Methods

Trial design: parallel (2 arms)

Location: Iran

Number of centres: 1

Study duration: April to September 2013

Participants

Inclusion criteria: full consciousness; suffering Hodgkin or non‐Hodgkin lymphoma or multiple myeloma; good oral health; isolation in a separate room; undergoing similar basic chemotherapy; undergoing first course of chemotherapy; undergoing autologous BMT

Exclusion criteria: patient dissatisfaction; loss of consciousness; susceptible to other diseases that could potentially disrupt treatment; use of analgesics continuously prior to start of study; receiving combined therapies such as radiotherapy; fever; neutropenia; mucositis prior to the treatment; respiratory diseases; oral infections; systemic diseases affecting oral health (especially periodontal tissues); more than 2 weeks interval between chemotherapy and transplantation; changes in treatment protocol during the study

Cancer type: haematological (Hodgkin: Gp A: 31%; Gp B: 46%; non‐Hodgkin: Gp A: 13%; Gp B: 23%; multiple myeloma: Gp A: 56%; Gp B: 31%)

Cancer treatment: melphalan for Hodgkin and non‐Hodgkin lymphoma; melphalan, cytarabine, etoposide, and lomustine for multiple myeloma ("There were no differences in terms of...treatment regimen")

Any other potentially important prognostic factors: "There were no differences in terms of...educational status"; smokers: Gp A: 13%; Gp B: 31%

Age at baseline (years): Gp A: 43 (range 19 to 66); Gp B: 39.8 (range 21 to 62)

Gender: Gp A: 56% male; Gp B: 62% male

Number randomised: 33 (Gp A: 17; Gp B: 16)

Number evaluated: 29 (Gp A: 16; Gp B: 13)

Interventions

Comparison: cryotherapy versus normal saline

Gp A: prior to BMT, ice cubes held in mouth 5 min before start of chemotherapy, held for 30‐min periods with maximum 20‐min breaks between each period, until 5 min after completion of chemotherapy

Gp B: prior to BMT, 30 to 50 cc of saline mouthwash used 30 min before start of chemotherapy, then again every half‐hour, until 6 hours after completion of chemotherapy

Compliance: not reported

Duration of treatment (intended): not reported but probably variable depending on chemotherapy regimen

Outcomes

• Oral mucositis: WHO 0 to 4 scale (assessed on days 3, 7, 14 and 21 and reported as a mean on each separate assessment day); we requested maximum score experienced per participant over the whole study period but the authors provided incidence of each grade on days 3, 7 and 14

• Neutrophil rate (not an outcome of this review)

Notes

Sample size calculation: based on detection of MD of 0.51, with 80% power at 5% significance level, and accounting for 40% attrition (14 per group required)

Adverse effects: not reported

Funding: "financial support of Tabriz University of Medical Sciences"

Declarations/conflicts of interest: "Authors declare no conflict of interest in this study"

Data handling by review authors: the authors provided us with data on the incidence of each oral mucositis grade on days 3, 7 and 14, and we used the data for day 7 in our meta‐analyses as the incidence of grades > 0 was highest and therefore probably most closely equates to the maximum score experienced per participant (as reported in the other studies in the meta‐analyses)

Other information of note: the information on this study is obtained from a pre‐publication copy of the study report provided to us by the authors, and also from correspondence with the authors

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The patients randomly were allocated into control and intervention groups using size‐2 random blocks and based on a 1:1 allocation ratio random numbers were generated by "Random software Allocation" software"

Comment: computer generated randomisation so probably done adequately

Allocation concealment (selection bias)

Low risk

Quote: "The patients randomly were allocated into control and intervention groups using size‐2 random blocks and based on a 1:1 allocation ratio random numbers were generated by "Random software Allocation" software"

Correspondence: "the allocation was performed by a person who was not involved in sampling and analysis"

Comment: appears to be third‐party randomisation which should have ensured that the allocation sequence was not manipulated

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

High risk

12% of randomised participants were not included in the analyses (Gp A: 6%; Gp B: 19%). All drop‐outs were due to fever but this could be a risk of bias if the fever was linked to oral mucositis

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: Pesaro, Italy

Number of centres: 1

Study duration: not reported

Participants

Inclusion criteria: first ever course of chemotherapy

Exclusion criteria: not reported

Cancer type: Gp A: 98% gastrointestinal, 2% prostrate; Gp B: 98% gastrointestinal, 2% prostrate

Cancer treatment: 5FU, different dosages and co‐treatments (LV, IFN, VP16) equally distributed between groups due to stratification

Any other potentially important prognostic factors: performance status (EOCG): Gp A: 0 = 50%, 1 = 32%, 2 = 18%; Gp B: 0 = 50%, 1 = 35%, 2 = 15%; denture wearers equally distributed between groups due to stratification

Age at baseline (years): Gp A: median 60 (range 38 to 73); Gp B: median 58 (range 44 to 72)

Gender: Gp A: 68% male; Gp B: 70% male

Number randomised: 84 (Gp A: 44; Gp B: 40)

Number evaluated: 84 (Gp A: 44; Gp B: 40)

Interventions

Comparison: cryotherapy versus no treatment

Gp A: ice chips placed in mouth 5 min before 5FU and continuously swished around, then replenished before the previous ice had completely melted, for total 30 min

Gp B: 5FU only

All participants were asked to remove dentures

Compliance: all Gp A participants received cryotherapy in the first cycle but 2 participants "noted an 'ice cream' headache which caused them to refuse this technique after the second and third cycle of chemotherapy, respectively"

Duration of treatment (intended): not reported (variable and dependent on number of cycles of cancer treatment)

Outcomes

• Oral mucositis: global assessment of the physician's judgement and participants' description on a 0 to 4 scale (very similar to WHO scale and NCI common toxicity criteria) based on methods of Mahood 1991 (assessed after each cycle and reported as first cycle only and all cycles, maximum score reported)

• Duration of oral mucositis (not an outcome of this review)

• Other adverse effects of cancer treatment (not an outcome of this review)

Notes

Sample size calculation: not reported

Adverse effects: 2 participants in the cryotherapy group "noted an 'ice cream' headache"

Funding: not reported

Declarations/conflicts of interest: not reported

Data handling by review authors: data reported as all cycles (so double‐counting is a problem) and first cycle only, so we used the data for first cycle only

Other information of note: mean oral mucositis score reported by smoking status for each group for the first cycle only (smokers had higher mean oral mucositis score than non‐smokers in both groups)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomised to a control arm or to receive cryotherapy"

Correspondence: "Randomisation using cards from a computer generated list in sealed envelopes was performed by a person not involved with the care or evaluation of the patient"

Comment: adequate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "randomised to a control arm or to receive cryotherapy"

Correspondence: "Randomisation using cards from a computer generated list in sealed envelopes was performed by a person not involved with the care or evaluation of the patient"

Comment: third‐party randomisation and use of sealed envelopes should have ensured that the allocation sequence was not manipulated

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analyses

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately. Although only the oral mucositis outcome was mentioned in the methods, this is more likely to be related to reporting quality rather than bias as the study pre‐dates the CONSORT statement (CONSORT 2010)

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: various locations in Italy

Number of centres: "multicentre" but unclear how many centres; co‐ordinated by the Institute of Hematology and Medical Oncology, University of Bologna

Study duration: October 2004 to January 2006

Participants

Inclusion criteria: undergoing allogeneic HSCT and MTX‐containing GVHD prophylaxis; minimum age 8 years

Exclusion criteria: clinical evidence of oral mucositis; participants not receiving at least 3 administrations of MTX following HSCT

Cancer type: haematological (types were equally distributed between groups)

Cancer treatment: pre‐transplant radio/chemotherapy generally comparable between groups; total body irradiation: Gp A: 30.6%; Gp B: 28.3%

Any other potentially important prognostic factors: stem cell donor related: Gp A: 45.1%; Gp B: 58.3%; stem cell source: Gp A: marrow = 33.9%, peripheral blood = 66.1%; Gp B: marrow = 28.3%, peripheral blood = 71.7%; folinic acid rescue: Gp A: 43.5%; Gp B: 38.3%

Age at baseline (years): Gp A: median 35.5 (range 9 to 59); Gp B: median 40 (range 8 to 66)

Gender: Gp A: 51.6% male; Gp B: 50% male

Number randomised: 130 (not reported by group)

Number evaluated: 122 (Gp A: 62; Gp B: 60)

Interventions

Comparison: cryotherapy versus no treatment

Gp A: after allogeneic HSCT, ice chips (mineral water) or popsicles placed in mouth for minimum 60 min starting from the time of low‐dose MTX administration (20 mg/m² on day +1, 15 mg/m² on days +3, +6 and +11) as an IV infusion lasting 5 min (± 2), and replenished when melted

Gp B: after allogeneic HSCT, MTX as above

Compliance: "Six patients enrolled in the cryotherapy arm did not actually complete cryotherapy as planned because of refusal or poor tolerance. However, the exclusion of these patients did not change the results"

Duration of treatment (intended): 4 occasions (minimum of 60 min) on 4 separate days (days 1, 3, 6 and 11)

Outcomes

• Oral mucositis: WHO 0 to 4 scale (assessed once daily for 20 to 30 days, maximum score reported)

• Duration of moderate to severe (grade 2 to 4) and severe (grade 3 to 4) oral mucositis (not an outcome of this review)

Notes

Sample size calculation: based on previous study, 90% power at 5% significance (unclear whether required sample size was achieved)

Adverse effects: not reported, only refers to the 6 participants who did not complete cryotherapy due to "refusal or poor tolerance"

Funding: "We thank the Italian HSCT Nurses Group (GITMO) for sponsoring the study"

Declarations/conflicts of interest: not reported

Data handling by review authors: data is maximum oral mucositis score across all cycles of MTX

Other information of note: univariate and multivariate analyses showed severe (grade 3 to 4) oral mucositis was significantly associated with total body irradiation and lack of folinic acid rescue

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "After giving their informed consent, patients were included in a preformed randomization list that was updated by the coordinating center. Randomization was performed at the ratio of 1 patient per arm with no further stratifications"

Comment: adequate method of random sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "After giving their informed consent, patients were included in a preformed randomization list that was updated by the coordinating center. Randomization was performed at the ratio of 1 patient per arm with no further stratifications"

Comment: co‐ordinating centre mentioned, but unclear whether or not they allocated participants remotely from this centre (central randomisation by a third party)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

6% of the participants were not included in the analyses but this attrition was not reported by group. However, the amount of attrition was low and reasons are fully reported

Selective reporting (reporting bias)

Low risk

Data for the primary outcome of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: Mashhad, Iran

Number of centres: 2

Study duration: March 2007 to April 2008

Participants

Inclusion criteria: able to undergo one of the chemotherapy regimens described in the study at a standard dose; normal laboratory levels (including complete blood counts); normal kidney and hepatic function; participant or carer able to read and write

Exclusion criteria: previous chemotherapy; not undergoing one of the combined courses of chemotherapy described in the study; treated with head and neck radiotherapy; diabetic

Cancer type: Gp A: 55% colorectal, 45% breast; Gp B: 45% colorectal, 55% breast

Cancer treatment:

• MAYO (mean infusion time 20 min): 5FU (425 mg/m²) and LV (25 mg/m²) for 5 days, repeated every 28 days: Gp A: 55%; Gp B: 45%

• CAF (mean infusion time 25 to 35 min): cyclophosphamide (500 mg/m²), adriamycin (50 mg/m²) and 5FU (500 mg/m²) on 1st day of cycle, repeated every 21 days: Gp A: 30%; Gp B: 42.5%

• CMF (mean infusion time 25 to 35 min): cyclophosphamide (600 mg/m²), MTX (40 mg/m²) and 5FU (600 mg/m²) on 1st day of cycle, repeated every 28 days: Gp A: 15%; Gp B: 12.5%

Any other potentially important prognostic factors: no statistically significant differences between groups in the following factors: tooth status, smoking status, mouthwash use, brushing habit, BMI, educational status

Age at baseline (years): Gp A: mean 59.5 (SD 12.35); Gp B: mean 63.25 (SD 15.06)

Gender: 40% male overall and reports that there were no statistically significant differences between groups

Number randomised: 80 (Gp A: 40; Gp B: 40)

Number evaluated: 80 (Gp A: 40; Gp B: 40)

Interventions

Comparison: cryotherapy versus no treatment

Gp A: ice chips placed in mouth 5 min before chemotherapy until 5 min after and continuously swished around, then replenished before the previous ice had completely melted

Gp B: chemotherapy only

All participants were asked to remove dentures

Compliance: well tolerated, no discontinuation of therapy, and most participants kept their mouths constantly cool for most of the chemotherapy session

Duration of treatment (intended): mean duration of cryotherapy was 20 to 45 min for a session; those receiving MAYO regimen (see above) had cryotherapy for each of the 5 days of treatment, whilst those receiving CAF/CMF regimen (see above) had cryotherapy on the single day of treatment

Outcomes

• Oral mucositis: WHO 0 to 4 scale assessed separately by participants and clinicians (first cycle‐only reported, assessed daily by participants or on days 1, 5, 14 and 21 for the 5‐day regimen (MAYO) and days 7, 14 and 21 for the single‐day regimens (CAF/CMF), maximum score reported)

Obtained from correspondence:

• Interruptions to cancer treatment: (assessed over first 2 cycles, reported as both event (dichotomous) data and continuous data in the form of mean number of days of interruption)

• Oral pain: 1 to 5 scale relating to duration of pain experience (1 = never, 2 = one day of week, 3 = 2 to 3 days of week, 4 = most of week, 5 = 7 days of week)

Notes

Sample size calculation: not reported

Adverse effects: 8 (20%) of participants in the cryotherapy group complained of chills

Funding: "This work was supported by the department of research, Mashhad University of Medical Science"

Declarations/conflicts of interest: not reported

Data handling by review authors: clinician judgement of oral mucositis was preferred over participant judgement as we deemed that this may be more objective and less biased; oral pain was measured in a different way to the other studies measuring intensity/severity of pain and therefore it is not appropriate to meta‐analyse using standardised mean difference, so we have presented the data in an additional table

Other information of note: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was performed by the use of a random numbers table"

Comment: adequate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was performed by the use of a random numbers table"

Correspondence: "We designed a list that numbered from 100 to 180. Then an external person involved assigning a letter (A, AB, B, and BA) to the each number randomly. The entire investigator was blinded about number and letters. As patients enrolled for study, the external person enters the patient's code in the list. In summary, we used an external person to allocate patient to the intervention or control group"

Comment: third‐party randomisation should have ensured that the allocation sequence was not manipulated

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analyses

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: Kerman, Iran

Number of centres: 1

Study duration: not reported

Participants

Inclusion criteria: partial or complete exposure of head and neck to radiation; minimum radiation dose of 2500 to 3000 cGy (trial registry says Gy) per session; beginning radiotherapy at the start of the study and continuing constantly for the following 2 weeks

Exclusion criteria: existing oral mucositis; systemic disease or medication affecting oral condition; less than 15 or more than 55 years of age

Cancer type: head and neck (not reported by group)

Cancer treatment: radiotherapy to the head and neck

Any other potentially important prognostic factors: no statistically significant difference between groups in smoking status or education level

Age at baseline (years): Gp A: mean 42.9 (SD 14.9); Gp B: mean 49.1 (SD 15.4)

Gender: 57.5% male overall and reports that there were no statistically significant differences between groups

Number randomised: 40 (Gp A: 20; Gp B: 20)

Number evaluated: 40 (Gp A: 20; Gp B: 20)

Interventions

Comparison: cryotherapy versus no treatment

Gp A: ice cubes placed in mouth and sucked for 5 min before radiotherapy and for a further 5 min after the session

Gp B: standard oral care

Both groups received standard oral care (use of soft toothbrush, nonabrasive toothpaste and dental floss twice daily)

Compliance: only states "no lapse during the study"

Duration of treatment (intended): 10 min per day for 2 weeks

Outcomes

• Oral mucositis: 0 to 4 scale assessed separately by participants and clinicians (very similar to WHO scale and NCI common toxicity criteria ‐ based on methods of Mahood 1991) (assessed on days 1, 7 and 14 and reported as a mean on each separate assessment day)

• Oral pain: scale not mentioned (assessed days 1, 7 and 14 and reported as a mean on each separate assessment day)

Notes

Sample size calculation: 80% power at 5% significance level to detect a 40% difference in treatment effect (as there were no drop‐outs, it is assumed that this was achieved)

Adverse effects: not reported but presumably none were expected due to the 5‐min periods of cryotherapy

Funding: "This study was financially supported by the Office of Vice Chancellor for Research of Kerman University of Medical Sciences"

Declarations/conflicts of interest: not reported

Data handling by review authors: we report MD and 95% CI for mucositis severity in an additional table; physician‐judged mucositis rating was preferred over participant judgement as we deemed that this may be more objective and less biased; we used the data on day 14 due to the highest control group mean; we were unable to use the oral pain data as the scale was not described

Other information of note: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The participants were divided into experimental and control groups using block randomization technique with the formula of AABB, ABAB, ABBA, BBAA, BABA, and BAAB"

Comment: random sequence appears to have been adequately generated

Allocation concealment (selection bias)

Unclear risk

Quote: "The participants were divided into experimental and control groups using block randomization technique with the formula of AABB, ABAB, ABBA, BBAA, BABA, and BAAB"

Comment: insufficient information to determine whether or not the random sequence was adequately concealed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analyses

Selective reporting (reporting bias)

High risk

Oral pain not mentioned in the trial registry record and not described in the methods of the published trial report. It is possible that this was reported because it showed favourable results for cryotherapy

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: Gaziantep, Turkey

Number of centres: 1

Study duration: not reported

Participants

Inclusion criteria: due to receive first course of chemotherapy; healthy oral mucosa; no dental problems

Exclusion criteria: receiving more than 1 combination chemotherapy course or antineoplastic drug treatment with half‐life of 30 min or more; discomfort in the mouth; head‐neck cancer

Cancer type: gastric 33.3%; colon 33.3%; rectal 16.9%; pancreatic 9.9%; unknown 6.6% (equal numbers per group); stage of disease equally distributed between groups

Cancer treatment: 5FU and LV

Any other potentially important prognostic factors: education level, denture wearers, toothbrushing habits, smoking status, nutrition, dry mouth, lack of appetite and systemic disease all equally distributed between groups

Age at baseline (years): not reported

Gender: 50% male in both groups

Number randomised: 60 (Gp A: 30; Gp B: 30)

Number evaluated: 60 (Gp A: 30; Gp B: 30)

Interventions

Comparison: cryotherapy versus routine care

Gp A: ice chips placed in mouth 5 min before 5FU + LV, during treatment and within 15 min after treatment, for total 30 min; continuously swished around, then replenished before the previous ice had completely melted; whole procedure repeated for 5 consecutive days

Gp B: routine care

All participants were asked to remove dentures

Compliance: "Oral cryotherapy was tolerated well by the patients. The majority of the patients reported that they managed to keep the oral cavity constantly cooled most of the time that the chemotherapy treatment was administered. Patients who experienced discomfort during the cryotherapy application continued their treatment after a maximum 30‐60 s break"

Duration of treatment (intended): 30 min per day for 5 days (first cycle only)

Outcomes

• Oral mucositis: WHO 0 to 4 scale (assessed and reported on days 7, 14 and 21 ‐ i.e. not reported as maximum score per participant)

Notes

Sample size calculation: not reported

Adverse effects: "The patients completed the procedure quite comfortably, without any problems during the application"

Funding: not reported

Declarations/conflicts of interest: "None declared"

Data handling by review authors: data were reported separately on the 3 assessment days rather than a maximum score per person over the whole assessment period. We used the data on the day with the highest incidence of grades > 0 (day 14), although we are not sure how valid this is because there was still a high incidence of severe oral mucositis at day 21

Other information of note: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed by MedCalc software to give equal chance to assign each intervention group"

Comment: computer generated randomisation so probably done adequately

Allocation concealment (selection bias)

Unclear risk

Quote: "Randomisation was performed by MedCalc software to give equal chance to assign each intervention group"

Comment: insufficient information to determine whether or not the random sequence was adequately concealed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analyses

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: Seattle, USA

Number of centres: 1

Study duration: August 2003 to June 2005

Participants

Inclusion criteria: minimum age 18 years with multiple myeloma; scheduled to receive single‐agent high‐dose melphalan (200 mg/m²) followed by autologous PBSCT 2 days later

Exclusion criteria: previous autologous PBSCT

Cancer type: haematological (multiple myeloma)

Cancer treatment: high‐dose melphalan (200 mg/m²) followed by autologous PBSCT

Any other potentially important prognostic factors: not reported

Age at baseline (years): Gp A: median 59 (range 51 to 71); Gp B: median 57 (range 33 to 72)

Gender: Gp A: 76.2% male; Gp B: 63.2% male

Number randomised: 41 (Gp A: 21; Gp B: 20)

Number evaluated: 40 (Gp A: 21; Gp B: 19) (above figures for age and gender are for evaluated participants)

Interventions

Comparison: cryotherapy versus saline rinse

Gp A: 2 days before stem cell infusion, 1 ounce of ice chips held in mouth 30 min prior to beginning single‐agent high‐dose melphalan (200 mg/m²) infusion, replenished when melted, procedure continued for 6 hours after the end of the 30‐min melphalan infusion

Gp B: 2 days before stem cell infusion, 1 ounce of room temperature normal saline swished around the mouth and spat out 30 min prior to beginning single‐agent high‐dose melphalan (200 mg/m²) infusion, procedure repeated every 30 min for 6 hours after the end of the 30‐min melphalan infusion

All participants instructed not to eat or drink anything extremely hot or cold during cryotherapy/saline treatment

Compliance: 14 participants had at least 5 hours of cryotherapy, and 2 had at least 2 hours, whilst 5 did not report the duration. Some participants stopped using the ice chips due to their coldness. Average frequency of use: cryotherapy: 1 cup/hour; saline: 1 to 4 rinses/hour

Duration of treatment (intended): 7 hours

Outcomes

• Oral mucositis: NCI‐CTC 0 to 4 scale (assessed until 30 days after cryotherapy/saline administration, maximum score reported)

• Normalcy of diet: duration of TPN (assessed until 30 days after cryotherapy/saline administration)

• Duration of IV narcotic use (assessed until 30 days after cryotherapy/saline administration)

• Duration of hospitalisation (assessed until 30 days after cryotherapy/saline administration)

• Weight loss (not an outcome of this review)

• First day 30% of calorific needs met (not an outcome of this review)

Patient‐reported events:

• Mouth and throat pain: 0 to 10 scale (assessed daily by questionnaire until 30 days after cryotherapy/saline administration)

• Adverse effects of cancer treatment: difficulties swallowing, drinking, eating, talking, sleeping and taste disturbance (not outcomes of this review)

Notes

Sample size calculation: required sample size was achieved ("sample size of 40 was chosen to provide 91% power to observe a statistically significant difference (at the 2‐sided significance level of 0.05) in the probability of grades 3–4 mucositis under the assumption that the true probabilities of severe mucositis are 0.25 for patients receiving ice chips and 0.75 for patients receiving normal saline")

Adverse effects: not reported, only refers to some participants that stopped using the ice chips due to their coldness

Funding: "This work was supported by Friends of Jose Carreras International Leukemia Foundation Presidential Award, NCI P01 CA‐18029"

Declarations/conflicts of interest: not reported

Data handling by review authors: for patient‐reported oral pain, we used the mean, number of participants and P value to calculate a single SD to be used for both groups (we used the overall mean pain scores rather than the number of days of pain or the mean of the highest value); only medians and ranges presented for the outcomes days of TPN, IV narcotics and hospitalisation, so we present the results, as reported in the study report, in an additional table

Other information of note: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients...were randomized to receive either ice chips or room temperature normal saline rinses"

Correspondence: "randomisation was accomplished using a computer program designed by one of our statisticians"

Comment: adequate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "patients...were randomized to receive either ice chips or room temperature normal saline rinses"

Correspondence: "Central randomization from the protocol office"

Comment: central randomisation should have ensured that the allocation sequence was not manipulated

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 randomised participant, from the control group, was not included in the analyses. The participant withdrew consent because he wanted to use ice chips

Selective reporting (reporting bias)

Low risk

Although the data for some outcomes of this review were not presented in a way amenable to meta‐analysis, this is unlikely to be due to bias

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: cross‐over (2 arms)

Location: USA

Number of centres: unclear (multicentre)

Study duration: not reported

Participants

Inclusion criteria: first ever course of chemotherapy

Exclusion criteria: not reported

Cancer type: not reported but must be solid due to chemotherapy regimen

Cancer treatment: 5FU and LV

Any other potentially important prognostic factors: not reported

Age at baseline (years): not reported

Gender: not reported

Number randomised: 95 (Gp A: 50; Gp B: 45)

Number evaluated: 93 (Gp A: 50; Gp B: 43)

Interventions

Comparison: cryotherapy versus no treatment

Gp A: ice chips placed in mouth 5 min before receiving 5FU (425 mg/m²) and LV (20 mg/m²) by IV over a few minutes, and continuously swished around, then replenished before the previous ice had completely melted, for total 30 min, whole procedure repeated for 5 consecutive days

Gp B: 5FU (425 mg/m²) and LV (20 mg/m²) only for 5 consecutive days

All participants were asked to remove dentures

Compliance: not clearly reported. Only states "well tolerated by most patients"

Duration of treatment (intended): 30 min per day for 5 days (first cycle only)

Outcomes

• Oral mucositis: physician judgement and participant judgement both on a 0 to 4 scale (very similar to WHO scale and NCI common toxicity criteria) (physician's judgement assessed by historical means approximately 1 month after treatment initiation, maximum score reported)

• Duration of oral mucositis (not an outcome of this review)

Notes

Sample size calculation: not reported

Adverse effects: "A few patients noted mild, temporary mouth numbness or an "ice cream" headache which rapidly resolved after cessation of cryotherapy. Also, some patients ascribed nausea to the oral ice chips (the nausea may have actually been from the 5FU)"

Funding: "supported in part by Public Health Service grants...and Community Clinical Oncology Program grants"

Declarations/conflicts of interest: not reported

Data handling by review authors: we only used the data from the first treatment cycle (rather than cross‐over data); physician judgement of oral mucositis was preferred over participant judgement as we deemed that this may be more objective and less biased

Other information of note: mean oral mucositis score reported by smoking status for each group for the first cycle only (smokers had statistically significantly lower mean oral mucositis score than non‐smokers, but data not available for all participants)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Prior to therapy, patients were stratified by age and whether or not they had dentures. They were then randomized to a control arm or to receive cryotherapy"

Comment: insufficient information to determine method of random sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "Prior to therapy, patients were stratified by age and whether or not they had dentures. They were then randomized to a control arm or to receive cryotherapy"

Comment: insufficient information to determine whether or not the random sequence was adequately concealed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 2 randomised participants, both from the control group, were not included in the physician‐judged oral mucositis analyses. We do not believe that this could pose a risk of bias significant enough to have led to a distortion of the true intervention effect

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: cross‐over (2 arms)

Location: USA

Number of centres: unclear (multicentre)

Study duration: not reported

Participants

Inclusion criteria: first course of chemotherapy

Exclusion criteria: not reported

Cancer type: not reported but must be solid due to chemotherapy regimen

Cancer treatment: 5FU and LV, different dosages taken orally or by IV, equally distributed between groups due to stratification

Any other potentially important prognostic factors: participants were stratified by smoking status, dentures and institution/centre; gum condition not used for stratification but Gp B (60 min cryotherapy) had worse gums at baseline (P = 0.02)

Age at baseline (years): Gp A: median 65 (range 24 to 79); Gp B: median 65 (range 25 to 85)

Gender: Gp A: 55% male; Gp B: 51% male

Number randomised: 179 (Gp A: 90; Gp B: 89)

Number evaluated: 178 (Gp A: 89; Gp B: 89)

Interventions

Comparison: 30 min of cryotherapy versus 60 min of cryotherapy

Gp A: ice chips placed in mouth 5 min before receiving 5FU and LV, and continuously swished around, then replenished before the previous ice had completely melted, for total 30 min, whole procedure repeated for 5 consecutive days

Gp B: as above but for total 60 min

All participants were asked to remove dentures

Compliance: well tolerated with high degree of compliance. Only a few participants stopped cryotherapy early (due to nausea, headache or chills). Many participants in the 60‐min group were unhappy with the duration of cryotherapy, indicating that 30 min of cryotherapy is preferred

Duration of treatment (intended): 30 or 60 min per day for 5 days (first cycle only)

Outcomes

• Oral mucositis: physician judgement and participant judgement both on a 0 to 4 scale (very similar to WHO scale and NCI common toxicity criteria) (physician's judgement assessed by historical means approximately 1 month after treatment initiation, maximum score reported)

• Duration of oral mucositis (not an outcome of this review)

Notes

Sample size calculation: not reported

Adverse effects: only a few participants stopped cryotherapy early (due to nausea, headache or chills)

Funding: "supported in part by Public Health Service grants...from the National Cancer Institute, Department of Health and Human Services"

Declarations/conflicts of interest: not reported

Data handling by review authors: we only used the data from the first treatment cycle (rather than cross‐over data); physician judgement of oral mucositis was preferred over participant judgement as we deemed that this may be more objective and less biased

Other information of note: in exploratory analyses, age over 65 years was statistically significantly (P < 0.001) associated with severity of mucositis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomized to receive cryotherapy for either 30 or 60 minutes"

Comment: insufficient information to determine method of random sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "Patients were randomized to receive cryotherapy for either 30 or 60 minutes"

Comment: insufficient information to determine whether or not the random sequence was adequately concealed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 randomised participant, from the cryotherapy group, was not included in the analyses due to an unrelated medical problem

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: Toronto, Canada

Number of centres: 1

Study duration: May to December 2007

Participants

Inclusion criteria: minimum 18 years of age; able to read and understand instructions on oral cryotherapy and basic oral care in English; diagnosis of multiple myeloma; due to receive high‐dose melphalan (200 mg/m²); due to receive growth factors as part of treatment protocol; no pre‐existing oral disease

Exclusion criteria: previous radiotherapy to the head and neck region; amyloidosis (when abnormal proteins collect together and build up in tissues/organs) involving the heart, kidneys, or tongue; receiving investigational drugs during the trial period

Cancer type: haematological (multiple myeloma)

Cancer treatment: high‐dose melphalan (200 mg/m²) followed by autologous SCT

Any other potentially important prognostic factors: college/university educated: Gp A: 43%; Gp B: 16%; smokers: Gp A: 17%; Gp B: 9%; drinks alcohol: Gp A: 35%; Gp B: 27%

Age at baseline (years): Gp A: mean 56 (SD 8.9) (range 43 to 72); Gp B: mean 62 (SD 7.7) (range 43 to 72)

Gender: Gp A: 61% male; Gp B: 55% male

Number randomised: 46 (Gp A: 23; Gp B: 23)

Number evaluated: 45 (Gp A: 23; Gp B: 22)

Interventions

Comparison: cryotherapy versus no treatment

Gp A: on day ‐1 (the day before autologous SCT), ice chips held in mouth 5 min prior to receiving high‐dose melphalan (200 mg/m²), replenished before melted, procedure continued until 5 min after melphalan infusion, for total 60 min. Basic oral care also received (described below) from day ‐1

Gp B: on day ‐1, basic oral care began (described below)

All participants received high‐dose melphalan on day ‐1 and SCT the following day (day 0). On average, participants stayed in hospital for 14 days after SCT. During the engraftment period, patients also received similar treatment and care protocols: prophylactic antimicrobial, antiviral and antacid (day 1), and growth factor (granulocyte colony‐stimulating factor) (day 7); and basic oral care protocol (day ‐1). Oral care protocol consisted of regular oral assessment and documentation, patient education on OM, and training in oral self care (toothbrushing with Toothette sponges dipped in sodium bicarbonate mouthwash, mouthrinsing with sodium bicarbonate mouthwash, and application of moisturiser to lips and oral cavity).

Compliance: all participants were able to perform the basic oral care procedures and all participants in the cryotherapy group complied with the intervention

Duration of treatment (intended): basic oral care from day ‐1 to day 12 (14 days); oral cryotherapy for 60 min on day ‐1

Outcomes

• Oral mucositis: WHO 0 to 4 scale (assessed on days 3, 6, 9 and 12 and reported as a mean on each separate assessment day ‐ not reported for day 3 as OM had not yet developed); we requested maximum score experienced per participant over the whole study period and the author provided this data

• Oral pain: 0 to 10 VAS (assessed on days 3, 6, 9 and 12 and reported as an overall mean score)

• Duration of hospital stay (mean number of days, measured as total number of days from admission to discharge ‐ all participants were treated as inpatients)

• Normalcy of diet: functional intake of food and fluids on 1 (solids) to 5 (nothing by mouth) scale (assessed on days 3, 6, 9 and 12 and reported in a mixed‐effects regression analysis)

• Time to onset, duration and time to resolution of oral mucositis (not an outcome of this review)

• Amount of opioid analgesics used (not an outcome of this review)

Notes

Sample size calculation: 17 participants per group needed to detect an effect size of 1 (presumably the authors mean a MD of 1 on the WHO scale) at 80% power and 5% significance

Adverse effects: 4 participants (17.4%) in the cryotherapy group experienced side effects (teeth sensitivity and chills)

Funding: "The authors acknowledge the financial support of the University Health Network Nursing Research and Canadian Nurses Foundation for the successful implementation of the project"

Declarations/conflicts of interest: "The authors have nothing to disclose and declare no conflicts of interest"

Data handling by review authors: the authors provided the maximum score experienced per participant over the whole study period; we were unable to use the data on normalcy of diet

Other information of note: although the authors report that the MD of 0.71 in OM severity (at day 9) was statistically significant, they state that it is not clinically significant because most participants only had OM grades of 0 to 1; conversely, the authors report that the difference in days of hospital stay was not statistically significant, but that the difference of approximately 1 day is clinically significant; we note an error in Table 2 where the mean in the control group at day 6 should be 0.5 rather than 0.05

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Participants were allocated based on a randomization process performed by the biostatistics staff at the study site, using consecutively numbered sealed envelopes containing a computer‐generated random number list patient assignment"

Comment: adequate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "Participants were allocated based on a randomization process performed by the biostatistics staff at the study site, using consecutively numbered sealed envelopes containing a computer‐generated random number list patient assignment"

Comment: these methods should have ensured that the allocation sequence was not manipulated

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Although described as blinded, the subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 randomised participant, from the control group, was not included in the analyses due to an adverse event related to the melphalan on the day of its administration

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (3 arms)

Location: Denmark

Number of centres: unclear (appears to be multicentre)

Study duration: 2001 to 2005

Participants

Inclusion criteria: gastric or colorectal cancers; due to receive first course of chemotherapy; healthy oral mucosa

Exclusion criteria: history of head and neck radiotherapy; symptoms of any infections; history of dental or mouth discomfort when consuming hot/cold food and drinks

Cancer type: approximately 95% colorectal cancer in each group, with the remainder having gastric cancer

Cancer treatment: 5FU and LV

Any other potentially important prognostic factors: participants were stratified by age, smoking status and dentures; performance status score was equally distributed between groups

Age at baseline (years): Gp A: 40 or older = 97%, median 62 (range 36 to 84); Gp B: 40 or older = 95%, median 61 (range 30 to 81); Gp C: 40 or older = 92%, median 62 (range 28 to 82)

Gender: Gp A: 60% male; Gp B: 53% male; Gp C: 53% male

Number randomised: 225 (Gp A: 75; Gp B: 75; Gp C: 75)

Number evaluated: reported in the study: 206 (Gp A: 67; Gp B: 66; Gp C: 73); data available for OM incidence: 197 (Gp A: 63; Gp B: 64; Gp C: 70)

Interventions

Comparison: cryotherapy versus saline rinse (placebo version of chlorhexidine) versus chlorhexidine rinse

Gp A: crushed ice placed in mouth 10 min before receiving 5FU (425 mg/m²) and LV (20 mg/m²) by IV, and for 35 min after the start of infusion (total 45 min), whole procedure repeated for 5 consecutive days every 4 weeks

Gp B: same cancer treatment but saline mouthwash (with same taste additives as Gp C), 10 ml swished around the mouth for 1 min, 3 times per day for 21 days

Gp C: same cancer treatment but chlorhexidine 0.1% mouthwash, same schedule as Gp B

All participants were asked to remove dentures; participants were "instructed to continue prophylaxis in case OM occurred, which was treated according to the discretion of the respective investigators"

Compliance: (complete) Gp A: 87%; Gp B: 80%; Gp C: 75%; (partial) Gp A: 13%; Gp B: 20%; Gp C: 25%

Duration of treatment (intended): 45 min per day for 5 days per chemotherapy cycle (cryotherapy); 3 min per day for 21 days per chemotherapy cycle (chlorhexidine and saline rinses)

Outcomes

• Oral mucositis: NCI‐CTC (2.0) 0 to 4 scale (first cycle‐only reported at day 28, participants kept daily record and self‐evaluated OM by questionnaire on days 14 and 28, physician also scored OM on days 14 and 28, participant score was reported as there were no statistically significant differences between participant and physician scores, maximum score reported)

• Duration of oral mucositis (not an outcome of this review)

• Compliance (not an outcome of this review)

• Haematologic toxicity (not an outcome of this review)

Notes

Sample size calculation: considering a 15% decrease in incidence of grade 3 to 4 OM as being clinically meaningful, with 80% power and at the 5% significance level, 75 patients required per group. Therefore, considering drop‐outs, required sample size was not achieved

Adverse effects: taste disturbance: Gp A: 24/67 (36%); Gp B: 25/66 (38%); Gp C: 35/73 (48%); headache: Gp A: 14/67 (21%); Gp B: 9/66 (14%); Gp C: 10/73 (14%)

Funding: "Supported by a grant from the National University Hospitals Research Foundation in Denmark"

Declarations/conflicts of interest: not reported

Data handling by review authors: the study authors report that data were available on 206 participants, however, for OM incidence, some of this number of participants are not given a grade and are listed as 'NA' (abbreviation not explained). We subtracted the 'NA' participants from the total number of participants and have addressed this problem under 'Incomplete outcome data (attrition bias)'

Other information of note: smoking status, performance status and being aged 40 or older (underpowered ‐ only 11 participants less than 40) were not statistically significantly associated with severity of OM

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were stratified...and randomized after informed consent to 1 of 3 prophylactic regimens"

Comment: insufficient information to determine method of random sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "Patients were stratified...and randomized after informed consent to 1 of 3 prophylactic regimens"

Comment: insufficient information to determine whether or not the random sequence was adequately concealed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

High risk

For OM incidence, 12% of randomised participants were not included in the analysis (Gp A: 16%; Gp B: 15%; Gp C: 9%). Reasons are not reported but there is a potential risk of bias if this differential drop‐out is related to outcomes/prognosis

Selective reporting (reporting bias)

Low risk

Data for outcomes of this review were reported appropriately

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (2 arms)

Location: Uppsala, Sweden

Number of centres: 1

Study duration: January 2002 to August 2004

Participants

Inclusion criteria: more than 18 years of age; able to communicate in Swedish; about to receive BMT

Exclusion criteria: not reported

Cancer type: 1 participant per group had testicular cancer, the remainder had haematological cancers

Cancer treatment: type of chemotherapy prior to BMT was fairly equally distributed between groups; participants were stratified by autologous BMT (both groups 79.5%) versus allogeneic URD BMT (both groups 20.5%)

Any other potentially important prognostic factors: tobacco use equally distributed between groups (Gp A: 17.9%; Gp B: 15.4%)

Age at baseline (years): Gp A: mean 49.8 (SD 14.4); Gp B: mean 54.3 (SD 11)

Gender: Gp A: 66.7% male; Gp B: 48.7% male

Number randomised: 78 (Gp A: 39; Gp B: 39)

Number evaluated: 78 (Gp A: 39; Gp B: 39)

Interventions

Comparison: cryotherapy versus no treatment

Gp A: prior to BMT (unclear how far in advance); ice chips placed in mouth or rinsing with ice‐cold water starting 5 min before receiving chemotherapy by IV, and replenished for the duration of the chemotherapy session

Gp B: chemotherapy prior to BMT

All participants received standard oral care during BMT

Compliance: 58% to 75% of the participants reported that they kept the mouth constantly cooled for the entire duration of the chemotherapy; 71% to 100% did so more than half the time

Duration of treatment: not reported (variable and dependent on type of chemotherapy)

Outcomes

• Oral mucositis: OMAS (seeAppendix 8 for details of scale) (assessed once daily for 21 days after start of chemotherapy by nurse, mean score reported on each day, reported separately for autologous/allogeneic BMT but no overall score reported)

• Oral mucositis: WHO 0 to 4 scale (incidence of severe mucositis i.e. grade 3 to 4, assessed once daily for 21 days after start of chemotherapy) (outcome reported in secondary publication); we requested maximum score experienced per participant over the whole study period and the author provided this data

• Oral pain: 0 to 10 VAS (assessed twice daily (morning and afternoon) for 21 days after start of chemotherapy, reported verbally to nurse)

• Duration of opioid use (mean number of days, assessed over period of 31 days after start of chemotherapy from medical records)

• Duration of hospital stay (outcome reported in secondary publication) (mean number of days, assessed over period of 31 days after start of chemotherapy)

• Normalcy of diet: incidence of TPN and duration of TPN (outcome reported in secondary publication) (we used mean number of days, assessed over period of 31 days after start of chemotherapy)

• Weight loss (not an outcome of this review)

• Duration of fever (not an outcome of this review)

• Antibiotic use (not an outcome of this review)

• Total dose of opioids (not an outcome of this review)

• White blood cell counts and c‐reactive protein levels (not outcomes of this review)

Notes

Sample size calculation: 36 participants per group needed for 80% power at 5% significance level (based on outcome 'duration of IV opioids')

Adverse effects: 7 (18%) of participants found cryotherapy unpleasant, with 4 of those (10%) finding it very unpleasant due to shooting pain from the teeth

Funding: "This study was in part supported by FoU funds, Uppsala läns landsting, Sweden"

Declarations/conflicts of interest: not reported

Data handling by review authors: we were unable to use the OMAS score but the authors provided full data for oral mucositis on the WHO scale; oral pain was not reported adequately so we were unable to report on this outcome

Other information of note: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A random assignment to EXP or CTR group was performed in blocks of six outside of the clinic by an independent researcher"

Comment: if using block‐randomisation, it could be assumed that the independent researcher would have done this adequately

Allocation concealment (selection bias)

Low risk

Quote: "A random assignment to EXP or CTR group was performed in blocks of six outside of the clinic by an independent researcher"

Comment: third‐party randomisation should have ensured that the allocation sequence was not manipulated

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analyses

Selective reporting (reporting bias)

High risk

Oral mucositis using OMAS and oral pain inadequately reported. Data are presented in the text for mucositis scores on day 10 (autologous patients) and day 16 (allogeneic patients), and this appears to be based on statistical significance. The study authors have since provided full data on the WHO scale. Therefore, our rating for this domain is based on the fact that the text only states that there was no significant differences for oral pain

Other bias

Low risk

45 staff members assessed mucositis using the OMAS instrument. Calibration is not mentioned. However, we were unable to use any data for this outcome so we can discount any potential bias

Methods

Trial design: parallel (3 arms)

Location: San Antonio, Texas, USA

Number of centres: 1

Study duration: first subject randomised August 2009; last subject randomised January 2013

Participants

Inclusion criteria: minimum 18 years of age; diagnosis of multiple myeloma and scheduled to receive high‐dose melphalan (70 to 100 mg/m²/day) for 2 days, as a single agent, for conditioning regimen prior to HSCT

Exclusion criteria: received palifermin (Kepivance) in the past 30 days; received any investigational drug in the past 30 days; received radiation therapy in the past 30 days; oral mucositis at the time of randomisation; altered mental status precluding understanding of the informed consent process and/or completion of the necessary assessments

Cancer type: haematological (multiple myeloma)

Cancer treatment: high‐dose melphalan, prior to autologous HSCT

Any other potentially important prognostic factors: no differences between groups in race/ethnicity, Karnofsky performance score, diabetes, denture wearing, smoking status

Age at baseline (years): Gp A: median 62 (range 39 to 75); Gp B: median 61.5 (range 43 to 70)

Gender: both groups 95% male

Number randomised: 78 (Gp A: 40; Gp B: 38) (numbers are for the 2 groups of interest to this review)

Number evaluated: 78 (Gp A: 40; Gp B: 38)

Interventions

Comparison: cryotherapy plus saline rinse versus saline rinse

The 3rd group involved using supersaturated calcium phosphate rinse (Caphosol®) but we have excluded this arm because the co‐intervention of cryotherapy plus saline may confound the comparison. The comparison of this 3rd group with the saline group will be included in our review of basic oral care interventions for the prevention of oral mucositis in cancer patients

Gp A: on day ‐2 and ‐1 (HSCT was on day 0), approximately 1 ounce of crushed ice held in the mouth 15 min prior to the initiation of melphalan infusion, replenished as soon as it had completely melted, this procedure continued during the melphalan infusion and for 90 min after the end of the infusion. After completion of cryotherapy, standard care was followed until the end of the study (see Gp B below)

Gp B: standard care (0.9% sodium chloride irrigation solution): rinsing of mouth twice, with 1 ounce (30 ml) of room temperature 0.9% NaCl (normal saline), 4 times daily after admission and until end of study

Compliance: 100% compliance with cryotherapy but 3 subjects from the saline group refused to follow protocol but were kept in study

Duration of treatment (intended): 2 consecutive days (exact duration of cryotherapy sessions unclear)

Outcomes

• Oral mucositis: WHO 0 to 4 scale (assessed daily until resolution or hospital discharge up to a maximum of 30 days, maximum score reported)

• Oral pain: scale not reported

• Narcotic use: unclear whether or not reported as duration of opioid use or amount of opioid use

• Quality of life: Patient‐Reported Oral Mucositis Symptom (PROMS) scale (assessed daily until resolution of oral mucositis)

• Duration of oral mucositis (not an outcome of this review)

Notes

Sample size calculation: "This study will achieve a power of 80% to detect a 0.30 reduction in the proportion of subjects experiencing mucositis relative to saline with 55 subjects per arm and relative to Caphosol with 43 subjects per arm, using 2‐sided pairwise Pearson chi‐square testing with the Bonferroni corrected significance level of 0.017 (PASS, Version 08.0.8, NCSS Kaysville, Utah 2008). Assuming no loss to follow‐up and complete data, the required sample size for this study is therefore 55 subjects per arm, giving a total required sample size of 165 subjects. The study was terminated early because of ethical concerns after an interim analysis"

Adverse effects: no serious adverse events

Funding: "There was no outside funding for this study"

Declarations/conflicts of interest: "No conflict of interest for all authors"

Data handling by review authors: the oral mucositis incidence of each WHO grade was presented as percentages so we converted this to numbers of persons experiencing each grade

Other information of note: only abstracts available but the authors have provided extra information through email correspondence to allow inclusion in this review. Study report is currently being written up and secondary outcome data have not yet been analysed, so we will include these in the next update of the review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "were randomized to the above mentioned groups"

Correspondence: "The computer program used to generate these sheets makes block stratified assignments with user selected block size"

Comment: adequate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "were randomized to the above mentioned groups"

Correspondence: "The random sequence list was kept at the principal investigator's office and only when a subject had signed the informed consent and agrees to participate in any of the three arms of the study, was the research co‐ordinator able to look at the list and assigned the treatment"

Comment: these methods should have ensured that the allocation sequence was not manipulated

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scale used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analyses

Selective reporting (reporting bias)

Low risk

This domain is not yet applicable as the study report is currently being written up

Other bias

Low risk

No other sources of bias are apparent

Methods

Trial design: parallel (4 arms)

Location: Beijing, China

Number of centres: 1

Study duration: June 2009 to May 2010

Participants

Inclusion criteria: patients due to receive high‐dose MTX

Exclusion criteria: not reported

Cancer type: osteosarcoma (bone cancer)

Cancer treatment: MTX plus vincristine plus LV

Any other potentially important prognostic factors: not reported

Age at baseline (years): not reported

Gender: not reported

Number randomised: 147 (Gp A: 52; Gp B: 66; Gp C: 29) (numbers are for the 3 groups of interest to this review)

Number evaluated: 147 (Gp A: 52; Gp B: 66; Gp C: 29)

Interventions

Comparison: cryotherapy versus LV versus high dose LV

The 4th group involved using the standard LV dose once OM symptoms appeared. This constitutes treatment rather than prevention and therefore we excluded this arm

Gp A: from the start of MTX, 100 ml ice water to be used for gargling (amount per gargle and frequency of gargling not specified), for 3 consecutive days

Gp B: from the start of MTX, 3 mg LV dissolved in 100 ml water to be used for gargling per day, for 3 consecutive days (amount per gargle not specified)
Gp C: from the start of MTX, 200 mg LV dissolved in 40 ml water to be used for gargling per day (10 ml 4 times daily), for 3 consecutive days

All participants received MTX (10 g/m² administered by IV over 4 to 6 hours), vincristine (2 mg), and LV (12 mg every 6 hours, beginning 6 to 8 hours after finishing the MTX IV drop ‐ it is not clear from the translation of the paper how long this occurred for or indeed if was just a single dose 6 to 8 hour after MTX). From 1 day prior to the start of MTX, participants had diuresis and alkalinising for 3 consecutive days, plus oral sodium bicarbonate (1 g) and allopurinol (200 mg) both 3 times daily for 4 consecutive days

Compliance: not reported

Duration of treatment (intended): 3 days (actual length of time the ice water or LV was held in the mouth is not reported)

Outcomes

• Oral mucositis: WHO and NCI‐CTC (3.0) 0 to 4 scale (assessed 1 and 10 days after start of chemotherapy ‐ reported as incidence of any OM over the study period and also by severity on the 4th day after MTX)

• Duration of oral mucositis (not an outcome of this review)

• MTX concentration in saliva (not an outcome of this review)

Notes

Sample size calculation: not reported

Adverse effects: not reported

Funding: not reported/not obtained from translation

Declarations/conflicts of interest: not reported/not obtained from translation

Data handling by review authors: we have used the data from Table 1 for the analysis of no mucositis versus any mucositis as this appears to be the incidence of any mucositis over the whole study period, and is therefore not at risk of bias; we have used the data on severity at day 4 but it may be at risk of bias due to selective reporting and readers should take this into consideration when interpreting the results

Other information of note: it is unclear why the authors report OM severity at day 4, after they state that symptoms usually occur 5 to 7 days after chemotherapy. No participants had severe OM (grades 3 or 4) on day 4. If any participants developed severe OM after day 4, then the study will not reflect this and the incidence of severe OM in this type of study will have been underestimated. We would recommend that authors report the maximum grade experienced by each participant in future publications, or at least report a range of appropriate time points

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were randomly allocated to 4 groups using a random number table"

Comment: random sequence appears to have been adequately generated

Allocation concealment (selection bias)

Unclear risk

Quote: "patients were randomly allocated to 4 groups using a random number table"

Comment: insufficient information to determine whether or not the random sequence was adequately concealed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not possible to blind participants and personnel to allocated groups

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The subjective elements in the scales used to measure oral mucositis could have introduced bias into the assessments

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were included in the analyses

Selective reporting (reporting bias)

High risk

Oral mucositis was measured on the day of chemotherapy and on day 10, but severity is reported on day 4

Other bias

Low risk

No other sources of bias are apparent