Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis

Mucositis: Perspectives and Clinical Practice Guidelines Supplement to Cancer
Clinical Practice Guidelines for the Prevention and
Treatment of Cancer Therapy–Induced Oral and
Gastrointestinal Mucositis
Edward B. Rubenstein,
BACKGROUND. Oral and gastrointestinal (GI) mucositis can affect up to 100% of
Douglas E. Peterson,
D.M.D., Ph.D.
patients undergoing high-dose chemotherapy and hematopoietic stem cell trans- Mark Schubert,
D.D.S., M.S.D.
plantation, 80% of patients with malignancies of the head and neck receiving Dorothy Keefe,
radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary Deborah McGuire,
R.N., Ph.D.
track mucositis increases mortality and morbidity and contributes to rising health Joel Epstein,
D.M.D., M.S.D.
care costs. Consequently, the Multinational Association of Supportive Care in Linda S. Elting,
Cancer and the International Society for Oral Oncology assembled an expert panel Philip C. Fox,
to evaluate the literature and to create evidence-based guidelines for preventing, Catherine Cooksley,
Stephen T. Sonis,
D.M.D., D.M.Sc.
METHODS. Thirty-six panelists reviewed literature published between January 1966
and May 2002. An initial meeting in January 2002 produced a preliminary draft of
for the Mucositis Study Section of the
guidelines that was reviewed at a second meeting the same year. Thereafter, a Multinational Association of Support-
ive Care in Cancer and the Interna-
writing committee produced a report on mucositis pathogenesis, epidemiology, tional Society for Oral Oncology.
and scoring (also included in this issue), as well as clinical practice guidelines.
RESULTS. Panelists created recommendations from higher levels of evidence and
1 Department of Palliative Care and Rehabilitation suggestions when evidence was of a lower level and there was a consensus regard- Medicine, The University of Texas M. D. AndersonCancer Center, Houston, Texas.
2 Department of Oral Diagnosis, University of Con-necticut Health Center, Farmington, Connecticut.
porate sponsors include Amgen (Thousand Oaks, Daniel, B.S.N., M.S., The University of Texas M. D.
CA), GelTex Pharmaceuticals (Waltham, MA), Helsinn Anderson Cancer Center (Houston, TX); J. Peter Department of Oral Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Healthcare SA (Pazzallo, Switzerland), Human Ge- Donnelly, Ph.D., University Hospital Nijmegen nome Sciences (Rockville, MD), McNeil Consumer (Nijmegen, The Netherlands); Linda Elting, Dr.P.H., 4 Department of Medical Oncology, Royal Adelaide and Specialty Pharmaceuticals (Fort Washington, PA), The University of Texas M. D. Anderson Cancer MGI Pharma (Bloomington, MN), MedImmune (Gaith- Center (Houston, TX); Loree Oberle-Edwards, ersburg, MD), OraPharma (Warminster, PA), and R.D.H., M.S., Scripps Center for Dental Care (La School of Nursing, University of Pennsylvania, Jolla, CA); Douglas Peterson, D.M.D., Ph.D., Uni-versity of Connecticut Health Center (Farmington, 6 Department of Oral Medicine and Diagnostic Sci- Panelists included the following individuals: Andrei CT); Judith Raber-Durlacher, D.D.S., Ph.D., Leiden Uni- ences, College of Dentistry, Chicago, Illinois.
Barasch, D.M.D., M.D.Sc., University of Detroit Mercy versity Medical Center (Leiden, The Netherlands); Ann School of Dentistry (Detroit, MI); B. Nebiyou Bekele, Rose, Ph.D., Vicro (Washington, DC); Edward B. Ruben- Department of Biostatistics and Applied Mathe- Ph.D., The University of Texas M. D. Anderson Cancer matics, The University of Texas M. D. Anderson stein, M.D., The University of Texas M. D. Anderson Center (Houston, TX); Rene-Jean Bensadoun, M.D., Cancer Center (Houston, TX); Mark M. Schubert, D.D.S., Center Antoine-Lacassagne (Nice, France); Michael M.S.D., Seattle Cancer Care Alliance (Seattle, WA); Sol 8 Department of Oral Medicine, Carolinas Medical Brennan, D.D.S., M.H.S., Carolinas Medical Center Silverman, M.A., D.D.S., University of San Francisco (San (Charlotte, NC); Mark Chambers, D.D.S., The Univer- Francisco, CA); Stephen T. Sonis, D.M.D., D.M.Sc., sity of Texas M. D. Anderson Cancer Center (Houston, Brigham and Women’s Hospital (Boston, MA); Fred Spi- Division of Oral Medicine, Brigham and Women’s TX); Catherine Cooksley, Ph.D., The University of jkervet, D.D.S., Ph.D., University Hospital Groningen Texas M. D. Anderson Cancer Center (Houston, TX); (Groningen, The Netherlands); Diane Talentowski, Supported by unrestricted educational grants to the Marcio Da Fonseca, D.D.S., M.S., University of Mich- D.D.S., Loyola University Medical Center (Maywood, Illi- Mucositis Study Section of the Multinational Associ- igan School of Dentistry (Ann Arbor, MI); Kathryn L.
nois); Inger von Bu¨ltzingslo¨wen, D.D.S., Ph.D., Go¨teborg ation of Supportive Care in Cancer (MASCC) and the Damato, R.D.H., M.S., C.C.R.P., University of Con- University (Gothenburg, Sweden); and Ralph Wong, International Society for Oral Oncology (ISOO). Cor- necticut Health Center (Farmington, CT); Betty M.D., University of Manitoba (Winnipeg, MB, Canada).
2004 American Cancer SocietyDOI 10.1002/cncr.20163Published online in Wiley InterScience (www.interscience.wiley.com).
Clinical Practice Guidelines for Mucositis/Rubenstein et al.
ing the interpretation of the evidence by the panel. Panelists identiﬁed gaps in evidence that made it impossible to recommend or not recommend use of speciﬁc agents.
CONCLUSIONS. Oral/GI mucositis is a common side effect of many anticancer
therapies. Evidence-based clinical practice guidelines are presented as a bench-
mark for clinicians to use for routine care of appropriate patients and as a springboard to challenge clinical investigators to conduct high-quality trials geared toward areas in which data are either lacking or conﬂicting. Cancer 2004;100(9
Suppl):2026 –2046. 2004 American Cancer Society.
KEYWORDS: stomatitis, oral mucositis, gastrointestinal mucositis, clinical practice
guidelines.
Oralmucositisisacommoncomplicationofcytore- apy, physicians, oral oncologists, investigators at the
ductive cancer chemotherapy and radiotherapy. It National Cancer Institute, and others have sought to is the dose-limiting toxicity of treatment modalities bring to the attention of the oncology community the like accelerated fractionation and hyperfractionated clinical and economic impact of mucosal injury sec- radiotherapy and of interventions that combine che- ondary to high-dose cancer therapy.1 During the last 5 motherapy and radiotherapy. Its counterpart, gastro- years, new models of the basic mechanisms of pro- intestinal (GI) mucositis, is a well recognized toxicity gression and healing and proposals for new research associated with some standard-dose chemotherapy and treatment strategies have emerged.1,3 Biotechnol- regimens commonly used in cancer treatment and ogy and pharmaceutical industry researchers have with radiotherapy encompassing any area of the GI joined academic clinical investigators in their at- tempts to develop interventions to prevent or treat Oral and GI mucositis may occur in up to 100% of patients undergoing high-dose chemotherapy with Although the basic mechanisms of mucosal barrier hematopoietic stem cell transplantation (HSCT). For injury still are being explored, several signiﬁcant ﬁndings patients receiving this treatment, a 1-point increase in have become evident from clinical investigations. First, an oral mucositis score has been found to be associ- because researchers employ different mucositis scoring ated with a signiﬁcant increase in days with fever, risk systems, each one measuring different endpoints or us- of infection, additional days of total parenteral nutri- ing one-of-a-kind composite endpoints, comparisons tion, use of intravenous narcotic analgesics, total hos- across studies are difﬁcult to make. Furthermore, no pital charges, and 100-day mortality.1 From the pa- comprehensive battery of questions provides a means of uniform evaluation. Second, variations among designs transplantation’s most debilitating side effects.2 of investigations have prevented generalization to re- Recognizing the dramatic clinical and psychologic lated cohorts, preventing reproducibility and inhibiting effects of mucositis and the barrier that this condition progress. Third, patterns of patient care appear to have sometimes becomes to what may be life-saving ther- evolved from a variety of clinical practice domains, in- Edward B. Rubenstein’s current address: MGI Pharma, Bloomington, Minnesota.
Address for reprints: Dorothy Keefe, M.D., Department of Medical Oncology, Royal Adelaide Hospital Cancer Center, Royal Adelaide Hospital, North Terrace, Adelaide,South Australia 5000, Australia; Fax: (011) 618-8232-2148; E-mail: dkeefe@mail.rah.sa.gov.au Dr. Rubenstein has received research funding from and is a member of the speakers program and advisory board at Merck (Whitehouse Station, NJ); he ownscommon stock in and is a member of the advisory board at MGI Pharma; and he is a member of the advisory boards at Endo Pharmaceuticals, McNeil Consumerand Specialty Pharmaceuticals, and OSI Pharmaceuticals.
Dr. Peterson has served as a paid consultant for Aesgen, Inc. (Princeton, NJ).
Dr. Schubert is a member of the advisory boards at Endo Pharmaceuticals, OSI Pharmaceuticals (Melville, NY), and McNeil Consumer and Specialty Pharmaceuticals.
Dr. Keefe has received research funding and speaker’s honoraria from Amgen.
Dr. Elting has received speaker’s honoraria from McNeil Consumer and Specialty Pharmaceuticals and from Endo Pharmaceuticals (Chadds Ford, PA).
Dr. Sonis has served as a consultant for Biomodels and Afﬁliates (Wellesley, MA).
Received December 19, 2003; accepted January 22, 2004.
CANCER Supplement May 1, 2004 / Volume 100 / Number 9
TABLE 1
Levels of Evidence, Grades of Recommendation, and Guideline Hierarchya
Source of evidence
Metaanalysis of multiple well designed, controlled studies; randomized trials with low false-positive and false-negative errors (high At least one well designed experimental study; randomized trials with high false-positive or high false-negative errors or both (low Well designed, quasiexperimental studies, such as nonrandomized, controlled, single-group, pretest-posttest comparison, cohort, Well designed, nonexperimental studies, such as comparative and correlational descriptive and case studies Evidence of Type I or consistent ﬁndings from multiple studies of Type II, III, or IV Evidence of Type II, III, or IV and ﬁndings are generally consistent Evidence of Type II, III, or IV, but inconsistent ﬁndings A recommendation is reserved for guidelines that are based on Level I or Level II evidence A suggestion is used for guidelines that are based on Level III, Level IV, and Level V evidence; this implies panel consensus on the No guideline possible is used when there is insufﬁcient evidence on which to base a guideline; this conclusion implies 1) that there is little or no evidence regarding the practice in question or 2) that the panel lacks a consensus on the interpretation of existingevidence.
a Adapted from: Somerﬁeld M, Padberg J, Pﬁster D, et al. ASCO clinical practice guidelines: process, progress, pitfalls, and prospects. Classic Papers Current Comments. 2000;4:881–886.4 cluding oral oncology, radiation oncology, medical on- surgeons, pathologists, nurses, dental hygienists, basic cology, and hematology, and the effect of this amalgam- scientists, microbiologists, epidemiologists, outcomes ation is unclear. Finally, because most current researchers, and a medical librarian from a compre- treatments seem to have evolved from empiricism rather hensive cancer center. The panel included established than from evidence, a methodologically vigorous review basic science, clinical, and health services investiga- of the literature on which treatments were based seemed tors whose research involves mucosal barrier injury and who publish in the peer-reviewed literature.
In response to these ﬁndings and developments, the Multinational Association of Supportive Care inCancer and the International Society for Oral Oncol- Process Overview
ogy (MASCC/ISOO) created the Mucositis Study Sec- Because of the anticipated scope of the literature tion in 1998 to bring together experts from a number search results and the size of the panel, the topic was of disciplines in oncology to address important issuesin mucositis treatment and research. Accordingly, in subdivided into subtopics, which were assigned to 2000, the study section established a panel of experts working groups of two to ﬁve members. These sub- to develop evidenced-based guidelines for the preven- topics included terminology, epidemiology (primary tion and treatment of oral and GI mucositis associated and agent-speciﬁc or therapy-speciﬁc), basic oral care with anticancer therapy. The resulting guidelines are and oral care protocols, bland oral rinses, analgesics, intended for oral health care specialists, oncology and cryotherapy, topical anesthetics, antimicrobial agents oral medicine patients, oncologists, clinical investiga- (systemic and topical), growth factors and cytokines, tors, and policy makers. This report describes the ob- jectives, methods, and results of the MASCC/ISOO agents, complementary and alternative medicine (in- Mucositis Study Section’s deliberations.
cluding natural agents), low-energy laser therapy, andhemorrhage. The GI Mucositis Working Group was MATERIALS AND METHODS
responsible for initial review of all the same areas as Expert Panel Composition
they related to GI mucositis. In their work, panelists The panel was composed of 36 oral oncologists, radi- employed a systematic weighting of both level and ation oncologists, hematologists, medical oncologists, Clinical Practice Guidelines for Mucositis/Rubenstein et al.
Literature Review and Data Collection
mendations. All panel members approved the ﬁnal A medical librarian, working with the panel cochairs, version submitted for publication, and the guidelines conducted the initial Medline and cancer literature search. Literature was drawn from as early as January1966 and as late as November 21, 2001. Additional Conﬂict of Interest Disclosure and Financial Disclosure
work extended the search through May 31, 2002.
The cost of the conference and administrative services An initial search of the English-language medical for developing the guidelines was paid from unre- literature published from January, 1966 to October, stricted educational grants in support of the MASCC/ 2001 produced more than 500,000 publications related ISOO Mucositis Study Section. The following compa- to cancer and its therapies. Mucositis is not a National nies provided grant support: Amgen (Thousand Oaks, Library of Medicine medical subject heading (MeSH), CA), GelTex Pharmaceuticals (Waltham, MA), Helsinn so stomatitis was used as the primary search term and Healthcare SA (Pazzallo, Switzerland), Human Ge- was combined with cancer. Because stomatitis is a nome Sciences (Rockville, MD), McNeil Consumer National Library of Medicine MeSH heading, articles and Specialty Pharmaceuticals (Fort Washington, PA), are indexed by that term, even if they use the term mucositis. Although the term stomatitis is used widely (Gaithersburg, MD), OraPharma (Warminster, PA), to refer to any mucosal inﬂammation, by deﬁnition, it and RxKinetix (Louisville, CO). Each company was is restricted to inﬂammatory diseases of the mouth, allowed to have representatives attend the guideline whereas the term mucositis has a broader deﬁnition development conference, but representatives were not that encompasses inﬂammation of any mucous mem- allowed to attend the closed administrative sessions or participate in any of the discussions or deliberations After the literature was narrowed to articles about of the panel. Furthermore, companies were informed cancer therapy–related mucosal toxicity, citations that they would not be allowed access to the guide- were sorted using the topic areas deﬁned for the lines until after they were published. The methods for smaller working groups, as described above. Further- the guidelines’ development, all drafts, and ﬁnal con- more, panel members were encouraged to contact tent and style were controlled strictly by the panel.
other investigators and sources for unpublished infor- Each panel member was required to complete a mation that could be used to assist in the guideline.
standardized conﬂict of interest disclosure form re-quiring revelation of all ties to any health care com-pany, companies, commercial products, or products Guideline Development Based on Evidence
in development that potentially could be affected by The literature was distributed to each group along the guidelines’ development and promulgation. Dis- with instructions and scoring sheets based on meth- closure included employment, consultancies, stock ods for reviewing and scoring the literature, according ownership, speaking honoraria, research funding, ex- to Hadorn et al.7 Each group returned its scoring pert testimony, and membership on company advi- sheets along with a bibliography of all publications sory boards. The panel made decisions on a case-by- reviewed. These were collated, copied, and distributed case basis about whether a member’s role should be to each panel member at a guideline development limited as a consequence of a conﬂict of interest.
conference held in Houston, Texas, on January 16 –20,2002. Each group presented draft guidelines before the Revision Dates
entire panel using the structured literature review and The panel expects to review the guidelines annually as guideline development methods of the American So- a routine activity of the MASCC/ISOO Mucositis Study ciety for Clinical Oncology.4 The guideline hierarchy Section and to reconvene every 3 years or more fre- allows for two subtypes of guidelines: 1) recommen- quently, as information warrants, to discuss potential dations and 2) suggestions (Table 1). The panel dis- cussed each guideline to ensure compliance with pub-lished standards for guideline development.8 BIOLOGIC BASIS AND PATHOGENESIS
The panel updated the draft guidelines at its sec- Oral Mucosal Injury
ond meeting, on June 23, 2002, in Boston, Massachu- Mucosal injury is the collective consequence of a setts. The article, which was prepared by a writing number of concurrent and sequential biologic pro- committee with assistance from a medical editor, was cesses. After radiotherapy or chemotherapy, oral mu- circulated to each panel member in two draft forms, cositis is heralded by an initiation phase that is char- giving them two additional opportunities to comment acterized by injury to tissues of the submucosa. After on the levels of evidence and grading of the recom- the up-regulation of a series of early-response genes, CANCER Supplement May 1, 2004 / Volume 100 / Number 9
TABLE 2
Summary of Clinical Practice Guidelines for Care of Patients with Oral and Gastrointestinal Mucositis
1. The panel suggests the use of oral care protocols that include patient education in an attempt to reduce the severity of mucositis from chemotherapy or radiation therapy.
2. The panel recommends patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing HSCT.
3. To reduce mucosal injury, the panel recommends the use of midline radiation blocks and three-dimensional radiation treatment.
4. The panel recommends benzydamine for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiotherapy.
5. The panel recommends that chlorhexidine not be used to prevent oral mucositis in patients with solid tumors of the head and neck who are undergoing radiotherapy.
6. The panel recommends that patients receiving bolus 5-FU chemotherapy undergo 30 min oral cryotherapy to prevent oral mucositis.
7. The panel suggests using 20–30 min oral cryotherapy in an attempt to decrease mucositis in patients treated with bolus doses of edatrexate.
8. The panel recommends that acyclovir and its analogues not be used routinely to prevent mucositis.
9. The panel recommends that chlorhexidine not be used to treat established oral mucositis.
High-dose chemotherapy with or without TBI plus HSCT: prevention 10. The panel does not recommend the use of pentoxifylline to prevent mucositis in patients undergoing HSCT.
11. LLLT requires expensive equipment and specialized training. Because of interoperator variability, clinical trials are difﬁcult to conduct, and their results are difﬁcult to compare; nevertheless, the panel is encouraged by the accumulating evidence in support of LLLT. For centers capable of supporting the necessary technology and training, the panel suggests the use of LLLT in an attempt to reduce theincidence of oral mucositis and its associated pain in patients receiving high-dose chemotherapy or chemoradiotherapy before HSCT.
1. The panel suggests using 500 mg oral sulfasalazine twice daily to help reduce the incidence and severity of radiation-induced enteropathy in patients receiving external-beam radiotherapy to the pelvis.
2. Oral sucralfate does not prevent acute diarrhea in patients with pelvic malignancies undergoing external beam radiotherapy; and, compared with placebo, it is associated with more gastrointestinal side effects, including rectal bleeding. Consequently, the panel recommends that oral sucralfate not be used.
3. The panel recommends that 5-aminosalicylic acid and its related compounds mesalazine and olsalazine not be used to prevent gastrointestinal mucositis.
4. The panel suggests the use of sucralfate enemas to help manage chronic, radiation-induced proctitis in patients with rectal bleeding.
Standard-dose and high-dose chemotherapy: prevention 5. The panel recommends either ranitidine or omeprazole for the prevention of epigastric pain after treatment with cyclophosphamide, methotrexate, and 5-FU or treatment with 5-FU with or without Standard-dose and high-dose chemotherapy: treatment 6. When loperamide fails to control diarrhea induced by standard-dose or high-dose chemotherapy associated with HSCT, the panel recommends octreotide at a dose of at least 100 ␮g administered Combined chemotherapy and radiotherapy: prevention 7. The panel suggests the use of amifostine to reduce esophagitis induced by concomitant chemotherapy and radiotherapy in patients with nonsmall cell lung cancer.
HSCT: hematopoietic stem cell transplantation; 5-FU: 5-ﬂuorouracil; TBI: total-body irradiation; LLLT: low-level laser therapy.
changes are observed in the endothelium, connective The ulcerative phase is exacerbated by local bacterial tissue, and extracellular matrix that are mediated by colonization, which results in a barrage of cell wall reactive oxygen species (ROS), the ceramide pathway, products penetrating into the submucosa and ampli- and a number of transcription factors, including nu- fying damaging mechanisms. Increased transcription clear factor-kappa ␤ (NF-␬B). The initial injury precip- factor activity and levels of cytokines and other medi- itates connective tissue deterioration and the rapid ators drive additional local responses, including an- up-regulation of a second set of genes that results in giogenesis. Ultimately, healing occurs as healthy epi- direct and indirect signaling and early apoptosis of thelium migrates from the wound margins, stimulated clonogenic stem cells in the basal epithelium. The by signals from the submucosa. A complete discussion proinﬂammatory cytokines (tumor necrosis factor-␣, of the biologic basis and pathogenesis of oral and GI interleukin 1␤, and interleukin 6) are likely to be mucositis may be found in the accompanying article among signaling molecules. These signaling mole- cules also have the ability to amplify the up-regulationof transcription factors (e.g., NF-␬B) further, leading to GI Mucosal Injury
production of additional proinﬂammatory cytokines, The pathobiology of mucositis in the alimentary tract tissue injury, and apoptosis. Reduced renewal of mu- beyond the oral cavity is similar to that described cosal epithelium occurs despite focal bursts of hyper- above for oral mucositis and poses the same potential proliferative activity in response to the early up-regu- threat to successful therapy because of dose delays or lation of genes associated with epithelium healing.
dose reductions. Setting the GI tract apart in its man- Epithelial apoptosis and necrosis exceed hyper- ifestation of mucosal injury are the morphologic and proliferative activity and result in an ulcerative phase functional differences between its sections. These in which full-thickness mucosal damage is apparent.
largely account for the differences in functional and Clinical Practice Guidelines for Mucositis/Rubenstein et al.
symptomatic outcomes between oral and GI mucositis administration of irinotecan often is associated with severe GI mucositis, which affects Ͼ 20% of patients The plethora of rapidly dividing cells in the GI receiving certain doses and regimens. Approximately tract make the tract particularly vulnerable to cyto- 75– 85% of bone marrow transplantation recipients toxic chemotherapeutic agents. On Day 1 after che- experience mucositis, and in some studies, oral mu- motherapy, the ﬁrst abnormality observed may be an cositis is the most common and most debilitating side increase in apoptosis. Afterward, reductions in crypt effect reported.1,2 Conditioning regimens that include length, villus area, and mitotic index follow, with each melphalan are associated with particularly high rates of these quantities reaching a nadir on Day 3. By Day 5, rebound hyperplasia is underway, and eventually, The risk of radiation-induced mucositis varies normalization follows.10 Abdominal pain, bloating, with the site of radiotherapy, dosage, and fraction- and diarrhea begin around Day 3 and settle by Day 7, ation. Radiotherapy to the head and neck or to the when oral symptoms typically are appearing. Func- pelvis or abdomen is associated with an increased tional changes, such as sugar permeability, however, incidence of Grade 3 and Grade 4 oral or GI mucositis, persist after recovery from symptoms and morpho- respectively, often exceeding 50% of patients.20 Among patients undergoing head and neck radiother- Intestinal permeability is also one of a number of apy, pain and decreased oral function may persist long changes that occur during fractionated radiotherapy.
after the conclusion of therapy.21 Accelerated fraction- Along with histologic injury, intestinal permeability ation increases the risk of mucositis to Ͼ 70% of pa- actually is maximal midcourse. These improve toward tients in most trials.20 Oral mucositis is particularly the end of the radiotherapy course, despite persistent profound and prolonged among HSCT recipients who injury and noticeably increasing symptoms, because receive total-body irradiation for conditioning.
of compensatory changes.12,13 Nonetheless, in manypatients, radiation’s toxicities result in such chronic CLINICAL PRACTICE GUIDELINES FOR CARE OF
functional disabilities as malabsorption and dysmotil- PATIENTS WITH ORAL MUCOSITIS
ity, in contrast to chemotherapy’s more transient ef- Foundations of Care
fects. Histologic changes include mucosal atrophy, in- testinal wall ﬁbrosis, and vascular sclerosis. Life- Lack of a consistent deﬁnition of which elements con- stitute basic oral care and highly variable study de- obstruction, perforation, or ﬁstula formation, can signs do not allow a guideline for basic oral care re- lated to mucositis prevention or treatment. There is Efforts to understand better the biologic and his- insufﬁcient evidence to conclude that actions such as tologic mechanisms and the quantitative roles of dif- brushing teeth using foam ‘toothbrushes’ or swabs, ferent factors in GI mucositis are made more difﬁcult ﬂossing, or using topical ﬂuoride will prevent or treat by the inaccessibility of signiﬁcant GI segments and cancer therapy–induced mucositis. A number of top- the problems inherent in obtaining sequential biopsy ical agents (bland rinses, antimicrobial rinses) that specimens. Approaches to alleviating toxicity also often are included in basic oral care are addressed in have included efforts to elucidate the mechanisms of Nonetheless, it is important to recognize that al- though there is not sufﬁcient scientiﬁc evidence to EPIDEMIOLOGY
provide a guideline for basic oral care, its importance The incidence of oral and GI mucositis varies, depend- in maintaining mucosal health, integrity, and function ing on chemotherapy regimen and on treatment mo- generally is accepted. The purpose of basic oral care is dality. Prolonged or profound oral and GI mucositis to reduce the impact of the oral microbial ﬂora, re- leads to signiﬁcant pain and morbidity, excess costs duce cancer therapy–related symptoms of pain and for supportive care and hospitalization, increased fre- bleeding, and prevent soft tissue infections that may quency of infection, and chemotherapy dose delays have systemic sequelae. In addition, maintenance of and reductions.15,16 Excluding very high-risk regi- good oral hygiene will reduce the risk of dental com- mens, HSCT, and radiotherapy, rates of mucositis are plications, including caries and gingivitis. For these generally in the 5–15% range. However, administra- reasons, basic oral care is an important component of tion of 5-ﬂurouracil (5-FU), with or without leucov- care of the patient with cancer.22 Although the impor- orin, is associated with oral mucositis in as much as tance of effective oral hygiene has been described in 40% of patients.17 Grade 3– 4 oral mucositis ap- many articles, the methods and techniques employed proaches 10 –15% among 5-FU recipients.18 Similarly, typically are based on preference and anecdotal expe- CANCER Supplement May 1, 2004 / Volume 100 / Number 9
rience. A single study23 demonstrated that tooth tolerability, and adherence in patients with leukemia brushing reduced the number of oral lesions in pa- and those undergoing transplantation.
tients receiving cancer chemotherapy. Using foam Improved oral status (i.e., reduced mucositis or toothbrushes is not equivalent to toothbrushing and increased oral comfort) was reported in three random- cannot be recommended for plaque control or caries ized clinical studies,30–32 and only one32 study re- ported no change in mucositis at the conclusion of thestudy. Despite ﬂaws, including failure to blind theinvestigator in one of the studies, measurement is- Oral care protocols and patient education sues, and a wide range of sample sizes (15–150 partic- Guideline: The panel suggests the use of oral care ipants), the collective results suggest that using a sys- protocols that include patient education in an attempt tematic protocol improves patient outcomes. A fourth to reduce the severity of mucositis from chemother- randomized clinical trial33 did not show a statistically apy or radiotherapy (level of evidence, III; grade of signiﬁcant difference between controls and those un- dergoing the intervention; however, participants who Oral care protocols are used in an attempt to were taught the protocols performed oral hygiene rou- prevent and manage mucositis, with an emphasis on tines more frequently compared with the control feasibility, adherence, and comprehensive patient ed- group and reported feeling more prepared to manage ucation about mucositis and oral care. The current review did not evaluate speciﬁc agents or approaches Three quasiexperimental, nonrandomized studies used in protocols, and insufﬁcient evidence prevents of oral care protocols also support their use in reduc- the recommendation of one protocol over any other.
ing the incidence or severity of mucositis. Beck24 re- Because oral care has long been integral to nursing ported on the implementation and testing of an oral practice,24,25 nurses are the health professionals who care protocol in patients with cancer and found that usually provide oral care to patients with mucositis; oral cavity physical condition improved and infection thus, many of the reports are drawn from the nursing decreased with implementation of an oral care proto- col. Levy-Polack et al.34 reported that pediatric pa- Implementation of oral care protocols is generally tients with leukemia who followed a daily preventive a systematic process in which speciﬁc agents are not protocol (plaque removal, chlorhexidine rinse, io- the main focus. Rather, the important components of dopovidone, and nystatin) experienced a signiﬁcant this implementation include feasibility, adherence, decrease in moderate mucositis and candidiasis and performance, and outcomes. Patient education refers had improved oral hygiene. Cheng et al.35 found that to comprehensive, theory-based, educational ap- an oral care protocol (tooth brushing, chlorhexidine proaches that prepare individuals for medical proce- rinse [0.2%], and saline) resulted in a 38% reduction in dures, including what to expect and how to cope, an incidence and a signiﬁcant reduction in severity and approach that also has been termed psychoeduca- associated oral pain in pediatric patients with cancer.
tion,26 because it addresses both physical and psycho- The remaining studies did not test oral care pro- logic aspects of the symptoms (e.g., distress, anxiety).
tocols formally but, rather, surveyed institutions or Programmatic reports provided support (although not health professionals about oral care. They revealed empiric evidence) for the value of implementing insti- widely disparate practices and little agreement on tutionalized oral care protocols or standards. Three standardized approaches to oral care.36–40 randomized clinical trials, despite their ﬂaws, andthree nonrandomized studies also yielded support.
Palliative care (including pain management) The ﬁndings of these investigations form the founda- Palliation of mucositis and acute oral pain is an im- portant component of patient care. Approaches in- With the speciﬁc objective of reducing mucositis, clude the use of systemic analgesics and other indi- Graham et al.27 initiated a unit-based oral care proto- col and teaching program and documented a reduc- (sometimes called magic or miracle mouthwash), tion in mucositis. Larson et al.28 used the PRO-SELF coating agents, and topical anesthetics/analgesics.
Mouth Aware Program in a study of outpatients re-ceiving chemotherapy and demonstrated feasibility of Systemic analgesics. Guideline: The panel recom- the program in maintaining oral hygiene. To improve mends patient-controlled analgesia (PCA) with mor- the consistency of oral care, Yeager et al.29 imple- phine as the treatment of choice for oral mucositis mented an oral care standard in two inpatient hema- pain in patients undergoing HSCT (level of evidence, I; tology/oncology units and demonstrated feasibility, grade of recommendation, A). Control of mucositis- Clinical Practice Guidelines for Mucositis/Rubenstein et al.
induced pain is achieved by PCA with intravascular niﬁcant dose modiﬁcation, have been studied. The morphine sulfate.41–49 Level I evidence supports PCA quality and modest numbers of publications describ- for oral mucositis pain in patients who undergo HSCT, ing these methods preclude the establishment of spe- but there is little evidence to recommend its use in ciﬁc guidelines. However, it has been shown that oral other patients and settings. Although other opiates mucosal injury secondary to radiotherapy may be re- may achieve similar pain control, morphine appears duced signiﬁcantly by the use of midline radiation to require relatively lower drug doses and may be blocks62 and by three-dimensional treatment delivery, tolerated better. Pediatric populations also can use which reduces the volume of mucosa exposed to irra- PCA efﬁciently. Initial studies of transdermal fentanyl have been published,44,49 but further study is requiredto conﬁrm its efﬁcacy.
Despite the limited evidence described above, in Guideline: The panel recommends benzydamine for general, pain management for mucositis should be the prevention of radiation-induced mucositis in pa- governed by prevailing clinical practice guidelines, tients with head and neck cancer receiving moderate- such as those promulgated by the World Health Orga- dose radiotherapy (level of evidence, I; grade of recom- nization and the Agency for Healthcare Research and mendation, A). Benzydamine hydrochloride is a Quality for managing acute pain.50,51 These guidelines unique agent with antiinﬂammatory effects. It is a include accepted approaches for the use of nonopi- nonsteroidal drug (although not a classic nonsteroidal oids, opioids, adjuvant medications, and assessment antiinﬂammatory drug) that is applied topically. In tools. Depending on the individual patient popula- addition to its antiinﬂammatory properties, benzy- tion, numerous routes may be considered, including damine has analgesic, anesthetic, and antimicrobial oral, transmucosal (oral and rectal), and transdermal capabilities, which make exact classiﬁcation of this routes, as well as various intravenous approaches drug difﬁcult. Recent studies have demonstrated that (continuous infusion, bolus, and PCA).
benzydamine also inhibits the production and effectsof proinﬂammatory cytokines, particularly TNF-␣.
Topical preparations and other approaches. Various These ﬁndings favor antiinﬂammatory effects as the topical preparations have been in widespread use for main mode of action for this agent. It has been shown the treatment of mucositis and its accompanying pain.
in single-center and multicenter, randomized, con- The most common ingredients include viscous lido- trolled clinical trials that topical benzydamine reduces caine, benzocaine, milk of magnesia, kaolin, pectin, the frequency and severity of ulcerative oral lesions chlorhexidine, and dyphenhydramine. Topical analge- and decreases pain in radiation-induced oral mucosi- sics that can be considered include the single agents tis.64–68 Although it is not currently available in the United States, a pivotal Phase III trial of this agent is Many topical agents have been compounded in mixtures. There is no signiﬁcant evidence of the effec- Benzydamine hydrochloride has been studied tiveness or tolerability of these mixtures.31,34,53–61 most extensively for the prevention and reduction of Some of these preparations may be minimally supe- the severity of radiation-induced mucositis of the oral rior to normal saline, although the evidence is not cavity. Several small, double-blinded, randomized tri- convincing. Thus, the lack of compelling evidence pre- als were reported in the 1980s. Two early studies64,67 vents the panel from recommending any palliative suggested that benzydamine was effective in reducing mixture for therapeutic intent in oral mucositis. How- the severity of the pain associated with oral mucositis.
ever, because concern exists regarding absorption of In 2001, the results of a large, multicenter, double- amide anesthetics (e.g., lidocaine) through damaged blinded, randomized trial were published68 and dem- mucosal surfaces, both individual agents and pallia- onstrated that benzydamine improved the ulcer-free tive mixtures require further study to determine their rate and diminished the incidence of ulceration and erythema. That study used a sophisticated mucositisscoring system that measured the severity of mucositis Radiotherapy: Prevention
and duration of mucositis by using an area-under-the- Use of blocks and three-dimensional treatment delivery curve analysis. The study also demonstrated a delay in Guideline: To reduce mucosal injury, the panel rec- the need for analgesics in patients who were treated ommends the use of midline radiation blocks and with benzydamine compared with patients who were three-dimensional radiation treatment (level of evi- treated with placebo. The study’s conclusions were dence, II; grade of recommendation, B). The effects of based on cumulative radiation doses of 50 grays (Gy), altering the delivery of cytotoxic therapy, without sig- and the efﬁcacy of the drug with higher doses or with CANCER Supplement May 1, 2004 / Volume 100 / Number 9
combination chemotherapy was not established. In a dence, IV; grade of recommendation, B). Recent non- small subgroup of patients who received accelerated randomized studies suggest that oral cryotherapy may radiation, benzydamine was not effective.
reduce oral mucositis related to edatrexate.76–78 Therationale for its use in this situation is related to the short serum half-life of edatrexate.
Guideline: The panel recommends that chlorhexidine It should be noted that oral cryotherapy is not not be used to prevent oral mucositis in patients with expected to be useful in preventing oral mucositis in solid tumors of the head and neck who are undergoing patients receiving 5-FU by continuous infusion or in radiotherapy (level of evidence: II; grade of recommen- patients undergoing administration of such agents as dation, B). Chlorhexidine is a broad-spectrum, topical methotrexate, doxorubicin, or other agents with a long antiseptic. The evidence from three studies was con- serum half-lives. This therapy’s low cost and minimal sistent in showing that this agent had no impact in preventing the development of oral mucositis in pa-tients with solid tumors of the head and neck under- going radiotherapy.69–71 Chlorhexidine may be used Guideline: The panel recommends that acyclovir and for its antiplaque and antifungal properties as part of its analogues not be used routinely to prevent mucosi- tis (level of evidence, II; grade of recommendation, B).
Acyclovir is effective in reducing herpes simplex virus Standard-Dose Chemotherapy: Prevention
(HSV) infection in patients with leukemia or lympho- ma,79,80 but oral mucositis still develops in patients Cryotherapy with bolus doses of 5-FU. Guideline: The routinely receiving acyclovir or one of its prodrugs for panel recommends that patients receiving bolus 5-FU prophylaxis. This suggests that HSV infection plays chemotherapy undergo 30 minutes of oral cryother- little or no role in causing oral mucositis.
apy to prevent oral mucositis (level of evidence, II;grade of recommendation, A). It was hypothesized thatplacing ice chips in the mouth, starting 5 minutes Standard-Dose Chemotherapy: Treatment
before 5-FU bolus injection and continuing for a total of 30 minutes, would cause cooling of the oral cavity, Guideline: The panel recommends that chlorhexidine which would lead to vasoconstriction. It was sug- not be used to treat established oral mucositis (level of gested that the vasoconstriction would allow less 5-FU evidence, II; grade of recommendation, A). Research to reach the oral mucosa, thereby attenuating 5-FU- has failed to produce evidence that supports the use of chlorhexidine to treat established mucositis. A well One randomized but nonblinded study of 95 pa- designed, multicenter, double-blind clinical trial con- tients was conducted in patients who were receiving ducted in 23 outpatient and ofﬁce settings evaluated bolus 5-FU. Mucositis was evaluated by questionnaire.
the effectiveness of a standardized oral care protocol Results from that trial illustrated that the group receiv- (PRO-SELF) plus ‘magic’ mouthwash, salt and soda ing oral cryotherapy exhibited a reduction of approx- rinses, and chorhexidine in reducing the duration of imately 50% in mucositis.72 Cascinu et al.73 randomly pain associated with oral mucositis induced by stoma- allocated 84 patients who were receiving 5-FU to re- totoxic chemotherapy.58 Patients initially were evalu- ceive oral cryotherapy, and again, a reduction of ap- ated by a physician or nurse to conﬁrm the presence proximately 50% in mucositis was observed among of oral mucositis. Patients then underwent a standard- those who received oral cryotherapy.
ized oral care protocol that taught self-care, and they A subsequent randomized clinical trial of oral cryo- subsequently received a 12-day supply of study therapy for either 30 minutes or 60 minutes reported mouthwash. There was no difference in the efﬁcacy of that extending the duration of oral cryotherapy did not the three treatments in time to resolution of mucositis provide additional beneﬁt; therefore, 3-minute cryother- or in pain relief; however, the salt and soda rinses apy was recommended.74 A study of ocular cryotherapy represented the least costly option. This study clearly (cold packs over the eyes) also showed reduction in demonstrated no signiﬁcant difference in pain ratings 5-FU-induced conjunctivitis (P ϭ 0.001).75 among the treatment groups, despite the fact thatmagic mouthwash included lidocaine and the chlo- Cryotherapy with edatrexate. Guideline: The panel rhexidine mouthwash contained alcohol, which can suggests using 20 –30 minutes of oral cryotherapy in sting on contact with oral mucosa. Other studies also an attempt to decrease mucositis in patients who are failed to ﬁnd any beneﬁt of chlorhexidine as a treat- treated with bolus doses of edatrexate (level of evi- ment for established oral mucositis.81,82 Clinical Practice Guidelines for Mucositis/Rubenstein et al.
High-Dose Chemotherapy With or Without Total-Body
cidence and severity of radiation-induced enteropathy Irradiation plus HSCT: Prevention
in patients receiving external-beam radiotherapy to the pelvis (level of evidence, II; grade of recommenda- Guideline: The panel does not recommend the use of tion, B). Radiation-induced enteropathy with abdom- pentoxifylline to prevent mucositis in patients under- inal pain and diarrhea occurs in 75–90% of patients going HSCT (level of evidence, II; grade of recommen- receiving external-beam radiotherapy for such com- dation, B). Six clinical trials utilizing pentoxifylline to mon pelvic malignancies as prostate, rectal, or cervical prevent mucositis were evaluated.83–88 Five of six trials cancer and typically begins in the second or third had no placebo control and no investigator blinding.
week of treatment. Kilic et al.91 conducted a well de- No randomization was made in four of the six clinical signed, randomized, double-blind controlled trial of trials. Of the six trials, four had signiﬁcant ﬂaws in sulfasalazine (500 mg twice daily) or placebo in 87 their designs. Both of the well designed, randomized patients who had a variety of pelvic malignancies and trials87,88 demonstrated that pentoxifylline failed to were scheduled to receive 46 –50 Gy in 23–25 fractions prevent the development of mucositis.
of external-beam radiotherapy to the whole pelvis.
Whereas the incidence of Grade 1– 4 diarrhea was 55% among sulfasalazine-treated patients, it was 86% Guideline: Low-level laser therapy (LLLT) requires ex- among patients receiving the placebo (P ϭ 0.001).
pensive equipment and specialized training. Because None of the patients in the sulfasalazine-treated group of interoperator variability, clinical trials are difﬁcult experienced Grade 4 diarrhea, compared with 16% of to conduct, and their results are difﬁcult to compare; patients in the placebo group. There was no signiﬁ- nevertheless, the panel is encouraged by the accumu- cant difference in toxicity between the two treatment lating evidence in support of LLLT. The panel suggests groups. Further work is required to explain the mech- that at centers that are capable of supporting the anism underlying the difference between sulfasalazine necessary technology and training, LLLT should be and other closely related compounds such as 5-amino used in an attempt to reduce the incidence of oral salicylic acid (5-ASA), melsalazine, and olsalazine (see mucositis and its associated pain in patients who are receiving high-dose chemotherapy or chemoradio-therapy prior to HSCT (level of evidence, II; grade of Guideline: Oral sucralfate does not prevent acute di- Over the last several years, appropriate laboratory arrhea in patients with pelvic malignancies who are and clinical evidence has been accumulating steadily undergoing external-beam radiotherapy. Compared to support the use of LLLT to promote biostimulation with placebo, sucralfate was found to be associated applications. It has been reported that LLLT promotes with increased GI side effects, including rectal bleed- wound healing and reduces pain and inﬂammation.
ing. Consequently, the panel recommends that oral Different effects appear to be related to laser charac- sucralfate not be used. (level of evidence, I; grade of teristics (wavelength and energy dose) and the partic- The North Central Cancer Treatment Group con- Helium-neon (He-Ne) laser (␭ ϭ 632.8 nm) treat- ducted a well designed, randomized controlled trial of ment has been the most frequently studied form of oral sucralfate (1.5 gm every 6 hours) and a placebo in LLLT for the prevention or reduction of oral mucositis 125 patients treated with 45–53.5 Gy external-beam and oral pain associated with cancer therapy (includ- radiotherapy in fractions of 1.7–2.1 Gy per day. Among ing HSCT).89,90 Research currently is underway on the the 123 evaluable patients, diarrhea was moderate to use of diode lasers with wavelengths ranging from 650 severe in 53% of patients receiving sucralfate but only to 905 nm. It appears that laser therapy produces no 41% of patients receiving placebo. Signiﬁcantly more toxicity and is atraumatic to patients. However, LLLT patients in the sucralfate group reported fecal incon- requires speciﬁc (often expensive) equipment, and tinence, the need for protective clothing, and more intense nausea compared with the placebo group (PϽ 0.05 for all comparisons).92 CLINICAL PRACTICE GUIDELINES FOR THE
In a multicenter, double-blind trial involving pa- PREVENTION AND TREATMENT OF GI MUCOSITIS
tients with clinically localized prostate malignancies Radiotherapy: Prevention
who were scheduled to receive deﬁnitive radiotherapy (Ն 60 Gy, with a superior limit of ﬁeld below the Guideline: The panel suggests the use of 500 mg of greater sciatic notch), 335 patients were randomized sulfasalazine orally twice daily to help reduce the in- to receive either 3 gm oral sucralfate twice daily or CANCER Supplement May 1, 2004 / Volume 100 / Number 9
placebo.93 There was no signiﬁcant difference in pa- Radiotherapy: Treatment
tient self-reports of stool frequency, consistency, mu- cus, or pain (P Ͼ 0.20 for all comparisons); however, Guideline: The panel suggests using sucralfate enemas the sucralfate-treated group had an increased inci- to help manage chronic radiation-induced proctitis in dence of rectal bleeding (64%) compared with the patients with rectal bleeding (level of evidence, III; placebo group (47%; P ϭ 0.001).
grade of recommendation, B). It is believed that O’Brien et al.94 evaluated the use of sucralfate chronic radiation-induced proctitis or proctosigmoid- rectal enemas versus a placebo, beginning at the itis is due to intestinal wall ﬁbrosis along with vascular onset of radiotherapy for prostate malignancy and sclerosis leading to ischemia. Its incidence ranges continuing for 2 weeks after completion of radio- from 2% to 20%. Risk factors for radiation-induced therapy, in preventing acute proctitis. Patients were proctitis include higher doses of radiotherapy, intra-cavitary radiation, and the use of radiosensitizers. This assessed monthly for 3 months and then every 6 condition may be more common in patients who have months for 5 years. Sucralfate was no better than experienced it previously. Clinical manifestations in- placebo at reducing the risk of acute radiation-in- clude diarrhea, tenesmus, urgency, and rectal bleed- duced proctitis. Cox proportional hazards modeling ing, which frequently is severe enough to require indicated that patient self-assessment of moderate blood transfusions. Kochhar et al.98,99 randomized 37 or severe rectal pain was the best predictor of sub- consecutive patients with radiation-induced proctitis sequent development of late radiation-related tox- to a 4-week course of sulfasalazine (3 gm orally plus icity. There were no signiﬁcant differences in the rectal prednisolone enemas twice daily) or rectal su- rates of late rectal bleeding between the sucralfate- cralfate enemas twice daily plus an oral placebo. Both regimens were associated with signiﬁcant clinical im-provement and with improvement observed at endo-scopic evaluation. In a second study, the same inves- tigators evaluated 26 consecutive patients with Guideline: The panel recommends that 5-ASA and the radiation-induced proctitis and persistent rectal related compounds mesalazine and olsalazine not be bleeding whose condition had failed to respond to used for the prevention of GI mucositis (level of evi- bulk-forming agents, sulfasalazine, and topical corti- dence, I; grade of recommendation, A). In three sepa- costeroids.99 All patients were treated with sucralfate rate studies,95–97 it was found that 5-ASA, mesalazine, rectal enemas (20 mL 10% sucralfate suspension in and olsalazine were of no beneﬁt or caused more water twice daily). After 4 weeks of therapy, all 26 diarrhea than placebo did in patients receiving pelvic patients exhibited a reduction in the severity of rectal radiotherapy. Baughan et al.95 randomized 73 patients bleeding (P Ͻ 0.01). At a median follow-up of 45.5 who were undergoing pelvic radiotherapy to receive months, 17 patients had no further bleeding.
either 5-ASA or placebo and reported more diarrhea (P Other therapies for chronic radiation proctitis ϭ 0.070), more severe diarrhea (P ϭ 0.014), and more with bleeding include argon beam coagulation, elec- days per week with diarrhea (P ϭ 0.026) in the 5-ASA trocoagulation, formalin treatment, and hyperbaric group compared with the placebo group. In a double- oxygen treatment.100–112 Although these therapies blind, multicenter study, Resbeut et al.96 randomized have not been examined in randomized controlledtrials, the results from cohort studies are encouraging, 153 patients who were receiving Ն 45 Gy of external- especially with respect to laser and formalin treat- beam pelvic radiotherapy to receive either 4 gm me- ments. Because of the lack of randomized trials and salazine per day or placebo. Diarrhea rates were sim- the limited experience with these therapies, the panel ilar in both groups (69% with mesalazine, compared believes that a speciﬁc guideline is not warranted at with 66% with placebo; P ϭ 0.22), although the me- salazine-treated group had more severe diarrhea atDay 15 compared with the placebo group (P ϭ 0.006).
Martenson et al.97 randomized patients who were un- Standard-Dose Chemotherapy: Prevention
dergoing pelvic radiotherapy to receive either 500 mg olsalazine administered orally twice daily or placebo.
Guideline: The panel recommends either ranitidine or Those authors terminated the study early for the 58 omeprazole for the prevention of epigastric pain after evaluable patients, because diarrhea occurred more treatment with cyclophosphamide, methotrexate, and frequently and was more severe among the olsalazine- 5-FU or after treatment with 5-FU with or without folinic acid chemotherapy (level of evidence, II; grade Clinical Practice Guidelines for Mucositis/Rubenstein et al.
of recommendation, A). In two well designed, random- gastrin, insulin, secretin, glucagons, and pancreatic ized, controlled trials led by the same principal inves- polypeptide), and preserves epithelial barrier func- tigator,113,114 it was found that these two drugs were tion. Multiple clinical trials of octreotide have demon- beneﬁcial. One hundred eighty-two patients with en- strated that it is effective in reducing chemotherapy- doscopically normal gastric and duodenal mucosa (or induced diarrhea associated with standard-dose with Ͻ 3 erosions) were assigned randomly to receive chemotherapy.115–120 Four studies involving patients misoprostol (400 ␮g twice daily), omeprazole (20 mg who received high-dose chemotherapy with HSCT once daily), or placebo prior to treatment with cyclo- suggest that octreotide also is effective in that setting.
phosphamide, methotrexate, and 5-FU or with 5-FU In preclinical models of fractionated radiothera- alone. Seven days after completing the second course py,121,122 octreotide administration during radiation of chemotherapy, all patients underwent follow-up and for 2 weeks after radiation was complete was endoscopy. Omeprazole was more effective than ei- associated with a reduction in both acute and subse- ther misoprostol or placebo in reducing clinically sig- quent chronic intestinal toxicity. Additional research niﬁcant epigastric pain and/or heartburn, and its use is needed to determine the role of octreotide as a was associated with fewer gastric and duodenal ulcer- mucosal protectant for patients receiving radiother- ations.113 In a follow-up study,114 228 patients with apy with or without concomitant chemotherapy.
endoscopically normal epigastric and duodenal mu-cosae (or with Ͻ 3 erosions) were assigned randomlyto receive omeprazole (20 mg once daily), ranitidine Combined Chemotherapy and Radiotherapy: Prevention
(300 mg once daily), or placebo before treatment ei- ther with cyclophosphamide, methotrexate, and 5-FU Guideline: The panel suggests using amifostine to re- or with 5-FU. Global endoscopic scores after chemo- duce esophagitis induced by concomitant chemother- therapy were signiﬁcantly higher than pretreatment apy and radiotherapy in patients with nonsmall cell scores in patients who were randomized to receive lung cancer (level of evidence, III: grade of recommen- placebo or ranitidine, but not omeprazole. Acute ul- cers were less common in patients who received ome- The use of combined-modality therapy, such as prazole (P ϭ 0.0001) or ranitidine (P ϭ 0.0315) com- concomitant radiotherapy and chemotherapy in non- pared with patients who received placebo; likewise, small cell lung cancer, improves tumor control rates epigastric pain and heartburn were signiﬁcantly less but is associated with higher rates of acute and common in the omeprazole (P ϭ 0.00124) and raniti- chronic esophagitis.123 Consequently, investigators dine (P ϭ 0.038) groups compared with the placebo have employed strategies utilizing radioprotectants to minimize these toxicities. Recently, Komaki et al.124reported interim results from a prospective random- Standard-Dose Chemotherapy: Treatment
ized Phase III study of combined chemotherapy and radiotherapy with and without amifostine for patients Guideline: When loperamide fails to control diarrhea with nonsmall cell lung cancer. Both groups received induced by standard-dose or high-dose chemotherapy 1.2 Gy per fraction, with 2 fractions per day adminis- associated with HSCT, the panel recommends oct- tered 5 times weekly, along with oral etoposide (50 mg reotide at a dose of at least 100 ␮g administered sub- twice daily) administered 30 minutes before radio- cutaneously twice daily (level of evidence, II: grade of therapy on Days 1–10 and repeated on Day 29 and recommendation, A). Chemotherapy-induced diarrhea cisplatin (50 mg/m2) administered intravenously on is a common clinical problem associated with certain Days 1, 8, 29, and 36. The amifostine-treated group drugs used to treat colon cancer and other solid tu- received 500 mg amifostine intravenously twice mors (5-FU, irinotecan) and with high-dose chemo- weekly before chemoradiation. Severe esophagitis (de- therapy coupled with HSCT. Irinotecan-induced diar- ﬁned as the need for morphine intake to control pain) rhea occurs in 2 phases: an acute syndrome (within was signiﬁcantly lower in the group that received ami- the ﬁrst 24 hours), which is mediated by acetylcholine fostine (7.4%) compared with the group that did not and blocked by atropine, followed by a delayed phase, receive amifostine (31%; P ϭ 0.03). These preliminary which is inﬂammatory. The rate of National Cancer ﬁndings in 53 patients also revealed a lower rate of Institute Common Toxicity Criteria Grade 3– 4 de- acute pneumonitis (3.7%) among patients who re- layed-phase diarrhea may approach 25%.
ceived amifostine compared with the control group Octreotide, a somatostatin analogue, regulates in- (23%; P ϭ 0.037). Transient hypotension was signiﬁ- testinal water and electrolyte transport, inhibits gut cantly more common in patients who received ami- hormones (serotonin, vasoactive intestinal peptide, fostine (70%) compared with the control group (3.8%; CANCER Supplement May 1, 2004 / Volume 100 / Number 9
P ϭ 0.0001); however, only 1 patient discontinued value; however, the methodologic deﬁciencies com- promised the panel’s ability to construct comprehen- The panel has limited its suggestion to the speciﬁc sive, prescriptive guidelines. Consequently, the panel clinical situation described above and offers the fol- offers the preceding guidelines as a benchmark and a lowing to clarify its view of the evidence. Amifostine is starting point for future revisions. Putting these ﬁnd- a thiol-containing prodrug that is dephosphorylated ings in a current context also requires that the Writing by alkaline phosphatase to its active metabolite WR- Committee summarize recent developments that were 1065, which acts as a potent scavenger of ROS. Theo- reported after the close of the panel’s full review.
retically, this mechanism of action would serve as a Since the panel last met, a number of agents for rational basis for using amifostine as an agent to pre- the prevention and treatment of mucositis have been vent the initiation of mucositis induced by chemo- reported at international meetings, in abstracts or ar- therapy, radiotherapy, and concomitant chemoradio- ticles, and in press releases from industry. Although therapy. Currently, amifostine is approved by the U.S.
some of these agents appear promising, and the evi- Food and Drug Administration (FDA) only for reduc- dence supporting their use is of a high level, the panel ing the cumulative renal toxicity associated with re- was unable to evaluate the evidence with the same peated doses of cisplatin in patients with advanced rigor it applied to the literature, which was subjected ovarian cancer or nonsmall cell lung cancer and for to full panel review. Nevertheless, these agents are of reducing the incidence of moderate-to-severe xerosto- sufﬁcient interest to warrant a brief summary.
mia in patients undergoing postoperative radiother-apy for head and neck malignancies. Some reports Late-Breaking Reports
have demonstrated that the use of amifostine is asso- Human keratinocyte growth factor 2 (KGF-2; repifer- ciated with a reduction in mucositis in patients receiv- min) was evaluated in a multicenter Phase II trial ing radiotherapy to the head and neck,124 pelvis,125 involving 42 patients with various malignancies who and thorax,127 whereas other studies have failed to received conditioning regimens with chemotherapy before undergoing autologous HSCT. Repifermin sig- The use of amifostine is complicated by its acute niﬁcantly reduced the incidence of Grade 2– 4 oral toxicity (namely, nausea, emesis, hypotension, allergic reactions, and taste disturbances), which may neces- growth factor 1 (rHuKGF-1; palifermin) was evaluated sitate the interruption or discontinuation of amifos- in a multicenter, randomized, double-blind, placebo- tine therapy. Furthermore, it is not clear whether the controlled Phase II trial in patients with head and neck acute toxicity of amifostine can be reduced by per- cancer who received standard or hyperfractionated forming subcutaneous administration, as opposed to radiotherapy with concomitant chemotherapy.133 The intravenous administration, which is the approved palifermin-treated group had a lower incidence and technique.126,131 Another signiﬁcant concern regard- shorter duration of mucositis compared with the ing the use of amifostine is the selectivity of its action group that received placebo. In a pivotal Phase III trial on normal tissues versus its action on tumor cells.
involving patients undergoing transplantation for a There are theoretic concerns that amifostine not only variety of hematologic malignancies, palifermin signif- may protect normal tissue but also may protect tumor icantly reduced the incidence and duration of severe cells from the effects of radiotherapy. No adequately powered trials addressing this issue have been pub- AES-14, which is L-glutamine administered in a lished, although the clinical trials in the literature do proprietary vehicle that increases its uptake, was eval- not suggest that amifostine-treated patients have a uated in a Phase III trial in patients with solid tumors survival disadvantage compared with control groups.
who were at high risk for chemotherapy-induced oral Accordingly, the panel considers the evidence on ami- mucositis.135 Patients who received AES-14 had a fostine to be insufﬁcient for the creation of guidelines lower incidence of Grade Ն 2 mucositis compared for the settings of radiotherapy alone and chemother- Iseganan, an analog of protegrin-1 and a naturally occurring peptide with broad-spectrum microbicidal DISCUSSION
activity, was evaluated in a randomized, double-blind, Using a modern, evidence-based approach, the placebo-controlled study in patients undergoing MASCC/ISOO panel evaluated the medical literature transplantation who were receiving stomatotoxic ther- of the last 36 years; in general, the quality of the apy. Unfortunately, 102 patients (32%) were affected reported clinical trials failed to meet current stan- by a drug-dispensing error caused by a ﬂawed com- dards. This is not to say that these studies do not have puterized allocation system. Between the 163 patients Clinical Practice Guidelines for Mucositis/Rubenstein et al.
who were randomized to receive iseganan and the 160 vented the formulation of guidelines. Trials included patients who were randomized to receive placebo, the single studies that were underpowered, studies that incidence of oral mucositis was not statistically signif- lacked an adequate control arm, studies that were not icantly different.136 In a subgroup of patients who investigator blinded or patient blinded, and studies were scheduled for HSCT and who underwent condi- that suffered from other design deﬁciencies. In other tioning regimens with high potential for inducing mu- instances, multiple studies reported conﬂicting re- cositis, oral triclosan reportedly decreased the inci- sults, which prevented the panel from establishing dence and duration of ulcerative oral mucositis.137 prescriptive recommendations or suggestions. New, In 2002, Gelclair was approved by the FDA as a well designed, sufﬁciently powered, and appropriately Class 1 medical device for the management and relief executed studies are needed to determine the value of of pain associated with oral lesions of various etiolo- these various agents, which may or may not be effec- gies, including oral mucositis or stomatitis, which may tive in preventing or treating mucositis. To be useful be caused by chemotherapy or radiotherapy. In an and to permit comparisons between studies, new in- open-label study involving 30 patients, Gelclair ap- vestigations should include a control arm that repre- peared to be safe and effective in improving pain sents the current standard of care, and they should use scores, swallowing endpoints, and nutritional end- a mucositis scoring scale with well established psy- points. Controlled clinical trial data are not yet avail- chometric properties. Standardized oral care proto- able for this mixture of polyvinylpyrrolidone, sodium cols should be the minimum for the control arm.
hyaluronate, and glycyrrhetinic acid.
These standard elements should be coupled with pro-tocol-prescribed analgesics and other supportive care Insufﬁcient Evidence
along with appropriate investigator and patient blind- To facilitate future research and to point out areas that ing. Future mucositis trials should have adequate would beneﬁt from well designed trials, the panel sample sizes for testing hypotheses.
provides a compilation of evidence that was reviewed Trials of radioprotectants should include long- yet was considered insufﬁcient to support a recom- term follow-up to calculate time to disease progres- mendation for or against the use of certain agents sion, along with response rates and survival rates, to (Table 3).57,60,124,127,138–205 The rationales and poten- ensure that patients do not suffer from poor tumor tial mechanisms of action for agents investigated as control in the interest of better supportive care. Fur- potential therapies are quite varied, and such agents thermore, the studies should report withdrawal rates, include mucosal surface protectants, antiinﬂamma- adverse event rates, and reasons for withdrawal. Dif- tory agents, antimicrobial agents, growth factors, and ferences in reasons for withdrawal are important, and agents that are difﬁcult to classify. From a mechanistic investigators should count patients who withdraw be- standpoint, some of these agents are potentially at- cause of mucositis treatment failure or toxicity asso- tractive, because they are associated with rationales ciated with the treatment agent as well as patients for targeting speciﬁc pathways known to be involved who withdraw because of other toxicities associated in the etiology of mucositis; however, the evidence in with anticancer therapy. Important secondary end- support of these agents’ efﬁcacy is not rigorous points should include resource utilization, functional enough for the creation of a prescriptive guideline.
outcomes, nutritional endpoints, infection rates, and Amifostine is a good example of one such agent. The rationale underlying the use of other potential agents Alimentary tract mucositis, which encompasses for the prevention or treatment of mucositis appears both oral and GI mucositis, is a complex process. It is to be limited, based on our current understanding of very unlikely that a single therapy will prevent or treat the pathobiology of mucositis. Based on their pro- this side effect of anticancer strategies. Local or topical posed mechanisms, antimicrobial agents, such as therapies may be useful in certain circumstances, or combined polymyxin E, tobrymycin, and amphoteri- they may be combined with other topical agents or cin or single-agent iseganan, appear to have no asso- systemically active agents. The bioavailability of local ciated mechanistic rationale for the prevention of mu- therapies should be evaluated early-stage to mid-stage cositis and probably could provide beneﬁt only for during development of clinical programs. It is likely patients with late-stage ulcerative mucositis, in which that in the future, combinations of agents will be used to prevent or treat difﬁcult mucositis problems likethose seen in patients receiving concomitant chemo- Lessons Learned and Future Directions
therapy and radiotherapy for head and neck cancer or The panel believes that many of the agents studied are lung cancer or in patients receiving high-dose chemo- potentially useful, but the trials’ shortcomings pre- therapy with allogeneic stem cell transplantation. The CANCER Supplement May 1, 2004 / Volume 100 / Number 9
TABLE 3
Agents with Evidence Insufﬁcient to Support a Guideline
Reference(s)
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a For more information on cytokines and growth factors, see Discussion.
b These investigators found that PTA was statistically signiﬁcantly superior to a rinse containing diphenhydramine and local anesthetic, but they expressed doubt that the clinical effect would be signiﬁcant.
incidence of mucositis in children receiving antican- of mucositis research needs to develop a scoring sys- cer therapy has been widely reported. Furthermore, tem or classiﬁcation system to determine the muco- studies of antimucositis agents in the pediatric popu- toxic potential of anticancer regimens. The panel en- lation are rare. The panel encourages clinical develop- courages investigators reporting studies of newer ment programs to begin testing promising agents in anticancer strategies to report mucositis rates of these children with cancer who are at risk of alimentary tract treatment modalities using standardized methods.
mucositis, and clinical investigators are encouraged to Lumping all grades of mucositis together prevents publish rates of mucositis from anticancer therapies in supportive care experts from learning the mucotoxic a fashion similar to those published for adults (see the potential of newer treatments. This classiﬁcation sys- accompanying article in this issue9). Finally, the ﬁeld tem is needed for use in clinical trials of newer agents Clinical Practice Guidelines for Mucositis/Rubenstein et al.
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