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Meta-Analysis
. 2017 Nov 28;11(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, Helen V Worthington, Anne Littlewood, Luisa M Fernandez Mauleffinch, Jan E Clarkson, Martin G McCabe
Affiliations
Meta-Analysis

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

Philip Riley et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

Conflict of interest statement

There was no industry funding to support the undertaking of this Cochrane Review.

Philip Riley: I am a salaried member of the Cochrane Oral Health editorial team. Anne‐Marie Glenny: none known. I am Deputy Co‐ordinating Editor of Cochrane Oral Health. Helen V Worthington: none know. I am Co‐ordinating Editor of Cochrane Oral Health. Anne Littlewood: I am a salaried member of the Cochrane Oral Health editorial team. Luisa M Fernandez Mauleffinch: I am a salaried member of the Cochrane Oral Health editorial team. Jan E Clarkson: none known. I am Co‐ordinating Editor of Cochrane Oral Health. Martin G McCabe: none known. I am an Editor with Cochrane Oral Health.

Figures

1
1
Study flow diagram.
 RCT = randomised controlled trial.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 KGF versus placebo, Outcome 1 Oral mucositis (any).
1.2
1.2. Analysis
Comparison 1 KGF versus placebo, Outcome 2 Oral mucositis (moderate + severe).
1.3
1.3. Analysis
Comparison 1 KGF versus placebo, Outcome 3 Oral mucositis (severe).
1.4
1.4. Analysis
Comparison 1 KGF versus placebo, Outcome 4 Interruptions to cancer treatment (unscheduled RT breaks of 5 or more days).
1.5
1.5. Analysis
Comparison 1 KGF versus placebo, Outcome 5 Interruptions to cancer treatment (chemotherapy delays/discontinuations).
1.6
1.6. Analysis
Comparison 1 KGF versus placebo, Outcome 6 Oral pain.
1.7
1.7. Analysis
Comparison 1 KGF versus placebo, Outcome 7 Normalcy of diet (use of supplemental nutrition).
1.8
1.8. Analysis
Comparison 1 KGF versus placebo, Outcome 8 Normalcy of diet (worst ability to eat score ‐ 1 to 4 scale).
1.9
1.9. Analysis
Comparison 1 KGF versus placebo, Outcome 9 Number of days in hospital.
1.10
1.10. Analysis
Comparison 1 KGF versus placebo, Outcome 10 Number of days of treatment with opioid analgesics.
2.1
2.1. Analysis
Comparison 2 KGF (dose comparison), Outcome 1 Oral mucositis (any).
2.2
2.2. Analysis
Comparison 2 KGF (dose comparison), Outcome 2 Oral mucositis (moderate + severe).
2.3
2.3. Analysis
Comparison 2 KGF (dose comparison), Outcome 3 Oral mucositis (severe).
2.4
2.4. Analysis
Comparison 2 KGF (dose comparison), Outcome 4 Oral pain (maximum score on 0 to 10 VAS).
2.5
2.5. Analysis
Comparison 2 KGF (dose comparison), Outcome 5 Normalcy of diet (use of TPN).
2.6
2.6. Analysis
Comparison 2 KGF (dose comparison), Outcome 6 Normalcy of diet (worst ability to eat score ‐ 1 to 4 scale).
2.7
2.7. Analysis
Comparison 2 KGF (dose comparison), Outcome 7 Number of days in hospital.
2.8
2.8. Analysis
Comparison 2 KGF (dose comparison), Outcome 8 Number of days of treatment with opioid analgesics.
3.1
3.1. Analysis
Comparison 3 KGF versus chlorhexidine, Outcome 1 Oral mucositis (any).
3.2
3.2. Analysis
Comparison 3 KGF versus chlorhexidine, Outcome 2 Oral mucositis (moderate + severe).
3.3
3.3. Analysis
Comparison 3 KGF versus chlorhexidine, Outcome 3 Oral mucositis (severe).
4.1
4.1. Analysis
Comparison 4 GM‐CSF versus placebo/no treatment, Outcome 1 Oral mucositis (any).
4.2
4.2. Analysis
Comparison 4 GM‐CSF versus placebo/no treatment, Outcome 2 Oral mucositis (moderate + severe).
4.3
4.3. Analysis
Comparison 4 GM‐CSF versus placebo/no treatment, Outcome 3 Oral mucositis (severe).
4.4
4.4. Analysis
Comparison 4 GM‐CSF versus placebo/no treatment, Outcome 4 Oral pain (maximum score on 0 to 10 VAS).
4.5
4.5. Analysis
Comparison 4 GM‐CSF versus placebo/no treatment, Outcome 5 Normalcy of diet (use of feeding tube/parenteral nutrition).
4.6
4.6. Analysis
Comparison 4 GM‐CSF versus placebo/no treatment, Outcome 6 Number of days of treatment with opioid analgesics.
5.1
5.1. Analysis
Comparison 5 GM‐CSF (dose comparison), Outcome 1 Oral mucositis (severe).
6.1
6.1. Analysis
Comparison 6 GM‐CSF versus sucralfate, Outcome 1 Oral mucositis (moderate + severe).
6.2
6.2. Analysis
Comparison 6 GM‐CSF versus sucralfate, Outcome 2 Oral mucositis (severe).
6.3
6.3. Analysis
Comparison 6 GM‐CSF versus sucralfate, Outcome 3 Interruptions to cancer treatment.
6.4
6.4. Analysis
Comparison 6 GM‐CSF versus sucralfate, Outcome 4 Normalcy of diet (use of PEG tube).
7.1
7.1. Analysis
Comparison 7 G‐CSF versus placebo/no treatment, Outcome 1 Oral mucositis (any).
7.2
7.2. Analysis
Comparison 7 G‐CSF versus placebo/no treatment, Outcome 2 Oral mucositis (moderate + severe).
7.3
7.3. Analysis
Comparison 7 G‐CSF versus placebo/no treatment, Outcome 3 Oral mucositis (severe).
7.4
7.4. Analysis
Comparison 7 G‐CSF versus placebo/no treatment, Outcome 4 Interruptions to cancer treatment (RT interruption).
7.5
7.5. Analysis
Comparison 7 G‐CSF versus placebo/no treatment, Outcome 5 Normalcy of diet (use of PEG tube).
8.1
8.1. Analysis
Comparison 8 G‐CSF (pegfilgrastim) versus G‐CSF (filgrastim), Outcome 1 Oral mucositis (any).
8.2
8.2. Analysis
Comparison 8 G‐CSF (pegfilgrastim) versus G‐CSF (filgrastim), Outcome 2 Oral mucositis (moderate + severe).
8.3
8.3. Analysis
Comparison 8 G‐CSF (pegfilgrastim) versus G‐CSF (filgrastim), Outcome 3 Normalcy of diet (use of supplemental nutrition).
9.1
9.1. Analysis
Comparison 9 EGF versus placebo, Outcome 1 Oral mucositis (moderate + severe).
9.2
9.2. Analysis
Comparison 9 EGF versus placebo, Outcome 2 Oral mucositis (severe).
9.3
9.3. Analysis
Comparison 9 EGF versus placebo, Outcome 3 Interruptions to cancer treatment (RT breaks > 2 consecutive days).
9.4
9.4. Analysis
Comparison 9 EGF versus placebo, Outcome 4 Normalcy of diet (use of supplemental nutrition).
10.1
10.1. Analysis
Comparison 10 ITF versus placebo, Outcome 1 Oral mucositis (any).
10.2
10.2. Analysis
Comparison 10 ITF versus placebo, Outcome 2 Oral mucositis (moderate + severe).
10.3
10.3. Analysis
Comparison 10 ITF versus placebo, Outcome 3 Oral mucositis (severe).
11.1
11.1. Analysis
Comparison 11 ITF (dose comparison), Outcome 1 Oral mucositis (any).
11.2
11.2. Analysis
Comparison 11 ITF (dose comparison), Outcome 2 Oral mucositis (moderate + severe).
11.3
11.3. Analysis
Comparison 11 ITF (dose comparison), Outcome 3 Oral mucositis (severe).
12.1
12.1. Analysis
Comparison 12 Erythropoietin versus placebo, Outcome 1 Oral mucositis (any).
12.2
12.2. Analysis
Comparison 12 Erythropoietin versus placebo, Outcome 2 Oral mucositis (moderate + severe).
12.3
12.3. Analysis
Comparison 12 Erythropoietin versus placebo, Outcome 3 Oral mucositis (severe).
12.4
12.4. Analysis
Comparison 12 Erythropoietin versus placebo, Outcome 4 Number of days in hospital.
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References

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Spielberger 2004 {published data only}
    1. Emmanouilides C, Spielberger R, Stiff P, Rong A, Isitt J, Bensinger W, et al. Palifermin treatment of mucositis in transplant patients reduces health resource use: phase III results. Journal of Supportive Oncology 2004;2(2):77‐8.
    1. Spielberger R, Emmanouilides C, Stiff P, Bensinger W, Gentile T, Weisdorf D, et al. Use of recombinant human keratinocyte growth factor (palifermin) can reduce severe oral mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation after radiation‐based conditioning. Journal of Supportive Oncology 2004;2(2):73‐4.
    1. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. New England Journal of Medicine 2004;351(25):2590‐8. - PubMed
    1. Stiff P, Bensinger W, Emmanouilides C, Gentile T, Weisdorf D, Shea T, et al. Treatment of mucositis with palifermin improves patient function and results in a clinically meaningful reduction in mouth and throat soreness: phase III results. Journal of Supportive Oncology 2004;2(2):75‐6.
    1. Stiff PJ, Emmanouilides C, Bensinger WI, Gentile T, Blazar B, Shea TC, et al. Palifermin reduces patient‐reported mouth and throat soreness and improves patient functioning in the hematopoietic stem‐cell transplantation setting. Journal of Clinical Oncology 2006;24(33):5186‐93. - PubMed
Su 2006 {published data only}
    1. Su YB. Double‐blind, randomized trial of granulocyte‐colony stimulating factor (GCSF) versus (v) placebo during postoperative radiation (RT) for advanced resectable squamous cell head and neck cancer (SCCHN): impact on mucositis. Journal of Clinical Oncology 2004;22 Suppl:14S.
    1. Su YB, Vickers AJ, Zelefsky MJ, Kraus DH, Shaha AR, Shah JP, et al. Double‐blind, placebo‐controlled, randomized trial of granulocyte‐colony stimulating factor during postoperative radiotherapy for squamous head and neck cancer. Cancer Journal 2006;12(3):182‐8. - PubMed
Vadhan‐Raj 2010 {published data only}
    1. Vadhan‐Raj S, Trent J, Patel S, Zhou X, Johnson MM, Araujo D, et al. Single‐dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomised trial. Annals of Internal Medicine 2010;153(6):358‐67. - PubMed
    1. Vadhan‐Raj S, Trent JC, Patel SR, Araujo DM, Ludwig LA, Bailey D, et al. Randomized, double‐blind, placebo‐controlled study of palifermin for the prevention of mucositis in patients receiving doxorubicin‐based chemotherapy. Journal of Clinical Oncology 2008;26(15 Suppl):9547.
van der Lelie 2001 {published data only}
    1. Lelie H, Thomas BL, Oers RH, Ek‐Post M, Sjamsoedin SA, Dijk‐Overtoom ML, et al. Effect of locally applied GM‐CSF on oral mucositis after stem cell transplantation: a prospective placebo‐controlled double‐blind study. Annals of Hematology 2001;80(3):150‐4. - PubMed
Wu 2009 {published data only}
    1. Ahn Y, Wu H, Song S, Kim Y, Oh Y, Lee C, et al. The therapeutic effect of recombinant human epidermal growth factor (rhEGF) on mucositis in patients with head and neck cancer undergoing radiotherapy with or without chemotherapy: a double‐blind placebo‐controlled prospective phase II multi‐institutional study. Journal of Clinical Oncology 2008;26(15 Suppl):6021.
    1. Lee S, Song S, Kim Y, Oh Y, Lee C, Keum K, et al. The therapeutic effect of recombinant human epidermal growth factor (rhEGF) on mucositis in patients with head and neck cancer undergoing radiotherapy with or without chemotherapy: a double‐blind placebo‐controlled prospective phase II multi‐institutional clinical trial. International Journal of Radiation Oncology, Biology, Physics 2008;72(1):S32.
    1. Wu HG, Song SY, Kim YS, Oh YT, Lee CG, Keum KC, et al. Therapeutic effect of recombinant human epidermal growth factor (RhEGF) on mucositis in patients undergoing radiotherapy, with or without chemotherapy, for head and neck cancer: a double‐blind placebo‐controlled prospective phase 2 multi‐institutional clinical trial. Cancer 2009;115(16):3699‐708. - PubMed

References to studies excluded from this review

Antin 2002 {published data only}
    1. Antin JH, Lee SJ, Neuberg D, Alyea E, Soiffer RJ, Sonis S, et al. A phase I/II double‐blind, placebo‐controlled study of recombinant human interleukin‐11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation. Bone Marrow Transplantation 2002;29(5):373‐7. - PubMed
de Koning 2007 {published data only}
    1. Koning BA, Philipsen‐Geerling B, Hoijer M, Hahlen K, Buller HA, Pieters R. Protection against chemotherapy induced mucositis by TGF‐beta(2) in childhood cancer patients: results from a randomized cross‐over study. Pediatric Blood & Cancer 2007;48(5):532‐9. - PubMed
Foncuberta 2001 {published data only}
    1. Foncuberta MC, Cagnoni PJ, Brandts CH, Mandanas R, Fields K, Derigs HG, et al. Topical transforming growth factor‐beta3 in the prevention or alleviation of chemotherapy‐induced oral mucositis in patients with lymphomas or solid tumors. Journal of Immunotherapy 2001;24(4):384‐8. - PubMed
Gebbia 1994 {published data only}
    1. Gebbia V, Valenza R, Testa A, Cannata G, Borsellino N, Gebbia N. A prospective randomized trial of thymopentin versus granulocyte‐colony stimulating factor with or without thymopentin in the prevention of febrile episodes in cancer patients undergoing highly cytotoxic chemotherapy. Anticancer Research 1994;14(2B):731‐4. - PubMed
Gladkov 2013 {published data only}
    1. Gladkov O, Buchner A, Bias P, Mueller U, Elsaesser R. Chemotherapy‐associated treatment burden in breast cancer patients receiving lipegfilgrastim or pegfilgrastim: secondary efficacy data from a phase III study. Haematologica 2013;98(Suppl 1):426. - PubMed
Gordon 1993 {published data only}
    1. Gordon B, Spadinger A, Hodges E, Coccia P. Effect of granulocyte macrophage colony stimulating factor (GMCSF) on oral mucositis after autologous bone marrow transplantation. Proceedings of the American Society of Clinical Oncology 1993;12:432. [Abs No 1489] - PubMed
Horsley 2007 {published data only}
    1. Horsley P, Bauer JD, Mazkowiack R, Gardner R, Bashford J. Palifermin improves severe mucositis, swallowing problems, nutrition impact symptoms, and length of stay in patients undergoing hematopoietic stem cell transplantation. Supportive Care in Cancer 2007;15(1):105‐9. - PubMed
Hunter 2009 {published data only}
    1. Hunter A, Mahendra P, Wilson K, Fields P, Cook G, Peniker A, et al. A randomized, double‐blind, placebo‐controlled, multicenter trial of ATL‐104, a swallowable mouthwash, in patients with oral mucositis following peripheral blood stem cell transplantation. Journal of Supportive Oncology 2007;5(4 Suppl 2):52‐3.
    1. Hunter A, Mahendra P, Wilson K, Fields P, Cook G, Peniket A, et al. Treatment of oral mucositis after peripheral blood SCT with ATL‐104 mouthwash: results from a randomized, double‐blind, placebo‐controlled trial. Bone Marrow Transplantation 2009;43(7):563‐9. - PubMed
Ifrah 1999 {published data only}
    1. Ifrah N, Witz F, Jouet JP, Francois S, Lamy T, Linassier C, et al. Intensive short term therapy with granulocyte‐macrophage‐colony stimulating factor support, similar to therapy for acute myeloblastic leukemia, does not improve overall results for adults with acute lymphoblastic leukemia. American Cancer Society 1999;86(8):1496‐505. - PubMed
Iwase 1997 {published data only}
    1. Iwase M, Yoshiya M, Kakuta S, Nagumo M. Clinical trial of recombinant granulocyte colony‐stimulating factor for chemotherapy‐induced neutropenia patients with oral cancer. Journal of Oral and Maxillofacial Surgery 1997;55(8):836‐40. - PubMed
Jones 1996 {published data only}
    1. Jones SE, Schottstaedt MW, Duncan LA, Kirby RL, Good RH, Mennel RG, et al. Randomized double‐blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate‐dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer. Journal of Clinical Oncology 1996;14(11):2976‐83. - PubMed
Karthaus 1998 {published data only}
    1. Karthaus M, Rosenthal C, Huebner G, Paul H, Elser C, Hertenstein B, et al. Effect of topical oral G‐CSF on oral mucositis: a randomised placebo‐controlled trial. Bone Marrow Transplantation 1998;22(8):781‐5. - PubMed
    1. Karthaus M, Rosenthal C, Paul H, Novotny J, Hóbner G, Fenchel K, et al. Effect of topical oral G‐CSF application on oral mucositis in high‐grade lymphoma patients treated with hd‐methotrexate (hd‐mtx) ‐ results of a randomized placebo‐controlled trial. Proceedings of the American Society of Clinical Oncology 1998;17:235.
Kubo 2016 {published data only}
    1. Kubo K, Miyazaki Y, Murayama T, Shimazaki R, Usui N, Urabe A, et al. A randomized, double‐blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma. British Journal of Haematology 2016;174(4):563‐70. - PMC - PubMed
Lee 2016 {published data only}
    1. Lee KH, Kim JY, Lee MH, Han HS, Lim JH, Park KU, et al. A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy‐induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10‐09. Supportive Care in Cancer 2016;24(4):1709‐17. - PMC - PubMed
Legros 1997 {published data only}
    1. Legros M, Fleury J, Bay JO, Choufi B, Basile M, Condat P, et al. rhGM‐CSF vs placebo following rhGM‐CSF‐mobilized PBPC transplantation: a phase III double‐blind randomized trial. Bone Marrow Transplantation 1997;19(3):209‐13. - PubMed
Limaye 2013 {published data only}
    1. Limaye SA, Haddad RI, Cilli F, Sonis ST, Colevas AD, Brennan MT, et al. Phase 1b, multicenter, single blinded, placebo‐controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer 2013;119(24):4268‐76. - PubMed
    1. Murphy B, Limaye SA, Sonis ST, Cilli F, Brennan MT, Hu KS, et al. Phase 1B study assessing safety, tolerability and efficacy of AG013 in subjects with head and neck cancer receiving induction chemotherapy. Supportive Care in Cancer 2012;20(1 Suppl):S259. [Abs No 1078]
Nabholtz 2002 {published data only}
    1. Nabholtz JM, Cantin J, Chang J, Guevin R, Patel R, Tkaczuk K, et al. Phase III trial comparing granulocyte colony‐stimulating factor to leridistim in the prevention of neutropenic complications in breast cancer patients treated with docetaxel/doxorubicin/cyclophosphamide: results of the BCIRG 004 trial. Clinical Breast Cancer 2002;3(4):268‐75. - PubMed
NCT00360971 {published data only}
    1. NCT00360971. Palifermin in lessening oral mucositis in patients undergoing radiation therapy and chemotherapy for locally advanced head and neck cancer [A randomized, phase III, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of palifermin (NSC# 740548; IND # 6370) for the reduction of oral mucositis in patients with locally advanced head and neck cancer receiving radiation therapy with concurrent chemotherapy (followed by surgery for selected patients)]. clinicaltrials.gov/show/NCT00360971 (first received 3 August 2006).
NCT00626639 {published data only}
    1. NCT00626639. A study of palifermin for the reduction of oral mucositis in patients with locally advanced head and neck cancer receiving postoperative radiotherapy and concurrent chemotherapy [A phase 1/2 study to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of weekly doses of palifermin (rHuKGF) for the reduction of oral mucositis in subjects with locally advanced head and neck cancer (HNC) receiving postoperative radiotherapy with concurrent chemotherapy]. clinicaltrials.gov/show/NCT00626639 (first received 21 February 2008).
Pettengell 1992 {published data only}
    1. Pettengell R, Gurney H, Radford JA, Deakin DP, James R, Wilkinson PM, et al. Granulocyte colony‐stimulating factor to prevent dose‐limiting neutropenia in non‐Hodgkin's lymphoma: a randomized controlled trial. Blood 1992;80(6):1430‐6. - PubMed
Ryu 2007 {published data only}
    1. Hoffman KE, Pugh SL, James JL, Scarantino C, Movsas B, Valicenti RK, et al. The impact of concurrent granulocyte‐macrophage colony‐stimulating factor on quality of life in head and neck cancer patients: results of the randomized, placebo‐controlled Radiation Therapy Oncology Group 9901 trial. Quality of Life Research 2014;23(6):1841‐58. - PMC - PubMed
    1. Ryu JK, Swann S, LeVeque F, Scarantino CW, Johnson D, Chen A, et al. The impact of concurrent granulocyte macrophage‐colony stimulating factor on radiation‐induced mucositis in head and neck cancer patients: a double‐blind placebo‐controlled prospective phase III study by Radiation Therapy Oncology Group 9901. International Journal of Radiation Oncology, Biology, Physics 2007;67(3):643‐50. - PubMed
Throuvalas 1995 {published data only}
    1. Throuvalas N, Antonadou D, Pulizzi M, Sarris G. Evaluation of the efficacy and safety of GM‐CSF in the prophylaxis of mucositis in patients with head and neck cancer treated with RT. European Journal of Cancer 1995;31 Suppl 5:S93. [Abs No 431]
Tsurusawa 2016 {published data only}
    1. Tsurusawa M, Watanabe T, Gosho M, Mori T, Mitsui T, Sunami S, et al. Randomized study of granulocyte colony stimulating factor for childhood B‐cell non‐Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study group B‐NHL03 study. Leukemia & Lymphoma 2016;57(7):1657‐64. - PubMed
Vitale 2014 {published data only}
    1. Vitale KM, Violago L, Cofnas P, Bishop J, Jin Z, Bhatia M, et al. Impact of palifermin on incidence of oral mucositis and healthcare utilization in children undergoing autologous hematopoietic stem cell transplantation for malignant diseases. Pediatric Transplantation 2014;18(2):211‐6. - PubMed

References to studies awaiting assessment

ACTRN12606000083594 {published data only}
    1. ACTRN12606000083594. Safety and efficacy trial of whey growth factor extract for oral mucositis [A multicentre, double‐blind, placebo‐controlled, safety and efficacy trial of whey growth factor extract (WGFEA) for oral mucositis in lymphoma patients undergoing carmustine, etoposide, cytosine arabinoside and melphalan (BEAM) chemotherapy and autologous stem cell transplantation]. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=1142 (first received 27 February 2006).
Antonadou 1998 {published data only}
    1. Antonadou D, Athanassiou E, Synodinou M, Koliarakis N, Panoussaki K, Karageorgis P, et al. Evaluation of the efficacy of granulocyte macrophage colony stimulating factor (GM‐CSF) in the prevention of radiation induced mucositis. Radiotherapy and Oncology 1998;48 Suppl 1:S39.
Elsaid 2001 {published data only}
    1. Elsaid A, Farouk M. Significance of anemia and role of erythropoietin in radiation induced mucositis in head and neck cancer patients. International Journal of Radiation Oncology, Biology, Physics 2001;51(3 Suppl 1):368.
Grzegorczyk 2006 {published data only}
    1. Grzegorczyk‐Jazwinska A, Dwilewicz‐Trojaczek J, Kozak I, Karakulska‐Prystupiuk E, Gorska R. Effect of locally applied G‐CSF on oral mucositis after autogeneic and allogeneic stem cell transplantation. Acta Haematologica Polonica 2006;37(2):225‐40.
    1. Grzegorczyk‐Jazwinska A, Dwilewicz‐Trojaczek J, Kozak I, Karakulska‐Prystupiuk E, Gorska R. Effect of locally applied G‐CSF on oral mucositis after autologic stem cell transplantation. Dental and Medical Problems 2004;41(4):695‐701.
Koga 2015 {published data only}
    1. Koga Y, Tsurusawa M, Watanabe T, Gosho M, Mori T, Mitsui T, et al. Randomized study of granulocyte colony stimulating factor for childhood B‐cell non‐Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study Group B‐NHL03 study. British Journal of Haematology 2015;171(Suppl S1):63‐4. - PubMed
NCT00293462 {published data only}
    1. NCT00293462. GM‐CSF mouthwash for preventing and treating mucositis in patients who are undergoing radiation therapy for head and neck cancer [Management of mucositis with GM‐CSF (sargramostim) mouthwash study protocol]. clinicaltrials.gov/show/NCT00293462 (first received 16 February 2006).
NCT00393822 {published data only}
    1. NCT00393822. A study of palifermin for the reduction of oral mucositis in subjects with stage 2B or 3 locally advanced, colon cancer [A randomized, double‐blind, placebo‐controlled study evaluating the efficacy and safety of palifermin (recombinant human keratinocyte growth factor) for reduction of oral mucositis in subjects with stage 2B or 3 locally advanced, colon cancer receiving 5‐FU and leucovorin as adjuvant therapy]. clinicaltrials.gov/show/NCT00393822 (first received 26 October 2006).
NCT02303197 {published data only}
    1. NCT02303197. Clinical trial on the efficacy and safety of Chining decoction in the treatment of radiation stomatitis [A randomized, controlled clinical trial on the efficacy and safety of Chining decoction in the treatment of radiation stomatitis]. clinicaltrials.gov/show/NCT02303197 (first received 25 November 2014).
NCT02313792 {published data only}
    1. NCT02313792. Palifermin for patients receiving hematopoietic stem cell transplantation [Efficacy, safety and quality of life of palifermin on reducing oral mucositis in patients with hematopoietic stem cell transplantation, prospective double‐blind randomized phase III trial]. clinicaltrials.gov/show/NCT02313792 (first received 5 December 2014).
Patte 2002 {published data only}
    1. Patte C, Laplanche A, Bertozzi AI, Baruchel A, Frappaz D, Schmitt C, et al. Granulocyte colony‐stimulating factor in induction treatment of children with non‐Hodgkin's lymphoma: a randomized study of the French Society of Pediatric Oncology. Journal of Clinical Oncology 2002;20(2):441‐8. - PubMed
Schuster 2007a {published data only}
    1. Schuster MW, Anaissie E, Hurd D, Bensinger W, Mason J, McCarty J, et al. Final analysis of the phase II, randomized, double‐blind, placebo‐controlled trial of single‐dose velafermin (CG53135‐05) for the prevention of oral mucositis. Journal of Supportive Oncology 2007;5(4 Suppl 2):58‐9.
Schuster 2007b {published data only}
    1. Schuster MW, Mehta J, Waller EK, Rifkin RM, Micallef I, Hurd D, et al. A randomized placebo controlled phase II trial of prevention of severe oral mucositis using single dose velafermin in patients receiving myeloablative therapy and autologous hematopoietic stem cell transplant (AHSCT). Blood 2007;110(11):615.
Shea 2007 {published data only}
    1. Shea TC, Kewalramani T, Mun Y, Jayne G, Dreiling LK. Evaluation of single‐dose palifermin to reduce oral mucositis (OM) in fractionated total body irradiation (fTBI) and high dose (HD) chemotherapy with autologous peripheral blood progenitor cell (PBPC) transplantation. Blood 2006;108(11 Part 1):875‐6.
    1. Shea TC, Kewalramani T, Mun Y, Jayne G, Dreiling LK. Evaluation of single‐dose palifermin to reduce oral mucositis in fractionated total‐body irradiation and high‐dose chemotherapy with autologous peripheral blood progenitor cell transplantation. Journal of Supportive Oncology 2007;5(4 Suppl 2):60‐2.
Spielberger 2001 {published data only}
    1. Spielberger RT, Stiff P, Emmanouilides C, Yanovich S, Bensinger W, Hedrick E, et al. Efficacy of recombinant human keratinocyte growth factor (rHuKGF) in reducing mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation (auto‐PBPCT) after radiation‐based conditioning ‐ results of a phase 2 trial. Proceedings of the American Society of Clinical Oncology 2001;20(Pt 1):7a. [Abs No 25]

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