Impact of late toxicities on quality of life for survivors of nasopharyngeal carcinoma

R E S E A R C H A R T I C L E

Open Access

Impact of late toxicities on quality of life for

survivors of nasopharyngeal carcinoma

Wen-Ling Tsai

, Tai-Lin Huang

, Kuan-Cho Liao

, Hui-Ching Chuang

, Yu-Tsai Lin

, Tsair-Fwu Lee

,

Hsuan-Ying Huang

and Fu-Min Fang

Abstract

Background: To investigate the impact of physician-assessed late toxicities on patient-reported quality of life (QoL) for nasopharyngeal carcinoma (NPC) patients with long-term survival.

Methods: A cross-sectional survey of QoL and late toxicities was conducted in 242 NPC patients with disease-free survival of more than 5 years after treatment. The QoL was assessed by the European Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Late toxicities including neuropathy, hearing loss, dysphagia, xerostomia, and neck fibrosis were recorded based on the criteria of Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0). The general linear model multiple analysis of variance (GLM-MANOVA) was performed to predict factors associated with the QoL.

Results: In the multifactor model of GLM-MANOVA, of the five late toxicities of CTCAE scales, neuropathy, hearing loss, and xerostomia were observed to be significantly associated with the overall outcome of the fifteen QLQ-C30 scales. A statistically significant trend (p <0.05) was observed, indicating that NPC survivors with more severe neuropathy, hearing loss or xerostomia had a worse outcome on global QoL, all five functional scales, and a variety of symptomatic scales.

Conclusions: To improve QoL outcome for NPC survivors, the development of a modern radiotherapeutic technique should not only focus on reduction of the dose to the salivary glands, but also on anatomical structures that are involved in neuropathy and hearing loss.

Background

Nasopharyngeal carcinoma (NPC) is a prevalent disease in Taiwan. With the advent of the treatment technique of radiotherapy (RT) or a combination of chemotherapy, NPC patients have a greater chance of living cancer free for an extended period of time. If the individual organ receives the radiation dose above the specific dose-tolerance limit, the so called late complications, which are usually chronic, irreversible and progressive, would be induced [1]. Conventionally, assessments of these sequelae were usually from the physicians’ point of view and measured according to physical outcome. Several systems for quantitatively scoring treatment-related toxicities have been developed and are continuously evolving. The National Cancer Institute Common Terminology Criteria

for Adverse Events (CTCAE) system is one of the most widely used tools for documenting toxic effects caused by cancer treatments in clinical trials [2]. The CTCAE grad-ing system not only takes into account adverse effects induced by RT, but also those induced by other treatment modalities such as chemotherapy or surgery.

In the past decades, quality of life (QoL) and its assess-ment have become increasingly important in health care. The concepts of QoL refer to patients’ own perception, and self-report of their physical, mental, and social func-tions, as well as other related symptoms [3]. There are now a variety of well-validated QoL instruments available for use in the field of oncology. The European Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) is a cancer-specific type of QoL instrument with good validation and has been widely used internationally for cancer patients [4].

Growing studies have involved the investigation of QoL for patients with head and neck cancer (HNC) treated

* Correspondence:fang2569@gmail.com

3

Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Full list of author information is available at the end of the article

© 2014 Tsai et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Tsaiet al. BMC Cancer 2014, 14:856

with RT. However, only a few have touched on the impact of RT-related late toxicity on the outcome of patients’ QoL [5,6]. In this study, we focused on NPC patients with long-term survival. We investigated the impact of the severity of late toxicities, which was graded by physicians based on CTCAE v.4.0, and on the QoL outcome, which was patient-reported by using the EORTC QLQ-C30. Methods

This is a cross-sectional study that adheres to STROBE guidelines for reporting observational research (Additional file 1). In total, 242 NPC patients with cancer-free survival of more than 5 years were enrolled. All of them were newly diagnosed NPC and treated at the Kaohsiung Chang Gung Memorial Hospital in Taiwan from January 1997 to December 2007; those with tumour relapse or second pri-mary cancers were excluded. As regards the existence of selection bias, we compared the distributions of sociode-mographic characteristics (including age, gender, marital status, and education level) and cancer stage between the study cohort and the other NPC survivors in the cancer registration database of the institute, but no statistically significant differences were found. The Medical Ethics and the Human Clinical Trial Committee at Chang Gung Memorial Hospital in Taiwan has approved the study (No. 103-1495B) and informed consent was obtained from all eligible patients. One hundred of the patients were treated with intensity-modulated RT (IMRT) and the others using non-IMRT, which included 2-dimensional RT (2DRT, n = 39), 3-dimensional conformal RT (3DCRT, n = 24), and 2DRT plus boost by 3DCRT (n = 79) at different time pe-riods. The detailed procedures of these techniques have been described in our previous publication [7]. Table 1 lists the distributions of patient characteristics including age, gender, marital status, education years, cancer stage, RT technique, chemotherapy, and survival years at the point of investigation. Cancer stage was recorded ac-cording to the American Joint Cancer Committee (AJCC) staging system, published in 2002. Five items of late toxicities, including neuropathy, hearing loss, dysphagia, xerostomia, and neck fibrosis, which are rou-tinely assessed by physicians for NPC survivors in our clinical practice, were recorded based on CTCAE v.4. The EORTC QLQ-C30 version 3.0 was used to assess the cancer-specific QoL status. The questionnaires have been tested in Taiwanese NPC patients and excellent reli-ability and validity were obtained [8]. EORTC QLQ-C30 incorporates a range of QoL issues that are relevant to a broad range of cancer patients and contains a global QoL scale, five functional scales (physical, role, cognitive, emo-tional, and social), three symptom scales (fatigue, pain, and nausea/vomiting), and six single items (dyspnoea, in-somnia, appetite loss, constipation, diarrhoea, and finan-cial difficulties). All scales pertaining to the QLQ-C30

range from 0 to 100. A higher score for global QoL or a functional scale indicates a relatively better level of glo-bal QoL or functioning, whereas a higher score for a symptom scale denotes greater severity of a symptom or problem(s) [4].

The mean scores of the QoL scales were calculated ac-cording to the EORTC QLQ scoring manual [9]. To deal with the missing data, the missing items were assumed to have values equal to the average of those items that were present for the respondents, if at least half of the items from the scale have been answered. For the miss-ing form, the mean imputation was used to replace the missing data in each scale.To analyse the predictive vari-ables associated with and the QoL scales, the general linear model multivariate analysis of variance (GLM-MANOVA)

Table 1 Patient characteristics (N = 242)

Variables No %

Age, median (range) years 46 (17–78)

≦40 73 30.2 41 ~ 60 154 63.6 >60 15 6.2 Gender Male 168 69.4 Female 74 30.6 Marital status With spouse 188 79.3 Without spouse 49 20.7 Education years ≦6 62 26.2 6 ~ 12 118 49.8 >12 57 24.0 AJCC stage I 21 8.7 II 107 44.2 III 74 30.6 IV 40 16.5 Radiotherapy IMRT 100 41.3 Non-IMRT 142 58.7 Chemotherapy Yes 160 66.1 No 82 33.9 Survival years 5 ~ 7 162 66.9 8 ~ 10 54 22.4 11 ~ 13 26 10.7

AJCC: American Joint of Cancer Committee published in 2002; IMRT: intensity modulated radiotherapy.

Tsaiet al. BMC Cancer 2014, 14:856 Page 2 of 8

hypoglossal palsy as grade 3 dysphagia and the other two cases with tube feeding but without tongue atrophy as grade 3 xerostomia.

Some reports have shown that radiation-induced dys-phagia in HNC plays an important role in QoL domains and have highlighted the importance of not only parotid sparing by modern IMRT techniques, but also preserving the pharyngeal muscles that are involved in swallowing function during irradiation [18-20]. However, in the report by Teguh et al., they observed that dysphagia was tumour site-specific, and that NPC patients suffered from less dys-phagia than oropharyngeal cancer patients did [18]. We found that, in contrast to other anatomic sites of HNC, NPC survivors presented some specific but common late sequelae related to the irradiation field, such as otitis media, hypothalamic-pituitary-thyroid dysfunction, and neuropathy related from temporal lobe necrosis, cranial nerve palsy, or carotid arterial stenosis, etc. [21-23]. Be-sides parotid sparing for the prevention of xerostomia or dysphagia, the modern conformal radiation technique should place more emphasis on the anatomic structures that are involved in these late complications, e.g. cochlea, thyroid and pituitary gland, temporal lobe, and carotid artery. Furthermore, regular examinations such as carotid duplex scanning or evaluation of thyroid function for early detection and possibly intervention of these potential late complications should be kept in mind in routine clinical practice especially for those with high risk factors and long term survival [22,23].

This study has several limitations. First, no pre-treatment QoL data were available in this cross-sectional study and the post-treatment late toxicities assessed by physicians were subjective. It was difficult to determine whether the late toxicities after treatment were the result of treatment or the result of the pre-existing cancer. Also, about two thirds of our patients were treated with a com-bination of chemotherapy, and we could not exclude the morbidity being related to chemotherapy. Second, only surviving patients receiving regular follow-up were en-rolled, which might have caused selection bias. Third, the study cohort included the evolved heterogeneous radio-therapeutic components from 2D, 3D conformal to IMRT techniques at different time periods and the dosimetric data were not provided in the cohort; therefore, it was difficult to establish the specific variables of the RT tech-nique and survival years that might have confounded the analysis.

Conclusions

To improve QoL outcome for NPC survivors, the devel-opment of a modern radiotherapeutic technique should not only focus on reduction of the dose to the salivary glands, but also on anatomical structures that are in-volved in neuropathy and hearing loss.

Additional file

Additional file 1: STROBE statement_{—checklist of items that should} be included in reports of observational studies.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Tsai WL: writing of manuscript; Fang FM: original idea and study coordinator; Huang TL: cases collection and data interpretation; Liao KC: statistic analysis; Chuang HC and Lin YT: cases collection; Lee TF and Huang HY: data interpretation. All authors read and approved the final manuscript.

Acknowledgements

The study was supported by the grants_{“CMRPG8A0201”, “CMRPG8A0202”} and“CMRPG8C1141” from the Chang Gung Memorial Hospital, Taiwan. Author details

1_{Department of Cosmetics and Fashion Styling, Cheng Shiu University,}

Kaohsiung, Taiwan.2Department of Hematology and Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.3_{Department of Radiation Oncology,}

Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.4Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.5_{Department of Electronics}

Engineering, National Kaohsiung University of Applied Sciences, Kaohsiung, Taiwan.6Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Received: 2 July 2014 Accepted: 14 November 2014 Published: 21 November 2014

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doi:10.1186/1471-2407-14-856

Cite this article as: Tsai et al.: Impact of late toxicities on quality of life for survivors of nasopharyngeal carcinoma. BMC Cancer 2014 14:856.

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