Introduction

The 45th Annual meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO) provided evidence through several different sessions that an optimal treatment for radiation- or chemotherapy-induced mucositis has yet to be identified. Following the FDA approval of Ethyol® and recent reports of the activity of palifermin in the management of mucositis, physicians are being presented with new tools and less toxic ways of administered cancer treatment. It is logical that ASTRO would take an interest in evaluating better ways to manage this significant side effect of radiation therapy.

This year, the ASTRO meeting included an educational session that summarized mechanisms for normal tissue damage, a panel discussion that evaluated the roles of drug therapy, IMRT, and fractionation in normal tissue protection, a satellite symposium that focused on managing mucositis with Ethyol®, and three oral abstracts on Ethyol®. Panel presenters Dr. Brizel, Dr. Eisbruch, and Dr. Ang discussed ways that the management of mucositis could be improved through drug therapy, IMRT, and fractionation, respectively. However, they also conceded that no single approach has emerged as the optimum strategy. This is in part due to the fact that it is difficult to determine which approach is “better” because current toxicity reporting is underdeveloped compared to efficacy measures, effectively limiting accurate evaluation of therapeutic benefit.

Currently, Ethyol® is the most widely studied drug therapy approach for the management of mucositis and several abstracts on Ethyol® were presented at ASTRO. However, evidence from previous trials as well as some of the recent results do not provide consistent support for the role of Ethyol® in the management of mucositis. The inconsistent results with Ethyol® were also highlighted by Dr. Brizel in the panel discussion. Results presented at ASTRO showed no decrease in the incidence or severity of esophagitis in NSCLC with Ethyol®, evidence for the tolerability of subcutaneous Ethyol®, and preclinical evidence for the radioprotective effects of Ethyol®.

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. One of the reasons that epithelial cells are more susceptible to the cytotoxic effects of radiation and chemotherapy is 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 mucositis, there is a breakdown in the saliva barrier, a disruption of epithelial cells, and a thinning of the epithelium often with ulceration. Mucositis can be severe enough to require narcotics for pain and can significantly interfere with oral nutrition resulting in weight loss. Mucositis is particularly acute 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.¹ 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.²

Mechanisms of Normal Tissue Damage from Radiation Therapy

Radiation pathology and mechanisms of normal tissue damage were the topic of an educational session at ASTRO 2003.

Radiation therapy depletes 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.3 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.

Strategies for Normal Tissue Protection in Head and Neck Cancers

A panel discussion held at ASTRO 2003 and mediated by Dr. Brizel addressed the differences between three approaches to normal tissue protection in head and neck cancers: drugs, IMRT, and fractionation. It is difficult to determine which approach is “better” because current toxicity reporting is underdeveloped compared to efficacy measures, effectively limiting accurate evaluation of therapeutic benefit. However, the presenters all concluded that progress can be made in tissue protection through each of these approaches and that further research is necessary to find the optimal solution.

Dr. Brizel presented evidence for effective normal tissue protection in head and neck cancer through drug therapy. Drugs that may be effective for the treatment of mucositis include Ethyol® and palifermin, a keratinocyte growth factor. Brizel emphasized that while both of these drugs have shown some activity in mucositis, the results have been mixed.

The pivotal trial which led to the FDA approval of Ethyol® for xerostomia only showed a shift toward lower grades of mucositis in retrospective subset analysis. Phase II trials have suggested efficacy for Ethyol® in the treatment of mucositis. However, Brizel pointed out that these retrospective subset analysis and results from small phase II trials must be considered “hypothesis generating” until confirmed in large, phase III trials.

Dr. Brizel also explained how results with palifermin are inconsistent. The results of a phase III trial evaluating palifermin in patients with non-Hodgkin’s lymphoma undergoing bone marrow transplantation (BMT) and total body irradiation (TBI) resulted in a statistically significant reduction in duration of severe oral mucositis. In this double-blind, placebo-controlled study, all patients received 12 Gy of TBI plus 60 mg/kg etoposide and 75 or 100 mg/kg cyclophosphamide as conditioning treatment before BMT. A total of 129 patients were randomized to receive placebo or palifermin 60 mg/kg/day for 3 days before TBI and/or 3 days after BMT resulting in three parallel groups: placebo pre- and post-BMT, palifermin pre-BMT only, and palifermin pre- and post-BMT. Patients who received palifermin pre- and post-BMT had a significantly lower duration of severe mucositis than those who received placebo (4 days vs. 7.7 days, p=0.001).4 However, Brizel reported that similar effects have not yet been demonstrated in patients with head and neck cancers.

Dr. Eisbruch from the University of Michigan presented evidence for IMRT in head and neck normal tissue protection. IMRT has been shown to reduce xerostomia by shielding salivary glands through unilateral treatment. However, after 2 years, xerostomia in bilaterally treated patients is not very different from those who received unilateral treatment. Problems that persist with IMRT include:

1. The submandibular salivary glands, which produce most of the basal saliva, cannot be spared when treating the head with IMRT

2. There is a need to determine the optimal dose for sparing the parotid glands. While there seems to be a steep reduction around 25-28 Gy, many investigators us different techniques and Gy, making it difficult to determine which regimen is best.

3. Research shows a weak or no correlation between saliva flow and expression of symptoms in patients,5 making efficacy difficult to measure.

Dr. Eisbruch concluded that IMRT may help to improve some but not all toxicities of head and neck radiation and that more and better clinical data regarding dose/volume effects are necessary.

Finally, Dr. Ang from the M.D. Anderson Cancer Center discussed the role of fractionation in normal tissue protection. He emphasized that while fractionation and physical blocking does protect normal tissue, more effective control will probably result from the combination of these techniques and other, newer approaches.

Ethyol®: A Cytoprotective Agent

Ethyol® is a radiation protector and the only drug that has been approved by the FDA for use in patients receiving radiation therapy for cancers of the head and neck. Clinical trials have demonstrated that Ethyol® can reduce both acute and late radiation-induced side effects. Ethyol® is effective in the prevention of xerostomia, and may prevent mucositis associated with radiation therapy.

Whether Ethyol® should be used for mucositis remains a topic of debate in the oncology community, largely because of toxicity and possible tumor protection. An article published in the Lancet Oncology in June 2003 detailed the salient issues in the debate over Ethyol®. The pro-Ethyol® position was by Dr. Brizel and the anti-Ethyol® position was by Dr. Overgaard of Denmark.

Dr. Brizel addressed both the tumor protection and toxicity issues. Regarding the former, he emphasized that “tumor protection will always be a potential risk of any cytoprotective strategy” and “in order to absolutely refute claims that anti-tumor efficacy is compromised by Ethyol®, an equivalence trial involving 1,246 patients would have to be done.” This trial is, however, highly impractical since the largest randomized head and neck trial took 8 years to enroll 1113 patients. Regarding the toxicity of Ethyol®, Brizel pointed out that while additional efforts to reduce the toxic effects associated with Ethyol® are necessary, “randomized trials of patients with head and neck and ovarian cancer provide evidence that Ethyol® has manageable toxicity.”

Dr. Overgaard asserted that there is no conclusive evidence to show that Ethyol® is selective for normal tissue and does not protect tumors. Overgaard pointed out that the Brizel study did not have enough statistical power to rule out tumor protection, a point on which the Panel that wrote the ASCO guidelines agreed.6 Furthermore, Overgaard cited two reviews that indicate “the extent of protection of normal tissue and tumor tissue in preclinical studies are of the same magnitude.”⁷

Pivotal trial of Ethyol® in head and neck cancers: The large multi-center clinical trial by Brizel and colleagues that lead to FDA approval of Ethyol® for xerostomia in head and neck cancers showed that while Ethyol® reduced the incidence or severity of xerostomia, there was no effect on the incidence, severity, or duration of oral mucositis. In this study, 300 patients with cancer of the head and neck were assigned to receive either radiation therapy combined with Ethyol® 200 mg/m2 or radiation therapy alone. The incidence of severe xerostomia for patients receiving Ethyol® was 51%, compared to 78% for patients receiving radiation therapy alone. One year following completion of radiation therapy, only 35% of patients who had received Ethyol® were still experiencing symptoms of xerostomia, whereas 57% of patients who had received radiation therapy alone were still experiencing symptoms.⁸

Phase II studies of Ethyol® for mucositis: Phase II studies have suggested that Ethyol® may prevent mucositis. However, these results can only be considered “hypothesis generating” because both studies were relatively small and they utilized a higher dose than the pivotal trial by Brizel.

Another published study that contributed to the FDA approval of Ethyol® for head and neck cancers demonstrated a significant decrease in both xerostomia and mucositis in head and neck patients treated with Ethyol® and radiochemotherapy compared to radiochemotherapy alone (see Table 1). This trial involved 50 patients who received 300 mg/m2 of Ethyol®.9

Table 1 Incidence of xerostomia and mucositis in patients with head and neck cancers

Greek researchers reported a significant reduction of pharyngeal, esophageal, and rectal mucositis in patients receiving Ethyol®. In this study, 40 patients with head and neck cancers and 40 with pelvic cancers were randomly allocated to receive or not receive subcutaneous Ethyol® 500 mg/m² 20 minutes before each dose of radiation. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in patients receiving Ethyol®. The delays in radiotherapy because of severe mucositis were significantly longer in the group of patients treated with radiation therapy alone. Ethyol® also significantly reduced the incidence of acute perineal skin and bladder toxicity.¹⁰

Ethyol® Data Presented at ASTRO

Results of Ethyol® that were presented at ASTRO showed no decrease in incidence or severity of esophagitis in NSCLC, evidence for the tolerability of subcutaneous Ethyol®, and preclinical evidence for the radioprotective effects of Ethyol®.

Ethyol® in NSCLC: Earlier this year, researchers from Greece reported that the addition of Ethyol® to radiochemotherapy for treatment of stage IIIA and IIIB NSCLC reduces the incidence of esophagitis without compromising the effectiveness of treatment.¹¹ However, at ASTRO 2003, Researchers from Germany reported that Ethyol® did not decrease the incidence or severity of esophagitis or esophagitis AUC in patients with stage II or unresected stage IIIA/B NSCLC. This study involved 243 patients with inoperable stage II and unresected stage IIIA/B NSCLC. All patients received induction paclitaxel/Paraplatin® followed by concurrent weekly paclitaxel/Paraplatin® and hyperfractionated radiation therapy. Patients were randomized to receive Ethyol® 500 mg IV once daily, four times per week to a total dose of 12,000 mg during concurrent chemo-radiotherapy or no Ethyol®. Ethyol® was administered before the morning radiation fraction in 15 patients and before the afternoon radiation fraction in 105 patients.

Median survival time was not different between the two arms (16.7 months). Incidence of acute esophagitis greater than grade 3 was slightly higher in the control arm, but not to a significant degree, 34% in the control arm and 30% in the Ethyol® arm. Time to development of esophagitis greater than grade 3 was the same for both arms.

Patient assessment showed a reduction in swallowing difficulty based on esophagitis AUC. This effect was particularly pronounced for patients younger than 65 years and females (see table 2). However, there was no difference in maximum swallowing grade.

Table 2 Esophagitis AUC from patient-based evaluation for elderly and female subgroups

There was no evidence of compromised overall survival in patients receiving Ethyol®.¹²

Tolerability of subcutaneous Ethyol®: Although not yet approved by the FDA, subcutaneous (SC) administration of Ethyol® may be preferable to IV because of easier logistics, particularly in the outpatient radiation therapy setting, and greater cost-effectiveness. A phase II study by Koukourakis and colleagues published in 2000 reported that SC Ethyol® was well-tolerated by 85% of patients, effectively reduced radiotherapy's early toxicity, and prevented delays in radiotherapy.¹³ A study reported at ASTRO 2003 also found SC Ethyol® to be well-tolerated.

This prospective, open-label, multi-center, safety study reported by researchers from Mt. Sinai Medical Center in Florida and Medimmune Oncology in Maryland was designed to identify treatment-related side effects of Ethyol® administered as a SC injection for the prevention of radiation-induced toxicities. Over 100 patients received 500 mg of Ethyol® by SC injection prior to daily radiation therapy. Four adverse events were evaluated for the occurrence and possible relationship with Ethyol®: local injection site reaction, skin rash, hypotension, and nausea/vomiting.

Thirty percent (31 events in 28 patients) of the reported adverse events being evaluated required permanent discontinuation of the study therapy, as evidenced in Table 3.

Table 3 Reasons for discontinuation of treatment with Ethyol®

The majority (78%) of the targeted adverse events were mild to moderate (grade 2 or less) and 67% (19 out of 28) of the reported serious adverse events were either not related or deemed only remotely related to the study therapy. Most of the patients (92%) did not require a change in the dose of Ethyol®. Eight patients received a lower dose of the drug throughout the study due to adverse events. Only 2 of these 8 did not increase back to the initial 500 mg dose.¹⁴

Recent preclinical findings with Ethyol®: German researchers reported at ASTRO 2003 that Ethyol® showed radioprotective effects and inter-individual differences in dose modifications in vitro and in vivo. The researchers suggested that the inter-individual might be due to different levels of reductive substances in the microenvironment of the donors.

In vitro methods involved leucocytes and freshly isolated lymphocytes from healthy volunteers with different concentrations of Ethyol® or alkaline phosphatase. For in vivo investigations, leucocytes were collected from 6 rectal cancer patients before and immediately after IV administration of 500 mg Ethyol® (no pretreatment with radiation or chemotherapy). The cells were irradiated in vitro and the DNA-damage was measured with the comet assay. The comet assay is a rapid technique for the evaluation of DNA damage and subsequent measurement of radioprotection at the level of single cells. Intra-individual comparisons were done to evaluate the effect with and without Ethyol® after irradiation and independent of the concentration of alkaline phosphatase.

Results showed that the prodrug of Ethyol® (WR-2721) had no radioprotective potential in vitro. Activation of Ethyol® in vitro, required at lease 1 U/ml of alkaline phosphatase. Higher concentrations of the enzyme did not increase the efficacy. After in vivo administration, a significant radioprotection was detected in all 6 investigated rectal cancer patients. The researchers reported that “a total dose of 500 mg Ethyol® IV seems to yield an adequate radioprotection which was only marginally improved by extremely high concentrations of amifostine in vitro.”¹⁵

The researchers also pointed out that “it remains unclear whether the serum concentration of alkaline phosphates and endothel-bound enzymes are sufficient to activate Ethyol® in-vivo; this would reduce the selective protection of normal tissues due to activation of the prodrug in the vessels.” Since serum alkaline phosphatase can be elevated by other conditions that increase bone remodeling activity, it will be important to answer this question with rigorous research.

Acupuncture for Xerostomia

An educational session held at ASTRO 2003 on complementary medicine in radiation oncology practice evaluated the evidence for acupuncture in the treatment of xerostomia. Acupuncture has been shown to increase parotid gland blood flow, release neuropeptides involved in salivary gland function, and may stimulate tissue regeneration in parotid glands damaged by radiotherapy. In a randomized study of acupuncture, 38 patients with radiation-induced xerostomia were randomized to classical accupunture (20) or superficial acupuncture as placebo (18). Among those patients who had had all their salivary glands irradiated, 50% in both groups showed increased salivary flow rates (>20%) by the end of the observation period of 1 year.¹⁶

Stephen Sagar from the Hamilton Regional Cancer Center in Ontario discussed a study that used an acupuncture-like transcutaneous nerve stimulation method that does not use invasive needles, called Codetron, to treat radiation-induced xerostomia. Patients with symptomatic xerostomia after radical radiotherapy for head and neck cancer but with evidence of residual salivary function were recruited into the study. Two 6-week courses of Codetron treatment of acupuncture points were given with a 2-week break between each course. For all patients, the increase in mean basal and citric acid-primed whole saliva production at 3 and 6 months after treatment completion was statistically significant (p<0.001 and p<0.0001, respectively). A prospective, randomized phase III trial with appropriate controls is being planned.¹⁷

Peter A.S. Johnstone from Emory University School of Medicine referenced a 2001 study which indicated that acupuncture reduces xerostomia in some patients otherwise refractory to best current management. In this study, 18 patients with xerostomia refractory to pilocarpine therapy after radiation for head and neck cancers were offered acupuncture as palliation. Nine patients had benefit of over 10 points on the xerostomia inventory.¹⁸

Conclusion

An optimal treatment for radiation or chemotherapy-induced mucositis has yet to be identified. Protection of normal tissue is possible through drug therapy, IMRT, and different fractionation regimens, yet no one approach has proven optimal. Early results with palifermin suggest that this compound may provide significant protection, but research with this agent is still ongoing. While there have been many published studies investigating Ethyol® and some indicate that it may be effective for preventing mucositis, definitive results have not been produced yet. Studies presented at ASTRO 2003 indicate that Ethyol® did not reduce mucositis in patients with NSCLC, but it did provide radioprotective effects in vitro and in vivo, and subcutaneous administration was reported to be tolerable. Until a clearly superior method for controlling mucositis emerges, the best approach for the treatment patients with radiation-induced oral side effects may be supportive care for xerostomia. Researchers presenting on CAM methods for radiation-induced side effects provided study data that suggests acupuncture may also reduce xerostomia in some patients.

References

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

2. 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.

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

4. Spielberger RT, Stiff P, Emmanouilides C, Yanovich S, et al. Efficacy of Recombinant Human Keratinocyte Growth Factor (rHuKGF) in Reducing Mucositis in Patients with Hematologic Malignancies Undergoing Autologous Peripheral Blood Progenitor Cell Transplantation (auto-PBPCT) After Radiation-Based Conditioning- Results of a Phase 2 Trial. Proceedings of the 39th meeting of the American Society of Oncology 2003;22: Abstract #25.

5. Logemann JA, Pauloski BR, Rademaker AW, Lazarus CL, et al. Xerostomia: 12-Month changes in saliva production and its relationship to perception and performance of swallow function, oral intake, and diet after chemoradiation. Head and Neck 2003;25:432-437.

6. Reflections and Reactions. Amifostine and chemoradiation therapy: ASCO responds. The Lancet Oncology 2003 4:593.

7. Brizel, DM, Overgaard J. Debate: Does amifostine have a role in chemoradiation treatment? The Lancet Oncology 2003;4:378-381.

8. 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.

9. Antonadou D, Pepelassi M, Synodinou M, Puglisi M, Throuvalas N, et al. Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head and neck cancer. Int J Radiat Oncol Biol Phys. 2002;52(3):739-47.

10. Koukourakis MI, Kyrias G, Kakolyris S, et al. Subcutaneous Administration of Amifostine During Fractionated Radiotherapy: A Randomized Phase II Study. J Clin Oncol 2000;18: 2226-2233.

11. 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.

12. Werner-Wasik M, Scott C, Movsas B, Langer C, et al. Amifostine as mucosal protectant in patients with locally advanced non-small cell lung cancer (NSCLC) receiving intensive chemotherapy and thoracic radiotherapy (RT): Results of the Radiation Therapy Oncology Group (RTOG) 98-01 Study. Proceedings from the 45th American Society of Therapeutic Radiation Oncologists meeting held in Salt Lake City UT, October 19-22, 2003 (Abstract #152).

13. Koukourakis MI, Kyrias G, Kakolyris S, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 2000;18: 2226-2233.

14. Samuels MA, Chico IM, Fullmer K, Hirsch RL, et al. Ongoing prospective multi-center safety study of subcutaneous cytoprotectant amifostine. Proceedings from the 45th American Society of Therapeutic Radiation Oncologists meeting held in Salt Lake City UT, October 19-22, 2003 (Abstract #166).

15. Mueller AC, Beyer C, Pigorsch SU, Haensgen G, et al. Radioprotective Effects of Amifostine In-Vivo and In-Vitro. Proceedings from the 45th American Society of Therapeutic Radiation Oncologists meeting held in Salt Lake City UT, October 19-22, 2003 (Abstract #62).

16. Blom M, Dawidson I, Fernberg JO, Johnson G, et al. Acupuncture treatment of patients with radiation-induced xerostomia. Eur J Cancer B Oral Oncol. 1996 May;32B(3):182-90

17. Wong RK, Jones GW, Sagar SM, Babjak AF, et al. A Phase I-II study in the use of acupuncture-like transcutaneous nerve stimulation in the treatment of radiation-induced xerostomia in head-and-neck cancer patients treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):472-80.

18. Johnstone PA, Peng YP, May BC, Inouye Ws, et al. Acupuncture for pilocarpine-resistnat xerostomia following radiotherapy for head and neck malignancies. Int J Radiat Oncol Biol Phys. 2001 Jun 1;50:353-7.