Japanese Journal of Clinical Oncology Advance Access originally published online on September 28, 2006
Japanese Journal of Clinical Oncology 2006 36(10):626-631; doi:10.1093/jjco/hyl098
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© 2006 Foundation for Promotion of Cancer Research
Factors Influencing the Parotid Function in Nasopharyngeal Carcinoma Treated with Parotid-Sparing Radiotherapy
1 Department of Radiation Oncology, 2 Department of Nuclear Medicine, 3 Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, Taiwan, 4 Institute of Medicine & Toxicology, 5 Institue of Medicine, 6 Institue of Public Health, Chung Shan Medical University, Taichung, Taiwan and 7 Department of Radiation Oncology, University of California, Los Angeles, USA
For reprints and all correspondence: Wen-Shan Liu, Department of Radiation Oncology, 110, Sec. 1, Chien-Kuo N. Road, Taichung 402, Taiwan. E-mail: p53_tw{at}yahoo.com.tw
Received April 16, 2006; accepted August 11, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: To evaluate the factors influencing post-irradiation parotid gland function in nasopharyngeal cancer treated with parotid-sparing radiotherapy.
Methods: This study consisted of 45 patients with nasopharyngeal cancer treated with radiotherapy including 3D conformal radiotherapy, intensity-modulated radiotherapy and high-dose-rate brachytherapy. The mean follow-up time was 37.5 months (range: 15–50 months). Objective parotid gland function was assessed by series sialoscintigraphy pre-irradiation and post-irradiation at 1, 6, 12 and 18 months. Subjective salivary function was recorded by the LENT/SOMA system. Wilcoxon signed-rank test was used to compare the secretion ratio (SR) of parotid gland before and after treatment. Mann–Whitney rank-sum test was used to determine the factors influencing the post-irradiated SR. Chi-square test was used to compare the correlation between subjective grading of xerostomia and objective grading of parotid glands.
Results: There was a significant difference between the pre-irradiation and post-irradiation parotid gland's SR at 1 (0.30 versus 0.01, P < 0.05) and 6 months (0.03 versus 0.08, P < 0.05). However, there was no significant difference compared with the pre-irradiation SR at 12 (0.30 versus 0.20, P > 0.05) and 18 months (0.30 versus 0.18, P > 0.05). There was significant correlation between subjective and objective salivary function (P = 0.024) at 12 months after radiotherapy. The factor that impacted the preservation of parotid function was mean dose to the parotid gland >38.0 Gy (P < 0.05).
Conclusions: Our results demonstrated that parotid function could recover 1 year after treatment with parotid-sparing radiotherapy in patients with nasopharyngeal cancer. The most important factor that influenced parotid function was the mean dose to the parotid gland.
Key Words: nasopharyngeal carcinoma • xerostomia • parotid-sparing radiotherapy • intensity-modulated radiotherapy • sialoscintigraphy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Radiotherapy is the most important primary treatment for nasopharyngeal carcinoma (NPC). Long-term survival rates can reach 40–90% according to the tumor stage (1,2). Although a high percentage of patients can be cured by radiotherapy, life quality of these patients is greatly impaired by the sequelae of treatment (3). Xerostomia is a chronic complication of treatment that causes significant suffering after radiotherapy. Among the salivary glands, the parotid glands are the most susceptible to radiation damage. Because these glands are within the treatment field through bilateral opposed treatment portals, the development of xerostomia is often inevitable. In the past few decades, several attempts at reducing post-irradiation xerostomia in patients with head and neck cancer had been evaluated. Oral pilocarpine has proven to be effective in 30–50% of patients who displayed symptoms of xerostomia (4). Protection of one side of the parotid gland may be feasible in patients with a unilateral head and neck tumor (5). However, this suggestion is not practical for NPC patients because bilateral para-pharyngeal space and bilateral upper cervical lymphatic chains that are beside the parotid glands must be included.
Nishioka et al. (3) demonstrated that using CT simulation for accurate targets and critical organs delineation combined with three-field irradiation could reduce radiation-induced xerostomia compared with conventional simulation and bilateral opposed treatment methods. Roesink et al. (6) studied stimulated parotid salivary flow in patients with head and neck tumor after radiotherapy. The dose to the parotid gland leading to a complication probability of 50% (TD50) was 35 and 39 Gy at 6 months and 1 year after radiotherapy, respectively. Intensity-modulated radiotherapy (IMRT) can produce more precise and complex 3D dose distributions than 3D-CRT techniques (7). This new methodology can deliver the radiation dose to the target volume while maintaining low doses to critical organs nearby (8,9). Previous investigators have reported pioneering experiences using IMRT for NPC; however, none of them used sialoscintigraphy methods to evaluate the function of parotid glands (10–13). The aims of the present study were (i) to evaluate the function of parotid gland in NPC patients treated with parotid-sparing radiotherapy (mainly with IMRT) by series radioisotope sialoscintigraphy before and after treatment and (ii) to determine the predisposing factors (including treatment and non-treatment factors) that may impair the function of parotid gland after treatment.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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From August 2000 to July 2003, 45 patients with histologically proven non-metastatic NPC were included in the study. The characteristics of these patients are listed in Table 1. There were 34 males and 11 females. The age of patients ranged from 21 to 76 years with a median age of 47.9 years. The disease was staged according to the 1997 American Joint Committee on Cancer staging classification (14). The staging was classified as 12 in Stage I, 13 in Stage II, 16 in Stage III and 4 in Stage IV.
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The details of the treatment method were described in our previous study (15). Briefly, patients were treated in the supine position. The immobilization device was a thermoplastic masks system and rigid pillows to support their neck and head position (MT-201-D, MEDTEC Inc.). We used a computerized tomographic simulator (GE HiSpeed Fx, GE Inc.) to acquire series images with 3 mm slide thickness throughout the examination. The treatment plans of three-dimensional conformal radiotherapy (3D CRT) and IMRT were based on these images. We used the Helio and Cadplan treatment planning system (Varian Oncology Systems, Palo Alto, CA) for calculating IMRT and 3D CRT treatment planning, respectively. Photon beams of 6-MV were delivered for both 3D CRT and IMRT treatments. The gross target volume (GTV) was defined as the volume of gross nasopharyngeal tumor. The GTV of metastatic lymph node(s) was defined as the volume of grossly visible metastatic lymph node(s). The clinical target volume (CTV) was defined as the volume including GTV and the volume of skull base, inferior two-thirds of the sphenoid sinus, retropharyngeal nodes, pterygoid fossae, posterior nasal cavity, posterior one-third to half maxillary sinuses, and level II and upper part of level IV neck lymphatic region. The lymphatic region below level II to the bilateral clavicle bone was irradiated with another anterior-posterior (AP) field. One iso-center and same positioning setup was used for both AP and IMRT fields in order to minimize junction errors between them. The planning target volume (PTV) was defined as the CTV plus 3 mm margins. We assigned different doses to different targets, which is same as the concept of simultaneous integrated boost technique (16). The goal of this design was to deliver a minimum dose of 70 Gy to the GTV-PTV (2.12 Gy per fraction), 55–60 Gy to the PTV (1.7–1.8 Gy per fraction) and 65–70 Gy (2.0–2.12 Gy per fraction) to the metastatic lymph node(s). The dose constraint to parotid glands was 35 Gy at 50% volume. There were 25 patients who received three-field conformal radiotherapy 9.0 Gy prior to the start of IMRT, and one patient received 19.8 Gy prior to the start of IMRT. IMRT was delivered by step and shoot technique via seven fixed-gantry angles with a Varian 21EX Linear Accelerator (Varian Corporation). Before treatment, all IMRT plans underwent a quality assurance test that included a film dosimetry for isodose comparison and absolute dose check with an ion-chamber at the iso-center under a cylindrical water phantom designed in-house. A total of 34 out of 45 cases received high-dose-rate brachytherapy boost with a dose of 7.0 Gy in two fractions after IMRT treatment. The dose calculation point was defined at the skull base. Distances from this point to sources ranged from 1.2 to 2.5 cm as measured by lateral simulation film. We did not calculate the brachytherapy dose contribution to the parotid glands due to the difficulty of dose combination of this treatment and external beam treatments. Besides, in our experience the dose contributed to the parotid glands by brachytherapy would be <1 Gy. There were 31 patients in this series who received concurrent chemo-radiotherapy, with two courses of chemotherapy given during radiotherapy. The regimen of chemotherapy was cisplatin (60 mg/m2) on Day 1 and Day 28 and 5-FU (600 mg/m2) on Day 1–4 and Day 28–31. The follow-up interval was defined as the period from the end of the radiotherapy to October 2004; it ranged from 15 to 50 months (mean 37.5 months).
Sialoscintigraphy was used as an objective method for evaluation of the function of parotid glands in this study. Pre-irradiation sialoscintigraphy was performed in all patients, and tests were repeated at intervals of 1 (43 cases), 6 (37 cases), 12 (39 cases) and 18 (36 cases) months after completion of radiotherapy. The stimulated parotid gland secretion ratio (SR) was used for comparison of parotid gland function at each session of follow-up. The procedure of SR measurement was similar to Tsujii's report (17). After administering 5 mCi 99mTc intravenously, sequential images over the anterior view of the head were acquired at 1 min per frame for 20 min. Ten minutes after the injection of the 99mTc, a 200 mg ascorbic acid tablet was placed on the dorsal surface of the tongue for salivary stimulation, and the study was continued for an additional 10 min. The definition of SR was according to the description of Nishioka et al. (3):
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Right and left parotid glands often received different radiation doses because the primary tumor often predominated on one side, and metastatic neck lymph nodes were not always equally affected bilaterally. Therefore, it is necessary to calculate and compare the SR of either parotid gland for each patient. The treatment factors included mean dose of parotid gland >38 Gy and concurrent chemotherapy. The non-treatment factors included sex, age >48 years, N (+) stage, T3–4 stage, pre-irradiation SR < 0.3, and volume of parotid gland <21.0 cm3. We analyzed these non-treatment factors because it was possible that they may influence the preservation of parotid function. For example, factors included lymph node positive stage, local advanced primary tumor stage, pre-irradiation SR and volume of the parotid gland.
We used the LENT/SOMA scoring system (18) for recording subjective salivary gland function impairment. The definition of this grading is as follows: Grade 0 = no dryness, Grade 1 = occasional dryness, Grade 2 = partial but persistent dryness, Grade 3 = complete dryness but non-debilitating and Grade 4 = complete dryness and debilitating. The definitions used in objective grading were Grade 1 = 76–95% of pretreatment value, Grade 2 = 51–75%, Grade 3 = 26–50% and Grade 4 = 0–25% of pretreatment value. We compared the correlation between subjective and objective salivary function grading based on this system. We divided the subjective salivary function into two groups: Grade 0–1 and Grade 2–4. The objective grading was calculated from parotid gland SR of pre-irradiation and post-irradiation at 12 months and was recorded as two groups: Grade 0–2 and Grade 3–4.
The Wilcoxon signed-rank test was used to compare the difference in the SR of parotid glands before and after radiotherapy. The Mann–Whitney rank-sum test was used to analyze the treatment and non-treatment related predisposing factors that may influence the parotid gland's SR after completion of treatment. Chi-square test was used to compare the correlation between subjective grading of xerostomia and objective grading of parotid glands. The 
level was defined as 0.05. The SPSS version 10 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The doses to the targets and parotid glands are given in Table 2. All the doses were calculated as the summation of both 3D CRT and IMRT treatments.
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The median pre-irradiated SRs of right and left parotid glands were 0.36 and 0.22 (range: right 0.0–0.67, left 0.0–0.57), respectively. The average of pretreatment median SR of bilateral parotid glands was 0.30 (range 0.0–0.67). Although the right and left parotid glands may receive different doses during radiotherapy, we found that the post-irradiation SR of right and left parotid glands presented the same pattern of recovery in our study (Fig. 1). Therefore, it is reasonable to evaluate the parotid gland function from the average of the SR of bilateral glands. The median post-irradiated SRs in 1 month (0.01) and 6 months (0.08) after radiotherapy of parotid glands showed significant difference compared with pre-irradiated data (P < 0.05, Table 3). After 12 months of parotid sparing radiotherapy, the median SR of parotid glands showed no significant difference compared with the pre-irradiation condition (12 months: 0.20, 18 months: 0.18, both P > 0.05, Table 3). We also noted that there was no significant difference in post-irradiated SR between 12 and 18 months (0.20 versus 0.18, P > 0.05).
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Further, we used post-irradiation data at 12 months for measurement of the predisposing factor for impairment of parotid function. The mean dose to the parotid gland >38 Gy was the risk factor for impairment of parotid gland function (Fig. 2). The parotid gland's mean doses were 34.1 Gy (95% CI: 32.1–36.1 Gy) for the <38 Gy group and 40.1 Gy (95% CI: 39.5–40.6 Gy) for the >38 Gy group. Other non-treatment related factors included sex, age >48 years, N (+) stage, T3–4 stage, pre-irradiation SR < 0.3, and volume of parotid gland <21.0 cm3, and all showed no significant difference (Table 3).
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At 12 months after treatment, 38 patients could be evaluated for salivary function. The subjective salivary grading of these patients was Grade 0 in 3, Grade 1 in 17, Grade 2 in 16 and Grade 3 in 2. According to the objective criteria of the LENT/SOMA system (18), there were 20 patients belonging to Grade 0–2 and 18 patients belonging to Grade 3–4. There was significant correlation between subjective and objective salivary function (P = 0.024).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Xerostomia is one of the most frequent and suffering late complications that impairs the quality of life in patients with nasopharyngeal cancer after curative radiotherapy (3,5). Most studies have found that the degree of xerostomia is correlated with the post-irradiation function of parotid glands (3,6,19). Roesink et al. (6) analyzed the stimulated parotid salivary flow after radiotherapy for patients with head and neck tumor. They found the parameter for parotid gland as specified in the normal tissue complication probability (NTCP) model; the dose to the whole parotid gland leading to a complication probability of 50% (TD50) was 35 and 39 Gy at 6 months and 1 year after radiotherapy, respectively. However, they did not find any threshold dose for parotid gland dysfunction. Eisbruch et al. (20) used a segmented regression model and found a mean threshold dose of 26 Gy at 1, 3, and 6 months for stimulated salivary output. Chao et al. (21) used an EUD-exponential model and predicted that the stimulated saliva reduced at a rate of 4% per Gy of mean parotid gland dose. Taken together, the radiation tolerance of the parotid gland is not completely understood yet, especially for those treated with IMRT. In the present study, we found that the mean dose of parotid gland >38 Gy influenced the post-irradiation SR significantly as measured at 12 months (P < 0.05). Our study showed that even the bilateral parotid glands received a mean dose as high as 38.2 Gy and there is a chance for parotid gland function to recover after 12 months of treatment (Fig. 1). Parotid function seems to become stable after 12 months because there was no difference between 12 and 18 months (P > 0.05). Different measurement facility and different models for analysis may explain the difference in results between the present study and other researchers' findings (6,19,21).
Regarding the parotid gland sparing treatment with IMRT in nasopharyngeal cancer, Lee et al. (13) reported that the percentage of Grade 2 xerostomia was 2.4% (1 out of 41 patients) at 24 months. Data of their study were based on subjective analysis. In this study, there are 47.4% patients (18/38) whose subjective salivary grading is greater than Grade 2. There was significant correlation between subjective and objective salivary function at 12 months after irradiation (P = 0.024). However, Leim et al. (22) did not find any significant correlation between subjective xerostomia scores and objective evaluation results for parotid gland function. They proposed that functional improvement could be caused by an adaptation effect. Lee et al. (13) reported that the mean dose to 50% volume of the parotids was 34 Gy. In our study, the mean dose to 50% volume of parotid gland of 34.5 Gy was similar to the result of Lee's study. For nasopharyngeal cancer treated by IMRT, our results and the UCSF (13) findings all indicated that parotid function could be preserved with 50% volume dose around 34 Gy. This dose level is much higher than 26 Gy, which Eisbruch et al. (20) suggested. In a recent study, Ng et al. (23) and Jen et al. (24) found that the degree of xerostomia in parotid-sparing radiotherapy is better than conventional radiotherapy.
In our results, other factors such as sex, age >48 years, LN positive stage, pre-irradiation SR < 0.3, volume of parotid gland <21.0 ml, T3–4 stage and concurrent chemotherapy were not correlated with the post-irradiation SR (Table 3). Based on our findings, we conclude that the key correlation factor of parotid function after irradiation in NPC patients is the dose to the parotid gland. Our findings implied that after 12 months of parotid-sparing radiotherapy mainly with IMRT, parotid function reached a plateau status. For better sparing of parotid function, it is important to restrict the mean dose to the parotid gland to <38 Gy.
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Acknowledgments |
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This study was sponsored by Taiwan National Science Council. Grant Number NSC91-2314-B-040-026.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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