Scope and epidemiology of cancer therapy-induced oral and gastrointestinal mucositis

Seminars in Oncology Nursing, Vol 20, No 1 (February), 2004: pp 3-10

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OBJECTIVE: To discuss the scope and epidemiology of cancer therapy-induced mucositis.

DATA SOURCE: Peer-reviewed articles and book chapters.

CONCLUSION: Mucositis is a frequent and costly complication of cancer treatment. The risk of cancer therapy-induced mucositis varies depending on a number of patient- and treatment-related factors.

IMPLICATIONS PRACTICE:

FOR

NURSING

An awareness of the risk factors associated with mucositis will allow nurses to identify cancer patients at greatest risk and incorporate supportive care measures into their management plans.

From the Section of Health Services Research, Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX. Elenir B.C. Avritscher, MD, MBA/MHA: Director of Research, Section of Health Services Research, Department of Biostatistics. Catherine Cooksley, DrPH: Management Analyst, Section of Health Services Research, Department of Biostatistics. Linda S. Elting, DrPH: Section Chief, Associate Professor, Section of Health Services Research, Department of Biostatistics. Address request reprints to Elenir B.C. Avritscher, MD, MBA/MHA, Section of Health Services Research-Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd–Unit 196, Houston, TX 77030-4009.

© 2004 Elsevier Inc. All rights reserved. 0749-2081/04/2001-0002$30.00/0 doi:10.1053/S0749-2081(03)00133-5

SCOPE AND EPIDEMIOLOGY OF CANCER THERAPYINDUCED ORAL AND GASTROINTESTINAL MUCOSITIS ELENIR B.C. AVRITSCHER, CATHERINE D. COOKSLEY, AND LINDA S. ELTING

M

UCOSITIS is a frequent and debilitating complication of cancer treatment resulting from the systemic effects of cytotoxic chemotherapy and the local effects of radiation to the oral and gastrointestinal (GI) mucosa. These modalities of cancer treatment, although aimed at destroying rapidly proliferating cancer cells, also destroy normal rapidly dividing cells, such as those of the epithelial mucosa of the oral cavity and the GI tract. In addition, they can produce a complex cascade of inflammatory and vascular processes in the mucosal tissue that contribute to ulceration, pain and related sequelae.1 The incidence and severity of oral and GI mucositis vary greatly according to patient characteristics and treatment regimens. Although numerous risk factors of mucositis have been identified in epidemiologic and clinical studies, the ability to compare results across these studies is often limited by the lack of a valid and reliable scale to measure GI mucositis and the use of several different scales to assess oral mucositis. In addition, because of the easy accessibility of the oral cavity, most research on cancer therapy-induced mucositis has traditionally focused on oral mucositis. In recent years, however, the mucotoxicity occurring throughout the entire alimentary tract has gained more attention. The purpose of this article is to discuss the scope and epidemiology of oral and GI mucositis associated with cancer treatment.

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AVRITSCHER, COOKSLEY, AND ELTING

CLINICAL OUTCOMES OF CANCER THERAPHY-INDUCED MUCOSITIS

T

he incidence of cancer therapy-induced oral and GI mucositis can be as high as 100% in some populations,2 depending on patient characteristics and treatment regimens. Mucositis induced by antineoplastic therapy significantly affects cancer patients’ morbidity and mortality by reducing their quality of life (QOL) and tolerance to cancer treatment. Mucositis is typically accompanied by oral and/or abdominal pain, ulceration, dysphagia, and diarrhea, which often result in communication impairment, reduction in fluid and food intake, and consequent dehydration and weight loss. In children, mucositis can be so severe as to lead to airway compromise.3 In neutropenic cancer patients, ulcerative mucositis is associated with life-threatening complications such as bacteremia and sepsis resulting from opportunistic infections of oral and GI origins.4,5 As a dose-limiting toxicity, mucositis can have a direct impact on survival by leading to treatment delays, interruptions, and dose reductions, which ultimately compromise the effectiveness of cancer treatment. Cancer therapy, particularly radiotherapy, may also have long-term mucotoxic effects on the oral cavity and GI tract that can be as devastating as the short-term effects. Late effects on the oral cavity are characterized by thinning of the oral mucosa resulting in chronic and nonhealing ulcers, which in the most severe cases may progress to soft tissue and bone necrosis.6 Late GI injury, in turn, may result in GI obstruction, necrosis, and perforation.7 The severity of these treatment sequelae can be especially burdensome to the pediatric population, as impaired development of soft and hard tissue during growth period may result in lifelong problems such as oral deformities and permanent dysfunctions.8 Although QOL has become an important outcome measure in oncology, no instrument to date has been developed to measure the specific effects of mucositis on the cancer patient’s QOL. In addition, there is no broad consensus on what constitutes the most relevant outcomes associated with this condition. To address this issue, Bellm et al9 convened an 11-person panel including a diverse group of health care professionals, patients, and representatives from the biotechnology industry in an attempt to determine the most meaningful outcomes for assessing mucosal changes and associated complications. The panel identified the

most important consequences of oral mucositis as being oral pain, the need for opioid analgesic, inability to eat soft foods, diminished QOL and functional status, increased length of stay in hospital, and inability to take medication orally.9 The panel also agreed that new interventions to prevent oral mucositis should improve each of these six functional outcomes by at least 1 to 3 days to represent a clinically meaningful advance in oral mucositis treatment.9 Despite its methodologic limitations, particularly the small sample size, this study represents a first step in the elucidation of the most relevant outcomes associated with oral mucositis, which could have an impact in the development of future therapeutic interventions and instruments to measure mucositis-related QOL. In an effort to examine the clinical outcomes of both oral and GI mucositis, Elting et al10 conducted a retrospective study of 599 myelosupressed patients receiving chemotherapy for treatment of solid tumors or lymphoma. The authors observed that dose-reductions in the next cycle of chemotherapy were twice as likely after cycles with oral and/or GI mucositis than after cycles without mucositis (23% v 11%; P ⫽ .0001).10 In this same study, infection episodes were significantly more common during cycles with oral and/or GI mucositis than those without (73% v 36%; P ⬍.001), even though the level and duration of neutropenia were similar in both groups.10 Interestingly, episodes of bleeding were significantly more common during cycles with GI mucositis when compared with those without any type of mucositis (13% v 8%; P ⫽ .04), despite their similarity in severity and duration of thrombocytopenia. The authors also reported that National Cancer Institute grade 3-4 pain occurred during 37% of cycles with either oral and/or GI mucositis, although opioid analgesia was prescribed in only 8.2% of the cycles, and that the risk of fatigue and weight loss was significantly higher when mucositis was present.10 Taken together, these findings underscore the clinical burden of mucositis and the potential negative impact it poses on the cancer patient’s QOL and survival.

ECONOMIC IMPACT OF CANCER THERAPYINDUCED MUCOSITIS

T

he economic burden caused by cancer therapy-induced mucositis can also be significant because it often requires the use of prescription

EPIDEMIOLOGY OF MUCOSITIS

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TABLE 1. Resource Utilization and Costs Associated With Presence of Oral and Gastrointestinal Mucositis

Study

Description of Study

Mucositis Groups

Elting et al, 200310

A retrospective study of clinical and economic outcomes of chemotherapy-induced mucositis among non-leukemic patients (n ⫽ 599 patients with 1,236 cycles)

Ruescher et al, 19984

A retrospective case-control study of the impact of oral mucositis in patients undergoing autologous BMT for hematologic malignancies (n ⫽ 69 patients) A retrospective study of the relationship between oral mucositis and economic outcomes in BMT recipients (n ⫽ 92 patients) A retrospective study of the costs associated with management of cancer therapy-induced oral mucositis in head and neck cancer patients (n ⫽ 45)

Sonis et al, 200111 Peterman et al, 200112

NCI grade 3-4 oral mucositis v no mucositis NCI grade 3-4 GI mucositis v no mucositis Oral ulceration v no oral ulceration

Additional Hospital Days (mean)

Estimated Additional Costs (USD)

4.3* 8.2*

$4,300* $8,200*

5.3

$23,850

Oral ulceration v no oral ulceration

Not reported

$43,000

No comparison groups (costs were assessed for all patients in study)

Not reported

$2,949 $4,037†

Abbreviations: NCI, National Cancer Institute; GI, gastrointestinal; BMT, bone marrow transplant. *Per cycle of chemotherapy. †Per cancer treatment episode.

medications, clinic visits, prophylactic antibiotics and, in more severe cases, prolonged hospitalization or unplanned re-admission for hydration, parenteral nutrition, and narcotic pain medication (Table 1). Elting et al10 reported that nonleukemic patients who developed chemotherapyinduced myelosuppression and experienced either severe oral or GI mucositis (National Cancer Institute grade 3-4) during chemotherapy were hospitalized 4.3 days and 8.2 days longer, respectively, than patients who didn’t experience mucositis. Ruescher et al4 reported that bone marrow transplant recipients with streptococcal bacteremia who experienced ulcerative oral mucositis were hospitalized, on average, 5.3 days longer than patients who did not experience ulceration, even though the duration of neutropenia was the same in the two groups. Sonis et al11 reported that total hospital charges were approximately $43,000 higher among stem cell transplant patients with oral ulceration when compared with the patients without. Peterman et al,12 studying the costs associated with management of cancer therapy-induced mucositis in 45 patients with head and neck cancer, estimated the mean direct medical costs due to mucositis to range from

$2,949 to $4,037 per cancer treatment episode, with hospitalization accounting for the largest portion of total costs. Although this may be an overestimate of mucositis-specific costs, because the authors in this latter study attributed all hospitalizations for rehydration to mucositis, the finding nevertheless indicates that mucositis can place a significant economic burden on an already burdened population. Furthermore, it coincides with the findings of Elting et al,10 who estimated the incremental cost of National Cancer Institute grade 1-2 mucositis at $2,725 per cycle and the incremental cost of grade 3-4 mucositis at $5,565 per cycle.

RISK FACTORS ASSOCIATED WITH CANCER THERAPY-INDUCED MUCOSITIS Patient-Related Factors Numerous patient-related factors such as age, gender, and oral health and hygiene have been associated with the frequency, duration, and severity of mucositis during cancer treatment (Table 2). Children and the elderly are reported to have an increased risk of cancer therapy-induced

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AVRITSCHER, COOKSLEY, AND ELTING

TABLE 2. Major Patient-Related Risk Factors for Mucositis 1. Age Children and the elderly are at greater risk of mucositis. 2. Gender Women are at greater risk for severe (grade ⱖ3) oral mucositis. 3. Oral health and hygiene Poor oral health and hygiene increase the risk of mucositis. 4. Salivary secretory function Reduced salivary flow increases susceptibility to oral mucositis. 5. Genetic factors Patients who express high levels of cytokines may be at higher risk of mucositis. 6. Body mass index Low body mass (BMI ⬍20 for male and ⬍19 for female) increase the risk of mucositis. 7. Renal function Decreased renal function increases the risk of mucositis. 8. Smoking Patients who smoke may be at higher risk of mucositis. 9. Previous cancer treatment Patients who received previous cancer treatment may be at higher risk of mucositis.

mucositis when compared with adults.13-20 The results of a retrospective study conducted by Sonis et al13 suggest that the prevalence of oral mucositis in pediatric patients with malignancies other than head and neck cancer is significantly higher than that for adults with the same malignancies. In a meta-analysis conducted by the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology, the risk of severe (grade 3-4) GI mucositis in pediatric patients who received total body irradiation (TBI) as conditioning for bone marrow transplant was 33%, compared with only 7% in their adult counterparts (Linda S. Elting, personal communication, June 2003). This may be related to the higher proliferation rate of cells of the mucosa in children and the higher incidence of hematologic malignances in this population, which is often accompanied by a high degree of immunosuppression.14-16 In contrast, Rocke et al17 reported the occurrence of more severe fluorouracil-induced oral mucositis in older patients, while McCarthy et al18 and Raber-Durlacher et al19 identified a non-

significant trend towards increased risk of oral mucositis following fluorouracil-based chemotherapy among GI cancer patients over the age of 50 when compared with their younger counterparts. The impact of age on mucositis has not been fully explained, but the reduction in renal function in the elderly population has been suggested to increase the toxicity of antineoplastic drugs by altering their pharmacokinetics and pharmacodynamics.20 The decreased renal function coupled with the compromised recovery of tissue losses caused by the decline in stem cell reserve associated with aging may result in more severe mucotoxicity.20 Gender has also been identified as a factor associated with risk of developing mucositis during cancer treatment. Several studies have shown a significant increase in frequency and severity of oral mucositis among women when compared with men while receiving fluorouracil-based chemotherapy.17,21,22 The results of a meta-analysis of six clinical trials of agents aimed at reducing fluorouracil-induced mucositis involving a total of 731 patients (from which all mucotoxicity criteria were converted into a 0 to 4 ordinal scale) indicated that women experience significantly greater incidence of any degree of patient-reported oral mucositis than men (63% v 52%; P ⫽ .002) and are twice as likely to develop severe (grade 3 and higher) oral mucositis.23 Following this study, Sloan et al24 expanded the analysis by including a wide range of toxicities in addition to oral mucositis and concluded that women experience significantly greater overall toxicity than men while receiving fluorouracil-based chemotherapy. It is worth noting that in this latter analysis, objectively measured toxicities, not subject to reporting bias such as leukopenia, were included. These results warrant further study because the underlying mechanisms involved in these gender differences in toxicity profiles remain largely unknown. Other patient-related risk factors associated primarily with oral mucositis include oral health, salivary secretory function, and the level of oral hygiene during therapy. Myelosuppressed cancer patients with pre-existing chronic periodontal disease have been reported to be at a higher risk for developing oral infection following cancer therapy than do patients with good oral health.25 In addition, because saliva performs a washing function and is rich in bactericidal proteins, reduced salivary flow can also predispose to the development of oral mucositis.16 McCarthy et al18 reported that

EPIDEMIOLOGY OF MUCOSITIS

reduced salivary flow significantly increased susceptibility to oral mucositis in fluorouracil-treated patients. By contrast, when compared with limited oral hygiene care, intensive oral hygiene care has shown to be associated with a significant reduction in the frequency of mucositis among cancer patients receiving bone marrow transplant,26 which suggests that the oral microflora may also play an important role in the pathophysiology of oral mucositis. The role played by factors such as genetics, body mass index, renal function, previous cancer treatment, and smoking habits has also been recently investigated. Genetic factors have been postulated to influence the risk of mucositis through modulation of the inflammatory response. Sonis and Fey16 suggest that, because pro-inflammatory cytokines are involved in the pathogenesis of mucositis, patients who express high levels of these immune mediators may be at higher risk of mucositis. Poor nutritional status, in turn, may increase the risk of mucositis by affecting mucosal regeneration and decreasing cellular renewal.27 Raber-Durlacher et al19 found that low body mass (⬍20 for males, ⬍19 for females) was an independent risk factor for oral mucositis, whereas McCarthy et al18 found no association between the two. In addition, decreased renal function has also been reported to increase the risk of mucositis by possibly increasing chemotherapy toxicity.28 Finally, patients who have a history of smoking or previous cancer treatment may also be at higher risk for developing mucositis because smoking can affect the healing capacity of the oral tissue, while prior antineoplastic therapy can make the oral and GI mucosa more vulnerable to cell damage.27,29 Treatment-Related Factors Several treatment-related factors such as chemotherapy regimen, schedule, dose, and the concomitant use and fractionation of radiation therapy have been associated with oral and GI mucositis during cancer treatment (Table 3). A substantial number of chemotherapeutic agents have been reported to produce mucositis in cancer patients.30 However, certain agents, in particular etoposide, methotrexate, irinotecan, and 5-fluorouracil (5-FU) are markedly mucotoxic, leading to increased risk of severe mucositis.29,31 Etoposide and methotrexate have a direct mucotoxic potential and are also excreted in the saliva,32 which might explain their marked oral

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TABLE 3. Major Therapy-Related Risk Factors for Mucositis 1. Chemotherapy agent 5-FU, methotrexate, and etoposide produce high rates of mucositis. 2. Chemotherapy dosage High-dose chemotherapy regimens are associated with greater risk and severity of mucositis. 3. Type of BMT Allogeneic BMT recipients experience higher rates of mucositis than autologous BMT patients. 4. Radiation site Radiation administered directly to the head and neck, thorax, abdomen, and anal-rectal region produce high rates of mucositis. 5. Radiation fractionation Altered fractionation schemes (hyperfractionation and acceleration) increase the risk of mucositis. 6. Combined modality The use of chemotherapy in conjunction with radiation therapy is associated with increased risk and severity of mucositis.

mucotoxicity. Irinotecan (CPT-11), in turn, is associated with a high risk of severe GI mucotoxicity in the form of a secretory, delayed diarrhea.33 In a study conducted by Rougier et al,34 the incidence of irinotecan-induced diarrhea among 213 patients with advanced colorectal cancer was 87%. Chemotherapy with 5-FU, the most commonly used agent in the treatment of colorectal cancer, is also highly mucotoxic and has been shown to produce high rates of severe mucositis in animal models and cancer patients.35 In a meta-analysis of five clinical trials involving a total of 2,448 patients (from which all mucotoxicity criteria were converted into a 0 to 5 ordinal scale), the incidence of severe (grade 3 and higher) fluorouracil-induced oral mucositis was reported to be approximately 14%.24 In addition, the degree and severity of fluorouracil-induced mucositis also appear to depend on the administration schedule of 5-FU. Higher incidence of mucositis has been associated with continuous infusion of 5-FU as opposed to intermittent bolus treatment.36 However, in a meta-analysis of randomized trials comparing continuous infusion versus intermittent bolus of 5-FU in a total of 1,219 patients, no significant difference in mucositis frequency or severity was found between these two schedules.37 The degree of mucositis is also dependent on the dose intensity of the chemotherapy regimen.

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AVRITSCHER, COOKSLEY, AND ELTING

The steep dose response curve associated with many antineoplastic agents in vitro has led to the increasing use of high-dose chemotherapy regimens for treatment of a variety of hematologic and solid malignancies.38 These regimens involve the administration of chemotherapy at doses several times greater than the standard therapeutic dose, but were often limited by myelosuppressive toxicity. However, the introduction of hematopoietic growth factors and the evolution of peripheral stem cell transplantation have facilitated the use of high-dose chemotherapy by ameliorating the neutropenia associated with the myelotoxic effects of dose escalation. As a result, nonhematologic toxicity, such as mucositis, is becoming increasingly more pronounced in high-dose chemotherapy regimens and has emerged as the main limiting effect of further treatment intensification. In a survey of patients who received high-dose chemotherapy followed by bone marrow or stem cell transplant, oral mucositis was reported as the single most debilitating side effect of the treatment.39 According to a review of the most important toxic effects of commonly used high-dose chemotherapy regimens for patients with solid tumors undergoing autologous transplant, the incidence of severe oral mucositis (grade 3 and higher from 0 to 4 and 1 to 4 scales) varied between 30% and 100%, depending on dose and type of chemotherapy.40 In spite of the recent advances in autologous transplantation, allogeneic marrow transplantation remains the only curative therapy for hematologic malignancies such as chronic myelogenous leukemia.41 And although allogeneic transplantation is also preceded by high-dose chemotherapy regimens, it has shown to be associated with higher risk and severity of mucositis than autologous transplantation.11,42 The increased mucotoxicity among the recipients of allogeneic transplants is believed to result from differences in conditioning regimens and the use of methotrexate, a marked mucotoxic agent, for the prevention of graft-versus-host disease.11 Sonis et al,11 studying the relationship between the severity of oral mucositis and selected clinical outcomes in 92 patients receiving stem cell transplant, noted that allograft recipients experienced significantly higher mucositis scores than autograft patients. In this study, 36% of the allograft recipients experienced grade 3 or greater mucositis (on a 0 to 5 scale) compared with only 21.4% of the autograft patients.11 Similarly, Rapoport et al42 reported more

severe oral mucositis as well as GI toxicity among patients receiving allogeneic transplantation, when compared with patients receiving autologous transplantations. Radiation therapy can also cause both oral and GI mucositis when administered directly to the head and neck, thorax, abdomen, and anal-rectal region. The risk and severity of mucositis is influenced by radiation fractionation and by the use of combined chemoradiation. Altered fractionation schemes, such as those involving hyperfractionation and acceleration, produce higher rates of mucositis. In addition, the use of chemotherapy in conjunction with radiation therapy introduces systemic toxicity, resulting in aggravation of mucositis,43 particularly in patients receiving radiation therapy to the head and neck. In a systematic review of 33 randomized clinical trials involving a total of 6,181 patients receiving radiotherapy for head and neck cancer, Trotti et al2 reported that 56% of the patient who received altered fractionation experienced severe mucositis (grade 3-4 from 0 to 4 and 1 to 4 scales), compared with 43% of patients receiving chemotherapy in conjunction with radiation therapy, and only 34% of those receiving conventional radiotherapy fractionation alone. Chemoradiation as conditioning for bone marrow transplantation, which usually involves TBI, also seems to produce high rates of mucositis. However, the published data on mucotoxicity of conditioning regimens with combined TBI and chemotherapy are somewhat inconsistent. Zerbe et al44 reported a trend for bone marrow transplant patients given chemoradiation regimens containing TBI to have slightly earlier onset and more severe mucositis than patients given busulfan-based chemotherapy alone for bone marrow ablation. In contrast, Woo et al45 reported a similar incidence and severity of ulcerative mucositis in bone marrow transplant patients receiving TBI compared with those receiving busulfan-based chemotherapy alone.

IMPLICATIONS

FOR

NURSING PRACTICE

AND

RESEARCH

W

ith the emergence of mucositis as one of the main dose-limiting effects of cancer therapy, a better understanding of the epidemiology of this condition has become crucial for nursing practice. By becoming more aware of the risk

EPIDEMIOLOGY OF MUCOSITIS

factors associated with oral and GI mucositis, nurses can more rapidly identify patients at greatest risk and subsequently incorporate supportive care measures into their management plans in an attempt to reduce and ultimately prevent the clinical and economic consequences of mucositis. In addition, it is important to emphasize that the quest for a better understanding of the pathophysiology and epidemiology of oral and GI mucositis creates numerous opportunities for nurses to engage in interdisciplinary research as leaders or active collaborators in epidemiologic and clinical research teams. Finally, by virtue of their clinical expertise and daily interactions with cancer patients, nurses are well positioned to play an expanded role in the development and testing of new interventions, QOL instruments, and measurement scales of oral and GI mucositis.

CONCLUSIONS

O

ral and GI mucositis are common, serious, and costly side effects of cancer therapy. In recent years, mucositis has become increasingly more pronounced with the intensification of can-

9

cer treatment, emerging as one of the major limiting effects of further therapy intensification. Although some of the primary clinical and epidemiologic risk factors of cancer therapy-induced oral mucositis have recently been described, more research is needed to define the full range of factors associated with both oral and GI mucositis. In addition, cancer therapy clinical trials need to be appropriately powered for stratified analysis if the estimates for the different relative risks for mucositis are to be valid. Also of note is that the numerous scales currently available to assess oral mucositis need to be standardized across studies of similar types (such as clinical trials of chemotherapy, radiation, or bone marrow transplant) to allow better comparison of intervention-specific toxicities. Most importantly, measurement scales of GI mucositis need to be developed and validated. This would contribute not only to a better understanding of the etiology and epidemiology of cancer therapy-induced oral and GI mucositis, but also to the development of successful preventive interventions, which could ultimately improve cancer patients’ QOL and tolerance to treatment.

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