INTRODUCTION. KEY WORDS: nasopharyngeal carcinoma, recurrence, intensitymodulated radiotherapy (IMRT), endoscopic nasopharyngectomy

Transcription

1 ORIGINAL ARTICLE Salvage endoscopic nasopharyngectomy and intensity-modulated radiotherapy versus conventional radiotherapy in treating locally recurrent nasopharyngeal carcinoma Xiong Zou, MD, 1,2 Fei Han, MD, PhD, 1,3 Wen-Juan Ma, MD, 1,2 Man-Quan Deng, MD, 1,2 Rou Jiang, MD, 1,2 Ling Guo, MD, 1,2 Qing Liu, MD, 1,4 Hai-Qiang Mai, MD, PhD, 1,2 Ming-Huang Hong, MD, 1,2 Ming-Yuan Chen, MD, PhD 1,2* 1 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People s Republic of China, 2 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, People s Republic of China, 3 Department of Radiation Oncology, Sun Yatsen University Cancer Center, Guangzhou, People s Republic of China, 4 Department of Epidemiology, Sun Yat-sen University Cancer Center, Guangzhou, People s Republic of China. Accepted 21 April 2014 Published online 11 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Although endoscopic nasopharyngectomy and intensity-modulated radiotherapy (IMRT) have been reported to be useful in treating isolated local recurrent nasopharyngeal carcinoma (NPC), their efficacy needs to be revaluated with comparison to 2D conventional radiotherapy (RT). Methods. Four hundred ten patients with recurrent NPC were retrospectively analyzed, among whom the patients underwent IMRT, endoscopic nasopharyngectomy, and 2D conventional RT. Results. The 5-year overall survival (OS) and distant metastasis-free survival were significantly higher in endoscopic nasopharyngectomy and IMRT groups than in 2D conventional RT group both in the entire series and in the subgroup of patients with recurrent T1 to 2 NPC (p <.05), except in the subgroup of recurrent T3 to 4 stratifications (IMRT vs 2D conventional RT; 28.8% vs 16.8%; p 5.351). Furthermore, endoscopic nasopharyngectomy was associated with better OS than IMRT in the recurrent T1 to 2 subgroup (79.2% vs 62.1%; p 5.007). Multivariate analysis indicated therapeutic modality was an independent predictor of OS and distant metastasis-free survival (p <.001). Conclusion. Endoscopic nasopharyngectomy and IMRT are associated with an improved OS and distant metastasis-free survival of patients with recurrent NPC compared to 2D conventional RT in early recurrent disease. VC 2014 Wiley Periodicals, Inc. Head Neck 37: , 2015 KEY WORDS: nasopharyngeal carcinoma, recurrence, intensitymodulated radiotherapy (IMRT), endoscopic nasopharyngectomy INTRODUCTION Radiotherapy (RT), with or without chemotherapy, is the primary method of treating initial untreated nasopharyngeal carcinoma (NPC), with a 5-year disease-free survival (DFS) of 75.9% to 76.7% for nonmetastatic NPC. 1,2 However, 5.1% to 10.9% of patients develop residual or recurrent disease at the primary site. 1,3 Several treatments, including salvage surgery, reirradiation, and chemotherapy, have been reported to be useful for the management of locally recurrent NPC. 3 6 It has been reported that both *Corresponding author: M.-Y. Chen, Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, No. 651 Dongfeng East Road, Guangzhou, Guangdong , People s Republic of China. chmingy@mail.sysu.edu.cn Xiong Zou, Fei Han, and Wen-Juan Ma contributed equally to this work. Contract grant sponsor: This work was supported by grants from the National Natural Science Foundation of China (No ), Training Programme Foundation for the Talents by Sun Yat-sen University Cancer Center, and Program for New Century Excellent Talents in University (NCET ), Sun Yat-Sen University Clinical Research 5010 Program (No ), Guangdong Provincial Natural Science Foundation of China (S ) (to M.Y. Chen). radical RT based on 2D conventional RT and external nasopharyngectomy provide significantly better overall survival (OS) than chemotherapy alone. 3 However, no significant survival difference was observed between 2D conventional RT and external nasopharyngectomy. Intensity-modulated radiotherapy (IMRT) was recently reported to be associated with a 5-year OS of 38% to 45.4% 7 9 in patients with recurrent NPC, which is much higher than the outcomes of 12% to 28% from 2D conventional RT in previous reports Endoscopic nasopharyngectomy, a new method of surgical treatment, shows promising results with a 5-year OS of 90% using microwave ablation in patients with recurrent T1 NPC, 5 and 2-year OS of 80% using endoscopic resection in early recurrent disease, 4 which are also higher than the 5-year DFS rate of 56% reported with traditional extranasal approaches. 13 However, few reports are available to compare the efficacy of these methods of treatment, and to identify the optimal therapy for recurrent NPC. In this retrospective study, we present our institutional experience in salvage treatments, including 2D conventional RT, IMRT, and endoscopic nasopharyngectomy, in the largest series of patients with recurrent NPC presented in the latest 10 years. The purposes of this study were to 1108 HEAD & NECK DOI /HED AUGUST 2015

2 ENDOSCOPIC NASOPHARYNGECTOMY AND IMRT IN RECURRENT NPC TABLE 1. Univariate analysis of patient characteristics for overall survival and distant metastasis-free survival (n 5 410). Characteristic No. of patients 5-y OS Chi-square p value 5-y distant metastasis-free survival Chi-square p value Sex Female Male Age, y > < Pathological type None* WHO I/II and others WHO III <.001 Diagnosis period of recurrence Interval time 27 mo >27 mo Initial T classification T T T T Initial N classification N N N N Recurrent T classification < Treatment categories Endoscopic nasopharyngectomy IMRT D conventional RT < Abbreviations: OS, overall survival; WHO, World Health Organization; IMRT, intensity-modulated radiotherapy; 2D conventional RT, 2-dimensional conventional radiotherapy. Interval time refers to the duration from the end of first course of radiotherapy to diagnosis time of primary site recurrence. * Refers to the diagnosis of recurrence based on imaging and clinical findings only. review the applicability and efficacy of endoscopic nasopharyngectomy and IMRT, and to identify the most effective treatment modality. MATERIALS AND METHODS Patient selection The patients with recurrent NPC were identified from a database of inpatients at Sun Yat-sen University Cancer Center in Guangzhou, China. The database listed 10,464 patients with pathologically diagnosed NPC who were admitted to Sun Yat-sen University Cancer Center between January 2000 and December During this period, 704 patients (704 of 10,464; 6.73%) presented local recurrence, with or without synchronous regional/ distant failure, after previous radical RT and underwent salvage anticancer treatments, including surgery, RT, or chemotherapy, at Sun Yat-sen University Cancer Center. Among 704 cases, 107 and 83 cases were excluded because of a combination with synchronous regional lymph nodes or distant metastasis, respectively, and only the rest 514 (514 of 10,464; 4.91%) were presented as isolated locally recurrent NPC. Among these 514 cases with isolated recurrent NPC, 67 and 37 cases were further excluded because of undergoing palliative chemotherapy alone or RT techniques rather than 2D conventional RT and IMRT (such as 3D conformal RT, fractionated stereotactic RT, and brachytherapy), and eventually, only 410 patients were included in the current study. Pathologyproven recurrent undifferentiated non-keratinizing carcinoma (World Health Organization [WHO] III), differentiated non-keratinizing carcinoma (WHO II), keratinizing squamous cell carcinoma (WHO I), and sarcoma were diagnosed in 355, 24, 4, and 2 patients, respectively. In the other 25 patients, diagnosis was based on clinical symptoms, signs, and imaging studies because tumor recurrences at the skull base and/or cavernous sinus rendered tissue access for biopsy impractical. Pretreatment evaluation of these patients, including a complete history, physical and neurologic examinations, hematology and biochemistry profiles, contrast-enhanced MRI (preferred) or CT scan of the head and neck, chest X-ray, abdominal HEAD & NECK DOI /HED AUGUST

3 ZOU ET AL. ultrasonography, and bone scan. Whole body fluor-18- fluorodeoxyglucose positron emission tomography with CT WAS obtained when clinical indicated. The disease was staged following the International Union Against Cancer/American Joint Committee on Cancer TNM classification (sixth edition, 2002). The clinicopathological characteristics of the patients are summarized in Table 1. Treatment of recurrence at referral Salvage treatments included chemotherapy, 2D conventional RT, IMRT, endoscopic microwave ablation, and endoscopic nasopharyngectomy, alone or in combination. The choice of salvage treatment was determined by the size, extent, and location of tumor, as well as patient intention and consultation of radiation oncologists and surgeons. In general, RT and/or chemotherapy were suitable for the treatment of all recurrent T classification cases, but salvage surgery was performed in early recurrent disease (recurrent T1 2a) or some highly selected recurrent T2b confined in superficial parapharyngeal space and recurrent T3 disease confined in the base wall of the sphenoid sinus. 4 The various treatment modalities have been described in detail previously, and are briefly summarized here: (1) 2D conventional RT was delivered a dose equivalent to 60 to 66 Gy with standard fractionation to local disease through 2 lateral, opposing front ear fields using megavoltage photons (6 or 8 MV), with or without a fractionated brachytherapy boost of a total dose of 10 to 20 Gy 14,15 ; (2) IMRT was delivered with a dynamic multileaf intensity-modulating collimator (NOMOS, Sewickley, PA) by a slice-by-slice arc rotation approach using 6 MV photons 7,8,16 ; (3) endoscopic nasopharyngectomy included endoscopic resection and microwave ablation, with or without posterior pedicle nasal mucoperiosteal flap resurfacing the nasopharyngeal defects 4,5,17,18 ; (4) chemotherapy was used as multidisciplinary treatment combined with surgery or reirradiation in selected patients. Cisplatin-based combination regimens were used initially. Statistical analysis The local relapse-free survival, distant metastasis-free survival, and OS were calculated using the Kaplan Meier method, and the differences were compared by log-rank test. The durations were calculated from the date of the recurrence diagnosis to the date of each event or the last follow-up. To evaluate the independent contribution of each variable to mortality, sex, age, and all covariates significantly associated with prognosis detected by univariate analyses were included in the multivariate analyses. Additional survival curves were plotted using the Cox multivariate model to adjust for patient selection bias. Associations of distributions were tested with the Pearson chi-square test. All analyses were performed with SPSS software (version 16.0; SPSS, Chicago, IL) and a 2-tailed p <.05 was considered statistically significant. RESULTS Improved overall survival and distant metastasis-free survival in patients with recurrent nasopharyngeal carcinoma who received endoscopic nasopharyngectomy and intensity-modulated radiotherapy Local reirradiation was delivered in 318 cases, including 100 and 218 patients who underwent 2D conventional RT and IMRT, respectively. Chemotherapy was administered in 167 cases, mostly combined in combination with RT (2D conventional RT: 47.0% vs IMRT: 50.5%; p 5.651), but significantly fewer combined with surgery (10.9%; p <.001). At the last follow-up date of January 1, 2013, there were 18, 13, 8, 5, 0, and 8 patients lost to follow-up in the first, second, third, fourth, fifth, and sixth years thereafter. The accumulated follow-up rate reached 95.6%, 90.5%, and 89.3% in 1, 3, and 5 year. The median follow-up was 33 months (range, months). During the follow-up, 69 and 49 patients, respectively, experienced a second locoregional recurrence and/or distant metastases. The 5-year local relapse-free survival and distant metastasis-free survival rates were 76.6% and 81.4%, respectively. Two hundred sixteen patients died, which included 28.2% of the patients who died of tumors in the locoregional site (20 patients), distant organs (23 patients), or both lesions (18 patients), and the rest of the 155 patients (71.8%) died of radiation injuries (150 patients, including postradiation nasopharyngeal necrosis, severe hemorrhage, encephalopathy, inflammation, or dyscrasia) or other disease/accident (5 patients). The 5-year OS was 43.7% (see Figure 1). FIGURE 1. The survival curves of the entire series. In all 410 patients with recurrent nasopharyngeal carcinoma (NPC), the 5-year locoregional relapse-free survival, distant metastasis-free survival, and overall survival (OS) were 74.8% (A), 83.0% (B), and 43.7%, respectively (C) HEAD & NECK DOI /HED AUGUST 2015

4 ENDOSCOPIC NASOPHARYNGECTOMY AND IMRT IN RECURRENT NPC FIGURE 2. The survival curves of different therapeutic modalities. Significantly better overall survival (OS) (A) and distant metastasis-free survival (C) was observed in patients treated with intensity-modulated radiation therapy (IMRT) and endoscopic nasopharyngectomy (ENPG) as compared to those treated with 2D conventional RT (2D-CRT). Additionally, survival curves estimated from the Cox multivariate model with adjustments for other prognostic factors further identified the same statistical significance in both OS (B) and distant metastasis-free survival (D). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] With regard to the impact of different salvage modalities on the survivals, no significant difference of local relapse-free survival was observed among patients treated with different treatments (p 5.123, data not shown). However, significantly higher distant metastasisfree survival and OS were observed in patients treated with IMRT (5-year OS and distant metastasis-free survival, 39.0% and 86.9%, respectively) and endoscopic nasopharyngectomy (5-year OS and distant metastasisfree survival, 78.1% and 88.6%, respectively) with comparison to those treated with 2D conventional RT (5- year OS and distant metastasis-free survival, 21.1% and 64.7%, respectively; p <.05, Table 1 and Figure 2A and 2C). Treatment category was found to be an independent prognostic factor for both overall survival and distant metastasis-free survival Multivariate analysis was performed to adjust for various prognostic factors and the treatment category was found to be an independent prognostic factor of both OS and distant metastasis-free survival (Table 2; p <.001). Furthermore, endoscopic nasopharyngectomy and IMRT were associated with a significant decrease of risks of death and distant metastasis compared to 2D conventional RT (p <.05). Notably, endoscopic nasopharyngectomy was also associated with better OS (p 5.001), but not distant metastasisfree survival (p 5.868) than the IMRT (Figure 2B and 2D). HEAD & NECK DOI /HED AUGUST

5 ZOU ET AL. TABLE 2. Multivariate analysis of overall survival and distant metastasis-free survival in patients with recurrent nasopharyngeal carcinoma. OS Variable Categorical variable HR 95% CI for HR p value Age y >46 y Reference Diagnosis period of recurrence Reference Recurrent T classification < < Reference Treatment categories <.001 Endoscopic nasopharyngectomy <.001 IMRT D conventional RT Reference Distant metastasis-free survival Interval duration mo >27 mo Reference Pathological type.002 None* <.001 WHO I/II and others WHO III Reference Treatment categories.003 Endoscopic nasopharyngectomy IMRT D conventional RT Reference Abbreviations: HR, hazard ratio; CI, confidence interval; OS, overall survival; IMRT, intensity-modulated radiotherapy; 2D conventional RT, 2-dimensional conventional radiotherapy; WHO, World Health Organization. All covariates significantly associated with prognosis detected by univariate analyses were taken into account by adjusted COX model, this included sex, age, initial and recurrent T classification, and treatment categories with respect to OS, and sex, age, pathological type, interval time, initial N classification, and treatment categories with respect to distant metastasis-free survival. Patients with early recurrence tended to be treated with endoscopic nasopharyngectomy, whereas those with advanced recurrence only tended to be treated with reirradiation Distribution analysis of different salvage modalities found recurrent T classification was a significant selection biases. Almost half of the patients restaged in recurrent T1 to 2 classifications (45.7%; 79 of 173 patients) tended to be treated with endoscopic nasopharyngectomy, whereas most patients restaged in recurrent T3 to 4 (94.5%; 224 of 237 patients) tended to be treated with reirradiation. However, no distribution difference was observed between IMRT and 2D conventional RT (p 5.156). In addition, distribution difference was not observed with regard to sex, age, pathological type, and interval from the end of the first course of RT to recurrence (Table 3). Endoscopic nasopharyngectomy and intensitymodulated radiotherapy were associated with survival benefits in recurrent T1 to 2 but not in recurrent T3 to 4 subgroups as compared to 2D conventional radiotherapy To eliminate the selection bias of recurrent T classification in patient assignment, we repeated the analysis in the subgroups of recurrent T1 to 2 and recurrent T3 to 4 patients. In the subgroup of patients with recurrent T1 to 2 NPC, 79, 57, and 37 patients underwent endoscopic nasopharyngectomy, IMRT and 2D conventional RT, respectively. Endoscopic nasopharyngectomy and IMRT were still associated with better survival than 2D conventional RT in OS and distant metastasis-free survival (p <.001). Furthermore, endoscopic nasopharyngectomy was found to have a better 5-year OS than IMRT (79.2% vs 62.1%; p 5.007; Figure 3A and 3B). In the subgroup of patients with recurrent T3 to 4 NPC, although endoscopic nasopharyngectomy still presented higher OS than IMRT and 2D conventional RT, all those patients who received endoscopic nasopharyngectomy were staged in recurrent T3 and highly selected with disease confined in the base wall of the sphenoid sinus. Surprisingly, IMRT was not associated with significantly better 5-year OS than 2D conventional RT (28.8% vs 16.8%; p 5.351; Figure 3C). No statistical difference was observed among IMRT, chemotherapy, and 2D conventional RT in distant metastasis-free survival (p >.05). DISCUSSION A previous study had shown that chemotherapy alone is associated with significantly lower OS than radical RT and nasopharyngectomy, 3 chemotherapy is usually used as palliative treatment in patients who were not suitable for salvage nasopharyngectomy or reirradiation because of the extensive disease or they refused to receive any aggressive treatment In this retrospective study, 1112 HEAD & NECK DOI /HED AUGUST 2015

6 ENDOSCOPIC NASOPHARYNGECTOMY AND IMRT IN RECURRENT NPC TABLE 3. Patient distributions in the chemotherapy, 2-dimensional conventional radiotherapy, intensity-modulated radiotherapy, and endoscopic nasopharyngectomy groups. Endoscopic nasopharyngectomy IMRT 2D conventional RT Parameter No. of patients % No. of patients % No. of patients % Chi-square p value Sex Female Male Age 46 y >46 y Pathological type None* WHO I/II and others WHO III Diagnosis period of recurrence <.001 Interval duration 27 mo >27 mo Recurrent T classification <.001 Abbreviations: IMRT, intensity-modulated radiotherapy; 2D conventional RT, 2-dimensional conventional radiotherapy; WHO, World Health Organization. * Refers to the diagnosis of recurrence based on imaging and clinical findings only. NOTE: Although the recurrent T1 to 4 classification distribution was significantly different among all 3 modalities using chi-square test (chi-square value, ; p <.001), no statistical difference was observed between 2 subgroups of IMRT and 2D conventional RT (chi-square value, 5.226; p 5.156). Furthermore, no statistical difference was observed among subgroups of endoscopic nasopharyngectomy, IMRT, and 2D conventional RT in recurrent T1 to 2 stratification (chi-square value, 4.295; p 5.117). chemotherapy was used as multidisciplinary treatment combined with surgery or reirradiation in selected patients. However, significantly fewer patients were selected to combine chemotherapy in the surgery group compared with the reirradiation group. We also failed to find that the patients who combined surgery with FIGURE 3. The survival curves of different therapeutic modalities in subgroup analysis. Significantly better overall survival (OS) (A) and distant metastasis-free survival (B) was observed in patients treated with intensity-modulated radiation therapy (IMRT) and endoscopic nasopharyngectomy (ENPG) as compared to those treated with 2D conventional RT (2D-CRT) in the subgroup of patients with recurrent T1 to 2 nasopharyngeal carcinoma (NPC; p <.005). Furthermore, endoscopic nasopharyngectomy was found to have a better 5-year OS than IMRT (p 5.007) (A). In the subgroup of patients with recurrent T3 to 4 NPC, endoscopic nasopharyngectomy were associated with significantly better 5-year OS than IMRT and 2D conventional RT (p <.005) but IMRT was not associated better OS than 2D conventional RT (p 5.351) (C). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] HEAD & NECK DOI /HED AUGUST

7 ZOU ET AL. chemotherapy had any survival benefit compared to others without chemotherapy both in univariate and multivariate analyses. The efficiency of chemotherapy in patients with recurrent NPC needs to be evaluated in more studies. RT offers a potential chance of cure for patients with recurrent NPC who are not suitable for treatment with salvage surgery alone. However, chemoradioresistance of recurrent disease was a well-known adverse factor for salvage reirradiation, and radiation intolerance of critical structures limits the delivery of adequate radiation doses with 2D conventional RT. The 5-year OS of 2D conventional RT was unsatisfactory at 21.1% in the current study, which is similar to other reports in which 5-year OS has been reported to range from 12% to 28% Other salvage RT options, including brachytherapy, 22 stereotactic radiosurgery, 23,24 and 3D conformal RT, 25,26 can enhance the therapeutic dose to tumors and reduce the radiation doses and affected volumes of critical organs surrounding the tumor. However, the use of stereotactic radiosurgery and brachytherapy alone is critically limited to the treatment of small recurrent lesions that normally can be treated by surgery. Three-dimensional conformal RT is not suitable for an irregular target, especially the typically concave lesions surrounding the brainstem or spinal cord. Furthermore, the incidence of late toxicities was not found to decrease as originally expected. 25 As a transitional technique, 3D conformal RT was soon replaced by IMRT, which could deliver differential total doses and fraction sizes to the tumor targets and adjacent sensitive organs, and thereby offer the prospect of improving the therapeutic dosage, which is regarded as an important factor for the local control of those more radioresistant clones of recurrent NPC. 8 Encouraging outcomes of IMRT was observed in our cohort with a 5-year OS of 39.0%, which was much higher than that of 2D conventional RT (12% to 28%) and similar to other reports of IMRT (38% to 45.4%). 7,8 However, further subgroup analysis found that IMRT had the advantage in the early recurrent disease (recurrent T1 2 classification) but not in the advanced disease (recurrent T3 4 classification) compared to 2D conventional RT. Although IMRT delivers a much lower total and fractional dose to adjacent sensitive organs than tumor targets, severe late radiation toxicities, such as severe xerostomia, trismus, hearing loss, and temporal lobe necrosis, are still inevitable in patients with recurrent NPC because of the previous radiation injury to those critical structures. Furthermore, high total and fractional dose reirradiation is inevitably accompanied by a high incidence of serious sequelae in the nasopharynx, including nasopharyngeal mucosal necrosis and massive hemorrhage. After salvage IMRT reirradiation, the incidence of new encephalopathy, severe hearing loss, trismus, and nasopharyngeal necrosis have been reported to be 28.5%, 38.1%, 22.2%, and 40.6%, respectively. 8 Han et al 8 had reported that patients with advanced restage (recurrent T3 4), as well as old age and extensive tumor progression, had a higher risk of death because of the complications of nasopharyngeal necrosis and/or massive hemorrhage. In the current analysis of patients with recurrent T3 to 4 NPC, IMRT lost its survival advantage compared to 2D conventional RT. Those results pose a very important question for IMRT reirradiation: How do you solve the contradiction between improving survival by increasing the radiation dose and avoiding its adverse impact on the patient s quality of life from radiationrelated toxicities? Salvage surgical resection is a reasonable option for some patients with relatively small lesions because of the advantages of removing radioresistant disease for satisfactory tumor control and the absence of further radiationrelated injuries, which benefits the patients with better quality of life. Because of the complexity of the nasopharyngeal anatomy and the many important surrounding structures, the nasopharynx is relatively inaccessible to extranasal surgical approaches. Of the traditional extranasal approaches, the maxillary swing approach provides adequate exposure of the nasopharynx, and a 5-year DFS rate of 56% has been reported, which is one of the best survival results in the treatment of recurrent NPC. 6 A study has also indicated that quality of life is good for patients with recurrent NPC after salvage nasopharyngectomy using the maxillary swing approach. 27 However, the maxillary bone needs to be freed, and the hard and soft palates have to be split during the maxillary swing approach, which results in some destructive complications, such as palatal defect, trismus, otitis media with effusion, dysphagia, and nasal regurgitation, with incidences of 55.6%, 66.7%, 66.7%, 33.3%, and 44.4%, respectively. 28 With the development of endonasal endoscopic approaches, endoscopic microwave ablation 5 and en bloc resection 4 of nasopharyngeal tumors have been used in patients with early recurrent NPC (recurrent T1 2) to avoid the complications of extranasal approaches. Help from the improved visualization, more convenient instrumentations, and modified technology in endoscopic nasopharyngectomy, en bloc resection has been successfully performed in 94.6% of patients (35 of 37). A positive margin occurred in only 1 case (2.6%) in the endonasal endoscopic approaches, 4 which had been considered impossible because of the narrowness of the nasal cavity. In the current study, the 5-year OS and distant metastasis-free survival of patients who underwent endoscopic nasopharyngectomy were 78.0% and 88.6%, respectively, which are also higher than the 5-years DFS rate of 42% to 56% reported with traditional extranasal approaches. 13,28 Furthermore, innovative techniques of a posterior pedicled middle turbinate mucoperiosteal flap 17 and nasal septum and floor flap 18 were successfully used to resurface the nasopharyngeal defects after endoscopic nasopharyngectomy to avoid delayed healing because previous radical RT had injured the nasopharyngeal mucosa. Although endoscopic nasopharyngectomy was associated with significantly better survival results in recurrent NPC than IMRT in both univariate and multivariate analysis, a comparison between IMRT and endoscopic nasopharyngectomy is controversial. Patients treated with surgery are usually highly selected, but not those patients treated with reirradiation. In the current study, a significantly higher distribution of recurrent T1 to 2 was found in the endoscopic nasopharyngectomy group, whereas a higher distribution of recurrent T3 to 4 was found in the IMRT group. Many previous studies had proven that 1114 HEAD & NECK DOI /HED AUGUST 2015

8 ENDOSCOPIC NASOPHARYNGECTOMY AND IMRT IN RECURRENT NPC recurrent T classification is an independent prognostic factor of survival, and a lower recurrent T classification is usually associated with better survival regardless of treatment modality. 7,8 In the subgroup of patients with recurrent T3 to 4 NPC, although endoscopic nasopharyngectomy presented an OS benefit better than IMRT and 2D conventional RT, the results could not conclude that endoscopic nasopharyngectomy is superior to reirradiation in recurrent T3 to 4 stratification because all those patients who received endoscopic nasopharyngectomy were highly selected recurrent T3 patients with the disease confined in the base wall of the sphenoid sinus. In order to eliminate bias in recurrent T classification selection, we analyzed the survival of different treatments in the subgroup of patients with recurrent T1 to 2 NPC. The results showed that endoscopic nasopharyngectomy was associated with best survival than IMRT and 2D conventional RT. CONCLUSIONS In conclusion, the results of this retrospective analysis suggest that endoscopic nasopharyngectomy and IMRT correlated with the improved OS and distant metastasisfree survival with comparison to 2D conventional RT of in patients with recurrent NPC with recurrent T1 to 2 disease. Furthermore, endoscopic nasopharyngectomy was even associated with significantly better OS than IMRT in patients with early recurrent disease. However, a wellbalanced cohort study in endoscopic nasopharyngectomy and IMRT should be created to identify the efficacy of endoscopic nasopharyngectomy. REFERENCES 1. Lai SZ, Li WF, Chen L, et al. How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011;80: Xiao WW, Huang SM, Han F, et al. Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study. Cancer 2011;117: Yu KH, Leung SF, Tung SY, et al. Survival outcome of patients with nasopharyngeal carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Head Neck 2005;27: Chen MY, Wen WP, Guo X, et al. Endoscopic nasopharyngectomy for locally recurrent nasopharyngeal carcinoma. Laryngoscope 2009;119: Mai HQ, Mo HY, Deng JF, et al. Endoscopic microwave coagulation therapy for early recurrent T1 nasopharyngeal carcinoma. Eur J Cancer 2009; 45: Chan JY, Wei WI. Recurrent nasopharyngeal carcinoma after salvage nasopharyngectomy. Arch Otolaryngol Head Neck Surg 2012;138: Hua YJ, Han F, Lu LX, et al. Long-term treatment outcome of recurrent nasopharyngeal carcinoma treated with salvage intensity modulated radiotherapy. Eur J Cancer 2012;48: Han F, Zhao C, Huang SM, et al. Long-term outcomes and prognostic factors of re-irradiation for locally recurrent nasopharyngeal carcinoma using intensity-modulated radiotherapy. Clin Oncol (R Coll Radiol) 2012;24: Qiu S, Lin S, Tham IW, Pan J, Lu J, Lu JJ. Intensity-modulated radiation therapy in the salvage of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2012;83: Lee AW, Foo W, Law SC, et al. Total biological effect on late reactive tissues following reirradiation for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2000;46: Oks uz DC, Meral G, Uzel O, Cagatay P, Turkan S. Reirradiation for locally recurrent nasopharyngeal carcinoma: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 2004;60: Chang JT, See LC, Liao CT, et al. Locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2000;54: Wei WI, Chan JY, Ng RW, Ho WK. Surgical salvage of persistent or recurrent nasopharyngeal carcinoma with maxillary swing approach critical appraisal after 2 decades. Head Neck 2011;33: Chen MY, Cao XP, Sun R, et al. Application of interstitial brachytherapy via parapharynx involvement transnasal approach to enhance dose in radiotherapy for nasopharyngeal carcinoma [in Chinese]. Ai Zheng 2007;26: Cao X, Chen K, He Z. Short- and long-term therapeutic effects of brachytherapy on intracavitary residual tumor in 563 nasopharyngeal carcinoma (NPC) patients [in Chinese]. Zhonghua Zhong Liu Za Zhi 1998;20: Lu TX, Mai WY, Teh BS, et al. Initial experience using intensitymodulated radiotherapy for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004;58: Chen MY, Hua YJ, Wan XB, et al. A posteriorly pedicled middle turbinate mucoperiosteal flap resurfacing nasopharynx after endoscopic nasopharyngectomy for recurrent nasopharyngeal carcinoma. Otolaryngol Head Neck Surg 2012;146: Chen MY, Wang SL, Zhu YL, et al. Use of a posterior pedicle nasal septum and floor mucoperiosteum flap to resurface the nasopharynx after endoscopic nasopharyngectomy for recurrent nasopharyngeal carcinoma. Head Neck 2012;34: Ma BB, Tannock IF, Pond GR, Edmonds MR, Siu LL. Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer 2002;95: Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 2003;39: You B, Le Tourneau C, Chen EX, et al. A phase II trial of erlotinib as maintenance treatment after gemcitabine plus platinum-based chemotherapy in patients with recurrent and/or metastatic nasopharyngeal carcinoma. Am J Clin Oncol 2012;35: Syed AM, Puthawala AA, Damore SJ, et al. Brachytherapy for primary and recurrent nasopharyngeal carcinoma: 20 years experience at Long Beach Memorial. Int J Radiat Oncol Biol Phys 2000;47: Wu SX, Chua DT, Deng ML, et al. Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69: Seo Y, Yoo H, Yoo S, et al. Robotic system-based fractionated stereotactic radiotherapy in locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2009;93: Zheng XK, Ma J, Chen LH, Xia YF, Shi YS. Dosimetric and clinical results of three-dimensional conformal radiotherapy for locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2005;75: Ozyigit G, Cengiz M, Yazici G, et al. A retrospective comparison of robotic stereotactic body radiotherapy and three-dimensional conformal radiotherapy for the reirradiation of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e263 e Chan YW, Chow VL, Wei WI. Quality of life of patients after salvage nasopharyngectomy for recurrent nasopharyngeal carcinoma. Cancer 2012; 118: King WW, Ku PK, Mok CO, Teo PM. Nasopharyngectomy in the treatment of recurrent nasopharyngeal carcinoma: a twelve-year experience. Head Neck 2000;22: HEAD & NECK DOI /HED AUGUST