Mucosal toxicity in hematological malignancies: prevention, management, and novel therapeutic insights

Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines

Mucositis is a common but poorly studied problem among patients with solid tumors. The authors examined the clinical and economic outcomes of oral and gastrointestinal (GI) mucositis among patients receiving myelosuppressive chemotherapy. A retrospective, random sample of 599 patients who developed chemotherapy-induced myelosuppression was followed for development of oral or GI mucositis and for development of subsequent episodes of bleeding or infection. Multilevel regression models of the risk of bleeding and infection were fit with chemotherapy cycles nested within patients. Mucositis developed during 37% of 1236 cycles of chemotherapy. Episodes of bleeding were significantly more common during cycles with GI mucositis than during cycles without GI mucositis (13% vs. 8%; P = 0.04). Episodes of infection were significantly more common during cycles with mucositis (especially GI mucositis) than during cycles without mucositis (73% vs. 36%; P < 0.0001). The mean durations of hospitalization were 4 days, 6 days, and 12 days during cycles with no mucositis, oral mucositis, and GI mucositis, respectively. After accounting for the depth and duration of myelosuppression and for other predictive factors, GI mucositis was associated with both bleeding (odds ratio [OR], 2.0; P = 0.01) and infection (OR, 2.24; P < 0.0001), whereas oral mucositis was associated with infection only (OR, 2.4; P < 0.0001). Mucositis was clinically and economically significant among patients with solid tumors who were receiving myelosuppressive chemotherapy. New preventive and therapeutic agents are needed.

Acute Enterocolitis Incidence in Patients with Hematological Malignancies Receiving Myelotoxic Therapy Requiring Hematopoietic Stem Cell Support - Palifermin Experience.

Objective To evaluate the efficiency of amifostine in protecting against oral and gastrointestinal mucositis in hematologic malignancies patients with high-dose total body irradiation following the hematopoietic stem cell transplantation, and assess the hematologic recovery as well as the potential side effect of amifostine. Methods Thirty-two hematologic malignancies patients underwent hematopoietic stem cell transplantation in our institution from 2012 to 2016 were retrospectively analyzed. All of them were treated with total body irradiation (700-1 200 cGy) and high-dose chemotherapy, in which 14 patients received 400 mg amifostine before radiotherapy. Prior institutional experience in 18 patients treated without amifostine was used as a historical comparison (no-amifostine group). Results Severe oral mucositis occurred in 14.3% of patients in the amifostine group while 77.2% in the no-amifostine group(χ2=10.62, P 0.05). The rates of grade 2 and 3 gastrointestinal mucositis were 35.7% and 61.5% in amifostine group, while in no-amifostine group the rates were 33.3% and 66.7%, respectively (P>0.05). No significant difference was found in engraftment times of granulocyte and platelet. No amifostine related side effects were observed. Conclusions The combination of amifostine and total body irradiation conditioning therapy during hematologic stem cell transplantation might reduce the severity of oral mucositis. The utilize of amifostine has no obvious effect on hematopoietic recovery and can be well tolerated. Key words: Amifostine; Total body irradiation; Protective effect; Hematologic stem cell transplantation

Oral and gastrointestinal (GI) mucositis are frequent complications of chemotherapy and radiotherapy for cancer, contributing to not only the morbidity of treatment but its cost as well. The risk associated with specific chemotherapeutic agents, alone and in combination, has been characterized previously. In the current study, we sought to estimate the risk associated with newer regimens for the treatment of non-Hodgkin's lymphoma (NHL) and common solid tumors. We reviewed published studies reporting phase II and III clinical trials of dose-dense regimens for breast cancer and NHL, TAC (docetaxel, adriamycin, cyclophosphamide) chemotherapy for breast cancer, and infusional 5-fluorouracil-based regimens for colorectal cancer. Platinum-, gemcitabine-, and taxane-based regimens for lung cancer, either alone or in combination with radiotherapy, were also considered. Using modified meta-analysis methods, we calculated quality-adjusted estimates of the risk for oral and GI mucositis by tumor type and regimen. Case reports are used to emphasize the relevance of the findings for patient care. Our findings demonstrate that mucosal toxicity remains an important complication of cancer treatment. Moreover, innovations in drug combinations, scheduling, or mode of administration significantly modulate the risk for both oral and GI mucositis. Ongoing review of the clinical trial experience will remain important as newer, targeted agents enter standard clinical practice.

Growth factors and cytokines may be useful in preventing chemotherapy (CT)- and radiotherapy (RT)-induced oral and gastrointestinal mucositis. Two systematic reviews of the medical literature on growth factors and cytokines for the amelioration of CT- and RT-induced mucositis throughout the alimentary tract were performed by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology. The aim of these evidence-based scientific reviews was to critically evaluate the literature and create evidence-based guidelines for the use of growth factors and cytokines in the prevention or treatment of CT- and RT-induced mucositis. The two reviews covered articles on clinical trials from January 1966 through May 2002 and preclinical studies from June 2002 through May 2005, respectively. The systematic review process was based on a well-established method for evaluating scientific literature. The number of articles in the first review was 29. In the second review, 23 articles were evaluated, 14 preclinical and 9 clinical studies. It was concluded from the first review that there was no sufficient evidence to provide any recommendations for clinical practice guidelines regarding growth factors and cytokines. From the second review, a guideline could be presented recommending the use of recombinant human keratinocyte growth factor-1 (palifermin) to prevent oral mucositis in patients receiving high-dose CT and total body irradiation followed by stem cell transplantation for haematological malignancies. A guideline could also be provided suggesting that granulocyte macrophage colony-stimulating factor mouthwash not be used for the prevention of oral mucositis in the transplant setting with high-dose CT and autologous or allogeneic stem cell transplantation. These systematic reviews have provided clarity and shown exciting new results. Further studies will provide new options for this debilitating side-effect of cancer therapy.

The study aimed to characterize the incidence of both oral and gastrointestinal (GI) mucositis, its' associated temporal changes in local and systemic pro-inflammatory cytokines, and to explore predictive clinical and immunological factors associated with their occurrences in hematopoietic stem cell transplant (HSCT). Autologous HSCT patients aged 18 years old and above were recruited from Hospital Ampang, Malaysia, between April 2019 to December 2020. Mucositis assessments were conducted daily, whilst blood and saliva were collected prior to conditioning regimen, on Day 0, Day+7 and 6-month. Baseline and inflammatory predictors in a repeated time measurement of moderate-severe mucositis were assessed by multiple logistic regression and generalized estimating equations, respectively. Of the 142 patients analyzed, oral mucositis and diarrhea (representing GI mucositis) were reported as 68.3% and 95.8%, respectively. Predictive factors for moderate-severe oral mucositis were BEAM or busulphan-based regimens (odds ratio (OR)=9.2, 95% confidence interval (CI)=1.16-72.9, p-value (p) = 0.005) and vomiting (OR=4.6, 95% CI 1.68-12.3, p= 0.004). Predictive factors for moderate-severe GI mucositis were BEAM or busulphan-based regimens (OR=3.9, 95% CI 1.05-14.5, p= 0.023), female sex (OR = 3.3, 95% CI 1.43-7.44, p= 0.004) and body mass index (OR=1.08, 95% CI 1.02-1.15, p= 0.010). Cytokines analyses were performed in 96 patients. Saliva and plasma interleukin-6 (OR=1.003, 95% CI 1.001-1.004, p< 0.001 and OR=1.01, 95% CI 1.001-1.015, p= 0.029), and plasma tumor necrosis factor-alpha (OR=0.91, 95% CI 0.85-0.99, p= 0.019) were predictive of moderate-severe oral mucositis in a time-dependent model. This study provides real-world evidence and insights into patient- and treatment-related factors affecting oral and GI mucositis in HSCT.

Oral and Gut Microbiota Dysbiosis is Associated with Mucositis Severity in Autologous Hematopoietic Stem Cell Transplantation: Evidence from an Asian Population

The field of terminology and assessment of oral and gastrointestinal mucosal injury caused by high-dose cancer therapies in cancer patients has undergone important evolution in recent years. The advances are important for several clinical and research reasons. These reasons include improved patient management and design and conduct of clinical trials based on molecularly targeted therapies. For several decades leading up to the 1980s, terminology was characterized by varying use of "mucositis" and "stomatitis" to describe oral mucosal inflammatory changes and ulceration caused by cancer treatments. In addition, oral mucositis was viewed principally as an epithelial event and one that likely did not intersect with causative mechanisms associated with gastrointestinal mucositis. The term "stomatitis" was directed to oral toxicities and seemed to isolate these conditions from parallel events occurring throughout the alimentary tract and potentially other tissues as well. These perspectives and varying use of these terms resulted in several dilemmas, including (1) difficulty in accurately reporting incidence and severity of oral mucositis and, (2) an under-appreciation of potential significance of alimentary tract mucosal toxicity relative to overall course of therapy, patient quality of life, and in some cases, survivorship. These and related components of the model relative to mucositis have undergone strategic shifts over the past 15 years. A 1989 National Institutes of Health Consensus Development Conference targeted oral mucositis research as one of the key areas for investigation relative to causation, clinical impact, and potential links with other complications in cancer patients. Research in this area over the past 15 years has evolved such that oral and gastrointestinal mucositis are now appropriately framed as a continuum of pathobiologic changes over time, with clinical impact that may well contribute to overall symptom clustering in selected patient cohorts. This paper will review history, current status, and new research directions associated with terminology and assessment of mucosal injury in cancer patients in the context described above.

Mucositis Management in Patients with Cancer

Oral ulcerative mucositis (UM) and gastrointestinal mucositis (GIM) have been associated with increased likelihood of systemic infection (bacteremia and sepsis) in patients being treated for hematological malignancies. To better define and contrast differences between UM and GIM, we utilized the United States 2017 National Inpatient Sample and analyzed patients hospitalized for the treatment of multiple myeloma (MM) or leukemia. We utilized generalized linear models to assess the association between adverse events-UM and GIM-among hospitalized MM or leukemia patients and the outcome of febrile neutropenia (FN), septicemia, burden of illness, and mortality. Of 71,780 hospitalized leukemia patients, 1255 had UM and 100 GIM. Of 113,915 MM patients, 1065 manifested UM and 230 had GIM. In an adjusted analysis, UM was significantly associated with increased risk of FN in both the leukemia (aOR = 2.87, 95% CI = 2.09-3.92) and MM cohorts (aOR = 4.96, 95% CI = 3.22-7.66). Contrastingly, UM had no effect on the risk of septicemia in either group. Likewise, GIM significantly increased the odds of FN in both leukemia (aOR = 2.81, 95% CI = 1.35-5.88) and MM (aOR = 3.75, 95% CI = 1.51-9.31) patients. Similar findings were noted when we restricted our analysis to recipients of high-dose condition regimens in preparation for hematopoietic stem-cell transplant. UM and GIM were consistently associated with higher burden of illness in all the cohorts. This first use of big data provided an effective platform to assess the risks, outcomes, and cost of care of cancer treatment-related toxicities in patients hospitalized for the management of hematologic malignancies.

Cancer is a broad group of different diseases involve the unregulated cell growth in which the cells divide uncontrollably forming the malignant tumors. The management are by chemotherapy, surgery, radiation therapy or by other treatments. Oral mucositis refers to the inflammation and ulceration that occurs in the mouth and considered as a side effect of chemotherapy and/or radiotherapy treatment for malignant tumor. The aim of this study was to review the incidence, risk factors, clinical features, scoring, pathophysiology and treatment of oral mucositis. The incidence of oral mucositis is varying from patient to patient depending on the type, dose and duration of the treatment the patient receives. The risk factors are the patient-related factors (like the age, gender, racial factor, poor oral hygiene, periodontal disease, nutritional status, xerostomia, co-existing diseases, tobacco use and alcohol consumption) and the treatment-related risk factors which includes the chemotherapy risk factors (like the type of chemotherapy, dose and duration) and the radiation therapy risk factors (like the anatomical area irradiated, volume of tissue irradiated, total dose, fractionation regimen) and the concomitant chemotherapy. Oral mucositis clinically starts with redness and then progresses to the development of large and very painful pseudomembranous lesions associated with dysphagia. The non-keratinized mucosa is mostly affected than the keratinized mucosa. The pain can be so debilitating to the oral activities like swallowing, mastication, drinking and speech. Both oral and gastro intestinal mucositis may be associated with infection-related deaths and can be a dose-limiting factor for chemotherapy which affect the patient survival. A variety of scales have been used to record the severity of oral mucositis like the WHO scale and the scoring systems by national cancer institute. The WHO scale is the most widely used and includes criteria which are the presence of erythema and ulceration oral pain and the patient’s inability to eat. Regarding the pathophysiology, five phases have been identified in the development of oral mucositis and mucosal restoration. In the initiation phase tissue injury occurs following the administration of radiation or chemotherapy in which the DNA strand breakdown occur. This is followed by the primary damage response which result in the activation of several transduction pathways that activate transcription factors such as p53 and nuclear factor-κB. Signal amplification by pro-inflammatory cytokines like TNF-α can intensify the response to primary damage. The signals are amplified due to apoptosis, tissue damage and vascular permeability. This result in painful ulceration and superficial bacterial colonization. Then healing occur once the cancer therapy ends. There are only a few established treatments for oral mucositis like the topically applied cryotherapy, laser therapy, antibiotic lozenges, benzydamine hydrochloride, chlorhexidine and some herb extract mouth washes. A systemic administration of indomethacin, amifostine, growth factors or palifermin can cause a significant reduction in the severity of oral mucositis. Keywords Oral mucositis; Chemotherapy; Radiation therapy; Oral ulcerations

Objective To evaluate the rates of hematologic and mucosal toxicities and treatment outcome of a weekly cisplatin (QW) and triweekly cisplatin (Q3W) regimens concurrent with intensity-modulated radiotherapy (IMRT) for local regionally advanced nasopharyngeal carcinoma (NPC). Methods A total of 148 patients with biopsy-proven NPC staged at Ⅲ to IVB were retrospectively enrolled from October 2009 to December 2013 in this study. Among all patients, 75 and 73 received QW and Q3W cisplatin chemotherapy regimens concurrent with IMRT, respectively. All patients received neoadjuvant chemotherapy. The χ2-test was used to compare clinical characteristics of the patients and hematologic and mucosal toxicities. Tumor response and survival rates were estimated through the Kaplan-Meier method with log-rank test. Results The mean total cycles of the cisplatin regimen was 3.64 in the QW group with 15 patients(20%) reaching five cycles and 1.86 in the Q3W group with 86% reaching two cycles. Grades 1, 2 leucopenia were 31% vs. 51% and 35% vs. 19%, respectively, in the QW and Q3W groups. The two groups showed significant differences in Grades 1 and 2 leucopenia (χ2= 6.150, 4.500, both P<0.05) but not for other hematological toxicities and mucositis (χ2= 0.137, P=0.934). The complete remission rates at 6 months after radiotherapy for the QW and QW3 groups were 98.7% and 98.6%, respectively. The 5-year estimated overall survival, disease-free survival, local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival rates of the QW and Q3W groups were 77.84% vs. 79.97% (χ2=3.78, P=0.059), 67.96% vs. 69.10% ( χ2=1.25, P=0.27), 88.76% vs. 86.96% (χ2=0.43, P=0.56), 91.49% vs. 90.84% (χ2=0.18, P=0.67), and 77.86% vs. 78.90% (χ2=0.31, P=0.56), respectively, and were not significantly different between the two groups. Conclusions Hematological toxicities associated with the QW3 regimen concurrent with IMRT for locally advanced NPC were milder than those associated with the QW weekly regimen. Mucositis and treatment outcome did not significantly differ between the two groups. Patients showed better compliance with the Q3W regimen than with the QW regimen. Key words: Nasopharyngeal neoplasms; Radiotherapy, intensity modulated; Drug cherapy; Cisplatin

Oral and gastrointestinal (GI) mucositis can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation, 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary track mucositis increases mortality and morbidity and contributes to rising health care costs. Consequently, the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an expert panel to evaluate the literature and to create evidence-based guidelines for preventing, evaluating, and treating mucositis. Thirty-six panelists reviewed literature published between January 1966 and May 2002. An initial meeting in January 2002 produced a preliminary draft of guidelines that was reviewed at a second meeting the same year. Thereafter, a writing committee produced a report on mucositis pathogenesis, epidemiology, and scoring (also included in this issue), as well as clinical practice guidelines. Panelists created recommendations from higher levels of evidence and suggestions when evidence was of a lower level and there was a consensus regarding the interpretation of the evidence by the panel. Panelists identified gaps in evidence that made it impossible to recommend or not recommend use of specific agents. Oral/GI mucositis is a common side effect of many anticancer therapies. Evidence-based clinical practice guidelines are presented as a benchmark for clinicians to use for routine care of appropriate patients and as a springboard to challenge clinical investigators to conduct high-quality trials geared toward areas in which data are either lacking or conflicting.

Radiotherapy and chemotherapy both play important roles in current cancer therapy, but there are still many unsolved problems about host-therapeutics interaction. The aim of this study was to investigate the host responses to these therapeutics by nuclear factor-κB (NF-κB) bioluminescence imaging-guided transcriptomic tool. Transgenic mice carrying the NF-κB-driven luciferase gene were exposed to a single dose of 8.5 Gy total-body irradiation. In vivo imaging showed that a maximal NF-κB-dependent bioluminescent intensity was observed at 3 h after irradiation and ex vivo imaging showed that liver, intestine, and brain displayed strong NF-κB activations. Microarray analysis of these organs showed that irradiation altered gene expression signatures in an organ-specific manner and several pathways associated with metabolism and immune systems were significantly altered. Additionally, the upregulation of fatty acid binding protein 4, serum amyloid A2, and serum amyloid A3 genes, which are participated in both inflammation and lipid metabolism, suggested that irradiation might affect the cross pathways of metabolism and inflammation. Moreover, the alteration of chemokine (CC-motif) ligand 5, chemokine (CC-motif) ligand 20, and Jagged 1 genes, which are involved in the inflammation and enterocyte proliferation, suggested that these genes might be involved in the radiation enteropathy. 5-Fluorouracil (5-FU) is a commonly used drug for the treatment of malignant cancers. However, approximately 80% of patients undergoing 5-FU treatment suffer from gastrointestinal mucositis. We wanted to identify the drug target for the 5-FU-induced intestinal mucositis. 5-FU-induced intestinal mucositis was established by intraperitoneally administering mice with 100 mg/kg 5-FU. Network analysis of gene expression profile and bioluminescent imaging were applied to identify the critical molecule associated with 5-FU-induced mucositis. Our data showed that 5-FU induced inflammation in the small intestine, characterized by the increased intestinal wall thickness and crypt length, the decreased villus height, and the increased myeloperoxidase activity in tissues and proinflammatory cytokine production in sera. Network analysis of 5-FU-affected genes by transcriptomic tool showed that the expression of genes was regulated by NF-κB, and NF-κB was the central molecule in the 5-FU-regulated biological network. NF-κB activity was activated by 5-FU in the intestine, which was judged by in vivo bioluminescence imaging and immunohistochemical staining. However, 5-aminosalicylic acid (5-ASA) inhibited 5-FU-induced NF-κB activation and proinflammatory cytokine production. Moreover, 5-FU-induced histological changes were improved by 5-ASA. In conclusion, this study described the comprehensive evaluation of host responses to ionizing radiation and chemotherapy. Our findings provided the fundamental information about the in vivo NF-κB activity and transcriptomic pattern after irradiation and chemotherapy. We also suggested that NF-κB was the critical molecule associated with the pathogenesis of 5-FU-induced mucositis, and inhibition of NF-κB activity ameliorated the mucosal damage caused by 5-FU. Moreover, novel targets involved in radiation injury were also suggested.