|Year : 2019 | Volume
| Issue : 4 | Page : 849-856
Evaluation of surgery plus postoperative radiotherapy or definitive radiotherapy in older patients with thoracic esophageal squamous cell cancer
Wanrong Jiang1, Xiangdong Sun2, Bin Zhou2, Chenglong Han2, Feng Liu2, Jingwei Zheng3, Xinchen Sun4
1 Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical College; Department of Radiotherapy, Jinling Hospital, Nanjing, China
2 Department of Radiotherapy, Jinling Hospital, Nanjing, China
3 Department of Clinical Research Center, Eye Hospital Affiliated To Wenzhou Medical University, Wenzhou, China
4 Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical College, Nanjing, China
|Date of Web Publication||14-Aug-2019|
Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical College, Nanjing
Source of Support: None, Conflict of Interest: None
Purpose: This study investigated the outcome of elderly patients (≥65 years) with thoracic esophageal squamous cell carcinoma (TESCC) treated with esophagectomy and postoperative radiotherapy (PORT) or definitive radiotherapy (DRT).
Patients and Methods: One hundred and ninety patients (median age of 72 years) who received PORT (n = 68) or DRT (n = 122) for TESCC were analyzed. Majority of them showed locally advanced disease (T3/4: 70.5%, N+: 70.5%, Stage III: 51.6%). Compared to patients who received DRT, those who received PORT had lower Age-Adjusted Charlson Comorbidity Index (AACCI) scores (2.49 ± 0.61 vs. 3.73 ± 1.28, χ2 = 7.283; P = 0.000) and higher Karnofsky Performance Scale (KPS) (χ2 = 9.016; P = 0.003) and were of younger ages (68.90 ± 3.00 vs. 75.17 ± 5.71, χ2 = 9.925; P = 0.000).
Results: Overall survival (OS) was significantly higher in the PORT group (median, 61.2 months; 95% confidence interval [CI], 46.04–76.36) than in the DRT group (median, 24.37 months; 95% CI, 15.43–33.31). Multivariate analysis showed that treatment method (hazard ratio [HR]: 2.38, 95% CI, 1.46–3.90; P = 0.001), clinical T stage (HR: 0.57, 95% CI, 0.34–0.95; P = 0.031), and lymph node metastasis (HR: 0.51, 95% CI, 0.31–0.84; P = 0.008) were independent prognostic factors. Regarding subgroup analysis, OS of patients receiving PORT was significantly higher than that of DRT in the T3–4 group (HR: 2.98, 95% CI, 1.80–4.92; P = 0.000) and the N+ group (HR: 2.20, 95% CI, 1.26–3.83; P = 0.006).
Conclusions: The efficacy of PORT for the treatment of elderly TESCC patients was superior to DRT. With regard to AACCI, KPS, and age, DRT is still a treatment option for elderly TESCC patients, especially for those >75 years of age.
Keywords: Age-Adjusted Charlson Comorbidity Index score, definitive, elderly, esophageal squamous cell carcinoma, postoperative, radiotherapy
|How to cite this article:|
Jiang W, Sun X, Zhou B, Han C, Liu F, Zheng J, Sun X. Evaluation of surgery plus postoperative radiotherapy or definitive radiotherapy in older patients with thoracic esophageal squamous cell cancer. J Can Res Ther 2019;15:849-56
|How to cite this URL:|
Jiang W, Sun X, Zhou B, Han C, Liu F, Zheng J, Sun X. Evaluation of surgery plus postoperative radiotherapy or definitive radiotherapy in older patients with thoracic esophageal squamous cell cancer. J Can Res Ther [serial online] 2019 [cited 2019 Aug 17];15:849-56. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/849/264303
| > Introduction|| |
The number of elderly patients with esophageal cancer (EC) has increased significantly over the recent decades due to higher life expectancies. Since older patients are at greater risks of morbidity and mortality compared to younger patients, managing elderly cancer patients has become a major concern. Treatment options for elderly patients with esophageal carcinoma have not been well studied. Most of the data available are from studies with younger patients, and it is unclear if these results can be translated to elderly patients.
Hence, the aim of this study was to review the institutional experience gathered from elderly patients with thoracic esophageal squamous cell carcinoma (TESCC) who were treated with postoperative radiotherapy (PORT) or definitive radiotherapy (DRT), to compare the efficacy of these two approaches, and to evaluate the possible factors influencing outcome and treatment decisions.
| > Patients and Methods|| |
Patient sample and data collection
We performed a retrospective analysis of 190 patients aged ≥65 years with TESCC who were treated with PORT (n = 68) or DRT (n = 122) with or without concomitant chemotherapy at our institution between May 2004 and May 2018. The inclusion criteria were newly diagnosed histologically proven SCC of the thoracic esophagus and age ≥65 years at the start of therapy. PORT or DRT was performed using three-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT) techniques. Patients were excluded from this retrospective analysis if they had distant metastases other than celiac or supraclavicular lymph node metastasis. The median age was 72 years (range, 65–93 years); 134 patients were male and 56 were female. Sixty-eight patients received PORT, whereas 122 patients received DRT. A systematic review of patients' clinical charts and reports was performed to gather data on patient and treatment characteristics and treatment outcomes. For the purpose of this study, all patients were restaged based on the 7th edition of the UICC TNM classification.
Initial work-up included at least clinical and laboratory examinations, endoscopy with biopsy, and computed tomography of the chest and abdominal ultrasound.
A transthoracic approach with two-field lymph node dissection was used for tumors extending proximally to the tracheal bifurcation. A transhiatal resection was used for tumors involving the esophagogastric junction. Peritruncal dissection was performed using both approaches. For all other tumors, the approach relied on patient features and doctors' preferences. Gastric tube reconstruction with cervical anastomosis was the preferred technique for restoring the continuity of the digestive tract.
Due to the length of this study, target delineation, radiation technique, and dose prescription varied largely. In general, patients were treated in the supine position using an alpha-cradle. For patients in the DRT group, the gross tumor volume (GTV) included the primary tumor and involved lymph nodes. The primary clinical target volume covered 3–5 cm in both directions along the longitudinal axis from the primary tumor and at least 1 cm of uninvolved mediastinal soft tissue in the axial direction, excluding adjacent lung tissue, for elective nodal irradiation. Radiation therapy was administered using multiple field techniques with IMRT (n = 122, 100%) with an intended dose of 50–70 Gy for conventional fractionation. Patients in the PORT group were treated as soon as possible after surgery. The target volume included postoperative tumor bed and high-risk lymphatic drainage areas. The total dose was 50–54 Gy and 1.8–2.0 Gy/fraction with 3D-CRT (n = 34, 50%) or IMRT (n = 34, 50%). Patients were scheduled for simultaneous chemotherapy (n = 58, 30.5%) or radiation alone (n = 132, 69.5%) based on performance status, comorbidity, and the presence of specific contraindications, as determined by the treating radiation oncologist. The chemotherapy regimens consisted mainly of single-agent tegafur, S-1 (tegafur, gimeracil, and oteracil), or capecitabine tablets administered orally.
Initial follow-up was generally scheduled at 6–8 weeks after PORT or DRT. The follow-up periods were scheduled at every 3–4 months for the 1st year, every 4–6 months for the 2nd year, every 6 months for the 3rd year, and annually thereafter. During this period, any abnormalities that manifested were reviewed. Local recurrence, regional lymph node metastasis, and distant metastasis were all considered treatment failures during follow-up.
Statistical and ethical considerations
For patients in the PORT group, overall survival (OS) was calculated from the date of surgery until the last follow-up period or until death using the Kaplan–Meier method, and for patients in the DRT group, the start date was the 1st day of radiation treatment. Differences between the subgroups with regard to OS were compared using a Cox proportional-hazards method for univariate and multivariate analysis. Differences in patients or treatment-related parameters between the subgroups were analyzed using the Chi-square test or Fisher's exact test for categorical and the t-test for continuous variables. P < 0.05 was considered statistically significant. The Age-Adjusted Charlson Comorbidity Index score (AACCI) represents the summation of 19 possible medical conditions, and for each decade after 40 years of age, a point is added (1 point for the age group of 50–59, 2 points for 60–69, 3 points for 70–79, and 4 points for 80–89 years). The study was performed in accordance to the latest version of the Declaration of Helsinki and was approved by our independent ethics committee. All patients provided written informed consent prior to treatment initiation. This retrospective study was approved by our institutional review board.
| > Results|| |
Characteristics of the patients
Of the 190 patients eligible for study analysis, 68 patients received PORT (of whom 20 [29.4%] were female and 48 [70.6%] were male) and 122 patients received DRT (of whom 36 [29.5%] were female and 86 [70.5%] were male). Compared to the DRT group, the PORT group had a lower AACCI score (2.49 ± 0.61 vs. 3.73 ± 1.28, χ2 = 7.283; P = 0.000) and higher Karnofsky Performance Scale (KPS) (χ2 = 9.016; P = 0.003) and was younger (68.90 ± 3.00 vs. 75.17 ± 5.71, χ2 = 9.925; P = 0.000). Although the baselines of the two groups were unbalanced at the T (χ2 = 7.126; P = 0.008) and N (χ2 = 13.230; P = 0.000) stages, their baseline was balanced at the clinical TNM stage (χ2 = 2.225; P = 0.136). The detailed patient and treatment characteristics are shown in [Table 1].
At the time of data cutoff, 64 of 122 patients (52.5%) in the DRT group died compared with the 40 of 68 patients (58.8%) in the PORT group. Median follow-up period for the entire cohort was 19.22 months (1–133 months) and the OS was 31.6 months. The 1-, 3-, and 5-year OS rates in the PORT group were 87.9%, 65.2%, and 53.1%, respectively. For patients in the DRT group, the 1-, 3-, and 5-year survival rates were 70.5%, 35.3%, and 22.4%, respectively. The median OS was 61.2 months (95% confidence interval [CI], 46.04–76.36) in the PORT group, which was substantially higher compared to the median OS in the DRT group (24.37 months [95% CI, 15.43–33.31], with an hazard ratio [HR] of 2.47 [95% CI, 1.56–3.91]; P = 0.000) [Figure 1]a.
|Figure 1: Overall survival by Kaplan–Meier method. (a) Overall survival in patients who received different treatment. (b) Overall survival with different T stage. (c) Overall Survival with different lymphnode metastasis. (d) Overall Survival with different TNM stage|
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In univariate analysis, OS was significantly associated with treatment method (HR: 2.47, 95% CI, 1.56–3.91; P = 0.000) [Figure 1]a, clinical T stage (HR: 0.57, 95% CI, 0.35–0.92; P = 0.021) [Figure 1]b, lymph node metastasis (HR: 0.43, 95% CI, 0.28–0.69; P = 0.000) [Figure 1]c, and clinical TNM stage (HR: 0.54, 95% CI, 0.36–0.80; P = 0.002) [Figure 1]d and [Table 2]. Considering the influence of confounding factors, multivariate analysis showed that treatment method (HR: 2.38, 95% CI, 1.46–3.90; P = 0.001), clinical T stage (HR: 0.57, 95% CI, 0.34–0.95; P = 0.031), and lymph node metastasis (HR: 0.51, 95% CI, 0.31–0.84; P = 0.008) were independent prognostic factors [Table 3].
|Table 2: Overall survival and univariate analysis of prognostic factors with Cox|
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In the PORT group, the OS was superior. This was observed across most of the predefined subgroups [Figure 2], [Figure 3], [Figure 4]. For patients with 65–70 years of age, the PORT group had an HR of 3.03 (95% CI, 1.48–6.21; P = 0.002) compared with DRT, for OS [Figure 4]. In terms of AACCI, patients with AACCI ≤3 in the PORT group had an HR of 2.18 (95% CI, 1.28–3.70; P = 0.004). OS of patients in the PORT group was also significantly higher compared to the DRT group in the T3–4 subgroup (HR: 2.98, 95% CI, 1.80–4.92; P = 0.000) and N1–2 subgroup (HR: 2.20, 95% CI, 1.26–3.83; P = 0.006) [Figure 2], [Figure 3], [Figure 4].
|Figure 2: Subgroup analysis for overall survival. (a) Overall survival of patients with age ≤75. (b) Overall survival of patients with age >75. (c) Overall survival of patients with Karnofsky>70. (d) Overall survival of patients with Age-Adjusted Charlson Comorbidity ≤3|
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|Figure 3: Subgroup analysis for overall survival. (a) Overall survival of T3-4 with DRT or PORT. (b) Overall survival of N+ with DRT or PORT. (c) Overall survival of clinical stage I-II with DRT or PORT. (d) Overall survival of clinical stage III with DRT or PORT. DRT: Definitive radiotherapy.PORT: Postoperative radiotherapy|
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| > Discussion|| |
EC is the eighth most common cancer worldwide and ranks as the sixth worst for prognosis, due to its aggressive nature and poor patient survival. Globally, SCC is still the most common type of EC with 79% of all SCC cases occurring in Asia.
Multimodal treatment is considered as the standard of care for patients with locally advanced EC. Based on encouraging results that preoperative CRT could improve the survival of patients when compared to surgery alone, preoperative chemotherapy or chemoradiation has become the standard of care for patients with locally advanced cancer of the esophagus or esophagogastric junction. The prognostic benefits of neoadjuvant chemoradiation for resectable tumor (clinical T3) have been shown in several prospective, randomized as well as in high-level retrospective matched-paired studies.,, Based on the National Comprehensive Cancer Network guidelines, PORT is recommended only for patients with a positive margin. However, in most hospitals around China, surgery is still the treatment of choice for EC patients. Treatment with PORT has been investigated for several years but remains controversial. Several meta-analysis studies have concluded that PORT significantly decreased postoperative mortality, local recurrence, and distant metastasis, with no increased postoperative complications in patients with resectable esophageal carcinoma.,, A series of large-scale retrospective studies have shown that PORT could significantly improve the OS of patients with lymph node positive and Stage III EC and was the most significant predictor of good prognosis.,,, For nonresectable tumors, definitive CRT may result in 5-year survival rates of approximately 20%. The inclusion of surgery has been shown to improve local control but not survival in locally advanced EC.
It can be speculated that a higher number of older patients will be diagnosed with esophageal carcinoma in the future. Aging is associated with a progressive loss of functional reserve, resulting in an increased prevalence of chronic diseases and debilitating conditions, called as geriatric syndromes, which often result in the underutilization of treatment options. However, a trend toward longer healthy life expectancy besides longer life expectancy exists. Therefore, studies focusing on elderly patients are necessary. While it may be true that some elderly patients are not suitable for multimodal treatment, age per se may not be a good parameter for treatment decisions. A recent Surveillance, Epidemiology, and End Results (SEER) analysis on elderly EC patients reported that elderly patients with locally advanced EC who received treatment (defined as receiving any medical or surgical therapy for EC) had improved 5-year survival rates compared to patients who were not treated. Another SEER analysis showed that, compared to patients younger than 70 years old, EC patients 70 years or older had distinctive clinical characteristics and poor survival and were less likely to be subjected to surgery or/and RT. Several studies have suggested that older age did not significantly influence the overall outcome or the complication rate in patients treated with extended esophagectomy. Weight loss, WHO performance status, and AACCI score could be used to select the appropriate treatment option for elderly patients.
In this study, elderly TESCC patients older than 65 years were selected for analysis. The age and AACCI of patients in the DRT group were higher compared to patients in the PORT group. Although there were differences in T and N stages, there were no statistical significant differences in the clinical TNM stage. Our analysis showed that the basic data for patients in the DRT and PORT group were statistically different, except for T and N. Patient ages, KPS, and AACCI were also statistically different. For patients over 75 years old and KPS <70 or AACCI >3 points, the preferred treatment was DRT, which was less invasive and better tolerated. This real-world data showed that age, KPS, and AACCI score affected the choice of treatment in elderly patients with TESCC. Performance status was used to assess the risk and choice of treatment decision. Ruol et al. demonstrated that elderly patients were more likely to select nonsurgical treatment options due to comorbidities (40% vs. 20%) compared to younger patients. In addition, several studies have demonstrated that comorbidities have a significant impact on long-term survival.,, Liu et al. found that poor pulmonary function and limited functional reserve were risk factors for higher mortality and morbidity after open esophagectomy (OE). In these studies, the value of performance status scores was discussed. Tougeron et al. demonstrated that the Charlson score could be used as a prognostic factor for median OS (13.9 ± 3.6 months' Charlson score ≤2 vs. 4.1 ± 2.6 months' Charlson score >2; HR = 2.1, 95% CI: 1.0–4.5; P = 0.046). Patients with a score ≥1 who underwent chemoradiotherapy were more likely to experience Grade 2 or higher toxicity (76.5% vs. 51.2%; P = 0.02) and chemotherapy delay (66.7% vs. 39.5%; P = 0.01). Steyerberg et al. demonstrated poorer survival in patients with a Charlson score ≥2.
This study selected patients based on the following inclusion criteria: 65 years and older with TESCC, clinical Stage I–III 7th edition of the UICC, clinically resectable, and inoperable patients. Our data showed that PORT was superior to DRT. Treatment option, T stage, and N stage were independent prognostic factors, whereas age and AACCI score were associated to treatment options but had no effect on prognosis. The study also indicated that T and N were still the main factors for survival in elderly patients with EC. Age and AACCI did not affect survival. Hence, for elderly patients with operable EC, surgery was still the first treatment option. In these patients, prediction of surgical risk, to reduce surgical complications and perioperative mortality, needs to be considered. The Comprehensive Complication Index is a promising scoring system that could be used to assess the severity of complications after esophagectomy. In recent years, measures have been taken to alleviate perioperative complications of elderly patients with EC. The introduction of minimally invasive approaches (MIE) had reduced postoperative mortality to <3%., Pulmonary complications, in particular, have been reduced using MIE versus OE. Another reason why postoperative mortality and complications have reduced after surgical resection is because of the introduction of enhanced recovery after surgery (ERAS) program.
Although PORT was shown to be superior to DRT for patients over 70 years of age with KPS ≤70 or AACCI >3, the differences were not significant. Hence, patients over 70 years of age with poor KPS and those with comorbidities may consider either PORT or DRT. For relatively younger patients in the 65–75 age group or patients with KPS >70 or AACCI ≤3, PORT was superior to DRT, and so PORT should be preferred. For patients in the T1–2 group, or the N0 group, although because of the low tumor burden, DRT and PORT achieved better results, PORT was still superior. For patients with early EC and precancerous lesions, endoscopic submucosal dissection was safe and reliable. For the T3–4 group, or patients in the N1–2 group, PORT was better compared to DRT. In the absence of surgical contraindications, surgery + PORT should be the preferred treatment option.
There are several limitations to this study. First, this was a single-institutional retrospective study without sufficient follow-up period and comprehensive information. Second, there were limitations in preoperative staging because this was a retrospective study. Many of the patients did not undergo endoscopic ultrasound and hence preoperative T staging had a certain bias, especially for patients in the DRT Group. Third, although there were no differences in clinical staging, the T staging (P = 0.008) and N staging (P = 0.000) were different. Due to the small number of patients, we did not perform propensity score matching, but performed multifactor COX regression correction. However, the results still showed that treatment, T stage, and N stage were independent prognostic factors. Fourth, due to synchronous chemotherapy and different doses, whether synchronous RT could improve the efficacy of treatment in elderly patients is uncertain. Fifth, the cause of death and the quality of life: no distinction between tumor-related death and nontumor death was investigated. Quality of life is also very important besides survival, but in our retrospective analysis, there were no accurate data on quality of life. Well-designed prospective studies need to be conducted to further investigate the potential prognostic factors for these two treatment strategies.
| > Conclusions|| |
The efficacy of PORT for elderly TESCC patients was superior to that of DRT. Treatment method, T stage, and lymph node metastasis were independent prognostic factors. This was particularly observed in patients with T3–4 or N+, where PORT was superior to DRT. Considering AACCI score, KPS, and age, DRT is still a treatment option for elderly patients with TESCC, especially for those >75 years of age.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]