Developing a predictive nomogram and web-based survival calculator for Locally Advanced hypopharyngeal cancer: A Propensity Score-Adjusted, Population-Based Study

Abstract

Background: Patients with locally advanced hypopharyngeal squamous cell carcinoma (LA-HPSCC) face poor survival with no consensus on optimized therapies. Understanding the clinical features and treatments for the disease is important for patient centered decision-making. This study aims to create a multi-factor nomogram predictive model and web-based calculator to predict post-therapy survival for patients with LA-HPSCC.

Methods: A retrospective cohort study analyzing Surveillance, Epidemiology, and End Results (SEER) database from 2004-to-2015 for patients diagnosed with LA-HPSCC was conducted and randomly divided into training and validation groups (7:3 ratio). The external validation cohort included 276 patients from Sichuan Cancer Hospital, China. Univariate and multivariate Cox-proportional-hazards regressions were used to identify independent factors associated with overall survival (OS) and cancer-specific survival (CSS), and nomogram models and web-based survival calculators were constructed. Propensity score matching (PSM) were used to compare survival with different treatment options.

Results: A total of 2526 patients were included in the prognostic model. The median OS and CSS for the entire cohort were 20 (18.6-21.3) months and 24 (21.7-26.2) months, respectively. Nomogram models integrating the seven factors demonstrated high predictive accuracy for 3-year and 5-year survival. PSM found that patients who received surgery-based curative therapy had better OSand CSS than those who received radiotherapy-based treatment (median survival times: 33 months vs. 18 months and 40 months vs. 22 months, respectively).

Conclusions: The nomogram model accurately predicted patient survival from LA-HPSCC. Surgery with adjuvant therapy yielded significantly better survival than definitive radiotherapy and should be prioritized for survival.

Introduction

The hypopharynx is a transitional structure that lies between the pharynx and cervical esophagus. Squamous cell carcinomas of the hypopharynx are usually diagnosed at an advanced stage and thus have a very poor prognosis^1-3. The treatment modalities for locally advanced hypopharyngeal cancer (LA-HPSCC) include surgery, radiotherapy, and chemotherapy. However, the optimal therapeutic combination remains controversial^4,5. The VALGSG⁶ and EORTC 24891 trials⁷ revealed that induction chemotherapy followed by radiotherapy (IC + RT) can be employed as a strategy for organ preservation in LA-HPSCC without loss of survival. The RTOG 91-11 trial⁸ further demonstrated that concomitant chemoradiotherapy (CRT) is superior to IC+RT for laryngectomy-free survival in laryngeal cancer, with an equal overall survival (OS). Based on these high-level clinical evidences, IC + RT and concomitant CRT have been widely used as frontline treatments for LA-HPSCC. However, real-world data on both laryngeal and hypopharyngeal cancers have raised the concern that organ preservation treatment might sacrifice patients’ OS^9-11. Careful analysis of patient data is essential to address the contradictions between trials and real-world observations.

The Surveillance, Epidemiology, and End Results (SEER) database contains information on cancer diagnosis and approaches for the first course of treatment. Several studies have analyzed the prognostic factors for LA-HPSCC using the SEER database, but have generated inconsistent results^11-13. Here, we carefully selected patients who received definitive radiotherapy (radiotherapy-based) or radical surgery (surgery-based) from the SEER database from 2004 to 2015 and analyzed the factors with prognostic impact. Nomogram models integrating multiple prognostic factors were built to predict the patient survival from LA-HPSCC¹⁴. The model was externally validated by an independent cohort of patients with LA-HPSCC from Sichuan Cancer Hospital, China.

Methods

Data source and selection criteria

The study was conducted in accordance with the Declaration of Helsinki (revised in 2013) and approved by the Institutional Review Board of the Sichuan Cancer Hospital (No.SCCHEC-02-2022-053). All data were de-identified, and the requirement for individual consent for this retrospective analysis was waived. This study followed the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) reporting guidelines for prognostic studies. Patient data were retrieved from the updated SEER database (https://seer.cancer.gov) and the SEER* Stat software (version 8.3.8; https://seer.cancer.gov/seerstat) was used to download the data.

The screening criteria were as follows: (1) patients diagnosed with hypopharyngeal squamous cell cancer between 2004 and 2015, which was coded as C13.0, C13.1, C13.2, C13.8, or C13.9, according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3); (2) those histopathologically confirmed (coded as 8050-8089 according to the ICD-O-3); (3) the patients whose survival time is known and > 1 month; (4) patients with complete follow-up data; (5) those with detailed information on variables, including vital status, survival months, age, sex, race, T/N/M stage, and treatment mode of the primary tumor (Figure 1). Treatment data were extracted from the following fields: radiation sequence with surgery, reason for no cancer-directed surgery, radiation recovery, and chemotherapy recovery. Patients were included in the surgery-based therapy group if they received surgery, including treatment categories of “radiation after surgery,” “radiation before and after surgery,” “radiation prior to surgery,” “sequence unknown, but both were given,” and “surgery both before and after radiation”. Patients were included in the radiotherapy-based therapy group if they received radiotherapy without surgery, including categories of “beam radiation,” “combination of beam with implantation,” and “radiation, NOS method or source”; subjects without any records of radiation or surgery were included in the chemotherapy/others group (Supplementary Figure 1). For external validation, we enrolled 276 patients with LA-HPSCC who were treated at the Sichuan Cancer Hospital between January 2004 and June 2016. 

Statistical analysis

The overall population data extracted from the SEER database was randomly divided into training and validation groups in a ratio of 7:3. All categorical variables were presented as frequencies and percentages and were analyzed using the chi-square test. Univariate and multivariate Cox proportional hazards regressions were used to estimate the relationship between predictor variables and survival outcomes. Independent prognostic variables (P < 0.05) were then selected to develop a prognostic nomogram. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. Discrimination was quantified using the area under the time-dependent receiver operating characteristic curve (time-dependent ROC) and the concordance index (C-index). Calibration curves were constructed to evaluate the concordance between the predicted survival probability and the observed probability. The decision curve analysis (DCA) was performed to compare the predictive value between our model and the American Joint Committee on Cancer (AJCC) stage. Propensity score matching (PSM) was used to analyze the survival differences between the treatment modalities. All analyses were performed with the SPSS 26.0 and R software version 4.1.1 (https://www.r-project.org/), using the rms, timeROC, DCA, DynNom, and shiny packages. Statistical significance was set at P < 0.05.

Results

Characteristics of patients

The entire cohort from the SEER database included a total of 2526 LA-HPSCC patients from 2004 to 2015 and met the inclusion criteria; thereafter, patients were randomly stratified into two groups in a ratio of 7:3, with 1768 and 758 patients in the training and validation groups, respectively. There was no statistical difference in the distribution of patients between the training and validation groups (P >0.05). The demographic and clinical characteristics of the patients are shown in Table 1. The majority of the patients were men (n=2084, 82.5%), white race (n=1884, 74.6%), insured (n=1787, 70.7%), and presented with lesions located in the pyriform sinus (n=1377, 54.5%). Concerning treatment modalities, the percentage of patients who received surgery-based, radiotherapy-based, and chemotherapy alone or other treatments were 14.7%, 72.4%, and 12.9%, respectively. Additionally, 276 patients with LA-HPSCC who were treated at the Sichuan Cancer Hospital were enrolled for external validation; their demographics and clinical characteristics are presented inSupplementary Table 1. For the entire population in the SEER database, the median survival time was 20 (18.6-21.3) months, and the median survival was 19 (17.4-20.5) months in the training group and 21(18.9-23.1) months in the validation group. For the external validation group, the median survival time was 19 (15.1-23.1) months.

Screening independent prognostic factors       

Univariate Cox regression analysis was performed on the training group to define the clinical parameters significantly associated with OS and cancer-specific survival (CSS) in LA-HPSCC patients. We found that age, race, insurance, marital status, primary site, T stage, N stage, AJCC stage, and treatment were significantly associated with OS and CSS (all P < 0.05, Table 2 and Supplementary Table 2). Furthermore, the Cox multivariate regression analysis determined all these factors to be independent, except the clinical stage (Table 2) because it was a combination of T and N stages and had a significant co-linearity with the TN stage. The OS and CSS curves of the patients grouped by each predictor are displayed in Supplementary Figures 2 and 3.

Construction and validation of the nomogram

The prognostic nomograms integrating all significant independent factors in the training group are shown in Figure 2. The C-indices for OS and CSS prediction of the nomogram models for the training, internal validation, and external validation groups were greater than those of the AJCC stage, suggesting that the models had significantly greater predictive power for the AJCC stage of the disease (Supplementary Table 3).

The calibration plots showed consistency between predictive survival and actual survival. For the training, internal validation, and external validation groups, the nomogram models revealed good accuracy for the 3-year and 5-year OS (Figure 3) and CSS prediction (Supplementary Figure 4). The ROC and DCA analyses both demonstrated that the models for OS (Figures 4, 5) and CSS (Supplementary Figure 5) were superior to the AJCC staging system in prognostic prediction . 

Development of an online survival estimate calculator 

An online version of our nomograms for OS and CSS in LA-HPSCC patients can be accessed at https://la-hpscc.shinyapps.io/DynNomappHPSCC/ and https://lahpscc.shinyapps.io/DynNomappHPSCCforCSS/ to further assist the researchers and clinicians. The predicted survival probability across time can be easily determined by inputting clinical features and reading output figures and tables generated by the web server.

Comparison between surgery-based and radiotherapy-based interventions and subgroup analysis

The PSM analysis was used to compare the survival differences between the surgery-based and radiotherapy-based treatments. Prior to the matched analysis, we observed that the surgery-based treatment had a better OS and CSS than the radiotherapy-based treatment, with median survival time and 5-year survival rates of 34 vs. 21 months, 42 vs. 26 months, and 35.5% vs. 28.0% and 43.9% vs. 36.8%, respectively (Figures 6A, D, and Supplementary Table 4). After matching for patient characteristics, surgery-based treatment still provided a significant benefit in OS and CSS, with median survival time and 5-year survival rates of 33 vs. 18 months, 40 vs. 22 months, and 35.5% vs. 27.2%, 42.3% vs. 33.7%, respectively (Figure 6B, E, and Supplementary Table 4). In addition, we also used PSM analysis to balance the clinical factors of patients treated with CRT and radiotherapy alone (Supplementary Table 5) and found that adding chemotherapy significantly improved the patient survival rates (Figures 6C, F).

Elder patients (>65 years) generally were excluded from prospective trials and the impact of age on survival of LA-HPSCC is unclear. We found that age group between 65 and 75 had slight but significant increase of death risk than age under 65 (HR 1.17, 95% CI, 1.05-1.30, P=0.004), whereas the risk increased to 1.82 (95% CI, 1.58-2.09, P<0.001) and 3.16 (95% CI, 2.35-4.23, P<0.001) for age between 75 and 85 and 85 beyond, respectively (Figure 6G). Among patients >75 years old, radical surgery (29 patients) provided superior OS (median, 19 months) than radiotherapy-based therapy (45 patients, median, 9 months) as in younger patients but with comparable CSS (median, 19 months vs 12 months, Supplementary Figure 6). However, due to limited patient number and lack of performance score records, the prolonged OS brought by surgery in the elderly needs further validation.    

Notably, there was great heterogeneity in the survival rates among the various clinical stages. We found that patients with stage T3N1 disease had a significantly poorer prognosis than those with other stage III diseases, with a median survival time of 15 vs. 35 months (Figure 6H). Patients staged T4aN0 and T1N2 had a better prognosis than other stage IVA patients, with median survival times of 38 and 57 vs. 17 months (Figure 6I), which suggests that these TN groups of HPSCC may need adjustment in staging, upgrade, or downgrade, respectively. 

Discussion

According to the SEER registration, there has been a significant shift from the surgery-based treatment to the radiotherapy-based treatment for HPSCC in the 1990s^15-17 and is likely inspired by several organ/function preservation trials^18-21 on laryngeal and hypopharyngeal cancer that were published in the early 1990s. According to Hochfelder et al. and the current study, the latest status of treatment selection for LA-HPSCC identified by analyzing the SEER records from 2004 to 2015 predominantly favored the radiotherapy-based treatment (4.3:1 in the Hochfelder study, 4.9:1 in the current study and 4.4:1 if T4b excluded from radiotherapy group). In an NCDB-based study²², the ratio was as high as 7.6:1. Given the great change in treatment strategy, the survival of LA-HPSCC remains poor, with a median survival of 20 months in the real world, reminding us that optimizing the current treatment setting and exploring new strategies to improve patient survival is the top requirement of LA-HPSCC instead of pursuing organ preservation. 

It has already been questioned whether organ preservation treatment may sacrifice patient survival for both laryngeal cancer and HPSCC²³. Hochfelder et al. concluded that compared with CRT, surgery with adjuvant radiotherapy/CRT (S+Adj) provides significant benefits for both OS (hazard ratio=0.70, 95% CI: 0.59-0.84) and CSS (HR=0.66, 95% CI: 0.54-0.82). After adjustment, S+Adj was associated with a longer CSS than CRT (HR=0.75, 95% CI: 0.57-0.99); however, this change was not observed with OS (HR=0.82, 95% CI: 0.66-1.04). The current study retrieved the SEER data within the same period as the Hochfelder study but applied a new criterion for treatment classification. Patients who received monotherapy were excluded from the Hochfelder study but were included in the current study. Local resection with radiotherapy was recognized as S+Adj in the Hochfelder study but was grouped into the radiotherapy-based group because radiotherapy acts as a definitive treatment in this setting. In the current study, only pharyngectomy and beyond (primary surgery codes 30 and 30+) were identified as radical surgery and thus classified as surgery-based treatment. Finally, we screened 371 patients who underwent radical surgery and confirmed that surgery-based treatment was superior to radiotherapy-based treatment in terms of both OS (HR=0.763, 95% CI: 0.664-0.877, P<0.001) and CSS (HR=0.775, 95% CI: 0.663-0.906, P=0.001). Notably, after adjusting for all baselines, the differences were observed to remain (OS: HR=0.715, 95% CI: 0.601-0.851, P<0.001; CSS: HR=0.708, 95% CI: 0.584-0.859, P<0.001).

Sanabria et al.²³ have given an in-depth discussion on the survival gap between organ preservation trials and real-world outcomes. In brief, the trials enrolled patients with strict criteria, whereas in the real world, radiotherapy may be recommended with loose judgement. The quality and timing of treatment were ensured in trials, whereas in the real world, both CRT and surgery might not have the same quality as observed in teaching hospitals, and salvage surgery might be delayed or not even offered. They concluded that in a non-academic setting, patients with T4 should receive total laryngectomy, whereas patients with T3 can receive a function preservation strategy with all resources guaranteed. Their discussion mainly focused on laryngeal cancer but also included HPSCC. However, the prognosis of HPSCC is much worse than that of other head and neck squamous cell carcinomas, including laryngeal cancer^24,25, the recommendation of CRT to patients with advanced HPSCC thus should be more cautious, and definitive radiotherapy should be applied with closer observation than that for other tumors. Indeed, in the EORTC 24891 trial⁷ designed specifically for LA-HPSCC, only 61.8% (60 of 97) of patients in the induction arm received definitive radiotherapy, with a radiotherapy/surgery ratio of approximately 1.8:1, showing a more stringent entry into radiotherapy than the real world.

Based on a detailed analysis of the records in the SEER database, the current study built a multidimensional predictive model for both OS and CSS. In addition to TN staging, factors including age, race, insurance, marital status, and importantly, treatment choice should all be considered when making treatment decisions. The models were validated not only by the internal cohort, but also externally by a cohort of patients treated in China. To facilitate comparison of the impact of different clinical factors, we created the OS and CSS online calculators that can be easily accessed and provide a quick estimation of survival.

As mentioned above, even if radical surgery with adjuvant treatment is provided, the survival rate of LA-HPSCC remains poor. A new strategy that can efficiently combine chemotherapy, radiotherapy, and surgery requires further investigation. One of the major limitations of the current study is that the SEER registration missed a few important clinical factors, including performance score, details of chemotherapy (cycles and regimens), and second line treatment. In addition, extranodal invasion has been found to be an important prognostic factor and is grouped into N3 in the 7^th AJCC staging system²⁶. This pathological indicator for poor prognosis was not recorded before 2015 in the SEER database, and the model may overestimate the survival of patients with extranodal invasion. 

Conclusion

In summary, through a detailed analysis of patient records in the SEER database between 2004-2015, we found that multiple factors have an independent impact on the OS and CSS in patients with LA-HPSCC. Compared with the 72.4% (1830 in 2526) of patients who received radiotherapy-based treatment, only approximately 14.7% (371 in 2526) received surgery-based treatment. However, patients receiving surgery-based treatment had significantly better survival (median survival time: 34 vs. 21 months) and a reduced HR in OS (HR=0.763; 95% CI:0.664-0.877, P<0.001). The current study strongly suggests that CRT for patients with LA-HPSCC should be recommended with caution. We provided online calculators for projecting survival to different treatment modalities under given clinical conditions, which will be helpful for physicians and patients to understand the prognosis and thus make treatment decisions accordingly.

Declarations

Data Availability

Research data are stored in an institutional repository and will be shared upon request with the corresponding authors.

Ethical Approval

The study was conducted in accordance with the Declaration of Helsinki (revised in 2013) and approved by the Institutional Review Board of the Sichuan Cancer Hospital (No.SCCHEC-02-2022-053).

Consent

Individual consent for this retrospective analysis was waived.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Authors Contributions

Shichuan Zhang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: S.Chen, S.Zhang, J.Liu. Acquisition, analysis, or interpretation of data: S.Chen, S.He, D.Wang, Y.Liu, S.Shao, Q.Shi, L.Tang, C.Li, F.Wang and J.Liu. Drafting of the manuscript: S.Chen, S.Zhang. Critical revision of the manuscript for important intellectual content: Q.Shi. Statistical analysis: S.Chen, Q.Shi, L.Tang, S.Zhang. Obtained funding: S.Zhang. Administrative, technical, or material support: S.Zhang. Supervision: S.Zhang, Q.Shi, C.Li.

Funding Statement

The study was supported by a grant from National Natural Science Foundation of China (Award Number: 81771921).

Acknowledgments

We are immensely grateful to all investigators involved in this study.

References

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Tables

Table 1 Characteristics of patients with LA-HPSCC in the training and validation group.

Abbreviations: LA-HPSCC: locally advanced hypopharyngeal squamous cell carcinoma; NOS: not otherwise specified; AJCC: American Joint Committee on Cancer

Table 2 Univariate and multivariate analyses of overall survival in the training group.

Abbreviations: LA-HPSCC: locally advanced hypopharyngeal squamous cell carcinoma; NOS: not otherwise specified; AJCC: American Joint Committee on Cancer