Abstract: Esophageal cancer (EC) is an extremely aggressive, lethal malignancy that is increasing in incidence worldwide. At present, definitive chemoradiotherapy is accepted as the standard treatment for locally advanced EC. The EC guidelines recommend a radiation dose of 50.4 Gy for definitive treatment, yet the outcomes for patients who have received standard-dose radiotherapy remain unsatisfactory. However, some studies indicate that a higher radiation dose could improve local tumor control, and may also confer survival benefits. Some studies, however, suggest that high-dose radiotherapy does not bring survival benefit. The available data show that most failures occurred in the gross target volume (especially in the primary tumor) after definitive chemoradiation. Based on those studies, we hypothesize that at least for some patients, more intense local therapy may lead to better local control and survival. The aim of this review is to evaluate the radiation dose, fractionation strategies, and predictive factors of response to therapy in functional imaging for definitive chemoradiotherapy in esophageal carcinoma, with an emphasis on seeking the predictive model of response to CRT and trying to individualize the radiation dose for EC patients.
Keywords: esophageal cancer, radiation dose, altered fractionation, predictive factors, individualization
Esophageal cancer (EC) is a common cause of cancer death around the world.1,2 In East Asia, squamous cell carcinoma (SCC) is the most common type of EC, whereas adenocarcinoma is predominant in Western countries.3,4 These two types may represent different diseases, each with a distinct pathogenesis, epidemiology, prognosis, and tumor biology, including the pattern of lymph node metastasis.5
At present, definitive concurrent chemoradiotherapy (CCRT) is the basic strategy for locally advanced inoperable EC patients based on the results of the pivotal study of Intergroup Radiation Therapy Oncology Group (RTOG)-8501, which significantly improved the local control (LC) and overall survival (OS) with CCRT compared with radiotherapy (RT) alone.6 Furthermore, another RTOG study (#90–12) found that escalating the dose to 64.8 Gy did not confer a benefit compared with standard doses and may have contributed to a higher incidence of treatment-related death.7 In the landmark INT0123 trial, dose escalation from 50.4 to 64.8 Gy also did not increase OS; this may have been due to higher toxicities and no therapeutic gain in dose escalation for pathological complete responses (pCRs) after planned radiation.8 On the basis of these results, 50.4 Gy has become the accepted standard dose in Europe and North America for patients undergoing definitive CRT (DCRT). Although radiation dose escalation has failed to improve LC or OS, a dose of 60.0 Gy or more is more popular in Asian countries, where SCC is the predominant histological type.9,10 However, the prognosis for EC patients treated by standard-dose CRT was still disappointing, and >50% of such patients eventually developed recurrence or distant metastases and died as a result.11 Many studies have been performed to describe patterns of recurrence after DCRT for EC, revealing that most failures in both early and advanced EC occurred in the gross target volume (GTV) (especially in the primary tumor) after CRT.12–18Significantly, the recurrent site in the patient undergoing surgery occurred mainly in the locoregional node as well as distant metastasis, while in patients treated with DCRT it occurred mainly in the primary lesion.19–21 This indicates that the standard dose (50.4 Gy in 28 fractions), at least for some patients, may be inadequate to achieve a high probability of LC. Hence, for EC patients treated with DCRT, efforts should be made to intensify the treatment to improve the LC rate, which may lead to survival benefits.
In addition, on the basis of the theory of radiation biology, a radiation dose of 45–50 Gy is adequate to control microscopic tumors, 60 Gy or more is required to control gross tumors, and nearly 100 Gy is needed to cure solid tumors at conventional fractionation.22 In recent years, continuous advancements in RT technology over the past decades have allowed for EC now being able to be treated with 3-dimensional (3D) treatment planning, including intensity-modulated RT (IMRT), volumetric-modulated arc therapy (VMAT) and helical tomotherapy. These modern techniques allow the oncologist to deliver higher doses of radiation with more precision to the tumor and with less toxicity to the surrounding normal tissue, which has dramatically reduced morbidity.23,24 Thus, with the improvements in RT techniques and chemotherapy regimens, the question has been raised as to whether high-dose RT given concurrently with effective chemotherapy could achieve similar or better survival rates compared with the standard treatment, especially for esophageal SCC (ESCC).
The aim of this review is to evaluate the radiation dose, fractionation strategies, and predictive factors of response to therapy in functional imaging for definitive CRT in EC, with an emphasis on seeking the predictive model of response to CRT and trying to individualize the radiation dose for EC patients.