Research Evidence Summaries
Giles, F.J., Rodriguez, R., Weisdorf, D., Wingard, J.R., Martin, P.J., Fleming, T.R., et al. (2004). A phase III, randomized, double-blind, placebo-controlled study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy. Leukemia Research, 28(6), 559–565.
Intervention Characteristics/Basic Study Process:
3 ml of iseganan (9 mg) oral solution (n = 251) or placebo, administered as oral rinse six times daily; instructed to rinse mouth with water before each dose, swish study drug to coat all surfaces, gargle and retain for 2 mins, and swallow. (Expectorate if unable to swallow.)
Started study day 1 – within 1 day of chemo or TBI for a minimum of 10 days, adm for 21 days unless neutrophil recovery with absence of OM.
Follow-up assessment 14 days after adm of study drug disc.
The study was comprised of 502 patients, with 251 blinded in each arm. The median age was 48/46.
> 7 yrs and scheduled to receive cytotoxic regimen associated with a >50% incidence of NCI CTC grade > 2 mucositis.
Randomized (stratified by study center and by stomatotoxic trt) strategy 1–non-ablative chemo, 2–ablative cytotoxic therapy followed by auto-SCT, or 3–ablative cytotoxic therapy followed by allogeneic bone marrow or peripheral blood SCT.
28 centers in the United States
Nov 2001 – June 2002
Multi site N = 502 large RCT
NCI CTC stomatitis grades, incidence of UOM in eight sites and opioid analgesic use.
Mouth pain and difficulty swallowing was assessed by use of questionnaires.
43% trt and 37% placebo patients did not have peak stomatitis, grade = 2, p = 0.182.
No significant difference in severity, incidence, peak mouth pain, peak difficulty swallowing, amountt of opiate, or adverse event type or incidence.
Iseganan–did not positively affect the severity of stomatitis or the rate of ulcerative oral mucositis.
H R. Redman and H Fuchs employed by IntraBiotics – probable supporter of study, as articulated in Trotti study.
Findings add to conflicting results in literature regarding efficacy impact of local antimicrobial trt as strategy to reduce severity of stomatitis or UOM.
Trotti, A., Garden, A., Warde, P., Symonds, P., Langer, C., Redman, R., et al. (2004). A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy. International Journal of Radiation Oncology, Biology, Physics, 58(3), 674–681.
Iseganan HCL oral solution for reduction of severity of oral mucositis in patients receiving radiotherapy for head and neck malignancy.
Intervention Characteristics/Basic Study Process:
9 mg doses of iseganan plus institute-specific standard of care (SOC) management of oral hygiene, or placebo plus SOC, or SOC alone (n = 81) in a 3;2;1 distribution. Drug administered within three days before and not more than two days after start RT and continued daily until last day of RT.
The study was comprised of 505 patients, ≥18 years old, with a median range of 56–58 years.
9 mg doses of iseganan plus institute-specific standard of care (SOC) management of oral hygiene (n = 253).
Placebo plus SOC (n = 171)
SOC alone (n = 81)
Head and neck cancer, scheduled to receive minimum of 60 Gy to no less than three protocol specified anatomic sites each a min of 2 cm2 area of mucosa.
Multi-site: 53 institutions US, Canada, France, Germany, UK
July 2000 – Dec 2001
Double blind if study drug or placebo
NCI-CTC radiation mucositis scale, pain, and difficulty swallowing (0 – 10)
Saliva samples for quantitative and qualitative microbiologic assessments
Assessments performed twice weekly during RT and four and eight weeks after completion.
No difference between iseganan and placebo groups for any study endpoint.
Iseganan group – fewer developed ulcerative OM and experienced less severe OM than SOC alone, also smaller proportion of placebo group developed ulcerative OM than SOC alone.
Emphasis on oral rinsing or the vehicle solution used may significantly reduce the incidence and severity of RT-induced ulcerative OM and associated clinical outcomes.
No positive effect
Study concludes with statement that “iseganan oral solution is safe and well tolerated in patients with compromised oral mucosa while receiving RT for head and neck cancer. Investigations with iseganan in clinical settings where infection is a known and significant factor should continue.” However, the treatment effect was not significant.
Sponsored by IntraBiotics Pharmaceuticals – R. Redman and H. Fuchs are employees of IntraBiotics; some authors were paid consultants.
No positive effect
Contributes to mixed findings regarding antimicrobial agents and mucositis
Saunders, D.P., Epstein, J.B., Elad, S., Allemano, J., Bossi, P., van de Wetering, M.D., . . . Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). (2013). Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients. Supportive Care in Cancer, 21, 3191—3207.doi: 10.1007/s00520-013-1871-y
STUDY PURPOSE: To develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis
TYPE OF STUDY: Systematic review
DATABASES USED: Ovid, MEDLINE
KEYWORDS: Acyclovir, amitriptyline, adhesive, amphotericin B, analgesic, analgesia, antacid, antibiotic, anti-infective, alfentanil, aqua oral, benzocaine, coating agent, clarithromycin, diclosan, doxepin, fentanyl, film, fluconazole, gabapentin, IB-367, hydromorphone, iseganan, kaopectate, ketamine, kefir, lidocaine, local anesthetic, “magic” or “miracle” mouthwash, mouth rinse or mouthwash, mucoadhesive, methadone, morphine, nystatin, patient controlled, polymyxin, povidone-iodine, polyvinylpyrrolidone, protegrin, sucralfate, tetracaine, tetracycline, tobramycin, topical, zilactin, xylocaine. In addition, the brand names of commercial products in these categories also were searched, including Gelclair®, MuGard®, and UlcerEase.
INCLUSION CRITERIA: Studies that focused on the use of antimicrobials, coating agents, anesthetics, and analgesics; English studies; published in MEDLINE on or before December 31, 2010; all age groups; and published in a peer-reviewed journal
EXCLUSION CRITERIA: Articles that did not report on effects of an intervention on mucositis, animal or in vitro studies, literature reviews, non-English papers
TOTAL REFERENCES RETRIEVED: 1, 384
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Only articles that reported on the effects of an antimicrobial, mucosal coating agent, anesthetic, or analgesic on oral mucositis that met the inclusion criteria described were included in the review. Also, articles did not have any major or minor flaws per Hadorn and levels of evidence were based on the Somerfield criteria. The results were sorted into three classifications: recommendation, suggestion, and no guidelines possible.
FINAL NUMBER STUDIES INCLUDED = 62
SAMPLE RANGE ACROSS STUDIES, TOTAL PATIENTS INCLUDED IN REVIEW: Not discussed in the review
KEY SAMPLE CHARACTERISTICS: Included patients actively being treated for head and neck cancers, hematologic cancers, and solid tumors with radiotherapy, chemotherapy, chemoradiotherapy, and high-dose total body irradiation for hematopoietic stem cell transplant
Phase of Care and Clinical Applications:
PHASE OF CARE: Active treatment
Recommendations were made against the use of topical antimicrobial agents for the prevention of mucositis, including recommendations against the use of iseganan for mucositis prevention in hematopoietic stem cell transplantation (HSCT) and head and neck radiation therapy (RT) and antimicrobial lozenges for mucositis prevention in head and neck RT. Recommendations were made against the use of sucralfate for the prevention and treatment of oral mucositis due to chemotherapy or RT. Recommendations were made for the use of patient-controlled analgesia with morphine in HSCT, transdermal fentanyl in HSCT and standard-dose chemotherapy treatment, and morphine and doxepin mouth rinse in patients with head and neck cancer undergoing RT. No guidelines were recommended for any of the other agents reviewed due to insufficient or conflicting evidence.
Additional well-designed RCT studies are needed on the prevention and management of oral mucositis. Studies that look at systemic dosing and absorption may be helpful.
Lack of high-level of evidence prevented the development of guidelines in many of the agents reviewed, such as topical anesthetics, antimicrobial agents, and mucosal coating agents.
The recommendations for use in clinical practice were made for the use of patient-controlled analgesia with morphine in patients undergoing HSCT and for transdermal fentanyl in HSCT and standard-dose chemotherapy treatment, and morphine and doxepin mouth rinse in patients with head and neck cancer undergoing RT. Any use of the other agents in this study were not recommended for use in the prevention or treatment of oral mucositis and should be used with caution.