The development of evidence-based guidelines on mouth care for children, teenagers and young adults treated for cancer.

The aim was to produce evidence-based guidelines on mouth care for children, teenagers and young adults receiving chemotherapy and/or radiotherapy. Systematic reviews were undertaken and research was graded according to the methods of the Scottish Intercollegiate Guidelines Network. Where no relevant research was identified, an opinion-gathering process was undertaken. 'Best practice' recommendations were developed with regard to appropriate dental care and basic oral hygiene. An evaluation of oral assessment tools identified seven which had been assessed for reliability and/or validity. Only Eilers' Oral Assessment Guide was felt to be relevant for daily clinical practice. A variety of interventions have been used for the management of oral mucositis, candidiasis, xerostomia and herpes simplex virus; few are supported by research evidence. Careful oral management of children treated for cancer can improve the quality of life during treatment. The guidelines have the potential to improve patient care by promoting interventions of proven benefit and discouraging use of ineffective or potentially harmful practices which may result in adverse patient outcomes.

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

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: The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Date of most recent searches: June 2006: CENTRAL (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone with cancer receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral mucositis; outcomes - prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalisation, cost and patient quality of life. DATA COLLECTION AND ANALYSIS: Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Collaboration statistical guidelines were followed and risk ratios (RR) calculated using random-effects models. MAIN RESULTS: Two hundred and seventy-seven studies were eligible. One hundred and eighty-eight were excluded for various reasons, usually as there was no useable information on mucositis. Of the 89 useable studies all had data for mucositis comprising 7523 randomised patients. Interventions evaluated were: acyclovir, allopurinol mouthrinse, aloe vera, antibiotic pastille or paste, benzydamine, beta carotene, calcium phosphate, camomile, Chinese medicine, chlorhexidine, etoposide, folinic acid, glutamine, granulocyte/macrophage colony-stimulating factor (GM-CSF), histamine gel, honey, hydrolytic enzymes, ice chips, iseganan, keratinocyte GF, misonidazole, pilocarpine, pentoxifylline, povidone, prednisone, propantheline anticholinergic, prostaglandin, sucralfate, systemic antibiotic clarithromycin, traumeel, zinc sulphate. Of the 33 interventions included in trials, 12 showed some evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis. Interventions where there was more than one trial in the meta-analysis finding a significant difference when compared with a placebo or no treatment were: amifostine which provided minimal benefit in preventing mild and moderate mucositis RRs = 0.95 (95% confidence interval (CI) 0.92 to 0.98) and 0.88 (95% CI 0.80 to 0.98); Chinese medicine showed a benefit at all three dichotomies of mucositis with RR values of 0.44 (95% CI 0.20 to 0.96), 0.44 (95% CI 0.33 to 0.59) and 0.16 (95% CI 0.07 to 0.35) for increasing levels of mucositis severity; hydrolytic enzymes reduced moderate and severe mucositis with RRs = 0.52 (95% CI 0.36 to 0.74) and 0.17 (95% CI 0.06 to 0.52); and ice chips prevented mucositis at all levels RRs = 0.64 (95% CI 0.50 to 0.82), 0.38 (95% CI 0.23 to 0.62), and 0.24 (95% CI 0.12 to 0.48). Other interventions showing some benefit with only one study were: benzydamine, calcium phosphate, etoposide bolus, honey, iseganan, oral care, zinc sulphate. The general reporting of RCTs, especially concealment of randomisation, was poor. However, the assessments of the quality of the randomisation improved when the authors provided additional information. AUTHORS' CONCLUSIONS: Several of the interventions were found to have some benefit at 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 well designed and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.

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

BACKGROUND: Treatment of cancer is increasingly effective but is associated with short and long term side effects. Oral side effects, including oral candidiasis, remain a major source of illness despite the use of a variety of agents to treat them. OBJECTIVES: To assess the effectiveness of interventions for the treatment of oral candidiasis for patients with cancer receiving chemotherapy or radiotherapy or both. SEARCH STRATEGY: Computerised searches of Cochrane Oral Health Group and PaPaS Trials Registers, CENTRAL, MEDLINE, EMBASE, CINAHL, CANCERLIT, SIGLE and LILACS were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches: June 2006: CENTRAL (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: All randomised controlled trials comparing agents prescribed to treat oral candidiasis in people receiving chemotherapy or radiotherapy for cancer. The outcomes were eradication of oral candidiasis, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and patient quality of life. DATA COLLECTION AND ANALYSIS: Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. Risk ratios were calculated using random-effects models. MAIN RESULTS: Nine trials involving 658 patients, satisfied the inclusion criteria and are included in this review. Only two agents, each in single trials, were found to be effective for eradicating oral candidiasis. A drug absorbed from the gastrointestinal tract, ketoconazole, was more beneficial than placebo in eradicating oral candidiasis (risk ratio (RR) = 3.61, 95% confidence interval (CI) 1.47 to 8.88) and clotrimazole, at a higher dose of 50 mg was more effective than a lower 10 mg dose in eradicating oral candidiasis, when assessed mycologically (RR = 2.00, 95% CI 1.11 to 3.60). Of the five trials included in these meta-analyses, three were at high risk of bias and two of moderate risk of bias. Another trial demonstrated no statistically significant difference between a 10 mg dose of the partially absorbed drug, clotrimazole, and placebo. No differences were found when comparing different absorbed drugs; and comparing absorbed drugs with drugs which are not absorbed. AUTHORS' CONCLUSIONS: There is weak and unreliable evidence that the absorbed drug, ketoconazole, may eradicate oral candidiasis and that a higher dose of the partially absorbed drug, clotrimazole, may give greater benefit than a lower 10 mg dose, however, researchers may wish to prevent rather than treat oral candidiasis. Further well designed, placebo-controlled trials assessing the effectiveness of old and new interventions for treating oral candidiasis are needed.

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

BACKGROUND: Treatment of cancer is increasingly effective but associated with short and long term side effects. Oral side effects, including oral mucositis (mouth ulceration), remain a major source of illness despite the use of a variety of agents to treat them. OBJECTIVES: To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy or radiotherapy or both. SEARCH STRATEGY: Computerised searches of Cochrane Oral Health Group's Trials Register; Cochrane Pain, Palliative and Supportive Care Group's Trials Register; CENTRAL; MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches June 2006: CENTRAL (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: All randomised controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy or radiotherapy or both. Outcomes were oral mucositis, time to heal mucositis, oral pain, duration of pain control, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and quality of life. DATA COLLECTION AND ANALYSIS: Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation, blindness and withdrawals. Quality assessment was carried out on these three criteria. The Cochrane Oral Health Group statistical guidelines were followed and risk ratio (RR) values calculated using fixed effect models. MAIN RESULTS: Twenty-six trials involving 1353 patients satisfied the inclusion criteria. Four agents, each in single trials, were found to be effective for improving (allopurinol RR 3.33, 95% confidence interval (CI) 1.06 to 10.49; granulocyte macrophage-colony stimulating factor RR 4.23, 95% CI 1.35 to 13.24; immunoglobulin RR 1.81, 95% CI 1.24 to 2.65; human placentral extract RR 4.50, 95% CI 2.29 to 8.86) or eradicating mucositis (allopurinol RR 19.00, 95% CI 1.17 to 307.63). Three of these trials were rated as at moderate risk of bias and one as at high risk of bias. The following agents were not found to be effective: benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and 'magic' (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension). Six trials compared the time to heal and mucositis was found to heal more quickly with two interventions: granulocyte macrophage-colony stimulating factor when compared to povidone iodine, with mean difference -3.5 days (95% CI -4.1 to -2.9) and allopurinol compared to placebo, with mean difference -4.5 days (95% CI -5.8 to -3.2). Three trials compared patient controlled analgesia (PCA) to the continuous infusion method for controlling pain. There was no evidence of a difference, however, less opiate was used per hour for PCA, and the duration of pain was shorter. One trial demonstrated that pharmacokinetically based analgesia (PKPCA) reduced pain compared with PCA: however, more opiate was used with PKPCA. AUTHORS' CONCLUSIONS: There is weak and unreliable evidence that allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin or human placental extract improve or eradicate mucositis. There is no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, however, less opiate was used per hour, and duration of pain was shorter, for PCA. Further, well designed, placebo-controlled trials assessing the effectiveness of allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin, human placental extract, other interventions investigated in this review and new interventions for treating mucositis are needed.

Interventions for preventing oral candidiasis for patients with cancer receiving treatment.

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 and treat them. One of these side effects is oral candidiasis. OBJECTIVES: To assess the effectiveness of interventions (which may include placebo or no treatment) for the prevention of oral candidiasis for patients with cancer receiving chemotherapy or radiotherapy or both. SEARCH STRATEGY: Computerised searches of Cochrane Oral Health Group and PAPAS Trials Registers, CENTRAL, MEDLINE, EMBASE, CINAHL, CANCERLIT, SIGLE and LILACS were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches: June 2006: CENTRAL (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral candidiasis; primary outcome - prevention of oral candidiasis. DATA COLLECTION AND ANALYSIS: Data were recorded on the following secondary outcomes if present: relief of pain, amount of analgesia, relief of dysphagia, incidence of systemic infection, duration of stay in hospital (days), cost of oral care, patient quality of life, death, use of empirical antifungal treatment, toxicity and compliance. Information regarding methods, participants, interventions, outcome measures and results were independently extracted, in duplicate, by two review authors. The Cochrane Oral Health Group statistical guidelines were followed and risk ratios (RR) calculated using random-effects models. Potential sources of heterogeneity were examined in random-effects metaregression analyses. MAIN RESULTS: Twenty-eight trials involving 4226 patients satisfied the inclusion criteria. Drugs absorbed and partially absorbed from the gastrointestinal (GI) tract were found to prevent oral candidiasis when compared to a placebo, or a no treatment control group, with RR for absorbed drugs = 0.47 (95% confidence interval (CI) 0.29 to 0.78). For absorbed drugs in populations with an incidence of 20% (mid range of results in control groups), this implies a NNT of 9 (95% CI 7 to 13) patients need to be treated to avoid one patient getting oral candidiasis. There was no significant benefit shown for drugs not absorbed from the GI tract. AUTHORS' CONCLUSIONS: There is strong evidence, from randomised controlled trials, that drugs absorbed or partially absorbed from the GI tract prevent oral candidiasis in patients receiving treatment for cancer. There is also evidence that these drugs are significantly better at preventing oral candidiasis than drugs not absorbed from the GI.

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

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: The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Date of most recent searches: April 2004. SELECTION CRITERIA: Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone with cancer receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral mucositis; outcomes - prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalisation, cost and patient quality of life. DATA COLLECTION AND ANALYSIS: Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Oral Health Group statistical guidelines were followed and risk ratios (RR) calculated using random-effects models. MAIN RESULTS: Two hundred and two studies were eligible. One hundred and thirty two were excluded for various reasons, usually as there was no useable information on mucositis. Of the 71 useable studies all had data for mucositis comprising 5217 randomised patients. Interventions evaluated were: acyclovir, allopurinol mouthrinse, aloe vera, amifostine, antibiotic pastille or paste, benzydamine, beta carotene, calcium phosphate, camomile, chlorhexidine, clarithromycin, folinic acid, glutamine, GM-CSF, honey, hydrolytic enzymes, ice chips, iseganan, keratinocyte GF, misonidazole, oral care, pentoxifylline, povidone, prednisone, propantheline, prostaglandin, sucralfate, traumeel and zinc sulphate. Of the 29 interventions included in trials, 10 showed some evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis. Interventions where there was more than one trial in the meta-analysis finding a significant difference when compared with a placebo or no treatment were: amifostine which provided minimal benefit in preventing moderate and severe mucositis RR = 0.84 (95% confidence interval (CI) 0.75 to 0.95) and 0.60 (95% CI 0.37 to 0.97), antibiotic paste or pastille demonstrated a moderate benefit in preventing mucositis RR = 0.87 (95% CI 0.79 to 0.97), hydrolytic enzymes reduced moderate and severe mucositis with RRs = 0.52 (95% CI 0.36 to 0.74) and 0.17 (95% CI 0.06 to 0.52), and ice chips prevented mucositis at all levels RR = 0.63 (95% CI 0.44 to 0.91), 0.43 (95% CI 0.23 to 0.81), 0.27 (95% CI 0.11 to 0.68). Other interventions showing some benefit with only one study were: benzydamine, calcium phosphate, honey, oral care protocols, povidone and zinc sulphate. The number needed to treat (NNT) to prevent one patient experiencing moderate or severe mucositis over a baseline incidence of 60% for amifostine is 10 (95% CI 7 to 33), antibiotic paste or pastille 13 (95% CI 8 to 56), hydrolytic enzyme 4 (95% CI 3 to 6) and ice chips 5 (95% CI 3 to 19). When the baseline incidence is 40%/90% the NNTs for amifostine are 16/7, for antibiotic paste or pastille 19/7, for hydrolytic enzyme 5/3 and for ice chips 7/3. The general reporting of RCTs was poor. However, the assessments of the quality of the randomisation improved when the authors provided additional information. AUTHORS' CONCLUSIONS: Several of the interventions were found to have some benefit at 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 well designed and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.

Genotoxicity of etoposide: greater susceptibility of MLL than other target genes.

The ability of topoisomerase 2 inhibitors to induce DNA breakage is well recognized. Previous studies, however, have concentrated on the effects on individual genes. The effects of etoposide on the MLL, RUNX1, and MLLT3 genes were simultaneously studied in the same hemopoietic cell population. We found MLL to be more susceptible to etoposide-induced cleavage than RUNX1 and MLLT3, with maximum cleavage at a lower drug concentration. A higher level of MLL than other gene cleavage was also detected after cellular exposure to all drug concentrations. Greater susceptibility to topoisomerase 2 inhibitor-induced cleavage may explain the more frequent involvement of MLL in treatment-related leukemogenesis.

Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.

BACKGROUND: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. METHODS: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. RESULTS: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. CONCLUSIONS: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

Effects of topoisomerase 2 inhibitors on the MLL gene in children receiving chemotherapy: a prospective study.

The molecular effects of etoposide in haemopoietic cells suggest that mixed lineage leukaemia (MLL) abnormalities can be biomarkers of patient susceptibility to the genotoxic effects of topoisomerase 2 (topo 2) inhibitors. We have prospectively studied treatment-related MLL cleavage and rearrangement in serial samples from 71 children receiving chemotherapy, using Southern blot analysis and panhandle PCR. The results were related to patient demographics, treatment details and outcome. MLL cleavage was identified in six bone marrow samples from five patients 2-10 months after the start of therapy. There was no obvious relationship between the degree of MLL cleavage and cumulative dose or schedule of topo 2 inhibitors. Three children with low percentage (23-30%) cleavage remained well and two were still receiving treatment at study completion. One child with two consecutively positive samples and higher level of MLL cleavage (45-48%) died from treatment-related toxicities and relapsed leukaemia. A patient with haemophagocytic lymphohistiocytosis developed the highest level of MLL cleavage (50%) at 3 months and a treatment-related leukaemia with MLL rearrangement 6 months after the start of treatment. It would appear that some patients are inherently more susceptible to the genotoxic effect of topo 2 inhibitors. The degree and persistence of MLL cleavage may identify patients at risk.

Coexistence of treatment-related MLL cleavage and rearrangement in a child with haemophagocytic lymphohistiocytosis.

Treatment-related acute myeloid leukaemia (t-AML) is a serious complication of topoisomerase 2 inhibitor therapy and is characterised by the presence of mixed lineage leukaemia (MLL) rearrangement. By molecular tracking, we were able to show that MLL cleavage preceded gene rearrangement by 3 months and before the clinical diagnosis of t-AML in a patient with haemophagocytic lymphohistiocytosis. This is the first report on the sequential detection of the two biomarkers in treatment-related leukaemogenesis.

Interventions for preventing oral candidiasis for patients with cancer receiving treatment.

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 and treat them. One of these side effects is oral candidiasis. OBJECTIVES: To assess the effectiveness of interventions (which may include placebo or no treatment) for the prevention of oral candidiasis for patients with cancer receiving chemotherapy and/or radiotherapy. SEARCH STRATEGY: Electronic databases: Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, MEDLINE Pre-indexed, EMBASE, CINAHL, CANCERLIT, SIGLE and LILACS were searched. Date of the most recent searches April 2004 (CENTRAL Issue 2, 2004). SELECTION CRITERIA: Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral candidiasis; primary outcome - prevention of oral candidiasis. DATA COLLECTION AND ANALYSIS: Data were recorded on the following secondary outcomes if present: relief of pain, amount of analgesia, relief of dysphagia, incidence of systemic infection, duration of stay in hospital (days), cost of oral care, patient quality of life, death, use of empirical antifungal treatment, toxicity and compliance. Information regarding methods, participants, interventions, outcome measures and results were independently extracted, in duplicate, by two reviewers (HW & JC). The Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using random effects models. Potential sources of heterogeneity were examined in random effects metaregression analyses. MAIN RESULTS: Twenty-eight trials involving 4226 patients satisfied the inclusion criteria. Drugs absorbed and partially absorbed from the gastrointestinal (GI) tract were found to prevent oral candidiasis when compared to a placebo, or a no treatment control group, with RR for absorbed drugs = 0.47 (95% CI 0.29 to 0.78). For absorbed drugs in populations with an incidence of 20% (mid range of results in control groups), this implies a NNT of 9 (95% CI 7 to 13) patients need to be treated to avoid one patient getting oral candidiasis. There was no significant benefit shown for drugs not absorbed from the GI tract. REVIEWERS' CONCLUSIONS: There is strong evidence, from randomised controlled trials, that drugs absorbed or partially absorbed from the GI tract prevent oral candidiasis in patients receiving treatment for cancer. There is also evidence that these drugs are significantly better at preventing oral candidiasis than drugs not absorbed from the GI.

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

BACKGROUND: Treatment of cancer is increasingly effective but associated with short and long-term side effects. Oral side effects, including oral mucositis (mouth ulceration), remain a major source of illness despite the use of a variety of agents to treat them. OBJECTIVES: To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy and/or radiotherapy. SEARCH STRATEGY: Computerised searches of Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches August 2003: (CENTRAL) (The Cochrane Library Issue 3, 2003). SELECTION CRITERIA: All randomised controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy and/or radiotherapy. Outcomes were oral mucositis, time to heal mucositis, oral pain, duration of pain control, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and quality of life. DATA COLLECTION AND ANALYSIS: Data were independently extracted, in duplicate, by two reviewers. Authors were contacted for details of randomisation, blindness and withdrawals. Quality assessment was carried out on these three criteria. The Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using fixed effect models. MAIN RESULTS: Twenty-five trials involving 1292 patients satisfied the inclusion criteria. Three agents, each in single trials, were found to be effective for improving (allopurinol RR 3.33, 95% CI 1.06 to 10.49; immunoglobulin RR 1.81, 95% CI 1.24 to 2.65; human placentral extract RR 4.50, 95% CI 2.29 to 8.86) or eradicating mucositis (allopurinol RR 19.00, 95% CI 1.17 to 307.63). Two of these trials were rated as at moderate risk of bias and one as at high risk of bias. The following agents were not found to be effective: benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and 'magic' (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension). Six trials compared the time to heal and mucositis was found to heal more quickly with two interventions: Granulocyte Macrophage-Colony Stimulating Factor when compared to povidone iodine, with mean difference -3.5 days (95% CI -4.1 to -2.9) and allopurinol compared to placebo, with mean difference -4.5 days (95% CI -5.8 to -3.2). Three trials compared patient controlled analgesia (PCA) to the continuous infusion method for controlling pain. There was no evidence of a difference, however, less opiate was used per hour for PCA, and the duration of pain was shorter. One trial demonstrated that pharmacokinetically based analgesia (PKPCA) reduced pain compared with PCA, however more opiate was used with PKPCA. REVIEWERS' CONCLUSIONS: There is weak and unreliable evidence that allopurinol mouthwash, vitamin E, immunoglobulin or human placental extract improve or eradicate mucositis. There is no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, however, less opiate was used per hour, and duration of pain was shorter, for PCA. Further, well designed, placebo-controlled trials assessing the effectiveness of allopurinol mouthwash, immunoglobulin, human placental extract, other interventions investigated in this review and new interventions for treating mucositis are needed.

A survey of current practice with regard to oral care for children being treated for cancer.

The aim of the study was to establish current UK oral care practice for children with cancer. A telephone survey of all 22 United Kingdom Children's Cancer Study Group (UKCCSG) centres was undertaken. Nineteen (86%) of the centres reported using guidelines/protocols for mouth care. The use of routine preventive oral care therapies showed the greatest variation between centres. Four centres (18%) did not use any prophylactic oral care therapy other than basic oral hygiene, whereas seven (32%) routinely used a combination of three or more agents. Chlorhexidine was the most frequently administered prophylactic therapy (17/22 centres, 77%), followed by nystatin (11/22 centres, 50%). There was little variation in advice given to parents/patients on basic oral hygiene. Regarding dental check-ups, 9/22 centres (41%) recommended children to attend a hospital-linked dental clinic. Only at 8/22 centres (36%) did children undergo a dental check-up before commencing cancer treatment. The survey identified significant variation in preventive oral care therapies and dental check-ups at the UKCCSG centres. Attention needs to be given to establishing evidence based, effective strategies.

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

BACKGROUND: Treatment of cancer is increasingly effective but is associated with short and long-term side effects. Oral side effects, including oral candidiasis, remain a major source of illness despite the use of a variety of agents to treat them. OBJECTIVES: To assess the effectiveness of interventions for the treatment of oral candidiasis for patients with cancer receiving chemotherapy and or radiotherapy. SEARCH STRATEGY: Computerised searches of Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information.Date of the most recent searches: August 2003: (CENTRAL) (The Cochrane Library Issue 3, 2003). SELECTION CRITERIA: All randomised controlled trials comparing agents prescribed to treat oral candidiasis in people receiving chemotherapy or radiotherapy for cancer. The outcomes were eradication of oral candidiasis, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and patient quality of life. DATA COLLECTION AND ANALYSIS: Data were independently extracted, in duplicate, by two reviewers. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using random effects models where significant heterogeneity was detected (P < 0.1). MAIN RESULTS: Eight trials involving 418 patients, satisfied the inclusion criteria and are included in this review. Only two agents, each in single trials, were found to be effective for eradicating oral candidiasis. A drug absorbed from the gastrointestinal tract, ketoconazole, was more beneficial than placebo in eradicating oral candidiasis (relative risk (RR) = 0.35, 95% confidence interval (CI) 0.20 to 0.61) and clotrimazole, at a higher dose of 50 mg was more effective than a lower 10 mg dose in eradicating oral candidiasis, when assessed mycologically (RR = 0.47, 95% CI 0.25 to 0.89). Another trial demonstrated no statistically significant difference between a 10 mg dose of the partially absorbed drug, clotrimazole, and placebo. No differences were found when comparing different absorbed drugs; and comparing absorbed drugs with drugs which are not absorbed. REVIEWER'S CONCLUSIONS: There is weak and unreliable evidence that the absorbed drug, ketoconazole, may eradicate oral candidiasis and that a higher dose of the partially absorbed drug, clotrimazole, may give greater benefit than a lower 10 mg dose, however, researchers may wish to prevent rather than treat oral candidiasis. Further well designed, placebo-controlled trials assessing the effectiveness of old and new interventions for treating oral candidiasis are needed.

Little or no space-time clustering found amongst cases of childhood lymphoma in North West England.

We have examined space-time clustering amongst cases of lymphoma in children, aged 0-14 years, using population-based data from the North West of England for the period 1954-2001. There was little or no evidence for space-time clustering amongst all the lymphomas or amongst those sub-groups identified in advance.

Association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia.

AIMS: To investigate the association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia. METHODS: Cerebrospinal fluid (CSF) samples from patients with acute myelogenous leukaemia (AML) at diagnosis (n = 2) and acute lymphoblastic leukaemia (ALL) at diagnosis (n = 14) were analysed for parvovirus B19 DNA by means of nested polymerase chain reaction. In addition, samples from patients with benign intracranial hypertension (BIH) (n = 10) and hydrocephalus (n = 13) were tested as controls. RESULTS: Four leukaemia cases were positive-common ALL (n = 2), null cell ALL (n =1), and M7 AML (n = 1)-whereas all controls were negative (Yates corrected chi(2) value, 3.97; p = 0.046; odds ratio, 16.92; confidence interval, 1.03 to 77.18). All four patients were significantly anaemic, but none was encephalitic or had evidence of central nervous system leukaemia. In three of these patients, serum tumour necrosis alpha, interferon gamma, interleukin 6, granulocyte-macrophage colony stimulating factor (range, 34.93-3800.06 pg/ml), and macrophage chemoattractant protein 1 were detectable. All of these four patients carried at least one of the HLA-DRB1 alleles, which have been associated with symptomatic parvovirus B19 infection. CONCLUSION: Erythroid suppression and immune cell proliferation are both associated with B19 infection and may also be important in the pathogenesis of acute leukaemia.

Vitamin K and childhood cancer: a report from the United Kingdom Childhood Cancer Study.

The relationship between neonatal vitamin K received by the intramuscular (i.m.) route and the development of leukaemia or other cancers was investigated as part of a national case-control study of childhood cancer, using data abstracted from obstetric and neonatal records. The analyses included 2530 children diagnosed with cancer before 15 years of age, 1174 of whom had leukaemia and 4487 control children without cancer. Overall, 39% of cases and 42% of controls had records of i.m. vitamin K administration, while 24% of cases and 22% of controls had no record of whether or not they had received vitamin K. Using subjects who received i.m. vitamin K as the baseline group, our analyses found no association between the administration of i.m. vitamin K and either leukaemia or other cancers as a group. We conclude that there is no convincing evidence that neonatal vitamin K administration, irrespective of the route by which it is given, influences the risk of children developing leukaemia or any other cancer.

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

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: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Date of most recent searches June 2002. SELECTION CRITERIA: Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone with cancer receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral mucositis; outcomes - prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalisation, cost and patient quality of life. DATA COLLECTION AND ANALYSIS: Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two reviewers. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using random effects models. MAIN RESULTS: One hundred and nine studies were eligible. Fifty-seven were excluded for various reasons, usually as there was no useable information on mucositis. Of the 52 useable studies all had data for mucositis comprising 3594 randomised patients. Interventions evaluated were: acyclovir, allopurinol mouthrinse, amifostine, antibiotic pastille or paste, benzydamine, camomile, chlorhexidine, clarithromycin, folinic acid, glutamine, GM-CSF, hydrolytic enzymes, ice chips, oral care, pentoxifyline, povidone, prednisone, propantheline, prostaglandin, sucralfate and traumeel. Of the 21 interventions included in trials, nine showed some evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis. Interventions where there was more than one trial and a significant difference compared with a placebo or no treatment were allopurinal with unreliable evidence for a reduction in the severity of mucositis OR = 0.01 (95% CI: 0 to 0.03), amifostine provided minimal benefit in preventing mucositis RR = 0.95 (95% CI: 0.91 to 0.99), antibiotic paste or pastille demonstrated a moderate benefit in preventing mucositis RR = 0.87 (95% CI: 0.79 to 0.97), GM-CSF prevented mucositis RR = 0.51 (95% CI: 0.29 to 0.91), hydrolytic enzymes reduced the severity of mucositis RR = 0.49 (95% CI: 0.30 to 0.81), and ice chips prevented mucositis OR = 0.42 (95% CI: 0.19 to 0.93). Other interventions showing some benefit with only one study were: benzydamine, oral care protocols and povidone. The NNT to prevent one patient experiencing mucositis over a baseline incidence of 60% for amifostine is 33 (95% CI: 20 to 100), antibiotic paste or pastille 13 (95% CI: 8 to 50), GM-CSF 3 (95% CI: 2 to 20) and ice chips 5 (95% CI: 2 to 31). When the baseline incidence is 40%/90% the NNTs for amifostine are 50/20, for antibiotic paste or pastille 20/8, for GM-CSF 5/2 and for ice chips 6/10. The general reporting of RCTs was poor. However, the quality of the randomisation improved when the authors provided additional information. REVIEWER'S CONCLUSIONS: Several of the interventions were found to have some benefit at 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 hat benefits may be specific for certain cancer types and treatment. There is a need for well designed and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.