Introduction

Trials addressing mucositis that were presented at the 45th annual meeting of the American Society of Hematology (ASH) continue to provide evidence that mucositis is an important factor in patient quality of life. Data on treatments presented included palifermin, Ethyol®, and troclosan solution. Updated results from the phase III trial previously reported at ASCO 2003 showed that palifermin use significantly reduced resource utilization and improved function and physical well-being. Results with Ethyol® continue to appear inconsistent. Two posters of Ethyol® in patients undergoing stem cell transplant indicate protective effects. However, preliminary results of an ongoing Brazilian trial indicate that Ethyol® did not produce protective affects when used with high-dose cyclophosphamide. Recent pharmacokinetic data of triclosan solution demonstrated a favorable safety profile with active ulcers and researchers suggest that this investigational drug may still be a candidate in the prevention of oral mucositis.

Background

Mucositis is a condition characterized by damage to the epithelium of the oral-pharyngeal cavity and gastrointestinal (GI) tract from radiation and/or chemotherapy. Epithelial cells are more susceptible to the cytotoxic effects of radiation and chemotherapy because of their relatively high rate of turnover compared to cells in other organs. In most instances, epithelial cells of the mucous membranes have a more rapid turnover than the cancer being treated and are vulnerable to damage by cytotoxic agents and radiation.

Chemotherapy and radiation therapy deplete stem cells of the basal epithelium resulting in a reduction of epithelial cell replacement. Damaged epithelial cells release cytokines which increase local vascularity and cause inflammation. This process leads to ulceration, pain, and breakdown of the mucosal barrier leading to entry of bacteria, fungi, and viruses. Based on animal and human studies, researchers believe that evidence for epithelial damage can be detected within 24 hours of beginning treatment with chemotherapy or radiation therapy.¹ Once the chemotherapy and radiation therapy are completed there is relatively rapid recovery of epithelial cells. In most cases, oral mucositis treatments are utilized until natural healing occurs.

In patients with mucositis there is a breakdown in the saliva barrier, a disruption of epithelial cells, and thinning of the epithelium often with ulceration. Mucositis can be severe enough to require narcotics for pain and can severely interfere with oral nutrition resulting in weight loss. Mucositis is particularly severe in patients with head and neck cancer receiving chemotherapy and radiation therapy. Severe mucositis can result in hospitalization and delay of scheduled treatment, compromising therapeutic efficacy.

Oral mucositis can be a very significant clinical and economic problem. Retrospective analysis of patient complaints following stem cell transplantation reveal that mouth sores were the single most debilitating side effect.² In another retrospective study using the new Oral Mucositis Assessment Scale, transplant patients with severe mucositis had an increased incidence and duration of fever and infection as well as more use of total parenteral nutrition and a four-fold increase in mortality.³

Impact of Oral Mucositis on Quality of Life

Two studies evaluated the impact of oral mucositis on quality of life. Both indicate that mucositis is a common and important toxicity, impacting a variety of daily activities.

In an outpatient survey, patients reported that oral mucositis is a common and distressing side effect of standard-dose chemotherapy, occurring in approximately one third of patients. Evaluation of 514 completed surveys out of approximately 1625 patients receiving cancer treatments in an outpatient clinic over a 2-week period showed that high-risk populations can be identified, including individuals with hematologic malignancies and those receiving specific chemotherapeutic agents. The researchers suggested that these high-risk populations should be targeted for primary prophylaxis with agents currently under development. Notably, the researchers also suggested that “since over half of patients experiencing mucositis develop recurrent ulcerations/oral soreness during latter cycles of treatment, secondary prophylaxis strategies may be the most appropriate approach.”

Overall, 32% of respondents (167 patients) reported experiencing oral mucositis during the course of their treatment. Oral mucositis was rated as an important chemotherapy side effect by 22% of respondents. Compared to other side effect, mucositis was considered the 6th most distressing complication behind fatigue, hair loss, nausea, numbness, and diarrhea. The majority of patients experienced primary mucositis (69%) and more than half of patients reported recurrent mucositis during later cycles of chemotherapy (53%). Factors associated with rating mucositis as an important toxicity were generally the same factors associated with developing mucositis (see table 1).⁴

Table 1 Factors associated with rating mucositis as an important toxicity and developing mucositis

NS= non significant

A study by researchers at Fred Hutchinson Cancer Research Center and the UCLA school of medicine provided support for the validity of the brief daily diary questionnaire developed to monitor the impact of mucositis on health-related quality of life (HRQOL). This questionnaire was used in a study of palifermin also presented at this meeting.⁸ Furthermore, patient-reported results indicated that mucositis negatively impacted a variety of activities. The daily questionnaire utilized in this study was refined through two focus groups of patients who were suffering or had suffered from mucositis. 

Forty-seven patients receiving hematopoietic cell transplantation or treatment for stage III or IV colorectal cancer or head and neck cancer completed the daily diary. Patients were evaluated for a mean of 15 days after the start of chemotherapy. On a 5-point mouth and throat soreness question, 28% reported “quite a lot” or “extreme” soreness, 19% reported “some” soreness, 30% reported “a little” soreness, and 23% reported “no” soreness.

Patient-reported mouth and throat soreness correlated well with HRQOL, performance status, and medication use. Patients taking opioids or receiving IV pain medication reported greater soreness (t=4.5, p<0.001 and t=4.9, p<0.001, respectively). Patient global ratings of HRQOL correlated negatively with mouth and throat soreness (r=-0.46, p=0.001) and nurse-rated ECOG Performance Status (r = 0.54, p<0.001). Severity of soreness related most strongly to the activities of swallowing, eating, and drinking. Other activities negatively affected by mucositis included sleeping, talking, and doing things for fun.⁵ 

Palifermin

Palifermin is a recombinant human keratinocyte growth factor (KGF) that has been developed through laboratory processes to protect the mucosal lining of the mouth and intestinal tract from damage caused by chemotherapy and/or radiation. KGF is a naturally produced substance that binds to specific cell-surface KGF receptors on epithelial cells and induces hyperproliferation. Epithelial cells comprise a significant portion of the mucosal lining. Thus, thickening of these cells provides protection against radiation and/or chemotherapy damage.

Results of a phase III study reported at ASCO 2003 demonstrated that palifermin significantly reduces the incidence and duration of severe mucositis in patients undergoing peripheral blood stem cell transplants.6 At ASH 2003, researchers reported resource use and quality of life analysis of this study. Results indicate that palifermin significantly reduced days of hospitalization, analgesic use, and incidence of parenteral feeding. Evaluation of patient reported quality of life factors indicate that palifermin produced a clinically meaningful reduction in mouth and throat soreness and improvements in daily activities as well as physical and functional well-being.

Palifermin and resource use: Palifermin use significantly reduces the incidence and duration of severe mucositis, resulting in significantly reduced days of hospitalization, analgesic use, and incidence of parenteral feeding (see table 2). This randomized, double-blind, placebo-controlled trial evaluated mucositis and subsequent resource use in patients with hematologic malignancies undergoing TBI and high-dose chemotherapy with peripheral blood progenitor cell transplantation. In the assessment of post-transplant, patient hospitalizations, outpatient hospital visits were excluded. Each arm of the study (palifermin and placebo) included 106 patients.⁷

Quality of life assessment: Quality of life (QOL) was assessed using a mucositis-specific daily diary questionnaire and the Functional Assessment of Cancer Therapy -General (FACT-G). Results of another study presented at ASH provided support for the validity of the brief daily diary questionnaire for monitoring the impact of mucositis on health-related quality of life.5 Mouth and throat soreness (MTS) was the primary QOL endpoint from the daily diary questionnaire, which was scored from 0 (no soreness) to 4 (extreme soreness).

Function and physical well-being were significantly improved in the palifermin group, which accounts for 2 out of 4 domains of the FACT-G. MTS was significantly improved in the palifermin group relative to placebo (see table 3). The daily diary also showed improvements in swallowing, eating, drinking, talking, and sleeping with palifermin.⁸

Table 3 FACT-G scores for palifermin and placebo

Two distinct methods were utilized to determine clinical relevance of mouth and throat soreness. Using method 1, a clinically meaningful change was defined as the mean change in MTS score on the day that the patient’s World Health Organization (WHO) score transitioned from stage 3 to stage 2. Using method 2, a clinically meaningful difference was a change in score greater than half of a standard deviation, which is consistent with proposals in the published literature. The observed difference in MTS between palifermin-treated patients and placebo-treated patients was 0.5, double the effect estimated as clinically meaningful using both methods.

In conclusion, the presenting researcher noted that MTS predicted WHO grade by 1-2 days. Thus, patient perception of mucositis may be more important than physician measures. High WHO grades and subsequent impact on quality of life may be prevented if treatment is initiated on the basis of patient reported symptoms.

Ethyol®

Two studies of Ethyol® in patients receiving stem cell transplantation (SCT) showed protective affects. One demonstrated a reduction in mucosal damage in patients with high-risk or advanced stage acute leukemia receiving allogeneic SCT and the second demonstrated a reduction in GI toxicity in myeloma patients receiving autologous SCT. However, preliminary results of an ongoing Brazilian trial indicate that Ethyol® did not produce protective affects when used with high-dose cyclophosphamide.

A small trial presented by researchers from Korea, showed that the administration of Ethyol® was well tolerated and can reduce mucosal damage and decrease the incidence of severe acute GVHD induced by the intensified conditioning for allogeneic SCT.This study involved 43 adult patients who had either advanced acute leukemia or were in complete remission and had poor cytogenetics. Patients were randomized to receive intensified conditioning for allogeneic SCT comprised of TBI, Ara-C, and melpharan (TAM). Ethyol® was administered prior to each treatment according to the following schedule:

• 15 min IV infusion 30 minutes before melphalan administration,
• 10 min IV infusion 15 min before Ara-C administration,
• 3 min IV infusion 15 min before TBI.

Ethyol® pretreatment significantly shortened time to neutrophil recovery, and significantly reduced the incidence and severity of severe diarrhea (7 days), but did not affect the incidence of grade III/IV oral mucositis. (see table 4).

Table 4 Effect of Ethyol® on efficacy measures

There was a trend toward improved survival, but this was not significant. Reduced incidence for GVHD was significant for grade I/II but not for grade III/IV, overall acute GVHD, or chronic GVHD.⁹

GI toxicity: Results of a study presented by the Australasian Leukaemia and Lymphoma Group (ALLG) suggest that Ethyol® effectively reduces the gastro-intestinal toxicity of high-dose melphalan in myeloma patients undergoing autologous stem cell transplatation (autoSCT). The 90 patients in this study were randomized to high-dose melphalan (200mg/m2) and autoSCT with or without Ethyol® (910 mg/m2 as a rapid IV infusion). All patients received filgrastim 5 micro-g/kg daily from day +1 until neutrophil recovery and a standardized anti-microbial prophylaxis regimen.Ethyol® pre-treatment resulted in a significant reduction in severe mucositis, 12% versus 33% (P=0.02). However, there was little difference the following endpoints:

• Median time to neutrophil and platelet recovery following ASCT
• Median number of red blood cell and platelet units transfused
• Median number of febrile days
• Requirements for non-prophylactic intravenous antibiotics (5 days for Ethyol® vs. 6 days for control)
• Narcotic and parenteral nutrition requirements
• While disease response appeared to be better in the Ethyol® group, there is also no statistically significant difference between the Ethyol® and control groups for either progression-free or overall survival (median follow-up 35 months, see table 5).¹⁰
  

Table 5 Effect of Ethyol® in myeloma patients undergoing autologous stem cell transplatation

Ethyol® with high-dose cyclophosphamide: Preliminary results of an ongoing trial in Brazil did not show differences in the incidence and severity of mucositis between patients who received and those who did not receive Ethyol® before high dose cyclophosphamide.

Patients with various hematological malignancies (see table 6) were randomized to receive or not receive Ethyol® (740mg/m ) before first and fifth cyclophosfamide infusion. Biopsy of the oral mucosa and minor salivary gland biopsy taken five days after high-dose cyclophosphamide and analyzed according to Sonis (1999) showed “normal” histopathology for both groups. WHO scores and ECOG performance status were similar for both groups.¹¹

Table 4 Effect of Ethyol® on efficacy measures

Triclosan Oral Solution

EN 3274 is an investigational drug which is an oral rinse comprised of 0.1% triclosan. In a phase III trial involving 355 patients, EN 3274 did not meet its primary endpoint of preventing oral mucositis when administered prior to autologous bone marrow or peripheral stem cell transplant therapy.

Recent pharmacokinetic data presented at ASH did demonstrate a favorable safety profile with active ulcers. This multicenter, U.S. study involved 9 adult and 8 pediatric patients with mucositis. Free triclosan from EN3247 was unmeasurable suggesting that EN3247 is unlikely to induce systemic effects. Based on these results, the researchers suggest that EN3247 may still be a candidate in the prevention of oral mucositis.¹²

Conclusions

Research continues to highlight mucositis as a significant side effect in terms of impact on quality of life and affect on administration of optimal treatment. However, treatment for mucositis is still an unmet need. Palifermin appears to be a promising approach to the prevention of mucositis. Ethyol® is proven in the treatment of xerostomia and continues to be investigated for the treatment of mucositis. Results presented at ASH 2003 suggest that it may be promising for patients undergoing SCT, but may not protect against high-dose cyclophosphamide. Further research is necessary to determine which situations Ethyol® may be effective.

References 

1. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998;34:39-43.

2. Bellm LA, Epstein JB, Rose-Ped A, et al. Patient Reports of Complications of Bone Marrow Transplantation. Support Care Cancer 2000;8:33-39.

3. Sonis ST, Oster G, Fuchs H. Oral Mucositis and the Clinical Economic Outcomes of Hematopoietic Stem-Cell Transplantation. J Clin Oncol 2001;19:2201-2205.

4. Goldberg SL, Chang L, Selina N, Hamarman S. Patient Perceptions about Oral Mucositis: Implications for Primary/Secondary Prophylaxis Strategies. Abstract #1818.

5. Syrjala KL, Hays RD, Kallich JD, Farivar SS, et al. Impact of Oral Mucositis and Its Sequelae on Quality of Life. Proc Am Soc Hem 2003;102(11):751a, Abstract #2771.

6. Spielberger R, Emmanouilides C, Stiff P. Use of recombinant human keratinocyte growth factor (rHuKGF) can reduce severe oral mucositis in patients (pts) with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation (auto-PBPCT) after radiation-based conditioning - results of a phase 3 trial. Proceedings of the 39th meeting of the American Society of Oncology 2003;22:Abstract #3642.

7. Emmanouilides C, Spielberger R, Stiff P, Rong A, et al. Palifermin Treatment of Mucositis in Transplant Patients Reduces Health Resource Use: Phase 3 Results. Proc Am Soc Hem 2003;102(11):251a, Abstract #883.

8. Stiff P, Bensinger W, Emmanouilides C, Gentil T, et al. Treatment of Mucositis with Palifermin Improves Patient Function and Results in a Clinically Meaningful Reduction in Mouth and Throat Soreness (MTS): Phase 3 Results. Proc Am Soc Hem 2003;102(11):194a, Abstract #676.

9. Lee JW, Bae SH, Park YH, Kim YJ, et al. A Randomized Trial of Ethyol Given with TBI, Ara-C and Melphalan (TAM) and Allogeneic Stem Cell Transplantation for Patients with High-Risk or Advanced Stage of Acute Leukemia. Abstract #1716.

10. Spencer A, Horvath A, Gibson J, Prince M, et al. Ethyol Reduces High-Dose Melphalan Related Gastro-Intestinal Toxicity: Results from an Australasian Leukaemia and Lymphoma Group (ALLG) Randomised Trial. Abstract #1707.

11. Patricia F. Gasparetto, Maria Elvira P. Correa, Katia B.B. Pagnano, Fabio L. Coracin, et al. Phase III Randomized Study Comparing Ethyol Protective Effects into Oral Cavity in Patients Submitted to High Dose Cyclophosphamide (7g/m ) Preliminary Results. Abstract #5396.

12. Goldberg S, Kletzel M, Pineiro L, Pieniaszek HJ. Pharmacokinetics and Tolerability of EN3247 0.1% Triclosan Antimucositic Oral Solution in Patients with Mucositis. Phase 3 Results. Proc Am Soc Hem 2003;102(11):436b, Abstract #5471.