Discussion

IC is an organ-preserving therapeutic approach for treating locally advanced hypopharyngeal cancers. Our study represents a retrospective single-center analysis of assessment of CCRT or RT after IC and demonstrated that IC+CCRT could improve LRPFS and OS in the group of IC responders. To the best of our knowledge, this study is the first to compare the efficacy and toxicity of CCRT and RT following IC in patients with HPSCC.
In our study, the CR rate for primary sites and survival were lower than their counterparts reported in the European Organization for Research and Treatment of Cancer (EORTC) 24891.9 Several factors could cause this difference. Firstly, it may be due to the majority of patients in our study belonging to T3-4 (79.5%) and stage IV (97.6%), according to the EORTC 24891, patients with T2 stage HPSCC (18/22, 82%) were found to be more accessible to CR (P =0.002) than patients with T3 (34/71, 48%) and T4 stages (0/4). Secondly, this is likely due to the different measurements involved in the efficiency assessment in our study. Both laryngoscopy and neck CT scan were involved in our study; however, a neck CT scan was not mandatory in EORTC 24891. Lastly, our study included patients with PR and non-responders besides CR patients.
Except for EORTC 24891, the OS in our study resembled that of a previous study.14 Some other RCTs showed higher CR rate and OS in patients with a higher proportion of T2-3 and N0-1 compared to our study.10, 15 Moreover, laryngeal cancer was included in the research cohorts in some of those RCTs.
In our study, higher LRPFS and OS occurred in the IC responders who received CCRT than in those who received RT alone. Based on our findings, an effort to improve responsiveness to IC becomes the key point. Admittedly, compared to CCRT alone, IC+CCRT has not yet been validated to be advantageous for the survival of patients with locally advanced head and neck cancers in phase III clinical trials.16, 17 But it has been demonstrated that IC could reduce the risk of distant metastasis 18. Besides, IC was considered advantageous for survival when performing in the patients with heavily affected primary sites or advanced nodal involvement (cN2c-N3) 19. Based on the high proportion of N2c (n=27, 32.5%) and N3b (n=37,44.6%) in our study, which had the high risk of distant metastasis, IC was chosen as the prior treatment.
A recent phase II/III trial indicated that patients who underwent IC followed by CCRT had better survival outcomes than those who underwent CCRT alone for head and neck cancer (median survival: 54.7 vs. 31.7%,P =0.03).20 Furthermore, a retrospective study aiming at laryngeal and hypopharyngeal cancers demonstrated a similar conclusion that IC+CCRT resulted in a longer median OS (64.7 vs. 21%,P =0.003) than CCRT alone for hypopharyngeal cancers, but no survival benefit was found in laryngeal cancers.21 IC plays a crucial role in laryngeal preservation(LP)-oriented combination therapy for HPSCCs. This is also supported by the NCCN guideline in which IC was recommended as a strategy for LP.13
As concluded in our study, the effect of CCRT after IC correlated with IC responses. The French Groupe d’Oncologie Radiothérapie Tête et Cou (GORTEC) 2000-01 trial, which included 213 patients with laryngeal or hypopharyngeal cancer, demonstrated the superiority of the TPF regimen over PF in terms of ORR (80.0% vs. 59.2%, P =0.002) and LP rate (70.3% vs. 57.5%, P =0.03).15 With the exception of ORR and LP rates, another two RCT trials showed that TPF markedly improved PFS and OS in locally advanced head and neck cancers.22, 23 Conceivably, aiming at the effectiveness of CCRT combined with IC, TPF should be prioritized for IC treatment rather than PF.
Regarding IC non-responders, more careful therapeutic considerations are required. Nowadays, with the advancement of individualized cancer care with increasing precision and more implications, and with the incorporation of multicenter novel therapies, such as immunotherapy, the access to an ideal trade-off status between the expected clinical outcomes and a less-affected quality of life potentially comes into real practice.24
Regarding the exclusiveness of this series, owing to the prevailing characteristics of many studies involving multiple sites of head and neck cancer, HPSCC comprises only a minority of the ensemble population due to its low prevalence. In some researchers about head and neck subsites, hypopharyngeal cancer generally merged with laryngeal cancer. Therefore, critical featured information for HPSCC treatment would be incomprehensive, leading to a shortage of definite conclusions. Exploration of optimal treatment for HPSCCs to some degree counts on the personal experiences of clinicians and the results, including the confounding factors that may render them less convincing. Herein, our study focused only on patients with HPSCC and offered exclusive information regarding their treatment, which will be helpful in clinical practice. The overall efficacy assessment for IC was used to group the patients in our study rather than only aiming for the primary sites, which brought about more reasonable evaluations for the comparison of CCRT and RT alone.
Regarding limitations of our study, due to the small sample size and retrospective nature of our study, the comparison of CCRT and RT alone according to IC responses requires further investigation with larger cohorts or prospective trials. Moreover, as no patients achieved CR after IC treatment, more studies are required to investigate the necessity of CCRT.