Esophageal cancer is a malignancy with strong invasiveness, poor prognosis, and high incidence. Of all its patients, about 35% have entered into advanced stage when they see a doctor, so these cases lose the opportunity to receive radical treatment and thus see unsatisfactory therapeutic effects, with a 5-year survival rate <5%.[1,2] Currently, evidence-based findings are insufficient for treating this malignancy, especially for those in advanced stages. In our research, we collected clinical data of 60 patients with stage IV esophageal cancer to retrospectively analyze the relationship of therapeutic regimens and clinical features with the cancer prognosis.
2 Materials and methods
2.1 Clinical data
Sixty patients with stage IV esophageal cancer receiving initial treatment in our department between January 30, 2013 and January 30, 2018 were collected for this study. Through biopsy for specimens from gastroscopy, the patients were pathologically confirmed as squamous cell carcinoma. Clinical staging was implemented on the basis of findings from endoscopic ultrasonography combined with enhanced computed tomography (CT) or positron emission tomography (PET)/CT, and their Eastern Cooperative Oncology Group (ECOG) score was between 0 and 2. The cases consisted of 36 men and 24 women aged between 50 and 75. Of them, 22 were no >65 years old while the others over this figure. Besides, 26 cases had lesions at neck and upper thoracic sections, and the others showed lesions at mid- and lower-thoracic sections. Before treatment, malnutrition was detected in 36 patients while the figure for anemia was 38. Of all patients, 33 underwent combined regimen of radiotherapy and chemotherapy, and the others only received chemotherapy. Stent installment was operated for 12 cases. And 38 patients simultaneously had visceral metastasis (not including distant nodal metastasis, simple bone metastasis, or cerebral metastasis), while the others had none. This study was supported by the Research Ethics Committee of Anqing Hospital Affiliated to Medical University of Anhui. All study subjects signed written informed consents before enrollment.
Staging criteria: According to Tumor Node Metastasis (TNM) Classification for esophageal cancer, 8th ed by Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) in 2017, stage IV esophageal cancer contains T4aN1-2M0, T4bNxM0, TxN3M0, and TxNxM1.
2.3 Prognostic nutritional index
Prognostic nutritional index (PNI) is a simple index only containing 2 parameters of peripheral blood, namely serum albumin (ALB) and total lymphocyte count (TLC), and calculated via the following equation: PNI = ALB (g/L) + 5 × TLC (109/L). PNI ≥45 meant normal nutritional status for patients.
2.4 Diagnostic criteria for anemia
In the light of Chinese clinical practise and therapeutic methods, anemia refers to hemoglobin (Hb) <120 g/L in men and Hb <110 g/L in women.
2.5 Chemotherapy regimen
All of 60 patients received combined chemotherapy for at least 4 cycles, with 23 taking DF (cisplatin+fluorouracil) regimen while 37 bearing TP (cisplatin+paclitaxel) scheme. Specifically, of 9 patients undergoing concurrent chemoradiotherapy, 6 orally took tegafur gimeracil and oteracil potassium during radiotherapy and adopted DF regimen for consolidation chemotherapy; while the other 3 experienced TP regimen weekly during their radiotherapy and accepted TP for consolidation. Of 24 patients facing sequential chemoradiotherapy, 14 encountered TP regimen while the others bore DF scheme. Among those only receiving chemotherapy, 20 had TP and 7 took DF.
2.6 Radiotherapy plan
All of the patients experienced three-dimensional conformal or intensity modulated radiotherapy. Total prescription dose was 54 to 60 Gy, and conventionally divided into 1.8 to 2.0 Gy each time per day, 5 times a week. Relevant requirements were as follows: 95% of planning target volume (PTV) were irradiated through 100% of the above mentioned prescribed dose, with whole lungs V5 ≤55% to 60%, V20 ≤25% to 30%, V30 ≤18%, heart Dmean ≤30 Gy, and spinal cord Dmax <45 Gy.
2.7 Observational index
Survival time was calculated during the period between initial chemotherapy or radiotherapy and the end date of follow-up: August 1, 2018. The influences of clinical features and therapy-related factors on prognosis were monitored.
2.8 Statistical method
SPSS 17.0 (SPSS, Inc., Chicago, IL) software was employed for statistical analyses, while Kaplan–Meier method was adopted to calculate overall survival (OS) and to plot survival curves. Log-rank tested P values and completed univariate prognosis analysis. And multivariate Cox regression model was applied for prognosis analysis. P < .05 stood for the presence of statistical significance in differences.
3.1 Univariate analysis
Univariate analysis was conducted for sex, age, lesion location, pretreatment nutritional status, with or without anemia before therapy, anti-tumor therapeutic method, with or without esophageal stent before therapy, and with or without combined visceral metastasis.
Median survival time was compared between men (n = 36) and women (24), and the result showed no significant difference (P = .074), indicating sex had no obvious influence on the prognosis of stage IV esophageal cancer.
Among 60 patients, 23 were no >65 years old while 37 exceeded this figure. Comparison on median survival between the 2 groups revealed no significant difference (P = .242), suggesting age harbored no substantial influence on the prognosis of stage IV esophageal cancer.
Of 60 patients, 34 had lesions at mid- and lower-thoracic sections while the others at neck and upper thoracic sections. Between these 2 groups, median survival time displayed no statistical difference (P = .579), demonstrating the location of primary focus possessed no significant effect on the prognosis of stage IV esophageal cancer.
Before therapy, 60 patients were classified into mulnutrition (n = 36) and normal nutrition (n = 24) groups. According to comparison findings, prognosis was poorer in mulnutritional group than in normal nutrition group, and difference between the 2 groups was statistically significant (P = .003).
Pretreatment anemia was observed in 38 patients while the others (n = 22) had no such symptom. The prognosis in anemia group was more miserable than the other group according to their median survival, showing statistical difference between the 2 groups (P < .001).
Among the patients, 33 adopted combined regimen of radiotherapy with chemotherapy while the other 27 ones received only chemotherapy. In comparing median survival, combination regimen group exhibited significantly better prognosis than chemotherapy-only group (P < .001).
Sixty patients were divided into 2 groups according to with (n = 38) or without (22) visceral metastasis. After comparing their median survival, we saw poorer prognosis for metastasis group than that without metastasis, and the difference was statistically significant (P < .001).
Esophageal stent was installed for 12 of our studied patients, while the others had none. According to result from comparing median survival, cases with the stent experienced poorer prognosis than those without the stent, showing statistical difference (P < .001).
All of the above findings demonstrated that nutritional status, anemia, therapeutic method, esophageal stent, and visceral metastasis were major factors affecting the prognosis of stage IV esophageal cancer (P = .003, P < .001, P < .001, P < .001, P = .002, respectively) (Table 1 and Figs. 1–8).
3.2 Multivariate Cox regression model analysis
Multivariate Cox regression analysis embraced all of the 5 elements exhibiting significant influences on prognosis in univariate analysis, namely nutritional status, anemia, therapeutic method, esophageal stent, and visceral metastasis. As a result, only visceral metastasis showed statistically significant influence on patients’ prognosis (P = .032, Table 2).
Esophageal cancer shows high incidence in China, with >90% of the cases as squamous carcinoma. This malignancy sees relatively poor prognosis, because even invasion into submucosa could lead to lymphatic distant metastasis or widespread skipping metastasis regardless of the cancer stage, owing to abundant lymphoid tissues in esophageal wall. Esophageal cancer mainly attacks people in remote rural regions, with evil dietary habits (like taking moldy, salted, hot, and high-salt foods) as its high risk factors. Restrained to medical conditions, patients in early stage generally ignore their choking when they eat, and when they see a doctor for the first time after developing evident symptoms, about 35% of them have been in stage IV, thus losing the opportunity for radical cure. Besides, most patients would develop mulnutrition due to difficulty in swallowing, and then their constitutions become weak, even unable to suffer systemic chemotherapy, facing extremely short survival time.[1,2]
In this study, we collected clinical data on 60 patients who were diagnosed as stage IV esophageal cancer, and then retrospectively analyzed the relationships of the patients’ clinical features and therapeutic methods with their prognosis. In univariate analysis, patients’ age, sex, or the location of esophageal lesion exhibited no relationship with prognosis. In comparing patients with and without anemia before therapy, we adopted Kaplan–Meier curve method to calculate OS and to plot survival curves, using Log-rank for testing, and found statistical difference between the 2 groups, indicating anemia acted as a risk factor for poor prognosis in esophageal cancer patients at advanced stage. According to current clinical researches, anemia affects not only radiotherapeutic and chemotherapeutic effects on esophageal cancer patients but also impacts the cases’ quality of life and survival time.[6–8]
In recent years, many indexes have been employed to assess nutritional status, like body mass index (BMI), Glasgow prognosis score, and PNI. Among others, PNI represents a relatively mature one in practical application, and offers a simpler and more convenient testing method. Therefore, we employed PNI in this study to evaluate pre-therapy nutritional status for patients with stage IV esophageal cancer. As a result, of total 60 patients, 38 were malnourished while the others well-nourished. For these 2 groups, Kaplan–Meier method was applied to calculate their OS and to establish corresponding survival curves. In Log-rank test, statistical difference was detected between the groups, suggesting malnutrition functioned as a risk factor for poor prognosis among patients with advanced esophageal cancer. Up to now, accumulating documents have confirmed that among esophageal cancer patients, malnutrition significantly increases adverse responses to chemotherapy and is also a trigger of poor prognosis.[4,6,8]
Treatment for stage I esophageal cancer mainly relies on surgery, while for patients with stage II and III cancer, universally accepted approach refers to comprehensively multi-disciplinary mode combining radiotherapy, chemotherapy, and surgery.[9,10] As for cases with stage IV esophageal cancer, whether local radiotherapy or esophageal stent should be adopted to alleviate patients’ difficulty in eating and whether these applications could prolong patients’ survival have been discussed by Lyu et al. In their retrospective research on stage IV esophageal cancer, the scholars compared therapeutic effects between concurrent radiochemotherapy and chemotherapy alone. As a result, median survival time reached 14 months in concurrent radiochemotherapy group and 11 months in chemotherapy-alone group, with statistical difference, manifesting concurrent radiochemotherapy could significantly prolong median survival for patients with stage IV esophageal cancer. Among 60 patients with advanced esophageal cancer in this study, 33 adopted extra radiotherapy for esophageal lesions, and only 9 of them received concurrent radiochemotherapy while the others underwent sequential radiotherapy and chemotherapy. According to corresponding analysis, median survival time reached 10 months among patients experiencing additional radiotherapy, and the figure was merely 8 months in those taking chemotherapy alone, showing statistical difference. Such findings suggested radiotherapy regimen could improve survival time for cases with stage IV esophageal cancer. Local radiotherapy can solve the problem of eating obstruction, and then further improve patients’ nutritional status, thus benefiting their survival. In that way, whether local installation of esophageal stent could also improve patients’ survival still should be probed, considering that such operation similarly relieves difficulty in swallowing. In the retrospective study by Lu et al on esophageal cancer, the incidence rate of esophageal fistula was compared between chemoradiotherapy combined with stent installation and chemoradiotherapy alone. As a result, such incidence rate achieved 87.5% in the group adopting stent and only 2.6% in the group without stent, showing statistically significant difference. Moreover, in their study, median survival time was 6 months in combination group and up to 16 months in the latter group, suggesting higher morbidity of esophageal fistula and higher mortality due to stent installation. In 12 cases with esophageal stent in our research, 10 showed chest pain, 6 developed esophageal fistula, and 3 had massive hemorrhage. Among 6 patients taking simultaneous radiotherapy, 5 developed esophageal fistula while 2 showed massive hemorrhage, with a median survival time of 7 months. And median survival was 9 months in the group without stent, exhibiting statistical difference between the groups with and without the stent. In other words, our findings also supported that median survival was obviously lower in stent group than in the group without stent, and that patients’ living quality was dramatically decreased in stent group as well. Yu et al compared the influences on patients’ nutritional status between stent installation, nasal feeding, and gastrostomy feeding during chemoradiotherapy. Consequently, the degrees of chest pain and ALB decrease were dramatically higher in patients adopting stent installation than in other groups, indicating that esophageal stent was unsuitable during chemoradiotherapy. In the present study, we observed a similar incidence rate of esophageal fistula to that in the research by Lu et al. And numerous studies have demonstrated that stent installation in esophageal cancer patients not only reduces their living quality but also possibly shortens their survival period. Therefore, we recommend that esophageal stent should be cautiously adopted among patients preparing for chemoradiotherapy.
Stage is a main influencing factor for the prognosis of all solid tumor patients. Focusing on patients with stage IV esophageal cancer, a study from Japan explored whether visceral metastasis could affect patients’ prognosis. Accordingly, among esophageal cancer patients receiving chemoradiotherapy for T4 and/or M1, the prognosis was obviously better in cases without M1 than those with M1. And in our research, median survival time was 8 months in patients with visceral metastasis and 10 months in those without metastasis, showing statistical difference, which also implied that visceral metastasis represented an adverse effector on prognosis among patients with stage IV esophageal cancer.
In the present study, Cox risk regression mode also encompassed all of the 5 components into analysis, which exhibited significant influences on patients’ prognoses in univariate analysis, namely anemia, therapeutic method, visceral metastasis, and esophageal stent. And relevant result presented that only visceral metastasis was related to poor prognosis among patients with stage IV esophageal cancer. Lacking significant impact for the other 4 aspects in multivariate analysis might be explained by the fact that as treatments begin to take effects and tumors shrink, anemia, and mulnutrition before therapy might be corrected to a certain degree. As for the impact of extra radiotherapy added in treatment on patients’ prognosis, some existing researches claimed that concurrent chemoradiotherapy could elevate the survival of patients with stage IV esophageal cancer when compared with chemotherapy alone. In our study, among 33 patients receiving chemoradiotherapy, only 9 adopted concurrent chemoradiotherapy, while 6 cases with esophageal stent took radiotherapy; all of these mentioned individuals developed severe complications which significantly affected median survival time of the patients adopting chemoradiotherapy. Therefore, the influence of radiotherapy on the survival of patients with stage IV esophageal cancer could not been determined yet, which need to be further explored by prospective studies with larger sample sizes. Until now, only retrospectively clinical researches have ever discussed the impact of esophageal stent installation on the prognosis of esophageal cancer patients, lacking findings from prospective studies. Since in our research only 12 patients had esophageal stent, a small number for analysis, we could not statistically regarded the stent as a risk factor for poor prognosis. But esophageal stent installation did obviously increase the incidence rate of esophageal fistula and chest pain, gravely affecting patients’ living quality.
In the current study, both univariate and multivariate analyses indicated visceral metastasis as an independent risk factor for poor prognosis of patients with stage IV esophageal cancer. Hence, we should proceed thorough evaluation on patients showing poor prognosis, and discretely consider whether active comprehensive therapeutic regimen could be employed. For stage IV esophageal cancer patients with PS score between 0 and 2 and free from visceral metastasis, we recommend concurrent chemoradiotherapy or sequential radiotherapy and chemotherapy; and esophageal stent installation should be avoided among patients preparing for chemoradiotherapy. Optimizing therapeutic mode possesses certain clinical significance in prolonging survival time and in improving patients’ living quality among cases with stage IV esophageal cancer.
Conceptualization: Chenghui Li.
Data curation: Chenghui Li, Qian Jiang.
Formal analysis: Chenghui Li, Zhiqiu Wang.
Funding acquisition: Chenghui Li, Aixiong Duan, Qian Jiang.
Investigation: Zhiqiu Wang.
Methodology: Chenghui Li, Zhiqiu Wang.
Project administration: Chenghui Li.
Resources: Zhiqiu Wang, Aixiong Duan, Qian Jiang.
Software: Chenghui Li, Zhiqiu Wang, Aixiong Duan.
Supervision: Aixiong Duan, Qian Jiang.
Validation: Chenghui Li, Zhiqiu Wang, Aixiong Duan.
Visualization: Qian Jiang.
Writing – original draft: Zhiqiu Wang, Qian Jiang.
Writing – review & editing: Chenghui Li, Zhiqiu Wang.
. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115–32.
. Zhang Y. Epidemiology of esophageal cancer. World J Gastroenterol 2013;19:5598–606.
. Rice TW, Ishwaran H, Ferguson MK, et al. Cancer of the esophagus and esophagogastric junction: an eighth edition staging primer. J Thorac Oncol 2017;12:36–42.
. Nakatani M, Migita K, Matsumoto S, et al. Prognostic significance of the prognostic nutritional index
in esophageal cancer patients undergoing neoadjuvant chemotherapy. Dis Esophagus 2017;30:1–7.
. Tachimori Y. Pattern of lymph node metastases of squamous cell esophageal cancer based on the anatomical lymphatic drainage system: efficacy of lymph node dissection according to tumor location. J Thorac Dis 2017;9:S724–30.
. Wang Q, Wang J, Wang Y. Effect of nutritional status and inflammatory markers on acute adverse reactions during concurrent chemoradiotherapy for esophageal carcinoma. Chin J Radiat Oncol 2017;26:1012–8.
. Yafei N, Ren C, Jikai X. The incidence of anemia in 386 patients with esophageal carcinoma undergoing radiotherapy and its effect on prognosis. Cancer Res Clin 2015;27:690–3.
. Yu FJ, Shih HY, Wu CY, et al. Enteral nutrition and quality of life in patients undergoing chemoradiotherapy for esophageal carcinoma: a comparison of nasogastric tube, esophageal stent
, and ostomy tube feeding. Gastrointest Endosc 2018;88:21.e4–31.e4.
. Courrech Staal EF, Aleman BM, Boot H, et al. Systematic review of the benefits and risks of neoadjuvant chemoradiation for oesophageal cancer. Br J Surg 2010;97:1482–96.
. Hara H, Tahara M, Daiko H, et al. Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma. Cancer Sci 2013;104:1455–60.
. Lyu J, Li T, Wang Q, et al. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for stage IV esophageal squamous cell carcinoma: a retrospective controlled study. Radiat Oncol 2018;13:233.
. Lu YF, Chung CS, Liu CY, et al. Esophageal metal stents with concurrent chemoradiation therapy for locally advanced esophageal cancer: safe or not? Oncologist 2018;23:1426–35.
. Jingu K, Umezawa R, Matsushita H, et al. Chemoradiotherapy for T4 and/or M1 lymph node esophageal cancer: experience since 2000 at a high-volume center in Japan. Int J Clin Oncol 2016;21:276–82.