Our results demonstrate that approximately 47.2% of the hypopharynx SCC patients were found local-regional failure and distant metastasis with median time to the initial treatment failure was 13 months (95% CI 6.4-19.6 months) for surgery, and 11 months (95% CI 9.1-12.9 months) for IMRT. The most commonly failures in hypopharynx SCC are mainly attributed to cervical lymph node failure, account for 32.5% of patients.
It is well know that hypopharynx SCC characterized by aggressive clinical behavior and high risk tendency to invade cervical lymph nodes.
The lymph node extension is an important prognostic factor, therefore, control of regional metastasis is an essential part of treatment for hypopharynx SCC. Presently, there is no agreement on the best treatment approach for hypopharyngeal SCC. Definitive chemoradiation strategy arose from the RTOG 91-11 trial [10,11] which demonstrated improved loco-regional control and laryngeal preservation rates has become an important approach for locally advanced hypopharyngeal SCC. By means of prophylactic neck irradiation (PNI), the incidence of nodal failure can be reduced to 4% in head and neck cancers . Therefore, PNI is an important IMRT component in the treatment of hypopharyngeal carcinoma.
In the present study, nodal involvement mainly concerned levels II (66.2%) and III (48.1%), then followed by levels IV, VI, and VII (13.0%, 13.0%, and 15.6%, respectively), while level V showed involvement in 5.1% of patients. As comparing with ipsilateral neck, the risk of metastasis for contralateral neck tend to be lower (LMI: 16.4% vs. 5.2%). These results are in agreement with our previous study and the literature . However, few studies have reported the outcomes of regional lymph node failure for locally advanced hypopharynx SCC after treatment with IMRT. Sommat et al.  reported a retrospective analysis of 58 patients (stage III-IVb 95%) with hypopharyngeal cancer treated with curative intent radiotherapy (RT). In Sommat’s study, 88% of patients managed to achieve complete response 3 months after completion of treatment, loco-regional recurrence remained the major cause of failure following curative intent RT. Most deaths occurred in patients who succumbed to loco-regional rather than systemic failure. However, only 50% of patients undergone IMRT in Sommat’s study, half part of patients treated using a 2-dimensional technique. Daly et al.  recruited 42 patients with newly diagnosed SCC of hypopharynx (23 patients) and larynx (19 patients) underwent IMRT, 11 postoperatively and 31 definitively at Stanford University Medical Center. Median follow-up was 30 months, 5 patients developed a loco-regional failure or had persistent disease, with a median time to failure of 12.1 months. Three local failures occurred within the high-dose region and 3 occurred in regional nodes. No marginal misses were observed. The author considered that loco-regional relapses occurred in the high-dose volumes, suggesting that target volume delineation was adequate but further dose-escalation and more aggressive treatment may be needed. Huang et al.  retrospectively reviewed 47 patients with locally advanced resectable SCC of hypopharynx underwent primary surgery or definitive IMRT with concurrent platinum-based chemotherapy (CCRT). The 5-year survival rate, disease-free survival, and loco-regional progression-free survival of surgery and CCRT group was 33% and 56%, 25% and 41%, 15% and 53%, respectively. Loco-regional progression was the main cause of failure in both groups. Eleven patients had neck failure; 8 in the ipsilateral neck, 2 in the contralateral neck, and 1 in the tracheostoma site. All were in-field failure in the PTV2 (60Gy). One retrospective study  reported by Chun et al. included 54 patients receiving definitive radiotherapy with or without chemotherapy. Thirty patients received IMRT and 24 patients received 3D-CRT. With median follow-up time was 42.3 months, there were 20 loco-regional failures discovered. Estimated crude loco-regional recurrence free survival at 3 years were 64.1%. Of the 20 loco-regional failures, 14 were isolated local failures, 4 were isolated regional nodal failures, and 2 were both. Of the 6 regional nodal failures, failures involved ipsilateral neck level II in 3 patients, ipsilateral neck level III in 1 patient, paraesophageal lymph node in 1 patient, and bilateral neck level II in 1 patient. Among the loco-regional failures, 17 were observed in the PTV high region, while 2 were in the PTV intermediate region and 1 patient had out-of-feld failure (paraesophageal lymph node), but was also accompanied by local failure within the PTV High region. Pignon et al.  found that IMRT failure in the low-neck supraclavicular field was very uncommon.
Our center has employed IMRT for the definitive treatment of head and neck cancers nearly for 10 years. Our study results demonstrated the poor outcome expected in hypopharyngeal cancer with median PFS rates were approximately one year after first-line treatment. The regional cervical lymph node recurrence and persistent disease remained the major cause of failure following curative intent of IMRT. Approximately 70% of nodal failures were observed in the PTV high or intermediate regions. In our study, the most commonly failure levels were the II (24.7%), and III (13.0%), then followed by VIb (5.0%), VII (2.5%), and IV (2.5%). The nodal failures at level IV and VII was found only in one patients, respectively. In our study, lymph node failure was mostly involved in ipsilateral neck, only 2 patients developed isolated level II failure in contralateral neck, and one patient developed level II failure in bilateral necks. Regarding our patients received IMRT enrolled in this study, more than half of patients have severe lymph node involvement and were not suitable candidates for selective lymph node dissection. Approximately 80% of them displayed lymph node metastasis with liquefactive necrosis in lymph nodes. After completion of IMRT treatment, majority of them in our cohort presented nodal residue. Pitifully, because of extra capsular extension (for example vessels and soft tissue invasion), or nodal failures accompanied by local recurrence or distant metastasis, or severe late treatment toxicities, ultimately only 2 patients received a salvage node dissection within 6 months of follow-up time. Aside from 5 patients with local-regional failure received salvage surgery after definitive radiotherapy, most patients with first-line treatment failure were received chemotherapy or combining with targeted therapy. Chun et al.  suggest that salvage surgery after definitive radiotherapy should be considered for patients who show residual disease after 6 months, because residual tumors show progression soon after 6 months.
In patients undergoing surgical resection with or without postoperative adjuvant IMRT. Seventeen patients were observed regional lymph node failure, 10 of them were isolated nodal failure, 4 patients accompanied by local recurrence, and 3 patients accompanied by distant metastasis. Of the 17 patients with nodal failure, failures involved ipsilateral neck level II in 7 patients, levels III and VIb both in 4 patients, level VII in 5 patients. Furthermore, nodal failure involved in ipsilateral neck level IV and V was both one patient. Regarding 46 patients undergone lymph node dissection with 35 ips- and 11 bilateral neck dissection in this study. Six of them observed contralateral neck failure, with level II in 4 patients, level III in 3 patients, level VIb and VII both in one patient. Among these 6 patients, 5 patients had received postoperative radiation with radiation dose of 50–66Gy. Previously multi-center randomized clinical trials have confirmed post-operative radiation or chemoradiation improves loco-regional control and overall survival in the presence of extra-capsular nodal extension [7,8]. Although we fail to analyzed the reasons of node failure after surgery in our study, we found that the most commonly failure levels were the II (15.2%), III (8.7%), VIb (8.7%), and VII (10.9%). Comparing with patients receiving definitive radiotherapy, node failure rates at levels II and III were lower for patients receiving surgery as first-line treatment (15.2% vs. 24.7%; 8.7% vs. 13.0%), whereas, node failure at levels VIb and VII were exhibited higher ( 8.7% vs. 5.0%; 10.9% vs. 2.5%). The reason probably because the selective neck dissection always included the nodes in level II and III, whereas, the nodes in level VI and VII failed to remove from patients routinely in our study.
One retrospective study  include larynx (110 patients) and hypopharynx (26 patients) SCC undergoing total laryngectomy or pharyngolaryngectomy with neck dissection. Levels IIa and III were invaded in 28.7% and 25.7% of patients, respectively. Level VIb lymph-node involvement was 23.8% in patients who underwent level VIb neck dissection. Lymph-node recurrence rate was 10.3% in levels II to IV, and 13.2% in VIb. The author concluded that because high rate of involvement and recurrence of level VIb, systematic elective bilateral neck dissection might be needed. Previous retrospective studies [20,21] indicated that pyriform sinus apex or postcricoid invasion, or tumor diameter exceeding 3.5cm showed a trend in favor of paratracheal lymph node involvement. In our previous study, esophagus invasion was also highly correlated with increased risk of developing level VIb metastasis. It is noteworthy that lymph node at level VII (retropharyngeal lymph node) can not be removed routinely by surgery, and hardly be detected by imaging before surgery. Currently, there is no consensus regarding the delineation of lymphatic clinical target volume for post-operative radiation therapy for hypopharyngeal cancer. Based on results found in our study, irradiation of the level VII should be recommended, especially for the primary tumors originated from posterior pharyngeal wall (PPW), or PPW invasion [22,23].
The limitations of our study include its retrospective nature. The follow up time is relatively short. We did not perform the dosimetric analysis of the patterns of failure, and fail to confirm if CTV delineation is adequate. The prognosis associated factors for hypopharyngeal carcinoma could not be taken into account, including the evaluation of the surgical margins, perineural invasion, and nodal extracapsular extension.
Based on our results, we concluded that whatever the treatment modality, levels II and III in ipsilateral neck were most commonly failure regions. The regional cervical lymph node recurrence and persistent disease remained the major cause of failure following curative intent of definitive IMRT. Because of high rate of node failure of level VIb and VII after surgery, post-operative radiation field should be include these territories, particularly in the setting of locally advanced disease. Our results provide a clear rationale for efforts in the future aimed at improving local-regional control, which including accurate target volume delineation, optimal prescribed radiation dose and fraction, possibly identification areas of radio-resistance within the tumour. Further clinical research is needed to assess the utilization of IMRT combined with novel systemic agents in locally advanced hypopharynx SCC.