THE IMPACT OF SOCIODEMOGRAPHIC FACTORS ON QUALITY OF LIFE AND FUNCTIONAL IMPAIRMENT IN PATIENTS TREATED OF OROPHARYNGEAL CARCINOMA

Backround/Aim: Considering the distinct increase in the incidence of oropharyngeal cancer over oral cavity cancers and changing epidemiology with Human Papilloma Virus (HPV) infection emerging as an important risk factor, there is a need to establish better treatment choices in specific groups of patients with oropharyngeal cancer. The aim of this study was to assess the quality of life (QOL) and functional performance and the impact of different demographical data, stage of disease, and treatment type on these parameters in patients with oropharyngeal cancer with successfully achieved locoregional control a year after the treatment. Methods: Study included 87 patients who underwent quality of life and functional impairment assessment with following questionnaires the European Organization for Research and Treatment of Cancer Quality-of Life-Questionnaire-C30 (EORTC QLQC30), European Organization for Research and Treatment of Cancer Quality ofLife Questionnaire-Head and Neck 35 (EORTC QLQ-H&N35) and The Karnofsky Performance Scale (KPS) 12 to 14 months after finished oncological treatment. Results: Specific groups of patients had significantly different post-treatment QOL scores. Factors associated with worse QOL scores were female gender, not being in a partnership, level of education and HPV status. Conclusions: Clinicians should consider socioeconomic factors and HPV status in planning the recovery after treatment of patients with oropharyngeal carcinoma. Gender, education level and employment are variables that form certain risk profiles associated with lower QOL.


Introduction
.2Although common risk factors are preventable and most of the cases are easily diagnosed by a standard oral exam, due to a huge lack of awareness, disease is usually detected in the advance stages. 3 the past decade, patient's quality of life (QOL) and functioning after the treatment has become an important additional tool of assessing the treatment outcome of oral cavity and oropharyngeal cancer. 4A number of recent studies assessed quality of life in patients with both entities combined, but it should be considered that oropharynx and oral cavity are two different anatomical sites, each with its own specific anatomy and functions.Oropharyngeal region includes following sub-sites: base of tongue, tonsil, and oropharynx, opposing to oral cavity region which includes lip, oral tongue, floor of mouth and gums, palate or other sections of the mouth.This distinctions became more important in light of the new patterns noticed in etiology and incidence trends.First, there is a distinct increase in the incidence of oropharyngeal cancer with the decrease in the incidence of oral cavity cancers. 5,6In the United States, tonsillar cancer showed to be most frequent diagnosed oropharyngeal cancer.Second most frequent diagnosed site was base of the tongue.Both sites showed increasing incidence during a period from 2000 to 2010 comparing to the trends for other anatomic sites of the oral cavity and oropharynx. 6condly, a shift in age of diagnosis has happened, making 6 th and 7 th decade of life high risk period for oropharyngeal cancer compared to oral cavity cancer. 6,7Thirdly, epidemiology of oropharyngeal cancer changed, with risk-factors like smoking and alcohol replaced with Human Papilloma Virus (HPV) infection.Oropharyngeal cancer caused with HPV occur in different population to that commonly associated with head and neck cancers, with significantly better prognosis than HPV negative cancers. 8These trends are forcing us to further narrow our focus on better treatment choices for oropharyngeal cancer, and post-treatment quality of life in specific groups of patients.Patients with oropharyngeal cancer confront substantial QOL issues after successful cancer management. 9Depending on the sociodemographic characteristic, choice of the treatment and stage of the disease, going back to regular diet, performing usual everyday tasks and professional duties requires a significant effort in these patients.
The aim of this study was to assess the impact of different demographical data, HPV status, stage of disease, and treatment type on quality of life and functional performance in patients with oropharyngeal cancer with successfully achieved locoregional control a year after the treatment.

Material and methods
Cross-sectional study included 87 patients diagnosed with carcinoma of the oropharynx in the Clinic for Otorhinolaryngology and Maxillofacial surgery of Clinical Centre of Serbia in Belgrade in a one-year period (from January 2009 to January 2010).This study was approved by the Institutional Ethical Committee (440/IX-3/09), and all patients signed informed consent form prior to their inclusion in the study.Patients were treated in the period from underwent necessary diagnostic procedures (clinical exam, tumor biopsy and histopathology verification, radiological diagnostics).The modality of treatment for every patient was decided on the Oncological board (consisting of radiotherapist, head and neck surgeons, oncologist and histopathologist).HPV positivity was confirmed with HPV16 in situ hybridisation and positive p16 immunohistochemical staining of the tissue samples. 10,11rgical therapy involved resection of the tumor (local resection or hemiglossectomy) with some form of neck dissection in case of cervical lymphadenopathy.Radiotherapy consisted of external radiotherapy with total dose of 60 to 70Gy in 30-35 fractions for 6-7 weeks.
Patients received chemotherapy concurrently with radiotherapy; three courses of cisplatin (CDDP) intravenously, on 1 st , 4 th and 7 th week of radiotherapy.In patients who were disease-free, quality of life and functional impairment assessment was conducted 12 to 14 months after finished oncological treatment.Patients with recurrent disease were excluded from the study.is a cancer-specific questionnaire, divided into five functioning scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/emesis and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and one global health and QOL scale.Scores were given as a 0-100 scale.Higher scores for the global QOL scale and for a functional scale indicated a higher level of functioning, and higher scores for a symptom scale or a single-item scale indicated more severe symptoms and worse QOL.The EORTC-H&N35 is a site-specific questionnaire designed to assess QOL in head and neck cancer patients made of seven symptom scales (pain, swallowing, sense, speech, social eating, social contact and sexuality) and eleven single items associated with the location, symptoms of the disease and treatment (teeth problems, mouth opening, dry mouth, sticky saliva, coughing, feeling ill, painkiller intake, nutritional supplements, feeding tube, weight loss and weight gain).The highest scores represented the highest level of symptoms.The scores were interpreted in to the scoring guidelines established by the EORTC manuals.The Karnofsky Performance Scale (KPS) Index was used to classify the patients' functional impairment.Scores range from 0 to 100; the higher score the patient is better able to carry out daily activities. 13Differences in EORTC QLQ-C30, EORTC QLQ-H&N35 and KPS Index scores were compared depending on age, gender, place of living, level of education, living arrangement/marital status, employment position, HPV status, American Joint Committee on Cancer (AJCC) stage of the disease and treatment choices of the patients.
Statistical analysis was performed using SPSS v20 (SPSS Inc., Chicago, IL).To determine differences between examined groups of patients, depending on investigated parameters, T test and ANOVA were used.Pearson's correlation test was used to determine the correlation between EORTC QLQ-C30, EORTC QLQ-H&N35 and KPS Index scores and other parameters.P-value less than 0.05 was considered statistically significant.

Results
The study included 87 patients (69 males and 18 females) of an average age of 59.6.Patients were diagnosed and treated of oropharyngeal carcinoma between October 2009 and October 2011 in the Clinic for Otorhinolaryngology and Maxillofacial surgery of Clinical Centre of Serbia in Belgrade.Basic demographic characteristics of the patients were given in the table 1. Patients were predominantly male, living in urban areas, in partnerships or married, laborers with high school education.Out of all patients included in the study, 39 (44.8%) were HPV positive.Most of the patients were diagnosed with stage IV oropharyngeal cancer (47.1%).Treatment modalities differed; most of the patients were treated operatively with postoperative radiotherapy (31%) or with radio/chemotherapy (31%).
Mean value and standard deviation of EORTC QLQ-C30, EORTC QLQ-H&N35 and Karnofsky Performance Scale Index scores were given in table 2 and 3. Regarding EORTC QLQ-C30 and Karnofsky Performance Index scores, women had significantly worse physical, emotional, cognitive and social functioning, and felt more fatigued, had more frequent dyspnea, insomnia, and appetite loss then men (table 4).Emotional and cognitive functioning was significantly worse in patients who were single (p=0.048 and p=0.046 respectively), than in those living in marriage or partnership.There was significantly higher global quality of life in patients with higher education (faculty and PhD) (p=0.039).Unemployed suffer more from insomnia that patients working in managerial positions (p=0.046).HPV positive patients were complaining significantly less of pain and dyspnea comparing to HPV negative patients (p=0.024 and p=0.043 respectively).Physical functioning was significantly better in patients in I stage of the disease comparing to patients in III and IV stage of the disease (p=0.2 and p=0.008 respectively).Social functioning was significantly better in patients who underwent surgery comparing to patients who underwent radio/chemotherapy and patients who underwent surgery with radio/chemotherapy (p=0.033 and p=0.025 respectively).In EORTC QLQ -H&N35 questioner, women had significantly higher scores than men regarding senses, contact, sexuality and felling ill (p˂0.05).Patients living in a partnership or in marriage had significantly less complaints about their sexual life (p=0.008),felt less ill (p=0.049) and used less painkillers (p=0.006)than patients who are single.Patients with stage I carcinoma complained about the senses problem significantly less than patients with III and IV stage carcinomas (p=0.221 and p=0.25 respectively).Patients treated with radio/chemotherapy felt significantly more pain than those treated operatively with postoperative radio/chemotherapy (p=0.017).
Pearson's correlation test was used to determine the correlation between EORTC QLQ-C30, EORTC QLQ -H&N35 and KPS Index and other parameters (table 5).
Karnofsky Performance Scale Index scores didn't correlate with any of the variables.Older age correlated positively with sexuality in patients, and negatively with occurrence of diarrhea.Level of education correlated positively with global quality of life and cognitive functioning, and negatively with symptoms of nausea, dyspnea, appetite loss, swallowing, eating and feeling ill.Different employment position didn't correlate with EORTC QLQ-C30, EORTC QLQ-H&N35 scores.There was a negative correlation between stage of the disease and physical and emotional functioning scores, also with occurrence of dyspnea, insomnia and swallowing.The more combined therapy modalities patient had, emotional and social functioning significantly has gotten worse.

Discussion
Oropharyngeal cancer has become a growing concern, with its' rising incidence in younger male patients. 6With developing more advanced strategies of head and neck cancer treatment 14,15 , locoregional control of the disease, along disease-specific survival, are significantly better.Expected QOL should be an important factor in choosing adequate treatment modality, given its' immense influence on patients social, physical, psychological and overall functioning. 16Clinicians are turning to QOL measures for decision making in daily practice, improving patient-doctor interaction and monitoring patient experience with treatment. 17,18st of the parameters of QOL, when assessed post-treatment are at the lowest 3 months after treatment 17 , but one year post-treatment major improvements in scores happen in disease free head and neck patients. 19,20The assessment of QOL parameters in our study was done in that period, which is considered to be a good time for assessment of QOL, because most of QLQ-C30 and QLQ-H&N35 scores are returning to preoperative values, depending on the treatment 21 , and variations are considered negligible in the absence of recurrent disease. 22ring this study, demographic and social factors significantly influenced QOL and functional performance in patients with oropharyngeal cancer, in addition to stage of the disease and treatment modality.This results were already proven to be significant. 23,24nsidering the different oropharyngeal sub sites involved, treatment is associated with wide range of functional and psychosocial deficits.Multiple QOL segments are influenced, and patients are forced to make permanent changes in their eating habits, swallowing, appearance and communication.It is reasonable to expect differences in QOL between patients treated of oropharyngeal carcinoma depending their age, marital and educational status and employment.In this study women had significantly worse scores in many aspects of functioning, and also regarding fatigue, dyspnea, insomnia, and appetite loss, senses, contact and sexuality, making gender significant factor which influences QOL scores in these patients.Marital status influenced limited aspects of QOL, mostly emotional and cognitive functioning, sexual life and felling ill.There were significant differences noted in patients living in rural areas; they had fewer problems with the senses, dry mouth, felt less nauseous and dyspneic, than those living in urban areas.There are studies that noted the differences in emotional, functional, and HNC-specific scores between head and neck cancer survivors living in rural and urban areas, in term of better QOL in rural areas. 25vel of education significantly influenced some QOL aspects, like global quality of life and cognitive functioning, nausea, dyspnea, appetite loss, swallowing, eating and feeling ill.This was generally noticed in patients with head and neck carcinoma. 23,26 ew possible explanations were offered.Patients with lower education level and lower socioeconomic classes have less accessible health care, which leads to delays in diagnosis and treatment. 23Some authors suggested that patients with higher social and cultural level had a better capability of coping with cancer and its consequences.Comparing to patients with higher education and less physically demanding work place, patients with employment that requires physical strength are more likely to be influenced by the disease, and have more trouble in adaptation to other work positions. 26Considering the structure of patients in our study, with 83.8% with high-school education and lower and 44% working s laborers, these claims are highly applicable.
The relation between HPV and QOL was explored in a few studies.Sharma et al.   found no association between HPV status and QOL one year post-treatment. 27On the other hand, Maxwell et al. 30 published that HPV positive patients had significantly better scores considering activity, recreation, swallowing, chewing, speech and overall quality of life a year after the treatment.Production of saliva in HPV positive was poorer comparing to HPV negative patients in first 12 months, but after that time, difference was no longer significant.A year after the treatment, HPV positive patients in our study complained significantly less of pain, dyspnea and on trouble with their senses.Global QOL was better in HPV positive patients, but differences weren't significant.Due to favorable reaction to radiotherapy and better survival rates, we could argue that HPV positivity surely influences postoperative QOL in patients with oropharyngeal carcinoma.Recommended modality treatment depending on HPV status would certainly be a subject for further discussion, with more knowledge accumulated on the subject.
Stage of disease, cancer site, and treatment type are predictors of post-treatment QOL, particularly disease-specific symptoms. 30In this study, patients with more advanced stage of the disease scored worse that those with less advances stage of the disease in all aspects of QLQ-C30, QLQ -H&N35 and KPS Index scale, which is consistent with previous papers on the subject. 30,31Significant differences were noted in physical functioning and with the senses between patients in I stage of the disease and patients in III and IV stage of the disease.Oates et al. 30 reported great deterioration for senses, teeth, saliva and coughing in patients with early-stage cancer and significant deterioration of sexual function and complains of dry mouth in patients 12 months after the treatment for all four stages of the disease.Findings of statistically significant differences in QOL scores favoring patients receiving a single therapy compared to combination therapies are not consistent across studies. 19In our patients, social functioning was significantly better for those who underwent operative treatment than in for those treated operatively with postoperative radiochemotherapy or just with adjuvant radiochemotherapy.Also, pain was significantly more severe in patients treated operatively with radiochemotherapy, than in patients treated with only radiochemotherapy.Some authors published similar findings 27,32 , but in most of the studies,results were inconclusive 33,34 .Good oncological results are the first objective of treatment, but functional preservation could be one of the main challenges after surgical treatment or radiochemotherapy.Comparing to surgery, patients treated primary with chemoradiotherapy 35 or with adjuvant therapy. 36,37In our study there were some differences in functional aspects (eating, swallowing, complaints of dry mouth and saliva production), but insignificant between groups of patients considering the treatment modality.Our findings could have been strongly influenced by the time of evaluation.
Differences between QOL scores in patients treated with different treatment modalities proved to be greatest three months after the treatment, and by 6 and 12 months of follow-up were significantly less pronounced. 30th rising incidence of patients diagnosed with oropharyngeal cancer, there is a great need for better understanding of recovery process, what significantly influences posttreatment quality of life and how to educate patients in terms what to expect after the treatment.After diagnosis and treatment of oropharyngeal cancer, patients are going back to their family and living environment, with distinct personal, social, and economic expectations and duties.These factors are of little variability and constantly present in patients' life before and post-treatment and it would be crucial to recognize their important influence on overall recovery and survival.
There are some limitations of the study.First, the study assessed quality of life and functional performance in patients with oropharyngeal cancer at a time point, not prospectively, so any changes between the influence of sociodemographic factors and quality of life over time wasn't followed.Second, the number of patients in the study was small, and the results of this study should be evaluated cautiously.Last, number of patients with different sub sites of the oropharyngeal carcinoma was also small and wasn't analyzed how different oropharyngeal sub sites involvement influenced quality of life and functional performance.

Conclusion
Clinicians should take in mind socioeconomic factors and HPV status planning recovery course after treatment in patients with oropharyngeal carcinoma.Gender, education level and employment are variables that form certain risk profiles associated with lower post-treatment QOL.This would ultimately lead to better functional results, faster recovery and return to everyday life and activities in patients with oropharyngeal cancer.

For
assessing the quality of life two types of questionnaires were used: the European Organization for Research and Treatment of Cancer Quality-of Life-Questionnaire-C30 (EORTC QLQ-C30) and the European Organization for Research and Treatment of Cancer Quality of-Life Questionnaire-Head and Neck 35 (EORTC QLQ-H&N35).12 The questionnaires have been translated into Serbian.The EORTC QLQ-C30 C30-European Organization for Research and Treatment of Cancer Quality-of Life-Questionnaire-C30, KPS-Karnofsky Performance Scale, OP-operation, RT radiotherapy, CT-chemotherapy Table 3. Mean value and standard deviation of EORTC QLQ -H&N35 scores depending on investigated parameters

Table 1 .
Demographic characteristics of the patients included in the study

Table 2
. Mean value and standard deviation of EORTC QLQ-C30 and Karnofsky Performance Scale Index scores depending on investigated parameters