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Prospective Randomized Study of Intensity-Modulated Radiotherapy on Salivary Gland Function in Early-Stage Nasopharyngeal Carcinoma Patients

Michael K.M. Kam, Sing-Fai Leung, Benny Zee, Ricky M.C. Chau, Joyce J.S. Suen, Frankie Mo, Maria Lai, Rosalie Ho, Kin-yin Cheung, Brian K.H. Yu, Samuel K.W. Chiu, Peter H.K. Choi, Peter M.L. Teo, Wing-hong Kwan, Anthony T.C. Chan

From the State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China

Address reprint requests to Anthony T.C. Chan, MD, Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, Hong Kong; e-mail: anthonytcchan{at}cuhk.edu.hk

	ABSTRACT

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Purpose This randomized trial compared the rates of delayed xerostomia between two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in the treatment of early-stage nasopharyngeal carcinoma (NPC).

Patients and Methods Between November 2001 and December 2003, 60 patients with T1-2bN0-1M0 NPC were randomly assigned to receive either IMRT or 2DRT. Primary end point was incidence of observer-rated severe xerostomia at 1 year after treatment based on Radiotherapy Oncology Group /European Organisation for the Research and Treatment of Cancer late radiation morbidity scoring criteria. Parallel assessment with patient-reported outcome, stimulated parotid flow rate (SPFR), and stimulated whole saliva flow rate (SWSFR) were also made.

Results At 1 year after treatment, patients in IMRT arm had lower incidence of observer-rated severe xerostomia than patients in the 2DRT arm (39.3% v 82.1%; P = .001), parallel with a higher fractional SPFR (0.90 v 0.05; P < .0001), and higher fractional SWSFR (0.41 v 0.20; P = .001). As for patient's subjective feeling, although a trend of improvement in patient-reported outcome was observed after IMRT, recovery was incomplete and there was no significant difference in patient-reported outcome between the two arms.

Conclusion IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC. Incomplete improvement in patient's subjective xerostomia with parotid-sparing IMRT reflects the need to enhance protection of other salivary glands.

	INTRODUCTION

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Incidental irradiation of the parotid glands with consequent long-term xerostomia is a well-recognized problem after radiation therapy for head and neck cancers. A number of studies have shown that intensity-modulated radiation therapy (IMRT) could minimize radiation dose to the parotid glands without compromising tumor dose.^1-4 Nonrandomized clinical studies also suggest that xerostomia was less common after IMRT compared with conventional two-dimensional radiotherapy (2DRT).^5-16

Salivary function protection is particularly difficult in the treatment of nasopharyngeal carcinoma (NPC) because the clinical target encompasses the parapharyngeal region and upper neck on both sides. Despite the use of IMRT, successful parotid sparing may only be safely performed in early-stage disease, but even so, the degree of benefit over 2DRT is still unclear, short of evidence from a randomized study. The objective of this randomized study was to compare salivary function in early-stage NPC patients after treatment with 2DRT and IMRT.

	PATIENTS AND METHODS

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Study Population and Design
Patients eligible for accrual had histologically proven NPC (WHO type II/III) with either T1, T2a or unilateral T2b disease (unilateral parapharyngeal extension), and N0 or N1 nodal status (American Joint Committee on Cancer staging classification, 1997). All underwent computed tomography and magnetic resonance imaging of the head and neck region for local staging. Chest x-ray and baseline blood examination were performed to rule out distant metastasis. Patients with concurrent use of chemotherapy or drugs that might affect salivary function were excluded. Figure 1 is the CONSORT diagram.

View larger version (40K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram.

Treatment
IMRT planning was performed by computer optimization. The gross tumor volume (GTV) included the primary tumor and abnormal lymph nodes. The clinical target volume (CTV) encompassed 1-cm margin around GTV and certain at-risk anatomic sites (inferior half of sphenoid sinus, anterior half of clivus, foramen ovales, foramen lacerum, medial pterygoid muscles, bilateral parapharyngeal spaces, and posterior nasal cavity). CTV also included bilateral upper cervical lymphatics (levels IB- II, upper part of level V) and retropharyngeal lymphatics as described by Nowak et al.¹⁷ The GTV and CTV were expanded by 2-mm and 3-mm margin, respectively, to form their corresponding planning target volumes (PTVg and PTVc) to allow for setup variability. The tumor targets in the nasopharynx and upper neck were treated by IMRT using seven coplanar beams, while the lower neck was treated by a separate anterior photon field. Sixty-six grays in 33 fractions/6.6 weeks were prescribed to the PTVg, and 60 Gy/33 fractions/6.6 weeks were prescribed to the PTVc. The anterior cervical field delivered 66 Gy/33 fractions to the node-positive region, and 54 to 60 Gy to the node-negative region. Attempts were made to spare the parotid glands, but not the other salivary glands.

2DRT consisted of two consecutive phases. During first phase, the primary tumor and upper cervical lymphatics were covered by a pair of laterally opposed faciocervical photon fields, while the lower neck was covered by an anterior cervical field with a midline shield. In the second phase, a three-field setup (anterior plus right and left lateral fields) was used for the primary tumor, and an anterior cervical field for the neck. Forty grays in 20 fractions/4 weeks were prescribed in phase I, and 26 Gy/13 fractions/2.6 weeks were prescribed in phase II. Tissue heterogeneity correction was not performed because 2DRT was not computer planned.

Patients with T1/T2a tumors received intracavitary brachytherapy (ICB) boost in both arms. To adjust for the difference in mean GTV dose between IMRT and 2DRT (69 v 62.5 Gy) due to the lack of tissue heterogeneity correction in the latter,¹ patients in IMRT arm received 12 Gy ICB (3 Gy/fraction, 2 fractions/wk), while those in the 2DRT arm received 18 Gy ICB (4.5 Gy/fraction, 2 fractions/wk).

Assessment Tools
Assessment was made before treatment (baseline), at 6 weeks, 6 months, and 1 year after treatment. The following tools were used for evaluation: Radiation Therapy Oncology Group(RTOG)/European Organisation for the Research and Treatment of Cancer (EORTC) xerostomia late radiation morbidity scoring (scored by physician)¹⁸; stimulated parotid flow-rate (SPFR); stimulated whole saliva flow rate (SWSFR); and a six-item xerostomia questionnaire (scored by patient).

The RTOG/EORTC xerostomia score was given by one of the three physicians involved in the study based on patients' symptoms and mucosal moisture. SPFR was performed by collecting parotid saliva for 15 minutes after stimulation (with lemon candy containing fixed content of citric acid) from each parotid gland using a suction cup attached to the orifice of the parotid duct. The amount of saliva was weighted and the SPFR was expressed in terms of mL per minute, assuming the density of saliva to be equal to 1.0 g/mL. The whole saliva measurement was performed by asking patients to try chewing gum for 1 minute before they expectorated all saliva into a container for 5 minutes. The SWSFR was converted into mL per minute. The patient-scored xerostomia questionnaire was based on the version published by Johnson et al,¹⁹ with a 100-mm visual analog scale to record their response to six specific questions which were listed as follows: overall mouth and tongue dryness; feeling of mouth/tongue during daytime; difficulty in sleeping at night; difficulty in speaking without drinking liquids; difficulty in chewing and swallowing food; and difficulty in wearing dentures.

Statistical Analysis
The primary end point for comparison between IMRT and 2DRT was the incidence of RTOG/EORTC grade 2 to 4 xerostomia at 1-year post-treatment. Since the incidence of RTOG grade 2 xerostomia by 2DRT was around 80%, we targeted to detect a 40% difference in favor of IMRT using a two-sided 5% level test with 80% power. We have also accounted for 10% dropout rate and the total sample size was 60 patients. Comparisons between the arms were also made with respect to xerostomia questionnaire score, SPFR, and SWSFR. ² test and t test were used to detect any difference in proportion and mean, respectively, and paired t test was used to observe the change in saliva flow-rates over time. Spearman rho correlation method was used to describe any relationship between radiation dose, saliva flow rates, and xerostomia scores. All statistical tests were two sided, and P values less than .05 were considered statistically significant.

	RESULTS

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Sixty patients were enrolled between November 2001 and December 2003, of whom three were excluded because of the magnetic resonance imaging findings of more advanced disease before treatment, and one was withdrawn at first week of treatment on patient's request. Fifty-six patients were randomly assigned, with equal number in each arm. The analysis was performed when all patients had completed a minimum follow-up of 1 year. Patients in the two arms were well balanced for age, sex, ECOG performance status, parotid gland volume, laterality of sparing, and baseline whole saliva production (Table 1). A wide range of volume of salivary production (whole and parotid) was noted between patients, and the average baseline SPFR was found to be higher in the 2DRT arm. In view of this, fractional SWSFR and SPFR (post-treatment/baseline) were used to assess the residual salivary function. Treatment and follow-up compliance were 100%. No major protocol violation was reported.

RTOG/EORTC Xerostomia Grading (physician score)
Patients in the IMRT arm had significantly less grade 2 to 4 xerostomia than those in the 2DRT arm at 6 weeks (46.4% v 85.7%, respectively; P = .002) and at 1 year (39.3% v 82.1%, respectively; P = .001). The difference reached borderline significance in favor of IMRT arm at 6 months post-treatment (75% v 92.9%, respectively; P = .069; Fig 2).

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Histogram showing the incidence of Radiation Therapy Oncology Group (RTOG)/European Organisation for the Research and Treatment of Cancer (EORTC) grade 2 to 4 xerostomia in patients treated by two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Changes in fractional stimulated parotid flow rate (SPFR) after two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT). Spread of data denoted by box whiskers plot: box limits represent 25 and 75 percentiles, line within box median, whisker ends 1 and 99 percentiles; comparison of means denoted in inserts.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Changes in fractional stimulated whole saliva flow rate (SWSFR) after two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT). Spread of data denoted by box whiskers plot: box limits represent 25 and 75 percentiles, line within box median, whisker ends 1 and 99 percentiles; comparison of means denoted in inserts.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Average scores of the six-item xerostomia questionnaire in two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) arms at various time point post-treatment. Positive score indicates improvement and negative score indicates deterioration. Spread of data denoted by box whiskers plot: box limits represent 25 and 75 percentiles, line within box median, whisker ends 1 and 99 percentiles; comparison of means denoted in inserts.

Correlation Between Fractional SPFR/SWSFR and Xerostomia Questionnaire
There was no significant correlation between fractional SPFR and xerostomia questionnaire scores. In contrast, significant correlation was shown between fractional SWSFR and difficulty in sleeping (question 3; r = 0.357; P = .009), as well as between fractional SWSFR and difficulty in speaking (question 4; r = 0.330; P = .015; Table 2).

	DISCUSSION

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Despite the favorable prospect of IMRT, there is a caveat of extrapolating the concept of parotid sparing to the case of NPC. Previous clinical studies included mainly patients with non- NPC primaries, in whom the necks contralateral to the primary lesion were node negative. In these patients, the contralateral high level II lymphatics near the skull base (the junctional nodes and high spinal accessory nodes) were generally not irradiated, thus facilitating substantial sparing of the contralateral parotid glands. In contrast, the PTV in NPC patients has to extend very close to both parotid glands in consideration of the high incidence of direct parapharyngeal tumor extension, bilateral retropharyngeal nodal spread, and bilateral level II nodal spread. As the ability to minimize parotid gland irradiation depends very much on the amount of overlap between the parotid gland and the PTV,²⁴ parotid gland sparing in NPC cannot be performed to the same extent as the other head and neck cancers. This is in accordance with the difference in mean parotid dose that can be achieved between NPC (range, 32.0 to 43.9 Gy)^2,3,8,25 and non-NPC (range, 21 to 30 Gy)^9-11,14-16 treatment from the literature. Despite this limitation, Lee et al³ observed excellent locoregional control and decreased xerostomia in a cohort of 67 NPC patients treated with IMRT at the University of California-San Francisco (San Francisco, CA). With a mean dose of 34 Gy to 50% of the parotid glands, they reported 98% 4-year locoregional progression-free rate and only 2% grade 2 xerostomia 2 years after treatment. Kwong et al⁸ observed a recovery of SPFR even at a mean parotid dose of 38.8 Gy in a homogenous group of early-stage NPC patients within the first 2 years after IMRT. Hsiung et al²⁵ observed a similar degree of parotid sparing efficacy with IMRT even in patients with advanced-stage NPC. Nevertheless, the magnitude of benefit of IMRT over 2DRT remained unclear from these studies because there was no direct prospective comparison of patients treated by the two techniques.

This randomized study shows that there was significantly less occurrence of physician-rated severe xerostomia after IMRT treatment of NPC compared with 2DRT. This was observed at 1-year post-RT and paralleled by a significant difference in both the SPFR and the SWSFR between the two arms. Within the same period, the parotid flow rates in patients treated by IMRT had already shown progressive improvement but this was not observed for patients treated by 2DRT. This dose-dependent recovery potential was in agreement with the findings from others.^{4,9,12,15,16,28} This improvement was paralleled by a significant trend of improvement in patient-reported xerostomia scores in the IMRT arm, but not in the 2DRT arm, during the first year. However, this did not result in a significant difference in xerostomia scores between the two arms at the end of the first year. The limited sample size might account for failure to detect a potential difference. Observations on longer follow-up is relevant, as there is evidence of continual recovery of xerostomia beyond the first year after parotid-sparing RT.^4,22,28

A randomized study of IMRT versus 2DRT for NPC was recently reported by Pow et al,³³ with emphasis on quality-of-life assessment. In that study, significant differences in xerostomia-related symptoms were found in some items on the EORTC head-and-neck module: the IMRT arm was more favorable with regard to speech problem and swallowing, but not for senses problem, dry mouth, or social eating problem. This concurs with the findings from our xerostomia questionnaire. It is of interest to note in the study by Pow et al, the scores within some subscale scores of the general quality-of-life instruments (EORTC QLQ-30 and SF-36) were also in favor of IMRT. However, we remain skeptical about the exceptionally low normal tissue complication probability (NTCP) (< 20%) in the IMRT arm of that study inspite of the relatively high mean parotid dose reported (42 Gy), at which dose level the NTCP was more than 90% in the Michigan study,⁹ and 50% in the Netherland study.¹²

The correlation between parotid flow rates and patient-rated xerostomia scores was weak. This phenomenon was also reported by several investigators,^5,16,22,29 while the correlation between whole saliva flow rates and xerostomia score were found to be more consistent.^{10,11,14,30-32} For example, the Michigan group found that xerostomia had strongest correlation with oral cavity dose, followed by submandibular gland dose, but its association with parotid saliva flow rate was weak.²² The same group also demonstrated poor correlation between observer-rated and patient-reported xerostomia, but a significant correlation between patient-reported xerostomia and total saliva output.³⁰ The information suggests that, apart from parotid protection, protection of the other mucin-secreting salivary glands (submandibular, sublingual, and other minor salivary glands within the oral cavity) is important to maintain lubrication and prevent moisture loss at rest phase. Nevertheless, dosimetric sparing of the submandibular glands should be done with great caution because the incidence of nodal disease around this region is high. Any overenthusiasm in sparing the submandibular glands may increase the chance of geographical miss.

It is of interest to note that, in contrast to a significant difference in physician-rated xerostomia, the change in the patient-reported xerostomia scores was not statistically different between the two arms. This conflicting phenomenon between physician score and patient score was also observed in other quality-of-life studies,^26,27 in which patients with head and neck cancer were found to report lower quality of life and more post-treatment adverse effects compared with the assessments made by their physicians. There are several possibilities to explain for this inconsistency. First, physician bias and patient bias may exist in an unblinded randomization setting. Second, the criteria used to differentiate between mild (grade 1) and moderate (grade 2) xerostomia in the RTOG scoring system is rather vague and may be subject to interobserver variation. Finally, the xerostomia questionnaire, similar to other quality-of-life assessment, may contain questions that are not specific to RT-induced mouth dryness. For instance, adverse feeling on the oral cavity may be induced by mucositis or taste alteration, and difficulty in chewing/swallowing may be aggravated by trismus and soft tissue degeneration other than xerostomia. Validation of the pure impact of xerostomia would then be difficult in the presence of other covariates. In view of all these, it is our opinion that the physician and patient scoring system are not directly comparable.

In conclusion, IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC. Incomplete improvement in patient's subjective xerostomia with parotid-sparing IMRT reflects the need to enhance protection of other salivary glands.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Michael K.M. Kam, Sing-Fai Leung, Benny Zee, Ricky M.C. Chau, Peter M.L. Teo

Administrative support: Sing-Fai Leung, Peter H.K. Choi, Wing-hong Kwan, Anthony T.C. Chan

Provision of study materials or patients: Michael K.M. Kam, Sing-Fai Leung, Ricky M.C. Chau, Joyce J.S. Suen, Maria Lai, Rosalie Ho, Kin-yin Cheung, Brian K.H. Yu, Samuel K.W. Chiu, Peter H.K. Choi, Peter M.L. Teo, Wing-hong Kwan, Anthony T.C. Chan

Collection and assembly of data: Michael K.M. Kam, Sing-Fai Leung, Benny Zee, Ricky M.C. Chau, Joyce J.S. Suen, Frankie Mo, Maria Lai, Rosalie Ho, Kin-yin Cheung, Brian K.H. Yu, Samuel K.W. Chiu, Peter H.K. Choi, Peter M.L. Teo, Wing-hong Kwan, Anthony T.C. Chan

Data analysis and interpretation: Michael K.M. Kam, Sing-Fai Leung, Benny Zee, Frankie Mo, Anthony T.C. Chan

Manuscript writing: Michael K.M. Kam

Final approval of manuscript: Michael K.M. Kam, Sing-Fai Leung, Wing-hong Kwan, Anthony T.C. Chan

	NOTES

 
Supported in part by Grant No. CUHK4041/01M from the Research Grants Council, Hong Kong.

Presented in part in at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted March 5, 2007; accepted July 27, 2007.

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