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"

Study ID

Adverse events results

Peterson 2009

"Only a minority of patients (six [6.1%] of 99 patients) reported mild to moderate treatment‐emergent adverse events on the study. The symptoms included abdominal pain, diarrhea, oral pain, headache, and hypertension (Table 2). Of these, four were considered related to study drug: one (3%) was in the placebo group, two (6%) were in the low‐dose rhITF group, and one (3%) was in the high‐dose rhITF group. The events were isolated and resolved spontaneously without sequelae"

Study ID

Population

Outcome

TGF‐beta(2)

Placebo

Result

Antoun 2009

CT alone for colorectal cancer

Oral mucositis (WHO 0 to 4 scale): any oral mucositis

0/9

2/4

RR 0.10 (95% CI 0.01 to 1.71); P = 0.11