Abstract
We investigated which prognostic factor could improve survival for esophageal cancer patients who received definite concurrent chemoradiation (CCRT). Eighty patients with age ≥18, Karnofsky Performance Scale (KPS) ≥ 60, and clinical stage T1‐4N0‐3M0 esophageal squamous cell carcinoma were enrolled from July 2004 to December 2015. They underwent definite intensity‐modulated radiotherapy (IMRT) with or without simultaneous integrated boost to the primary tumor, and reception of concurrent chemotherapy ≥ 1 cycle. The primary endpoints were overall survival (OS), locoregional progression‐free survival (LRPFS) and distant metastasis‐free survival (DMFS). The median follow‐up duration for alive patients was 21.5 months. The rates of 2‐, 3‐ and 5‐year OS/LRPFS/DMFS were 23.8%/53.5%/49.3%, 19.1%/44.6%/49.3%, and 13.0%/44.6%/43.9%, respectively. Only the non‐clinical complete response (non‐cCR) after CCRT was an independent poor prognostic factor in OS (HR 3.101, 95% CI 1.535–6.265, p = 0.0016). Radiation dose >50.4 Gy and chemotherapy ≥4 cycles significantly predicted better LRPFS (p = 0.0361 and 0.0163, respectively). Poorly differentiated tumor and stage III disease have poor DMFS (p = 0.0336 and 0.0411, respectively), and chemotherapy ≥ 4 cycles was a better predictor (p = 0.0004). In subgroup analysis, patients who received radiation dose ≤50.4 Gy with concurrent chemotherapy ≥4 cycles had the best survival outcome with 1‐, 2‐, 3‐ and 5‐year survival rates of 73.7%, 39.4%, 31.5% and 17.5%, respectively. In conclusion, definite radiotherapy with concurrent chemotherapy ≥4 cycles improved the survival for patients with inoperable or locally‐advanced esophageal squamous cell carcinoma.
Keywords: Chemoradiotherapy, Esophageal neoplasms, Squamous cell carcinoma
Introduction
Cancer of the esophagus is a fatal disease and ranked the 6th most common cause of cancer‐related death worldwide [1]. The squamous cell carcinoma accounts for the majority of the esophageal cancer (>90%) in Taiwan [2]. According to the increasing evidence of previous published literature, the trimodality therapy including neoadjuvant CCRT followed by surgery has become the standard of treatment for locally‐advanced esophageal cancer [[3], [4], [5], [6], [7], [8], [9], [10]].
Although trimodality therapy can achieve a better survival benefit, many factors, such as tumor size, location, extent of tumor involvement, patients' performance status, and comorbidities dramatically influence the probability of surgery. Only 30–40% of patients can receive operation as initial therapy or as one component of the multimodality treatment [11]. The standard non‐surgical treatment option is mainly based on the results of the Radiation Therapy Oncology Group (RTOG) 85‐01, which showed the definite CCRT had better 5‐year survival rate than radiation alone and a projected 10‐year survival rate of 20% [[12], [13]].
However, there are still several questions needed to be overcome. Firstly, the high local recurrence rate of 46% after definite CCRT in the RTOG 85‐01 study is of concern, and a subsequent study (INT 0123) failed to show better local control by escalating the radiation dose up to 64.8 Gy [14]. This dose‐escalation study failed to demonstrate improved local control might be attributed to its conventional radiation technique (Both of the RTOG 85‐01 and INT 0123 were conducted before the era of 3D‐conformal radiotherapy [3D‐CRT]), which had higher treatment‐related toxicities. The ≥ grade 3 treatment‐related toxicities in the RTOG 85‐01 study and the INT 0123 study were 48% and 71%, respectively. The modern technology of IMRT is an advanced form of 3D‐CRT, which uses non‐uniform radiation beams to maximize the radiation dose of the target volume and simultaneously minimize the radiation dose of the surrounding normal tissues. The IMRT is better than conventional 3D‐CRT in treating esophageal cancer not only in dose homogeneity of target volume, but also in decreasing the radiation dose to the organs at risk [[15], [16], [17], [18], [19]]. Most importantly, by using IMRT with simultaneous integrated boost to the primary tumor, it is possible to do dose escalation of the target volume with safety dose constrains of the surrounding normal tissues. It is speculated that using modern technique of IMRT with dose escalation of the target volume can achieve better local control without increasing treatment‐related toxicities.
Secondary, the chemotherapy was prescribed for total of 4 cycles in the protocol of the RTOG 85‐01 study, but about one‐fifth of patients had distant metastasis. It is reasonable to interpret that adding more cycles of chemotherapy can decrease the rate of distant metastasis, and further improve the survival outcome.
In current study, we will illustrate the treatment outcomes for patients with locally‐advanced or inoperable esophageal squamous cell carcinoma who underwent definite CCRT by using IMRT with or without simultaneous integrated boost and a total chemotherapy ≥ or <4 cycles.
Methods
Patients
From July 2004 to December 2015, 92 patients with locally advanced esophageal cancer were retrospectively reviewed. The eligibility criteria included (1) age ≥ 18 years old, (2) biopsy‐proved squamous cell carcinoma of esophagus, (3) KPS ≥ 60, (4) clinical stage T1‐4N0‐3M0 according to the American Joint Committee on Cancer (AJCC) TNM staging 7th edition, (5) patients who received definite IMRT with or without simultaneous integrated boost to the primary tumor, and (6) patients who received concurrent chemotherapy ≥ 1 cycle. Exclusion criteria included (1) initial distant metastatic disease, (2) adenocarcinoma of esophagus, (3) incomplete treatment course of definite CCRT, and (4) disease progression during the definite CCRT. Four patients were initially diagnosed with metastatic disease, three had adenocarcinoma, four had incomplete definite CCRT, and one had disease progression (brain metastasis) during the period of definite CCRT. Therefore, 80 patients were enrolled into the analysis.
All patients received a complete pretreatment staging workup, including medical history, physical examination, gastroscopy, bronchoscopy, biopsy of esophagus, complete blood cell count, serologic biochemistry data of liver and kidney, chest X‐ray, diagnostic chest computed tomography scan, abdominal sonography, and whole body bone scan. The positron emission tomography scan was performed if clinical indicated. Tumor staging was defined based on the AJCC clinical stages, 7th edition.
Definite CCRT
The radiotherapy treatment plan was performed according to the protocol described in our previous studies [[15], [16]]. All patients underwent IMRT with or without simultaneous integrated boost to the gross esophageal tumor plus concurrent chemotherapy. The treatment planning of IMRT was the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA, USA). The radiation was delivered by using a dynamic multileaf linear accelerator with photon energy of 6 MV or 10 MV. Five to seven radiation beam angles were designed according to the specific shape of the clinical tumor volume (CTV). A vacuum fixed pad was used to immobilize the patient and lift of both arms was scheduled before CT simulation and daily treatment.
Gross tumor volume (GTV) was defined as the gross esophageal tumor. GTV‐N was defined as the mediastinal lymph nodes ≥1 cm. The CTV included 1.0‐cm expansion of the GTV in circumferential direction, 5‐cm extension of the GTV in the cephalade caudad direction, lymph nodes at the mediastinum, supraclavicular area (for tumors located in cervical esophagus, upper and middle third of thoracic esophagus), and celiac trunk region (for tumors located in lower third of thoracic esophagus). The planned target volume (PTV) was contoured by the CTV with a 0.5 cm margin superiorly, inferiorly, and radially for daily setup error and organ motion. A total radiation dose of 40–56 Gy with or without concomitant boost to the primary tumor, 1.8–2.0 Gy per fraction, five fractions per week, was delivered to the PTV. Dose constraint were mean lung dose <15 Gy, V20 of lung <30%, and V35 of heart <30%.
The regimen of the concurrent chemotherapy consisted of cisplatin 20 mg/m2 intravenous infusion for 1 h plus fluorouracil 800 mg/m2 continuous intravenous infusion for 24 h from day 1 to day 4 every 4 weeks for 2 cycles. Additional 2–4 cycles of the same chemotherapy regime after radiotherapy, was prescribed according to the patients' clinical condition and the physician's decision.
Statistical analysis
The primary endpoints of this study were overall survival (OS), locoregional progression‐free survival (LRPFS) and distant metastasis‐free survival (DMFS). OS was defined as the start date of radiotherapy to the date of death from any cause or last follow‐up. LRPFS was calculated from the start date of radiotherapy to the date of any evidence of locoregional progression (LRP) or last follow‐up. DMFS was measured from the start date of radiotherapy to the date of evidence of distant metastasis. Locoregional or distant failure was defined as biopsy‐proven recurrence or distant metastasis, or progression of disease on serial image studies.
The second endpoints were the treatment‐related acute toxicities, treatment compliance, and clinical tumor response after treatment. Acute skin, gastrointestinal, pulmonary and hematological toxicities of definite CCRT were weekly assessed by using the toxicity criteria of the RTOG [20]. The treatment response was defined as cCR, partial response (cPR), or disease progression (cPD) according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). The cCR was defined as no evidence of disease on the post‐treatment image studies, such as chest computed tomography or positron emission tomography scan, and no residual tumor according to the pathologic report of post‐treatment gastroscopic biopsy. The patients who did not have post‐treatment biopsies were divided into cPR or cPD. Survival times were estimated by Kaplan–Meier method and a log‐rank test was used to compare differences between subgroups. The univariate and multivariate analysis were incorporated into the Cox proportional hazards regression model. All statistical analyses were performed by using SAS 9.3 statistical software (SAS Institute Inc., Cary, NC, USA) and a 2‐sided p value ≤ 0.05 was considered a statistically significant.
For patients' follow‐up, re‐evaluation including chest computed tomography, gastroscopy, and/or positron emission tomography scan were arranged 3 weeks after the latest cycle of chemotherapy. Thereafter, the follow‐up of patients including the physical examinations, gastroscopy and imaging studies were performed every 3 months for the first 3 years, and every 6 months during years 4–5, and then annually after 5 years.
Results
Patient characteristics
Detailed information related to the patients, tumors, and treatments are described in Table 1. The median age was 56.6 years old (range, 38.9–84.6) and men were predominantly (95%). Most of patients had KPS ≤70 (66.3%). Sixty‐five patients (81.3%) had locally‐advanced clinical stage III disease and the median tumor size was 6.8 cm (range, 1–19.2). The median radiation dose was 50.4 Gy (range, 40–66 Gy). Twenty‐nine patients underwent IMRT with simultaneous integrated boost to the gross esophageal tumor and the median total dose was 56 Gy (range, 53.76–66 Gy). More than 60% of the patients could tolerate chemotherapy ≥4 cycles.
Table 1.
Patient characteristics.
| Variables | N | % |
|---|---|---|
| Sex | ||
| Men | 76 | 95.0 |
| Women | 4 | 5.0 |
| Karnofsky performance status scale | ||
| >70 | 27 | 33.8 |
| ≤70 | 53 | 66.3 |
| Differentiation | ||
| Well differentiation | 1 | 1.3 |
| Moderately differentiation | 28 | 35.0 |
| Poorly differentiation | 44 | 55.0 |
| Unknown | 7 | 8.8 |
| Stage | ||
| IB | 1 | 1.3 |
| IIA | 1 | 1.3 |
| IIB | 13 | 16.3 |
| IIIA | 33 | 41.3 |
| IIIB | 20 | 25.0 |
| IIIC | 12 | 15.0 |
| Tumor size | ||
| <8 cm | 53 | 66.3 |
| ≥8 cm | 27 | 33.8 |
| Tumor location | ||
| Cervical | 7 | 8.8 |
| Upper third of thoracic esophagus | 21 | 26.3 |
| Middle third of thoracic esophagus | 32 | 40.0 |
| Lower third of thoracic esophagus | 20 | 25.0 |
| Chemotherapy cycles | ||
| <4 | 31 | 38.8 |
| ≥4 | 49 | 61.3 |
| Clinical tumor response | ||
| Clinical complete response | 46 | 57.5 |
| Clinical partial response | 18 | 22.5 |
| Clinical progression disease | 4 | 5.0 |
| Unknown | 12 | 15.0 |
| Radiation dose | ||
| IMRT without SIB (≤50.4 Gy) | 51 | 63.8 |
| IMRT with SIB (>50.4 Gy) | 29 | 36.3 |
N: numbers of different characteristics.
IMRT: intensity‐modulated radiotherapy.
SIB: simultaneous integrated boost.
Survival outcomes
The median follow‐up duration for alive patients was 21.5 months (range, 1–118). There were 64 patients dead and the causes of death were disease‐related in 33 patients, non‐disease related in 22 patients, treatment complication‐related in 6 patients, and unknown in 3 patients, respectively. The 2‐, 3‐ and 5‐year OS rates were 23.8%, 19.1% and 13.0%, respectively (Fig. 1A).
Figure 1.
Kaplan–Meier survival curves of (A) overall survival (OS), (B) loco‐regional progression‐free survival (LRPFS), and (C) distant metastasis‐free survival (DMFS).
Sixteen patients had LRP alone, 16 patients had distant metastasis alone, and 11 patients had both LRP and distant metastasis. The median durations from initial treatment to LRP and distant metastasis were 8 months (range, 1–118) and 8 months (range, 2–46), respectively. The 2‐, 3‐ and 5‐year LRPFS rates were 53.5%, 44.6% and 44.6%, respectively (Fig. 1B). The 2‐, 3‐ and 5‐year DMFS rates were 49.3%, 49.3% and 43.9%, respectively (Fig. 1C).
Multivariate analysis
In multivariate analysis, only the non‐cCR after definite CCRT is an independently significant poor prognostic factor in survival (hazard ratio [HR] 3.101, 95% confidence interval [CI] 1.535–6.265, p = 0.0016). Tumor size ≥8 cm had a trend toward poor OS (HR 1.940, 95% CI 0.995–3.783, p = 0.0518). Patients who had received chemotherapy ≥4 cycles had a trend toward better survival outcome (HR 0.5630, 95% CI 0.288–1.099, p = 0.0925) (Table 2A).
Table 2A.
Univariate and multivariate analysis in overall survival (OS).
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |
| Radiation dose (>vs. ≤ 50.4 Gy) | 1.378 | (0.835–2.275) | 0.2099 | 0.966 | (0.513–1.816) | 0.9134 |
| Age (≥vs. <55 years) | 1.262 | (0.764–2.086) | 0.3638 | 1.583 | (0.810–3.097) | 0.1794 |
| Sex (men vs. women) | 4.130 | (0.991–17.204) | 0.0514 | 2.669 | (0.595–11.976) | 0.1999 |
| KPS (>vs. ≤ 70) | 2.406 | (1.358–4.263) | 0.0026 | 1.359 | (0.700–2.639) | 0.3646 |
| Tumor differentiation | ||||||
| PD vs. WD + MD | 1.111 | (0.653–1.890) | 0.6976 | 0.966 | (0.515–1.815) | 0.9155 |
| Unknown vs. WD + MD | 1.754 | (0.749–4.108) | 0.1959 | 1.206 | (0.461–3.152) | 0.7026 |
| Stage (III vs. IB‐IIB) | 1.644 | (0.870–3.108) | 0.1258 | 0.921 | (0.416–2.039) | 0.8393 |
| Tumor size (≥8 vs. < 8 cm) | 2.538 | (1.467–4.390) | 0.0009 | 1.940 | (0.995–3.783) | 0.0518 |
| Tumor location | ||||||
| Tu vs. cervical | 1.101 | (0.435–2.786) | 0.8396 | 1.061 | (0.383–2.943) | 0.9087 |
| Tm vs. cervical | 1.075 | (0.435–2.655) | 0.8758 | 0.920 | (0.309–2.737) | 0.8812 |
| Tl vs. cervical | 1.272 | (0.495–3.264) | 0.6174 | 0.713 | (0.234–2.171) | 0.5518 |
| Chemotherapy cycles (≥vs. < 4) | 0.406 | (0.243–0.677) | 0.0006 | 0.563 | (0.288–1.099) | 0.0925 |
| Clinical tumor response (non‐cCR vs. cCR) | 3.987 | (2.325–6.837) | <0.0001 | 3.101 | (1.535–6.265) | 0.0016 |
KPS: Karnofsky performance status scale.
WD: well differentiation; MD; moderately differentiation; PD: poorly differentiation.
Tu: upper third of thoracic esophagus; Tm: middle third of thoracic esophagus; Tl: lower third of thoracic esophagus.
cCR: clinical tumor response.
In LRPFS, radiation dose >50.4 Gy and chemotherapy ≥4 cycles were significant prognostic factors in predicting better locoregional control (HR 0.251, 95% CI 0.069–0.914, p = 0.0361; and HR 0.225, 95% CI 0.067–0.760, p = 0.0163, respectively). The tumor located in the upper and middle third of thoracic esophagus had better locoregional control compared with the tumor located in the cervical esophagus (HR 0.058, 95% CI 0.010–0.324, p = 0.0012; and HR 0.036, 95% CI 0.005–0.258, p = 0.0009, respectively). Stage III disease, tumor size ≥8 cm, tumor in the lower third of thoracic esophagus compared with tumor in the cervical esophagus, and non‐cCR after treatment showed borderline impact on LRPFS (Table 2B).
Table 2B.
Univariate and multivariate analysis in loco‐regional progression‐free survival (LRPFS).
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |
| Radiation dose (>vs. ≤ 50.4 Gy) | 0.510 | (0.206–1.266) | 0.1467 | 0.251 | (0.069–0.914) | 0.0361 |
| Age (≥vs. <55 years) | 0.670 | (0.312–1.436) | 0.3029 | 0.719 | (0.288–1.794) | 0.4798 |
| Sex (men vs. women) | 3.029 | (0.404–22.698) | 0.2807 | 1.718 | (0.200–14.774) | 0.6221 |
| KPS (>vs. ≤ 70) | 1.015 | (0.469–2.197) | 0.9700 | 1.115 | (0.406–3.062) | 0.8333 |
| Tumor differentiation | ||||||
| PD vs. WD + MD | 0.885 | (0.395–1.984) | 0.7666 | 1.069 | (0.380–3.004) | 0.8993 |
| Unknown vs. WD + MD | 3.599 | (0.959–13.508) | 0.0577 | 9.798 | (1.528–62.822) | 0.0161 |
| Stage (III vs. IB‐IIB) | 1.225 | (0.559–2.685) | 0.6129 | 2.672 | (0.950–7.513) | 0.0625 |
| Tumor size (≥8 vs. < 8 cm) | 1.280 | (0.545–3.006) | 0.5711 | 2.522 | (0.872–7.295) | 0.0878 |
| Tumor location | ||||||
| Tu vs. cervical | 0.234 | (0.057–0.968) | 0.0450 | 0.058 | (0.010–0.324) | 0.0012 |
| Tm vs. cervical | 0.444 | (0.135–1.456) | 0.1802 | 0.036 | (0.005–0.258) | 0.0009 |
| Tl vs. cervical | 0.948 | (0.296–3.037) | 0.9283 | 0.231 | (0.047–1.142) | 0.0723 |
| Chemotherapy cycles (≥vs. < 4) | 0.532 | (0.232–1.218) | 0.1352 | 0.225 | (0.067–0.760) | 0.0163 |
| Clinical tumor response (non‐cCR vs. cCR) | 1.334 | (0.541–3.292) | 0.5316 | 0.300 | (0.075–1.192) | 0.0871 |
KPS: Karnofsky performance status scale.
WD: well differentiation; MD; moderately differentiation; PD: poorly differentiation.
Tu: upper third of thoracic esophagus; Tm: middle of thoracic esophagus; Tl: lower third of thoracic esophagus.
cCR: clinical tumor response.
Patients who had poorly differentiated tumor and stage III disease were at a higher risk of distant metastasis (HR 3.871, 95% CI 1.111–13.487, p = 0.0336; and HR 2.685, 95% CI 1.041–6.928, p = 0.0411, respectively), and those who received chemotherapy ≥ 4 cycles had better DMFS (HR 0.102, 95% CI 0.029–0.358, p = 0.0004) (Table 2C).
Table 2C.
Univariate and multivariate analysis in distant metastasis‐free survival (DMFS).
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |
| Radiation dose (>vs. ≤ 50.4 Gy) | 0.714 | (0.312–1.632) | 0.4240 | 0.669 | (0.238–1.881) | 0.4457 |
| Age (≥vs. <55 years) | 1.419 | (0.656–3.069) | 0.3746 | 0.974 | (0.933–1.017) | 0.2388 |
| KPS (>vs. ≤ 70) | 1.335 | (0.606–2.939) | 0.4733 | 0.642 | (0.232–1.777) | 0.3934 |
| Tumor differentiation | ||||||
| PD vs. WD + MD | 3.510 | (1.314–9.375) | 0.0122 | 3.871 | (1.111–13.487) | 0.0336 |
| Unknown vs. WD + MD | 2.438 | (0.471–12.611) | 0.2878 | 2.364 | (0.397–14.083) | 0.3446 |
| Stage (III vs. IB‐IIB) | 2.439 | (1.136–5.237) | 0.0222 | 2.685 | (1.041–6.928) | 0.0411 |
| Tumor size (≥8 vs. < 8 cm) | 1.684 | (0.752–3.770) | 0.2054 | 1.732 | (0.639–4.696) | 0.2801 |
| Tumor location | ||||||
| Tu vs. cervical | 1.870 | (0.396–8.841) | 0.4296 | 2.708 | (0.449–16.317) | 0.2770 |
| Tm vs. cervical | 1.602 | (0.351–7.325) | 0.5431 | 1.173 | (0.187–7.355) | 0.8651 |
| Tl vs. cervical | 1.755 | (0.363–8.476) | 0.4838 | 0.951 | (0.136–6.651) | 0.8651 |
| Chemotherapy cycles (≥vs. < 4) | 0.240 | (0.111–0.523) | 0.0003 | 0.102 | (0.029–0.358) | 0.0004 |
| Clinical tumor response (non‐cCR vs. cCR) | 2.419 | (1.079–5.423) | 0.0320 | 0.947 | (0.268–3.346) | 0.9331 |
KPS: Karnofsky performance status scale.
WD: well differentiation; MD; moderately differentiation; PD: poorly differentiation.
Tu: upper third of thoracic esophagus; Tm: middle of thoracic esophagus; Tl: lower third of thoracic esophagus.
cCR: clinical tumor response.
In subgroup analysis, patients who received radiation dose ≤50.4 Gy plus chemotherapy ≥4 cycles had the best survival outcome with 1‐, 2‐, 3‐ and 5‐year survival rates of 73.7%, 39.4%, 31.5% and 17.5%, respectively (Fig. 2A).
Figure 2.
Kaplan–Meier survival curves of (A) overall survival (OS), (B) loco‐regional progression‐free survival (LRPFS), and (C) distant metastasis‐free survival (DMFS) between IMRT with or without simultaneous integrated boost to the primary tumor (radiation dose ≤ vs. > 50.4 Gy) and different chemotherapy cycles (≥vs. < 4 cycles). Group I means the radiation dose ≤50.4 Gy and chemotherapy <4 cycles. Group II means the radiation dose ≤50.4 Gy and chemotherapy ≥4 cycles. Group III means the radiation dose >50.4 Gy and chemotherapy <4 cycles. Group IV means the radiation dose >50.4 Gy and chemotherapy ≥4 cycles.
The patients who received radiation dose > 50.4 Gy plus chemotherapy ≥ 4 cycles had the best LRPFS with 1‐, 2‐, 3‐ and 5‐year LRPFS rates of 86.5%, 86.5%, 69.2% and 69.2%, respectively (Fig. 2B).
The patients who received radiation dose >50.4 Gy plus chemotherapy ≥4 cycles had the best DMFS with 1‐, 2‐, 3‐ and 5‐year DMFS rates of 83.9%, 83.9%, 83.9% and 62.9%, respectively (Fig. 2C).
Those patients who received radiation dose >50.4 Gy plus chemotherapy <4 cycles had the worst OS, LRPFS and DMFS.
Clinical tumor response after definite CCRT
Among all patients, 46 patients had cCR and 18 patients achieved a cPR. The overall response rate (cCR and cPR) was 80%. In patients who received a radiation dose of ≤50.4 Gy, 30 patients (30/51) had a cCR and 9 patients (9/51) had a cPR. In patients who received a radiation dose of >50.4 Gy, 11 patients (16/29) showed a cCR and 9 patients (9/29) had a cPR. The response rates in these two groups (≤50.4 Gy versus > 50.4 Gy) were 76.4% and 86.2%, respectively.
The treatment‐related toxicities and compliance
Thirty‐one patients who received a radiation dose of ≤50.4 Gy (31/51, 60.8%) could tolerate ≥ 4 cycles of chemotherapy, compared with 18 patients who received a radiation dose of >50.4 Gy (18/29, 62.1%).
The treatment‐related toxicities between the 2 radiation dose groups were compared and the results are presented in Table 3. The most common ≥ grade 3 acute toxicity was hematologic toxicities, and the leukopenia was predominantly. No difference of ≥ grade 3 acute treatment‐related toxicities was noted between different radiation groups, except more grade 1–2 skin reaction in patients who received radiation dose >50.4 Gy.
Table 3.
Acute treatment‐related toxicities between IMRT with or without simultaneous integrated boost to the primary tumor (radiation dose ≤ vs. > 50.4 Gy).
| RT ≤ 50.4 Gy (n = 51) | RT > 50.4 Gy (n = 29) | p value | |||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Pneumonitis | |||||
| No | 34 | 66.67 | 20 | 68.97 | 0.9999 |
| Grade 1‐2 | 17 | 33.33 | 9 | 31.03 | |
| Esophagitis | |||||
| No | 13 | 25.49 | 6 | 20.69 | 0.9176 |
| Grade 1‐2 | 35 | 68.63 | 22 | 75.86 | |
| Grade 3‐4 | 3 | 5.88 | 1 | 3.45 | |
| Skin reaction | |||||
| No | 41 | 80.39 | 15 | 51.72 | 0.0166 |
| Grade 1‐2 | 9 | 17.65 | 12 | 41.38 | |
| Grade 3‐4 | 1 | 1.96 | 2 | 6.90 | |
| Hematologic | |||||
| No | 1 | 1.96 | 0 | 0.00 | 0.7755 |
| Grade 1‐2 | 27 | 52.94 | 14 | 48.28 | |
| Grade 3‐4 | 23 | 45.10 | 15 | 51.72 | |
| Leukopenia | |||||
| No | 6 | 11.76 | 2 | 6.90 | 0.8399 |
| Grade 1‐2 | 26 | 50.98 | 15 | 51.72 | |
| Grade 3‐4 | 19 | 37.25 | 12 | 41.38 | |
| Anemia | |||||
| No | 13 | 25.49 | 4 | 13.79 | 0.3382 |
| Grade c | 33 | 64.71 | 20 | 68.97 | |
| Grade 3‐4 | 5 | 9.80 | 5 | 17.24 | |
| Thrombocytopenia | |||||
| No | 30 | 58.82 | 16 | 55.17 | 0.7339 |
| Grade 1‐2 | 11 | 21.57 | 5 | 17.24 | |
| Grade 3‐4 | 10 | 19.61 | 8 | 27.59 | |
Discussion
Although trimodality therapy with neoadjuvant CCRT followed by surgery is the standard of treatment for locally‐advanced esophageal cancer, not all patients are eligible for surgery. Based on the RTOG 85‐01, the definite CCRT has become the standard treatment option for those who are not suitable for surgery and reported the 5‐ and 10‐year survival outcomes of 27% and 20%, respectively [[12], [13]]. In current study, the 5‐year OS rate for all patients was 13.0%, which was much lower than the result of the RTOG 85‐01. But in subgroup analysis, patients who received chemotherapy ≥4 cycles had 3‐ and 5‐year survival rates of 27.7% and 17.8%, respectively. The result is similar to the INT 0123, but shorter than the RTOG 85‐01. The shorter survival in current study might be contributed to poor KPS in our enrolled patients (66.3% of the patients had KPS ≤ 70 in our study versus < 10% in the RTOG 85‐01), which inevitably influenced the compliance of receiving chemotherapy (about 40% of the patients received chemotherapy < 4 cycles). Besides, a higher proportion of our enrolled patients (81.3%) had locally‐advanced stage III disease compared with the RTOG 85‐01 and INT 0123, which had inherently poorer survival outcome.
Three published articles using National Cancer Database and Taiwan Cancer Registry database showed the patients with stage I‐IIIC esophageal cancer who received definite CCRT had 5‐year survival about 15–20% [[11], [21], [22]]. Despite >80% of the patients had stage III disease in our current study, we found patients who received chemotherapy ≥4 cycles had similar survival outcome. The possible reason to explain the better compliance of receiving concurrent chemotherapy ≥4 cycles might be contributed to the use of IMRT, which reduce the acute treatment‐related side‐effects during the treatment.
The 5‐year LRP rate in current study was about 55%, which was mainly contributed to a higher proportion of locally‐advanced disease in our enrolled patients. The patient who received IMRT with simultaneous integrated boost to the primary tumor with total radiation dose >50.4 Gy had a lower incidence of LRP compared with those with radiation dose ≤50.4 Gy (5‐year LRP rates were 44% and 60%, respectively). Chen and Kim both reported that higher radiation dose ≥60 Gy could improve OS and local control in non‐operated esophageal squamous cell carcinoma [[23], [24]]. In current study, higher radiation dose >50.4 Gy also showed better LRPFS, but it did not translate into better survival. We used IMRT for our enrolled patients and found no difference in ≥ grade 3 acute treatment‐related toxicities between radiation dose ≤ with >50.4 Gy. In contrast to the conventional 2D or 3D‐CRT used in the previous studies, the IMRT had superior dose conformity/homogeneity and reduction of radiation dose to normal organs [[15], [16], [17], [25], [26]]. Therefore, better local control rate by dose escalation using IMRT is expected and need further investigations to establish the ideal range of radiation dose.
In the current study, we found that patients who had a radiation dose of >50.4 Gy and chemotherapy <4 cycles had the worst survival. Possible reasons for this result include (1) poor compliance of chemotherapy, which would interfere the synergistic effect of CCRT and (2) the relatively poorer performance status of our enrolled patients. Although escalation of radiation dose could be achieved by IMRT technique, this treatment is still insufficient without chemotherapy for inoperable or unresectable esophageal cancer. In the INT 0123 study, about 60% of patients could receive the scheduled chemotherapy in either the high‐dose or standard‐dose arms. Escalation of radiation dose certainly appears to confer clinical benefits, but poor compliance with chemotherapy might be a critical issue for esophageal cancer patients.
Combination of concurrent chemotherapy with taxane and platinum showed better tumor response in either adenocarcinoma or squamous cell carcinoma of the esophagus with acceptable toxicities [[7], [8], [27], [28]]. If surgery is planned as a component of treatment, this regimen combined with reduction of neoadjuvant radiation does is feasible [[7], [8]]. Noronha reported that definite radiotherapy with mean dose of 58.7 Gy plus concurrent carboplatin and paclitaxel had superior 3‐year survival outcome of 39% [27]. It is encouraging that new chemotherapy regimen could provide more survival benefit, but further investigation is needed to establish the ideal dose of definite radiation and concurrent chemotherapy regimens.
In our current study, only the cCR is an independent prognostic factor in OS. However, since surgical intervention was not one of the treatment modalities in our study, no definite evidence for pathologic complete response could be evaluated. Although a higher rate of locally persistent or recurrent disease was noted in patients with esophageal cancer who did not receive further surgery [[12], [29]], the necessity of surgery in patients undergoing definite CCRT is controversial. Two randomized trials directly compared CCRT alone to CCRT followed by surgery [[30], [31]] and both failed to demonstrate survival difference. Both of them showed better locoregional control and a reduced need for palliative procedures when surgery is a component of multimodality treatment.
The chemotherapy ≥4 cycles is a significant better prognostic factor in LRPFS and DMFS. Since the esophageal cancer is a highly lethal malignancy with a high tendency of local recurrence and distant failure, the systemic treatment seems to play an important role in disease control. More therapeutic‐effect and gentle side‐effects chemotherapy regimens are urgently needed, and further investigations are required.
Limitations of our current study include its retrospective nature, the small number of patients, and the lack of data of late toxicities of definite CCRT. Although the case number was too small to yield a statistically survival difference between two different radiation dose groups, definite IMRT with radiation dose >50.4 Gy showed a better local control without increasing treatment‐related toxicities. Further randomized trial to compare the dose escalation by using modern radiation technique in definite CCRT for patients with inoperable esophageal cancer is needed to explore the impact of survival and local control and further establish the treatment basis. In conclusion, it is helpful to improve the survival for the patients with inoperable esophageal squamous cell carcinoma by treating with reasonable dose‐escalated IMRT plus chemotherapy ≥4 cycles.
Supporting information
Supplementary data
Supplementary data
Supplementary data related to this article can be found at https://doi.org/10.1016/j.kjms.2017.12.005.
Conflicts of interest: All authors declare no conflicts of interests.
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