The present study is the first large, single-arm study to assess the efficacy and toxicity of radiation dose escalation for LA-NPC in patients with local and/or regional residual lesion(s) after they received IC + CCRT. Our study showed high 5-year rates in all patients who received boost irradiation: LRFS, 90.2%; RRFS, 89.1%; LRRFS, 79.5%; DMFS, 87.9%; FFS, 69.0%; and OS, 86.3%.

Biopsy and histopathology are the gold standard for detecting residual lesion(s). A pathological examination should be performed when residual lesions are suspected, if conditions permit. In the present study, patients who were suspected to have residual lesions via electronic nasopharyngoscopy routinely underwent a biopsy. When MRI indicated residual lesion(s) in cervical lymph nodes after RT, an ultrasound-guided fine-needle puncture was routinely used to confirm whether live tumor cells were present. However, most residual lesions at the primary site of LA-NPC are located in the deep tissue, such as the skull base, parapharyngeal space, intracranial area, and paranasal sinuses, where biopsy cannot be performed. In such cases, enhanced MRI was performed to determine the presence of the above residual tumors.

Selecting the best time node is crucial to evaluate residual tumor(s). The advantage of immediately evaluating for a residual tumor at the end of RT is that immediate treatment can be initiated that can improve the curative effect. The disadvantage is that initiating evaluation for residual tumor(s) at the end of RT may be associated with a certain false-positive rate. In such cases, over-treatment may occur, which may lead to increase in toxicity and adverse effects. The advantage of delayed evaluation is that overtreatment can be avoided in false-positive patients, but the disadvantage is that treatment may be delayed in true-positive patients resulting in poor prognosis. The best time for evaluation for residual lesion(s) is three months after RT in patients with NPC who previously have received conventional two-dimensional radical RT because nearly 80% residual lesion(s) subside spontaneously within three months after RT [13].

Currently, IMRT followed by IC has become the standard management for LA-NPC. The regression mode of NPC has remarkably changed. Previous studies found that about 10%-22% patients achieved CR after IC [6, 14, 15]. Our previous study found that about 90% patients achieved CR after IC + CCRT, which is much higher than that for patients who received RT alone or CCRT [7, 8, 16, 17].

In two retrospective studies [7, 18] in patients with LA-NPC on the prognostic value of MRI-detected residual lesion(s) immediately after IMRT, patients with residual tumor(s) following IMRT had a worse prognosis than patients without residual lesion(s). Lv et al. [8] assessed the prognostic value of residual lesion(s) detected by MRI three months after IMRT in 664 NPC patients and found that patients without residual lesion(s) three months after IMRT had a better prognosis than those with MRI-detectable residual tumor(s) (5-year OS: 93.8% vs. 76.6%, P < 0.001; 5-year LRRFS: 93.4% vs. 80.4%, P = 0.002; 5-year PFS: 84.7% vs. 67.9%, P = 0.006; 5-year DMFS: 90.3% vs. 87.9%, P = 0.305). Although 86.4% patients (28.3% at stage I or II) received chemotherapy, the proportion of patients receiving IC was not specified. To investigate the relationship between tumor regression and prognosis, Wenfeng Li et al. [19] retrospectively conducted a study of 556 NPC patients. At 3–4 months after IMRT, patients with a clinical complete response (cCR) had a greater local–regional control rate than patients without a cCR (92.9% vs. 73.1%, P < 0.001). The same phenomenon was observed 6–9 months after IMRT (92.9% vs. 54.2%, P < 0.001). The authors also noted that early (3–4 month) and delayed (6–9 month) cCR had better outcomes compared with those without cCR (5-year OS: 92.1% vs. 90.6% vs. 65.4%, P < 0.001; 5-year LRRFS: 92.6% vs. 93.3% vs. 54.2%, P < 0.001; 5-year FFS: 83.8% vs. 84.4% vs. 48.5%, P < 0.001). The percentage of patients who received IC was not specified, and 25.7% patients had stage I or II diseases. Wang-Zhong Li et al. [20] retrospectively evaluated the predictive value of residual retropharyngeal lymph node(s) detected by MRI three months after IMRT in 1,103 NPC patients. The retropharyngeal lymph node area had residual lesion(s) in 28.2% patients. Their findings demonstrated that patients with residual lesions in the retropharyngeal lymph node(s) had worse outcomes than those who did not have residual lesions in the retropharyngeal lymph node (3-year OS: 89.5% vs. 95.0%, P < 0.001; 3-year LRRFS: 93.3% vs. 96.9%, P < 0.001; 3-year PFS: 78.4% vs. 90.4%, P < 0.001; 3-year DMFS: 83.6% vs. 94.7%, P < 0.001). Only 54.3% patients received IC and 10.4% patients had stage I or II diseases. Liu et al. [21] conducted a retrospective study of 82 NPC patients to investigate the prognosis of patients who had MRI-detected residual cervical lymphadenopathy three months after radiation. Based on the postoperative pathology of cervical lymph node dissection, 83% (62/82) patients with MRI-detected residual cervical lymphadenopathy were diagnosed with residual tumor. Besides, the authors found that in half of the patients, tumors had progressed, and the prognosis of patients without tumor cells in cervical lymph nodes was better than that of those with tumor cells in cervical lymph nodes (3-year OS: 100% vs. 83.2%, P = 0.005; P = 0.014; 3-year PFS: 83.3% vs. 49.9%, P = 0.008; 3-year RRFS: 100% vs.73.0%, 3-year LRRFS: 91.7% vs. 53.9%, P = 0.005).

Studies on whether local–regional residual tumors should be treated with boost irradiation have bene performed. In the He et al. [7] study described above the prognosis of patients with radiation boost (dose > 73.92 Gy) was not better than that of patients without radiation boost (3-year OS: 83% vs. 85%, P > 0.05; 3-year LRRFS: 93% vs. 94%, P > 0.05; 3-year DFS 76% vs. 75%, P > 0.05). Radiation boost was only administered to patients with large residual tumors and two-thirds of patients without RT boost had no residual tumor after RT. Thus, the prognosis of patients in the RT boost arm may have been significantly worse than that of patients in the non-RT boost arm. Ou et al. [22] retrospectively conducted a study of 553 patients with LA-NPC to assess the prognostic value of residual tumors based on clinical and radiologic examination immediately after IMRT. In total, 87.5% patients received IC and 13.4% had residual lesion(s) at the end of RT. Local residual diseases were treated with a boost of 2.2–4.4 Gy, once or twice a day by small-field IMRT or 8–16 Gy, once or twice a week by intracavitary afterloading treatment. Palpable residual cervical nodes were treated with a boost of 4–6 Gy in two or three fractions a day by electron field. The authors found that the prognosis of patients with radiation boost (prescribed dose > 73.92 Gy) was even worse than that of patients without radiation boost (5-year LRFS: 73.7% vs. 89.5%, P = 0.004; 5-year RRFS: 83.1% vs. 93.8%, P < 0.001; 5-year DFS 52.2% vs. 71.1%, P = 0.004). Patients without radiation boost had no residual diseases, indicating that the prognosis of patients in the radiation boost arm was significantly worse than that of patients in the non-radiation boost arm. In the Liang et al. [18] study described above, 51.9% (206/397) patients had a residual tumor(s) immediately after IMRT; 21.4% (44/206) patients received boost irradiation. The results indicated that, in patients with MRI-detected residual tumors, the outcomes of patients with radiation boost were better than that of those who did not receive radiation boost (5-year LRRFS: 95.3% vs. 83%, P = 0.034). In the present study, adding boost RT to primary RT was an effective treatment for patients with local and/or regional residual lesion(s) after receiving IC + CCRT, which is consistent with Liang et al.’s study results [18] but different from the results of He et al.’s and Ou et al’s study [7, 22]. The main reasons for these differences could be the different proportions of patients with LA-NPC and those receiving IC, as well as the timing of and criteria for residual tumor evaluation.

Although the incidence of late radiotherapy-related toxic effects was similar compared to that reported in a previous study in which patients only received IC followed by CCRT [23], our study revealed that boost RT increased the grade 3–4 symptomatic temporal lobe necrosis, followed by grade 1–2 cranial neuropathy, grade 3–4 eye damage, grade 3–4 hearing impairment, grade 3–4 dry mouth, and grade 3–4 neck tissue damage. Two (0.8%) patients developed radiative nasopharyngeal necrosis, and symptoms were alleviated after endoscopic debridement and local or systemic antibiotic treatment.

The current study has several limitations: First, this is a retrospective study and has limitations inherent to such studies; second, most patients did not receive boost RT immediately after RT; last, the boost RT doses were not uniform.

Nonetheless, our study is noteworthy since this is the first large-scale, real-world study to show that adding boost RT with primary RT is an option for LA-NPC in patients with local and/or regional residual lesions after receiving IC + CCRT. Future clinical trials should focus on appropriate patient selection, appropriate criteria for residual lesion evaluation (such as biopsy, fine-needle aspiration, plasma EBV DNA, and positron emission tomography-computed tomography/positron emission tomography-MRI scan), appropriate timing of boost RT, optimal boost RT irradiation dose selection, biomarker identification, as well as the optimal drugs in combination with boost RT that can be used to overcome RT resistance.