Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines.

PURPOSE: The aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM). METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible. RESULTS: A total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged. CONCLUSIONS: Of the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.

Pharmacological modulation of radiation-induced oral mucosal complications.

Radiation-induced mucositis is a common toxicity, especially in patients with head and neck cancers. Despite recent technological advances in radiation therapy, such as intensity-modulated radiotherapy, radiation-induced mucositis is still causing treatment disruptions, negatively affecting patients' long and short term quality of life, and impacting medical resources use with economic consequences. The objective of this article was to review the latest updates in the management of radiation-induced mucositis, with a focus on pharmaceutical strategies for the prevention or treatment of mucositis. Although numerous studies analysing the prevention and management of oral radiation-induced mucositis have been conducted, there are still few reliable data to guide daily clinical practice. Furthermore, most of the tested drugs have shown no (anti-inflammatory cytokine, growth factors) or limited (palifermin) effect. Therapies for acute oral mucositis are predominantly focused on improving oral hygiene and providing symptoms control. Although low-level laser therapy proved efficient in preventing radiation-induced oral mucositis in patients with head and neck cancer, this intervention requires equipment and trained medical staff, and is therefore insufficiently developed in clinical routine. New effective pharmacological agents able to prevent or reverse radio-induced mucositis are required.

Advances in the understanding and management of mucositis during stem cell transplantation.

PURPOSE OF REVIEW: Mucositis is a severe and common side effect of anticancer treatments, with an incidence of between 40 and 80% depending on the cytotoxic regimen used. The most profound mucositis burden is experienced during conditioning regimens for hematopoietic stem cell transplant (HSCT), where the use of highly mucotoxic agents with or without total body irradiation leads to serious damage throughout the alimentary tract. Currently, the assessment and management of both oral and gastrointestinal mucositis lack authoritative guideline, with recommendations only achieved in narrow clinical scenarios. This review provides a brief overview of current management guidelines for mucositis in both adult and pediatric patients receiving HSCT, highlights recent advances in mucositis prevention and discusses future research avenues. RECENT FINDINGS: The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) guidelines for the prevention of mucositis in HSCT are scarce, with low level laser therapy (photobiomodulation) and palifermin only recommended for oral mucositis. Loperamide and octreotide remain gold-standard for the treatment of diarrhea, despite poor efficacy. Although several interventions have been trialled in pediatric cohorts, no recommendations currently exist for children receiving high-dose chemotherapy or total body irradiation for HSCT. SUMMARY: HSCT continues to be associated with mucositis, which impacts on patients' ability and willingness to receive engraftment, and worsens clinical outcome. Research into the prevention and treatment of mucositis in this setting remains limited, with an overwhelming amount of small, single-center studies that fail to achieve a sufficient level of evidence that warrant recommendation(s). As such, our ability to manage mucotoxic side effects of high-dose chemotherapy and irradiation is limited, particularly in children.

Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy.

BACKGROUND: Salivary gland dysfunction is an 'umbrella' term for the presence of either xerostomia (subjective sensation of dryness), or salivary gland hypofunction (reduction in saliva production). It is a predictable side effect of radiotherapy to the head and neck region, and is associated with a significant impairment of quality of life. A wide range of pharmacological interventions, with varying mechanisms of action, have been used for the prevention of radiation-induced salivary gland dysfunction. OBJECTIVES: To assess the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 14 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 14 September 2016); MEDLINE Ovid (1946 to 14 September 2016); Embase Ovid (1980 to 14 September 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 14 September 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 14 September 2016); Zetoc Conference Proceedings (1993 to 14 September 2016); and OpenGrey (1997 to 14 September 2016). We searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials, irrespective of their language of publication or publication status. Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region. Participants could be outpatients or inpatients. We included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention. Comparisons of radiation techniques were excluded. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 39 studies that randomised 3520 participants; the number of participants analysed varied by outcome and time point. The studies were ordered into 14 separate comparisons with meta-analysis only being possible in three of those.We found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.19 to 0.67; P = 0.001, 3 studies, 119 participants), and up to three months after radiotherapy (RR 0.66, 95% CI 0.48 to 0.92; P = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95% CI 0.40 to 1.23; P = 0.21, 7 studies, 682 participants). We found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95% CI 0.09 to 0.55; P = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95% CI 1.13 to 1.86; P = 0.004, 1 study, 175 participants). However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates. There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures. There was some very low-quality evidence of a small benefit for amifostine in terms of quality of life (10-point scale) at 12 months after radiotherapy (MD 0.70, 95% CI 0.20 to 1.20; P = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to three months postradiotherapy. A further study showed no evidence of a difference at 6, 12, 18 and 24 months postradiotherapy. There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95% CI 2.87 to 8.38; P < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95% CI 2.84 to 29.83; P = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95% CI 1.81 to 3.74; P < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95% CI 1.40 to 40.39; P = 0.02, 3 studies, 524 participants).We found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and quality of life. There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95% CI 1.43 to 6.22; P = 0.004, 5 studies, 389 participants).We found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin). AUTHORS' CONCLUSIONS: There is some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months postradiotherapy). However, it is less clear whether or not this effect is sustained to 12 months postradiotherapy. The benefits of amifostine should be weighed against its high cost and side effects. There was insufficient evidence to show that any other intervention is beneficial.

Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation.

PURPOSE: To develop an evidence-based clinical practice guideline for the prevention of oral mucositis in children (0-18 years) receiving treatment for cancer or undergoing haematopoietic stem cell transplantation (HSCT). METHODS: The Mucositis Prevention Guideline Development Group was interdisciplinary and included internationally recognised experts in paediatric mucositis. For the evidence review, we included randomised controlled trials (RCTs) conducted in either children or adults evaluating the following interventions selected according to prespecified criteria: cryotherapy, low level light therapy (LLLT) and keratinocyte growth factor (KGF). We also examined RCTs of any intervention conducted in children. For all systematic reviews, we synthesised the occurrence of severe oral mucositis. The Grades of Recommendation, Assessment, Development and Evaluation approach was used to describe quality of evidence and strength of recommendations. RESULTS: We suggest cryotherapy or LLLT may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. We also suggest KGF may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there is a lack of efficacy and toxicity data in children, and a lack of long-term follow-up data in paediatric cancers. No other interventions were recommended for oral mucositis prevention in children. CONCLUSIONS: All three specific interventions evaluated in this clinical practice guideline were associated with a weak recommendation for use. There may be important organisational and cost barriers to the adoption of LLLT and KGF. Considerations for implementation and key research gaps are highlighted.

Recombinant Human Keratinocyte Growth Factor Induces Akt Mediated Cell Survival Progression in Emphysematous Mice.

INTRODUCTION: Emphysema has been associated with decreased VEGF and VEGFR-2 expression and the presence of high numbers of apoptotic alveolar cells. Keratinocyte growth factor stimulates VEGF synthesis which in turn confers normal lung structure maintenance via the Akt pathway. In this study the potential role of rHuKGF in the improvement of deregulated Akt mediated cell survival pathway in emphysematous mice was investigated. METHODS: Three experimental groups, i.e., emphysema, treatment and control groups, were prepared. Lungs of mice were treated on 3 occasions by oropharyngeal instillation of 10mg rHuKGF per kg body weight after induction of emphysema with porcine pancreatic elastase. Subsequently, lung tissues from mice were collected for histopathology and molecular biology studies. RESULTS AND DISCUSSION: Histopathology photomicrographs and destructive index analysis have shown that elastase-induced airspace enlargement and loss of alveoli recovered in the treatment group. rHuKGF stimulates VEGF production which in turn induces the Akt mediated cell survival pathway in emphysematous lungs. mRNA expression of VEGF, VEGFR, PI3K and Akt was significantly increased while Pten, Caspase-9 and Bad was notably decreased in treatment group when compared with emphysema group, being comparable with the control group. Moreover, VEGF protein expression was in accordance with that found for mRNA. CONCLUSION: Therapeutic rHuKGF supplementation improves the deregulated Akt pathway in emphysema, resulting in alveolar cell survival through activation of the endogenous VEGF-dependent cell survival pathway. Hence rHuKGF may prove to be a potential drug in the treatment of emphysema.

[Radio-induced oral and pharyngeal mucositis: management updates]. / Mucites radio-induites buccopharyngées : actualités sur la prise en charge.

Mucositis is a major side effect induced by radiotherapy and/or chemotherapy of head and neck cancer. This toxicity impacts patient's quality of life and may compromise optimal treatments. Pathophysiology, risk factors, incidence and consequences of mucositis will be discussed in this review. Its management remains principally supportive (pain medication and nutritional support); however, in recent years several studies have revealed that the use of low level energy laser is particularly useful in the prevention and treatment of chemo- and radio-induced mucositis.

A supersaturated calcium phosphate solution seems to effectively prevent and treat oral mucositis in haematopoietic stem cell transplanted cancer patients - single centre experience.

PURPOSE: Oral mucositis (OM) is one of the most frequent and bothersome complications of high-dose chemotherapy with subsequent auto- and allogeneic haematopoietic stem cell transplantation (HSCT). We have assessed the effectiveness of supersaturated calcium phosphate rinse (Caphosol ®) and palifermin (Kepivance®) in the prophylaxis of OM caused by HSCT. METHODS: Caphosol® and Kepivance® were prospectively evaluated in OM prophylaxis in 64 patients after HSCT and compared against themselves and an historical control group. RESULTS: Grade 3 and 4 OM was not observed in patients treated with Caphosol® and palifermin. None of those patients needed total parenteral nutrition (TPN), too. In the Caphosol® group 40.9% of the patients did not develop OM, and 70% of patients treated with palifermin were free of any kind of OM symptoms. In the control group OM was observed in all cases. CONCLUSION: Caphosol® seems to decrease the incidence, severity and duration of OM, the demand for opioids and for TPN. It needs to be tested in randomized trials, because its easy administration and cost-effectiveness may render it a valuable addition to the standard care in the treatment of OM.

Keratinocyte growth factor: a new mesothelial targeted therapy to reduce postoperative pericardial adhesions.

BACKGROUND: Several methods have been utilized to prevent pericardial and retrosternal adhesions, but none of them evaluated the mesothelial regenerative hypothesis. There are evidences that the mesothelial trauma reduces pericardial fibrinolytic capability and induces an adhesion process. Keratinocyte growth factor (KGF) has proven to improve mesothelial cells proliferation. This study investigated the influence of keratinocyte growth factor in reducing post-surgical adhesions. METHODS: Twelve pigs were operated and an adhesion protocol was employed. Following a stratified randomization, the animals received a topical application of KGF or saline. At 8 weeks, intrapericardial adhesions were evaluated and a severity score was established. The time spent to dissect the adhesions and the amount of sharp dissection used, were recorded. Histological sections were stained with sirius red and morphometric analyses were assessed with a computer-assisted image analysis system. RESULTS: The severity score was lower in the KGF group than in the control group (11.5 vs 17, p=0.005). The dissection time was lower in the KGF group (9.2+/-1.4 min vs 33.9+/-9.2 min, p=0.004) and presented a significant correlation with the severity score (r=0.83, p=0.001). A significantly less sharp dissection was also required in the KGF group. Also, adhesion area and adhesion collagen were significantly lower in the KGF group than in the control group. CONCLUSION: The stimulation of pericardial cells with KGF reduced the intensity of postoperative adhesions and facilitated the re-operation. This study suggests that the mesothelial regeneration is the new horizon in anti-adhesion therapies.

Effect of recombinant human keratinocyte growth factor (rHuKGF, Palifermin) on radiation-induced mouse urinary bladder dysfunction.

PURPOSE: To determine the effect of Palifermin (rHuKGF) on acute and late radiation effects in mouse urinary bladder. METHODS AND MATERIALS: Graded radiation doses were applied on day 0. Single subcutaneous injections of Palifermin (15 mg/kg) were given on day -2 or day +2. Changes in bladder function (i.e., a reduction in bladder volume by >or=50% of the individual preirradiation value) were assessed by cystometry. RESULTS: Early changes in mouse bladder after irradiation occur in two phases. In the first early phase, a single injection of Palifermin on day -2 increased the ED(50) (dose associated with a positive bladder response in 50% of the mice) from 20.0 +/- 3.3 Gy to 27.1 +/- 6.9 Gy (p < .0051). Palifermin given on day +2 was not beneficial. No significant effects of Palifermin were seen in the second early phase. However, Palifermin administration before, but not after, irradiation, also modified late radiation effects, with an ED50 of 22.2 +/- 4.8 Gy compared with 16.2 +/- 4.9 Gy in control animals (p < .0187). CONCLUSIONS: Initial early functional changes in the mouse urinary bladder after irradiation as well as late effects can be significantly reduced by a single administration of Palifermin before irradiation.

Palifermin improves severe mucositis, swallowing problems, nutrition impact symptoms, and length of stay in patients undergoing hematopoietic stem cell transplantation.

GOAL OF WORK: The aim of this study was to compare palifermin, a recombinant form of human keratinocyte growth factor, with standard treatment on outcomes in patients receiving a high dose of chemotherapy conditioning regimen, undergoing hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: Over a 1-year period, a series of 59 patients were included: 32 patients (palifermin) were compared with 27 patients (standard treatment). Outcomes assessed at day 8 posttransplantation were mucositis, swallowing, nutrition impact symptoms, dietary intake, time to engraftment, length of stay, infection, and cumulative dose and duration of narcotic administration. MAIN RESULTS: There was a significant reduction in the incidence of severe oral mucositis (13 vs 48%, p=0.003), swallowing problems (p=0.044), number of nutrition impact symptoms experienced (4.9 vs 6.0, p=0.003), and length of stay (14 vs 18 days, p=0.026) in the palifermin group compared to standard care. There was no significant difference in infection, dietary intake, time to engraftment or cumulative dose and duration of narcotic administration between groups. CONCLUSIONS: Beneficial outcomes were observed from the use of palifermin in patients undergoing HSCT after a high dose of chemotherapy conditioning regimen. A randomized clinical trial is needed to confirm these results.

New strategies for management of oral mucositis in cancer patients.

Oral mucositis can be a significant problem for cancer patients and is frequently seen in the patient population receiving high-dose head and neck radiation therapy (85%-100%), stem cell transplantation (75%-100%), and myelosuppressive chemotherapy for solid tumors (5%-40%). Current guidelines published through the joint efforts of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology recommend strategies for the prevention and treatment of mucositis in the setting of radiation therapy, chemotherapy, and combined chemoradiation therapy. An improved understanding of its pathologic basis has led to the development of targeted agents to combat mucositis. One of these drugs, palifermin, is a keratinocyte growth factor agent approved for patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. Another agent is AES-14, an uptake-enhanced L-glutamine suspension that has shown efficacy in phase III trials in reducing the risk of developing oral mucositis in breast cancer patients receiving chemotherapy. As the understanding of the pathobiology of mucositis improves, clinicians should be able to customize future therapies based on each patients risk for developing the condition.

Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting.

PURPOSE: To describe patient-reported outcomes of mouth and throat soreness (MTS) and related sequelae on daily activities from a phase III study of palifermin in the autologous hematopoietic stem-cell transplantation (HSCT) setting and to compare patient self-evaluations with clinicians' assessments of oral mucositis using objective scales. PATIENTS AND METHODS: Patients (n = 212) received palifermin (60 microg/kg/d) or placebo for 3 days before total-body irradiation (12 Gy), etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg, and 3 days after HSCT. Patients completed a daily questionnaire (Oral Mucositis Daily Questionnaire [OMDQ]) evaluating MTS severity and its effects on daily functional activities. Patients' self-assessment data were compared with clinicians' assessments of oral mucositis using the objective scales. RESULTS: Palifermin reduced the incidence and duration of severe oral mucositis, as assessed by both clinicians and patients. Comparisons between patient and clinician assessments demonstrated that the average daily scores between mucositis grade and subjective (MTS) instruments were similar, although patients reported MTS onset, peak, and resolution earlier (1 to 3 days) than clinicians' assessments. Patients receiving palifermin reported statistically significant improvements (P < .001) in daily functioning activities (swallowing, drinking, eating, talking, sleeping) and required significantly less narcotic opioids (P < .001); improvement in the patient's overall physical and functional well-being was also reported. This was confirmed by the results of the Functional Assessment of Cancer Treatment questionnaire. CONCLUSION: These results support the clinical benefit of palifermin in the HSCT setting, providing evidence that a patient's self-assessment instrument (OMDQ) may serve as an alternative tool to assess oral mucositis severity in clinical trials.

Chemotherapy-induced oral mucositis: new approaches to prevention and management.

Oral mucositis is a common and significant toxicity of cancer chemotherapy. It is under-reported and not well treated, particularly in patients that receive high-dose therapy with an autologous or allogenic stem cell transplant. Two recently published retrospective analyses of patient complaints following stem cell transplantation have identified oral mucositis as the worst toxicity reported by patients, and what is more important is that patients indicated that oncology healthcare team members do a poor job of managing and providing methods of symptom relief. Twenty percent of patients surveyed indicated they received no symptom relief at all.