Dose fractionation strategies for DCRT

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The prognosis for EC patients treated with conventional RT alone remains discouraging despite the advances in radiotherapeutic techniques. The low survival rate and high incidence of locoregional treatment failure in EC have initiated a modification of conventionally fractionated RT. Recent studies are consistent in revealing that the accelerated reproliferation of carcinoma stem cells after RT is an important reason for the failure of RT.37,38 Therefore, it is speculated that the rates of LC and survival can be improved by controlling the accelerated reproliferation of carcinoma stem cells after RT. In this respect, it has been revealed that 3–4 weeks after RT, carcinoma stem cells started to have accelerated reproliferation, which provides the theoretical principle for accelerated hyperfraction RT later in the treatment process.

Several studies have investigated whether it would be possible to achieve a better curative effect from RT by adopting a late-course accelerated hyperfraction (LCAF). A Japanese Phase II study of accelerated hyperfraction plus 5fluorouracil/cisplatin chemotherapy showed a promising result.39Similarly, Shi et al40 initiated a study of late-course accelerated hyperfractionated RT (LCAFRT) for ESCC treatment and it yielded encouraging results. They found that patients with the LCAFRT regime could achieve a better 5year survival rate (34% vs 15% for patients with conventional fractionation) and LC rate (55% vs 21% for patients with conventional fractionation). A prospective study by Zhao et al also revealed that the LCAFRT regimen offers better LC and survival compared to standard chemotherapy plus RT, as in the RTOG 8501 and 9405 trials.41 A meta-analysis from China strengthened the evidence supporting the therapeutic benefits of LCAFRT compared with conventional fractionation for EC.42 In addition, a randomized controlled trial was recently undertaken to investigate whether LCAF 3D conformal RT could achieve better results than conventional fraction (CF).43 The resulting data showed that the 1-, 2- and 3-year survival rates were 79.2%, 56.3%, and 43.8%, respectively, in the LCAF group; and, in the CF group, the 1-, 2- and 3-year survival rates were 74%, 54%, and 36%, respectively (p=0.476). The 1-, 2- and 3-year LC rates were 81.3%, 62.5%, and 50%, respectively, in the LCAF group; in the CF group, the 1-, 2- and 3-year LC rates were 78%, 58%, and 42%, respectively (p=0.454). In the CF group, the incidence of radiation-induced esophagitis was lower than that in the LCAF group (72% vs 93.8%; p=0.008). It was concluded that EC patients in the LCAF group did have a slightly improved survival compared to those who received RT using conventional fractionation; the radiation toxicities, however, were greater in the LCAF group than those in the CF group. In a Phase III randomized study of LCAFRT plus concurrent chemotherapy for patients with ESCC, Zhao reported patients who received LCAFRT with concurrent chemotherapy had a tendency to better survival. But the incidence rates of grade 3 and 4 toxicities seemed higher in the LCAHRT+ CT arm (46%) than those in the LCAHRT arm (25%), and the grade 5 toxicities for the two group were 6% and 0%, respectively.44

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These studies suggest that the accelerated hyperfractionated schedules were effective but with an increased incidence of acute III–IV grade toxicity, which limited the combination of concurrent chemotherapy with RT. The advent of modern RT techniques and low-toxicity chemotherapy drugs may improve the clinical efficacy. The medical effects and safety observations of this kind of combination should be verified in prospective trials.

Future thinking

Much evidence has shown that there is a positive correlation between OS rate and the scale of chemoradiation in the histopathological response of patients with EC.45–47 Patients with CRs had a 5year OS rate of 61.6%, which is higher than patients with an incomplete response or no response.45We speculated that if more patients with incomplete or no responses after planned radiation could achieve CR through limited radiation dose escalation, their prognosis would be better. Besides, this scheme would avoid an increase in toxicity and a decrease in survival caused by dose escalation in patients with CRs.

But how to predict the response to therapy? A great number of studies have reported the response rates after CCRT in EC.6,8,16–18,48 The CR rate by stage was 89.7%–97% for T1, 50%–60% for T2 to T3, and 17%–39% for T4. For early-stage EC, most patients achieved a CR after CRT, while for locally advanced patients, CRT generally resulted in CR rates of 20%–50%. Apart from the tumor stage, patients with EC receiving RT also showed disparate treatment responses. Unfortunately, a large number of patients were resistant to CRT, which resulted in persistent disease or immediate local failure. For radiosensitive patients, the standard radiation dose of 50.4 Gy may be sufficient to obtain a pCR. But for the resistant lesions or advanced-stage EC, it is difficult to achieve a pCR at this dose. Even a dose escalation could not produce a better response; it may merely increase treatment-related toxicities in such refractory cases. We speculated that a subgroup of patients with partial remission after the standard radiation of 50.4 Gy could achieve better responses through limited radiation dose escalations without increased treatment toxicities. Hence, the identification of the predictive and prognostic factors will help to guide the oncologist in making informed decisions regarding the optimal radiation dose for treating ESCC, and indicate who have greater possibility benefit from limited radiation dose escalation.