Mucosal toxicity grading scales

Discussions about mucosal injury are hampered by a lack of consistency among investigators when describing toxicity. Grading scales vary among institutions. The most commonly used is that of the World Health Organization¹² (see Table 2), which is similar to that of the National Cancer Institute and the cooperative oncology groups (ECOG, SWOG, CALGB).^13,14 These scales are simple and easily applied, but variability among graders is common. Other grading systems, including the Oral Mucosal Assessment Scale¹⁵ and the University of Nebraska Oral Assessment Scale¹⁶ are more detailed and may be more reproducible. In the late 1980s,^17,18 a grading system specific for patients undergoing bone marrow transplantation was published. Commonly known as the 'Bearman Criteria,' it provides a grading scale from 1 to 3 for all major organs, including the oral mucosa, which may be affected following HPCT. While the Bearman criteria have limitations, they have held up well in HPCT studies. More recently,¹⁵ a newer scoring system – the Oral Mucosal Assessment Score – was developed and validated in a large-scale study. A panel of experts including nurses, dental hygienists, physicians and dentists agreed on a grading scheme based on a consensus of mucositis indicators. Indicators were either primary (ulceration, pseudomembrane formation, erythema in specific sites within the mouth) or secondary (oral pain, swallowing and the ability to eat as assessed by the patient). It has been validated in several large-scale studies with high interobserver consistency and scores that demonstrated good correlation with symptoms. It is, however, more cumbersome and time consuming for the clinician who scores the mucosal pathology. The University of Nebraska Oral Assessment Score¹⁶ takes into consideration not only the appearance of the oral mucosa and swallowing function, but also voice quality, lips, saliva and teeth assessment. Other grading systems include the Western Consortium for Cancer Nursing Research (WCCNR) Staging System and the Oral Assessment Guide (OAG).¹⁹ Unfortunately, the multitude of grading scales, although attempting to provide for uniformity, often provide confusion in interpreting the toxicities associated with a particular therapy. Grade 0 is understood as 'normal' to all investigators. However, the severity of grade 2 or 3 toxicity is quite variable from one scoring system to the next. As reflected in the multiplicity of grading schemes, no single system has emerged which is consistently applied in clinical trials.

Table 2 - Grading scales.

Full table

Thus, the need for prevention or early intervention is obvious. As noted above,¹¹ the Surgeon General has made oral health a priority. He has included patients receiving chemotherapy and those undergoing HPCT. As investigators learn more about the pathophysiology of mucosal damage in this setting, newer approaches and agents will be developed. These are described in further detail below and in Table 3, and include both attempts at prophylaxis and treatment. In addition, efforts must be made to understand each individual patient's risk prior to undergo high-dose therapy. It has been recommended that all patients undergo a pretransplant oral examination by a qualified dentist prior to embarking on this course.²⁰

Table 3 - Oral factors.

Full table

Oral cryotherapy

Decreasing blood flow to oral mucosa should also serve to decrease mucosa exposure to the drug. Therefore, it is assumed that oral cryotherapy will, through vasoconstriction, decrease the toxicity of agents associated with mucosal damage. When used with agents with short half-lives, such as 5-fluoruracil (5-FU) and melphalan, this should be particularly efficacious. This has been studied most consistently with 5-FU, but could be applied more broadly. Mahood et al ²¹ randomized 95 patients to receive a short course of cryotherapy during 5-FU and leucovorin therapy. Patients who were randomized to receive therapy were asked to suck on ice chips for 30 min, starting 5 min prior to a 5-FU infusion. During a second cycle of 5-FU and leucovorin, patients who had previously received no therapy were asked to use cryotherapy, whereas those who had used the ice chips for the first cycle then received no therapy. Mucosal toxicity, as graded by patients, and duration of mucositis, was significantly decreased during cycles when patients received cryotherapy. Subsequently, Cascinu et al²² performed a similar study in 84 patients with similar results in terms of oral mucositis. Toxicity was the same in both studies and limited primarily to the 'ice cream headache' sensation associated with the ice chips. However, while mucosal toxicity was significantly improved in terms of pain control, other side effects of chemotherapy including diarrhea, nausea and emesis did not differ. Roche et al²³ examined cryotherapy for 30 min vs 60 min and found that there was no advantage in prolonging cryotherapy past the 30 min mark. Interesting observations from the three studies include a trend towards more mucositis in older patients, but less in cigarette smokers.

Chlorhexidine

Chlorhexidine is a broad-spectrum topical antimicrobial that has been effective in preventing gingivitis and oral infection. Mouth rinses with chlorhexidine have been used in many transplant centers as part of 'standard of care' for many years. However, in a randomized study of 100 patients,²⁴ chlorhexidine use resulted in a trend towards improved oral hygiene and oral candidiasis, but there was no distinct therapeutic advantage of chlorhexidine over placebo in reducing mucositis, oral pain, or oral (re) infection with herpes simplex virus.

Oral decontamination

Other attempts have been made at oral decontamination both in patients undergoing HPCT and those undergoing other therapies with a high incidence of mucositis. For example, Symonds et al ²⁵ studied 275 patients undergoing radiation therapy for head and neck malignancies. Patients were randomized to receive an antibiotic pastille (polymyxin E 2 mg, tobramycin 1.8 mg, and amphotericin B 10 mg) or placebo four times a day from the start of radiation through the resolution of radiation induced symptoms. There was a beneficial effect for patients receiving the antibiotic pastilles in terms of functional consequences of mucosal injury, including dysphagia and weight loss. There was also a striking decrease in the number of oral yeast infections, but no difference in the oral carriage of Gram-negative rods. A similar study, by Okumo et al,²⁶ also looked at the use of these pastilles in comparison to chlorhexidine or placebo mouth rinses. Patients who were receiving radiation therapy that involved at least one-third of the oral cavity were randomized to receive one of the three therapies four times daily. The arms of the study that included chlorhexidine and placebo mouth rinses were closed early when the chlorhexidine was found to be detrimental. The study continued with a randomization between a placebo lozenge and the antibiotic lozenge. There were no difference in the mucositis scores or in the incidence or duration of radiation therapy interruptions. Patients may have found some relief in symptoms, but there was no significant difference to warrant recommending use of the pastilles in this patient group. Given the decrease in dysphagia and oral yeast infections described by Symonds,²⁵ it is possible that patients at particularly high risk for theses complications, including HPCT recipients receiving radiation therapy or particularly stomatoxic therapy, may benefit. Further studies in this patient group are warranted.

Several different rinses have been used to prevent or treat mucosal injury. These are frequently favorite remedies of the treating clinician, rather than products which have undergone vigorous testing. Often they are remedies passed on from patient to patient. Recently, Dodd et al²⁷ looked at three of the more commonly used regimens in a randomized clinical trial. Adult patients undergoing 'stomatoxic' therapy who developed mucositis were invited to participate in the study. Patients undergoing induction therapy for acute leukemia, HPCT or patients with acquired immune deficiency syndrome were excluded. All patients received instruction regarding good oral hygiene as part of the PRO-SELF Mouth Aware Program and all patients undertook 12 days of mouth rinses four times daily. Patients were randomized to one of three rinses: chlorhexidine gluconate mouthwash (0.12%), 'Magic Mouthwash' (viscous lidocaine – 0.5%, 5 ml + diphenhydramine hydrochloride – 0.0312%, 0.25 ml + aluminum hydroxide suspension 14.75 ml), or 'salt and soda' mouth wash (1 teaspoon of salt and 1 teaspoon of sodium bicarbonate per pint of water). There was no benefit provided by any of the three rinses beyond that provided by the use of a systematic oral hygiene program.

Glutamine

Multiple studies have been performed to assess the effects of oral or intravenous glutamine on chemotherapy induced mucositis. Glutamine is the most abundant amino acid in plasma and is reduced significantly in plasma and tissue during sepsis or nutritional depletion. Its role in maintaining gastrointestinal integrity has been described previously.²⁸ Both animal models and human trials have demonstrated an increased glutamine requirement during certain catabolic states.²⁹ While the intravenous formulation has provided little benefit, oral glutamine has been found to be effective in reducing bacteremia and mucositis associated with methotrexate administration.³⁰ Studies of low-dose oral glutamine (2 g amino acid/m² b.i.d) in patients receiving standard doses of anthracycline-based chemotherapy regimens have shown a decrease in both severity and duration of oral mucositis.³¹ There has been a mixed response to glutamine supplementation in HPCT patients. While one study suggested decreased ulceration, pain and oral bleeding in patients who received oral glutamine,³² these findings did not reach statistical significance. Other studies^33,34 have not shown a consistent benefit. However, given the trends which have been noted, additional studies are ongoing, including combination therapy with glutamine and other agents. There have been at least 20 randomized controlled clinical trials of glutamine in parenteral nutrition in adults or children. Most indicate some benefit from supplemental glutamine. Adding supplemental glutamine to parenteral nutrition in recipients of HPCT has led to increased glutamine levels and improved nitrogen balance without any adverse side effects. It has been associated with improved number of circulating lymphocytes and attenuation of extracellular fluid. However, there have been mixed results in terms of effects on diarrhea and mucositis. Oral glutamine has generally not been beneficial. However, in one study, Anderson et al³⁵ did show improved survival on day 28 post-HPCT and significantly less mouth pain and narcotic use in patients who received oral glutamine. In general, the use of either oral or parenteral glutamine has not been shown to be detrimental. Patients receiving parenteral nutrition should have particular attention paid to glutamine supplementation and nitrogen balance. However, ongoing studies are needed to further clarify the specific role of glutamine therapy in recipients of HPCT.

Pentoxifylline

Several studies have examined the use of pentoxifylline for the prevention of not only mucosal injury, but also other transplant-related toxicities. Pentoxifylline is a xanthine derivative capable of downregulating TNF-. In preclinical models,³⁶ it decreased the production of radiation-induced TNF- and decreased endotoxin production. In an interesting study by Bianco et al,³⁷ pentoxifylline was given to patients undergoing HPCT in a dose escalation study (1200, 1600 and 2000 mg/day). A total of 26 patients underwent allogeneic HPCT and four underwent autologous HPCT. Out of 30 patients, 24 received preparative regimens that included total body irradiation and six received preparative regimens that included only chemotherapy. Patients who received pentoxifylline had less mucositis, less hepatic veno-occlusive disease, less renal insufficiency, required less parenteral nutrition and were less likely to develop grade II graft-versus-host disease (GVHD). A larger prospective randomized study³⁶ was conducted in 140 patients who received 1600 mg of pentoxifylline daily (400 mg, four times per day) starting with the first day of the preparative regimen and continuing through 100 days following HPCT. A total of 89 patients received autologous grafts, while 51 received allogeneic grafts. In all 62% received preparative regimens that included total body irradiation, while 38% received only chemotherapy. Patients who received an allogeneic graft received methotrexate for GVHD prophylaxis on days 1, 3 and 6 following HPCT. While there were no adverse side effects attributable to the pentoxifylline, there was also no difference in mucositis, veno-occlusive disease, survival, hematologic toxicity, renal toxicity, or septicemia. Thus, while pentoxifylline offered some early promise, its use cannot be advocated outside of a clinical trial setting.

GM-CSF

GM-CSF (sargramostim) has been used in an attempt to reduce the severity and duration of mucositis. GM-CSF is known to stimulate migration and proliferation of endothelial cells and to promote keratinocyte growth.^38,39 Preclinical data have shown that topical application of GM-CSF to wounds results in improved wound healing.^40,,42 Results of trials with patients suffering from mucositis following high-dose chemotherapy have been mixed. Several trials have looked at the use of intravenous GM-CSF in this setting. Nemunaitis et al⁴³ reported on 109 patients who were randomized to receive either 250 g/m²/day or placebo. He found that patients receiving GM-CSF were less likely to develop Grade III/IV mucositis (8 vs 29%; P=0.005); however, the overall incidence of mucositis was no different from one group to another. In a study comparing a dose of 125 mg/m²/day continuous intravenous infusion with no growth factor, Gordon et al⁴⁴ reported a shorter duration of mucositis in patients receiving GM-CSF (12.2 vs 20.3 days; P=0.02). However, this was only observed in patients who received a preparative regimen of thiotepa, etoposide and total body irradiation. There was no difference in the severity or duration of mucositis when patients received a preparative regimen of thiotepa, etoposide and cyclophosphamide. Conversely, both Legros et al⁴⁵ and Atkinson et al⁴⁶ reported no reduction in the severity or duration of mucositis when patients received GM-CSF.

Other investigators have studied the use of topical GM-CSF in gel formulations or mouthwashes. Studies using GM-CSF prophylactically have not shown any benefit.^47,48 Therapeutic use of GM-CSF mouth washes, starting with first sign or symptom of mucositis, has shown both a reduced severity and a decreased duration of mucositis.^49,50

Sucralfate

In a double-blind randomized control of sucralfate for the prevention of mucositis in patients undergoing HPCT,⁵¹ severe mucositis was less frequent in patients who received sucralfate (29%) than in those who did not (47%; P=0.07). Patients who received sucralfate were also less likely to develop diarrhea (25 vs 53%; P=0.005). Although sucralfate has been used extensively for esophagitis related to gastroesophageal reflux disease and has been given in an attempt to ameliorate the toxicities of radiotherapy and chemotherapy in patients undergoing standard dose therapy for head and neck cancers, it has not otherwise been studied extensively in the HPCT setting. Additional studies are needed to investigate this agent, particularly with combination therapy.

Keratinocyte growth factors (KGF)

KGF are members of the fibroblast growth factor family, which have been shown in preclinical models to protect animals from chemotherapy and radiation induced gastrointestinal damage.^52,53 In a study performed recently in normal monkeys,⁵² investigators administered repifermin (keratinocyte growth factor 2), either intravenously or subcutaneously daily. Epithelial hyperplasia was found in the buccal mucosa and dorsal tongue of all monkeys, and esophageal thickening was also noted. The frequency and degree of hyperplasia was dose-dependent, with monkeys receiving 200 g/kg/day IV developing more hyperplasia than those who received lower doses. While there were no gastric changes seen, there was mucosal and goblet cell hyperplasia in the intestine. These changes were greatly reduced, or resolved following discontinuation of repifermin. In vitro studies of more than a dozen cell lines⁵⁴ have not shown any enhanced neoplastic transformation with repifermin. Similarly, subcutaneous injection of repifermin in tumor-bearing nude mice did not promote tumor growth.⁴⁰

In a phase I study conducted in patients with colorectal cancer,⁵⁵ patients received KGF by intravenous bolus on days 1–3 followed by 5-fluoruracil and leucovorin on days 4–8. All cohorts who had received doses of at least 10 g/kg/day had decreased grades II–IV mucositis. In a recent phase 2 study in the autologous HPCT setting,⁵⁶ 91 patients were randomized to receive repifermin or placebo. Repifermin was administered intravenously for 14 days at doses ranging from 1 to 50 g/kg. Preparative regimens were expected to provide at least a 50% incidence of grade III or IV mucositis. The Oral Mucosal Assessment Scale was used to grade mucositis. The overall incidence of grade III or IV mucositis was only 38%. Minimal side effects, including hyperamylasemia, fever, and infection, occurred in similar numbers in patients receiving repifermin or placebo.

KGF may also provide other benefits in the allogeneic HPCT setting. Delayed immune reconstitution following transplant and the associated infectious complications are a significant cause of morbidity and mortality. Preclinical work has shown KGF to provide protection from thymic epithelial cell injury, thereby allowing more rapid immune recovery.⁵⁷ Furthermore, in a murine GVHD model, KGF was administered from day 3 through day 7 and significantly reduced the mortality and severity of the GVHD. While GVHD was reduced, the graft-versus-leukemia effect was not compromised in mice receiving lethal doses of leukemia cells, as evidenced by a prolonged leukemia-free survival.⁵⁸

Iseganan

Iseganan is a novel Protegrin-derived antimicrobial peptide preparation (oral solution) which has been studied in patients undergoing high-dose therapy and HPCT. In a recent randomized double-blind, placebo-controlled phase 3 trial,⁵⁹ patients received myeloablative chemotherapy that was expected to cause at least grade II mucosal toxicity (National Cancer Institute – Common Toxicity Criteria). Patients were followed for the development of infections, hospitalizations, and death. These events were more common in patients with peak stomatitis grades of III or IV than in those with lesser grades of mucosal toxicity (47.4 vs 32.9%, P=0.0145). The Iseganan oral solution was found to reduce stomatitis severity, oral pain and swallowing dysfunction.

Immunol oral rinse

Triclosan is a compound which has demonstrated antimicrobial, anti-inflammatory, analgesic, and anticytotoxic properties through downregulation of PGE2 production induced by TNF- and IL1 in preclinical models. It is used throughout the world for treatment of gingivitis. Immunol oral rinse is a formulation of triclosan in an oral rinse which has recently been studied in a multicenter, double-blind randomized trial to prevent mucositis in patients undergoing HPCT.^60,61 Patients were randomized to receive either Immunol or antibiotic containing vehicle rinses four times daily from the start of the preparative regimen until engraftment or healing of all ulcers. Patients who received preparative regimens containing melphalan, etoposide, busulfan or TBI were more likely to develop severe mucositis. However, in this group, erythema and/or ulceration developed in 90.24% of patients in the control arm compared with only 68.89% in the treatment arm. There was also a significant reduction in the duration of mucositis (5.18 vs 7.88 days, P=0.011).

Interleukin 11

Interleukin-11 (rhIL-11) has been used to treat thrombocytopenia in patients receiving chemotherapy. Several investigators^62,63 have looked into the use of IL-11 in preclinical models and found it to decrease the severity, frequency and duration of mucositis and to inhibit the release of proinflammatory mediators, leading to decreased levels of tumor necrosis factor, interleukin 12 and interferon . There are less data in humans at present. However, given that IL-11 has been shown to block Th1 differentiation, by inhibition of IL-12, it was studied in a phase I investigation in patients with psoriasis.⁶⁴ Patients received subcutaneous injections of IL-11 in a dose escalation study. Out of 12 patients, seven responded with decreased keratinocyte production and decreased cutaneous inflammation. In a recently reported study,⁶⁵ patients who received a preparative regimen of busulfan, melphalan and thiotepa were randomized to receive rhIL-11 or placebo daily for 15 days following autologous HPCT. While patients who received rhIL-11 did have other side effects, including infections, sepsis, and veno-occlusive disease, there was a trend towards decreasing severity, incidence and duration of oral mucositis in this group.

Amifostine

Amifostine is an organic thiophosphate prodrug that is dephosphorylated in the tissues to its active metabolite (WR-1065) by membrane-bound alkaline phosphatase. Differences in the alkaline phosphatase concentration of normal vs malignant tissues result in greater activation in normal tissues,⁶⁶ resulting in selective cytoprotection. By acting as a potent scavenger of free radicals, amifostine has been shown to protect against the toxicities of both chemotherapy,^{67,68,69,70,71} and radiotherapy ^72,73,74,75 in normal cells, without diminishing the effects of therapy on malignant tissues.⁶⁶ It was originally approved to ameliorate the renal toxicity associated with cis-platin-based chemotherapy regimens. However, it has been shown in various settings to decrease mucosal toxicity associated with both radiation- and chemotherapy-induced injury. Low doses of amifostine (200 mg/m²), when given within 30 min prior to radiotherapy, can decrease the mucositis which is problematic in patients being treated for cancers of the head and neck.⁷⁶ Higher doses (740–910 mg/m²) will decrease toxicity related to high dose chemotherapy.^77,78,79 In an ongoing study⁷⁷ using amifostine at a dose of 910 mg/m², we have been able to escalate the dose of idarubicin in induction therapy for acute myelogenous leukemia to 23 mg/m² daily for 3 days. In the HPCT setting,⁷⁸ patients with various hematologic and non hematologic malignancies have received a dose of 740 mg/m² prior to treatment with escalating doses of melphalan (200300 mg/m²), with dose-limiting side effects reached at the 300 mg/m² dose. Surprisingly, even at 280 and 300 mg/m², mucosal toxicity was no worse, and frequently less, than that seen with the more commonly used 200 mg/m².

Transforming growth factor beta

Transforming Growth Factor Beta 3 (TGF-3) is one of the family of growth factors, including TGF-1, TGF-2, and TGF-3, which act by arresting or prolonging cell cycling in G1, providing potent negative regulation of epithelial and hematopoietic stem cell growth.⁸⁰ In hamsters, both topical and submucosal injections of TGF-3 have been shown to decrease proliferation of oral mucosal cells. In hamsters treated with 5-fluorouracil, TGF-3 decreased the severity and duration of mucositis, leading to less weight loss and prolonged survival. Early studies in humans have also shown promising results. In a dose escalation study,⁸¹ 11 patients with breast cancer received chemotherapy, with or without stem cell rescue with TGF-3 mouthwashes four times daily for 4 days starting with the first day of chemotherapy. All dose levels (20, 50 and 100 g/ml) were well tolerated. Further studies are needed to evaluate the efficacy.

Laser therapy

An interesting study, using laser therapy, was conducted in patients who received preparative regimens of total body irradiation (2 Gy BID, days -3 through -1) combined with high-dose cyclophosphamide (60 mg/kg, days -5 and -4) or high-dose melphalan (140 mg/kg, day –4) prior to autologous bone marrow transplant.⁸² On days -5 through -1, patients also received helium–neon laser (632.8 nm wavelength, power 60 mW) applications to five sites on the oral mucosa, or sham treatments. Oral assessment was performed through day 20 following transplant. Oral mucositis including time of onset, peak severity and duration were reduced in patients who received laser treatments, as were associated pain, narcotic use, and xerostomia. However, the need for parenteral nutrition was not. Low-energy lasers are known to provide wound healing, presumably by increasing collagen production stimulating fibroblast transformation into myofibroblasts.

Summary

HPCT is based on the concept that dose escalation can eradicate residual microscopic burdens of malignancy. Regimen-related toxicity has been reduced by the acceleration of hematopoietic recovery and shorter durations of neutropenia. In this setting, reducing the incidence and severity of other post-transplant toxicities is the next crucial step to making HPCT safer and/or allowing further dose escalation. The multiplicity of agents tested in the hopes that they might provide protection of the gastrointestinal mucosa attests to the importance of this problem in the transplant community. While no single agent has definitively demonstrated benefit, a number of agents show clinical promise and warrants further trials either as single agents or as combination therapy. Many centers are attempting to adjust current strategies, including the use of mycophenolate mofetil instead of methotrexate for GVHD prophylaxis, the use of decreased doses of total body irradiation and the use of nonmyeloablative transplant regimens. While there may be promise in such endeavors, each has its own risk, including that of graft rejection, relapse or GVHD. Thus, these endeavors are best suited to investigational studies.

Specific recommendations can be made for all patients undergoing HPCT (Table 4). These include: pretransplant oral evaluation by a qualified dentist, good routine oral health maintenance during the peritransplant period, use of appropriate analgesics including parenteral narcotics as necessary, active participation in investigational studies of new agents, and maintenance of adequate platelet and neutrophil counts (as far as possible) to improve healing.

Table 4 - Recommendations for patients undergoing HPCT.

Full table

References

1. Sonis ST, Oster G, Fuchs H et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001; 19: 2201–2205. | PubMed | ISI | ChemPort |
2. Schubert MM, Peterson DE, Lloid ME. Oral complications. In: Thomas KG, Forman Blume SJ (eds). Hematopoietic Stem Cell Transplantation, 2nd edn. Blackwell Science: Malden, MA, 1999.
3. Rapoport AP, Miller Watelet LF, Linder T et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 1999; 17: 2446–2453. | PubMed | ISI | ChemPort |
4. Morgan RJ, Doroshow JH, Leong L et al. Phase II trial of high-dose intravenous doxorubicin, etoposide, and cyclophosphamide with autologous stem cell support in patients with residual or responding recurrent ovarian cancer. Bone Marrow Transplant 2001; 28: 859–863. | Article | PubMed | ISI | ChemPort |
5. Moreau P, Facon T, Attal M et al. Comparison of 200 mg/m² melphalan and 8 Gy total body irradiation plus 140 mg/m² melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood 2002; 99: 731–735. | Article | PubMed | ISI | ChemPort |
6. Stiff P. Mucositis associated with stem cell transplantation: current status and innovative approaches to management. Bone Marrow Transplant 2001; 27(Suppl. 2): S3–S11. | Article | PubMed | ISI |
7. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998; 34: 39–43. | Article | PubMed | ISI | ChemPort |
8. Sezer O, Eucker J, Metzner B et al. Mucositis is associated with increased rate of documented infections and treatment related mortality after high-dose therapy with autologous peripheral stem-cell transplantation. Proc ASCO 2000; (abstr. 216).
9. Ruescher TJ, Sodeifi A, Scrivani SJ et al. The impact of mucositis on -hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer 1998; 82: 2275–2281. | Article | PubMed | ISI | ChemPort |
10. Avigan D, Richardson P, Elias A et al. Neutropenic enterocolitis as a complication of high dose chemotherapy with stem cell rescue in patients with solid tumors: a case series with a review of the literature. Cancer 1998; 83: 409–414. | Article | PubMed | ISI | ChemPort |
11. U.S. Department of Health and Human Services. Oral Health in America: a report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, National Institutes of Dental and Craniofacial Research, National Institutes of Health, 2000.
12. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214. | Article | PubMed | ISI | ChemPort |
13. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. | Article | PubMed | ChemPort |
14. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–655. | Article | PubMed | ISI | ChemPort |
15. Sonis ST, Eilers JP, Epstein JB et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Cancer 1999; 85: 2103–2113. | Article | PubMed | ISI | ChemPort |
16. Eilers J, Berger AM, Peterson MC. Development, testing and application of the Oral Assessment Guide. Oncol Nurs Forum 1988; 15: 325–330. | PubMed | ChemPort |
17. Bearman SI, Appelbaum FR, Buckner CD et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568. | PubMed | ISI | ChemPort |
18. Bearman SI, Appelbaum FR, Back A et al. Regimen-related toxicity and early post transplant survival in patients undergoing marrow transplantation for lymphoma. J Clin Oncol 1989; 7: 1288–1294. | PubMed | ISI | ChemPort |
19. Anonymous. Development of a staging system for chemotherapy induced stomatitis. Western Consortium for Cancer Nursing Research. Cancer Nurs 1991; 14: 6–12. | PubMed | ISI |
20. Khan SA, Wingard JR. Infection and mucosal injury in cancer. J Natl Cancer Inst Monogr 2001; 21: 31–36.
21. Mahood DJ, Dose AM, Loprinzi CL et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 1991; 9: 449–452. | PubMed | ISI | ChemPort |
22. Cascinu S, Fedeli A, Fedeli SL et al. Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. Oral Oncol Eur J Cancer 1994; 30B: 234–236.
23. Roche LK, Loprinzi CL, Lee JK et al. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 1993; 72: 2234–2238. | Article | PubMed | ISI | ChemPort |
24. Weisdorf DJ, Bostrom B, Raether D et al. Oropharyngeal mucositis complicating bone marrow transplantation: prognostic factors and the effect of chlorhexidine mouth rinse. Bone Marrow Transplant 1989; 4: 89–95. | PubMed | ISI | ChemPort |
25. Symonds RP, McIlroy P, Khorrami J et al. The reduction of radiation mucositis by selective decontamination antibiotic pastilles: a placebo-controlled double-blind trial. Br J Haematol 1996; 74: 312–317. | ChemPort |
26. Okumo SH, Foote RL, Loprinzi CL et al. A randomized trial of nonabsorbable antibiotic lozenge given to alleviate radiation induced mucositis. Cancer 1997; 79: 2193–2199. | Article | PubMed | ISI | ChemPort |
27. Dodd MJ, Dibble SL, Miaskowski C et al. Randomized clinical trial of the effectiveness of 3 commonly used mouthwashes to treat chemotherapy induced mucositis. Oral Surg Oral Med Oral Pathol Oral Rad Endod 2000; 90: 39–47. | ISI | ChemPort |
28. Fox AD, Kripke SA, DePaula J et al. Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis. J Parenter Enteral Nutr 1988; 12: 325–331. | ISI | ChemPort |
29. Ziegler TR. Glutamine supplementation in cancer patients receiving bone marrow transplantation and high dose chemotherapy. J Nutr 2001; 131: 2578S–2584S. | PubMed | ISI | ChemPort |
30. Souba WW, Klimberg VS, Plumley DA et al. Current research review: the role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990; 48: 383–391. | Article | PubMed | ISI | ChemPort |
31. Anderson PM, Schroeder G, Skubitz KM. Oral glutamine reduces the duration and severity of stomatitis after cytotoxic chemotherapy. Cancer 1998; 83: 1433–1439. | Article | PubMed | ISI | ChemPort |
32. Cockerham MB, Weinberger BB, Lerchie SB. Oral glutamine for the prevention of oral mucositis associated with high dose paclitaxel and melphalan for autologous bone marrow transplantation. Ann Pharmacother 2000; 34: 300–303. | Article | PubMed | ISI | ChemPort |
33. Coghlin Dickson TM, Wong RM, Offrin RS et al. Effect of oral glutamine supplementation during bone marrow transplantation. J Parenter Enteral Nutr 2000; 24: 61–66. | ChemPort |
34. Schloerb PR, Skikne BS. Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study. J Parenter Enteral Nutr 1999; 23: 117–122. | ISI | ChemPort |
35. Anderson PM, Ramsay NKC, Shu XO et al. Effect of low dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant 1998; 22: 339–344. | Article | PubMed | ISI | ChemPort |
36. Attal M, Huquet F, Rubie H et al. Prevention of regimen-related toxicities after bone marrow transplantation by pentoxifylline: a prospective, randomized trial. Blood 1993; 83: 732–736.
37. Bianc JA, Appelbaum FR, Neumatis J et al. Phase I-II trial of pentoxifylline for the prevention of transplant-related toxicities following bone marrow transplantation. Blood 1991; 78: 1205–1211. | PubMed | ISI | ChemPort |
38. Hancock GE, Kaplan G, Cohn ZA. Keratinocyte growth regulation by the products of immune cells. J Exp Med 1988; 168: 1395–1402. | Article | PubMed | ISI | ChemPort |
39. Bussolino F, Wang JM, Defilippi P et al. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature 1989; 337: 471–473. | Article | PubMed | ISI | ChemPort |
40. Vyalov S, Desmouliere A, Gabbiani G. GM-CSF-induced granulation tissue formation: relationships between macrophage and myofibroblast accumulation. Virchows Arch B Cell Pathol 1993; 63: 231–239. | ISI | ChemPort |
41. Kucukcelebi A, Carp SS, Hayward PG. Granulocyte–macrophage colony-stimulating factor reverses the inhibition of wound contraction caused by bacterial contamination. Wounds 1992; 4: 241–247. | ISI |
42. Jyung RW, Wu L, Pierce GF, Mustoe TA. Granulocyte–macrophage colony-stimulating factor and granulocyte colony-stimulating factor: differential action on incisional wound healing. Surgery 1994; 115: 325–334. | PubMed | ISI | ChemPort |
43. Neumanitis J, Rosenfeld C, Ash R et al. Phase III randomized, double-blind placebo controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplant 1995; 15: 949–954. | PubMed | ISI | ChemPort |
44. Gordon B, Spadinger A, Hodges E et al. Effect of granulocyte–macrophage colony-stimulating factor on oral mucositis after hematopoietic stem cell transplantation. J Clin Oncol 1994; 12: 1917–1922. | PubMed | ISI | ChemPort |
45. Legros M, Fleury J, Bay JO et al. RhGM-CSF vs placebo following rhGM-CSF mobilized PBPC transplantation: a phase II double-blind randomized trial. Bone Marrow Transplant 1997; 19: 209–213. | Article | PubMed | ISI | ChemPort |
46. Atkinson K, Biggs JC, Downs K et al. GM-CSF after allogeneic bone marrow transplantation: accelerated recovery of neutrophils. monocytes and lymphocytes. Aust N Z J Med 1991; 21: 686–692. | PubMed | ISI | ChemPort |
47. Evans G, Mahendra P, Brightwell M et al. A double blind randomised trial of oral GM-CSF mouthwash versus placebo in the treatment of mucositis following PBSC/bone marrow transplantation. Bone Marrow Transplant 1998; 21(Suppl. 1): S88 (abstr. 310). | ISI |
48. van der Lelie J, Thomas L, Van Oers M et al. Effect of locally applied GM-CSF on oral mucositis after stem cell transplantation: a prospective placebo controlled double blind study. Blood 1999; 94(Suppl. 1): 363b (abstr. 4849). | ISI |
49. Ovila-Martinez R, Rubio ME, Borbolla JR et al. GM-CSF mouthwashes as treatment for mucositis in BMT patients. Blood 1994; 84(Suppl. 1): 717a (abstr. 2853).
50. Bez C, Demarosi F, Sardella A et al. GM-CSF mouthrinses in the treatment of severe oral mucositis. Oral Surg Oral Med Oral Pathol Oral Rad Endod 1999; 88: 311–315. | ISI | ChemPort |
51. Castagna L, Benhamou E, Pedraza E et al. Prevention of mucositis in bone marrow transplantation: a double blind randomised controlled trial of sucralfate. Ann of Oncol 2001; 12: 953–955. | ISI | ChemPort |
52. Parry TJ, Fikes JD. Repifermin (keratinocyte growth factor-2) promotes mucosal hyperplasia throughout the alimentary tract in normal monkeys. Biol Blood Marrow Transplant 2001; 7: 84 (abstr. 76).
53. Okunieff P, Li M, Liu W et al. Keratinocyte growth factors radioprotect bowel and bone marrow but not KHT sarcoma. Am J Clin Oncol 2001; 24: 491–495. | Article | PubMed | ISI | ChemPort |
54. Connolly KM, Alderson R, Vance C et al. Efficacy of Repifermin (keratinocyte growth factor-2) in models of intestinal injury: lack of oncogenic activity. Proc ASCO 2001 (abstr. 2956).
55. Meropol NJ, Gutheil J, Pelley R et al. Keratinocyte growth factor (KGF) as a mucositis protectant: a randomized phase I trial. Proc ASCO 2000; (abstr. 2374).
56. Freytes C, LeVeque F, Meisenberg B et al. Safety and efficacy of repifermin (KGF-2) in reducing mucositis in patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) – results of a phase 2a trial. Blood 2001; 98(suppl 1a): 346b, (abstr. 5154). | ISI |
57. Min D, Taylor P, Chung B et al. Protection from thymic epithelial cell (TEC) injury by pre-BMT keratinocyte growth factor (KGF): a new approach to speed thymic reconstitution after lethal irradiation. Blood 2000; 96(Suppl. 1): 474a (abstr. 2039). | ISI |
58. Krijanovski OI, Hill GR, Cooke KR et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 2000; 94: 825–831. | ISI |
59. Giles FJ, Redman R, Yazji S, Bellm L. Iseganan HCl: a novel antimicrobial agent. Expert Opin Investig Drugs 2002; 11: 1161–1170. | PubMed | ISI | ChemPort |
60. Goldberg SL, Pineiro L, Schuster MW et al. Randomized vehicle controlled study of Immunol oral rinse for the prevention of oral mucositis in bone marrow transplant patients undergoing intensive chemotherapy and/or radiotherapy. Blood 2001; 98: 854a (abstr. 3547). | ISI |
61. Goldberg SL, Pineiro L, Schuster MW et al. Prevention of mucositis by Immunol oral rinse: final results of a randomized, vehicle controlled study. Biol Blood Marrow Transplant 2002; 8: 74 (abstr. 45).
62. Berl T, Schwertschlag U. Preclinical pharmacologic basis for clinical use of rhIL-11 as an effective platelet support agent. Oncology 2000; 14(Suppl. 8): 12–20. | PubMed | ChemPort |
63. Du XX, Doerschuk CM, Orazi A et al. A bone marrow stromal-derived growth factor, interleukin-11, stimulates recovery of small intestinal mucosal cells after cytoablative therapy. Blood 1994; 83: 33–37. | PubMed | ISI | ChemPort |
64. Trepicchio WL, Ozawa M, Walters IB et al. Interleukin-11 therapy selectively downregulates type 1 cytokine proinflammatory pathways in psoriasis lesions. J Clin Invest 1999; 104: 1527–1537. | PubMed | ISI | ChemPort |
65. Schwerkoske J, Schwartzberg L, Weaver CH et al. A phase 1 double-masked, placebo-controlled study to evaluate tolerability of neumega^® (rhIL-11; Oprelvekin) to reduce mucositis in patients with solid tumors or lymphoma receiving high-dose chemotherapy (CT) with autologous peripheral blood stem cell reinfusion (PBSCT). Proc ASCO 1999, (abstr. 2256).
66. Capizzi RL. The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine. Sem Oncol 1999; 26: 3–21. | ISI | ChemPort |
67. Valeriote F, Tolen S. Protection and potentiation of nitrogen mustard cytotoxicity by WR-2721. Cancer Res 1982; 42: 4330–4331. | PubMed | ISI | ChemPort |
68. Douay L, Hu C, Giarratana MC et al. Amifostine improves the antileukemic therapeutic index of mafosfamide: implications for bone marrow purging. Blood 1995; 86: 2849–2855. | PubMed | ISI | ChemPort |
69. Treskes M, Boven E, van de Loosdrecht AA et al. Effects of the modulating agent WR2721 on myelotoxicity and antitumour activity in carboplatin-treated mice. Eur J Cancer 1994; 30: 183–187. | Article |
70. Yuhas JM, Culo F. Selective inhibition of the nephrotoxicity of cisdichlorodiammineplatinum (II) by WR-2721 without altering its antitumor properties. Cancer Treat Rep 1980; 64: 57–64. | PubMed | ISI | ChemPort |
71. Yuhas JM. Differentiated protection of normal and malignant tissues against the cytotoxic effects of mechlorethamine. Cancer Treat Rep 1979; 63: 971–976. | PubMed | ISI | ChemPort |
72. McDonald S, Meyerowitz C, Smudzin T, Rubin P. Preliminary results of a pilot study using WR-2721 before fractionated irradiation of the head and neck to reduce salivary gland dysfunction. Int J Radiat Oncol Biol Phys 1994; 29: 747–754. | PubMed | ISI | ChemPort |
73. Davidson DE, Grenan MM, Sweeney TR. Biological characteristics of some improved radioprotectors. In: Brady LW (ed). Radiation Sensitizers: Their Use in the Clinical Management of Cancer. Masson Publishing: New York, 1980: 309.
74. Buntzel J, Kutner K, Frohlich D, Glatzel M. Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer. Ann Oncol 1998; 9: 505–509.
75. Liu T, Liu Y, He S et al. Use of radiation with or without WR-2721 in advanced rectal cancer. Cancer 1992; 69: 2820–2825. | Article | PubMed | ISI | ChemPort |
76. Brizel DM, Wasserman TH, Henke M et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000; 18: 3339–3345. | PubMed | ISI | ChemPort |
77. Flomenberg N, Garcia-Manero G, Grosso D et al. High CR rate and normal organ cytoprotection using dose escalation of idarubicin with amifostine in high risk patients with AML (abstract 37) Proc ASCO 2000; 19: 12a.
78. Phillips GL, Meisenburg B, Hale GA, et al. Amifostine (AF) cytoprotection (CP) of escalating doses of melphalan (MEL) and autologous hematopoietic stem cell transplantation (AHSCT): final results of a phase 1 II study (abstract 24). Proc ASCO 2001; 20: 7a.
79. Capelli D, Santini G, DeSouza C et al. Amifostine can reduce mucosal damage after high-dose melphalan conditioning for peripheral blood progenitor cell autotransplant: a retrospective study. Br J Haematol 2000; 110: 300–307. | Article | PubMed | ISI | ChemPort |
80. Sonis ST, Van Vugt AG, O'Brien JP et al. Transforming Growth Factor-3 mediated modulation of cell cycling and attenuation of 5-fluoruracil induced oral mucositis. Oral Oncol 1997; 33: 47–54. | Article | PubMed | ChemPort |
81. Wymenga ANM, van der Graaf WTA, Hofstra LS et al. Phase I study of transforming growth factor-3 mouthwashes for prevention of chemotherapy-induced mucositis. Clin Cancer Res 1999; 5: 1363–1368. | PubMed | ISI | ChemPort |
82. Cowen D, Tardieu C, Schubert M et al. Low energy helium-neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial. Int J Radiat Onc Biol Phys 1997; 38: 697–703. | ISI | ChemPort |