Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors

Philip Riley; Anne‐Marie Glenny; Helen V Worthington; Anne Littlewood; Luisa M Fernandez Mauleffinch; Jan E Clarkson; Martin G McCabe

doi:10.1002/14651858.CD011990.pub2

. 2017 Nov 28;2017(11):CD011990. doi: 10.1002/14651858.CD011990.pub2

Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors

Philip Riley ^1,^✉, Anne‐Marie Glenny ², Helen V Worthington ¹, Anne Littlewood ¹, Luisa M Fernandez Mauleffinch ¹, Jan E Clarkson ³, Martin G McCabe ⁴

Editor: Cochrane Oral Health Group

PMCID: PMC6486203 PMID: 29181845

Abstract

Background

Oral mucositis is a side effect of chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high‐risk patients. Ulceration can lead to severe pain and difficulty with eating and drinking, which may necessitate opioid analgesics, hospitalisation and supplemental nutrition. These complications may disrupt cancer therapy, which may reduce survival. There is also a risk of death from sepsis if pathogens enter the ulcers of immunocompromised patients. Ulcerative oral mucositis can be costly to healthcare systems, yet there are few preventive interventions proven to be beneficial. Cytokines and growth factors may help the regeneration of cells lining of the mouth, thus preventing or reducing oral mucositis and its negative effects.

Objectives

To assess the effects of cytokines and growth factors for preventing oral mucositis in patients with cancer who are receiving treatment.

Search methods

Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (searched 10 May 2017); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4) in the Cochrane Library (searched 10 May 2017); MEDLINE Ovid (1946 to 10 May 2017); Embase Ovid (7 December 2015 to 10 May 2017); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 10 May 2017); and CANCERLIT PubMed (1950 to 10 May 2017). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials.

Selection criteria

We included parallel‐design randomised controlled trials (RCTs) assessing the effects of cytokines and growth factors in patients with cancer receiving treatment.

Data collection and analysis

Two review authors independently screened the results of electronic searches, extracted data and assessed risk of bias. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, we reported mean differences (MD) and 95% CIs. We pooled similar studies in random‐effects meta‐analyses. We reported adverse effects in a narrative format.

Main results

We included 35 RCTs analysing 3102 participants. Thirteen studies were at low risk of bias, 12 studies were at unclear risk of bias, and 10 studies were at high risk of bias.

Our main findings were regarding keratinocyte growth factor (KGF) and are summarised as follows.

There might be a reduction in the risk of moderate to severe oral mucositis in adults receiving bone marrow/stem cell transplantation after conditioning therapy for haematological cancers (RR 0.89, 95% CI 0.80 to 0.99; 6 studies; 852 participants; low‐quality evidence). We would need to treat 11 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 6 to 112). There might be a reduction in the risk of severe oral mucositis in this population, but there is also some possibility of an increase in risk (RR 0.85, 95% CI 0.65 to 1.11; 6 studies; 852 participants; low‐quality evidence). We would need to treat 10 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 5 to prevent the outcome to 14 to cause the outcome).

There is probably a reduction in the risk of moderate to severe oral mucositis in adults receiving radiotherapy to the head and neck with cisplatin or fluorouracil (RR 0.91, 95% CI 0.83 to 1.00; 3 studies; 471 participants; moderate‐quality evidence). We would need to treat 12 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 7 to infinity). It is very likely that there is a reduction in the risk of severe oral mucositis in this population (RR 0.79, 95% CI 0.69 to 0.90; 3 studies; 471 participants; high‐quality evidence). We would need to treat 7 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 5 to 15).

It is likely that there is a reduction in the risk of moderate to severe oral mucositis in adults receiving chemotherapy alone for mixed solid and haematological cancers (RR 0.56, 95% CI 0.45 to 0.70; 4 studies; 344 participants; moderate‐quality evidence). We would need to treat 4 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 3 to 6). There might be a reduction in the risk of severe oral mucositis in this population (RR 0.30, 95% CI 0.14 to 0.65; 3 studies; 263 participants; low ‐quality evidence). We would need to treat 10 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 8 to 19).

Due to the low volume of evidence, single‐study comparisons and insufficient sample sizes, we found no compelling evidence of a benefit for any other cytokines or growth factors and there was no evidence on children. There did not appear to be any serious adverse effects of any of the interventions assessed in this review.

Authors' conclusions

We are confident that KGF is beneficial in the prevention of oral mucositis in adults who are receiving: a) radiotherapy to the head and neck with cisplatin or fluorouracil; or b) chemotherapy alone for mixed solid and haematological cancers. We are less confident about a benefit for KGF in adults receiving bone marrow/stem cell transplant after conditioning therapy for haematological cancers because of multiple factors involved in that population, such as whether or not they received total body irradiation (TBI) and whether the transplant was autologous (the patients' own cells) or allogeneic (cells from a donor). KGF appears to be a relatively safe intervention.

Due to limited research, we are not confident that there are any beneficial effects of other cytokines and growth factors. There is currently insufficient evidence to draw any conclusions about the use of cytokines and growth factors in children.

Plain language summary

Can cytokines and growth factors help prevent mouth soreness and ulcers (oral mucositis) in patients being treated for cancer?

Review question

This review has been produced to assess whether or not the use of cytokines and growth factors during cancer treatment, can help prevent mouth soreness and ulcers.

Background

Sore mouth and ulcers (oral mucositis) is a side effect of treatment for cancer including chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high‐risk patients. Ulcers can lead to severe pain and difficulty with eating and drinking. Sufferers may need strong painkillers, possibly have to go into hospital and even be fed through a tube into their stomach or their veins.

These complications may disrupt their cancer therapy, meaning they are not receiving the best treatment, which may reduce survival. Cancer patients have weakened immune systems due to their treatment and are less able to fight infections. An ulcer is an open wound and there is a risk that bacteria can enter the body leading to infection or sepsis (a dangerous inflammatory reaction of the body to infection).

Mouth soreness and ulcers can be costly to healthcare systems, yet there are few preventive interventions or treatments proven to be beneficial. Cytokines and growth factors may help the regeneration of cells lining the mouth, thus preventing or reducing oral mucositis and its negative effects.

Study characteristics

Authors from Cochrane Oral Health carried out this review of existing studies and the evidence is current up to 10 May 2017. It includes 35 studies (published between 1993 and 2017) with 3102 participants, all patients being treated for cancer, aged from 1 to 87 years old. Review authors included studies comparing cytokines and growth factors for the prevention of oral mucositis. The studies were carried out all over the world and often featured multiple sites, although most took place in high‐income countries.

Main results

The main findings were regarding keratinocyte growth factor (KGF). KGF is likely to reduce the risk of oral mucositis in adults who are receiving either radiotherapy to the head and neck with chemotherapy (cisplatin or fluorouracil), or chemotherapy alone for mixed solid and blood cancers. KGF may also reduce the risk of oral mucositis in adults receiving bone marrow/stem cell transplant after conditioning therapy for blood cancers, but these results are less clear because of multiple complicating factors. KGF appears to be a relatively safe intervention. There did not appear to be any serious adverse effects of any of the interventions assessed in this review.

Due to limited research, review authors are uncertain of any beneficial effects of other cytokines and growth factors. There is currently insufficient evidence to draw any conclusions about the use of cytokines and growth factors in children.

Quality of the evidence

For reducing oral mucositis in adults receiving radiotherapy to the head and neck with chemotherapy, review authors rated the evidence for KGF as moderate to high quality. For reducing oral mucositis in adults receiving chemotherapy alone for mixed solid and blood cancers, they rated the evidence for KGF as low to moderate quality. This evidence was downgraded due to there not being enough data and because some results have not yet been published. For reducing oral mucositis in adults receiving bone marrow/stem cell transplant after conditioning therapy for blood cancers, they rated the evidence for KGF as low quality because results were not similar across the studies and some results have not yet been published. Evidence on side effects of KGF was poorly reported and inconsistent.

Summary of findings

Summary of findings for the main comparison. Keratinocyte growth factor (KGF) compared to placebo for preventing oral mucositis in adults with cancer receiving treatment.

KGF compared to placebo for preventing oral mucositis in adults with cancer receiving treatment
Patient or population: adults^ receiving treatment for cancer (see subgroup for treatment type)  Setting: hospital  Intervention: KGF  Comparison:** placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with KGF
Oral mucositis (moderate + severe)	BMT/SCT after conditioning for haematological cancers		RR 0.89  (0.80 to 0.99)	852  (6 studies)	⊕⊕⊝⊝  LOW¹	There might be a benefit for KGF in this population NNTB = 11 (95% CI 6 to 112)
	848 per 1000	755 per 1000  (678 to 839)
	RT to head and neck with cisplatin/5FU		RR 0.91  (0.83 to 1.00)	471  (3 studies)	⊕⊕⊕⊝  MODERATE²	There is probably a benefit for KGF in this population NNTB = 12 (95% CI 7 to ∞)
	932 per 1000	848 per 1000  (773 to 932)
	CT alone for mixed cancers		RR 0.56  (0.45 to 0.70)	344  (4 studies)	⊕⊕⊕⊝  MODERATE³	It is likely that there is a benefit for KGF in this population NNTB = 4 (95% CI 3 to 6)
	631 per 1000	353 per 1000  (284 to 441)
Oral mucositis (severe)	BMT/SCT after conditioning for haematological cancers		RR 0.85  (0.65 to 1.11)	852  (6 studies)	⊕⊕⊝⊝  LOW⁴	There might be a benefit for KGF in this population, but there is also some possibility of an increase in risk NNTB = 10 (95% CI 5 NNTB to 14 NNTH)
	677 per 1000	575 per 1000  (440 to 751)
	RT to head and neck with cisplatin/5FU		RR 0.79  (0.69 to 0.90)	471  (3 studies)	⊕⊕⊕⊕  HIGH	It is very likely that there is a benefit for KGF in this population NNTB = 7 (95% CI 5 to 15)
	700 per 1000	553 per 1000  (483 to 630)
	CT alone for mixed cancers		RR 0.30  (0.14 to 0.65)	263  (3 studies)	⊕⊕⊝⊝  LOW⁵	There might be a benefit for KGF in this population NNTB = 10 (95% CI 8 to 19)
	154 per 1000	46 per 1000  (22 to 100)
Adverse events	Adverse events that were attributed to the study drugs rather than the cancer therapy were typically oral‐related or skin‐related. Events were mostly mild to moderate with very few incidences of serious events. However, reporting was poor and inconsistent, meaning that it was not appropriate to meta‐analyse data
^The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  ^Only 1 study in the subgroup BMT/SCT after conditioning for haematological cancers' included some children (but the median age of participants was 46 years). ^The number of people that would need to receive KGF in order to prevent 1 additional person from developing the outcome. Calculated as 1 divided by the absolute risk reduction (which is the control arm event rate minus the experimental arm event rate). NNTH means the number of people that would need to receive KGF to cause 1 additional person to develop the outcome. All decimal places have been rounded up to the nearest whole number (i.e. 6.1 = 7).    ∞: infinity; 5FU: fluorouracil; BMT: bone marrow transplantation; CI: confidence interval; CT: chemotherapy; KGF: keratinocyte growth factor; NNTB: number needed to treat to benefit^; NNTH:* number needed to treat to harm; RR: risk ratio; RT: radiotherapy; SCT: stem cell transplantation.
GRADE Working Group grades of evidence   High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

GM‐CSF compared to placebo/no treatment for preventing oral mucositis in adults with cancer receiving treatment
Patient or population: adults^ receiving treatment for cancer (see subgroup for treatment type)  Setting: hospital  Intervention: GM‐CSF  Comparison:** placebo/no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with placebo/no treatment	Risk with GM‐CSF
Oral mucositis (moderate + severe)	BMT/SCT after conditioning for haematological cancers		RR 0.94  (0.79 to 1.13)	109  (1 study)	⊕⊝⊝⊝  VERY LOW¹	There is insufficient evidence to determine a benefit for GM‐CSF in this population NNTB = 20 (95% CI 6 NNTB to 10 NNTH)
	839 per 1000	789 per 1000  (663 to 948)
	RT to head and neck		RR 0.72  (0.49 to 1.06)	29  (1 study)	⊕⊝⊝⊝  VERY LOW²	There is insufficient evidence to determine a benefit for GM‐CSF in this population NNTB = 4 (95% CI 3 NNTB to 14 NNTH)
	929 per 1000	669 per 1000  (455 to 984)
Oral mucositis (severe)	BMT/SCT after conditioning for mixed cancers		RR 0.74  (0.33 to 1.67)	235  (3 studies)	⊕⊕⊝⊝  LOW³	There is insufficient evidence to determine a benefit for GM‐CSF in this population NNTB = 12 (95% CI 5 NNTB to 5 NNTH)
	347 per 1000	257 per 1000  (115 to 580)
	RT to head and neck		RR 0.31  (0.01 to 7.09)	29  (1 study)	⊕⊝⊝⊝  VERY LOW⁴	There is insufficient evidence to determine a benefit for GM‐CSF in this population NNTB = 21 (95% CI 15 NNTB to 3 NNTH)
	71 per 1000	22 per 1000  (1 to 506)
	CT alone for mixed cancers		RR 0.59  (0.05 to 7.11)	65  (2 studies)	⊕⊝⊝⊝  VERY LOW⁵	There is insufficient evidence to determine a benefit for GM‐CSF in this population NNTB = 5 (95% CI 3 NNTB to 2 NNTH)
	500 per 1000	295 per 1000  (25 to 1000)
Adverse events	Adverse events that were attributed to the study drugs rather than the cancer therapy were typically bone pain, nausea, fever and headache. Events were not reported as being serious. Some studies did not report adverse events and 1 even reported that there were none. However, reporting was poor and inconsistent, meaning that it was not appropriate to meta‐analyse data
^The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  ^There were no studies conducted on children. ^The number of people that would need to receive GM‐CSF in order to prevent 1 additional person from developing the outcome. Calculated as 1 divided by the absolute risk reduction (which is the control arm event rate minus the experimental arm event rate). NNTH means the number of people that would need to receive GM‐CSF to cause 1 additional person to develop the outcome. All decimal places have been rounded up to the nearest whole number (i.e. 6.1 = 7).    BMT: bone marrow transplantation; CI: confidence interval; CT: chemotherapy; GM‐CSF: granulocyte‐macrophage colony‐stimulating factor; NNTB: number needed to treat to benefit^; NNTH:* number needed to treat to harm; RR: risk ratio; RT: radiotherapy; SCT: stem cell transplantation.
GRADE Working Group grades of evidence   High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

G‐CSF compared to placebo/no treatment for preventing oral mucositis in patients with cancer receiving treatment
Patient or population: adults^ receiving treatment for cancer (see subgroup for treatment type)  Setting: hospital   Intervention: G‐CSF  Comparison:** placebo/no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with placebo/no treatment	Risk with G‐CSF
Oral mucositis (moderate + severe)	CT alone for breast cancer		RR 0.33  (0.12 to 0.95)	14  (1 study)	⊕⊝⊝⊝  VERY LOW¹	There is very weak evidence that there might be a benefit for G‐CSF in this population NNTB = 2 (95% CI 2 to 20)
	1000 per 1000	330 per 1000  (120 to 950)
Oral mucositis (severe)	RT to head and neck		RR 0.37  (0.15 to 0.87)	54  (2 studies)	⊕⊕⊝⊝  LOW²	There is weak evidence that there might be a benefit for G‐CSF in this population NNTB = 3 (95% CI 3 to 15)
	519 per 1000	192 per 1000  (78 to 451)
Adverse events	There was limited evidence of adverse events for G‐CSF. 2 of the 6 studies did not report adverse events. There were low rates of mild to moderate events, the most common of which appeared to be bone pain. However, reporting was poor and inconsistent, meaning that it was not appropriate to meta‐analyse data
^The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  ^There were no studies conducted on children. ^The number of people that would need to receive G‐CSF in order to prevent 1 additional person from developing the outcome. Calculated as 1 divided by the absolute risk reduction (which is the control arm event rate minus the experimental arm event rate). NNTH means the number of people that would need to receive G‐CSF to cause 1 additional person to develop the outcome. All decimal places have been rounded up to the nearest whole number (i.e. 6.1 = 7).    CI: confidence interval; CT: chemotherapy; G‐CSF: granulocyte‐colony stimulating factor; NNTB: number needed to treat to benefit^; NNTH:* number needed to treat to harm; RR: risk ratio; RT: radiotherapy.
GRADE Working Group grades of evidence   High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Study ID	Adverse events results
Blazar 2006	AEs with incidence ≥ 10% greater in KGF group: higher rate of skin rash in KGF group (65/69 versus 21/31; RR 1.39, 95% CI 1.08 to 1.79; P = 0.01). Insufficient evidence of a difference in edema, infection, or local pain Grade 3 to 4 (WHO and NCI‐CTC 0 to 4 toxicities scales) AEs with higher incidence in KGF group: insufficient evidence of a difference in skin reactions, diarrhoea, local pain, or cardiac events
Blijlevens 2013	KGF‐related AE (NCI‐CTC): higher rate in KGF group (141/220 versus 17/57; RR 2.15, 95% CI 1.43 to 3.24; P = 0.0003) KGF‐related serious AE (no definition of 'serious' given) (NCI‐CTC): insufficient evidence of a difference (4/220 versus 0/57; P = 0.56) KGF‐related severe AE (NCI‐CTC grade 3, 4 or 5) (grade 5 = death): insufficient evidence of a difference (23/220 versus 0/57; P = 0.08)
Bradstock 2014	Insufficient evidence of a difference in infection or Grade 3 to 4 (NCI‐CTC 0 to 4 toxicity scale) skin rash/desquamation
Brizel 2008	The study authors state that most adverse events were considered to be caused by the cancer treatment or the underlying cancer itself and not related to study treatment. 2 participants in the palifermin group had serious adverse events considered to be related to the intervention: 1 had increased sputum production; the other had dehydration, dysphagia, pain (including abdominal), pancreatitis, and subsequently had schistosomiasis
Fink 2011	Total of 28 side effects in palifermin group occurring in 11 of 22 patients (50%) who received at least 4 of the 6 doses. Most frequent (90.9%) were cases of erythema or exanthema, often associated with itching (54.5%). Often (54.5%) a swelling of the oral mucosa including the tongue occurred. In 4 out of 6 patients, this was accompanied by taste disturbance. The severity of side effects were classified as mild to moderate. The CTC Grade 3 occurred only once in the form of a strong heat sensation In 1 of the 11 cases, there was premature discontinuation of palifermin due to severe facial swelling with eyelid and laryngeal pain as well as painful swelling of the hands following the second injection
Freytes 2004	25 different adverse events were reported and were mostly not KGF‐related. There was insufficient evidence of a difference for diarrhoea, abdominal pain, infection or rash
Gholizadeh 2016	"..two patients reported knee joint pain, skin rash was observed in one patient, two patients had abnormal taste, and one showed lingual mucosal thickening" (control group was chlorhexidine mouthrinse. The authors do not report the events by treatment group)
Henke 2011	"Initially, patients were allocated to three arms: palifermin (180 g/kg/wk) throughout radiochemotherapy (ie, for at least seven doses); palifermin (180 g/kg/wk) for four doses and then placebo throughout the remainder of radiochemotherapy; or placebo throughout radiochemotherapy. However, after one serious adverse event of respiratory insufficiency was reported in one of the first 10 patients, the data monitoring committee concluded that the study should be restarted with a lower palifermin dose (120 g/kg/wk)" "Most patients (97%) experienced at least one adverse event......One serious adverse event (febrile neutropenia) considered related to study drug was reported for one patient in the palifermin arm"
Jagasia 2012	KGF‐related AEs with incidence ≥ 5% in KGF group: higher rate of gastrointestinal disorders in KGF group (18/78 versus 2/73; RR 8.42, 95% CI 2.02 to 35.04; P = 0.003). Insufficient evidence of a difference in any AE, tongue coating, tongue disorder, skin and subcutaneous tissue disorders, rash, pruritus, or erythema
Le 2011	"Study drug–related AEs were reported for 35% of palifermin and 11% of placebo patients. The most frequent study drug–related AEs (palifermin, placebo) were rash (9%, 2%), flushing (5%, 0%), dysgeusia (5%, 1%), nausea (4%, 1%),and vomiting (3%, 1%). None of these events led to study withdrawal. Serious AEs considered related to study treatment were reported for five palifermin patients (5%; one each with necrotic pancreatitis, hypersensitivity, tracheostomy malfunction, peritoneal carcinoma, and convulsion) and two placebo patients (2%; one each with hepatitis/hepatic enzyme increase and cryptogenic organizing pneumonia)"
Lucchese 2016a	"The administration of palifermin was generally safe and without considerable complications. The only adverse reactions were rashes (lasting for 48–72 hours) localized to the face, upper neck and shoulders, erythema, and altered taste (consistent with the pharmacologic action of palifermin of oral epithelium and skin), most of which were of NCI grade 1 or 2 severity"
Lucchese 2016b	"The administration of palifermin was mostly safe and without substantial complications. The mean duration of the OM and the number of adverse event was significant less in the palifermin group (Tables II, III, Figure 1). The main adverse episodes were erythema, cutaneous rashes and altered taste and three of the patients in the palifermin group showed a light thickness of the tongue, mouth and palate"
Meropol 2003	"Although the predefined frequency of DLTs attributable to KGF was not reached with KGF doses between 1 and 80 µg/kg/d, there were three adverse reactions involving the skin that required discontinuation of KGF in the 18 patients treated with 60 or 80 µg/kg (Table 5). Overall, skin and oral adverse events (rash, flushing, pruritis, edema, hypoesthesia, paresthesia, tongue disorder [thickening], and alteration in taste sensation) attributed to KGF occurred in 13 of 18 patients treated with 60 and 80 µg/kg of KGF (eight patients, grade 1; four patients, grade 2; and one patient, grade 3) and in three of 11 patients treated with 40 µg/kg (all grade 1). These events were reported in 16 of 39 patients (41%) dosed with KGF at > 20 µg/kg/d, whereas these symptoms were reported in only two of 21 subjects (10%) treated with placebo. The skin and oral toxicities associated with KGF were generally mild to moderate in severity, with onset approximately 36 hours after the first dose of KGF and resolution 7 to 10 days thereafter"
Rosen 2006	"As expected based on the pharmacologic activity of palifermin, oral‐related AEs were reported more frequently in palifermin than in patients receiving placebo (Table 3). During cycle 1, 50% of patients receiving palifermin experienced an oral‐related AE, compared with 33% of patients receiving placebo (P = 0.13). Similarly, 56% of patients receiving palifermin during the second chemotherapy cycle had at least one oral‐related AE, compared with 38% of patients receiving placebo (P = 0.26). The overall incidences of skin‐related AEs, reported as a palifermin‐related AE in other clinical settings, were comparable between the two treatment groups (Table 3). During cycle 1, skin‐related AEs were 56% in the placebo group versus 43% in patients receiving palifermin. During cycle 2, these incidences between the two groups were comparable (palifermin, 52%; placebo, 50%)" There were no serious KGF‐related AEs in either group and either cycle
Spielberger 2004	"The incidence, frequency, and severity of adverse events were similar in the two groups, and most were attributable to the underlying cancer, cytotoxic chemotherapy, or total‐body irradiation. Those that occurred with an incidence that was at least 5 percentage points higher in the palifermin group than in the placebo group are listed in Table 3. Most of these adverse events were consistent with the pharmacologic action of palifermin on skin and oral epithelium (e.g., rash, pruritus, erythema, paresthesia, mouth and tongue disorders, and taste alteration). All these events were mild to moderate in severity, transient (occurring approximately three days after the third dose of palifermin and lasting approximately three days), and not a cause for the discontinuation of study drug. Serious adverse events considered to be related to treatment occurred in one palifermin recipient (rash) and one placebo recipient (hypotension)"
Vadhan‐Raj 2010	"Many patients who received palifermin sensed thickening of the oral mucosa and tongue" (first 2 blinded cycles: 72% versus 31%, P = 0.007) "Treatment with palifermin was well tolerated. Table 3 shows the common adverse effects that occurred during the first 2 blinded cycles, which included symptoms of thickness of oral mucosa, tongue, and lips (Figure 4); altered taste; flushing; warm sensation; and increased saliva. These adverse effects were mild to moderate and transient in nature. Similar side effects were observed during later cycles...but they did not worsen in severity"

Study ID	Adverse events results
Cartee 1995	2 participants (group allocation not reported) withdrew by day 3 due to intolerance to their mouthwash (dry mouth); 1 participant receiving GM‐CSF (1 µg/mL) had mouthwash withdrawn by day 3 due to possible allergic reaction (sensation of fullness in the posterior pharyngeal area) but resolved within 4 hours (the participant was withdrawn but appears to have been included in the analysis)
Chi 1995	"One patient had fever and chills, and two patients had general malaise and headache during GM‐CSF treatment. No patient had evidence of fluid retention after GM‐CSF"
Dazzi 2003	Not reported
Makkonen 2000	(Sucralfate given to both groups) "Only 2 of the 20 patients treated with GM‐CSF and sucralfate did not experience any side effects related to the drugs, but most side effects were mild (WHO Grade 1 or 2). The most common side effects were local skin reactions, fever, bone pain, and mild nausea...In the control group only 1 patient complained of nausea possibly related to the use of sucralfate, and another patient interrupted sucralfate treatment because of the same reason"
McAleese 2006	"12 patients who received GM‐CSF had elevated white cell counts (WCC). The range of maximal WCC was 7.2–30.5 (median 19.7). All WCC had returned to normal within 3 weeks of completing injections (median 2 weeks). Three patients developed influenza‐like symptoms with the GM‐CSF and in one patient the injections were stopped because of this symptom. One patient developed an erythematous rash at his injection sites after completing his course of 14 injections (Figure 3). He had a past history of allergy to radiographic contrast medium"
Nemunaitis 1995	"The incidences of grades III or IV toxicities between rhGM‐CSF or placebo occurring with a > 10% frequency included anorexia (38% vs. 36%), nausea (26% vs. 29%), diarrhea (19% vs. 7%), stomatitis (19% vs. 14%) and hypertension (13% vs. 20%)" "The following events were reported with higher frequency in the rhGM‐CSF group compared with placebo: diarrhea (81% vs. 66%), bone pain (21% vs. 5%), abdominal pain (38% vs. 23%), vomiting (70% vs. 57%), pharyngitis (23% vs. 13%), pruritis (23% vs. 13%) and occular hemorrhage (11% vs. 0%)" "Placebo‐treated patients had higher occurrence of unspecified pain (36% vs. 17%), back pain (18% vs. 9%), peripheral edema (21% vs. 15%), hematuria (21% vs. 9%) and pneumonia (7% vs. 0%)"
Saarilahti 2002	(Comparator was sucralfate) "Both mouthwashes were well tolerated, and none of the patients reported any adverse effects related to the mouthwashes. Adverse effects commonly associated with subcutaneous GM‐CSF administration, such as nausea, vomiting, bone pain, headaches, and fever, were not observed"
van der Lelie 2001	Not reported

Study ID	Population	Outcome	GM‐CSF	Placebo	Result
Linch 1993	BMT/SCT after conditioning for haematological cancers	Oral mucositis: no scale described	No data	No data	"There was no difference in the frequency of stomatitis (defined as a sore, infected or ulcerated mouth, lips or pharynx), the incidence being between 29 and 33% in all groups"

Study ID	Adverse events results
Cesaro 2013	"Both pegfilgrastim and filgrastim were well tolerated and no significant adverse effects were associated with their use" (G‐CSF versus G‐CSF)
Crawford 1999	Approximately 20% of participants receiving G‐CSF experienced mild to moderate skeletal pain which was resolved by using oral analgesics; 6% of participants in both groups reported mild generalised rash/itching; 3 participants experienced an event thought to be G‐CSF‐related and which caused them to request withdrawal from the study: abdominal pain, diffuse aches and pains, and a flare‐up of pre‐existing eczema
Katano 1995	Not reported
Linch 1993	"There was no difference in the overall frequency of adverse clinical or laboratory events between the groups or in the frequency of adverse events thought by the clinicians to be possibly or probably due to study medication"
Schneider 1999	Not reported
Su 2006	"In general, toxicities typical of postoperative RT to the head and neck were observed. Additional toxicities attributable to G‐CSF and/or daily injections were as follows: elevated WBC requiring G‐CSF dose reduction by prospectively planned guidelines occurred in nine patients in the GCSF arm; grade 2–3 bone pain was observed in two patients in the G‐CSF arm; three patients refused injection (2 G‐CSF, 1 placebo)"

Study ID	Adverse events results
Kim 2017	"Adverse events were similar in both groups (Table 3). The most common adverse event in the rhEGF group was nausea (n = 7, 10.4%). The incidence of other adverse events including oral pain, dry mouth, and taste alteration was low. All the adverse events were mild and transient. No grade 3 or 4 adverse events were noted during the study period" (there were no differences between groups in any adverse event)
Wu 2009	"The frequency of minor and serious adverse events was similar in all groups. Most adverse events were related to primary disease status and treatment modalities"

Oral cavity ulceration		Oral cavity erythema
Grade 0	No lesion	Grade 0	None
Grade 1	Lesion < 1 cm²	Grade 1	Not severe
Grade 2	Lesion 1 cm² to 3 cm²	Grade 2	Severe
Grade 3	Lesion > 3 cm²	‐	‐

Grade 0	No mucositis
Grade 1	Painless ulcers, erythema or mild soreness
Grade 2	Painful erythema, edema, or ulcers, but can eat
Grade 3	Painful erythema, edema, or ulcers, and cannot eat
Grade 4	Requires parenteral or enteral support

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Oral mucositis (any)	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 BMT/SCT after conditioning for haematological cancers	4	655	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.88, 1.05]
1.2 RT to head & neck with cisplatin	2	374	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.90, 1.00]
1.3 CT alone for mixed cancers	2	215	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.60, 0.85]
2 Oral mucositis (moderate + severe)	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 BMT/SCT after conditioning for haematological cancers	6	852	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.80, 0.99]
2.2 RT to head & neck with cisplatin/5FU	3	471	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.83, 1.00]
2.3 CT alone for mixed cancers	4	344	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.45, 0.70]
3 Oral mucositis (severe)	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 BMT/SCT after conditioning for haematological cancers	6	852	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.11]
3.2 RT to head & neck with cisplatin/5FU	3	471	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.69, 0.90]
3.3 CT alone for mixed cancers	3	263	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.14, 0.65]
4 Interruptions to cancer treatment (unscheduled RT breaks of 5 or more days)	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 RT to head & neck with cisplatin/5FU	3	473	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.65, 1.59]
5 Interruptions to cancer treatment (chemotherapy delays/discontinuations)	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 RT to head & neck with cisplatin	2	374	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.62, 1.47]
6 Oral pain	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1 BMT/SCT after conditioning for haematological cancers	1	42	Mean Difference (IV, Random, 95% CI)	‐0.85 [‐3.00, 1.30]
6.2 RT to head & neck with cisplatin	2	374	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.27, 0.02]
7 Normalcy of diet (use of supplemental nutrition)	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 BMT/SCT after conditioning for haematological cancers	4	714	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.58, 1.34]
7.2 RT to head & neck with cisplatin/5FU	3	473	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.77, 1.37]
8 Normalcy of diet (worst ability to eat score ‐ 1 to 4 scale)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.1 BMT/SCT after conditioning for haematological cancers	1	42	Mean Difference (IV, Random, 95% CI)	‐0.5 [‐1.21, 0.21]
9 Number of days in hospital	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
9.1 BMT/SCT after conditioning for haematological cancers	1	281	Mean Difference (IV, Random, 95% CI)	0.0 [‐1.64, 1.64]
10 Number of days of treatment with opioid analgesics	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
10.1 BMT/SCT after conditioning for haematological cancers	2	323	Mean Difference (IV, Random, 95% CI)	‐1.41 [‐3.33, 0.51]

Methods	Trial design: parallel (2 arms) Location: Institut Gustave Roussy, Villejuif, France Number of centres: 1 Study duration: February 2005 to September 2006  Trials registry number: none/unknown
Participants	Inclusion criteria: adults with metastatic colorectal adenocarcinoma (grade 3 to 4); life expectancy greater than 3 months; receiving 5FU‐based chemotherapy Exclusion criteria: HIV; pregnant or lactating; unlikely to comply with interventions; participation in another trial in the previous 12 months (unless regarding chemotherapeutic protocols); undergone a total colectomy; state of subocclusion; chronic inflammatory diseases of the digestive tract; radiation enteropathy Cancer type: metastatic colorectal adenocarcinoma (grade 3 to 4) Cancer treatment: 5FU‐based chemotherapy Age at baseline (years): median 60 (not reported by group) Gender: not reported Number randomised: 22 (not reported by group) Number evaluated: 13 (Group A: 9; Group B: 4)
Interventions	Comparison: TGF‐beta(2) versus placebo Group A: nutritional supplement of proteins, carbohydrates, fats, vitamins and minerals, with TGF‐beta(2) (2 ng/mg protein); formulas were in powder form, mixed with cool previously boiled water at 0.23 g/mL (100 kcl/100 mL); during each cycle participants received 750 mL to 1000 mL per day plus any other food desired; formula administered for 2 days before, 2 days during, and 3 days after chemotherapy (7 days/cycle) Group B: same as above without the TGF‐beta(2) Compliance: "Nine randomised patients who never ate the formula were excluded from the study" (not reported by group) Duration of treatment: "3 months (test or control formula), for a minimum of one and a maximum of eight cycles of treatment"
Outcomes	Oral mucositis: WHO 0 to 4 scale (no details reported on who assessed this, or when it was assessed; only reports incidence of any mucositis) Chemotherapy‐induced diarrhoea (not an outcome of this review)
Notes	Sample size calculation: not reported Funding: "This study was funded by Nestec Ltd" ‐ Nestlé (manufacturer of the intervention) Declarations/conflicts of interest: 6 of the 9 authors were either consultants (1) or employees (5) of Nestlé Data handling by review authors: reported in additional table Other information of note: "Due to low accrual of patients (22 patients were enrolled and randomised in 18 months), the study was prematurely stopped"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "randomly assigned" Comment: insufficient information to determine method of random sequence generation
Allocation concealment (selection bias)	Unclear risk	Quote: "randomly assigned" Comment: insufficient information to determine whether or not the random sequence was adequately concealed
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blind" and "The test formula differed only by containing an additional..." Comment: the use of a placebo should have ensured that blinding was successful
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double‐blind" Comment: it is not clear who was blinded. There are subjective elements to the assessment of oral mucositis using this scale, requiring the patient's assessment of pain/soreness and their ability to swallow but, as the participants were unaware of their group allocation, the assessment of oral mucositis can be considered to be blinded
Incomplete outcome data (attrition bias)   All outcomes	High risk	Overall attrition was 41% although it was not reported by group
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 (7 arms) dose‐ranging study Location: Universities of Minnesota and Michigan, USA Number of centres: 2 Study duration: not reported  Trials registry number: none/unknown
Participants	Inclusion criteria: aged 3 to 65 years; diagnosed with haematological malignancy (including myelodysplastic syndromes); ECOG score of 0 to 2; eligible for allogeneic HSCT after conditioning treatment with chemotherapy with or without TBI Exclusion criteria: received previous allogeneic HSCT; due to receive a T‐cell‐depleted donor graft; active chronic skin disease; pre‐existent inflammatory bowel disease; uncontrolled (antibiotic‐resistant) bacterial infection; hepatitis; HIV Cancer type: haematologic: ALL (Group A: 12%; Group B: 3%); AML (Group A: 35%; Group B: 39%); CML (Group A: 10%; Group B: 26%); MDS (Group A: 9%; Group B: 19%); NHL (Group A: 19%; Group B: 3%); Hodgkin's (Group A: 1%; Group B: 0%); Other (Group A: 14%; Group B: 10%) Cancer treatment: both centres had allogeneic HSCT on day 0 but differed in conditioning regimen and GVHD prophylaxis as follows: Minnesota centre (n = 54): conditioning with cyclophosphamide (60 mg/kg per day for 2 days) on days ‐7 and ‐6 and TBI (total dose 13.2 Gy, fractionated as 165 cGy twice daily for 4 days) on days ‐4 to ‐1; GVHD prophylaxis with methotrexate (15 mg/m², IV bolus on day +1, and 10 mg/m², IV bolus on days 3, 6, and 11) and cyclosporine A (starting from day ‐3); Group A: 69%; Group B: 31% Michigan centre (n = 46): conditioning with busulfan (1 mg/kg per dose given 4 times daily for 4 days) on days ‐8 to ‐5 and cyclophosphamide (60 mg/kg per day for 2 days) on days ‐3 and ‐2; GVHD prophylaxis with methotrexate (15 mg/m², IV bolus on day +1, and 10 mg/m², IV bolus on days 3, 6, and 11) and tacrolimus or cyclosporine A (starting from day ‐3); Group A: 70%; Group B: 30% Both centres received G‐CSF (filgrastim) 5 µg/kg per day from 24 hours after HSCT until neutrophil recovery Age at baseline (years): Group A: median 46 (range 7 to 65); Group B: median 46 (range 7 to 63) Gender: both groups 58% male Number randomised: 100 (Group A: 69; Group B: 31) Number evaluated: 96 (Group A: 65; Group B: 31)
Interventions	Comparison: KGF (palifermin) versus placebo (4 KGF arms and 3 placebo arms were each combined into a single arm) Group A: KGF (n = 8): 40 µg/kg per day in 6 doses on days ‐11, ‐10, ‐9 and 0, 1, 2 (total dose = 240 µg/kg) (n = 10): 60 µg/kg per day in 6 doses on days ‐11, ‐10, ‐9 and 0, 1, 2 (total dose = 360 µg/kg) (n = 14): 60 µg/kg per day in 9 doses on days ‐11, ‐10, ‐9 and 0, 1, 2 and 7, 8, 9 (total dose = 540 µg/kg) (n = 37): 60 µg/kg per day in 12 doses on days ‐11, ‐10, ‐9 and 0, 1, 2 and 7, 8, 9 and 14, 15, 16 (total dose = 720 µg/kg) Group B: placebo with matching schedule to either the 6, 9 or 12 dose regimen    Mode of administration not described but presumably IV as in other KGF studies Compliance: Group A: 20 did not receive all study doses (17 of these were replaced to allow a full assessment of safety); Group B: 2 did not receive all study doses (1 replaced) Duration of treatment: varied from 13 days (6 doses) to 27 days (12 doses) ‐ see above
Outcomes	Oral mucositis: WHO 0 to 4 scale (measured 3 times per week during hospitalisation by designated observers, maximum score reported) Adverse effects (assessed daily during study period using WHO and NCI‐CTC toxicities scale) Incidence and severity of acute GVHD (not an outcome of this review) Overall survival (not an outcome of this review) Incidence of transplantation‐related toxicity (not an outcome of this review) Time to marrow engraftment (not an outcome of this review)
Notes	Sample size calculation: not reported Funding: government grants from NIH and FDA, and also supported by Amgen (pharmaceutical industry) Declarations/conflicts of interest: not reported Data handling by review authors: the data for incidence of mucositis were not reported separately for each dose and therefore it was not possible to include head‐to‐head comparisons of different dosages in this review; the data for incidence of mucositis were presented in subgroups of those that did or did not receive the final methotrexate infusion on day 11 but we used the overall data in our meta‐analyses (the study authors report that there was no difference between these subgroups) Other information of note: the study authors report a greater decrease in incidence of grade 3 to 4 (severe) oral mucositis due to palifermin in the Minnesota participants (who received a more mucotoxic conditioning regimen) than in the Michigan participants
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "patients...were randomly assigned..." Comment: insufficient information to determine method of random sequence generation
Allocation concealment (selection bias)	Unclear risk	Quote: "patients...were randomly assigned..." Comment: insufficient information to determine whether or not the random sequence was adequately concealed
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" Comment: the use of a placebo should have ensured that blinding was successful
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" Comment: it is not clear who was blinded. There are subjective elements to the assessment of oral mucositis using this scale, requiring the patient's assessment of pain/soreness and their ability to swallow but, as the participants were unaware of their group allocation, the assessment of oral mucositis can be considered to be blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "Data for all patients randomly assigned and who received a transplant were used in all other analyses (intent‐to‐treat)" Comment: although 18 participants (Group A: 17; Group B: 1) were replaced to allow a full assessment of safety, it seems that the originally randomised participants were included in the analyses Overall attrition was 4% (Group A: 6%; Group B: 0%) for the oral mucositis incidence outcome. The reasons were unclear but this proportion of attrition is unlikely to have biased the results
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: Europe (Italy, France, the Netherlands, Ireland, Germany, UK, Denmark, Austria, Switzerland, Czech Republic, Sweden, Hungary, Belgium, Finland) Number of centres: 39 Study duration: December 2006 to February 2009  Trials registry number: NCT00434161
Participants	Inclusion criteria: aged between 18 and 70 years; due to receive high‐dose melphalan; ECOG score of 0 to 2 (or 3, if reason was due to multiple myeloma); at least 2 x 10⁶ CD34+ cells per kg; corrected carbon monoxide diffusing capacity 50% or higher of predicted; absolute neutrophil count at least 1.5 x 10⁹/L and platelets at least 100 x 10⁹/L; total bilirubin 2 mg/dL or lower; aspartate aminotransferase and/or alanine aminotransferase 4 x institutional upper limit of normal or lower Exclusion criteria: not reported Cancer type: multiple myeloma Cancer treatment: 1‐day administration of high‐dose melphalan (200 mg/m²) on day ‐2, followed by auto‐SCT on day 0 Age at baseline (years): Group A: median 55 (range 32 to 69); Group B: median 58 (range 40 to 68); Group C: median 58 (range 41 to 68) Gender: Group A: 54% male; Group B: 55% male; Group C: 58% male Number randomised: 281 (Group A: 109; Group B: 115; Group C: 57) Number evaluated: 281 (Group A: 109; Group B: 115; Group C: 57)
Interventions	Comparison: KGF versus placebo Group A: KGF (60 µg/kg) daily IV on days ‐6, ‐5, and ‐4, then placebo on days 0 (the day of auto‐SCT), 1, and 2 (total dose = 180 µg/kg) Group B: KGF (60 µg/kg) daily IV on days ‐6, ‐5, ‐4, 0, 1, and 2 (total dose = 360 µg/kg) Group C: placebo daily IV on days ‐6, ‐5, ‐4, 0, 1, and 2 Compliance: Group A: 8% discontinued; Group B: 12% discontinued; Group C: 4% discontinued; (point of discontinuation or number of treatments not stated for any group) Duration of treatment: 6 treatment days (over 9 days)
Outcomes	Oral mucositis: WHO 0 to 4 scale (assessed daily by nurses and physicians from day ‐2 to day 32, maximum score reported) (duration of grade 2 to 4 and 3 to 4 oral mucositis also measured but not outcomes of this review) Oral pain: OMDQ 5‐point scale for mouth and throat soreness (higher = worse pain) (assessed daily by participants from day ‐2 to day 32, data reported as AUC, not used) Quality of life: EQ‐5D 0 (worst imaginable health) to 10 (best imaginable health) scale, incorporating mobility, self‐care, usual activities, pain/discomfort and anxiety/depression (assessed daily by participants from day ‐2 to day 32, mean reported only at day 7 and with no SD, no usable data) Normalcy of diet (measured as incidence of TPN) (duration of TPN also measured but not used for analysis in review) Adverse events (NCI‐CTC version 3.0 toxicity scale) Number of days in hospital Number of days of treatment with opioid analgesics (incidence of opioid analgesic use also measured and reported but not an outcome of this review) Febrile neutropenia (not an outcome of this review) Significant infections (not an outcome of this review) Anti‐infective (IV) drug use (not an outcome of this review) Blood product use (not an outcome of this review) Nonopioid analgesic use (not an outcome of this review)
Notes	Sample size calculation: 275 participants required at 95% power and 5% significance to detect an odds ratio of at least 3.5 between placebo and KGF in grade 2 to 4 oral mucositis Funding: sponsored by Swedish Orphan Biovitrum (pharmaceutical industry); KGF and placebo manufactured and packaged by Amgen (pharmaceutical industry) Declarations/conflicts of interest: 2 authors were employees of the sponsors; the remaining authors declared no competing financial interests Data handling by review authors: we combined the 2 KGF groups to make a single pairwise comparison against placebo; we also made a separate comparison of the 2 KGF regimens 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 using an interactive‐voice‐response‐system before planned admission" Comment: large multicentre trial using high‐tech randomisation method ‐ likely to be done properly
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was performed by using an interactive‐voice‐response‐system before planned admission" Comment: large multicentre trial using high‐tech randomisation method ‐ likely to be done properly
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" and "Study drug...packaged...in identical vials" Comment: the use of a placebo should have ensured that blinding was successful
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" Comment: it is not clear who was blinded. There are subjective elements to the assessment of lower grades of oral mucositis using the WHO scale, requiring the patient's assessment of pain/soreness and their ability to swallow. Higher grades have more objective elements so may not be affected by potential lack of blinding of the assessor. This would be the same for other subjective and objective outcomes
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 quality of life reported with no SD or P values, this does not affect the risk of bias judgement for other outcomes)
Other bias	Low risk	No other sources of bias are apparent

Methods	Trial design: parallel (2 arms) Location: Australia Number of centres: 23 Study duration: recruitment from September 2006 to April 2010  Trials registry number: ACTRN012605000095662 (mentioned in trial report)
Participants	Inclusion criteria: aged 15 to 60 years with newly diagnosed and previously untreated (except for hydroxycarbamide for high presenting white blood cell count) acute myeloid leukaemia ‐ all subtypes except t(15;17) or variants, or core‐binding factor AML (t(8;21) or inv(16) or variants); ECOG score of 0 to 3; no history of cancer (other than basal cell skin cancer or carcinoma of the cervix in situ, or other localised cancer treated by surgical excision only more than 5 years earlier without evidence of recurrence in the intervening period) Exclusion criteria: not reported Cancer type: acute myeloid leukaemia Cancer treatment: induction chemotherapy consisting of: idarubicin 9 mg/m² daily IV infusion on days 1 to 3; etoposide 75 mg/m² daily IV infusion on days 1 to 7; cytarabine 3 g/m² 12‐hourly IV infusion on days 1, 3, 5, and 7 All participants received G‐CSF (pegfilgrastim) 6 mg subcutaneously on day 8 Age at baseline (years): Group A: mean 46 (SD 12; range 17 to 60); Group B: mean 44 (SD 12; range 16 to 60) Gender: Group A: 61% male; Group B: 67% male Number randomised: 160 (Group A: 79; Group B: 81) Number evaluated: 151 (Group A: 73; Group B: 78)
Interventions	Comparison: KGF (palifermin) versus placebo Group A: KGF (60 µg/kg) daily IV on days ‐3, ‐2, ‐1 prior to chemotherapy and for 3 days after completion of chemotherapy (total dose = 360 µg/kg) Group B: same schedule with placebo Compliance: received all 3 pre‐chemotherapy doses: Group A: 97%; Group B: 100%; received all 3 post‐chemotherapy doses: Group A: 95%; Group B: 96% Duration of treatment: 6 treatment days (over 14 days)
Outcomes	Oral mucositis: WHO 0 to 4 scale (assessed daily by investigators and specifically trained site personnel from the first day of chemotherapy and until the earlier of the date of discharge or day 28 after the start of chemotherapy, maximum score reported) (duration of grade 3 to 4 oral mucositis also measured but not an outcome of this review) Adverse events (NCI‐CTC version 2.0 toxicity scale) Incidence of severe gastrointestinal toxicities related to the induction chemotherapy (not an outcome of this review) Complete response to chemotherapy (not an outcome of this review)
Notes	Sample size calculation: 128 per group required to detect a reduction in grade 3 to 4 mucositis from 22% to 10% at 70% power and 5% significance Funding: "This study was funded in part from Project Grant 302133 from the National Health and Medical Research Council of Australia" (government); KGF and placebo provided by Amgen (pharmaceutical industry) Declarations/conflicts of interest: "The authors have no conflicts of interest to declare" Data handling by review authors: N/A Other information of note: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Eligible patients were randomized 1:1 using a block randomization technique and stratification by participating centre to receive placebo or palifermin" Comment: large multicentre trial using block randomisation and stratification ‐ likely to be done properly
Allocation concealment (selection bias)	Unclear risk	Quote: "Eligible patients were randomized 1:1 using a block randomization technique and stratification by participating centre to receive placebo or palifermin" Comment: insufficient information to determine whether or not the random sequence was adequately concealed
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "placebo‐controlled" and "Both investigators and patients were blinded to the randomization outcome" Comment: the use of a placebo should have ensured that blinding was successful
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "placebo‐controlled" and "Both investigators and patients were blinded to the randomization outcome" Comment: investigators assessed oral mucositis, which would have partly relied on patient's assessment of pain/soreness and their ability to swallow; both investigators and patients were blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Overall attrition was 6% (Group A: 8%; Group B: 4%) for the oral mucositis incidence outcome. The reasons were similar between groups and this proportion of attrition is unlikely to have biased the results
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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Oral mucositis (severe)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 CT alone for breast cancer	1	36	Risk Ratio (M‐H, Random, 95% CI)	2.75 [1.07, 7.04]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Oral mucositis (moderate + severe)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 RT to head & neck	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.80, 1.14]
2 Oral mucositis (severe)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 RT to head & neck	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.24, 1.21]
3 Interruptions to cancer treatment	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 RT to head & neck	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.13 [0.01, 2.36]
4 Normalcy of diet (use of PEG tube)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 RT to head & neck	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.01, 3.56]

Methods	Trial design: parallel (5 arms) dose‐ranging study Location: Duke University Medical Centre, Durham, North Carolina, USA Number of centres: 1 Study duration: not reported  Trials registry number: none/unknown
Participants	Inclusion criteria: premenopausal or perimenopausal patients with histologically confirmed metastatic breast cancer who had chemotherapy for inoperable or metastatic disease; performance status of 0 or 1 (CALGB criteria) Exclusion criteria: metastatic disease involving the central nervous system; pregnant Cancer type: stage IV breast Cancer treatment: AFM regimen (21‐day cycle): 5FU (500 mg/m²/day) continuous infusion on days 1 to 5; adriamycin (25 mg/m²) IV bolus on days 3 to 5; methotrexate (250 mg/m²) IV on day 15 (if oral mucositis less than grade 3)    All participants received G‐CSF (filgrastim) subcutaneously (5 µg/kg/day) on days 7 to 13 and from day 16 until resolution of neutropenia Age at baseline (years): mean 44 (not reported by group) Gender: 49 female; 1 male (not reported by group) Number randomised: 50 (not reported by group) Number evaluated: 45 (Group A: 36; Group B: 9)
Interventions	Comparison: GM‐CSF (molgramostim) versus placebo Group A: GM‐CSF (n = 9 analysed): 15 mL of mouthwash (0.01 µg/mL) gently swirled in the mouth for 2 minutes before expectorating it; 4 times daily (after mealtimes, even if a meal was not eaten, and at bedtime) after routine oral care procedures; no eating/drinking for 15 minutes after using mouthwash; beginning within 24 hours of the start of 5FU and continued for the 21‐day AFM cycle (total dose = 12.6 µg) (n = 9 analysed): same schedule with 0.1 µg/mL mouthwash (total dose = 126 µg) (n = 9 analysed): same schedule with 1 µg/mL mouthwash (total dose = 1260 µg) (n = 9 analysed): same schedule with 10 µg/mL mouthwash (total dose = 12,600 µg) Group B: (n = 9 analysed) same schedule with matching placebo mouthwash Compliance: (not reported by group) mouthwash therapy was discontinued if the participant experienced oral mucositis of grade 3 or above; 30 participants took at least 80% of their prescribed doses; 11 participants discontinued mouthwash therapy within 3 days prior to day 15; 4 participants discontinued mouthwash therapy between day 15 and day 21 Duration of treatment: 21 days (first treatment cycle of AFM)
Outcomes	Oral mucositis: CALGB 0 to 4 scale (measured on days 1 to 5, 8 to 10, 15 and 22, reported as incidence of grade 3 to 4 i.e. severe) (duration of grade 3 to 4 oral mucositis also measured but not an outcome of this review) Adverse effects (assessed during study period) Blood measurements (platelet, WBC, granulocyte, lymphocyte) (not an outcome of this review) Myelosuppression (not an outcome of this review) GM‐CSF plasma concentrations (not an outcome of this review)
Notes	Sample size calculation: this was done but the numbers required are not reported Funding: "...supported in part by National Cancer Institute (Bethesda, MD) grant number PO1‐47741‐A4" Declarations/conflicts of interest: not reported Data handling by review authors: we combined the 4 GM‐CSF groups to make a single pairwise comparison against placebo and, in order to make a head‐to‐head comparison of doses, we grouped the 2 lower doses (0.01 µg/mL and 0.1 µg/mL) together and grouped the 2 higher doses (1 µg/mL and 10 µg/mL) together to make pairwise groups for comparison 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 by the Duke Cancer Center Protocol Office according to a block randomization scheme and assigned a unique identifier number which designated the GM‐CSF dose level to be received" Comment: method of sequence generation not fully described but was done by a dedicated specialist centre so was probably done adequately
Allocation concealment (selection bias)	Low risk	Quote: "Patients were randomized by the Duke Cancer Center Protocol Office" and "The patient supply of mouthwash was labelled to correspond with the assigned identifier number and dispensed by the Pharmacy. The patient assignment information was maintained by the Pharmacy" Comment: the entire randomisation process was performed by third party so the random sequence is unlikely to have been manipulated
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" Comment: the use of a placebo should have ensured that blinding was successful
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" and "The patient assignment information was maintained by the Pharmacy" Comment: it is not clear who was blinded. There are subjective elements to the assessment of oral mucositis using this scale, requiring the patient's assessment of pain/soreness and their ability to swallow but, as the participants were unaware of their group allocation, the assessment of oral mucositis can be considered to be blinded
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Overall attrition was 10%. Reasons for attrition fully reported. If all participants would have developed severe oral mucositis or dropped out due to severe oral mucositis and were all from 1 particular group, this would have biased the results. However, attrition was not reported by group, so it is unclear
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: Cancer Centre and Department of Otolaryngology, Veterans General Hospital, Taiwan, Republic of China Number of centres: 1 Study duration: not reported  Trials registry number: none/unknown
Participants	Inclusion criteria: diagnosed stage IV SCC of head and neck, previously untreated or locally recurrent after previous surgery or radiotherapy or both; ECOG score of 2 or above; adequate bone marrow, liver and renal function Exclusion criteria: concurrent medical illness; local radiotherapy to oropharynx region in the previous 3 months Cancer type: head and neck: nasopharyngeal (Group A: 44%; Group B: 27%); tongue (Group A: 22%; Group B: 36%); hypopharynx (Group A: 11%; Group B: 18%); buccal (Group A: 11%; Group B: 9%); tonsillar (Group A: 11%; Group B: 9%) Cancer treatment: PFL regimen (21‐day cycle): cisplatin (20 mg/m²/day), 5FU (800 mg/m²/day) and leucovorin (90 mg/m²/day) IV for days 1 to 4; cycle repeated every 3 weeks (study consisted of 2 cycles) Age at baseline (years): Group A: median 44 (range 36 to 62); Group B: median 49 (range 40 to 66) Gender: Group A: 89% male; Group B: 91% male Number randomised: 20 (Group A: 9; Group B: 11) ‐ figures for first cycle Number evaluated: 20 (Group A: 9; Group B: 11)
Interventions	Comparison: GM‐CSF versus no treatment Group A: GM‐CSF (4 µg/kg) subcutaneously from day 5 to 14 (total dose = 40 µg) Group B: no treatment Compliance: not reported Duration of treatment: 10 days (days 5 to 14 of 21‐day cycle)
Outcomes	Oral mucositis: RTOG 0 to 4 scale (measured on days 5 to 21 by both physician's objective gross score and participant's subjective functional score, reported as area under the curve and also in the text as incidence of severe gross mucositis i.e. grade 3 to 4) (duration of grade 2 to 4 and 3 to 4 oral mucositis also measured but not an outcome of this review) Adverse effects (assessed across both cycles)
Notes	Sample size calculation: not reported Funding: "..supported in part by Department of Health, Taiwan, Republic of China, research grant no. DOH 83‐HR‐202" and "GM‐CSF (supplied by Schering Plough Corp, Kenilworth, NJ)" (pharmaceutical industry) Declarations/conflicts of interest: not reported Data handling by review authors: as stated in the methods section, we would only include first‐period data from cross‐over studies due to potential for period effects (which were reported in this study). The only usable data in this study were reported in the text as incidence of severe gross mucositis for the first cycle Other information of note: the authors report a significant period effect of GM‐CSF (P < 0.01), whereby the benefits continued into the second cycle    GM‐CSF administration only began after the 4‐day chemotherapy was completed, by which point oral mucositis may have already begun to develop
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were randomized to receive GM‐CSF or no therapy" Comment: insufficient information to determine method of random sequence generation
Allocation concealment (selection bias)	Unclear risk	Quote: "Patients were randomized to receive GM‐CSF or no therapy" 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	Comparison with no treatment so blinding not possible
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	It would be possible to blind the outcome assessor, as the data we used were assessed by a physician using an objective scale. However, it was not mentioned
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All randomised participants appear to be included in the analyses
Selective reporting (reporting bias)	Low risk	Although most of the data were not usable in this review, this does not seem to be due to selective reporting
Other bias	Low risk	No other sources of bias are apparent

Methods	Trial design: parallel (5 arms) Location: UK Number of centres: 12 Study duration: recruitment from August 1989 to July 1990  Trials registry number: none/unknown
Participants	Inclusion criteria: adults due to receive BMT after conditioning Exclusion criteria: myeloid malignancies Cancer type: mixed haematologic and solid (not reported by group): Hodgkin's disease (29%); non‐Hodgkin's lymphoma (33%); multiple myeloma (Group A: 20%); ALL (15%); solid (3%) Cancer treatment: prior to receiving BMT (autologous 84%; allogeneic 16%), participants received a conditioning regimen which consisted of chemotherapy only (71%) or with TBI (29%) Age at baseline (years): median 36 (range 17 to 64) (not reported by group) Gender: 69% male (not reported by group) Number randomised: 121 (Group A: 96; Group B: 25); Group A represents 4 arms with different dosages Number evaluated: 121 (Group A: 96; Group B: 25)
Interventions	Comparison: G‐CSF versus placebo Group A: G‐CSF (2 µg/kg, 5 µg/kg, 10 µg/kg or 15 µg/kg) by 30‐minute IV daily starting from the day after BMT transplant and continuing until neutrophil count was > 1.0 x 10⁹/L for 3 consecutive days or until day 28, whichever occurred first Group B: as above but with placebo Compliance: not reported Duration of treatment: variable and dependent on neutrophil recovery
Outcomes	Oral mucositis: unspecified scale (frequency of measurement not mentioned, no usable data) Adverse events Number of days in hospital (median reported, no usable data) Neutropenia‐related outcomes (not outcomes of this review) Antibiotic use (not an outcome of this review) Fever (not an outcome of this review) Sepsis (not an outcome of this review) Blood product use (not an outcome of this review)
Notes	Sample size calculation: not reported Funding: "Financial support for this trial was provided by Chugai Rhone Poulene" (pharmaceutical industry) Declarations/conflicts of interest: 1 author was employed by the funders Data handling by review authors: oral mucositis reported narratively in additional table Other information of note: G‐CSF administration only began after the conditioning and BMT transplant were completed, by which point oral mucositis may have already begun to develop (although time scale of conditioning/BMT transplant not reported)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomised...in blocks of five by a computer‐generated randomisation schedule" Comment: adequate method used
Allocation concealment (selection bias)	Unclear risk	Quote: "Patients were randomised...in blocks of five by a computer‐generated randomisation schedule" Comment: insufficient information to determine whether or not the random sequence was adequately concealed
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "single blind...vehicle‐controlled" Comment: the use of a placebo (the 'vehicle') should have ensured that blinding was successful
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: "single blind...vehicle‐controlled" Comment: the quote implies that outcome assessment was not blinded
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 not mentioned in the methods section as 1 of the study end points. It is only mentioned in the results narratively as there being no difference between any group, but with no data or P value
Other bias	Low risk	No other sources of bias are apparent

Methods	Trial design: parallel (7 arms) Location: USA Number of centres: 10 Study duration: not reported  Trials registry number: none/unknown
Participants	Inclusion criteria: 18 years or older; metastatic colon or rectal adenocarcinoma; scheduled to receive palliative 5FU and leucovorin chemotherapy; ECOG performance status 0 to 2 (ambulatory at least 50% of waking hours); life expectancy of at least 4 months; free of lesions and no recent history (within 30 days before baseline examination) of oral ulceration, herpes simplex, oral candidiasis, severe gingivitis, or the presence of active or chronic mucositis, xerostomia, or diarrhoea; absolute neutrophil count ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; serum creatinine ≤ 2.0 mg/dL; serum bilirubin ≤ 2.0 mg/dL; serum aspartate amino transferase less than 5 times the upper limit of normal; absence of other serious concurrent medical illness Exclusion criteria: received chemotherapy, radiotherapy, or other investigational drugs within 4 weeks of enrolment (6 weeks for chemotherapy with mitomycin or nitrosoureas); any unresolved adverse event from previous therapy; major surgery within 2 weeks before study entry; history of insulin‐dependent diabetes mellitus; pregnant or breastfeeding; of child‐bearing potential and not using adequate contraceptive precautions; previous hypersensitivity reaction to leucovorin calcium or Escherichia coli‐derived material Cancer type: metastatic colorectal Cancer treatment: (palliative) leucovorin 20 mg/m² by rapid IV injection, followed immediately by 5FU 425 mg/m² by rapid IV injection for 5 consecutive days on days 4 to 8 of each 28‐day cycle Age at baseline (years): Group A: mean 62 (SD 10; range 44 to 84); Group B: mean 66 (SD 13; range 41 to 86) Gender: Group A: 57% male; Group B: 59% male Number randomised: 81 (Group A: 54; Group B: 27) Number evaluated: 81 (Group A: 54; Group B: 27)
Interventions	Comparison: KGF (recombinant human) versus placebo Group A: KGF (n = 7): 1 µg/kg per day by IV bolus on days 1 to 3 (total dose = 3 µg/kg) (n = 8): 10 µg/kg as above (total dose = 30 µg/kg) (n = 10): 20 µg/kg as above (total dose = 60 µg/kg) (n = 11): 40 µg/kg as above (total dose = 120 µg/kg) (n = 8): 60 µg/kg as above (total dose = 180 µg/kg) (n = 10): 80 µg/kg as above (total dose = 240 µg/kg) Group B: placebo as above Compliance: 3 participants stopped KGF treatment due to adverse reactions involving the skin (1 in 60 and 2 in 80 µg/kg group) Duration of treatment: 3 days
Outcomes	Oral mucositis: WHO 0 to 4 scale (assessed on days 1, 4, 8, 15 and 28, reported as incidence of grade 2 to 4; first cycle data only) (duration of mucositis also measured but not an outcome of this review) Oral pain: self‐assessed daily questionnaire including mouth and throat pain assessed on both a 5‐point ordinal scale (reported graphically, no usable data) and a 0 to 10 VAS (reported as AUC, not used) Adverse events: WHO 0 to 4 scale (reported as events of any grade that differed by at least 10% between any KGF group and placebo; events were not reported if they occurred in less than 10% of KGF group; also reported as incidence of grade 3 to 4 events) Blood measurements (not an outcome of this review)
Notes	Sample size calculation: not reported Funding: "Supported by a grant from Amgen, Inc" (pharmaceutical industry) Declarations/conflicts of interest: not reported Data handling by review authors: we combined the 6 KGF groups to make a single pairwise comparison against placebo; in order to make a head‐to‐head comparison of doses we grouped the 3 lower doses (1 µg/kg, 10 µg/kg and 20 µg/kg) together and grouped the 3 higher doses (40 µg/kg, 60 µg/kg and 80 µg/kg) together to make pairwise groups for comparison Other information of note: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "This study was a multicenter, randomized, double‐blinded, placebo‐controlled, phase I study"    Comment: insufficient information to determine method of random sequence generation
Allocation concealment (selection bias)	Unclear risk	Quote: "This study was a multicenter, randomized, double‐blinded, placebo‐controlled, phase I study"    Comment: insufficient information to determine whether or not the random sequence was adequately concealed
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blinded, placebo‐controlled" Comment: the use of a placebo should have ensured that blinding was successful; incidence of adverse events does not appear to differ enough between groups to cause unblinding
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double‐blinded, placebo‐controlled" Comment: it is not clear who was blinded but the outcome is grade 2 to 4 WHO‐scale mucositis and it is unlikely that this would be affected by any lack of blinding
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 (4 arms) Location: South Korea Number of centres: 6 Study duration: recruitment from January to August 2007  Trials registry number: none/unknown
Participants	Inclusion criteria: 18 years or older with histological evidence of head and neck cancer; due to receive at least 5 weeks of primary RT, primary chemoradiotherapy, or postoperative RT; agreement to have complete medical history and physical examination; ECOG score of 0 to 2; white blood counts 3 x 10³/L or higher; platelet counts 100 x 10³/L or higher Exclusion criteria: oral ulcers; herpes simplex virus; severe periodontal disease; serum creatine levels greater than 2 mg/dL; ALT/AST values greater than 200 IU/L; cytotoxic chemotherapy or RT within 3 weeks of the start of the study; systemic or topical corticosteroids within 30 days of the start of the study; participated in another clinical study within 30 days of the start of the study Cancer type: head and neck: nasopharynx (Group A: 36%; Group B: 32%); oropharynx (Group A: 24%; Group B: 25%); oral cavity (Group A: 19%; Group B: 25%); hypopharynx (Group A: 2%; Group B: 4%); other (Group A: 19%; Group B: 14%) Cancer treatment: Radiotherapy: conventional fractionation once daily in 2 (± 0.25) Gy fractions, 5 times per week, for at least 5 weeks Chemotherapy: concurrent cisplatin was allowed (just over 50% per group received this) Age at baseline (years): Group A: median 56 (range 18 to 75); Group B: median 51 (range 18 to 77) Gender: Group A: 69% male; Group B: 57% male Number randomised: 113 (Group A: 85; Group B: 28) Number evaluated: 103 (Group A: 76; Group B: 27) for incidence of moderate to severe mucositis; 94 (Group A: 70; Group B: 24) for incidence of severe mucositis
Interventions	Comparison: EGF (recombinant human) versus placebo Group A: EGF (n = 29): 10 µg daily by oral spray, applied twice daily, sprayed over the entire oral mucosa and then swallowed, no oral intake for 30 minutes afterwards; starting on first day of RT and continuing for 5 weeks (n = 29): 50 µg daily as above (n = 27): 100 µg daily as above Group B: placebo as above    All participants gargled with chlorhexidine to maintain oral hygiene Compliance: not reported Duration of treatment: 5 weeks
Outcomes	Oral mucositis: RTOG 0 to 4 scale (assessed weekly by radiation oncologists, reported as incidence of grade 2 to 4 and grade 3 to 4 at week 4 or 5; unclear reporting for grade 3 to 4, unable to use data) (time to develop mucositis also assessed but not an outcome of this review) WHO oral toxicity grade (assessed weekly, not clear whether this is the WHO 0 to 4 scale for oral mucositis, no data reported) Interruptions to cancer treatment (incidence of 3 or more consecutive days of interruption to RT) Oral pain (assessed weekly, no description of scale used, no data reported) Averse events (no data reported; narrative only) Opioid analgesic use (assessed weekly, not clear if duration, quantity or incidence of use was assessed, no data reported) Weight (not an outcome of this review) Laboratory measurements (not an outcome of this review)
Notes	Sample size calculation: allowing for 10% attrition, 26 participants per group required Funding: "This study was supported by a grant from the National R&D Program for Cancer Central, Ministry of Health, Welfare and Family Affairs, Republic of Korea (0620270)" (government) and "The EGF and placebo treatments were supplied free of charge" (presumably pharmaceutical industry) Declarations/conflicts of interest: not reported Data handling by review authors: we combined the 3 EGF groups to make a single pairwise comparison against placebo; no formal statistical analysis was undertaken for the different EGF dosages Other information of note: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "We assigned patients randomly to 4 arms" Comment: insufficient information to determine method of random sequence generation
Allocation concealment (selection bias)	Unclear risk	Quote: "We assigned patients randomly to 4 arms" Comment: insufficient information to determine method of random sequence generation
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" and "Three concentrations of EGF and a placebo containing the drug delivery vehicle were manufactured, packaged, and supplied in a double‐blind fashion" Comment: the use of a placebo should have ensured that blinding was successful
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "double‐blind, placebo‐controlled" Comment: it is not clear who was blinded. There are subjective elements to the assessment of most grades of oral mucositis using the RTOG scale, requiring the patient's assessment of pain. Grade 4 is more objective so may not be affected by potential lack of blinding of the assessor
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Overall attrition was 9% (Group A: 11%; Group B: 4%). Slight differential between groups but the reasons were reported and mostly unrelated to interventions/outcomes. Unlikely to have biased the results
Selective reporting (reporting bias)	High risk	Several outcomes were assessed but not properly reported ("No secondary endpoint showed any difference between the placebo and study groups")
Other bias	Low risk	No other sources of bias are apparent

Study	Reason for exclusion
Antin 2002	Recombinant human interleukin‐11 versus placebo. Study stopped early due to adverse event triggering preset stopping rule ‐ data only for 10 patients in rhIL group and 3 placebo
de Koning 2007	TGF‐beta(2) versus placebo. Cross‐over study with no first period data reported (see Types of studies)
Foncuberta 2001	TGF‐beta(3) versus placebo. Participants assigned sequentially, not randomised
Gebbia 1994	G‐CSF versus thymopentin versus G‐CSF plus thymopentin versus placebo. Oral mucositis not mentioned (unknown if measured)
Gladkov 2013	G‐CSF (lipegfilgrastim) versus G‐CSF (pegfilgrastim). Oral mucositis not mentioned (unknown if measured). Insufficient information (abstract)
Gordon 1993	GM‐CSF versus no treatment. Unclear if randomised or not. Only 13 participants. Insufficient information (abstract)
Horsley 2007	KGF (palifermin) versus standard care. No random allocation
Hunter 2009	ATL‐104 versus placebo. Not RCT ‐ this study combines patients who were in cohorts with increasing doses of mouthrinse to assess safety, with an RCT
Ifrah 1999	GM‐CSF versus placebo. Primary outcome was survival/cure, with mucositis as a toxicity. Unclear if mucositis was oral or gastrointestinal
Iwase 1997	G‐CSF versus no treatment. No mention of randomisation and no description of when intervention given in relation to cancer treatment
Jones 1996	GM‐CSF versus placebo. Unclear if mucositis was oral or gastrointestinal
Karthaus 1998	G‐CSF versus placebo. Only 8 patients, 32 chemotherapy cycles and results presented assuming independent
Kubo 2016	G‐CSF (pegfilgrastim) versus G‐CSF (filgrastim). Incidence of stomatitis reported in adverse events table  Trials registry number: JapicCTI‐111394
Lee 2016	G‐CSF (pegteograstim) versus G‐CSF (pegfilgrastim). Incidence of stomatitis reported in adverse events table  Trials registry number: NCT01328938
Legros 1997	GM‐CSF versus placebo. Unclear if mucositis was oral or gastrointestinal
Limaye 2013	AG013 versus placebo. AG013 is composed of recombinant Lactococcus lactis engineered to secrete human Trefoil Factor 1. Randomised at first but participants not developing oral mucositis in chemotherapy cycle 1 were excluded from the next phase where oral mucositis was measured, so randomisation was lost  Trials registry number: NCT00938080
Nabholtz 2002	G‐CSF (leridistim) versus G‐CSF (filgrastim). Incidence of stomatitis reported in adverse events table
NCT00360971	KGF (palifermin) versus placebo. Study terminated at 21 participants (298 planned) due to positive preliminary results from other palifermin studies
NCT00626639	KGF (palifermin) versus placebo. Study terminated at 5 participants due to departure of principal investigator and slow enrolment
Pettengell 1992	G‐CSF versus no treatment. Unclear if mucositis was oral or gastrointestinal
Ryu 2007	GM‐CSF versus placebo. Some participants (6%) had oral mucositis at baseline  Trials registry number: NCT00008398
Throuvalas 1995	GM‐CSF versus no treatment. Probably not RCT ‐ described as comparative study. Only 10 participants. Insufficient information (abstract)
Tsurusawa 2016	G‐CSF versus no treatment. Incidence of stomatitis reported in adverse events table  Trials registry number: UMIN ID: 000000675
Vitale 2014	KGF (palifermin) versus no treatment. From full text it is not RCT ‐ retrospective and allocation of KGF/no KGF based on doctor's decision

Methods	Multicentre, double‐blind, randomised placebo‐controlled trial
Participants	18 years or older with lymphoma and due to undergo high‐dose BEAM chemotherapy and autologous stem cell transplantation as inpatient
Interventions	Whey growth factor extract at 13.5 mg/mL in sterile saline versus placebo (sterile saline)
Outcomes	Oral mucositis: WHO 0 to 4 scale Normalcy of diet: incidence of enteral/parenteral feeding Duration of opiate analgesics Quality of life: OMDQ Adverse events
Notes	Funding: commercial sector/industry (TGR Biosciences, Australia) Contact: correspondence with pharmaceutical company suggests no benefit

Methods	Multicentre, randomised controlled trial (no placebo)
Participants	Head and neck cancer; receiving continuous course of radiotherapy for 6 to 7 weeks
Interventions	GM‐CSF (subcutaneous) versus no treatment
Outcomes	Signs and symptoms of oral mucositis: erythema, pain and dysphagia each measured on 0 to 3 scale
Notes	Abstract only (we were unable to link this abstract to a full‐text report) Some P values suggest benefit for GM‐CSF at some time points Quote: "GM‐CSF reduces the incidence and severity of radiation mucositis and allows the completion of the XRT treatment without protraction"

PERMALINK

Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors

Philip Riley

Anne‐Marie Glenny

Helen V Worthington

Anne Littlewood

Luisa M Fernandez Mauleffinch

Jan E Clarkson

Martin G McCabe

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings for the main comparison. Keratinocyte growth factor (KGF) compared to placebo for preventing oral mucositis in adults with cancer receiving treatment.

Summary of findings 2. Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) compared to placebo/no treatment for preventing oral mucositis in adults with cancer receiving treatment.

Summary of findings 3. Granulocyte‐colony stimulating factor (G‐CSF) compared to placebo/no treatment for preventing oral mucositis in adults with cancer receiving treatment.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Presentation of main results

Results

Description of studies

Results of the search

1.

Included studies

Characteristics of the trials

Study design

Number of arms

Country

Number of centres

Trials registries

Sample size calculation

Funding and conflicts of interest

Characteristics of the participants

Number randomised/analysed

Age and sex

Cancer type

Cancer treatment

Characteristics of the interventions and comparisons

Keratinocyte growth factor (KGF)

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)

Granulocyte‐colony stimulating factor (G‐CSF)

Epidermal growth factor (EGF)

Intestinal trefoil factor (ITF)

Erythropoietin

Transforming growth factor (TGF)

Characteristics of the outcomes

Primary outcome

Methods	Randomised controlled trial (no placebo)
Participants	Anaemic participants with head and neck cancer receiving radiotherapy once daily (1.8 Gy or 2 Gy) to doses of 66 Gy to 70 Gy
Interventions	Recombinant human erythropoietin versus no treatment
Outcomes	Incidence of grade 3 mucositis and dermatitis
Notes	Abstract only (we were unable to link this abstract to a full‐text report) Higher rate of mucositis in the no‐treatment group (5.9% versus 0%)

Methods	Randomised placebo‐controlled trial
Participants	Adults (aged 19 to 68 years) undergoing haematopoietic stem cell transplantation
Interventions	G‐CSF versus placebo
Outcomes	Oral mucositis: WHO 0 to 4 scale Oral pain: 0 to 10 VAS Neutrophil counts
Notes	Translation provided insufficient information. Discrepancy between graph legends and descriptions  Unable to contact author

Methods	Double‐blind, randomised placebo‐controlled trial (1 of the 3 arms is a cross‐over)
Participants	18 years or older with head and neck cancer due to receive conventional or hyperfractionated radiotherapy or intensity‐modulated radiotherapy (IMRT) with or without concurrent chemotherapy
Interventions	GM‐CSF mouthwash versus salt and soda mouthwash versus both (cross‐over arm)
Outcomes	Oral mucositis: scale/s unclear Quality of life: 0 to 10 scale Oral pain: 0 to 10 scale Functional status by Karnofsky performance status scale
Notes	Trials registry number: NCT00293462 Funding: University of California, San Francisco; National Cancer Institute (NCI)