Mucositis as a Complication of Radiation Therapy in Nasopharyngeal Carcinoma: A Systematic Review

Christine M. D’Aguillo, BA1 · Qasim Husain, MD1 · Chirag Gordhan, BS1 · Soly Baredes, MD, FACS1,2 · Jean Anderson Eloy, MD, FACS1,2,3

[1] Department of Otolaryngology—Head and Neck Surgery, Rutgers New Jersey Medical School (NJMS), Newark, NJ · [2] Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey, Rutgers NJMS, Newark, NJ · [3] Department of Neurological Surgery, Rutgers NJMS, Newark, NJ

Abstract

OBJECTIVE: 1) Review the current literature on mucositis in patients with nasopharyngeal carcinoma (NPC) treated with radiation therapy. 2) Describe the rate of mucositis, grade, sequelae, and dose-limiting mucositis toxicity during radiation therapy for NPC. DATA SOURCES: PubMed database. METHODS: A systematic review of studies published regarding the treatment of NPC from 1990 to 2012 was conducted. A PubMed search for articles using the search terms “mucositis”, “radiation therapy”, and “nasopharyngeal carcinoma”, along with a review of the articles’ bibliographies was performed. Criteria for inclusion were clinical studies that reported radiation therapy as a treatment modality, and mucositis as a complication. Demographics, treatment type, treatment order, mucositis grade, percentage of mucositis sufferers, mucositis sequelae, and dose-limiting mucositis toxicity were recorded. RESULTS: A total of 65 journal articles were included representing 7876 patients. Radiation therapy alone was used in treatment for NPC in 2845 patients, while some combination of radiation therapy and chemotherapy was used in 5031 patients. Grade 1 or higher mucositis was reported in 4798 patients, and 2142 patients reported Grade 3 or higher mucositis. Overall, 69.7% of patients treated for NPC developed some level of mucositis. Of the 14 articles that specifically reported dose-limiting toxicity, 95 out of a total of 890 patients (10.6%) stopped treatment due to intolerable mucositis. Of the 14 articles that specifically reported alternate feeding requirements, 104 out of a total of 1517 patients (6.9%) required percutaneous endoscopic gastrostomy or nasogastric tube placement. CONCLUSION: This study examines mucositis as a complication of radiation therapy specifically for NPC. Mucositis is a common and painful complication during radiotherapy for NPC, affecting the majority of patients, adversely affecting quality of life outcomes in most, and limiting or altering treatment regimens in a few.

Background •Oral mucositis (OM) is a relatively common and potentially serious complication for patients undergoing radiation therapy for head and neck cancers, including nasopharyngeal carcinoma (NPC).1,2 The incidence of mucositis in head and neck cancer has ranged from 50% to 90%, as it varies based on radiation intensity, schedule, and accompanying chemotherapy regimen.2,3 •OM has a significant effect on quality of life, resulting in increased pain and inability to eat due to difficulties with chewing and swallowing. In addition, there is typically a decline in activity and performance, as well as the need to utilize feeding tubes. It is also associated with increased hospitalization and cost.1,4 •Due to the location of the tumor in NPC, radiation therapy (RT), rather than surgery, has traditionally been the mainstay of treatment.5 •RT is associated with a high rate of OM because the mucosa of the oropharynx is particularly sensitive to the DNA-damaging effects of RT due to the high cell turnover of the oral epithelium.6

• We aimed to characterize the role of mucositis in the treatment of NPC by analyzing the rate, sequelae, and dose-limiting toxicity.

Methods •A biomedical literature search was performed using the MEDLINE/PubMed search engine using the following key words: “mucositis AND radiation treatment AND nasopharyngeal carcinoma” and “mucositis AND radiation AND complication.” •Inclusion criteria included:

•Clinical studies with at least 5 patients regarding treatment for NPC •English •Human studies •Full text available

•Two independent observers extracted data and input it into the database. Outcome measures extracted included:

•Demographics •Treatment type and order •Percentage of mucositis cases •Mucositis grade •Dose-limiting toxicity

•Summary statistics were calculated for all measures. All reported categories were weighted based on the number of patients before calculation of the summary statistic. •The severity of mucositis (when reported) was analyzed by looking at the number of patients within each grade. This study used Microsoft Excel (Version 2010; Microsoft, Redmond, WA) for data aggregation and analysis.

Results •The literature search revealed a total 65 relevant journal articles, representing 7876 patients who underwent treatment for NPC that involved radiation therapy. Treatment and patient characteristics are reported in Table 1 and 2. •Radiation therapy alone was used in treatment for NPC in 2845 patients (36.1%) and some combination of radiation therapy and chemotherapy was seen in 5031 patients (63.9%). •Grade 1 or higher mucositis was reported in 4798 patients (69.7%), and 2142 patients (27.2%) reported Grade 3 or higher mucositis. •Of the 14 articles that specifically reported dose-limiting toxicity, 95 out of a total of 890 patients (10.6%) stopped treatment due to intolerable mucositis. Of the 14 articles that specifically reported alternate feeding requirements, 104 out of a total of 1517 patients (6.9%) required percutaneous endoscopic gastrostomy or nasogastric tube placement. •Of the 2845 patients that had radiation therapy alone as their form of treatment for NPC, 1516 or 53.1% developed mucositis. For the patients that received a combined treatment of chemotherapy and radiation therapy, 3318 or 74.6% developed mucositis. •For the 1413 patients that received combination chemotherapy/radiation therapy 31.8% developing Grade 3 or higher mucositis, compared to 729 patients (25.5%) that received radiation therapy alone (P < 0.0001) (Table 3).

Figure 1: Included and excluded studies.

RT-T: traditional radiation therapy. RT-Other: IMRT, AFRT, HFRT. CCRT: radiation and concurrent chemotherapy. RT-Neo/Adj: radiation and adjuvant, neoadjuvant or induction chemotherapy

Discussion

Limitations

References

•OM is a common toxicity of radiation therapy in head and neck cancers, with a significant impact on quality of life and clinical management. However, altered RT fractionation and novel adjuvant chemotherapeutic regimens developed over the past two decades have been accompanied by a concomitant increase in OM.2,4

•OM substantially affects key quality of life indicators, such as ability to eat and subsequent weight loss and decreased performance status, difficulty speaking leading to a decline in social wellbeing, the presence of chronic pain and complex and time-consuming mouth care regimens. OM may also promote bacteremia in these patients who are already vulnerable to infection.2,4,7 Our analysis revealed that the majority of patients, regardless of treatment type, developed some degree of mucositis (69.7%). •A significant risk of receiving RT and chemotherapy for NPC treatment is the necessity of interrupting therapeutic regimens as a result of severe OM. A review from 2003 covering nearly 4,000 patients receiving therapy for head and neck cancers found that nearly 11% of these patients had unanticipated changes to their RT treatment.2 Our review found 10.6% patients stopped treatment due to mucositis. However, only 14 studies reported this outcome. •The trend in the management of NPC has shifted away from RT alone and towards the increased use of concurrent chemotherapy regimens. Addition of a chemotherapy regimen has had a positive impact on local control, distant metastases, and overall survival.4,5 We found the addition of a chemotherapy regimen resulted in 31.8% of patients experiencing severe mucositis (grade 3-4), as compared to 25.5% of patients receiving RT only, a difference which is statistically significant.

•This study predominantly included prospective clinical investigations, and the quality of this analysis is directly reflected by the quality of data available in the literature. •Mucositis was not always described as a complication in all relevant articles focusing on the treatment of NPC, demonstrating that the overall incidence of this complication is likely underreported. •Lack of uniform reporting also decreased the effectiveness of the study in its ability to stratify and make statistical comparisons between treatment types and severity of mucositis.

•Only 23.9% of the articles included in this analysis included data about the role of mucositis in treatment dose-limitation, suggesting that the amount of dose-limitation is likely underreported. •No standardization exists regarding mucositis grade.

• Due to the lack of uniform reporting, we were not able to analyze the development of mucositis by treatment groups such as radiation type/field/fractionation, or chemotherapeutic agent/dose/type. These factors contribute to the development of mucositis and should be included in future analyses.

1. Liu YJ, Zhu GP, Guan XY. Comparison of the NCI-CTCAE version 4.0 and version 3.0 in assessing chemoradiation-induced oral mucositis for locally advanced nasopharyngeal carcinoma. Oral Oncol 2012;48:554-9.

2. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 2003;66:253-62.

3. Vera-Llonch M, Oster G, Hagiwara M, et al. Oral mucositis in patients undergoing radiation treatment for head and neck carcinoma. Cancer 2006;106:329-36.

4. Elting LS, Cooksley CD, Chambers MS, et al. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 2007;68:1110-20.

5. Agulnik M, Epstein JB. Nasopharyngeal carcinoma: current management, future directions and dental implications. Oral Oncol 2008;44:617-27.

6. Ps SK, Balan A, Sankar A, et al. Radiation induced oral mucositis. Indian J Palliat Care 2009;15:95-102.

7. Trotti A. Toxicity in head and neck cancer: a review of trends and issues. Int J Radiat Oncol Biol Phys 2000;47:1-12.

Refers to the number of treatment arms where the median age fell within the stated ranges. **40 studies reporting AJCC tumor stage

RT-Any: Radiation therapy only, any type (RT-C, RT-AF, HFRT, IMRT). RT-T: traditional radiation therapy only. RT+CT: Any combination of radiation therapy and chemotherapy.

Jean Anderson Eloy, MD, FACS Associate Professor and Vice Chairman

Director, Rhinology and Sinus Surgery Co-Director, Endoscopic Skull Base Surgery Program

Department of Otolaryngology – Head and Neck Surgery Rutgers New Jersey Medical School

90 Bergen Street., Suite 8100 Newark, NJ 07103

jean.anderson.eloy@gmail.com

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