Radiotherapy is the major treatment modality for NPC. Prior to the advent of IMRT, conventional two-dimensional (2D) or 3DCRT techniques were used and the treatment outcomes were suboptimal. IMRT is a complex form of 3DCRT and could deliver non-uniform doses to the targets via multiple intensity-modulated beams. Due to the excellent dosimetric advantages for target coverage and normal tissue sparing by using IMRT, there were results showing significant improvement in treatment outcomes compared with 2D radiotherapy [2,3,9,21,23]. However, there were also some reports indicating that IMRT has no advantage over conventional 2D or 3D radiotherapy [33–35].
In this article, we reported the treatment outcomes of NPC patients treated with IMRT. Compared with our historical report for NPC treated with 2D techniques [36], substantial improvement was observed in patients treated with IMRT. Locoregional control is the main goal of radiotherapy. Compared with our historical results of patients treated with conventional techniques, the 5-year LC rate improved from 78% to 91.3%. The incidence of local failure decreased from 22% to 9.2%. The reported incidence of local failure for NPC patients treated with IMRT ranged from 4.2% to 10.9% [3,5,7,8,10–12,15,18,20,34,37–41]. For patients with T4 disease treated with IMRT, the reported incidence of local failure ranged from 7.3% to 22.9% [14,19,22]. In our study, the incidence of local failure was 9.2% for the entire cohort of patients and 14.8% for those with T4 diseases. Compared with the reported series, there was still room for improvement. The role of T-category on local control was still controversial. T-category was ever reported as an independent prognostic factor for local control [20]. Some investigators demonstrated that T-category was no longer a significant predictor for local control in the IMRT era [4,6,15,18,42]. In our study, T-category was demonstrated as the only independent prognostic factor for local control. The 5-year local control rates for T1/2 and T3/4 were 94.8% and 84.8% respectively (p<0.001). According to our current treatment protocol, the prescribed radiation doses were the same between different T-categories. Radiation dose-response relationship has been observed in several retrospective studies [43,44]. Therefore, the delivery of higher radiation dose for locally advanced diseases, might play an important role in improving the local control rate. Our further study will explore the impact of the delivery of boost irradiation for patients with T3/4 tumors. Another way to improve the local control might be the use of IGRT techniques. By using the On-Board Imager and Cone Beam CT, radiation dose could be delivered more accurately to the targets. In our study, the LC rates for patients treated with IGRT techniques and their counterpart were 93.3% and 90.0% respectively (p = 0.325). The RC rates for patients treated with and without IGRT techniques were 98.4% and 95.6% respectively (p = 0.144). Although the difference is not statistically significant, a trend toward better locoregional control in patients treated with IGRT was observed. Currently, the use of IGRT is not covered by our national health insurance reimbursement. It is necessary to collect more data to confirm the positive impact of IGRT on treatment outcomes and justify the routine use of IGRT.
For regional control, compared with our historical results [36], the 5-year RC rate improved from 93.7% to 96.8%. N-category was reported to be an independent predicator for regional nodal control [18,45]. Our results also demonstrated similar results and those with N3 lesions have the worst 5-year RC rate. Because significant shrinkage of the nodal lesions and change of soft tissue contour due to body weight loss were frequently observed during the radiotherapy course, the anatomical variations and subsequent loss of adequate immobilization might have impact on the dose distribution and might also cause the residual LAP to move partially outside of the PTV volume. Therefore, the application of IGRT and frequent replanning to adapt the LN shrinkage and contour change, especially for patients with N3 diseases, should be considered to improve the regional control.
In this study, retropharyngeal LAP was found to be an independent prognostic factor for OS, DFS, and DFF. The 5-year OS rates for patients without and with retropharyngeal LAP are 88.5% and 69% (Figure 1). Our results were consistent with other study [12]. Because CT-simulation with contrast enhancement has been the routine workup for NPC, it is less likely to miss the retropharyngeal LAP while defining targets. In our study, underdose of retropharyngeal LAP due to sparing of spinal cord or parotid glands was also not observed. The reason why retropharyngeal LAP was associated with higher incidence of distant failure and leaded to a poor treatment outcomes needed to be explored by further novel studies.
IGRT is a method of incorporating imaging techniques throughout a course of radiotherapy to maximize the precision and accuracy of the delivery of radiotherapy and the sparing of critical surrounding tissue. Although there is no large randomized data of improving outcomes or decreasing radiation-related toxicities with the use of IGRT techniques, some articles reported that IGRT was associated with an improvement in clinical outcomes and radiation-induced complications [46]. In our study, univariate analysis demonstrated that IGRT were associated with significantly better OS and DFS. The 5-year DFS rates for patient without and with IGRT are 66.2% and 77.6% (Figure 2). A trend toward better LC, RC and DFF was also noted for patients treated with IGRT techniques. The use of IGRT was further demonstrated as an independent predictor for DFS. For patients with and without IGRT, the 5-year LC, RC and DFF rates were 93.3% vs 90.0%, 98.4% vs 95.6% and 88.6% vs 82.9% respectively. Therefore, the better OS and DFS for patients with IGRT might be attributed to the lower local, regional and distant failure. It is reasonable that improvement of the precision and accuracy of radiation delivery could lead to improvement of treatment outcomes. In the future, in order to amplify the advantage of IGRT, efforts should be made to improve the breadth of personnel experience and to upgrade the software and hardware for IGRT.
Traditionally, higher BMI was considered as unhealthy and increased body weight was associated with increased death rates for all cancers [47]. However, higher BMI has been reported to be associated with better treatment outcomes in NPC patients [48,49]. In our study, higher BMI was also found to be an independent prognostic factor for OS, DFS and DFF. Body weight loss was common in patients treated with radiotherapy. In our study, body weight loss ranging from 0.3% to 27.1% (0.2–20.3 kg) occurred in 324 patients (99.4%). For patients with higher BMI, the negative impact of body weight loss and malnutrition might be less and this might account for the better treatment outcomes. However, further research is still warranted to explore the mechanism of the influence of BMI on treatment outcomes.
Treatment interruption was inevitable during radiotherapy course due to acute radiation-related toxicities, holidays, machine breakdown, or personal factors. The prolongation of overall treatment time has ever been reported to be an independent adverse prognostic factor for NPC [20,50]. On the other hand, a recent study demonstrated that prolonged treatment time had no influence on treatment outcomes for NPC treated with IMRT [17]. Our results showed that treatment interruption was associated with poorer OS, DFS and DFF. Multivariate analysis further confirms its independent prognostic significance for OS. Therefore, we have to recommend that treatment interruption caused by any reason should be avoided if at all possible.
The importance of age as a determinant of treatment outcomes has been observed by many investigators [4,11,12,17,18,40,48,50–52], although other studies have not shown its prognostic significance [7,20,35,45,49]. Our study also showed that older patients had significantly poorer OS, DFS and LC compared with their counterpart. Multivariate analysis also confirms its independent prognostic significance for OS and DFS. Due to the conflicting reports as to the effect of age on prognosis, we currently would not propose a different treatment strategy for older patients.
Based on the randomized clinical trials and meta-analyses, concurrent chemoradiotherapy with or without adjuvant chemotherapy is recommended for patients with locally advanced NPC [53–55]. Compared with our prior results of patients treated with radiotherapy alone [36], the 5-year DFF rate improved from 74.7% to 85.2%. The improvement of distant failure rate might be partly attributed to the addition of chemotherapy. However, the distant failure rate is still far from satisfactory. Although further efforts in improving locoregional control might have some contribution to the decrease of distant failure, a novel strategy of powerful systemic therapy will be most crucial for decreasing the distant failure.
The most prevalent late radiation-related complication for patients with nasopharyngeal cancer is xerostomia and it is associated with significant deterioration of quality of life. In our study, 49% of patients still complained of xerostomia at one year after the completion of radiotherapy. Although our result concurred with the findings of other investigators [10,56], this result was far from satisfactory. Recently published research on noncoplanar beam delivery techniques suggests the potential of significant improvement in target coverage and critical organ sparing for head and neck cancer [57]. Further research is needed to validate its use in parotid sparing.
Biochemical hypothyroidism is a common late radiation-related complication. For patients with NPC treated with radiotherapy, the incidence of hypothyroidism has been reported to be around 20% [58,59]. The 5-year estimated risk of radiation-induced biochemical hypothyroidism after primary radiotherapy for head and neck squamous cell carcinoma was reported to be 25.6% [60]. Since subclinical hypothyroidism has been reported to increase the risk of cardiac disease and mortality, thyroid hormone replacement therapy should be considered [61,62]. In our study, the incidence of biochemical hypothyroidism was 46.6%. Because the thyroid glands were very close to the high-risk neck lymphatics region, the radiation dose to the thyroid glands was quite high. Lin et al. suggested that keeping the mean thyroid dose below 50 Gy was important in preventing radiation-induced thyroid damage [58]. Lee et al. demonstrated that the absolute thyroid volume spared from 45 Gy and 60 Gy should be considered as dose constraints against hypothyroidism during IMRT optimization [59]. In order to reduce the incidence of biochemical hypothyroidism, clinical trials investigating the relationship between radiation dose and the occurrence of hypothyroidism is necessary for determining the appropriate dose constraint for thyroid glands. Whether sparing of thyroid glands will compromise the neck lymphatics control also needs to be investigated by further clinical trial.