Clinical Investigation
Effect of Intensity Modulated Radiation Therapy With Concurrent Chemotherapy on Survival for Patients With Cervical Esophageal Carcinoma

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Purpose

We evaluated the effect of consecutive protocols on overall survival (OS) for cervical esophageal carcinoma (CEC).

Methods and Materials

All CEC cases that received definitive radiation therapy (RT) with or without chemotherapy from 1997 to 2013 in 3 consecutive protocols were reviewed. Protocol 1 (P1) consisted of 2-dimensional RT of 54 Gy in 20 fractions with 5-fluorouracil plus either mitomycin C or cisplatin. Protocol 2 (P2) consisted of 3-dimensional conformal RT (3DRT) of ≥60 Gy in 30 fractions plus elective nodal irradiation plus cisplatin. Protocol 3 (P3) consisted of intensity modulated RT (IMRT) of ≥60 Gy in 30 fractions plus elective nodal irradiation plus cisplatin. Multivariable analyses were used to assess the effect of the treatment protocol, RT technique, and RT dose on OS, separately.

Results

Of 81 cases (P1, 21; P2, 23; and P3, 37), 34 local (P1, 11 [52%]; P2, 12 [52%]; and P3, 11 [30%]), 16 regional (P1, 6 [29%]); P2, 3 [13%]; and P3, 7 [19%]), and 34 distant (P1, 10 [48%]; P2, 9 [39%]; and P3, 15 [41%]) failures were identified. After adjusting for age (P=.49) and chemotherapy (any vs none; hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.3-0.9; P=.023), multivariable analysis showed P3 had improved OS compared with P1 (HR 0.4, 95% CI 0.2-0.8; P=.005), with a trend shown for benefit compared with P2 (HR 0.6, 95% CI 0.3-1.0; P=.061). OS between P1 and P2 did not differ (P=.29). Analyzed as a continuous variable, higher RT doses were associated with a borderline improved OS (HR 0.97, 95% CI 0.95-1.0; P=.075). IMRT showed improved OS compared with non-IMRT (HR 0.57, 95% CI 0.3-0.8; P=.008).

Conclusions

The present retrospective consecutive cohort study showed improved OS with our current protocol (P3; high-dose IMRT with concurrent high-dose cisplatin) compared with historical protocols. The outcomes for patients with CEC remain poor, and novel approaches to improve the therapeutic ratio are warranted.

Introduction

Cervical esophageal carcinoma (CEC) is a rare but aggressive tumor arising in the short segment of the esophagus between the cricopharyngeus and the sternal notch. The incidence in North America is approximately 5 per million, accounting for <5% of all esophageal cancers 1, 2. Treatment-related morbidity and cancer-related mortality are high in patients with CEC, owing to the late presentation, treatment toxicity, and moderate to high risk of local, regional, and distant failure.

The optimal management of CEC has not been established. Until recently, no prospective trials had been attempted, and the results had been confined to small, retrospective single-institutional and population-level series from which only limited conclusions could be drawn (3). Historically, in some centers, surgery was preferred for highly selected patients and often necessitated pharyngo-laryngo-esophagectomy for which postoperative mortality and long-term survival were poor 2, 4, 5, 6, 7, 8. Primary radiation therapy (RT) (with or without chemotherapy [CTx]) is an alternative approach for those unsuitable for surgery and has been an accepted standard of care for ≥2 decades 2, 9, 10. Although CEC was not included in the landmark trials establishing concurrent chemoradiation therapy (CCRT) compared with RT alone as the optimal organ-sparing approach for mucosal head and neck cancer (HNC), cisplatin-based CCRT has been recommended as first-line treatment in international guidelines 11, 12, 13. Contemporary chemoradiation therapy series, predominantly using 3-dimensional conformal RT (3DRT), have reported comparable outcomes to surgery, with locoregional control (LRC) of 33% to 88% 3, 8, 14, 15, 16, 17, 18 and 5-year survival of 19% to 55% 3, 8, 14, 15, 17, 18, 19, 20. Although intensity modulated RT (IMRT) has revolutionized HNC treatment, reports for CEC have been limited and inconclusive 21, 22. Although IMRT improved target volume coverage and conformality with a decreased dose to normal structures in a dosimetric study of CEC (23), a clinical benefit has not yet been demonstrated.

Definitive RT with or without CTx has long been the preferred approach for CEC at our institution. We have viewed CEC as more closely resembling hypopharyngeal squamous cell carcinoma than lower esophageal cancers, with most of the latter being adenocarcinoma. This principle has guided the evolution of our treatment protocols. Our institutional policy has evolved during the past 2 decades with changes in RT techniques, dose, and volume and CTx regimens, resulting in 3 different treatment protocols since 1997 (Table 1). These changes reflect efforts to maximize LRC, through improved tumor targeting, dose escalation, or enhanced systemic regimens. The aim of the present study was to assess the effect of the most recent shift in treatment protocol (implementation of IMRT) and to identify the effect of individual treatment factors, such as radiation dose and the use of IMRT. Although our previous report comparing the first 2 protocols did not show a statistically significant improvement in the patterns of failure or survival, we hoped that additional follow-up and patient data from our most recent protocol would confirm our clinical impression of improved outcomes with our contemporary protocol (15).

Section snippets

Patient population

A retrospective review was conducted of all patients with newly diagnosed histologically confirmed CEC who had undergone primary RT (with or without CTx) from 1997 to 2013 at our institution. Patients were identified from a prospectively maintained database after institutional research ethics board approval. Staging was in accordance with the 1983 American Joint Committee on Cancer clinical staging system (24), because the T category in the most recent Union for International Cancer Control,

Patient characteristics

A total of 81 patients were eligible and included 21 in the P1, 23 in the P2, and 37 in the P3 cohort. The median follow-up period was 1.6 years (range 0.3-13). The baseline demographics are listed in Table 2. No significant differences were present among the protocols with respect to follow-up length for surviving patients, gender, age, alcohol or smoking history, tumor length, GTV, or tumor grade. However, more P3 patients had Eastern Cooperative Oncology Group performance status 2 (P1 vs P2

Discussion

CEC is a rare and aggressive disease with a propensity for both locoregional and distant recurrence. The historical outcomes have routinely been poor, irrespective of whether surgery or primary RT was used. Although CCRT with ENI to 60 to 66 Gy is recommended as first-line treatment, higher doses (>50 Gy) have not been supported by randomized evidence, and no consensus has been reached on the most appropriate radiation dose 11, 26. Series comparing contemporary and historical outcomes have

Conclusions

Our institutional policy has evolved, with our most recent protocol demonstrating improved survival compared with historical cohorts. High-dose RT (70 Gy in 35 fractions), with ENI delivered with IMRT, and concurrent high-dose cisplatin is our standard based on our results demonstrating improved survival and lower rates of long-term swallowing dysfunction. The outcomes remain poor, and further research is required focusing on improving LRC and DC and minimizing treatment-related toxicity.

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  • Conflict of interest: none.

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