Treatment patterns and survival outcomes in advanced hypopharyngeal squamous cell carcinoma

Background This study aimed to evaluate the the or concurrent chemoradiotherapy (CCRT) as the carcinoma (HPSCC). Methods A retrospective cohort study of HPSCC patients with stage III-IV HPSCC in four tertiary referral centers consecutively enrolled from 2003 to 2012, total of 213 (32.6%) patients received PS, and 439 (67.4%) patients received CCRT as their primary treatment. Overall survival (OS) and disease-free survival (DFS) were analyzed by Kaplan-Meier method and Cox regression models. Results The 5-year OS and DFS for patients undergoing PS and CCRT were 45.0% vs 33.1% and 36.2% vs 28.9% ( p < 0.001 and 0.003, respectively). In subgroup analysis, PS was associated with better OS in patients with stage IVA of the disease ( p = 0.002), specifically in those with T4 or N2 classification ( p = 0.021 and 0.002, respectively). Multivariate analysis indicated that stages IVA and IVB and CCRT were independent adverse prognostic factors for OS ( p = 0.004, <0.001, and 0.014, respectively). Furthermore, CCRT was also significantly associated with lower OS rates than PS in stage IVA patients more than 65 years of age and with N2 classification ( p = 0.027 and 0.010, respectively). Conclusions In with advanced significantly and should be considered a favorable disease, if they


Introduction
Hypopharyngeal squamous cell carcinoma (HPSCC) accounts for 3 ~ 5% of all head and neck cancers, and approximately 60-85% of HPSCC patients have advanced stage III/IV disease at the time of diagnosis, [1][2][3] carrying a poor prognosis irrespective of contemporary aggressive multidisciplinary treatments. [4] Delayed diagnosis due to the lack of initial symptoms, the propensity of submucosal spread, the high rate of clinically positive nodes at presentation, and high incidences of recurrence and second primary tumors may also contribute to this result. [5] , [6] , [7] Because of the anatomic proximity of the larynx, and the desire to preserve respiratory, deglutition, and speech functions, extra consideration is necessary when choosing treatment modalities for HPSCC patients. Before the 1990s, radical surgery with total/partial laryngectomy has been regarded as the mainstay of treatment for advanced-stage HPSCC, and the five-year survival rates varied from 10-60%. [3,8,9] Since the late 1990s, the results of retrospective and prospective studies, including the Veterans Affairs trials, EORTC trial 24891 (definitive treatment) and EORTC trial 22931 and RTOG trial 9501 (adjuvant), began a trend of nonsurgical treatments involving radiotherapy combined with platinumbased chemotherapy as favorable alternatives to surgery for laryngeal preservation of resectable advanced-stage HPSCCs. [10][11][12][13] However, despite the wide acceptance of concurrent chemoradiotherapy (CCRT) as a primary treatment modality for HPSCC, recent evidence suggests that radical primary surgery (PS) might provide superior survival outcomes in HPSCC patients. [14,15] There remains controversy regarding the optimal initial treatment of advanced-stage HPSCC patients. [16] To demonstrate the oncological results of PS with/without adjuvant therapy and definitive CCRT as the initial primary treatment modality and to illustrate which of these could be the optimal initial treatment in different subgroups (specifically, T or N classifications) of advanced-staged HPSCC, we conducted a retrospective study in a multicenter setting. The primary end point of the present study was to review and analyze the long-term survival outcomes of patients with advanced-stage HPSCC treated with definitive CCRT or PS followed by adjuvant therapy as needed in a multicenter setting.
The second end point of the study was to investigate which subgroups of patients with advancedstage HPSCC could have better survival probability following treatment with PS or CCRT.

Materials And Methods Data source
The current study extracted data from the Cancer Registry and Death Registration of Chang Gung Medical Foundation and enrolled advanced-stage HPSCC patients from four major hospitals within the healthcare system in Taiwan. This database provides complete information regarding the individual demographics, clinical diagnosis codes, cancer stages, tumor histology, and primary treatment details, which have been suggested to be of high quality. [17] The study followed strict confidentiality guidelines according to the regulations about personal electronic data protection and was approved by the Institutional Review Board of Chang Gung Medical Foundation.

Study population and design
We included all subjects from the database who were newly diagnosed with advanced-stage (stages III, IVA and IVB) HPSCC between January 1, 2003 and December 31, 2012, and all the medical records of the study cohort were extracted and analyzed from the database. Demographic characteristics, including age at diagnosis, overall clinical stages (T and N classifications) based on the AJCC (7th edition, 2010), and the duration and dosage of the chemoradiotherapy, were recorded. Patients with a prior cancer before the first day of HPSCC diagnosis, synchronous second primary malignancy, distant metastasis at presentation, no cancer treatment of either arm for more than 3 months after diagnosis, treatment with chemotherapy or radiotherapy alone, incomplete CCRT course or neoadjuvant therapy (chemotherapy or radiotherapy) prior to surgery, primary tumor excised by transoral laser or robotic surgery were all excluded from the study. All enrolled subjects were followed-up until the end of 2015 or death. The flow chart of the current study is depicted in Fig. 1.
Outcome endpoints for survival analyses were 5-year overall survival (OS) and disease-free survival (DFS). Patients treated with PS underwent total/partial laryngopharyngectomy with or without regional or free-flap tissue transfer based on the disease extent and physicians' preference, and all patients underwent unilateral or bilateral neck dissection at the same time. If definitive CCRT was selected as initial treatment, the radiotherapy dose was at least 70 Gy.

Statistical analysis
Kaplan-Meier plotting was used to demonstrate 5-year OS and DFS, and the log-rank method was used for univariate comparison between the survival curves. Cox proportional hazards models were adapted to measure the hazard ratios (HRs) and the accompanying 95% confidence intervals (CIs) in the univariate and multivariate analyses after adjusting for the treatment modalities and clinical characteristics. A p-value of less than 0.05 was used to indicate statistical significance. All analyses were conducted by using SAS statistical software (version 9.2; SAS Institute, Cary, NC, USA).

Patient characteristics
Between January 1, 2003 and December 31, 2012, there were 1057 new patients diagnosed with clinical stages III and IV HPSCC in four individual hospitals. Patients who received first treatment more than 90 days after diagnosis (n=221), underwent radiotherapy alone (n=21), or received chemotherapy alone (n=163) were excluded from the study (Fig. 1). Thus, a total of 652 patients were enrolled in this study and followed up until the end of 2015 or were censored due to death.
During the study period, 213 patients (32.7%) underwent PS, and 439 patients (67.3%) underwent definitive CCRT as the initial treatment modality. In the PS group, 151 patients (70.8%) received postoperative adjuvant therapy, while salvage surgery was performed in 168 patients (38.3%) of the CCRT group. The characteristics of all subjects are demonstrated in Table 1.

Survival analysis in the advanced-stage HPSCC
The median follow-up duration of all subjects was 30.6 months, and the 5-year OS and DFS were 37.5% and 31.3%, respectively, for all patients. Clinical stage was a significant predictor of prognosis, as shown in Fig. 2. Kaplan-Meier survival analysis indicated that the 5-year OS rates of patients with stages III, IVA, and IVB were 54.3%, 39.1%, 19.4%, respectively, and the 5-year DFS rates of stages III, IVA, and IVB were 48.4%, 33.4%, and 13.3%, respectively (both log-rank p < 0.001; Fig  These results indicated that the long-term prognosis of the PS group was superior to that of the definitive CCRT group. We further analyzed the survival outcomes between PS and CCRT by clinical stage. In patients with stage III HPSCC, the 5-year OS and DFS rates in the PS and CCRT groups were similar but without statistical significance (Figs. 3A and 3B). As shown in Fig. 3C and 3D, for patients with clinical stage IVA HPSCC, the PS group (vs. CCRT group) showed significantly better 5-year OS rates (46.7% vs. 35.0%, respectively, p = 0.002) and 5-year DFS rates (38.1% vs. 31.0%, respectively, p = 0.041). For patients with stage IVB HPSCC, the 5-year OS rates were 22.7% and 19.3% in the PS and CCRT groups, respectively (p = 0.235, Fig. 3E), and the 5-year DFS rates were 15.1% and 9.1% in the PS and CCRT groups, respectively (p = 0.696, Fig. 3F). Although the PS seems to have better 5-year OS and DFS rates in stage IVB patients, these differences were not statistically significant.

Subgroup survival analysis of stage IVA HPSCC by treatment modality
To investigate which subgroup of patients with stage IVA HPSCC would benefit the most from PS treatment, we conducted subgroup analysis based on patient age (≥ 65 or <65 years old), T and N classification, and treatment methods. As shown in Fig. 4A and 4B, PS provided significantly better 5-year OS rates than CCRT treatment in patients both less than (44.4% vs. 34.9%, respectively, p = 0.018, Fig. 4A) and more than 65 years old (64.2% vs. 35.5%, respectively, p = 0.022, Fig. 4B).
Notably, the difference between treatment methods is even more prominent in those more than 65 years old. For stage IVA patients stratified by early (T1-T3) and advanced (T4) T classification, the PS group showed better 5-year OS rates than those of the CCRT group, with marginal significance (51.8% vs. 39.4%, respectively, p = 0.052, fig. 4C) in those with T1-T3 disease. The PS group also had better 5-year OS rates than those of the CCRT group in the patients with advanced T4 classification (44.1% vs. 33.1%, respectively, p = 0.021, Fig. 4D). Similarly, when we stratified stage IV patients by early (N0-1) and advanced (N2) nodal spread, the PS group showed significantly better 5-year OS rates for patients with N2 classification (47.2% vs. 33.2% for the CCRT group, p = 0.002, Fig. 4F), but there was no significant difference with regard to OS in the patients with N0-N1 classification (44.5% for the PS group vs. 41.2% for the CCRT group, p = 0.551, fig. 4E).

Multivariate analysis of survival outcomes
Multivariate analysis revealed that clinical stage as well as initial treatment modality (CCRT vs. PS) were independent predictors of 5-year OS and that advanced stages were also predictors for worse 5-year DFS (table 2). For patients with advanced HPSCC, initial treatment with PS appeared to be

Discussion
The current study investigates the survival outcomes of patients with advanced-stage HPSCC who received either definitive CCRT or radical PS followed by adjuvant therapy, which have both been considered feasible options for the treatment of advanced HPSCC. This multicenter retrospective review showed a significant survival advantage for PS, regardless of OS and DFS, in the treatment of advanced HPSCC. Multivariate analysis confirmed the survival advantage of PS over CCRT with a 27% risk reduction in overall mortality, which in part has been explained because of the diminished tumor volume leading to potentially better local control rates. [7] , [18] [24] Subgroup analysis based on clinical stage showed that for patients with stage IVA disease, PS offered a more favorable OS and DFS compared with definitive CCRT and reduced risk of death in the 5-year OS by 31%.
Furthermore, for stage IVA patients with N2 classification, PS reduced the risk of death by nearly 30% in both 5-year OS and DFS, consistent with the results of two previous studies that demonstrated that the neck nodal metastatic burden significantly affected the survival outcome and organ preservation rate. [6,19] For stage IVA patients more than 65 years old, PS dramatically reduced the risk of overall mortality by 67%. These results suggest that PS followed with/without adjuvant therapy may provide improved survival compared to definitive CCRT in the treatment of advanced-stage HPSCC, particularly in those with stage IVA of the disease.
The advantage of the current study is that the results were derived from a relatively large population of advanced HPSCC patients from four different hospitals with a wide variety of clinicopathological characteristics regarding tumor histology, cancer staging and primary treatments based on a variety of physicians' preferences. The results provide a cross-sectional view of the management of advanced HPSCC during the study period and render a fair comparison of the survival outcomes between two major different treatment modalities. Another clinical implication generated by the current study is that in stage III HPSCC, if the patients had medical disadvantages for surgery or refused to have surgery first, CCRT was still a reasonable and feasible alternative treatment choice in terms of survival outcomes.
Both PS and CCRT treatment for advanced HPSCC result in unneglectable complications and sequalae and mandate a detailed multidisciplinary consultation with the patients. First, the results of organ preservation treatment for advanced HPSCC are significantly inferior to the results reported for laryngeal preservation protocols of laryngeal cancer; furthermore, treatment toxicity is common and usually severe. [12,20] Definitive CCRT has also been reported to be accompanied by more drastic complications in patients with T4a classification, [21] such as high feeding tube placement rates, [22] high prevalence of multiple surgical interventions, [16] and serious and intractable complications in salvage surgery, such as poor wound healing and pharyngocutaneous fistulae. [23] Consequently, organ preservation therapy, such as CCRT in the current study, for advanced HPSCC might result in the preservation of a dysfunctional organ but a possibly poorer survival based on the current study results. Because PS could provide a higher local control rate, fewer complications, and better survival outcomes than definitive CCRT (according to the results of a previous study and the current study), it may be the optimal treatment in patients with stage IVA HPSCC, particularly in those more than 65 years old and/or with N2 nodal spread. nodal volume, nodal counts, and nodal levels were significant factors that affected survival outcome and the organ preservation rate in HPSCC patients treated by CCRT. [7,19] These studies suggest that PS followed by adjuvant treatment may greatly minimized the tumor and nodal burden, and therefore PS results in a better survival advantage than CCRT in patients with advanced HPSCC.
For patients with stage IVB of the disease with either extensive primary tumors (T4b) or a large nodal burden (N3), it is still unclear if PS followed by adjuvant therapy provides a survival benefit when compared with definitive CCRT. Because most stage IVB diseases were considered unresectable at the time of diagnosis, only 14.8% of stage IVB patients received PS treatment as the initial intervention in the present study, and the Kaplan-Meier survival analysis showed no statistically significant difference between initial PS and definitive CCRT treatment. Previous studies have reported the effectiveness of organ preservation treatments in advanced HPSCC, including stage IVB diseases. [10,27] Slotman et al. reviewed fifty-four patients with advanced HPSCC in the pyriform sinus and found that the regional control rate was significantly lower in patients with N3 classification than in those with N0-N2 despite the higher radical radiotherapy dose. [5] In patients diagnosed with clinical T4b HPSCC, the tumor invades the prevertebral fascia and cannot be well differentiated from nonneoplastic changes in the prevertebral space based on magnetic resonance or CT imaging,[28] so some proportion of patients with clinical T4b may be overestimated based on imaging studies; the usual treatment was the nonsurgical modality in most of these case scenarios. Further investigations enrolling larger cohorts are needed to elucidate the best treatment strategy in patients with stage IVB HPSCC in the future.

Conclusion
Despite the current use of multidisciplinary treatment, HPSCC is still a devastating disease with a relatively poor prognosis among the major head and neck malignancies. In this multi-institutional review of the survival outcomes from four hospitals, the current study demonstrated that primary treatment with PS could provide better OS and DFS in patients with advanced HPSCC with clinical stage IVA, particularly those with N2 classification, and ages greater than 65 years old. In stage III or IVB HPSCC, CCRT was still a reasonable and feasible treatment modality in terms of survival outcomes and organ preservation. Further investigations are mandated to elucidate the best personalized treatment for these patients.

Funding
This study was supported by the grants (CORPG3G0171, CMRPG3H0852 and CIRPG3B0014) from Chang Gung Memorial Hospital, Taiwan.

Author Contributions
YTT, drafting the article; final approval of the version to be published; WCC, acquisition of the data; agreement to be accountable for all aspects of the work; CYC, study conception and design; CMH and YCL, acquisition of the data; final approval of the version to be published; agreement to be accountable for all aspects of the work; MST, acquisition of the data; final approval of the version to be published; agreement to be accountable for all aspects of the work; MHL and CHL, analyses and interpretation of the data; final approval of the version to be published; agreement to be accountable for all aspects of the work; KPC, study conception and design; analyses and interpretation of the data; final approval of the version to be published; agreement to be accountable for all aspects of the work.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
This retrospective study was approved by the institutional review board of the Chang Gung Memorial Hospital, and the requirement for patient's informed consent was waived by the institutional review board. Abbreviations: CCRT, concurrent chemoradiotherapy; WD, well-differentiated squamous cell carcinoma; MD, moderately differentiated squamous cell carcinoma; PD, poorly differentiated squamous cell carcinoma; UD, undifferentiated carcinoma.  Table 3 CCRT versus primary radical surgery in subgroup analysis by age and T and N classification following multivariate analysis of stage IVA HPSCC patients