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Mucositis: Perspectives and Clinical Practice Guidelines
Perspectives on cancer therapy-induced mucosal injury
Pathogenesis, measurement, epidemiology, and consequences for patients
Article first published online: 19 APR 2004
Copyright © 2004 American Cancer Society
Volume 100, Issue S9, pages 1995–2025, 1 May 2004
How to Cite
Sonis, S. T., Elting, L. S., Keefe, D., Peterson, D. E., Schubert, M., Hauer-Jensen, M., Bekele, B. N., Raber-Durlacher, J., Donnelly, J. P. and Rubenstein, E. B. (2004), Perspectives on cancer therapy-induced mucosal injury. Cancer, 100: 1995–2025. doi: 10.1002/cncr.20162
- Issue published online: 19 APR 2004
- Article first published online: 19 APR 2004
- Manuscript Accepted: 22 JAN 2004
- Manuscript Received: 19 DEC 2003
- Mucositis Study Section of the Multinational Association of Supportive Care in Cancer (MASCC)
- International Society for Oral Oncology (ISOO)
- Amgen (Thousand Oaks, CA)
- GelTex Pharmaceuticals (Waltham, MA)
- Helsinn Healthcare SA (Pazzallo, Switzerland)
- Human Genome Sciences (Rockville, MD)
- McNeil Consumer and Specialty Pharmaceuticals (Fort Washington, PA)
- MGI Pharma (Bloomington, MN)
- MedImmune (Gaithersburg, MD)
- OraPharma (Warminster, PA)
- RxKinetix (Louisville, CO)
- oral mucositis;
- gastrointestinal mucositis;
- mucosal barrier injury;
- mucositis clinical assessment scales;
- mucositis etiopathogenesis
- Top of page
- BIOLOGIC BASIS AND PATHOGENESIS
- CLINICAL MUCOSITIS ASSESSMENT SCALES
- EPIDEMIOLOGY AND OUTCOMES
A frequent complication of anticancer treatment, oral and gastrointestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to dose reductions, increases healthcare costs, and impairs patients' quality of life. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and treatment of mucositis.
The panelists examined medical literature published from January 1966 through May 2002, presented their findings at two separate conferences, and then created a writing committee that produced two articles: the current study and another that codifies the clinical implications of the panel's findings in practice guidelines.
New evidence supports the view that oral mucositis is a complex process involving all the tissues and cellular elements of the mucosa. Other findings suggest that some aspects of mucositis risk may be determined genetically. GI proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps explaining differences in the frequency with which mucositis occurs at different sites. Studies of mucositis incidence in clinical trials by quality and using meta-analysis techniques produced estimates of incidence that are presented herein for what to our knowledge may be a broader range of cancers than ever presented before.
Understanding the pathobiology of mucositis, its incidence, and scoring are essential for progress in research and care directed at this common side-effect of anticancer therapies. Cancer 2004;100(9 Suppl):1995–2025. © 2004 American Cancer Society.
Oral mucositis is a frequent complication of cytoreductive cancer chemotherapy and radiotherapy. In many patients, it is associated with considerable pain and, thus, can significantly impair quality of life; in neutropenic patients with cancer, mucositis represents a clinically significant risk factor for sepsis.1 Furthermore, in some patients, it becomes a dose-limiting toxicity, slowing or preventing continuation of selected cancer therapies, including accelerated fractionation and hyperfractionation in radiotherapy and interventions that combine chemotherapy and radiotherapy.
Gastrointestinal (GI) mucositis, which represents injury of the rest of the alimentary tract, also is becoming recognized increasingly as a toxicity associated with many standard-dose chemotherapy regimens commonly used in the treatment of cancer and with radiation to any part of the GI tract. After chemotherapy, GI mucositis is most prominent in the small intestine, but it also occurs in the esophagus, stomach, and large intestine. Radiation esophagitis and radiation proctitis are also manifestations of GI mucositis.
Over the past 5 years, investigators have developed insight into the basic molecular mechanisms of mucosal barrier injury, prompting new strategies for prevention and treatment. Equally significant are recent studies that have defined the epidemiologic aspects of mucositis further, because they form the basis for any analysis in which the potential efficacy of an intervention is evaluated.1 Furthermore, because interpreting the epidemiologic data depends on understanding the scoring systems used to measure and objectively classify mucositis, the strengths and limitations of the scoring systems are reviewed before the epidemiologic data are presented. Therefore, in this article, we describe the most current view of mucositis pathobiology, the scoring systems, the current epidemiology, and the economic and clinical consequences of mucositis for patients. The epidemiologic data are drawn from a comprehensive, evidence-based literature review that was conducted by the Mucositis Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology, as part of the effort to create clinical practice guidelines (see the accompanying article in this issue2).
BIOLOGIC BASIS AND PATHOGENESIS
- Top of page
- BIOLOGIC BASIS AND PATHOGENESIS
- CLINICAL MUCOSITIS ASSESSMENT SCALES
- EPIDEMIOLOGY AND OUTCOMES
The biologic complexities underlying mucosal barrier injury and, in particular, oral mucositis have been appreciated only recently. In fact, our understanding of the molecular, cellular, and tissue events that lead to this common and often dose-limiting toxicity continue to evolve. Historically, mucositis was viewed solely as an epithelium-mediated event that was the result of the nonspecific toxic effects of radiation or chemotherapy on dividing epithelial stem cells.3 It was believed that direct damage by chemotherapy or radiation therapy to the basal epithelial cell layer led to loss of the renewal capacity of the epithelium, resulting in clonogenic cell death, atrophy, and consequent ulceration. This direct, somewhat linear process failed to account for several more recent findings about the role of other cells and the extracellular matrix in the submucosal region. These observations outlined below indicate that the mechanisms that result in mucositis are not so direct or simple.4
Microvascular injury (e.g., injury mediated by endothelial apoptosis) may play a significant role in the development of radiation-induced intestinal injury.5 Morphologic evidence provided by electron microscopy demonstrates that endothelial and connective tissue damage precedes epithelial changes in irradiated oral mucosa,4 suggesting that endothelial injury is an early event in the development of radiation-induced mucosal injury. Whether endothelial injury has a sustaining role is unclear, however, inasmuch as morphologic evidence of vascular damage was not observed in human material obtained from patients who had received cumulative radiation doses of 30 grays, despite increased expression of adhesion molecules.6 The finding that the inhibition of platelet aggregation is associated with reduced mucosal toxicity also suggests a possible role for vascular endothelium and platelets in the pathogenesis of mucositis.7
Further evidence suggesting that mucositis is not just an epithelial process comes from examining the relation between proinflammatory cytokines and mucosal toxicity in animal and human studies. Increased peripheral blood levels of tumor necrosis factor-alpha (TNF-α) and interleukins 1 and 6 (IL-1 and IL-6) correlate with the extent of nonhematologic toxicities in patients following chemotherapy.8 Similarly, mucosal levels of IL-1β and gene expression of TNF-α are associated with the development of mucositis in animal models.4 Agents known to attenuate the expression of both cytokines have demonstrated efficacy in the prevention of both experimental4 and clinical9 mucositis. For example, in a radiation-injury mucositis model, IL-11, a pleotrophic cytokine, can decrease TNF-α levels, an event associated with a reduction in mucositis scores. Furthermore, it has been noted recently that tissue apoptotic rates that vary in different disease states (in psoriasis, antiapoptotic; in Addison disease, proapoptotic) are associated with opposing risks for mucositis compared with controls without either condition (Chen E, unpublished data).
Increasing direct and indirect experimental evidence supports the concept that virtually all the cells and tissues of the oral mucosa, including the extracellular matrix, contribute to barrier injury. The sequence of cell and tissue changes further implies that nothing occurs within the mucosa as a biologically isolated event. Rather, it appears that interactions among the various mucosal components, including those influenced by the oral environment, collectively lead to mucositis.
For illustrative purposes, mucosal barrier injury can be viewed as having five phases: initiation, up-regulation with generation of messengers, signaling and amplification, ulceration with inflammation, and, finally, healing. This model of injury is demonstrated best in the oral mucosa but also may take place in the rest of the alimentary canal. Although the model as described seems linear, injury occurs very quickly and simultaneously in all tissues.
Whatever the target tissue, generation of oxidative stress and reactive oxygen species (ROS) by chemotherapeutic agents or radiation appears to be a primary event in most pathways leading to mucositis. The consistent reports of ROS generation after exposure to stomatotoxic agents10 and the results of studies that demonstrate successful attenuation of mucosal injury by agents that effectively block or scavenge oxygen-free radicals11 suggest a significant role for ROS in injury induction. Whether they are generated by chemotherapy or radiation exposure, ROS directly damage cells, tissues, and blood vessels. The activation of ROS and their subsequent ability to stimulate a number of transcription factors seem to characterize the acute tissue response to a stomatotoxic challenge and are considered the hallmark of the initiation phase of mucositis leading to other biologic events.
Up-regulation and generation of messenger signals
During the second phase, multiple events occur simultaneously. ROS cause DNA damage and subsequent clonogenic cell death in the epithelial layer. Importantly, direct clonogenic death of basal epithelial cell death is insufficient to account for the extent of mucositis observed. Given the observed sequence of cellular and tissue events, the search for a pivotal biologic event that drives mucositis is compelling. Of the transcription factors that may be significant, nuclear factor-κB (NF-κB) has many of the characteristics that suggest that it may be a key element in the genesis of mucositis: It is activated by either radiotherapy or chemotherapy, the 26S proteasome is detectable in stressed mucosa, it has the capacity to up-regulate a large panel of genes with the potential to elicit a broad range of tissue responses, and it can respond differently to varying challenges. Once activated, NF-κB leads to the up-regulation of many genes, including those that result in the production of the proinflammatory cytokines TNF-α, IL-1β, and IL-6. This leads to tissue injury and apoptosis. Upregulation of other genes causes the expression of adhesion molecules, subsequent activation of the cyclooxgenase-2 pathway, and consequent angiogenesis (Fig. 1).
It would be naïve to suggest that NF-κB is the sole pathway leading to chemotherapy-induced or radiotherapy-induced normal tissue apoptosis. For example, ROS can activate sphyngomyelinase, chemotherapy can activate ceramide synthase directly, and the ceramide pathway may work in parallel or sequentially to induce primary apoptosis.12 Fibronectin break-up also occurs during the up-regulation and message-generating phase of mucositis. Macrophages are activated subsequently, leading matrix metalloproteinases to then cause tissue injury directly or leading to more production of TNF-α. The end result of the up-regulation and message-generation phase of mucositis is one of simultaneous events in all involved tissues at all levels (see Fig. 2).
Signaling and amplification
It seems likely that, in addition to exerting a direct damaging effect on mucosal target cells, proinflammatory cytokines also play an indirect role in amplifying mucosal injury initiated by radiation and chemotherapy. For example, TNF-α is a very capable activator of a number of pathways that can lead to tissue injury, including the ceramide and caspase pathways and the transcription pathway mediated by NF-κB. These signals lead to further production of the proinflammatory cytokines TNF-α, IL-1β, and IL-6. In addition, activation of the ceramide pathway by TNF-α may provide an effector mechanism for secondary TNF-α-mediated tissue damage. The ultimate consequence of this phase is that the tissue is altered biologically, even though it may appear normal (Fig. 3).
Mucositis, especially that induced by radiation, frequently is referred to as an inflammatory process; however, the phrase may misrepresent the significance of inflammation in mucosal barrier injury. An acute inflammatory infiltrate is not identifiable histologically during the early stages of radiation-induced mucositis. Furthermore, stomatotoxicity occurs during periods of maximum myeloablation in patients treated with chemotherapy. Despite the lack of a robust neutrophil infiltrate during the development of mucositis, a round cell infiltrate, comprised largely of reparative RM3/1 positive macrophages, has been reported in response to increasing doses of radiation.13 This infiltrate most likely is the consequence of a sequence of events triggered by oxidative stress, mediated by activated T cells, and preceded by the production of adhesion molecules. It has been suggested that the presence of these cells represents an intermediate, antiinflammatory response.13 Mast cells have been observed in irradiated rat intestinal mucosa, and investigators have speculated that these cells have a protective role.14 Not unexpectedly, the ulcerative phase of mucositis is characterized by a robust inflammatory infiltrate comprised of both polymorphonuclear and round inflammatory cells.
During the ulcerative phase of mucositis, bacterial colonization occurs with gram-positive, gram-negative, and anaerobic organisms. The role of such oral environmental factors as bacteria and their products is unclear. Cell wall products from bacteria can activate tissue macrophages, leading to more production of the proinflammatory cytokines TNF-α, IL-1β, and IL-6. Although bacterial cell wall products have the ability to amplify and accelerate local tissue damage markedly by stimulating a variety of pathways, the effect of directly reducing the bacterial load on the course of mucositis has been erratic. Similarly, changes in the composition and amount of saliva presumably may influence the susceptibility of tissue to cytotoxic agents and the tissue's ability to heal. Nonetheless, to our knowledge, outcomes of mucositis studies in which salivary function is targeted are unclear. Ultimately, the consequences of ulceration are further cytokine amplification, inflammation, and pain, and the patient is at increased risk for bacteremia and sepsis (Fig. 4).
A review of the physiology of wound healing is far beyond the scope of this report; however, the healing phase of oral mucositis starts with a signal from the extracellular matrix. This leads to a renewal of epithelial proliferation and differentiation and reestablishment of the local microbial flora. Depending on the clinical setting, other associated clinical events simultaneously return to normal. For example, in hematopoietic stem cell transplantation (HSCT), the healing phase also is marked by leukocyte recovery. After the healing phase, the oral mucosa appears normal; however, despite its normal appearance, the mucosal environment has been altered significantly. There is residual angiogenesis, and the patient is now at increased risk of future episodes of oral mucositis and its complications with subsequent anticancer therapy.
Genetic risk and modulation of mucositis
All of the tissue changes described above may occur in the context of tissue that either is primed genetically or is resistant to regimen-related toxicities. Mounting evidence suggests that some aspects of mucositis risk may be determined genetically. Three lines of evidence support this hypothesis. Differences in individual susceptibility to chemotherapy-induced and radiotherapy-induced toxicities have been noted for years. Recently reported studies have concluded that murine strains vary in their mucosal response to radiation.15 Single nucleotide polymorphisms have been identified that are associated with the metabolism of a number of chemotherapeutic agents. Individuals who express phenotypes that result in deficiencies of enzymes needed for metabolism of specific chemotherapy drugs are at increased risk for toxicity. For example, polymorphisms that predispose to methotrexate-related toxicities have been noted in bone marrow transplantation recipients with increased levels of mucositis.16 These findings, as well as results suggesting that the risk of toxicity is determined in part by gender or ethnicity, undoubtedly will be topics for additional investigation.
The effect of NF-κB on apoptosis is paradoxical. There are numerous reports demonstrating that activation of NF-κB is antiapoptotic and, therefore, that regimen-related toxicity may lead to the conclusion that chemotherapy-induced or radiotherapy-induced NF-κB activation in normal cells is not only not cytoprotective but also proapoptotic. This concept suggests that there are differences in the way in which normal cells and tumor cells respond to cytotoxic challenges and potentially presents a huge opportunity for targeted mucositis interventions that do not jeopardize therapy-induced tumor kill.17 Consequently, the role of NF-κB, and other transcription factors in the pathogenesis of mucositis is of great potential interest.
Although to our knowledge much of the mechanistic basis for regimen-related mucosal injury has yet to be determined, based on the data available, it is evident that mucositis is much more than just an epithelial event. This five-phase model helps to provide a mechanistic understanding of the complex biology of mucositis. It also serves as a basis for understanding the rationale for therapeutic interventions as single agents or combination therapies.
In contrast to earlier thinking, there is no reason to assume that the pathobiology of intestinal mucositis is any less complex than the pathobiology suggested for oral mucositis. The common embryologic development of the entire GI tract makes it likely that the basic pathogenesis of mucositis is similar, with local differences due to the specialized differentiation in each area. In fact, it is likely that the initiating events in both tissue types are similar. However, in addition to the obvious morphologic differences observed between the most proximal and distal elements of the GI tract and its intestinal elements, specific functional components also make each section distinctive.
Teleologically, it might be assumed that chemotherapy-derived or radiotherapy-derived, cell-damaging or cell-destroying mechanisms must share a certain degree of commonality. It could be argued that the damage that occurs in the intestine is similar to the damage that occurs in the basal epithelium of stratified mucosa but acts at a much faster rate. In addition, the functional and symptomatic outcomes of gut toxicity are very different from the outcomes noted secondary to oral, esophageal, or rectal injury.
Similar to oral mucositis, in GI mucositis, it was believed historically that radiation caused direct cytocidal injury (clonogenic and apoptotic cell death), direct functional injury, and a number of reactive (indirect) changes. Although, to a large extent, acute toxicity is a result of crypt cell death, resulting in the breakdown of the mucosal barrier and in mucosal inflammation, controversy exists regarding whether this effect, in fact, is direct or is mediated through a series of intermediate steps. Paris et al.,5 as noted earlier, argued that crypt cell death is actually an indirect consequence of endothelial cell apoptosis and that endothelial cell apoptosis, therefore, is the primary lesion responsible for the intestinal radiation syndrome. Although these findings are not accepted universally, they provide strong evidence that intestinal injury may be the consequence, at least in part, of intermediate events mediated by nonepithelial tissues. This hypothesis may be supported by the finding that during fractionated radiation therapy, a number of compensatory changes also occur. For example, during pelvic radiation therapy, intestinal permeability and histologic injury actually are maximal in the middle of the radiation course and then improve toward the end, despite continued daily irradiation and increasing symptoms of intestinal toxicity.18, 19 This suggests that mechanisms other than histologically detectable changes in the mucosa are responsible for bowel symptoms (nausea, emesis, diarrhea,and pain) in patients during fractionated radiation therapy.
Although aspects of GI radiation-induced injury have been studied in all segments of the alimentary tract (esophagus, stomach, duodenum, small intestine, colon, and rectum) and have been reviewed recently by Fajardo et al.20 and Hauer-Jensen et al.,21 to our knowledge, investigations of chemotherapy-induced GI mucositis have been focused mainly on the small intestine.
Many cytotoxic chemotherapeutic agents kill rapidly dividing cells, making the GI tract particularly vulnerable. In the small intestine, cytotoxic agents act at different levels of the crypt cell hierarchy, leading to crypt hypoplasia followed by regeneration.22, 23 The first abnormality noted in the human small intestine is an increase in apoptosis on Day 1 after chemotherapy; this is followed by reductions in crypt length, villus area, and mitotic index, which reach their nadir on Day 3. Rebound hyperplasia follows on Day 5, prior to normalization.24 This has now been modeled in rats, in which it follows a similar pattern over a shorter time course.25–27 However, Pritchard et al.28 have shown that an increase in apoptosis does not necessarily correlate with the severity of overt mucositis, suggesting a contribution from p53 and p21. Gibson et al.29 confirmed this in the DA rat model. Further research has shown30 that the ratio of proapoptotic genes to antiapoptotic genes of the bcl-2 family changes along the GI tract. There is a higher ratio of proapoptotic to antiapoptotic genes in the small intestine than in the large intestine, which may help explain the differences in mucositis that occur. The different ratio of proapoptotic to antiapoptotic genes found at the different levels of the GI tract most likely relates to the differences in function, with the small intestine receiving a large volume of potential toxins, most of which have been neutralized prior to arrival in the colon. It also may help to explain the rarity of small intestinal malignancy compared with colonic malignancy. Because chemotherapy acts on tumors partly through apoptosis, antiapoptotic strategies to prevent mucositis would need to be very specific to the GI tract rather than tumor. Gibson et al. have shown that the small intestine damage caused by irinotecan (CPT-11) is the same as that caused by drugs such as methotrexate, but that there is more colonic crypt goblet cell hyperplasia.31
The esophagus is lined by nonkeratinized epithelium with a lamina propria and muscularis mucosa. Chemotherapy damages the dividing and differentiating cells, leading to a thin and ulcerated epithelium.32 Chemotherapy also alters the proliferative rate of connective tissue cells within the lamina propria, which results in increased vascular permeability and an inflammatory infiltrate. Fibrosis and tissue ischemia ensue. There is little information in the literature regarding esophageal mucositis because most symptoms localized to the esophagus usually are attributed to gastroesophageal reflux disease or to either viral or fungal infections, which can coexist with any direct chemotherapy-induced toxicity.
Likewise, little data exist concerning mucositis of the stomach. Sartori et al. described gastric erosions after chemotherapy with combined cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) or with 5-FU alone.33, 34 The colon is not considered an area that is particularly susceptible to chemotherapy-induced mucositis. Gibson et al.26 reported crypt damage in the colon after methotrexate and CPT-11 therapy, but the damage observed was less than that noted in the small intestine. Typhlitis, or postchemotherapy enterocolitis (usually involving the cecum), has been reported in several articles,35–39 but to our knowledge no histopathologic studies have been performed. It appears to be increasing in incidence with the advent of newer chemotherapeutic agents, such as the taxanes.
Whatever the initiating event, it is likely that mucosal barrier injury in the GI tract and the oral mucosa share similar mechanisms. Although more molecular events have been elucidated in the pathogenesis of oral mucositis relative to its GI counterpart, future research is likely to demonstrate that the oral cavity and the GI tract have sufficient homology that differences between them will be due to local differences in specialized cell differentiation.
CLINICAL MUCOSITIS ASSESSMENT SCALES
- Top of page
- BIOLOGIC BASIS AND PATHOGENESIS
- CLINICAL MUCOSITIS ASSESSMENT SCALES
- EPIDEMIOLOGY AND OUTCOMES
From routine patient care to sophisticated clinical research settings, the importance of being able to describe precisely, classify objectively, and measure reproducibly the severity of mucosal damage cannot be overestimated. Ideally, a mucositis scoring system should be objective, validated, and reproducible across all clinical situations and applications. The scale should be sufficiently sensitive to measure appropriate parameters of the mucositis experience consistently across different treatment modalities, including cancer chemotherapy, radiotherapy, and chemoradiotherapy. It also should precisely measure elements associated with mucositis consistently (i.e., content validity). Minimal training should be necessary to produce systematic, accurate results, and the scale should be characterized by intrarater and interrater reliability. No scale established to date meets all these criteria or is accepted universally.
Because the need for mucositis measurement instruments has become more acute, a number of different scoring systems have been developed (Table 1).40–54 A few scales measure GI mucositis, but the majority of the scales measure oral mucositis. Oral mucositis scales range considerably in their complexity and have undergone varying degrees of validation.
|Scale (use)||Source||Elements measured||Advantages||Disadvantages|
|Simple, combined-variable mucositis scoring scales|
|NCI-CTC (clinical and research)||Trotti et al., 200040 (see also http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf41)||Combined elements: symptom (pain), signs (erythema, ulceration); function; type of dietary intake||Used widely in research and clinical care settings; specific scales for mucositis in patients undergoing head/neck radiation, chemotherapy, or HSCT||Research assessment potentially confounded by combination of symptoms, signs, and functional changes|
|WHO (clinical and research)||WHO, 197942||Combined elements: symptom (pain), signs (erythema, ulceration); function: type of dietary intake||Used widely in research and clinical care settings; specific scales for mucositis in patients undergoing head/neck radiation, chemotherapy, or HSCT||Research assessment potentially confounded by combination of symptoms, signs, and functional changes|
|RTOG (clinical and research)||RTOG (see http://www.rtog.org/members/toxicity/acute.html43)||Combined elements: symptom (pain), signs (unspecified); function: unspecified||Used widely in research and clinical care settings||Research assessment potentially confounded by combination of symptoms, signs, and functional changes|
|Detailed, objective mucositis scoring scales|
|OMI for HSCT (research)||Schubert et al., 199244||Thirty-four mucosal changes: signs (atrophy, erythema, ulceration/pseudomembrane, edema, and selected sites); pain scores (separate VAS)||Specific to 11 oral anatomic sites, thereby permitting subanalyses of changes across the oral mucosa; eliminates confounders of symptoms and functional disturbances; cores consistent with NCI and WHO scores||Requires more examiner experience and time than NCI-CTC and WHO scales; only tested in patients undergoing HSCT|
|Twenty-item OMI for HSCT (research)||McGuire et al., 200245||Twenty mucosal changes: signs (atrophy, erythema, ulceration/pseudomembrane edema, and selected sites)||Specific to nine oral anatomic sites; clinical objective changes scored as in full OMI||Requires less expertise than OMI|
|OMAS for chemotherapy, radiation, and HSCT (research)||Sonis et al., 199946||Signs (erythema, ulceration)||Same advantages as OMI with fewer oral anatomic sites scored||Requires more examiner experience and time than NCI-CTC and WHO scales but less time than OMI|
|Spijkervet Radiation Mucositis Scale (research)||Spijkervet, 198947||White discoloration, erythema, pseudomembrane ulceration||Permits objective measure of tissue injury of tissue injury||Detailed mathematical calculation required; requires further validation in multicenter setting|
|Combined objective/functional/symptom scales|
|Oral Assessment Guide (clinical)||Eilers et al. (1988)47||Signs (erythema), symptoms (pain, salivary changes), functional disturbances (swallowing, voice)||Global scale that can reflect clinical status/outcomes; suitable for nursing care decision making||Not all variables necessarily link with clinical status; some variables not continuous|
|Western Consortium for Cancer Nursing Scale (clinical)||Western Consortium for Cancer Nursing Research, 199149||Lesions, color, bleeding, subjective variables||Global scale that can reflect clinical status/outcomes; refined in 1998, based on elimination of five measures other than lesions, color, or bleeding||Mixed objective, subjective, and functional variables; difficult to score precisely|
|Walsh Quantitative Scoring System for Oral Mucositis (clinical and research)||Walsh et al., 199950||Mucosal changes, functional changes, salivary function, pain||Conceptual elements of NCI or WHO scale applied to specific anatomic sites; moderate training||Not validated; only tested in HSCT patients|
|Tardieu Quantitative Scale of Oral Mucositis for HSCT (research)||Tardieu et al., 199651||Mucosal changes, salivary function, function (voice, swallow), pain||Includes four anatomic sites, range of severity||Not validated (pilot study only); only tested in HSCT patients; detailed, requires moderate to significant training|
|Daily Mucositis Scale for HSCT (research and clinical)||Donnelly et al., 199252||Erythema, oral edema, pain, dysphagia||Global scale that can reflect clinical status/outcomes; less detailed than most||Validation in multicenter study needed|
|MacDibbs Mouth Assessment (research and clinical)||Dibble et al., 199653||Patient symptoms, ulcerations, erythema/hyperkeratosis, sputum smear/herpes simplex virus culture||Ease of administration generalized assessment (not oral site-specific)||Only reported for radiation mucositis; not validated (pilot study only)|
|In vitro measurement|
|Epithelial Viability Scale (research)||Wymenga et al., 199754||Trypan blue-based exclusion, based on oral epithelial smears||Easily administered; in vitro objective measure; studied with both chemotherapy-induced and radiation-induced mucositis||Early in development; requires additional validation|
Scoring of Oral Mucositis
The mucositis scales used most commonly were designed to define in global terms stomatotoxicity resulting from different cancer treatments. These tools are comprised of four-point or five-point scales that rate the overall status of the mouth relative to the clinically observed mucosal appearance, severity of patient pain, and, in some instances, the patient's functional capabilities relative to his or her oral status (e.g., the ability to eat). Historically, many of these simple, combined, variable toxicity scales have been based on a scale developed by the World Health Organization (WHO) for the clinical assessment of patients receiving cancer therapy. A number of similar scales have been developed and promoted as part of the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) scales, which are used frequently by cooperative oncology groups and oncology researchers (Table 1).
A second group of scales has evolved out of these simpler scales, and developed as nursing management and clinical research tools. These can be characterized as utilizing a combination of objective, functional, and symptomatic variables. Like the simpler toxicity scales, the oral mucositis scales combining objective, functional, and symptomatic descriptors apply them to specific anatomic areas, adding greater specificity with various aspects of oral function and subjective patient responses. A third series of scales, the detailed objective scoring scales, were designed for clinical research trials and tend to focus on directed, separately scored, objective and subjective end points (for a description of these scales, see Table 2).
|Scale||Side effect(s)||Grade 0 (none)||Grade 1 (mild)||Grade 2 (moderate)||Grade 3 (severe)||Grade 4 (life-threatening)||Grade 5 (death)|
|WHO||Oral mucositis (stomatitis)||None||Oral soreness, erythema||Oral erythema, ulcers, solid diet tolerated||Oral ulcers, liquid diet only||Oral alimentation impossible||—|
|NCI-CTC||Chemotherapy-induced stomatitis/pharyngitis (oral/pharyngeal mucositis)||None||Painless ulcers, erythema, or mild soreness in the absence of lesions||Painful erythema, edema, or ulcers but eating or or swallowing possible||Painful erythema, edema, or ulcers requiring IV hydration||Severe ulceration or requiring parenteral or enteral nutritional support or prophylactic intubation||Death related to toxicity|
|NCI-CTC||Associated with HSCT (stomatitis/pharyngitis, oral/pharyngeal mucositis)||None||Painless ulcers, erythema, or mild soreness in the absence of lesions||Painful erythema, edema, or ulcers but swallowing possible||Painful erythema, edema, or ulcers preventing swallowing or requiring hydration or parenteral (or enteral) nutritional support||Severe ulceration requiring prophylactic intubation or resulting in documented aspiration pneumonia||Death related to toxicity|
|NCI-CTC||Mucositis due to radiation||None||Erythema of the mucosa||Patchy, pseudomembranous reaction (patches generally < 1.5 cm in greatest dimension and noncontiguous)||Pseudo-membranous reaction (contiguous patches generally > 1.5 cm in greatest dimension)||Ulceration and occasional bleeding not induced by minor trauma or abrasion||Death related to toxicity|
|RTOG||Acute oral mucous membrane toxicity caused by radiation||No change over baseline||Injection, may experience mild pain not requiring analgesic||Patchy mucositis that may produce inflammatory serosanguinitis discharge; may experience moderate pain requiring analgesia||Confluent, fibrinous mucositis, may include severe pain requiring narcotic||Ulceration, hemorrhage, or necrosis||—|
The most relevant scales for clinical management appear to be those based on NCI or WHO design. As noted earlier, symptoms, signs, and functional disturbances are assessed, and a global score is achieved readily. Analysis of approximately 400 trials, as a component of the evidence-based review for the clinical practice guidelines, determined that most of the studies utilized the NCI (43%) or WHO (38%) scales. Ten percent of studies employed a study-specific scale, and 5% used a cooperative group scale, such as scales used by the Radiation Therapy Oncology Group or the Eastern Cooperative Oncology Group (ECOG). Remaining scales, including the Stanford and Herzig scales, were used by < 0.5% of studies each.
Regardless of the scale used, increasing evidence confirms the importance of training and standardization to improving the accuracy and consistency of mucositis assessment. It is interesting to note that the clinical qualifications of the evaluator (M.D., D.M.D., R.N. degrees) appear to be less important, ultimately, than training and experience with using the scale.55
The frequency with which mucosal health needs to be assessed is a function of the objective of the examination. Whereas daily evaluations are of value for a nursing care plan, an intense, twice-weekly examination may be effective for an interventional study. In contrast, the success of a study in which mucositis duration is a primary endpoint may require daily evaluations.
Similar to other aspects of physical examination, sensitivity and accuracy are often a function of the conditions under which the examination takes place. Examination conditions are an issue of practicality—if the examiner cannot conduct an adequate visual inspection of the area to be examined, then results will be compromised. Adequate illumination of oral tissues is critical for an accurate assessment.
Halogen light sources can provide consistent intensity and color. In contrast, flashlights can vary significantly in intensity and may cast patterns based on the quality and type of light bulb, reflector, and lens. In addition, depending on bulb type (e.g., element and gas parameters), the color of light emitted from the flashlight can distort the color of the oral tissues and produce variable light intensity.
The convenience and comfort of both the examiner and the patient during the examination can influence the quality of the overall examination results. For example, whether the patient is being evaluated in a hospital bed, on a medical examination table, or in a dental chair may influence access and inspection of oral tissues.
Visualization of the oral cavity becomes compromised and, along with it, accuracy and reproducibility as a patient's medical condition deteriorates and/or as mucositis worsens. Oral debris, pseudomembranous candidiasis, and topical oral care therapies can obscure tissue conditions. If a patient requires orotracheal intubation, it becomes all but impossible to examine the entire oral cavity unless arrangements are made to examine the patient when tube care and retaping occur. At times, oral hemorrhage can compromise observation of oral tissues significantly.
Many scoring systems have not compensated for instances in which a patient cannot be examined because of these and other compromising situations—bleeding, pain, nausea, or emesis. Although, in some instances, the clinical situation may be a direct extension of the severity of the oral mucositis, whereas at other times it may be unrelated. Consideration must be given to these clinical parameters, especially if the scale is administered for research purposes and the assessment accuracy is paramount.
There is clear utility in separately scoring objective measures of mucosal damage and other variables related to oral mucositis (e.g., subjective variables such as pain and dryness and functional variables such as talking, swallowing, or ability to eat). Investigators have demonstrated that detailed oral mucositis scores, such as the Oral Mucositis Index and the Oral Mucositis Assessment Scale, correlate closely with oral mucositis pain scores.44, 56 Conversely, scoring of functional variables may not be correlated directly with oral mucosal events. For example, oral mucositis assessed with a scale such as the NCI-CTC scale may be rated Grade 4, which describes the patient as requiring “parenteral or enteral nutrition or support.” However, in the HSCT setting, many patients are placed on total parenteral nutrition because of intestinal toxicity; otherwise, they very well could continue with oral nutritional intake. Similar problems exist for the NCI-CTC Grade 3 oral toxicity category, in which the patient requires intravenous hydration. Consideration of how best to integrate these issues with the specific outcomes of the study should be determined during protocol design.
Scoring of GI Mucositis
Most of the available information regarding the incidence of GI toxicity relates to symptoms and functional changes. Making accurate evaluation of damage impossible are the problems of obtaining sequential biopsy before, during, and after treatment; the specimens' typically superficial nature; and the inaccessibility of important segments of the GI tract. With chemotherapy, 40–100% of patients experience GI mucositis, depending on the dose and type of chemotherapy.57 It is difficult to identify when the problem is based solely on symptoms: pain and diarrhea are universal and cannot be traced easily to the section of the GI tract that is affected (for a comparison of scoring systems used to assess GI tract mucositis, see Table 3).
|Organ, tract, and symptoms||Grade 0||Grade 1||Grade 2||Grade 3||Grade 4|
|RTOG: Acute radiation morbidity scoring criteria|
|Pharynx and esophagus||No change over baseline||Mild dysphagia or odynophagia; may require topical anesthetic or nonnarcotic analgesis; may require soft diet||Moderate dysphagia or odynophadga; may require narcotic analgesics; may require purée or liquid diet||Severe dysphagia or odynophagia with dehydration or weight loss (> 15% from pretreatment baseline) requiring NG tube feeing and IV fluids or hyperalimentation||Complete obstruction, ulceration, perforation, fistula|
|Larynx||No change over baseline||Mild or intermittent hoarseness/though not requiring antitussive/erythema of mucosis||Persistent hoarseness but able to vocalize; referred ear pain, sore throat, patchy fibrinous exudates or mild arytenoid edema not requiring narcotics/cough requiring antitussive||Whispered speech, throat pain or referred ear pain requiring narcotic, confluent fibrinous exudate, marked arytenoid edema||Marked dyspnea, stridor, or hemoptysis with tracheostomy or intubation necessary|
|Upper GI tract||No change||Anorexia with ≤ 5% weight loss from pretreatment baseline, nausea not requiring antiemetics, abdominal discomfort not requiring parasympatholytis drugs or analgesics||Anorexia with ≤ 15% weight loss from pretreatment baseline, nausea and/or emesis requiring antemetics, abdominal pain requiring analgesics||Anorexia with > 15% weight loss from pretreatment baseline or requiring NG tube or parenteral support; nausea and/or emesis requiring tube or parenteral support; abdominal pain severe despite medication; hematemesis or melena; abdominal distention (flat-plate radiograph demonstrates distended bowel loops)||Ileus, subacute or acute obstruction, perforation. GI bleeding requiring transfusion, abdominal pain requiring tube decompression or bowel diversion|
|Lower GI tract, including pelvis||No change||Increased frequency or change in quality of bowel habits not requiring medication, rectal discomfort not requiring analgesics||Diarrhea requiring parasympatholytic drugs (e.g., Lomotil [diphenoxylate atropine]); mucous discharge not necessitating sanitary pads; rectal or abdominal pain requiring analgesics||Diarrhea requiring parenteral support, severe mucous or blood discharge necessitating sanitary pads, abdominal distention (flat-plate radiograph demonstrates distended bowel loops)||Acute or subacute obstruction, fistula or perforation, GI bleeding requiring transfusion; abdominal pain or tenesmus requiring tube decompression or bowel diversion|
|RTOG chronic toxicity: GI tract|
|Nausea||None||Able to eat, reasonable intake||Intake significantly decreased, but patient can eat||No significant intake||—|
|Emesis||None||One episode in 24 hrs||Two to 5 episodes in 24 hrs||Six to 10 episodes in 24 hrs||Greater than 10 episodes in 24 hrs or requiring parenteral support|
|Diarrhea||None||Increase of 2 to 3 stools per day over pretreatment level||Increase of 4 to 6 stools per day, nocturnal stools, or moderate cramping||Increase of 7 to 9 stools per day or incontinence or severe cramping||Increase of ≥ 10 stools per day or macroscopically bloody diarrhea, or need for parenteral support|
|RTOG-EORTC: Late radiation morbidity scoring system|
|Esophagus||None||Mild fibrosis, slight difficulty in swallowing solids, no pain on swallowing||Unable to take solid food normally, swallowing semisolid food, dilatation may be indicated||Severe fibrosis, able to swallow only liquids, may have pain on swallowing, dilatation required||Necrosis, perforation, fistula|
|Small/large intestine||None||Mild diarrhea, mild cramping, bowel movement 5 times daily, slight rectal discharge or bleeding||Moderate diarrhea and colic, bowel movement > 5 times daily, excessive rectal mucus or intermittent bleeding||Obstruction or bleeding requiring surgery||Necrosis, perforation, fistula|
|Emesis episodes/24 hr||—||1||2–5||6–10||> 10 or parenteral support|
|Diarrhea (increased frequency over normal)||—||2–3||4–6 or nocturnal||7–9 or incontinence or severe cramping||> 9, macroscopic blood, enteral support|
EPIDEMIOLOGY AND OUTCOMES
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- BIOLOGIC BASIS AND PATHOGENESIS
- CLINICAL MUCOSITIS ASSESSMENT SCALES
- EPIDEMIOLOGY AND OUTCOMES
Most data supporting the computation of incidence of mucositis are derived from clinical trials of chemotherapy and radiotherapy regimens in which the reporting of mucositis is a secondary objective. Not unexpectedly, in the current review, we found that virtually all trials were underpowered and unable to produce stable estimates of rarely occurring events, such as toxicities, and most studies included only limited discussion of methods for analyzing toxicity data. The quality of articles was graded on three parameters: adequate definition of mucositis, blinded or independent assessment of mucositis, and sample size. Articles that provided either a definition of mucositis or named a standard grading system, such as the systems of the NCI, the ECOG, or the National Cancer Institute of Canada, were assigned 1 quality point. Articles with a blinded or independent assessment of mucositis were assigned 1 quality point. The quality score was obtained by summing the quality points and adding the sum to 1 (the quality score for the lowest quality article). Therefore, all articles were scored on a scale of 1 to 3. Sample size and the quality scores were incorporated in the computation of the average incidence of mucositis as follows: We defined the overall quality-adjusted mucositis rate, poverall, as:
in which qsj is the quality score for the jth study, nj is the sample size for the jth study, and pj is the mucositis rate observed in the jth study. This method is a modification of that of Berard and Bravo.58 Because some of the study sample sizes were small, it was believed that the Gaussian approximation to the binomial distribution was not applicable (because the Gaussian approximation is a large-sample result). Therefore, an estimate of the 95% confidence interval for the overall quality-adjusted mucositis rate was obtained using the bootstrap method described by Efron.59
One thousand bootstrap samples were generated for a given treatment regimen using the SAS/IML statistical software package (SAS Inc., Cary, NC). For each of the bootstrap samples, the overall mucositis rate was calculated. These bootstrap mucositis rates then were ordered from smallest to largest. The 2.5th percentile and 97.5th percentile bootstrap mucositis rates then were used to report the 95% bootstrap confidence interval for the treatment regimen.
To our knowledge, Grades 1 and 2 mucositis are not reported uniformly in clinical trials of chemotherapy; therefore, for estimates of incidence, only Grade 3 and 4 mucositis, which were combined across all scoring systems (Grade 3–4), are reported. For the few reports that used study-specific scoring systems, scores that corresponded with ulceration or that were considered severe have included.
Risk of Grade 3–4 Oral or GI Mucositis
The incidence of oral and GI mucositis varied significantly among different treatment regimens and modalities (Table 4).60–398 Most anthracycline-based regimens were associated with rates of oral mucositis in the 1–10% range, except when regimens included 5-FU. Included among these are the standard regimens for adjuvant therapy in patients with breast cancer (5-FU, doxorubicin, and cyclophosphamide; doxorubicin and cyclophosphamide; or 5-FU, epirubicin, and cyclophosphamide) as well as regimens for patients with non-Hodgkin lymphomas, including cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). To our knowledge, it has not been demonstrated that the addition of rituximab to CHOP increases the risk of oral or GI mucositis. Other new agents, such as imatinib, are associated with a very low incidence of oral and GI mucositis. Similar rates are reported with taxane-based and platinum-based regimens, again except for regimens containing 5-FU. However, radiation therapy to the head and neck or to the pelvis or abdomen was associated with increased incidence of Grade 3–4 oral or GI mucositis, respectively, often exceeding 50% of patients.
|Regimen||No. of studies||No. of patients||Risk of Grade 3–4 oral mucositis||Risk of Grade 3–4 GI mucositis|
|%||95% CI||%||95% CI|
|+ 5-FU/cyclophosphamide (FAC, FEC)||8||1382||3||2–4||1||< 1–1|
|+ Paclitaxel||10||790||11||9–13||< 1||< 1–1|
|Docetaxel + XRT||1||21||98||90–98||NR||NR|
|Paclitaxel + XRT||7||117||48||39–56||6||6–15|
|Paclitaxel/5-FU + XRT||2||113||75||67–83||1||1–2|
|Docetaxel/platinum + XRT||1||15||20||3–40||NR||NR|
|Paclitaxel/platinum + XRT||10||346||60||56–64||2||2–8|
|Docetaxel and others||3||77||18||9–27||13||4–23|
|Paclitaxel and others||6||257||13||9–17||4||3–6|
|Platinum + XRT||6||309||11||8–14||11||7–16|
|Oxaliplatin + XRT||1||29||31||17–48||NR||NR|
|Platinum and any taxane||10||671||2||1–3||3||2–5|
|Platinum/taxane + XRT||12||329||64||59–69||2||2–8|
|5-FU CI + XRT||1||84||6||1–12||12||6–19|
|5-FU/platinum + XRT||12||687||38||35–41||14||10–17|
|5-FU/other misc drugs||5||543||6||4–8||5||4–8|
|5-FU CI/other misc drugs||7||213||12||8–17||6||3–13|
|5-FU/other misc drugs + XRT||1||9||11||6–33||NR||NR|
|5-FU/leucovorin/other misc drugs||8||338||4||2–6||4||3–7|
|5-FU/leucovorin/other misc drugs + XRT||1||43||7||1–16||7||1–16|
|Irinotecan/5-FU + XRT||2||36||36||22–47||71||50–93|
|Irinotecan/5-FU CI + XRT||1||22||NR||NR||18||5–36|
|Busulfan conditioning regimen (no TBI)||10||360||52||47–55||10||7–14|
|Other conditioning regimens (no TBI)||3||439||31||27–35||15||11–19|
|Stem cells: Myeloma||5||139||36||30–43||14||8–23|
|Stem cells: Solid tumors||9||266||27||24–31||6||4–9|
|With busulfan/etoposide/cyclophosphamide conditioning (no TBI)||3||36||27||13–42||NR||NR|
|With melphalan/carboplatin/etoposide conditioning (no TBI)||4||59||31||25–40||14||3–36|
|Other pediatric regimens|
|Ara-C, idarubicin, fludarabine||4||192||20||10–33||13||7–21|
In contrast, the administration of 5-FU often was associated with rates of Grade 3–4 oral mucositis > 15%, whereas CPT-11 was associated with similarly high rates of GI mucositis. The addition of radiation therapy to 5-FU-based and CPT-11-based regimens may increase the risk of Grade 3–4 oral and GI mucositis to > 30%. Because these agents form the basis of most regimens for patients with GI malignancies, the severe mucositis resulting from these agents is of particular clinical importance.
Patients who underwent HSCT, particularly those who received total body irradiation, experienced high rates of mucositis. The highest rates were observed when total body irradiation was used, with the rate of Grade 3–4 mucositis exceeding 60% in most reports. However, incidence rates approached 30–50% without total body irradiation. Slightly lower rates were noted among some of those patients, depending on the chemotherapy regimen received. Children who underwent HSCT also experienced a high incidence of oral mucositis, particularly when total body irradiation was used for conditioning. Rates with other chemotherapy regimens varied from very low (1–2%) with single-agent therapy with topotecan or etoposide to very high (> 20%) with combination regimens, including high doses of ifosfamide or anthracyclines.
Because they frequently receive radiation therapy, 5-FU, or CPT-11, patients with GI or gynecologic malignancies experience Grade 3–4 GI mucositis at significantly higher rates than their counterparts with other malignancies (Table 5).60–398 Patients with cancers of the head and neck, esophagus, or upper GI tract were found to be at high risk of Grade 3–4 oral mucositis for the same reasons. Acute damage to the GI mucosa is a consequence of radiotherapy in 85% of patients symptomatically and in 100% of patients histologically.
|Diagnosis||No. of studies||No. of patients||Risk of Grade 3–4 oral mucositis||Risk of Grade 3–4 gastrointestinal mucositis|
|%||95% CI||%||95% CI|
|Acute myelogenous leukemia||11||262||12||10–16||6||5–11|
|Acute lymphoblastic leukemia||3||64||34||25–44||NR||NR|
|Chronic myelogenous leukemia||2||36||7||3–17||3||3–12|
|Small cell lung cancer||9||753||9||8–12||3||2–5|
|Nonsmall cell lung cancer||15||622||6||4–8||5||3–8|
|Head and neck cancer||58||2206||42||40–44||6||5–8|
|Gynecologic cancers—various||1||125||< 1||< 1–2||NR||NR|
|Renal cell cancer||1||24||8||2–21||NR||NR|
|Germ cell cancer||2||52||23||12–35||3||3–27|
These data are supported by recent reports of the incidence of mucositis among patients with solid tumors receiving myelosuppressive chemotherapy. Elting et al. observed oral mucositis in 22% of cycles of myelosuppressive chemotherapy, GI mucositis in 7% of cycles, and both oral and GI mucositis in 8% of cycles.1
Outcomes and Cost of Oral and GI Mucositis
Even rates of 5–15% for Grade 3–4 oral or GI mucositis are significant clinically because of the serious clinical outcomes that result from this condition. In approximately 35% of patients with Grade 3–4 mucositis, the subsequent cycle of chemotherapy is delayed. The doses of chemotherapy are reduced in approximately 60% of patients (range, 15–100%), and the regimen is discontinued in approximately 30% of patients (range, 8–100%). Among patients receiving standard-dose chemotherapy regimens, 70% of patients with Grade 3–4 oral mucositis require feeding tubes to maintain adequate nutrition, approximately 60% of patients have fever, and 62% of patients require hospitalization. Among adult HSCT recipients and patients receiving high-dose chemotherapy with HSCT support, 87% require feeding tubes. Opioid analgesics are required in 80% of HSCT recipients. Sonis et al. reported 5.8 additional days of narcotics and 1.9 additional days of total parenteral nutrition among HSCT recipients who had oral ulceration compared with patients who did not have ulceration.65 Those investigators also reported 2 additional febrile days per patient with oral ulcers compared with patients without oral ulcers. The association between oral ulceration and infection was observed previously by Ruescher et al, who reported that oral ulceration was three times more common among bone marrow transplantation recipients with streptococcal bacteremias than among patients without streptococcal bacteremias.66
Among patients with solid tumors who receive myelosuppressive chemotherapy, infection occurs during 73% of cycles complicated by mucositis, but during only 36% of cycles with similar myelosuppression without mucositis. Fatigue also is more common during cycles with mucositis than in cycles without mucositis (9% compared with 5%; P = 0.0007).1 In the same report, the high incidence of serious clinical outcomes during cycles with mucositis led to an increase of > 2-fold in the average number of hospital days per cycle (7.7 days vs. 3.9 days; P < 0.0001).
Severe oral mucositis is a particularly ominous clinical sign among children because of the risk of airway compromise. Among pediatric bone marrow transplantation recipients, airway compromise due to oral mucositis was reported in 2–19% of all patients. Death or anoxia-induced brain damage occurred occasionally. Likewise, > 90% of pediatric HSCT recipients with Grade 3–4 mucositis required feeding tubes, total parenteral nutrition, and opioid analgesics. These occasionally are associated with systemic infection. Although these interventions are required less commonly for standard-dose chemotherapy regimens, maintenance of proper nutrition is a particularly important goal among children.
Because of its serious clinical consequences, Grade 3–4 mucositis would be expected to be a financially significant event; however, the financial implications of mucositis have been reported only rarely. Groener et al.166 reported that Grade 3–4 mucositis accounted for 3% of resource utilization ($17) during cycles of raltitrexed and 21% of resource utilization ($113) during cycles of 5-FU and leucovorin. The additional days of fever, hospitalization, narcotic usage, and total parenteral nutrition reported by Sonis et al. among HSCT recipients with oral ulcers also translated into additional hospital charges of $42,749 per patient.65 Elting et al. reported incremental costs of $2725 and $5565 per cycle for Grade 1–2 mucositis and Grade 3–4 mucositis, respectively.1
The cost of GI mucositis has not been studied formally, but includes a reduction in cure rate as a result of treatment interruptions or inadequate treatment as well as the cost of the symptom management itself. Data regarding the influence of overall treatment time outside of the head and neck are most reliable for cervical cancer. The effect of prolonging treatment time reportedly results in a decrease in control of between 0.55% and 1.4% per day.399
Although this report focuses on acute manifestations and short-term outcomes, permanent damage to both oral and GI mucosa may occur as a result of radiotherapy. Yeoh et al.400, 401 have shown that permanent damage and dysfunction occur in 70–90% of patients undergoing radiotherapy, depending on the treatment site and radiation dose. Radiotherapy also causes changes in motility proximal to the site at which radiation is administered.402–404 Because patients treated for pelvic or gastric cancer constitute the majority of long-term cancer survivors, the prevalence of chronic toxicity is significant. Moreover, some patients may be asymptomatic but still exhibit severe functional changes, including reductions in B12 and calcium absorption, which have the potential to cause substantial problems.
- Top of page
- BIOLOGIC BASIS AND PATHOGENESIS
- CLINICAL MUCOSITIS ASSESSMENT SCALES
- EPIDEMIOLOGY AND OUTCOMES
Mucositis can be a frequent and clinically significant event elicited by drug and radiation cancer therapy. Although mucositis typically has been associated with specific patient populations, such as those receiving conditioning regimens for HSCT and radiotherapy for head and neck cancer, its incidence and impact also have been appreciated recently in other patients with solid tumors. Defining the epidemiology of mucositis has been confounded historically by a number of variables, including underreporting, differences in the terminology used to describe it, differences in assessment techniques and scales, and the correlation between mucositis and other clinically important sequelae. However, establishing strong multiprofessional and interdisciplinary collaborations has resulted in marked advances in the improvement of psychometric and utilization components of mucositis scales.
The pathobiology of mucositis long has been considered to be limited to direct epithelial injury. A continuum of mechanistic studies conducted in recent years has revealed that, in fact, mucositis is the culmination of a series of biologically complex and interactive events that occur in all tissues of the mucosa. Although the complete definition of mucositis as a biologic process remains a work in progress, the current understanding of cellular and molecular events that lead to mucosal injury has provided a number of potential interventional targets. Consequently, for the first time, directed, biologically rational therapies are now in various stages of development. Furthermore, mechanistically based risk prediction and disease monitoring appear to be realistic goals for the not-too-distant future.
- Top of page
- BIOLOGIC BASIS AND PATHOGENESIS
- CLINICAL MUCOSITIS ASSESSMENT SCALES
- EPIDEMIOLOGY AND OUTCOMES
The MASCC and ISOO Mucositis Study Section thank medical librarian Ronald D. Hutchins and medical editor Beth W. Allen.
- Top of page
- BIOLOGIC BASIS AND PATHOGENESIS
- CLINICAL MUCOSITIS ASSESSMENT SCALES
- EPIDEMIOLOGY AND OUTCOMES
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- 234FOLFOX2 regimen in treatment of metastatic colorectal cancer (MCRC) [abstract 1099]. Prog Proc Am Soc Clin Oncol. 2000; 19: 281a., , , , , .
- 235High dosage (HD) FAC neoadjuvant chemotherapy in operable breast cancer (BC) presenting a high S-Phase fraction (SPF) [abstract 593]. Prog Proc Am Soc Clin Oncol. 2000; 19: 150a., , , , , .
- 236Adjuvant combined modality therapy for resected, high-risk adenocarcinoma of the pancreas using cisplatin (CDDP), 5 FU, and alpha-interferon (IFN) as radiosensitizing agents: update of a Phase II trial [abstract 1034]. Prog Proc Am Soc Clin Oncol. 2000; 19: 267a., , , , , .
- 237Bimonthly leucovorin, 5-fluorouracil infusion and hydroxyurea followed by CPT-11 (FOLFIRI-2) in pretreated patients with metastatic colorectal cancer [abstract 1151]. Prog Proc Am Soc Clin Oncol. 2000; 19: 294a., , , , , .
- 238Chronomodulated (CRM) bimonthly 48 hour (hr) 5-fluorouracil (FU), folinic acid (FA), oxaliplatin (OXA) “FOLFOX CRM” in FU-refractory (FUR) advanced colorectal cancer (ACRC) patients (Pts): Phase II study [abstract 1242]. Prog Proc Am Soc Clin Oncol. 2000; 19: 314a., , , et al.
- 239Cisplatin, epirubicin and fluorouracil (PEF) for measurable advanced gastric carcinoma: evaluation of two different schedules [abstract 1064]. Prog Proc Am Soc Clin Oncol. 2000; 19: 273a., , , , , .
- 240Combined irinotecan, oxaliplatin, 5-FU in patients (Pts) with metastatic colorectal cancer (MCC) [abstract 1008]. Prog Proc Am Soc Clin Oncol. 2000; 19: 259A., , , , , .
- 241Gemcitabine (GEM) and continuous infusional 5-FU (CIF) is active and well tolerated in advanced or metastatic pancreatic cancer [abstract 1280H]. Prog Proc Am Soc Clin Oncol. 2000; 19: 326a., , , , , .
- 242Induction chemotherapy (IC) with paclitaxel (P), cisplatinum (c) and 5FU followed by concomitant chemoradiotherapy (CRT) in locally advanced head and neck cancer (IAHNC) [abstract 1691]. Prog Proc Am Soc Clin Oncol. 2000; 19: 428a., , .
- 243Infusional 5-FU and leucovorin plus mitomycin-C as second line treatment in metastatic colorectal cancer [abstract 1084]. Prog Proc Am Soc Clin Oncol. 2000; 19: 278a., , , , , .
- 244Intensive weekly chemotherapy with cisplatin, epi-doxorubicin, leucovorin, 5 fluorouracil, gluthatione and lenograstim versus 5 fluorouracil/leucovorin combination as adjuvant treatment for high risk gastric cancer [abstract 1070]. Prog Proc Am Soc Clin Oncol. 2000; 19: 274a., , , , , .
- 245Irinotecan (CPT-11) in combination with 5-fluorouracil/folinic acid (5-FU/Fa) as a weekly schedule in previously untreated patients with metastatic colorectal cancer (MCRC) [abstract 1249]. Prog Proc Am Soc Clin Oncol. 2000; 19: 316a., , , , .
- 246Irinotecan (CPT-11) in combination with high-dose infusional 5-FU (TtD schedule) in advanced colorectal cancer (CrC): preliminary results of a Phase I/II study [abstract 1280A]. Prog Proc Am Soc Clin Oncol. 2000; 19: 324a., , , , , .
- 247Mitomycin-C added to schedule-specific biochemical modulation of 5-FU in advanced colorectal cancer (CRC) [abstract 1065]. Prog Proc Am Soc Clin Oncol. 2000; 19: 273a., , , , , .
- 248Modified Mayo Clinic bolus 5-FU and leucovorin plus oxaliplatin in advanced, pretreated colorectal cancer [abstract 1086]. Prog Proc Am Soc Clin Oncol. 2000; 19: 278a., , , , , .
- 249Multicenter trial of a simplified schedule of bi-monthly folinic acid (FA) and 5-fluorouracil (Fu) bolus and continuous infusion (C.I.) advanced colorectal cancer patients [abstract 1280C]. Prog Proc Am Soc Clin Oncol. 2000; 19: 324a., , , , , .
- 250Oxaliplatin (OX) and 5-day 5-fluorouracil (5-FU) + leuvocovorin (LV) as salvage treatment for advanced colorectal cancer (ACC) [abstract 1195]. Prog Proc Am Soc Clin Oncol. 2000; 19: 304a., , , , .
- 251Phase I/II study in advanced pancreatic adenocarcinoma (APA) and carcinoma if unknown primary (CUP): a combination of leucovorin (LV), 5 FU bolus and infusion, gemcitabine (GEM) and oxaliplatine (L.OHP) (FOLFU GEMOX regimen) [abstract 913]. Prog Proc Am Soc Clin Oncol. 2000; 19: 233a., , , , , .
- 252Phase II randomized study of oxaliplatin (OXA), and its combination with 5-FU (OXA-FU) in hormone refractory prostate cancer (HRPC) patients (Pts) [abstract 1415]. Prog Proc Am Soc Clin Oncol. 2000; 19: 359a., , , , , .
- 253Phase II study of gemcitabine (G) and continuous intravenous infusion (CIV) 5-fluorouracil (5-FU) in advanced pancreatic cancer (PC): a University of Chicago Phase II consortium study [abstract 1126]. Prog Proc Am Soc Clin Oncol. 2000; 19: 288a., , , , , .
- 254Phase II trial with gemcitabine (GEM) + 5-fluorouracil (5-FU) in advanced pancreatic cancer [abstract 1110]. Prog Proc Am Soc Clin Oncol. 2000; 19: 284a., , , .
- 255Prospective analysis of severe toxicity associated with 5-FU and leucovorin (Mayo Clinic regimen) in colorectal cancer patients [abstract 1046]. Prog Proc Am Soc Clin Oncol. 2000; 19: 269a., , , , , .
- 256Randomized Phase II–III trial of oxaliplatin (OXA) with 5-fluorouracil (5FU) continuous infusion (CI) versus a control arm with either 5FU or irinotecan (CPT11) in previously treated metastatic colorectal cancer (MCRC) patients (Pts) [abstract 1088]. Prog Proc Am Soc Clin Oncol. 2000; 19: 279a., , , et al.
- 257Resected gastric adenocarcinoma: randomized trial of adjuvant chemotherapy with 5 FU-cisplatin (FUP). Final results of the FFCD 8801 trial [abstract 932]. Prog Proc Am Soc Clin Oncol. 2000; 19: 241a., , , , , .
- 258Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer: 10 year results of a Phase II study [abstract 1149]. Prog Proc Am Soc Clin Oncol. 2000; 19: 294a., , , , .
- 259Trimetrexate modulation of weekly 24-hour infusional fluorouracil/leucovorin: a Phase I/II study in advanced malignancies [abstract 870]. Prog Proc Am Soc Clin Oncol. 2000; 19: 223a., , , , , .
- 260Paclitaxel, carboplatin, and topotecan in the treatment of small cell lung cancer: a Phase II trial of the Minnie Pearl Cancer Research Network [abstract 1931]. Prog Proc Am Soc Clin Oncol. 2000; 19: 494a., , , , , .
- 261A prospective randomized trial evaluating response rate and toxicities of CAF vs CMF in locally advanced breast cancer patients, in a neo-adjuvant setting [abstract 571]. Prog Proc Am Soc Clin Oncol. 2000; 19: 144a., , , .
- 262GAMEC: a novel protocol for patients with germ cell tumours (GCT) relapsing following conventional treatment or with de novo IGCCCG poor prognosis [abstract 1466]. Prog Proc Am Soc Clin Oncol. 2000; 19: 371a., , , , , .
- 263Sequential oral methotrexate (OMTX) and carboplatin (CBDCA) in advanced ovarian cancer (OC): a Phase II study [abstract 1611]. Prog Proc Am Soc Clin Oncol. 2000; 19: 407a., , , , , .
- 264Comparisons of CMF to AC in the practice of treating early stage breast cancer [abstract 558]. Prog Proc Am Soc Clin Oncol. 2000; 19: 141a., , , , , .
- 265Bendamustin, MTX, 5-FU (BMF) vs. cyclophosphamide, MTX, 5-FU (CMF) as first line therapy of metastatic breast cancer. A safety interim analysis [abstract 465]. Prog Proc Am Soc Clin Oncol. 2000; 19: 120a., , , , , .
- 266De-escalating study of VP-16 with fixed doses of busulfan plus cyclophosphamide as conditioning regimen in patients with AML undergoing stem cell transplantation [abstract 39]. Prog Proc Am Soc Clin Oncol. 2000; 19: 12a., , , , , .
- 267Doxorubicin (A)/taxol (T) versus doxorubicin/cyclophosphamide (C) as first line chemotherapy in metastatic breast cancer (MBC): a Phase III study [abstract 282]. Prog Proc Am Soc Clin Oncol. 2000; 19: 73a., , , , , .
- 268The cyclophosphamide/fludarabine (CF) regimen in mantle cell lymphoma (MCL) [abstract 50]. Prog Proc Am Soc Clin Oncol. 2000; 19: 15a., , , , .
- 269Phase II study of weekly paclitaxel (Taxol) and liposomal doxorubicin (Doxil) in patients with locally advanced and metastatic breast cancer [abstract 451]. Prog Proc Am Soc Clin Oncol. 2000; 19: 116a., , , , , .
- 270Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide (CDE) plus the anti-CD20 monoclonal antibody rituximab in HIV-associated non-Hodgkin's lymphoma (NHL) [abstract 170]. Prog Proc Am Soc Clin Oncol. 2000; 19: 44a., , , , .
- 271Sequential doxorubicin/gemcitabine (AG) and ifosfamide, paclitaxel, and cisplatin (ITP) chemotherapy (AG-ITP) in patients (pts) with metastatic or locally advanced transitional cell carcinoma of the urothelium (TCC) [abstract 1344]. Prog Proc Am Soc Clin Oncol. 2000; 19: 342a., , , , , .
- 272A Phase I/II trial of accelerated radiotherapy plus concurrent 96-hour paclitaxel infusion for unresectable squamous cell carcinoma of the head and neck (SCCHN) [abstract 1676]. Prog Proc Am Soc Clin Oncol. 2000; 19: 424a., , , , , .
- 273A Phase II and pharmacokinetic/dynamic study of doxil and weekly paclitaxel chemotherapy for recurrent Mullerian tumors [abstract 1623]. Prog Proc Am Soc Clin Oncol. 2000; 19: 401a., , , et al.
- 274Carboplatin + paclitaxel in the treatment of extensive small cell lung cancer (SCLC). A multicenter Phase II study [abstract 1928]. Prog Proc Am Soc Clin Oncol. 2000; 19: 493a., , , , , .
- 275Concurrent radiotherapy and paclitaxel (P) twice a week as a radiosensitizer in Stage III–IV head and neck carcinoma [abstract 1670]. Prog Proc Am Soc Clin Oncol. 2000; 19: 423a., , , , , .
- 276Multicenter Phase II study of preoperative concurrent paclitaxel, carboplatin and radiotherapy in Stage III/IV resectable cancer of the oropharynx and oral cavity: an interim analysis [abstract 1658]. Prog Proc Am Soc Clin Oncol. 2000; 19: 420a., , , , , .
- 277Paclitaxel, carboplatin and oral etoposide in the treatment of patients (PTS) with cancer of unknown primary site (CUPS) [abstract 2279C]. Prog Proc Am Soc Clin Oncol. 2000; 19: 579a., , , , , .
- 278Phase II study of oral etoposide with intravenous paclitaxel in patients with metastatic breast cancer (MBC): a North Central Cancer Treatment Group trial [abstract 440]. Prog/Proc Am Soc Clin Oncol. 2000; 19: 114a., , , , , .
- 279Phase II study of weekly carboplatin and paclitaxel concurrent with radiation therapy (RT) in patients (Pts) with locally advanced, inoperable squamous cell carcinoma of the head and neck (HNSCC) [abstract 1667]. Prog/Proc Am Soc Clin Oncol. 2000; 19: 422a., , , , , .
- 280Pilot trial of concurrent chemoradiotherapy with paclitaxel and conventional fractionated irradiation in advanced unresectable squamous cell carcinoma of the head and neck [abstract 1694J]. Prog/Proc Am Soc Clin Oncol. 2000; 19: 431a., , , , .
- 281Pilot trial of concurrent low-dose weekly paclitaxel and radiotherapy in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) [abstract 1685]. Prog Proc Am Soc Clin Oncol. 2000; 19: 426a., , , , .
- 282Preliminary results of a Phase II study of paclitaxel (P) and cisplatin (C) in recurrent or metastatic head and neck cancer (HNC) [abstract 1694D]. Prog Proc Am Soc Clin Oncol. 2000; 19: 429a., , , , , .
- 283Weekly cisplatin-epirubicin-paclitaxel (PET) with G-CSF support in advanced breast cancer. A Southern Italy Cooperative Oncology Group (SICOG) [abstract 490]. Prog Proc Am Soc Clin Oncol. 2000; 19: 126a., , , , , .
- 284Combination of docetaxel (T) as a first-line chemotherapy in metastatic breast cancer (MBC) [abstract 468]. Prog Proc Am Soc Clin Oncol. 2000; 19: 121a., , , , .
- 285ATN (Adriamycin-Taxotere-Navelbine): a Phase I–II multicentre study in first line therapy of metastatic breast cancer (MBC) [abstract 401]. Prog Proc Am Soc Clin Oncol. 2000; 19: 104a., , , , , .
- 286Alternating chemo-radiation with docetaxel (D)/cisplatin (C) and involved field radiotherapy for recurrent, inoperable, and previously irradiated head and neck cancer (HNC) [abstract 1649]. Prog Proc Am Soc Clin Oncol. 2000; 19: 418a., , , .
- 287A comparison of two schedules of docetaxel (D) in combination with gemcitabine(G) given every other week [abstract 828]. Prog Proc Am Soc Clin Oncol. 2000; 19: 212a., , , , , .
- 288A pilot study of docetaxel (D) plus paclitaxel (P) in anthracycline/taxane pretreated metastatic breast cancer (MBC) [abstract 456]. Prog Proc Am Soc Clin Oncol. 2000; 19: 118a., , .
- 289Docetaxel (T) in combination with epirubicin (E) as treatment of metastatic breast cancer (MBC) [abstract 462]. Prog Proc Am Soc Clin Oncol. 2000; 19: 199a., , , , , .
- 290Docetaxel (TXT) monotherapy and G-CSF for advanced breast cancer (ABC) in elderly patients (EP) [abstract 425]. Prog Proc Am Soc Clin Oncol. 2000; 19: 110a., , , , , .
- 291Docetaxel and vinorebine every 14 days in patients with metastatic breast cancer after using anthracyclines. Final results [abstract 418]. Prog Proc Am Soc Clin Oncol. 2000; 19: 108a., , , , , .
- 292Dose-dense chemotherapy with sequential doxorubicin (D) and docetaxel (Dt) for initial treatment of operable and inoperable Stage II–IIIb breast cancer [abstract 524]. Prog Proc Am Soc Clin Oncol. 2000; 19: 134a., , , , , .
- 293Doxil (D) and docetaxel (Taxotere, T): pharmacokinetic (PK) results at the recommended Phase II dose (RPTD) [abstract 825]. Prog Proc Am Soc Clin Oncol. 2000; 19: 212a., , , , , .
- 294Final results of Phase II study of patients (Pts) with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN) treated with docetaxel (D) and 5-fluorouracil (5-FU) [abstract 1656]. Prog Proc Am Soc Clin Oncol. 2000; 19: 419a., , , , , .
- 295High pathological complete response (PCR) after neoadjuvant chemotherapy with doxorubicin and docetaxel in locally advanced breast cancer [abstract 492]. Prog Proc Am Soc Clin Oncol. 2000; 19: 126a., , , , , .
- 296Multiple high-dose chemotherapy (HDCT) with docetaxel (T), epirubicin (E) and cyclophosphamide (C), (HD-TEC) for high risk breast cancer (HRBC). Clinical results of a Phase II study [abstract 218]. Prog Proc Am Soc Clin Oncol. 2000; 19: 57a., , , , , .
- 297Neoadjuvant chemotherapy with carboplatin (C) and docetaxel (D) in locally advanced primary (LACC) and recurrent cervical cancer (RCC) [abstract 1606]. Prog Proc Am Soc Clin Oncol. 2000; 19: 405a., , , , , .
- 298Phase II study of doxorubicin, docetaxel, and 5-fluorouracil (FAT) in patients with locally advanced breast cancer [abstract 510]. Prog Proc Am Soc Clin Oncol. 2000; 19: 130a., , , , , .
- 299Phase II trial of a sequential docetaxel-cisplatin-epirubicin regimen as first-line chemotherapy (CT1) in advanced ovarian cancer (AOC): safety and surgical responses [abstract 1574]. Prog Proc Am Soc Clin Oncol. 2000; 19: 398a., , , , , .
- 300Phase II trial of single agent Taxotere (T) in malignant pleural mesothelioma (MPM) [abstract 2277]. Prog Proc Am Soc Clin Oncol. 2000; 19: 578a., , , , , .
- 301Phase II trial of weekly docetaxel (Taxotere) alone or in combination with trastuzumab (Herceptin) in patients with metastatic breast cancer [abstract 586]. Prog Proc Am Soc Clin Oncol. 2000; 19: 148a., , , , , .
- 302Response and preliminary survival results of a Phase II study of docetaxel (D) + estramustine (E) in patients (Pts) with androgen-independent prostate cancer (AIPCA) [abstract 1312]. Prog Proc Am Soc Clin Oncol. 2000; 19: 334a., , , , , .
- 303Retrospective study of docetaxel (TXT) in heavily pretreated metastatic breast cancer (MBC) patients (Pts): response and toxicity [abstract 570]. Prog Proc Am Soc Clin Oncol. 2000; 19: 144a., , .
- 304Second-line chemotherapy with weekly gemcitabine (GEM) and monthly docetaxel (DOC) in patients (PTS) with non-small cell lung cancer (NSCLC): a Phase II study. [abstract 1968]. Prog Proc Am Soc Clin Oncol. 2000; 19: 503a., , , , , .
- 305Weekly schedule of gemcitabine (G) plus docetaxel (D) in refractory advanced breast cancer (BC): a dose-finding study [abstract 609I]. Prog Proc Am Soc Clin Oncol. 2000; 19: 156a., , , , , .
- 306Alternating chemo-radiotherapy treatment of advanced head and neck cancer [abstract 1680]. Prog Proc Am Soc Clin Oncol. 2000; 19: 425a., , , , , .
- 307Carboplatin + epirubicin + VP-16 + lenograstim (CEV-L) followed by thoracic radiotherapy + daily carboplatin (RT-C) as radiosensitizer in limited small cell lung cancer (SCLC). A multicenter Phase II study [abstract 2133]. Prog Proc Am Soc Clin Oncol. 2000; 19: 541a., , , , , .
- 308Neoadjuvant (NEO) chemotherapy (CT) followed by radiochemotherapy (RTC) in advanced head and neck carcinoma (CHN) [abstract 1694E. Prog Proc Am Soc Clin Oncol. 2000; 19: 430a., , , , , .
- 309Phase II study of low dose daily cisplatin with concurrent radiotherapy for locally advanced inoperable head and neck cancer (HNC) [abstract 1692]. Prog Proc Am Soc Clin Oncol. 2000; 19: 428a., , , .
- 310International Phase III study of oral eniluracil (EU) plus 5-fluorouracil (5-FU) versus intravenous (IV) 5-FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC) [abstract 522]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 131a., , , , , .
- 311Phase II study of vinorelbine and continuous infusion 5-fluourouracil in metastatic breast cancer following anthracyclines [abstract 1923]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 44b., , , , , .
- 312Methotrexate 5-fluorouracil + ocaliplatin: a new adjunct to an old regimen for advanced colorectal cancer [abstract 2232]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 120b., , , , , .
- 313Gemcitabine, cisplatin and 5-flurouracil in advanced pancreas cancer [abstract 2341]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 148b., , , , , .
- 314Interim results of a Phase II trial of raltitrexed (RAL) + protracted-venous-infusion-5-fluorouracil (PVI-5-FU) in advanced colorectal cancer [abstract 2233]. Prog Proc Am Soc Clin Oncol. 2001; 20: 1216., , , et al.
- 315High response rate to combination cisplatin, 5-fluorouracil and interferon alpha in the treatment of advanced esophageal carcinoma: a confirmatory Phase II trial [abstract 637]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 160a., , , , , .
- 316Five-day continuous infusion fluorouracil (5-FU) plus vinorelbine (VNR) as third line therapy in metastatic breast cancer (MBC) [abstract 1965]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 54b., , , , , .
- 317Irinotecan, oxaliplatin plus 5-FU/leucovorin in advanced colorectal cancer [abstract 542]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 136a., , , , , .
- 318Oxaliplatin (Ox)/5-fluourouracil (5FU)/leucovorin (LV)-folfox 4 is an effective chemotherapy combination for advanced colorectal carcinoma (CRC) in an Asian population [abstract 2205]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 114b., , , , , .
- 319Biweekly oxaliplatin in combination with a modified de Gramont 5-FU/leucovorin regimen in previously treated patients with advanced colorectal carcinoma (ACRC) [abstract 560]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 141a., , , , , .
- 320Irinotecan combined with gemcitabine, 5-FU (5-fluorouracil), LV (leucovorin), and cisplatin (G-FLIP) is an effective and non-crossresistant regimen for refractory metastatic adenocarcinoma of the exocrine pancreas (MPAC) [abstract 615]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 155a., , , , , .
- 321Neoadjuvant concurrent chemoradiotherapy (CT-RT) with paclitaxel (TAXOL) and 5-fluorouracil (5-FU) followed by 5-FU-epirubicine-cyclophosphamide (FEC) and surgery in patients (Pts) with locally advanced breast cancer (LABC) [abstract 1815]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 176., , , , .
- 322Phase-II trial of trimetrexate (TMTX), 5-fluorouracil (5-FU) and leucovorin (LV) in patients (Pts) with metastatic colorectal carcinoma (MCC) [abstract 2202]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 113b., , , , , .
- 323http://www.asco.org/ac/1,1003,_12-0022640-00_19-003128,00.asp [accessed March 5, 2004]., , , , , . Weekly cisplatin plus 24-hour infusion of high-dose 5-fluorouracil and leucovorin (P-HDFL), a low-toxic and moderately active regimen, for advanced transitional cell carcinoma (TCC) [abstract 3128]. Available from URL:
- 3245-Fluorouracil, leucovorin and irinotecan in patients with metastatic colorectal cancer: a Phase II study [abstract 2227]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 119b., , , , , .
- 325Improving patient convenience: a modified schedule of FOLFOX (oxaliplatin combined with 5FU) with high activity and tolerability in untreated metastatic colorectal cancer (CRC) [abstract 578]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 145a., , , , .
- 326A Phase II study of doxil/caelyx (D) in relapsed epithelial ovarian cancer (OC) patients [abstract 2511]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 190b., , , et al.
- 327High-dose ifosfamide (IFO) and doxorubicin (DOX) for the treatment of gynecological sarcomas. Prog Proc Am Soc Clin Oncol. 2001; 20: 362a., , , et al.
- 328Doxil/caelyx (D) plus paclitaxel (T) in patients with metastatic breast cancer (MBCa): update of a Phase II efficacy and safety study [abstract 2017]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 67b., , , , , .
- 329Sequential primary chemotherapy with doxorubicin-Taxol (AT), fluorouracil-vinorelbine (FU-VNB) and cyclophosphamide (CTX) in locally advanced breast cancer [abstract 1942]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 49b., , , , , .
- 330A feasibility study of hepatic arterial infusion (HAI) with continuous infusion (CI) of oxaliplatin in patients with unresectable liver metastases from colorectal cancer (CRC) [abstract 2217]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 117b., , , , , .
- 331Salvage treatment with oxaliplatin (LOHP)-based chemotherapy (CT) in heavily pretreated colorectal carcinoma (CRC) [abstract 2189]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 110b., , , et al.
- 332The safety and efficacy of three-hour paclitaxel (Anzatax) infusion as salvage chemotherapy for metastatic breast cancer [abstract 1931]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 46b., , , et al.
- 333Concurrent carboplatin, paclitaxel (Taxol), and hyperfractionated radiotherapy in unresectable head and neck cancer [abstract 2563]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 203b., , , , , .
- 334Phase II study: concomitant chemotherapy (CRT) with paclitaxel and cisplatin as primary therapy for locoregionally advanced nasopharyngeal carcinoma (NPC) [abstract 2532]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 195b., , , , , .
- 335Intracavitary paclitaxel in the multimodality management of malignant pleural mesothelioma [abstract 1460]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 366a., , , , , .
- 336Intensified concurrent chemotherapy with 5-fluorouracil, paclitaxel and hydroxyurea and conventional radiotherapy (FTHX) is feasible in locally advanced undifferentiated nasopharyngeal carcinoma (NPC) [abstract 2543]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 198b., , , , , .
- 337Concurrent chemoradiotherapy for advanced inoperable head and neck cancer: a three-year follow-up [abstract 927]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 232a., , , , , .
- 338High dose daily cisplatin (C) and radiotherapy (RT) in poor-prognostic head and neck squamous cell carcinoma (HNSCC) [abstract 2561]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 203b., , , , , .
- 339A Phase II study of preoperative concurrent chemotherapy and escalating dose radiotherapy in patients with adenocarcinoma of the rectum [abstract 2184]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 108b., , , , , .
- 340Induction cisplatin/5-fluorouracil (5-FU) (CIF) is active and well tolerated in advanced or metastatic pancreatic cancer [abstract 2572]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 205b., , , et al.
- 341Concurrent chemoradiation in advanced stage nasopharyngeal cancer (NPC) [abstract 2540]. Prog Proc Am Soc Clin Oncol. 2001; 20: 197b., , .
- 342A Phase II trial of epirubicin, cisplatin and infusional 5-fluorouracil followed by radiotherapy and concurrent cisplatin in patients with locally advanced nasopharyngeal cancer [abstract 904]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 227a., , , , , .
- 343Preoperative paclitaxel, carboplatin, 5-FU and radiation therapy for localized esophageal cancer; final results of a Minnie Pearl Cancer Research Network Phase II trial [abstract 636]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 160a., , , , , .
- 344Phase II study of single agent docetaxel in carcinoma of unknown primary site [abstract 2151]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 100b., , , , , .
- 345Weekly docetaxel in patients with recurrent and/or metastatic head and neck cancer [abstract 2544]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 198b., , , , , .
- 346Updated analysis of the combination of docetaxel (Taxotere) (T) and cisplatin (P) in anthracycline-pretreated advanced breast cancer (ABC) [abstract 1934]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 47b., , , , , .
- 347Docetaxel and vinorebine, in a biweekly regimen with G-CSF, in advanced and metastatic breast cancer after using anthracyclines. Preliminary results. [abstract 1957]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 52b., , , , , .
- 348A Phase II study of high-dose epirubicin plus docetaxel in locally advanced breast cancer (BC) [abstract 1878]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 33b., , , , , .
- 349Preliminary results of a Phase I/II study of weekly docetaxel (Taxotere) combined with intermittent capecitabine (Xeloda) for patients with anthracycline pre-treated metastatic breast cancer [abstract 2016]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 67b., , , , , .
- 350Epirubicin (E) and docetaxel (T) as first-line therapy in patients with advanced breast cancer (ABC) [abstract 2010]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 65b., , , , , .
- 351A Phase II study of docetaxel and cisplatin as first line treatment in locally advanced or metastatic non-small-cell lung cancer (NSCLC) [abstract 2827]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 269b., , , , , .
- 352Doxorubicin and docetaxel as first-line chemotherapy for metastatic breast cancer. A multicenter nonrandomized study [abstract 1916]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 42b., , , , .
- 353A Phase II study of gemcitabine plus docetaxel as first line treatment in non-small-cell lung cancer (NSCLC). An Oncopaz and Associated Hospitals study [abstract 2833]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 270b., , , , .
- 354A Phase I/II trial of concurrent docetaxel (T) and once daily radiation following induction chemotherapy in squamous cell cancer of the head and neck [abstract 930]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 233a., , , , , .
- 355Phase II study of weekly docetaxel (Doc) and epirubicin (Epi) as first-line chemotherapy for metastatic breast cancer (MBC) [abstract 1929]. Prog/Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 45b., , , .
- 356A Phase II study of a combination of docetaxel and gemcitabine in a weekly schedule as first line treatment in Stages IIIB/IV non-small-cell lung cancer (NSCLC). Goti Study Group [abstract 2777]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 256b., , , , , .
- 357A Phase II study of sequential treatment with docetaxel and cyclophosphamide/doxorubicin as first line treatment in metastatic breast cancer (MBC) [abstract 2007]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 65b., , , , , .
- 358Mitoxantrone, topotecan, and cytosine-arabinoside (MTC) in patients with relapsed or refractory acute myeloid leukemia (AML) or chronic myeloid leukemia in blast crisis—interim results [abstract 1205]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 302a., , , , , .
- 359Topotecan (TPT) as second-line treatment in small cell lung cancer [abstract 2883]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 283b., , , , , .
- 360A Novel induction therapy for patients with acute myeloid leukemia over the age of 60: times sequential therapy using topotecan, ara-C and mitoxantrone at University of Maryland Greenbaum Cancer Center [abstract 1206]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 302a., , , , .
- 361Comparison between elderly and non-elderly patients (Pts), of efficacy and tolerability of FOLFOX2 schedule in advanced colorectal cancer (COL) [abstract 2195]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 111b., , , , , .
- 362Chemotherapy with continuous 5-FU and low-dose consecutive CDDP for the treatment of advanced colorectal cancer [abstract 2349]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 150b., , , , .
- 3635-FU. folinic acid and oxaliplatin as first line chemotherapy in advanced colorectal cancer [abstract 2234]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 121b., , , , , .
- 364A Phase II study of bi-weekly oxaliplatin, fluorouracil 4 hour infusion and folinic acid in pretreated metastatic colorectal cancer (MCRC) [abstract 2206]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 114b., , , , , .
- 365Phase I/II trial of fortnightly irinotecan and protracted venous infusion 5FU in patients with previously untreated advanced colorectal cancer [abstract 2176]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 107b., , , , , .
- 366A Phase II study of first-line low dose weekly infusional 5-fluorouracil (5FU) and every two week paclitaxel (T) in metastatic breast cancer (BrCa) [abstract 2033]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 71b., , , , .
- 367Bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs. weekly high-dose 24H 5-FU infusion/FA + oxaliplatin (OXA) in advanced colorectal cancer [abstract 496]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 125a., , , , , .
- 368Phase II trial of preoperative radiotherapy, protracted venous infusion 5-fluorouracil and weekly CPT-11, followed by surgery for ultrasound staged T3/T4 rectal cancer [abstract 589]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 148a., , , , , .
- 369Biweekly schedule of irinotecan (CPT-11) and 5-fluorouracil (5-FU) as first line treatment in advanced colorectal cancer (CRC). Prog Proc Am Soc Clin Oncol. 2001; 20: 109b., , , et al.
- 370Oxaliplatin (OXA), 5-fluoro-uracil (FU) and folinic acid (FA) (FOLFOX6 6) in advanced/metastatic gastric carcinoma (A/MGC) patients (Pts): final results of a multicenter Phase II study [abstract 654]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 164a., , , , , .
- 371Multicentric gercor feasibility study of bimonthly combination of leucovorin-5FU and gemcitabine (6 cycles) followed by chemoradiotherapy (CRT) with 5FU for locally advanced non metastatic pancreatic adenocarcinoma (LAPA) [abstract 616]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 155a., , , , , .
- 372Outpatient combination chemotherapy with gemcitabine and docetaxel in patients (Pts) with cancer of the biliary system [abstract 2272]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 130b., , , , , .
- 373Second line docetaxel and carboplatin in patients (Pts) with advanced non-small cell lung cancer (NSCLC). A Phase I study [abstract 2814]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 266b., , , , , .
- 374Second line chemotherapy with docetaxel (D) and vinorelbine (V) for non-small-cell cancer previously treated with platinum-based chemotherapy [abstract 2822]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 268b., , , , , .
- 375Salvage chemotherapy with docetaxel (TXT) and gemcitabine (GEM) in metastatic breast cancer (MBC): preliminary results of a multicenter Phase II trial of GOIM (Gruppo Oncologico dell'Italia Meridionale) [abstract 1956]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 52b., , , , , .
- 376Analysis of the efficacy and toxicity of caelyx in the treatment of heavily pretreated patients with recurrent advanced ovarian cancer: a Phase II study [abstract 881]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 221a., , , , , .
- 377Hyperthermia (HT) + doxil significantly enhances drug delivery and efficacy in metastatic breast cancer of the chest wall (CW): a Phase I/II study [abstract 184]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 47a., , , , , .
- 378A Phase II study of sequential (GEP-GT) chemotherapy in advanced non-small cell lung cancer (NSCLC): preliminary report [abstract 2787]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 259b., , , , , .
- 379A Phase II randomized trial of paclitaxel plus carboplatin (PC) or paclitaxel plus gemcitabine (PG) in inoperable, chemonaïve non-small-cell lung cancer (NSCLC) [abstract 1358]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 340a., , , , , .
- 380Primary chemotherapy in locally advanced breast cancer (BC) with gemcitabine, Adriamycin and paclitaxel (GAT). A Phase II trial and predictive value of Erb2 [abstract 1872]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 31b., , , , , .
- 381Toxicity and activity of alternating paclitaxel (T), cisplatin (C), fluorouracil (F) and radiotherapy (RT) in advanced squamous cell carcinoma of the head and neck [abstract 2535]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 196b., , , , , .
- 382Multicenter randomized Phase II study of 1 hour (H) infusion paclitaxel (T), fluorouracil (F) and hydroxyurea (H) with concomitant hyperfractionated radiotherapy (2XRT) with or without erythropoietin (EPO) for advanced head and neck cancer (HNC) [abstract 902]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 226a., , , , , .
- 383Epirubicin and paclitaxel (ET) followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in the treatment of high risk breast cancer (HRBC) [abstract 1855]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 27b., , , , , .
- 384Phase I/II study of sequential high dose VIP plus paclitaxel (T) in patients (pts) with “poor prognosis” germ cell tumor (GCT) [abstract 691]. Prog Proc Am Soc Clin Oncol. 2001; 20: 173a., , , , , .
- 385Multimodality treatment in pleural malignant mesothelioma patients: a multicentre Phase II study [abstract 2746]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 52b., , , , , .
- 386Maximizing local control and organ preservation in advanced squamous cell head and neck cancer (SCHNC) with hyperfractionated radiation (HRT) and concurrent chemotherapy [abstract 893]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 224a., , , et al.
- 387Dose-intense Phase II study of weekly cisplatin and epidoxorubicin plus medroxyprogesterone acetate and recombinant interleukin 2 in Stage IIIb-IV non-small-cell lung cancer [abstract 2701]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 237b., , , , , .
- 388Treatment of multiple myeloma (MM) in patients (PTS) with tandem autologous stem cell transplantation (ASCT) using high-dose (HD) melphalan (MEL) followed by busulfan (BU) [abstract 57]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 15a., , , , , .
- 389Troxacitabine is active in heavily pretreated patients with blastic phase chronic myeloid leukemia (CML-BP) [abstract 1147]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 287a., , , , , .
- 390Phase II study of 10-propargyl-10-deazaaminopterin (PDX) in previously-treated patients with advanced non-small cell lung cancer (NSCLC) [abstract 1321]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 331a., , , , , .
- 391Phase II trial of the use of raltitrexed (R) and mitomycin-C (MMC) in the treatment of advanced colorectal cancer (ACRC) after 5-FU failure: final results [abstract 2188]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 109b., , .
- 392Vinorelbine/capecitabine (VINOCAP) combination remission induction therapy for metastatic breast cancer (MBC) [abstract 1939]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 2): 48b., , .
- 393A Phase II study of troxacitabine, a novel nucleoside analog, in patients with leukemia [abstract 1212]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 304a., , , , , .
- 395Induction 5-fluorouracil (5-FU)/cisplatin (CP) followed by combined external beam radiation therapy (XRT) and chemotherapy in locally advanced anal canal cancer. Prog Proc Am Soc Clin Oncol. 2000; 19: 301a., , , .
- 396Phase II study of induction chemotherapy with paclitaxel (T), ifosfamide (I), and carboplatin (C) in patients (PTS) with locally advanced squamous cell carcinoma of the head and neck [abstract 1659]. Prog Proc Am Soc Clin Oncol. 2000; 19: 420a., , , , , .
- 397Alternating chemo-radiotherapy versus partly accelerated radiotherapy in advanced squamous cell carcinoma of the head and neck: results of a Phase III randomized trial [abstract 1631]. Prog Proc Am Soc Clin Oncol. 2000; 19: 413a., , , et al.
- 398Biweekly sequential gemcitabine, 5-FU (5-fluorouracil), LV (leucourvin), and cisplatin (GFP): a highly active novel combination for metastatic adenocarcinoma of the exocrine pancreas (MPAC) [abstract 617]. Prog Proc Am Soc Clin Oncol. 2001; 20(Pt 1): 155a., , , , , .