By Jenny Maxon, RN. January 2007

Introduction

Oncology nurses are at the forefront of delivering the bulk of the treatment and care required by cancer patients. Among their many responsibilities, oncology nurses play a critical role in the prevention, identification, and management of side effects, including oral mucositis.

Oral mucositis (OM) is one of the most debilitating and common side effects of treatment for cancer, particularly in patients undergoing high doses of therapy prior to stem cell transplantation (SCT). The overall impact of OM is enormous for patients, caregivers, and the medical system, as it can be directly related to reduced overall survival in patients, as well as reduced quality of life and increased medical costs.¹,²,³,⁴,⁵,⁶

Oral 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. In patients with OM, there is a breakdown in the saliva barrier, a disruption of epithelial cells, and thinning of the epithelium, often with ulceration.

Until recently, OM represented a significant unmet medical need in the oncology setting, with its enormous impact and no proven therapeutic approach to reduce or prevent its occurrence or severity. However, the past year has brought significant advances in the understanding and management of OM. The approval of new agents, such as Kepivance™ (palifermin), for the management of OM represents a major breakthrough for patients, as well as their doctors and families.⁷ The prevention or reduction of OM with agents such as Kepivance™ improves quality of life and reduces the overall medical costs of stem cell transplantation.

Recent advances in the management of oral mucositis include:

• Management of OM
• Reducing the Impact of OM
• New Methods of Assessment for OM

Managing Oral Mucositis

Prevention Versus Management: The best strategy for managing OM would be to prevent it from occurring altogether. Preventing OM and the resulting downstream sequelae may ultimately lead to a significantly improved quality of life, reduced medical costs, and perhaps most importantly, optimal long-term survival. During 2004, the results from clinical trials evaluating several novel anti-mucositis agents were presented.⁸,⁹,¹⁰,¹¹,¹²,¹³ The results from clinical trials evaluating Kepivance™, a novel keratinocyte growth factor led to its approval by the Food and Drug Administration as the first agent for the prevention of OM.

Kepivance™: Kepivance™ is a recombinant keratinocyte growth factor that increases cellular proliferation, mediates epithelial cell repair, reduces TNF-alpha and IFN-gamma, decreases epithelial cell apoptosis, and exerts an anti-apoptotic effect via Bcl-2 up-regulation. All of these properties aid in the prevention and healing of oral mucositis. Kepivance™ is currently approved for the treatment and prevention of severe OM in patients with hematologic cancers undergoing high-dose chemotherapy with or without radiation prior to SCT.

The pivotal clinical trial that led to the approval of Kepivance™ evaluated 212 patients with hematological malignancies treated with a conditioning regimen of cyclophosphamide, etoposide, and total body irradiation (CyTBIVP16), a standard regimen used to treat lymphoid malignancies.⁸,⁹ Patients were randomly allocated to receive placebo or Kepivance™ 60 micrograms/kg for each of 3 days prior to initiation of cytotoxic therapy and 3 days following stem cell infusion. Mucositis was graded using the WHO scale.¹⁴

Kepivance™ reduced the duration and severity of OM and led to decreased resource utilization and improved patient QOL. (See Table 1) Grade 3-4 OM developed in 98% of patients in the placebo group, compared to 63% of the patients treated with Kepivance™. Grade 3-4 OM lasted an average of 9 days in patients treated with placebo, compared to an average of 6 days in patients treated with Kepivance™. Notably, Kepivance™ had the greatest impact on severe OM; grade 4 OM occurred in 62% of the placebo group and lasted an average of 6 days, compared to the Kepivance™ group, in which only 20% of patients developed grade 4 OM lasting an average of 2 days. Only 31% of patients who received Kepivance™ received parenteral feeding, compared to 55% of patients who received placebo.

The overall quantity and duration of narcotic use for pain relief was significantly less for patients receiving Kepivance™. In addition, febrile neutropenia occurred in 92% of the placebo group, compared to 75% in the Kepivance™ group. Importantly, there were no adverse effects on engraftment, relapses or the development of secondary leukemia. Reported adverse events included skin rash, pruritis, erythema, cough, edema, taste alteration, white film coating mouth or tongue, rhinitis, arthralgia, sensation of tongue thickness, perianal pain, numbness, taste loss and paresthesia. However, these side effects were reversible and did not interfere with treatment.

Table 1: Primary Endpoints of Study Comparing Kepivance™ and Placebo

Quality of life (QOL) was also assessed in this trial using a categorical scale (Likert scale), with patients reporting a 38% reduction in median scores of mouth and throat soreness. Other patient-reported sequelae of mucositis indicated significantly higher scores for physical and functional well-being in those treated with Kepivance™ compared to placebo, including the ability to drink, eat, talk and sleep.

AES-14: Clinical data was reported on another novel anti-mucositis agent, AES-14 (Saforis ™). AES-14 is L-glutamine delivered in a proprietary base that provides delivery enhancement directly to the oral mucosa. L-glutamine is thought to reduce mucosal injury caused by chemotherapy and radiation, as it is a primary glycolytic nutrient for mucosal epithelial cells and lymphocytes, as well as an important shuttle of nitrogen between tissues.¹⁵ At the 2004 ASCO Annual Meeting, researchers presented results of a randomized, double-blind, placebo-controlled, crossover, multi-center trial to determine the efficacy of AES-14 in reducing the severity and duration of OM.¹⁰ In this trial, 326 breast cancer patients received an anthracycline-based chemotherapy treatment regimen along with AES-14 or placebo over two subsequent crossover cycles. AES-14 reduced the incidence of clinically significant OM by 22% compared to the placebo group. Unexpectedly, patients who crossed over from AES-14 to placebo had a 36% lower incidence of OM, suggesting a carryover benefit. The pharmacokinetic results of AES-14 in healthy volunteers were also presented, indicating no appreciable differences between the AES-14 and L-glutamine plasma levels or ammonia levels (the latter is a metabolite of L-glutamine), further supporting the safety of this agent.

At the 2004 San Antonio Breast Cancer Symposium (SABCS), AES-14 was evaluated in a larger phase III, randomized, placebo-controlled trial including 2,084 women with breast cancer undergoing anthracycline and cyclophosphamide-based chemotherapy.¹¹ Patients who developed grades 2-3 OM (based on the WHO and OMAS scale) were randomized to AES-14 or placebo. The duration of overall OM was reduced by 29% in patients treated with AES-14 compared to placebo (p=0.0479). The incidence of severe OM was reduced by 80% in patients treated with AES-14 compared to placebo (p=0.0136). The safety of AES-14 was comparable to that of placebo. AES-14 is now in the latter phases of clinical trials for the evaluation of OM in various settings.

Ethyol®: Ethyol® (amifostine) is a radiation protector and the only drug that has been approved by the FDA for this use in patients receiving radiation therapy for cancers of the head and neck. Previous clinical trials have demonstrated that Ethyol® can reduce both acute and late radiation-induced side effects.¹⁶,¹⁷

At the 2004 ASH meeting, researchers reported the results from a retrospective study in which patients with multiple myeloma were treated with a regimen consisting of vincristine, doxorubicin and dexamethasone (VAD), high-dose melphalan and an autologous SCT.¹² One group of patients received Ethyol® prior to transplant, while the other group of patients did not. Opioid analgesics were necessary in only 20% of patients treated with Ethyol®, compared to 69% of patients not treated with Ethyol®. Furthermore, parenteral nutrition was necessary in only 10% of patients treated with Ethyol®, compared with 50% of patients not treated with Ethyol®. Importantly, there was no statistical difference in disease response between the two groups of patient, suggesting that Ethyol® did not protect cancer cells against the anti-tumor activity of treatment. Future randomized, placebo-controlled studies will be necessary to determine the role of Ethyol® in the management of OM.

Mucotrol™ (MF5232): The oral hydrogel wafer, Mucotrol™ (MF5232), was recently approved as a medical device for the treatment or management of pain associated with OM.¹³ Mucotrol™ includes extracts from licorice root and aloe vera and dissolves in the mouth of a patient. The clinical trial prompting FDA approval was a randomized, placebo-controlled trial that included 30 patients who were undergoing treatment for cancer and had developed OM. Overall, patients benefited from Mucotrol™ compared to the placebo group. Future clinical trials directly comparing Mucotrol™ to other pain relievers for mucositis are necessary to determine the true clinical benefit of Mucotrol™ in cancer patients with OM.

Impact of Oral Mucositis

The impact of OM is far-reaching for patients, caregivers and the medical system. Oral mucositis results in severe physical consequences for patients, impacting their quality of life and resulting in life-threatening complications. Ultimately, the development of OM not only impacts long-term outcomes, but also leads to a significant financial and emotional burden for patients and the medical system.³,⁴,⁵,⁶

Physical Impact: Oral mucositis is known to cause severe pain, often leading to the need for narcotics, as well as significantly reducing the ability of patients to chew, swallow, or talk. This can lead to dehydration, malnutrition, anorexia, cachexia, and tube feeding or TPN. This, in turn, prolongs hospitalization, reduces quality of life and increases medical costs. Patients often become depressed or agitated, as well as fatigued, when suffering from OM and its sequelae. In addition, ulceration with OM can lead to systemic infection with downstream effects including anti-infective use, a delay in treatment, hospitalization, increased medical costs, and ultimately, the potential for suboptimal long-term survival.⁵,⁶ Oral mucositis is also recognized as a key dose-limiting toxicity in cancer treatment that includes mucositis-inducing agents.

Financial Impact: In addition to the side effects caused by OM and the negative consequences on long-term outcomes in patients who suffer from severe OM, the financial burden accrued in medical expenses that are directly attributable to OM can be significant. Physicians have established that severe ulcerative mucositis may increase costs by as much as $43,000 compared to less severe mucositis.³ Results from an analysis of the recent phase 3 trials comparing Kepivance™ to placebo were presented at the 2004 meeting of the American Society of Hematology (ASH). Daily hospital rates for patients undergoing autologous stem cell transplants including total body irradiation were reported to be $2,702.⁴ The downstream costs of OM (bacteremia, febrile neutropenia, intubation, total parenteral nutrition) raised the cost to more than $5,000 per day. Overall, the mean cost per patient was $61,160 for patients who received Kepivance™, compared to $76,104 for those who received placebo. Factors such as hospitalization, anti-infective use, TPN, narcotic use, or other associated effects of OM contribute to the mounting medical costs for patients and the healthcare system.

Assessing Oral Mucositis

In order to manage OM, it is important to assess it properly. The assessment of OM can fall into 3 categories:

• Understanding the Stages of OM
• Grading OM
• Risk Assessment for OM

Stages of OM: Some researchers believe that better treatments can be developed by understanding the underlying mechanisms of OM. Recently, researchers have developed a 5-stage model that is an overview of the process of mucositis.¹⁸(Table 2)

Table 2: Stages of OM

Several of the phases occur simultaneously and, depending on the type of therapy, can be repeated.

Grading OM: Consistent grading is very important for evaluating the impact of intervention in OM. Historically, the most commonly used grading systems were the WHO grading system (See Table 3) and the NCI-CTC grading system.¹⁴,¹⁹ At present, most researchers are still utilizing the WHO grading system and a consensus is trying to be reached to determine the most accurate way in which to grade OM. Both the NCI and WHO have separate grading systems for conventional-dose chemotherapy, high-dose chemotherapy with stem cell support, and radiation therapy. There are also specific grading systems used by various radiation oncology groups. The main criticism of these assessment scales is that combinations of signs, symptoms, and functional changes observed can be confounding and interfere with accurate grading.

Table 3: WHO Grading System

Because of the perceived weaknesses of existing OM grading systems, a new international grading system was established called the Oral Mucositis Assessment Scale (OMAS)(See Table 4).²⁰OMAS measures ulceration on a 0-3 scale, erythema on a 0-2 scale, and evaluates pain, difficulty swallowing, and impact on food intake. For studies of severe OM, food intake evaluation may be the most valuable assessment tool and is graded as normal, only soft solid foods, or no foods or liquids. The major criticism of the OMAS grading system is that it requires more examiner experience and time than the NCI-CTC and WHO grading systems. There are, however, other more detailed grading systems than the OMAS scale, which at present are used specifically for research purposes.²¹

Table 4: Oral Mucositis Assessment Scale (OMAS)

Risk Assessment: Thus far, several variables have been noted that appear to place a patient at a higher risk of OM than others. Currently, the most important known risk factors for OM are the specifics of the cancer therapy, such as the dose and schedule of radiation and/or chemotherapy. All chemotherapy drugs can cause OM; however, specific chemotherapy agents, as well as the dose and schedule of the drug or regimen, can increase the risk of developing OM. Oral mucositis is particularly severe in patients with head and neck cancer receiving radiation and chemotherapy and almost all patients receiving an autologous or allogeneic stem cell transplant. 3 Once OM is established, management is focused on treating local infection, particularly with candida albicans and herpes simplex since there are specific and active treatments for these disorders, reducing pain, and preventing its progression.

Patients undergoing high-dose cytotoxic therapy and stem cell support represent a group of patients that are in clear need of preventive measures of OM, as it is estimated that nearly all patients who undergo high-dose chemotherapy and/or high-dose radiation prior to a stem cell or bone marrow transplantation will develop OM.⁸ The high doses of therapy typically involved in stem cell transplant procedures are particularly damaging to the mucosal lining of the mouth. In this patient population, maintaining therapeutic dose levels of treatment is a crucial component to optimal outcomes, necessitating a medical need to reduce the incidence or severity of OM so that treatment doses do not need to be reduced or delayed. Furthermore, with the use of such myelosuppressive therapy, patients are placed at an increased risk for infection, coupled with a reduced ability to fight life-threatening infection. These issues stress the fact that it is imperative that OM be prevented if possible in patients undergoing high-dose therapeutic regimens. Results from a retrospective study indicated that transplant patients with severe OM had a four-fold increase in mortality over their counterparts.⁵ Furthermore, an additional retrospective analysis of patient complaints following stem cell transplantation revealed that mouth sores were the single most debilitating side effect from treatment.[6] Results using the new OMAS revealed that transplant patients with severe OM had an increased incidence and duration of fever and infection, as well as more use of total parenteral nutrition (TPN).⁴ Kepivance™ is specifically indicated for this group of patients and it is administered 3 days prior to cytotoxic therapy in an attempt to completely prevent OM altogether.

Michelet, et al conducted a large retrospective study of 633 autologous PBSC transplant patients that was designed to determine prognostic factors for ulcerative oral mucositis (UOM).²² Mulitivariate logistic regression analysis showed that the most important risk for OM was conditioning regimens and the most significant risk for UOM was delayed neutrophil recovery. The contribution of neutrophil engraftment is less clear and requires further study. It may well be linked with an inability to “protect” tissues once they become “ulcerated” and bacterial influences are possible.

Numerous factors, including pre-existing oral infections and trauma/irritation, appear to contribute to OM as well (as opposed to being causative). Patient gender and age are suspected to play a role in susceptibility of developing OM and these roles continue to be evaluated in clinical studies. Researchers from the Mayo Clinic and Mayo Foundation performed a meta-analysis on 402 men and 329 women who received 5-FU chemotherapy and found that women reported OM both more often and with greater severity than did men, suggesting that female gender may be a consideration when establishing risk stratification for OM.²³ There is also growing evidence that genetics plays a role in patient susceptibility to OM resulting from certain types of chemotherapy.²⁴ Additionally, genetic variance relative to production of inflammatory cytokines will likely be shown to be important.

Results presented at the 2004 meeting of the American Society of Hematology (ASH) indicated that levels of C-reactive protein (CRP) allow for early identification of patients who are at an increased risk of developing OM after melphalan and autologous stem cell transplantation for multiple myeloma.²⁵ These results will be validated in a prospective trial. Results from another trial presented at 2004 ASH indicated that graft-versus-host-disease (GVHD) prophylaxis with sirolimus/tacrolimus (ST) appears to decrease the risk of OM compared with tacrolimus/methotrexate (TM) in patients undergoing HLA-matched sibling allogeneic transplants after cyclophosphamide-total body irradiation conditioning.²⁶ Patients treated with prophylaxis of ST had significantly reduced severe OM, which led to reduction in TPN use, as well as a reduced duration of TPN use, a reduction of narcotic use in the hospital, and a reduced time from transplant to discharge. Results from yet another clinical trial presented at 2004 ASH evaluating possible patient or treatment variables with an increased risk of developing OM revealed that patients undergoing high melphalan doses based on body surface area (BSA) measurements are at an increased risk of developing OM if pre-transplant variables include low creatinine clearance (CrCl), high lactate dehydrogenase (LDH) levels, and/or low pulmonary diffusion capacity (DLCO).²⁷

Conclusion

Oral mucositis is a common and debilitating side effect in all patients undergoing stem cell transplantation and many other patients undergoing cancer treatment. The severity of OM ranges from a slight irritation of the mucosal lining to severe ulceration and the downstream complications associated with its development can have enormous consequences on patient quality of life, delivery of care, medical costs, and ultimately, long-term outcomes. The approval of Kepivance™ provides caregivers with a new tool to help reduce the severity and duration of OM in susceptible patients. Research is ongoing to determine the optimal way to use Kepivance™ and other novel agents in various settings with the hope of further reducing the severity and duration of OM as a side effect of cancer treatment. Ultimately, further research and understanding of OM will help establish reliable methods for preventing and managing this complication, which will have a major impact on patient well-being and an improvement in the outcomes of cancer treatment.

References:

¹ 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. Blood. 2003;102(11):251a, Abstract #883.

² 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. Blood. 2003;102(11):751a, Abstract #2771.

³ Elting L, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003; 98:1531-1539.

⁴ Elting L, Shih Y, Stiff W, et al. Palifermin reduces estimated downstream costs of autologous stem cell transplant (SCT): Analysis of Phase 3 Trial results. Proc Am Soc Hem. Blood. 2004: Abstract #2191.

⁵ 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.

⁶ Bellm LA, Epstein JB, Rose-Ped A, et al. Patient Reports of Complications of Bone Marrow Transplantation. Support Care Cancer. 2000;8:33-39.

⁷ Kepivance Prescribing Information. Available at:http://www.kepivance.com/pdf/pi.pdf. Accessed December 2004

⁸ Amgen. FDA Approves Kepivance for Severe Oral Mucositis in Cancer Patients Undergoing Bone Marrow Transplant. Available at:http://www.amgen.com/news/viewPR.jsp?id=655220. Accessed December 2004.

⁹ Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. New England Journal of Medicine. 2004; 351:2590-2598

¹⁰ Peterson DE, Petit RG. Phase III study: AES-14 in patients at risk for mucositis secondary to anthracycline-based chemotherapy. Proc Am Soc Clin Oncol. 2004;22:2917, Abstract #8008.

¹¹ Peterson D, Petit R. AES-14 (Saforis™) treatment reduces the severity and duration of oral mucositis in three common breast cancer chemotherapy regimens. Proceedings from the 2004 annual San Antonio Breast Cancer Symposium. December 2004. Abstract #6029.

¹² Italiano A, Chamorey E, Foa C, et al. Amifostine can reduce oral mucositis after high-dose melphalan conditioning in patients with multiple myeloma: a retrospective study. Proceedings from the 2004 annual meeting of the American Society of Hematology. December 2004. Abstract #5022.

¹³ Food and Drug Administration. Available at:http://www.fda.gov/cdrh/pdf4/k042400.pdf. Accessed December 2004.

¹⁴ World Health Organization. Handbook for reporting results of cancer treatment. Geneva: WHO 1979:15-22 .

¹⁵ Petit R, Shinal E, French C. AES-14 facilitates rapid intracellular transport of high levels of L-Glutamine in mucosal epithelial cells. Proceedings from the 2000 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #2410

¹⁶ Antonadou D, Throuvalas N, Petridis A, et al. Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small cell lung cancer. International Journal of Radiation Oncology Biology Physics. 2003;57:402-408.

¹⁷ 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.

¹⁸ Sonis ST. A biological approach to mucositis. J Supportive Onc. 2004;2:21-36.

¹⁹ Trotti A, Byhardt R, Stetz J, et al, Common Toxicity Criteria: Version 2.0. An Improved Reference for Grading the Acute Effects of Cancer Treatment: Impact on Radiotherapy. Int J Radiat Oncolo Biol Phys. 2000;47:13-47.http://ctep.cancer.gov/forms/CTCv20 4-30-992.pdf

²⁰ Sonis ST, Eilers JP, Epstein JB, et al. Validation of a new scoring system for assessment of clinical trial research of oral mucositis induced by validation or chemotherapy: mucositis study group. Cancer. 1999;85:2103-13.

²¹ Schubert MM, Williams BE, Lloid ME, et al. Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer. 1992;69:2469-2477.

²² Michelet M, Desmery P, Juni M, et al. Prognostic factors for high-dose chemotherapy-induced oral mucositis with autologous peripheral blood stem-cell transplant (APBSCT): a single institutional experience. Supportive Care in Cancer, 12:390. MASCC/ISOO 16th International Symposium Supportive Care in Cancer. 2004. Abstract #76.

²³ Sloan JA, Loprinzi CL, Novotny PJ. Sex Differences in Fluorouracil-Induced Stomatitis. J Clin Oncol. 2000;18:412.

²⁴ Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, Ariail KS, Keener CL, Li s, Liu H, Farin FM, Potter JD. Pharmacogenetics of methotrexate: Toxicity among marrow transplantation patients is modified by the 5,10-methylene-tetrahydrofolate reductase C677T polymorphism. Blood. 2001;98 (1): 231-234.

²⁵ Anaissie E, Grazziutti M, Fassas A, et al. Daily C-Reactive protein (CRP) levels allow early identification of patients with severe complications after melphalan (MEL) and autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Proceedings from the 2004 annual meeting of the American Society of Hematology. December 2004. Abstract #5040.

²⁶ Cutler C, Shuli L, Haesook K, et al. Oral mucositis incidence and severity after methotrexate and non-methotrexate containing GVHD prophylaxis regimens. Proceedings from the 2004 annual meeting of the American Society of Hematology. December 2004. Abstract #351.

²⁷ Anaissie E, Grazziutti M, Li D, et al. The conventional body surface area (BSA) method of calculating the dose of melphalan (MEL) results in widely variable MEL exposure and mucositis risk in myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). Proceedings from the 2004 annual meeting of the American Society of Hematology. December 2004. Abstract #1159.