- Email: [email protected]
Can Intensity-Modulated Radiotherapy Preserve Oral Health-Related Quality of Life of Nasopharyngeal Carcinoma Patients?
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Head and Neck Cancer
Can Intensity-Modulated Radiotherapy Preserve Oral Health-Related Quality of Life of Nasopharyngeal Carcinoma Patients? Edmond H.N. Pow, Ph.D.,* Dora L.W. Kwong, M.D., F.R.C.R.,y Jonathan S.T. Sham, M.D., F.R.C.R.,y Victor H.F. Lee, M.B.B.S., F.R.C.R.,y and Sherry C.Y. Ng, Ph.D.y *Oral Rehabilitation, The University of Hong Kong Faculty of Dentistry, Hong Kong Special Administrative Region, People’s Republic of China; and yDepartment of Clinical Oncology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong Special Administrative Region, People’s Republic of China Received Jul 15, 2011, and in revised form Dec 3, 2011. Accepted for publication Dec 9, 2011
Summary The oral health-related quality of life of 57 patients with early-stage nasopharyngeal carcinoma who had received intensity-modulated radiotherapy was followed up for 2 years. The parotid saliva flow had recovered fully after 1 year and whole saliva flow had recovered to 40% of baseline. A general trend of deterioration in most quality of life scales was observed after intensitymodulated radiotherapy, followed by a gradual recovery. Persistent oral-related symptoms were found 2 years after treatment.
Purpose: To investigate the changes in salivary function and oral health-related quality of life for patients with nasopharyngeal carcinoma treated by intensity-modulated radiotherapy (IMRT). Methods and Materials: A total of 57 patients with early-stage nasopharyngeal carcinoma received IMRT. The parotid and whole saliva flow was measured, and the Medical Outcomes Study 36-item short form, European Organization for Research and Treatment of Cancer Quality of Life questionnaire-C30, European Organization for Research and Treatment of Cancer Quality of Life questionnaire 35-item head-and-neck module, and Oral Health Impact Profile questionnaires were completed at baseline and 2, 6, 12, 18, and 24 months after IMRT. Results: Parotid saliva flow recovered fully after 1 year and maintained. Whole saliva flow recovered partially to 40% of baseline. A general trend of deterioration in most quality of life scales was observed after IMRT, followed by gradual recovery. Persistent oral-related symptoms were found 2 years after treatment. Conclusion: IMRT for early-stage nasopharyngeal carcinoma could only partially preserve the whole salivary function and oral health-related quality of life. Ó 2012 Elsevier Inc.
Reprint requests to: Edmond H. N. Pow, Ph.D., Oral Rehabilitation, The University of Hong Kong Faculty of Dentistry, 34 Hospital Road,
Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. e213ee221, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.12.040
Hong Kong. Tel: (852) 2859-0309; Fax: (852) 2858-6114; E-mail: [email protected] Conflict of interest: none.
e214 Pow et al.
International Journal of Radiation Oncology Biology Physics
Introduction
involved in lateral extension of the NPC. Thus, the part of parotid gland overlapping into the PTV would have the prescribed dose to the PTV in IMRT planning. A dose constraint of 25 Gy was set to the superficial part of the parotid gland that was outside the PTV. To estimate the actual dose received by the bilateral parotid glands, we separately contoured the whole parotid without the PTV and overlaid the treatment plan on the parotid glands. The same was applied for the submandibular glands. Because NPC is a midline tumor and has a high propensity for bilateral lymphatic involvement, especially to the jugulodigastric nodes, the posterior part of both submandibular glands were included in the PTV. The true doses received by the submandibular glands were also estimated by separately contouring the submandibular glands without the PTV. Only the nasopharnyx and upper neck were treated with IMRT in the present study. The neck was irradiated with a separate anterior cervical field with a midline shield, matched with the lower border of the IMRT fields. The prescribed dose to the anterior cervical field was 60e66 Gy at 100% isodose level, in 30e33 fractions. The matching between the IMRT and anterior cervical field was inferior to the chin or inferior to enlarged neck nodes. The midline shield was 3 cm wide at the level of the larynx and 2 cm inferior to the larynx, shielding the cervical spine. Because the Corvus planning system did not allow summation of the dose from IMRT and the conventional anterior cervical field, the exact doses to the larynx and hypopharynx were not known. However, because all patients in the present series had early-stage disease, the field matching was usually just inferior to the chin, and the larynx and hypopharynx should be protected by the midline shield in the anterior cervical field, and were assumed to have received only scattered dose. At 8e10 weeks after IMRT completion, nasopharyngoscopy and biopsies were performed to assess the disease control in the nasopharynx. Thereafter, the patients were followed up every month during the first year, every 2 months in the second year, and every 3e6 months thereafter. The first post-treatment computed tomography scan was performed at 3e6 months after RT completion, and afterward regular computed tomography or magnetic resonance imaging was performed every 6 months or when indicated clinically.
Nasopharyngeal carcinoma (NPC) is rare in caucasians but common in the southern Chinese. Hong Kong is one of the cities with a high age-adjusted incidence of NPC (1). NPC is primarily treated by radiotherapy (RT) because the tumor is highly radiosensitive. However, conventional radiotherapy induces long-term irreversible deleterious oral complications that compromise patients’ quality of life (QOL) (2e4). However, intensitymodulated RT (IMRT), which spares the salivary glands from radiation damage, has been shown to preserve the salivary function and QOL without compromising the disease control in earlystage NPC patients (5e9). The QOL is now regarded as one of the primary outcomes of medical care. Various validated measures specific for the assessment of head-and-neck cancer are available (10). Although oral complications are the major problems in NPC survivors, no prospective studies have been published on the oral health-related QOL (OHRQOL) in NPC patients undergoing IMRT. The present study was aimed to assess the changes of salivary function and OHRQOL of southern Chinese with early-stage NPC 2 years after IMRT.
Methods and Materials The present study was a prospective longitudinal study performed between 2000 and 2007. A total of 65 consecutive patients with histologically confirmed Stage I and II (T1-T2N0-N1M0 disease) primary NPC were recruited. All patients were treated with a full course of IMRT at the Department of Clinical Oncology, Queen Mary Hospital, Hong Kong. No adjunctive chemotherapy was used for this group of patients with early-stage disease. The patients who had undergone previous head-and-neck RT were excluded. The institutional review board of the University of Hong Kong/Hong Kong Hospital Authority West Cluster, Hong Kong, approved the study. All patients provided written informed consent.
Intensity-modulated RT
Questionnaires Intensity-modulated RT was performed using the Corvus system, version 3.0 (NOMOS, Sewickley, PA) (11). In brief, the patient was immobilized in a cast, and the planning computed tomography scan of the head and neck was used for localization of the targets and organs at risk. The primary gross tumor volume (GTV) included the gross tumor in the nasopharynx and any extension of tumor outside the nasopharynx. The primary clinical target volume covered the potential sites of local tumor infiltration, including the whole nasopharynx, and 1-cm margin around the GTV. Enlarged neck nodes were localized as the nodal GTV. The nodal CTV included 0.5-cm margin around the nodal GTV and elective nodal RT to both upper neck sides (level IB-II and IVa). A 3-mm margin was added to both CTVs to create the planning target volume (PTV), which covered the skull base to the upper cervical lymphatics. The prescribed dose to the PTV was 66e68 Gy in 34 fractions within 7 weeks. The dose to the primary GTV was 68e72 Gy. The Corvus system did not allow for overlapping volumes. The deep lobe of the parotid gland was included in the PTV, because it is in close proximity to the parapharynx, which is commonly
All participants completed the Medical Outcomes short form 36-item questionnaire (SF-36), the European Organization for Research and Treatment of Cancer (EORTC) QOL core questionnaire (EORTC QLQ-30 [þ3]), the EORTC head-and-neck module (EORTC QLQ-H&N35), and the Oral Health Impact Profile (OHIP-49) assisted by a trained interviewer. The interviewer was not involved in any aspect of the medical or dental care of the participants. The questionnaires were completed after diagnosis and before RT at the pre-RT dental care visit (baseline) and then at 2, 6, 12, 18, and 24 months after therapy. All questionnaires have been translated and validated (12e15).
Salivary gland function Salivary function was assessed by 1 dentist before treatment and at 2, 6, 12, 18, and 24 months after IMRT completion. The saliva sampling was performed in the morning (9e11 AM) to minimize bias from the diurnal variation in saliva flow. Stimulated whole
Volume 83 Number 2 2012 saliva (SWS) and stimulated parotid saliva (SPS) were collected and assessed using the previously described protocol (16). Duplicate collections of saliva were performed on another day for 1 of 10 patients before treatment throughout the study period. The 95% agreement limit for SWS flow and SPS flow was 0.45e0.78 mL/min and 0.01e0.05 mL/min, respectively. The 95% agreement limit for the SWS pH was 0.61e0.74.
Statistical analysis Repeated measures analysis of variance was used to compare the differences in the QOL measures and salivary flow at six points. A univariate approach was adopted to test the within-subjects effects, the Huynh-Feldt Epsilon correction factor was used to adjust the univariate test degrees of freedom if the assumption of sphericity was violated (determined by Mauchly’s test of sphericity). Bonferroni multiple comparisons were performed to detect any differences in QOL measures and salivary parameters over the follow-up points. Cochran Q tests were used to compare the overall differences in salivary buffer capacity at the six points, and McNemar’s tests were used to compare the pairwise differences between the examination points. Spearman’s rank correlation was used to explore the correlation between various parameters, including radiation dosage, salivary function, and QOL outcomes. The level of significance was set at p Z 0.05. For multiple pairwise comparisons, the level of significance was set at p Z 0.01.
Results Study population background A total of 65 consecutive patients with Stage T1 and T2 disease who had undergone IMRT were recruited for the present study. All participants completed QOL, salivary function, and clinical assessments before IMRT and periodically until 24 months after therapy. Three patients withdrew because of a time conflict. One patient had persistent disease after treatment, and 3 patients developed disease recurrence during the study period. Thus, a total of 7 patients were excluded from the analyses. All patients had undifferentiated or poorly differentiated carcinoma. The patient, tumor, and treatment characteristics are listed in Table 1. The average mean dose to the parotid glands was 39.8 Gy. The average mean dose to the submandibular glands, excluding the anterior part, was 65.4 Gy, greater than the dose to the parotids, because no specific attempt was made to spare these structures during IMRT planning. All the biopsy results were negative (i.e., showing complete remission after IMRT).
Salivary gland function The stimulated whole and parotid saliva characteristics at baseline before RT and at 2, 6, 12, 18, and 24 months after therapy are listed in Table 2. Significant changes over time were found in all tested salivary parameters. There was an initial, significant reduction in SWS and SPS flow after RT, followed by a progressive recovery. The mean SPS flow returned to baseline at 12 months after RT and remained stable at 18 and 24 months after RT. However, the recovery of SWS flow was insignificant from 12 months after RT onward, and the mean SWS flow at 24 months after RT was still significantly lower than at baseline. Regarding
Can IMRT preserve OHRQOL of NPC patients? e215 Table 1
Patient and treatment characteristics (n Z 58) Variable
Age (y) Mean SD Range Gender (n) Male Female AJCC tumor stage (n) I II T stage (n) 1 2 N stage (n) 0 1 Dose (Gy) Gross tumor volume (n) 68 Gy 70 Gy 72 Gy Planning target volume (n) 66 Gy 68 Gy
Value 46.9 9.5 28e70 41 (59.4) 17 (40.6) 26 32 23 35 34 24
12 33 13 30 28
Abbreviation: AJCC Z American Joint Committee on Cancer. Data in parentheses are percentages.
the salivary qualities, a significant decrease occurred in the mean pH and the proportion of subjects with high/medium buffer capacity of the whole saliva after RT. Significant improvements in both parameters were found over time. At 24 months of follow-up, a full recovery of buffer capacity was observed, but the mean pH value was still significantly less than at baseline.
QOL measures The data from the SF-36 subscales at baseline and at 2, 6, 12, 18, and 24 months after treatment are listed in Table 3. Significant changes occurred over time in all subscales. Multiple comparisons showed that the mean scores of all subscales, except for the mental health subscale, were lowest at 2 months after RT. The mean scores of the physical function, bodily pain, and general health subscales had recovered at 6 months after RT and were maintained onward. The role-physical and vitality scores had recovered at 12 months after RT and maintained onward. The mean scores of the social functioning and mental health subscales from 6 months after RT onward were significantly greater compared with the baseline and the role-emotional scores from 12 months after RT onward was significantly greater than at baseline. The data from the EORTC QLQ-C30 (þ3) scales and items at the six points are listed in Table 4. Significant changes were seen over time in all the scales and items, except for the cognitive function, pain, dyspnea, constipation, and diarrhea subscales. For the global health status scale, an increase in the scores indicating better QOL were observed from 6 months onward after IMRT. For the functional scale, the physical functioning and role functioning scores were significantly lower at 2 and 6 months after RT. However, both scores recovered to baseline from 12 months after
International Journal of Radiation Oncology Biology Physics
e216 Pow et al. Table 2
Saliva characteristics at baseline and 2, 6, 12, 18, and 24 months after radiotherapy (n Z 58 except for 1 item) Follow-up (mo)
Variable SWS Flow rate (mL/min) pH (n Z 56)
Buffer capacity High/medium Low/nil SPS Flow rate (mL/min)
Baseline
2
6
12
18
24
p*
0.90 0.56
0.13 0.12
0.20 0.18
0.28 0.25
0.32 0.25
0.36 0.32
<0.001
7.2 0.4
6.4 0.5
6.6 0.6
6.8 0.5
6.9 0.5
7.0 0.5
93.1
27.6
41.4
56.9
62.1
75.9
6.9
72.4
58.6
43.1
37.9
24.1
0.08 0.11
0.02 0.04
0.03 0.06
0.06 0.10
0.08 0.12
0.08 0.10
Multiple comparisons*
2, 6 < 12, 18, 24 < baseline <0.001 2, 6 < 12, 18, 24 < baseline 12 < 24 <0.001
2, 6, 12, 18 < baseline 2 < 12, 18, 24 6 < 24
<0.001
2, 6 < 12, 18, 24, baseline
Abbreviations: SWS Z stimulated whole saliva; SPS Z stimulated parotid saliva. Data presented as mean standard deviation. * Comparing differences in scores over six examination points.
The scale and item data included in the EORTC QLQ-H&N35 assessment are detailed in Table 5. Significant changes occurred over time in all items, except for the teeth, felt ill, pain killers, nutrition supplement, and feeding tube scales. Within the scales, the pain, swallowing, senses problem, speech problem, trouble social eating, trouble social contact, less sexuality, dry mouth, and sticky saliva scores were significantly greater at 2 months after RT compared with those at baseline. The speech problem and less sexuality scores returned to baseline from 6 month onward and the pain and trouble social contact scores returned to baseline from 12 months onward. The senses problem, dry mouth, trouble social eating, and sticky saliva showed significant improvement from 6
RT onward. The emotional function scores of all post-RT evaluation points were significantly greater than at baseline. The social function score showed significant improvement at 6 months after RT, and the mean score at 12 and 24 months after RT was significantly greater than baseline. Within the symptom scale, the fatigue and nausea/vomiting scores had increased significantly at 2 months after RT but had returned to baseline from 12 months and 6 months after RT onward, respectively. The appetite item score was significantly reduced from 6 months onward after IMRT, indicating an improvement in appetite. The financial difficulties item score at 24 months after RT was significantly less than that at baseline.
Table 3
SF-36 subscale scores at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57) Follow-up (mo)
Subscale
Baseline
2
94.1 12.0 88.6 9.3
Physical function Role-physical
71.9 34.5 25.9 38.1
Bodily pain General health
89.1 19.4 75.7 27.9 60.7 21.8 50.9 20.0
Vitality
70.2 15.8 53.7 17.2
Social functioning
83.6 23.3 69.1 27.4
Role-emotional 56.7 40.3 43.3 45.4
Mental health
72.5 16.9 76.8 17.3
6
12
18
24
p*
Multiple comparisons*
91.7 11.2 92.6 13.2 94.0 13.6 94.3 11.4 <0.001 2 < 12, 18, 24, baseline 58.8 40.0 79.0 36.0 86.4 28.0 84.2 30.5 <0.001 2 < 6 < 12, 18, 24, baseline 83.6 22.8 85.3 23.6 88.3 20.4 86.4 21.2 0.003 2 < 18, baseline 55.3 23.4 62.3 22.8 64.8 20.5 63.2 24.3 <0.001 2 < 12, 18, 24, baseline 62.6 16.0 68.7 16.6 72.5 14.6 69.7 17.2 <0.001 2 < 6 < 12, 18, 24, baseline 87.9 19.5 91.0 17.8 93.0 18.0 92.8 19.2 <0.001 2 < baseline < 6, 12, 18, 24 Baseline < 18, 24 68.4 41.5 79.0 36.0 87.7 27.2 87.1 30.1 <0.001 2, baseline < 12, 18, 24 2 < 6 < 18, 24 79.9 15.3 82.5 15.9 81.1 15.3 81.1 15.5 <0.001 Baseline < 6, 12, 18, 24
Abbreviation: SF-36 Z Medical Outcomes Study short-form 36-item questionnaire. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
EORTC QLQ-C30 (þ3) data at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57) Follow-up (mo) Baseline
2
6
12
18
24
p*
Multiple comparisons*
52.2 15.6
54.1 15.0
63.9 17.6
65.6 17.9
66.1 17.0)
61.7 17.5
<0.001
54.0 15.3
53.7 13.7
63.6 16.9
64.8 17.4
65.6 16.9)
62.1 16.8
<0.001
Baseline < 6, 12, 18, 24 2 < 6, 12, 18 Baseline, 2 < 6, 12, 18, 24
92.8 9.9
83.6 9.2
87.3 11.6
90.1 11.1
91.8 11.0
91.7 10.6
<0.001
Role-functioning
98.3 6.1
93.3 12.6
95.0 9.4
97.1 7.1
97.1 7.1
97.4 6.9
Role-functioning (revised)
88.0 15.0
80.1 19.8
89.8 18.6
95.3 11.3
94.7 16.1
93.9 15.0
<0.001
Emotional function Cognitive function Social function
78.5 13.3 90.1 14.4 84.2 18.8
86.7 14.3 85.1 17.2 78.4 23.4
89.3 13.7 85.7 12.8 90.4 13.7
90.8 13.3 87.7 15.3 92.4 15.1
91.7 13.8 86.3 17.3 91.5 16.4
91.2 15.3 88.0 16.9 93.9 15.0
<0.001 0.186 <0.001
12.5 13.9 2.9 7.1 6.2 10.8
23.8 16.6 7.0 14.8 10.5 20.3
16.4 15.0 0.3 2.2 7.3 13.4
12.9 14.4 0.6 3.1 6.4 14.0
11.1 14.6 0.9 3.8 5.0 12.2
11.9 18.2 0.9 3.8 7.0 12.6
<0.001 0.001 0.239
0.077 0.009 <0.001 0.201 0.134 0.007
Scale/item Global health status/QOL Global health status Global health status (revised) Functional scales Physical functioning (revised)
8.2 21.1 12.9 4.7 4.7 13.5
15.8 27.2 18.6 11.7 11.7 20.8
10.5 17.0 26.9 9.4 1.8 11.7
20.1 23.7 23.1 18.6 7.5 19.4
8.8 11.1 9.4 6.4 5.3 8.8
14.8 22.1 15.1 14.7 13.8 19.5
5.3 11.7 7.6 7.6 4.1 5.9
12.3 19.4 14.1 17.8 11.0 14.3
4.1 11.1 4.7 4.7 2.3 7.0
11.0 21.2 11.7 13.3 8.6 17.5
5.3 13.5 4.7 5.3 1.8 5.3
Abbreviations: EORTC QLQ-30 Z European Organization for Research and Treatment of Cancer core questionnaire; QOL Z quality of life. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
12.3 21.7 13.3 13.8 7.5 16.4
2, 6 < baseline 2 < 12, 18, 24 6 < 18, 24 2, 6 < baseline 2 < 24 2 < 6, 12, 18, 24 Baseline Baseline < 2, 6, 12, 18, 24 Baseline < 12, 24 2 < 6, 12, 18, 24 2 > baseline, 12, 18, 24 2 > 6, 12, 18
2 > baseline, 6, 12, 18, 24 Baseline > 24
Can IMRT preserve OHRQOL of NPC patients? e217
Symptom scales Fatigue Nausea/vomiting Pain Symptom items Dyspnea Insomnia Appetite loss Constipation Diarrhea Financial difficulties
0.001
Volume 83 Number 2 2012
Table 4
e218 Pow et al.
Table 5
EORTC QLQ-H&N35 data at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57 except for one item) Follow-up (mo) 2
6
12
18
24
p*
Multiple comparisons*
Pain Swallowing Senses problem
7.3 9.2 1.0 2.8) 4.7 12.1)
16.4 13.9 10.7 9.9 39.8 21.5
12.7 11.0 10.0 9.0 24.0 18.6
8.2 11.5 9.2 9.0 20.2 19.1
7.0 9.2 8.2 8.1 15.2 17.3
7.0 9.3 8.9 8.2 17.0 19.3
<0.001 <0.001 <0.001
Speech problem Trouble social eating
5.7 9.4 1.9 5.0
12.5 14.7 21.9 20.0
9.2 10.7 14.5 15.5
6.6 11.5 8.6 10.9
6.6 12.2 9.0 11.8
6.4 12.9 8.2 11.6
0.003 <0.001
Trouble social contact
1.4 4.5
8.1 10.0
4.8 6.5
2.7 6.7
2.9 7.1
4.0 8.3
<0.001
16.3 18.9
31.9 34.9
25.5 29.3
19.9 29.6
14.9 27.0
16.0 25.3
0.001
Teeth Open mouth
6.4 14.7 1.2 6.2
11.1 18.2 8.2 15.8
9.4 15.1 17.0 18.0
8.8 14.8 10.5 15.6
9.9 17.8 5.3 12.3
8.8 14.8 9.4 15.1
0.648 <0.001
Dry mouth Sticky saliva
14.6 20.9 6.2 13.1
74.3 25.2 57.0 36.3
63.2 26.5 42.1 28.7
49.1 26.8 31.6 26.8
41.5 25.4 25.4 25.0
41.5 25.4 24.6 21.5
<0.001 <0.001
Coughing Felt ill Pain killers Nutrition supplement Feeding tube Weight loss Weight gain
17.5 5.3 14.0 22.8 0.0 28.1 10.5
0.011 0.378 0.257 0.174 d <0.001 0.001
2, 6 > baseline, 12, 18, 24 2, 6, 12, 18, 24 > baseline 2, 6, 12, 18, 24 > baseline 2 > 6, 12, 18, 24 6 > 18 2 > baseline 2, 6, 12, 18, 24 > baseline 2 > 12, 18, 24 6 > 12, 24 2, 6 > baseline 2 > 12, 18, 24 6 > 12 2 > baseline 2 > 18, 24 d 6, 12, 24 > baseline 6 > 2, 18 2 > 6 > 12, 18, 24 > baseline 2, 6, 12, 18, 24 > baseline 2 > 12, 18, 24 6 > 18, 24 Baseline > 18 d d d d Baseline, 2 > 12, 18, 24 18 > 24
Lower sexuality (n Z 47)
19.0 12.3 35.0 42.3 0.0 45.3 36.3
14.6 6.4 7.0 40.4 0.0 26.3 14.0
19.9 13.3 25.8 49.5 0.0 44.4 35.0
11.7 3.5 5.3 33.3 0.0 10.5 17.5
19.4 10.3 22.5 47.6 0.0 31.0 38.4
10.5 5.3 5.3 35.1 0.0 5.3 35.1
16.9 12.3 22.5 48.2 0.0 22.5 48.2
7.0 2.9 5.3 28.1 0.0 5.3 35.1
13.7 9.5 22.5 45.3 0.0 22.5 48.2
10.5 7.0 12.3 28.1 0.0 3.5 14.0
18.0 13.7 33.1 45.3 0.0 18.6 35.0
Abbreviation: EORTC QLQ-H&N35 Z European Organization for Research and Treatment of Cancer head-and-neck cancer-specific module. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
International Journal of Radiation Oncology Biology Physics
Baseline
Scale/item
Volume 83 Number 2 2012 Table 6
Can IMRT preserve OHRQOL of NPC patients? e219
OHIP subscale and summary scores at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57) Follow-up (mo)
Subscale
Baseline
2 mo
6 mo
12 mo
18 mo
24 mo
6.5 3.8
11.2 4.7
10.3 4.4
9.0 5.1
8.6 4.5
8.5 4.3
4.5 3.9 2.1 2.8
6.6 5.0 3.8 3.8
5.8 4.2 2.4 3.0
5.1 3.9 2.1 2.9
4.8 4.0 1.8 2.6
4.7 1.6
2.3 3.0
8.5 4.8
7.3 3.7
6.3 4.8
5.3 4.4
5.0
Psychological disability
0.7 1.7
4.7 4.5
2.8 4.2
2.3 3.9
1.8 3.3
1.2
Social disability Handicap
0.3 0.9 0.9 1.6
1.3 2.4 3.1 3.6
1.0 2.3 2.3 2.9
0.7 2.2 2.2 2.9
0.6 1.9 1.8 2.5
0.6 1.8
Addition method Function limitation Physical pain Psychological discomfort Physical disability
OHIP-ADD
OHIP-SC
17.2 13.7 39.2 22.8 31.8 18.7 27.8 20.9 24.7 18.4 23.3
1.9 2.1
6.3 4.6
4.2 2.7
3.6 3.6
3.2 3.0
3.1
p*
Multiple comparisons*
<0.001 2, 6, 12 > baseline 2 > baseline, 12, 18, 24 3.9 0.003 2 > baseline 2.6 <0.001 2 > baseline, 12, 18, 24 4.5 <0.001 2, 6, 12, 18, 24 > baseline 2 > 12, 18, 24 6 > 18, 24 2.6 <0.001 2, 6, 12 > baseline 2 > 12, 18, 24 6 > 24 2.0 0.006 2 > baseline 2.7 <0.001 2, 6, 12 > baseline 17.9 <0.001 2, 6, 12, 18 > baseline 2 > 6, 12, 18, 24 6 > 18, 24 2.8 <0.001 2, 6, 12, 18 > baseline 2 > 6, 12, 18, 24 6 > 24
Abbreviation: OHIP Z Oral Health Impact Profile. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
or 12 months after RT onward; however, the scores of the 4 items at 24 months after RT were still significantly greater than at baseline. The swallowing score did not show any improvement at all from 2 months after RT onward, and the open mouth score had significantly increased from 6 months after RT onward. The weight loss score at baseline and 2 months after RT was significantly greater than the scores from 12 months after RT onward, and the weight gain score at 18 months was significantly greater than at 24 months after RT. The data from the OHIP are listed in Table 6. Significant changes occurred over time in all subscales. Multiple comparisons showed that the mean scores of all subscales were greatest at 2 months after RT, indicating poorer ORHQOL. The physical pain, psychological discomfort, and social disability scores returned to baseline from 6 months after RT onward, and the functional limitation and psychological disability scores had returned to baseline from 18 months after RT onward. The physical disability score showed significant improvement from 12 months after RT onward. However, the score at 24 months after RT was still significantly greater than at baseline, indicating incomplete recovery. Both summary scores (OHIP-ADD i.e. addition of scores across all statements, OHIP-SC i.e. simple counts of negative impacts) showed continuous improvement after IMRT, and the scores had returned to baseline at 24 months after treatment. Correlations between the salivary flow rates or parotid radiation dosage with the QOL outcomes that were persistently compromised at 24 months after RT were performed (i.e., OHIP physical disability score, H&N35 swallowing, senses problem,
trouble social eating, dry mouth, and sticky saliva scores). Significant correlations were found between swallowing and SPS flow rate at 24 months (Rs Z 0.269, p Z 0.043). Trouble with social eating correlated significantly with SWS flow rate at 6 months (Rs Z 0.271, p Z 0.042), 12 months (Rs Z 0.289, p Z 0.029), 18 months (Rs Z 0.366, p Z 0.005), and 24 months (Rs Z 0.402, p Z 0.002). Dry mouth correlated significantly with the SPS flow rate at baseline (Rs Z 0.297, p Z 0.025), 6 months (Rs Z 0.293, p Z 0.027), and 12 months (Rs Z 0.262, p Z 0.049). Sticky saliva correlated significantly with SWS flow rate (Rs Z 0.364, p Z 0.008) and SPS flow rate at baseline (Rs Z 0.378, p Z 0.006). However, no significant correlation was found between the parotid radiation dosage and selected QOL outcomes.
Discussion Many studies investigated the effect of IMRT on salivary function and QOL in patients with NPC. However, the study population might not be homogenous in terms of ethnic origin and tumor staging. In addition, treatment mode was often compounded by various forms of chemotherapy or brachytherapy that might complicate the data interpretation. To minimize the potential confounding variables, early-stage NPC subjects underwent IMRT only were selected in the present study. Stimulated flow measurement using Lashley cup was standard. It has been shown to correlate well with the mean parotid gland
e220 Pow et al.
International Journal of Radiation Oncology Biology Physics
dose and regarded as the best method for evaluating parotid gland function in patients receiving head-and-neck RT (17). To minimize the effect of diurnal variation of saliva flow, a specific period of collection of each subject was standardized during the study period. All measurements were done by 1 examiner to minimize interexaminer variation. The intraexaminer reliabilities were also shown to be good. When measuring HRQOL for head-and-neck conditions, a combination of generic and specific measures are recommended to encompass broad constructs of general health and those specific to the head-and-neck region (18). To the best of our knowledge, this is the first study revealing the complete picture of QOL changes of early-stage NPC patients treated by IMRT using validated generic (SF-36), cancer-specific (EORTC QLQ-30), head-and-neck cancer-specific (EORTC QLQ-H&N35), and oral-specific (OHIP-49) instruments. The initial decrease in saliva flow, followed by recovery over time, was reported by other IMRT studies of NPC patients (6, 8, 16). At 2 months after RT, the mean SPS flow was reduced by 75.0% compared with baseline, and the mean SWS flow was reduced by 85.6%. The mean SPS flow had fully recovered at 12 months after RT and was maintained for 24 months. In contrast, incomplete recovery and no further improvement was observed in the mean SWS flow after 12 months, with 60% reduction of the mean SWS flow still present at 24 months after RT compared with baseline. An incomplete recovery of salivary qualities was also observed at 24 months after RT. The results indicate that parotidsparing IMRT can only preserve less than one-half of the total salivary gland function. The SF-36 data revealed that QOL in general was impaired shortly after IMRT. At 6 and 12 months after RT, most subscales had recovered completely and the social functioning, roleemotional, and mental health domain scores were significantly greater than baseline. The EORTC core data showed a similar pattern of impaired physical and role functioning, increased fatigue, nausea/vomiting, and appetite loss at 2 months after RT followed by a gradual recovery. In addition, the global health status and social and emotional function from 6 months after RT onward were significantly improved compared with baseline. The initial adverse impairment on physical functioning was most probably due to the direct effects of IMRT. Most treatment- and NPC-related symptoms had subsided by 6 months after IMRT, resulting in significant improvements in the overall QOL. The specific head-and-neck cancer measure showed that many scales and items related to oral and social functioning were compromised after IMRT. Although a number had returned to baseline over time, many oral-related items such as senses, dry mouth, sticky saliva, swallowing, and open mouth were still significantly impaired at 24 months after RT; this could also explain the persistent poorer trouble with social eating item score. The OHIP data also showed that OHRQOL was significantly affected after IMRT, followed by a gradual improvement. Although most subscale scores returned to normal, the physical disability score was still significantly poorer at 24 months after RT than at baseline. The findings of the present study are comparable with those from Fang et al. (7), who also showed incomplete improvement of oral-related items 2 years after IMRT or three-dimensional conformal RT. Although xerostomia has been arbitrary defined as post-RT salivary flow <25% of the pre-RT flow (19), the present study showed significant xerostomia and impairment of OHRQOL for NPC patients, even with a mean post-RT salivary flow
of around 40% of the pre-RT value. The cutoff for the definition of xerostomia might need to be revisited. Correlation analyses showed that both SWS and SPS flow rates at a number of points were significantly correlated with several OHRQOL outcomes that remained compromised 2 years after IMRT. This finding implies that salivary flow rates might potentially be used for prediction of certain QOL outcomes after IMRT. The present study showed that IMRT could only partially preserve whole salivary function and might explain the persistent oral symptoms and compromised oral HRQOL in early-stage NPC patients. Although long-term follow-up studies are needed, it seems unlikely that there will be additional improvement or complete recovery of salivary function and OHRQOL. Future developments should therefore aim at protecting or sparing the submandibular and/or sublingual glands from radiation damage during NPC treatment.
References 1. Sanguineti G, Corvo R. Treatment of nasopharyngeal carcinoma: State of the art and new perspectives (review). Oncol Rep 1999;6:377e391. 2. Pow EH, McMillan AS, Leung WK, et al. Oral health condition in southern Chinese after radiotherapy for nasopharyngeal carcinoma: Extent and nature of the problem. Oral Dis 2003;9:196e202. 3. Pow EH, McMillan AS, Leung WK, et al. Salivary gland function and xerostomia in southern Chinese following radiotherapy for nasopharyngeal carcinoma. Clin Oral Invest 2003;7:230e234. 4. McMillan AS, Pow EH, Leung WK, et al. Oral health-related quality of life in southern Chinese following radiotherapy for nasopharyngeal carcinoma. J Oral Rehabil 2004;31:600e608. 5. McMillan AS, Pow EH, Kwong DL, et al. Preservation of quality of life after intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: Results of a prospective longitudinal study. Head Neck 2006;28:712e722. 6. Kwong DL, Pow EH, Sham JS, et al. Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: A prospective study on disease control and preservation of salivary function. Cancer 2004;101:1584e1593. 7. Fang FM, Chien CY, Tsai WL, et al. Quality of life and survival outcome for patients with nasopharyngeal carcinoma receiving threedimensional conformal radiotherapy vs. intensity-modulated radiotherapydA longitudinal study. Int J Radiat Oncol Biol Phys 2008;72: 356e364. 8. Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in earlystage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25: 4873e4879. 9. Lin S, Pan J, Han L, et al. Nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy: Report on the 3-year outcome of a prospective series. Int J Radiat Oncol Biol Phys 2009;75:1071e1078. 10. Bjordal K, de Graeff A, Fayers PM, et al. A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group. Eur J Cancer 2000;36:1796e1807. 11. Webb S. Inverse planning for IMRT: The role of simulated annealing. In: Sternick ES, editor. The theory and practice of intensity modulated radiation theory. Proceedings of the first NOMOS IMRT workshop, Durango, Colorado. Madison: Advanced Medical Publishing; 1997. p. 51e73. 12. Lam CL, Gandek B, Ren XS, et al. Tests of scaling assumptions and construct validity of the Chinese (HK) version of the SF-36 Health Survey. J Clin Epidemiol 1998;51:1139e1147. 13. Fayers P, Aaronson N, Bjordal K, et al. EORTC QOL-C30 scoring manual. 2nd ed. Brussels: EORTC Quality of Life Study Group; 1999.
Volume 83 Number 2 2012 14. Slade GD, Spencer AJ. Development and evaluation of the Oral Health Impact Profile. Community Dent Health 1994;11:3e11. 15. Wong MC, Lo EC, McMillan AS. Validation of a Chinese version of the Oral Health Impact Profile (OHIP). Community Dent Oral Epidemiol 2002;30:423e430. 16. 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;66:981e991.
Can IMRT preserve OHRQOL of NPC patients? e221 17. Roesink JM, Schipper M, Busschers W, et al. A comparison of mean parotid gland dose with measures of parotid gland function after radiotherapy for head-and-neck cancer: Implications for future trials. Int J Radiat Oncol Biol Phys 2005;63:1006e1009. 18. Gliklich RE, Goldsmith TA, Funk GF. Are head and neck specific quality of life measures necessary? Head Neck 1997;19:474e480. 19. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45:577e587.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Head and Neck Cancer
Can Intensity-Modulated Radiotherapy Preserve Oral Health-Related Quality of Life of Nasopharyngeal Carcinoma Patients? Edmond H.N. Pow, Ph.D.,* Dora L.W. Kwong, M.D., F.R.C.R.,y Jonathan S.T. Sham, M.D., F.R.C.R.,y Victor H.F. Lee, M.B.B.S., F.R.C.R.,y and Sherry C.Y. Ng, Ph.D.y *Oral Rehabilitation, The University of Hong Kong Faculty of Dentistry, Hong Kong Special Administrative Region, People’s Republic of China; and yDepartment of Clinical Oncology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong Special Administrative Region, People’s Republic of China Received Jul 15, 2011, and in revised form Dec 3, 2011. Accepted for publication Dec 9, 2011
Summary The oral health-related quality of life of 57 patients with early-stage nasopharyngeal carcinoma who had received intensity-modulated radiotherapy was followed up for 2 years. The parotid saliva flow had recovered fully after 1 year and whole saliva flow had recovered to 40% of baseline. A general trend of deterioration in most quality of life scales was observed after intensitymodulated radiotherapy, followed by a gradual recovery. Persistent oral-related symptoms were found 2 years after treatment.
Purpose: To investigate the changes in salivary function and oral health-related quality of life for patients with nasopharyngeal carcinoma treated by intensity-modulated radiotherapy (IMRT). Methods and Materials: A total of 57 patients with early-stage nasopharyngeal carcinoma received IMRT. The parotid and whole saliva flow was measured, and the Medical Outcomes Study 36-item short form, European Organization for Research and Treatment of Cancer Quality of Life questionnaire-C30, European Organization for Research and Treatment of Cancer Quality of Life questionnaire 35-item head-and-neck module, and Oral Health Impact Profile questionnaires were completed at baseline and 2, 6, 12, 18, and 24 months after IMRT. Results: Parotid saliva flow recovered fully after 1 year and maintained. Whole saliva flow recovered partially to 40% of baseline. A general trend of deterioration in most quality of life scales was observed after IMRT, followed by gradual recovery. Persistent oral-related symptoms were found 2 years after treatment. Conclusion: IMRT for early-stage nasopharyngeal carcinoma could only partially preserve the whole salivary function and oral health-related quality of life. Ó 2012 Elsevier Inc.
Reprint requests to: Edmond H. N. Pow, Ph.D., Oral Rehabilitation, The University of Hong Kong Faculty of Dentistry, 34 Hospital Road,
Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. e213ee221, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.12.040
Hong Kong. Tel: (852) 2859-0309; Fax: (852) 2858-6114; E-mail: [email protected] Conflict of interest: none.
e214 Pow et al.
International Journal of Radiation Oncology Biology Physics
Introduction
involved in lateral extension of the NPC. Thus, the part of parotid gland overlapping into the PTV would have the prescribed dose to the PTV in IMRT planning. A dose constraint of 25 Gy was set to the superficial part of the parotid gland that was outside the PTV. To estimate the actual dose received by the bilateral parotid glands, we separately contoured the whole parotid without the PTV and overlaid the treatment plan on the parotid glands. The same was applied for the submandibular glands. Because NPC is a midline tumor and has a high propensity for bilateral lymphatic involvement, especially to the jugulodigastric nodes, the posterior part of both submandibular glands were included in the PTV. The true doses received by the submandibular glands were also estimated by separately contouring the submandibular glands without the PTV. Only the nasopharnyx and upper neck were treated with IMRT in the present study. The neck was irradiated with a separate anterior cervical field with a midline shield, matched with the lower border of the IMRT fields. The prescribed dose to the anterior cervical field was 60e66 Gy at 100% isodose level, in 30e33 fractions. The matching between the IMRT and anterior cervical field was inferior to the chin or inferior to enlarged neck nodes. The midline shield was 3 cm wide at the level of the larynx and 2 cm inferior to the larynx, shielding the cervical spine. Because the Corvus planning system did not allow summation of the dose from IMRT and the conventional anterior cervical field, the exact doses to the larynx and hypopharynx were not known. However, because all patients in the present series had early-stage disease, the field matching was usually just inferior to the chin, and the larynx and hypopharynx should be protected by the midline shield in the anterior cervical field, and were assumed to have received only scattered dose. At 8e10 weeks after IMRT completion, nasopharyngoscopy and biopsies were performed to assess the disease control in the nasopharynx. Thereafter, the patients were followed up every month during the first year, every 2 months in the second year, and every 3e6 months thereafter. The first post-treatment computed tomography scan was performed at 3e6 months after RT completion, and afterward regular computed tomography or magnetic resonance imaging was performed every 6 months or when indicated clinically.
Nasopharyngeal carcinoma (NPC) is rare in caucasians but common in the southern Chinese. Hong Kong is one of the cities with a high age-adjusted incidence of NPC (1). NPC is primarily treated by radiotherapy (RT) because the tumor is highly radiosensitive. However, conventional radiotherapy induces long-term irreversible deleterious oral complications that compromise patients’ quality of life (QOL) (2e4). However, intensitymodulated RT (IMRT), which spares the salivary glands from radiation damage, has been shown to preserve the salivary function and QOL without compromising the disease control in earlystage NPC patients (5e9). The QOL is now regarded as one of the primary outcomes of medical care. Various validated measures specific for the assessment of head-and-neck cancer are available (10). Although oral complications are the major problems in NPC survivors, no prospective studies have been published on the oral health-related QOL (OHRQOL) in NPC patients undergoing IMRT. The present study was aimed to assess the changes of salivary function and OHRQOL of southern Chinese with early-stage NPC 2 years after IMRT.
Methods and Materials The present study was a prospective longitudinal study performed between 2000 and 2007. A total of 65 consecutive patients with histologically confirmed Stage I and II (T1-T2N0-N1M0 disease) primary NPC were recruited. All patients were treated with a full course of IMRT at the Department of Clinical Oncology, Queen Mary Hospital, Hong Kong. No adjunctive chemotherapy was used for this group of patients with early-stage disease. The patients who had undergone previous head-and-neck RT were excluded. The institutional review board of the University of Hong Kong/Hong Kong Hospital Authority West Cluster, Hong Kong, approved the study. All patients provided written informed consent.
Intensity-modulated RT
Questionnaires Intensity-modulated RT was performed using the Corvus system, version 3.0 (NOMOS, Sewickley, PA) (11). In brief, the patient was immobilized in a cast, and the planning computed tomography scan of the head and neck was used for localization of the targets and organs at risk. The primary gross tumor volume (GTV) included the gross tumor in the nasopharynx and any extension of tumor outside the nasopharynx. The primary clinical target volume covered the potential sites of local tumor infiltration, including the whole nasopharynx, and 1-cm margin around the GTV. Enlarged neck nodes were localized as the nodal GTV. The nodal CTV included 0.5-cm margin around the nodal GTV and elective nodal RT to both upper neck sides (level IB-II and IVa). A 3-mm margin was added to both CTVs to create the planning target volume (PTV), which covered the skull base to the upper cervical lymphatics. The prescribed dose to the PTV was 66e68 Gy in 34 fractions within 7 weeks. The dose to the primary GTV was 68e72 Gy. The Corvus system did not allow for overlapping volumes. The deep lobe of the parotid gland was included in the PTV, because it is in close proximity to the parapharynx, which is commonly
All participants completed the Medical Outcomes short form 36-item questionnaire (SF-36), the European Organization for Research and Treatment of Cancer (EORTC) QOL core questionnaire (EORTC QLQ-30 [þ3]), the EORTC head-and-neck module (EORTC QLQ-H&N35), and the Oral Health Impact Profile (OHIP-49) assisted by a trained interviewer. The interviewer was not involved in any aspect of the medical or dental care of the participants. The questionnaires were completed after diagnosis and before RT at the pre-RT dental care visit (baseline) and then at 2, 6, 12, 18, and 24 months after therapy. All questionnaires have been translated and validated (12e15).
Salivary gland function Salivary function was assessed by 1 dentist before treatment and at 2, 6, 12, 18, and 24 months after IMRT completion. The saliva sampling was performed in the morning (9e11 AM) to minimize bias from the diurnal variation in saliva flow. Stimulated whole
Volume 83 Number 2 2012 saliva (SWS) and stimulated parotid saliva (SPS) were collected and assessed using the previously described protocol (16). Duplicate collections of saliva were performed on another day for 1 of 10 patients before treatment throughout the study period. The 95% agreement limit for SWS flow and SPS flow was 0.45e0.78 mL/min and 0.01e0.05 mL/min, respectively. The 95% agreement limit for the SWS pH was 0.61e0.74.
Statistical analysis Repeated measures analysis of variance was used to compare the differences in the QOL measures and salivary flow at six points. A univariate approach was adopted to test the within-subjects effects, the Huynh-Feldt Epsilon correction factor was used to adjust the univariate test degrees of freedom if the assumption of sphericity was violated (determined by Mauchly’s test of sphericity). Bonferroni multiple comparisons were performed to detect any differences in QOL measures and salivary parameters over the follow-up points. Cochran Q tests were used to compare the overall differences in salivary buffer capacity at the six points, and McNemar’s tests were used to compare the pairwise differences between the examination points. Spearman’s rank correlation was used to explore the correlation between various parameters, including radiation dosage, salivary function, and QOL outcomes. The level of significance was set at p Z 0.05. For multiple pairwise comparisons, the level of significance was set at p Z 0.01.
Results Study population background A total of 65 consecutive patients with Stage T1 and T2 disease who had undergone IMRT were recruited for the present study. All participants completed QOL, salivary function, and clinical assessments before IMRT and periodically until 24 months after therapy. Three patients withdrew because of a time conflict. One patient had persistent disease after treatment, and 3 patients developed disease recurrence during the study period. Thus, a total of 7 patients were excluded from the analyses. All patients had undifferentiated or poorly differentiated carcinoma. The patient, tumor, and treatment characteristics are listed in Table 1. The average mean dose to the parotid glands was 39.8 Gy. The average mean dose to the submandibular glands, excluding the anterior part, was 65.4 Gy, greater than the dose to the parotids, because no specific attempt was made to spare these structures during IMRT planning. All the biopsy results were negative (i.e., showing complete remission after IMRT).
Salivary gland function The stimulated whole and parotid saliva characteristics at baseline before RT and at 2, 6, 12, 18, and 24 months after therapy are listed in Table 2. Significant changes over time were found in all tested salivary parameters. There was an initial, significant reduction in SWS and SPS flow after RT, followed by a progressive recovery. The mean SPS flow returned to baseline at 12 months after RT and remained stable at 18 and 24 months after RT. However, the recovery of SWS flow was insignificant from 12 months after RT onward, and the mean SWS flow at 24 months after RT was still significantly lower than at baseline. Regarding
Can IMRT preserve OHRQOL of NPC patients? e215 Table 1
Patient and treatment characteristics (n Z 58) Variable
Age (y) Mean SD Range Gender (n) Male Female AJCC tumor stage (n) I II T stage (n) 1 2 N stage (n) 0 1 Dose (Gy) Gross tumor volume (n) 68 Gy 70 Gy 72 Gy Planning target volume (n) 66 Gy 68 Gy
Value 46.9 9.5 28e70 41 (59.4) 17 (40.6) 26 32 23 35 34 24
12 33 13 30 28
Abbreviation: AJCC Z American Joint Committee on Cancer. Data in parentheses are percentages.
the salivary qualities, a significant decrease occurred in the mean pH and the proportion of subjects with high/medium buffer capacity of the whole saliva after RT. Significant improvements in both parameters were found over time. At 24 months of follow-up, a full recovery of buffer capacity was observed, but the mean pH value was still significantly less than at baseline.
QOL measures The data from the SF-36 subscales at baseline and at 2, 6, 12, 18, and 24 months after treatment are listed in Table 3. Significant changes occurred over time in all subscales. Multiple comparisons showed that the mean scores of all subscales, except for the mental health subscale, were lowest at 2 months after RT. The mean scores of the physical function, bodily pain, and general health subscales had recovered at 6 months after RT and were maintained onward. The role-physical and vitality scores had recovered at 12 months after RT and maintained onward. The mean scores of the social functioning and mental health subscales from 6 months after RT onward were significantly greater compared with the baseline and the role-emotional scores from 12 months after RT onward was significantly greater than at baseline. The data from the EORTC QLQ-C30 (þ3) scales and items at the six points are listed in Table 4. Significant changes were seen over time in all the scales and items, except for the cognitive function, pain, dyspnea, constipation, and diarrhea subscales. For the global health status scale, an increase in the scores indicating better QOL were observed from 6 months onward after IMRT. For the functional scale, the physical functioning and role functioning scores were significantly lower at 2 and 6 months after RT. However, both scores recovered to baseline from 12 months after
International Journal of Radiation Oncology Biology Physics
e216 Pow et al. Table 2
Saliva characteristics at baseline and 2, 6, 12, 18, and 24 months after radiotherapy (n Z 58 except for 1 item) Follow-up (mo)
Variable SWS Flow rate (mL/min) pH (n Z 56)
Buffer capacity High/medium Low/nil SPS Flow rate (mL/min)
Baseline
2
6
12
18
24
p*
0.90 0.56
0.13 0.12
0.20 0.18
0.28 0.25
0.32 0.25
0.36 0.32
<0.001
7.2 0.4
6.4 0.5
6.6 0.6
6.8 0.5
6.9 0.5
7.0 0.5
93.1
27.6
41.4
56.9
62.1
75.9
6.9
72.4
58.6
43.1
37.9
24.1
0.08 0.11
0.02 0.04
0.03 0.06
0.06 0.10
0.08 0.12
0.08 0.10
Multiple comparisons*
2, 6 < 12, 18, 24 < baseline <0.001 2, 6 < 12, 18, 24 < baseline 12 < 24 <0.001
2, 6, 12, 18 < baseline 2 < 12, 18, 24 6 < 24
<0.001
2, 6 < 12, 18, 24, baseline
Abbreviations: SWS Z stimulated whole saliva; SPS Z stimulated parotid saliva. Data presented as mean standard deviation. * Comparing differences in scores over six examination points.
The scale and item data included in the EORTC QLQ-H&N35 assessment are detailed in Table 5. Significant changes occurred over time in all items, except for the teeth, felt ill, pain killers, nutrition supplement, and feeding tube scales. Within the scales, the pain, swallowing, senses problem, speech problem, trouble social eating, trouble social contact, less sexuality, dry mouth, and sticky saliva scores were significantly greater at 2 months after RT compared with those at baseline. The speech problem and less sexuality scores returned to baseline from 6 month onward and the pain and trouble social contact scores returned to baseline from 12 months onward. The senses problem, dry mouth, trouble social eating, and sticky saliva showed significant improvement from 6
RT onward. The emotional function scores of all post-RT evaluation points were significantly greater than at baseline. The social function score showed significant improvement at 6 months after RT, and the mean score at 12 and 24 months after RT was significantly greater than baseline. Within the symptom scale, the fatigue and nausea/vomiting scores had increased significantly at 2 months after RT but had returned to baseline from 12 months and 6 months after RT onward, respectively. The appetite item score was significantly reduced from 6 months onward after IMRT, indicating an improvement in appetite. The financial difficulties item score at 24 months after RT was significantly less than that at baseline.
Table 3
SF-36 subscale scores at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57) Follow-up (mo)
Subscale
Baseline
2
94.1 12.0 88.6 9.3
Physical function Role-physical
71.9 34.5 25.9 38.1
Bodily pain General health
89.1 19.4 75.7 27.9 60.7 21.8 50.9 20.0
Vitality
70.2 15.8 53.7 17.2
Social functioning
83.6 23.3 69.1 27.4
Role-emotional 56.7 40.3 43.3 45.4
Mental health
72.5 16.9 76.8 17.3
6
12
18
24
p*
Multiple comparisons*
91.7 11.2 92.6 13.2 94.0 13.6 94.3 11.4 <0.001 2 < 12, 18, 24, baseline 58.8 40.0 79.0 36.0 86.4 28.0 84.2 30.5 <0.001 2 < 6 < 12, 18, 24, baseline 83.6 22.8 85.3 23.6 88.3 20.4 86.4 21.2 0.003 2 < 18, baseline 55.3 23.4 62.3 22.8 64.8 20.5 63.2 24.3 <0.001 2 < 12, 18, 24, baseline 62.6 16.0 68.7 16.6 72.5 14.6 69.7 17.2 <0.001 2 < 6 < 12, 18, 24, baseline 87.9 19.5 91.0 17.8 93.0 18.0 92.8 19.2 <0.001 2 < baseline < 6, 12, 18, 24 Baseline < 18, 24 68.4 41.5 79.0 36.0 87.7 27.2 87.1 30.1 <0.001 2, baseline < 12, 18, 24 2 < 6 < 18, 24 79.9 15.3 82.5 15.9 81.1 15.3 81.1 15.5 <0.001 Baseline < 6, 12, 18, 24
Abbreviation: SF-36 Z Medical Outcomes Study short-form 36-item questionnaire. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
EORTC QLQ-C30 (þ3) data at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57) Follow-up (mo) Baseline
2
6
12
18
24
p*
Multiple comparisons*
52.2 15.6
54.1 15.0
63.9 17.6
65.6 17.9
66.1 17.0)
61.7 17.5
<0.001
54.0 15.3
53.7 13.7
63.6 16.9
64.8 17.4
65.6 16.9)
62.1 16.8
<0.001
Baseline < 6, 12, 18, 24 2 < 6, 12, 18 Baseline, 2 < 6, 12, 18, 24
92.8 9.9
83.6 9.2
87.3 11.6
90.1 11.1
91.8 11.0
91.7 10.6
<0.001
Role-functioning
98.3 6.1
93.3 12.6
95.0 9.4
97.1 7.1
97.1 7.1
97.4 6.9
Role-functioning (revised)
88.0 15.0
80.1 19.8
89.8 18.6
95.3 11.3
94.7 16.1
93.9 15.0
<0.001
Emotional function Cognitive function Social function
78.5 13.3 90.1 14.4 84.2 18.8
86.7 14.3 85.1 17.2 78.4 23.4
89.3 13.7 85.7 12.8 90.4 13.7
90.8 13.3 87.7 15.3 92.4 15.1
91.7 13.8 86.3 17.3 91.5 16.4
91.2 15.3 88.0 16.9 93.9 15.0
<0.001 0.186 <0.001
12.5 13.9 2.9 7.1 6.2 10.8
23.8 16.6 7.0 14.8 10.5 20.3
16.4 15.0 0.3 2.2 7.3 13.4
12.9 14.4 0.6 3.1 6.4 14.0
11.1 14.6 0.9 3.8 5.0 12.2
11.9 18.2 0.9 3.8 7.0 12.6
<0.001 0.001 0.239
0.077 0.009 <0.001 0.201 0.134 0.007
Scale/item Global health status/QOL Global health status Global health status (revised) Functional scales Physical functioning (revised)
8.2 21.1 12.9 4.7 4.7 13.5
15.8 27.2 18.6 11.7 11.7 20.8
10.5 17.0 26.9 9.4 1.8 11.7
20.1 23.7 23.1 18.6 7.5 19.4
8.8 11.1 9.4 6.4 5.3 8.8
14.8 22.1 15.1 14.7 13.8 19.5
5.3 11.7 7.6 7.6 4.1 5.9
12.3 19.4 14.1 17.8 11.0 14.3
4.1 11.1 4.7 4.7 2.3 7.0
11.0 21.2 11.7 13.3 8.6 17.5
5.3 13.5 4.7 5.3 1.8 5.3
Abbreviations: EORTC QLQ-30 Z European Organization for Research and Treatment of Cancer core questionnaire; QOL Z quality of life. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
12.3 21.7 13.3 13.8 7.5 16.4
2, 6 < baseline 2 < 12, 18, 24 6 < 18, 24 2, 6 < baseline 2 < 24 2 < 6, 12, 18, 24 Baseline Baseline < 2, 6, 12, 18, 24 Baseline < 12, 24 2 < 6, 12, 18, 24 2 > baseline, 12, 18, 24 2 > 6, 12, 18
2 > baseline, 6, 12, 18, 24 Baseline > 24
Can IMRT preserve OHRQOL of NPC patients? e217
Symptom scales Fatigue Nausea/vomiting Pain Symptom items Dyspnea Insomnia Appetite loss Constipation Diarrhea Financial difficulties
0.001
Volume 83 Number 2 2012
Table 4
e218 Pow et al.
Table 5
EORTC QLQ-H&N35 data at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57 except for one item) Follow-up (mo) 2
6
12
18
24
p*
Multiple comparisons*
Pain Swallowing Senses problem
7.3 9.2 1.0 2.8) 4.7 12.1)
16.4 13.9 10.7 9.9 39.8 21.5
12.7 11.0 10.0 9.0 24.0 18.6
8.2 11.5 9.2 9.0 20.2 19.1
7.0 9.2 8.2 8.1 15.2 17.3
7.0 9.3 8.9 8.2 17.0 19.3
<0.001 <0.001 <0.001
Speech problem Trouble social eating
5.7 9.4 1.9 5.0
12.5 14.7 21.9 20.0
9.2 10.7 14.5 15.5
6.6 11.5 8.6 10.9
6.6 12.2 9.0 11.8
6.4 12.9 8.2 11.6
0.003 <0.001
Trouble social contact
1.4 4.5
8.1 10.0
4.8 6.5
2.7 6.7
2.9 7.1
4.0 8.3
<0.001
16.3 18.9
31.9 34.9
25.5 29.3
19.9 29.6
14.9 27.0
16.0 25.3
0.001
Teeth Open mouth
6.4 14.7 1.2 6.2
11.1 18.2 8.2 15.8
9.4 15.1 17.0 18.0
8.8 14.8 10.5 15.6
9.9 17.8 5.3 12.3
8.8 14.8 9.4 15.1
0.648 <0.001
Dry mouth Sticky saliva
14.6 20.9 6.2 13.1
74.3 25.2 57.0 36.3
63.2 26.5 42.1 28.7
49.1 26.8 31.6 26.8
41.5 25.4 25.4 25.0
41.5 25.4 24.6 21.5
<0.001 <0.001
Coughing Felt ill Pain killers Nutrition supplement Feeding tube Weight loss Weight gain
17.5 5.3 14.0 22.8 0.0 28.1 10.5
0.011 0.378 0.257 0.174 d <0.001 0.001
2, 6 > baseline, 12, 18, 24 2, 6, 12, 18, 24 > baseline 2, 6, 12, 18, 24 > baseline 2 > 6, 12, 18, 24 6 > 18 2 > baseline 2, 6, 12, 18, 24 > baseline 2 > 12, 18, 24 6 > 12, 24 2, 6 > baseline 2 > 12, 18, 24 6 > 12 2 > baseline 2 > 18, 24 d 6, 12, 24 > baseline 6 > 2, 18 2 > 6 > 12, 18, 24 > baseline 2, 6, 12, 18, 24 > baseline 2 > 12, 18, 24 6 > 18, 24 Baseline > 18 d d d d Baseline, 2 > 12, 18, 24 18 > 24
Lower sexuality (n Z 47)
19.0 12.3 35.0 42.3 0.0 45.3 36.3
14.6 6.4 7.0 40.4 0.0 26.3 14.0
19.9 13.3 25.8 49.5 0.0 44.4 35.0
11.7 3.5 5.3 33.3 0.0 10.5 17.5
19.4 10.3 22.5 47.6 0.0 31.0 38.4
10.5 5.3 5.3 35.1 0.0 5.3 35.1
16.9 12.3 22.5 48.2 0.0 22.5 48.2
7.0 2.9 5.3 28.1 0.0 5.3 35.1
13.7 9.5 22.5 45.3 0.0 22.5 48.2
10.5 7.0 12.3 28.1 0.0 3.5 14.0
18.0 13.7 33.1 45.3 0.0 18.6 35.0
Abbreviation: EORTC QLQ-H&N35 Z European Organization for Research and Treatment of Cancer head-and-neck cancer-specific module. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
International Journal of Radiation Oncology Biology Physics
Baseline
Scale/item
Volume 83 Number 2 2012 Table 6
Can IMRT preserve OHRQOL of NPC patients? e219
OHIP subscale and summary scores at baseline and 2, 6, 12, 18 and 24 months after radiotherapy (n Z 57) Follow-up (mo)
Subscale
Baseline
2 mo
6 mo
12 mo
18 mo
24 mo
6.5 3.8
11.2 4.7
10.3 4.4
9.0 5.1
8.6 4.5
8.5 4.3
4.5 3.9 2.1 2.8
6.6 5.0 3.8 3.8
5.8 4.2 2.4 3.0
5.1 3.9 2.1 2.9
4.8 4.0 1.8 2.6
4.7 1.6
2.3 3.0
8.5 4.8
7.3 3.7
6.3 4.8
5.3 4.4
5.0
Psychological disability
0.7 1.7
4.7 4.5
2.8 4.2
2.3 3.9
1.8 3.3
1.2
Social disability Handicap
0.3 0.9 0.9 1.6
1.3 2.4 3.1 3.6
1.0 2.3 2.3 2.9
0.7 2.2 2.2 2.9
0.6 1.9 1.8 2.5
0.6 1.8
Addition method Function limitation Physical pain Psychological discomfort Physical disability
OHIP-ADD
OHIP-SC
17.2 13.7 39.2 22.8 31.8 18.7 27.8 20.9 24.7 18.4 23.3
1.9 2.1
6.3 4.6
4.2 2.7
3.6 3.6
3.2 3.0
3.1
p*
Multiple comparisons*
<0.001 2, 6, 12 > baseline 2 > baseline, 12, 18, 24 3.9 0.003 2 > baseline 2.6 <0.001 2 > baseline, 12, 18, 24 4.5 <0.001 2, 6, 12, 18, 24 > baseline 2 > 12, 18, 24 6 > 18, 24 2.6 <0.001 2, 6, 12 > baseline 2 > 12, 18, 24 6 > 24 2.0 0.006 2 > baseline 2.7 <0.001 2, 6, 12 > baseline 17.9 <0.001 2, 6, 12, 18 > baseline 2 > 6, 12, 18, 24 6 > 18, 24 2.8 <0.001 2, 6, 12, 18 > baseline 2 > 6, 12, 18, 24 6 > 24
Abbreviation: OHIP Z Oral Health Impact Profile. Data presented as mean standard deviation. * Comparing differences in scores over six follow-up points.
or 12 months after RT onward; however, the scores of the 4 items at 24 months after RT were still significantly greater than at baseline. The swallowing score did not show any improvement at all from 2 months after RT onward, and the open mouth score had significantly increased from 6 months after RT onward. The weight loss score at baseline and 2 months after RT was significantly greater than the scores from 12 months after RT onward, and the weight gain score at 18 months was significantly greater than at 24 months after RT. The data from the OHIP are listed in Table 6. Significant changes occurred over time in all subscales. Multiple comparisons showed that the mean scores of all subscales were greatest at 2 months after RT, indicating poorer ORHQOL. The physical pain, psychological discomfort, and social disability scores returned to baseline from 6 months after RT onward, and the functional limitation and psychological disability scores had returned to baseline from 18 months after RT onward. The physical disability score showed significant improvement from 12 months after RT onward. However, the score at 24 months after RT was still significantly greater than at baseline, indicating incomplete recovery. Both summary scores (OHIP-ADD i.e. addition of scores across all statements, OHIP-SC i.e. simple counts of negative impacts) showed continuous improvement after IMRT, and the scores had returned to baseline at 24 months after treatment. Correlations between the salivary flow rates or parotid radiation dosage with the QOL outcomes that were persistently compromised at 24 months after RT were performed (i.e., OHIP physical disability score, H&N35 swallowing, senses problem,
trouble social eating, dry mouth, and sticky saliva scores). Significant correlations were found between swallowing and SPS flow rate at 24 months (Rs Z 0.269, p Z 0.043). Trouble with social eating correlated significantly with SWS flow rate at 6 months (Rs Z 0.271, p Z 0.042), 12 months (Rs Z 0.289, p Z 0.029), 18 months (Rs Z 0.366, p Z 0.005), and 24 months (Rs Z 0.402, p Z 0.002). Dry mouth correlated significantly with the SPS flow rate at baseline (Rs Z 0.297, p Z 0.025), 6 months (Rs Z 0.293, p Z 0.027), and 12 months (Rs Z 0.262, p Z 0.049). Sticky saliva correlated significantly with SWS flow rate (Rs Z 0.364, p Z 0.008) and SPS flow rate at baseline (Rs Z 0.378, p Z 0.006). However, no significant correlation was found between the parotid radiation dosage and selected QOL outcomes.
Discussion Many studies investigated the effect of IMRT on salivary function and QOL in patients with NPC. However, the study population might not be homogenous in terms of ethnic origin and tumor staging. In addition, treatment mode was often compounded by various forms of chemotherapy or brachytherapy that might complicate the data interpretation. To minimize the potential confounding variables, early-stage NPC subjects underwent IMRT only were selected in the present study. Stimulated flow measurement using Lashley cup was standard. It has been shown to correlate well with the mean parotid gland
e220 Pow et al.
International Journal of Radiation Oncology Biology Physics
dose and regarded as the best method for evaluating parotid gland function in patients receiving head-and-neck RT (17). To minimize the effect of diurnal variation of saliva flow, a specific period of collection of each subject was standardized during the study period. All measurements were done by 1 examiner to minimize interexaminer variation. The intraexaminer reliabilities were also shown to be good. When measuring HRQOL for head-and-neck conditions, a combination of generic and specific measures are recommended to encompass broad constructs of general health and those specific to the head-and-neck region (18). To the best of our knowledge, this is the first study revealing the complete picture of QOL changes of early-stage NPC patients treated by IMRT using validated generic (SF-36), cancer-specific (EORTC QLQ-30), head-and-neck cancer-specific (EORTC QLQ-H&N35), and oral-specific (OHIP-49) instruments. The initial decrease in saliva flow, followed by recovery over time, was reported by other IMRT studies of NPC patients (6, 8, 16). At 2 months after RT, the mean SPS flow was reduced by 75.0% compared with baseline, and the mean SWS flow was reduced by 85.6%. The mean SPS flow had fully recovered at 12 months after RT and was maintained for 24 months. In contrast, incomplete recovery and no further improvement was observed in the mean SWS flow after 12 months, with 60% reduction of the mean SWS flow still present at 24 months after RT compared with baseline. An incomplete recovery of salivary qualities was also observed at 24 months after RT. The results indicate that parotidsparing IMRT can only preserve less than one-half of the total salivary gland function. The SF-36 data revealed that QOL in general was impaired shortly after IMRT. At 6 and 12 months after RT, most subscales had recovered completely and the social functioning, roleemotional, and mental health domain scores were significantly greater than baseline. The EORTC core data showed a similar pattern of impaired physical and role functioning, increased fatigue, nausea/vomiting, and appetite loss at 2 months after RT followed by a gradual recovery. In addition, the global health status and social and emotional function from 6 months after RT onward were significantly improved compared with baseline. The initial adverse impairment on physical functioning was most probably due to the direct effects of IMRT. Most treatment- and NPC-related symptoms had subsided by 6 months after IMRT, resulting in significant improvements in the overall QOL. The specific head-and-neck cancer measure showed that many scales and items related to oral and social functioning were compromised after IMRT. Although a number had returned to baseline over time, many oral-related items such as senses, dry mouth, sticky saliva, swallowing, and open mouth were still significantly impaired at 24 months after RT; this could also explain the persistent poorer trouble with social eating item score. The OHIP data also showed that OHRQOL was significantly affected after IMRT, followed by a gradual improvement. Although most subscale scores returned to normal, the physical disability score was still significantly poorer at 24 months after RT than at baseline. The findings of the present study are comparable with those from Fang et al. (7), who also showed incomplete improvement of oral-related items 2 years after IMRT or three-dimensional conformal RT. Although xerostomia has been arbitrary defined as post-RT salivary flow <25% of the pre-RT flow (19), the present study showed significant xerostomia and impairment of OHRQOL for NPC patients, even with a mean post-RT salivary flow
of around 40% of the pre-RT value. The cutoff for the definition of xerostomia might need to be revisited. Correlation analyses showed that both SWS and SPS flow rates at a number of points were significantly correlated with several OHRQOL outcomes that remained compromised 2 years after IMRT. This finding implies that salivary flow rates might potentially be used for prediction of certain QOL outcomes after IMRT. The present study showed that IMRT could only partially preserve whole salivary function and might explain the persistent oral symptoms and compromised oral HRQOL in early-stage NPC patients. Although long-term follow-up studies are needed, it seems unlikely that there will be additional improvement or complete recovery of salivary function and OHRQOL. Future developments should therefore aim at protecting or sparing the submandibular and/or sublingual glands from radiation damage during NPC treatment.
References 1. Sanguineti G, Corvo R. Treatment of nasopharyngeal carcinoma: State of the art and new perspectives (review). Oncol Rep 1999;6:377e391. 2. Pow EH, McMillan AS, Leung WK, et al. Oral health condition in southern Chinese after radiotherapy for nasopharyngeal carcinoma: Extent and nature of the problem. Oral Dis 2003;9:196e202. 3. Pow EH, McMillan AS, Leung WK, et al. Salivary gland function and xerostomia in southern Chinese following radiotherapy for nasopharyngeal carcinoma. Clin Oral Invest 2003;7:230e234. 4. McMillan AS, Pow EH, Leung WK, et al. Oral health-related quality of life in southern Chinese following radiotherapy for nasopharyngeal carcinoma. J Oral Rehabil 2004;31:600e608. 5. McMillan AS, Pow EH, Kwong DL, et al. Preservation of quality of life after intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: Results of a prospective longitudinal study. Head Neck 2006;28:712e722. 6. Kwong DL, Pow EH, Sham JS, et al. Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: A prospective study on disease control and preservation of salivary function. Cancer 2004;101:1584e1593. 7. Fang FM, Chien CY, Tsai WL, et al. Quality of life and survival outcome for patients with nasopharyngeal carcinoma receiving threedimensional conformal radiotherapy vs. intensity-modulated radiotherapydA longitudinal study. Int J Radiat Oncol Biol Phys 2008;72: 356e364. 8. Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in earlystage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25: 4873e4879. 9. Lin S, Pan J, Han L, et al. Nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy: Report on the 3-year outcome of a prospective series. Int J Radiat Oncol Biol Phys 2009;75:1071e1078. 10. Bjordal K, de Graeff A, Fayers PM, et al. A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group. Eur J Cancer 2000;36:1796e1807. 11. Webb S. Inverse planning for IMRT: The role of simulated annealing. In: Sternick ES, editor. The theory and practice of intensity modulated radiation theory. Proceedings of the first NOMOS IMRT workshop, Durango, Colorado. Madison: Advanced Medical Publishing; 1997. p. 51e73. 12. Lam CL, Gandek B, Ren XS, et al. Tests of scaling assumptions and construct validity of the Chinese (HK) version of the SF-36 Health Survey. J Clin Epidemiol 1998;51:1139e1147. 13. Fayers P, Aaronson N, Bjordal K, et al. EORTC QOL-C30 scoring manual. 2nd ed. Brussels: EORTC Quality of Life Study Group; 1999.
Volume 83 Number 2 2012 14. Slade GD, Spencer AJ. Development and evaluation of the Oral Health Impact Profile. Community Dent Health 1994;11:3e11. 15. Wong MC, Lo EC, McMillan AS. Validation of a Chinese version of the Oral Health Impact Profile (OHIP). Community Dent Oral Epidemiol 2002;30:423e430. 16. 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;66:981e991.
Can IMRT preserve OHRQOL of NPC patients? e221 17. Roesink JM, Schipper M, Busschers W, et al. A comparison of mean parotid gland dose with measures of parotid gland function after radiotherapy for head-and-neck cancer: Implications for future trials. Int J Radiat Oncol Biol Phys 2005;63:1006e1009. 18. Gliklich RE, Goldsmith TA, Funk GF. Are head and neck specific quality of life measures necessary? Head Neck 1997;19:474e480. 19. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45:577e587.