BACKGROUND: Treatment of cancer is increasingly more effective but is associated with short and long term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. One of these side effects is oral mucositis (mouth ulcers). OBJECTIVES: To evaluate the effectiveness of prophylactic agents for oral mucositis in patients with cancer receiving treatment, compared with other potentially active interventions, placebo or no treatment. SEARCH STRATEGY: Electronic searches of Cochrane Oral Health Group and PaPaS Trials Registers (to 16 February 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE via OVID (1950 to 16 February 2011), EMBASE via OVID (1980 to 16 February 2011), CINAHL via EBSCO (1980 to 16 February 2011), CANCERLIT via PubMed (1950 to 16 February 2011), OpenSIGLE (1980 to 2005) and LILACS via the Virtual Health Library (1980 to 16 February 2011) were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. SELECTION CRITERIA: Randomised controlled trials of interventions to prevent oral mucositis in patients receiving treatment for cancer. DATA COLLECTION AND ANALYSIS: Information regarding methods, participants, interventions, outcome measures, results and risk of bias were independently extracted, in duplicate, by two review authors. Authors were contacted for further details where these were unclear. The Cochrane Collaboration statistical guidelines were followed and risk ratios calculated using random-effects models. MAIN RESULTS: A total of 131 studies with 10,514 randomised participants are now included. Overall only 8% of these studies were assessed as being at low risk of bias. Ten interventions, where there was more than one trial in the meta-analysis, showed some statistically significant evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis, compared to either a placebo or no treatment. These ten interventions were: aloe vera, amifostine, cryotherapy, granulocyte-colony stimulating factor (G-CSF), intravenous glutamine, honey, keratinocyte growth factor, laser, polymixin/tobramycin/amphotericin (PTA) antibiotic pastille/paste and sucralfate. AUTHORS' CONCLUSIONS: Ten interventions were found to have some benefit with regard to preventing or reducing the severity of mucositis associated with cancer treatment. The strength of the evidence was variable and implications for practice include consideration that benefits may be specific for certain cancer types and treatment. There is a need for further well designed, and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.

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Interventions for treating oral mucositis for patients with cancer receiving treatment.

It has been estimated that 30–40 percent of all cancers can be prevented by lifestyle and dietary measures alone. Obesity, nutrient sparse foods such as concentrated sugars and refined flour products that contribute to impaired glucose metabolism (which leads to diabetes), low fiber intake, consumption of red meat, and imbalance of omega 3 and omega 6 fats all contribute to excess cancer risk. Intake of flax seed, especially its lignan fraction, and abundant portions of fruits and vegetables will lower cancer risk. Allium and cruciferous vegetables are especially beneficial, with broccoli sprouts being the densest source of sulforophane. Protective elements in a cancer prevention diet include selenium, folic acid, vitamin B-12, vitamin D, chlorophyll, and antioxidants such as the carotenoids (α-carotene, β-carotene, lycopene, lutein, cryptoxanthin). Ascorbic acid has limited benefits orally, but could be very beneficial intravenously. Supplementary use of oral digestive enzymes and probiotics also has merit as anticancer dietary measures. When a diet is compiled according to the guidelines here it is likely that there would be at least a 60–70 percent decrease in breast, colorectal, and prostate cancers, and even a 40–50 percent decrease in lung cancer, along with similar reductions in cancers at other sites. Such a diet would be conducive to preventing cancer and would favor recovery from cancer as well.

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Nutrition and cancer: A review of the evidence for an anti-cancer diet

Radiation therapy is a common treatment for cancer patients. One of the most common side effects of radiation is acute skin reaction (radiation dermatitis) that ranges from a mild rash to severe ulceration. Approximately 85% of patients treated with radiation therapy will experience a moderate-to-severe skin reaction. Acute radiation-induced skin reactions often lead to itching and pain, delays in treatment, and diminished aesthetic appearance-and subsequently to a decrease in quality of life. Surveys have demonstrated that a wide variety of topical, oral, and intravenous agents are used to prevent or to treat radiation-induced skin reactions. We conducted a literature review to identify trials that investigated products for the prophylaxis and management of acute radiation dermatitis. Thirty-nine studies met the pre-defined criteria, with thirty-three being categorized as prophylactic trials and six as management trials.For objective evaluation of skin reactions, the Radiation Therapy Oncology Group criteria and the U.S. National Cancer Institute Common Toxicity Criteria were the most commonly used tools (65% of the studies). Topical corticosteroid agents were found to significantly reduce the severity of skin reactions; however, the trials of corticosteroids evaluated various agents, and no clear indication about a preferred corticosteroid has emerged. Amifostine and oral enzymes were somewhat effective in preventing radiation-induced skin reactions in phase II and phase III trials respectively; further large randomized controlled trials should be undertaken to better investigate those products. Biafine cream (Ortho-McNeil Pharmaceuticals, Titusville, NJ, U.S.A.) was found not to be superior to standard regimes in the prevention of radiation-induced skin reactions (n = 6).In conclusion, the evidence is insufficient to support the use of a particular agent for the prevention and management of acute radiation-induced skin reactions. Future trials should focus on comparing agents and approaches that, in phase I and II trials, suggest efficacy. These future phase III randomized controlled trials must clearly distinguish between preventive and management strategies for radiation-induced dermatitis. Only then can evidence-based guidelines be developed, with the hope of standardizing the approach across centres and of improving the prevention and management of radiation-induced dermatitis.

https://www.mdpi.com/1718-7729/17/4/493/pdf

Prophylaxis and management of acute radiation-induced skin reactions: a systematic review of the literature

Ionizing radiation is an important treatment modality for a variety of malignant conditions. However, development of radiation-induced skin changes is a significant adverse effect of radiation therapy (RT). Cutaneous repercussions of RT vary considerably in severity, course, and prognosis. When they do occur, cutaneous changes to RT are commonly graded as acute, consequential-late, or chronic. Acute reactions can have severe sequelae that impact quality of life as well as cancer treatment. Thus, dermatologists should be informed about these adverse reactions, know how to assess their severity and be able to determine course of management. The majority of measures currently available to prevent these acute reactions are proper skin hygiene and topical steroids, which limit the severity and decrease symptoms. Once acute cutaneous reactions develop, they are treated according to their severity. Treatments are similar to those used in prevention, but incorporate wound care management that maintains a moist environment to hasten recovery. Chronic changes are a unique subset of adverse reactions to RT that may develop months to years following treatment. Chronic radiation dermatitis is often permanent, progressive, and potentially irreversible with substantial impact on quality of life. Here, we also review the etiology, clinical manifestations, pathogenesis, prevention, and management of late-stage cutaneous reactions to radiotherapy, including chronic radiation dermatitis and radiation-induced fibrosis.

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Acute and Chronic Cutaneous Reactions to Ionizing Radiation Therapy

To develop a practice guideline report on the questions: What are the optimal methods to prevent acute skin reactions (occurring within the first 6 months of irradiation) related to radiation therapy? What are the optimal methods to manage acute skin reactions related to radiation therapy?
 Cancer Care Ontario’s Supportive Care Guidelines Group (SCGG) conducted a systematic review of literature on this topic. Evidence-based recommendations were formulated to guide clinical decision making, and a formal external review process was conducted to validate the relevance of these opinions for Ontario practitioners. Twenty-eight trials meeting the inclusion criteria were identified. Of the twenty-three trials that evaluated preventative methods, washing was the only practice which significantly prevented skin reaction. Some evidence suggested topical steroid creams and calendula ointment might be effective. None of the five trials evaluating skin reaction management detected a positive effect using steroid cream, sucralfate cream, or dressings. Skin washing, including gentle washing with water alone with or without mild soap, should be permitted in patients receiving radiation therapy to prevent acute skin reaction. There is insufficient evidence to support or refute specific topical or oral agents for the prevention or management of acute skin reaction. In the expert opinion from the SCGG, the use of a plain, non-scented, lanolin-free hydrophilic cream may be helpful in preventing radiation skin reactions. In addition, a low dose (i.e., 1%) corticosteroid cream may be beneficial in the reduction of itching and irritation.

The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline

Purpose: Based on in vitro and on clinical evidence of protection against acute side effects of radiation, a prospective randomized, open study was performed to determine the efficacy of an oral proteolytic enzyme preparation in patients with head and neck cancer receiving conventional fractionated radiation therapy. Methods: Patients with stage T3/T4 head and neck cancer were eligible. One hundred patients from two centres were entered into the study. 60Co gamma-radiation was delivered at a standard daily radiation dose of 2 Gy in 25–35 fractions over a period of 6–7 weeks. Two lateral parallel opposing fields were used with a portal area of 10 × 15 cm. Patients assigned to the test group arm additionally received enzyme tablets orally t.i.d. starting 3 days prior to radiation therapy, and continuing up to 5 days after completion of the course of radiation therapy. Patients in the control arm were not given any drug or placebo. Acute radiation side effects were described as mucositis, skin reaction, dysphagia, and were graded at each visit during and after radiation therapy, following RTOG/EORTC criteria. Results: The severity (maximum extent) of acute radiation therapy side effects was significantly less in enzyme-treated patients than in control patients: mucositis (mean: 1.3 vs 2.2, P < 0.001), skin reaction (1.2 vs 2.4, P < 0.001) and dysphagia (1.4 vs 2.2, P < 0.001). The duration of these side effects as well as the sum scores of side effects were also less in the study arm. Conclusions: Combination of enzyme therapy with conventional fractionated radiation therapy was feasible and well-tolerated. There was significant protection against acute side effects of radiation therapy in the study arm. Not only was the severity of acute side effects less but the duration was shorter and the time to onset was also delayed. Prospective randomized double-blind studies would verify this role of an oral enzyme therapy as standard co-medication with radiation therapy to the head and neck region.

Efficacy of hydrolytic enzymes in preventing radiation therapy-induced side effects in patients with head and neck cancers.

Purpose: The use of additional therapy with an oral enzyme preparation containing trypsin, chymotrypsin and papain has been suggested for the reduction of toxicity due to radiation therapy. This study was conducted to test the efficacy and tolerability of this enzyme combination in preventing or reducing the acute side effects of radiation therapy in patients with locally advanced cervical cancer. Methods: A prospective, randomised, open, clinical trial was carried out on 120 patients (aged 24–85 years) with locally advanced, biopsy-proven carcinomas of the uterine cervix (stages IIa, IIb or IIIb). Patients received 50 Gy of external radiation therapy over a period of 5 weeks, followed by intra-cavitary brachytherapy (20–30 Gy). Patients assigned to the test group (60 patients) received additional treatment with enzymes. Patients were evaluated at weekly intervals for acute radiation therapy-related side effects, according to the RTOG/EORTC grading criteria, and then after the end of radiation therapy for another 8 weeks. Occurrence of adverse events, if any, was also recorded. Results: The study revealed that the maximum extent of acute radiation side effects was reduced in the enzyme group: skin reactions (mean: 0.97 vs 1.68 in the control group, P < 0.001), vaginal mucosal reactions (0.55 vs 0.85, P=0.10), genitourinary symptoms (0.93 vs 1.38, P < 0.001) and gastrointestinal reactions (1.12 vs 1.30, P=0.12). The sum-scores during treatment, expressed as area under the curve, were significantly less in the enzyme treated patients. In the follow-up visits all observed side effects of radiation therapy were of lower intensity in the enzyme group than in the control group. Conclusions: In patients with locally advanced cancer of the uterine cervix, oral enzyme therapy was found to be effective in significantly reducing radiation therapy-related side effects such as genitourinary symptoms, subcutaneous changes and reactions of the vaginal mucosa.

Chetan P. Tamhankar

Papers

Efficacy of hydrolytic enzymes in preventing radiation therapy-induced side effects in patients with head and neck cancers.

Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects.