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Leukemia & Lymphoma, ISSN 1042-8194, 4/2011, Volume 52, Issue 4, pp. 587 - 596
Journal Article
Clinical Cancer Research, ISSN 1078-0432, 12/2009, Volume 15, Issue 23, pp. 7322 - 7329
Journal Article
Journal of Clinical Oncology, ISSN 0732-183X, 05/2001, Volume 19, Issue 9, pp. 2509 - 2516
Purpose: To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC).... 
Journal Article
Journal Article
The New England Journal of Medicine, ISSN 0028-4793, 09/2004, Volume 351, Issue 10, pp. 971 - 977
Journal Article
The New England Journal of Medicine, ISSN 0028-4793, 10/2007, Volume 357, Issue 15, pp. 1496 - 1506
Journal Article
International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, 2012, Volume 83, Issue 3, pp. 814 - 820
Journal Article
Haematologica, ISSN 0390-6078, 09/2017, Volume 102, Issue 10, pp. 1727 - 1738
Journal Article
Journal Article
by AUTHORS and Chandni Ravi and Maureen Gang and PEER REVIEWER and Steven M Winograd, MD and The keys to identifying toxicity from checkpoint inhibitor therapy are knowing the patient has received such therapy and connecting the various symptoms and signs to one cause The toxicity from checkpoint inhibitor therapy resembles autoimmune disorders, with skin, intestinal, endocrine, and pulmonary manifestations appearing in that sequence Toxicity from adoptive cell therapy can produce the cytokine release syndrome, causing patients to present with fever, tachycardia, hypotension, and multi-organ failure The febrile neutropenic patient should be evaluated carefully for an occult bacterial infection and managed with the expectation of empiric broad-spectrum antibiotics initiated in the emergency department Scoring systems to identify low-risk patients with febrile neutropenia have not yet been prospectively validated for patients presenting to the emergency department Early consultation with the patient’s oncologist can be helpful in directing the assessment and disposition of patients with cancer therapy-related toxicity ------------ Cancer therapy has been an area of constant discovery and evolution over the past two centuries, with innovative therapeutic strategies being developed as understanding of the underlying biologic processes increases This has led to an expansion of treatment options in recent years with newer, more effective, and better-tolerated alternatives developed seemingly daily Until the early 20th century, surgical excision of tumors remained the mainstay of cancer therapy Perhaps the most influential individual to have shaped the surgical approach to cancer was William Halstead (1852-1922) through his advocacy for the en bloc resection of the tumors and enough surrounding tissue to remove all the cancer cells However, this approach was useful only for solid tumors that had not spread beyond their site of origin With the discoveries of X-rays by Roentgen and radium by Pierre and Marie Curie, radiation therapy was introduced as a second modality to combat cancer1 Nitrogen mustard, used during the first World War as an agent of chemical warfare, was noted to have destructive effects on white blood cells, and subsequently was approved by the US Food and Drug Administration (FDA) as a chemotherapeutic agent against Hodgkin lymphoma2 This marked the advent of cancer chemotherapy as an adjuvant to surgery and radiation Successful trials involving Hodgkin lymphoma and childhood leukemia using regimens such as MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) and prednisone with 6-MP (6-mercaptopurine) introduced the concepts of combination chemotherapy in the 1960s3,4 For the next several decades, surgery, radiation, and chemotherapy would remain the mainstays of cancer therapy In recent years, a paradigm shift has occurred in cancer therapeutics A vast number of newer treatment modalities are being used today, including targeted therapies, cancer vaccines, and, most recently, immunotherapy Since 2006, the FDA has approved more than 130 new cancer drugs and indications for their use5 Such major improvements in the ability to fight cancer have led to a 27% decline in death rates and increased five-year survival rates Two-thirds of people diagnosed with cancer live at least five years after diagnosis The projected population living with a cancer diagnosis is expected to grow to nearly 26 million by 2040, with 73% of survivors 65 years of age or older5,6 In turn, this increase in survivors will increase the number of emergency department (ED) visits of patients experiencing both acute and chronic complications related to cancer therapy Although emergency providers are familiar with the adverse effects of older therapies, such as neutropenic fever and tumor lysis syndrome, the rapidly changing landscape of cancer therapy requires providers not only to keep abreast of treatment guidelines for these better-known complications, but also to familiarize themselves with the newer modalities and their associated toxicities and treatment options Newer Strategies in Cancer Treatment Immuno-oncology currently is perhaps the most exciting area in cancer research and has created a paradigm shift in the management of cancer Immunotherapy works by potentiating the patient’s immune response to tumor cells, as opposed to traditional modalities that target the tumor directly7,8 Several classes of immunological agents have been developed or are being studied currently These agents include immune checkpoint inhibitors (ICIs), targeted therapies, adoptive cell immunotherapy, and cancer vaccines Immune Checkpoint Inhibitors By evading the intrinsic immune checkpoints, cancer cells can escape the immune mechanism that is supposed to eliminate the cells expressing tumor antigens9 Immune checkpoints are comprised of multiple pathways that regulate crucial steps of T-cell mediated immunity to maintain tolerance to self-antigens and prevent autoimmunity10 These pathways are initiated primarily through T-cell inhibiting and stimulating receptors and their ligands, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1) protein, and programmed cell death ligand-1 (PD-L1)7 The upregulation of CTLA-4 or PD-1 by some tumors can suppress the immune system in fighting disease by putting brakes on T cells By acting against these receptors, checkpoint inhibitors block the immune evasion by cancer cells and encourage their destruction by the host immune system11,12 Immune checkpoint inhibitors became an area of great interest over the past decade following clinical trials demonstrating improved survival in advanced melanoma patients Previously there was no approved therapy for advanced melanoma The first agent to be studied and approved by the FDA was the anti-CTLA-4 monoclonal antibody ipilimumab13,14 Next to emerge were antibodies against PD-1 or its ligand PD-L1, which resulted in long-term responses and minimal side effects in patients with several types of cancer, including melanoma and lung, kidney, bladder, and triple-negative breast cancer and and chemotherapy-refractory Hodgkin disease11,12 Anti-PD-1 therapy was found to be superior to standard-of-care chemotherapy as well as CTLA-4 inhibition in some cases In 2014, the FDA approved pembrolizumab and nivolumab, two drugs in this class15 Several ICIs, which are approved for use in a variety of cancers, have emerged as a result of the rapid pace of ongoing research (See Table 1) A combination of CTLA-4 and PD-1 inhibitors has been associated with more favorable outcomes than with either monotherapy, leading to the development of various combination therapies15-17 In addition to cancer, researchers also are studying ICIs for their potential role in the treatment of HIV19,20 and autoimmune disease type 1 diabetes21 Emergency providers will be more likely to encounter patients receiving checkpoint inhibition therapy in the future given the growing expansion of indications for its use Mechanism of Action of Anti-CTLA-4 and Anti-PD-1 Agents An APC presents a foreign or perceived non-self-peptide fragment via its MHC, which binds and stimulates a TCR Activation of the TCR leads to expression of CTLA-4, which binds with a greater affinity to CD80/86 and promotes self-tolerance and prevents autoimmunity in normal conditions The anti-CTLA-4 therapies inhibit this co-inhibitory pathway and lead to enhanced T-cell stimulation and tumor surveillance On the right side of the figure, a similar mechanism is seen for the anti-PD-1/PD-L1 agents PD-L1 is expressed on cancer cells (among others) and also inhibits T-cell activation when binding to the PD-1 expressed on the surface of the T cell Anti-PD-1/PD-L1 treatment leads to the inhibition of this inhibitory pathway and leads to enhanced T-cell activity against tumors APC = antigen presenting cell and MHC = major histocompatibility complex and TCR = T-cell receptor Reprinted with permission from: Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ Management of immune checkpoint inhibitor toxicities: A review and clinical guideline for emergency physicians J Emerg Med 2018 and 55:489-502 Drug Class Drug Name Indication CTLA-4 Inhibitor Ipilimumab Advanced melanoma, melanoma after surgery PD-1 Inhibitor Nivolumab Hodgkin lymphoma, HNSCC, advanced lung cancer, metastatic renal cell cancer, advanced melanoma, high microsatellite instability tumors, Merkel cell carcinoma Pembrolizumab Recurrent/metastatic HNSCC, metastatic NSCLC, advanced melanoma, renal cell carcinoma, Merkel cell carcinoma PD-L1 Inhibitor Atezolizumab Melanoma, HNSCC, renal cell carcinoma, classical Hodgkin lymphoma, high microsatellite instability tumors, Merkel cell carcinoma, metastatic NSCLC, urothelial carcinoma Durvalumab Melanoma, HNSCC, renal cell carcinoma, classical Hodgkin lymphoma, high microsatellite instability tumors, Merkel cell carcinoma Avelumab Melanoma, HNSCC, renal cell carcinoma, classical Hodgkin lymphoma, high microsatellite instability tumors HNSCC = head and neck squamous cell carcinoma, NSCLC = non-small cell lung cancer Toxicity Related to Checkpoint Inhibitor Therapy ICIs have improved the treatment of various cancers significantly by producing effective antitumor responses However, because of their blockade of down regulators of the immune system, they can be associated with unique immune-related adverse events (IRAEs) IRAEs commonly are seen in up to 90% of patients receiving CTLA-4 inhibitors and up to 70% of patients receiving anti-PD-1/PD-L1 agents22 The recently approved combination therapy of ipilimumab (CTLA-4 inhibitor) with nivolumab (PD-1 inhibitor) is associated with a more severe adverse effect profile than with either individual agent23 IRAEs comprise a wide range of toxicities that can closely resemble autoimmune disease Several features distinguish the toxicity profiles of IRAEs from those of conventional chemotherapy or targeted therapy IRAEs potentially can involve every organ system in the body They also can cause long-term effects that may present in a delayed manner months to years following the discontinuation of checkpoint inhibitor therapy (See Table 2) Simultaneous Multiple types of IRAEs can occur at the same time Heterochronus IRAEs emerge one after the other in varying intervals Persistent IRAEs can occur months to years after cessation of treatment Association with response Patients with IRAEs have demonstrated greater clinical benefits and overall survival compared to those without IRAEs IRAE = Immune-related adverse event These features make it challenging to manage the complications arising from immune checkpoint therapy in the ED because most providers may not be familiar with their presentation or have access to patients’ medical history In a recent study, researchers found that one-fourth of ED visits by cancer patients at a comprehensive cancer center were related to IRAEs24 Immune checkpoint therapy usually can be continued with close monitoring in the presence of mild IRAEs, while moderate to severe reactions may be associated with organ dysfunction and death, emphasizing the significance of prompt recognition of these adverse effects by emergency providers The gastrointestinal, dermatological, endocrine, and pulmonary systems typically are involved in IRAEs, while involvement of the cardiovascular, renal, musculoskeletal, hematologic, neurological, and ocular systems has been reported less frequently18,23,26,27 (See Table 3) Organ Manifestations Neurologic Aseptic meningitis, encephalitis, transverse myelitis Ocular Uveitis, iritis, epscleritis, blepharitis Hematologic Autoimmune hemolytic anemia, thrombotic thrombocytopenic purpura/immune thrombocytopenia, lymphopenia, acquired hemophilia Dermatologic Inflammatory dermatitis, bullous dermtoses, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome Endocrine Hypophysitis, primary hypothyroidism, hyperthyroidism, primary adrenal insufficiency Renal Nephritis Cardiovascular Myocarditis, pericarditis, arrhythmias, heart failure, vasculitis Gastrointestinal Diarrhea, colitis, hepatitis Musculoskeletal Inflammatory arthritis, polymyalgia, myositis, myasthenia gravis, Guillain-Barre Respiratory Pneumonitis The kinetics of IRAE onset follow a predictable pattern Dermatologic toxicities appear first, followed by colitis after one to three doses of ICIs Autoimmune hepatitis and endocrinopathies occur late in the treatment course and at times can be seen as late as 24 weeks after treatment28 Reactions to ICIs are graded by severity, with grades 1 and 2 signifying mild severity, and grades 3 and 4 indicating more significant toxicity Grade 5 refers to death related to the adverse event29 (See Table 4) Severity Grade (CTCAE) Grade 1 Grade 2 Grade 3 Grade 4 Grade definition Asymptomatic or mild symptoms Moderate and limiting ADL Severe but not immediately life-threatening Life-threatening consequences Type of care Ambulatory Ambulatory Hospitalization Hospitalization and consider ICU Checkpoint inhibitor Continue with close monitoring Continue if dermatologic or endocrine, suspend if other Suspend, resume based on risk vs benefit Discontinue permanently Common IRAEs and Their Management Dermatitis Diffuse rash < 10% BSA, mild pruritis Maculopapular rash 10% to 30% BSA, intense pruritis Maculopapular rash > 30% BSA with bullae, ulceration, or hemorrhage, SJS/TEN Management Oral antihistamine, topical steroid Topical steroid and oral antihistamine, consider systemic steroid Systemic steroids – Prednisone 05 to 1 mg/kg/day Oral antihistamine, GABA-agonist Monitor for progression to SCAR Diarrhea and colitis Asymptomatic or < 4 to 6 stools/day Abdominal pain, blood in stool Severe abdominal pain, ileus, fever Peritoneal signs, bowel perforation > 7 stools/day, incontinence, IV hydration Management Observation Prednisone oral 1 to 2 mg/kg/day Prednisone IV 1 to 2 mg/kg/day, prophylaxis antibiotic, GI/surgery consult Endocrinopathy Asymptomatic or mild, lab finding Signs of endocrine dysfunction, IRAE requiring urgent medical intervention Suspicion of adrenal crisis, severe headache, visual field cut Management No intervention Endocrinology consult Hypophysitis: MRI pituitary – prednisone 1 to 2 mg/kg/day if abnormal, hormone replacement Central adrenal insufficiency: hydrocortisone 100 mg IV Central hypothyroidism: levothyroxine 1 mg/kg Hyperthyroidism: Graves’ disease guidelines Type 1 diabetes: Start insulin, assess for DKA Rule out sepsis, prednisone 1 mg/kg/day, ICU management of adrenal crisis Pneumonitis Asymptomatic to mild symptoms Symptomatic, limiting ADLs, mild hypoxia Severe symptoms, worsening hypoxia Management Monitor, O2 sat, low threshold for imaging Pulmonary and infectious disease consults Prednisone 1 mg/kg/day Prophylactic antibiotics, admit Pulmonary consult and infectious disease consults Methylprednisolone IV 2 mg/kg/day infliximab, cyclophosphamide, IVIG, or mycophenolate for severe symptoms, ICU admission Prophylactic antibiotics Hepatitis AST, ALT > ULN to 3 x ULN (or) T Bili > ULN to 15 x ULN AST, ALT > 3 x to 5 x ULN (or) T Bili 15 x to 3 x ULN AST, ALT > 5 x ULN (or) T Bili > 3 x ULN Management Rule out other drug-induced liver injury, infectious, malignant, thrombotic Close follow-up Rule out other etiologies Start prednisone 05 to 1 mg/kg/day Prednisone 1 to 2 mg/kg/day Consider prophylactic antibiotics Consult GI CTCAE = common terminology criteria for adverse events and ICU = Intensive care unit and BSA = body surface area and GI = gastroenterology and ADL = activities of daily living and SJS = Stevens-Johnson syndrome and TEN = toxic epidermal necrolysis and SCAR = severe cutaneous adverse reaction and IV = intravenous and IVIG = intravenous immunoglobulin and ULN = upper limit of normal and AST = aspartate aminotransferase and ALT = alanine aminotransferase and LFT = liver function test and T Bili = total bilirubin Dermatologic Toxicities Dermatologic toxicities are the earliest and most commonly seen IRAEs from both CTLA-4 and PD-1/ PD-L1 inhibitor therapy30 Although symptoms such as a maculopapular rash, vitiligo, lichenoid reactions, eczema, or pruritis often can be mild, they still can be dose-limiting and therefore may limit the efficacy of the treatment regimen The development of serious skin toxicities, such as severe rash with eosinophilia to Stevens-Johnson syndrome or toxic epidermal necrolysis, has been reported in about 4% of patients18 Cutaneous sarcoidosis and Sweet syndrome (acute febrile neutrophilic dermatosis) have been reported Mucosal involvement, including dry eyes, dry mouth, and mucositis, has been noted with PD-1 agents30 Grade 1 and 2 dermatitis can be managed with topical emollients, topical or oral glucocorticoids, and oral antihistamines Grade 3 and 4 dermatitis is managed with oral corticosteroids Gastrointestinal Toxicities Gastrointestinal adverse events typically present as diarrhea or in a more severe form as colitis These effects occur more commonly with ipilimumab (a CTLA-4 inhibitor) than with anti-PD-1 agents22 Identifying severe forms of colitis is crucial, given that diarrhea is a very common IRAE associated with ipilimumab, with nearly 30% to 40% of patients receiving the drug developing this complaint13 The emergency provider needs to assess the patient carefully and perform necessary investigations, including computed tomography (CT) imaging if needed, to determine the etiology of the diarrhea Serious forms of colitis, including small bowel obstruction, diverticulitis, enterocolitis, gastrointestinal bleeding, and perforation, can occur In some instances, colitis with CTLA-4 inhibitors can present like Crohn’s disease with ulcerations and granulomas22 Testing for Clostridium difficile and cytomegalovirus is recommended in cases of severe diarrhea and abdominal pain31 Treatment of grade 1-2 colitis ranges from supportive care to oral corticosteroids, with high-dose intravenous steroids reserved for more severe cases If the patient appears unstable or critically ill, there should be a low threshold to initiate treatment with the anti-TNF-alpha agent infliximab18,22,33 Infliximab also should be started in patients with colitis without a response to high-dose corticosteroids within three days or in those who experience a relapse of symptoms during a steroid taper28 Hepatic Dysfunction Hepatic dysfunction caused by ICIs usually is asymptomatic and is detected during routine laboratory testing as an elevation in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) Severe grade 3 hepatitis is rare among patients being treated with a single ICI, but it can be seen in about 14% of patients using combination therapy Management involves corticosteroid administration In severe cases that do not respond to steroids, mycophenolate may be administered, as infliximab has the potential to worsen hepatotoxicity18 Endocrine Toxicities Endocrine toxicities associated with checkpoint inhibitor therapy account for about 10% of IRAEs They are unique because they can be permanent, as in cases of adrenal insufficiency, or transient They also can precipitate underlying chronic endocrinopathies and require long-term treatment for months to years after discontinuation of the offending agent18,28,30 Thyroid disorders and hypophysitis comprise the majority of endocrine IRAEs Adrenal insufficiency, type 1 diabetes, and hypercalcemia are observed less commonly Hypophysitis is a condition in which either the pituitary gland or its stalk is inflamed It can result in hypopituitarism with hypogonadotropic hypogonadism, hypothyroidism, and central adrenal insufficiency Hypophysitis usually develops about two to four months after initiation of checkpoint inhibitor treatment and occurs in 10% to 17% of patients taking ipilimumab18 Undiagnosed hypophysitis may be fatal It can present with vague symptoms, such as anorexia, insomnia, headache, nausea, fatigue, and decreased libido Because of these nonspecific symptoms, a high index of clinical suspicion is needed to prevent this life-threatening complication of treatment The diagnosis can be made with laboratory markers for hypopituitarism, such as thyroid-stimulating hormone (TSH), or with magnetic resonance imaging (MRI), which will demonstrate pituitary enlargement or thickening of the pituitary stalk Hypothyroidism is seen in about 4% of patients receiving PD-1/PD-L1 treatment Hyperthyroidism also may occur but is associated more with CTLA-4 inhibitors Cancer patients receiving checkpoint blockade therapy may present to t