In our study, concomitant chemoradiotherapy significantly improved 3-year and 5-year OS rates compared with radiotherapy alone. Subgroup analysis showed that concomitant chemoradiotherapy significantly improved the 5-year OS rate especially for patients in the category rT3–4, stages III–IV, recurrence interval >30 months, and tumor volume >26 cm3.
Concomitant chemoradiotherapy can enhance tumor control, act as a radiotherapy sensitizer, and eradicate distant micrometastases. Most locally recurrent NPCs have a similar pathology to primary tumors, with local recurrence occurring predominantly at the advanced T category [15]. Tumor in locally recurrent NPC is often poorly sensitive to radiotherapy, which can be attributed to tissue fibrosis and vascular changes. Therefore, radiotherapy, combined with effective concomitant chemotherapy, may improve clinical treatment outcomes.
Tumor remission rates following treatment with either a single agent or combination chemotherapy have been shown to be 10%–30% and 40%–50%, respectively; however, OS was only extended 5–6 months [16]. Previous studies demonstrated that re-irradiation of locally recurrent NPC resulted in poor outcomes, with reported 5-year OS rates ranging from 5.8% to 40.0% and local control rates ranging from 14 to 61% [4, 13, 17]. The advent of IMRT has offered the potential of improving dose and conformation of radiation to the target, thus sparing critical structures. The clinical advantages of IMRT as a salvage treatment with respect to both disease control and adverse effect profiles have been demonstrated for locally recurrent NPC. Although IMRT can achieve control in 71.0% –85.8% of cases, it is associated with a high incidence of late complications that are attributable to excessively high doses, which occur in 26% –80% of cases; these complications include nasopharyngeal mucosal necrosis/massive hemorrhage and radiation encephalopathy, which are a major cause of treatment death [5, 18].
It is unclear whether decreasing the dose of IMRT during concomitant chemoradiotherapy improves survival in patients with locally recurrent NPC. In previous studies, concomitant chemoradiotherapy improved local tumor control and prolonged survival in patients with recurrent head and neck squamous cell carcinoma [19, 20]. To date, however, the effects of the addition of concomitant chemotherapy to radiotherapy on survival of patients with locally recurrent NPC have not been confirmed. In many studies, concomitant chemoradiotherapy was adopted due to its unique advantages in direct targeting of tumors and potential synergistic effects with radiotherapy. The role of concomitant chemoradiotherapy with cisplatin as the optimal treatment for newly diagnosed advanced NPC has been quite well established by a number of prospective studies and meta-analyses [8, 21–24]. Poon et al. [10] performed a retrospective analysis of 35 patients with locoregional recurrent NPC, of which 23 patients (66%) had rT3 or rT4 disease. In this cohort treated with concomitant chemoradiotherapy plus adjuvant chemotherapy, they observed a response rate of 58% (29% complete response and 29% partial response). The 5-year OS and progression-free survival (PFS) rates were 26% and 15%, respectively. Nakamura et al. [9] presented the outcomes of re-treatment of 36 patients with recurrent NPC using cisplatin-scheduled chemoradiotherapy. With a median follow-up of 40 months, the 3-year OS rate was 58.3%. Our data showed statistically significant survival benefits with the 3-year and 5-year OS rates of 68.7% and 41.8%, respectively, in the concomitant chemoradiotherapy group. Further subgroup analysis showed improved OS rates in patients with rT3–4 disease, stages III–IV disease, and a tumor volume >26 cm3. The potential explanations for these outcomes include the following: (1) the effects of concomitant chemoradiotherapy were not evident for NPC at early tumor stages and with small volumes; or (2) concomitant chemotherapy could yield long-term survival benefits for patients with advanced and bulky tumors by reducing the tumor volume and extent. Improved vascular distribution could improve drug transport, enhancing radiosensitivity and reducing nasopharyngeal mucosal necrosis.
The results of our study also suggest that concomitant chemoradiotherapy could improve the OS of patients with recurrence intervals of more than 30 months. This may be due to the increased tissue recovery time which could reduce the incidence of nasopharyngeal mucosal necrosis/massive bleeding and other fatal complications during repeated radiochemotherapy.
The total dose of re-irradiation was a key factor in determining the effects of repeated radiotherapy. Most studies have recommended a dose of at least 60 Gy since this is associated with improved control and/or survival during re-irradiation. Wang et al. [17] showed that, for early-stage disease, the 5-year OS rate was approximately 45% when more than 60 Gy was delivered to the tumor, whereas no patients survived for more 5 years when the dose was less than 60 Gy (P = 0.0001). Lee et al. [4] performed a retrospective analysis of 654 cases of recurrent NPC. In the study, the 5-year local control rate of early disease was 40%, 35%, and 14% when a biological effective dose (BED) of the second course was given at >70 Gy, 60–70 Gy, and <60 Gy, respectively. The hazard ratio for local failure decreased by 1.7% per BED (1 Gy) in the repeated course.
However, high re-irradiation doses are associated with severe late complications. Teo et al. [5] found that the severe complications caused by high-dose re-irradiation (radiation dose of more than 60 Gy) could outweigh the potential benefits for survival. They found a high 5-year incidence of serious late complications including trismus (69.9%) and temporal lobe necrosis (20.4%). Similarly, in a study of 86 patients treated with three-dimensional conformal radiotherapy, Zheng et al. [6] reported that the 5-year incidence of grade 3 and grade 4 late toxicities was up to 100% and 49%, respectively, when the mean dose to the tumor was 68 Gy in 34 fractions, and that toxicity was the main cause of death. Previous studies determined the occurrence of severe late toxicities after re-irradiation to be 6%–45% [5, 25, 26] and found that the rate of fatal late toxicities including nasopharyngeal mucosal necrosis/massive hemorrhage was 2.0%–40.6% [5, 12, 27]. Poon et al. [10] analyzed clinical data from 35 patients with locally recurrent NPC who were treated with cisplatin-based concurrent chemoradiotherapy plus adjuvant chemotherapy and found that the incidence of grades 3 and 4 late toxicity was 12% and 23% at 2 and 5 years, respectively, and included mainly temporal lobe necrosis (11% and 11%), cranial nerve palsy (6% and 6%), and endocrine abnormalities (6% and 18%).
In our study, the prescribed dose was 60 Gy for 27 fractions and the BED was approximately 66 Gy according to biological models. The incidence of grade 3 and grade 4 acute toxicity, mainly oral mucositis and dysphagia, was higher in concomitant chemotherapy group (17.6%) than in radiotherapy alone group (8.6%), although no patients halted radiotherapy. Serious late toxicities, such as nasopharyngeal mucosal necrosis, radiation encephalopathy, and cranial nerve palsies were similar between the two groups. The incidence of nasopharyngeal massive hemorrhage was significantly lower in the concomitant chemotherapy group than in the radiotherapy alone group (χ2 = 6.180, P = 0.013). Chemoradiotherapy might be able to shrink the tumor faster and accelerate the blood supply to the surrounding tissues, thus reducing the probability of nasopharyngeal mucosal necrosis. Therefore, IMRT with concomitant weekly cisplatin (i.e., concomitant chemoradiotherapy) is a treatment that could improve long-term outcomes in patients with locally recurrent NPC and should be studied as an alternative to IMRT alone.
In conclusion, concomitant chemoradiotherapy can improve OS of patients with locally recurrent NPC when compared with radiotherapy alone. Patients with advanced T category (rT3–4) and stage (III–IV) disease, recurrence interval >30 months, and tumor volume >26 cm3 could significantly benefit from concomitant chemoradiotherapy. Clinical trials with a large sample size are needed to fully assess survival rates and confirm the role of concomitant chemoradiotherapy in the treatment of locally recurrent NPC.