The changing paradigm for supportive care in cance

Authors: Alexandre Chan Jude Lees Dorothy Keefe

Publish Date: 2014/04/10

Volume: 22, Issue: 6, Pages: 1441-1445

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Abstract

With scientific advances in cancer supportive care and the incorporation of effective supportive care strategies into contemporary cancer treatment there has been a substantial reduction in the occurrence of severe toxicities traditionally associated with cytotoxic chemotherapy over the past two decades For example appropriate prophylaxis with antiemetics including a 5HT3 antagonist corticosteroid and NK1 antagonist has greatly reduced chemotherapyinduced nausea and vomiting colonystimulating factors have curbed febrile neutropenia and the integrated use of mouth care and palifermin has decreased the severity of oral mucositis In addition the introduction of structured management and care pathways into clinical practice has widely promoted these supportive care strategies for patients We may not currently have all the answers on the prevention of chemotherapyinduced toxicities but most oncology clinicians today can capably handle toxicities which were previously considered difficult to manageInnovations in cancer therapeutics have improved the oncologist’s toolkit to cure and control many cancers previously difficult to manage Targeted therapy agents are now commonly used in the management of cancers ranging from chronic myeloid leukemia to renal cell carcinoma and new indications and increased lines of therapy continue to arise Initially “targeted” drugs were thought to have unique mechanisms for targeting cancer cells and were considered to produce fewer side effects than traditional cytotoxic chemotherapy Importantly however clinicians are now observing a number of emerging and highly prevalent side effects associated with the use of targeted therapies 1 These agents which carry with them significant financial cost are also associated with an increase in chronic complications that can decrease a patient’s quality of life 2 We must therefore strive to understand and be responsive to the side effects of these novel therapeutics to enable optimal patient adherence to and participation in their treatmentIn this commentary we highlight toxicities that are commonly associated with targeted therapies namely dermatological gastrointestinal diarrhea and stomatitis hepatotoxicity cardiotoxicity neurotoxicity and immunotoxicity More importantly we will emphasize the current impediments to understanding the mechanisms behind emerging side effects and the lack of effective strategies for managing these toxicitiesCommonly associated with targeted agents is a range of dermatological toxicities which are different from the skin toxicities seen with traditional cytotoxic chemotherapy The first of these classrelated skin toxicities is observed with epidermal growth factor receptor inhibitors EGFRI including agents used for the treatment of lung gefitinib erlotinib and afatinib pancreatic erlotinib breast lapatinib head and neck cetuximab and colorectal cancers cetuximab and panitumumab They usually manifest as papulopustular rash also referred to as acneiform rash pruritus xerosis/skin fissures hair and nail changes and mucositis It is important to note that dermatological side effects of EGFRI are known to correlate with increased drug responses and the improvement of survival in several settings 3 Despite the benefits these side effects may result in significant physical and emotional discomfort to patients 4 therefore it is critical to maximize supportive care measures The Multinational Association of Supportive Care in Cancer MASCC through its Skin Toxicities Study Group has reviewed current literature and proposed important steps to address these dermatological issues MASCC has published a guideline for the management of the skin toxicities associated with EGFRI 5 However it is important to note that quality studies that investigate the management of these dermatological toxicities are still sparse hence research in this area is urgently neededOther nonEGFRItargeted therapy agents are associated with various dermatological toxicities Vascular endothelial growth factor inhibitors such as sorafenib and sunitinib are commonly associated with hand foot syndrome HFS which is well documented to cause pain and reduce healthrelated quality of life 6 7 Limited information is available to predict which patients are at risk of developing HFS and effective management strategies are also lacking Vemurafenib which is a BRAF inhibitor also causes rash pruritus and HFS All grades of toxicity are observed in 19  of the patients receiving vemurafenib with 2  experiencing highgrade toxicities 8 Similar to the aforementioned targeted agents patients experiencing severe dermatological toxicities from vemurafenib may require dose adjustmentSeveral types of gastrointestinal toxicities such as diarrhea and stomatitis are commonly associated with targeted therapies Diarrhea is selflimiting with all grades of diarrhea reported for approximately 50–60  of patients treated with tyrosine kinase inhibitors TKIs and 30  of patients treated with mammalian target of rapamycin mTOR inhibitors 9 It usually develops as early as 2 weeks into treatment It has been suggested that there are three mechanisms of targeted therapy diarrhea—secretive diarrhea with most of the EGFRI direct ischemic mucosal damage and colitis with VEGF inhibitors and immunotoxicity related diarrhea ipilimumab The severity of diarrhea varies among patients and ranges from mild symptoms to fecal incontinence Patients experiencing mild symptoms can find support in antidiarrheal medications such as loperamide and diphenoxylate Those experiencing severe symptoms may require dose interruptions and treatment adjustmentsSimilar to diarrhea stomatitis/mucositis is a major concern and usually occurs as early as 4–14 days after the initiation of targeted treatment Several classes of agents including mTOR inhibitors such as temsirolimus and everolimus and EGFRI are known to cause stomatitis In contrast to chemotherapyinduced stomatitis/mucositis with local inflammation and visible tissue damage mucosal damage due to targeted therapies is less specific and differs according to types of targeted treatment For instance in contrast to ulceration associated with radiotherapy and chemotherapy stomatitis observed with mTOR inhibitors presents with discrete aphthouslike ulcerations 10 It is likely that impaired wound healing plays a role in the development of ulceration in patients using mTOR inhibitors On the other hand the proposed mechanism of EGFRIinduced stomatitis involves follicular occlusion by keratinocytes leading to an inflammatory response These toxicities may be exacerbated when the EGFRI is used in combination with radiotherapy and/or chemotherapy 5 A clear understanding of the mechanisms that lead to stomatitis can provide insight into the prevention and therapeutic strategies necessary to improve patient care

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