Updated clinical practice guidelines for the prevention and treatment of mucositis

Updated Clinical Practice Guidelines for thePrevention and Treatment of Mucositis Considerable progress in research and clinical application has been made since the original guidelines for managing mucositis in cancer patients were published in 2004, and the first active drug for the prevention and treatment of this condi- tion has been approved by the United States Food and Drug Administration and other regulatory agencies in Europe and Australia. These changes necessitate an updated review of the literature and guidelines. Panel members reviewed the bio- medical literature on mucositis published in English between January 2002 and May 2005 and reached a consensus based on the criteria of the American Society of Clinical Oncology. Changes in the guidelines included recommendations for the use of palifermin for oral mucositis associated with stem cell transplantation, amifostine for radiation proctitis, and cryotherapy for mucositis associated with high-dose melphalan. Recommendations against specific practices were intro- duced: Systemic glutamine was not recommended for the prevention of gastro- intestinal mucositis, and sucralfate and antimicrobial lozenges were not recommended for radiation-induced oral mucositis. Furthermore, new guidelines suggested that granulocyte–macrophage-colony stimulating factor mouthwashes 1 Department of Medical Oncology, Royal Ade- not be used for oral mucositis prevention in the transplantation population.
laide Hospital, Adelaide, Australia.
Advances in mucositis treatment and research have been complemented by an 2 School of Dentistry, University of Washington,Seattle, Washington.
3 Department of Biostatistics, The University ofTexas M. D. Anderson Cancer Center, Houston The opinions or views expressed in this pro- fessional review are those of the authors and Adam S Garden, Ian Hewson, Fred Spijkervet, do not necessarily reflect the opinions or Department of Surgery Research, Brigham and recommendations of the publisher or the com- Mike Brennan, Andrea Stringer, Andrei Bar- Women’s Hospital, Boston, Massachusetts.
panies that provided grants toward this pro- asch, Kathryn Damato, Sharon Elad, Arnold 5 Department of Hematology, Leiden University cess. This article is being published with the Altman, Loree Oberle-Edwards, Judith John- Medical Center, Leiden, the Netherlands.
full knowledge and consent of the authors.
son, Patricia Wienandts, M. Elvira P. Correa, This article may discuss pharmaceutical pro- Rene-Jean Bensadoun, and Rajesh V. Lalla.
6 Department of Diagnostic Sciences, NOVA ducts and/or uses of products that have not Southeastern University, Fort Lauderdale, Florida.
Address for reprints: Dorothy M. Keefe, MD, 7 School of Nursing, University of Maryland, Bal- Administration or other regulatory authorities Department of Medical Oncology, Royal Ade- outside of the United States. For approved laide Hospital Cancer Centre, Royal Adelaide product information, consult the manufac- Hospital, North Terrace, Adelaide, South Aus- 8 Research Medical Library, The University of turer’s prescribing information or the applica- tralia 5000, Australia; Fax: (011) 618-8222- Texas M. D. Anderson Cancer Center Houston, ble regulatory authority. Dosages, indications, 4358; E-mail: dorothy.keefe@health.sa.gov.au and methods of use for compounds that are referred to in this article may be derived from School of Dental Medicine, University of Con- Mark M. Schubert is currently an advisory the professional literature or other sources. In necticut Health Center, Farmington, Connecticut.
board participant for MGI Pharma and on the vitro and animal data may not correlate with speakers’ bureau (Kepivance) for Amgen; pre- clinical results and do not demonstrate clinical viously he has served as an advisory board Supported by unrestricted educational grants to participant for McNeil Pharmaceuticals and on the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ Chastain in the preparation of this article.
Received October 5, 2006; revision received ISOO). Corporate sponsors included Novartis, MGI The Mucositis Study Section of MASCC/ISOO Pharma, Curagen, RxKinetics, and Laclede.
included Marisol Michelet, Elenir Avritscher, DOI 10.1002/cncr.22484Published online 5 February 2007 in Wiley InterScience (www.interscience.wiley.com).
Updated Mucositis Practice Guidelines/Keefe et al.
increased rate of publication on mucosal injury in cancer. However, additional and sustained efforts will be required to gain a fuller understanding of the pathobiology, impact on overall patient status, optimal therapeutic strategies, and improved edu- cational programs for health professionals, patients, and caregivers. These efforts are likely to have significant clinical and economic impact on the treatment of cancer patients. Cancer 2007;109:820–31. Ó 2007 American Cancer Society.
KEYWORDS: cancer therapy, clinical practice guidelines, mucosal barrier injury,mucositis (alimentary, gastrointestinal [GI], oral), mucositis pathogenesis.
In 2004, the Mucositis Study Group of the Multina- MATERIALS AND METHODS tional Association of Supportive Care in Cancer (MASCC) and the International Society for Oral On- Our panel consisted of 30 mucositis-involved health cology (ISOO) published 2 articles as a supplement care professionals, including oral oncologists, radia- in the journal Cancer. The first article addressed the pathogenesis, measurement, epidemiology, and con- nurses, dentists, dental hygienists, basic scientists, sequences for patients of oral and GI mucositis1; the epidemiologists, outcomes researchers, and a medi- second article provided evidenced-based clinical practice guidelines for the management (preventionand treatment) of the condition.2 However, few spe- cific guidelines were possible based on the published Using the Ovid interface to Medline and a publication literature available at that time. We anticipated that time frame of January 2002 to May 2005, we retrieved an updated review would be required approximately 3974 articles, only 622 of which were of sufficient qual- every 3 years given the pace and direction of ity and relevance to be included in our final recom- advances in the field: The current report represents mendations. At the time of the search, mucositis was not a Medical Subject Heading (MeSH); thus, we Management strategies for oral and GI mucositis searched for mucositis as a text word in article titles and increasingly are driven by key scientific advances.
abstracts. We also searched for the following terms to These strategies are setting the stage for regulatory identify all publications that had addressed mucositis: approval of drugs and devices, which, in turn, pro- stomatitis, a MeSH that we exploded to include related vide opportunities for multidisciplinary expert panels terms of Stevens-Johnson syndrome and stomatitis to produce evidence-based guidelines. Table 1 shows (aphthous, denture, herpetic); mucous membrane, a the history of mucositis research over the last 40 MeSH that we exploded to include related terms of gas- years and delineates the temporal relations between tric mucosa, goblet cells, intestinal mucosa, mouth mu- important developments in scientific discovery, phar- maceutical products, cancer treatment and support- ive care, and related professional organizations, pathophysiology, and radiation effects and injury to conferences, regulations, protocols, and guidelines.
narrow the retrieval to publications in which the mu- Such factors are likely to have had multidirectional cosa was injured and to limit the search to specific influence on the growth of this field, resulting in subject areas that were assigned to the various incremental gains as well as sudden significant reviewers. By exploding the MeSH term neoplasms, we limited the search to neoplastic disease. Our final Mucositis remains a morbid side effect of many step was to limit the retrieval to articles that were anticancer treatments. Alimentary mucositis (AM) is a term we recommend to describe cancer therapy-associated mucosal injury of the alimentary tract(mouth to anus). This unifying term acknowledges the similarities along the entire GI tract while allow- The medical librarian conducted separate literature ing for regional differences that require discussion reviews, working closely with the group leaders for of oral and GI mucositis separately at times based each of 8 subject domains: 1) epidemiology, econom- on pathophysiologic responses and clinical charac- ics, and outcome; 2) pathogenesis; 3) terminology, definition, and scales; 4) growth factors and cyto- Updated Mucositis Practice Guidelines/Keefe et al.
kines; 5) antimicrobials, mucosal coating agents, anesthetics, and analgesics; 6) alternative and natural therapies, laser, ice, etc; 7) basic oral care, bland A recommendation is reserved for guidelines that rinses, protocol development and education, and are based on Level 1 or Level 2 evidence.
good clinical practice; and 8) anti-inflammatory A suggestion is used for guidelines that are based agents and amifostine. Each group reviewed both on Level III, Level IV, and Level V evidence; this implies preclinical and clinical articles relating to the entire panel consensus on the interpretation of this evidence.
alimentary tract. The systematic weighting of both No guideline possible is used when there is insufficient evidence on which to base a guideline; this conclusion level and grade of evidence followed the same pro- implies 1) that there is little or no evidence regarding the cess that was used for the original guidelines based practice in question, or 2) that the panel lacks a consensus on criteria of the American Society of Clinical Oncol- on the interpretation of existing evidence.
ogy that rated the level of evidence on a scale from Ito V and refined this by grading each recommenda- * Used with permission from the publisher. Adapted from: Somerfield M, Padberg J, Pfister D, et al.
ASCO clinical practice guidelines: process, progress, pitfalls, and prospects. Classic Pap Curr Com- tion from A to D.3,4 Level I evidence is reserved for meta-analyses of randomized controlled trials or ran-domized trials with high power. Level II evidenceincludes randomized trials with lower power, and attended the workshop, nor were they allowed access Level III evidence includes nonrandomized trials, to the guidelines prior to publication. The guideline- such as cohort or case-controlled series. Level IV evi- development process was determined entirely by the dence includes descriptive and case studies, and panel. Each panel member completed a conflict-of- Level V evidence includes case reports and clinical interest disclosure form that revealed all relation- examples. Grade A is reserved for Level I evidence or ships with pharmaceutical companies that could be consistent findings from multiples studies of Level II, affected by the development and publication of these III, or IV evidence. Grade B is for Level II, III, or IV evidence with generally consistent findings. Grade Cis similar to grade B but with inconsistencies; and Grade D implies little or no evidence.
Revision planThe panel will continue to review the literature every 2 to 3 years and will publish updates to guidelines as We distributed the publications in the finalized set of necessary. The current process has created the op- literature to each group with instructions based on portunity for Web-based storage of the publication methods for reviewing and scoring the literature inventory as well as for future reviews.
published by Hadorn et al.4 At least 2 panel membersreviewed each article. Preclinical studies were not used to create guidelines per se; rather, they were In recognition of the importance and challenge of used as indicators of future directions for preclinical disseminating and using these guidelines in clinical and clinical studies. Each group presented its report oncology practice, the review team is considering co- and draft of guideline revisions at a workshop in operative strategies with other professional oncology Geneva, Switzerland on June 27 and 28, 2005. The organizations as well as methodologies to assess the entire panel discussed each guideline to ensure that scope and durability of the impact of the guidelines it met the correct standards and to achieve a consen- sus (see Table 2). The current report includes thenew guidelines that were developed based on thisprocess. Each group also has published a companion article in Supportive Care in Cancer5–17 that elabo- rates on the extent of preclinical and clinical litera- Efforts to understand the biological basis for AM include research of mechanism-based therapy, riskprediction, long-term toxicity, and associations with Conflict of Interest and Financial Disclosure other side effects of cancer treatment. GI toxicities The costs for the workshop and for administrative from the targeted cancer therapies have yet to be assistance in guideline preparations were paid from included in this field. It is likely that there are macro- unrestricted educational grants made to the Mucosi- scopic factors as well as molecular or cellular factors tis Study Group of MASCC/ISOO. No representatives that are fundamental to the expression of GI toxicity, from any of the companies that provided grants that both categories are generic or specific,7 and that they will provide opportunities for intervention. In els have continued to characterize oral and GI muco- the future, it may be possible to predict an individual sitis as a continuum of injury rather than biologically patient’s risk of particular toxicities from radiother- and clinically independent toxicities,23,27,28 new mod- apy and from each different chemotherapy or combi- els for the assessment of genetic risk for mucositis29 nation therapy. We recommend future research into and the totality of impact for the condition23 may de- mucotoxicity that focuses on identifying its generic velop as research in this area progresses); 4) develop- and tissue-specific causes, analyzing its genetic com- ment of an epidemiological burden-of-illness study ponents using genetic versus nongenetic controls, by researchers from the Mucositis Study Group to and establishing evidence-based grading for and evaluate the impact of AM on patients after treatment hierarchical characterization of mucotoxicity.
with standard-dose chemotherapy and/or radiother-apy; that study uses patient-reported outcome tools to measure impact and investigates the relations Advancements in terminology and in the assessment between various patient-reported toxicities as well as of AM in patients receiving cytoreductive cancer the true regimen-related incidence and severity of therapies have resulted in better patient management practices and enhanced drug development to reduce toxicity. Factors of note since publication of the origi-nal guidelines in 2004 include: 1) publication of the Common Terminology Criteria for Adverse Events version 3.0,18 which defines a comprehensive, multi- Our literature searches did not identify any prospec- modality grading system for both acute and chronic tive studies of the incidence of mucosal toxicity asso- effects of cancer treatment; 2) implementation of the ciated with standard, multicycle chemotherapy for term mucositis as a MeSH category, effective January common solid tumors. Therefore, we reviewed 99 2006, which will improve future search capabilities recent clinical trials of standard chemotherapy regi- and increase the visibility of the term during related mens for non-Hodgkin lymphoma or breast, lung, or searches (this change was a direct result of a recom- colorectal cancer for incidence of severe (grade 3 or mendation to the National Library of Medicine in 4) oral mucositis, diarrhea, and esophagitis.8 We February 2005 by the review group from the original aggregated the estimates of incidence using pre- Mucositis Guideline Project and, thus, represents an viously described methods1 and weighted the esti- important outcome of the original project); 3) publi- mates based on the quality of the adverse event cation and presentation of additional models depict- reporting and the sample size for each trial. We ing the potential impact of oral and GI mucositis assigned quality points for the use of standardized relative to symptom clusters19–26 (although the mod- Updated Mucositis Practice Guidelines/Keefe et al.
TABLE 3Risk of Grade 3 or 4 Oral Mucositis and Diarrhea by Chemotherapy Regimen* CHOP-14: Cyclophosphamide, doxorubicin, vincristine, and prednisone CHOP-DI-14: Cyclophosphamide, doxorubicin, vincristine, and prednisone (dose-intensified) CHOEP-14: Cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone CEOP/IMVP-Dexa: cyclophosphamide, etoposide, vincristine, prednisone/ifosfamide, A?T?C: Doxorubicin, taxane, and cyclophosphamide (administered sequentially)y AC?T Doxorubicin, cyclophosphamide, and taxane (administered sequentially) A?CT: Doxorubicin, cyclophosphamide, and taxane (administered sequentially) A?T: Doxorubicin and taxane (administered sequentially) FAC (weekly): 5-FU, doxorubicin, and cyclophosphamide AC (weekly): Doxorubicin and cyclophosphamide TAC: docetaxel, doxorubicin, and cyclophosphamide FOLFOX: 5-FU, leucovorin, and oxaliplatin 95% CI indicates 95% confidence interval; NHL, non-Hodgkin lymphoma; 5-FU, 5-fluorouracil; XRT, radiotherapy.
* Adapted from Jones JA, Avritscher EBC, Cooksley CD, Michelet M, Bekele BN, Elting LS. Epidemiology of treatment-associated mucosal injury after treatment with newer regimens for lymphoma, breast, lung,or colorectal cancer. Support Care Cancer. 2006;14:505–515.8y Taxane is paclitaxel or docetaxel.
assessment of toxicity, and for midcycle assessment patients with lung cancer who receive platinum- of toxicity (as opposed to limiting assessments to based doublets and triplets, even when radiotherapy is administered concurrently. However, among thesepatients, severe (grade 3 or 4) radiotherapy-induced Incidence of mucositis associated with standard, esophagitis has been a major concern, occurring in multicycle chemotherapy (with or without radiotherapy) >15% of patients. Based on several studies8 that included 280 patients, 18% (range, 14.2–22.9%) of patients who receive carboplatin and paclitaxel plus Table 3 shows that standard chemotherapy regimens radiotherapy develop severe esophagitis. The risk of for non-Hodgkin lymphoma occasionally have re- severe esophagitis may be lower (10.6%; range, 2.1– sulted in severe oral mucositis (3–10%) or diarrhea 20.2%) among patients who receive amifostine; (1–3%). Similar rates of AM are observed among although this estimate was derived from a single women who receive standard doxorubicin- and tax- study of 47 patients. Patients with advanced colorec- ane-based regimens for breast cancer. Severe oral tal cancers who receive common chemotherapy regi- mucositis and severe diarrhea are rare among mens have a low risk of severe oral mucositis but a high risk (16%) of diarrhea overall, which approaches preventive oral care regimen should be part of rou- 25% when both irinotecan and oxaliplatin are used.
tine supportive care along with a therapeutic oral Reports of newly emerging standards of care using care regimen if mucositis develops. Regular, system- targeted therapies for lung and colorectal cancers fell atic, oral care hygiene with brushing, flossing, bland outside the time frame of the current review; thus, rinses, and moisturizers using a standardized oral the impact of these agents on the risk of mucosal care protocol should be implemented for all patients.
damage and diarrhea has yet to be described.
It is noteworthy that an interdisciplinary approach tooral care (nurse, physician, dentist, dental hygienist, Updated Clinical Practice Guidelines for the dietician, pharmacist, and others as relevant) will provide the most comprehensive means of providing To provide clinicians with the current recommenda- supportive care. Dental examinations and treatment tions in a single document, the guidelines presented are important prior to the start of cancer therapy for in Table 4 represent the integration of the original all patients, especially for those with head and neck guidelines from 20042 plus the new guidelines devel- cancer, and should continue throughout active treat- oped at the Geneva workshop. The text below addresses the guideline revisions only. The reader isreferred to the original Cancer supplement publica-tion for more detail on the original guidelines.2 Radiotherapy: Prevention and/or TreatmentAntimicrobial lozenge Basic oral care and good clinical practice principles Guideline. The panel recommends that antimicrobial The results from a survey that was conducted by panel lozenges not be used for the prevention of radiation- members showed that incorporating management induced oral mucositis (Level II evidence, grade B guidelines into routine clinical practice will require the recommendation). Despite the often postulated role successful dissemination and adoption of the guide- of infection in the pathogenesis of mucositis, no con- lines, which can be achieved by educating relevant clusive evidence for it has been published. Two new target audiences.14 Barriers to such efforts include studies of oral lozenges that contained polymixin, challenges to dissemination, knowledge deficits, resist- tobramycin, and amphoteracin B or bacitracin, clo- ance to changing traditional practices, and a variety of trimazole, and gentamicin showed no improvement administrative issues.31 We have addressed some of in the incidence or severity of radiation-induced these barriers through a focus on education, quality- improvement processes, and good clinical practices.
The panel suggests interdisciplinary development of systematic oral care protocols that are geared to- Guideline. The panel recommends that sucralfate not ward the individual needs of the patient; educational be used for the treatment of radiation-induced oral approaches to promulgating them that include the mucositis (Level II evidence, grade A recommenda- patient, family, and staff; and quality-improvement tion). Sucralfate is a mucosal coating agent that has processes to evaluate them. It also suggests the use of been postulated to offer protection to the mucosa. All a soft-bristle toothbrush that is replaced on a regular studies have been negative in the radiation arena, basis. A lack of research in these areas renders out- and the new randomized, controlled trial of sucralfate come assessment an extremely important component in radiation treatment has confirmed this lack of ben- of oral supportive care to document the benefits of efit, showing no difference between micronized these practices. The updated guidelines also address sucralfate and salt and soda mouth washes.34 good clinical practices that should occur regardless ofthe amount of research-based evidence.13 AmifostineGuideline. The panel suggests that intravenous ami- Guidelines. Based on expert opinion and the limited fostine at a dose 340 mg/m2 daily prior to radio- published literature, the panel recommends the fol- therapy may prevent radiation proctitis in patients lowing: Regular assessment of oral pain is essential who are receiving standard-dose radiotherapy for and should be performed using validated, self-report rectal cancer (Level III evidence, grade B recommen- pain instruments. Topical anesthetics or other agents dation). Amifostine is an organic thiophosphate that should be considered to promote oral comfort. Initial is used as a normal tissue protector during cytotoxic and ongoing assessment of the oral cavity is essential therapy.35,36 Most of the amifostine studies that have using validated instruments that include both patient been published since the initial guidelines were self-report and professional examination. Use of a established have been small, single-center studies Updated Mucositis Practice Guidelines/Keefe et al.
TABLE 4Summary of Evidence-based Clinical Practice Guidelines for Care of Patients With Oral and Gastrointestinal Mucositis (2005 Update) Basic oral care and good clinical practices 1. The panel suggests multidisciplinary development and evaluation of oral care protocols, and patient and staff education in the use of such protocols to reduce theseverity of oral mucositis from chemotherapy and/or radiation therapy. As part of the protocols, the panel suggests the use of a soft toothbrush that is replaced on aregular basis. Elements of good clinical practice should include the use of validated tools to regularly assess oral pain and oral cavity health. The inclusion of dentalprofessionals is vital throughout the treatment and follow-up phases.
2. The panel recommends patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing HSCT. Regular oral painassessment using validated instruments for self-reporting is essential.
3. The panel recommends the use of midline radiation blocks and 3-dimensional radiation treatment to reduce mucosal injury.
4. The panel recommends benzydamine for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy.
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 antimicrobial lozenges not be used for the prevention of radiation-induced oral mucositis.
7. The panel recommends that sucralfate not be used for the treatment of radiation-induced oral mucositis.
8. The panel recommends that patients receiving bolus 5-FU chemotherapy undergo 30 minutes of oral cryotherapy to prevent oral mucositis.
9. The panel suggests the use of 20 to 30 min of oral cryotherapy to decrease mucositis in patients treated with bolus doses of edatrexate.
10. The panel recommends that acyclovir and its analogues not be used routinely to prevent mucositis.
11. The panel recommends that chlorhexidine not be used to treat established oral mucositis.
High-dose chemotherapy with or without total body irradiation plus HCST: Prevention 12. In patients with hematologic malignancies who are receiving high-dose chemotherapy and total body irradiation with autologous stem cell transplantation, the panelrecommends the use of keratinocyte growth factor-1 (palifermin) in a dose of 60 lg/kg per d for 3 d prior to conditioning treatment and for 3 d posttransplantation for theprevention of oral mucositis.
13. The panel suggests the use of cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan.
14. The panel does not recommend the use of pentoxifylline to prevent mucositis in patients undergoing HSCT.
15. The panel suggests that GM-CSF mouthwashes not be used for the prevention of oral mucositis in patients undergoing HSCT.
16. The panel suggests the use of LLLT to reduce the incidence of oral mucositis and its associated pain in patients receiving high-dose chemotherapy orchemoradiotherapy before HSCT if the treatment center is able to support the necessary technology and training, because LLLT requires expensive equipment andspecialized training. Because of interoperator variability, clinical trials are difficult to conduct, and their results are difficult to compare; nevertheless, the panel isencouraged by the accumulating evidence in support of LLLT.
Basic bowel care and good clinical practices 17. The panel suggests that basic bowel care should include the maintenance of adequate hydration, and that consideration should be given to the potential for transientlactose intolerance and the presence of bacterial pathogens.
18. The panel suggests the use of 500 mg sulfasalazine orally twice daily to help reduce the incidence and severity of radiation-induced enteropathy in patients receivingexternal beam radiotherapy to the pelvis.
19. The panel suggests that amifostine in a dose 340 mg/m2 may prevent radiation proctitis in patients who are receiving standard-dose radiotherapy for rectal cancer.
20. The panel recommends that oral sucralfate not be used to reduce related side effects of radiotherapy; it does not prevent acute diarrhea in patients with pelvicmalignancies undergoing external beam radiotherapy; and, compared with placebo, it is associated with more GI side effects, including rectal bleeding.
21. The panel recommends that 5-amino salicylic acid and its related compounds mesalazine and olsalazine not be used to prevent GI mucositis.
22. The panel suggests the use of sucralfate enemas to help manage chronic radiation-induced proctitis in patients who have rectal bleeding.
Standard-dose and high-dose chemotherapy: Prevention 23. The panel recommends either ranitidine or omeprazole for the prevention of epigastric pain after treatment with cyclophosphamide, methotrexate, and 5-FU ortreatment with 5-FU with or without folinic acid chemotherapy.
24. The panel recommends that systemic glutamine not be used for the prevention of GI mucositis.
Standard-dose and high-dose chemotherapy: Treatment 25. When loperamide fails to control diarrhea induced by standard-dose or high-dose chemotherapy associated with HSCT, the panel recommends octreotide at a dose100 lg subcutaneously, twice daily.
Combined chemotherapy and radiotherapy: Prevention 26. The panel suggests the use of amifostine to reduce esophagitis induced by concomitant chemotherapy and radiotherapy in patients with nonsmall cell lung cancer.
HSCT indicates hematopoietic stem cell transplantation; 5-FU: 5-fluorouracil; GM-CSF, granulocyte-macrophage–colony stimulating factor; LLLT: low-level laser therapy; GI, gastrointestinal.
with conflicting results that do not help to delineate randomized, controlled studies. Prophylactic intrave- the role of amifostine in the reduction of mucositis.
nous injections were given for 3 days prior to each However, 4 small studies on the prevention of procti- chemotherapy cycle in a Phase I study. Doses ranged tis in patients receiving radiotherapy for pelvic can- from 1 lg/kg per day to 80 lg/kg per day in 6 differ- cers all showed a reduction in symptoms, suggesting ent cohorts, and 1 group of patients was given pla- cebo. The drug generally was tolerated well inbiologically active doses, and the results suggested a positive effect on oral mucositis.44 In a double-blind, Although no new guideline is possible for benzyda- Phase III, multicenter study in which the effects of mine, because no new trials have been published palifermin were evaluated in 212 patients with hema- since the 2004 supplement, it is important to note tologic malignancies who were undergoing a stoma- that a study in the United States sponsored by totoxic conditioning regimen in preparation for McNeil had aimed to confirm the results of an earlier autologous hematopoietic stem cell transplantation randomized, placebo-controlled American/Canadian (HSCT), the incidence and duration of clinically multicenter trial41 on which the original guideline meaningful oral mucositis was reduced significantly was based. However, the McNeil study was stopped in patients who were receiving palifermin. Palifermin early after the receipt of results from an interim anal- (60 lg/kg per day) or placebo was administered for ysis and the recommendations of the Data Monitor- 3 consecutive days immediately before the initiation of myeloablation and on Days 0, 1, and 2 after trans-plantation. Palifermin also favorably affected the High-dose Chemotherapy With or Without Total-body incidence of blood-borne infections, the use of parental opioids, and a variety of patient-reported outcomes45 in a well-conducted, double-blind, ran- domized, placebo-controlled, multicenter study.
Guideline. In patients with hematologic malignancieswho are receiving high-dose chemotherapy and total body irradiation with autologous stem cell transplan- Guideline. The panel suggests the use of cryotherapy tation, the panel recommends the use of keratinocyte to prevent oral mucositis in patients who are receiv- growth factor-1 (KGF1) (palifermin) at a dose of ing high-dose melphalan (as a conditioning agent in 60 lg/kg per day for 3 days prior to conditioning HSCT; Level II evidence, grade A recommendation).
treatment and for 3 days post-transplantation for the Cryotherapy was recommended in the previous guide- prevention of oral mucositis (Level I evidence, grade lines for the prophylaxis of oral mucositis in patients A recommendation). In the previous review,2 clinical who were receiving bolus 5-fluorouracil and possibly studies on growth factors and cytokines for the pre- etidronate (both drugs with short half-lives). Melpha- vention and treatment of oral mucositis showed lan is another such drug, and the studies, although inconsistent results, and there was not enough evi- small, showed consistent results in favor of using dence to make any recommendations for clinical cryotherapy,46,47 which obviously is a cost-effective preventive strategy. For some patients, compliance Recombinant human KGF1 (fibroblast growth may be confounded by the physically uncomfortable factor 7 [FGF-7] or palifermin) is a member of the sensation they experience while holding ice in the FGF super class. Initially, the tissue-protective capa- city of palifermin was attributed to its mitogeniceffect, which results in increased thickness of muco- Granulocyte–macrophage-colony stimulating factor sal epithelium. However, palifermin also up-regulates Guideline. The panel suggests that granulocyte– the expression of transcription factor Nrf2 in kerati- nocytes, which leads to the up-regulation of genes mouthwashes not be used for the prevention of oral that encode a series of reactive oxygen species- mucositis in patients undergoing HSCT (Level II evi- scavenging enzymes.42 It stimulates the generation of dence, grade C recommendation). GM-CSF stimu- the anti-inflammatory cytokine interleukin-13 (IL-13), lates cells of the innate immune system in mucosal which reduces tumor necrosis factor, a proinflamma- tissues. GM-CSF for oral mucositis was evaluated in tory cytokine that plays a key role in the pathogene- 4 studies48–51 with conflicting results. However, a sis of mucositis. In addition, palifermin exerts randomized, controlled study using a GM-CSF pro- antiapoptotic effects and reduces angiogenesis.43 phylactic mouthwash51 and another randomized, Palifermin was used to prevent oral mucositis in 2 controlled trial using a GM-CSF mouthwash as a Updated Mucositis Practice Guidelines/Keefe et al.
Late-breaking Reports and Agents With Insufficient patients who were receiving high-dose chemother- apy48 demonstrated no positive effects on the dura- Human KGF2 2 (repifermin) has been withdrawn from study because of poor performance in a PhaseII study. The reasons for the poor performance areunclear and may relate to scheduling. It has been Standard-dose and High-dose Chemotherapy: Prevention reported in a Phase I trial that whey growth factor extract reduced oral mucositis in the HSCT setting Guideline. The panel recommends that systemic glu- compared with historic controls.56 Well-designed, tamine not be used for the prevention of GI mucositis randomized, controlled trials are warranted before a because of severe toxicity (Level II evidence, grade C valid assessment of benefit can be made.
recommendation). Glutamine is an amino acid that A single Phase III trial of Saforis (L-glutamine in a is a favored food of the GI tract. It is necessary for proprietary oral drug-delivery system) recently showed cell mitosis. Multiple trials studying its effect on a reduction in oral mucositis among patients who were mucositis prevention and treatment in various parts receiving anthracycline-based chemotherapy,57 but of the alimentary canal have produced conflicting further trials have been requested by the United States results. Pytlik and colleagues performed a double- Food and Drug Administration and are awaited.
blind, randomized trial in 40 bone marrow transplan- RK-0202 is N-acetylcysteine in a proprietary tation patients who received either intravenous ala- mouth rinse formulation that was studied recently in a nyl-glutamine dipeptide or placebo52 and observed Phase II, double-blind, placebo-controlled trial among that oral mucositis was more severe in the treatment patients who were undergoing radiotherapy for head group, although diarrhea was reduced, suggesting a and neck cancer. In that trial, RK-0202 significantly differential effect down the GI tract. However, those reduced the incidence of oral mucositis (World Health authors observed an increase in disease recurrences Organization and National Cancer Institute clinical grade >2) by 29% (P ¼ .04) and 46% (P ¼ .005), respec- Major advances in the field of mucositis have Updating the management guidelines for mucositis occurred over the past 3 years, including increased has been a productive enterprise, reflecting the pub- understanding of the epidemiology and pathobiology lished evidence to improve clinical practice in muco- of the condition; a realization that symptom clusters sitis management. The publication of guidelines is occur in patients, suggesting that genetic risk predic- only the first step toward ensuring that all patients tion for toxicity soon may be a reality; and the avail- have access to evidence-based protocols for the ability of new mechanism-based treatments. The management of their potential mucositis. Work needs registration of palifermin and the recommendation to be done on promulgation of the guidelines; devel- for its use in the prevention of oral mucositis in the opment of protocols that are based on them; educa- HSCT setting is a first in the field. Other drugs are in tion of patients, caregivers, and staff; and assessment development, and rapid progress finally is being of outcomes from their use. Improved risk assess- made in this under-appreciated area.
ment needs to occur as well as continued research at In the time after the endpoint for inclusion of the basic and clinical levels into epidemiology, bur- studies in the original guidelines (May 2002),2 the den of illness, cost of care, prevention, and treat- pace of publication of mucositis studies has in- ment.16 Most patients are not followed for toxicity creased. However, the quality of these studies for sufficient duration in clinical trials; thus, these remains variable, with many studies remaining small, problems largely are underestimated. Although pro- poorly designed, and, thus, unable to answer the gress is being made toward addressing some of these questions posed. Some of the recent studies indeed areas, 2 important areas of assessment remain: are of high quality, and it is those studies that have led to the important changes in the guidelines (Table agents, such as palifermin, are expensive and cannot 3). New agents continue to be developed. However, be justified for prevention when the risk of severe the panel is unable to incorporate these agents into mucositis is low. However, if clinicians could predict the guidelines until peer-reviewed clinical studies which patients on standard-dose treatments would appear in the literature.48–51,53–56 Future guideline suffer mucositis, then the newer, more expensive reviews will address the outcomes of those studies.
agents could be targeted in a cost-effective manner.
We anticipate that the new guidelines will need 16. Bensadoun RJ, Schubert MM, Lalla RV, Keefe D. Amifostine updating in 2 or 3 years, and we look forward to in the management of radiation-induced and chemo- published studies on the burden of illness and risk induced mucositis. Support Care Cancer. 2006;14:566–572.
17. Brennan MT, Bultzingslowen IV, Schubert MM, Keefe D. Al- prediction as well as evaluations of strategies to imentary mucositis: putting the guidelines into practice.
improve the uptake and use of the guidelines.
Support Care Cancer. 2006;14:573–579.
18. Trotti A, Colevas AD, Setser A, et al. Common Terminology Criteria for Adverse Events version 3.0: development of a comprehensive grading system for the adverse effects of Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer cancer treatment. Semin Radiat Oncol. 2003;13:176–181.
therapy-induced mucosal injury: pathogenesis, measure- 19. Cella D, Pulliam J, Fuchs H, et al. Evaluation of pain asso- ciated with oral mucositis during the acute period after Cancer. 2004;100(9 suppl):1995–2025.
administration of high-dose chemotherapy. Cancer. 2003;98: Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of 20. Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symp- cancer therapy-induced oral and gastrointestinal mucositis.
toms of cancer and cancer treatment due to a shared bio- Cancer. 2004;100(9 suppl):2026–2046.
logic mechanism? A cytokine-immunologic model of Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the qual- cancer symptoms. Cancer. 2003:97:2919–2925.
ity of evidence for clinical practice guidelines. J Clin Epide- 21. Dodd MJ, Miaskowski C, Lee KA. Occurrence of symptom clusters. J Natl Cancer Inst Monogr. 2004;32:76–78.
Somerfield M, Padberg J, Pfister D, et al. ASCO clinical 22. Eilers J, Epstein JB. Assessment and measurement of oral practice guidelines: process, progress, pitfalls, and pro- mucositis. Semin Oncol Nurs. 2004;20:22–29.
spects. Classic Pap Curr Comments. 2000;4:881–886.
23. Elting LS, Sonis ST, Keefe DM. Treatment-induced gastroin- Keefe DM. Mucositis guidelines: what have they achieved, and testinal toxicity in patients with cancer. Educational book, where to from here? Support Care Cancer. 2006;14:489–491.
Proc Am Soc Clin Oncol. 2004;536–541.
Keefe DM, Peterson DE, Schubert MM. Developing evi- 24. Miaskowski C, Dodd M, Lee K. Symptom clusters: the new dence-based guidelines for management of alimentary frontier in symptom management research. J Natl Cancer mucositis: process and pitfalls. Support Care Cancer. 2006; 25. Illman J, Corringham R, Robinson D Jr, et al. Are inflam- Peterson DE, Keefe DM, Hutchins RD, Schubert MM. Ali- matory cytokines the common link between cancer-asso- mentary tract mucositis in cancer patients: impact of ter- ciated cachexia and depression? J Support Oncol. 2005: practice. Support Care Cancer. 2006;14:499–504.
26. Kim HJ, McGuire DB, Tulman L. Symptom clusters: con- Jones JA, Avritscher EBC, Cooksley CD, Michelet M, Bekele cept analysis and clinical implications for cancer nursing.
BN, Elting LS. Epidemiology of treatment-associated muco- sal injury after treatment with newer regimens for lym- 27. Sonis ST, Peterson DE, McGuire DB, Williams DA, eds. Mu- phoma, breast, lung, or colorectal cancer. Support Care cosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr. 2001;29:1–54.
Anthony L, Bowen J, Garden A, Hewson I, Sonis S. New 28. Keefe DM. Gastrointestinal mucositis: a new biological thoughts on the pathobiology of regimen-related mucosal model. Support Care Cancer. 2004;12:6–9.
injury. Support Care Cancer. 2006;14:516–518.
29. Peterson DE, Sonis ST. Executive summary. J Natl Cancer 10. von Bultzingslowen I, Brennan MT, Spijkervet FKL, et al.
Growth factors and cytokines in the prevention and treat- 30. Sonis S, Elting L, Keefe D. Burden of illness and economic ment of oral and gastrointestinal mucositis. Support Care impact of mucosal injury (MUI) in solid tumour—a multi- national prospective observational study design. MASCC 11. Barasch A, Elad S, Altman A, Damato K, Epstein J. Antimi- abstract. Support Care Cancer. 2006;14:633. Abstract 16– crobials, mucosal coating agents, anesthetics, analgesics, and nutritional supplements for alimentary tract mucositis.
31. McGuire DB. Barriers and strategies in implementation of Support Care Cancer. 2006;14:528–532.
oral care standards for cancer patients. Support Care Can- 12. Migliorati CA, Oberle-Edwards L, Schubert M. The role of alternative and natural agents, cryotherapy, and/or laser 32. Stokman MA, Spijkervet FK, Burlage FR, et al. Oral mucosi- for the management of alimentary mucositis. Support Care tis and selective elimination of oral flora in head and neck cancer patients receiving radiotherapy: a double-blind ran- 13. McGuire DB, Correa MEP, Johnson J, Wienandts P. The role domised clinical trial. Br J Cancer. 2003;88:1012–1016.
of basic oral care and good clinical practice principles in 33. El-Sayed S, Nabid A, Shelley W, et al. Prophylaxis of radiation- the management of oral mucositis. Support Care Cancer.
associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, Phase III, randomized, 14. McGuire DB, Johnson J, Migliorati C. Promulgation of controlled trial evaluating the clinical efficacy of an antimi- guidelines for mucositis management: educating health crobial lozenge using a validated mucositis scoring system.
care professionals and patients. Support Care Cancer. 2006: 34. Dodd MJ, Miaskowski C, Greenspan D, et al. Radiation- 15. Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. Anti- induced mucositis: a randomized clinical trial of micro- inflammatory agents in the management of alimentary nized sucralfate versus salt and soda mouthwashes. Cancer mucositis. Support Care Cancer. 2006;14:558–565.
Updated Mucositis Practice Guidelines/Keefe et al.
35. Ben-Josef E, Han S, Tobi M, et al. Intrarectal application of Results of a randomized double-blind placebo-controlled amifostine for the prevention of radiation-induced rectal study. Bone Marrow Transplant. 2002;29:783–787.
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49. Rossi A, Rosati G, Colarusso D, Manzione L. Subcutaneous 36. Kouvaris J, Kouloulias V, Kokakis J, et al. Cytoprotective effect of amifostine in radiation-induced acute mucositis: a mucositis induced by an adjuvant 5-fluorouracil plus leu- retrospective analysis. Onkologie. 2002;25:364–369.
covorin regimen. Oncology. 2003;64:353–360.
37. Ben-Josef E, Han S, Tobi M, et al. A pilot study of topical 50. Mantovani G, Massa E, Astara G, et al. Phase II clinical trial intrarectal application of amifostine for prevention of late of local use of GM-CSF for prevention and treatment of radiation rectal injury. Int J Radiat Oncol Biol Phys. 2002; chemotherapy- and concomitant chemoradiotherapy-in- duced severe oral mucositis in advanced head and neck 38. Athanassiou H, Antonadou D, Coliarakis N, et al. Protective cancer patients: an evaluation of effectiveness, safety and effect of amifostine during fractionated radiotherapy in costs. Oncol Rep. 2003;10:197–206.
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CSF mouthwashes does not reduce frequency and duration 39. Kouvaris J, Kouloulias V, Malas E, et al. Amifostine as of severe oral mucositis in patients with solid tumors radioprotective agent for the rectal mucosa during irradia- undergoing high-dose chemotherapy with autologous pe- tion of pelvic tumors. A Phase II randomized study using ripheral blood stem cell transplantation rescue: a double various toxicity scales and rectosigmoidoscopy. Strah- blind, randomized, placebo-controlled study. Ann Oncol.
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56. Prince HM, Regester G, Gates P, et al. A Phase Ib clinical 46. Aisa Y, Mori T, Kudo M, et al. Oral cryotherapy for the pre- trial of PV701, a milk-derived protein extract, for the pre- vention of high-dose melphalan-induced stomatitis in allo- vention and treatment of oral mucositis in patients under- geneic hematopoietic stem cell transplant recipients.
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47. Tartarone A, Matera R, Romano G, Vigliotti ML, Di Renzo 57. Peterson DE, Jones JB, Petit RG. Phase III study: rando- N. Prevention of high-dose melphalan-induced mucositis mized, placebo-controlled trial of Saforis for prevention by cryotherapy. Leuk Lymphoma. 2005;46:633–634.
and treatment of oral mucositis in breast cancer patients 48. Valcarcel D, Sanz MA Jr, Sureda A, et al. Mouth-washings receiving anthracycline-based chemotherapy. Cancer. In with recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) do not improve grade III-IV 58. Chambers MS. Welsh V, Scrimger RA, et al. RK-0202 for oropharyngeal mucositis (OM) in patients with haematolo- radiation-induced oral mucositis., J Clin Oncol, 2006 ASCO gical malignancies undergoing stem cell transplantation.
Annual Meeting Proc. 2006;5523. Abstract 5523.

Source: http://cdhb-haem.streamliners.co.nz/Keefe_Cancer_2007.pdf

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