Multivariate analysis of quality of life outcome for nasopharyngeal carcinoma patients after treatment

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Quality of life after radiotherapy

Multivariate analysis of quality of life outcome for nasopharyngeal carcinoma

patients after treatment

Fu-Min Fang

a,⇑

, Wen-Ling Tsai

b

, Tsair-Fwu Lee

a,c

, Kuan-Cho Liao

a

, Hui-Chun Chen

a

, Hsuan-Chih Hsu

a a_{Department of Radiation Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan;}b_{Department of} Cosmetic Application and Management, Yung Ta Institute of Technology & Commerce, Pintung, Taiwan;c

National Kaohsiung University of Applied Sciences, Taiwan

a r t i c l e

i n f o

Article history:

Received 17 August 2009

Received in revised form 9 March 2010 Accepted 18 May 2010 Keywords: Nasopharyngeal carcinoma Quality of life EORTC QLQ-C30 EORTC QLQ-H&N35 Intensity-modulated radiotherapy

a b s t r a c t

Purpose: The study analyzed the prognostic factors of quality of life (QoL) for patients with nasopharyn-geal carcinoma (NPC) after treatment, with focusing on the therapeutic beneﬁts of the technological advances in radiotherapy (RT).

Materials and methods: A cross-sectional investigation was conducted to assess the QoL of 356 NPC patients with cancer-free survival of more than 2 years. Among them, 106 patients were treated by two-dimensional RT (2DRT), 108 by 2DRT plus three-dimensional conformal RT (3DCRT) boost, 58 by 3DCRT alone, and 84 by intensity-modulated RT (IMRT). The QoL was assessed by the EORTC QLQ-C30 questionnaire and QLQ-H&N35 module. The clinical difference of QoL scores between groups was calcu-lated using Cohen’s D coefﬁcient.

Results: We found NPC survivors who had a higher education level or annual family income and who had received more advanced RT treatments had better QoL outcomes. Compared with 2DRT, the impact of 3DCRT was small on most scales and moderate (Cohen’s D: 0.53–0.67) on emotional functioning, pain, and mouth opening; the impact of IMRT was moderate on nine scales and large (Cohen’s D: 0.80–0.88) on swallowing, social eating, teeth, and mouth opening.

Conclusions: In addition to socioeconomic levels, advances in RT technique played a signiﬁcant role in improving QoL of NPC patients.

Conventionally, the endpoints of medical care for cancer pa-tients usually focused on the survival rate, local control rate, or complication rate. These endpoints were typically assessed from the physician’s points of view and lacked knowledge of patients’ mental or emotional well being. Quality of life (QoL) refers to the perception of the effects of disease and its impact on the patient’s daily functioning; QoL is a multi-dimensional issue, incorporating physical, psychological, social, and emotional domains, and it must be self-reported according to the patient’s own experiences[1]. In perhaps no other group of cancer patients is QoL as important as in head and neck cancer (HNC) patients. This is because they may have obvious debilitating problems with swallowing, speech, and hearing, as well as psychological effects associated with loss of function and change in body image[2].

Nasopharyngeal carcinoma (NPC) is a prevalent disease in Tai-wan. NPC is unique among forms of HNC. It affects a younger group of patients, usually with no history of smoking or alcohol abuse and with a higher socioeconomic status at the time of presentation. With modern radiotherapy (RT) technology alone or in combination with

chemotherapy, many NPC patients can be cured, even at advanced stages of the disease[3,4]. Thus, the assessment of QoL for NPC sur-vivors has become an important issue for the following reasons. First, knowing differences in QoL between NPC survivors treated by differ-ent methods might be an indicator of the success of a novel strategy. Second, identifying speciﬁc functional impairments after NPC treat-ment may help clinicians target possible late effects that need spe-cial attention during patient follow-up. Third, information on the variables correlated with QoL in NPC survivors may help healthcare planners identify which patients need more services, such as physi-cal rehabilitation, social support, or psychologiphysi-cal consultation.

Several well-validated QoL instruments are now available for use in HNC patients. In the current study, we used the European Re-search and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), version 3.0, together with the Head and Neck module (QLQ-H&N35)[5,6]. The questionnaires are comprehensive, and their validity, internal consistency, and reliability in patients using different languages, including the Taiwan Chinese version, have been tested with excellent results[7]. The study analyzed the prognostic factors of QoL for NPC patients with cancer-free survival after treatment, with focusing on the therapeutic beneﬁts of the technological advances in RT at our institute at different time periods.

⇑Corresponding author. Address: Department of Radiation Oncology, Chang Gung Memorial Hospital – Kaohsiung Medical Center, 123 Ta-Pei Rd., Niao Sung Hsian, Kaohsiung Hsien, Taiwan.

E-mail address:fang2569@adm.cgmh.org.tw(F.-M. Fang).

Radiotherapy and Oncology 97 (2010) 263–269

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Radiotherapy and Oncology

j o u r n a l h o m e p a g e : w w w . t h e g r e e n j o u r n a l . c o m

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Materials and methods

There were 989 newly diagnosed NPC patients consecutively treated by curative RT at the department of radiation oncology at Chang Gung Memorial Hospital – Kaohsiung Medical Center from January 1995 to December 2005. Among them, 295 patients died of treatment failure, 52 died of other causes, and 37 were lost to follow-up, as recorded in the cancer registration database of the institute. This study was a cross-sectional investigation to assess the QoL for NPC patients treated during this period and with can-cer-free survival more than 2 years after treatment. Of the remain-ing 605 NPC survivors, the QoL data from 356 patients were collected. The cancer-free status of patients was conﬁrmed by re-sults of clinical examinations and recent image studies. Informed consent was obtained from all subjects. As regards the technolog-ical evolution of RT in the hospital, radtechnolog-ical RT for treating NPC was routinely delivered by 2DRT before the introduction of 3DCRT in April 1996. From April 1996 to March 2002, 3DCRT was gradually used to replace 2DRT in the boost phase for curable NPC cases or in salvage treatment of recurrent disease. After becoming familiar with the techniques of 3DCRT and implementation of the IMRT system by March 2002, the physicians and physicists in the insti-tute began to use the two techniques as a standard strategy in treating NPC. The choice of 3DCRT or IMRT mainly depended on the preference of the physicians and the availability of the Linac machines equipped with. Among the 356 patients with QoL avail-able in the study, 214 patients were treated by conventional RT (2DRT: 106 patients, and 2DRT plus 3DCRT boost: 108 patients) during January 1995 – March 2002, and 142 patients by conformal

RT (3DCRT: 58 patients, and IMRT: 84 patients) for the whole treat-ment course during March 2002 – December 2005. The patient characteristics, including sociodemographic variables and cancer-and treatment-related variables, are listed inTable 1. Cancers trea-ted prior to 2002 were re-staged according to the American Joint Cancer Committee (AJCC) staging system published in 2002 based on their previous image reports. Comorbidity status was recorded according to the Charlson comorbidity index (CCI), by review of charts, and on the basis of self-reported information[8].

Regarding sociodemographic factors, 68.8% of the patients had more than 6 years of education, 53.3% had an annual family income P120 104_{NTD (1 USD = 33 NTD), and 78.9% had spouses. Of the} patients, 279 (78.4%) had AJCC stage II or III disease, and 138 (38.8%) patients had at least one kind of comorbidity. Of the pa-tients, 106 (29.8%) were treated by two-dimensional RT (2DRT), 108 (30.3%) by 2DRT plus three-dimensional conformal RT (3DCRT) boost, 58 (16.3%) by 3DCRT alone, and 84 (23.6%) by intensity-modulated RT (IMRT). The median (range) survival years for pa-tients after treatment when their QoL data were collected were 6.6 (2.0–15.2): speciﬁcally, 7.6 (3.8–15.2), 6.4 (3.1–11.3), 4.9 (2.4–7.2), and 3.7 (2.0–6.1) years in the 2DRT, 2DRT plus 3DCRT boost, 3DCRT, and IMRT groups, respectively.

RT techniques 2DRT

The detailed portal arrangement and dosing of 2DRT have been described previously[4]. Brieﬂy, 2DRT was given in two phases, be-fore and after 45–46.8 Gy of the spinal cord tolerance dose. In the

Table 1

Patient characteristics (n = 356).

Variables Total 2DRT (n = 106) 2DRT + 3DCRT boost (n = 108) 3DCRT (n = 58) IMRT (n = 84) p Age, median (range) years 47 (15–81) 48 (15–75) 46 (19–81) 50 (24–79) 46 (23–78) 0.231

540 49 (13.8%) 18 (17.0%) 14 (13.0%) 5 (8.6%) 12 (14.3%) 40–65 261 (73.3%) 70 (66.0%) 80 (74.1%) 44 (75.9%) 67 (79.8%) >65 46 (12.9%) 18 (17.0%) 14 (13.0%) 9 (15.5%) 5 (6.0%) Gender 0.683 Male 256 (71.9%) 72 (67.9%) 81 (75.0%) 43 (74.1%) 60 (71.4%) Female 100 (28.1%) 34 (31.2%) 27 (25.0%) 15 (25.9%) 24 (28.6%) Marital status 0.101 With spouse 281 (78.9%) 75 (70.8%) 90 (83.3%) 48 (82.8%) 68 (81.0%) Without spouse 75 (21.1%) 31 (29.2%) 18 (16.7%) 10 (17.2%) 16 (19.0%) Education years 0.147 5₆ _{111 (31.2%)} _{40 (37.7%)} _{28 (25.9%)} _{24 (41.4%)} _{19 (22.6%)} 6–12 161 (45.2%) 44 (41.5%) 51 (47.2%) 22 (37.9%) 44 (52.4%) >12 84 (23.6%) 22 (20.8%) 29 (26.9%) 12 (20.7%) 21 (25.0%)

Annual family income, (104_NTD) _0.412

<60 34 (9.6%) 12 (11.3%) 7 (6.5%) 4 (6.9%) 11 (13.1%) 60–120 132 (37.1%) 43 (40.6%) 42 (38.9%) 23 (39.7%) 24 (28.6%) P120 190 (53.3%) 51 (48.1%) 59 (54.6%) 31 (53.4%) 49 (58.3%) CCI score 0.576 0 218 (61.2%) 68 (64.2%) 66 (61.1%) 31 (53.4%) 53 (63.1%) =1 138 (38.8%) 38 (35.8%) 42 (38.9%) 27 (46.6%) 31 (36.9%) AJCC stage 0.751 I 21 (5.9%) 8 (7.5%) 7 (6.5%) 2 (3.4%) 4 (4.8%) II 162 (45.5%) 52 (49.1%) 42 (38.8%) 26 (44.8%) 42 (50.0%) III 117 (32.9%) 31 (29.2%) 41 (38.0%) 18 (31.1%) 27 (32.1%) IV 56 (15.7%) 15 (14.2%) 18 (16.7%) 12 (20.7%) 11 (13.1%)

RT dose, median (range), Gy 72.0 (64.8–81.0) 72.0 (64.8–81.0) 72.0 (64.8–81.0) 72.0 (64.8–81.0) 70.2 (64.8–81.0) 0.311

<72.0 168 (47.2%) 52 (49.1%) 48 (44.4%) 24 (41.4%) 44 (52.4%)

P72.0 188 (52.8%) 54 (50.9%) 60 (55.6%) 34 (58.6%) 40 (47.6%)

Chemotherapy 0.875

No 231 (64.9%) 69 (65.1%) 66 (61.1%) 38 (65.5%) 58 (69.0%)

Yes 125 (35.1%) 37 (34.9%) 42 (38.9%) 20 (34.5%) 26 (31.0%)

Survival years, median (range) <0.001

2–5 120 (33.7%) 15 (14.2%) 30 (27.8%) 29 (50.0%) 46 (54.8%)

5–10 190 (53.4%) 53 (50.0%) 70 (64.8%) 29 (50.0%) 38 (45.2%)

>10 46 (12.9%) 38 (35.8%) 8 (7.4%) 0 (0.0%) 0 (0.0%)

NTD: New Taiwan Dollar (1 USD = 33 NTD); CCI: Charlson comorbidity index; AJCC: American Joint of Cancer Committee published in 2002; RT: radiotherapy; 2DRT: two-dimensional RT; 3DCRT: three-two-dimensional conformal RT; IMRT: intensity-modulated RT.

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first phase, patients were irradiated with a 6-MV photon beam, with a daily fraction of 1.8 Gy (5–6 fractions per week), via bilateral opposing faciocervical fields and one lower anterior cervical field to cover the anatomical structures at risk of tumor invasion in the vicinity of the nasopharynx and regional neck lymphatics. In the second phase, the RT dosage for primary tumor and retropha-ryngeal area was boosted to 64.8–70.2 Gy for T1–2 tumors and 72.0–75.6 Gy for T3–4 tumors, via bilateral opposing photon beams to shield the spinal cord. Residual neck lymph nodes were simultaneously boosted by a 9- or 12-MeV electron beam to 59– 79 Gy, depending on the nodal size.

3DCRT

The fractionation of dose and total dose of 3DCRT or IMRT in treat-ing NPC primarily followed the guidelines for 2DRT. The Pinnacle 3D treatment planning system (ADAC Laboratories, Milpitas, CA) was used. The technical details of 3DCRT of NPC have been addressed pre-viously[3]. For patients treated with 3DCRT for the whole treatment course, the clinical target volume (CTV) included the gross tumor volume (GTV), the nearby anatomic structures (including the medial pterygoid muscles, the parapharyngeal spaces, carotid space, the sphenoid sinus, posterior nasal cavity, and the anterior half of the cli-vus), and bilateral upper neck lymphatics. The lower neck was not in-cluded in the 3DCRT technique, but was irradiated with a matched anterior field with a central block. Shrinkage of the CTV volume was usually performed after the tumoricidal dose of 50.4 Gy was reached for the microscopic lesions. The numbers and directions of beams depended on the extent of individual tumors. Typically, five co-planar beams were the most common plans generated in 3DCRT. For cases with a tumor above the level of the eyeball, non-coplanar fields with beam directions from the vertex were usually designed to spare the lens. The critical organs including the spinal cord, brain stem, temporal lobes, parotid glands, optic nerves, and ear canals were spared as much as was possible. The 90–95% isodose volume to cover the planning target volume (PTV), with the spinal cord strictly limited below the 60% isodose line, was usually applied. The technique and target delineation for cases selected to use 3DCRT as a boost after the first phase of 2DRT also followed the principles above; the difference was that the spinal cord was kept completely out of the radiation field. The dosimetric details of this technique have been addressed by Hsiung et al.[9,10].

IMRT

The immobilization, target deﬁnition and delineation, and dose/ fractionation prescription of IMRT were approximately the same as described above for 3DCRT. The difference was that the lower neck lymphatics were usually included in the IMRT planning. We used the CadPlan or Pinnacle treatment planning system to perform in-verse planning and dose optimization. For each patient, IMRT plans with ﬁve or seven co-planar portals were created. The constraints of organs at risk and dose calculation, as well as the dosimetric comparison of IMRT versus 3DCRT have been described previously

[9,10]. The delivery of the plans was performed in Linac machines equipped with multi-leaf collimators.

Chemotherapy

A total of 125 patients (35.1%) with advanced AJCC stage were treated with a combination of systemic chemotherapy as adjuvant or concurrent sequence. The regimens used involved a combina-tion of cisplatin and 5-ﬂuorouracil, administered intravenously. QoL instruments

The Taiwan Chinese versions of the EORTC C30 and QLQ-H&N35 questionnaires were obtained from the Quality of Life Unit,

EORTC Data Center in Brussels, Belgium[5,6]. The EORTC QLQ-C30 is a widely used questionnaire. It incorporates a range of QoL issues relevant to a broad range of cancer patients. It has been translated into many languages and validated for many types of cancer, including head and neck cancer. It contains five functional scales (physical, role, cognitive, emotional, social), three symptom scales (fatigue, pain, nausea/vomiting), a global QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties). The QLQ-H&N35 is a module used specifically for assessing the QoL for HNC patients. It incorporates seven multi-ple-item scales that assess the symptoms of pain, swallowing abil-ity, senses (taste/smell), speech, social eating, social contact, and sexuality. Also included are six single-item scales that survey the presence of symptomatic problems associated with teeth, mouth opening, dry mouth (xerostomia), sticky saliva, coughing, and feel-ing ill. Scores on all scales pertainfeel-ing to the EORTC QLQ-C30 and QLQ-H&N35 range from 0 to 100. A high score for a functional or global QoL scale represents a relatively high/healthy level of func-tioning or global quality of life, whereas a high score for a symptom scale represents the presence of a symptom or problem.

Statistical analyses

The mean scores on the QoL scales were calculated according to the EORTC QLQ scoring manual[11]. To analyze the correlations between the factors and the QoL scales, general linear model (GLM) multivariate of variance (MANOVA) was used. The GLM-MANOVA approach is used to test the hypothesis of a significant association between a set of interrelated dependent variables (the QoL scales) and independent variables. The independent vari-ables analyzed in the present study consisted of five sociodemo-graphic variables including age (<40 vs. 40–65 vs. >65 years), gender (male vs. female), years of education (66 vs. 6–12 vs. >12 years), marital status (with vs. without spouse), and annual family income (<60 vs. 60–120 vs. P120 104_{NTD), and five} clin-ical factors including CCI score (0 vs. P1), AJCC stage (stage I vs. II vs. III vs. IV), RT technique (2DRT vs. 2DRT plus 3DCRT boost vs. 3DCRT vs. IMRT), chemotherapy (yes vs. no), and survival years (2–5 vs. 5–10 vs. >10 years).

The GLM-MANOVA was performed for EORTC QLQ-C30 and QLQ-H&N35 separately, and in the following two steps. First, to investigate the association of a given factor with QoL scales, a uni-variate analysis was conducted to establish whether the factor was associated significantly with any of the QoL scales. Wilks’ k was used to test the impact of each variable included in the model. Sec-ond, all variables were then entered into the multi-factor model. In case of a significant association between a factor and all QoL scales taken together, a second ANOVA was performed to investigate the association between that prognostic factor and each QoL scale sep-arately, with post hoc testing using the Bonferroni method. The clinical relevance of the difference in the mean scores of the QoL scales between groups was further measured by calculating the ef-fect size using Cohen’s D coefficient. Efef-fect sizes of <0.50, 0.50– 0.79, and P0.80 are generally considered small, moderate, and large, respectively[12,13]. Analyses were performed using the sta-tistical software package SPSS for Windows (version 13.0; SPSS Inc., Chicago, IL).

Results

Test of potential selection bias

Regarding selection bias, we compared the distributions of soci-odemographic characteristics (including age, gender, marital sta-tus, and education level) between NPC survivors in the study (n = 356) and all other surviving NPC patients (n = 249) in the same

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sites of cancer patients, socioeconomic status remained one of the most significant variables correlated with QoL in our cohort. Those who had a higher economic status or a higher education level tended to enjoy a better QoL. For example, Penson et al. reported that prostate cancer patients with lower socioeconomic status had significantly lower QoL scores on most functional domains of the SF-36 before and after treatment[25]. Ramsey et al. reported that lower income status in survivors of colorectal cancer was associated with worse outcome for reported pain, ambulation, and social and emotional status[26]. These findings might suggest that patients’ individual capabilities and the resources available to cope with the cancer threats and complications remained a strong variable affecting their later QoL.

It should be noted that EORTC QLQ-C30 and QLQ-H&N35 still have some limitations with regard to the interpretation of QoL in NPC patients because they do not deal with some specific but com-mon late sequelae in NPC survivors, such as deafness, otitis media, and the symptoms from temporal lobe necrosis, radiation neurop-athy, or hypopituitarism. Another limitation of this study is that without pre-treatment QoL data available for our cohort, potential selection bias might exist in a cross-sectional investigation. Although the time of survival differed significantly among the four groups when the QoL scales were completed, no significant effect of time on QoL was found in the results. One possible explanation is the response shift in our cohort. All the patients survived for >2 years when the QoL questionnaire was completed, which might have enabled them to adapt to treatment-related side effects, reap-praise their life circumstances, review their life goals and plans, or alter their life satisfaction.

In conclusion, in addition to socioeconomic levels, advanced RT techniques were observed to play a significant role in improving the QoL outcome of NPC survivors. However, the impact size from conventional 2DRT to 3DCRT or IMRT varied on different QoL scales. The therapeutic benefit of IMRT over 2DRT, especially on the swallowing-related QoL scales, should be explored further. Conflict of interest statement

No actual or potential conﬂict of interest exists. Acknowledgments

The study was supported by the Grants ‘‘CMRPG860501” and ‘‘CMRPG860502” from the Chang Gung Memorial Hospital, Taiwan. The authors thank Yang Wei-Jiuan, Su Ching-Ju, and Huang Mei-Yueh for their assistance of data collection.

References

[1] List MA, Stracks J. Evaluation of quality of life in patients deﬁnitively treated for squamous carcinoma of head and neck. Curr Opin Oncol 2000;12:215–20. [2] Terrell JE, Nanavati K, Esclamado RM, Bradford CR, Wolf GT. Health impact of

head and neck cancer. Otolaryngol Head Neck Surg 1999;120:852–9. [3] Fang FM, Tsai WL, Ko SF, et al. Implications of quantitative tumor and nodal

regression rates for nasopharyngeal carcinomas after 45 Gy of RT. Int J Radiat Oncol Biol Phys 2001;50:961–9.

[4] Fang FM, Leung SW, Wang CJ, et al. Computed tomography ﬁndings of bony regeneration after RT for nasopharyngeal carcinoma with skull base destruction: implications for local control. Int J Radiat Oncol Biol Phys 1999;44:305–9.

[5] Aronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76.

[6] Bjordal K, Hammerlid E, Ahlner-Elmqvist M, et al. Quality of life in head and neck cancer patients: validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35. J Clin Oncol 1999;17:1008–19.

[7] Chie WC, Hong RL, Lai CC, Ting LL, Hsu MM. Quality of life in patients of nasopharyngeal carcinoma: validation of the Taiwan Chinese version of the EORTC QLQ-C30 and the EORTC QLQ-H&N35. Qual Life Res 2003;12:93–8. [8] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying

prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83.

[9] Hsiung CY, Yorke ED, Chui CS, et al. Intensity-modulated radiotherapy versus conventional three-dimensional conformal radiotherapy for boost or salvage treatment of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2002;53:638–47.

[10] Hsiung CY, Hunt MA, Yorke ED, et al. Intensity-modulated radiotherapy as the boost or salvage treatment of nasopharyngeal carcinoma: the appropriate parameters in the inverse planning and the effect of patient’s anatomic factors on the planning results. Radiother Oncol 2005;77:53–7.

[11] Fayers P, Aaronson NK, Bjordal K, et al. EORTC QLQ-C30 scoring manual. 2nd ed. Brussels, Belgium: EORTC Data Center; 1999.

[12] Middel B, Stewart R, Bouma J, et al. How to validate clinically important change in health-related functional status: is the magnitude of the effect size consistently related to magnitude of change as indicated by a global question rating? J Eval Clin Pract 2001;7:399–410.

[13] Cohen D. Statistical power analysis for the behavioral sciences. 2nd ed. NJ, Erlbaum: Hillsdale; 2007.

[14] Fang FM, Chiu HC, Kuo WR, et al. Health-related quality of life for nasopharyngeal carcinoma patients with cancer-free survival after treatment. Int J Radiat Oncol Biol Phys 2002;53:959–68.

[15] Teo PML, Ma BBY, Chan ATC. Radiotherapy for nasopharyngeal carcinoma— transition from two-dimensional to three-dimensional methods. Radiother Oncol 2004;73:163–72.

[16] Jen YM, Shih R, Lin YS, et al. Parotid gland-sparing 3-dimensional conformal radiotherapy results in less severe dry mouth in nasopharyngeal cancer patients: a dosimetric and clinical comparison with conventional radiotherapy. Radiother Oncol 2005;75:204–9.

[17] Saarilahti K, Kouri M, Collan J, et al. Intensity modulated radiotherapy for head and neck cancer: evidence for preserved salivary gland function. Radiother Oncol 2005;74:251–8.

[18] Kwong DLW, Pow EHN, Sham JST, et al. Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: a prospective study on disease control and preservation of salivary function. Cancer 2004;101:1584–93.

[19] Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981–91.

[20] Vergeer MR, Doornaert PA, Rietveld DH, Leemans CR, Slotman BJ, Langendijk JA. Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: results of a nonrandomized prospective study using a standardized follow-up program. Int J Radiat Oncol Biol Phys 2009;74:1–8.

[21] Fang FM, Chien CY, Tsai WL, et al. Quality of life and survival outcome for patients with nasopharyngeal carcinoma receiving three-dimensional conformal radiotherapy vs. intensity-modulated radiotherapy—A longitudinal study. Int J Radiat Oncol Biol Phys 2008;72:356–64.

[22] Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, Leemans CR, Aaronson NK, Slotman BJ. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol 2008;26:3770–6.

[23] Levendag PC, Teguh DN, Voet P, et al. Dysphagia disorders in patients with cancer of the oropharynx are signiﬁcantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose–effect relationship. Radiother Oncol 2007;85:64–73.

[24] Teguh DN, Levendag PC, Noever I, et al. Treatment techniques and site considerations regarding dysphagia-related quality of life in cancer of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 2008;72:1119–27. [25] Penson DF, Stoddard ML, Pasta DJ, et al. The association between socioeconomic status, health insurance coverage, and quality of life in men with prostate cancer. J Clin Epidemiol 2001;54:350–8.

[26] Ramsey SD, Andersen MR, Etzioni R, et al. Quality of life in survivors of colorectal carcinoma. Cancer 2000;88:1294–303.