance to the RA (S_cvO₂) or a pulmonary artery catheter (PAC) (S_vO₂).

Limitations

Serial measurements provide the most reliable information, which may be more useful in patients who spend extended periods of their resuscitation in the ED. In comparison to other measures of global tissue hypoxia, work by Jones et al⁴¹ suggests non-inferiority of peripherally sampled, serial lactate measurements as an alternative to S_cvO₂. This, in conjunction with the requirement for an internal jugular CVC, subclavian CVC, or PAC with their associated risks, may make S_cvO₂ a less attractive guide for the resuscitation of critically ill patients in the ED.

Monitoring Devices

Background

As noted throughout this review, it is important not only to identify and rapidly treat shock, but to also correctly identify the type of shock, such that treatment can be appropriately directed at its underlying cause. However, prior work suggests that EPs are unable to grossly estimate CO or systemic vascular resistance when compared to objective measurements of these parameters.⁴² This is in agreement with the overall poor performance of physical examination and clinical evaluation as a means of predicting volume responsiveness or guiding resuscitation, as discussed previously. Fortunately, a wide variety of devices to objectively monitor hemodynamics are now available to the EP.

In 1970, Swan et al⁴³ published their initial experience with pulmonary artery catheterization at the bedside, using a balloon-tipped, flow-guided PAC in lieu of fluoroscopy, which had been mandated by earlier techniques. The ability to measure CO, right heart pressures, pulmonary arterial pressures, and estimate LV end diastolic pressure ushered in an era of widespread PAC use, despite an absence of evidence for causation of improved patient outcomes. The utilization of PACs has fallen, as the literature suggests that the empiric placement of PACs in critically ill patients does not improve mortality, length of stay, or cost, and significant complication rates have been reported in large trials.^44,45Subsequently, a number of non-invasive or less-invasive HDM devices have been developed. Amongst the more commonly encountered modern devices, the techniques utilized for providing hemodynamic assessments include thermodilution and pulse contour analysis (PiCCO^TM), pulse contour analysis (FloTrac/Vigileo^TM), and lithium chemodilution with pulse power analysis (LiDCOplus^TM).⁴⁶ The primary utility of these devices for the EP lies in the ability to quantify CO, stroke volume, and stroke volume or pulse pressure variation (PPV) to predict or assess response to resuscitative interventions (volume administration, vasopressors, inotropes, etc).

Benefits

Many of these devices require placement of an arterial catheter. Some require the addition of a CVC. Both of these procedures are well within the clinical scope of the EP, and are performed with fair frequency on critically ill patients. This is a distinct advantage when compared to pulmonary artery catheterization, a higher risk procedure that is rarely performed outside of the intensive care unit or cardiac catheterization laboratory. In addition, all of the devices below present hemodynamic data in a graphical, easy-to-read format, in real time. All of the devices discussed report stroke volume variation (SVV) or PPV continuously.

Limitations

Though these measures have validated threshold values that predict volume responsiveness, they require the patient to be intubated with a set tidal volume of greater than or equal to 8 mL/kg without spontaneous respirations and cardiac arrhythmias, in order to accurately do so. All of the HDM devices that rely on pulse contour analysis as the primary means of CO measurement cannot be used in the presence of significant cardiac arrhythmias (ie, atrial fibrillation), or mechanical circulatory assistance devices (ie, intra-aortic balloon counterpulsation). None of these devices are capable of monitoring microcirculatory changes, felt to be of increasing clinical importance in the critically ill.

The use of HDM devices to monitor CO with a reasonable degree of accuracy, trend CO, and assess for volume responsiveness using a number of previously validated parameters such as SVV is now in little doubt. However, these devices are still invasive, if less so than a pulmonary artery. The crux of the discussion of HDM devices for use in ED resuscitation revolves around whether or not the use of such devices to drive previously validated, protocolized care results in better outcomes for patients. The EP can now have continuous knowledge of a large number of hemodynamic parameters at their fingertips with relatively minimal additional efforts. At the time of this writing, though, this is both untested and unproven, with respect to the ED population.

Point-of-Care Ultrasound

Background

Over the past two decades, ultrasound (US) has become an integral part of the practice of emergency medicine (EM), and is now included in all United States Accreditation Council for Graduate Medical Education Emergency Medicine Residency Programs.^47,48 It has emerged as a very important bedside tool performed by the clinician to identify type of shock and guide resuscitation, and has been endorsed by both EM and critical care societies.^49-51 This section reviews the utility of US as a modality in identifying shock and guiding resuscitation, in addition to the pitfalls and limitations of this important tool.

In 2010, Perera et al⁴⁷ described in their landmark article the Rapid Ultrasound in SHock (RUSH) examination, which describes a stepwise (the pump, tank, pipes) approach to identify the type of shock (cardiogenic, hypovolemic, obstructive, or distributive) in the crashing, hypotensive ED patient. We do not describe the full RUSH examination in this review, but discuss key elements of it as examples of how POCUS can assist the EP to make a rapid diagnosis and aid in the management of patients in shock. The “pump” is the heart, which is assessed in four different views to identify a pericardial effusion and possible tamponade, assess contractility or ejection fraction of the LV (severely decreased, decreased, normal, or hyperdynamic), and right heart strain which is identified by an RV that is larger than the LV, indicative of a potential pulmonary embolus.

The “tank” is then assessed by visualizing the IVC in the subxiphoid plane, and is evaluated for respiratory collapsibility (CI) and maximum size. This has been quite the debated topic over the last two decades. In 1988, Simonson and Schiller⁵² were the first to describe a correlation in spontaneously breathing patients between IVC caliber (measured 2 cm from the cavoatrial junction) and variation and RAP, where a larger IVC diameter and less respiratory variation correlated with a high RAP. Kircher et al⁵³ later went on to describe that a CI greater than 50% correlated with an RAP of less than 10 mm Hg and vice versa in spontaneously breathing patients. Since then there have been more studies attempting to verify these findings in both spontaneously breathing and mechanically ventilated patients.^54-56 The purpose of performing these measurements is not to estimate CVP, but to assess fluid responsiveness (ie, a blood pressure response to a fluid challenge). It can be assumed in states of shock that a small IVC, or one with a high CI, in the presence of a hyperdynamic heart is indicative of an underfilled ventricle and fluid responsiveness, especially if the IVC size increases with fluid.^55,57 However, there are several caveats to this. First, in mechanically ventilated patients, the IVC is already plethoric due to positive pressure ventilation, and increases in diameter with inspiration and decreases with expiration as compared to spontaneously breathing patients. Second, the CI value to predict volume responsiveness in ventilated patients is set at 15% instead of 50%.⁵⁵ Third, it is important to always take the clinical scenario in context; a dilated IVC with small CI is not necessarily only due to volume overload and congestive heart failure, but can be due to elevated RAP from obstructive shock due to cardiac tamponade or massive pulmonary embolus, which is why it is important to assess the “pump” first.^47,58 It is also crucial to not forget to assess the abdominal and thoracic cavities, as intraperitoneal or pleural fluid with a collapsed IVC can potentially make a diagnosis of hemorrhagic or hypovolemic shock depending on the clinical scenario.⁴⁷ The final part of the RUSH protocol is to evaluate the “pipes,” inclusive of the lower extremity deep venous system for evaluation of potential thrombosis that could increase suspicion for a pulmonary embolism causing obstructive shock, and the aorta with the common iliac arteries if there is concern for aortic dissection or aneurysmal rupture.

Benefits

Some of the most significant advantages to the use of POCUS to guide resuscitation is that it is quick, non-invasive, does not use ionizing radiation, and can be easily repeated. As noted above, it is a requirement for EM residencies to teach its use, so that contemporary graduates are entering the specialty competent in applying it to the care of their patients. Furthermore, POCUS is done at the bedside, limiting the need to potentially transport unstable patients.

In the most basic applications, POCUS provides direct visualization of a patient’s cardiac function, presence or absence of lung sliding to suggest a pneumothorax, presence of pulmonary edema, assessment of CVP pressures or potential for fluid responsiveness, as well as identification of potential thoracic, peritoneal, or pelvic cavity fluid accumulation that may suggest hemorrhage. There is literature to support that these assessments performed by the EP have been shown to be comparable to those of cardiologists.^59,60 With continued practice and additional training, it is possible for EPs to even perform more “advanced” hemodynamic assessments to both diagnose and guide therapy to patients in shock (Figures 3 and 4).⁶¹

Limitations

Although POCUS has been shown as a remarkable tool to help assist the EP in making rapid decisions regarding resuscitation, it is always important to remember its limitations. Most of the studies regarding its use are of very small sample sizes, and further prospective studies have to be performed in order for this modality to be fully relied on.⁶²Compared to some of the previously mentioned HDM devices that may provide continuous data, POCUS needs to be performed by the treating physician, thereby occurring intermittently. Emergency physicians need to be aware of their own experience and limitations with this modality, as errors in misdiagnosis can lead to unnecessary procedures, with resulting significant morbidity and mortality. Blanco and Volpicelli⁶³ describe several common errors that include misdiagnosing the stomach as a peritoneal effusion, assuming adequate volume resuscitation when the IVC is seen to be plethoric in the setting of cardiac tamponade, or mistaking IVC movement as indicative of collapsibility, amongst other described misinterpretations. Several other studies have shown that, despite adequate performance of EPs in POCUS, diagnostic sensitivities remained higher when performed by radiologists.^64-67 Thus it remains important for the EPs to be vigilant and not anchor on a diagnosis when in doubt, and to consult early with radiology, particularly if there is any question, to avoid potential adverse patient outcomes.

Summary

There are several ways to diagnose and track resuscitation in the ED, which include physical examination, assessment of serum laboratory values, monitoring of hemodynamic status, and use of POCUS. Unfortunately, none of these methods provides a perfect assessment, and no method has been proven superior and effective over the others. Therefore, it is important for EPs treating patients in shock to be aware of the strengths and limitations of each assessment method (Table).

In patients with distributive shock, the risk of atrial fibrillation may be lower when vasopressin is administered along with catecholamine vasopressors, results of a recent systematic review and meta-analysis suggest.

The relative risk of atrial fibrillation was reduced for the combination of vasopressin and catecholamines versus the current standard of care, which is catecholamines alone, according to study results published in JAMA.

Beyond atrial fibrillation, however, findings of the meta-analysis were consistent with regard to other endpoints, including mortality, according to William F. McIntyre, MD, of McMaster University, Hamilton, Ont., and his coinvestigators.

Mortality was lower with the combination approach when all studies were analyzed together. Yet, when the analysis was limited to the studies with the lowest risk of bias, the difference in mortality versus catecholamines alone was not statistically significant, investigators said.

Nevertheless, the meta-analysis does suggest that vasopressin may offer a clinical advantage regarding prevention of atrial fibrillation in patients with distributive shock, a frequently fatal condition most often seen in patients with sepsis.

Vasopressin is an endogenous peptide hormone that decreases stimulation of certain myocardial receptors associated with cardiac arrhythmia, the authors noted.

“This, among other mechanisms, may translate into a reduction in adverse events, including atrial fibrillation, injury to other organs, and death,” they said in their report.

SOURCE: McIntyre WF et al. JAMA. 2018;319(18):1889-900.

In patients with distributive shock, the risk of atrial fibrillation may be lower when vasopressin is administered along with catecholamine vasopressors, results of a recent systematic review and meta-analysis suggest.

The relative risk of atrial fibrillation was reduced for the combination of vasopressin and catecholamines versus the current standard of care, which is catecholamines alone, according to study results published in JAMA.

Beyond atrial fibrillation, however, findings of the meta-analysis were consistent with regard to other endpoints, including mortality, according to William F. McIntyre, MD, of McMaster University, Hamilton, Ont., and his coinvestigators.

Mortality was lower with the combination approach when all studies were analyzed together. Yet, when the analysis was limited to the studies with the lowest risk of bias, the difference in mortality versus catecholamines alone was not statistically significant, investigators said.

Nevertheless, the meta-analysis does suggest that vasopressin may offer a clinical advantage regarding prevention of atrial fibrillation in patients with distributive shock, a frequently fatal condition most often seen in patients with sepsis.

Vasopressin is an endogenous peptide hormone that decreases stimulation of certain myocardial receptors associated with cardiac arrhythmia, the authors noted.

“This, among other mechanisms, may translate into a reduction in adverse events, including atrial fibrillation, injury to other organs, and death,” they said in their report.

SOURCE: McIntyre WF et al. JAMA. 2018;319(18):1889-900.

In patients with distributive shock, the risk of atrial fibrillation may be lower when vasopressin is administered along with catecholamine vasopressors, results of a recent systematic review and meta-analysis suggest.

The relative risk of atrial fibrillation was reduced for the combination of vasopressin and catecholamines versus the current standard of care, which is catecholamines alone, according to study results published in JAMA.

Beyond atrial fibrillation, however, findings of the meta-analysis were consistent with regard to other endpoints, including mortality, according to William F. McIntyre, MD, of McMaster University, Hamilton, Ont., and his coinvestigators.

Mortality was lower with the combination approach when all studies were analyzed together. Yet, when the analysis was limited to the studies with the lowest risk of bias, the difference in mortality versus catecholamines alone was not statistically significant, investigators said.

Nevertheless, the meta-analysis does suggest that vasopressin may offer a clinical advantage regarding prevention of atrial fibrillation in patients with distributive shock, a frequently fatal condition most often seen in patients with sepsis.

Vasopressin is an endogenous peptide hormone that decreases stimulation of certain myocardial receptors associated with cardiac arrhythmia, the authors noted.

“This, among other mechanisms, may translate into a reduction in adverse events, including atrial fibrillation, injury to other organs, and death,” they said in their report.

SOURCE: McIntyre WF et al. JAMA. 2018;319(18):1889-900.

For patients with suspected low-grade non–muscle-invasive bladder cancer, immediate postresection treatment with intravesicular gemcitabine significantly cut recurrence rates in a double-blind, multicenter, randomized, placebo-controlled trial.

In the intention-to-treat analysis, estimated rates of 4-year recurrence were 35% with gemcitabine and 47% with placebo saline (hazard ratio, 0.66; 95% confidence interval, 0.48-0.90; P less than .001), reported Edward D. Messing of the University of Rochester, New York, and his associates. Gemcitabine also significantly outperformed placebo in the preplanned analysis of patients with confirmed low-grade non–muscle-invasive urothelial cancer (estimated 4-year recurrence rates , 4% and 54% respectively; HR, 0.53; 95% CI, 0.35-0.81; P = .001).

Intravesicular gemcitabine did not significantly reduce all-cause mortality or tumor progression to muscle invasion. “In an underpowered post hoc subgroup analysis, there [also] was no evidence of a benefit of immediate post-TURBT [transurethral resection of bladder tumor] gemcitabine in patients with high-grade non–muscle-invasive urothelial cancer,” the researchers wrote. The report was published May 8 in JAMA.

Robust data already support single-dose intravesicular chemotherapy with mitomycin C or epirubicin immediately after patients undergo TURBT. But in reality, this practice is uncommon in the United States. Meanwhile, systemic gemcitabine already is used to treat bladder cancer, and its intravesicular use appears safe and at least as effective as other chemotherapies, the investigators noted. Therefore, the SWOG S0337 trial enrolled 416 symptomatic patients with suspected low-grade papillary urothelial cancer who received a single intravesicular instillation of either gemcitabine (2 g in 100 mL saline) or saline (100 mL) within 3 hours after transurethral resection of TURBT.

Ten percent of patients did not receive study drug instillation, usually for medical reasons. There were no grade 4-5 adverse events. Grade 3 or lower adverse events did not significantly differ between groups. The study did not capture reliable data on tumor size or treatment at or after recurrence, the researchers said. Taken together, the findings “support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents.”

The National Cancer Institute provided funding. Eli Lilly provided the gemcitabine used in the study. Dr. Messing reported having no relevant conflicts of interest. Three coinvestigators disclosed ties to BioCancell, Incyte, and various other biopharmaceutical companies.

SOURCE: Messing EM et al. JAMA. 2018 May 8;319(18):1880-8.

For patients with suspected low-grade non–muscle-invasive bladder cancer, immediate postresection treatment with intravesicular gemcitabine significantly cut recurrence rates in a double-blind, multicenter, randomized, placebo-controlled trial.

In the intention-to-treat analysis, estimated rates of 4-year recurrence were 35% with gemcitabine and 47% with placebo saline (hazard ratio, 0.66; 95% confidence interval, 0.48-0.90; P less than .001), reported Edward D. Messing of the University of Rochester, New York, and his associates. Gemcitabine also significantly outperformed placebo in the preplanned analysis of patients with confirmed low-grade non–muscle-invasive urothelial cancer (estimated 4-year recurrence rates , 4% and 54% respectively; HR, 0.53; 95% CI, 0.35-0.81; P = .001).

Intravesicular gemcitabine did not significantly reduce all-cause mortality or tumor progression to muscle invasion. “In an underpowered post hoc subgroup analysis, there [also] was no evidence of a benefit of immediate post-TURBT [transurethral resection of bladder tumor] gemcitabine in patients with high-grade non–muscle-invasive urothelial cancer,” the researchers wrote. The report was published May 8 in JAMA.

Robust data already support single-dose intravesicular chemotherapy with mitomycin C or epirubicin immediately after patients undergo TURBT. But in reality, this practice is uncommon in the United States. Meanwhile, systemic gemcitabine already is used to treat bladder cancer, and its intravesicular use appears safe and at least as effective as other chemotherapies, the investigators noted. Therefore, the SWOG S0337 trial enrolled 416 symptomatic patients with suspected low-grade papillary urothelial cancer who received a single intravesicular instillation of either gemcitabine (2 g in 100 mL saline) or saline (100 mL) within 3 hours after transurethral resection of TURBT.

Ten percent of patients did not receive study drug instillation, usually for medical reasons. There were no grade 4-5 adverse events. Grade 3 or lower adverse events did not significantly differ between groups. The study did not capture reliable data on tumor size or treatment at or after recurrence, the researchers said. Taken together, the findings “support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents.”

The National Cancer Institute provided funding. Eli Lilly provided the gemcitabine used in the study. Dr. Messing reported having no relevant conflicts of interest. Three coinvestigators disclosed ties to BioCancell, Incyte, and various other biopharmaceutical companies.

SOURCE: Messing EM et al. JAMA. 2018 May 8;319(18):1880-8.

For patients with suspected low-grade non–muscle-invasive bladder cancer, immediate postresection treatment with intravesicular gemcitabine significantly cut recurrence rates in a double-blind, multicenter, randomized, placebo-controlled trial.

In the intention-to-treat analysis, estimated rates of 4-year recurrence were 35% with gemcitabine and 47% with placebo saline (hazard ratio, 0.66; 95% confidence interval, 0.48-0.90; P less than .001), reported Edward D. Messing of the University of Rochester, New York, and his associates. Gemcitabine also significantly outperformed placebo in the preplanned analysis of patients with confirmed low-grade non–muscle-invasive urothelial cancer (estimated 4-year recurrence rates , 4% and 54% respectively; HR, 0.53; 95% CI, 0.35-0.81; P = .001).

Intravesicular gemcitabine did not significantly reduce all-cause mortality or tumor progression to muscle invasion. “In an underpowered post hoc subgroup analysis, there [also] was no evidence of a benefit of immediate post-TURBT [transurethral resection of bladder tumor] gemcitabine in patients with high-grade non–muscle-invasive urothelial cancer,” the researchers wrote. The report was published May 8 in JAMA.

Robust data already support single-dose intravesicular chemotherapy with mitomycin C or epirubicin immediately after patients undergo TURBT. But in reality, this practice is uncommon in the United States. Meanwhile, systemic gemcitabine already is used to treat bladder cancer, and its intravesicular use appears safe and at least as effective as other chemotherapies, the investigators noted. Therefore, the SWOG S0337 trial enrolled 416 symptomatic patients with suspected low-grade papillary urothelial cancer who received a single intravesicular instillation of either gemcitabine (2 g in 100 mL saline) or saline (100 mL) within 3 hours after transurethral resection of TURBT.

Ten percent of patients did not receive study drug instillation, usually for medical reasons. There were no grade 4-5 adverse events. Grade 3 or lower adverse events did not significantly differ between groups. The study did not capture reliable data on tumor size or treatment at or after recurrence, the researchers said. Taken together, the findings “support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents.”

The National Cancer Institute provided funding. Eli Lilly provided the gemcitabine used in the study. Dr. Messing reported having no relevant conflicts of interest. Three coinvestigators disclosed ties to BioCancell, Incyte, and various other biopharmaceutical companies.

SOURCE: Messing EM et al. JAMA. 2018 May 8;319(18):1880-8.

Coaching adults with stage 3 chronic kidney disease (CKD) to increase water intake did not significantly slow decline in kidney function, results of a randomized clinical trial show.

Compared with coaching to maintain water intake, coaching to increase water intake did in fact increase water intake but did not prevent a decrease in estimated glomerular filtration rate (eGFR) over 1 year, according to findings of the study, which was published in JAMA..

However, the study may have been underpowered to detect a clinically important difference in this primary endpoint, and certain secondary endpoints did suggest a favorable effect of the intervention, according to William F. Clark, MD, of the London (Ontario) Health Sciences Centre and his coauthors.

“The increased water intake achieved in this trial was sufficient to lower vasopressin secretion, as assessed by plasma copeptin concentrations,” Dr. Clark and his colleagues said in their report

An increasing number of studies suggest that drinking water may benefit the kidneys. In some human studies, water intake was associated with reduced risk of kidney stones and better kidney function.

However, it remains unknown whether increasing water intake would benefit patients with CKD. To evaluate this question, Dr. Clark and colleagues initiated CKD WIT (Chronic Kidney Disease Water Intake Trial), a randomized clinical trial conducted in 9 centers in Ontario.

The study included 631 patients with stage 3 CKD and a 24-hour urine volume below 3 L. Patients randomized to the hydration group were coached to increase water intake gradually to 1-1.5 L/day for 1 year, while those randomized to the control group were coached to maintain their usual water intake.

SOURCE: Clark WF et al. JAMA. 2018;319(18):1870-9.

Coaching adults with stage 3 chronic kidney disease (CKD) to increase water intake did not significantly slow decline in kidney function, results of a randomized clinical trial show.

Compared with coaching to maintain water intake, coaching to increase water intake did in fact increase water intake but did not prevent a decrease in estimated glomerular filtration rate (eGFR) over 1 year, according to findings of the study, which was published in JAMA..

However, the study may have been underpowered to detect a clinically important difference in this primary endpoint, and certain secondary endpoints did suggest a favorable effect of the intervention, according to William F. Clark, MD, of the London (Ontario) Health Sciences Centre and his coauthors.

“The increased water intake achieved in this trial was sufficient to lower vasopressin secretion, as assessed by plasma copeptin concentrations,” Dr. Clark and his colleagues said in their report

An increasing number of studies suggest that drinking water may benefit the kidneys. In some human studies, water intake was associated with reduced risk of kidney stones and better kidney function.

However, it remains unknown whether increasing water intake would benefit patients with CKD. To evaluate this question, Dr. Clark and colleagues initiated CKD WIT (Chronic Kidney Disease Water Intake Trial), a randomized clinical trial conducted in 9 centers in Ontario.

The study included 631 patients with stage 3 CKD and a 24-hour urine volume below 3 L. Patients randomized to the hydration group were coached to increase water intake gradually to 1-1.5 L/day for 1 year, while those randomized to the control group were coached to maintain their usual water intake.

SOURCE: Clark WF et al. JAMA. 2018;319(18):1870-9.

Coaching adults with stage 3 chronic kidney disease (CKD) to increase water intake did not significantly slow decline in kidney function, results of a randomized clinical trial show.

Compared with coaching to maintain water intake, coaching to increase water intake did in fact increase water intake but did not prevent a decrease in estimated glomerular filtration rate (eGFR) over 1 year, according to findings of the study, which was published in JAMA..

However, the study may have been underpowered to detect a clinically important difference in this primary endpoint, and certain secondary endpoints did suggest a favorable effect of the intervention, according to William F. Clark, MD, of the London (Ontario) Health Sciences Centre and his coauthors.

“The increased water intake achieved in this trial was sufficient to lower vasopressin secretion, as assessed by plasma copeptin concentrations,” Dr. Clark and his colleagues said in their report

An increasing number of studies suggest that drinking water may benefit the kidneys. In some human studies, water intake was associated with reduced risk of kidney stones and better kidney function.

However, it remains unknown whether increasing water intake would benefit patients with CKD. To evaluate this question, Dr. Clark and colleagues initiated CKD WIT (Chronic Kidney Disease Water Intake Trial), a randomized clinical trial conducted in 9 centers in Ontario.

The study included 631 patients with stage 3 CKD and a 24-hour urine volume below 3 L. Patients randomized to the hydration group were coached to increase water intake gradually to 1-1.5 L/day for 1 year, while those randomized to the control group were coached to maintain their usual water intake.

SOURCE: Clark WF et al. JAMA. 2018;319(18):1870-9.

The USPSTF recommends that, to reduce the risk of false positives and unnecessary complications from prostate cancer screening and treatment, physicians and their male patients aged 55-69 years should review together the pros and cons.

Clinicians should not conduct prostate cancer screening in men aged 55-69 years who do not ask for it (level C recommendation), according to the USPSTF recommendations, published in JAMA, which also recommend against any prostate cancer screening for men aged 70 years and older (level D recommendation). The recommendations replace those from 2012, and upgrade the statement against routine screening from a D to a C.

“The change in recommendation grade further reflects new evidence about and increased use of active surveillance of low-risk prostate cancer, which may reduce the risk of subsequent harms from screening,” according to the USPSTF.

The recommendations apply to asymptomatic adult men in the general United States population with no previous diagnosis of prostate cancer, as well as those whose ethnicity or family history put them at increased risk of death from prostate cancer.

In the evidence report published in JAMA, Joshua J. Fenton, MD, professor in the department of family and community medicine of the University of California, Davis, Sacramento, and his colleagues reviewed 63 studies comprising 1,904,950 individuals. The researchers examined the findings for information including the effectiveness of PSA screening and the potential harms associated with both screening and cancer treatment if disease was identified.

Overdiagnosis of prostate cancer ranged from 21% to 50% for cancers detected by screening, and one randomized trial of more than 1,000 men found no significant reduction in mortality for prostatectomy or radiation therapy compared with active monitoring.

Overall, men randomized to PSA screening had no significant reduction in risk of prostate cancer mortality in trials from the United States or the United Kingdom, although data from a European trial showed a significant reduction. Complications requiring hospitalization occurred in 0.5%-1.6% of men who had biopsies after screening showed abnormal results.

The evidence review was limited by several factors including a lack of data on newer treatments such as cryotherapy and high-intensity focused ultrasound, the researchers noted.

However, the data support an individualized approach to PSA screening for prostate cancer, in which each man can weigh the potential risks and benefits of screening, according to the USPSTF.

The research was funded by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose.

SOURCE: Fenton J et al. JAMA. 2018;319(18):1914-31. and JAMA. 2018;319(18):1901-13.

The USPSTF recommends that, to reduce the risk of false positives and unnecessary complications from prostate cancer screening and treatment, physicians and their male patients aged 55-69 years should review together the pros and cons.

Clinicians should not conduct prostate cancer screening in men aged 55-69 years who do not ask for it (level C recommendation), according to the USPSTF recommendations, published in JAMA, which also recommend against any prostate cancer screening for men aged 70 years and older (level D recommendation). The recommendations replace those from 2012, and upgrade the statement against routine screening from a D to a C.

“The change in recommendation grade further reflects new evidence about and increased use of active surveillance of low-risk prostate cancer, which may reduce the risk of subsequent harms from screening,” according to the USPSTF.

The recommendations apply to asymptomatic adult men in the general United States population with no previous diagnosis of prostate cancer, as well as those whose ethnicity or family history put them at increased risk of death from prostate cancer.

In the evidence report published in JAMA, Joshua J. Fenton, MD, professor in the department of family and community medicine of the University of California, Davis, Sacramento, and his colleagues reviewed 63 studies comprising 1,904,950 individuals. The researchers examined the findings for information including the effectiveness of PSA screening and the potential harms associated with both screening and cancer treatment if disease was identified.

Overdiagnosis of prostate cancer ranged from 21% to 50% for cancers detected by screening, and one randomized trial of more than 1,000 men found no significant reduction in mortality for prostatectomy or radiation therapy compared with active monitoring.

Overall, men randomized to PSA screening had no significant reduction in risk of prostate cancer mortality in trials from the United States or the United Kingdom, although data from a European trial showed a significant reduction. Complications requiring hospitalization occurred in 0.5%-1.6% of men who had biopsies after screening showed abnormal results.

The evidence review was limited by several factors including a lack of data on newer treatments such as cryotherapy and high-intensity focused ultrasound, the researchers noted.

However, the data support an individualized approach to PSA screening for prostate cancer, in which each man can weigh the potential risks and benefits of screening, according to the USPSTF.

The research was funded by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose.

SOURCE: Fenton J et al. JAMA. 2018;319(18):1914-31. and JAMA. 2018;319(18):1901-13.

The USPSTF recommends that, to reduce the risk of false positives and unnecessary complications from prostate cancer screening and treatment, physicians and their male patients aged 55-69 years should review together the pros and cons.

Clinicians should not conduct prostate cancer screening in men aged 55-69 years who do not ask for it (level C recommendation), according to the USPSTF recommendations, published in JAMA, which also recommend against any prostate cancer screening for men aged 70 years and older (level D recommendation). The recommendations replace those from 2012, and upgrade the statement against routine screening from a D to a C.

“The change in recommendation grade further reflects new evidence about and increased use of active surveillance of low-risk prostate cancer, which may reduce the risk of subsequent harms from screening,” according to the USPSTF.

The recommendations apply to asymptomatic adult men in the general United States population with no previous diagnosis of prostate cancer, as well as those whose ethnicity or family history put them at increased risk of death from prostate cancer.

In the evidence report published in JAMA, Joshua J. Fenton, MD, professor in the department of family and community medicine of the University of California, Davis, Sacramento, and his colleagues reviewed 63 studies comprising 1,904,950 individuals. The researchers examined the findings for information including the effectiveness of PSA screening and the potential harms associated with both screening and cancer treatment if disease was identified.

Overdiagnosis of prostate cancer ranged from 21% to 50% for cancers detected by screening, and one randomized trial of more than 1,000 men found no significant reduction in mortality for prostatectomy or radiation therapy compared with active monitoring.

Overall, men randomized to PSA screening had no significant reduction in risk of prostate cancer mortality in trials from the United States or the United Kingdom, although data from a European trial showed a significant reduction. Complications requiring hospitalization occurred in 0.5%-1.6% of men who had biopsies after screening showed abnormal results.

The evidence review was limited by several factors including a lack of data on newer treatments such as cryotherapy and high-intensity focused ultrasound, the researchers noted.

However, the data support an individualized approach to PSA screening for prostate cancer, in which each man can weigh the potential risks and benefits of screening, according to the USPSTF.

The research was funded by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose.

SOURCE: Fenton J et al. JAMA. 2018;319(18):1914-31. and JAMA. 2018;319(18):1901-13.

Nikesh Ardeshna, MD, MS, FAES

Case

A 73-year-old right-handed male presents with a history of mild depression (since his retirement about 2 years prior to the office visit) and benign prostatic hypertrophy.  For about 8 months, the patient had episodes of right hand tapping, or right foot tapping accompanied by staring, and sometimes by what was described as a pronounced swallow/gulp.  The total duration of these symptoms was less than one minute. The patient denied having any falls, major illness, or head trauma prior to the onset of symptoms. On initial evaluation the patient was diagnosed with anxiety. He elected not to start any medication.  

The symptoms continued, and the patient was not aware that they were occurring. For example, one episode occurred at the dinner table with guests. The patient tapped on the adjacent dinner plate, and the guests thought he was playing a joke. The patient’s wife took him for a re-evaluation, and an episode occurred in the physician’s office.

The physician ordered a routine electroencephalogram (EEG). The EEG showed frequent left frontal temporal sharp and slow waves. No seizures were recorded. The patient was referred to an epileptologist. He was started on lacosamide, with a slowly escalating dose.  Since being on a therapeutic dose the patient has not experienced any events, as reported by others.

Question 1: What is the patient’s diagnosis?

1. Anxiety
2. Depression
3. Tics
4. Partial epilepsy
5. Unknown

Answer: d) Partial Epilepsy

Partial epilepsy (recurrent partial seizures) can manifest with a combination of tapping, chewing, staring, and blinking, but it is not limited to these symptoms. These abnormal, unintended movements are automatisms.

Question 2: Which adverse events may take greater precedence in the elderly and must be considered when choosing which anti-seizure medication to prescribe?

1. Drowsiness
2. Cognitive slowing/slow processing
3. Unsteady gait
4. Double vision
5. All of the above

Answer: e) All of the above

Different anti-seizure drugs (ASDs) can have different adverse events. But, many potential adverse events are common to all ASDs although to differing extents, including but not limited to sleepiness/drowsiness and cognitive slowing/memory loss.  Elderly patients are more prone to falls, and may have preexisting memory or cognitive issues. Adverse events should be minimized to the greatest extent possible in the elderly.  Physicians should remember that each individual/case is unique.

Question 3: Which of the following demonstrates the correct match of a cause (etiology) of epilepsy and when seizures may begin due to that cause:

1. Stroke – 6 months
2. Brain tumor – 3 months
3. Dementia – 1 year
4. Idiopathic (unknown etiology) – childhood years
5. None of the above

Answer: e) None of the above

The above is only a partial list of causes of epilepsy. For symptomatic epilepsy – epilepsy due to a stroke, brain tumor, or dementia, there is not a specific timeframe in which/by which the seizures have to begin. Also, a significant number of cases of epilepsy are of unknown cause (idiopathic), and in these situations seizures can begin at any age, as is the case above.

Nikesh Ardeshna, MD, MS, FAES

Case

A 73-year-old right-handed male presents with a history of mild depression (since his retirement about 2 years prior to the office visit) and benign prostatic hypertrophy.  For about 8 months, the patient had episodes of right hand tapping, or right foot tapping accompanied by staring, and sometimes by what was described as a pronounced swallow/gulp.  The total duration of these symptoms was less than one minute. The patient denied having any falls, major illness, or head trauma prior to the onset of symptoms. On initial evaluation the patient was diagnosed with anxiety. He elected not to start any medication.  

The symptoms continued, and the patient was not aware that they were occurring. For example, one episode occurred at the dinner table with guests. The patient tapped on the adjacent dinner plate, and the guests thought he was playing a joke. The patient’s wife took him for a re-evaluation, and an episode occurred in the physician’s office.

The physician ordered a routine electroencephalogram (EEG). The EEG showed frequent left frontal temporal sharp and slow waves. No seizures were recorded. The patient was referred to an epileptologist. He was started on lacosamide, with a slowly escalating dose.  Since being on a therapeutic dose the patient has not experienced any events, as reported by others.

Question 1: What is the patient’s diagnosis?

1. Anxiety
2. Depression
3. Tics
4. Partial epilepsy
5. Unknown

Answer: d) Partial Epilepsy

Partial epilepsy (recurrent partial seizures) can manifest with a combination of tapping, chewing, staring, and blinking, but it is not limited to these symptoms. These abnormal, unintended movements are automatisms.

Question 2: Which adverse events may take greater precedence in the elderly and must be considered when choosing which anti-seizure medication to prescribe?

1. Drowsiness
2. Cognitive slowing/slow processing
3. Unsteady gait
4. Double vision
5. All of the above

Answer: e) All of the above

Different anti-seizure drugs (ASDs) can have different adverse events. But, many potential adverse events are common to all ASDs although to differing extents, including but not limited to sleepiness/drowsiness and cognitive slowing/memory loss.  Elderly patients are more prone to falls, and may have preexisting memory or cognitive issues. Adverse events should be minimized to the greatest extent possible in the elderly.  Physicians should remember that each individual/case is unique.

Question 3: Which of the following demonstrates the correct match of a cause (etiology) of epilepsy and when seizures may begin due to that cause:

1. Stroke – 6 months
2. Brain tumor – 3 months
3. Dementia – 1 year
4. Idiopathic (unknown etiology) – childhood years
5. None of the above

Answer: e) None of the above

The above is only a partial list of causes of epilepsy. For symptomatic epilepsy – epilepsy due to a stroke, brain tumor, or dementia, there is not a specific timeframe in which/by which the seizures have to begin. Also, a significant number of cases of epilepsy are of unknown cause (idiopathic), and in these situations seizures can begin at any age, as is the case above.

Nikesh Ardeshna, MD, MS, FAES

Case

A 73-year-old right-handed male presents with a history of mild depression (since his retirement about 2 years prior to the office visit) and benign prostatic hypertrophy.  For about 8 months, the patient had episodes of right hand tapping, or right foot tapping accompanied by staring, and sometimes by what was described as a pronounced swallow/gulp.  The total duration of these symptoms was less than one minute. The patient denied having any falls, major illness, or head trauma prior to the onset of symptoms. On initial evaluation the patient was diagnosed with anxiety. He elected not to start any medication.  

The symptoms continued, and the patient was not aware that they were occurring. For example, one episode occurred at the dinner table with guests. The patient tapped on the adjacent dinner plate, and the guests thought he was playing a joke. The patient’s wife took him for a re-evaluation, and an episode occurred in the physician’s office.

The physician ordered a routine electroencephalogram (EEG). The EEG showed frequent left frontal temporal sharp and slow waves. No seizures were recorded. The patient was referred to an epileptologist. He was started on lacosamide, with a slowly escalating dose.  Since being on a therapeutic dose the patient has not experienced any events, as reported by others.

Question 1: What is the patient’s diagnosis?

1. Anxiety
2. Depression
3. Tics
4. Partial epilepsy
5. Unknown

Answer: d) Partial Epilepsy

Partial epilepsy (recurrent partial seizures) can manifest with a combination of tapping, chewing, staring, and blinking, but it is not limited to these symptoms. These abnormal, unintended movements are automatisms.

Question 2: Which adverse events may take greater precedence in the elderly and must be considered when choosing which anti-seizure medication to prescribe?

1. Drowsiness
2. Cognitive slowing/slow processing
3. Unsteady gait
4. Double vision
5. All of the above

Answer: e) All of the above

Different anti-seizure drugs (ASDs) can have different adverse events. But, many potential adverse events are common to all ASDs although to differing extents, including but not limited to sleepiness/drowsiness and cognitive slowing/memory loss.  Elderly patients are more prone to falls, and may have preexisting memory or cognitive issues. Adverse events should be minimized to the greatest extent possible in the elderly.  Physicians should remember that each individual/case is unique.

Question 3: Which of the following demonstrates the correct match of a cause (etiology) of epilepsy and when seizures may begin due to that cause:

1. Stroke – 6 months
2. Brain tumor – 3 months
3. Dementia – 1 year
4. Idiopathic (unknown etiology) – childhood years
5. None of the above

Answer: e) None of the above

The above is only a partial list of causes of epilepsy. For symptomatic epilepsy – epilepsy due to a stroke, brain tumor, or dementia, there is not a specific timeframe in which/by which the seizures have to begin. Also, a significant number of cases of epilepsy are of unknown cause (idiopathic), and in these situations seizures can begin at any age, as is the case above.

The addition of the two latest treatment regimens for hepatitis C essentially closes the circle on treatment of this disease. Don’t shorten therapy for older, sicker cellulitis patients, apixaban and rivaroxaban reversal agent gets FDA approval, and do black women pay a price for hair care products?

Listen to the MDedge Daily News podcast for all the details on today’s top news.






 

The addition of the two latest treatment regimens for hepatitis C essentially closes the circle on treatment of this disease. Don’t shorten therapy for older, sicker cellulitis patients, apixaban and rivaroxaban reversal agent gets FDA approval, and do black women pay a price for hair care products?

Listen to the MDedge Daily News podcast for all the details on today’s top news.






 

The addition of the two latest treatment regimens for hepatitis C essentially closes the circle on treatment of this disease. Don’t shorten therapy for older, sicker cellulitis patients, apixaban and rivaroxaban reversal agent gets FDA approval, and do black women pay a price for hair care products?

Listen to the MDedge Daily News podcast for all the details on today’s top news.






 

NEW YORK – The proportion of physicians who commit suicide each year is greater than the proportion of Americans who die of an opioid overdose, according to a series of sobering statistics on physician burnout presented at the American Psychiatric Association annual meeting.

“There are about 400 physician suicides very year, which is proportional rate that is about twice the suicide rate in the general population,” reported Darrell G. Kirch, MD, president and chief executive officer of the Association of American Medical Colleges, Washington.

humonia/Thinkstock

Many tools already generated by this collaboration can be found in the NAM website at nam.edu/clinicianwellbeing. This section of the website not only includes data about burnout as well as presentation slides for download on the topic, but it is expected to be “a growing repository for solutions that work,” Dr. Kirch said.

Ted Bosworth/MDedge News

“It strikes me that if you need a chief wellness officer who not only can understand the dynamics of burnout but can understand what a short path it is from being burned out to being depressed, suicidal, or addicted, who would be better suited than a psychiatrist? I really think that in many ways, this may be a career path for psychiatrists,” Dr. Kirch said.

Even with the appointment of chief wellness officers, the problem will not soon go away. Although Dr. Kirch believes interventions are needed from the beginning of medical training, he acknowledged that eliminating burnout “is a heavy lift, because there is no single solution.” Listing regulatory burdens, administrative burdens, lack of support staff, and a sense of isolation among documented causes of burnout, he believes identifying all of the solutions to relieve stress and improve clinical satisfaction “will be a journey.”

Dr. Kirch reported no potential conflicts of interest.

NEW YORK – The proportion of physicians who commit suicide each year is greater than the proportion of Americans who die of an opioid overdose, according to a series of sobering statistics on physician burnout presented at the American Psychiatric Association annual meeting.

“There are about 400 physician suicides very year, which is proportional rate that is about twice the suicide rate in the general population,” reported Darrell G. Kirch, MD, president and chief executive officer of the Association of American Medical Colleges, Washington.

humonia/Thinkstock

Many tools already generated by this collaboration can be found in the NAM website at nam.edu/clinicianwellbeing. This section of the website not only includes data about burnout as well as presentation slides for download on the topic, but it is expected to be “a growing repository for solutions that work,” Dr. Kirch said.

Ted Bosworth/MDedge News

“It strikes me that if you need a chief wellness officer who not only can understand the dynamics of burnout but can understand what a short path it is from being burned out to being depressed, suicidal, or addicted, who would be better suited than a psychiatrist? I really think that in many ways, this may be a career path for psychiatrists,” Dr. Kirch said.

Even with the appointment of chief wellness officers, the problem will not soon go away. Although Dr. Kirch believes interventions are needed from the beginning of medical training, he acknowledged that eliminating burnout “is a heavy lift, because there is no single solution.” Listing regulatory burdens, administrative burdens, lack of support staff, and a sense of isolation among documented causes of burnout, he believes identifying all of the solutions to relieve stress and improve clinical satisfaction “will be a journey.”

Dr. Kirch reported no potential conflicts of interest.

NEW YORK – The proportion of physicians who commit suicide each year is greater than the proportion of Americans who die of an opioid overdose, according to a series of sobering statistics on physician burnout presented at the American Psychiatric Association annual meeting.

“There are about 400 physician suicides very year, which is proportional rate that is about twice the suicide rate in the general population,” reported Darrell G. Kirch, MD, president and chief executive officer of the Association of American Medical Colleges, Washington.

humonia/Thinkstock

Many tools already generated by this collaboration can be found in the NAM website at nam.edu/clinicianwellbeing. This section of the website not only includes data about burnout as well as presentation slides for download on the topic, but it is expected to be “a growing repository for solutions that work,” Dr. Kirch said.

Ted Bosworth/MDedge News

“It strikes me that if you need a chief wellness officer who not only can understand the dynamics of burnout but can understand what a short path it is from being burned out to being depressed, suicidal, or addicted, who would be better suited than a psychiatrist? I really think that in many ways, this may be a career path for psychiatrists,” Dr. Kirch said.

Even with the appointment of chief wellness officers, the problem will not soon go away. Although Dr. Kirch believes interventions are needed from the beginning of medical training, he acknowledged that eliminating burnout “is a heavy lift, because there is no single solution.” Listing regulatory burdens, administrative burdens, lack of support staff, and a sense of isolation among documented causes of burnout, he believes identifying all of the solutions to relieve stress and improve clinical satisfaction “will be a journey.”

Dr. Kirch reported no potential conflicts of interest.

From the Karmanos Cancer Institute, Detroit, MI (Dr. Mamdani) and the Indiana University School of Medicine, Indianapolis, IN (Dr. Jalal). 

Abstract

• Objective: To review the clinical aspects and current practices of management of small cell lung cancer (SCLC).
• Methods: Review of the literature.
• Results: SCLC is an aggressive cancer of neuroendocrine origin with a very strong association with smoking. Approximately 25% of patients present with limited-stage disease while the remaining majority of patients have extensive-stage disease, defined as disease extending beyond one hemithorax at the time of diagnosis. SCLC is often associated with endocrine or neurologic paraneoplastic syndromes. The treatment of limited-stage disease consists of platinum-based chemotherapy administered concurrently with radiation. Patients with partial or complete response should be offered prophylactic cranial radiation (PCI). Extensive-stage disease is largely treated with platinum-based chemotherapy and the role of PCI is more controversial. The efficacy of second-line chemotherapy after disease progression on platinum based chemotherapy is limited.
• Conclusion: Despite a number of advances in the treatment of various malignancies over the period of past several years, the prognosis of patients with SCLC remains poor. There have been a number of clinical trials utilizing novel therapeutic agents to improve outcomes of these patients; however, few of them have shown marginal success in a very select subgroup of patients.

Key words: lung cancer; small-cell lung cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer of neuroendocrine origin, accounting for approximately 15% of all lung cancer cases, with approximately 33,000 patients diagnosed annually [1]. The incidence of SCLC in the United States has steadily declined over the past 30 years presumably because of decrease in the percentage of smokers and change to low-tar filter cigarettes [2]. Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1 [3]. Nearly all cases of SCLC are associated with heavy tobacco exposure, making it a heterogeneous disease with complex genomic landscape consisting of thousands of mutations [4,5]. Despite a number of advances in the treatment of non-small cell lung cancer over the past decade, the therapeutic landscape of SCLC remains narrow with median overall survival (OS) of 9 months in patients with advanced disease.

Case Study

Initial Presentation

A 61-year-old man presents to the emergency department with progressive shortness of breath and cough over the period of past 6 weeks. He also reports having had 20-lb weight loss over the same period of time. He is a current smoker and has been smoking one pack of cigarettes per day since the age of 18 years. A chest x-ray performed in the emergency department shows a right hilar mass. Computed tomography (CT) scan confirms the presence of a 4.5 cm right hilar mass with presence of enlarged mediastinal lymph nodes bilaterally.

What are the next steps in diagnosis?

SCLC is characterized by rapid growth and early hematogenous metastases. Consequently, only 25% of patients have limited-stage disease at the time of diagnosis. According to the VA staging system, limited-stage disease is defined as tumor that is confined to one hemithorax and can be encompassed within one radiation field. This typically includes mediastinal lymph nodes and ipsilateral supraclavicular lymph nodes. Extensive-stage disease is the presentation in 75% of the patients where the disease extends beyond one hemithorax. Extensive-stage disease includes presence of malignant pleural effusion and/or distant metastasis [6]. The Veterans Administration Lung Study Group (VALG) classification and staging system is more commonly used compared to the AJCC TNM staging system since it is less complex, directs treatment decisions, and correlates closely with prognosis. Given its propensity to metastasize quickly, none of the currently available screening methods have proven to be successful in early detection of SCLC. Eighty-six percent of the 125 patients that were diagnosed with SCLC while undergoing annual low-dose chest CT scans on National Lung Cancer Screening Trial had advanced disease at diagnosis [7,8]. These results highlight the fact that he majority of the SCLC develop in the interval between annual screening imaging.

SCLC frequently presents with a large hilar mass that is symptomatic. In addition, SCLC usually presents with centrally located tumors and bulky mediastinal adenopathy. Common symptoms include shortness of breath and cough. SCLC is commonly located submucosally in the bronchus and therefore hemoptysis is not a very common symptom at the time of presentation. Patients may present with superior vena cava (SVC) syndrome from local compression by the tumor. Not infrequently, SCLC is associated with paraneoplastic syndromes (PNS) owing to the ectopic secretion of hormones or antibodies by the tumor cells. The PNS can be broadly categorized into endocrine and neurologic; and are summarized in Table 1. 

The common sites of metastases include brain, liver, and bone. Therefore, the staging workup should include fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan. Contrast-enhanced CT scan of chest and abdomen and bone scan can be obtained for staging in lieu of PET scan. Due to the physiologic FDG uptake, cerebral metastases cannot be assessed with sufficient certainty using the PET-CT. Therefore, brain imaging with contrast enhanced CT or MRI is also necessary. Although the incidence of metastasis to bone marrow is less than 10%, bone marrow aspiration and biopsy is warranted in case of unexplained cytopenias, especially when associated with teardrop red cells or nucleated red cells on peripheral blood smear indicative of marrow infiltrative process. The tissue diagnosis is established by obtaining a biopsy of the primary tumor or one of the metastatic sites. In case of localized disease, bronchoscopy (if necessary, with endobronchial ultrasound) with biopsy of centrally located tumor and/or lymph node is required. Histologically, SCLC consists of monomorphic cells, a high nucleus:cytoplasmic ratio, and confluent necrosis. The tumor cells are positive for chromogranin, synaptophysin, and CD56 by immunohistochemistry. Very frequently the cells are also positive for TTF1. Although serum tumor markers, including neuron-specific enolase (NSE) and progastrin-releasing peptide (prGRP), are frequently elevated in patients with SCLC, they are of limited value in clinical practice owing to their lack of sensitivity and specificity.

Case Continued

The patient underwent FDG-PET scan that showed the presence of hypermetabolic right hilar mass in addition to enlarged and hypermetabolic bilateral mediastinal lymph nodes. There were no other areas of FDG avidity. His brain MRI did not show any evidence of brain metastasis. Thus, he was confirmed to have limited-stage SCLC.

What is the standard of care for limited-stage SCLC?

SCLC is exquisitely sensitive to both chemotherapy and radiation, especially at the time of initial presentation. The standard of care for the treatment of limited stage SCLC is 4 cycles of platinum-based chemotherapy in combination with thoracic radiation started within the first 2 cycles of chemotherapy (Figure 1). 

Choice of Chemotherapy

Etoposide and cisplatin is the most commonly used initial combination chemotherapy regimen [9]. This combination has largely replaced anthracycline-based regimens given its favorable efficacy and toxicity profile [10–12]. Several small randomized trials have shown comparable efficacy of carboplatin and etoposide in extensive stage SCLC [13–15]. A meta-analysis of 4 randomized trials, including 663 patients with SCLC, comparing cisplatin-based versus carboplatin-based regimens where 32% of patients had limited stage disease and 68% had extensive stage disease showed no statistically significant difference in the response rate, progression free survival (PFS), or OS between the two regimens [16]. Therefore, in clinical practice carboplatin is frequently used instead of cisplatin in patients with extensive-stage disease. In patients with limited-stage disease, cisplatin is still the drug of choice. However, the toxicity profile of the two regimens is different. Cisplatin based regimens are more commonly associated with neuropathy, nephrotoxicity, and chemotherapy induced nausea/vomiting [13], while carboplatin-based regimens are more myelosuppressive [17]. In addition, the combination of thoracic radiation with either of these regiments is associated with higher risk of esophagitis, pneumonitis, and myelosuppression [18]. The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation [19]. Of note, intravenous (IV) etoposide is always preferred over oral etoposide, especially in curative setting given unreliable absorption and bioavailability of oral formulations.

Thoracic Radiation

The addition of thoracic radiation to platinum-etoposide chemotherapy improves local control and OS. Two meta-analyses of 13 trials including more than 2000 patients have shown 25% to 30% decrease in local failure and 5% to 7% increase in 2-year OS with chemoradiation compared to chemotherapy alone in limited stage SCLC [20,21]. Early (with the first 2 cycles) concurrent thoracic radiation is superior to delayed and/or sequential radiation in terms of local control and OS [18,22,23]. The dose and fractionation of thoracic radiation in limited-stage SCLC has remained a controversial issue. The ECOG/RTOG randomized trial compared 45 Gy radiation delivered twice daily over a period of 3 weeks with once a day over 5 weeks, concurrently with chemotherapy. The twice a day regimen led to 10% improvement in 5-year OS (26% vs 16%), but higher incidence of grade 3 and 4 adverse events [24]. Despite the survival advantage demonstrated by hyperfractionated radiotherapy, the results need to be interpreted with caution because the radiation doses are not biologically equivalent. In addition the difficult logistics of patients receiving radiation twice a day has limited the routine implementation of this strategy. Subsequently, another randomized phase III trial (CONVERT) compared 45 Gy twice daily with 66 Gy once daily radiation in this setting. This trial did not show any difference in OS. The patients in twice daily arm had higher incidence of grade 4 neutropenia [25]. Considering the results of these trials, both strategies—45 Gy fractionated twice daily or 60 Gy fractionated once daily, delivered concurrently with chemotherapy—are acceptable in the setting of limited-stage SCLC. However, quite often hyperfractionated regimen is not feasible for the patients and many radiation oncology centers. Hopefully the CALBG 30610 study, which is ongoing, will clarify the optimal radiation schedule for limited-stage disease.

Prophylactic Cranial Irradiation

Approximately 75% of patients with limited-stage disease experience disease recurrence and brain is the site of recurrence in approximately half of these patients. Prophylactic cranial irradiation (PCI) consisting of 25 Gy radiation delivered in 10 fractions has been shown to be effective in decreasing the incidence of cerebral metastases [26–28]. Although individual small studies have not shown survival benefit of PCI because of small sample size and limited power, a meta-analysis of these studies has shown 25% decrease in the 3-year incidence of brain metastasis and 5.4% increase in 3-year OS [27]. The majority of patients included in these studies had limited-stage disease. Therefore, PCI is the standard of care for patients with limited-stage disease who attain a partial or complete response to chemoradiation.

Role of Surgery

Surgical resection may be an acceptable choice in a very limited subset of patients with peripherally located small (< 5 cm) tumors where mediastinal lymph nodes have been confirmed to be uninvolved with complete mediastinal staging [29,30]. Most of the data in this setting are derived from retrospective studies [31,32]. A 5-year OS of 40% to 60% has been has been reported with this strategy in patients with clinical stage I disease. In general, when surgery is considered, lobectomy with mediastinal lymph node dissection followed by chemotherapy (if no nodal involvement) or chemoradiation (if nodal involvement) is recommended [33,34]. Wedge or segmental resections are not considered to be optimum surgical options.

Case Continued

The patient received 4 cycles of cisplatin and etoposide along with 70 Gy radiation concurrently with the first 2 cycles of chemotherapy. His post-treatment CT scans showed partial response (PR). The patient underwent PCI 6 weeks after completion of treatment. Eighteen months later, the patient comes to the clinic for routine follow-up. He is doing generally well except for mildly decreased appetite and unintentional loss of 5 lb weight. His CT scans demonstrate multiple hypodense liver lesions ranging from 7 mm to 2 cm in size and a 2 cm left adrenal gland lesion highly concerning for metastasis. FDG PET scan confirmed the adrenal and liver lesions to be hypermetabolic. In addition, the PET showed multiple FDG avid bone lesions throughout the spine. Brain MRI was negative for any brain metastasis.

What is the standard of care for extensive-stage SCLC?

For extensive-stage SCLC, chemotherapy is the mainstay of treatment, with the goals of treatment being prolongation of survival, prevention or alleviation of cancer-related symptoms, and improvement in quality of life. The combination of etoposide with a platinum agent (carboplatin or cisplatin) is the preferred first-line treatment option (Figure 2). 

Multiple attempts at improving first-line chemotherapy in extensive-stage disease have failed to show any meaningful difference in OS. For example, addition of ifosfamide, palifosfamide, cyclophosphamide, taxane, or anthracycline to platinum doublet failed to show improvement in OS and led to more toxicity [39–42]. Additionally, the use of alternating or cyclic chemotherapies in an attempt to curb drug resistance has also failed to show survival benefit [43–45]. The addition of antiangiogenic agent bevacizumab to standard platinum-based doublet has not yielded prolongation of OS in SCLC and led to unacceptably higher rate of tracheoesophageal fistula when used in conjunction with chemoradiation in limited-stage disease [46–51]. Finally, the immune checkpoint inhibitor ipilimumab in combination with platinum plus etoposide failed to improve PFS or OS compared to platinum plus etoposide alone in a recent phase III trial and maintenance pembrolizumab after completion of platinum-based chemotherapy did not improve PFS [52,53].

Patients with extensive-stage disease who have brain metastasis at the time of diagnosis can be treated with systemic chemotherapy first if brain metastases are asymptomatic and there is significant extracranial disease burden. In that case, whole brain radiotherapy should be given after completion of systemic therapy.

Second-Line Therapy

Despite being exquisitely chemo-sensitive, SCLC is associated with very poor prognosis largely because of invariable disease progression following first-line therapy and lack of effective second-line treatment options that can lead to appreciable disease control. The choice of second-line treatment is predominantly determined by the time of disease relapse since first-line platinum based therapy. If this interval is 6 months or longer, re-treatment utilizing the same platinum doublet is appropriate. However, if the interval is 6 months or less, second-line systemic therapy options should be explored. Unfortunately, the response rate tends to be less than 10% with most of the second-line therapies in platinum-resistant disease (defined as disease progression within 3 months of receiving platinum-based therapy). If the disease progression occurs between 3 to 6 months since platinum-based therapy, the response rate with second-line chemotherapy is in the range of 25% [54,55]. A number of second-line chemotherapy options have been explored in small studies, including topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, oral etoposide, gemcitabine, bendamustine, and CAV (cyclophosphamide, adriamycin, vincristine) (Table 2). 

Immunotherapy

The role of immune checkpoint inhibitors in the treatment of SCLC is evolving and currently there are no FDA-approved immunotherapy agents in SCLC. A recently conducted phase I/II trial (CheckMate 032) of anti-PD-1 antibody nivolumab with or without anti-CTLA-1 antibody ipilimumab in patients with relapsed SCLC reported a response rate of 10% with nivolumab 3 mg/kg and 21% with nivolumab 1 mg/kg + ipilimumab 3 mg/kg. The 2-year OS was 26% with the combination and 14% with single agent nivolumab [56,57]. Only 18% of patients had PD-L1 expression of ≥ 1% and the response rate did not correlate with PD-L1 status. The rate of grade 3 or 4 adverse events was approximately 20% and only 10% of patients discontinued treatment because of toxicity. Based on these data, nivolumab plus ipilimumab is now included in the NCCN guidelines as one of the options for patients with SCLC who experience disease relapse within 6 months of receiving platinum-based therapy; however, it is questionable whether routine use of this combination is justified based on currently available data. However the evidence for the combination of nivolumab and ipilimumab remains limited. This efficacy and toxicity data of both randomized and nonrandomized cohorts were presented together making it hard to interpret the results.

Another phase Ib study (KEYNOTE-028) utilizing anti-PD-1 antibody pembrolizumab 10 mg/kg IV every 2 weeks in patients with relapsed SCLC after receiving one or more prior lines of therapy and PD-L1 expression of ≥ 1% showed a response rate of 33% with median duration of response of 19 months and 1-year OS of 38% [58]. Although only 28% of screened patients had PD-L1 expression of ≥ 1% , these results indicated that at least a subset of SCLC patients are able to achieve durable responses with immune checkpoint inhibition. A number of clinical trials utilizing immune checkpoint inhibitors in various combinations and settings are currently underway.

Role of Prophylactic Cranial Irradiation

The role of PCI in extensive-stage SCLC is not clearly defined. A randomized phase III trial conducted by EORTC comparing PCI with no PCI in patients with extensive-stage SCLC who had attained partial or complete response to initial platinum-based chemotherapy showed decrease in the incidence of symptomatic brain metastasis and improvement in 1-year OS with PCI. However, this trial did not require mandatory brain imaging prior to PCI and therefore it is unclear if some patients in the PCI group had asymptomatic brain metastasis prior to enrollment and therefore received therapeutic benefit from brain radiation. Additionally, the dose and fractionation of PCI was not standardized across patient groups. A more recent phase III study conducted in Japan that compared PCI (25Gy in 10 fractions) with no PCI reported no difference in survival between the two groups. As opposed to EORTC study, the Japanese study did require baseline brain imaging to confirm absence of brain metastasis prior to enrollment. In addition, the patients in the control arm underwent periodic brain MRI to allow early detection of brain metastasis [59]. Given the emergence of the new data, the impact of PCI on survival in patients with extensive-stage SCLC is unproven and PCI likely has a role in a highly select small group of patients with extensive-stage SCLC. PCI is not recommended for patients with poor performance status (ECOG PS 3–4) or underlying neurocognitive disorders [33,60]. NMDA receptor antagonist memantine can be used in patients undergoing PCI to delay the occurrence of cognitive dysfunction [61]. Memantine 20 mg daily delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared to placebo in patients receiving whole brain radiation [61].

Role of Radiation

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiation after completion of platinum-based chemotherapy. A randomized trial including patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiation in combination with continued chemotherapy versus chemotherapy alone [62]. The median OS was longer with the addition of thoracic radiation compared to chemotherapy alone. Another phase III trial did not show improvement in 1-year OS with consolidative thoracic radiation, but 2-year OS and 6-month PFS were longer [63]. In general, consolidative thoracic radiation benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy [64]. In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiation should be utilized for palliative purposes in patients with painful bone metastasis, spine cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy with extensive stage disease. Whole brain radiotherapy is preferred over SRS because of frequent presence of micrometastasis even in the setting of one or two radiographically evident brain metastasis.

Novel Therapies

A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate; however, at the same time this complexity can form the basis for effective targeted therapy for the disease. One of the major limitations to the development of targeted therapies in SCLC is limited availability of tissue owing to small tissue samples and frequent presence of significant necrosis in the samples. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them, including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors, have been unsuccessful in showing a survival advantage in this disease. Several others including PARP inhibitors, cellular developmental pathway inhibitors and antibody drug conjugates are being tested. A phase I study of veliparib combined with cisplatin and etoposide in patients with previously untreated extensive-stage SCLC demonstrated complete response in 14.3%, partial response in 57.1%, and stable disease in 28.6% of patients with acceptable safety profile [65]. So far, none of these agents are approved for use in SCLC and the majority are in early phase clinical trials [66].

One of the emerging targets in the treatment of SCLC is DLL3. DLL3 is expressed on > 80% SCLCL tumor cells and cancer stem cells. Rovalpituzumab tesirine (ROVA-T) is an antibody drug conjugate consisting of humanized anti-DLL3 monoclonal antibody linked to SC-DR002, a DNA-crosslinking agent. A phase I trial of ROVA-T in patients with relapsed SCLC after 1 or 2 prior lines of therapies reported a response rate of 31% in patients with DLL3 expression of ≥ 50%. The median duration of response and mPFS were 4.6 months [67]. ROVA-T is currently in later phases of clinical trials and has a potential to serve as one of the options for patients with extensive-stage disease after disease progression on platinum-based therapy.

Response Assessment/Surveillance

For patients undergoing treatment for limited-stage SCLC, response assessment with contrast-enhanced CT of the chest/abdomen should be performed after completion of 4 cycles of chemotherapy and thoracic radiation. The surveillance guidelines consist of history, physical exam, and imaging every 3 months during 1st 2 years, every 6 months during the 3rdyear, and annually thereafter. If PCI is not performed, brain MRI or contrast enhanced CT scan should be performed every 3 to 4 months during the first 2 years of follow-up. For extensive-stage disease, response assessment should be performed after every 2 cycles of therapy. After completion of therapy, history, physical exam, and imaging should be done every 2 months during the 1st year, every 3 to 4 months during year 2 and 3, every 6 months during years 4 and 5, and annually thereafter. Routine use of PET scan for surveillance is not recommended. Any new pulmonary nodule should prompt evaluation for a second primary lung malignancy. Finally, smoking cessation counseling is an integral part of management of any patient with SCLC and should be included with every clinic visit.

Corresponding author: Hirva Mamdani, MD, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, [email protected].

Financial disclosures: None.

From the Karmanos Cancer Institute, Detroit, MI (Dr. Mamdani) and the Indiana University School of Medicine, Indianapolis, IN (Dr. Jalal). 

Abstract

• Objective: To review the clinical aspects and current practices of management of small cell lung cancer (SCLC).
• Methods: Review of the literature.
• Results: SCLC is an aggressive cancer of neuroendocrine origin with a very strong association with smoking. Approximately 25% of patients present with limited-stage disease while the remaining majority of patients have extensive-stage disease, defined as disease extending beyond one hemithorax at the time of diagnosis. SCLC is often associated with endocrine or neurologic paraneoplastic syndromes. The treatment of limited-stage disease consists of platinum-based chemotherapy administered concurrently with radiation. Patients with partial or complete response should be offered prophylactic cranial radiation (PCI). Extensive-stage disease is largely treated with platinum-based chemotherapy and the role of PCI is more controversial. The efficacy of second-line chemotherapy after disease progression on platinum based chemotherapy is limited.
• Conclusion: Despite a number of advances in the treatment of various malignancies over the period of past several years, the prognosis of patients with SCLC remains poor. There have been a number of clinical trials utilizing novel therapeutic agents to improve outcomes of these patients; however, few of them have shown marginal success in a very select subgroup of patients.

Key words: lung cancer; small-cell lung cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer of neuroendocrine origin, accounting for approximately 15% of all lung cancer cases, with approximately 33,000 patients diagnosed annually [1]. The incidence of SCLC in the United States has steadily declined over the past 30 years presumably because of decrease in the percentage of smokers and change to low-tar filter cigarettes [2]. Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1 [3]. Nearly all cases of SCLC are associated with heavy tobacco exposure, making it a heterogeneous disease with complex genomic landscape consisting of thousands of mutations [4,5]. Despite a number of advances in the treatment of non-small cell lung cancer over the past decade, the therapeutic landscape of SCLC remains narrow with median overall survival (OS) of 9 months in patients with advanced disease.

Case Study

Initial Presentation

A 61-year-old man presents to the emergency department with progressive shortness of breath and cough over the period of past 6 weeks. He also reports having had 20-lb weight loss over the same period of time. He is a current smoker and has been smoking one pack of cigarettes per day since the age of 18 years. A chest x-ray performed in the emergency department shows a right hilar mass. Computed tomography (CT) scan confirms the presence of a 4.5 cm right hilar mass with presence of enlarged mediastinal lymph nodes bilaterally.

What are the next steps in diagnosis?

SCLC is characterized by rapid growth and early hematogenous metastases. Consequently, only 25% of patients have limited-stage disease at the time of diagnosis. According to the VA staging system, limited-stage disease is defined as tumor that is confined to one hemithorax and can be encompassed within one radiation field. This typically includes mediastinal lymph nodes and ipsilateral supraclavicular lymph nodes. Extensive-stage disease is the presentation in 75% of the patients where the disease extends beyond one hemithorax. Extensive-stage disease includes presence of malignant pleural effusion and/or distant metastasis [6]. The Veterans Administration Lung Study Group (VALG) classification and staging system is more commonly used compared to the AJCC TNM staging system since it is less complex, directs treatment decisions, and correlates closely with prognosis. Given its propensity to metastasize quickly, none of the currently available screening methods have proven to be successful in early detection of SCLC. Eighty-six percent of the 125 patients that were diagnosed with SCLC while undergoing annual low-dose chest CT scans on National Lung Cancer Screening Trial had advanced disease at diagnosis [7,8]. These results highlight the fact that he majority of the SCLC develop in the interval between annual screening imaging.

SCLC frequently presents with a large hilar mass that is symptomatic. In addition, SCLC usually presents with centrally located tumors and bulky mediastinal adenopathy. Common symptoms include shortness of breath and cough. SCLC is commonly located submucosally in the bronchus and therefore hemoptysis is not a very common symptom at the time of presentation. Patients may present with superior vena cava (SVC) syndrome from local compression by the tumor. Not infrequently, SCLC is associated with paraneoplastic syndromes (PNS) owing to the ectopic secretion of hormones or antibodies by the tumor cells. The PNS can be broadly categorized into endocrine and neurologic; and are summarized in Table 1. 

The common sites of metastases include brain, liver, and bone. Therefore, the staging workup should include fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan. Contrast-enhanced CT scan of chest and abdomen and bone scan can be obtained for staging in lieu of PET scan. Due to the physiologic FDG uptake, cerebral metastases cannot be assessed with sufficient certainty using the PET-CT. Therefore, brain imaging with contrast enhanced CT or MRI is also necessary. Although the incidence of metastasis to bone marrow is less than 10%, bone marrow aspiration and biopsy is warranted in case of unexplained cytopenias, especially when associated with teardrop red cells or nucleated red cells on peripheral blood smear indicative of marrow infiltrative process. The tissue diagnosis is established by obtaining a biopsy of the primary tumor or one of the metastatic sites. In case of localized disease, bronchoscopy (if necessary, with endobronchial ultrasound) with biopsy of centrally located tumor and/or lymph node is required. Histologically, SCLC consists of monomorphic cells, a high nucleus:cytoplasmic ratio, and confluent necrosis. The tumor cells are positive for chromogranin, synaptophysin, and CD56 by immunohistochemistry. Very frequently the cells are also positive for TTF1. Although serum tumor markers, including neuron-specific enolase (NSE) and progastrin-releasing peptide (prGRP), are frequently elevated in patients with SCLC, they are of limited value in clinical practice owing to their lack of sensitivity and specificity.

Case Continued

The patient underwent FDG-PET scan that showed the presence of hypermetabolic right hilar mass in addition to enlarged and hypermetabolic bilateral mediastinal lymph nodes. There were no other areas of FDG avidity. His brain MRI did not show any evidence of brain metastasis. Thus, he was confirmed to have limited-stage SCLC.

What is the standard of care for limited-stage SCLC?

SCLC is exquisitely sensitive to both chemotherapy and radiation, especially at the time of initial presentation. The standard of care for the treatment of limited stage SCLC is 4 cycles of platinum-based chemotherapy in combination with thoracic radiation started within the first 2 cycles of chemotherapy (Figure 1). 

Choice of Chemotherapy

Etoposide and cisplatin is the most commonly used initial combination chemotherapy regimen [9]. This combination has largely replaced anthracycline-based regimens given its favorable efficacy and toxicity profile [10–12]. Several small randomized trials have shown comparable efficacy of carboplatin and etoposide in extensive stage SCLC [13–15]. A meta-analysis of 4 randomized trials, including 663 patients with SCLC, comparing cisplatin-based versus carboplatin-based regimens where 32% of patients had limited stage disease and 68% had extensive stage disease showed no statistically significant difference in the response rate, progression free survival (PFS), or OS between the two regimens [16]. Therefore, in clinical practice carboplatin is frequently used instead of cisplatin in patients with extensive-stage disease. In patients with limited-stage disease, cisplatin is still the drug of choice. However, the toxicity profile of the two regimens is different. Cisplatin based regimens are more commonly associated with neuropathy, nephrotoxicity, and chemotherapy induced nausea/vomiting [13], while carboplatin-based regimens are more myelosuppressive [17]. In addition, the combination of thoracic radiation with either of these regiments is associated with higher risk of esophagitis, pneumonitis, and myelosuppression [18]. The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation [19]. Of note, intravenous (IV) etoposide is always preferred over oral etoposide, especially in curative setting given unreliable absorption and bioavailability of oral formulations.

Thoracic Radiation

The addition of thoracic radiation to platinum-etoposide chemotherapy improves local control and OS. Two meta-analyses of 13 trials including more than 2000 patients have shown 25% to 30% decrease in local failure and 5% to 7% increase in 2-year OS with chemoradiation compared to chemotherapy alone in limited stage SCLC [20,21]. Early (with the first 2 cycles) concurrent thoracic radiation is superior to delayed and/or sequential radiation in terms of local control and OS [18,22,23]. The dose and fractionation of thoracic radiation in limited-stage SCLC has remained a controversial issue. The ECOG/RTOG randomized trial compared 45 Gy radiation delivered twice daily over a period of 3 weeks with once a day over 5 weeks, concurrently with chemotherapy. The twice a day regimen led to 10% improvement in 5-year OS (26% vs 16%), but higher incidence of grade 3 and 4 adverse events [24]. Despite the survival advantage demonstrated by hyperfractionated radiotherapy, the results need to be interpreted with caution because the radiation doses are not biologically equivalent. In addition the difficult logistics of patients receiving radiation twice a day has limited the routine implementation of this strategy. Subsequently, another randomized phase III trial (CONVERT) compared 45 Gy twice daily with 66 Gy once daily radiation in this setting. This trial did not show any difference in OS. The patients in twice daily arm had higher incidence of grade 4 neutropenia [25]. Considering the results of these trials, both strategies—45 Gy fractionated twice daily or 60 Gy fractionated once daily, delivered concurrently with chemotherapy—are acceptable in the setting of limited-stage SCLC. However, quite often hyperfractionated regimen is not feasible for the patients and many radiation oncology centers. Hopefully the CALBG 30610 study, which is ongoing, will clarify the optimal radiation schedule for limited-stage disease.

Prophylactic Cranial Irradiation

Approximately 75% of patients with limited-stage disease experience disease recurrence and brain is the site of recurrence in approximately half of these patients. Prophylactic cranial irradiation (PCI) consisting of 25 Gy radiation delivered in 10 fractions has been shown to be effective in decreasing the incidence of cerebral metastases [26–28]. Although individual small studies have not shown survival benefit of PCI because of small sample size and limited power, a meta-analysis of these studies has shown 25% decrease in the 3-year incidence of brain metastasis and 5.4% increase in 3-year OS [27]. The majority of patients included in these studies had limited-stage disease. Therefore, PCI is the standard of care for patients with limited-stage disease who attain a partial or complete response to chemoradiation.

Role of Surgery

Surgical resection may be an acceptable choice in a very limited subset of patients with peripherally located small (< 5 cm) tumors where mediastinal lymph nodes have been confirmed to be uninvolved with complete mediastinal staging [29,30]. Most of the data in this setting are derived from retrospective studies [31,32]. A 5-year OS of 40% to 60% has been has been reported with this strategy in patients with clinical stage I disease. In general, when surgery is considered, lobectomy with mediastinal lymph node dissection followed by chemotherapy (if no nodal involvement) or chemoradiation (if nodal involvement) is recommended [33,34]. Wedge or segmental resections are not considered to be optimum surgical options.

Case Continued

The patient received 4 cycles of cisplatin and etoposide along with 70 Gy radiation concurrently with the first 2 cycles of chemotherapy. His post-treatment CT scans showed partial response (PR). The patient underwent PCI 6 weeks after completion of treatment. Eighteen months later, the patient comes to the clinic for routine follow-up. He is doing generally well except for mildly decreased appetite and unintentional loss of 5 lb weight. His CT scans demonstrate multiple hypodense liver lesions ranging from 7 mm to 2 cm in size and a 2 cm left adrenal gland lesion highly concerning for metastasis. FDG PET scan confirmed the adrenal and liver lesions to be hypermetabolic. In addition, the PET showed multiple FDG avid bone lesions throughout the spine. Brain MRI was negative for any brain metastasis.

What is the standard of care for extensive-stage SCLC?

For extensive-stage SCLC, chemotherapy is the mainstay of treatment, with the goals of treatment being prolongation of survival, prevention or alleviation of cancer-related symptoms, and improvement in quality of life. The combination of etoposide with a platinum agent (carboplatin or cisplatin) is the preferred first-line treatment option (Figure 2). 

Multiple attempts at improving first-line chemotherapy in extensive-stage disease have failed to show any meaningful difference in OS. For example, addition of ifosfamide, palifosfamide, cyclophosphamide, taxane, or anthracycline to platinum doublet failed to show improvement in OS and led to more toxicity [39–42]. Additionally, the use of alternating or cyclic chemotherapies in an attempt to curb drug resistance has also failed to show survival benefit [43–45]. The addition of antiangiogenic agent bevacizumab to standard platinum-based doublet has not yielded prolongation of OS in SCLC and led to unacceptably higher rate of tracheoesophageal fistula when used in conjunction with chemoradiation in limited-stage disease [46–51]. Finally, the immune checkpoint inhibitor ipilimumab in combination with platinum plus etoposide failed to improve PFS or OS compared to platinum plus etoposide alone in a recent phase III trial and maintenance pembrolizumab after completion of platinum-based chemotherapy did not improve PFS [52,53].

Patients with extensive-stage disease who have brain metastasis at the time of diagnosis can be treated with systemic chemotherapy first if brain metastases are asymptomatic and there is significant extracranial disease burden. In that case, whole brain radiotherapy should be given after completion of systemic therapy.

Second-Line Therapy

Despite being exquisitely chemo-sensitive, SCLC is associated with very poor prognosis largely because of invariable disease progression following first-line therapy and lack of effective second-line treatment options that can lead to appreciable disease control. The choice of second-line treatment is predominantly determined by the time of disease relapse since first-line platinum based therapy. If this interval is 6 months or longer, re-treatment utilizing the same platinum doublet is appropriate. However, if the interval is 6 months or less, second-line systemic therapy options should be explored. Unfortunately, the response rate tends to be less than 10% with most of the second-line therapies in platinum-resistant disease (defined as disease progression within 3 months of receiving platinum-based therapy). If the disease progression occurs between 3 to 6 months since platinum-based therapy, the response rate with second-line chemotherapy is in the range of 25% [54,55]. A number of second-line chemotherapy options have been explored in small studies, including topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, oral etoposide, gemcitabine, bendamustine, and CAV (cyclophosphamide, adriamycin, vincristine) (Table 2). 

Immunotherapy

The role of immune checkpoint inhibitors in the treatment of SCLC is evolving and currently there are no FDA-approved immunotherapy agents in SCLC. A recently conducted phase I/II trial (CheckMate 032) of anti-PD-1 antibody nivolumab with or without anti-CTLA-1 antibody ipilimumab in patients with relapsed SCLC reported a response rate of 10% with nivolumab 3 mg/kg and 21% with nivolumab 1 mg/kg + ipilimumab 3 mg/kg. The 2-year OS was 26% with the combination and 14% with single agent nivolumab [56,57]. Only 18% of patients had PD-L1 expression of ≥ 1% and the response rate did not correlate with PD-L1 status. The rate of grade 3 or 4 adverse events was approximately 20% and only 10% of patients discontinued treatment because of toxicity. Based on these data, nivolumab plus ipilimumab is now included in the NCCN guidelines as one of the options for patients with SCLC who experience disease relapse within 6 months of receiving platinum-based therapy; however, it is questionable whether routine use of this combination is justified based on currently available data. However the evidence for the combination of nivolumab and ipilimumab remains limited. This efficacy and toxicity data of both randomized and nonrandomized cohorts were presented together making it hard to interpret the results.

Another phase Ib study (KEYNOTE-028) utilizing anti-PD-1 antibody pembrolizumab 10 mg/kg IV every 2 weeks in patients with relapsed SCLC after receiving one or more prior lines of therapy and PD-L1 expression of ≥ 1% showed a response rate of 33% with median duration of response of 19 months and 1-year OS of 38% [58]. Although only 28% of screened patients had PD-L1 expression of ≥ 1% , these results indicated that at least a subset of SCLC patients are able to achieve durable responses with immune checkpoint inhibition. A number of clinical trials utilizing immune checkpoint inhibitors in various combinations and settings are currently underway.

Role of Prophylactic Cranial Irradiation

The role of PCI in extensive-stage SCLC is not clearly defined. A randomized phase III trial conducted by EORTC comparing PCI with no PCI in patients with extensive-stage SCLC who had attained partial or complete response to initial platinum-based chemotherapy showed decrease in the incidence of symptomatic brain metastasis and improvement in 1-year OS with PCI. However, this trial did not require mandatory brain imaging prior to PCI and therefore it is unclear if some patients in the PCI group had asymptomatic brain metastasis prior to enrollment and therefore received therapeutic benefit from brain radiation. Additionally, the dose and fractionation of PCI was not standardized across patient groups. A more recent phase III study conducted in Japan that compared PCI (25Gy in 10 fractions) with no PCI reported no difference in survival between the two groups. As opposed to EORTC study, the Japanese study did require baseline brain imaging to confirm absence of brain metastasis prior to enrollment. In addition, the patients in the control arm underwent periodic brain MRI to allow early detection of brain metastasis [59]. Given the emergence of the new data, the impact of PCI on survival in patients with extensive-stage SCLC is unproven and PCI likely has a role in a highly select small group of patients with extensive-stage SCLC. PCI is not recommended for patients with poor performance status (ECOG PS 3–4) or underlying neurocognitive disorders [33,60]. NMDA receptor antagonist memantine can be used in patients undergoing PCI to delay the occurrence of cognitive dysfunction [61]. Memantine 20 mg daily delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared to placebo in patients receiving whole brain radiation [61].

Role of Radiation

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiation after completion of platinum-based chemotherapy. A randomized trial including patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiation in combination with continued chemotherapy versus chemotherapy alone [62]. The median OS was longer with the addition of thoracic radiation compared to chemotherapy alone. Another phase III trial did not show improvement in 1-year OS with consolidative thoracic radiation, but 2-year OS and 6-month PFS were longer [63]. In general, consolidative thoracic radiation benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy [64]. In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiation should be utilized for palliative purposes in patients with painful bone metastasis, spine cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy with extensive stage disease. Whole brain radiotherapy is preferred over SRS because of frequent presence of micrometastasis even in the setting of one or two radiographically evident brain metastasis.

Novel Therapies

A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate; however, at the same time this complexity can form the basis for effective targeted therapy for the disease. One of the major limitations to the development of targeted therapies in SCLC is limited availability of tissue owing to small tissue samples and frequent presence of significant necrosis in the samples. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them, including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors, have been unsuccessful in showing a survival advantage in this disease. Several others including PARP inhibitors, cellular developmental pathway inhibitors and antibody drug conjugates are being tested. A phase I study of veliparib combined with cisplatin and etoposide in patients with previously untreated extensive-stage SCLC demonstrated complete response in 14.3%, partial response in 57.1%, and stable disease in 28.6% of patients with acceptable safety profile [65]. So far, none of these agents are approved for use in SCLC and the majority are in early phase clinical trials [66].

One of the emerging targets in the treatment of SCLC is DLL3. DLL3 is expressed on > 80% SCLCL tumor cells and cancer stem cells. Rovalpituzumab tesirine (ROVA-T) is an antibody drug conjugate consisting of humanized anti-DLL3 monoclonal antibody linked to SC-DR002, a DNA-crosslinking agent. A phase I trial of ROVA-T in patients with relapsed SCLC after 1 or 2 prior lines of therapies reported a response rate of 31% in patients with DLL3 expression of ≥ 50%. The median duration of response and mPFS were 4.6 months [67]. ROVA-T is currently in later phases of clinical trials and has a potential to serve as one of the options for patients with extensive-stage disease after disease progression on platinum-based therapy.

Response Assessment/Surveillance

For patients undergoing treatment for limited-stage SCLC, response assessment with contrast-enhanced CT of the chest/abdomen should be performed after completion of 4 cycles of chemotherapy and thoracic radiation. The surveillance guidelines consist of history, physical exam, and imaging every 3 months during 1st 2 years, every 6 months during the 3rdyear, and annually thereafter. If PCI is not performed, brain MRI or contrast enhanced CT scan should be performed every 3 to 4 months during the first 2 years of follow-up. For extensive-stage disease, response assessment should be performed after every 2 cycles of therapy. After completion of therapy, history, physical exam, and imaging should be done every 2 months during the 1st year, every 3 to 4 months during year 2 and 3, every 6 months during years 4 and 5, and annually thereafter. Routine use of PET scan for surveillance is not recommended. Any new pulmonary nodule should prompt evaluation for a second primary lung malignancy. Finally, smoking cessation counseling is an integral part of management of any patient with SCLC and should be included with every clinic visit.

Corresponding author: Hirva Mamdani, MD, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, [email protected].

Financial disclosures: None.

From the Karmanos Cancer Institute, Detroit, MI (Dr. Mamdani) and the Indiana University School of Medicine, Indianapolis, IN (Dr. Jalal). 

Abstract

• Objective: To review the clinical aspects and current practices of management of small cell lung cancer (SCLC).
• Methods: Review of the literature.
• Results: SCLC is an aggressive cancer of neuroendocrine origin with a very strong association with smoking. Approximately 25% of patients present with limited-stage disease while the remaining majority of patients have extensive-stage disease, defined as disease extending beyond one hemithorax at the time of diagnosis. SCLC is often associated with endocrine or neurologic paraneoplastic syndromes. The treatment of limited-stage disease consists of platinum-based chemotherapy administered concurrently with radiation. Patients with partial or complete response should be offered prophylactic cranial radiation (PCI). Extensive-stage disease is largely treated with platinum-based chemotherapy and the role of PCI is more controversial. The efficacy of second-line chemotherapy after disease progression on platinum based chemotherapy is limited.
• Conclusion: Despite a number of advances in the treatment of various malignancies over the period of past several years, the prognosis of patients with SCLC remains poor. There have been a number of clinical trials utilizing novel therapeutic agents to improve outcomes of these patients; however, few of them have shown marginal success in a very select subgroup of patients.

Key words: lung cancer; small-cell lung cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer of neuroendocrine origin, accounting for approximately 15% of all lung cancer cases, with approximately 33,000 patients diagnosed annually [1]. The incidence of SCLC in the United States has steadily declined over the past 30 years presumably because of decrease in the percentage of smokers and change to low-tar filter cigarettes [2]. Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1 [3]. Nearly all cases of SCLC are associated with heavy tobacco exposure, making it a heterogeneous disease with complex genomic landscape consisting of thousands of mutations [4,5]. Despite a number of advances in the treatment of non-small cell lung cancer over the past decade, the therapeutic landscape of SCLC remains narrow with median overall survival (OS) of 9 months in patients with advanced disease.

Case Study

Initial Presentation

A 61-year-old man presents to the emergency department with progressive shortness of breath and cough over the period of past 6 weeks. He also reports having had 20-lb weight loss over the same period of time. He is a current smoker and has been smoking one pack of cigarettes per day since the age of 18 years. A chest x-ray performed in the emergency department shows a right hilar mass. Computed tomography (CT) scan confirms the presence of a 4.5 cm right hilar mass with presence of enlarged mediastinal lymph nodes bilaterally.

What are the next steps in diagnosis?

SCLC is characterized by rapid growth and early hematogenous metastases. Consequently, only 25% of patients have limited-stage disease at the time of diagnosis. According to the VA staging system, limited-stage disease is defined as tumor that is confined to one hemithorax and can be encompassed within one radiation field. This typically includes mediastinal lymph nodes and ipsilateral supraclavicular lymph nodes. Extensive-stage disease is the presentation in 75% of the patients where the disease extends beyond one hemithorax. Extensive-stage disease includes presence of malignant pleural effusion and/or distant metastasis [6]. The Veterans Administration Lung Study Group (VALG) classification and staging system is more commonly used compared to the AJCC TNM staging system since it is less complex, directs treatment decisions, and correlates closely with prognosis. Given its propensity to metastasize quickly, none of the currently available screening methods have proven to be successful in early detection of SCLC. Eighty-six percent of the 125 patients that were diagnosed with SCLC while undergoing annual low-dose chest CT scans on National Lung Cancer Screening Trial had advanced disease at diagnosis [7,8]. These results highlight the fact that he majority of the SCLC develop in the interval between annual screening imaging.

SCLC frequently presents with a large hilar mass that is symptomatic. In addition, SCLC usually presents with centrally located tumors and bulky mediastinal adenopathy. Common symptoms include shortness of breath and cough. SCLC is commonly located submucosally in the bronchus and therefore hemoptysis is not a very common symptom at the time of presentation. Patients may present with superior vena cava (SVC) syndrome from local compression by the tumor. Not infrequently, SCLC is associated with paraneoplastic syndromes (PNS) owing to the ectopic secretion of hormones or antibodies by the tumor cells. The PNS can be broadly categorized into endocrine and neurologic; and are summarized in Table 1. 

The common sites of metastases include brain, liver, and bone. Therefore, the staging workup should include fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan. Contrast-enhanced CT scan of chest and abdomen and bone scan can be obtained for staging in lieu of PET scan. Due to the physiologic FDG uptake, cerebral metastases cannot be assessed with sufficient certainty using the PET-CT. Therefore, brain imaging with contrast enhanced CT or MRI is also necessary. Although the incidence of metastasis to bone marrow is less than 10%, bone marrow aspiration and biopsy is warranted in case of unexplained cytopenias, especially when associated with teardrop red cells or nucleated red cells on peripheral blood smear indicative of marrow infiltrative process. The tissue diagnosis is established by obtaining a biopsy of the primary tumor or one of the metastatic sites. In case of localized disease, bronchoscopy (if necessary, with endobronchial ultrasound) with biopsy of centrally located tumor and/or lymph node is required. Histologically, SCLC consists of monomorphic cells, a high nucleus:cytoplasmic ratio, and confluent necrosis. The tumor cells are positive for chromogranin, synaptophysin, and CD56 by immunohistochemistry. Very frequently the cells are also positive for TTF1. Although serum tumor markers, including neuron-specific enolase (NSE) and progastrin-releasing peptide (prGRP), are frequently elevated in patients with SCLC, they are of limited value in clinical practice owing to their lack of sensitivity and specificity.

Case Continued

The patient underwent FDG-PET scan that showed the presence of hypermetabolic right hilar mass in addition to enlarged and hypermetabolic bilateral mediastinal lymph nodes. There were no other areas of FDG avidity. His brain MRI did not show any evidence of brain metastasis. Thus, he was confirmed to have limited-stage SCLC.

What is the standard of care for limited-stage SCLC?

SCLC is exquisitely sensitive to both chemotherapy and radiation, especially at the time of initial presentation. The standard of care for the treatment of limited stage SCLC is 4 cycles of platinum-based chemotherapy in combination with thoracic radiation started within the first 2 cycles of chemotherapy (Figure 1). 

Choice of Chemotherapy

Etoposide and cisplatin is the most commonly used initial combination chemotherapy regimen [9]. This combination has largely replaced anthracycline-based regimens given its favorable efficacy and toxicity profile [10–12]. Several small randomized trials have shown comparable efficacy of carboplatin and etoposide in extensive stage SCLC [13–15]. A meta-analysis of 4 randomized trials, including 663 patients with SCLC, comparing cisplatin-based versus carboplatin-based regimens where 32% of patients had limited stage disease and 68% had extensive stage disease showed no statistically significant difference in the response rate, progression free survival (PFS), or OS between the two regimens [16]. Therefore, in clinical practice carboplatin is frequently used instead of cisplatin in patients with extensive-stage disease. In patients with limited-stage disease, cisplatin is still the drug of choice. However, the toxicity profile of the two regimens is different. Cisplatin based regimens are more commonly associated with neuropathy, nephrotoxicity, and chemotherapy induced nausea/vomiting [13], while carboplatin-based regimens are more myelosuppressive [17]. In addition, the combination of thoracic radiation with either of these regiments is associated with higher risk of esophagitis, pneumonitis, and myelosuppression [18]. The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation [19]. Of note, intravenous (IV) etoposide is always preferred over oral etoposide, especially in curative setting given unreliable absorption and bioavailability of oral formulations.

Thoracic Radiation

The addition of thoracic radiation to platinum-etoposide chemotherapy improves local control and OS. Two meta-analyses of 13 trials including more than 2000 patients have shown 25% to 30% decrease in local failure and 5% to 7% increase in 2-year OS with chemoradiation compared to chemotherapy alone in limited stage SCLC [20,21]. Early (with the first 2 cycles) concurrent thoracic radiation is superior to delayed and/or sequential radiation in terms of local control and OS [18,22,23]. The dose and fractionation of thoracic radiation in limited-stage SCLC has remained a controversial issue. The ECOG/RTOG randomized trial compared 45 Gy radiation delivered twice daily over a period of 3 weeks with once a day over 5 weeks, concurrently with chemotherapy. The twice a day regimen led to 10% improvement in 5-year OS (26% vs 16%), but higher incidence of grade 3 and 4 adverse events [24]. Despite the survival advantage demonstrated by hyperfractionated radiotherapy, the results need to be interpreted with caution because the radiation doses are not biologically equivalent. In addition the difficult logistics of patients receiving radiation twice a day has limited the routine implementation of this strategy. Subsequently, another randomized phase III trial (CONVERT) compared 45 Gy twice daily with 66 Gy once daily radiation in this setting. This trial did not show any difference in OS. The patients in twice daily arm had higher incidence of grade 4 neutropenia [25]. Considering the results of these trials, both strategies—45 Gy fractionated twice daily or 60 Gy fractionated once daily, delivered concurrently with chemotherapy—are acceptable in the setting of limited-stage SCLC. However, quite often hyperfractionated regimen is not feasible for the patients and many radiation oncology centers. Hopefully the CALBG 30610 study, which is ongoing, will clarify the optimal radiation schedule for limited-stage disease.

Prophylactic Cranial Irradiation

Approximately 75% of patients with limited-stage disease experience disease recurrence and brain is the site of recurrence in approximately half of these patients. Prophylactic cranial irradiation (PCI) consisting of 25 Gy radiation delivered in 10 fractions has been shown to be effective in decreasing the incidence of cerebral metastases [26–28]. Although individual small studies have not shown survival benefit of PCI because of small sample size and limited power, a meta-analysis of these studies has shown 25% decrease in the 3-year incidence of brain metastasis and 5.4% increase in 3-year OS [27]. The majority of patients included in these studies had limited-stage disease. Therefore, PCI is the standard of care for patients with limited-stage disease who attain a partial or complete response to chemoradiation.

Role of Surgery

Surgical resection may be an acceptable choice in a very limited subset of patients with peripherally located small (< 5 cm) tumors where mediastinal lymph nodes have been confirmed to be uninvolved with complete mediastinal staging [29,30]. Most of the data in this setting are derived from retrospective studies [31,32]. A 5-year OS of 40% to 60% has been has been reported with this strategy in patients with clinical stage I disease. In general, when surgery is considered, lobectomy with mediastinal lymph node dissection followed by chemotherapy (if no nodal involvement) or chemoradiation (if nodal involvement) is recommended [33,34]. Wedge or segmental resections are not considered to be optimum surgical options.

Case Continued

The patient received 4 cycles of cisplatin and etoposide along with 70 Gy radiation concurrently with the first 2 cycles of chemotherapy. His post-treatment CT scans showed partial response (PR). The patient underwent PCI 6 weeks after completion of treatment. Eighteen months later, the patient comes to the clinic for routine follow-up. He is doing generally well except for mildly decreased appetite and unintentional loss of 5 lb weight. His CT scans demonstrate multiple hypodense liver lesions ranging from 7 mm to 2 cm in size and a 2 cm left adrenal gland lesion highly concerning for metastasis. FDG PET scan confirmed the adrenal and liver lesions to be hypermetabolic. In addition, the PET showed multiple FDG avid bone lesions throughout the spine. Brain MRI was negative for any brain metastasis.

What is the standard of care for extensive-stage SCLC?

For extensive-stage SCLC, chemotherapy is the mainstay of treatment, with the goals of treatment being prolongation of survival, prevention or alleviation of cancer-related symptoms, and improvement in quality of life. The combination of etoposide with a platinum agent (carboplatin or cisplatin) is the preferred first-line treatment option (Figure 2). 

Multiple attempts at improving first-line chemotherapy in extensive-stage disease have failed to show any meaningful difference in OS. For example, addition of ifosfamide, palifosfamide, cyclophosphamide, taxane, or anthracycline to platinum doublet failed to show improvement in OS and led to more toxicity [39–42]. Additionally, the use of alternating or cyclic chemotherapies in an attempt to curb drug resistance has also failed to show survival benefit [43–45]. The addition of antiangiogenic agent bevacizumab to standard platinum-based doublet has not yielded prolongation of OS in SCLC and led to unacceptably higher rate of tracheoesophageal fistula when used in conjunction with chemoradiation in limited-stage disease [46–51]. Finally, the immune checkpoint inhibitor ipilimumab in combination with platinum plus etoposide failed to improve PFS or OS compared to platinum plus etoposide alone in a recent phase III trial and maintenance pembrolizumab after completion of platinum-based chemotherapy did not improve PFS [52,53].

Patients with extensive-stage disease who have brain metastasis at the time of diagnosis can be treated with systemic chemotherapy first if brain metastases are asymptomatic and there is significant extracranial disease burden. In that case, whole brain radiotherapy should be given after completion of systemic therapy.

Second-Line Therapy

Despite being exquisitely chemo-sensitive, SCLC is associated with very poor prognosis largely because of invariable disease progression following first-line therapy and lack of effective second-line treatment options that can lead to appreciable disease control. The choice of second-line treatment is predominantly determined by the time of disease relapse since first-line platinum based therapy. If this interval is 6 months or longer, re-treatment utilizing the same platinum doublet is appropriate. However, if the interval is 6 months or less, second-line systemic therapy options should be explored. Unfortunately, the response rate tends to be less than 10% with most of the second-line therapies in platinum-resistant disease (defined as disease progression within 3 months of receiving platinum-based therapy). If the disease progression occurs between 3 to 6 months since platinum-based therapy, the response rate with second-line chemotherapy is in the range of 25% [54,55]. A number of second-line chemotherapy options have been explored in small studies, including topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, oral etoposide, gemcitabine, bendamustine, and CAV (cyclophosphamide, adriamycin, vincristine) (Table 2). 

Immunotherapy

The role of immune checkpoint inhibitors in the treatment of SCLC is evolving and currently there are no FDA-approved immunotherapy agents in SCLC. A recently conducted phase I/II trial (CheckMate 032) of anti-PD-1 antibody nivolumab with or without anti-CTLA-1 antibody ipilimumab in patients with relapsed SCLC reported a response rate of 10% with nivolumab 3 mg/kg and 21% with nivolumab 1 mg/kg + ipilimumab 3 mg/kg. The 2-year OS was 26% with the combination and 14% with single agent nivolumab [56,57]. Only 18% of patients had PD-L1 expression of ≥ 1% and the response rate did not correlate with PD-L1 status. The rate of grade 3 or 4 adverse events was approximately 20% and only 10% of patients discontinued treatment because of toxicity. Based on these data, nivolumab plus ipilimumab is now included in the NCCN guidelines as one of the options for patients with SCLC who experience disease relapse within 6 months of receiving platinum-based therapy; however, it is questionable whether routine use of this combination is justified based on currently available data. However the evidence for the combination of nivolumab and ipilimumab remains limited. This efficacy and toxicity data of both randomized and nonrandomized cohorts were presented together making it hard to interpret the results.

Another phase Ib study (KEYNOTE-028) utilizing anti-PD-1 antibody pembrolizumab 10 mg/kg IV every 2 weeks in patients with relapsed SCLC after receiving one or more prior lines of therapy and PD-L1 expression of ≥ 1% showed a response rate of 33% with median duration of response of 19 months and 1-year OS of 38% [58]. Although only 28% of screened patients had PD-L1 expression of ≥ 1% , these results indicated that at least a subset of SCLC patients are able to achieve durable responses with immune checkpoint inhibition. A number of clinical trials utilizing immune checkpoint inhibitors in various combinations and settings are currently underway.

Role of Prophylactic Cranial Irradiation

The role of PCI in extensive-stage SCLC is not clearly defined. A randomized phase III trial conducted by EORTC comparing PCI with no PCI in patients with extensive-stage SCLC who had attained partial or complete response to initial platinum-based chemotherapy showed decrease in the incidence of symptomatic brain metastasis and improvement in 1-year OS with PCI. However, this trial did not require mandatory brain imaging prior to PCI and therefore it is unclear if some patients in the PCI group had asymptomatic brain metastasis prior to enrollment and therefore received therapeutic benefit from brain radiation. Additionally, the dose and fractionation of PCI was not standardized across patient groups. A more recent phase III study conducted in Japan that compared PCI (25Gy in 10 fractions) with no PCI reported no difference in survival between the two groups. As opposed to EORTC study, the Japanese study did require baseline brain imaging to confirm absence of brain metastasis prior to enrollment. In addition, the patients in the control arm underwent periodic brain MRI to allow early detection of brain metastasis [59]. Given the emergence of the new data, the impact of PCI on survival in patients with extensive-stage SCLC is unproven and PCI likely has a role in a highly select small group of patients with extensive-stage SCLC. PCI is not recommended for patients with poor performance status (ECOG PS 3–4) or underlying neurocognitive disorders [33,60]. NMDA receptor antagonist memantine can be used in patients undergoing PCI to delay the occurrence of cognitive dysfunction [61]. Memantine 20 mg daily delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared to placebo in patients receiving whole brain radiation [61].

Role of Radiation

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiation after completion of platinum-based chemotherapy. A randomized trial including patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiation in combination with continued chemotherapy versus chemotherapy alone [62]. The median OS was longer with the addition of thoracic radiation compared to chemotherapy alone. Another phase III trial did not show improvement in 1-year OS with consolidative thoracic radiation, but 2-year OS and 6-month PFS were longer [63]. In general, consolidative thoracic radiation benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy [64]. In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiation should be utilized for palliative purposes in patients with painful bone metastasis, spine cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy with extensive stage disease. Whole brain radiotherapy is preferred over SRS because of frequent presence of micrometastasis even in the setting of one or two radiographically evident brain metastasis.

Novel Therapies

A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate; however, at the same time this complexity can form the basis for effective targeted therapy for the disease. One of the major limitations to the development of targeted therapies in SCLC is limited availability of tissue owing to small tissue samples and frequent presence of significant necrosis in the samples. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them, including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors, have been unsuccessful in showing a survival advantage in this disease. Several others including PARP inhibitors, cellular developmental pathway inhibitors and antibody drug conjugates are being tested. A phase I study of veliparib combined with cisplatin and etoposide in patients with previously untreated extensive-stage SCLC demonstrated complete response in 14.3%, partial response in 57.1%, and stable disease in 28.6% of patients with acceptable safety profile [65]. So far, none of these agents are approved for use in SCLC and the majority are in early phase clinical trials [66].

One of the emerging targets in the treatment of SCLC is DLL3. DLL3 is expressed on > 80% SCLCL tumor cells and cancer stem cells. Rovalpituzumab tesirine (ROVA-T) is an antibody drug conjugate consisting of humanized anti-DLL3 monoclonal antibody linked to SC-DR002, a DNA-crosslinking agent. A phase I trial of ROVA-T in patients with relapsed SCLC after 1 or 2 prior lines of therapies reported a response rate of 31% in patients with DLL3 expression of ≥ 50%. The median duration of response and mPFS were 4.6 months [67]. ROVA-T is currently in later phases of clinical trials and has a potential to serve as one of the options for patients with extensive-stage disease after disease progression on platinum-based therapy.

Response Assessment/Surveillance

For patients undergoing treatment for limited-stage SCLC, response assessment with contrast-enhanced CT of the chest/abdomen should be performed after completion of 4 cycles of chemotherapy and thoracic radiation. The surveillance guidelines consist of history, physical exam, and imaging every 3 months during 1st 2 years, every 6 months during the 3rdyear, and annually thereafter. If PCI is not performed, brain MRI or contrast enhanced CT scan should be performed every 3 to 4 months during the first 2 years of follow-up. For extensive-stage disease, response assessment should be performed after every 2 cycles of therapy. After completion of therapy, history, physical exam, and imaging should be done every 2 months during the 1st year, every 3 to 4 months during year 2 and 3, every 6 months during years 4 and 5, and annually thereafter. Routine use of PET scan for surveillance is not recommended. Any new pulmonary nodule should prompt evaluation for a second primary lung malignancy. Finally, smoking cessation counseling is an integral part of management of any patient with SCLC and should be included with every clinic visit.

Corresponding author: Hirva Mamdani, MD, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, [email protected].

Financial disclosures: None.

From the Division of Gastroenterology University of Washington, Seattle, WA (Dr. Tiderington), and the Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center and The Ohio State University Inflammatory Bowel Disease Center, Columbus, OH (Dr. Afzali).

Abstract

• Objective: To provide a practical approach to the management of patients with inflammatory bowel disease (IBD) following tumor necrosis factor (TNF) alpha antagonist failure.
• Methods: Review of the literature.
• Results: TNF alpha antagonists play a central role in the treatment of IBD. Unfortunately, some patients will not respond to therapy with TNF antagonists, and others will lose response during treatment. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. In this paper we review the mechanisms of drug failure, the use of reactive therapeutic drug monitoring to guide clinical decision making, and propose an evidence-based method for managing this common clinical scenario.
• Conclusion: Despite the improved clinical outcomes seen since the introduction of TNF antagonists for the management of IBD, there remains a significant need for additional medical therapies. Fortunately, the armamentarium is expected to expand dramatically over the next decade.

Key words: TNF antagonists; therapeutic drug monitoring; biologic failure; Crohn’s disease treatment; ulcerative colitis treatment.

Ulcerative colitis and Crohn’s disease are the two types of inflammatory bowel disease (IBD), and they are characterized by chronic, immunologically mediated inflammation involving the gastrointestinal tract [1]. Guided by an understanding of the role of tumor necrosis factor (TNF) alpha in the pathogenesis of IBD, TNF antagonists have played a central role in modern treatment algorithms [2]. Unfortunately, roughly one third of patients will not have a clinical response when given induction dosing of the currently available anti-TNF agents, and of those who do respond to treatment, up to one half will lose response to treatment within the first year [3]. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. Once the clinician has confirmed that active IBD is present based on endoscopic, cross-sectional imaging and/or biochemical markers of inflammation, the next step is to identify the cause of the treatment failure, as this guides management. Here we review the body of literature that guides our understanding of treatment failure as well as therapeutic drug monitoring and propose an evidence-based algorithm for managing this common clinical scenario.

Defining Treatment Failure

Patients who receive anti-TNF therapy but demonstrate active IBD should be classified as having either primary nonresponse or secondary loss of response. Primary nonresponse is defined as having either no response, or only partial response, to induction with anti-TNF therapy [4]. Data from pivotal trials and meta-analyses suggest that about one third of patients will not show any clinical response to induction with anti-TNF therapies, with response typically being defined using composite endpoints favoring clinical symptoms and only sometimes incorporating endoscopic findings [5]. An additional one third of patients will have only a partial response, without remission. Patients with ulcerative colitis are at a slightly increased risk of primary nonresponse compared to patients with Crohn’s disease. Though the time frame for defining primary nonresponse is different for each agent because each agent has a slightly different induction schedule, in general the maximal response to therapy is typically seen by week 12, and it is reasonable to use this as a time cutoff [6].

Secondary loss of response is likewise defined as recrudescence of clinically active disease after an initial response. In general, the presence of secondary loss of response should not be invoked until week 12 of therapy. In most pivotal trials, secondary loss of response was seen in roughly half of patients at 1 year. In clinical practice, however, particularly as therapeutic drug monitoring has become more common, the observed rates of secondary loss of response have been lower [6].

Applying these definitions appropriately is important because it dictates the next steps in management. When a patient presents with symptoms suggesting active IBD while on anti-TNF therapy, either during induction when primary nonresponse is possible, or in maintenance when secondary loss of response would be invoked, the first step is to determine if active IBD is the etiology for the presenting symptoms. The initial evaluation should rule out common infectious causes of symptoms mimicking IBD. In particular, Clostridium difficile infection should be ruled out with stool testing. In certain circumstances, ruling out cytomegalovirus (CMV) colitis is important, so an endoscopic evaluation with colonic biopsies should be considered. In the absence of infectious colitis, the presence of active inflammation can often be identified endoscopically, or can be inferred from noninvasive markers with a fair degree of certainty. Fecal calprotectin is an ideal choice for this purpose. In ulcerative colitis it is estimated to have a sensitivity of 0.88 and a specificity of 0.79 for the prediction of endoscopically active disease. The estimated sensitivity for detecting endoscopically active Crohn’s disease is essentially the same (0.87), and the specificity is only slightly lower (0.67). C-reactive protein demonstrates a better specificity (0.92), but has a marginal sensitivity (0.49) [7]. Other etiologies for the patient’s symptoms should also be considered, including medication side effects including use of nonsteroidal anti-inflammatory medications, bile acid malabsorption, small intestinal bacterial overgrowth (SIBO), irritable bowel syndrome (IBS), diverticular disease, ischemic colitis, fibrostenotic strictures, and cancer, depending on comorbidities and the history of present illness.

Once it has been determined that active IBD is the etiology for the patient’s symptoms, the patient should be classified as having either primary nonresponse or secondary loss of response as described above. For the clinician, the next question is how to alter or optimize therapy.

The decision of how to optimize therapy will largely depend on which anti-TNF therapy the patient is currently receiving, and whether they are receiving it as monotherapy or as combination therapy with an immunomodulator. Optimizing therapy will involve either increasing the dose or frequency of administration of the anti-TNF therapy, increasing the dose of azathioprine if indicated, adding an immunomodulator if the patient is on anti-TNF monotherapy, changing to a different anti-TNF agent, or changing to a different class of medication with a different mechanism of action. The recently released American Gastroenterological Association (AGA) guidelines on therapeutic drug monitoring in IBD provide a framework for making these decisions [8]. In general, the clinical choice will be dictated by the etiology of the drug failure.

Types of TNF Antagonist Drug Failure

Our understanding of the causes of biologic treatment failure are evolving but are typically classified as due to mechanistic failure, non-immune-mediated pharmacokinetic failure, or immune-mediated pharmacokinetic failure [9]. Differentiating between these classes of treatment failure requires therapeutic drug monitoring (TDM), which will be discussed in more detail below.

Mechanistic failure is encountered when the underlying biology does not favor a response to a particular therapy. Studies indicate a strong association between particular genetic phenotypes and the probability of a response to induction with anti-TNF agents [10]. This suggests that some individuals have IBD driven by a biochemical inflammatory cascade in which TNF features prominently, while others have alternative mechanistic drivers of inflammation without significantly elevated TNF levels. Mechanistic failure will typically present as primary nonresponse, but can also be seen in patients with secondary loss of response. Mechanistic failure can be elucidated clinically by the use of TDM. In the case of mechanistic failure, active disease is seen in the presence of adequate drug level, without the presence of anti-drug antibodies. The AGA recommends considering switching to a biologic with a different mechanism of action when mechanistic failure is identified [8].

Non-immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to a drug at adequate drug levels experiences suboptimal drug levels because of pharmacokinetic factors. In the case of anti-TNF therapy, this can be conceptualized as either an increased clearance of anti-TNF from the body (eg, in patients with significant hypoalbuminemia or severe colitis), a reduction in the average serum anti-TNF level because of the redistribution of drug in patients with a large body mass index, or inadequate saturation of the total body burden of TNF-alpha in subjects with a high baseline level of inflammation [11]. Non-immune-mediated pharmacokinetic failure can also be identified clinically through TDM. In this case, active disease is seen in the presence of a suboptimal drug level, without the presence of anti-drug antibodies. The AGA recommends considering dose-escalation of the current TNF antagonist when non-immune-mediated pharmacokinetic failure is identified [8], as this can improve clinical response in an estimated 82% of patients [9].

Finally, immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to the current biologic therapy when at adequate drug concentration levels experiences suboptimal drug levels because of increased drug clearance mediated by anti-drug antibodies [9]. Because anti-TNF agents are monoclonal antibodies, they are inherently immunogenic, and it is well established that episodic dosing and lower serum drug concentrations are strong risk factors for the development of anti-drug antibodies [12]. When anti-drug antibodies are present, and are associated with both a decreased serum drug concentration and active inflammatory bowel disease, immune-mediate pharmacokinetic failure can be invoked. When anti-drug antibodies are present, but at a low level, the AGA recommends dose escalation of current TNF antagonist. When anti-drug antibodies are present at a high level, the AGA recommends considering either the addition of an immunomodulator (if not already being used), or changing to a different class of biologic therapy [8]. This recommendation is based in part on data showing that the proportion of patients with sustained anti-drug antibodies during the first year of therapy with an TNF antagonist is likely between 14% and 20% for those on monotherapy, but between 1% and 5% for those on concomitant immunomodulatory therapy [13,14].

Therapeutic Drug Monitoring of Anti-TNF Agents

As described above, TDM, which is the process of testing the patient’s serum for both the concentration of the TNF antagonist and for the presence and concentration of anti-drug antibodies, can help differentiate between mechanistic failure, non-immune-mediated pharmacokinetic failure, and immune-mediated pharmacokinetic failure (Table 1). 

Therapeutic drug monitoring can be classified as either proactive or reactive. Proactive TDM is performed during induction or maintenance therapy when the patient does not have signs or symptoms of active disease to suggest a loss of response. Theoretically, this would allow dose modification and optimization, including dose de-escalation in certain circumstances, and could thus provide cost savings with minimal impact on clinical outcomes. The TAXIT trial provides the most robust evaluation of proactive TDM in TNF antagonist therapy. In this study, patients with Crohn’s disease or ulcerative colitis who had a stable clinical response while on maintenance infliximab were first dose optimized proactively to a target trough concentration of 3–7 μg/mL, then randomized to having dose modifications made based on clinical factors alone, defined as reactive monitoring, or dose modifications based on proactive monitoring, performed by checking the drug concentration and antibody levels before each infusion. At 1 year there was no statistically significant difference in the proportion of patients in remission. In addition, some patients in the proactive TDM group were able to have a dose reduction without a subsequent flare of disease, thus providing cost savings [15]. This study suggests that proactive TDM may have a role in drug optimization, particularly with respect to cost-effectiveness, but provides only indirect evidence of a clinical benefit, since all subjects enrolled in the study were proactively dose optimized prior to randomization. This study had a limited follow-up time of 1 year so was not able to assess for longer-term benefits and risks associated with proactive TDM.

More recently, a large, multicenter, retrospective cohort study provided additional evidence that proactive TDM may provide a clinical benefit in addition to cost savings. This study retrospectively evaluated consecutive patients receiving maintenance infliximab for Crohn’s disease between 2006 and 2015, with a median follow-up time of 2.4 years. They were classified as having had either proactive TDM or reactive TDM. Proactive TDM was associated with statistically significant reductions in the risk of treatment failure (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.09–0.27), the need for surgery (HR 0.30, 95% CI 0.11–0.80), hospitalization (HR 0.16, 95% CI 0.07–0.33), and anti-drug antibody formation (HR 0.25, 95% CI 0.07–0.84) [16].

To date, however, no randomized controlled trials have been published comparing proactive TDM to reactive TDM in treatment-naive patients. Because of the paucity of prospective studies, the AGA currently makes no recommendation regarding the use of proactive TDM in clinical practice. However, the current AGA guidelines do recommend reactive TDM in the setting of secondary loss of response based on the results of one randomized controlled trial (RCT) and several observational studies. The RCT was small (n = 69), and enrolled patients with Crohn’s disease on maintenance therapy with infliximab. Similar to the TAXIT trial, the study did not show a statistically significant difference in rates of clinical remission when subjects were randomized to either empiric dose escalation (to 5 mg/kg every 4 weeks) based on symptoms, or to dose escalations based on the results of reactive TDM. Also similar to the TAXIT trial, it showed an estimated cost savings of about 34% based on local prices in Denmark for reactive TDM over empiric dose escalation [17].

Meanwhile, the observational studies for reactive TDM provided additional support to the clinical benefit of reactive TDM, but also to the underlying hypotheses that drive reactive TDM, namely that subjects with mechanistic failure benefit from a change in drug class, those with non-immune-mediated pharmacokinetic failure benefit from dose escalation, and that those with immune-mediated pharmacokinetic failure may benefit from either dose escalation or a change in mechanism of action, depending on antibody titers. Specifically, on pooled analysis of 2 of these studies, 82% of subjects who were found to have non-immune-mediated pharmacokinetic failure responded to empiric dose escalation, whereas only 8% of subjects who were found to have immune-mediated pharmacokinetic failure with high anti-drug antibody titers responded to dose escalation [9]. Likewise, in a retrospective study involving subjects who were being treated with infliximab and then had reactive TDM performed, when non-immune-mediated pharmacokinetic failure was identified, a clinical response was seen in 86% of subjects who underwent dose escalation, and only 33% among those who were switched to a different anti-TNF (P < 0.016). Conversely, dose escalation resulted in a clinical response only 17% of the time when anti-drug antibodies were detectable, compared to a 92% response rate when the subject was switched to a different anti-TNF (P < 0.004) [18].

Interpreting the Results of Reactive Therapeutic Drug Monitoring

The implementation of reactive TDM involves obtaining a serum drug and antibody level and then interpreting what those results suggest about the mechanism of drug failure, in order to decide on a course of action. The serum drug level should be a trough concentration, so it should be obtained just prior to a timed dose, while on a stable treatment regimen. Exactly what serum drug concentration we should be targeting in reactive therapeutic drug monitoring remains an area of investigation. No RCTs have been published. There is ample observational, cross-sectional data from cohorts of patients on maintenance therapy, though heterogeneity in study design and study populations, as well as use of different assays, limit interpretation of the data. In a secondary analysis of data from 6 observational studies of patients on infliximab maintenance therapy, there was a highly statistically significant concentration-dependent trend in rates of clinical remission depending on the measured infliximab trough concentration, with 96% of those with infliximab > 7 μg/mL in remission, 92% of those with infliximab > 5 μg/mL in remission, and 75% of those with infliximab > 1 μg/mL in remission. Likewise, data from 4 studies of patients receiving adalimumab showed a statistically significant concentration-dependent trend in clinical remission, with 90% of those with adalimumab trough concentrations > 7.5 μg/mL being in clinical remission, compared with only 83% of those with concentrations > 5 μg/mL. Similarly, data from 9 studies suggested that a certolizumab trough concentration > 20 μg/mL was associated with a 75% probability of being in clinical remission, compared to a 60% probability when the trough concentration was > 10 μg/mL [9]. Based on these analyses, the AGA suggests target trough concentrations for reactive therapeutic drug monitoring of anti-TNF agents of ≥ 5 μg/mL for infliximab, ≥ 7.5 μg/mL for adalimumamb, and ≥ 20 μg/mL for certolizumab. They did not suggest a target trough concentration for golimumab because of insufficient evidence [8].

When interpreting TDM test results, it is important to know if the test you have used is drug-sensitive or drug-tolerant (Table 2). Drug-sensitive tests will be less likely to reveal the presence of anti-drug antibodies when the drug level is above a certain threshold. A post-hoc analysis of the TAXIT trial recently suggested that subjects who have antibodies detected on a drug-tolerant test which were not detected on a drug-sensitive test are more likely to respond to higher doses of infliximab [19]. It follows that there should be a threshold anti-drug antibody titer below which someone who has immune-mediated pharmacokinetic failure will still respond to TNF antagonist dose escalation, but above which they will fail to respond to dose escalation. To be sure, our understanding of the clinical implications of a drug-tolerant test demonstrating an adequate drug level while also detectable anti-drug antibodies is evolving. Complicating the issue further is the fact that anti-drug antibody concentrations cannot be compared between assays because of assay-specific characteristics. As such, though the presence of low antibody titers and high antibody titers seems to be clinically important, recommendations cannot yet be made on how to interpret specific thresholds. Furthermore, development of transient versus sustained antibodies requires further clinical investigation to determine impact and treatment algorithms.

Optimizing Therapy

Once you have determined the most likely cause of drug failure, the next step is to make a change in medical therapy. 

When switching within class (to another anti-TNF agent), the choice of which agent to use next will largely depend on patient preference (route of administration, infusion versus injection), insurance, and costs of treatment. When making the decision to switch within class, it should be kept in mind that the probability of achieving remission is modestly reduced compared to the probability seen in anti-TNF-naive patients [20], and even more so when the patient is switching to their third anti-TNF agent [21]. Thus, for the patient who has already previously switched from one TNF antagonist to a second TNF antagonist, it may be better to switch to a different class of biologic rather than attempting to capture a clinical remission with a third TNF antagonist.

When adding an immunomodulator (azathioprine or methotrexate), the expectation is that the therapy will increase the serum concentration of the anti-TNF agent [14] and/or reduce the ongoing risk of anti-drug antibody formation [22]. There could also be a direct treatment effect on the bowel disease by the immunomodulator.

When switching to an alternate mechanism of action, the currently FDA-approved options include the biologic agents vedolizumab (for both moderate-to-severe ulcerative colitis and moderate-to-severe Crohn’s disease) and ustekinumab (for moderate-to-severe Crohn’s disease), as well as the recently FDA-approved oral, small-molecule JAK1 and JAK3 inhibitor tofacitinib (for moderate-to-severe ulcerative colitis). Prospective comparative effectiveness studies for these agents are lacking and are unlikely to be performed in part due to the cost and time required to accomplish these studies. A recent post-hoc analysis of clinical trials data suggests that there are no significant differences in the rates of clinical response, clinical remission, or in adverse outcomes to vedolizumab or ustekinumab when they are used in patients who have failed anti-TNF therapy [23]. Thus, one cannot be recommended over the other, and the decision of which to use is usually guided by patient preference and insurance coverage.

Meanwhile, the role of tofacitinib in the treatment algorithm of patients who have failed anti-TNF therapy remains unclear. The phase III clinical trials OCTAVE 1, OCTAVE 2, and OCTAVE Sustain showed efficacy for both the induction and maintenance of remission in patients with moderate-to-severe ulcerative colitis who had previously failed anti-TNF agents. However, there remain concerns about the safety profile of tofacitinib compared to vedolizumab and ustekinumab, particularly regarding herpes zoster infection, dyslipidemia, and adverse cardiovascular events. Notable findings from the tofacitinib induction trials include robust rates of clinical remission (18.5% vs 8.2% for placebo in Octave 1, and 16.6% vs 3.6% in Octave 2, P < 0.001 for both comparisons) and mucosal healing (31.3% vs 15.6% for placebo in Octave 1, and 28.4% and 11.6% in Octave 2, P < 0.001 for both comparisons) after 8 weeks of induction therapy [24]. These results suggest that tofacitinib, or other JAK inhibitors that become approved in the future, may be excellent oral agents for the induction of remission in moderate-to-severe ulcerative colitis, and may demonstrate a better side effect profile than steroids. Whether cost factors (compared to steroid therapy) will limit the role of JAK-inhibitor therapy in induction, and whether safety concerns will limit their use in maintenance therapy, remains to be seen.

Off-Label Rescue Therapy and Surgery

Though the armamentarium of IBD therapies has expanded greatly over the past 2 decades, and will continue to do so for the foreseeable future, there are still a limited selection of therapies available to patients. Patients who have failed anti-TNF therapy, and subsequently fail vedolizumab and/or ustekinumab, have limited options. These options include clinical trials, off-label small molecule rescue therapy, and surgery. Patients who are felt to require any of these options should be referred to a tertiary center for evaluation by a gastroenterologist specializing in the treatment of IBD and/or a colorectal surgeon specializing in the surgical management of IBD.

Tacrolimus

Tacrolimus, a macrolide calcineurin inhibitor, has been studied as a small molecule therapy for IBD, though not in randomized controlled trials. There is biological plausibility for its use as a disease modifying agent. Mucosal T cells in subjects with active Crohn’s disease have been found to express increased levels of mRNA encoding IL-2, and tacrolimus acts primarily by reducing IL-2 production [25]. The largest observational cohort evaluating the use of tacrolimus, published by Thin et al, included patients with both ulcerative colitis (n = 24) and Crohn’s disease (n = 11) who had moderate to severely active IBD. All patients had failed dose-optimized thiopurine therapy, 89% had primary nonresponse or secondary loss of response to at least one anti-TNF agent, and 74% were either steroid-refractory or steroid-dependent at the time tacrolimus was started. With close monitoring, they targeted a tacrolimus trough of 8–12 ng/mL. At 30 days, 66% had a clinical response, and 40% were in clinical remission. At 90 days, 60% had a clinical response, and 37% were in clinical remission. At 1 year, 31% had a clinical response, and 23% were in clinical remission. Of those in clinical remission at 1 year, 88% were either off of steroids or on less than 5 mg of prednisone per day. Renal impairment was seen in 25% of patients, including severe renal impairment in 11%, requiring drug cessation. Infectious complications were seen in 9% of patients. Headaches, tremor, and pancreatitis were also observed, though less commonly. The majority of patients ultimately had a surgical intervention, particularly if they were steroid-refractory at baseline, but the time to surgery was delayed in those who achieved a response or remission in the first 90 days of tacrolimus therapy. The authors suggested that while tacrolimus may lack clear long-term benefit in patients with medically refractory IBD, a therapeutic trial should be considered in select patients with the goal of medical and nutritional optimization before surgical intervention [26].

Cyclosporine

Cyclosporine, which also exerts its effect by inhibiting IL-2 production, has an established role in the management of severe ulcerative colitis. Data from randomized, placebo-controlled trials, along with numerous open label observational studies, have shown that intravenous cyclosporine can induce remission and potentially obviate the need for urgent/emergent colectomy in steroid-refractory patients who are hospitalized with severe ulcerative colitis [27,28]. Its use in maintenance therapy remains controversial, however. Older observational data suggest that even among those who have an initial clinical response to cyclosporine induction, 33% will undergo colectomy by 1 year, and 88% will undergo colectomy by 7 years [27). Though the concomitant administration of a thiopurine may delay the need for colectomy [29,30], cyclosporine seems to be, at best, a temporizing therapy for patients with severe ulcerative colitis. Studies on the use of cyclosporine for the induction of remission in Crohn’s disease have been less robust, as have studies on the use of cyclosporine for the maintenance of remission in Crohn’s disease [31]. Dose-dependent toxicity also remains a concern, particularly when being considered as maintenance therapy. Though some observational data suggest that the absolute risks of serious side effects from maintenance cyclosporine are small, cyclosporine is still generally avoided as a maintenance therapy [30].

Mycophenolate Mofetil

Mycophenolate mofetil (MMF), which inhibits both B and T cell proliferation by inhibiting de novo purine synthesis, has been studied in both Crohn’s disease and ulcerative colitis. Studies have been small, observational, and heterogeneous. On the whole, they suggest that MMF does have some efficacy, but it is not necessarily more effective than azathioprine and may have a slightly increased risk of side effects [32]. Given that the side effects of MMF include diarrhea, and an IBD-like enterocolitis (MMF-induced colitis) when given to subjects without an established diagnosis of IBD, it is likely best to avoid using the drug in patients with IBD [33].

Surgery

Finally, when medical management has failed, or when fibrostenotic and/or penetrating complications of inflammatory bowel disease are present, surgery should be considered. Surgery can provide a cure in patients with ulcerative colitis, and can induce remission in patients with Crohn’s disease. Managing IBD medications around the time of surgery is always challenging. Multiple large, retrospective cohort studies have suggested that the risk for postoperative infectious complications, anastomotic leaks, and thrombotic complications do not differ between those who receive anti-TNF therapy within several months of surgery and those who do not. Nevertheless, some surgeons may prefer to time elective surgery halfway between doses of anti-TNF therapy. Additionally, there is some data to suggest that patients who are on both thiopurines and anti-TNF agents have an increased risk of postoperative complications compared to those who are on anti-TNF agents alone [34].

After a surgical evaluation, a plan of action should be formulated in a multidisciplinary fashion to determine how medical management will proceed. For those with an established diagnosis of ulcerative colitis, medical therapy can often be stopped postoperatively and the patient can be monitored prospectively for pouch complications including possible new-onset Crohn’s disease. For those who undergo surgery for the management of Crohn’s disease, though a resection completed with negative margins does induce remission, nearly 90% can be expected to have histologic, endoscopic, or clinical recurrence by 1 year. A randomized controlled trial showed that postoperative anti-TNF therapy can reduce this risk to 9% [35]. Unfortunately, a subsequently conducted large, multicenter, randomized controlled trial comparing postoperative infliximab to placebo was terminated early because of a lack of a statistically significant difference in clinical recurrence between the 2 groups at week 74. However, this lack of demonstrated efficacy may have been obscured by the relatively mild phenotype of the enrolled participants, who had a median CDAI score of 105.5 at baseline [36]. Based on available data, the AGA does conditionally recommend postoperative anti-TNF and/or thiopurine therapy for those patients with Crohn’s disease who are in a surgically induced remission [37]. The patients who are most likely to benefit from postoperative medical therapy are those who have the highest risk of recurrence, namely those who were young at the time of diagnosis, had a short disease duration prior to surgery, have multiple sites of disease, and who use tobacco products [34].

Emerging and Future Options

Despite the improved clinical outcomes seen since the introduction of TNF antagonists for the management of IBD, there remains a significant need for additional medical therapies. Fortunately, the armamentarium is expected to expand dramatically over the next decade.

Based on our improved, and evolving understanding of the pathogenesis of IBD, several new biochemical targets have emerged, offering novel ways to modulate the cytokine cascade which drives IBD [38]. Well over a dozen phase II and phase III trials for IBD therapeutic agents are ongoing, including biologic agents targeting interleukin-23, β7-Integrin, and MAdCAM-1, as well as small molecule agents targeting the JAK/STAT pathway and the sphingosine-1-phosphate receptor modulators [39]. As new agents are approved, it may be possible to develop a more patient-centered approach to care by targeting therapies to the particular pathogenesis of each patient’s disease. Nevertheless, integrating these therapies into practice algorithms will remain a challenge in the absence of meaningful comparative effectiveness trials [40].

Conclusion

When evaluating a patient who seems to have failed anti-TNF therapy for IBD, the first step is to confirm that active inflammatory disease is present. This process includes ruling out other potential causes of the patient’s symptoms, including infectious colitis, and ideally includes obtaining objective evidence of inflammation, whether through non-invasive biomarkers, an endoscopic evaluation and/or cross-sectional imaging. Once active IBD is confirmed, reactive therapeutic drug monitoring can help elucidate the likely mechanism of drug failure, which in turn can guide medical decision making.

Corresponding author: Anita Afzali MD, MPH, The Ohio State University Wexner Medical Center, 395 West 12th Ave, Room 280, Columbus, OH 43210, [email protected].

Financial disclosures: Dr. Afzali has served as a speaker/consultant for Abbvie, UCB, Takeda, Pfizer, Janssen; on the advisory board of Abbvie, UCB; received grant support from UCB; and is a board member of IBD Horizons.

From the Division of Gastroenterology University of Washington, Seattle, WA (Dr. Tiderington), and the Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center and The Ohio State University Inflammatory Bowel Disease Center, Columbus, OH (Dr. Afzali).

Abstract

• Objective: To provide a practical approach to the management of patients with inflammatory bowel disease (IBD) following tumor necrosis factor (TNF) alpha antagonist failure.
• Methods: Review of the literature.
• Results: TNF alpha antagonists play a central role in the treatment of IBD. Unfortunately, some patients will not respond to therapy with TNF antagonists, and others will lose response during treatment. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. In this paper we review the mechanisms of drug failure, the use of reactive therapeutic drug monitoring to guide clinical decision making, and propose an evidence-based method for managing this common clinical scenario.
• Conclusion: Despite the improved clinical outcomes seen since the introduction of TNF antagonists for the management of IBD, there remains a significant need for additional medical therapies. Fortunately, the armamentarium is expected to expand dramatically over the next decade.

Key words: TNF antagonists; therapeutic drug monitoring; biologic failure; Crohn’s disease treatment; ulcerative colitis treatment.

Ulcerative colitis and Crohn’s disease are the two types of inflammatory bowel disease (IBD), and they are characterized by chronic, immunologically mediated inflammation involving the gastrointestinal tract [1]. Guided by an understanding of the role of tumor necrosis factor (TNF) alpha in the pathogenesis of IBD, TNF antagonists have played a central role in modern treatment algorithms [2]. Unfortunately, roughly one third of patients will not have a clinical response when given induction dosing of the currently available anti-TNF agents, and of those who do respond to treatment, up to one half will lose response to treatment within the first year [3]. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. Once the clinician has confirmed that active IBD is present based on endoscopic, cross-sectional imaging and/or biochemical markers of inflammation, the next step is to identify the cause of the treatment failure, as this guides management. Here we review the body of literature that guides our understanding of treatment failure as well as therapeutic drug monitoring and propose an evidence-based algorithm for managing this common clinical scenario.

Defining Treatment Failure

Patients who receive anti-TNF therapy but demonstrate active IBD should be classified as having either primary nonresponse or secondary loss of response. Primary nonresponse is defined as having either no response, or only partial response, to induction with anti-TNF therapy [4]. Data from pivotal trials and meta-analyses suggest that about one third of patients will not show any clinical response to induction with anti-TNF therapies, with response typically being defined using composite endpoints favoring clinical symptoms and only sometimes incorporating endoscopic findings [5]. An additional one third of patients will have only a partial response, without remission. Patients with ulcerative colitis are at a slightly increased risk of primary nonresponse compared to patients with Crohn’s disease. Though the time frame for defining primary nonresponse is different for each agent because each agent has a slightly different induction schedule, in general the maximal response to therapy is typically seen by week 12, and it is reasonable to use this as a time cutoff [6].

Secondary loss of response is likewise defined as recrudescence of clinically active disease after an initial response. In general, the presence of secondary loss of response should not be invoked until week 12 of therapy. In most pivotal trials, secondary loss of response was seen in roughly half of patients at 1 year. In clinical practice, however, particularly as therapeutic drug monitoring has become more common, the observed rates of secondary loss of response have been lower [6].

Applying these definitions appropriately is important because it dictates the next steps in management. When a patient presents with symptoms suggesting active IBD while on anti-TNF therapy, either during induction when primary nonresponse is possible, or in maintenance when secondary loss of response would be invoked, the first step is to determine if active IBD is the etiology for the presenting symptoms. The initial evaluation should rule out common infectious causes of symptoms mimicking IBD. In particular, Clostridium difficile infection should be ruled out with stool testing. In certain circumstances, ruling out cytomegalovirus (CMV) colitis is important, so an endoscopic evaluation with colonic biopsies should be considered. In the absence of infectious colitis, the presence of active inflammation can often be identified endoscopically, or can be inferred from noninvasive markers with a fair degree of certainty. Fecal calprotectin is an ideal choice for this purpose. In ulcerative colitis it is estimated to have a sensitivity of 0.88 and a specificity of 0.79 for the prediction of endoscopically active disease. The estimated sensitivity for detecting endoscopically active Crohn’s disease is essentially the same (0.87), and the specificity is only slightly lower (0.67). C-reactive protein demonstrates a better specificity (0.92), but has a marginal sensitivity (0.49) [7]. Other etiologies for the patient’s symptoms should also be considered, including medication side effects including use of nonsteroidal anti-inflammatory medications, bile acid malabsorption, small intestinal bacterial overgrowth (SIBO), irritable bowel syndrome (IBS), diverticular disease, ischemic colitis, fibrostenotic strictures, and cancer, depending on comorbidities and the history of present illness.

Once it has been determined that active IBD is the etiology for the patient’s symptoms, the patient should be classified as having either primary nonresponse or secondary loss of response as described above. For the clinician, the next question is how to alter or optimize therapy.

The decision of how to optimize therapy will largely depend on which anti-TNF therapy the patient is currently receiving, and whether they are receiving it as monotherapy or as combination therapy with an immunomodulator. Optimizing therapy will involve either increasing the dose or frequency of administration of the anti-TNF therapy, increasing the dose of azathioprine if indicated, adding an immunomodulator if the patient is on anti-TNF monotherapy, changing to a different anti-TNF agent, or changing to a different class of medication with a different mechanism of action. The recently released American Gastroenterological Association (AGA) guidelines on therapeutic drug monitoring in IBD provide a framework for making these decisions [8]. In general, the clinical choice will be dictated by the etiology of the drug failure.

Types of TNF Antagonist Drug Failure

Our understanding of the causes of biologic treatment failure are evolving but are typically classified as due to mechanistic failure, non-immune-mediated pharmacokinetic failure, or immune-mediated pharmacokinetic failure [9]. Differentiating between these classes of treatment failure requires therapeutic drug monitoring (TDM), which will be discussed in more detail below.

Mechanistic failure is encountered when the underlying biology does not favor a response to a particular therapy. Studies indicate a strong association between particular genetic phenotypes and the probability of a response to induction with anti-TNF agents [10]. This suggests that some individuals have IBD driven by a biochemical inflammatory cascade in which TNF features prominently, while others have alternative mechanistic drivers of inflammation without significantly elevated TNF levels. Mechanistic failure will typically present as primary nonresponse, but can also be seen in patients with secondary loss of response. Mechanistic failure can be elucidated clinically by the use of TDM. In the case of mechanistic failure, active disease is seen in the presence of adequate drug level, without the presence of anti-drug antibodies. The AGA recommends considering switching to a biologic with a different mechanism of action when mechanistic failure is identified [8].

Non-immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to a drug at adequate drug levels experiences suboptimal drug levels because of pharmacokinetic factors. In the case of anti-TNF therapy, this can be conceptualized as either an increased clearance of anti-TNF from the body (eg, in patients with significant hypoalbuminemia or severe colitis), a reduction in the average serum anti-TNF level because of the redistribution of drug in patients with a large body mass index, or inadequate saturation of the total body burden of TNF-alpha in subjects with a high baseline level of inflammation [11]. Non-immune-mediated pharmacokinetic failure can also be identified clinically through TDM. In this case, active disease is seen in the presence of a suboptimal drug level, without the presence of anti-drug antibodies. The AGA recommends considering dose-escalation of the current TNF antagonist when non-immune-mediated pharmacokinetic failure is identified [8], as this can improve clinical response in an estimated 82% of patients [9].

Finally, immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to the current biologic therapy when at adequate drug concentration levels experiences suboptimal drug levels because of increased drug clearance mediated by anti-drug antibodies [9]. Because anti-TNF agents are monoclonal antibodies, they are inherently immunogenic, and it is well established that episodic dosing and lower serum drug concentrations are strong risk factors for the development of anti-drug antibodies [12]. When anti-drug antibodies are present, and are associated with both a decreased serum drug concentration and active inflammatory bowel disease, immune-mediate pharmacokinetic failure can be invoked. When anti-drug antibodies are present, but at a low level, the AGA recommends dose escalation of current TNF antagonist. When anti-drug antibodies are present at a high level, the AGA recommends considering either the addition of an immunomodulator (if not already being used), or changing to a different class of biologic therapy [8]. This recommendation is based in part on data showing that the proportion of patients with sustained anti-drug antibodies during the first year of therapy with an TNF antagonist is likely between 14% and 20% for those on monotherapy, but between 1% and 5% for those on concomitant immunomodulatory therapy [13,14].

Therapeutic Drug Monitoring of Anti-TNF Agents

As described above, TDM, which is the process of testing the patient’s serum for both the concentration of the TNF antagonist and for the presence and concentration of anti-drug antibodies, can help differentiate between mechanistic failure, non-immune-mediated pharmacokinetic failure, and immune-mediated pharmacokinetic failure (Table 1). 

Therapeutic drug monitoring can be classified as either proactive or reactive. Proactive TDM is performed during induction or maintenance therapy when the patient does not have signs or symptoms of active disease to suggest a loss of response. Theoretically, this would allow dose modification and optimization, including dose de-escalation in certain circumstances, and could thus provide cost savings with minimal impact on clinical outcomes. The TAXIT trial provides the most robust evaluation of proactive TDM in TNF antagonist therapy. In this study, patients with Crohn’s disease or ulcerative colitis who had a stable clinical response while on maintenance infliximab were first dose optimized proactively to a target trough concentration of 3–7 μg/mL, then randomized to having dose modifications made based on clinical factors alone, defined as reactive monitoring, or dose modifications based on proactive monitoring, performed by checking the drug concentration and antibody levels before each infusion. At 1 year there was no statistically significant difference in the proportion of patients in remission. In addition, some patients in the proactive TDM group were able to have a dose reduction without a subsequent flare of disease, thus providing cost savings [15]. This study suggests that proactive TDM may have a role in drug optimization, particularly with respect to cost-effectiveness, but provides only indirect evidence of a clinical benefit, since all subjects enrolled in the study were proactively dose optimized prior to randomization. This study had a limited follow-up time of 1 year so was not able to assess for longer-term benefits and risks associated with proactive TDM.

More recently, a large, multicenter, retrospective cohort study provided additional evidence that proactive TDM may provide a clinical benefit in addition to cost savings. This study retrospectively evaluated consecutive patients receiving maintenance infliximab for Crohn’s disease between 2006 and 2015, with a median follow-up time of 2.4 years. They were classified as having had either proactive TDM or reactive TDM. Proactive TDM was associated with statistically significant reductions in the risk of treatment failure (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.09–0.27), the need for surgery (HR 0.30, 95% CI 0.11–0.80), hospitalization (HR 0.16, 95% CI 0.07–0.33), and anti-drug antibody formation (HR 0.25, 95% CI 0.07–0.84) [16].

To date, however, no randomized controlled trials have been published comparing proactive TDM to reactive TDM in treatment-naive patients. Because of the paucity of prospective studies, the AGA currently makes no recommendation regarding the use of proactive TDM in clinical practice. However, the current AGA guidelines do recommend reactive TDM in the setting of secondary loss of response based on the results of one randomized controlled trial (RCT) and several observational studies. The RCT was small (n = 69), and enrolled patients with Crohn’s disease on maintenance therapy with infliximab. Similar to the TAXIT trial, the study did not show a statistically significant difference in rates of clinical remission when subjects were randomized to either empiric dose escalation (to 5 mg/kg every 4 weeks) based on symptoms, or to dose escalations based on the results of reactive TDM. Also similar to the TAXIT trial, it showed an estimated cost savings of about 34% based on local prices in Denmark for reactive TDM over empiric dose escalation [17].

Meanwhile, the observational studies for reactive TDM provided additional support to the clinical benefit of reactive TDM, but also to the underlying hypotheses that drive reactive TDM, namely that subjects with mechanistic failure benefit from a change in drug class, those with non-immune-mediated pharmacokinetic failure benefit from dose escalation, and that those with immune-mediated pharmacokinetic failure may benefit from either dose escalation or a change in mechanism of action, depending on antibody titers. Specifically, on pooled analysis of 2 of these studies, 82% of subjects who were found to have non-immune-mediated pharmacokinetic failure responded to empiric dose escalation, whereas only 8% of subjects who were found to have immune-mediated pharmacokinetic failure with high anti-drug antibody titers responded to dose escalation [9]. Likewise, in a retrospective study involving subjects who were being treated with infliximab and then had reactive TDM performed, when non-immune-mediated pharmacokinetic failure was identified, a clinical response was seen in 86% of subjects who underwent dose escalation, and only 33% among those who were switched to a different anti-TNF (P < 0.016). Conversely, dose escalation resulted in a clinical response only 17% of the time when anti-drug antibodies were detectable, compared to a 92% response rate when the subject was switched to a different anti-TNF (P < 0.004) [18].

Interpreting the Results of Reactive Therapeutic Drug Monitoring

The implementation of reactive TDM involves obtaining a serum drug and antibody level and then interpreting what those results suggest about the mechanism of drug failure, in order to decide on a course of action. The serum drug level should be a trough concentration, so it should be obtained just prior to a timed dose, while on a stable treatment regimen. Exactly what serum drug concentration we should be targeting in reactive therapeutic drug monitoring remains an area of investigation. No RCTs have been published. There is ample observational, cross-sectional data from cohorts of patients on maintenance therapy, though heterogeneity in study design and study populations, as well as use of different assays, limit interpretation of the data. In a secondary analysis of data from 6 observational studies of patients on infliximab maintenance therapy, there was a highly statistically significant concentration-dependent trend in rates of clinical remission depending on the measured infliximab trough concentration, with 96% of those with infliximab > 7 μg/mL in remission, 92% of those with infliximab > 5 μg/mL in remission, and 75% of those with infliximab > 1 μg/mL in remission. Likewise, data from 4 studies of patients receiving adalimumab showed a statistically significant concentration-dependent trend in clinical remission, with 90% of those with adalimumab trough concentrations > 7.5 μg/mL being in clinical remission, compared with only 83% of those with concentrations > 5 μg/mL. Similarly, data from 9 studies suggested that a certolizumab trough concentration > 20 μg/mL was associated with a 75% probability of being in clinical remission, compared to a 60% probability when the trough concentration was > 10 μg/mL [9]. Based on these analyses, the AGA suggests target trough concentrations for reactive therapeutic drug monitoring of anti-TNF agents of ≥ 5 μg/mL for infliximab, ≥ 7.5 μg/mL for adalimumamb, and ≥ 20 μg/mL for certolizumab. They did not suggest a target trough concentration for golimumab because of insufficient evidence [8].

When interpreting TDM test results, it is important to know if the test you have used is drug-sensitive or drug-tolerant (Table 2). Drug-sensitive tests will be less likely to reveal the presence of anti-drug antibodies when the drug level is above a certain threshold. A post-hoc analysis of the TAXIT trial recently suggested that subjects who have antibodies detected on a drug-tolerant test which were not detected on a drug-sensitive test are more likely to respond to higher doses of infliximab [19]. It follows that there should be a threshold anti-drug antibody titer below which someone who has immune-mediated pharmacokinetic failure will still respond to TNF antagonist dose escalation, but above which they will fail to respond to dose escalation. To be sure, our understanding of the clinical implications of a drug-tolerant test demonstrating an adequate drug level while also detectable anti-drug antibodies is evolving. Complicating the issue further is the fact that anti-drug antibody concentrations cannot be compared between assays because of assay-specific characteristics. As such, though the presence of low antibody titers and high antibody titers seems to be clinically important, recommendations cannot yet be made on how to interpret specific thresholds. Furthermore, development of transient versus sustained antibodies requires further clinical investigation to determine impact and treatment algorithms.

Optimizing Therapy

Once you have determined the most likely cause of drug failure, the next step is to make a change in medical therapy. 

When switching within class (to another anti-TNF agent), the choice of which agent to use next will largely depend on patient preference (route of administration, infusion versus injection), insurance, and costs of treatment. When making the decision to switch within class, it should be kept in mind that the probability of achieving remission is modestly reduced compared to the probability seen in anti-TNF-naive patients [20], and even more so when the patient is switching to their third anti-TNF agent [21]. Thus, for the patient who has already previously switched from one TNF antagonist to a second TNF antagonist, it may be better to switch to a different class of biologic rather than attempting to capture a clinical remission with a third TNF antagonist.

When adding an immunomodulator (azathioprine or methotrexate), the expectation is that the therapy will increase the serum concentration of the anti-TNF agent [14] and/or reduce the ongoing risk of anti-drug antibody formation [22]. There could also be a direct treatment effect on the bowel disease by the immunomodulator.

When switching to an alternate mechanism of action, the currently FDA-approved options include the biologic agents vedolizumab (for both moderate-to-severe ulcerative colitis and moderate-to-severe Crohn’s disease) and ustekinumab (for moderate-to-severe Crohn’s disease), as well as the recently FDA-approved oral, small-molecule JAK1 and JAK3 inhibitor tofacitinib (for moderate-to-severe ulcerative colitis). Prospective comparative effectiveness studies for these agents are lacking and are unlikely to be performed in part due to the cost and time required to accomplish these studies. A recent post-hoc analysis of clinical trials data suggests that there are no significant differences in the rates of clinical response, clinical remission, or in adverse outcomes to vedolizumab or ustekinumab when they are used in patients who have failed anti-TNF therapy [23]. Thus, one cannot be recommended over the other, and the decision of which to use is usually guided by patient preference and insurance coverage.

Meanwhile, the role of tofacitinib in the treatment algorithm of patients who have failed anti-TNF therapy remains unclear. The phase III clinical trials OCTAVE 1, OCTAVE 2, and OCTAVE Sustain showed efficacy for both the induction and maintenance of remission in patients with moderate-to-severe ulcerative colitis who had previously failed anti-TNF agents. However, there remain concerns about the safety profile of tofacitinib compared to vedolizumab and ustekinumab, particularly regarding herpes zoster infection, dyslipidemia, and adverse cardiovascular events. Notable findings from the tofacitinib induction trials include robust rates of clinical remission (18.5% vs 8.2% for placebo in Octave 1, and 16.6% vs 3.6% in Octave 2, P < 0.001 for both comparisons) and mucosal healing (31.3% vs 15.6% for placebo in Octave 1, and 28.4% and 11.6% in Octave 2, P < 0.001 for both comparisons) after 8 weeks of induction therapy [24]. These results suggest that tofacitinib, or other JAK inhibitors that become approved in the future, may be excellent oral agents for the induction of remission in moderate-to-severe ulcerative colitis, and may demonstrate a better side effect profile than steroids. Whether cost factors (compared to steroid therapy) will limit the role of JAK-inhibitor therapy in induction, and whether safety concerns will limit their use in maintenance therapy, remains to be seen.

Off-Label Rescue Therapy and Surgery

Though the armamentarium of IBD therapies has expanded greatly over the past 2 decades, and will continue to do so for the foreseeable future, there are still a limited selection of therapies available to patients. Patients who have failed anti-TNF therapy, and subsequently fail vedolizumab and/or ustekinumab, have limited options. These options include clinical trials, off-label small molecule rescue therapy, and surgery. Patients who are felt to require any of these options should be referred to a tertiary center for evaluation by a gastroenterologist specializing in the treatment of IBD and/or a colorectal surgeon specializing in the surgical management of IBD.

Tacrolimus

Tacrolimus, a macrolide calcineurin inhibitor, has been studied as a small molecule therapy for IBD, though not in randomized controlled trials. There is biological plausibility for its use as a disease modifying agent. Mucosal T cells in subjects with active Crohn’s disease have been found to express increased levels of mRNA encoding IL-2, and tacrolimus acts primarily by reducing IL-2 production [25]. The largest observational cohort evaluating the use of tacrolimus, published by Thin et al, included patients with both ulcerative colitis (n = 24) and Crohn’s disease (n = 11) who had moderate to severely active IBD. All patients had failed dose-optimized thiopurine therapy, 89% had primary nonresponse or secondary loss of response to at least one anti-TNF agent, and 74% were either steroid-refractory or steroid-dependent at the time tacrolimus was started. With close monitoring, they targeted a tacrolimus trough of 8–12 ng/mL. At 30 days, 66% had a clinical response, and 40% were in clinical remission. At 90 days, 60% had a clinical response, and 37% were in clinical remission. At 1 year, 31% had a clinical response, and 23% were in clinical remission. Of those in clinical remission at 1 year, 88% were either off of steroids or on less than 5 mg of prednisone per day. Renal impairment was seen in 25% of patients, including severe renal impairment in 11%, requiring drug cessation. Infectious complications were seen in 9% of patients. Headaches, tremor, and pancreatitis were also observed, though less commonly. The majority of patients ultimately had a surgical intervention, particularly if they were steroid-refractory at baseline, but the time to surgery was delayed in those who achieved a response or remission in the first 90 days of tacrolimus therapy. The authors suggested that while tacrolimus may lack clear long-term benefit in patients with medically refractory IBD, a therapeutic trial should be considered in select patients with the goal of medical and nutritional optimization before surgical intervention [26].

Cyclosporine

Cyclosporine, which also exerts its effect by inhibiting IL-2 production, has an established role in the management of severe ulcerative colitis. Data from randomized, placebo-controlled trials, along with numerous open label observational studies, have shown that intravenous cyclosporine can induce remission and potentially obviate the need for urgent/emergent colectomy in steroid-refractory patients who are hospitalized with severe ulcerative colitis [27,28]. Its use in maintenance therapy remains controversial, however. Older observational data suggest that even among those who have an initial clinical response to cyclosporine induction, 33% will undergo colectomy by 1 year, and 88% will undergo colectomy by 7 years [27). Though the concomitant administration of a thiopurine may delay the need for colectomy [29,30], cyclosporine seems to be, at best, a temporizing therapy for patients with severe ulcerative colitis. Studies on the use of cyclosporine for the induction of remission in Crohn’s disease have been less robust, as have studies on the use of cyclosporine for the maintenance of remission in Crohn’s disease [31]. Dose-dependent toxicity also remains a concern, particularly when being considered as maintenance therapy. Though some observational data suggest that the absolute risks of serious side effects from maintenance cyclosporine are small, cyclosporine is still generally avoided as a maintenance therapy [30].

Mycophenolate Mofetil

Mycophenolate mofetil (MMF), which inhibits both B and T cell proliferation by inhibiting de novo purine synthesis, has been studied in both Crohn’s disease and ulcerative colitis. Studies have been small, observational, and heterogeneous. On the whole, they suggest that MMF does have some efficacy, but it is not necessarily more effective than azathioprine and may have a slightly increased risk of side effects [32]. Given that the side effects of MMF include diarrhea, and an IBD-like enterocolitis (MMF-induced colitis) when given to subjects without an established diagnosis of IBD, it is likely best to avoid using the drug in patients with IBD [33].

Surgery

Finally, when medical management has failed, or when fibrostenotic and/or penetrating complications of inflammatory bowel disease are present, surgery should be considered. Surgery can provide a cure in patients with ulcerative colitis, and can induce remission in patients with Crohn’s disease. Managing IBD medications around the time of surgery is always challenging. Multiple large, retrospective cohort studies have suggested that the risk for postoperative infectious complications, anastomotic leaks, and thrombotic complications do not differ between those who receive anti-TNF therapy within several months of surgery and those who do not. Nevertheless, some surgeons may prefer to time elective surgery halfway between doses of anti-TNF therapy. Additionally, there is some data to suggest that patients who are on both thiopurines and anti-TNF agents have an increased risk of postoperative complications compared to those who are on anti-TNF agents alone [34].

After a surgical evaluation, a plan of action should be formulated in a multidisciplinary fashion to determine how medical management will proceed. For those with an established diagnosis of ulcerative colitis, medical therapy can often be stopped postoperatively and the patient can be monitored prospectively for pouch complications including possible new-onset Crohn’s disease. For those who undergo surgery for the management of Crohn’s disease, though a resection completed with negative margins does induce remission, nearly 90% can be expected to have histologic, endoscopic, or clinical recurrence by 1 year. A randomized controlled trial showed that postoperative anti-TNF therapy can reduce this risk to 9% [35]. Unfortunately, a subsequently conducted large, multicenter, randomized controlled trial comparing postoperative infliximab to placebo was terminated early because of a lack of a statistically significant difference in clinical recurrence between the 2 groups at week 74. However, this lack of demonstrated efficacy may have been obscured by the relatively mild phenotype of the enrolled participants, who had a median CDAI score of 105.5 at baseline [36]. Based on available data, the AGA does conditionally recommend postoperative anti-TNF and/or thiopurine therapy for those patients with Crohn’s disease who are in a surgically induced remission [37]. The patients who are most likely to benefit from postoperative medical therapy are those who have the highest risk of recurrence, namely those who were young at the time of diagnosis, had a short disease duration prior to surgery, have multiple sites of disease, and who use tobacco products [34].

Emerging and Future Options

Despite the improved clinical outcomes seen since the introduction of TNF antagonists for the management of IBD, there remains a significant need for additional medical therapies. Fortunately, the armamentarium is expected to expand dramatically over the next decade.

Based on our improved, and evolving understanding of the pathogenesis of IBD, several new biochemical targets have emerged, offering novel ways to modulate the cytokine cascade which drives IBD [38]. Well over a dozen phase II and phase III trials for IBD therapeutic agents are ongoing, including biologic agents targeting interleukin-23, β7-Integrin, and MAdCAM-1, as well as small molecule agents targeting the JAK/STAT pathway and the sphingosine-1-phosphate receptor modulators [39]. As new agents are approved, it may be possible to develop a more patient-centered approach to care by targeting therapies to the particular pathogenesis of each patient’s disease. Nevertheless, integrating these therapies into practice algorithms will remain a challenge in the absence of meaningful comparative effectiveness trials [40].

Conclusion

When evaluating a patient who seems to have failed anti-TNF therapy for IBD, the first step is to confirm that active inflammatory disease is present. This process includes ruling out other potential causes of the patient’s symptoms, including infectious colitis, and ideally includes obtaining objective evidence of inflammation, whether through non-invasive biomarkers, an endoscopic evaluation and/or cross-sectional imaging. Once active IBD is confirmed, reactive therapeutic drug monitoring can help elucidate the likely mechanism of drug failure, which in turn can guide medical decision making.

Corresponding author: Anita Afzali MD, MPH, The Ohio State University Wexner Medical Center, 395 West 12th Ave, Room 280, Columbus, OH 43210, [email protected].

Financial disclosures: Dr. Afzali has served as a speaker/consultant for Abbvie, UCB, Takeda, Pfizer, Janssen; on the advisory board of Abbvie, UCB; received grant support from UCB; and is a board member of IBD Horizons.

From the Division of Gastroenterology University of Washington, Seattle, WA (Dr. Tiderington), and the Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center and The Ohio State University Inflammatory Bowel Disease Center, Columbus, OH (Dr. Afzali).

Abstract

• Objective: To provide a practical approach to the management of patients with inflammatory bowel disease (IBD) following tumor necrosis factor (TNF) alpha antagonist failure.
• Methods: Review of the literature.
• Results: TNF alpha antagonists play a central role in the treatment of IBD. Unfortunately, some patients will not respond to therapy with TNF antagonists, and others will lose response during treatment. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. In this paper we review the mechanisms of drug failure, the use of reactive therapeutic drug monitoring to guide clinical decision making, and propose an evidence-based method for managing this common clinical scenario.
• Conclusion: Despite the improved clinical outcomes seen since the introduction of TNF antagonists for the management of IBD, there remains a significant need for additional medical therapies. Fortunately, the armamentarium is expected to expand dramatically over the next decade.

Key words: TNF antagonists; therapeutic drug monitoring; biologic failure; Crohn’s disease treatment; ulcerative colitis treatment.

Ulcerative colitis and Crohn’s disease are the two types of inflammatory bowel disease (IBD), and they are characterized by chronic, immunologically mediated inflammation involving the gastrointestinal tract [1]. Guided by an understanding of the role of tumor necrosis factor (TNF) alpha in the pathogenesis of IBD, TNF antagonists have played a central role in modern treatment algorithms [2]. Unfortunately, roughly one third of patients will not have a clinical response when given induction dosing of the currently available anti-TNF agents, and of those who do respond to treatment, up to one half will lose response to treatment within the first year [3]. When patients present with persistent or recurrent symptoms suggesting active IBD while on anti-TNF therapy it can present a dilemma for the clinician. Once the clinician has confirmed that active IBD is present based on endoscopic, cross-sectional imaging and/or biochemical markers of inflammation, the next step is to identify the cause of the treatment failure, as this guides management. Here we review the body of literature that guides our understanding of treatment failure as well as therapeutic drug monitoring and propose an evidence-based algorithm for managing this common clinical scenario.

Defining Treatment Failure

Patients who receive anti-TNF therapy but demonstrate active IBD should be classified as having either primary nonresponse or secondary loss of response. Primary nonresponse is defined as having either no response, or only partial response, to induction with anti-TNF therapy [4]. Data from pivotal trials and meta-analyses suggest that about one third of patients will not show any clinical response to induction with anti-TNF therapies, with response typically being defined using composite endpoints favoring clinical symptoms and only sometimes incorporating endoscopic findings [5]. An additional one third of patients will have only a partial response, without remission. Patients with ulcerative colitis are at a slightly increased risk of primary nonresponse compared to patients with Crohn’s disease. Though the time frame for defining primary nonresponse is different for each agent because each agent has a slightly different induction schedule, in general the maximal response to therapy is typically seen by week 12, and it is reasonable to use this as a time cutoff [6].

Secondary loss of response is likewise defined as recrudescence of clinically active disease after an initial response. In general, the presence of secondary loss of response should not be invoked until week 12 of therapy. In most pivotal trials, secondary loss of response was seen in roughly half of patients at 1 year. In clinical practice, however, particularly as therapeutic drug monitoring has become more common, the observed rates of secondary loss of response have been lower [6].

Applying these definitions appropriately is important because it dictates the next steps in management. When a patient presents with symptoms suggesting active IBD while on anti-TNF therapy, either during induction when primary nonresponse is possible, or in maintenance when secondary loss of response would be invoked, the first step is to determine if active IBD is the etiology for the presenting symptoms. The initial evaluation should rule out common infectious causes of symptoms mimicking IBD. In particular, Clostridium difficile infection should be ruled out with stool testing. In certain circumstances, ruling out cytomegalovirus (CMV) colitis is important, so an endoscopic evaluation with colonic biopsies should be considered. In the absence of infectious colitis, the presence of active inflammation can often be identified endoscopically, or can be inferred from noninvasive markers with a fair degree of certainty. Fecal calprotectin is an ideal choice for this purpose. In ulcerative colitis it is estimated to have a sensitivity of 0.88 and a specificity of 0.79 for the prediction of endoscopically active disease. The estimated sensitivity for detecting endoscopically active Crohn’s disease is essentially the same (0.87), and the specificity is only slightly lower (0.67). C-reactive protein demonstrates a better specificity (0.92), but has a marginal sensitivity (0.49) [7]. Other etiologies for the patient’s symptoms should also be considered, including medication side effects including use of nonsteroidal anti-inflammatory medications, bile acid malabsorption, small intestinal bacterial overgrowth (SIBO), irritable bowel syndrome (IBS), diverticular disease, ischemic colitis, fibrostenotic strictures, and cancer, depending on comorbidities and the history of present illness.

Once it has been determined that active IBD is the etiology for the patient’s symptoms, the patient should be classified as having either primary nonresponse or secondary loss of response as described above. For the clinician, the next question is how to alter or optimize therapy.

The decision of how to optimize therapy will largely depend on which anti-TNF therapy the patient is currently receiving, and whether they are receiving it as monotherapy or as combination therapy with an immunomodulator. Optimizing therapy will involve either increasing the dose or frequency of administration of the anti-TNF therapy, increasing the dose of azathioprine if indicated, adding an immunomodulator if the patient is on anti-TNF monotherapy, changing to a different anti-TNF agent, or changing to a different class of medication with a different mechanism of action. The recently released American Gastroenterological Association (AGA) guidelines on therapeutic drug monitoring in IBD provide a framework for making these decisions [8]. In general, the clinical choice will be dictated by the etiology of the drug failure.

Types of TNF Antagonist Drug Failure

Our understanding of the causes of biologic treatment failure are evolving but are typically classified as due to mechanistic failure, non-immune-mediated pharmacokinetic failure, or immune-mediated pharmacokinetic failure [9]. Differentiating between these classes of treatment failure requires therapeutic drug monitoring (TDM), which will be discussed in more detail below.

Mechanistic failure is encountered when the underlying biology does not favor a response to a particular therapy. Studies indicate a strong association between particular genetic phenotypes and the probability of a response to induction with anti-TNF agents [10]. This suggests that some individuals have IBD driven by a biochemical inflammatory cascade in which TNF features prominently, while others have alternative mechanistic drivers of inflammation without significantly elevated TNF levels. Mechanistic failure will typically present as primary nonresponse, but can also be seen in patients with secondary loss of response. Mechanistic failure can be elucidated clinically by the use of TDM. In the case of mechanistic failure, active disease is seen in the presence of adequate drug level, without the presence of anti-drug antibodies. The AGA recommends considering switching to a biologic with a different mechanism of action when mechanistic failure is identified [8].

Non-immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to a drug at adequate drug levels experiences suboptimal drug levels because of pharmacokinetic factors. In the case of anti-TNF therapy, this can be conceptualized as either an increased clearance of anti-TNF from the body (eg, in patients with significant hypoalbuminemia or severe colitis), a reduction in the average serum anti-TNF level because of the redistribution of drug in patients with a large body mass index, or inadequate saturation of the total body burden of TNF-alpha in subjects with a high baseline level of inflammation [11]. Non-immune-mediated pharmacokinetic failure can also be identified clinically through TDM. In this case, active disease is seen in the presence of a suboptimal drug level, without the presence of anti-drug antibodies. The AGA recommends considering dose-escalation of the current TNF antagonist when non-immune-mediated pharmacokinetic failure is identified [8], as this can improve clinical response in an estimated 82% of patients [9].

Finally, immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to the current biologic therapy when at adequate drug concentration levels experiences suboptimal drug levels because of increased drug clearance mediated by anti-drug antibodies [9]. Because anti-TNF agents are monoclonal antibodies, they are inherently immunogenic, and it is well established that episodic dosing and lower serum drug concentrations are strong risk factors for the development of anti-drug antibodies [12]. When anti-drug antibodies are present, and are associated with both a decreased serum drug concentration and active inflammatory bowel disease, immune-mediate pharmacokinetic failure can be invoked. When anti-drug antibodies are present, but at a low level, the AGA recommends dose escalation of current TNF antagonist. When anti-drug antibodies are present at a high level, the AGA recommends considering either the addition of an immunomodulator (if not already being used), or changing to a different class of biologic therapy [8]. This recommendation is based in part on data showing that the proportion of patients with sustained anti-drug antibodies during the first year of therapy with an TNF antagonist is likely between 14% and 20% for those on monotherapy, but between 1% and 5% for those on concomitant immunomodulatory therapy [13,14].

Therapeutic Drug Monitoring of Anti-TNF Agents

As described above, TDM, which is the process of testing the patient’s serum for both the concentration of the TNF antagonist and for the presence and concentration of anti-drug antibodies, can help differentiate between mechanistic failure, non-immune-mediated pharmacokinetic failure, and immune-mediated pharmacokinetic failure (Table 1). 

Therapeutic drug monitoring can be classified as either proactive or reactive. Proactive TDM is performed during induction or maintenance therapy when the patient does not have signs or symptoms of active disease to suggest a loss of response. Theoretically, this would allow dose modification and optimization, including dose de-escalation in certain circumstances, and could thus provide cost savings with minimal impact on clinical outcomes. The TAXIT trial provides the most robust evaluation of proactive TDM in TNF antagonist therapy. In this study, patients with Crohn’s disease or ulcerative colitis who had a stable clinical response while on maintenance infliximab were first dose optimized proactively to a target trough concentration of 3–7 μg/mL, then randomized to having dose modifications made based on clinical factors alone, defined as reactive monitoring, or dose modifications based on proactive monitoring, performed by checking the drug concentration and antibody levels before each infusion. At 1 year there was no statistically significant difference in the proportion of patients in remission. In addition, some patients in the proactive TDM group were able to have a dose reduction without a subsequent flare of disease, thus providing cost savings [15]. This study suggests that proactive TDM may have a role in drug optimization, particularly with respect to cost-effectiveness, but provides only indirect evidence of a clinical benefit, since all subjects enrolled in the study were proactively dose optimized prior to randomization. This study had a limited follow-up time of 1 year so was not able to assess for longer-term benefits and risks associated with proactive TDM.

More recently, a large, multicenter, retrospective cohort study provided additional evidence that proactive TDM may provide a clinical benefit in addition to cost savings. This study retrospectively evaluated consecutive patients receiving maintenance infliximab for Crohn’s disease between 2006 and 2015, with a median follow-up time of 2.4 years. They were classified as having had either proactive TDM or reactive TDM. Proactive TDM was associated with statistically significant reductions in the risk of treatment failure (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.09–0.27), the need for surgery (HR 0.30, 95% CI 0.11–0.80), hospitalization (HR 0.16, 95% CI 0.07–0.33), and anti-drug antibody formation (HR 0.25, 95% CI 0.07–0.84) [16].

To date, however, no randomized controlled trials have been published comparing proactive TDM to reactive TDM in treatment-naive patients. Because of the paucity of prospective studies, the AGA currently makes no recommendation regarding the use of proactive TDM in clinical practice. However, the current AGA guidelines do recommend reactive TDM in the setting of secondary loss of response based on the results of one randomized controlled trial (RCT) and several observational studies. The RCT was small (n = 69), and enrolled patients with Crohn’s disease on maintenance therapy with infliximab. Similar to the TAXIT trial, the study did not show a statistically significant difference in rates of clinical remission when subjects were randomized to either empiric dose escalation (to 5 mg/kg every 4 weeks) based on symptoms, or to dose escalations based on the results of reactive TDM. Also similar to the TAXIT trial, it showed an estimated cost savings of about 34% based on local prices in Denmark for reactive TDM over empiric dose escalation [17].

Meanwhile, the observational studies for reactive TDM provided additional support to the clinical benefit of reactive TDM, but also to the underlying hypotheses that drive reactive TDM, namely that subjects with mechanistic failure benefit from a change in drug class, those with non-immune-mediated pharmacokinetic failure benefit from dose escalation, and that those with immune-mediated pharmacokinetic failure may benefit from either dose escalation or a change in mechanism of action, depending on antibody titers. Specifically, on pooled analysis of 2 of these studies, 82% of subjects who were found to have non-immune-mediated pharmacokinetic failure responded to empiric dose escalation, whereas only 8% of subjects who were found to have immune-mediated pharmacokinetic failure with high anti-drug antibody titers responded to dose escalation [9]. Likewise, in a retrospective study involving subjects who were being treated with infliximab and then had reactive TDM performed, when non-immune-mediated pharmacokinetic failure was identified, a clinical response was seen in 86% of subjects who underwent dose escalation, and only 33% among those who were switched to a different anti-TNF (P < 0.016). Conversely, dose escalation resulted in a clinical response only 17% of the time when anti-drug antibodies were detectable, compared to a 92% response rate when the subject was switched to a different anti-TNF (P < 0.004) [18].

Interpreting the Results of Reactive Therapeutic Drug Monitoring

The implementation of reactive TDM involves obtaining a serum drug and antibody level and then interpreting what those results suggest about the mechanism of drug failure, in order to decide on a course of action. The serum drug level should be a trough concentration, so it should be obtained just prior to a timed dose, while on a stable treatment regimen. Exactly what serum drug concentration we should be targeting in reactive therapeutic drug monitoring remains an area of investigation. No RCTs have been published. There is ample observational, cross-sectional data from cohorts of patients on maintenance therapy, though heterogeneity in study design and study populations, as well as use of different assays, limit interpretation of the data. In a secondary analysis of data from 6 observational studies of patients on infliximab maintenance therapy, there was a highly statistically significant concentration-dependent trend in rates of clinical remission depending on the measured infliximab trough concentration, with 96% of those with infliximab > 7 μg/mL in remission, 92% of those with infliximab > 5 μg/mL in remission, and 75% of those with infliximab > 1 μg/mL in remission. Likewise, data from 4 studies of patients receiving adalimumab showed a statistically significant concentration-dependent trend in clinical remission, with 90% of those with adalimumab trough concentrations > 7.5 μg/mL being in clinical remission, compared with only 83% of those with concentrations > 5 μg/mL. Similarly, data from 9 studies suggested that a certolizumab trough concentration > 20 μg/mL was associated with a 75% probability of being in clinical remission, compared to a 60% probability when the trough concentration was > 10 μg/mL [9]. Based on these analyses, the AGA suggests target trough concentrations for reactive therapeutic drug monitoring of anti-TNF agents of ≥ 5 μg/mL for infliximab, ≥ 7.5 μg/mL for adalimumamb, and ≥ 20 μg/mL for certolizumab. They did not suggest a target trough concentration for golimumab because of insufficient evidence [8].

When interpreting TDM test results, it is important to know if the test you have used is drug-sensitive or drug-tolerant (Table 2). Drug-sensitive tests will be less likely to reveal the presence of anti-drug antibodies when the drug level is above a certain threshold. A post-hoc analysis of the TAXIT trial recently suggested that subjects who have antibodies detected on a drug-tolerant test which were not detected on a drug-sensitive test are more likely to respond to higher doses of infliximab [19]. It follows that there should be a threshold anti-drug antibody titer below which someone who has immune-mediated pharmacokinetic failure will still respond to TNF antagonist dose escalation, but above which they will fail to respond to dose escalation. To be sure, our understanding of the clinical implications of a drug-tolerant test demonstrating an adequate drug level while also detectable anti-drug antibodies is evolving. Complicating the issue further is the fact that anti-drug antibody concentrations cannot be compared between assays because of assay-specific characteristics. As such, though the presence of low antibody titers and high antibody titers seems to be clinically important, recommendations cannot yet be made on how to interpret specific thresholds. Furthermore, development of transient versus sustained antibodies requires further clinical investigation to determine impact and treatment algorithms.

Optimizing Therapy

Once you have determined the most likely cause of drug failure, the next step is to make a change in medical therapy. 

When switching within class (to another anti-TNF agent), the choice of which agent to use next will largely depend on patient preference (route of administration, infusion versus injection), insurance, and costs of treatment. When making the decision to switch within class, it should be kept in mind that the probability of achieving remission is modestly reduced compared to the probability seen in anti-TNF-naive patients [20], and even more so when the patient is switching to their third anti-TNF agent [21]. Thus, for the patient who has already previously switched from one TNF antagonist to a second TNF antagonist, it may be better to switch to a different class of biologic rather than attempting to capture a clinical remission with a third TNF antagonist.

When adding an immunomodulator (azathioprine or methotrexate), the expectation is that the therapy will increase the serum concentration of the anti-TNF agent [14] and/or reduce the ongoing risk of anti-drug antibody formation [22]. There could also be a direct treatment effect on the bowel disease by the immunomodulator.

When switching to an alternate mechanism of action, the currently FDA-approved options include the biologic agents vedolizumab (for both moderate-to-severe ulcerative colitis and moderate-to-severe Crohn’s disease) and ustekinumab (for moderate-to-severe Crohn’s disease), as well as the recently FDA-approved oral, small-molecule JAK1 and JAK3 inhibitor tofacitinib (for moderate-to-severe ulcerative colitis). Prospective comparative effectiveness studies for these agents are lacking and are unlikely to be performed in part due to the cost and time required to accomplish these studies. A recent post-hoc analysis of clinical trials data suggests that there are no significant differences in the rates of clinical response, clinical remission, or in adverse outcomes to vedolizumab or ustekinumab when they are used in patients who have failed anti-TNF therapy [23]. Thus, one cannot be recommended over the other, and the decision of which to use is usually guided by patient preference and insurance coverage.

Meanwhile, the role of tofacitinib in the treatment algorithm of patients who have failed anti-TNF therapy remains unclear. The phase III clinical trials OCTAVE 1, OCTAVE 2, and OCTAVE Sustain showed efficacy for both the induction and maintenance of remission in patients with moderate-to-severe ulcerative colitis who had previously failed anti-TNF agents. However, there remain concerns about the safety profile of tofacitinib compared to vedolizumab and ustekinumab, particularly regarding herpes zoster infection, dyslipidemia, and adverse cardiovascular events. Notable findings from the tofacitinib induction trials include robust rates of clinical remission (18.5% vs 8.2% for placebo in Octave 1, and 16.6% vs 3.6% in Octave 2, P < 0.001 for both comparisons) and mucosal healing (31.3% vs 15.6% for placebo in Octave 1, and 28.4% and 11.6% in Octave 2, P < 0.001 for both comparisons) after 8 weeks of induction therapy [24]. These results suggest that tofacitinib, or other JAK inhibitors that become approved in the future, may be excellent oral agents for the induction of remission in moderate-to-severe ulcerative colitis, and may demonstrate a better side effect profile than steroids. Whether cost factors (compared to steroid therapy) will limit the role of JAK-inhibitor therapy in induction, and whether safety concerns will limit their use in maintenance therapy, remains to be seen.

Off-Label Rescue Therapy and Surgery

Though the armamentarium of IBD therapies has expanded greatly over the past 2 decades, and will continue to do so for the foreseeable future, there are still a limited selection of therapies available to patients. Patients who have failed anti-TNF therapy, and subsequently fail vedolizumab and/or ustekinumab, have limited options. These options include clinical trials, off-label small molecule rescue therapy, and surgery. Patients who are felt to require any of these options should be referred to a tertiary center for evaluation by a gastroenterologist specializing in the treatment of IBD and/or a colorectal surgeon specializing in the surgical management of IBD.

Tacrolimus

Tacrolimus, a macrolide calcineurin inhibitor, has been studied as a small molecule therapy for IBD, though not in randomized controlled trials. There is biological plausibility for its use as a disease modifying agent. Mucosal T cells in subjects with active Crohn’s disease have been found to express increased levels of mRNA encoding IL-2, and tacrolimus acts primarily by reducing IL-2 production [25]. The largest observational cohort evaluating the use of tacrolimus, published by Thin et al, included patients with both ulcerative colitis (n = 24) and Crohn’s disease (n = 11) who had moderate to severely active IBD. All patients had failed dose-optimized thiopurine therapy, 89% had primary nonresponse or secondary loss of response to at least one anti-TNF agent, and 74% were either steroid-refractory or steroid-dependent at the time tacrolimus was started. With close monitoring, they targeted a tacrolimus trough of 8–12 ng/mL. At 30 days, 66% had a clinical response, and 40% were in clinical remission. At 90 days, 60% had a clinical response, and 37% were in clinical remission. At 1 year, 31% had a clinical response, and 23% were in clinical remission. Of those in clinical remission at 1 year, 88% were either off of steroids or on less than 5 mg of prednisone per day. Renal impairment was seen in 25% of patients, including severe renal impairment in 11%, requiring drug cessation. Infectious complications were seen in 9% of patients. Headaches, tremor, and pancreatitis were also observed, though less commonly. The majority of patients ultimately had a surgical intervention, particularly if they were steroid-refractory at baseline, but the time to surgery was delayed in those who achieved a response or remission in the first 90 days of tacrolimus therapy. The authors suggested that while tacrolimus may lack clear long-term benefit in patients with medically refractory IBD, a therapeutic trial should be considered in select patients with the goal of medical and nutritional optimization before surgical intervention [26].

Cyclosporine

Cyclosporine, which also exerts its effect by inhibiting IL-2 production, has an established role in the management of severe ulcerative colitis. Data from randomized, placebo-controlled trials, along with numerous open label observational studies, have shown that intravenous cyclosporine can induce remission and potentially obviate the need for urgent/emergent colectomy in steroid-refractory patients who are hospitalized with severe ulcerative colitis [27,28]. Its use in maintenance therapy remains controversial, however. Older observational data suggest that even among those who have an initial clinical response to cyclosporine induction, 33% will undergo colectomy by 1 year, and 88% will undergo colectomy by 7 years [27). Though the concomitant administration of a thiopurine may delay the need for colectomy [29,30], cyclosporine seems to be, at best, a temporizing therapy for patients with severe ulcerative colitis. Studies on the use of cyclosporine for the induction of remission in Crohn’s disease have been less robust, as have studies on the use of cyclosporine for the maintenance of remission in Crohn’s disease [31]. Dose-dependent toxicity also remains a concern, particularly when being considered as maintenance therapy. Though some observational data suggest that the absolute risks of serious side effects from maintenance cyclosporine are small, cyclosporine is still generally avoided as a maintenance therapy [30].

Mycophenolate Mofetil

Mycophenolate mofetil (MMF), which inhibits both B and T cell proliferation by inhibiting de novo purine synthesis, has been studied in both Crohn’s disease and ulcerative colitis. Studies have been small, observational, and heterogeneous. On the whole, they suggest that MMF does have some efficacy, but it is not necessarily more effective than azathioprine and may have a slightly increased risk of side effects [32]. Given that the side effects of MMF include diarrhea, and an IBD-like enterocolitis (MMF-induced colitis) when given to subjects without an established diagnosis of IBD, it is likely best to avoid using the drug in patients with IBD [33].

Surgery

Finally, when medical management has failed, or when fibrostenotic and/or penetrating complications of inflammatory bowel disease are present, surgery should be considered. Surgery can provide a cure in patients with ulcerative colitis, and can induce remission in patients with Crohn’s disease. Managing IBD medications around the time of surgery is always challenging. Multiple large, retrospective cohort studies have suggested that the risk for postoperative infectious complications, anastomotic leaks, and thrombotic complications do not differ between those who receive anti-TNF therapy within several months of surgery and those who do not. Nevertheless, some surgeons may prefer to time elective surgery halfway between doses of anti-TNF therapy. Additionally, there is some data to suggest that patients who are on both thiopurines and anti-TNF agents have an increased risk of postoperative complications compared to those who are on anti-TNF agents alone [34].

After a surgical evaluation, a plan of action should be formulated in a multidisciplinary fashion to determine how medical management will proceed. For those with an established diagnosis of ulcerative colitis, medical therapy can often be stopped postoperatively and the patient can be monitored prospectively for pouch complications including possible new-onset Crohn’s disease. For those who undergo surgery for the management of Crohn’s disease, though a resection completed with negative margins does induce remission, nearly 90% can be expected to have histologic, endoscopic, or clinical recurrence by 1 year. A randomized controlled trial showed that postoperative anti-TNF therapy can reduce this risk to 9% [35]. Unfortunately, a subsequently conducted large, multicenter, randomized controlled trial comparing postoperative infliximab to placebo was terminated early because of a lack of a statistically significant difference in clinical recurrence between the 2 groups at week 74. However, this lack of demonstrated efficacy may have been obscured by the relatively mild phenotype of the enrolled participants, who had a median CDAI score of 105.5 at baseline [36]. Based on available data, the AGA does conditionally recommend postoperative anti-TNF and/or thiopurine therapy for those patients with Crohn’s disease who are in a surgically induced remission [37]. The patients who are most likely to benefit from postoperative medical therapy are those who have the highest risk of recurrence, namely those who were young at the time of diagnosis, had a short disease duration prior to surgery, have multiple sites of disease, and who use tobacco products [34].

Emerging and Future Options

Despite the improved clinical outcomes seen since the introduction of TNF antagonists for the management of IBD, there remains a significant need for additional medical therapies. Fortunately, the armamentarium is expected to expand dramatically over the next decade.

Based on our improved, and evolving understanding of the pathogenesis of IBD, several new biochemical targets have emerged, offering novel ways to modulate the cytokine cascade which drives IBD [38]. Well over a dozen phase II and phase III trials for IBD therapeutic agents are ongoing, including biologic agents targeting interleukin-23, β7-Integrin, and MAdCAM-1, as well as small molecule agents targeting the JAK/STAT pathway and the sphingosine-1-phosphate receptor modulators [39]. As new agents are approved, it may be possible to develop a more patient-centered approach to care by targeting therapies to the particular pathogenesis of each patient’s disease. Nevertheless, integrating these therapies into practice algorithms will remain a challenge in the absence of meaningful comparative effectiveness trials [40].

Conclusion

When evaluating a patient who seems to have failed anti-TNF therapy for IBD, the first step is to confirm that active inflammatory disease is present. This process includes ruling out other potential causes of the patient’s symptoms, including infectious colitis, and ideally includes obtaining objective evidence of inflammation, whether through non-invasive biomarkers, an endoscopic evaluation and/or cross-sectional imaging. Once active IBD is confirmed, reactive therapeutic drug monitoring can help elucidate the likely mechanism of drug failure, which in turn can guide medical decision making.

Corresponding author: Anita Afzali MD, MPH, The Ohio State University Wexner Medical Center, 395 West 12th Ave, Room 280, Columbus, OH 43210, [email protected].

Financial disclosures: Dr. Afzali has served as a speaker/consultant for Abbvie, UCB, Takeda, Pfizer, Janssen; on the advisory board of Abbvie, UCB; received grant support from UCB; and is a board member of IBD Horizons.