INTRODUCTION
Beyond Quality of Life: Advances in the Understanding and Treatment of Mucositis in Patients Undergoing HSCT
Paper Symposium
Activity Date: April 2005  — Activity Info: Volume 5, (4B)
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Mucositis In Hematopoietic Stem Cell Transplantation: Beyond Quality Of Life
Stephen J. Noga, MD, PhD,* and Jerry L. Spivak, MD 

Mucositis is a common, painful, and potentially devastating complication in patients who have undergone blood and marrow transplantation. Because of its high turnover and complex microflora, the mucosal lining of the oral cavity and the gastrointestinal (GI) tract is especially susceptible to complications from the distinctive high-dose myeloablative chemotherapy and radiotherapy used for conditioning in bone marrow transplantation (BMT) and hematopoietic stem cell transplantation (HSCT). In fact, oral mucositis is so ubiquitous, so expected, and so practically unpreventable in this population that, until recently, few researchers have bothered to measure its incidence or severity. In those few studies that have investigated oral mucositis, this toxicity has been noted at rates of 70%, 76%, 83%, and 88% in various transplantation settings.1-3 The occurrence was approximately twice the 40% rate of mucositis typically associated with primary chemotherapy for cancers other than head and neck.4,5

A recent comprehensive review of cancer therapy-induced mucosal injury documented what most oncologists grasp intuitively: the risk of oral and GI mucositis depends largely on the regimen and modality.6 In adult HSCT, grade 3/4 oral mucositis was seen in 61% to 68% of the patients who received total body irradiation (TBI) as part of their conditioning versus 30% to 50% in those patients without TBI; the incidence was even lower in those patients with certain chemotherapy-only regimens. Although the trend in allogeneic transplantation procedures is toward less-intensive conditioning, thus perhaps less-severe mucositis, many high-intensity conditioning regimens for autologous HSCT procedures are still virtually guaranteed to cause severe mucositis. One recent study in this setting found that TBI plus cyclophosphamide and etoposide led to a 98% baseline rate of World Health Organization grade 3/4 mucositis.7 Although the nature of the conditioning regimen heavily influences the degree of mucositis in patients undergoing HSCT, other factors such as gender, body weight, and genetics also appear to play a role.8,9

Although often accepted as clinically inevitable, the mucositis seen in patients undergoing HSCT is far from clinically insignificant. In the short term, mucositis greatly diminishes a patient's quality of life. The treatment-related irritation, sores, and ulcers inside the mouth are often so painful that patients have trouble swallowing, eating, speaking, and sleeping. The extreme discomfort often leads to decreased food and fluid intake, dehydration, and malnutrition, in addition to the need for a narcotic analgesic. In addition to the sore throat and mouth ulcers, many patients develop ulcerations and erosions in the esophagus and stomach, severe diarrhea, electrolyte loss, and hemorrhaging. In one multicenter study involving autologous and allogeneic procedures, 80% of patients undergoing HSCT required opioids for mucositis and 87% of the patients needed feeding tubes.3 Another study focusing on autologous stem cell transplantation found mucositis to be the dose-liming toxicity, with 97% of the patients requiring a narcotic analgesic for mouth pain.10

Patient surveys indicate that mouth sores are the single most debilitating side effect of the whole transplantation procedure and ranked higher in discomfort levels than nausea and vomiting, diarrhea, and fatigue.11 This result contrasts with reports of side effects after standard-dose cyclic chemotherapy, in which patients ranked oral mucositis as only the sixth most distressing complication.12 Serious infections, such as Streptococcal bacteremia, are also much more common in patients undergoing BMT with oral ulcerations compared to those patients without,13 as is the need for total parenteral nutrition (TPN).3 In fact, each 1-point increase in the mucositis severity score is associated with significant increases in fever, risk of infection, need for TPN, days of injectable narcotic therapy, and hospital days.3 The extra costs of inpatient services to manage the range of mucositis complications has been estimated at more than $42 000 per patient undergoing HSCT3 and $2725 per cycle for grade 1/2 mucositis to $5565 per cycle for grade 3/4 mucositis per patient receiving chemotherapy for solid tumors.14

Although these immediate clinical and economic consequences of mucositis capture the most attention, the potential long-term impact of mucositis on cancer treatment outcomes must also be acknowledged. Although severe mucositis has been correlated with increased 100-day mortality, this is probably associative (ie, a signal of toxicities or physiologic weaknesses at other sites) rather than causative.3 Mucositis is likely not directly life-threatening in the manner of chemotherapy-associated neutropenia. Instead, the long-term impact of mucositis may lie in its subtler influences on decisions regarding the transplantation conditioning regimen. For example, in some cases, clinicians have abandoned certain conditioning regimens known to be highly effective (eg, the BMT trials of the Southwest Oncology Group in the 1990s) because of their highly caustic effects on the oral mucosa. In other situations, awareness of the high likelihood of mouth pain and related difficulties may lead the doctor or the patient to reconsider or delay transplantation, thus limiting prompt access to a potential cure.

If the dose-limiting effect of mucositis can be prevented or limited, then perhaps the most intensive conditioning regimen can be used in a manner that narrows the chance of recurrent hematologic disease. For example, some recent evidence indicates that amifostine, a cytoprotective agent, may limit mucositis and thus allow administration of higher than usual doses of melphalan as autologous stem cell support.15 These results, and the promising outcomes and the recent US Food and Drug approval of the recombinant keratinocyte growth factor (ie, palifermin),7,16 will require longer-term study before researchers can definitively say that preventing severe mucositis improves overall cancer outcomes in HSCT, but the promise is there.

In short, mucositis is not simply a quality-of-life issue for patients. Because mucositis often requires extra efforts by the nursing and support staff, leads to expensive and extended admissions to the hospital, and may temper the aggressiveness of clinicians or patients in pursuing a maximally effective transplantation cure, this common toxicity remains a major hurdle to improved outcomes in HSCT. For this reason, clinicians and nurses who provide supportive care for patients undergoing HSCT must remain up-to-date on the management of mucositis.

In the first article in this issue of Advanced Studies in Medicine, Dr Douglas E. Peterson reviews the pathogenesis of mucositis and explains how new insights into the surprisingly complex molecular mechanisms of this condition are advancing improvements in therapies. Recent reports that the recombinant human keratinocyte growth factor (ie, palifermin) significantly reduces severe mucositis in patients undergoing HSCT7,16 illustrate the potential for improved outcomes with more specific therapies, thus the importance of understanding the underlying pathophysiology. Tests designed to limit mucositis in the HSCT setting continue to be used with other novel agents, such as the antioxidant amifostine, the "special-delivery" form of L-glutamine known as AES-14, and interleukin-11.

What's happening today in the prevention and treatment of mucositis? Every transplantation center, it seems, has developed its own unique approach, ranging from special homemade mouth rinses to cryotherapy, topical and systemic antimicrobials, biological mucosal protectants, and laser therapy. In a clinician interview with Dr Ricardo Spielberger, he shares his view of the challenges of mucositis management and provides an overview of how clinicians at the City of Hope Medical Center and Kaiser Permanente in southern California approach oral care, pain control, and nutrition in patients undergoing HSCT.

Until recently, few guidelines were available to help transplantation groups, such as Dr Spielberger's, establish protocols for the prevention and treatment of mucositis. For the most part, these institutional protocols were based on their staff's training, empirical findings, and review of single studies. In-house procedures were also driven by the program's own priorities and outcomes of interest. However, with the development of new therapies for mucositis, the standards for measurement and reporting have been elevated. As a result, the overall quality of mucositis research has been improving. In a joint interview, Drs William I. Bensinger and Stephen J. Noga comment on the recent attempt by the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society for Oral Oncology (ISOO) to create comprehensive guidelines for the prevention and treatment of cancer therapy-induced oral and GI mucositis.17

As described in the interview with these clinicians, the MASCC/ISOO guidelines are a worthy effort but remain disappointingly limited in scope because of the fundamental inadequacies of the underlying database. Despite the handful of specific take-home messages for nurses and doctors who manage supportive care for patients undergoing HSCT, the new guidelines perform a service by revealing the many areas in which clinicians are unclear on how to limit mucositis in patients. As new studies are published, these MASCC/ ISOO guidelines will be updated and will provide an increasingly valuable touchstone for disseminating the best method to prevent or treat mucositis, thus improving the short- and long-term outcomes of patients undergoing HSCT.


REFERENCES
1. McGuire DB, Yeager KA, Dudley WN, et al. Acute oral pain and mucositis in bone marrow transplant and leukemia patients: data from a pilot study. Cancer Nurs. 1998; 21:385-393.
2. Woo SB, Sonis ST, Monopoli MM, Sonis AL. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer. 1993;72:1612-1617.
3. Sonis ST, Oster G, Fuchs H, et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol. 2001;19:2201-2205.
4. National Cancer Institute. Oral complications of chemotherapy and head/neck radiation (PDQ). National Cancer Institute Web site. Available at: www.nci.nih.gov/cancertopics/pdq/supportivecare/oralcomplications. Accessed October 29, 2004.
5. Sonis ST, Costa JW. Oral complications. In: Kufe DW, et al, eds. Holland-Frei Cancer Medicine. 6th ed. Hamilton, Ontario; Lewiston, NY: BC Decker Inc; 2003.
6. Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(suppl 9):1995-2025.
7. Bensinger W, Weisdorf D, Gentile T, et al. Palifermin reduces severe oral mucositis (OM), improves patient quality of life, and reduces health resource use in patients with hematopoietic malignancies receiving high-dose chemotherapy (HDCT) and total body irradiation (TBI) with autologous peripheral blood stem cell (PBSC) support: results from a phase III trial [abstract]. Biol Blood Marrow Transplant. 2004;10:31.
8. Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001;98:231-234.
9. Robien K, Schubert MM, Bruemmer B, et al. Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. J Clin Oncol. 2004;22:1268-1275.
10. Shea TC, Bruner R, Wiley JM, et al. An expanded phase I/II trial of cyclophosphamide, etoposide, and carboplatin plus total body irradiation with autologous marrow or stem cell support for patients with hematologic malignancies.
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11. Bellm LA, Epstein JB, Rose-Ped A, et al. Patient reports of complications of bone marrow transplantation. Support Care Cancer. 2000;8:33-39.
12. Goldberg SL, Chiang L, Selina N, Hamarman S. Patient perceptions about chemotherapy-induced oral mucositis: implications for primary/secondary prophylaxis strategies. Support Care Cancer. 2004;12:526-530.
13. Ruescher TJ, Sodeifi A, Scrivani SJ, et al. The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer. 1998;82:2275-2281.
14. Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003; 98:1531-1539.
15. Phillips GL, Meisenberg B, Reece DE, et al. Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: a phase I study. Biol Blood Marrow Transplant. 2004;10:473-483.
16. Spielberg R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590-2598.
17. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004:100(suppl 9):2026-2046.

*Associate Professor, Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Director, Medical Oncology and Hematology, The Alvin & Lois Lapidus Cancer Institute, Baltimore, Maryland.

Professor, Department of MedicineƐHematology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Address correspondence to: Stephen J. Noga, MD, PhD, Associate Professor, Department of Oncology and Pathology, Johns Hopkins University School of Medicine, 2401 W. Belvedere Avenue, Baltimore, MD 21215. E-mail:
nogast@jhmi.edu.

     
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