Outcomes and prognostic factors for patients with cervical esophageal cancer undergoing definitive radiotherapy or chemoradiotherapy

  • Xin-xin Du Department of Radiotherapy, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot; Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China; Research Group for Reproductive Medicine and IVF-Laboratory, Department of Obstetrics and Genecology, University of Cologne, Cologne, Germany
  • Rong Yu Department of Radiotherapy, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
  • Zhen-fei Wang Department of Radiotherapy, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University; Tumor Molecular Diagnostic Laboratory, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
  • De-cheng Du Department of Radiotherapy, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
  • Qiao-yun Liu Department of Radiotherapy, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
  • Run-mei Wang Department of Radiotherapy, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
  • Shi-rong Kang Department of Thoracic Surgery, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
  • Hao Yang Department of Radiotherapy, Inner Mongolia Cancer Hospital, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
Keywords: Cervical esophageal carcinoma, radiotherapy, chemoradiotherapy, prognosis, disease management, survival, 3DCRT, IMRT, concurrent chemoradiotherapy

Abstract

Cervical esophageal cancer (CEC) is uncommon, accounting for less than 5% of all esophageal cancers. The management of CEC is controversial. This study investigated treatment outcomes and prognostic factors of survival in CEC patients undergoing definitive radiotherapy or concurrent chemoradiotherapy (CCRT). Ninety-one CEC patients were treated by intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT) between July 2007 and September 2017. The mean prescription dose was 64 Gy (range 54-70 Gy) delivered as 1.8-2.2 Gy per fraction per day, 5 days a week. Out of 91 patients, 34 received concurrent cisplatin-based chemotherapy (CT) including 18 patients who also received neoadjuvant CT. Overall survival (OS), locoregional failure-free survival (LRFFS), and progression-free survival (PFS) were estimated by the Kaplan–Meier method. Prognostic factors of survival were determined in univariate (log-rank test) and multivariate (Cox proportional hazard model) analysis. Treatment-related toxicity was also assessed. Median follow-up time for all patients was 19 months. Two-year OS, LRFFS and PFS of all patients were 58.2%, 52.5% and 48.1%, respectively. Clinical stage was an independent prognostic factor for OS (HR = 2.35, 95% CI: 1.03-5.37, p = 0.042), LRFFS (HR = 3.84, 95% CI: 1.38-10.69, p = 0.011), and PFS (HR = 2.68, 95% CI: 1.11-6.45, p = 0.028). Hoarseness was an independent prognostic factor for OS (HR = 2.10, 95% CI: 1.05-4.19, p = 0.036). CCRT was independently associated with better LRFFS (HR = 0.33, 95% CI: 0.14-0.79, p = 0.012). 3DCRT and IMRT with concurrent CT is well-tolerated and may improve local tumor control in CEC patients. Advanced clinical stage and hoarseness are adverse prognostic factors for OS, LRFFS, and PFS in CEC.

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References

Mendenhall WM, Sombeck MD, Parsons JT, Kasper ME, Stringer SP, Vogel SB. Management of Cervical Esophageal Carcinoma. Semin Radiat Oncol 1994; 4(3):179-191.

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(4):340-345.

Ma JB, Song YP, Yu JM, Zhou W, Cheng EC, Zhang XQ, et al. Feasibility of involved-field conformal radiotherapy for cervical and upper-thoracic esophageal cancer. Onkologie 2011; 34(11):599-604.

Cao C, Luo J, Gao L, Xu G, Yi J, Huang X, et al. Definitive radiotherapy for cervical esophageal cancer. Head Neck 2015; 37(2):151-155.

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(7):678-684.

Miyata H, Yamasaki M, Takahashi T, Kurokawa Y, Nakajima K, Takiguchi S, et al. Larynx-preserving limited resection and free jejunal graft for carcinoma of the cervical esophagus. World J Surg 2013; 37(3):551-557.

Chou SH, Li HP, Lee JY, Huang MF, Lee CH, Lee KW. Radical resection or chemoradiotherapy for cervical esophageal cancer? World J Surg 2010; 34(8):1832-1839.

Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA, Jr., Al-Sarraf M, 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(17):1623-1627.

Adelstein DJ. An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer. Journal of Clinical Oncology 2003; 21(1):92-98.

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354(6):567-578.

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(3):287-291.

Freilich J, Hoffe SE, Almhanna K, Dinwoodie W, Yue B, Fulp W, et al. Comparative outcomes for three-dimensional conformal versus intensity-modulated radiation therapy for esophageal cancer. Dis Esophagus 2015; 28(4):352-357.

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(3):4732.

Wu Z, Xie C, Hu M, Han C, Yi J, Zhou Y, et al. Dosimetric benefits of IMRT and VMAT in the treatment of middle thoracic esophageal cancer: is the conformal radiotherapy still an alternative option? J Appl Clin Med Phys 2014; 15(3):4641.

Zhang WZ, Zhai TT, Lu JY, Chen JZ, Chen ZJ, Li DR, et al. Volumetric Modulated Arc Therapy vs. c-IMRT for the Treatment of Upper Thoracic Esophageal Cancer. PLoS One 2015; 10(3):e0121385.

Zhang P, Xi M, Zhao L, Qiu B, Liu H, Hu YH, et al. Clinical efficacy and failure pattern in patients with cervical esophageal cancer treated with definitive chemoradiotherapy. Radiother Oncol 2015; 116(2):257-261.

Huang SH, Lockwood G, Brierley J, Cummings B, Kim J, Wong R, et al. Effect of concurrent high-dose cisplatin chemotherapy and conformal radiotherapy on cervical esophageal cancer survival. Int J Radiat Oncol Biol Phys 2008; 71(3):735-740.

Stuschke M, Stahl M, Wilke H, Walz MK, Oldenburg AR, Stuben G, et al. Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the cervical oesophagus. Oncology 1999; 57(2):99-105.

Suzuki G, Yamazaki H, Ogo E, Abe T, Eto H, Muraki K, et al. Multimodal approach for cervical esophageal carcinoma: role of neoadjuvant chemotherapy. Anticancer Res 2014; 34(4):1989-1992.

Tong DK, Law S, Kwong DL, Wei WI, Ng RW, Wong KH. Current management of cervical esophageal cancer. World J Surg 2011; 35(3):600-607.

Kadota H, Sakuraba M, Kimata Y, Hayashi R, Ebihara S, Kato H. Larynx-preserving esophagectomy and jejunal transfer for cervical esophageal carcinoma. Laryngoscope 2009; 119(7):1274-1280.

Ott K, Lordick F, Molls M, Bartels H, Biemer E, Siewert JR. Limited resection and free jejunal graft interposition for squamous cell carcinoma of the cervical oesophagus. Br J Surg 2009; 96(3):258-266.

Sun F, Li X, Lei D, Jin T, Liu D, Zhao H, et al. Surgical management of cervical esophageal carcinoma with larynx preservation and reconstruction. Int J Clin Exp Med 2014; 7(9):2771-2778.

Cao CN, Luo JW, Gao L, Xu GZ, Yi JL, Huang XD, et al. Primary radiotherapy compared with primary surgery in cervical esophageal cancer. JAMA Otolaryngol Head Neck Surg 2014; 140(10):918-926.

Liu SY, Chiu PW, Teoh AY, Yung MY, Lam CC, Wong SK, et al. Chemoradiotherapy or Pharyngo-Laryngo-Esophagectomy for Cervical Esophageal Squamous Cancer. Gastroenterology 2011; 140(5, Supplement 1):S-1033.

Dudhat SB, Mistry RC, Fakih AR. Complications following gastric transposition after total laryngo-pharyngectomy. Eur J Surg Oncol 1999; 25(1):82-85.

Lam KH, Wong J, Lim ST, Ong GB. Pharyngogastric anastomosis following pharyngolaryngoesophagectomy. Analysis of 157 cases. World J Surg 1981; 5(4):509-516.

Triboulet JP, Mariette C, Chevalier D, Amrouni H. Surgical management of carcinoma of the hypopharynx and cervical esophagus: analysis of 209 cases. Arch Surg 2001; 136(10):1164-1170.

Burri RJ, Lee NY. Concurrent chemotherapy and radiotherapy for head and neck cancer. Expert Rev Anticancer Ther 2009; 9(3):293-302.

Tai P, Van Dyk J, Yu E, Battista J, Schmid M, Stitt L, et al. Radiation treatment for cervical esophagus: patterns of practice study in Canada, 1996. Int J Radiat Oncol Biol Phys 2000; 47(3):703-712.

Uno T, Isobe K, Kawakami H, Ueno N, Shimada H, Matsubara H, et al. Concurrent chemoradiation for patients with squamous cell carcinoma of the cervical esophagus. Dis Esophagus 2007; 20(1):12-18.

Yamada K, Murakami M, Okamoto Y, Okuno Y, Nakajima T, Kusumi F, et al. Treatment results of radiotherapy for carcinoma of the cervical esophagus. Acta Oncol 2006; 45(8):1120-1125.

Cao CN, Luo JW, Gao L, Xu GZ, Yi JL, Huang XD, et al. Intensity-modulated radiotherapy for cervical esophageal squamous cell carcinoma: clinical outcomes and patterns of failure. Eur Arch Otorhinolaryngol 2016; 273(3):741-747.

Kogo M, Watahiki M, Sunaga T, Kaneko K, Yoneyama K, Imawari M, et al. Analysis of the risk factors for myelosuppression after chemoradiotherapy involving 5-fluorouracil and platinum for patients with esophageal cancer. Hepatogastroenterology 2011; 58(107-108):802-808.

Ludmir EB, Palta M, Wu Y, Willett CG, Czito BG. Definitive chemoradiation therapy for cervical esophageal carcinoma: a single-institution experience. Int J Radiat Oncol Biol Phys 2014; 90(1):S348.

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(2):205-208.

Outcomes and prognostic factors for patients with cervical esophageal cancer undergoing definitive radiotherapy or chemoradiotherapy
Published
2019-05-20
How to Cite
1.
Du X- xin, Yu R, Wang Z- fei, Du D- cheng, Liu Q- yun, Wang R- mei, Kang S- rong, Yang H. Outcomes and prognostic factors for patients with cervical esophageal cancer undergoing definitive radiotherapy or chemoradiotherapy. Bosn J of Basic Med Sci [Internet]. 2019May20 [cited 2021Apr.19];19(2):186-94. Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/3873
Section
Translational and Clinical Research

INTRODUCTION

Cervical esophageal cancer (CEC) is relatively uncommon, accounting for less than 5% of all esophageal cancers [1]. The management of CEC is controversial due to the low incidence and a lack of studies investigating specifically treatment strategies and outcomes in CEC. In most available studies, CEC is analyzed together with carcinomas of the hypopharynx and thoracic esophagus, even though it is anatomically distinct from both [2,3]. Treatment modalities for CEC include surgical resection with or without neoadjuvant chemoradiotherapy (CRT) and definitive radiotherapy (RT) with or without concurrent chemotherapy (CT) [4-6].

Minimally invasive surgical approaches that preserve organ shape and function were the treatment of choice for CEC, however, the risk of complications and morbidity and mortality rates associated with surgical resection of CEC remain high. RT, on the other hand, has a major positive impact on the quality of life (QOL) of patients with CEC, since it allows the preservation of both the larynx and esophagus [7]. Therefore, RT has become the preferred treatment for CEC in recent years. Moreover, randomized trials on esophageal cancer [8] and squamous cell head and neck cancer [9,10] showed that neoadjuvant chemotherapy (NAC) and concurrent CRT (CCRT) improve the locoregional tumor control and organ preservation in patients.

Technological advances led to the development of improved radiation delivery techniques such as intensity-modulated radiation therapy (IMRT) and its novel form volumetric-modulated arc therapy (VMAT), which have several advantages in cancer treatment over three-dimensional conformal radiation therapy (3DCRT). Studies comparing the efficacy of 3DCRT and IMRT in the treatment of esophageal cancer show that IMRT provides improved planning target volume coverage and dose conformity as well as a reduced dose to adjacent normal tissues [11-15].

In the current study, we investigated treatment outcomes and prognostic factors of survival in CEC patients undergoing definitive RT or CCRT, with the overall goal to help guide decision making for treatment of CEC.

MATERIALS AND METHODS

Patients

A total of 91 patients met the following inclusion criteria: 1) pathological confirmation of cervical esophageal squamous cell carcinoma (CESCC); 2) permission with upper mediastinal lymph node metastasis (M1 lymph node/stage IV esophageal cancer), with no evidence of other distant metastases; 3) completed RT with/without CT; 4) Karnofsky Performance Status (KPS) score ≥70; and 5) age of 75 years or younger. All patients underwent definitive RT or CCRT at our institution from July 2008 to June 2015. Prior to RT, a detailed medical history was obtained from patients and physical examination, barium-swallow X-ray examination, a computed tomography (CT) scan of the neck, chest and abdomen, bronchoscopy, endoscopic ultrasound of the esophagus, and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) were performed. Tumors were staged according to the 6th edition of the American Joint Committee on Cancer (AJCC) staging system for esophageal cancer.

Radiotherapy

3DCRT and IMRT, optimized using the Pinnacle treatment planning system (Pinnacle3 version 9.6, Philips Medical Systems, Andover, MA), were applied to all patients. Treatments were delivered using a linear accelerator with dynamic multileaf collimator system (6 MV photon beams) and multiple field technique.

The gross tumor volume (GTV) included the primary tumor and involved regional lymph nodes, determined by multiple imaging examinations. The clinical target volume (CTV) was defined as GTV and additional 0.8–1.0-cm margins in the radial direction and 3-cm margins in the cranial-caudal direction from the GTV. Elective nodal irradiation, including the area drained by adjacent involved lymph nodes, bilateral levels II–IV of the cervical lymph node area, supraclavicular fossa, and upper mediastinal of the lymph node area [16]. The planning target volume (PTV) included the CTV plus a 0.5-cm margin. The organs at risk (OARs) were contoured and comprised the larynx, parotid gland, thyroid gland, trachea, spinal cord, lungs, and heart.

The prescribed dose was 54−70 Gy for 95% GTV delivered as 1.8−2.2 Gy per fraction, once per day, five days per week. The prophylactic dose was 50−54 Gy for 95% CTV. The doses received by OARs were constrained as follows: lungs V20 <30 %, V30 <20%; heart V30 <40%, V40 <30%; and a maximum dose for the spinal cord of <45 Gy.

Chemotherapy

Out of 91 patients treated with RT, 18 patients (19.8%) also received NAC consisting of two cycles of intravenous cisplatin (75 mg/m2) and 5-fluorouracil (5-FU, 1000 mg/m2/day) administered as continuous 24-hour infusion for four days every three weeks. A total of 34 patients (37.4%) received CCRT consisting of cisplatin alone (40 mg/m2) every week, cisplatin/5-FU or cisplatin (75 mg/m2)/paclitaxel (60 mg/m2) every three weeks. The remaining 57 patients (62.6%) received RT alone due to concerns about adverse effect or intolerance to CCRT.

Patient follow-up

Patients were followed up one month after treatment completion, every three months during the first two years, every six months for three to five years, and annually after five years. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. Evaluation tools included imaging techniques and biopsy when tumor recurrence was suspected.

Statistics

Statistical analyses were performed using SPSS for Windows, Version 13.0. (SPSS Inc., Chicago, IL, USA). The endpoints were overall survival (OS), locoregional failure-free survival (LRFFS) and progression-free survival (PFS). Each endpoint was calculated from the date of initial diagnosis by biopsy. LRF was defined as local tumor persistence/recurrence, regional lymph node persistence/recurrence, or death. OS, LRFFS and PFS was defined as the time from initial diagnosis to death from any cause or last follow-up, locoregional tumor persistence/recurrence and evidence of tumor progression, respectively. Locoregional recurrence was defined as recurrence at the primary site or regional lymph nodes. Survival data were analyzed using the Kaplan–Meier method and log-rank test. Univariate analysis of prognostic factors of OS, LRFFS and PFS was performed using the log-rank test and multivariate analysis was carried out using the Cox proportional hazards model. Two-sided tests were used and p <0.05 was considered statistically significant.

RESULTS

Patients

A total of 91 patients with CEC who were treated with RT were included in the study. Thirty-four patients (37.4%) received concurrent cisplatin-based CT, including 18 patients who also received NAC. Fifty-seven patients (62.6%) were treated with RT alone. Table 1 summarizes clinicopathological characteristics and treatment of CEC patients.

TABLE 1: Demographic and clinicopathological characteristics of patients

Acute and late treatment-related toxicities

Among 91 CEC patients, the most frequently observed acute toxicities were grade 1 and 2. Common grade 1 and 2 acute toxicities were mucositis and esophagitis, observed in 20 (22%) and 22 (24.2%) cases, respectively. Nine patients (10%) experienced grade 3 acute hematologic toxicity. Three patients (3.3%, all three treated with CCRT only) developed grade 3 acute gastrointestinal toxicity. Dysphagia was the most common late toxicity, and six patients (6.6%) experienced severe dysphagia requiring intervention. Other late toxicities were grade 1 radiation pneumonitis and radiation-induced brachial plexus injury.

Survival

The median follow-up time for all patients was 19 months. The two-year OS, LRFFS and PFS for all patients were 58.2%, 52.5% and 48.1%, respectively (Figure 1).

FIGURE 1: OS, LRFFS and PFS of 91 CEC patients (A). The two-year OS, LRFFS and PFS for all patients were 58.2%, 52.5% and 48.1%, respectively. Advanced clinical stage was a poor prognostic factor of PFS (B). CEC: Cervical esophageal cancer; OS: Overall survival; LRFFS: Locoregional failure-free survival; PFS: Progression-free survival.

Prognostic factors

Table 2 shows prognostic factors of survival in CEC according to the univariate analysis. Hoarseness, advanced clinical stage (III-IV), tumor length (>5 cm), GTV volume (≥45 cc) and treatment time (>42 days) were significant prognostic factors for poor OS, LRFFS and PFS. GTV dose (<66 Gy), number of fractions (>30 fractions), and 3DCRT technique had an adverse effect on OS. Weight loss (≥10%), distant metastasis (nonregional lymph nodes) and non-CCRT were associated with a worse LRFFS. Lymph node metastasis (N1) was associated with a worse PFS (Figure 2).

TABLE 2: Univariate analysis of two-year OS, LRFFS and PFS in CEC patients
FIGURE 2: Hoarseness (A) and clinical stage (B) were independent prognostic factors of OS in CEC. Clinical stage (C) and CCRT (D) were independent prognostic factors of LRFFS. CEC: Cervical esophageal cancer; OS: Overall survival; LRFFS: Locoregional failure-free survival.

Table 3 summarizes the multivariate analysis results. Hoarseness (HR = 2.10, 95% CI: 1.05–4.19, p = 0.036) and clinical stage III-IV (HR = 2.35, 95% CI: 1.03–5.37, p = 0.042) were independent prognostic factors of OS. Clinical stage III-IV was also an independent factor of LRFFS (HR = 3.84, 95% CI: 1.38–10.69, p = 0.011) and PFS (HR = 2.68, 95% CI: 1.11–6.45, p = 0.028). CCRT was independently associated with a better LRFFS (HR = 0.33, 95% CI: 0.14–0.79, p = 0.012).

TABLE 3: Multivariate analysis of two-year OS, LRFFS and PFS in CEC patients

DISCUSSION

The management of CEC remains controversial. Prospective randomized data for CEC are lacking, due to its low incidence and a small number of clinical studies specifically investigating treatment outcomes and prognostic factors of survival in CEC patients. RT has become the primary treatment option for CEC, due to the fact that it allows preservation of the esophagus and adjacent organs. Nevertheless, studies investigating outcomes of CEC patients treated with RT, CCRT, or surgery showed controversial results. For example, the two- and five-year survival rates of patients treated with CRT are 24% to 60% and 20% to 55%, respectively [5,17-20], while the five-year survival rates of CEC patients undergoing surgical resection with larynx preservation are higher, i.e. between 40.6% and 57.8% (Table 4) [6,21-23]. Moreover, 23.8% to 40.7% of CEC patients treated with CRT undergo salvage surgery [17-20]. On the other hand, other studies showed comparable disease control and survival between surgery with/without larynx preservation and RT with/without concurrent CT in CEC patients [7,20,24,25]. Chou et al. [7] retrospectively analyzed 15 patients who underwent radical resection (total laryngopharyngectomy with neck dissection, total esophagectomy, and reconstruction with stomach) and 14 patients who received CCRT. They showed no significant difference in the QOL and survival between the two treatment groups (mean survival time was 36.2 months for surgical resection vs. 34.4 months for CCRT [p = 0.97]) [7]. In a matched-case analysis of 58 patients with CEC, Cao et al. [24] did not show any significant differences in two-year survival rates between surgery group (in most cases pharyngolaryngoesophagectomy [PLE] was performed) and RT group (47.7% and 55.6%, respectively [p = 0.71]). Tong et al. [20] compared the outcomes of 107 CEC patients treated either with PLE (n = 62), upfront CCRT (n = 21), or palliative treatment (n = 24). The median survival duration was not statistically different between PLE and CCRT group in their study, i.e. 20 and 25 months respectively (p = 0.39) [20]. Liu et al. [25] performed a retrospective analysis of 57 patients with CEC who received PLE (n = 17) or definite CCRT (n = 40). The two groups were comparable for age, gender, American society of anesthesiologists (ASA) class and clinical stage. In a median follow-up of 14.4 months, the authors observed no significant difference in local recurrence rate (42.5% vs. 52.9%, p = 0.469), distant recurrence rate (32.5% vs. 29.4%, p = 0.819) and OS (17.1 vs. 14.4 months, p = 0.943) between CCRT and PLE groups. Among the above-described studies three performed PLE, thus increasing the possibility of a better therapeutic effect due to radical surgical approach. Furthermore, some studies reported that PLE is associated with high mortality rate and risk of complications in CEC patients [20,26-28]. Generally, a direct comparison between RT and surgery in CEC is difficult due to the retrospective design and inherent selection bias of these studies. In our study, the two-year OS, LRFFS and PFS of CEC patients treated with RT were 58.2%, 52.5% and 48.1%, respectively and only mild complications were recorded for these patients. Similar findings were reported by other studies [4,5]. Thus, CCRT appears to be optimal treatment strategy for CEC and should be considered individually.

TABLE 4: Outcomes of radiotherapy and surgery with larynx preservation in cervical esophageal cancer

Randomized studies on esophageal cancer [8] and squamous cell head and neck cancer [9,10] showed that CCRT results in organ preservation and improves patient OS compared with RT alone. A rationale for CCRT is that CT can sensitize tumors to RT by preferentially killing hypoxic cells, inhibiting tumor repopulation, inhibiting the sublethal radiation damage repair, and by improving blood supply and reoxygenation of organ [29]. However, in CEC, local and regional failure rates after CCRT remain high [1,29,30]. Studies with adequate follow-up reported a local relapse rate between 34% and 85% in CEC patients treated with CCRT [4,5,17,18,31,32] suggesting that a more aggressive local approach, such as the use of NAC or higher radiation doses, may be helpful. Our study showed that CCRT improved LRFFS in CEC patients. Several other studies on CEC patients reported a weak positive trend between OS or LRFFS and CCRT, although without significant difference compared to RT alone. Overall, CCRT may improve local tumor control in CEC patients [17,31,33]. In addition, Huang et al. [17] showed no significant difference in OS (p = 0.94) and LRFFS (p = 0.19) between patients treated with a lower dose, hypofractionated, 2D RT with 5-FU–based CT protocol and those treated with high-dose cisplatin-based, conventionally fractionated, conformal CCRT with prophylactic nodal RT.

Similar to previous studies [4,16,34], we showed that hoarseness was a significant prognostic factor for OS in CEC patients, i.e., it was associated with advanced clinical stage and disease progression. Hoarseness results from recurrent laryngeal nerve involvement due to direct tumor invasion or lymph node metastasis. Therefore, hoarseness can be considered as a late symptom of CEC and should be taken into account when planning the treatment.

Due to the low incidence of CEC, relatively short follow-up and patient heterogeneity, only a few studies have investigated the effect of advanced stage on survival in CEC. In the studies of Ludmir et al. [35] and Cao et al. [4] advanced stage had a significant impact on LRFFS and PFS in patients treated with definite RT or CCRT. In our study advanced clinical stage, together with hoarseness, was an adverse prognostic factor for OS, LRFFS and PFS. I.e., CEC patients with clinical stage I-II had a better OS (71.4% vs. 40.0%, p = 0.000), LRFFS (76.5% vs. 36.6%, p = 0.000) and PFS (72.0% vs. 32.9%, p = 0.000) compared to patients with stage III-IV. Moreover, CEC patients with advanced clinical stage with N1 and M1 (nonregional lymph node metastasis) tended to have a worse OS, LRFFS and PFS in our study.

The major limitations of our study are retrospective design, small number of included patients, selection bias, and heterogeneity among patients. Larger prospective randomized studies are necessary for better insight into the effect of CCRT on CEC.

CONCLUSION

In summary, 3DCRT and IMRT with concurrent CT is well-tolerated and may improve local tumor control in CEC patients. Advanced clinical stage and hoarseness are adverse prognostic factors for OS, LRFFS, and PFS in CEC.

Acknowledgements

ACKNOWLEDGMENTS

This study was supported by Natural Science Foundation of China (81860534, 81760552), Natural Science Foundation of Inner Mongolia (2015MS0896), Inner Mongolia autonomous region health and family planning commission (201702104, 201701077), Science and technology million engineering joint project of Inner Mongolia medical university (YKD2017KJBW(LH)004) and The Affiliated Hospital of Inner Mongolia Medical University project (NYFY ZD 015). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

DECLARATION OF INTERESTS

The authors declare no conflict of interests.

REFERENCES

  1. , , , , , (). Management of cervical esophageal carcinoma. Semin Radiat Oncol. https://doi.org/10.1016/S1053-4296(05)80066-9
  2. , , , , , (). Comparison of free jejunal graft with gastric pull-up reconstruction after resection of hypopharyngeal and cervical esophageal carcinoma. Dis Esophagus. https://doi.org/10.1111/j.1442-2050.2007.00781.x
  3. , , , , , (). Feasibility of involved-field conformal radiotherapy for cervical and upper-thoracic esophageal cancer. Onkologie. https://doi.org/10.1159/000334194
  4. , , , , , (). Definitive radiotherapy for cervical esophageal cancer. Head Neck. https://doi.org/10.1002/hed.23572
  5. , , , , , (). Long-term results of definitive radiochemotherapy in locally advanced cancers of the cervical esophagus. Dis Esophagus. https://doi.org/10.1111/dote.12146
  6. , , , , , (). Larynx-preserving limited resection and free jejunal graft for carcinoma of the cervical esophagus. World J Surg. https://doi.org/10.1007/s00268-012-1875-7
  7. , , , , , (). Radical resection or chemoradiotherapy for cervical esophageal cancer?. World J Surg. https://doi.org/10.1007/s00268-010-0595-0
  8. , , , , , (). Chemoradiotherapy of locally advanced esophageal cancer:Long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. https://doi.org/10.1001/jama.281.17.1623
  9. (). An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. https://doi.org/10.1200/JCO.2003.01.008
  10. , , , , , (). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. https://doi.org/10.1056/NEJMoa053422
  11. , , , , , (). Dosimetric comparison of IMRT vs. 3D conformal radiotherapy in the treatment of cancer of the cervical esophagus. Radiother Oncol. https://doi.org/10.1016/j.radonc.2008.08.008
  12. , , , , , (). Comparative outcomes for three-dimensional conformal versus intensity-modulated radiation therapy for esophageal cancer. Dis Esophagus. https://doi.org/10.1111/dote.12203
  13. , , , , (). Applying the technique of volume-modulated arc radiotherapy to upper esophageal carcinoma. J Appl Clin Med Phys. https://doi.org/10.1120/jacmp.v15i3.4732
  14. , , , , , (). Dosimetric benefits of IMRT and VMAT in the treatment of middle thoracic esophageal cancer:Is the conformal radiotherapy still an alternative option?. J Appl Clin Med Phys. https://doi.org/10.1120/jacmp.v15i3.4641
  15. , , , , , (). Volumetric modulated arc therapy vs. c-IMRT for the treatment of upper thoracic esophageal cancer. PLoS One. https://doi.org/10.1371/journal.pone.0121385
  16. , , , , , (). Clinical efficacy and failure pattern in patients with cervical esophageal cancer treated with definitive chemoradiotherapy. Radiother Oncol. https://doi.org/10.1016/j.radonc.2015.07.011
  17. , , , , , (). Effect of concurrent high-dose cisplatin chemotherapy and conformal radiotherapy on cervical esophageal cancer survival. Int J Radiat Oncol Biol Phys. https://doi.org/10.1016/j.ijrobp.2007.10.022
  18. , , , , , (). Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the cervical oesophagus. Oncology. https://doi.org/10.1159/000012015
  19. , , , , , (). Multimodal approach for cervical esophageal carcinoma:Role of neoadjuvant chemotherapy. Anticancer Res.
  20. , , , , , (). Current management of cervical esophageal cancer. World J Surg. https://doi.org/10.1007/s00268-010-0876-7
  21. , , , , , (). Larynx-preserving esophagectomy and jejunal transfer for cervical esophageal carcinoma. Laryngoscope. https://doi.org/10.1002/lary.20493
  22. , , , , , (). Limited resection and free jejunal graft interposition for squamous cell carcinoma of the cervical oesophagus. Br J Surg. https://doi.org/10.1002/bjs.6437
  23. , , , , , (). Surgical management of cervical esophageal carcinoma with larynx preservation and reconstruction. Int J Clin Exp Med.
  24. , , , , , (). Primary radiotherapy compared with primary surgery in cervical esophageal cancer. JAMA Otolaryngol Head Neck Surg. https://doi.org/10.1001/jamaoto.2014.2013
  25. , , , , , (). Chemoradiotherapy or pharyngo-laryngo-esophagectomy for cervical esophageal squamous cancer. Gastroenterology. https://doi.org/10.1016/S0016-5085(11)64292-3
  26. , , (). Complications following gastric transposition after total laryngo-pharyngectomy. Eur J Surg Oncol. https://doi.org/10.1053/ejso.1998.0605
  27. , , , (). Pharyngogastric anastomosis following pharyngolaryngoesophagectomy. Analysis of 157 cases. World J Surg. https://doi.org/10.1007/BF01655003
  28. , , , (). Surgical management of carcinoma of the hypopharynx and cervical esophagus:Analysis of 209 cases. Arch Surg. https://doi.org/10.1001/archsurg.136.10.1164
  29. , (). Concurrent chemotherapy and radiotherapy for head and neck cancer. Expert Rev Anticancer Ther. https://doi.org/10.1586/14737140.9.3.293
  30. , , , , , (). Radiation treatment for cervical esophagus:Patterns of practice study in Canada, 1996. Int J Radiat Oncol Biol Phys. https://doi.org/10.1016/S0360-3016(00)00484-3
  31. , , , , , (). Concurrent chemoradiation for patients with squamous cell carcinoma of the cervical esophagus. Dis Esophagus. https://doi.org/10.1111/j.1442-2050.2007.00632.x
  32. , , , , , (). Treatment results of radiotherapy for carcinoma of the cervical esophagus. Acta Oncol. https://doi.org/10.1080/02841↞00609768
  33. , , , , , (). Intensity-modulated radiotherapy for cervical esophageal squamous cell carcinoma:Clinical outcomes and patterns of failure. Eur Arch Otorhinolaryngol. https://doi.org/10.1007/s00405-015-3576-y
  34. , , , , , (). Analysis of the risk factors for myelosuppression after chemoradiotherapy involving 5-fluorouracil and platinum for patients with esophageal cancer. Hepatogastroenterology.
  35. , , , , (). Definitive chemoradiation therapy for cervical esophageal carcinoma:A single-institution experience. Int J Radiat Oncol Biol Phys. https://doi.org/10.1016/j.ijrobp.2014.05.1135
  36. , , , , (). Thirty-four patients with carcinoma of the cervical esophagus treated with chemoradiation therapy. Arch Otolaryngol Head Neck Surg. https://doi.org/10.1001/archotol.126.2.205