In this retrospective study including 90 inoperable ESCC patients receiving IMRT, we found higher radiation doses brought significantly better PFS and OS than lower radiation doses (≤ 60 Gy). In addition, a persistent trend toward better LRC and DMFS in the high dose group was also observed. Meanwhile, no additional grade ≥ 3 treatment-related toxicities were present in the high dose group. These results suggested that IMRT at a radiation dose > 60 Gy would be necessary and safe for inoperable patients with locally advanced ESCC. Our work contributed to explore the optimal dose of IMRT for ESCC patients.
The RTOG8501 study [11] established concurrent CRT as the standard therapeutic strategy for EC patients. Shortly afterwards, the RTOG9405 study [5] identified an optimal dose of concurrent CRT at 50.4 Gy for EC patients. However, there is still a lack of consensus on the optimal radiotherapy dose for locally advanced EC. First, although there were more deaths in the high dose group than the low dose group (11 vs 2), 7 of the 11 patients in the higher dose group died before the radiotherapy dose reached 50.4 Gy. Therefore, higher risk of death might not result from the higher radiation doses [5]. Second, more than 60% EC patients in the RTOG9405 trial were at early clinical stages. Third, higher distant metastasis rate might result from the higher proportion of stage III patients in the high dose group. Fourth, both squamous cell carcinoma (85%) and adenocarcinoma (15%) were included in the RTOG9405 study, which might have different optimal radiation dose since ESCC was more sensitive to radiotherapy. Fifth, the lower fluorouracil dose in the high dose group of RTOG9405 trial might impact the prognosis. Finally, patients received conventional rather than modern radiotherapy techniques in the RTOG9405 trial. The radiotherapy technology has been improved over the last decades, and the recommended radiation dose should be updated accordingly.
Our study aimed to investigate the efficacy of IMRT at the high dose (> 60 Gy) compared with the low dose (≤ 60 Gy) for inoperable ESCC patients with advanced clinical stages (Ⅱ-ⅣA). The OS and PFS of patients were better in the high dose group than the low dose group in our study (P < 0.05). Previous studies also indicated that increased radiotherapy dose improved the therapeutic effects of CRT on EC patients, as shown in Table 4 [6, 9, 12–16]. The higher radiation doses resulted in significantly better OS (P < 0.05) [9, 12, 15, 16]. In our study, we also found that the higher radiation doses increased OS rates compared with the lower doses (1-year OS 57.5% vs 39.5%; 2-year OS 31.4% vs 15.8%, P = 0.007). However, Suh et al. [13] reported that higher doses (≥ 60 Gy) had higher 2-year LCR (69% vs 32%, P < 0.01) and 2-year PFS rate (47% vs 20%, P = 0.01). The median OS of the high and low dose groups were 28 and 18 months, respectively (P = 0.26). Zhang et al. [6] reported that > 51 Gy had significantly better LCR than ≤ 51 Gy in EC patients with clinical stages II or III (P = 0.01). Our study also suggested a persistent trend toward better LRC in the high dose group (P = 0.707). In addition to Chang et al., the other 6 studies did not consider the possible effects of the radiation technique on patients (Table 2). Our data indicated that the higher radiation doses of IMRT might improve the PFS of inoperable patients with locally advanced ESCC. This finding complements previous studies reported by Chang et al. which failed to provide detailed information of the patients, as well as progression free survival (PFS).
Table 4
High versus low dose group radiotherapy for esophageal cancer.
Author | Year | Study design | No. of patients | Clinical Stage | Radiation dose | Radiation technology | Pathology (SCC/AC) | OS | P value |
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Zhang [6] | 2005 | Retrospective | 69 | Ⅱ-Ⅲ | > 51 Gy ≤ 51 Gy | 2DRT/ 3DCRT | 47/20 2Unknown | 13% (3y) 3% | 0.054 |
Wang [12] | 2006 | Retrospective | 35 | Ⅰ-Ⅲ | > 50 Gy < 50 Gy | 2DRT/ 3DCRT | 31/4 | 29% (5y) 0% | 0.002 |
Suh [13] | 2014 | Retrospective | 126 | Ⅱ-Ⅲ | ≥ 60 Gy < 60 Gy | 2DRT/ 3DCRT | 117/6 3Unknown | 52.4% (2y) 45.2% | 0.26 |
He [14] | 2014 | Retrospective | 193 | Ⅰ-Ⅳ | ≥ 50.4 Gy < 50.4 Gy | 3DCRT | 193/0 | 41.7% (5y) 33.0% | 0.617 |
Kim [15] | 2016 | Retrospective | 236 | Ⅱ-Ⅲ | ≥ 60 Gy < 60 Gy | 3DCRT/ IMRT | 230/6 | 35.1 mons (MST) 22.3 mons | 0.043 |
Chang [9] | 2017 | Retrospective | 2061 | ⅠA-ⅢC | ≥ 60 Gy < 60 Gy | IMRT | - | 35.47% (2y) 26.74% | \(cript>\)0.0001 |
Deng [16] | 2017 | Retrospective | 137 | Ⅰ-Ⅲ | ≥ 59.4 Gy 50-50.4 Gy | 3DCRT/ IMRT | 137/0 | 30% (3y) 24% | 0.037 |
Abbreviations: 2DRT, two-dimensional radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; SCC, squamous cell carcinoma; AC, adenocarcinoma; MST, median survival time; OS, overall survival. |
EC tumor length was included in the TNM staging system until 1987. For EC patients, the current clinical T stage of UICC/AJCC edition 8 [10] is based on the depth of tumor invasion into surrounding tissues, which is different from most solid tumors depending on tumor length. However, in our study, the multivariate Cox regression analysis showed that tumor length (≥ 5 vs < 5 cm) was identified as a prognostic factor for PFS (HR: 2.29; 95% CI: 1.05–4.99; P = 0.037). Currently, increasing researches explore the relationship between tumor length and EC prognosis. Eloubeidi et al. [17] retrospectively analysed 10,441 patients with EC in SEER database and found that tumor length was an independent factor for prognosis. The longer the tumor length, the deeper the tumor infiltration, and the more lymph node metastasis. Serum hemoglobin levels were used as indicators of the patient's nutritional status in our study. Patients with hemoglobin ≥ 132.1 g/L had better OS and PFS. Hemoglobin is the main oxygen carrier in erythrocytes, as a marker of nutritional, immunity and tumor-tolerance [18]. Retrospective studies confirmed that patients with lower hemoglobin values had poorer prognosis in cervical cancer, ovarian cancer, non-small cell lung cancer, and head and neck tumors [19–22]. In our study, the optimal cut-off was defined as the hemoglobin value with the smallest P-value of log-rank tests. Patients with hemoglobin levels < 132.1 g/L should be concerned and the patients’ hemoglobin levels should be raised before treatment. Our data identified critically prognostic factors in inoperable patient with locally advanced EC with IMRT. Additional studies are still required for validation.
IMRT becomes increasingly popular since it improves target conformality and decreases treatment-related toxicity [23]. Other studies also confirmed that IMRT decreased the radiation doses to protect the normal tissues, such as lungs, heart and thyroid [9, 24–27]. In our study, no patient died of treatment-related toxicity. No significant difference between the high and the low dose groups on treatment-related toxicities of grade ≥ 3, including hematologic toxicity, radiation esophagitis, radiodermatitis and fistula (P = 0.402).
It should be noted that this study had several limitations. First, it was a retrospective study in a single institution, which inevitably resulted in a selection bias and treatment heterogeneity. Second, the number of patients included in this study is relatively small. In the future, a large-scale randomized prospective trial is required to further confirm the conclusion.