Mucosal Injury during Anti-Cancer Treatment: From Pathobiology to Bedside

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Abstract

Mucositis is one of the most common debilitating side effects related to chemotherapy (CT), radiation therapy (RT), targeted agents and immunotherapy. It is a complex process potentially involving any portion of the gastrointestinal tract and injuring the mucosa, leading to inflammatory or ulcerative lesions. Mechanisms and clinical presentation can differ according both to the anatomic site involved (oral or gastrointestinal) and the treatment received. Understanding the pathophysiology and management of mucosal injury as a secondary effect of anti-cancer treatment is an important area of clinical research. Prophylaxis, early diagnosis, and adequate management of complications are essential to increase therapeutic success and, thus, improve the survival outcomes of cancer patients. This review focuses on the pathobiology and management guidelines for mucositis, a secondary effect of old and new anti-cancer treatments, highlighting recent advances in prevention and discussing future research options.

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Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

James Larkin, Vanna Chiarion-Sileni, Rene Gonzalez … (2015)

New England Journal of Medicine, 373(1), 23-34

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Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.

Kimberly E Beck, Joseph A. Blansfield, Khoi Tran … (2006)

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is an inhibitory receptor on T cells. Knocking out CTLA4 in mice causes lethal lymphoproliferation, and polymorphisms in human CTLA4 are associated with autoimmune disease. Trials of the anti-CTLA4 antibody ipilimumab (MDX-010) have resulted in durable cancer regression and immune-mediated toxicities. A report on the diagnosis, pathology, treatment, clinical outcome, and significance of the immune-mediated enterocolitis seen with ipilimumab is presented. We treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab. The overall objective tumor response rate was 14%. We observed several immune mediated toxicities including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Enterocolitis, defined by grade 3/4 clinical presentation and/or biopsy documentation, was the most common major toxicity (21% of patients). It presented with diarrhea, and biopsies showed both neutrophilic and lymphocytic inflammation. Most patients who developed enterocolitis responded to high-dose systemic corticosteroids. There was no evidence that steroid administration affected tumor responses. Five patients developed perforation or required colectomy. Four other patients with steroid-refractory enterocolitis appeared to respond promptly to tumor necrosis factor alpha blockade with infliximab. Objective tumor response rates in patients with enterocolitis were 36% for MM and 35% for RCC, compared with 11% and 2% in patients without enterocolitis, respectively (P = .0065 for MM and P = .0016 for RCC). CTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients.

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Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.

Thomas Bachelot, Celine Bourgier, Claire Cropet … (2012)

Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs). This open-label, phase II study randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned. The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.

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Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 20 June 2019

Publication date Collection: June 2019

Volume: 11

Issue: 6

Electronic Location Identifier: 857

Affiliations

[1 ]Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; deborabasile1090@ 123456gmail.com (D.B.); carla.corvaja@ 123456cro.it (C.C.); silvioken.garattini@ 123456cro.it (S.K.G.); giacomo.pelizzari@ 123456cro.it (G.P.); camilla.lisanti@ 123456cro.it (C.L.); lucia.bortot@ 123456cro.it (L.B.); michele.bartoletti@ 123456cro.it (M.B.); fabio.puglisi@ 123456cro.it (F.P.)

[2 ]Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; paola.dinardo@ 123456cro.it (P.D.N.); lucia.daros@ 123456cro.it (L.D.R.); davide.lombardi@ 123456cro.it (D.L.)

[3 ]Intensive Care Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; matteo.borghi@ 123456cro.it

Author notes

[* ]Correspondence: gerratana.lorenzo@ 123456spes.uniud.it

Author information

Paola Di Nardo https://orcid.org/0000-0002-8918-1201

Lorenzo Gerratana https://orcid.org/0000-0002-8313-4834

Fabio Puglisi https://orcid.org/0000-0003-0573-4938

Article

Publisher ID: cancers-11-00857

DOI: 10.3390/cancers11060857

PMC ID: 6627284

PubMed ID: 31226812

SO-VID: 898e54c8-9e82-4b53-96ae-96e71ded9886

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Mucosal Injury during Anti-Cancer Treatment: From Pathobiology to Bedside

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Anti-Trafficking Review

Most cited references 87

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.

Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.

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