Cervical esophageal cancer: A population-based study

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1 ORIGINAL ARTICLE Cervical esophageal cancer: A population-based study G. Daniel Grass, BS, 1 S. Lewis Cooper, MD, 1* Kent Armeson, MS, 2 Elizabeth Garrett Mayer, PhD, 2 Anand Sharma, MD 1 1 Department of Radiation Oncology, Medical University of South Carolina, Charleston, South Carolina, 2 Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina. Accepted 6 March 2014 Published online 19 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to present our analysis of outcomes, prognostic factors, and treatment for cervical esophageal carcinoma using the Surveillance, Epidemiology, and End Results (SEER) database. Methods. A query of the SEER database from 1998 to 2008 was performed for patients with nonmetastatic adenocarcinoma or squamous cell carcinoma (SCC) of the cervical esophagus. Disease-specific survival (DSS) rates were calculated using Kaplan Meier method, and predictive factors were analyzed by Cox proportional hazards regression. Results. We identified 362 patients; 92% of the patients had SCC, 16% received no definitive therapy, 5% received surgery, 71% received radiation therapy (RT), and 8% received both. Chemotherapy data were not available. Median DSS was 49 months for adenocarcinoma and 15 months for SCC. On multivariate analysis, histology (p 5.02), RT (p <.001), and surgery plus RT (p <.001) were associated with DSS. Conclusion. Survival in patients with cervical esophageal carcinoma remains poor. Further studies should define the use of RT, surgery, and chemotherapy. VC 2014 Wiley Periodicals, Inc. Head Neck 37: , 2015 KEY WORDS: cervical esophagus, squamous cell carcinoma, adenocarcinoma, radiotherapy, esophagectomy *Corresponding author: S. L. Cooper, Department of Radiation Oncology, Medical University of South Carolina, 169 Ashley Avenue, MSC 318, Charleston, SC coopersl@musc.edu Presented at the ASTRO 2012 Annual Meeting. INTRODUCTION The cervical esophagus is a small (approximately 5 cm) portion of the esophagus that begins superiorly at the cricopharyngeus (corresponding to a plane at the inferior border of the cricoid cartilage) and extends down to the sternal notch. Despite the short length of the cervical esophagus, management of cancers at this site is challenging and requires multidisciplinary management as they are uncommon, often locally advanced at presentation, and may involve nearby structures. 1 Cervical esophageal carcinomas often have early lymph node spread and involve the larynx, hypopharynx, and can extend down into the thorax. Squamous cell carcinoma (SCC) histology predominates in the cervical esophagus and these cancers are primarily associated with risk factors such as smoking and alcohol use. 2 4 Cancers at this site account for approximately 5% of all esophageal cancers, and their incidence is decreasing in the United States along with the declining incidence of SCC of the esophagus. 1,3,5 Unfortunately, population-based data has not revealed any improvement in survival of cervical esophageal carcinoma in the United States. 3 SCC of the cervical esophagus was historically managed with surgery; however, the surgery that is required is a cervical or total esophagectomy and often with a laryngopharyngectomy, depending on the superior extent of disease. Reconstruction is most often with gastric transposition or jejunal graft. A 1994 review found that the 5-year survival with surgery was 12% to 27% and that surgical resection was associated with postoperative mortality of 6% to 20% and significant morbidity. The addition of preoperative or postoperative radiation therapy (RT) yielded no improvement with 5-year survival of 4% to 17%. RT alone provided a 5-year survival of 15% to 32%. 1 Because of these results, RT emerged as the preferred modality in the management of cervical esophagus SCC. Subsequent randomized trials of carcinoma of the esophagus and SCC of the head and neck have demonstrated improved survival with chemoradiotherapy (CRT) compared to RT alone; however, these trials have not included cervical esophageal carcinoma. 6,7 Data from these studies has been applied to cervical esophageal carcinoma treatment, and CRT is generally recommended for definitive treatment of SCC of the cervical esophagus. 8 Because of the lack of randomized evidence, there are considerable practice variations in the management of cervical esophageal carcinoma worldwide. Recent literature demonstrates that cervical esophageal carcinoma is managed with definitive CRT, neoadjuvant CRT followed by surgical resection, surgical resection alone, or surgical resection followed by adjuvant RT In addition, these reports are largely from single institutions, and it is not known if results from any 1 institution can be applied broadly. No recent studies have evaluated the outcomes of cervical esophageal carcinoma in a population-based database. In this study, we examined 362 patients diagnosed with nonmetastatic cervical esophageal carcinoma 808 HEAD & NECK DOI /HED JUNE 2015

2 CERVICAL ESOPHAGEAL CANCER TABLE 1. Characteristic Patient characteristics. No. of patients (N 5 362) % Age, range (median) 11 99y (68y) <60 y y Sex Male Female Race White African American Other Diagnosis year Region Pacific Coast East Northern Plains Southwest 16 4 Type Adenocarcinoma 30 8 SCC T Classification Unknown* 12 N Classification Unknown* 51 Classification I IIa IIb III Unknown* 39 Radiation Yes No Unknown* 8 Surgery Yes No Unknown* 1 Tumor size, mm, n Q1, median, Q3 30, 40, 60 Abbreviation: SCC, squamous cell carcinoma. * Not included in percent calculations. in the Surveillance, Epidemiology, and End Results (SEER) database. MATERIALS AND METHODS The SEER database is a population-based cancer registry that covers up to 26% of the United States population and is supported by the National Cancer Institute. 13 The SEER 17 database contains information on patient demographics, primary tumor site, tumor morphology, stage at diagnosis, first course of treatment, and follow-up for vital status between the years 1973 and Data for 362 patients diagnosed with cervical esophageal carcinoma between 1998 and 2008 were obtained from the SEER 17 dataset last updated in November 2010 and released in April 2011 for analysis. 14 We included patients with primary site-labeled recode diagnosis of C15.0-Cervical esophagus, histology recode-broad groupings squamous cell neoplasms and adenomas and adenocarcinomas, multiple primary sequence number of one primary only or 1st of 2 or more primaries, and summary stage 2000 (19981) grouping of localized or regional disease. Patients coded as summary stage 2000 (19981) grouping distant disease or collaborative stage metastasis at diagnosis as yes were excluded. Tumor primary and nodal stage was determined based on the derived American Joint Committee on Cancer T code, collaborative stage extension code, and derived American Joint Committee on Cancer N code for years 2004 to For patients diagnosed from 1998 to 2003, the extent of disease 10-extent and extent of disease 10- nodes were used to determine the tumor primary and nodal stage. Patients were coded as having surgery if the Surg Prim Site (19981) was coded as having an esophagectomy performed (39 patients). Patients listed in the SEER registry as none or refused under RT status were coded as not receiving RT. Patients listed as receiving some form of RT were coded as receiving RT, and patients listed as unknown or recommended; unknown if given were coded as unknown. Incidence, demographics, prognostic variables, outcomes, and treatment modalities were analyzed. Treatment modalities included surgery alone, RT, or surgery and RT. Chemotherapy information is not included in the SEER database. Differences between the receipt of surgery and RT were evaluated for sex, race, SEER region, histology, T classification, N classification, overall stage, and tumor size. Continuous variables were compared with the t test and categorical variables were compared with Pearson s chi-square test or the Fisher exact test. Kaplan Meier methods were used to estimate survival time for time to event endpoints, overall survival (OS), and disease-specific survival (DSS). OS is defined as the time from diagnosis until death from any cause. DSS is the time from diagnosis to death because of disease, with deaths from other causes censored at the time of death. The log-rank test was used to evaluate differences in survival distributions for various strata. Cox proportional hazards regression was used to assess the effects of age, sex, race, year of diagnosis, region, histology, stage, receipt of RT, receipt of surgery, and tumor size on DSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. All p values were 2-sided, with a p value <.05 considered statistically significant. The statistical analysis was completed using R v RESULTS The demographic and clinicopathologic characteristics of the 362 patients are presented in Table 1. The median follow-up for all 362 patients was 58 months. The majority of patients were men (65%) and white (74%). The Pacific Coast SEER region accounted for 50% of the patient population. SCC was the predominant histology HEAD & NECK DOI /HED JUNE

3 GRASS ET AL. FIGURE 1. Disease specific survival, by histology (A) and for squamous cell carcinoma (SCC) by treatment received (B). with 332 patients (92%), whereas 30 patients (8%) had adenocarcinoma. The median age at diagnosis was 68 years (range, years). There was no significant difference in mean age at presentation in those with adenocarcinoma (62.5 years) and those with SCC (66.6 years; p 5.08). In patients with documented stage, the majority of patients presented with locally advanced disease, with 50% being stage III and 26% stage II (stage IIA was 15% and stage IIB was 11%). Thirty-nine patients had unknown stage. The majority of patients presented with locally advanced primaries with 58% having primary tumor classification of T3 or T4. Forty-seven percent of patients had positive nodal disease; however, 51 patients had unknown nodal status. In 208 patients with documented tumor size, the median size was 4.0 cm. In this cohort, 79% of patients were treated with RT (251 patients) and 11% of patients received surgery (39 patients). The majority of patients who received surgery also received RT (27 patients), with only 11 receiving surgery alone. Patients were evaluated as to whether demographic or clinicopathologic parameters were related to treatment decisions. Patients were more likely to receive RT than no RT if they were younger, had SCC, presented with locally advanced disease, or had nodal involvement. In contrast, patients were more likely to receive surgery than no surgery if they were younger, had adenocarcinoma, presented with early stage disease, or had no nodal involvement. When analyzing by tumor size, patients who underwent surgery were more likely to have larger primary tumors and those who underwent RT were more likely to have smaller primary tumors. Survival analysis The median OS and DSS for the population were 14 and 16 months, respectively. Patients with adenocarcinoma had a significantly better OS than SCC (p 5.016). Median OS and DSS were both 49 months for adenocarcinoma compared to 11 and 15 months for those with SCC histology (Figure 1). Two-year and 5-year OS for patients with adenocarcinoma of the cervical esophagus were 51% and 41%, respectively. There was no significant difference in DSS by T classification, but patients with positive nodes had a median DSS of 15 months compared to 23 months for those with negative nodes (p 5.047). Median DSS was 5 months in patients who received no local therapy. Median DSS for surgery alone was 8 months for SCC and not reached for adenocarcinoma. For patients with adenocarcinoma or SCC, the median DSS was 17 months with RT and 54 months with surgery plus RT. Two-year and 5-year DSS for patients treated with RT were 40% and 29%, respectively. Twoyear and 5-year DSS for patients treated with surgery and RT were 71% and 46%, respectively. Univariate analysis using proportional hazards regression for OS demonstrated that lower age (p <.001), tumor adenocarcinoma (vs SCC; p 5.016), lower disease stage (p 5.04), receipt of RT (p <.001), and receipt of surgery (p 5.003) were associated with improved OS (Table 2). Older age was associated with poorer OS with an HR of 1.03 for a 1-year difference (95% CI, ). Adenocarcinoma was associated with an improved OS with a HR of 0.53 (95% CI, ). Similar analysis for DSS demonstrated statistically significant differences for age (p.001), tumor histology (p 5.041), receipt of RT (p <.001), and receipt of surgery (p 5.005). When grouping diagnosis years 1998 to 2003 and 2004 to 2008, there was no difference in OS or DSS between the 2 time periods. Multivariable regression analysis adjusted for age, sex, disease stage, and region demonstrated that tumor histology (p 5.017), receipt of RT (p <.001), or receipt of both RT and surgery (p <.001) were predictive of DSS (Table 3). Adenocarcinoma was associated with improved 810 HEAD & NECK DOI /HED JUNE 2015

4 CERVICAL ESOPHAGEAL CANCER TABLE 2. Cox proportional hazards regression (one at a time). One factor at a time OS One factor at a time DSS Variable HR 95% CI p value HR 95% CI p value Age, per 10-y increase < <.0001 Male vs female Diagnosis year Adenocarcinoma vs SCC AJCC Stage Grouping IIa vs I IIb vs I III vs I Radiation, yes vs no < <.0001 Surgery, yes vs no Size, per 10 mm increase Abbreviations: OS, overall survival; DSS, disease-specific survival; HR, hazard ratio; CI, confidence interval; SCC, squamous cell carcinoma. DSS with an HR of 0.46 (95% CI, ). RT was associated with improved DSS with an HR of 0.38 (95% CI, ). Surgery combined with RT had improved DSS with an HR of 0.19 (95% CI, ). When multivariate analysis was performed on SCC alone, receipt of RT (p <.001) and surgery plus RT (p <.001) were associated with improved DSS with similar HRs. When patients with SCC were contrasted for differences in risk by treatment, RT plus surgery versus RT alone, patients treated with combined modality treatment had improved DSS (HR, 0.45; 95% CI, ; p 5.02). DISCUSSION The analysis presented in this article evaluates the SEER database for prognostic factors, treatment trends, and associated outcomes of patients with localized adenocarcinoma or SCC of the cervical esophagus with no prior primaries. Cancers of the cervical esophagus account for less than 5% of all esophageal cancers and survival has not significantly changed over the past several decades in multiple population-based registries. 3,16 Similar to earlier study cohorts, 73% of the patients in this population were 60 years old and there was approximately a 2-fold increased incidence of cervical esophageal carcinoma in men compared to women. Ninety-two percent of the patients had SCC histology compared to only 8% with adenocarcinoma histology. This is concordant with earlier studies in which SCC histology accounted for approximately 95% of all cervical esophagus and hypopharyngeal cancers. 2 Half of this patient cohort presented with stage III disease and close to half of the patients also had nodal disease; 58% had T3 or T4 primaries. This supports the increased incidence of advanced disease at presentation seen in clinical practice and in the literature. 9,11,12 The current treatment management of cervical esophageal carcinoma requires multidisciplinary management because of the advanced disease presentation and the complex morbidities associated with treatment and progression of disease. Optimal management of SCC of the cervical esophagus is controversial and considerable variations to treatment approach are seen. In the United States, the treatment standard for SCC of the cervical esophagus has been CRT, and this is reflected in current guidelines; however, some centers in other countries manage this disease surgically. 8,10,11 Our analysis reveals that, in the United States, SCC of the cervical esophagus is predominantly managed with definitive RT, with 86% of patients managed with local therapy receiving RT alone. Three-fourths of patients who received surgery also received neoadjuvant or adjuvant RT. Of those who received surgery and RT, one half received RT before surgery and the other half received adjuvant RT.Inourseries,itisdifficult to analyze for treatmentrelated mortality as the date of surgery is not known. However, there were 5 deaths within 5 months of diagnosis in patients treated with surgery indicating that some of these could be because of treatment-related mortality. TABLE 3. Multivariable Cox proportional hazards regression for disease-specific survival. Adenocarcinoma and SCC (N 5 316) SCC only (N 5 287) Variable HR 95% CI p value HR 95% CI p value Adenocarcinoma vs SCC NA Treatment None (reference) 1.0 RT < <.0001 Surgery RT 1 surgery < <.0001 Abbreviations: SCC, squamous cell carcinoma; HR, hazard ratio; CI, confidence interval; NA, not applicable; RT, radiation therapy. Adjusted for age, sex, stage, race, and region. HEAD & NECK DOI /HED JUNE

5 GRASS ET AL. TABLE 4. Literature on surgery and radiation therapy for squamous cell carcinoma of the cervical esophagus since No. of patients Surgery for SCC of the cervical esophagus RT, % OS, % Treatment-related Neoadj Adj mortality, % LC, % 2 y 3 y 5 y Tong et al Kadota et al Ott et al * 47 Daiko et al Wang et al Shirakawa et al Triboulet et al Grass et al, current study No. of patients CRT for SCC of the cervical esophagus RT dose, Gy Treatment-related mortality, % LC, % OS, % 2y 3y 5y Tong et al Huang et al Uno et al Wang et al Yamada et al Burmeister et al Stuschke et al Grass et al, current study Abbreviations: SCC, squamous cell carcinoma; RT, radiotherapy; Neoadj, neoadjuvant; Adj, Adjuvant; LC, local control; OS, overall survival; CRT, chemoradiotherapy. * In patients who received R0 resection. Adenocarcinoma of the cervical esophagus is exceedingly uncommon, and no current treatment guidelines exist. 17 Our report is the largest series of adenocarcinoma of the cervical esophagus that has been reported to date with a total of 30 patients. Seventy percent of patients received definitive local therapy. Of the patients who received local therapy, 66% received definitive RT. Of those who received surgery, 30% received neoadjuvant RT. Multivariate analysis revealed improved OS and DSS for patients with adenocarcinoma of the cervical esophagus compared to those with SCC. Disease stage was an influential variable for survival with p 5.04 for OS and p 5.07 for DSS. An earlier study by Mendenhall et al 1 found no significant differences in OS, DSS, or local control when comparing differences in disease stages in SCC of the cervical esophagus treated with RT alone. This could be due to the low number of patients in the analysis by Mendenhall et al, 1 or SCC of the cervical esophagus may not have the same prognostic factors seen in all esophageal cancers. However, Daiko et al 11 reported differences in OS in SCC of the cervical esophagus based on disease stage. Patients reported on by Daiko et al 11 were staged surgically, which could account for the better prognostic value of disease stage compared to patients reported on by Mendenhall et al, 1 which were predominantly staged clinically. We did find that patients with positive lymph nodes had a significantly worse prognosis than those with negative lymph nodes. An earlier analysis by Mendenhall et al 1 evaluated multiple studies and found that surgery alone, RT alone, or surgery combined with neoadjuvant or adjuvant RT for SCC of the cervical esophagus resulted in a 5-year OS of 12% to 27%, 15% to 32%, and 4% to 17%, respectively. Our analysis showed that the median 5-year DSS for patients with SCC histology managed with the above treatment approaches was 26%, 28%, and 48%, respectively. However, the number of patients treated with surgery was small and multivariate analysis showed inferior survival in patients with SCC of the cervical esophagus treated with surgery alone compared to RT or surgery and RT. Reviewing the literature since 1999, the 5-year OS for patients treated with surgery is 14% to 47% and for patients treated with CRT is 19% to 55% (Table 4) ,18 25 One of the challenges of surgical management of SCC of the cervical esophagus is the high rates of morbidity and operative mortality. Mendenhall et al 1 reported an operative mortality of 11% to 24% for patients treated with surgery. More recent series report treatment-related mortality of 2.8% to 9.8% in patients treated surgically with or without RT ,18,20,21 In the 3 largest series (over 70 patients each), the treatment-related mortality was 2.8% to 4.8%, indicating that increased experience with managing cervical esophageal carcinoma surgically may result in decreased operative mortality. 10,11,21 The anastomotic leak rate varies from 10% to 27% with complication rates up to 74.3% ,18,19,21 Rates of local control vary from 51% to 88% ,19,21 The use of neoadjuvant and adjuvant RT varied greatly among institutions ,18,21 Patients treated with CRT in contemporary series report a low treatment-related mortality of 0% to 6%. 12,18,19,23, HEAD & NECK DOI /HED JUNE 2015

6 CERVICAL ESOPHAGEAL CANCER However, most series report low rates of local control from 33% to 52% in patients treated with CRT. 12,19,23,25 Although, Burmeister et al 24 reported a local control rate of 88% in patients treated with CRT, the high rate of local control seen in this series is possibly because of the early stage of disease in the majority of patients, with 70% being stage I or IIA. Another difficulty in interpreting these series of patients treated with CRT is the different RT dose, fractionation, and chemotherapy regimens used. Our present analysis of the SEER database for treatment trends and outcomes for patients with cervical esophageal carcinoma is similar to previously published studies. CRT is the standard management for SCC of the cervical esophagus; however, no trial has compared CRT versus RT for this site. Radiation Therapy Oncology Group demonstrated improved OS with CRT versus RT alone in esophageal carcinoma with a 26% OS benefit at 5 years for CRT; however, this trial is criticized for the poor OS in the control arm that was inferior to historical series of RT alone. 6 The Meta-Analyses of Chemotherapy in Head and Neck Cancer meta-analysis demonstrated a 4.5% OS benefit with CRT in patients with SCC of the head and neck. 7 One series from Princess Margaret Hospital found no OS benefit and only a trend toward a local recurrence-free survival benefit for CRT compared to RT or surgery alone. 9 It is likely there is a benefit to CRT compared to RT alone in SCC of the cervical esophagus, but the magnitude of this benefit is unknown. Recent studies reporting on the use of RT in SCC of the cervical esophagus all include concurrent chemotherapy ,18 25 We were unable to evaluate any survival parameters or treatment trends associated with chemotherapy as this data is not available in the SEER database. Because our analysis parameters included patients diagnosed between 1998 and 2008, our assumption is that the majority of patients treated with RT also received concomitant chemotherapy. Younger patients were more likely to be treated with definitive therapy and would be more likely to receive concurrent chemotherapy. In our series, 76% of patients who received RT as definitive therapy were 70 or younger and would likely be candidates to receive chemotherapy. At least 1 study has found that RT dose is related to survival in SCC of the cervical esophagus, with a dose less than 50 Gy being associated with inferior OS. 12 Another series found no difference between high dose CRT (70 Gy) compared to CRT to 54 Gy. 9 The SEER database does not include information on radiation dose, fractionation, treatment volumes, or technique, which also makes the information on patients treated with RT more difficult to interpret. Curative RT doses for esophageal or head and neck SCC would be at least 50 Gy. Our assumption would be that patients receiving RT for their cervical esophageal carcinoma were treated with curative intent. Another limitation to our analysis is that not all carcinomas of the cervical esophagus may have been captured. Esophageal cancers can be coded in the SEER database using upper third, middle third, or lower third. In addition, esophageal cancers can be coded as cervical esophagus, thoracic esophagus, or abdominal esophagus. The upper third of the esophagus includes both the cervical esophagus and the upper portion of the thoracic esophagus, so we did not include these because of the ambiguity of their exact location. We also do not have information on how patients were staged clinically. Inaccuracies in staging could have resulted in the T classification not being significant for DSS. Finally, the SEER database does not include information on toxicity and patterns of failure, so these could not be analyzed. CONCLUSION Cervical esophageal carcinoma is uncommon and this study represents the largest series reported to date. In the United States, SCC of the cervical esophagus is predominately managed with RT, but survival has not improved in the past decade and the prognosis remains poor. 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