Prognostic factors and the role of locoregional treatment in patients with distantly metastatic hypopharyngeal cancer: a retrospective cohort study based on SEER database

Introduction

As is well known, hypopharyngeal cancer is one of the most malignant cancers in the head and neck region. Hypopharyngeal cancer accounts for 3% of all head and neck malignancies (1). The vast majority of hypopharyngeal cancers are squamous cell carcinoma. Hypopharyngeal cancer has aggressive biological traits and is often asymptomatic due to its concealed location. At the time of initial diagnosis, seventy percent of patients with hypopharyngeal cancer present with advanced-stage (2), and up to 13% of the patients develop distant metastasis (3). The 5-year overall survival (OS) was about 13.5% for hypopharyngeal cancer with distant metastasis (4), while it was estimated to be 52.3% for patients without distant metastasis (5). Remarkable advancements in multidisciplinary approaches have led to substantial improvements in locoregional control for hypopharyngeal cancer in recent years (6), but treatment for distant metastasis remains a dilemma.

The primary goals of treatment for metastatic hypopharyngeal cancer (MHPC) are palliation of symptoms, improvement of quality of life, and prolongation of survival. The treatment options include the best supportive care, locoregional treatment based on primary sites, systemic therapy, and the newly popular strategy immunotherapy. Locoregional treatment (LRT, surgery or/and radiotherapy) delivered in this setting is usually to reduce the tumor burden and alleviate symptoms such as pain, bleeding, ulceration, dyspnea and dysphagia. Multiple previously studies have shown that LRT effectively improve the quality of life in patients with metastatic head and neck cancers (7,8). However, Little attention has been paid to the survival outcomes associated with LRT. There is also a scarcity of literature regarding the prognosis of hypopharyngeal cancer with distant metastasis.

The incidence of hypopharyngeal cancer is very low, and cases with distant metastases are even scarce. Any single-center or multi-center study might fail to collect enough patients for the trial. Moreover, performing randomized trials in these patients may not be ethically appropriate. The Surveillance, Epidemiology and End Results (SEER) database covers approximately 28% of the United States population and has one of the largest cohorts of patients with hypopharyngeal cancer. Accordingly, the purpose of this study was to investigate the prognostic factors and the effect of LRT on survival in patients with MHPC using the SEER database. We present the following article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-21-2953/rc).

Methods

Data collection

Data of hypopharyngeal cancer with distant metastasis were extracted from the SEER database. Patients diagnosed from 2010 to 2018 were selected since the information of metastatic sites was only available after 2010. The “Derived AJCC M6^th ed” code was “M1” (n=588). The exclusion criteria were as follows: (I) not squamous cell cancer (n=12), (II) not the first tumor (n=63), (III) patient-related information such as pathological grade, T, and N stage, was unknown (n=50). The data extraction and analysis were performed in compliance with the relevant guidelines of the SEER database. Because SEER does not contain patient identity information, this study was exempt from review by the Institutional Ethic Committee of Peking University People’s Hospital and individual consent for this retrospective analysis was waived. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Variables in the database consisting of age, sex, marital status, race, insurance, tumor location, pathologic grade, TNM classification (AJCC, 6^th edition), treatment modality, survival time, and survival status were included in the analysis. Surgery for the primary tumor included local tumor excision (surgery codes 20-27) and pharyngectomy with or without laryngectomy (surgery codes 40-42). Information about radiotherapy and systemic therapy was also extracted from the database. LRT was defined as surgery for the primary tumor, radiotherapy for the primary tumor, and a combination of both. Patients were divided into four groups based on treatment modality: no treatment, LRT, systemic therapy alone, and LRT combined with systemic therapy. In our analysis, all LRT were performed in the setting of established metastatic hypopharyngeal cancer. Patients who were diagnosed with metastatic diseases later after LRT were excluded from our criteria.

Statistical analysis

Cox regression analysis was used to determine the independent risk factors for cancer-specific survival (CSS) and OS and estimate the hazard ratio (HR). The Kaplan-Meier method and log-rank test were used to compare survival curves between treatment modalities. In many situations in survival analysis, there are likely multiple endpoints competing with each other. For instance, patients dying from heart failure would not die from cancer. Therefore, competing risk analysis was performed when comparing survival outcomes between systemic therapy and combined treatment of LRT and systemic therapy. To assess the treatment effect on OS in various baseline subgroups, subgroup analysis was performed, and interactions between treatment modalities and patient characteristics were also tested. A P value <0.05 was considered statistically significant in these analyses. We performed the analyses using SPSS 22.0 software (IBM Corporation, Armonk, NY, USA) and the R language package (version 3.4.3, The R Foundation).

Results

Patient- and tumor-related characteristics

In total, 463 eligible patients with distant metastasis of hypopharyngeal cancer were included in the analysis. The incidence of distant metastasis was 8.3% (463/5,578) for hypopharyngeal squamous carcinoma. The clinical information of the study cohort is summarized in Table 1. The average age of this cohort of patients was 62.7±11.8 years. The majority of patients were male, white, and single, with proportions of 89.1%, 71.4%, and 58.4%, respectively. Three hundred and eighty-four patients (83.0%) had primary tumors located in the pyriform sinus. Two hundred and thirty-four patients (50.5%) presented with T4 disease. The most common (n=260, 56.2%) regional lymph node status was N2. The most common metastatic site was the lung, presenting in 55.1% of the patients, followed by the bone (20%) and the liver (12.5%). 280 (60.5%) and 68 (14.7%) patients presented with single organ metastasis and multiple organ metastases, respectively. Two hundred and ninety-five patients (63.8%) received systemic therapy. Two hundred and eighty-five patients (61.6%) received locoregional therapy, including surgery (n=17), radiotherapy (n=235), and surgery combined with radiotherapy (n=33). The types of surgery included local tumor excision (n=30) and pharyngectomy with or without laryngectomy (n=20). Neck dissection was performed in 18 of these patients. Systemic therapy combined with LRT was the most common treatment modality (n=217, 47.0%), followed by no therapy (n=100, 21.6%), systemic therapy alone (n=78, 16.7%), and LRT alone (n=68, 14.6%).

Survival analysis

Three hundred eighty-eight patients (83.8%) died of hypopharyngeal cancer. Forty-seven patients (10.2%) died of other causes such as lung and bronchus diseases, pneumonia and influenza, and heart diseases. Twenty-eight patients (6%) were still alive at the last follow-up. The median overall survival time was 7 (95% CI: 5.53–8.47) months, with a 1-year OS rate of 28.3% (95% CI: 21.8%–34.8%). In univariate analysis (Table 1), age, primary tumor site, bone metastasis, number of metastases, and treatment modality had significant influences on CSS. Patients with younger age (<65 years), pyriform sinus carcinoma, without bone metastasis, with solitary distant metastasis, and those who received systemic therapy plus LRT had better survival. Patients with higher age (>65 years), posterior wall cancer, bone metastasis, metastases involving two or more sites, and those without any treatment experienced poor prognosis. For overall survival, only bone metastasis, treatment modality, and the number of metastases were statistically significant. We further performed Kaplan-Meier analysis and log-rank test to examine OS stratified by different treatment modalities (Figure 1). LRT combined with systemic therapy showed the most favorable survival outcome compared with other treatment modalities (vs. no treatment, P<0.001; vs. systemic therapy, P=0.021; vs. LRT, P=0.021), followed by systemic therapy (vs. no treatment, P=0.021). The curves of OS between the LRT group and the no-treatment group were comparable (P=0.08). The no-treatment group was associated with a dismal prognosis, with a median OS of 2 months (95% CI: 1.25–2.75) and a 1-year OS rate of 8.8% (95% CI: 0.2%–17.0%). In comparison, the 1-year OS rates of the systemic therapy, LRT, and LRT plus systemic therapy group were 23.2%, 20.1%, and 41.4%, respectively (Table 1).

Figure 1 Overall survival curves of patients with distantly metastatic hypopharyngeal cancer undergoing different treatment modalities.

We next performed multivariable Cox analysis and patient-related variables in Table 1 were included in the analysis. After adjusting confounding factors such as age, gender, insurance status, tumor characteristics (primary site and pathological grade), and disease burden (T and N stage, number of metastases), our results demonstrated that bone metastasis, liver metastasis, and treatment modality were independent prognostic factors for survival (Table 2). Patients with bone metastasis (OS, HR =2.01, 95% CI: 1.27–3.17) and liver metastasis (OS, HR =1.80, 95% CI: 1.10–2.95) had poor survival outcomes. Compared with systemic therapy, patients who received no therapy had a significantly increased risk of death (OS, HR =2.70, 95% CI: 1.51–4.84). Compared with systemic therapy, LRT and systemic therapy significantly reduced the risk of death (OS, HR =0.65, 95% CI: 0.39–0.92). In addition, the LRT alone strategy was likely to increase the risk of death compared with systemic therapy (OS, HR =1.41, 95% CI: 0.73–2.70), but the difference did not reach a significant level.

Since systemic therapy is the first choice for MHPC, we further performed survival analyses just between the systemic therapy group and LRT plus systemic therapy group. The clinicopathological features were summarized in Table 3. The Chi-square test was used for comparison. The patients with systemic therapy presented with a lower percentage of insurance (34.6% vs. 52.0%), higher age (patients >65 years of age 41% vs. 27.6%), a higher percentage of T3 diseases (32% vs. 12.9%), a higher percentage of lung metastasis (61.5% vs. 50.7%), bone metastasis (30.7% vs. 13.8%), and multiple metastases (30.7% vs. 11.5%) in comparison with patients received LRT plus systemic therapy. This reflects the fact that patients with systemic therapy alone had a more extensive burden of disease, higher age, and possibly poorer health status. After adjusting for confounding variables in Table 3, bone metastasis, liver metastasis, and treatment remained to be independent prognostic factors for survival (Table 4). LRT plus systemic therapy yielded a 37% decreased risk of death compared with systemic therapy alone (OS, HR =0.63, 95% CI: 0.38–0.92). To reduce the impact of death from other causes, we performed competing risk analysis between the two treatment groups. Our results indicated that systemic therapy alone was associated with an increased risk of cancer-specific mortality compared with LRT plus systemic therapy (P<0.01, Figure 2). The risk of other causes of mortality was not significantly different among the two therapeutic methods (P=0.32). We further performed subgroup analysis in patients treated with the two methods and found that the survival benefit of LRT plus systemic therapy was significant in subgroups including younger age, single status, pyriform sinus originated, and lung metastasis (Figures 3-5, P<0.05). To explore the interaction between treatment effects and patient-related characteristics, we performed interaction analysis. However, the P value for interaction only showed a significant level for the age variable (P=0.01, Figure 6), indicating that younger patients (<65 years) were more likely to achieve survival benefit if they were treated with LRT and systemic therapy.

Figure 2 Competing risk analysis for patients with distantly metastatic hypopharyngeal cancer. ST, systemic therapy; LRT, locoregional treatment.

Figure 3 Overall survival curves for patients stratified by age, gender, and marital status.

Figure 4 Overall survival curves for patients stratified by pathological grade, T and N stage.

Figure 5 Overall survival curves for patients stratified by primary site, lung metastasis, and number of metastases.

Figure 6 Forest plot of the treatment effect on overall survival by patient and tumor characteristics. ST, systemic therapy; LRT, locoregional treatment. A hazard ratio of less than 1 indicates a survival benefit of locoregional treatment combined with systemic therapy. There was an interaction between treatment effect and age variable (P for interaction =0.01).

Discussion

Hypopharyngeal cancer with distant metastasis often heralds an incurable disease. According to a study of the National Cancer Database, LRT combined with systemic therapy was the most common (39.2%) treatment modality in M1 head and neck cancers (9). Other than in the setting of palliative intention, the role of LRT is controversial in metastatic HNSCC. The survival benefit of LRT for primary tumor and metastatic diseases has been demonstrated in many other cancers such as prostate cancer (10), lung cancer (11), and brain metastases (12). Although NCCN guidelines recommended LRT (surgery and radiotherapy) for selected patients with limited metastasis, the survival influence of LRT is poorly documented in the literature.

To our knowledge, we have explored the survival benefit of LRT and the prognostic factors for patients with MHPC for the first time. Multiple studies have reported factors associated with metastatic HNSCC and considered that T and N stages were associated with distant metastasis (13,14). And for laryngeal cancer with distant metastasis, Pan et al. found that the T stage was a significant risk factor for survival in their population-based retrospective study (15). In our work, the incidence of T4 or N2-N3 diseases in MHPC was 50.6% or 70.8%, respectively. Cox analysis indicated that bone and liver metastasis were independent predictors for survival, while T and N classifications were not. Perhaps T and N classifications are not important for prognosis once distant metastasis occurs. This is consistent with a retrospective single-institution study reported by Schulz et al. (16). They analyzed the outcomes of patients with metachronous distant metastasis of head and neck cancers after specific therapy and found relationships between survival and liver as well as bone metastasis. Although univariate survival analysis showed poorer survival outcomes in patients with multiple metastases, the multivariate analysis suggested the number of metastases was not an independent risk factor for survival. In our work, the site of metastasis (liver/bone) seems to have a greater influence than the number of metastases on survival. This was contrary to the results reported in laryngeal cancer and breast cancer (15,17).

LRT in our analysis includes surgery (17/285, 6%), radiotherapy (235/285, 82.4%), and surgery combined with radiotherapy (33/285, 11.6%). Surgery as a palliative intent in advanced head and neck cancers mainly includes nutritional support surgery (percutaneous gastrostomy and open jejunostomy), tumor debulking surgery, and tracheotomy, and so on. Types of surgery in the present study included 30 cases of local tumor excision and 20 cases of pharyngectomy with or without laryngectomy. Local excision in the SEER database requires specimens sent to pathology from this surgical event. However, we were unable to speculate about the extent of tumor excision and the situation at that time. Given the invasive nature of the procedure, the role of surgery in metastatic head and neck cancers has diminished. We believe that two types of local excision could be considered as effective local therapies. First, the primary tumor was quite small and able to be completely removed by surgery. Second, the primary lesion had severe complications such as respiratory obstruction and bleeding and had to be operated on. Considering that patients receiving radiotherapy accounted for 94% of all patients with locoregional treatment in our work, in fact, the results of this study are more instructive for local radiotherapy. This is also in line with the current status of locoregional treatment for metastatic hypopharyngeal cancer. Many patients received palliative radiotherapy with or without systemic therapy (18,19).

A recent study has demonstrated the safety and effectiveness of concurrent systemic therapy and palliative radiotherapy in advanced head and neck cancers, with an objective response rate up to 85.7% (19). Our results showed that systemic therapy and LRT yield a 37% decreased risk of death compared with systemic therapy alone (Table 4). Although the evidence of direct comparison is missing, patients with distantly metastatic HNSCC treated with palliative chemotherapy had a median survival of 7.4 months (20), which was evidently higher than 3.8 months reported for patients with no therapy (21). Our results showed that the risk of mortality in patients with systemic therapy was significantly lower than that of patients with no therapy (HR =2.70, Table 2). In Kaplan-Meier analysis, the survival curves of the LRT group and no treatment group were not significantly different. Besides, LRT was likely to increase the risk of mortality than systemic therapy in cox regression analysis (OS, HR =1.41, 95% CI: 0.73–2.70). These results implied that only LRT would not benefit survival if a patient does not receive systemic therapy.

Patients with distant diseases often have advanced primary tumors, poor performance status, and other comorbidities. LRT may be correlated with a high risk of morbidity and mortality. Consequently, we performed competing risk analysis to determine whether different treatment modalities influenced multiple survival outcomes. Our results showed that LRT combined with systemic therapy was associated with improved cancer-specific mortality for patients with MHPC without affecting other-cause mortality compared to systemic therapy alone.

There are several reasons to explain the favorable effect of LRT. First, hypopharyngeal cancer is adjacent to the vital blood vessels and nerves in the head and neck region responsible for essential biological functions, such as respiration, swallowing, and phonation. Locoregional progression is often the primary cause of morbidity and mortality for head and neck cancers, even for those with distant metastasis (22). Second, LRT reduces the tumor burden and facilitates inhibiting tumor growth and distant metastasis. The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer distant from the irradiated site (23). The effect is often mediated by the immunological mechanisms evoked by locally dead cancer cells (24). In addition, primary tumors have been reported to produce systemic signals, such as inflammatory cytokines and exosomes, affecting distant organs by constructing premetastatic niches (25). Consequently, the ablation of primary tumors may contribute to an abscopal effect on systemic diseases.

Not all patients achieved survival benefits from LRT. Although subgroup analysis demonstrated survival benefits of LRT and systemic therapy in many subgroups such as younger age, single status, pyriform sinus originated, and lung metastasis (Figures 3-5), the interaction analysis suggested that only the age variable significantly influenced the treatment effect, which suggested that younger patients were more likely to benefit from LRT with improved survival. Interaction analysis can examine a situation in which the effect of treatment on a survival outcome depends on another covariate. As shown in Figure 6, estimates of HR were indeed similar among subgroups defined by variables such as marital status, primary site, and lung metastasis. Young patients tend to have better tolerance to LRT than the elderly. Many palliative radiotherapy regimens will decide whether to deliver a higher dose of radiotherapy according to the patient’s tolerance (18), while radiotherapy dose has been considered to be an independent factor affecting survival (26). However, we could not validate this hypothesis due to the limited information regarding radiotherapy regimens in the SEER database. Although NCCN guidelines recommended surgery and radiotherapy for patients with limited metastasis, we did not observe a survival benefit of LRT in patients with a single metastasis (Figure 5E).

The time of LRT might have an impact on the survival of patients. A study of metastatic head and neck cancers using the NCDB database suggested that the effect of early local treatment (<6 months) might be greater than that of later local treatment (>6 months) (27). However, the authors also acknowledged that such results may be due to the bias that patients with early response to chemotherapy were more likely to receive local treatment. Because no information about treatment time was available in the SEER database, we were unable to conduct further analyses. In another study using the NCDB database to evaluate the role of local radiotherapy in metastatic head and neck cancers (28), they reported that 46.7% of patients with radiotherapy and systemic therapy received concurrent chemoradiotherapy, 41.2% received chemotherapy after radiotherapy, and 12.1% received radiotherapy after chemotherapy. In our clinical practice, the timing of local radiotherapy is individualized. Generally speaking, patients with good performance status, limited distant metastases, and small primary tumors are preferred to give concurrent chemoradiotherapy. For patients with extensive primary tumors and severe lymphatic metastases, chemotherapy is preferred to be delivered first, and then local radiotherapy is decided according to therapeutic responses.

The lack of radiation dose is a major drawback of the present study. Because the survival benefit of radiotherapy may be dose-dependent. An NCDB database study suggested that high-intensity radiotherapy (>60 Gy) may be beneficial for survival of patients with M1 head and neck cancers (27). The commonly used dose of palliative radiotherapy in North America is of 4,400 cGy, and whether to give a higher dose was determined based on the patient’s tolerance and therapeutic responses (8). Although patients in our analysis who were treated with local radiotherapy might have received palliative doses (<60 Gy), our results still showed a survival benefit for the locoregional treatment combined with systemic therapy group. For metastatic hypopharyngeal cancer with a median survival of only 7–8 months, the optimal radiotherapy dose should take full account of the performance status, life expectancy, quality of life, and patient’s will. Whether the appropriate dose of radiotherapy is beneficial for survival in metastatic head and neck cancers remains to be tested in high-quality randomized control trials.

There are several limitations to keep in mind when interpreting our results. First, potential selection bias may exist among treatment groups. Patients treated with systemic therapy alone were older and had a more extensive tumor burden compared with patients with LRT plus systemic therapy. However, the Cox regression analysis still confirmed the survival benefit of LRT plus systemic therapy after adjusting the imbalance of these covariables. Second, there was no data on comorbidity and performance status of patients included in our analysis owing to the limitation of the data source. These variables may affect treatment choice and survival outcomes in patients with advanced head and neck cancer (29,30). Interestingly, our competing risk analysis suggested that LRT has mitigated cancer-related mortality. It is reasonable to speculate that the improved cancer-related mortality was due to the biological characteristics of tumor and treatment choice rather than well performance status or fewer comorbidities. Third, an immortal time bias, in which patients must have survived until fulfilling their LRT, could have contributed to results in favor of LRT. Consequently, it is insufficient to offer LRT as standard of care based on our work, and further clinical trials are still needed to validate our results. But our study suggests promising information that LRT, which is often used as palliative therapy in distantly metastatic cancers, was associated with improved survival in selected patients with MPHC.

Conclusions

Our results revealed that bone metastasis, liver metastasis, and treatment modality were independent factors affecting the survival of patients with distantly metastatic hypopharyngeal cancer. Locoregional treatment and systemic therapy was associated with prolonged survival compared with systemic therapy alone in selected patients. Furthermore, younger patients (<65 years) may be more likely to benefit from locoregional treatment with improved overall survival.

Acknowledgments

We thank Professor Yalin Chen from the Department of Radiotherapy of Peking University People’s Hospital for his excellent academic assistance.

Funding: This work was supported by the National Natural Science Foundation of China (No. 82071034).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-21-2953/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-21-2953/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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