Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 6, Num. 4, 2010, pp. 448-451

Journal of Cancer Research and Therapeutics, Vol. 6, No. 4, October-December, 2010, pp. 448-451

Original Article

Risk-scoring system for predicting mucositis in patients of head and neck cancer receiving concurrent chemoradiotherapy [rssm-hn]

A.V.S Suresh¹, P Pratap Varma², Sudha Sinha¹, Satya Deepika¹, Raghu Raman³, M Srinivasan³, T Mandapal⁴, C Obula Reddy⁵, BB Anand²

¹ Department of Medical Oncology, MNJ Institute of Oncology, Hyderabad, India
² Department of Surgical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India
³ Department of Radiation Oncology, MNJ Institute of Oncology, Hyderabad, India
⁴ Department of Radio diagnosis, MNJ Institute of Oncology, Hyderabad, India
⁵ Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India

Correspondence Address: A.V.S Suresh, Department of Medical Oncology, MNJ Institute of Oncology and Regional Cancer Center, Red Hills, Hyderabad-500004, India, sureshattili@yahoo.com

PMID: 21358078

DOI: 10.4103/0973-1482.77100

Abstract

Keywords: Head and neck cancer, mucositis, scoring system, chemoradiotherapy, India.

Introduction

The physiological basis of both chemotherapy and radiotherapy is the ability to selectively kill the proliferating cells [typically malignant]. However, other proliferative systems namely mucosal and hematopoietic systems will also be affected resulting in complications like myelosuppression and mucositis, respectively. However, the systemic therapy like chemotherapy results predominantly myelosupression and local therapy like radiation often results in mucositis. The synergistic antitumor effect of chemoradiation is proven beyond doubt, at the same time more mucositis with the combined modality is expected. Mucositis is one of the most common adverse events of concurrent chemoradiotherapy. It often results in compromised quality of life owing to multiple mechanisms like restricted oral intake; thereby reducing the nutritional status as well as immunity, pain and excessive salivation leading to social problems. The breached mucosa acts as sites of secondary infection and a portal for invasion of native oral flora. Relatively, immunocompromised patients are vulnerable to uncontrolled infection due to poor oral intake and chemotherapy. ^[1] These factors often result in treatment interruption and dose reduction, thereby leading to reduced disease-free and overall survivals in the adjuvant/neoadjuvant settings. ^[2] The distribution of this adverse event is not uniform across the globe or for disease conditions and its incidence may vary from 15 to 70%. ^[2] The major factors influencing the incidence, besides non-uniform reporting are the primary diagnosis, age, status of oral hygiene, nutritional status, history of oral tobacco consumption and the nature of treatment (dose, frequency of radiation as well as drugs). ^[3]

However, the striking difference in its incidence among different patients receiving same protocol often makes the decision difficult to adopt preventive strategies. Head and neck cancer is one of the most common malignancies considering all anatomical sites in the head and neck region together in Indian subcontinent. ^[4] Till date there is no comprehensive tool to assess the actual risk for the development of mucositis in the head and neck cancer patients receiving chemoradiotherapy from Southern India. Hence, this study was conducted to develop a risk-scoring system to predict the probable incidence and severity of mucositis in head and neck cancer patients on chemoradiotherapy. The treatment protocol is standardized and we studied a single group of indication i.e., head and neck cancer to maintain homogeneity.

Materials and Methods

This is a retrospective analysis conducted at a tertiary care cancer center with approximately 2,000 new cases of head and neck cancer patients annually. All the case records of patients of head and neck cancer in 2 units of radiation oncology were reviewed. Patient characters and laboratory details were noted from the case records. Only those patients, who were receiving cisplatin 40 mg/m ² /week along with local radiation of 60-70 Gy, were enrolled to maintain uniformity of the population as far as treatment is concerned. Based on the previous publication, ^[2] we hypothesized age, comorbid conditions, leucocyte count, nutritional status, oral hygiene, tobacco use, erythrocyte sedimentation rate (ESR) levels, Eastern Cooperative Oncology Group (ECOG) performance status (PS), TNM (tumor, node, metastasis) group stage as possible risk factors. Receiver operating characteristic (ROC) curves were drawn to predict the cutoff values and the final scoring system was presented with sensitivity and specificity data. Medical version 7.0 for Windows (MedCalc Software, Mariakerke, Belgium) was used for the analysis.

Risk was assessed by 10-year interval for age, 500/mm ³ interval for WBC count, units of 1 for disease stage (I-IV), units of 1 for ECOG PS, 0.5 gm/dL intervals for albumin levels, and number of times above upper limit of normal for ESR. For comorbid conditions, tobacco consumption and oral hygiene were indicated as present or absent and assigned a score of 1 and 0, respectively. For all the remaining parameters values above cutoff were scored as 1 and values below cutoff were scored as indicated by ROC curves. Sensitivity and specificity for the final score were assessed for each score level, and based on the percentage of patients experiencing severe mucositis; they were grouped into low-, intermediate-, and high-risk groups.

Results

A total of 218 patients receiving the standard protocol were enrolled in the study. The baseline characters of the patients in the study are represented in [Table - 1]. The present study population is dominated by middle-aged males of 34 years, half had stage III disease and only 10% had stage IV disease, relatively lower incidence of comorbid conditions like diabetes, and around 10% of our population in ECOG PS 4 received radiotherapy.

The ROC curves plotted for the hypothesized risk factors are shown in [Figure - 1].

The cutoff values for high vs. low risk indicated by ROC curve analysis were age > 40 years, ESR > 3 times upper limit, albumin < 3.0 g/dL, WBC less than 3000/ μL, PS of more than 2, stage III or above disease, use of tobacco and presence of any comorbid condition. The absence of any of these parameters was assigned a score of 0. For developing a risk score a score of 1 was assigned for each of the parameters having a value above the cutoff values as indicated by ROC curves.

After the scoring system, the categories were chosen again by using the ROC curves and scores of 3 or less, and 6 or above predicted the differences in the incidence of mucositis with considerable accuracy. The sensitivity and specificity of the scores based on the percentage of patients experiencing mucositis is represented in [Table - 2].

Discussion

The pathophysiology of the mucositis is an evolving field. The hypothesis for its development in patients receiving the concurrent chemoradiotherapy is due to direct inhibition of the DNA replication by chemotherapy as well as DNA damage by radiation of the mucosal epithelial cells which are in proliferation phase, decrease in renewal capabilities of the basal epithelium ultimately results in collagen break down with atrophy leading to breach of the mucosa (mucositis). ^[5] In addition, poor nutritional status and chemotherapy make patient immunocompromised, where the native mucosal flora becomes infective, breached epithelium acts as a portal of entry of the native flora as well as secondary pathogens. The resulting ongoing inflammation and secondary infections delays the healing process and damage to new vessels delays the process of recovery. The local radiation often leads to dry mouth, which further results in poor healing. To summarize various host and treatment-related factors play a crucial role in the development of mucositis. ^[6],[7]

In the present study patients had a mean age of 34 years and majority were males. This might be due to tobacco consumption which typically starts in the teenage. The study is in agreement with the national trends as suggested by Indian national cancer registry, where most of the cases are diagnosed in the middle age. ^[4] The relatively lower incidence of comorbid conditions like diabetes is due to age distribution (only 20% [44 patients] of the study population is above 45 years, which is the median age for development of diabetes in Indian population). Although hospital statistics suggest that more than 35% of the head and neck cases are diagnosed at stage IV, in the present study we have only 10% (22) of such cases. This is due to the eligibility criteria, where we excluded the patients receiving palliative radiotherapy. Further, these 10% cases of stage IV disease are only due to the loco-regional disease rather than distant metastasis. In contrary to the most of the recommendations, around 10% (22 patients) of our population in ECOG PS of 4 received radiotherapy. In all such cases the PS 4 is due to the sever malnutrition rather than any other causes. When compared with previous hospital records we observed a decreased incidence of the mucositis, as better radiation techniques such three-dimensional conformal radiation therapy and intensity-modulated radiation therapy were used in 65% (142 patients) cases.

Therapy-related factors such as dose, schedule and use and site of radiotherapy affect the severity and duration of mucositis. ^[6] The present study included only patients with head and neck cancer receiving cisplatin 40 mg/m ² /week with concurrent radiotherapy at 60-70 Gy, minimizing the differences in treatment-related factors. Therefore these factors were not analyzed further.

As the impact of the therapy-related factors was minimized as stated above, we could state that the development of mucositis is influenced by a panorama of patient-related factors such as age of the patient, type of malignancy, stage, condition of oral hygiene prior to and during the treatment, nutritional and immune status as well as PS. Our data suggest that with increasing number of risk factors, the likely hood of risk, duration and severity of mucositis increases. ^[2],[6],[7] In patient-related factors, there are consensus regarding the performance and nutritional status; reflecting immune status and repairing capacity of the mucosa, comorbid conditions reflecting the healing capacity of mucosa, and tobacco usage increases free radical levels and increases the damage to mucosa.

In the present study, we found a positive correlation between the markers of local immunity (total WBC counts, comorbid conditions, tobacco use, nutritional status as reflected by the albumin levels), markers of inflammation (ESR which indicate ongoing damage) and markers of healing capacity (performance and nutritional status and comorbid conditions) with the severity and incidence of mucositis. In the present study poor oral hygiene and tobacco usage lead to increased probability of mucositis. These results are in accordance with the previous studies. Similarly, more advanced disease stage, which requires larger radiation portals, is also recognized as a risk factor for mucositis. Hence our observation that patients in advanced stage are at higher risk of mucositis is not surprising.

We observed that older patients at higher risk for development of mucositis probably due to the poor healing capacity. This is in coherence with our previous experience, ^[2] but in contrast to few other studies, where it was observed that younger patients are at higher risk of mucositis (hypothesized that young patients have high levels of growth factor receptors in mucosa and had more mucosal cells in proliferative phase). ^[6]

In conclusion, the current scoring tool developed is accurate in predicting development of mucositis in Indian patients receiving concurrent chemoradiotherapy for head and neck cancer. This will further help the clinicians to adopt preventive strategies like the use of growth factors and topical agents as well as better counseling of the patients. However, we are planning a larger study across various other indications, so that the same tool could be validated for all the patients on chemoradiotherapy.

References

Copyright 2010 - Journal of Cancer Research and Therapeutics

The following images related to this document are available:

Photo images