Higher dose RT for DCRT
Continuous advancements in RT technology allow the oncologist to deliver higher radiation doses to the tumor with less toxicity to the surrounding normal tissue. This has led to a dramatic decline in morbidity.23,24 Furthermore, the simultaneous integrated boost (SIB) technique has been applied to many tumors, including in EC. Use of an SIB technique enables delivery of a higher dose to the primary tumor (2.2 Gy/f), whereas lower doses to the subclinical disease (1.8 Gy/f).25,26
With the improvements in treatment techniques, some researchers have tried to address the potential benefit of a higher radiation dose for EC. In the retrospective analysis by Suh et al the results also showed that patients who received a total dose ≥50.4 Gy of RT had significantly better loco-regional control (LRC, 69% vs 32%, p<0.01) and progression-free survival (PFS, 47% vs 20%, p=0.01), than patients receiving <50 Gy when treated with concurrent chemotherapy. High-dose radiation ≥50.4 Gy showed no significant OS benefit for patients with EC (28 vs 18 months, p=0.26).27 He et al used modern radiation delivery techniques to determine whether high radiation dose could confer benefits in terms of LC or OS.28 The results showed that high radiation dose provided a significant lower rate of local recurrence (17.9% vs 34.3%, p=0.024) compared with patients receiving low radiation dose. Furthermore, patients receiving high radiation dose did have a marginally better 5-year local-regional recurrence-free survival (68.7% vs 55.9%, p=0.052) than in the low-dose group. The 5-year OS rate showed no significant difference between the two groups (p=0.617). Although IMRT reduced the overall incidence of treatment-related toxicity, the rates of grade 3 or greater skin reaction and esophageal strictures were higher in the higher dose group. Considering the potential for better tumor LC but more severe toxicity with the higher radiation dose, He et al recommends that individualized treatment strategies be designed for patients treated with DCRT. Indeed, these studies found that radiation doses over 50.4 Gy could improve LC but not OS for EC patients.
However, some studies have shown that high-dose RT may provide a survival benefit. The study of Zhang et al found that the median survival time was 9 months for the lower dose group (≤51 Gy) and 14.5 months for the higher dose group (>51 Gy) among 69 patients treated with CCRT (p=0.054).29 In line with these findings, Kim et al evaluated the correlation between radiation dose and survival for EC patients treated with DCRT. The results showed that patients in the high-dose group (≥60 Gy) had significantly better 2-year LRC (69.1% vs 50.3%, p=0.002), median PFS (16.7 vs 11.7 months, p=0.029), and median OS (35.1 vs 22.3 months, p=0.043) than in the low-dose group (<60 Gy).30Similar to these results, a retrospective study found that higher radiation dose may bring a survival benefit for EC patients.31 Wolf et al also concluded that the use of radiation doses exceeding 54 Gy was associated with better OS (p=0.002).32 Semrau et al in a retrospective analysis, showed that patients receiving high radiation dose had a greater 2-year OS (26.8%, vs 7.5%; p=0.0001), and PFS (17.4% vs 5.0%; p=0.0001) than the low-dose group.33 A pooled analysis by Song et al investigated whether high-dose (>60 Gy) RT in DCRT could confer survival benefits compared with the low-dose RT for patients with EC.34 Those results showed advantages in response rate, 5-year OS, locoregional recurrence, and distant failure compared with the standard RT arm. However, there is no evidence from prospective randomized trials to support that a higher radiation dose could bring survival benefit for EC patients.
In a recently published Phase I dose-escalation study, Yu et al suggest that it is feasible to deliver up to 70 Gy (2.8 Gy/F) to the GTV based on positron emission tomography/computed tomography (PET/CT) in EC patients.35 Thus, the use of a novel dose-escalation technique may be more likely than high-dose (>60 Gy) RT to lead to better LC and OS. A Phase II study by Chen et al evaluated the efficacy of radiation dose escalation using SIB in 60 EC patients.36 RT consisted of 66 Gy at 2.2 Gy per fraction to the gross tumor and 54 Gy at 1.8 Gy per fraction to subclinical diseases simultaneously. The result showed that the 1-year LRC, distant metastasis-free survival (DMFS), disease-free survival (DFS), and OS rates were 87.6%, 78.6%, 86.0%, 80.5%, respectively. And the 2-year LRC, DMFS, DFS, and OS rates were 75.6%, 64.4%, 86.7%, 72.7%, respectively. This indicates that SIB combined with concurrent chemotherapy is feasible, with tolerable acute toxicities in EC patients, and a trend of significant improvements in LRC and OS was shown.
Radiation dose escalation for DCRT studies are summarized in Table 1. In summary, a few studies have demonstrated that higher doses than standard RT can improve local tumor control and may lead to better survival for EC patients. Although no evidence from Phase III prospective randomized trials support the additional survival benefit of dose-escalated RT in the whole population, these results may suggest that a subgroup of patients may benefit from limited dose escalation. Considering the potential survival benefits but more severe toxicity in the higher radiation dose group, the optimal radiation dose should be managed on an individual basis. Nevertheless, Phase III trials comprising a standard-dose arm using modern RT technique are warranted in the right subgroup population.
(To view a larger version of Table 1, click here.)