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      The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea

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          Abstract

          Purpose

          Diarrhea is recognized as a common adverse event associated with tyrosine kinase inhibitors (TKIs), with those targeting the ErbB family of receptors being associated with the highest rate of diarrhea.

          Methods

          This paper reviews data on the incidence, timing, and duration of diarrhea associated with US Food and Drug Administration-approved ErbB family-targeted TKIs from the published literature, and sets forth recommendations for management.

          Results

          In the absence of anti-diarrheal prophylaxis the incidence of any-grade diarrhea varies and typically occurs early during the course of treatment. Although it is difficult to determine if the incidence and severity of diarrhea is related to inhibition of a particular kinase target because of the multi-targeted and overlapping activity of many agents, evidence suggests that second-generation TKIs with broader target profiles (i.e., afatinib, lapatinib, neratinib) result in a higher incidence of diarrhea compared with highly specific first- (erlotinib, gefitinib) or third- (osimertinib) generation agents. The mechanisms responsible for TKI-associated diarrhea are not fully understood and are likely multi-factorial, involving dysregulated ion transport, inflammation, and mucosal injury. Management strategies have been developed—and continue to be refined—to prevent and reduce the severity and duration of TKI-associated diarrhea. For agents associated with more significant symptoms, anti-diarrheal prophylaxis reduces the incidence and severity of diarrhea, and ongoing studies are evaluating specific strategies to further reduce incidence and duration of TKI-associated diarrhea.

          Conclusions

          Continued investigations into risk factors and pharmacogenomic markers for diarrhea may further improve management of this common toxicity.

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          Most cited references41

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          Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

          ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.
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            Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.

            Erlotinib, docetaxel, and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer (NSCLC), but no head-to-head data from large clinical trials are available. We undertook the Tarceva In Treatment of Advanced NSCLC (TITAN) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC. TITAN was an international, randomised multicentre, open-label, phase 3 study that was done at 77 sites in 24 countries. Chemotherapy-naive patients with locally advanced, recurrent, or metastatic NSCLC received up to four cycles of first-line platinum doublet chemotherapy, after which patients with disease progression during or immediately after chemotherapy were offered enrolment into TITAN. Enrolled patients were randomly assigned (1:1) by a minimisation method to ensure balanced stratification, to receive erlotinib 150 mg/day or chemotherapy (standard docetaxel or pemetrexed regimens, at the treating investigators' discretion), until unacceptable toxicity, disease progression, or death. Patients were stratified by disease stage, Eastern Cooperative Oncology Group performance status, smoking history, and region of residence. The primary endpoint was overall survival in the intention-to-treat population. TITAN was halted prematurely because of slow recruitment. This study is registered with ClinicalTrials.gov, number NCT00556322. Between April 10, 2006, and Feb 24, 2010, 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy, of whom 424 had disease progression and were enrolled into TITAN. 203 patients were randomly assigned to receive erlotinib and 221 were assigned to receive chemotherapy. Median follow-up was 27·9 months (IQR 11·0-36·0) in the erlotinib group and 24·8 months (12·1-41·6) in the chemotherapy group. Median overall survival was 5·3 months (95% CI 4·0-6·0) with erlotinib and 5·5 months (4·4-7·1) with chemotherapy (hazard ratio [HR] 0·96, 95% CI 0·78-1·19; log-rank p=0·73). The adverse-event profile of each group was in line with previous studies. Rash (98/196 [50%] in the erlotinib group vs 10/213 [5%] in the chemotherapy group for all grades; nine [5%] vs none for grade 3 or 4) and diarrhoea (36 [18%] vs four [2%] for all grades; five [3%] vs none for grade 3 or 4) were the most common treatment-related adverse events with erlotinib, whereas alopecia (none vs 23 [11%] for all grades; none vs one [<1%] for grade 3/4) was the most common treatment-related adverse event with chemotherapy. No significant differences in efficacy were noted between patients treated with erlotinib and those treated with docetaxel or pemetrexed. Since the toxicity profiles of erlotinib and chemotherapy differ, second-line treatment decisions should take into account patient preference and specific toxicity risk profiles. F Hoffmann-La Roche. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Recommended guidelines for the treatment of cancer treatment-induced diarrhea.

              To update and expand on previously published clinical practice guidelines for the treatment of cancer treatment-induced diarrhea. An expert multidisciplinary panel was convened to review the recent literature and discuss recommendations for updating the practice guidelines previously published by this group in the Journal of Clinical Oncology in 1998. MEDLINE searches were performed and the relevant literature published since 1998 was reviewed by all panel members. The treatment recommendations and algorithm were revised by panel consensus. A recent review of early toxic deaths occurring in two National Cancer Institute-sponsored cooperative group trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer has led to the recognition of a life-threatening gastrointestinal syndrome and highlighted the need for vigilant monitoring and aggressive therapy for this serious complication. Loperamide remains the standard therapy for uncomplicated cases. However, the revised guidelines reflect the need for recognition of the early warning signs of complicated cases of diarrhea and the need for early and aggressive management, including the addition of antibiotics. Management of radiation-induced diarrhea is similar but may not require hospitalization, and chronic low- to intermediate-grade symptoms can be managed with continued loperamide. With vigilant monitoring and aggressive therapy for cancer treatment-induced diarrhea, particularly in patients with early warning signs of severe complications, morbidity and mortality may be reduced.
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                Author and article information

                Contributors
                415 353 7618 , Hope.Rugo@ucsf.edu
                jdipalma@health.southalabama.edu
                dtripathy@mdanderson.org
                RBryce@pumabiotechnology.com
                SMoran@pumabiotechnology.com , sm@qedtx.com
                eolek@pumabiotechnology.com
                lbosserman@coh.org
                Journal
                Breast Cancer Res Treat
                Breast Cancer Res. Treat
                Breast Cancer Research and Treatment
                Springer US (New York )
                0167-6806
                1573-7217
                22 January 2019
                22 January 2019
                2019
                : 175
                : 1
                : 5-15
                Affiliations
                [1 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Medicine (Hematology/Oncology), , University of California San Francisco Helen Diller Family Comprehensive Cancer Center, ; 1600 Divisadero St., Box 1710, San Francisco, CA 94143-1710 USA
                [2 ]ISNI 0000 0000 9552 1255, GRID grid.267153.4, Division of Gastroenterology, , University of South Alabama College of Medicine, ; 75 S. University Blvd., Mobile, AL 36688 USA
                [3 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Breast Medical Oncology, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe, Unit 1354, Houston, TX 77030 USA
                [4 ]ISNI 0000 0004 0585 0952, GRID grid.476660.5, Puma Biotechnology, Inc., ; 10880 Wilshire Blvd. Suite 2150, Los Angeles, CA 90024 USA
                [5 ]ISNI 0000 0004 0585 0952, GRID grid.476660.5, Puma Biotechnology, Inc., ; 701 Gateway Blvd, Suite 500, South San Francisco, CA 94080 USA
                [6 ]ISNI 0000 0004 0421 8357, GRID grid.410425.6, City of Hope Medical Group, Inc, ; 1500 E Duarte Rd, Duarte, CA 91010 USA
                [7 ]Present Address: QED Therapeutics, 421 Kipling St, Palo Alto, CA 94301 USA
                Author information
                http://orcid.org/0000-0001-6710-4814
                Article
                5102
                10.1007/s10549-018-05102-x
                6491395
                30671765
                0147ae59-1d03-46ea-8b3f-6b7251e6cb00
                © The Author(s) 2019

                OpenAccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 8 December 2018
                : 12 December 2018
                Categories
                Review
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2019

                Oncology & Radiotherapy
                cancer,diarrhea,erbb receptor,tyrosine kinase inhibitor
                Oncology & Radiotherapy
                cancer, diarrhea, erbb receptor, tyrosine kinase inhibitor

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