Multidisciplinary treatment for cervical lymph nodes or the recurrence of NPC after IMRT has seldom been reported in previous studies. Neck dissection is the preferred choice for the neck failure of NPC, with better treatment outcomes and a lower rate of treatment complications than reirradiation and/or chemotherapy4. In our study, it was remarkable that the treatment outcome was significantly better in those who received surgery, and the outcome was much worse for those who did not undergo surgical dissection. Therefore, evaluating patient eligibility for surgery is the primary task when dealing with the regional failure of NPC. The decision regarding treatment modality should be made by an experienced multidisciplinary team, which should be made up of not only radiation oncologists and radiologists but also, most importantly, surgeons specializing in head and neck surgery. In the MDT team in our center, when a patient had neck recurrence, we first evaluated the patient’s general condition and excluded contradictions for surgery and then went through all the images before and after prior treatment and the images indicating node failure. After a detailed review of the patient’s medical history, we evaluated whether the patient was eligible for surgery. Surgeons’ experience is important in the decision regarding surgery. For more complicated cases, an experienced surgeon who has performed a considerable number of surgeries may a better chance of performing a total dissection and achieving better long-term survival. The selection of radical neck dissection or selective neck dissection was also discussed by the team based on the imaging studies of the patient. According to a former study by our center, selective neck dissection was demonstrated to be safe and effective for the treatment of neck residual disease of NPC for selected patients5. Considerations made by the MDT team are illustrated in Fig. 2. As long as the team considered the patient eligible for resection with no contradictions for surgery, we strongly suggested that the patient accept surgical interventions. Whether systemic treatment or radiotherapy might bring additional survival benefits before or after surgery was also determined by the MDT team.
Under certain circumstances (e.g., for patients who presented with synchronous local recurrence, patients who were predicted to hardly benefit from surgery, or patients with contraindications to surgery), a more conservative approach may be adopted. Over the past several decades, many potentially efficacious treatment options have emerged for the therapeutic management of regional recurrence in NPC patients who are not eligible for surgery6. Only a very limited proportion of our patients received reirradiation for regional recurrence and subsequently presented with severe complications secondary to cumulative irradiation injury, such as skin necrosis, soft tissue fibrosis, or brachial plexus injury. Chemotherapy was a comparatively more palliative strategy, as resistance to chemotherapy was common in cervical recurrence cases and the response rate was not satisfactory. Toxicity is often intolerable after several cycles and multiple lines of chemotherapy. Therefore, for patients with regional recurrence, indications for surgery must be carefully considered, and proper and personalized comprehensive treatment modalities should be identified. Our 10-year data indicated that having MDT discussions regarding each case and not neglecting a single case eligible for surgery, the best treatment choice would be selected for patients.
It is notable that according to our data and consistent with other studies7, the distribution of recurrent or residual nodes was not as extensive as in primary NPC cases; 60.7% of patients presented with a comparatively limited range of recurrence, involving only one level on one side, and 86.3% presented with lymph nodes with diameters less than 3 cm. Level II (84.2%) was the most common site of nodal recurrence. Prior radical radiotherapy may have impaired the cervical lymphatic drainage function, thereby reducing the secondary cervical metastasis of the tumor. The interval between the end of prior treatment and the diagnosis of neck recurrence was much shorter in the neck dissection group than in the non-neck dissection group, suggesting that patients with indications for neck dissection are more likely to be diagnosed at an early stage of disease. A relatively large proportion of patients went on for routine follow-up after prior treatment, which occurred every 3 months within the first 2 years and every 6 months in the 3rd to 5th years after treatment. The peak of recurrence diagnosis occurred at approximately 20 months, ranging from 2.4 months to 105 months, so intensive follow-up should always be recommended for NPC patients who finish definitive prior treatment. It was also proposed by our previous study that close follow-up is still important for the early detection of recurrence in years 3–4 after treatment8. Those who were considered to benefit less from surgery or lost the chance for surgery may have not had regular follow-up until the clinical presentation was too severe, for example, when the recurrent lymph nodes might have been too large, or might have too extensive involvement of the adjacent structures, making a total dissection difficult to perform. Therefore, for nasopharyngeal carcinoma patients, regular follow-up after treatment completion is crucial, and the early detection of regional recurrence may provide a better chance of complete resection.
Univariate analysis showed that age older than 50, synchronous local recurrence, extracapsular spread, not receiving surgery and receiving chemotherapy were related to a significantly worse prognosis. Previous studies9 reported similar results, suggesting that younger patients (age < 40–50 years) had a better prognosis for cervical recurrence. Older patients tend to have a lower KPS and worse heart or lung function, making surgery or even other comprehensive treatment modalities intolerable. Therefore, treatment selection for older patients should be performed more cautiously. Cervical recurrence with concurrent primary site recurrence in the nasopharynx is not rare and might originate from specific malignant cells with resistance to prior chemoradiotherapy. The treatment decision for this group of patients varies and is still based on each patient’s specific condition. For those with a limited range of local recurrence that could be managed by endoscopic surgery or reirradiation and cervical recurrence that could benefit from surgery, the separate management of recurrence in both sites might be effective. It was suggested in a study from Hong Kong that neck dissection is efficacious in patients with nasopharyngeal carcinoma with nodal failure with or without synchronous local failure10. Systemic treatment should also be considered for some patients. However, the control rate of local recurrence is not always satisfactory, with considerable rates of nasopharyngeal necrosis and hemorrhage shortly after treatment, especially in patients receiving reirradiation. In this case, each case should be discussed in detail by an MDT team to select the best treatment. Extracapsular spread is usually considered related to worse outcomes11,12, regardless of primary or recurrent nodes. Extensive soft tissue and muscle invasion are barriers to complete resection, and adjuvant local reirradiation or chemotherapy might be indispensable for effective regional control. However, a recent study proposed that within a group of 46 patients who received neck dissection after the diagnosis of nodal recurrence, ECS was not correlated with a worse survival. They proposed that an absolute number of positive lymph nodes greater than five and a lymph node density greater than 20% were potentially useful prognostic factors13. Patients who received chemotherapy were usually not eligible for surgery, so it could be speculated that chemotherapy is related to a worse prognosis, as shown in the univariate analysis. Multivariate analysis revealed that surgery and age older than 50 were the only 2 independent prognostic factors for OS, suggesting the dominant role of surgery in the management of cervical recurrence.
Several other studies have demonstrated that patients with cervical node residual disease after prior radical irradiation may have a better prognosis than patients who present with node recurrence. This was also observed in our colleague Zhang’s former study based on conventional radiotherapy14. In the current study, however, patients with cervical node residual disease did not have better survival than those with cervical node recurrence, even though the range of the cervical residual disease was usually limited, and there was a greater chance of neck total resection. A review of the data showed that there was a larger proportion of N3 patients in the residual disease group than in the recurrence group (51.8% vs. 24.3%), so the possible survival advantages of patients with residual disease might be offset by the larger proportion of N3 patients, who obviously had worse clinical outcomes. In addition, in our study, all patients received IMRT as prior treatment for primary NPC. Compared with conventional radiotherapy, IMRT achieves better survival, with benefits of a better dose distribution, i.e., better dose heterogeneity within the target volume and a lower dose to organs at risk (OAR). Thus, residual lymph nodes after IMRT might usually be comparatively more radiation resistant. In our study, 22.4% of patients received a boost for obvious lymph node residual disease when the IMRT course finished, and the rate was much higher than the reported rate of 8.3% in general in a previous study from our center1.
IMRT technology has been used at our center for NPC patients since 2005. Most patients who received prior treatment returned to our center for follow-up, and subsequent treatment for treatment failure was also received here. A total of 355 patients with neck residual disease or the recurrence of NPC after 2D-RT who underwent radical neck dissection over a 10-year period from 1998 to 2007 were reported before. The 3- and 5-year overall survival rates were 54.1% and 26.0%, respectively. In this study, within a decade, the survival of nasopharyngeal carcinoma improved, and cases of failure decreased significantly. Only 139 patients underwent neck dissection at our center. This group of patients achieved much higher 3- and 5-year overall survival rates of 73.4% and 52.8%, respectively. In addition to improvements in radiation techniques, advances in systemic treatment and more accurate imaging techniques, such as MRI and PET/CT 15,16, also contributed to better clinical outcomes. Moreover, new advances in systemic therapy, especially immunotherapy, have provided promising preliminary results for recurrent and metastatic nasopharyngeal carcinoma17–19. Including immunotherapy in multidisciplinary treatment is a new trend, and the best combination of surgery, radiotherapy and systemic therapy should be further examined and discussed.
The retrospective nature was a major limitation of our study. Patients’ conditions varied, and strategies for each case were determined by the MDT team based on their clinical features. Based on the current findings and experiences, we will perform further prospective studies focusing on developing a clearer standard that could allow patients to benefit from surgery and identify the best comprehensive treatment strategies for patients.
In conclusion, for recurrent or residual nodes of NPC after prior chemoradiotherapy, radical neck dissection could be the best choice after a comprehensive multidisciplinary evaluation of the patients’ condition. Regular, close follow-up after treatment and access to an experienced MDT team to make optimal treatment decisions for patients are key components to a better clinical outcome for the regional failure of NPC.