Supportive care for patients undergoing immunotherapy

Transcription

1 DOI /s MEETING REPORT Supportive care for patients undergoing immunotherapy Bernardo Leon Rapoport 1,2 & Ronwyn van Eeden 1 & Vincent Sibaud 3,4 & Joel B. Epstein 5 & Jean Klastersky 6 & Matti Aapro 7 & Devan Moodley 8 Received: 31 March 2017 /Accepted: 18 June 2017 # Springer-Verlag GmbH Germany 2017 Abstract Immune checkpoint inhibitors, a new class of cancer therapeutic agents, play an important role in the management of melanoma, NSCLC, and other malignancies. A workshop organized by three MASCC Study Groups: Oral Care, Skin Toxicities, and Neutropenia, Infection, and Myelosuppression during the MASCC Annual Meeting held in Adelaide, Australia on June, 2016 focused on the new class of anti-cancer therapeutic agents. Topics in the workshop included the mechanism of action and clinical uses of immune anti-ctl4 and anti-pd1 antibodies, checkpoint inhibitor toxicities, including skin adverse events, gastrointestinal toxicities, oral complications, pulmonary toxicities, and endocrinological and immune-related infections. Checkpoint inhibitors have been approved for use in different malignancies including metastatic melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, refractory Hodgkin s lymphoma, metastatic bladder cancer, and advanced head and neck cancer, and the list continues to grow. In general, these agents seem to be better tolerated in most patients and less toxic compared to conventional chemotherapy. However, the toxicities here, termed immune-related adverse events (iraes), are unique and different from what we have seen in the past. There is no prospective data on these toxicities, and guidelines or recommendations are currently based on symptomatic management from the ongoing clinical trials. Treating oncologists need to be aware and alert themselves to the subtleties in presentation and the big difference in the way we manage the iraes. Although most iraes are lowgrade and manageable, they have the potential to be lifethreatening and extremely severe if not promptly treated. Additionally, iraes could even lead to death, if managed incorrectly. The MASCC workshop addressed the various iraes, per organ system, clinical presentation, management recommendations, and individual toxicities. Proceedings of a workshop co-sponsored by MASCC Oral Care Study Group, MASCC Skin Toxicities Study Group, and MASCC Neutropenia, Infection, and Myelosuppression Study Group during the MASCC Annual Meeting held in Adelaide, Australia June, * Bernardo Leon Rapoport brapoport@rosebankoncology.co.za 4 Department of Oncodermatology, Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse Oncopole, France The Medical Oncology Centre of Rosebank129 Oxford Road, Saxonwold 2196, Johannesburg, South Africa Department of Immunology, Faculty of Health Sciences, University of Pretoria, PO Box 2040, Parklands 2121, Pretoria 0001, South Africa Department of Medical Oncology and Clinical Research Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse Oncopole, France Cedars-Sinai Health System, Samuel Oshin Comprehensive Cancer Institute, Los Angeles, CA, USA Institut Jules Bordet, Université Libre de Bruxelles, Centre des Tumeurs de l ULB, Rue Héger Bordet, 1, 1000 Brussels, Belgium Institut Multidisciplinaire d Oncologie, Clinique de Genolier, Genolier, Switzerland University of the Witwatersrand and Wits Donald Gordon Medical Center, Johannesburg, South Africa

2 Keywords Immune-related adverse events. irae. Immune checkpoint inhibitors. Colitis. Pneumonitis. Nephritis. Endocrinopathy. Vitiligo. Skin rash. Anti-CTLA-4. Anti-PD-1. Anti-PDL-1 Introduction Immunotherapy is a new advance in the management of malignant disease and comprises the enhancement, suppression, or induction of the body s own immune system to treat cancer [1]. There has been a paradigm shift towards immunooncology treatment, and its side effects are referred to as immune-related adverse events (iraes). These side effects are unique and different than those associated with cytotoxic chemotherapy, radiotherapy, or targeted therapies. The spectrum of iraes is frequently low-grade and manageable; however, the iraes reported is largely suboptimal [2]. Oncologists should be aware that there is a broad range of added toxicities and side effects that can be both unpredictable and even severe in nature. For the purpose of this workshop, the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 published on May 28, 2009 (v4.03: June 14, 2010) was used [3]. The CTCAE v4.03 describes different grading of autoimmune toxicities that in certain cases may be applicable to some of the irae described below in Table 1 [3]. Toxicities associated with program cell death inhibitors (PD-1) and program cell death ligand inhibitors (PDL-1) are usually less severe than those related with cytotoxic T cell lymphocyte antigen 4 (CTLA-4) inhibitors; however, grade 3 4 toxicities have been reported in approximately 21% of immunotherapy cases [4, 5]. The following monoclonal antibodies are presently registered: anti-pd-1 (nivolumab and pembrolizumab), anti-pd-l1 (atezolizumab), and anti-ctla-4 antibodies (ipilimumab) [6, 7]. Pathogenesis The pathogenesis of iraes can be comprehended by the immune pathophysiology that leads to activation of T cells. PD-1 and CTLA-4 are immune checkpoints that are expressed on the antigen-presenting cell surface in the initiator and effector phase of T cell activation, respectively. These immune checkpoints are responsible for modulating and Bswitching off^ T cell effects. Inhibition of these checkpoints allows for overexpression of the immune system, which is a powerful mechanism to kill cancer cells. The expression of CTLA-4 by T cells represents a mechanism to avoid overstimulation of the immune system. CTLA-4 has a 100-fold higher affinity with the B7 complex than CD28, and this interaction is associated with an inhibitory function on the T cell [8]. Again, inhibition of CTLA-4 allows an increase of T cell function. Dermatological and oral toxicity Given their mechanism of action as immune-modulating agents that trigger T cell activation, these monoclonal antibodies are associated with a specific toxicity profile, with a spectrum of dermatologic adverse events that are mostly due to immune-mediated mechanisms [9 11]. Although adequate prospective dermatological studies are lacking, it is clearly apparent that cutaneous toxicities represent one of the most frequent iraes of any grade induced by anti-pd-1 agents, affecting more than 40% of melanoma patients (Table 2) [12 15]. Pembrolizumab and nivolumab therapy both act by blocking the PD-1 receptor and present with similar profiles of dermatologic adverse events [11]. Although the global toxicity profile of the immune checkpoint inhibitors compares favorably with anti-ctla-4 (ipilimumab, tremelimumab), the overall incidence of dermatologic iraes appears roughly similar in comparative studies without new safety signals [14, 15]. Dermatologic safety profile of anti-pd-l1 also appears similar to that reported with anti-pd-1 antibodies [16]. Skin toxicities induced by immune checkpoint inhibitors mainly manifest in the form of a non-specific maculopapular rash with pruritus. More characteristic dermatologic complications, however, can also occur including vitiligo, lichenoid dermatitis, exacerbated psoriasis or oral involvement with mucosal inflammatory reactions (e.g., lichenoid reactions), Table 1 Grading of autoimmune toxicity Autoimmune disorder A disorder resulting from loss of function or tissue destruction of an organ or multiple organs arising from humoral or cellular immune responses of the individual to his own tissue constituents Grade 1: Asymptomatic, serologic, or other evidence of autoimmune. : Evidence of autoimmune reaction involving a non-essential organ or function (e.g., hypothyroidism). : Autoimmune reactions involving major organ (e.g., colitis, urgent intervention indicated anemia, myocarditis, kidney). Grade 4: Life-threatening consequences.

3 Table 2 Severe immune-related adverse events associated with anti-pd-1 and anti-ctla-4 Pembro 1 Nivo 2 Ipi 3 Nivo + Ipi Rash (general) % % % % Rash (maculopapular) % % % % Pruritus % % % % Vitiligo % % % % Pneumonitis 0.4% 3% 3% 7.8% Colitis 7.6% 0.5% 0.6% 7% Diarrhea 4.6% 1% 1.2% 9% Hypothyroidism 1.2% 7.0% 4.2% 6.4% Hyperthyroidism 0.3% 2.8% 0.3% 7.1% Adrenal insufficiency 5.5% 0.2% 0.3% 4.9% 1 Pembro (pembrolizumab) 2 Nivo (nivolumab) 3 Ipi (ipilimumab) xerostomia, and taste change. It may also be noted that these dermatologic iraes appear to have a shorter time to onset than those affecting other organs. To date, the majority of dermatologic complications occurring with PD-1/PD-L1 blockade therapy are mild, reversible, and readily manageable with supportive care. Although uncommonly, they may result in significant morbidity or permanent discontinuation of immunotherapy (less than 5%) [9 12, 17]. Early management appears crucial for limiting treatment discontinuation. In addition, it has recently been suggested that the occurrence of dermatologic iraes with anti-pd-1 antibodies may represent a positive prognostic factor [17 19] with a higher survival benefit or objective response rate. Skin rashes The incidence of all-grade skin rash with anti-pd-1 agents ranges from 13 to 22% [13 15, 20, 21] inmelanomapatients (Table 2), with a calculated overall incidence of 14.3 and 16.7% for nivolumab and pembrolizumab, respectively [11]. In a large majority of cases, skin rash remains self-limiting, with less than 2% of grade 3 toxicity [11]. By comparison, the overall incidence determined by meta-analysis was slightly higher with anti-ctla-4 ipilimumab (24.3%) [22]. Maculopapular rashes A predominantly non-specific macular-papular rash represents the most prevalent cutaneous adverse event inducedbyanti-pd-1therapy[17, 23]. Patients generally develop lesions after the first doses [10, 17], although delayed eruptions have also been described (up to 2 years). Lesions can also worsen after each treatment cycle. Lesions are mainly located on the trunk and extremities, usually sparing the face. They mainly consist of faint erythematous macules combined with flattopped, minimally scaly papules. Itching is commonly associated. The extent of skin surface involved varies, but lesions usually remain self-limiting (grade 1 or 2, covering less than 30% of body surface area). A skin biopsy should be systematically recommended in the case of atypical lesions or persistent/recurrent grade 2 or grade 3 exanthematous rash. Indeed, more specific histological features can occasionally be isolated (e.g., psoriasiform or lichenoid reactions). It must be remembered that macular and/or papular rash may also represent the first manifestation of more severe skin toxicity. Indeed, life-threatening skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been sporadically reported with ipilimumab. Such severe skin reactions with pembrolizumab and nivolumab therapy have also already been recorded in pharmacovigilance databases [23]. Early recognition, diagnosis, intervention, and adequate monitoring are required for maintaining dose intensity and preventing exacerbation of the lesions. Symptomatic management mainly includes prescription of oral antihistamines, high- to very-high potency topical steroids (e.g., betamethasone or clobetasol propionate, cream or ointment), and/or moisturizers. In most cases, management of maculo-papular rash does not require treatment interruption or permanent discontinuation. Nevertheless, immunotherapy should be delayed and oral corticosteroids considered (0.5 1 mg/kg/day) in the case of persistent or intolerable grade 2 and grade 3 rash. Once improving, systemic steroids should be tapered over 1 month and immunotherapy resumed within 12 weeks of the last dose and when the steroid dose is <10-mg/day prednisone equivalent. Table 3 summarizes the management of maculo-papular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis skin toxicity associated with immune checkpoint inhibitor treatment.

4 Table 3 of maculopapular rash, pruritus, Stevens- Johnson syndrome, and toxic epidermal necrolysis Rash maculo-papular Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of events, frequently affecting the upper trunk, spreading centripetally, and associated with pruritus. Grade 1 Macules/papules covering <10% BSA with or without symptoms (e.g., pruritus, burning, tightness) Oral antihistamines, high-potency topical steroids (e.g., betamethasone, cream, or ointment), and/or moisturizers. Reassess after 2 weeks and monitor for change in severity Macules/papules covering 10 30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL. Oral antihistamines, high- or very high-potency topical steroids (e.g., betamethasone or clobetasol propionate, cream or ointment) and/or moisturizers. In the case of atypical, persistent or intolerable grade 2, a skin biopsy should be performed. Treatment with checkpoint inhibitor agent should be delayed and oral corticosteroids (0.5 1 mg/kg/day) should be considered once improving, systemic steroids should be tapered over 1 month and immunotherapy resumed within 12 weeks of the last dose and when the steroid dose is <10 mg/day prednisone equivalent. If worsened, manage as a grade 3. Macules/papules covering >30% BSA with or without associated symptoms; limiting self-care ADL. A skin biopsy should be performed. Oral corticosteroids should be considered (0.5 1 mg/kg/day). Once improving, systemic steroids should be tapered over 1 month and checkpoint inhibitor treatment resumed within 12 weeks of the last dose and when the steroid dose is <10 mg/day prednisone equivalent. If persistent or worsened: discontinue treatment with checkpoint inhibitor agent permanently. Pruritus Definition: A disorder characterized by an intense itching sensation. Grade 1 Mild or localized Topical (moisturizers, topical steroids) and oral intervention (e.g., antihistamines) indicated. Do not delay treatment with checkpoint inhibitor agent. Intense or widespread; intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, lichenification, oozing/crusts); limiting instrumental ADL. A skin biopsy should be performed. Topical (moisturizers, topical steroids) and oral intervention (e.g., antihistamines) indicated. If worsened, manage as a grade 3. Intense or widespread; constant; limiting self-care ADL or sleep. A skin biopsy should be performed. Oral corticosteroids should be considered (0.5 1 mg/kg/day)

5 Table 3 (continued) Potentially life-threatening skin reactions (blisters, exfoliative rash, associated fever, facial edema, Nikolsky sign ) Definitions: Stevens-Johnson syndrome: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes. Toxic epidermal necrolysis: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes. Urgent management with supportive measures in specialized unit. Pruritus Pruritus is also common with anti-pd-1/anti-pdl-1 agents and can severely impact on health-related quality of life. It affects between 11 and 21% of treated patients [12, 13, 15 17] with a rate of high-grade lesions of less than 3% [11]. By contrast, ipilimumab induces pruritus more frequently than pembrolizumab or nivolumab (Table 2). Pruritus also develops rapidly after the start of immunotherapy, either alone or associated with a skin rash [17]. Lichenoid dermatitis Maculopapular rashes can sometimes present as lichenoid reaction. Lichenoid dermatitis has been sporadically reported [24] but is not rare in clinical practice, either with anti-pd-1 or with anti-pdl1 therapy [25]. Lichenoid reactions can also develop on genital or oral mucosae [25]. Conservative management with high-potency topical steroids is generally sufficient and interruption of immunotherapy is usually not required. Psoriasis Both anti-pd-1 and ipilimumab therapy may also induce exacerbation or occurrence of psoriasis [26, 27]. We have also observed new onset psoriasis with anti-pdl-1 agents. Patients chiefly exhibit asymptomatic psoriasiform lesions with sharply bordered, scaly erythematous plaques on the trunk and limbs. Involvement of palmar areas or inverse and guttate psoriasis [23, 26] can also sometimes be observed. Vitiligo The development of vitiligo represents a well-recognized adverse event in melanoma patients treated with anti-ctla-4 and anti-pd-1/pdl-1 antibodies. Depigmentation results from induction of anti-melanoma immunity through a cytotoxic T cell-mediated response (e.g., MART-1, GP100, TRP1 2, tyrosinase) [18, 19]. The calculated all-grade incidence of newly developed vitiligo with PD-1 inhibitors is about 8% [11]. Vitiligoid lesions occur more frequently with anti-pd-1 agents than with other immunotherapies previously used in melanoma, including anti-ctla-4 [14, 15] (Table2). Finally, vitiligo has not been described to date in other types of solid cancers treated with PD-1/PDL1 antibodies [11, 16, 17]. Vitiligo usually develops after several months of treatment and can be preceded by erythematous inflammatory lesions [17, 18]. Lesions are mainly diffuse and bilateral but focal or segmental presentations can also be seen. Associated hair depigmentation can also be observed (scalp hair, eyelashes). Vitiligo usually persists beyond the completion of immunotherapy. Oral manifestations Oral manifestations may occur in 10% or more of patients on a single agent checkpoint inhibitor [13, 16, 24, 25, 28 30]. Mucosal changes are the most common oral manifestations associated with immune checkpoint inhibitors, presenting as inflammatory/immune conditions, most commonly as lichenoid reactions. Histology shows lichenoid changes on biopsy [25, 28]. Additional presentations of inflammatory conditions may include non-specific patchy erythema and as gingival erythema and sloughing. Dry mouth (hyposalivation) has been reported in approximately 5% of patients, by patient report, although studies assessing salivary production have not been reported. Dry mouth may lead to risk of secondary oral infection (e.g., candidiasis), increase risk of dental and periodontal disease, affect taste function, and increase risk of mucosal trauma. In addition, if topical or systemic steroids are used in management, dry mouth may increase the risk of secondary candidiasis. Independent impact upon taste has also been reported [13, 28] but not evaluated in clinical study. As the involvement of oral tissue may be mild and with few symptoms, the frequency of occurrence may be underestimated, as the oral symptoms and oral examination may not be evaluated in the medical setting. The current approaches to management are derived from the care of oral conditions such as other immune mucosal conditions and other complications of cancer therapy, specifically graft versus host disease (Table 4)[31 34]. These therapies should be studied in patients with oral complications of immune checkpoint inhibitor treatment.

6 Table 4 of oral mucositis Mucositis Definition: A disorder characterized by inflammation of the oral mucosal. Grade 1 Oral lesions asymptomatic or mild symptoms Oral coating, lubricating, wetting agents, moderate or high-potency topical steroids applied to affected areas. Reassess after 2 weeks and monitor for change in severity. Oral lesions with moderate pain, modified diet may be required. Oral coating, lubricating, wetting agents, high- or very high-potency topical steroids applied to affected areas, topical analgesic/anesthetic agents, systemic analgesic agents. Reassess after 1 2 weeks and monitor for change in severity. Delay treatment with checkpoint inhibitor agent if persistent (or intolerable grade 2). Consider oral corticosteroids (0.5 1 mg/kg/day). Once improved, taper steroids over 1 month and resume treatment with checkpoint inhibitor agent when systemic steroid dose is <10 mg prednisone equivalent. If worsened, manage as grade 3. Oral lesions, severe pain interfering with oral intake Above treatments and oral steroids ( mg/kg/day) Delay treatment with checkpoint inhibitor agent, reassess after several days, and monitor for change in severity. Permanently discontinue treatment with checkpoint inhibitor agent and supportive if symptoms persistent or worsened. If improved to grade 1: Taper steroids over 1 month and resume immunotherapy when systemic steroid dose is <10 mg prednisone or equivalent doses. Close follow-up, evaluate and support oral intake Early intervention and continuing monitoring are required to limit exacerbation of the oral changes. Mucosal changes may be managed with topical anti-inflammatory agents (high- or very high-potency topical steroid gel/ cream applications and oral rinse formulation for widespread involvement). Systemic prednisone may be required in addition to topical therapy in more severe cases as described for skin rashes. In severe cases, immunotherapy may be delayed or discontinued and oral corticosteroids considered. In addition, the potential risk of dysplasia in lichenoid lesions should be remembered. If mucosal pain is present, topical coating agents, topical analgesics, and anesthetics may be considered (e.g., doxepin rinse), and systemic analgesics if pain is not controlled with topical agents [35]. Dry mouth management may include salivary gland stimulation (sialogogues) and mouth-wetting agents, and management of dental risk in the presence of hyposalivation is needed [36, 37]. Mouth wetting, lubrication, caries prevention, and management of possible secondary mucosal infection (e.g., candidiasis) may be necessary. Lip lubrication and hydration should also be addressed. Intervention for taste dysfunction has not been evaluated following use of checkpoint inhibitors, but may include dietary guidance, saliva management, oral hygiene improvement, and possibly specific taste interventions [38]. Table 4 summarizes the management of mucositis associated with checkpoint inhibitor treatment. Specific situations Preexisting autoimmune disorders Safety of anti-pd-1 or anti-pdl1 agents in patients with preexisting autoimmune diseases is not established and some concerns remain. It has recently been described retrospectively that anti-ctla-4 ipilimumab led to reactivation of preexisting immune-related diseases, including psoriasis or sarcoidosis [27]. Likewise, the development of dermatomyositis or bullous pemphigoid has been reported in patients treated with anti-pd-

7 1/PDL-1 [39]. Therefore, caution should be taken in patients suffering from recent or ongoing autoimmune dermatologic conditions. Dual checkpoint blockade Although the safety profile of combination blockage of CTLA-4 and PD-1 receptors appear acceptable and consistent with previous experience with nivolumab or ipilimumab in monotherapy, dermatologic iraes are notably increased with a higher rate of all-grade skin select adverse events (42, 55, and 59 71% for nivolumab, ipilimumab, and combination, respectively) (Table 2) [14, 21]. Checkpoint blockade and targeted agents and cytotoxic therapy Combined therapies may become utilized and may result in multiple combined and potentially more complex adverse events that may require combined approaches to management. Gastrointestinal Diarrhea and colitis Diarrhea and colitis are commonly observed side effects of checkpoint inhibitors, and they are more frequently documented in patients treated with anti-ctla-4 than anti-pdl- 1 inhibitors. This toxicity has been reported in about 30% of patients receiving anti-ctla-4 treatment, where as little as only 1 2% of patients were receiving anti-pdl-1 treatment [3, 5, 40, 41]. The incidence is greater and the severity in toxicity grade higher when bigger doses are used as reported in the ipilimumab trials comparing 10 vs. 3 mg [5, 41, 42]. It is also more commonly observed and with a higher incidence of grade 3 and grade 4 events when the combination of two checkpoint inhibitors is used [2, 4, 14, 43]. Colitis is almost certainly to manifest within the first 6 weeks after checkpoint inhibitor therapy has been started, slightly later than dermatological iraes, although this is not absolute, as it can also occur anytime in the course of treatment [37, 44, 45]. Diarrhea, which is an increase in the frequency of stool, is related to but a different clinical entity from colitis. The CTCAE states that symptoms related to colitis are associated with abdominal pain and include patients who have blood or mucus in their stool [3].If there is evidence of inflammation in an endoscopic investigation or radiographically, it is also then defined as colitis. The differential diagnosis of diarrhea and colitis includes other infectious causes of diarrhea, for example, Clostridium difficile infection [5, 9, 44]. In very selected situations, where patients have symptoms of high fevers and leukocytosis, prophylactic antibiotics can be prescribed [44]. A colonoscopy can be considered in patients with severe or persistent symptoms or if the cause is unclear [9, 41, 44]. In severe cases, perforation can occur and lead to death and must be excluded in patients with peritonitis symptoms. These patients may require surgery and possible colostomy [4, 44]. Mild symptoms can be treated symptomatically with rehydration, electrolyte replacements, and loperamide [4, 5, 8, 41]. iraes requires the offending immunotherapy agent to be omitted. If symptoms are ongoing for more than 1 week, there should be an immediate commencement of oral corticosteroid therapy at a dose of 1 mg/kg/day. When symptoms are resolved, the immunotherapy treatment can be restarted [5, 7, 9, 41, 46]. Severe or life-threatening colitis and symptoms consistent with perforation, ileus, or fever are serious complications. High-dose intravenous corticosteroids at a starting dose of 2 mg/kg/day must be initiated promptly [44, 47]. If symptoms persist, a single dose of immunosuppressive infliximab therapy at 5 mg/kg must be considered unless there is a contraindication [41, 44, 47]. The dose of infliximab can be repeated after 2 weeks if symptoms persist [13, 15, 24]. Mycophenolate mofetil can also be considered in severe and refractory cases [44]. The most crucial part of the management of a patient with colitis is recognition and early initiation of aggressive treatment including early treatment with infliximab if the patient does not respond to corticosteroids. Diarrhea treatment guidelines have been shown to reduce bowel perforation and colectomy rates and severe iraes by up to 50% when this is done. There is anecdotal evidence that indicates that high-dose therapy initiated for iraes does not affect the efficacy of treatment [2, 14]. Furthermore, it is suggested that the severity of the irae correlates with a better treatment response [42, 43, 48]. Table 2 summarizes the incidence of diarrhea and colitis associated with checkpoint inhibitor treatment. Table 5 summarizes the management of diarrhea, colitis, and colonic perforation associated with checkpoint inhibitor treatment. Hepatic Hepatotoxicity can occur following treatment with anti- CTLA4 or anti-pd-1/anti-pdl-1 therapy usually at about 6 weeks after treatment initiation. It frequently manifests as an asymptomatic increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or total bilirubin. Hepatotoxicity has been observed in 3 to 9% of patients receiving ipilimumab [46, 49]. A meta-analysis of nine randomized controlled trials in patients with solid tumors determined that the use of PD-1 inhibitors, when compared to the control group of either chemotherapy or everolimus, significantly

8 Table 5 of diarrhea, colitis, and colonic perforation Diarrhea Definition: A disorder characterized by frequent and watery bowel movements. Grade 1 Increase of <four stools per day over baseline; mild increase in ostomy output compared to baseline. Symptomatically with rehydration, electrolyte replacements, and loperamide. Increase of four to six stools per day over baseline; moderate increase in ostomy output compared to baseline. Oral corticosteroid therapy at a dose of 1 mg/kg/day. When symptoms are resolved, treatment with checkpoint inhibitor agent can be restarted. Increase of seven stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care ADL. High-dose intravenous corticosteroids at a starting dose of 2 mg/kg/day must be initiated promptly. If symptoms persist, a single dose of immunosuppressive infliximab therapy at 5 mg/kg must be considered unless there is a contraindication. The dose of infliximab can be repeated after 2 weeks if symptoms persist. Mycophenolate mofetil can also be considered in severe and refractory cases. Discontinue treatment with checkpoint inhibitor agent permanently. Grade 4 Life-threatening consequences; urgent intervention indicated. High-dose intravenous corticosteroids at a starting dose of 2 mg/kg/day must be initiated promptly. If symptoms persist, a single dose of immunosuppressive infliximab therapy at 5 mg/kg must be considered unless there is a contraindication. The dose of infliximab can be repeated after 2 weeks if symptoms persist. Mycophenolate mofetil can also be considered in severe and refractory cases. Colitis Definition: A disorder characterized by inflammation of the colon. Grade 1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated. Symptomatically with rehydration, electrolyte replacements, and loperamide. Abdominal pain; mucus or blood in stool. Oral or intravenous corticosteroid therapy (in the form of predinisone at a dose of 1 mg/kg/day or equivalent). When symptoms are resolved, treatment with checkpoint inhibitor agent can be restarted. Severe abdominal pain; change in bowel habits; medical intervention indicated; peritoneal signs. Oral or intravenous corticosteroid therapy (in the form of predinisone at a dose of 1 mg/kg/day or equivalent). Grade 4 Life-threatening consequences; urgent intervention indicated.

9 Table 5 (continued) Oral or intravenous corticosteroid therapy (in the form of predinisone at a dose of 1 mg/kg/day or equivalent). Colonic perforation Definition: A disorder characterized by a rupture in the colonic wall. Symptomatic Medical intervention indicated. Oral or intravenous corticosteroid therapy (in the form of predinisone at a dose of 1 mg/kg/day or equivalent). Severe symptoms. Elective operative intervention indicated. Grade 4 Life-threatening consequences. Urgent intervention indicated. increased the risk of developing all but high-grade hepatic AEs. Additionally, the risk of all grades of hepatic AEs was considerably higher when a nivolumab and ipilimumab combination was used compared to ipilimumab monotherapy. No significant differences in the risk of all-grade and high-grade hepatic iraes were found between PD-1 inhibitors monotherapy and ipilimumab monotherapy [50]. The differential diagnosis of immunerelated hepatotoxity in patients undergoing checkpoint inhibitor treatment includes progressive metastatic liver disease, viral hepatitis, or another drug-specific toxic reaction. Diagnostic workup includes viral hepatitis studies, liver imaging, and excluding other drug-related causes for abnormal liver functions. A liver biopsy is indicated when the etiology is unclear [41]. It is critical to call attention to the fact that hepatic toxicity can occur in the absence of symptoms, and therefore, baseline liver functions should be obtained before beginning of therapy [41, 47]. When derangements are documented, other infectious causes, concurrent medications used by patients, alcohol intake, and disease progression must be excluded by appropriate investigations [41, 47]. Severe hepatotoxicity requires permanent discontinuation of immunotherapy. Additionally, high-dose intravenous glucocorticosteroids for 24 to 48 h, followed by an oral steroid taper with dexamethasone at a dose of 4 mg every 4 h or prednisone at 1 to 2 mg/kg tapered over not less than 30 days. If the levels of serum transaminase do not decrease 48 h after initiation of systemic steroids, oral mycophenolate mofetil 500 mg every 12 h should be considered [51]. The use of infliximab is associated with hepatotoxicity and should be avoided in this clinical setting. Table 6 summarizes the management of hepatobiliary disorders associated with checkpoint inhibitor treatment. Pneumonitis The incidence of pneumonitis is around 3% with nivolumab (seven studies) or pembrolizumab (four studies); this incidence has been calculated for a total of 3300 patients with melanoma, non-small cell lung cancer, or renal cell carcinoma. The incidence of grade 3/4 adverse events was estimated at 0.3% (See Table 7). As far as ipilimumab is concerned (five studies) and tremelimumab (one study), in 1700 patients with melanoma, the incidence of adverse effects was 0.4% with 0.2% of grade 3/4 events. [52] This is an irae that can occur both with anti-ctla-4 or anti-pd-1 agents. It has been described in approximately 1% of patients treated with anti-pd-1 agents and appears to be more frequently seen than with the anti-ctla-4 agent ipilimumab. Mortalities related to immune-related pneumonitis have been reported in NSCLC patients undergoing treatment with checkpoint inhibitors. For the combination of nivolumab and ipilimumab (407 patients), the incidence of pneumonitis was 7.8% with 1.2% of grade 3/4 events and 0.2% deaths. The presentation of pneumonitis, from the clinical point of view, is specific: cough, dyspnea, tachypnea, hypoxia, and various non-specific aspects on imaging such as reticulomodular infiltrates, ground glass appearance, and consolidation. This makes the precise diagnosis difficult and requires a broad differential diagnosis taking into consideration

10 Table 6 of hepatobiliary disorders Table 7 of pneumonitis Hepatobiliary disorder Grade 1 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Observation Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental ADL. Observation Infectious causes, concurrent medications used by patients, alcohol intake, and disease progression must be excluded by appropriate investigations. Severe or medically significant but not immediately life- threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL. Medical intervention indicated. Treatment with high-dose intravenous glucocorticosteroids for 24 to 48 h (methyl-prednisone at a dose of 2 mg/kg, followed by an oral steroid taper with dexamethasone at a dose of 4 mg every 4 h or prednisone at 1 to 2 mg/kg tapered over not less than 30 days. If serum transaminase does not decrease 48 h after initiation of systemic steroids, treatment with oral mycophenolate mofetil 500 mg every 12 h should be considered. The use of infliximab is associated with hepatotoxicity and should be avoided in this clinical setting. Grade 4: Life-threatening consequences; urgent intervention indicated. Medical intervention indicated. Oral or intravenous corticosteroid therapy (in the form of predinisone at a dose of 1 mg/kg/day or equivalent). infection, cancer, and many other possibilities. These include disease progression of cancer, alveolar hemorrhage, lymphangitis carcinomatosis, opportunistic infections, pulmonary tuberculosis, severe pneumonitis, early cardiac failure, or congestive cardiac failure. Invasive procedures such as bronchoscopy with bronchoalveolar lavage and lung biopsy should be contemplated to rule out other causes such as infectious etiologies before starting treatment, especially in moderate to severe cases. Additionally, radiological abnormalities should be monitored carefully. [53] Grade 1 (asymptomatic) pneumonitis does not require any intervention but delaying therapy is probably appropriate in Pneumonitis Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma. Grade 1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated. Observation Symptomatic; medical intervention indicated; limiting instrumental ADL. Start prednisone at a dose of 1 mg/kg. Severe symptoms; limiting self-care ADL; oxygen indicated. Start prednisone at a dose of 2 mg/kg. If symptoms improve, tapering of corticoids can be done over 6 weeks; if not, additional immunosuppressive therapy should be considered. Grade 4 Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation). Start prednisone at a dose of 2 mg/kg. If symptoms improve, tapering of corticoids can be done over 6 weeks. most cases. (symptomatic with limiting instrumental activities of daily living) requires discontinuation of therapy and initiation of prednisone therapy (1 mg /kg); therapy can be reconsidered if the toxic event resolves without complications. (severe symptoms and limitations to self-care activities) pneumonitis requires the permanent discontinuation and high-dose prednisone (2 mg/kg) administration; pulmonary and infectious disease consults are indicated as well as possible bronchoscopy and lung biopsy. If symptoms improve, tapering of corticoids can be done over 6 weeks; if not, additional immunosuppressive therapy (infliximab, cyclophosphamide) should be considered. Table 7 summarizes the management of pneumonitis associated with checkpoint inhibitor treatment. Endocrinological side effects Hypophysitis has been reported with an incidence of 11% in a large retrospective study [13]; the most common presenting

11 symptoms were headache and fatigue; hormonal disturbances (thyroid, gonads) and pituitary enlargement were reported in 20% of the cases each. Hypophysitis led to the discontinuation of therapy in 22% of the patients, and the endocrinological consequences were usually permanent and required hormonal replacement. A review of the therapeutic series with ipilimumab or tremelimumab in melanoma patients shows an incidence of hypophysitis of 2.5 and 1.8%, respectively (See Table 2). Similar series with nivolumab, lambrolizumab, or pembrolizumab report an incidence of hypophysitis of 0.3%. In three studies with ipilimumab + nivolumab, the incidence of hypophisitis was 7.2%. The next most common endocrinological side effect with CI is hypothyroidism; it was reported with an incidence of 1.2% with ipilimumab and 4 7% with nivolumab, lambrozumab, or pembrolizumab. The combination of ipilimumab and nivolumab resulted in an incidence of hypothyroidism of 1.4%. Hyperthyroidism was reported with ipilimumab in 0.8 and % with nivolumab, lambrozumab, and pembrolizumab; the combination of ipilimumab and nivolumab resulted in a 7.1% incidence of hyperthyroidism. Adrenal insufficiency is the last endocrinological side effect to have been reported with a significant frequency with the use of CI. Its incidence was 5.5% with ipilimumab, % with nivolumab and pembrolizumab, and 1.9% with the combination nivolumab and ipilimumab. [54] The clinical presentation of hypothyroidism, hyperthyroidism, and adrenal insufficiency is often typical of these endocrinological syndromes and requires specific classical therapies. It should be stressed, however, that the clinical presentation of these syndromes might be sometimes atypical, and that a high level of suspicion should be maintained. Ophthalmological Ophthalmological iraes are very rare and occur in less than 1% of patients treated with anti-ctla-4 therapy. The incidence of anti-pd-1 antibodies remains unknown [55, 56]. Besides from direct toxicity of immunotherapy drugs, the eye can also indirectly be affected via other immune-related adverse endocrinopathies such as hyperthyroidism form of autoimmune thyroiditis [56, 57]. There have been case reports of Grave s ophthalmopathy with symptoms and signs of proptosis associated with swelling of extra-ocular muscles and xerophthalmia [55, 57, 58]. Ophthalmological side effects include episcleritis, conjunctivitis, and uveitis [4]. A case report of bilateral iridocyclitis and bilateral choroidal neovascularization has been reported [5, 55, 59]. Most cases can be controlled with corticosteroids given topically [52]. Systemic corticosteroids can be implemented in patients who do not respond to topical treatment or in grade 3 or grade 4 cases. It is always advised to consult with an ophthalmologist [59]. Neurological Neurological symptoms can vary widely and present as a range of different conditions. It has been postulated that neurological toxicity can occur in about 1 3% of patients from literature reviews [60]. Most information collected about neurological toxicity from immunotherapy is from case reports. Posterior reversible encephalopathy syndrome, Guillain- Barre, aseptic meningitis, enteric neuropathy, and transverse myelitis cases have been described [5, 9]. There have also been isolated reports of chronic inflammatory demyelinating polyneuropathy and a myasthenia-gravis type syndrome [61]. Most times, if the adverse event is low-grade, stopping the offending agent until symptoms disappear or commencing low-dose oral corticosteroids is sufficient [47, 61]. In grade 3 or grade 4 events, high-dose intravenous corticosteroids are warranted and at times, plasmapheresis and intravenous immunoglobulin are justified [5, 61]. It is worthwhile to involve neurologist to assist with the diagnosis to advise with the treatment according to the severity of the case [5, 61]. Hematological The incidence of hematological side effects associated with checkpoint inhibitors is extremely low. The evidence regarding hematological side effects is all anecdotal and based on case reports as well. Severe anemia requiring transfusions and febrile neutropenia requiring support with granulocyte colony stimulating factor (GCSF) may occur [5, 62]. One case reported a patient with neutropenia receiving a CTLA-4 inhibitor that was refractory to GCSF treatment and responded immunoglobulin therapy [63]. Red cell aplasia, acquired hemophilia A, and thrombocytopenia have all been published [5, 61]. Recently, cases of hemolytic-uremic syndrome occurring in a patient receiving ipilimumab have been reported [64]. Most hematological iraes respond to steroid therapy, but in severe cases may need more intense therapy. Renal Renal toxicity due to checkpoint inhibitors is exceedingly rare. A case series of 13 patients provides information on different clinical presentations of patients with immunerelated nephritis and different histological diagnoses [65]. It showed that the median time to develop kidney injury from immune-checkpoint inhibitors was around 90 days though it ranged widely. Roughly 1 2% of patients can have acute

12 kidney injury from checkpoint inhibitors, with less than 1% of those patients having a severe grade 3 or 4 events [37, 65]. Renal histology in these patients shows dominance of tubuleinterstitial nephritis and in one patient showed a thrombotic microangiopathy [65, 66]. Initiating early corticosteroid therapy and stopping treatment are the recommended treatments of patients with documented acute kidney injury/interstitial nephritis from checkpoint inhibitor therapy. Most patients respond to steroid therapy [41]. Other causes of kidney injury such as infection or drug induced by other medications should be excluded, and when etiology is doubtful, unless contraindicated, a renal biopsy should always be carried out. Close monitoring of patient s serum creatinine should be done during treatment, especially if there is even a slight increase in creatinine. Grade 1 toxicity according to management guidelines is defined as an increase in creatinine up to 1.5 times above baseline, grade 2 or 3, defined as a creatinine above 1.5 times above baseline to six times above normal. Grade 4 events are life-threatening [41]. Mycophenolate mofetil in refractory cases can be used; anti-tnf agents may be useful [65]. There is very limited data regarding management in these patients, and general supportive measures should be carried out as well such as fluid replacement therapy and electrolyte correction. Early involvement with a nephrologist is advised, as there was dialysis requiring patients in the series as well [41, 65]. Pancreatitis There have been reports of elevated amylase and lipase levels in clinical trials with unknown clinical significance. It is not recommended in general guidelines to monitor pancreatic enzymes unless there is a clinical suspicion of acute pancreatitis. There have been very few case reports of patients who developed fulminant pancreatitis. General guidelines for irae should be followed with close monitoring in these patients [41, 56, 67]. Cardiac Cardiac iraes are also exceedingly rare. There are case reports of varying cardiac conditions in patients with toxicity from checkpoint inhibitors. In a series, eight cases of immunerelated cardiac toxicity were analyzed. Patients were asymptomatic of any cardiac-related issues before initiating treatment with checkpoint inhibitors. Cases ranged from myocarditis and cardiomyopathy that responded well to systemic corticosteroid therapy as well as cases that were fatal and refractory to treatment. Myocardial fibrosis was found in one patient s autopsy findings, in combination with multiorgan failure. The patients in this series were either very young or very elderly with no cardiac history and included patients with predisposing cardiac dysfunction. A patient also suffered a cardiac arrest. Sixty-three percent of patients had other organ systems involved in combination with the cardiac toxicity [68]. The review can allude to many hypotheses about cardiac-related toxicity. As with other uncommon iraes, more prospective data is required. More case reports are emerging and include fulminant myocarditis and pericardial effusions with tamponade [69, 70]. It is clear that treating physicians need to be aware of the possibility of this irae and to start treatment with supportive and corticosteroid therapy promptly to avoid serious complications and death. There is currently no recommendations regarding monitoring of cardiac enzymes during therapy [68]. Conclusions Side effects with immune checkpoint inhibitors are fairly common but they are rarely severe; pneumonitis and endocrinological side effects occur in <10% of the patients and, if they do occur, lead to the checkpoint inhibitor discontinuation in about 20%. These side effects are less frequent than fatigue (25%), dermatitis (20%), or colitis (10%). Pneumonitis and endocrinological side effects are, to some extent, drug-dependent: pneumonitis is uncommon with ipilimumab and related compounds, while hypophysitis is more often associated with ipilimumab. The combination of ipilimumab with nivolumab clearly increases the frequency of both pneumonitis and endocrinological side effects. The clinical presentation of pneumonitis, and occasionally of endocrinological syndromes, can be nonspecific and requires a broad-spectrum differential diagnosis and may require appropriate specialist consults (pneumology, endocrinology, infectious disease). Because these side effects can be occasionally, although rarely, life-threatening or even fatal, a high level of suspicion should be maintained while treating patients with checkpoint inhibitors, when atypical or systemic symptoms and/or signs are observed. Mild toxicities can be dealt with by just discontinuing the checkpoint inhibitors. The problem, in that case, is to decide whether and when therapy with checkpoint inhibitors can be resumed; in any case, such a restart of therapy should be closely followed up. In more severe cases of pneumonitis, immunosuppressive therapy with oral corticosteroids should be started and, in case of no response, more aggressive immunosuppression should be initiated. For the endocrinological complications, discontinuation of checkpoint inhibitors and replacement therapy, if indicated, is probably sufficient in most cases.

13 Finally, early irae recognition and aggressive immunosuppressive treatment are crucial to prevent morbidity and mortality. Combinations of toxicities are possible involving different sites and systems, presenting as a cluster of manifestations. Compliance with ethical standards Conflict of interest Bernardo Leon Rapoport: Has speaking, consultant, advisory board roles, and contract research with Merck and Co. and BMS South Africa. Also, has funded research grant from BMS South Africa. Ronwyn van Eeden: None. Vincent Sibaud: Has a speaking, consultant, or advisory role with Roche, GlaxoSmithKline, Pierre Fabre, Merck, Bristol-Myers Squibb, Bayer, and Boehringer Ingelheim. Joel B. Epstein: Has funded research supported by Dr. Falk Pharma, Amgen Inc., OraHealth Inc., and Synedgen Inc. and has advisory roles for Dara Biosciences, Galera Pharmaceuticals, Medactive Biopharmaceuticals, Onxeo Inc., and Vigilant Biosciences. Jean Klastersky: Has a speaking, consultant, or advisory role with TEVA and Amgen. Matti Aapro: Has speaking, consultant, and advisory board roles with BMS, Amgen, Pfizer, and MSD. Devan Moodley: None. References 1. Ryungsa K, Manabu E, Kazuak T (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology 121: Chen T, Razak A, Bedard P et al (2015) A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol 26: CTCAE v4.0 (2010) _ _QuickReference_8.5x11.pdf. Last accesed the 03 Jan Bertrand A, Kostine M, Barnetche T (2015) Immune related adverse events associated with anti-ctla-4 antibodies: systematic review and meta-analysis. BMC Med 13(211): Tarhini A (2013) Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management, Scientifica (Cairo). No Redman JM, Gibney GT, Atkins MB (2016) Advances in immunotherapy for melanoma. BMC Med 6: Tsiatas M, Grivas P (2016) Immunobiology and immunotherapy in genitourinary malignancies. Ann Transl Med 14: Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12: Postow MA (2015) Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book 35: Naidoo J, Page DB, Li BT et al (2015) Toxicities of the anti-pd-1 and anti PD-L1 immune checkpoint antibodies. Ann Oncol 26: Belum VR, Benhuri B, Postow MA et al (2016) Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 60: Larkin J, Lao CD, Urba WJ et al (2015) Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wildtype advanced melanoma: a pooled analysis of 4 clinical trials. JAMA Oncol 1: Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372: Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. NEnglJMed373: Robert C, Schachter J, Long GVet al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372: McDermott DF, Sosman JA, Sznol M et al (2016) Atelizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 34(8): Sanlorenzo M, Vujic I, Daud A et al (2015) Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol 151: Hua C, Boussemart L, Mateus C et al (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152: Lo JA, Fisher DE, Flaherty KT (2015) Prognostic significance of cutaneous adverse events associated with pembrolizumab therapy. JAMA Oncol 9: Wolchok JD, Kluger H, Callahan MK et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369: Postow MA, Chesney J, Pavlick AC et al (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372: Minkis K, Garden BC, Wu S et al (2013) The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol 69:e121 e Sibaud V, Meyer N, Lamant L et al (2016) Dermatologic complications of anti-pd-1/pd-l1 immune checkpoint antibodies. Curr Opin Oncol 28: Scheberg KB, Novoa RA, Wakelee HA et al (2016) Immunohistochemical analysis of lichenoid reactions in patients treated with anti-pd-l1 and anti-pd-1 therapy. J Cutan Pathol 43: Shi VJ, Rodic N, Gettinger S et al (2016) Clinical and histologic features of lichenoid mucocutaneous eruptions due to antiprogrammed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA Dermatol 152: Bonigen J, Raynaud-Donzel C, Hureaux J et al (2016) Anti-PD1- induced psoriasis. A study of 21 patients. J Eur Acad Dermatol Venereol. doi: /jdv Johnson DB, Sullivan RJ, Ott PA et al (2016) Ipilimumab therapy in patients with advanced melanoma and pre-existing autoimmune disorders. JAMA Oncol 2: Jackson LK, Johnson DB, Sosman JA et al (2015) Oral health in oncology: impact of immunotherapy. Support Care 23: Ansell SM, Lesokhin AM, Borrello I et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin s lymphoma. N Engl J Med 372: Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small cell cancer. N Engl J Med 373: Epstein JB, Smutzer G, Doty RL (2016) Understanding the impact of taste changes in oncology care. Support Care Cancer 24: Elad S, Jensen SB, Raber-Durlacher JE et al (2015) Clinical approach in the management of oral chronic graft-versus-host disease (cgvhd) in a series of specialized medical centers. Support Care Cancer 23: Saunders DP, Epstein JB, Elad SA et al (2013) For the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of antimicrobials, mucosal coating agents,