ABSTRACT
Background
The efficacy of consolidation chemotherapy (CCT) following concurrent chemoradiotherapy (CCRT) has not been clearly defined in esophageal squamous cell carcinoma (ESCC). This study determined which patients with stage II‐IVA ESCC benefitted from CCT.
Methods
351 patients with ESCC were retrospectively reviewed. 185 patients received CCRT alone and 166 received CCRT plus CCT. Subset analyses were conducted on all patients' characteristics. Factors associated with survival were analyzed using the Kaplan–Meier method and a Cox proportional hazards model. The Propensity score matching (PSM) technique was used to compensate for differences in patients' characteristics.
Results
The median OS were 17.7 months and 38.4 months in the CCRT alone group and CCRT+CCT group (p = 0.002), respectively. Multivariable Cox regression analysis determined that CCT was associated with improved OS (p = 0.002, HR 0.592, 95% CI 0.423–0.829); After PSM, relative to the CCRT group, patients who received CCT experienced improved OS (17.7 months vs. 38.4 months, p = 0.0139). Subgroup analysis showed that CCT was more effective in radiation dose < 60 Gy (p = 0.002, HR 0.368, 95% CI 0.194–0.700). After matching between radiation dose, in the low dose cohort, the median OS was 13.2 months and 20.7 months in the CCRT alone group and CCRT+CCT group, respectively (p = 0.0028), the multivariate analysis results showed that CCT retained its statistical significance (p = 0.002, HR 0.353, 95% CI 0.183–0.681). In the high dose cohort, the median OS were 21.6 months and 23.6 months in the CCRT alone group and CCRT+CCT group, respectively (p = 0.5512).
Conclusions
We recommend that CCT treatment should be considered for ESCC patients who underwent CCRT using < 60 Gy. Further studies are needed to confirm these results.
Keywords: chemoradiotherapy, consolidation chemotherapy, ESCC
Abbreviations
- 2D‐CRT
2‐dimensional conformal radiotherapy
- 3D‐CRT
3‐dimensional conformal radiotherapy
- AJCC
American Joint Committee on Cancer
- CCRT
concurrent chemoradiotherapy
- CCT
consolidation chemotherapy
- CT
computerized tomography
- CTV
clinical target volume
- ESCC
esophageal squamous cell carcinoma
- EUS
endoscopic ultrasonography
- GTV
gross tumor volume
- IMRT
intensity‐modulated radiotherapy
- PSM
Propensity score matching
- PTV
planning target volume
1. Introduction
In China, esophageal cancer has emerged as the third most common malignant tumor and the fourth leading cause of cancer deaths. The annual incidence rate of ESCC is 477.9 per 100 000 people, while the standard mortality rate is 375.0 per 100 000 people [1]. Esophageal squamous cell carcinoma (ESCC) is the major type of esophageal cancer in China and accounts for half of all global ESCC cases [2].
The results of the prospective, randomized Chemoradiotherapy for Esophageal Cancer (CROSS) trial suggest that neoadjuvant chemoradiotherapy plus surgery should be the standard of care for patients with resectable locally advanced esophageal cancer [3]. Concurrent chemoradiotherapy (CCRT) is an alternative to surgery in select circumstances: patients with cervical tumors, unresectable tumors that were diagnosed at a late stage which are, as well as not suitable for surgery due to poor general condition [4]. However, the outcomes of CCRT in patients with esophageal cancer were not satisfactory. These patients had an overall median survival time of 11.2–34.5 months as determined in previous perspective trials [5, 6, 7, 8, 9, 10, 11, 12]. Even though intensity‐modulated radiotherapy (IMRT) has demonstrated superiority in dosimetric conformity compared with 2‐dimensional conformal radiotherapy (2D‐CRT) and 3‐dimensional conformal radiotherapy (3D‐CRT) [13], many esophageal cancer patients treated with IMRT still experienced relapse (50%) and metastasis (48%) [14].
In landmark studies, consolidation chemotherapy (CCT) has been introduced to improve patients' survival after CCRT, which involved two cycles of CCT followed by two cycles concurrent chemotherapy using the same regimen [9, 15, 16]. In contrast, CCT was not adopted in others studies for reasons that has not yet been clarified [10, 17]. As far as we know, the efficacy of CCT after CCRT in ESCC has not been assessed in randomized controlled trial, while retrospective studies reported different outcomes due to inherent bias [18, 19, 20, 21]. However the survival benefits of CCT in certain subgroups has not been previously reported. In this study, we retrospectively assessed the role of CCT for patients with ESCC who received CCRT to identify which patients would benefit from it.
2. Patients and Methods
2.1. Patients and Pretreatment Evaluation
For this retrospective study, we enrolled a consecutive series of ESCC patients who underwent definitive chemoradiotherapy at The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital and Tianjin Medical University Cancer Institute & Hospital between March 1, 2018 and September 31, 2022. Our study protocols were approved by the Zhengzhou University.
All patients had pretreatment evaluation that included a complete blood count, serum chemistry, endoscopic ultrasonography (EUS), barium swallow radiography, external ultrasonography of the neck, and a thoraco‐abdominal computerized tomography (CT) scan and PET/CT when available. Before initiation of treatment, each patient was evaluated by a multidisciplinary team. Patients with curative intent but with unresectable tumors were treated with CCRT.
The inclusion criteria were defined as follows: an ESCC diagnosis with pathological evidence, an age ≥ 18 years, and American Joint Committee on Cancer (AJCC) 8th clinical stages II‐IVA without metastasis, treated with CCRT of no less than 40 Gy. The exclusion criteria were: a history of cancer before ESCC diagnosis, distant metastasis, unclear staging, a non‐ESCC histology, or the patients received other treatment before CCRT.
2.2. Treatment
Radiation was delivered by using IMRT. The gross tumor volume (GTV) was defined as the primary tumor and positive lymph nodes on CT and EUS. The clinical target volume (CTV) was defined as the primary tumor plus 3 cm proximal and distal margins and a radial margin of 1.0 cm. The nodal CTV (CTVn) was defined as the nodal GTV (GTVn) plus a 1.0‐cm expansion. CTVn also encompassed the region draining the lymphatics based on the discretion of radiation oncologists. The planning target volume (PTV) was determined by adding a 0.5 cm margin to the CTV. The PTV was covered by at least 95% isodose surface. The maximum dose within the PTV was not allowed to exceed 110% of the prescribed dose. The organs at risk for treatment planning included: lungs (the volume of lung receiving 20 Gy was ≤ 30%, and V30 ≤ 20%), heart (the volume of heart receiving 40 Gy was ≤ 30%), and the spinal cord (the maximum dose was ≤ 45Gy). The median total dose and fraction size of radiotherapy in the low dose group and high dose group were 50.0 Gy (40–59.4 Gy, fraction size: 1.80–2.00 Gy) and 60.0 Gy (60.0–70.0 Gy, fraction size: 2.00 Gy), respectively.
Different concurrent chemotherapy regimens were administered during the study period. The majority of study patients received paclitaxel or docetaxel/cisplatin(65.8%), followed by fluorouracil/cisplatin (21.4%), and others (12.8%). CCT was conducted with the same regimen between 4 and 6 weeks after the completion of radiotherapy if patients did not present local progression or distant metastases. The median numbers of treatment cycles were 3 and 2 for concurrent chemotherapy and CCT.
2.3. Evaluation and Follow‐Up
After completion of CCRT, patients were subsequently evaluated every 3 months during the first year, then every 6 months until 5 years. During follow‐up visits, clinical examinations included a complete blood count, serum chemistry blood tests, periodic EUS, barium swallow radiography, ultrasonography of the neck, thoraco‐abdominal CT, and PET/CT when available. Recurrences and metastasis were established using histologic, cytologic, or explicit radiologic proof. After the period of clinical follow up, recurrence and survival data were obtained by telephone from the patient or the patients' family practitioner. The data was last updated in September, 2023. The median follow‐up time was 28.1 months.
2.4. Statistical Analysis
We compared overall survival (OS) in this study, since OS is the gold standard to judge the curative effect of cancer patients [22]. The OS was calculated from the beginning of CCRT until death from any cause or the last follow‐up. The survival curves were constructed using the Kaplan–Meier method. Differences between the curves were analyzed using the log‐rank test. Univariate and multivariate analyses using a Cox‐proportional hazards model were performed to evaluate potential prognostic factors for OS. Hazard ratios were calculated with the use of a Cox regression model including treatment alone (primary analysis) and after adjustment for baseline stratification factors. Either the Chi‐square or the Fisher exact test was used for categorical data. PSM (including age, sex, tumor location, Karnofsky scale, weight loss, tumor length, T stage, N stage, radiation dose) was performed to minimize the effects of treatment selection bias and potential confounding factors. All patients in the CCRT group were matched at a ratio of 1:1 to those in the CCRT+CCT group according to the propensity scores by means of the global optimum method. All P values are two‐sided. p values of less than 0.05 were considered to indicate statistical significance. Statistical calculations were performed using SPSS software (version 24.0).
3. Results
3.1. Patient Characteristics
We enrolled 351 patients with ESCC who did not have distant metastases and received CCRT (Table 1). The majority of patients were male (86.0%). The median age of the whole group was 62 years (range, 34–80 years). These patients had tumors located in the cervical, the upper, middle, or lower thoracic regions were 39(11.1%), 129(36.8%), 153(43.6%), and 30(8.5%), respectively. 98(27.9%) of patients had weight loss before treatment, and 256(72.9%) of patients had tumor length ≥ 4.5 cm. 244(63.8%) of patients had clinical T4 disease. 116(33.0%) received radiotherapy < 60Gy (median: 50.0 Gy, mean: 49.9 Gy, 36–59.40 Gy) and 235(67.0%) received radiotherapy ≥ 60 Gy (median: 60.0 Gy, mean: 60.7 Gy, 60–70 Gy) with IMRT. Among these patients, 185(52.7%) received CCRT alone (CCRT group) and 166(47.3%) received CCRT plus CCT (CCRT+CCT group).
TABLE 1.
Clinical characteristics and survival‐related factors of 351 patients with ESCC in univariate and multivariate analysis.
| Characteristic | Patients, no. (%) | Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|---|---|
| 1‐year (%) | 2‐year (%) | 3‐year (%) | Median (month) | p | p | |||
| Sex | ||||||||
| Male | 302 (86.0) | 50 | 45 | 40 | 22.6 | 0.953 | ||
| Female | 49 (14.0) | 47 | 45 | 41 | 22.4 | |||
| Age at diagnosis (y) | ||||||||
| < 65 | 239 (68.1) | 52 | 49 | 47 | 24.6 | 0.095 | ||
| ≥ 65 | 112 (31.9) | 46 | 38 | 23 | 19.0 | |||
| Tumor location | ||||||||
| Cervical | 39 (11.1) | 56 | 49 | 43 | 40.4 | 0.186 | ||
| Upper thoracic | 129 (36.8) | 53 | 48 | 43 | 31.7 | |||
| Middle thoracic | 153 (43.6) | 46 | 41 | 37 | 18.3 | |||
| Lower thoracic | 30 (8.5) | 47 | 37 | 30 | 22.5 | |||
| Karnofsky scale | ||||||||
| 60–80 | 130 (37.0) | 53 | 45 | 36 | 26.8 | 0.785 | ||
| ≥ 90 | 221 (63.0) | 48 | 45 | 39 | 21.6 | |||
| Weight loss | ||||||||
| No | 253 (72.1) | 52 | 46 | 38 | 24.8 | 0.020 | 1.523 (1.059–2.190) | 0.023 |
| Yes | 98 (27.9) | 38 | 32 | 27 | 16.4 | |||
| Tumor length | ||||||||
| < 4.5 cm | 95 (27.1) | 60 | 51 | 42 | 39.5 | 0.027 | ||
| ≥ 4.5 cm | 256 (72.9) | 43 | 39 | 35 | 18.3 | |||
| T classification | ||||||||
| T2 | 26 (7.4) | 75 | 53 | 32 | 40.5 | 0.057 | 1.363 (1.028–1.807) | 0.031 |
| T3 | 111 (31.6) | 54 | 49 | 45 | 26.8 | |||
| T4 | 214 (61) | 45 | 40 | 37 | 18.8 | |||
| N classification | ||||||||
| N0 | 82 (23.4) | 62 | 56 | 50 | 38.4 | 0.009 | 1.342 (1.114–1.616) | 0.002 |
| N1 | 134 (38.2) | 54 | 50 | 46 | 26.8 | |||
| N2 | 112 (31.9) | 37 | 33 | 31 | 17.4 | |||
| N3 | 23 (6.6) | 40 | 24 | 14 | 12.9 | |||
| Radiation dose | ||||||||
| < 60 Gy | 116 (33.0) | 40 | 37 | 33 | 17.4 | 0.024 | ||
| ≥ 60 Gy | 235 (67.0) | 54 | 47 | 40 | 28.0 | |||
| Consolidation chemotherapy | ||||||||
| No | 185 (52.7) | 45 | 37 | 30 | 17.7 | 0.002 | 0.592 (0.423–0.829) | 0.002 |
| Yes | 166 (47.3) | 55 | 52 | 49 | 38.4 | |||
3.2. Univariate and Multivariate Cox Proportional Hazard Analysis
The 1, 2, and 3‐year OS rates were 50%, 44% and 40% for the entire study population. The median OS was 22.6 months. In the CCRT alone group, the 1, 2, and 3‐year OS rates were 45%, 37%, 30%; in the CCRT+CCT group, the 1, 2, and 3‐year OS rates were 55%, 52%, 49% (Table 1). The median OS were 17.7 months and 38.4 months in the CCRT alone group and CCRT+CCT group (p = 0.002), respectively (Figure 1A). Univariate analysis demonstrated that weight loss, tumor length, N classification, radiation dose, and CCT were significant predictive prognostic factors for OS. All variables were then put into a multivariate Cox proportional hazard analysis and the results showed that CCT was associated with an improved OS (p = 0.002, HR 0.592, 95% CI 0.423–0.829). In addition, weight loss, T classification, and N classification were associated with an increased risk of death.
FIGURE 1.
Kaplan–Meier survival curves for the CCRT plus CCT group and the CCRT alone group. (A) Overall survival for entire group. (B) Overall survival after matching. CCRT: Concurrent chemoradiotherapy; CCT: Consolidation chemotherapy. p values were calculated by the unadjusted log‐rank test.
3.3. Survival After Matching Propensity Scores
Before matching, compared with the patients in CCRT group, a greater number of patients in the CCRT+CCT group were < 65 years (75.3% vs. 61.1%), had tumors located in cervical (11.4% vs. 10.8%) and upper thoracic areas (45.2% vs. 29.2%), with Karnofsky scale ≥ 90 (73.5% vs. 53.5%), and received radiotherapy ≥ 60 Gy (71.9% vs. 61.6%), (Table 2). After matching, patients characteristics were balanced between the high dose and low dose cohorts (p > 0.05), each group consisted of 123 patients. Relative to the CCRT group, patients who received CCT experienced improved OS (17.7 months vs. 38.4 months, p = 0.0139), (Figure 1B).
TABLE 2.
Clinical characteristics of 351 patients in the CCRT and CCRT+CCT groups after propensity score matching.
| Characteristic | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| CCRT (N = 185) | CCRT+CCT (N = 166) | p | CCRT (N = 123) | CCRT+CCT (N = 123) | p | |
| Sex | ||||||
| Male | 159 | 143 | 0.957 | 109 | 103 | 0.268 |
| Female | 26 | 23 | 14 | 20 | ||
| Age at diagnosis (y) | ||||||
| < 65 | 114 | 125 | 0.006 | 87 | 86 | 0.889 |
| ≥ 65 | 71 | 41 | 36 | 37 | ||
| Tumor location | ||||||
| Cervical | 29 | 19 | 0.004 | 17 | 13 | 0.466 |
| Upper thoracic | 54 | 75 | 42 | 50 | ||
| Middle thoracic | 89 | 64 | 52 | 53 | ||
| Lower thoracic | 22 | 8 | 17 | 7 | ||
| Karnofsky scale | ||||||
| 60–80 | 86 | 44 | < 0.001 | 48 | 42 | 0.427 |
| ≥ 90 | 99 | 122 | 75 | 81 | ||
| Weight loss | ||||||
| No | 127 | 126 | 0.130 | 96 | 88 | 0.240 |
| Yes | 58 | 40 | 27 | 35 | ||
| Tumor length | ||||||
| < 4.5 cm | 45 | 55 | 0.222 | 24 | 32 | 0.224 |
| ≥ 4.5 cm | 140 | 116 | 99 | 91 | ||
| T classification | ||||||
| T2 | 14 | 12 | 0.847 | 12 | 10 | 0.610 |
| T3 | 56 | 55 | 35 | 42 | ||
| T4 | 115 | 99 | 76 | 71 | ||
| N classification | ||||||
| N0 | 47 | 35 | 0.402 | 29 | 32 | 0.873 |
| N1 | 66 | 68 | 44 | 47 | ||
| N2 | 57 | 55 | 41 | 37 | ||
| N3 | 15 | 8 | 9 | 7 | ||
| Radiation dose | ||||||
| < 60 Gy | 71 | 45 | 0.025 | 34 | 42 | 0.270 |
| ≥ 60 Gy | 114 | 121 | 99 | 81 | ||
3.4. Subgroup Analysis
The results of subgroup analyses of overall survival are shown in Table 3. CCT was more effective in males (p = 0.001, HR 0.535, 95% CI 0.371–0.772), age < 65 years (p = 0.004, HR 0.564 95% CI 0.374–0.860), Karnofsky scale ≥ 90 (p = 0.001, HR 0.499, 95% CI 0.323–0.772), Tumor length ≥ 4.5 cm (p = 0.005, HR 0.570, 95% CI 0.383–0.848), T4 stage (p = 0.001, HR 0.500, 95% CI 0.327–0.764), radiation dose < 60 Gy (p = 0.002, HR 0.368, 95% CI 0.194–0.700). The OS was 24.8 months/13.2 months (CCRT+CCT group/CCRT alone group) in patients with radiation dose < 60 Gy (Figure 2A). The OS was not significantly different in the ≥ 60 Gy cohort (Figure 2B).
TABLE 3.
Univariate hazard ratio plots for treatment effect on overall survival by baseline characteristics (HR < 1 favors consolidation chemotherapy).
|
FIGURE 2.
Kaplan–Meier survival curves for the CCRT plus CCT group and the CCRT alone group subgroup by radiation dose. (A) Overall survival for low dose cohort. (B) Overall survival for high dose cohort. (C) Overall survival for low dose cohort after matching. (D) Overall survival for high dose cohort after matching. CCRT: Concurrent chemoradiotherapy; CCT: Consolidation chemotherapy. p values were calculated by the unadjusted log‐rank test.
3.5. PSM According to Radiation Dose
After matching, patients characteristics were balanced between the high dose and low dose cohort (p > 0.05), (Table 4). Each group consisted of 110 patients. In the low dose cohort, 45 received CCT, the median OS for this cohort was 13.2 months and 20.7 months in the CCRT alone group and CCRT+CCT group, respectively (p = 0.0028), the multivariate analysis results showed that CCT retained its statistical significance (p = 0.002, HR 0.353, 95% CI 0.183–0.681) (Table 5, Figure 2C). In the high dose cohort, 42 patients received CCT. In this cohort the median OS was 21.6 months and 23.6 months in the CCRT alone group and CCRT+CCT group, respectively (p = 0.5512), (Figure 2D).
TABLE 4.
Clinical characteristics of 351 patients in the low dose and high dose groups after propensity score matching.
| Characteristic | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Low dose (N = 116) | High dose (N = 235) | p | Low dose (N = 110) | High dose (N = 110) | p | |
| Sex | ||||||
| Male | 102 | 200 | 0.473 | 96 | 94 | 0.694 |
| Female | 14 | 35 | 14 | 16 | ||
| Age at diagnosis (y) | ||||||
| < 65 | 76 | 163 | 0.467 | 72 | 72 | 1.000 |
| ≥ 65 | 40 | 42 | 38 | 38 | ||
| Tumor location | ||||||
| Cervical | 7 | 32 | 0.012 | 7 | 12 | 0.115 |
| Upper thoracic | 36 | 93 | 36 | 31 | ||
| Middle thoracic | 64 | 89 | 60 | 51 | ||
| Lower thoracic | 9 | 21 | 7 | 16 | ||
| Karnofsky scale | ||||||
| 60–80 | 41 | 89 | 0.645 | 41 | 42 | 0.889 |
| ≥ 90 | 75 | 146 | 69 | 68 | ||
| Weight loss | ||||||
| No | 77 | 176 | 0.094 | 77 | 74 | 0.663 |
| Yes | 39 | 59 | 33 | 36 | ||
| Tumor length | ||||||
| < 4.5 cm | 25 | 70 | 0.102 | 25 | 25 | 1.000 |
| ≥ 4.5 cm | 91 | 165 | 85 | 85 | ||
| T classification | ||||||
| T2 | 7 | 19 | 0.787 | 7 | 8 | 0.493 |
| T3 | 37 | 74 | 36 | 28 | ||
| T4 | 72 | 142 | 67 | 74 | ||
| N classification | ||||||
| N0 | 20 | 62 | 0.083 | 20 | 26 | 0.677 |
| N1 | 42 | 92 | 42 | 38 | ||
| N2 | 43 | 69 | 38 | 39 | ||
| N3 | 11 | 12 | 10 | 7 | ||
| Consolidation chemotherapy | ||||||
| No | 71 | 114 | 0.025 | 65 | 68 | 0.679 |
| Yes | 45 | 121 | 45 | 42 | ||
TABLE 5.
Cox Proportional Hazard Regression Multivariate Model of Factors Predicting Survival in low dose cohort.
| Characteristic | HR (95% CI) | p |
|---|---|---|
| Sex | 0.893 | |
| Age | 0.645 | |
| Tumor location | 0.876 | |
| Karnofsky scale | 0.947 | |
| Weight loss | 0.892 | |
| Tumor length | 0.604 | |
| T classification | 0.222 | |
| N classification | 1.518 (1.087–2.119) | 0.014 |
| Consolidation chemotherapy | 0.353 (0.183–0.681) | 0.002 |
3.6. Comparing Chemotherapy Regimens
Here we compare the survival outcomes of CCT Regimens with either paclitaxel or docetaxel/cisplatin(DC), or fluorouracil/cisplatin(CF). In DC group, 132/231 received CCT, the 1, 2, and 3‐year OS rates were 57%, 55%, 51%; in CF group, 38/75 received CCT, the 1, 2, and 3‐year OS rates were 49%, 46%, 44% (Table 1). The median OS were 39.5 months and 32.6 months in DC group and CF group (p = 0.150), respectively (Table 6), The OS was higher in the DC group, although the difference between the two group was not significant(p = 0.150).
TABLE 6.
Survival outcome of 170 patients received CCT with ESCC in univariate analysis.
| Characteristic | Patient no. CCT/CCRT | Univariate analysis | p | |||
|---|---|---|---|---|---|---|
| 1‐year (%) | 2‐year (%) | 3‐year (%) | Median (month) | |||
| Chemotherapy regimens | 0.150 | |||||
| Paclitaxel or docetaxel/cisplatin | 132/231 | 57 | 55 | 51 | 39.5 | |
| Fluorouracil/cisplatin | 38/75 | 49 | 46 | 44 | 32.6 | |
3.7. Impact of Radiation Dose and CCT on N Classifications
In the 8th TNM classification, N classification was no significant difference in prognosis when comparing the low and high dose groups or when comparing the CCRT alone group and CCRT+CCT group. High radiation dose only show a survival benefit for N3 stage(p = 0.045). In the 6th TNM classification, positive lymph nodes in the cervical or abdominal cavity are considered distant metastases, so we attempted to classify patients by lymph regions. Notably, in subgroup analysis, patients with positive Cervical/abdominal lymph node, OS was 12.9 months in low dose group and 22.5 months in high dose group(p = 0.000, HR 0.333, 95% CI 0.155–0.598). Similar OS improvement also observed in CCRT+CCT group compared with CCRT alone group, OS was 25.6 months and 14.4 months, respectively. (p = 0.000, HR 0.339, 95% CI 0.195–0.747) The association between treatment effect and node metastasis region in this study was similar to that both radiation dose and CCT involvement. In conclusion, lymph node metastasis based on region is a useful predictor in patient undergoing both radiation therapy and CCT (Table 7).
TABLE 7.
Radiation and CCT treatment effect on overall survival by N classification.
| Characteristic | Radiation dose | p | HR | CCT | p | HR | ||
|---|---|---|---|---|---|---|---|---|
| Low | High | No | Yes | |||||
| N classification (8th) | ||||||||
| N0 | NA | NA | 0.237 | 40.1 | 28.6 | 0.112 | ||
| N1 | 17.6 | NA | 0.313 | 26.8 | 26.8 | 0.325 | ||
| N2 | 15.8 | 17.5 | 0.336 | 19.0 | 15.4 | 0.058 | ||
| N3 | 12.6 | 34.5 | 0.045 | 0.227 | 24.8 | 7.1 | 0.111 | |
| Cervical/abdominal lymph node | ||||||||
| Negative | 25.6 | 23.6 | 0.721 | 24.6 | 28.0 | 0.218 | ||
| Positive | 12.9 | 22.5 | 0.000 | 0.333 | 14.4 | 25.6 | 0.001 | 0.339 |
3.8. Acute Adverse Events
As acute adverse effects, Grade 3–4 anemia were observed in 72 patients, including 24/116 in low dose group and 48/235 in high dose group. Grade 3–4 leukopenia was relatively high in both groups, 65/116 in low dose group and 113/235 in high dose group. Grade 3–4 thrombocytopenia and ALT/AST increasing were rare in both group. No Grade 3–4 creatinin increasing occurred. All of above hematologic toxicity were not significant between low dose group and high dose group (p > 0.05). Grade 3–4 radiation esophagitis was observed in 9/116 patients in low dose group and 22/235 in low dose group. The grade 3–4 radiation esophagitis was higher in high dose group but difference was not significant may be related to the small sample size (p = 0.063). All of those patients recovered soon after completion of radiotherapy. There were no patients who had Grade 5 adverse effects. As a retrospective study, we missed some important data in the late phase, such as pulmonary fibrous change, pericardial effusion when were observed in some cases during clinical work (Table 8).
TABLE 8.
Acute adverse events (CTCAE5.0).
| Grade | |||
|---|---|---|---|
| Grade 0–2 | Grade 3–4 | p | |
| Anemia | |||
| Low dose | 92 | 24 | 0.567 |
| High dose | 187 | 48 | |
| Leukopenia | |||
| Low dose | 51 | 65 | 0.170 |
| High dose | 122 | 113 | |
| Thrombocytopenia | |||
| Low dose | 102 | 14 | 0.373 |
| High dose | 213 | 22 | |
| ALT/AST increasing | |||
| Low dose | 111 | 5 | 0.343 |
| High dose | 228 | 7 | |
| Creatinin increasing | |||
| Low dose | 116 | 0 | 1 |
| High dose | 235 | 0 | |
| Radiation esophagitis | |||
| Low dose | 107 | 9 | 0.062 |
| High dose | 213 | 22 |
4. Discussion
In this study, a poor survival outcome was observed in the T4 stage, N3 stage, with weight loss or treatment with a radiation dose < 60 Gy and CCRT alone stage. Our study addressed the survival outcome of CCRT alone and CCRT plus CCT in stage II‐IVA ESCC patients. We demonstrated that CCT was associated with an improved OS (38.4 vs. 17.7 months, p = 0.002) compared with CCRT alone. Multivariate analysis revealed that CCT was an independent prognostic factor (p = 0.002, HR 0.592, 95% CI 0.423–0.829). CCT remained a significant predictive prognostic factor for OS after PSM (p = 0.0182).
To the best of our knowledge, no randomized trial to date has investigated the effectiveness of CCT after CCRT. CCT followed by CCRT has been administered in previous large prospective studies such as the RTOG 85–01 trial. In this trial two cycles of consolidation cisplatin/5‐FU were performed in the CCRT group, resulting in a 5‐year OS rate of 26% [23]. In addition, FFCD 9102 was a randomized trial that compared the OS of CCRT with CCRT followed by surgery. The same consolidation regimens were given in the CCRT arm. Patients who response to CCRT had a similar overall survival in both arms(17.7 months in the surgery arm compared with 19.3 months in the nonsurgery arm) [9]. The PRODIGE5/ACCORD17 trial added another 3 and 2 cycles CCT in the FOLFOX and cisplatin/5‐FU arms, which resulted in median PFS scores of 9.7 and 9.4 months, respectively [5].
To date few studies have examined the effect of CCT in ESCC patients after CCRT. Retrospective studies performed in China evaluated CCT followed by CCRT. Wu et al. enrolled 67 ESCC patients who attained clinical complete response after CCRT. CCT improved the median OS (53.4 vs. 27.0 months, p = 0.04, HR 0.67, 95% CI 0.44–0.99) compared with CCRT alone, but failed to show an additional survival benefit after PSM [20]. This result was significantly better than our study but this was due in part because that study selected patients who had attained a complete clinical response after CCRT, which was associated with significantly improved survival than those responding poorly to CCRT [24, 25]. Chen et al. investigated 812 ESCC patients treated with CCRT, after PSM the median OS was 34.6 months in the observation group and 35.0 months in the consolidation group, with no statistical difference observed between groups (HR 0.96, 95% CI, 0.80–1.23, p = 0.92) [26]. The OS was also superior compared with ours, However that may be primarily due to the fact that our study included more T4 (61.0% vs. 30.9%) and N3 (6.6% vs. 1.1%) stage patients, which have a decreased survival rate. Wang et al. system reviewed six retrospective studies identified that CCT improved short term survival benefit(HR 0.542, p < 0.001, in 1 year) but not in long term(HR 0.923, p = 0.555, in 5 year) [18]. Lin et al. initiated population‐based study found that CCT significantly prolonged OS for locally advanced ESCC patients after PSM(HR 0.67, 95% CI 0.52–0.86, p = 0.002) [27].
The role of CCT after CCRT for ESCC was controversial before the initiation of this study. Our findings are not consistent with the results of previous studies. However, our analysis initially demonstrated that the effect of CCT after CCRT in prolonging OS may be associated with patients' disease status and treatment. A benefit in terms of increased OS after CCT was not consistently observed across all prespecified subgroups. CCT was more effective in males, age < 65 years and with KPS > 90, mainly because those patients had better general conditions. The benefit of CCT towards OS was almost equivalent among different tumor locations. Whether weight loss or not did not affect the efficacy of CCT. CCT had limitations for patients with tumor length < 4.5 cm and T2‐3 stages, CCRT alone might be appropriate for such patients. A significant benefit was observed in patients in the T4 stage (HR 0.500, 95% CI 0.327–0.764) and tumor length ≥ 4.5 cm (HR 0.570, 95% CI 0.383–0.848). There was no difference in the hazard ratio associated with the N stage.
Remarkably, CCT interaction with radiation was significant. Among patients treated with radiation doses lower than 60 Gy, the median OS was 11.6 months longer among patients who received CCT than among those who received CCRT alone (24.8 months vs. 13.2 months, p = 0.002). Risk reduction by CCT was more evident among patients who received radiation doses lower than 60Gy compared with those receiving higher than 60 Gy (HR 0.368 95% CI 0.194–0.700 vs. HR 0.730, 95% CI 0.485–1.099). When we used PSM and split the data into a low dose cohort and a high dose cohort, CCT remained a significant predictive prognostic factor for OS in the low dose cohort (p = 0.002). Similar results were not observed in the high dose cohort. Current NCCN guidelines recommend a standard dose of 50.40 Gy for the treatment of esophageal cancer, according to the INT 0123 (Radiation Therapy Oncology Group 94–05) phase III trial [15]. This study reported a higher treatment‐related mortality rate in the patients assigned to the 64.8Gy group but without survival benefit compared with 50.4 Gy (13.0 months vs. 18.1 months). However, the INT 0123 trial had its limitations. This study had a minority of patients with T4 stage (7.8%) and N+ stage (21.6%). In addition, treatment with conventional radiotherapy can lead to more potential damage to the lungs and heart compared with IMRT. Suh YG et al. reported that esophageal cancer patients treated with 2D‐CRT and 3D‐CRT of 60Gy or higher had better locoregional control and progression‐free survival without a significant increase of in treatment‐related toxicity [28]. Chang CL et al. analyzed 2061 patients with thoracic ESCC without distant metastasis who received CCRT with IMRT. Administration of a radiation dose > 60 Gy was a significant independent prognostic factor for overall survival (p < 0.0001, HR 0.75, 95% CI 0.68–0.83) [29]. However, recent multicenter phase 3 trial showed high dose radiation (60 Gy30 f/2 Gy, 59.4 Gy/33f/1.8 Gy) has no survival benifit but led to higher severe toxicities compared with low dose radiation (50 Gy25 f/2 Gy, 50.4 Gy/28f/1.8 Gy) [30, 31]. It should be noted that their scheme includes 2 cycles of consolidation chemotherapy after 6 cycles of concurrent chemotherapy. In our study, there was a tendency to increase the overall survival in the high dose group (28.0 months vs. 17.4 months, p = 0.024). The overall survival was significantly worse in the low dose group without CCT (13.2 months).
Several limitations were present in this study. First of all, the biases inherent to the nature of single‐center and retrospective investigations were not completely avoided. However, we did utilize propensity score matching analysis to adjust the selection bias. Secondly, the lack of PET‐CT in some patients may affect the accuracy of the staging. In addition, some important characteristics were not recorded such as tumor differentiation due to this being a non‐operation type of therapy. The last limitation was that the median follow‐up time was 28.1 months. Our study still needs further follow‐up.
Consolidation chemotherapy was initially proposed as postoperative chemotherapy. Potential metastasis that cannot be detected clinically may occur before surgery. Chemotherapy is used to kill these residual cancer cells in order to prevent cancer recurrence and metastasis. Consolidation chemotherapy can eliminate small residual lesions in the blood or lymphatic system, reduce tumor recurrence rates, and improve cure rates. Postoperative adjuvant chemotherapy can improve the overall survival rate and disease‐free survival of patients with esophageal squamous cell carcinoma after radical resection, but may only be effective for certain subgroups of patients depending on pathological stage or lymph node metastasis status. Radiation therapy uses high‐energy radiation to directly attack cancer cells, disrupting their DNA structure and preventing them from further dividing. The residual cancer cells caused by insufficient radiotherapy dose can be equivalent to surgical failure to achieve R0 resection, especially T4 and positive lymph nodes in the cervical or abdominal cavity as mentioned earlier. For these high‐risk patients, consolidation chemotherapy after radiotherapy further kills residual tumor cells and prolongs survival.
5. Conclusion
In conclusion, our data indicate that CCT improves overall survival in patients received radiation dose < 60 Gy. We recommend that CCT should be considered for ESCC patients who underwent CCRT < 60 Gy, but not for those ≥ 60 Gy radiation. Further prospective studies are needed to confirm these results.
Author Contributions
H.Z., Q.W., B.T., and P.W. performed data acquisition, the statistical analysis and drafted the manuscript. H.Z. performed data acquisition and the statistical analysis. B.T. critically reviewed the manuscript,conceived of the study, and participated in its design. All authors read and approved the final manuscript.
Ethics Statement
The respective study was approval by Human Investigation Committee of The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China. The Human Investigation Committee allowed the use of patient data for research, provided that any person's related data are kept anonymous.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no Conflicts of Interest.
Acknowledgments
The authors have nothing to report.
Funding: The authors received no specific funding for this work.
Data Availability Statement
There are ethical restrictions on sharing of de‐identified data for this study. The ethics committee has not agreed to the public sharing of data as we do not have the participants' permission to share their anonymous data. It is likely given the nature of the dataset that patients may still be identifiable despite efforts to anonymise the data. Qualified and interested researchers may request access to the data by contacting Human Investigation Committee of The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
There are ethical restrictions on sharing of de‐identified data for this study. The ethics committee has not agreed to the public sharing of data as we do not have the participants' permission to share their anonymous data. It is likely given the nature of the dataset that patients may still be identifiable despite efforts to anonymise the data. Qualified and interested researchers may request access to the data by contacting Human Investigation Committee of The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital.