Conditional survival and annual hazard of death in elderly patients with esophageal cancer receiving definitive chemoradiotherapy

doi:10.21203/rs.3.rs-3333764/v1

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Conditional survival and annual hazard of death in elderly patients with esophageal cancer receiving definitive chemoradiotherapy

https://doi.org/10.21203/rs.3.rs-3333764/v1

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Background: Definitive chemoradiotherapy is one of the primary treatment modalities for elderly patients with esophageal cancer (EC). It remains inadequately studied how prognosis evolves over time and how non-EC deaths affect overall survival (OS). We examined the conditional survival and annual hazard of death in elderly patients with EC after chemoradiotherapy.

Methods: The data of patients with EC aged 65 or older registered in the Surveillance, Epidemiology, and End Results database during 2000–2019 were collected. Conditional survival was defined as the probability of survival given a specific time survived. Annual hazard of death was defined the yearly event rate.

Results: Among 3739 patients, the 3-year conditional OS increased by 7%-10% annually. Non-EC causes accounted for 18.8% of deaths, with cardio-cerebrovascular diseases as the leading cause. Death hazard decreased from 40% to 10% in the first 6 years and then increased to 20% in the tenth year. The hazard of death from non-EC causes exceeded that from EC causes, starting 5 years after treatment. Older patients and those in early stages had higher risks of death from non-EC causes (HR = 1.36, 95% CI: 1.15-1.62, P < 0.001 and HR = 0.82, 95% CI: 0.68-0.98, P = 0.035, respectively). Tumor histology had no significant impact on non-EC death risk (HR = 1.17, 95% CI: 0.98-1.39, P = 0.081).

Conclusions: For elderly patients with EC treated with chemoradiotherapy, survival probability increases with time. Stress on the management of comorbidities can extend the survival of older patients and those with early-stage disease.

Esophageal cancer

elderly

conditional survival

death hazard

As global populations continue to age, the incidence of cancer is expected to rise significantly. By the year 2030, it is projected that approximately 70% of new cancer cases diagnosed will be in the elderly. [^1–3] Among the various types of cancer, esophageal cancer (EC) is particularly common in elderly individuals, with more than 60% of new cases being diagnosed in patients aged 65 years or older. Definitive chemoradiotherapy (CRT) is currently the standard treatment modality for inoperable locoregional EC, particularly among the elderly population.[^4–7] Unfortunately, the prognosis remains poor, with the 5-year overall survival (OS) rate being only 21.7%. [⁸] Uncertainty about prognosis can cause psychological stress and even affect post-treatment prognosis. [^{9, 10}]

Conditional survival is an important concept in the field of oncology [^11–15]; it refers to the dynamic change in the likelihood of survival over time after diagnosis or treatment. [^{16, 17}] This dynamic measurement can provide updated survival estimates at specific time points after treatment and help guide long-term follow-up strategies. Elderly patients with EC often face complex health challenges due to the presence of multiple comorbidities [¹⁸], but conditional survival and changes in cause of death over time have not been well studied in this age group.

This study aimed to assess the conditional survival probability and change in annual hazard of death over time in patients diagnosed with EC at the age of 65 years or older and treated with definitive CRT. The study findings could help clinicians better understand the disease process and improve overall management.

Patients

The Surveillance, Epidemiology, and End Results (SEER) database was searched to identify patients diagnosed with EC from 2000 to 2019. Permission was obtained (reference number 11564-Nov2019) to access SEER Research Plus Data, 17 Registries, Nov 2021Sub (2000–2019). Patients were eligible for inclusion in this study if they 1) were ≥ 65 years old; 2) had pathologically confirmed locoregional EC; 3) had received definitive CRT; and 4) EC served as the first primary malignancies. We excluded patients with 1) unknown age or missing data on summary stage or survival time; and 2) diagnosis established solely through autopsy or death certificate (Fig. 1).

This study was granted an exemption from review by the institutional review board as only de-identified preexisting data were used.

Definitions

EC was classified as per the International Classification of Diseases for Oncology (ICD-0-3) codes and included adenocarcinoma (8140–8389, 8480, 8481, 8570, 8574), and squamous cell carcinoma (8050–8089). The location of the primary tumor was classified as thoracic upper (C15.0 and C15.3), middle (C15.4 and C15.1), and lower (C15.2 and C15.5). The TNM stage was reclassified according to the AJCC 8th edition staging system.

Statistical analysis

Statistical analysis was conducted using R 4.1.0 (https://www.r-project.org/). OS was defined as the time from the start of treatment to death from any cause. Cancer-specific survival (CSS) was defined as the time from the start of treatment to death from EC. Other cause–specific survival (OCSS) was defined as the time from the start of treatment to death from non-EC causes (e.g., cardiovascular disease). Considering the unique circumstances of elderly patients, we chose 3 years as the time horizon for cancer care instead of the conventional 5 years. Conditional OS was introduced to assess the probability of surviving for an additional number of years, given that a patient had already survived a certain number of years from the start of treatment. [¹⁶] Thus, the 3-year conditional OS at 2 years was the conditional probability of surviving an additional 3 years, given that the patient had already survived 2 years. Additionally, extensions of the concept of conditional survival were applied to determine conditional CSS and OCSS, i.e., the probability of CSS or OCSS for an additional number of years given that the patient had survived a certain number of years without death from EC or other causes. The survival rate was estimated by the Kaplan–Meier method and compared using the log-rank test. Conditional survival was calculated by using the “condsurv” package in R. [¹⁹]

Annual hazard of death was estimated as the annual number of deaths divided by the number of patients at risk in that year and was depicted with smoothed hazard curves. The annual hazard rate was calculated for the overall cohort and subgroups of cancer histology, age, and cancer stage. The restricted cubic spline (RCS) analysis was used to identify the association of age at diagnosis with mortality. All tests were two-sided, and the statistical significance was at P < 0.05.

Baseline Characteristics

Table 1 presents the baseline characteristics of the 3739 patients included in this study. The median age of the patients was 74 years, and the male-to-female ratio was 3:1. While 2072/3739 (55.4%) patients had adenocarcinoma, 1667/3739 (44.6%) had squamous cell carcinoma. Most than half of the lesions (56.3%) had spread beyond the esophageal wall (T3-4), and 56.2% of the lesions were located in the lower esophagus. A large proportion of patients (42.3%) presented with node-positive disease, and approximately 75% of patients had stage II-III disease. After a median follow-up of 63 months, the 1-, 3- and 5-year OS rates were 58%, 26.8%, and 16.6%, respectively, with a median OS of 16 months. The 1-, 3- and 5-year CSS rates were 62.5%, 33.0%, and 24.3%, respectively, with a median CSS of 18 months.

Table 1

Baseline characteristics of patients
Characteristics	Overall (n = 3739)
Sex, n (%)
Female	969 (25.9)
Male	2770 (74.1)
Age, years, median (IQR)	74.0 (69.0, 80.00)
Marital status, n (%)
Married	2115 (56.6)
Unmarried	1624 (43.4)
Race, n (%)
Black	334 (8.9)
Other	239 (6.4)
White	3166 (84.7)
Histology, n (%)
Squamous cell carcinoma	1667 (44.6)
Adenocarcinoma	2072 (55.4)
Location, n (%)
Upper	426 (11.4)
Middle	889 (23.8)
Lower	2101 (56.2)
Other	323 (8.6)
Grade, n (%)
I-II	1617 (43.2)
III-IV	1420 (38.0)
Unknown	702 (18.8)
T-stage, n (%)
T1	808 (21.6)
T2	639 (17.1)
T3	1823 (48.8)
T4	282 (7.5)
TX	187 (5.0)
N-stage, n (%)
N0	1326 (35.5)
N1	1075 (28.8)
N2	201 (5.4)
N3	38 (1.0)
N+	267 (7.1)
Nx	832 (22.3)
Stage, n (%)
I	672 (18.0)
II	1314 (35.1)
III	1494 (40.0)
IVA	15 (0.4)
Other	244 (6.5)

In the overall cohort, 57.5% (2151/3739) died from EC, while 18.8% (702/3739) died from non-EC causes. Cardiovascular and cerebrovascular diseases were the predominant causes of non-EC deaths, accounting for 198 (28.2%) deaths. Respiratory diseases (chronic obstructive pulmonary disease, pneumonia, and so on) followed closely behind, accounting for 102 (14.5%) deaths. Other causes of non-EC deaths included digestive tract disease (n = 92), neoplasm-related death (n = 59), and septicemia (n = 27).

Conditional Survival and Annual Hazards Over Time for the Overall Cohort

Figure 2A and Fig. 2B show the survival curves for conditional OS and conditional CSS, respectively. Unlike the 3-year OS rate, the 3-year conditional OS rates exhibited a progressive increase, reaching 36% (95% CI, 34%-39%) in patients with 1-year survivorship, 46% (95% CI, 43%-50%) in those with 2-year survivorship, 52% (95% CI, 47%-56%) in those with 3-year survivorship, 56% (95% CI, 51%-61%) in those with 4-year survivorship, and 63% (95% CI, 57%-69%) in those with 5-year survivorship. Likewise, the 3-year conditional CSS rates increased to 44% (95% CI, 42%-47%) for patients with 1-year survivorship, 59% (95% CI, 55%-62%) for those with 2-year survivorship, 66% (95% CI, 62%-70%) for 3-year survivorship, 73% (95% CI, 68%-78%) for 4-year survivorship, and 80% (95% CI, 73%-84%) for 5-year survivorship. Notably, the 3-year conditional OS and CSS showed an initial rapid increase of more than 10% during the initial two years, with a less rapid increase thereafter (Fig. 2C). Figure 2D shows the dynamics of the annual hazard of all-cause death, death from EC, and death from non-EC causes. The death hazard from all causes exhibited a “U” shape, with the hazard rate decreasing from 40–10% in the first 6 years and then increasing to 20% in the tenth year. Additionally, for the overall cohort, the hazard of death from non-EC causes surpassed death from EC causes, starting 5 years after treatment.

Annual Hazard Analysis in Subgroups

The RCS plot (Fig. 3A-C) illustrates the relationship between age at diagnosis and hazard of all-cause death, death from EC, and death from non-EC causes. The hazard of death consistently increased with advancing age, following a linear relationship (all P-overall < 0.001 and P-non-linear > 0.05).

Using the median age of 74 years as the cutoff, the overall cohort was divided into two groups: a 65-74-year age group (n = 1964) and a ≥ 75-year age group (n = 1775). The ≥ 75-year age group had significantly inferior 3-year OS (23.9% vs. 29.4%, P < 0.001), and a h igher risk of death from non-EC causes (HR = 1.36, 95% CI: 1.15–1.62, P < 0.001). Furthermore, the contribution of non-EC causes to death began earlier in the ≥ 75-year age group, starting at the fifth year versus the seventh year in the 65-74-year age group (Fig. 4A-B).

The 3-year OS rate was significantly higher in patients with squamous cell cancer than in patients with adenocarcinoma (32.2% vs. 22.2%, P < 0.001). The hazard of death from non-EC causes was similar in patients with the two cancer histologies (HR = 1.17, 95% CI: 0.98–1.39, P = 0.081). Additionally, non-EC deaths exceeded EC deaths by the fifth year for both cancer histologies (Fig. 4C-D).

Patients in stage I-II (n = 1986) showed significantly better survival than patients in stage III-IV (n = 1509), with 3-year OS rates of 31.0% vs. 21.6%, respectively (P < 0.001). Consequently, patients in stage I-II were more likely to die from non-EC causes (HR = 0.82, 95% CI: 0.68–0.98, P = 0.035). Moreover, the hazard of death from non-EC causes exceeded death from EC starting from the fifth year for patients in stage I-II compared to the seventh year for patients in stage III-IV (Fig. 4E-F).

The incidence of EC has been steadily rising among elderly patients, and the prognosis is often influenced by comorbidities that are common at this age. Patients with cancer often want to know their probability of further survival after having already survived a certain period. In this study of 3739 elderly patients (aged 65 years or older) with EC treated with definitive CRT, we observed that non-EC-related deaths—primarily deaths due to cardio-cerebrovascular and pulmonary diseases—accounted for approximately 25% of all deaths. Moreover, the conditional OS and CSS consistently increased over time, and the annual hazard of death from non-EC causes surpassed that of death from EC starting from the fifth year after treatment. The hazard of death exhibited a linear increase with advancing age. The risk of death from non-EC causes was significantly higher in older patients (≥ 75 years) and in those with early-stage (I-II) disease.

Definitive chemoradiotherapy is an effective and well-tolerated treatment modality for elderly patients with EC. Compared to younger patients, elderly patients might have lower tolerance to intravenous chemotherapy and experience worse survival outcomes. [^20–22] However, two phase III randomized clinical trials demonstrated that definitive radiotherapy concurrent with oral S-1 is well-tolerated by elderly patients with EC and provides significant survival benefits over radiotherapy alone [^{23, 24}] In our study, elderly patients with EC treated with definitive CRT had 3-year OS and CSS rates of 26.8% and 33.0%, respectively, with median OS and CSS of 16 and 18 months, respectively. These results are in line with previous studies reporting a median OS of around 15 months. [^25–28] In addition, we found that the estimated 3-year conditional OS rates increased at a rate of 7%-10% per year, reaching 60% in patients who had survived for 5 years. In a previous study of 1883 elderly patients with EC who received complete resection, Shin et al. [²⁹] also found that the conditional OS increased over time. These findings indicate that the residual hazard of death from cancer substantially diminishes over time following radical treatment.

Several authors have investigated the dynamic risk of cancer recurrence or mortality. Liu et al. [³⁰] investigated patients with early-stage extranodal natural killer/T-cell lymphoma after radiotherapy and found that the survival probability increased and the hazard of failure decreased in a risk-dependent manner. In our study, we found that the change in the annual hazard of all-cause death had a U-shape, implying a possible transition in the causes of death over time. During the initial 5-year period after treatment, the annual hazard of death was primarily due to EC, with the highest rate being 40% in the first year when EC deaths accounted for ~ 85% of all deaths. However, as time progressed, the proportion of EC deaths gradually declined and, by the sixth year, the annual death from EC reached its lowest point at 10%, and non-EC deaths started to dominate. Non-EC deaths gradually increased over time, reaching 15% in the tenth year. These findings are consistent with the study by Chesney et al., [³¹] which found that, among elderly patients with all cancer types, the cumulative incidence of non-cancer deaths exceeded cancer deaths at five years. These findings indicate the importance of prioritizing the prevention or treatment of comorbidities at five years after definitive CRT.

The different dynamics of the annual hazard of death among subgroups provide valuable guidance for initial treatment and surveillance strategies. First, a linear increase in the hazard of death was observed with advancing age for both EC and non-EC deaths. Specifically, in the fifth year, the annual hazard of death from non-EC causes in the ≥ 75 years age group was three times higher than that in the 65–74 age group (11.0% vs. 3.5%, HR = 1.36, 95% CI: 1.15–1.62, P < 0.001). This underscores the importance of equal emphasis on the management of comorbidities and EC during the entire treatment, particularly in older individuals. Furthermore, although patients with squamous cell carcinoma had a more favorable prognosis than those with adenocarcinoma (3-year OS, 32.2% vs. 22.2%, P < 0.001), tumor histology was not a prognostic factor for non-EC death in our study (HR = 1.17, 95% CI: 0.98–1.39, P = 0.081). Notably, patients in stage I-II experienced a higher risk of non-EC death than patients in stage III-IVA (HR = 0.82, 95% CI: 0.68–0.98, P = 0.035). This might be due to the longer survival duration of individuals with early-stage EC and the consequent greater likelihood of encountering non-EC-related deaths.

This study has several limitations. First, the lack of detailed information on chemotherapy regimens, radiation doses, and treatment durations prevented in-depth analyses of treatment effects. However, the effect of these factors has been examined in previous studies and likely does not impact the results of our study. Second, our study focused only on patients who received chemoradiotherapy; so it is not possible to generalize our results to those undergoing curative surgery. Finally, the inability to assess pre-existing comorbidities and their impact on cardiovascular disease–related mortality can be considered a limitation. These limitations will have to be addressed in future studies to provide a more comprehensive understanding of mortality factors in elderly patients with EC.

Among elderly patients with esophageal cancer the conditional overall survival, increases over time at a rate of 7%-10% per year, to reach 60% in patients who have survived for 5 years. Furthermore, there is a gradual transition in the annual hazard of death due to esophageal cancer and other causes. Older patients, especially, can be expected to gain survival benefits from good management of comorbidities during the entire treatment and surveillance. The relationship between non–esophageal cancer mortality and treatment toxicities in this age group needs to be clarified in future research.

Funding

This work was supported by the Beijing Hospitals Authority’s Ascent Plan (grand number DFL 20220902), National Natural Science Foundation (grand number 82073333), and the Beijing Municipal Science & Technology Commission (grand number Z181100001718192).

Acknowledgments

We would like to thank the funding supported by the Beijing Hospitals Authority’s Ascent Plan (grand number DFL 20220902), National Natural Science Foundation (grand number 82073333), and the Beijing Municipal Science & Technology Commission (grand number Z181100001718192).

Conflict of interest

All authors declare that they have no potential conflicts of interest in this manuscript.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (revised in 2013). Since SEER is a publicly available database with anonymized data, ethical approval was not required.

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Conditional survival and annual hazard of death in elderly patients with esophageal cancer receiving definitive chemoradiotherapy

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Version 1

Abstract

Figures

Introduction

Methods

Patients

Definitions

Statistical analysis

Results

Baseline Characteristics

Conditional Survival and Annual Hazards Over Time for the Overall Cohort

Annual Hazard Analysis in Subgroups

Discussion

Conclusions

Declarations

References

Supplementary Files

Status:

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