Original Article. Hao Yang, 1,3 Cong Feng, 2 Bo-Ning Cai, 1 Jun Yang, 1 Hai-Xia Liu, 1 Lin Ma 1,

Transcription

1 Diseases of the Esophagus (2017) 30, 1 8 DOI: /dote Original Article Comparison of three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy in the treatment of cervical esophageal carcinoma Hao Yang, 1,3 Cong Feng, 2 Bo-Ning Cai, 1 Jun Yang, 1 Hai-Xia Liu, 1 Lin Ma 1, 1 Department of Radiation Oncology and, 2 Emergency Medicine, Chinese PLA General Hospital, Beijing, China, and 3 Department of Radiation Oncology, Inner Mongolia Cancer Hospital and The Affiliated People s Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China SUMMARY. The aim of this study was to evaluate the effectiveness and toxicities of three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), and volumetric-modulated arc therapy (VMAT) in patients with cervical esophageal cancer. Specifically, we asked whether technological advances conferred an advantage with respect to the clinical curative effect. Seventy-eight patients with cervical esophageal cancer treated with definitive radiotherapy with or without concomitant chemotherapy at our institution between 2007 and 2014 were enrolled in the study: 26 received 3DCRT, 30 were treated with IMRT, and 22 underwent VMAT. Kaplan Meier analysis and the Cox proportional hazard model were used to analyze overall survival (OS) and failure-free survival (FFS). Treatment-related toxicity was also assessed. For all patients, the 2-year OS and FFS rates were 56.2 and 53.9%, respectively. The 2-year OS for the 3DCRT, IMRT, and VMAT groups was 53.6, 55.6, and 60.6%, respectively (P = 0.965). The corresponding 2-year FFS rates were 49.5, 56.7, and 60.1% (P = 0.998). A univariate analysis of the complete response to treatment showed an advantage of treatment modality with respect to OS (P < 0.001). The development of acute hematologic toxicity was not significantly different among the three groups. The survival rates of patients treated with IMRT and VMAT were comparable to the survival of patients administered 3DCRT, while lower lung mean dose, V20, maximum dose of brachial plexus and spinal cord. Grade 1 radiation pneumonitis occurred significantly less in patients treated with IMRT and VMAT than with 3DCRT (P = 0.011). A complete response was the most important prognostic factor of the patients with cervical esophageal cancer. KEY WORDS: cervical esophageal cancer, three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, volumetric-modulated arc therapy. INTRODUCTION Cervical esophageal cancer (CEC) is relatively uncommon, accounting for <5% of all esophageal cancers. 1 Its treatment has been poorly studied because these patients are often included with those with carcinomas of the hypopharynx and thoracic esophagus, even though CEC is anatomically distinct from both of these cancers. 2,3 The therapies currently used to treat CEC include surgical resection, neoadjuvant chemoradiotherapy followed by surgery, and Address correspondence to: Dr. Lin Ma, MD, Department of Radiation Oncology, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing , China. malinpharm@sina.com H. Yang, C. Feng, and B.-N. Cai contributed equally to this manuscript. Conflicts of interest: The authors declare that they have no conflict of interest. definitive radiotherapy with or without concurrent chemotherapy. 4,5 However, a standard therapeutic strategy for patients with CEC has yet to be developed because of the low incidence of the disease and thus the paucity of clinical studies. Radiotherapy, whether as primary or adjuvant treatment, plays a predominant role in CEC because of protecting esophageal shape and function. In the last decade, three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), and volumetric-modulated arc therapy (VMAT) have been used to treat cervical and thoracic esophageal cancers and the feasibility of all three techniques in the treatment of CEC has been demonstrated. 6 9 However, IMRT and VMAT were shown to provide superior target volume coverage and conformality, with lower doses to normal structures. For both cervical and upper esophageal cancer, C 2016 International Society for Diseases of the Esophagus 1

2 2 Diseases of the Esophagus VMAT compared with IMRT with Varian Eclipse v8.6 (Varian Medical Systems, Palo Alto, CA) or Pinnacle 3 treatment planning systems (Philips Healthcare, Andover, MA), reduced the treatment time, low dose volumes of lung, and total MU, with similar or better sparing of the organs at risk (OAR) and target coverage. 8,10 The clinical efficacy of 3DCRT, IMRT, and VMAT in the treatment of CEC and whether technological advances confer an advantage in the form of an improved clinical curative effect have not been determined. Therefore, the purpose of this study was to analyze the outcomes of CEC patients treated at a single institution with 3DCRT, IMRT, and VMAT. MATERIALS AND METHODS Patients This retrospective study initially included 86 patients with confirmed pathological cervical esophageal squamous cell carcinoma who were treated with definitive radiotherapy alone or concurrent chemoradiotherapy (CRT) at our institution from 2007 to The study included the metastasis upper mediastinal lymph nodes (M1 lymph/stage IV). Eight patients were subsequently excluded for the following reasons: palliative intention, receiving insufficient radiation dose, and lost to follow-up. CEC was staged according to the American Joint Committee on Cancer 2002 staging system. The imaging examination at staging included a barium-swallow X-ray examination, a computed tomography (CT) scan of the neck, chest, and abdomen, 18 F-FDG-positron emission tomography ( 18 F-FDG PET), bronchoscopy, and endoscopic ultrasound of the esophagus. Chemotherapy Among the 78 patients included in the study, 22 received concurrent chemoradiotherapy consisting of cisplatin alone, cisplatin-5-fluorouracil (5FU), or cisplatin-paclitaxel. Eleven patients received cisplatin and 5FU-based induction chemotherapy. Thus, the majority of patients (n = 56) received radiotherapy alone, on an outpatient basis. Radiotherapy target volume All patients were immobilized with a thermoplastic head-neck-shoulder mask and underwent CT simulation with a slice thickness of 2 3 mm. The gross tumor volume (GTV), including the primary tumor and involved positive regional lymph nodes, was determined by means of multiple imaging studies, including barium studies, endoscopy, CT, magnetic resonance imaging, and 18 F-FDG-PET/CT. The clinical target volume (CTV) contained the GTV and additional cm radial and cranio-caudal margins of at least 3 cm with respect to the GTV. Elective nodal irradiation, including bilateral levels II IV of the cervical lymph node area, supraclavicular fossa, and upper mediastinal area according to the area drained by adjacent involved lymph nodes, is referred to in the following as CTV-elective. Irrelevant bony structures, muscles, and lung tissue were excluded from the CTV. The planning target volume (PTV) was generated with a 0.5 cm margin relative to the CTV and CTV-elective. It is referred to as the pgtv, PTV, and PTV-elective. The OARs to be contoured were the spinal cord, parotid gland, thyroid gland, lung, heart, larynx, and trachea. Treatment planning and delivery Pinnacle system (Pinnacle3 version 9.6, Phillips Medical Systems, Andover, MA) was used for 3DCRT, IMRT, and VMAT planning. Dose calculation was performed with anisotropic analytic algorithm. Patients received IMRT (Elekta Synergy linear accelerator: Elekta, Crawley, UK) and VMAT (Varian Truebeam linear accelerator: Varian Medical Systems, Palo Alto, CA) using a simultaneously integrated boost with daily image guidance. A total prescription dose of Gy was delivered to GTV at in Gy per daily fraction with five fractions per week. For PTV, the dose was Gy, in Gy fractions, and for PTV-elective Gy, in Gy fractions. The IMRT plan was singleisocenter, coplanar, with five to nine fields delivered using dynamic multi-leaf collimation. For the VMAT plan, two coplanar complete arcs were used. 3DCRT consisted of two phases. In the first phase, the patients were treated using a multiple-field technique, with four to seven beams delivering Gy for PTV and PTVelective, in Gy. In the second phase, a booster dose of Gy was given to the pgtv patients by using multiple fields to shield the spinal cord, for a total dose of Gy. The dose received by OARs was constrained as follows: both lungs V20 < 30%, V30 < 20%; heart V30 < 40%, V40 < 30%; and a maximum dose to the spinal cord of <45 Gy. All plans were optimized to reach clinically acceptable PTV coverage and OAR sparing. At least 95% of the PTV had to be covered by 95% of the prescription dose. Patient follow-up After completing treatment, the patients were evaluated at 3-month intervals for 1 years, at 6-month intervals for 2 3 years, and annually thereafter. The treatment response was assessed according to the response evaluation in solid tumors (RECIST) criteria 2 3 months after radiotherapy. Tumor responses were classified as complete response (CR), partial

3 3 response (PR), stable disease (SD), and progressive disease (PD). Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Statistics All statistical analyses were performed using SPSS software (version 14.0, SPSS, Inc., Chicago, IL). The characteristics of the patients in the three groups were compared using the Wilcoxon rank sum test for continuous characteristics and Pearson s χ 2 test for categorical characteristics. Survival data were analyzed using the Kaplan Meier method and a log-rank test to evaluate the end points of overall survival (OS) and failure-free survival (FFS). Each end-point was calculated from the date of the initial diagnostic biopsy. FFS was the time to any treatment failure or death. Statistical tests were based on a two-sided significance level. P < 0.05 was considered to indicate statistical significance. RESULTS Follow-up The median follow-up time of the 78 CEC patients receiving 3DCRT, IMRT, or VMAT (n = 26, 30, and Table 1 Patients characteristics 22, respectively) was 28 months. The median followup time for each group was 28 (range 5 104), 28 (range 8 56), and 31 (range 5 31) months, respectively. The characteristics of the patients and of their treatment are summarized in Tables 1 and 2. Treatment time, number of fractions, Lung V20, brachial plexus and spinal cord maximum dose differed significantly between the three groups (Table 2). Short-term effects Treatment efficacy was evaluated after 2 3 months. The CR, PR, SD, and PD rates of the patients in the three groups combined were 57.7% (45/78), 28.2% (22/78), 11.5% (9/78), and 2.6% (2/78), respectively. Survival and prognostic factors The 2-year OS and FFS of the 78 patients was 56.2 and 53.9%, respectively. In the IMRT and VMAT groups, the corresponding rates were 55.7 and 56.0%, respectively. Figure 1 shows the OS and FFS for all patients. There were no differences in the OS and FFS of patients receiving 3DCRT, IMRT, or VMAT. The 2-year OS was 53.6, 55.6, and 60.6% for the 3DCRT, IMRT, and VMAT groups, respectively (P = 0.965). The 2-year FFS was 49.5, 56.7, and 60.1% (P = 0.998). A univariate analysis of CR showed that it conferred an advantage with respect to OS and FFS. The hazard Characteristics 3DCRT (%) IMRT (%) VMAT (%) P value Mean age (standard deviation) 62.5 (12.2) 64.0 (8.7) 62.6 (8.9) Gender Male 21 (80.8) 16 (53.3) 15 (68.2) Female 5 (19.2) 14 (46.7) 7 (31.8) Weight loss 10% 10 (38.5) 9 (30.0) 10 (45.5) <10% 16 (61.5) 21 (70.0) 12 (54.5) Hoarseness Yes 4 (15.4) 4 (13.3) 5 (22.7) No 22 (84.6) 26 (86.7) 17 (77.3) Bleeding Yes 2 (7.7) 3 (10.0) 2 (9.1) No 24 (92.3) 27 (90.0) 20 (90.9) T stage T1-2 8 (30.8) 13 (43.3) 7 (31.8) T3 17 (65.4) 13 (43.3) 13 (59.1) T4 1 (3.8) 4 (13.4) 2 (9.1) N stage N0 13 (50.0) 14 (46.7) 9 (40.9) N1 13 (50.0) 16 (53.3) 13 (59.1) M stage M0 25 (96.2) 28 (93.3) 18 (81.8) M1 1 (3.8) 2 (6.7) 4 (18.2) Stage I II 15 (57.7) 17 (56.7) 8 (36.4) III IV 11 (42.3) 13 (43.3) 14 (63.6) Tumor extension CE 10 (38.5) 11 (36.7) 7 (31.8) CE + HP 0 (0.0) 2 (6.7) 3 (13.6) CE + TE 16 (61.5) 17 (56.6) 12 (54.6) Tumor length 5 cm 15 (57.7) 21 (70.0) 12 (54.5) >5 cm 11 (42.3) 9 (30.0) 10 (45.5) GTV volume <46 cc 12 (46.2) 18 (60.0) 13 (59.1) cc 14 (53.8) 12 (40.0) 9 (40.9) Short-term effects CR 16 (61.5) 20 (66.7) 9 (40.9) PR 7 (26.9) 5 (16.7) 10 (45.5) SD 2 (7.7) 4 (13.3) 3 (13.6) PD 1 (3.9) 1 (3.3) 0 (0.0) CE, cervical esophagus; HP, hypopharyngeal extension; TE, thoracic esophageal extension; CCRT, concurrent chemoradiotherapy; CR, complete response; PR, partial response; SD, stable disease; P, progressive disease; GTV, gross tumor volume.

4 4 Diseases of the Esophagus Table 2 Treatment characteristics Characteristics 3DCRT (%) IMRT (%) VMAT (%) P value Fig. 1 CCRT Yes 5 (19.2) 11 (36.7) 6 (27.3) No 21 (80.8) 19 (63.3) 16 (72.7) Treatment time 42 days 8 (44.4) 16 (53.3) 16 (72.7) >42 days 18 (55.6) 14 (46.7) 6 (27.3) Number of fractions <32 fraction 1 (3.8) 26 (86.7) 18 (81.8) fraction 25 (96.2) 4 (13.3) 4 (18.2) GTV dose <66 Gy 9 (34.6) 12 (40.0) 5 (22.7) Gy 17 (65.4) 18 (60.0) 17 (77.3) Lung V20 (%) (standard deviation) 22.4 (4.9) 16.3 (3.3) 15.4 (3.9) Lung Dmean (Gy) (standard deviation) 11.5 (2.2) 10.1 (2.5) 9.9 (2.7) Brachial plexus max dose (Gy) (standard deviation) 60.8 (4.6) 55.3 (4.9) 56.9 (4.7) Spinal cord max dose (Gy) (standard deviation) (1.1) 40.6 (2.1) 39.9 (2.2) CCRT, concurrent chemoradiotherapy; max, maximum; GTV, gross tumor volume. GTV dose given as equivalent dose 2 Gy per fraction. Kaplan Meier analysis of the OS and FFS for all patients in the treatment of CEC. (A) OS. (B) FFS. ratios determined in a multivariate analysis of OS and FFS are provided in Table 3. The 2-year OS and FFS rates were significantly better in patients reaching CR than in those who did not (OS: 80.8 vs. 29.6%, P < 0.001; FFS: 78.0 vs. 18.8%, P < 0.001). Figure 2 shows the OS and FFS rates in patients stratified by treatment method. Acute hematologic toxicity The most frequently observed acute hematologic toxicity, including leukocytopenia, anemia, and thrombocytopenia, was mainly grade 1 or 2. The incidence of grade 3 or 4 acute hematologic toxicity was 11.5, 10.0, and 9.1% in the 3DCRT, IMRT, and VMAT groups, respectively. The differences were not statistically significant (P = 0.960). Late toxicities The IMRT and VMAT plans generated a significantly lower lung mean dose and V20 than the 3DCRT plan. Lung mean dose was respectively 11.5, 10.1 and 9.9 Gy for 3DCRT, IMRT and VMAT (P = 0.041). Lung V20 was respectively 22.4, 16.3 and 15.4% for 3DCRT, IMRT, and VMAT (P = 0.001). Table 4 compared the rates of late toxicities by treatment method. Late toxicities were more severe in the 3DCRT group than in the IMRT and VMAT groups. Grade 1 radiation pneumonitis, diagnosed by chest CT scan in 6 months after completion of radiotherapy with diffuse haziness or fuzziness and relatively sharp edge corresponding to the shape and size of the radiation field, occurred significantly less often in patients treated with IMRT and VMAT than in those treated with 3DCRT (P = 0.011). MRT and VMAT could decrease maximum dose to brachial plexus and spinal cord with statistically significant (Table 2). Six patients with cervical or supraclavicular lymphatic metastasis adjacent to the brachial plexus experienced radiationinduced brachial plexus injury because in the initial treatment plans it was not limited maximum dose (Dmax > 66 Gy) because brachial plexus injury was scarcely reported. We retrospectively analyzed six treatment plans. After re-planning for the six patients using IMRT and VMAT with limiting its maximum

5 5 Table 3 Hazard ratios in multivariate analysis for overall survival (OS) and failure-free survival (FFS) Hazard ratios for OS Hazard ratios for FFS Parameter 95% CI P value 95% CI P value Age (>60 vs. 60) Gender (male vs. female) Weight loss ( 10% vs. <10%) Hoarseness (Yes vs. No) Bleeding T stage (T1-2 vs. T3 vs. T4) N stage (N0 vs. N1) Stage (stage I-II vs. III-IV) Tumor extension CE vs. (CE + HP) vs. (CE + TE) Tumor length (>5vs. 5 cm) CCRT (Yes vs. No) Treatment time ( 42 vs. >42 days) Technique (3DCRT vs. IMRT vs. VMAT) GTV dose (<66 vs. 66) GTV volume (<46 vs. 46 cc) Radiation fractionation (<32 vs. 32 F) Short-term effects (CR vs. non-cr) < <0.001 HP, hypopharyngeal extension; TE, thoracic esophageal extension; CCRT, concurrent chemoradiotherapy; GTV, gross tumor volume; GTV, plan gross tumor volume; F, fractionation; CR, complete response; non-cr, no complete response. Fig. 2 Kaplan Meier analysis of the OS and FFS by radiation techniques in the treatment of CEC. (A) OS by radiation techniques of 3DCRT, IMRT, and VMAT. (B) FFS by radiation techniques of 3DCRT, IMRT, and VMAT. Table 4 Late toxicities by different treatment techniques Toxicity 3DCRT (%) IMRT (%) VMAT (%) P value Feeding tube 2/26 (7.7) 3/30 (10.0) 3/22 (13.6) Dysphagia 3/26 (11.5) 4/30 (13.3) 3/22 (13.6) Radiation pneumonitis 16/26 (61.5) 9/30 (30.0) 5/22 (22.7) Brachial plexus injury 3/26 (11.5) 2/30 (6.7) 1/22 (4.5) Bleeding 2/226 (7.7) 3/30 (10.0) 2/22 (9.1) Total toxicities 26/130 (20.0) 21/150 (14.0) 14/110 (12.7) DCRT, three-dimensional conformal radiation therapy; IMRT, intensity modulated radiation therapy; VMAT, volumetric-modulated arc therapy. dose to <66 Gy, a maximum dose of <62 Gy was achieved for six plans, with no effect on dosimetry. DISCUSSION Although prospective randomized data are not available, clinical research and methodological studies of the treatment of cervical and thoracic esophageal cancers have shown that IMRT and VMAT are better than 3DCRT with respect to improved target coverage and conformality and less radiation to adjacent organs. 6,9-11 However, whether these advantages translate into clinical benefits for CEC patients is largely unknown. Fenkell et al. 9 reported that in the treatment of these patients, IMRT provided

6 6 Diseases of the Esophagus superior target volume coverage and conformality than 3DCRT, with lower mean doses to the spinal cord, brainstem, and parotid gland. In our study OS, FFS, and acute hematologic toxicities did not significantly differ among the three groups, perhaps because the majority of our study patients received radiotherapy alone (78.9 vs. 21.1%). However, the incidence of late toxicities was lower in patients treated with IMRT and VMAT, suggesting that these advanced radiotherapy techniques are able to improve outcomes and alleviate toxicities in CEC patients treated with current standard concurrent chemoradiation. Although data from retrospective clinical studies support the use of IMRT and VMAT, their clinical efficacy for CEC has not been determined. Cao et al. 12 reported on 64 patients (42 with radiotherapy alone, 22 with concurrent chemoradiotherapy) with CEC who were treated with definitive IMRT. The median follow-up time was 14.5 months, with 2-year local FFS, regional FFS, distant FFS, and an OS of 74.5, 88.0, 66.6, and 42.5%, respectively. Our overall 2-year OS and FFS rates were similar to those reported by Cao et al. 12 : 55.7 and 56.0% in the IMRT and VMAT groups, respectively. In addition, those authors likewise found that neither treatment modality conferred survival benefits compared with conventional radiotherapy and 3DCRT. However, the small number of patients, the relatively short follow-up, and the heterogeneity of the patients limited the power of our study to detect small differences in outcome. Our study provides the first comparison of clinically relevant toxicities among 3DCRT, IMRT, and VMAT when used to treat patients with CEC. Several studies of CEC patients receiving concurrent chemotherapy during 3DCRT reported acute hematologic side effects of grade 3, including leukocytopenia (19 29%), anemia (7%), and thrombocytopenia (5 22%). 5,13,14 However, among the patients of Cao et al., 12 those who were administered IMRT had lower grade 3 leukocytopenia (10.9%), probably because the majority (65.6%) of patients in that group received radiotherapy alone. In our study, there were no significant differences in acute hematologic toxicities among the three treatment groups. In other studies of patients receiving concurrent chemoradiation for head-neck squamous cell carcinoma and esophageal cancer there were also no differences in hematologic toxicities between the 3DCRT and IMRT groups. 7,15,16 As the efficacy of treatment and thus the survival of patients with CEC improve, late toxicities will become an increasingly important consideration. We found that late toxicities associated with 3DCRT were slightly more severe than those occurring following IMRT and VMAT. The incidence of grade 1 radiation pneumonitis, as diagnosed by imaging, was much lower in the IMRT and VMAT groups than in the 3DCRT group because of the lower dose-volume to the lung in the former. Patients in these two groups also had no associated symptoms. Because the target volumes of CEC involve only the apex of the lung, it may be more resistant to radiation pneumonitis than the base of the lung In the study of Uno et al., 14 the incidence of radiation pneumonitis was 14% (3/21) among patients receiving concurrent chemoradiation for CEC. This percentage was similar to that determined in our study. In addition, The IMRT and VMAT plans were with significantly lowering lung mean dose and V20 than the 3DCRT plan, suggested better to protect the lung. Radiation-induced injury to the brachial plexus is a devastating complication after radiotherapy, but it has been poorly evaluated in patients with CEC. 1 In the series of Burmeister et al., 20 1(3%)ofthe 34 patients with CEC who received chemoradiation therapy developed neurological toxic effects because of radiation-induced brachial plexus injury. This patient exhibited Lhermitte s sign (transient shocklike sensation on head flexion) 7 months after therapy completion. Chen et al. 21 examined the relationship between brachial-plexus-associated neuropathy and radiotherapy techniques for head-and-neck cancer. They found that, for brachial plexus-associated symptoms, the 5-year symptom-free rate was lower using IMRT than non-imrt modalities, although the difference was not statistically significant (78 vs. 92%; P = 0.11). Additionally, there was no difference in the absence of neuropathic symptoms between patients in whom the brachial plexus was delineated as an OAR in the radiation planning process compared with those in whom it was not (5-year estimates: 82 vs. 81%, respectively, P = 0.52). IMRT and VMAT could reduce maximum dose to brachial plexus and spinal cord. IMRT and VMAT might be the preferred treatment option as these modalities better protecting the brachial plexus and spinal cord. Thus, the brachial plexus should be delineated and limit its maximum dose for patients with CEC and cervical or supraclavicular lymphatic metastasis adjacent to the brachial plexus. We also compared the short-term clinical efficacy and OS for CEC patients receiving radiotherapy and found a better OS for those with a CR. The improved survival was probably the result of both the CR of the tumor and the eradication of micrometastases by radiotherapy or concurrent chemoradiotherapy. Aoyama et al. 22 reported a 5-year OS of 62.4% for the 106 patients for whom adequate data regarding a continuing clinical CR were available. The marked survival effect of CR following chemotherapy and/or radiation therapy for carcinoma of the esophagus was consistent with our own findings. Numerous studies have shown that a pathological complete response (pcr) after neoadjuvant treatment correlated with better OS and disease-specific survival in patients with esophageal cancer. 23,24 Thus, an

7 7 important goal in the treatment of CEC is to improve CR and thereby increase the survival rate of these patients. Within this group, the dose of radiation, neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and concurrent chemoradiotherapy correlates significantly with pcr and CR. 23,24 The survival rate of patients with concurrent chemotherapy and radiation therapy for carcinoma of the esophagus was significantly better than the rate achieved with chemotherapy or radiotherapy alone (P = 0.027). 22 Randomized studies of esophageal cancer and head and neck cancer have shown that concurrent chemotherapy with radiation therapy (CCRT) can result in organ preservation and improved overall survival compared with radiotherapy alone. 25 However, the most common problem related to treatment outcome after CCRT for CEC is local and regional failure, rather than distant metastatis, 1,14 suggesting the need for a more aggressive local approach using higher radiation doses and radiosensitizing effects of chemotherapy. No statistically significant difference was observed in OS or FFS for the patients receiving CCRT and radiotherapy alone in the present study. Chances are that few patients (22/78, 28.2%) were given CCTR. Although in several studies there was no statistically significant difference in OS or locoregional FFS with CCRT vs. radiotherapy alone, a weak trend was observed. 12,14 In this era of advanced therapies (e.g. IMRT, VMAT, and helical tomotherapy), the role of concurrent chemotherapy or targeted therapy in CEC needs further investigation. IMRT and VMAT combined with concurrent chemotherapy or targeted therapy are the preferred treatments for patients with CEC, based on a tendency of improved survival and no increase in acute toxicities. However, comparisons of the results obtained with different therapeutic approaches to CEC are difficult because of the rarity of the disease. This has also hindered prospective randomized studies with larger numbers of patients. In conclusion, our results showed that IMRT- and VMAT-based radiotherapy/chemoradiation for CEC results in a survival rate comparable to that achieved with 3DCRT, while lower lung mean dose, V20, maximum dose of brachial plexus and spinal cord. IMRT and VMAT may be the preferred treatment option as these modalities better protect the lung, brachial plexus and spinal cord. A CR was the most important prognostic factor of the patients with cervical esophageal cancer. ACKNOWLEDGMENTS This study was supported by Clinical Research Support Funds of Chinese PLA General Hospital (No. 2012FC-TSYS-1010) and the Natural Science Foundation of Inner Mongolia (2015MS0896). References 1 Mendenhall W M, Sombeck M D, Parsons J T, Kasper M E, Stringer S P, Vogel S B. Management of cervical esophageal carcinoma. Semin Radiat Oncol 1994; 4: Ferahkose Z, Bedirli A, Kerem M, Azili C, Sozuer EM, Akin M. Comparison of free jejunal graft with gastric pull-up reconstruction after resection of hypopharyngeal and cervical esophageal carcinoma. Dis Esophagus 2008; 21: MaJB,SongYP,YuJMet al. Feasibility of involved-field conformal radiotherapy for cervical and upper-thoracic esophageal cancer. Onkologie 2011; 34: Cao C, Luo J, Gao L et al. Definitive radiotherapy for cervical esophageal cancer. Head Neck 2015; 37: Gkika E, Gauler T, Eberhardt W, Stahl M, Stuschke M, Pottgen C. Long-term results of definitive radiochemotherapy in locally advanced cancers of the cervical esophagus. Dis Esophagus 2014; 27: Zhang W Z, Zhai T T, Lu J Y et al. Volumetric modulated arc therapy vs. c-imrt for the treatment of upper thoracic esophageal cancer. PLoS One 2015; 10: e Freilich J, Hoffe S E, Almhanna K et al. Comparative outcomes for three-dimensional conformal versus intensity-modulated radiation therapy for esophageal cancer. Dis Esophagus 2015; 28: Ma P, Wang X, Xu Y, Dai J, Wang L. Applying the technique of volume-modulated arc radiotherapy to upper esophageal carcinoma. J Appl Clin Med Phys 2014; 15: Fenkell L, Kaminsky I, Breen S, Huang S, Van Prooijen M, Ringash J. Dosimetric comparison of IMRT vs. 3D conformal radiotherapy in the treatment of cancer of the cervical esophagus. Radiother Oncol 2008; 89: Yin Y, Chen J, Xing L et al. Applications of IMAT in cervical esophageal cancer radiotherapy: a comparison with fixed-field IMRT in dosimetry and implementation. J Appl Clin Med Phys 2011; 12: Nicolini G, Ghosh-Laskar S, Shrivastava SK et al. Volumetric modulation arc radiotherapy with flattening filter-free beams compared with static gantry IMRT and 3D conformal radiotherapy for advanced esophageal cancer: a feasibility study. Int J Radiat Oncol Biol Phys 2012; 84: Cao C N, Luo J W, Gao L et al. Intensity-modulated radiotherapy for cervical esophageal squamous cell carcinoma: clinical outcomes and patterns of failure. Eur Arch Otorhinolaryngol 2015; 273: Yamada K, Murakami M, Okamoto Y et al. Treatment results of radiotherapy for carcinoma of the cervical esophagus. Acta Oncol 2006; 45: Uno T, Isobe K, Kawakami H et al. Concurrent chemoradiation for patients with squamous cell carcinoma of the cervical esophagus. Dis Esophagus 2007; 20: Gupta T, Agarwal J, Jain S et al. Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol 2012; 104: Kruser TJ, Rice SR, Cleary KP et al. Acute hematologic and mucosal toxicities in head and neck cancer patients undergoing chemoradiotherapy: a comparison of 3D-CRT, IMRT, and helical tomotherapy. Technol Cancer Res Treat 2013; 12: Tucker SL, Liao ZX, Travis EL. Estimation of the spatial distribution of target cells for radiation pneumonitis in mouse lung. Int J Radiat Oncol Biol Phys 1997; 38: Liao ZX, Travis EL, Tucker SL. Damage and morbidity from pneumonitis after irradiation of partial volumes of mouse lung. Int J Radiat Oncol Biol Phys 1995; 32: Bradley JD, Hope A, El Naqa I et al. A nomogram to predict radiation pneumonitis, derived from a combined analysis of RTOG 9311 and institutional data. Int J Radiat Oncol Biol Phys 2007; 69:

8 8 Diseases of the Esophagus 20 Burmeister BH, Dickie G, Smithers BM, Hodge R, Morton K. Thirty-four patients with carcinoma of the cervical esophagus treated with chemoradiation therapy. Arch Otolaryngol Head Neck Surg 2000; 126: Chen AM, Wang PC, Daly ME et al. Dose-volume modeling of brachial plexus-associated neuropathy after radiation therapy for head-and-neck cancer: findings from a prospective screening protocol. Int J Radiat Oncol Biol Phys 2014; 88: Aoyama N, Koizumi H, Minamide J, Yoneyama K, Isono K. Prognosis of patients with advanced carcinoma of the esophagus with complete response to chemotherapy and/or radiation therapy: a questionnaire survey in Japan. Int J Clin Oncol 2001; 6: van Hagen P, Wijnhoven BP, Nafteux P et al. Recurrence pattern in patients with a pathologically complete response after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer. Br J Surg 2013; 100: Smit JK, Guler S, Beukema JC et al. Different recurrence pattern after neoadjuvant chemoradiotherapy compared to surgery alone in esophageal cancer patients. Ann Surg Oncol 2013; 20: Cooper JS, Guo MD, Herskovic A et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. Jama 1999; 281: