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© 1999 American Society for Clinical Oncology Analysis of Factors That Correlate With Mucositis in Recipients of Autologous and Allogeneic Stem-Cell TransplantsFrom the University of Rochester Medical Center, Rochester, NY; University of Maryland, Greenebaum Cancer Center, Baltimore, MD; and Genetics Institute, Cambridge, MA. Address reprint requests to Aaron P. Rapoport, MD, Greenebaum Cancer Center, University of Maryland, 22 S Greene Street, Baltimore, MD 21201; email arapopo{at}umcc01.umcc.ab.umd.edu
PURPOSE: To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy. PATIENTS AND METHODS: Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality.
RESULTS: A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK CONCLUSION: Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.
HIGH-DOSE CHEMOTHERAPY and radiotherapy induce profound changes in the integrity of the mucosal epithelia that line the oral cavity, esophagus, and gastrointestinal tract. At the microscopic level, these changes include a decline in mitotic cells within intestinal crypts, the appearance of pyknotic or apoptotic cells, a reduction in crypt cellularity and size, and villus blunting.1,2 As a consequence, the mucosa becomes denuded, leading to bacterial, viral, or fungal invasion of the bowel wall, sepsis syndromes, ulceration, malabsorption, diarrhea, bleeding, and pain. These effects contribute to transplant-related morbidity and mortality and add to transplant-related costs by prolonging hospital stays, increasing antibiotic usage (prophylactic and therapeutic), and requiring patients to receive parenteral nutritional support. In addition, current models of graft-versus-host disease (GVHD) suggest that alterations in the cytokine or microbial milieu caused by tissue injury from cytotoxic agents may help initiate or perpetuate the immunopathogenic processes that lead to GVHD lesions of the gastrointestinal tract.3,4 Recently, several agents have been shown to have the potential to reduce mucositis and gastrointestinal toxicity in human or animal recipients of cytotoxic therapy, including glutamine, interleukin 11 (IL-11), and keratinocyte growth factor (KGF).5-10 Oral or intravenous glutamine supplements may reduce mucositis by providing an essential energy source for intestinal and oral epithelium, whereas interleukin 11 and KGF may inhibit apoptosis and induce proliferation of clonogenic mucosal epithelial cells after chemotherapy or radiation. The design of clinical studies to test the ability of these and other agents to mitigate the mucositis and gastrointestinal toxicity induced by high-dose chemoradiotherapy will be facilitated by knowledge of which clinical end points reliably reflect the severity of mucosal injury and which patient or treatment characteristics determine these end points. To this end, a prospective database was developed based on 202 patients who received high-dose therapy followed by autologous or allogeneic mobilized blood or marrow stem-cell rescue at the University of Rochester Medical Center during 1995 and 1996. This time period was selected in order to take into account the current methods of supportive care.
Patients Two hundred two consecutive patients underwent autologous or allogeneic marrow or peripheral-blood stem-cell transplantation in 1995 and 1996 for a variety of malignancies and marrow conditions at the University of Rochester Medical Center. All patients provided written informed consent for the transplantation procedures.
Supportive Care
Definition of Mucositis End Points
• MUC13: The total number of days with a mucositis score greater than 12. A score above 12 was considered to indicate presence of at least mild oral mucositis. • MUC18: The total number of days with a mucositis score  18, indicating moderate to severe mucositis. Scores in this range would correspond roughly to gastrointestinal toxicity levels of grade 3 or 4 in the Cancer and Leukemia Group B expanded common toxicity criteria. • MUCDUR12: The number of days required for the mucositis score to decrease from the peak level to  12. • PNDUR: The total number of days of parenteral nutritional support. • DIARPEAK: The peak daily volume of diarrhea after completion of high-dose therapy. (It should be noted that patients who developed potential diarrhea-causing infections such as Clostridium difficile or cytomegalovirus colitis were not excluded from analysis). • DIAR300: The total number of days (after completion of high-dose therapy) in which the volume of diarrhea was 300 mL/d. • PO500: The number of days (after completion of high-dose therapy) in which the oral intake was 500 mL/d. • PO1000: The number of days (after completion of high-dose therapy) in which the oral intake was 1,000 mL/d. • NARCDUR: Days of narcotic analgesic usage. In addition, data were collected for the following clinical end points: Incidence of blood infections (bacterial or fungal) and transplant-related mortality (during the admission for the transplantation procedure).
University of Nebraska Oral Assessment Score
Statistical Analysis: Selection of End Points
Univariate Analysis Pairwise comparisons between levels of each characteristic were made using the Mann-Whitney test. For characteristics with more than two levels, the significance level across all pairwise comparisons was controlled at 0.05 using the Steel-Dwaas method.12
All comparisons of proportions were made using the
Multivariate Analysis
Statistical Packages
Univariate Analyses Table 1 lists the characteristics of the patients included in this study and their treatments. Summary statistics are also included for the three mucositis end points to help in the planning of further studies.
Table 2 lists the median values of the peak oral mucositis scores (MUCPEAK) for the various covariates studied. Oral mucositis was significantly higher for patients who received marrow-derived stem cells, unrelated or sibling donor grafts, or carried a diagnosis of acute leukemia or myelodysplasia. In addition, patients who were conditioned with a regimen containing total body irradiation (TBI) had more severe mucositis than recipients of any other regimen except busulfan/cyclophosphamide. Also recipients of busulfan/cyclophosphamide or melphalan/etoposide/cyclophosphamide had more severe mucositis than recipients of carmustine/etoposide/cytarabine/cyclophosphamide. A delay in neutrophil recovery to day 13 or beyond was also associated with increased oral mucositis. Interestingly, younger patients exhibited more severe mucositis than older adults, perhaps reflecting higher tissue growth rates in younger patients or the use of more intensive treatment regimens.
A similar analysis is shown in Table 3 using the median duration of parenteral nutritional support (PNDUR) as the measure of mucositis and gastrointestinal toxicity. This analysis yielded similar results to those obtained in Table 2 using the oral assessment score. Statistically significant longer durations of parenteral support were required for younger patients and patients who received marrow cells, received unrelated or related allogeneic grafts, carried a diagnosis of acute leukemia, or myelodysplasia, received TBI as conditioning, or exhibited a delay in neutrophil recovery to 13 days or beyond. A nonsignificant trend toward shorter courses of nutritional support was observed among female patients.
In contrast, the univariate analysis shown in Table 4 using the peak daily output of diarrhea (DIARPEAK) as an end point showed few significant differences associated with the covariates tested.
Multivariate Analysis
Relation Between End Points and Treatment-Related Infections and Mortality
The duration of parenteral nutritional support (PNDUR) also correlated strongly with the occurrence of blood infections and transplant-related mortality. The median duration of nutritional support was 16 days for patients with a positive blood culture and only 8 days for patients without a blood infection (P = .0001); the median duration of nutritional support was 17.5 days for patients who died during transplantation hospitalization versus 10 days for patients who did not (P = .003). Among the patients who received nutritional support for No significant associations were identified between DIARPEAK and the occurrence of blood infections or transplant-related mortality. To exclude the possibility that the associations between the mucositis end points and blood infections or treatment-related mortality merely reflected parallel increases in mucositis, rates of infection, and mortality among the allogeneic transplant recipients, this analysis was performed separately for the autotransplantation and allotransplantation subgroups (sibling and unrelated donors combined). As shown in Table 6, blood infections mainly occurred among autotransplant recipients who had high values of MUCPEAK or PNDUR, whereas a marginally significant association between MUCPEAK and blood infections was observed for the allogeneic subgroup. In contrast, almost all of the transplant-related deaths occurred in the allogeneic subgroup, and these were again associated with high levels of MUCPEAK but not high levels of PNDUR or DIARPEAK.
The availability and widespread clinical use of hematopoietic growth factors, including granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor, has significantly shortened the duration of severe marrow aplasia after high-dose therapy and may have contributed to the reduction in transplant-associated morbidity and possibly mortality that has been observed during the last 3 to 5 years.13 However, mucositis and gastrointestinal toxicity from high-dose therapy continues to be a major source of patient discomfort, gastrointestinal bleeding, transplant-related costs, and may predispose to serious infections and mortality, as demonstrated in this report. Indeed, an important finding from this study was that the severity of mucositis as measured by an oral assessment score (MUCPEAK) and the duration of parenteral nutritional support (PNDUR) were associated with an increased risk of blood infections or treatment-related mortality. When this analysis was performed separately for the autologous and allogeneic (sibling plus unrelated) subgroups, these associations remained, but they applied differently to the two subgroups: blood infections but not mortality were increased among autotransplant recipients with severe mucositis, whereas treatment-related mortality and blood infections were increased (but only marginally) among allotransplant recipients with severe mucositis. These findings clearly emphasize the importance of developing strategies to ameliorate treatment-related gastrointestinal toxicity. At least several agents have been recently demonstrated to have mucosal protection activities. Glutamine, considered a "nonessential" amino acid and usually absent from commercially available parenteral nutrition formulations because of its shorter shelf-life, is an important energy source for intestinal epithelium.14 In a randomized study involving 45 patients, the group that received parenteral solutions supplemented with L-glutamine (0.57 gm/kg/d) had significantly improved nitrogen balance, fewer clinical infections, and shorter hospital stays.5 In a second trial, 193 marrow transplantation patients were randomized to receive placebo or glutamine (1.0 gm/m2) four times per day as an oral rinse.6 A significant decrease in oral pain and opiate use was observed in the autotransplantation subgroup, but no such decreases were observed in the sibling or unrelated allogeneic transplantation subgroups. However, 28-day survival was significantly better for allogeneic transplantation patients who were randomized to receive glutamine. IL-11 is a pleiotropic cytokine that protects the gastrointestinal mucosa of rodents from radiation- or chemoradiation-induced injury when administered shortly before or immediately after treatment.7-9,15 This effect is apparently due to prevention of apoptosis and enhanced proliferation of clonogenic cells of the intestinal crypts as evidenced by a treatment-induced increase in the mitotic index of the crypt cells and increased immunodetection of the proliferating-cell nuclear antigen. The mechanisms that are responsible for this protection effect are not entirely clear but may include direct IL-11 receptor–mediated stimulation of intestinal epithelial cells or modulation of inflammatory cytokine production by accessory cells such as macrophages.16-18 Also, recent data from a murine marrow transplantation model suggest that IL-11 may prevent lethal GVHD through these mechanisms as well as through modulation of donor T-cell responses to recipient antigens.19 Although IL-11 has been shown to promote thrombopoiesis in humans after nonmyeloablative chemotherapy,20 its clinical role as a mucosal protectant has not been specifically investigated. KGF, a member of the fibroblast growth factor family, increased mitotic figures and Ki67 immunostaining in buccal mucosal biopsies of normal volunteers who received this cytokine for 3 consecutive days.10 These data provide a framework for further studies of IL-11, KGF, and glutamine in recipients of high-dose therapy. Because the ability to safely obtain relevant tissue biopsies from patients with extensive mucositis may be limited, the identification of reliable and noninvasive clinical assessment tools will be needed to evaluate the mucosal protection effect of these or future agents. In this study of 202 consecutive transplant recipients, two potentially useful clinical end points were identified: the peak value of the University of Nebraska Oral Assessment Score (MUCPEAK) and the duration of parenteral nutrition support (PNDUR). The basis for this claim is twofold: (1) These two end points were associated with patient and treatment characteristics that a priori were thought to affect the severity of therapy-induced mucositis and gastrointestinal toxicity (Tables 2 and 3), and (2) they correlated strongly with important clinical outcomes, including development of blood infections and treatment-related mortality (Tables 5 and 6). Although oral assessments and decisions about the need for parenteral nutritional support may vary between observers and treating physicians, several attributes of this study may have minimized this problem. First, the oral mucositis score used in this study was based on a system that numerically graded each aspect of the oral assessment according to well-defined clinical criteria (see Patients and Methods under Definition of Mucositis End Points). Second, mucositis scoring was performed at least once per day by experienced clinical transplantation nurses who were generally assigned to the same patient every day. Third, parenteral nutritional support was begun and discontinued using specific guidelines (as described in Patients and Methods under Supportive Care). Interestingly, diarrhea volume, which is traditionally considered to reflect the severity of mucosal and gastrointestinal injury, did not correlate with the occurrence of blood infections or transplant-related mortality or, in fact, with other mucositis indicators. It is conceivable that a relationship between diarrhea volume and mucositis predictors could have been obscured by the inclusion of patients who developed intestinal infections, but a large prospective study suggested that infections account for a minority (approximately 13%) of diarrheal episodes in hematopoietic stem-cell transplant recipients.21 Additionally, a relationship between diarrhea volume and mucositis predictors might have been demonstrated if the measurement period were limited to the first 5 to 7 days after finishing therapy when the impact of treatment factors (rather than antibiotic usage, infections, or GVHD) might have been proportionately greater. Clearly, other more objective noninvasive measures of mucosal integrity would be useful in assessing the response to putative gut protectants. Intestinal absorption tests may be valuable in this regard. Intestinal absorption of D-xylose becomes progressively impaired during weeks 1 to 3 after high-dose or antileukemic therapy and shows recovery by weeks 4 to 5 posttreatment.22-25 Lactulose and mannitol are two nonmetabolizable sugar probes that undergo differential changes in absorption after intestinal injury: lactulose absorption generally increases and mannitol absorption generally decreases. The ratio of the serum concentrations or urinary excretions of the two sugars adjusts for changes in bowel transit time, gastric emptying rate, or renal function and, when increased, seems to correlate with gastrointestinal mucosal injury and possibly later development of gastrointestinal GVHD.26,27 Several patient and treatment characteristics were associated with mucositis severity or the duration of parenteral nutrition support. These included diagnosis, treatment protocol, rate of neutrophil recovery, transplantation type, stem-cell source, and patient age. In future studies of agents that may mitigate mucositis, these variables should be controlled or serve as criteria for stratification. Due to the correlations among the covariates considered in this study, there were many regression models with different combinations of covariates that all fit the data almost equally well. Therefore, it was not possible with our data to identify a single set of covariates that could be used to predict mucositis. The development of strategies to reduce transplant-related mucosal injury will represent an important advance in the supportive care of patients who require high-dose chemoradiotherapy, especially as transplantation care moves to the outpatient setting. The clinical end points and predictors for mucositis identified in the present analysis may assist in the design of efficacy trials for potential gut protectants.
Supported in part by an unrestricted grant from Genetics Institute.
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Du XX, Doerschuk CM, Orazi A, et al: A bone marrow stromal-derived growth factor, interleukin-11, stimulates recovery of small intestinal mucosal cells after cytoablative therapy. Blood83:33-37, 1994 8. Potten CS: Interleukin-11 protects the clonogenic stem cells in murine small-intestinal crypts from impairment of their reproductive capacity by radiation. Int J Cancer62:356-361, 1995[Medline] 9. Orazi A, Du X, Yang Z, et al: Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation. Lab Invest75:33-42, 1996[Medline] 10. Serdar CM, Heard R, Prathikanti R, et al: Safety, pharmacokinetics and biologic activity of rHuKGF in normal volunteers: Results of a placebo-controlled randomized double-blind phase I study. Blood 90:172a, 1997 (abstr 761)
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Rapoport AP, DiPersio JF, Martin BA, et al: Patients 12. Hochberg Y, Tamhane AC: Multiple Comparison Procedures. New York, John Wiley & Sons, 1987 13. Rowe J, Rapoport AP, Liesveld JL: Use of hematopoietic growth factors in hematological malignancies, in Freireich EJ, Kantarjian HM (eds): Medical Management of Hematological Malignant Diseases. New York, NY, Marcel Deeker, Inc, 1998, pp 421-478 14. Windmueller HG: Glutamine utilization by the small intestine. Adv Enzymol53:201-237, 1987 15. Turner KJ, Clark SC: Interleukin-11: Biological and clinical perspectives in Mertelsmann R, Herrmann F (eds): Hematopoietic Growth Factors in Clinical Applications (ed 2). New York, NY, Marcel Deeker, Inc, 1994, pp 315-336 16. Du XX, Yang ZX, Wang GM, et al: Analysis of murine interleukin-11 gene expression in vivo. Blood 86:424a, 1995 (abstr) 17. Peterson RL, Trepicchio WL, Bozza MM, et al: G1 growth arrest and reduced proliferation of intestinal epithelial cells induced by rhIL-11 may mediate protection against mucositis. Blood 86:311a, 1995 (abstr) 18. Trepicchio WL, Bozza M, Dorner AJ: Recombinant human interleukin-11 attenuates the inflammatory response through downregulation of proinflammatory cytokine production and nitric oxide release. Blood 86:424a, 1995 (abstr) 19. Hill GR, Cooke KR, Teshima T, et al: Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation. J Clin Invest102:115-123, 1998[Medline]
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Gordon MS, McCaskill-Stevens WJ, Battiato LA, et al: A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy. Blood87:3615-3624, 1996 21. Cox GJ, Matsui SM, Lo RS, et al: Etiology and outcome of diarrhea after marrow transplantation: A proposed study. Gastroenterology107:1398-1407, 1994[Medline] 22. Craig RM, Atkinson AJ: D-Xylose testing: A review. Gastroenterology95:223-231, 1988[Medline] 23. Guyotat D, VuVan H, Pigeon R, et al: Intestinal absorption tests after bone marrow transplantation. Exp Hematol12:118-119, 1984 24. Haeney MR, Culank LS, Montgomery RD, et al: Evaluation of xylose absorption as measured in blood and urine: A one hour blood xylose screening test in malabsorption. Gastroenterology75:393-400, 1978[Medline]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. 
