Health-related Quality of life in 640 head and neck cancer survivors after radiotherapy using EORTC QLQ-C30 and QLQ-H&N35 questionnaires

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

Open Access

Health-related Quality of life in 640 head and

neck cancer survivors after radiotherapy using

EORTC QLQ-C30 and QLQ-H&N35 questionnaires

Stephen Wan Leung

, Tsair-Fwu Lee

, Chih-Yen Chien

, Pei-Ju Chao

, Wen-Ling Tsai

and Fu-Min Fang

Abstract

Background: With the advances in modern radiotherapy (RT), many patients with head and neck cancer (HNC) can be effectively cured, and their health-related quality of life (HR-QoL) has become an important issue. In this study, we evaluated the prognosticators of HR-QoL in a large cohort of HNC patients, with a focus on the result from technological advances in RT.

Methods: A cross-sectional investigation was conducted to assess the HR-QoL of 640 HNC patients with cancer-free survival of more than 2 years. Among them, 371 patients were treated by two-dimensional RT (2DRT), 127 by three-dimensional conformal RT (3DCRT), and 142 by intensity-modulated RT (IMRT). The EORTC QLQ-C30

questionnaire and QLQ-H&N35 module were used. A general linear model multivariate analysis of variance was used to analyze the prognosticators of HR-QoL.

Results: By multivariate analysis, the variables of gender, annual family income, tumor site, AJCC stage, treatment methods, and RT technique were prognosticators for QLQ-C30 results, so were tumor site and RT technique for H&N35. Significant difference (p < 0.05) of HR-QoL outcome by different RT techniques was observed at 2 of the 15 scales in QLQ-C30 and 10 of the 13 scales in H&N35. Compared with 2DRT, IMRT had significant better outcome in the scales of global QoL, physical functioning, swallowing, senses (taste/smell), speech, social eating, social contact, teeth, opening mouth, dry mouth, sticky saliva, and feeling ill.

Conclusions: The technological advance of RT substantially improves the head-and-neck related symptoms and broad aspects of HR-QoL for HNC survivors.

Background

Health-related quality of life (HR-QoL) and its assess-ment have become increasingly important in health care, especially in the field of chronic diseases. Conven-tionally, the endpoints of medical care for cancer patients usually focused on the so-called survival rate, local control rate, or complication rate. These endpoints were usually assessed from the physician’s points of view. These assessments lacked knowledge and under-standing of the patients’ mental and emotional well being. HR-QoL generally refers to the patient’s percep-tion of the effects of the disease and the impact on the

patient’s daily functioning, and has two fundamental premises. First, it is a multi-dimensional survey incor-porating physical, psychological, social, and emotional functional domains. Second, it is subjective and must be self-reporting, according to the patient’s own experi-ences [1].

Determining how to measure and quantify the subjec-tive experience of HR-QoL has been a challenging issue. There are now a variety of well-validated HR-QoL instruments available for use in the field of oncology. Three types of methods have been categorized. They include the generic type, e.g. the Short Form-36 (SF-36), the cancer specific type, e.g. the Functional Assessment of Cancer Treatment (FACT-G), the European Organi-zation of Research and Treatment of Cancer Quality of Life Core Questionnaire, version 3.0 (EORTC QLQ-C30), and the cancer site-specific type, e.g. the head and

* Correspondence: fang2569@adm.cgmh.org.tw † Contributed equally

5

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

© 2011 Wan Leung 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/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

neck modules in EORTC (EORTC QLQ-HN35), and FACT (FACT-HN) [2-6].

Perhaps in no other group of cancer patients does HR-QoL present as important a role as in HNC patients. This is because they may have obviously debili-tating problems with swallowing, speech, and hearing, as well as the psychological effects of loss of function and change in body image [7]. Radiotherapy is one of the most important treatment modalities for HNC patients, either in a definite way or a combination with surgery and/or chemotherapy (C/T). Over the past decade, the advances of RT techniques for treating HNC have emerged from so-called two-dimensional RT (2DRT) to the three-dimensional conformal RT (3DCRT) and intensity-modulated RT (IMRT). 2DRT has proven effective in the treatment of HNC. However, complica-tions associated with irradiation of sensitive normal structures, such as the salivary glands in the path of the irradiation, are still remarkable and often lifelong. The reliance of 3DCRT and IMRT on computed tomogra-phy-guided 3D planning allows better delineation of tumor target and organs at risk with clearer radiological visualization of their spatial relations, thus providing a potentially therapeutic benefit of dose escalation to tumor tissue with reduced toxicity to normal tissues [8].

IMRT represents an advanced form of 3DCRT. It employs inverse planning algorithms and iterative com-puter-driven optimization to generate treatment fields with varying beam intensity. Combinations of intensity-modulated fields produce custom-tailored conformal dose distributions around the tumor, with steep dose gradients at the transition to adjacent normal tissues. Growing reports have shown that the technical and dosimetric superiority of 3DCRT and IMRT over 2DRT can translate into clinical benefits, such as reduced nor-mal tissue toxicity (e.g., parotid gland sparing), improved local control, or even patient survival [9-14].

Radical RT for treating HNC was routinely delivered by 2DRT in our hospital before the introduction of 3DCRT in April 1996. From April 1996 to March 2002, 3DCRT was gradually used to replace 2DRT. After becoming familiar with the techniques of 3DCRT and implementation of the IMRT system by March 2002, the physicians and physicists in our institute began to use the two techniques in treating HNC. In a previous publication, we have reported that HNC survivors had significantly poorer HR-QoL outcomes compared with Taiwanese norms [15,16]. In this study, we further com-pared the HR-QoL results assessed by the EORTC QLQ-C30 and QLQ-H&N35 modules for HNC survi-vors who, as a result of technological advances in RT at our institute, were treated with 2DRT, 3DCRT, or IMRT in different time periods.

Methods

Study population

This study is a cross sectional investigation, analyzing HR-QoL data of HNC patients who were cancer free when their HR-QoL was assessed during the period from January 2005 to December 2008. Eligibility criteria of patients included 1) pathologically proven HNC at nasopharynx, oral cavity, oropharynx, hypopharynx, or larynx, 2) receiving RT and regular follow-up at the department of radiation oncology at Chang Gung Mem-orial Hospital - Kaohsiung Medical Center, 3) cancer free survival more than two years after RT, and 4) com-pletion of the self-reported questionnaire. Six hundred and forty HNC patients, treated with definite or post-operative RT, were collected and informed consent was obtained from all of them. They included 371 patients treated by 2DRT and 269 patients by conformal RT (3DCRT: 127 patients, IMRT: 142 patients). Concerning the existence of selection bias, we compared the distri-butions of sociodemographic characteristics (including age, gender, marital status, and education level) between HNC survivors in the study and all other surviving HNC patients (n = 221) found in the cancer registry database in the department. No statistically significant differences were found between them (data not shown).

Patient characteristics including sociodemographic variables and cancer- or treatment- related variables are listed in Table 1. The cancer stages were according to the staging system of the American Joint Committee on Cancer (AJCC 6th edition) published in 2002. The comorbidity status was recorded according to the Charl-son comorbidity index by review of chart and on the basis of self-report [17]. A summary of the primary can-cer site included 316 cases (49%) of nasopharyx, 129 (20%) of oral cavity, 75 (12%) of oropharynx, 75 (12%) of hypopharynx, and 45 (7%) of larynx. As regards the sociodemographic information, 86% of them were edu-cated≦12 years, 53% with an annual family income ≦1.2 million NTD (1USD = 33NTD), 65% not employed, and 19% without a spouse (unmarried or divorced). Four hundred and thirty patients (67%) had AJCC stage III or IV disease and 267 (42%) patients had at least one kind of comorbidity. The major treatment was surgery in 249 (39%) patients and RT alone or plus C/T in 391 (61%) patients. Uneven distribution existed between the 2DRT and 3DCRT/IMRT group. The 3DCRT/IMRT group had a higher distribution in patients with lower annual family income, non-nasopharyngeal cancer site, stage III-IV, surgery, chemotherapy, or shorter survival years. The median (range) follow-up years of patients after treatment when their HR-QoL data were collected were 5.2 (2.8-14.1), 3.9 (2.1-10.3), and 3.1 (2.0-6.5) years in the 2DRT, 3DCRT, and IMRT group, respectively. This

study was approved by the appropriate institutional review boards (IRB) of the hospital.

Techniques of RT 2DRT

The detailed portal arrangement and dosing of conven-tional 2DRT in HNC have been described previously

[18,19]. Briefly, 2DRT was given in two phases, namely before and after 44~46.8 Gy of the spinal cord tolerance dose. In the first phase, patients were irradiated by a 6-MV photon beam with a daily fraction of 1.8 or 2.0 Gy (5~6 fractions per week) via bilateral opposing faciocer-vical fields and one lower anterior cerfaciocer-vical field. For definite RT, the target covers the primary tumor with surrounding anatomic area and regional neck lympha-tics. For postoperative cases, the surgical tumor and nodal bed as well as the prophylactic risky nodal area were included. In the second phase, the gross tumor was boosted to 64.8~81 Gy in definite RT and tumor bed to 57.6~64.8 Gy in postoperative cases via bilateral opposing photon beams to shield the spinal cord. Resi-dual neck lymph nodes or risky nodal bed area were simultaneously boosted by a 9- or 12-Mev electron beam to 56~79 Gy, depending on the nodal situation.

3DCRT

The immobilization, treatment targets, and dose/fractio-nation prescription of 3DCRT in treating HNC in our institute primarily followed the guidelines for 2DRT. The Cadplan (Varian, Milpitas, CA) or Pinnacle 3D treatment planning system (Pinnacle3, Philips, Fitch-burg, WI) was used. The technical details of 3DCRT in HNC have been addressed [19,20]. For each patient, 5 or 7 coplanar portals were usually designed. Shrinkage of the clinical target volume (CTV) volume was usually performed after the tumoricidal dose of 45.0-50.4 Gy was reached for the microscopic lesions. The 90-95% isodose volume to cover the planning target volume (PTV) with the spinal cord strictly limited below the 60% isodose line was applied.

IMRT

The immobilization, target definition and delineation, and dose/fractionation prescription of IMRT for HNSCC treated by combined modality were approxi-mately the same as described above for 3DCRT. We used the Cadplan or Pinnacle treatment planning system to perform the inverse planning and dose optimisation. For each patient, IMRT plans with five or seven copla-nar portals were created. The delivery of the plans was performed in Varian machines equipped with dynamic multi-leaf collimators. The dose/fractionation prescrip-tion of IMRT primarily followed the guidelines for 3DRT [16,21].

Instruments of HR-QoL

The Taiwan Chinese versions of the EORTC QLQ-C30 and QLQ-H&N35 questionnaires were obtained from the Quality of Life Unit, EORTC Data Center in Brus-sels, Belgium [4,6,22]. The EORTC questionnaires were chosen for this research because it is one of the most widely implemented questionnaires, with over 10 years of research invested to develop an integrated, modular

Table 1 Patient characteristics (n = 640)

Variables Total 2DRT 3DCRT IMRT

Patient number 640 371 127 142

Age, median (range) years 52 (15-87) 52 (15-87) 53 (31-83) 51 (23-79) Male/female 537/103 297/74 117/10 123/19 Education years ≦6 245 147 52 46 6~12 305 168 64 73 >12 90 56 11 23

Annual family income, (104 NTD) <60 119 53 30 36 60~120 218 125 47 46 ≥ 120 303 193 50 60 Marital status With spouse 518 298 102 118 Without spouse 122 73 25 24 Employment Yes 225 139 36 50 No 415 232 91 92 Cancer sites Nasopharynx 316 226 31 59 Oral cavity 129 64 33 32 Oropharynx 75 41 21 13 Hypoppharynx 75 20 28 27 Larynx 45 20 14 11 AJCC stage I-II 210 145 26 39 III-IV 430 226 101 103 Radiation dose ≦70.2Gy 281 126 81 74 >70.2Gy 359 245 46 68 Surgery No 391 264 53 74 Yes 249 107 74 68 Chemotherapy No 343 237 57 49 Yes 297 134 70 93 Comorbidity score 0 373 219 66 88 ≧1 267 152 61 54

Follow-up years, median 4.3 5.2 3.9 3.1

Abbreviations: RT = radiotherapy; 2DRT = two dimensional RT; 3DCRT = three dimensional conformal RT; IMRT = intensity-modulated RT; 1USD = 33NTD; AJCC = American Joint Committee on Cancer, 6th edition; Comorbidity score was based on Charlson comorbidity index.

modality in most of our subjects, we found that the dosimetric improvement for 3DCRT compared with IMRT might not be sufficiently large to demonstrate any significant difference in HR-QoL.

Besides radiation technique, socioeconomic status, comorbidity, and tumor site were also found to be sig-nificant prognosticators on HR-QoL outcome. With the relatively heterogeneous nature of HNC patients and experienced treatments including varying tumor stages, sites, and the frequently diverse treatment modalities applied and involved administering institutions, the fac-tors affecting the HR-QoL after treatment for HNC patients usually appear to be somewhat discordant and complicated in the literature. For example, Hammerlid et al. found those HNC survivors with tumor located at larynx, aged below 65 years, or female patients had sig-nificantly better HR-QoL than their counterparts three years after treatment [33] and de Graeff et al. reported female sex, higher cancer stage, and combination treat-ment were found to be associated with more sympto-matic problems and worse HR-QoL [34].

Although being comprehensive and well validated with recognized internal consistency and reliability, EORTC QLQ-C30 and QLQ-H&N35 still have some limitations in the interpretation of HR-QoL of HNC patients, because they do not deal with some specific but common late sequelae, such as deafness, otitis media, symptoms from temporal lobe necrosis, or radiation neuropathy, or hypopituitarism in nasophar-yngeal cancer survivors. A tumor site-specific assess-ment tool of HR-QoL might provide more specific and sensitive information to discriminate site-related differ-ences of HR-QoL in HNC patients with various tumor sites treated by different strategies. Furthermore, with-out pre-treatment HR-QoL data available in our cohort, potential selection bias might still exist in the cross sectional study, though the confounding variables adjusted by multivariate analysis. A longitudinal study assessing the changes of HR-QoL will be justified to more accurately detect the differences between the groups.

Conclusions

With the advance of modern RT technology, head-and-neck related symptoms after RT could be significantly reduced and reflected to the improvement of broad aspects of HR-QoL in HNC survivors. However, there may still be some undetected factors, which are related to global QoL or some specific functional domains, to be explored in future investigation.

Abbreviations

HR-QoL: health-related quality of life; HNC: head and neck cancer; EORTC QLQ-C30: European Organization for Research and Treatment of Cancer

Quality of Life Core questionnaire; H&N35: Head and Neck Module; GLM-MANOVA: general linear model multivariate of variance; NTD: New Taiwan Dollar (1 USD = 33 NTD); CCI: Charlson comorbidity index; AJCC: American Joint of Cancer Committee published in 2002; S: surgery; RT: radiotherapy; C/ T: chemotherapy; 2DRT: two dimensional RT; 3DCRT: three dimensional conformal RT; IMRT: intensity modulated RT;β: un-standardized regression coefficient; SE: standard error; NS: not significant.

Acknowledgements

The study was supported by the grants“CMRPG860501”, “CMRPG860502”, “CMRPG890062”, and “NSC 99-2221-E-151-010”.

Author details

1

Department of Radiation Oncology, Yuan’s General Hospital, Kaohsiung City, Taiwan.2_{Department of Radiological Technology, Central Taiwan University}

of Science and Technology, Taichung City, Taiwan.3Medical Physics & Informatics Lab., Department of Electronics Engineering, National Kaohsiung University of Applied Sciences, Kaohsiung, Taiwan.4Department of Otolaryngology, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.5_Radiation

Oncology, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

6

Department of Biotechnical Cosmetology, Cheng Shiu University, Kaohsiung, Taiwan.

Authors’ contributions

SW Leung and TFL: writing of manuscript and study coordinator. FMF: original idea, concept and final revision of manuscript. CC, TFL, WLT and PJC: design and development of study. WLT: statistical analysis. All authors read and approved the final manuscript

Competing interests

The authors declare that they have no competing interests.

Received: 12 August 2010 Accepted: 12 April 2011 Published: 12 April 2011

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Cite this article as: Wan Leung et al.: Health-related Quality of life in 640 head and neck cancer survivors after radiotherapy using EORTC QLQ-C30 and QLQ-H&N35 questionnaires. BMC Cancer 2011 11:128.

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