鼻咽癌以耳下腺保護放射治療的唾液腺功能評估之研究

Assessment of Salivary Function Change in Nasopharyngeal Carcinoma Treated by Parotid-sparing Radiotherapy

劉文山(Wen-Shan Liu)

指導教授 ： 李輝

中山醫學大學/醫學院/醫學研究所/博士(2007年)

https://doi.org/10.6834/CSMU.2007.00043

摘要

台灣地區鼻咽癌的發生率大約是每十萬人283人，其發生率在所有癌症中，男性排名第十，女性則為第十八名。而在鼻咽癌之死亡率方面，男性是第九名，女性則是第十一名。雖然鼻咽癌的發生率較其他主要癌症相對較低，但是台灣地區鼻咽癌的盛行率是歐美國家的25至50倍，因此鼻咽癌的防治是台灣重要之醫學研究課題之一。放射治療是鼻咽癌的主要治療方法，第一期患者經過放射治療可獲得70 – 80% 的五年存活率，但是第四期患者則降低至 40% 以下。近年來對於鼻咽癌的治療有兩項重要的發展，第一是同步放射化療法，第二是強度調控放射治療法的局部及淋巴區域的控制，可以大幅提高鼻咽癌患者的療效。因此如何降低治療副作用以及改善生活品質即成為重要的研究課題。在眾多後遺症中，口乾症是最常見者，不僅會造成患者口乾，還會嚴重影響生活品質。強度調控放射治療之劑量學之改變確實可以保護一部份耳下腺之功能，但是這些劑量學上的優點，是否真能使病患生活品質改善？那些因素會影響保護耳下腺的功能？以及患者主觀感覺的口乾嚴重程度是否有客觀方法驗證？這些都是本研究之研究動機以及研究課題。本研究自西元2000年8月至2003年7月共收集了45位未轉移的鼻咽癌病患，以強度調控放射治療來保護耳下腺的功能，為了要利用強度調控放射治療所能發揮的物理及輻射生物學上的優點，在相同時間內針對不同目標給予不同劑量。計畫目標是給予GTV最少70Gy，PTV給予55-60Gy，GTV-LN給予66-70Gy，以上這些目標區的分次劑量各為2.12Gy、1.7-1.8Gy、2.0-2.12Gy；至於及耳下腺的劑量限制在33 Gy至 35Gy。共有31位患者接受同步放射治療法，使用藥物為cisplatin (60 mg/m2) 注射一天與5-FU (600 mg/m2) 連續四天，每四週一循環。依照SOMA/LENT標準評估主觀與客觀的口乾症等級，並以唾液腺閃爍攝影評估唾液分泌率(secretion ratio, SR)。同時患者在放射治療前及治療後1、6、12、及18個月，接受唾液腺閃爍攝影評估耳下腺功能恢復與治療時程之相關性。本研究以Mann-Whitney rank-sum test分析影響耳下腺功能的因子，以Spearman rank-order correlation test分析SOMA/LENT主觀與客觀的相關性。結果腫瘤劑量為69.96至73.60Gy，平均總劑量為71.8Gy，PTV平均劑量為 65.9Gy。患者轉移的淋巴結的平均治療劑量為72.7 Gy。兩側耳下腺的平均中值劑量為34.6 Gy。全部45位患者治療前平均耳下腺的SR為0.3 (範圍為0.0至0.67)，左右的平均耳下腺SR各為0.22與0.36 (範圍為0.0至0.57與 0.0至0.67)，左右耳下腺並無統計差異 (p > 0.05)。病患 (45位) 之平均耳下腺SR在治療後一、六、十二、與十八個月分別為0.01、0.08、0.20、與0.18；治療後第一及六個月的耳下腺功能與治療前的SR (SR = 0.3) 有顯著差異，但治療後第十二及十八個月的耳下腺功能與治療之前並無差異。對於比較唾液腺主客觀副作用分析的34位患者的耳下腺，在一至十八個月疾病同側或對側的耳下腺之間其平均SR亦無差異，治療後第一個月 (SR = 0.01，P = 0.000) 及第六個月 (SR = 0.08，P = 0.002)的耳下腺功能均與治療之前的功能 (SR = 0.3) 達到統計上之差異。但治療後第十二 (SR = 0.22，P = 0.734) 及十八個月(SR = 0.16，P = 0.885) 則與治療之前的功能 (SR = 0.3) 無差異。治療後的頷下腺功能在第一至十八個月均與治療前 (SR = 0.29) 有差異。依SOMA/LENT分析34位病患，治療之前患者主觀感覺屬Grade 0的有30位，Grade 1的有4位。治療之後，前半年大部份的病人屬Grade 2 (67.6 %及76.5 %)，治療後一年主觀的等級多為Grade 1 (47.1 % 及52.9%)。比較口乾症主觀與客觀等級之相關性，在治療結束一個月時，兩者並無相關性 (r = 0.393，p = 0.063)。但自六個月後口乾症的主觀與客觀等級及有顯著相關 (6個月，r = 0.657， p = 0.000) (12 個月，r = 0.480，p = 0.013) (18個月，r = 0.591，p = 0.002)。當分析可能影響耳下腺功能的因子，包括：性別、年齡大於48歲、頸部淋巴結轉移、T3-4期別、治療前SR大於0.3、耳下腺體積大於21.0ml、耳下腺平均劑量大於38 Gy、化學治療與否等。結果發現各種因子中僅有耳下腺平均劑量是否大於38 Gy，對於治療後的耳下腺功能會造成影響。在34位平均追蹤42個月患者的治療成效，所有患者都沒有鼻咽部復發，兩位病患在區域淋巴腺復發，六位有遠端轉移。四年的loco-regional progression–free 存活率及disease–free存活率分別為 94.1 % 與 82.4 %，總存活率為 91.2 %。總之，本研究結果發現鼻咽癌以強度調控放射治療在保護耳下腺的功能上，在兩側耳下腺的中值劑量達到34.6 Gy的狀況下 (平均 38.2 Gy)，其唾液分泌功能仍能在治療12個月後有明顯回復。但是治療後追蹤至12個月和18個月，唾液腺功能並不沒有進一步改善。以唾液腺閃爍攝影測量耳下腺唾液功能分析客觀口乾症等級時發現，與病患主觀口乾症等級間有顯著相關。分析各種可能會影響耳下腺功能的因子僅發現耳下腺平均劑量大於38 Gy會影響治療後的耳下腺功能。

關鍵字

鼻咽癌 ； 放射治療 ； 唾液腺閃爍攝影 ； 後遺症

並列摘要

The crude incidence of nasopharyngeal cancer (NPC) in Taiwan is 283 cases per 100 thousands people per year. This disease occupies 10th place in incidence of cancer in men and eighteenth in women. As for the death rate position, NPC is 9th in men and eleventh in women. Though the incidence of this disease is not very high compared to other cancers in Taiwan, the incidence is about 25 to 50 times higher than the general incidence of the world. Hence, we must depend on our own efforts to study this disease. Compared to other sites of head and neck cancer, NPC has a totally different epidemiology and etiology. External beam radiotherapy has remained the major treatment method for this disease. Although we could get about 70 - 80 % five-year survival by radiotherapy alone for early stage patients, the long-term survival would be as low as 40 % for stage four disease. There have been two major improvements in the treatment of NPC. First, many researches proved that concurrent chemo-radiotherapy (CCRT) could increase the survival, and disease-free survival, in locally advanced disease. Second, using intensity-modulated radiotherapy (IMRT) could increase the local regional control rate in both early and advanced stage patients. Apart from the improvement of treatment method, many researchers have tried to find prognostic factors other than the clinical stage. For example, Dr. Lin found that EBV DNA copies numbers could be a ‘stand-alone’ prognostic factor for this disease. How to control the side effects becomes a most important issue when more and more patients could become survivors. The xerostomia is the most frequent late sequel after the treatment of NPC. This symptom could impair the life quality of the survivors. Xerostomia impairs chewing, swallowing and speech functions. IMRT could protect the parotid glands in the dosimetric study; however, whether this dosimetric benefit could translate to clinical benefit is the question. Which factor could affect the success of parotid gland protection? Is subjective sensation compatible with the objective findings of parotid gland impairment? All these questions became our motivation for further studying.

From August 2000 to July 2003, 45 patients with histological proven, non-metastatic nasopharyngeal carcinoma were included in this study. There were 34 males and 11 females. For the maximum benefit of both physics and biology, we adopt the simultaneous integrated boost (SIB) method in planning the treatment for these patients. The dose to the gross target volume (GTV), PTV and GTV-LN were as least 70 Gy, 55-60 Gy, 66-70 Gy, respectively. Hence, the fraction-size of the above targets was: 2.12 Gy, 1.7-1.8 Gy, and 2.0-2.12 Gy, respectively. The dose constraint to parotid glands was 33 – 35 Gy. There were thirty-one patients in this series that received CCRT. The regimen of chemotherapy was cisplatin (60mg/m2) on Day 1 and Day 28 and 5-FU (600mg/m2) on Day 1-4 and Day 28-31. We used SOMA/LENT scale for recording both subjective and objective dry mouth grading. The sialoscintigraphy was used as an objective method for the evaluation of the function of parotid glands in this study. The pre-irradiation sialoscintigraphy was performed in all patients, and the tests were repeated at intervals of one (43 cases), six (37 cases), twelve (39 cases), and eighteen (36 cases) months after the completion of radiotherapy. The Wilcoxon signed-rank pair test was used to compare the difference in the SR of salivary glands before and after radiotherapy. The Mann-Whitney rank-sum test was used to compare the difference of SR between parotid and submandibular glands. Spearman rank-order correlation tests were used to evaluate correlations between LENT/SOMA subjective and objective scoring. The mean dose administered to the GTV and PTV was 71.8 Gy and 65.9 Gy, respectively. The dose to the metastatic neck LN was 72.7 Gy. The median dose administered to the parotid glands was 34.6 Gy. The mean SR of the parotid gland was 0.3 (ranged from 0.0 to 0.67). The SR of the right and left parotid gland was 0.36 and 0.22, respectively. There was no significant difference between them. The mean SR after treatment in one, six, twelve, and eighteen months were: 0.01, 0.08, 0.20, and 0.18, respectively. There were significant differences between the pre- and post-irradiation parotid gland SR after one and six months. However, there was no significant difference between pre- and post-irradiation after twelve and eighteen months (Figure 5). As for the group use for studying the correlation between subjective and objective xerostomia grading patients (34 cases), there were no significant differences between ipsilateral and contralateral parotid glands. There were significant difference between pre- (SR=0.3) and one month (SR=0.01, p=0.000), and six months (SR=0.08, p=0.002). However, there were no significant differences compared to the pre-irradiation data up to twelve (SR=0.22, p=0.734), and eighteen (SR=0.16, p=0.885) months. The function of submandibular glands had significant impairment after one to eighteen months following treatments. Based on the SOMA/LENT scale, the numbers of subjective grading of pre-irradiation were: 30 patients belonging to Grade 0 and 4 patients belonging to Grade 1. Up to six months after radiotherapy, most of our patients belonged to Grade 2 (67.6% and 76.5%). However, the most frequent grading became Grade 1 (47.1% and 52.9%), after one year of radiotherapy. After 1 month of radiotherapy, there was no significant correlation between LENT/SOMA subjective and objective xerostomia grading scores (r=0.393, p=0.063). However, there was a significant correlation between scores at 6 months (r=0.657, p=0.000), 12 months (r=0.480, p=0.013), and 18 months (r=0.591, p=0.002). The factor impacting the preservation of parotid function was a mean dose of parotid gland greater than 38.0 Gy (p<0.05). The mean follow-up time was 42.0 months (range, 27-50 months). No patient had local recurrence at the primary site. There were two patients who had regional lymph node recurrences. A total of six patients developed distant metastases. Four-year loco-regional progression–free and disease–free survival rates were 94.1 % and 82.4 %, respectively. Four-year overall survival was 91.2 %.

Even though patients with NPC received a median dose of 34.6 Gy (mean 38.2 Gy) to the bilateral parotid glands, gland function recovered significantly by 12 months after radiotherapy. But there was no further recovery from 12 months to 18 months after radiotherapy. Based on sialoscintigraphy examination, there were significant rank-order correlations between LENT/SOMA subjective and objective (analytic) grading scores measured by SR per sialoscintigraphy after 6 to 18 months of follow-up. The mean dose over 38 Gy was the only factor that affected the function of the parotid gland after treatment.

並列關鍵字

nasopharyngeal carcinoma ； radiotherapy ； sialoscintigraphy ； sequela

參考文獻

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Ahn YC, Lee KC, Kim DY et al. Fractionated stereotactic radiation therapy for extracranial head and neck tumors. Int J Radiat Oncol Biol Phys 2000; 48: 501-505.

Al-Sarraf, M, LeBlanc, M, Giri, PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup study 0099. J Clin Oncol 1998; 16:1310.

Al-Sarraf, M, LeBlanc, M, Giri, P, et al. Superiority of five year survival with chemo-radiotherapy vs radiotherapy in patients with locally advanced nasopharyngeal cancer. Intergroup (0099) (SWOG 8892, RTOG 8817, ECOG 2388) Phase III study. Final Report (abstract). Proc Am Soc Clin Oncol 2001; 20:227