Definitive radiotherapy for cervical esophageal cancer

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1 ORIGINAL ARTICLE Definitive radiotherapy for cervical esophageal cancer Caineng Cao, MD, Jingwei Luo, MD, * Li Gao, MD, Guozhen Xu, MD, Junlin Yi, MD, Xiaodong Huang, MD, Kai Wang, MD, Shiping Zhang, MD, Yuan Qu, MD, Suyan Li, MD, Jianping Xiao, MD, Zhong Zhang, MD Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People s Republic of China. Accepted 10 December 2013 Published online 3 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The role of contemporary radiotherapy (RT) has not yet been elucidated, mainly because of the low incidence of cervical esophageal cancer. The purpose of this study was to analyze the outcome in patients with cervical esophageal cancer treated with definitive RT. Methods. A total of 115 patients with cervical esophageal cancer treated with definitive RT during January 2001 through April 2012 in our center were analyzed. Eighty patients received RT alone and 35 patients received concurrent chemoradiotherapy with cisplatin administered either weekly (30 mg/m2) or every 3 weeks (80 mg/m2). Results. The median follow-up time was 17.1 months. For all patients, the overall 2-year local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure-free survival (DFFS), and overall survival (OS) rate was 68.3%, 83.3%, 75.7%, and 47.6%, respectively. Conclusion. Definitive RT accomplished a satisfactory local control rate and contributed to organ preservation for patients with cervical esophageal cancer. VC 2014 Wiley Periodicals, Inc. Head Neck 37: , 2015 KEY WORDS: cervical esophageal cancer, treatment, radiotherapy, survival, organ preservation INTRODUCTION Cervical esophageal cancer is relatively uncommon, representing <5% of all esophageal cancers. 1 The management of cervical esophageal cancer is controversial. The choice of treatment has been surgical resection, 2 5 radiotherapy (RT), 6 11 or a combination of the two. Surgery requiring laryngopharyngoesophagectomy is usually associated with disruption of speech and swallowing, and compromises patients quality of life. RT has undergone notable advances during the past decade. Three-dimensional (3D) conformal RT and intensity-modulated radiation therapy (IMRT) based on CT images and multileaf collimator have contributed to conformal RT in delivering high doses accurately to the target, sparing normal tissues. Concurrent chemoradiotherapy () or targeted therapy has improved survival and locoregional control of locally advanced head and neck squamous cell carcinoma. 12,13 These advances in RT and diagnostic imaging have promoted RT as a possible treatment for preserving organ function. However, the role of contemporary RT has not yet been elucidated, mainly because of the low incidence of cervical esophageal cancer. The purpose of this study was to analyze the outcome in patients with cervical esophageal cancer treated with definitive RT. PATIENTS AND METHODS Patients and patient workup The Case Recording System was approved to identify the patients diagnosed with cervical esophageal cancer in our center during January 2001 through April During the years 2001 through 2012, 133 patients with cervical esophageal cancer received RT alone or. Of the 133 patients, 18 were excluded from this study for the following reasons: refusing further RT or distant metastasis (n 5 11), esophageal perforation (n 5 3), pneumonia (n 5 2), upper gastrointestinal hemorrhage (n 5 1), and acute laryngemphraxis (n 5 1). This study included the remaining 115 patients. The pretreatment workup included a complete medical history and physical examination, liver and renal biochemistry, complete blood count, barium contrast study, endoscopy, CT scans of the neck and thorax, and ultrasonography of the abdominal region and the cervical region with or without fine-needle aspiration cytology when cervical nodal metastasis was detected. Endoscopic ultrasonography and positron emission tomography fusion with CT scans have been available since September In addition, bronchoscopy should be performed for patients with local advanced diseases unless the patient s condition is not suitable or when the patient declines. All patients underwent disease staging using the American Joint Committee on Cancer 2002 staging system. The clinical characteristics are listed in Table 1. *Corresponding author: J. Luo, Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People s Republic of China. jingweiluo2013@163.com Treatment In this study, 80 patients received RT alone and 35 patients received with cisplatin administered either weekly (30 mg/m2) or every 3 weeks (80 mg/m2). Nine HEAD & NECK DOI /HED FEBRUARY

2 CAO ET AL. TABLE 1. Patient characteristics (n 5 115). Characteristic No. of patients (%) Age, y Median 60 Range Male 86 (74.8) Female 29 (25.2) Dysphagia grade* G (35.7) G (64.3) Yes 21 (18.3) No 94 (81.7) 10% 16 (13.9) <10% 99 (86.1) 1 22 (19.1) 2 22 (19.1) 3 13 (11.3) X 58 (50.4) Tumor extension CE 48 (41.7) HP 1 CE 22 (19.1) CE 1 TE 35 (30.4) HP 1 CE 1 TE 10 (8.7) Conventional RT 37 (32.2) 3D conformal RT 14 (12.2) IMRT 64 (55.7) Yes 35 (30.4) No 80 (69.6) Concurrent targeted therapy Yes 10 (8.7) No 105 (91.3) T1 2 (1.7) T2 8 (7.0) T3 47 (40.9) T4 58 (50.4) N1 63 (54.8) N0 52 (45.2) Overall stage (2002 UICC) IIa 29 (25.2) IIb 7 (6.1) III 79 (68.7) Multiple primary carcinoma Synchronous 5 (4.3) Metachronous 8 (7.0) FIGURE 1. Kaplan Meier curve showing overall survival (OS), local failure free survival (LRRS), regional failure free survival (RFFS), and distant failure free survival (DFFS) of patients with cervical esophageal cancer in the study. fields at a daily dose of 2 Gy, 14 were irradiated using 3D conformal RT at a daily dose of 1.8 to 2 Gy, whereas 64 cases were treated using IMRT at a daily dose range of 2 to 2.12 Gy to the gross tumor volume. The field of radiation covered the gross tumor with an additional radial margin of at least 1 cm and longitudinal margins of at least 3 cm. Adjacent involved lymph nodes were included, if any, in the radiation field. Eighty patients who were treated with RT alone received a median dose of 68 Gy (range, Gy). Thirty-five patients who were treated with received a median dose of 64 Gy (range, Gy). Treatment monitoring All patients were evaluated weekly during RT, and were required to be followed-up after the completion of treatment: 1 month after the completion of treatment, every 3 months in the first 2 years, every 6 months from year 3 through year 5, and annually thereafter. Each follow-up included a complete examination, including Abbreviations: CE, cervical esophagus; HP, hypopharyngeal extension; TE, thoracic esophageal extension; RT, radiotherapy; IMRT, intensity-modulated radiotherapy;, concurrent chemoradiotherapy; UICC, Union Internationale Contre le Cancer. * G0, none; G1, mild dysphagia, but can eat regular diet; G2, dysphagia, requiring predominantly pureed, soft, or liquid diet; G3, dysphagia, requiring intravenous hydration. patients were given cetuximab or nimotuzumab. One patient was given tarceva. One patient received salvage pharyngo-laryngo-esophagectomy for palliation of dysphagia. Nine patients received salvage pharyngo-laryngoesophagectomy for local failure. Thirty-seven patients were irradiated using conventional techniques by anteroposterior opposing fields or oblique FIGURE 2. The details of the 55 patients with treatment failure are shown. 152 HEAD & NECK DOI /HED FEBRUARY 2015

3 DEFINITIVE RT FOR CERVICAL ESOPHAGEAL CANCER TABLE 2. Impact of prognostic factors on treatment results by univariate analysis. 2-y LFFS 2-y RFFS 2-y DFFS 2-y OS Items % p value % p value % p value % p value Male Female Age >60 y y Yes No Dysphagia G G % <10% Hypopharyngeal extension No Yes Thoracic esophageal extension No Yes G G1, 2, x T T1, 2, N N Overall stage II III D-RT D conformal RT IMRT Yes No RT 66 Gy Yes No Abbreviations: LFFS, local failure free survival; RFFS, regional failure free survival; DFFS, distant failure free survival; OS, overall survival; RT, radiotherapy; 2D-RT, 2-dimensional radiotherapy; IMRT, intensity-modulated radiotherapy;, concurrent chemoradiotherapy. basic serum chemistry, barium contrast study, endoscopy, and ultrasonography of the abdominal region and the cervical region. CT scans of the neck and thorax was performed after the completion of treatment and then every 6 months. RT-induced toxicities were assessed and scored according to the Radiation Therapy Oncology Group radiation morbidity scoring criteria at each follow-up. 14 Statistical analyses The Statistical Package for Social Sciences software, version 17.0 (SPSS, Chicago, IL), was used for statistical analysis. The local failure free survival (LFFS), distant failure free survival (DFFS), regional failure-free survival (RFFS), and overall survival (OS) were estimated by use of the Kaplan Meier method. LFFS, DFFS, RFFS, and OS were measured from day 1 of treatment to the date of the event. The log-rank test was used in univariate analysis and the Cox proportional hazards model was used to determine any significant predictors of LFFS, DMFS, RFFS, and OS. Statistical tests were based on a 2-sided significance level. Any p <.05 was considered to indicate statistical significance. RESULTS Treatment outcomes The median follow-up time was 17.1 months. For all patients, the overall 2-year LFFS, RFFS, DFFS, and OS HEAD & NECK DOI /HED FEBRUARY

4 CAO ET AL. TABLE 3. Impact of prognostic factors on treatment results by multivariate analysis (p value). Factors 2-y LFFS 2-y RFFS 2-y DFFS 2-y OS Male vs female Age >60 y vs 60 y No vs yes Dysphagia G0 1 vs G % vs <10% Hypopharyngeal extension No vs yes Thoracic esophageal extension No vs yes vs 1, 2, x T4 vs T1, 2, N0 vs N Overall stage II vs III D-RT vs 3D conformal RT vs IMRT Yes vs no RT 66 Gy Yes vs no Abbreviations: LFFS, local failure free survival; RFFS, regional failure free survival; DFFS, distant failure free survival; OS, overall survival; RT, radiotherapy; 2D-RT, 2-dimensional radiotherapy; IMRT, intensity-modulated radiotherapy;, concurrent chemoradiotherapy. rate was 68.3%, 83.3%, 75.7%, and 47.6%, respectively (Figure 1). Although no statistically significant difference was observed in LFFS (p 5.571) and RFFS (p 5.110) between the patients receiving 66 Gy and in the patients receiving <66 Gy, the 2-year OS rate was significantly better in the patients receiving 66 Gy (55.6% vs 37.5%; p 5.018). Furthermore, no statistically significant difference was observed in LFFS, RFFS, OS, and DFFS among the 3 different groups (p >.05). Failure patterns At their last follow-up visit, 55 patients had developed treatment failure. Of the 55 patients, 23, 13, and 2 had developed local failure, regional failure, and distant metastasis, respectively, and 4 had developed distant metastasis and failure at the primary and nodal site. The details of the 55 patients with treatment failure are shown in Figure 2. The metastatic sites included the lung in 16 patients, the bone in 5 patients, the liver in 3 patients, the brain in 1 patient, the subcutis in 1 patient, the mediastinal lymph nodes in 6 patients, and other distant lymph nodes in 6 patients. Toxicities The most frequently observed acute toxicity was mainly grade 1 or grade 2. The incidence of acute grade 3 mucositis (including pharyngitis), skin reaction, and leukopenia was 4.3%, 10.4%, and 7.0%, respectively. Severe dysphagia requiring intervention (insertion of enteral feeding tube, gastrostomy, or esophageal dilation) was recorded in 7 of the 115 patients (6.1%). One patient died of carotid blowout 8 months after treatment. One patient died of upper gastrointestinal hemorrhage 1 month after RT termination for esophageal perforation. One patient had hypothyroidism requiring lifelong thyroxine replacement. Prognostic factors The value of various potential prognostic factors include age, sex, hoarseness, dysphagia, weight loss, hypopharyngeal extension, thoracic esophageal extension, histologic grade,,, overall stage,,, and RT 66 Gy on predicting LFFS, RFFS, DFFS, and OS were evaluated. The outcomes are shown in Tables 2 and 3. DISCUSSION In the present study, analysis of a large number of patients with cervical esophageal cancer (n 5 115) treated with definitive RT showed that the 2-year LFFS, RFFS, DFFS, and OS rates were 68.3%, 83.3%, 75.7%, and 47.6%, respectively. Table 4 summarizes the key features and the results achieved at various oncology centers TABLE 4. Results of radiotherapy for cervical esophageal cancer. Investigator No. of patients (%) Radiation dose (Gy) C (%) LRC (%) 2-y OS 5-y OS Mendenhall et al (mean 67.5) No 25.8 (5-y) 34% 17% Stuschke et al Yes 33 (2-y) 24% N/A Burmeister et al (mean 61.2) Yes (100) N/A N/A 55% Yamada et al (mean 66) Yes (85.2) 13 (5-y)* 38% 38% Wang et al (13) (median 50.4) Yes 47.7 (5-y) N/A 18.5% Huang et al Yes (52) 37 (2-y) 35% 21% Tong et al Yes (100) N/A 46.9% N/A Present study Yes (30.4) 68.3 (2-y) 47.6% N/A Abbreviations: C, concurrent chemoradiotherapy; LRC, locoregional control; OS, overall survival; N/A, not available. * Disease-free survival. With upper thoracic esophageal cancer (upper thoracic esophageal cases). Twenty-nine patients were given 54 Gy and 42 patients were given 70 Gy. Locoregional relapse-free survival. Local failure free survival. 154 HEAD & NECK DOI /HED FEBRUARY 2015

5 DEFINITIVE RT FOR CERVICAL ESOPHAGEAL CANCER The 2-year OS rate of these patients who were treated with RT was 24% to 46.9%, which was similar to the results of our study. Tong et al 5 reported the outcomes of surgical treatment for cervical esophageal cancer (n 5 62). The median survival times and 2-year survival rate were 19.9 months and 37.6% for cervical esophageal cancer, respectively. The 5-year survival rate of these patients who were treated with surgery was 14% to 31.2%. 2 5 These results are approximately equal to the results of definitive RT. Radiation Therapy Oncology Group indicated that higher doses of RT (64.8 Gy vs 50.4 Gy) did not result in improved locoregional control or survival, although this could be attributed to the significantly higher treatment-related toxicity and death in the highdose group, which did not seem to be related to the higher radiation dose. However, Dinshaw et al. 16 reported the outcomes of radical RT for head and neck squamous cell cancers. The 5-year local control (59% vs 48%; p ), locoregional control (47% vs 41%; p ), and DFS (44% vs 37%; p ) were significantly better in patients receiving 66 Gy. A definite dose-response relationship exists with higher total doses, leading to better local control, locoregional control, and disease-free survival in all stages. An association between a higher radiation dose (60 69 Gy vs Gy) and improved 5-year survival (10.6% vs 2%) was also reported by Sun 17 when RT was the sole therapeutic modality for esophageal carcinoma. Although no statistically significant difference was observed in LFFS (p 5.571) and RFFS (p 5.110) between the patients receiving 66 Gy and in the patients receiving <66 Gy, the 2-year OS rate was significantly better in the patients receiving 66 Gy in this study (55.6% vs 37.5%; p 5.018). Recent advances in radiation oncology and treatment planning led to the implementation of inverse planned IMRT. This treatment technique allows the optimization of target volume coverage while allowing reduction of the dose to surrounding organs at risk. Therefore, an increased total dose could be achieved with better coverage of the target volume. Wang et al 18 retrospectively analyzed 6 patients treated by 5 to 9 beam IMRT with concurrent chemotherapy for locally advanced cervical and upper thoracic esophageal cancer. The prescription dose was Gy in 28 to 33 fractions; in 5 patients, a simultaneous integrated boost technique was used. In this study, all 6 patients achieved complete remission. CONCLUSION We evaluated the clinical outcome of definitive RT for cervical esophageal cancer. Contemporary RT accomplished a satisfactory locoregional control rate and contributed to organ preservation. REFERENCES 1. Mendenhall WM, Sombeck MD, Parsons JT, Kasper ME, Stringer SP, Vogel SB. Management of cervical esophageal carcinoma. 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