The present study is the first large sample, single-arm study to assess the efficacy and toxicity of radiation dose escalation for LA-NPCs who have locally and/or regionally residual lesion(s) after receiving IC + CCRT. Our study revealed that 5-year LRFS, RRFS, LRRFS, DMFS, FFS and OS for all patients received boost irradiation were 90.2%, 89.1%, 79.5%, 87.9%, 69.0%, 86.3%, respectively.
The gold standard for detecting a residual lesion is to find tumor cells by biopsy and histopathology. The pathological examination should be carried out when suspicious residual lesions are found as long as conditions permit. In the present study, patients with electronic nasopharyngoscope-detected suspected residual lesions routinely underwent a biopsy to determine if it was a tumor residue. When MRI indicated residual cervical lymph nodes after radiotherapy, the ultrasound-guided fine-needle puncture was routinely used to confirm whether there had live tumor cells. However, most residual lesions in the primary site of LA-NPC patients are located in deep tissue, such as the skull base, parapharyngeal space, intracranial area, and paranasal sinuses, where biopsy could not be reached. Enhanced MRI was performed to diagnose the above residues.
It is crucial to select the best time node to evaluate the residue. The advantage of immediate evaluation at the end of RT is that it can immediately strengthen the treatment to improve the curative effect if there are residual lesion(s). The disadvantage is that there is a certain false-positive rate in immediate evaluation. The over-treatment might be conducted for these patients, which leads to an increase in toxicity and side effects. The advantage of delayed evaluation is that it can avoid over-treatment for false-positive patients, but the disadvantage is apparent that it will lead to the delay of treatment for true-positive patients resulting in poor prognosis. The best time for residual evaluation is three months after RT for patients with NPC receiving conventional two-dimensional radical radiotherapy because nearly 80% of the residual lesions can subside spontaneously within three months after RT [13].
Currently, IMRT followed IC has become the standard management for LA-NPC. The regression mode of NPC has remarkably changed. Previous studies found that about 10–22% of patients had CR after IC [6, 14–15]. Our previous study found that about 90% of patients had CR after IC + CCRT, which was much higher than patients receiving RT alone or CCRT [7–8, 16–17].
He et al. [7] retrospectively collected 358 LA-NPCs and analyzed the prognostic value of MRI-detected residual lesion(s) immediately after IMRT. They discovered that patients who have residual tumor(s) following IMRT had a worse prognosis than patients without residual lesion(s) (3-year OS: 73% vs. 90%, P = 0.007; 3-year LRRFS: 89% vs. 97%, P = 0.002; 3-year DFS 67% vs. 82%, P = 0.001). Although 94.4% of patients received chemotherapy, it should be noted that the proportion of patients receiving IC was not specified. Liang et al. [18] conducted a retrospective study of 397 NPC patients to assess the prognostic relevance of MRI-detected residual tumor(s) immediately after IMRT. Their findings revealed that 51.9% of patients had MRI-detected residual tumor(s), and that patients with residual tumor(s) had a worse prognosis than patients without residual tumor (5-year OS: 75.1% vs. 86%, P = 0.009; 5-year LRRFS: 85.8% vs. 94.9%, P = 0.003; 5-year DFS 76.5% vs. 83.3%, P = 0.030). It should be noted that only 48.1% of patients received IC and 29.5% of patients had stage I or II diseases. Lv et al. [8] assessed the prognosis value of residual lesion(s) detected by MRI three months after IMRT in 664 NPC patients. They discovered that patients without residual lesion 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% of patients received chemotherapy, it should be noted that the proportion of patients receiving IC was not specified and 28.3% of patients had stage I or II diseases. 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 at 6–9 months after IMRT (92.9% vs. 54.2%, P < 0.001). They also discovered that early (3–4 month) and delayed (6–9 month) cCR had better outcomes when 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). It’s worth noting that the percentage of patients that received IC was not specified, and 25.7% of 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 1103 NPC patients. The retropharyngeal lymph node area had residual lesion(s) in 28.2% of patients. Their findings demonstrated that patients with residual retropharyngeal lymph node(s) had worse outcomes than those who did not have residual 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). It should be noted that only 54.3% of patients received IC and 10.4% of 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) of patients with MRI-detected residual cervical lymphadenopathy were diagnosed as tumor residue. Besides, they found that half of the patients developed tumor progression, and the prognosis of patients without tumor cells in cervical lymph nodes is better than 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).
Researchers have conducted a lot of research on whether local-regional residual tumors should be treated with boost irradiation. He et al. [7] retrospectively carried out a study of 358 LA-NPCs to evaluate the prognostic value of MRI-detected residual tumor(s) immediately after IMRT and found that the prognosis of patients with radiation boost (dose > 73.92 Gy) was not better than 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). It should be noted that radiation boost was only given to the patients with large residual tumors and two-thirds of patients without radiation boost had no tumor residue after radiotherapy. It means that the prognosis of patients in the radiation boost arm should have been significantly worse than patients in the non-radiation boost arm. Ou et al. [22] retrospectively conducted a study of 553 LA-NPCs to assess the prognostic value of residual tumors based on clinical and radiologic examination immediately after IMRT. 87.5% of patients received IC and 13.4% have 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 2 or 3 fractions a day by electron field. They found that the prognosis of patients with radiation boost (prescribed dose > 73.92 Gy) was even worse than 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). It should be noted that the patients without radiation boost have no residual diseases, which means that the prognosis of patients in the radiation boost arm should have been significantly worse than that of patients in the non-radiation boost arm. Liang et al. [18] retrospectively evaluated the prognostic relevance of residual tumor(s) detected by MRI immediately after IMRT among 397 patients with NPC. 51.9% (206/397) of patients had a residual tumor(s) immediately after IMRT. 21.4% (44/206) of patients received boost irradiation. Their results indicated that the outcomes of patients with radiation boost were better than patients without radiation boost (5-year LRRFS: 95.3% vs. 83%, P = 0.034) in patients with MRI-detected residual tumors. In the present study, we found that adding boost RT to primary RT was an effective treatment for patients who have locally and/or regionally residual lesion(s) after receiving IC + CCRT, which is consistent with Liang’s research [18] but different from He’s and Ou’s research [7, 22]. The main reasons are the different proportions of LA-NPCs, the different proportions of patients receiving IC, the different times of residue evaluation, and the different criteria of residue evaluation.
The current study still included several limitations: Firstly, it was a retrospective study; secondly, most patients did not receive boost irradiation immediately after radiotherapy; lastly, the boost irradiation 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 was an optional treatment for LA-NPCs who had locally and/or regionally residual lesions after receiving IC + CCRT. Therefore, randomized, multi-center, prospective, controlled trials were warranted. Future clinical trials should focus on appropriate patient selection, appropriate criteria of residue evaluation, appropriate timing of boost irradiation, optimal boost irradiation dose selection, biomarker identification, as well as the optimal drugs in combination with boost irradiation that can be used to overcome the resistance of radiotherapy.