Impressive clinical data of NPC treated by IMRT have been reported in recent years. In one study, the 4-year local progression-free and regional progression-free rates for loco-regional advanced NPC patients were 97% and 98%, respectively . Recent results from Hong Kong and the Memorial Sloan-Kettering cancer center have also shown similar findings [[13–15]]. However, with integration of aggressive concurrent chemoradiotherapy schedules, the changing failure pattern has been noted in several publications [[12, 16, 17]] and the distant metastases rates, nevertheless, can be as high as 30% .
To conquer the problem of distant metastases, adding neoadjuvant chemotherapy or adjuvant chemotherapy with concurrent chemoradiation is still an attractive approach that needs to be clarified, although post experience is very sparse. A study conducted in Hong Kong  reported that 24/25 locally advanced NPC patients achieved partial remissions after induction chemotherapy. Additionally, the 3-year local-PF, regional-PF, and DM-PF survival rates were 89.6%, 87.2%, and 80.4%, respectively. China has report the largest series of concurrent chemotherapy and IMRT data, with 323 locoregionally advanced NPC patients with neoadjuvant or adjuvant chemotherapy . The overall 3-year local-PF, regional-PF, DM-PF, and overall survival rates were 93.6%, 93.3%, 86.6%, and 87.2%, respectively. A study in Japan demonstrated the first experience of HT plus chemotherapy for 20 patients with a limited observation period. However, 18 patients who underwent chemotherapy with NDP (cis-diammineglycolatoplatinum, Nedaplatin) and 5FU were in alternating settings. During the alternating chemoradiotherapy and with a median FU of 10.9 months, one patient failed in the regional node and another one failed in the liver. The 10-month OS was 95% . In the current study, induction chemotherapy and CCRT with HT were well tolerated. During neoadjuvant chemotherapy, only one patient occurred grade 3 leukopenia. No patients experienced grade 3 anemia or thrombocytopenia. Four patients developed grade 3 leukopenia and 1 patient developed grade 3 anemia during the following CCRT with HT treatment. The median treatment time for CCRT was 54 days. The estimated 3-year PF for local, regional, and locoregional survival rates were 92.4%, 95.7%, and 88.4%, respectively. HT for locoregionally advanced NPC was shown to be feasible and effective in regard to locoregional control with high compliance, even after neoadjuvant chemotherapy.
Even though nearly 90% of our patients had locally advanced disease (stage III and IV), patients had excellent locoregional control rates after HT plus chemotherapy or even salvage therapy. However, of the 7 relapsed patients in the current study, 4 patients presented distant metastases. The regiment of induction chemotherapy in the current study was CDDP/Epirubicin/5-FU/Leucovoren (60/40/2000/300 mg/m2). Compared to the other studies, the doses of CDDP and Epirubicin in the current study were lower than the other studies [[14, 21, 22]]. The 3-year DMF survival rate was 78%, suggesting that distant metastases are still the major obstacle to be broken through. Moreover, present regimens of chemotherapy are not effective enough in preventing distant metastases and should be reevaluated.
Higher irradiation doses deliver high rates of locoregional control, progression-free survival for head and neck cancer . However, we may need to be concerned about late complications if the dose is escalated and the volume of tissues are exposed to high doses . On the other hand, if the volume of tissues exposed to high doses is reduced with image-guided IMRT, there is a possibility that treatment could achieve higher locoregional control rate and the probability of such complications could be reduced simultaneously. In the current study, the locoregional failure of 3 patients all belonged to in-field failure. The D95 in PTV70 ranged from 68.8 Gy to 72 Gy and the V97 in PTV70 ranged from 97.3% to 100%, respectively. (Table 2) None of the out-field or marginal failures noted in the current study showed 3 mm of PTV's margin, confirming the potential benefits of treating NPC patients with image-guided radiation modality. This finding also suggests that using 3 mm as the PTV margin in image-guided radiation therapy settings is feasible. Additionally, limited grade 3 of xerostomia, dysphagia and dermatitis were noted in the current setting (Table 6). Moreover, most of patients are normal to grade 1 of late toxicities. Only 4/28 patient had grade 2 xerostomia and 1/28 had grade 2 hearing loss. With accurate image-guided modality, dose escalation with reduced increase of toxicity for OARs becomes more reliable, providing relief for locoregionally advanced NPC patients.
One patient died of cardiac dysfunction, and the possibility that the toxicity was related to epirubicin used in induction chemotherapy should be considered. The range of total dose for epirubicin that cause cardiac toxicities is around 560-600 mg/m2[11, 25]. Bonneterre J, et al  reported that there were 2/85 cases of congestive heart failure observed after adjuvant treatment with six cycles of fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 for breast cancer patients in the 8 years follow up. Hasbini A, et al  used mitomycin, 5-fluorouracil, epirubicin, and cisplatin to treat recurrent and metastatic undifferentiated carcinoma of nasopharyngeal and one 42-year-old patient died of cardiac failure which was probably related to the anthracycline-chemotherapy. In the current study, three cycles of 40 mg/m2 induction epirubicin was prescribed and the total dose was 120 mg/m2. Although, the total dose of epirubicin is far from the doses that cause cardiac toxicity.
Even though this innovative approach acquired favorable outcomes with impressive locoregional control and survival result, several limitations need to be addressed. First, our study was retrospective and was carried with inherent biases usual to such a study design. Second, our sample size was small. Thus, these findings should be considered as preliminary and in need of validation in a larger patient group. Third, the study lacked in-house comparable results such as tomotherapy versus conventional IMRT or current regimen versus concurrent chemoradiation. Furthermore, the observation of long-term toxicities should be reported in the future. The clinical benefit of modern IGRT using tomotherapy, hence, could not be fully determined. Due to these limitations, this combination protocol must not be used in the daily practice of treatment for locally advanced NPC.