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Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus

Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus
Authors:
Michael K Gibson, MD, PhD, FACP
Florence K Keane, MD
Section Editors:
Richard M Goldberg, MD
Christopher G Willett, MD
Brian E Louie, MD, MHA, MPH, FRCSC, FACS
Deputy Editor:
Diane MF Savarese, MD
Literature review current through: Dec 2022. | This topic last updated: Oct 21, 2022.

INTRODUCTION — Cancer of the esophagus is a highly lethal malignancy. There are approximately 20,640 people diagnosed with esophageal cancer each year in the United States and 16,410 deaths from the disease [1]. Data on global incidence and mortality are available from the World Health Organization GLOBOCAN database.

The management of local-regional esophageal cancer has undergone a major evolution over the past 15 years. The low cure rates after locoregional therapy alone prompted the inclusion of systemic chemotherapy in multimodality treatment regimens, to control distant micrometastatic disease and enhance local radiation effects.

Classification and management of esophagogastric junction (EGJ) tumors have also evolved over time. In the current (2017, eighth edition) revision of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging classification [2], tumors involving the EGJ with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal cancers (table 1), while EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers, as are all cardia cancers not involving the EGJ, even if they are within 2 cm of the EGJ (table 2). (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'TNM staging criteria' and "Clinical features, diagnosis, and staging of gastric cancer", section on 'TNM staging criteria'.)

Most clinicians now treat EGJ and proximal gastric (ie, cardia (figure 1)) cancers as esophageal cancers, using preoperative chemoradiotherapy. However, these tumors have been included in many of the trials examining the benefit of perioperative chemotherapy for gastric cancer, and this approach is also widely used. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)

This topic review will focus on the efficacy of radiation therapy (RT) and chemotherapy and multimodality management of localized and locoregional cancer involving the thoracic esophagus. Management of cervical esophageal tumors is also considered briefly.

Multimodality approaches to cancer of the EGJ, neoadjuvant and adjuvant approaches for true gastric tumors, principles of surgical treatment for localized esophageal and EGJ cancer, nutritional support during multimodality therapy, endoscopic methods for palliation of dysphagia during neoadjuvant treatment, issues specific to superficial and locally advanced unresectable disease, and treatment of metastatic disease are discussed elsewhere.

(See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)

(See "Adjuvant and neoadjuvant treatment of gastric cancer".)

(See "Surgical management of resectable esophageal and esophagogastric junction cancers".)

(See "The role of parenteral and enteral/oral nutritional support in patients with cancer".)

(See "Endoscopic stenting for palliation of malignant esophageal obstruction", section on 'Other stents'.)

(See "Endoscopic palliation of esophageal cancer".)

(See "Management of superficial esophageal cancer".)

(See "Management of locally advanced, unresectable and inoperable esophageal cancer".)

(See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer".)

SQUAMOUS CELL VERSUS ADENOCARCINOMA — There are two major histologies of esophageal cancer: squamous cell carcinoma (SCC) and adenocarcinoma (AC). Although most clinical studies have not differentiated between the two histologies, an increasing amount of evidence supports the view that they differ in terms of pathogenesis, epidemiology, tumor biology, and prognosis. In acknowledgment of these differences, the Tumor, Node, Metastasis (TNM) staging system provides separate stage groupings (but similar definitions for T, N, M, and grade [G] categories) for SCCs and ACs of the esophagus and esophagogastric junction (EGJ) (table 1). In addition, tumor location (for SCCs only) is incorporated into stage grouping. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer".)

However, it remains unclear as to whether and how histology should dictate the therapeutic approach, and largely due to the lack of data on the impact of histology on treatment outcomes, the approach tends to be similar for both histologies, at least initially. However, pathologic complete response rates are higher in SCC following chemoradiotherapy (CRT), and if an endoscopic complete response is achieved, non-operative management is an option following initial CRT. By contrast, few data exist on the adequacy of nonoperative management for ACs, and most patients are recommended to undergo surgery after upfront CRT. (See 'Necessity for surgery' below.)

Future studies in esophageal cancer should analyze and report separately the results of therapeutic strategies according to histology.

Differences — An increasing amount of evidence supports the view that esophageal SCC and ACs differ in terms of pathogenesis, epidemiology, tumor biology, and prognosis:

The incidence of SCC is declining in the United States while that of AC has increased markedly over the last 20 years, suggesting underlying etiologic differences. SCC almost always occurs in individuals with histories of tobacco and/or alcohol abuse while ACs are associated with gastroesophageal reflux disease (GERD) and high body mass. (See "Epidemiology and pathobiology of esophageal cancer".)

The precursor lesion of SCC is epithelial dysplasia, which when untreated sequentially progresses to carcinoma in situ, and finally to invasive carcinoma [3]. By contrast, ACs usually arise in the setting of persistent GERD, which can initiate intestinal metaplasia in the distal esophagus. Carcinogenesis begins with genetic alterations which endow the metaplastic cells with a growth advantage, permitting them to hyperproliferate. As the cells progressively acquire DNA damage, they become morphologically dysplastic, and eventually, frankly malignant. (See "Barrett's esophagus: Pathogenesis and malignant transformation", section on 'Adenocarcinoma'.)

Although SCCs tend to be diagnosed on average 10 years earlier than ACs, perioperative mortality is higher for SCC than for a Barrett's associated AC, likely related to associated comorbidities and tumor location [4,5]. The sequelae of GERD involve mostly the distal esophagus/EGJ, and 94 percent of cancers associated with Barrett's esophagus are located below the tracheal bifurcation. By contrast, 65 percent of SCCs are located above this location [6]. Patients with tumors located in the upper third of the esophagus who undergo resections have significantly higher rates of postoperative death. (See "Surgical management of resectable esophageal and esophagogastric junction cancers" and "Epidemiology and pathobiology of esophageal cancer" and "Barrett's esophagus: Pathogenesis and malignant transformation".)

Histology also influences the pattern of first recurrence after resection. Upper or mid-thoracic SCCs (figure 2) tend to recur locoregionally first, while distal esophageal ACs more commonly recur with distant dissemination.

Despite these data, many (but not all [7]) contemporary series suggest that the prognosis of AC is better than that of SCC, particularly in early stage disease [7-13]. One reason may be the lower prevalence of lymphatic spread for Barrett's-associated ACs than for SCCs [7,8].

It has been proposed that the difference in tumor location and histology also has implications for the choice of therapy:

Some suggest that induction chemotherapy alone may suffice for ACs, while results are superior with CRT for SCCs because of the greater need for tumor downsizing to achieve a complete radical resection and possibly because of the increased propensity for regional lymphatic spread [8].

Others note the higher degree of radiosensitivity for SCC, and the lack of survival improvement when CRT has been added to chemotherapy and surgery in contemporary series in which ACs predominate [14]. (See 'Chemotherapy versus chemoradiotherapy' below.)

However, there is controversy about this viewpoint and little agreement as to whether histologic type should be used as a factor in selecting the treatment strategy. A major area where data are lacking is nonsurgical management for ACs. (See 'Necessity for surgery' below.)

THORACIC ESOPHAGUS TUMORS

Clinical T3-4 or node-positive disease

Overview of our suggested initial approach — Our suggested approach to patients with clinical T3-4 or node-positive thoracic esophageal cancer is as follows:

We recommend combined modality therapy, rather than surgery alone, regardless of histology (table 1). (See 'Preoperative chemoradiotherapy' below.)

For most patients, we suggest concurrent chemoradiotherapy (CRT) instead of chemotherapy alone for neoadjuvant therapy. (See 'Chemotherapy versus chemoradiotherapy' below.)

Although the optimal type, dose, combination, and schedule of drugs has not been definitively established, we suggest the low-dose weekly carboplatin plus paclitaxel regimen (table 3) as was used in the Dutch CROSS trial rather than two courses of cisplatin plus fluorouracil (FU) as was used in CALGB 9781. (See 'Concurrent chemoradiotherapy' below.)

Many clinicians also treat esophagogastric junction (EGJ) and proximal gastric (ie, cardia, (figure 1)) cancers with preoperative CRT as well. However, these tumors have been included in many of the trials examining the benefit of perioperative chemotherapy alone for gastric cancer, and this is also a widely accepted approach. The specific therapeutic approach to tumors of the EGJ is addressed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)

Given the higher rate of locally persistent/recurrent disease after CRT alone and a lack of data on nonsurgical management of patients with adenocarcinomas (ACs), who have a low rate of pathologic complete response (pCR) after CRT, we suggest inclusion of surgery rather than definitive CRT for clinically resectable ACs. (See 'Necessity for surgery' below.)

We also suggest inclusion of surgery rather than definitive CRT for squamous cell carcinoma (SCC). However, for those with SCC who have an endoscopic complete response, nonoperative management is an option, balancing the risks of surgical mortality versus improved locoregional control. Nonoperative management may be preferred for a patient with a higher burden of comorbidities who is less likely to tolerate surgery and/or has a tumor located in the proximal esophagus (eg, close to the larynx) where laryngectomy would be necessary in order to obtain optimal resection margins. (See 'Chemoradiotherapy responders' below.)

An important point is that the optimal way to define "complete CRT responders" and detect those with residual disease is not established. At some institutions, an endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) biopsy is routinely undertaken [15,16], but others (including the National Comprehensive Cancer Network [NCCN] [17]) advise only upper endoscopy with biopsy if avoidance of surgery is being considered.

Until further data are available, we suggest against using postinduction therapy positron emission tomography (PET) scanning as an exclusive determinant in order to select patients for nonsurgical therapy. (See 'Utility of postinduction therapy PET scans' below.)

Surgery is an important component of treatment for those patients with less than a complete tumor response to neoadjuvant CRT. (See 'Nonresponders' below.)

For patients who have residual disease at the time of surgery after neoadjuvant CRT, we suggest adjuvant nivolumab.

These recommendations are consistent with year 2020 and updated year 2021 guidelines for treating locally advanced esophageal cancer from the American Society of Clinical Oncology (ASCO) [18,19] and with guidelines from the NCCN [20].

Efficacy of individual strategies

Surgery alone — Although only 30 to 40 percent of patients have potentially resectable disease at presentation, surgery has been the standard treatment for early-stage thoracic esophageal cancer. Its utility as monotherapy has been challenged [21-27]. More recently, contemporary surgical series report five-year survival rates of as high as 30 to 46 percent for surgery alone, with the most favorable outcomes in patients with node-negative SCC [28-31]. In one analysis of 4627 patients with esophageal cancer who were treated with surgery alone, without adjuvant or neoadjuvant therapy, five-year survival rates were 42 percent, but they were <50 percent for all disease stages except T1N0 cases (table 1), and they were 15 percent for any patient with node-positive disease [28].

This relatively poor long-term outcome has prompted an evaluation of neoadjuvant (preoperative), adjuvant (postoperative), and nonoperative strategies aimed at improving survival in patients with apparently localized disease. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Thoracic cancer resection'.)

Radiation therapy — Before the era of modern chemotherapy and CRT, radiation therapy (RT) alone was frequently used for local control of esophageal cancer. Modern radiation techniques (eg, three-dimensional conformal radiation therapy [3D-CRT], intensity-modulated radiation therapy [IMRT]) are associated with more favorable toxicity profiles than those associated with units which deliver lower energy radiation that were used in earlier years. The success of advanced radiation technology can be illustrated by a Chinese trial in which surgery was compared with RT alone in 269 patients with esophageal SCC [32]. RT was planned using 3D-CRT technique, and 69 Gy were delivered in 41 fractions over 45 days (45 Gy in 25 fractions over five weeks followed by 24 Gy in twice daily 1.5 Gy fractions for eight days using IMRT). Three- and five-year overall survival rates in the RT alone group (56 and 35 percent, respectively) were not significantly different from those in the surgery group (62 and 37 percent, respectively). These results cannot be extrapolated to patients with AC.

Although these data are encouraging, the strategy of treating with RT alone has been supplanted by combined CRT in the majority of patients because of significantly better outcomes [33,34], despite a higher rate of treatment-related toxicity.

Preoperative chemoradiotherapy — Several trials and meta-analyses [34] have demonstrated better survival with preoperative concurrent chemoradiation as compared with local therapy alone, and this approach is generally preferred for potentially resectable stage T3 or 4, or node-positive localized cancer of the thoracic esophagus. However, the optimal regimen is not established.

The poor long-term survival associated with surgery alone and the radiosensitizing effect of concurrent chemotherapy provided the impetus to evaluate preoperative CRT. At least seven trials have directly compared surgery with or without preoperative CRT for patients with potentially resectable esophageal carcinoma [24,35-40]. Three studies demonstrated a significant survival benefit from combined modality therapy, all using a concurrent rather than sequential approach [39-41]. A survival benefit from preoperative CRT over surgery alone was confirmed in a network meta-analysis (hazard ratio [HR] for death for CRT over surgery alone 0.75, 95% CI 0.67-0.85) [34].

Concurrent chemoradiotherapy

Versus RT alone – In randomized trials and a meta-analysis, the addition of cisplatin-based chemotherapy to RT significantly improved survival over RT alone [34,42-44]. However, the available data are almost exclusively in patients with SCC, and none of the trials have performed adequate pretreatment staging to reliably correlate outcome with locoregional tumor extent (ie, locally advanced unresectable versus potentially operable disease). The following sections will summarize the data for patients with disease confined to the primary and regional nodes based upon radiographic imaging.

RTOG 85-01 – A landmark RTOG trial compared RT alone (64 Gy in 32 fractions over 6.5 weeks) versus concurrent CRT (two cycles of infusional FU [1000 mg/m2 per day, days 1 to 4, weeks 1 and 5] plus cisplatin [75 mg/m2 day 1 of weeks 1 and 5] and RT [50 Gy in 25 fractions over five weeks]) in patients with locoregional thoracic esophageal cancer [42]. Patients were required to have no evidence of spread beyond mediastinal and supraclavicular lymph nodes; 90 percent had SCC. The CRT group received two additional chemotherapy cycles, three weeks apart, after RT. Surgery was not part of the treatment schema.

The trial was closed prematurely with 121 patients, when an interim analysis showed a significant survival advantage for CRT (five-year overall survival 26 versus 0 percent) [43]. Analysis of failure patterns showed a significant reduction in both locoregional and distant failure for CRT. However, despite this benefit, 46 percent of patients in the CRT group had locally recurrent or persistent disease in the esophagus at 12 months. (See 'Necessity for surgery' below.)

As a result of this trial, definitive CRT became the standard of care for patients with inoperable disease (see "Management of locally advanced, unresectable and inoperable esophageal cancer"). The issue of the unacceptably high locoregional failure rate was addressed in a follow-up trial, INT 0123.

INT 0123 – In the United States Intergroup Study 0123 (INT 0123), 236 patients with non-metastatic esophageal SCC or AC received concurrent cisplatin and FU (as in RTOG 85-01), and were randomly assigned to one of two different RT doses: 50.4 Gy (28 fractions of 1.8 Gy each, five fractions per week) or 64.8 Gy (36 fractions of 1.8 Gy each, five fractions per week) [45]. Higher RT doses were not associated with a higher median (13 versus 18 months) or two-year survival (31 versus 40 percent), nor did it appear to affect the incidence of locoregional persistent or recurrent disease (56 versus 52 percent for the high dose and control groups, respectively). High-dose RT was significantly more toxic.

The reason for the failure to demonstrate better survival or locoregional control with higher RT doses is unclear. However, this study was conducted between 1995 and 1999 and before the era of 3D-CRT. At present, 50.4 Gy of RT plus concurrent cisplatin and FU remains a standard approach.

More recent studies are investigating the role of newer chemotherapy regimens combined with RT (eg, FOLFOX [46] or weekly carboplatin plus paclitaxel as was used in the CROSS trial [47]).

IMRT plus chemotherapy – Newer radiation techniques, such as IMRT, are associated with more favorable toxicity profiles. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

Although few trials have been conducted, IMRT with concurrent chemotherapy is beginning to be studied for the treatment of esophageal cancer [48-50]. At least one Chinese trial of 170 patients with locally advanced esophageal cancer suggests that definitive CRT using the combination of IMRT plus concurrent cisplatin plus docetaxel improved local control and prolonged survival over IMRT alone, but side effects were more prominent [48]. No trial has compared IMRT plus concurrent chemotherapy with the same chemotherapy regimen plus standard fractionation 3D-CRT, and thus, the safety and efficacy of this approach compared with standard 3D-CRT remains undefined.

Versus surgery alone – Of the six completed randomized trials that compared preoperative concurrent CRT with surgery alone, three showed a statistically significant survival benefit for CRT [39,41,51], and three others did not, two of which were underpowered [35,40,52]. The three most important trials are the Dutch CROSS, CALGB 9781, and NEOCRTEC5010 trials:

CROSS trial – Dutch investigators randomly assigned 363 patients with potentially resectable esophageal or esophagogastric junction (EGJ) cancer (86 SCC, 273 AC, 4 other; majority distal esophageal, 11 percent EGJ) to preoperative CRT using weekly paclitaxel 50 mg/m2 plus carboplatin (area under the curve of concentration X time [AUC] of 2) plus concurrent RT (41.4 Gy over five weeks) or surgery alone [53]. Preoperative CRT was well tolerated, with grade 3 or worse hematologic toxicity in 7 percent, and grade 3 or higher non-hematologic toxicity in <13 percent; there were also no differences in postoperative morbidity or mortality between the two groups. The microscopically complete (R0) resection rate was higher with CRT (92 versus 69 percent), and 29 percent of those treated with CRT had a pCR. At a median follow-up of 32 months, median overall survival was significantly better with preoperative CRT (HR for death 0.657, 95% CI 0.495-0.871, three-year survival rate 58 versus 44 percent).

The survival benefit persisted with longer follow-up (five-year survival 47 versus 33 percent, HR for death 0.67, 95% CI 0.51-0.87 [54]; 10-year survival 38 versus 25 percent, HR for death 0.70, 95% CI 0.55-0.89 [55]). In the latest analysis, although there was a clear effect of neoadjuvant CRT on reducing isolated locoregional and synchronous locoregional plus distant relapses, isolated distant relapse rates were not significantly different in the two groups [55].

CALGB 9781 – CALGB 9781 was originally designed as a randomized Intergroup trial of trimodality therapy versus surgery in 500 patients with stages I-III esophageal or EGJ cancer, staged with esophagogastroduodenoscopy, barium esophagram, and computed tomography (CT). Staging EUS and thoracoscopy/laparoscopy were encouraged. Due to poor accrual, the study was closed prematurely with only 56 patients enrolled (42 ACs, 14 SCC). A pCR was achieved in 10 of 25 assessable patients in the trimodality arm (40 percent), and neither perioperative morbidity nor mortality were increased compared with surgery alone [40]. Five-year survival was 39 versus 16 percent in favor of trimodality therapy, although the difference was not statistically significant.

NEOCRTEC5010 trial – In a Chinese trial, 451 patients with potentially resectable thoracic esophageal SCC were randomly assigned to neoadjuvant CRT (RT concurrent with vinorelbine plus cisplatin) or surgery alone [41]. At surgery, the pCR rate was 43 percent in those receiving CRT. Compared with surgery alone, patients receiving neoadjuvant CRT had a higher R0 resection rate (98 versus 91 percent), and a similar incidence of postoperative complications. In the latest analysis (median follow-up 54 months), neoadjuvant therapy was associated with better five-year overall (60 versus 49 percent, HR 0.74, 95% CI 0.57-0.97), and disease-free survival (64 versus 43 percent, HR 0.60, 95 CI 0.45-0.80) [56].

Meta-analyses – Several meta-analyses have addressed the benefit of trimodality therapy over surgery alone for esophageal cancer [18,34,57,58]. One of the most recent and largest of these included 12 randomized comparisons of neoadjuvant CRT (either concurrent or sequential) versus surgery alone for esophageal or EGJ cancer, including the FFCD 9901, CALGB 9781, and CROSS trials [57]. The HR for all-cause mortality for neoadjuvant CRT was 0.78 (95% CI 0.70-0.88), and this translated into an absolute survival benefit of 8.7 percent at two years and a number needed to treat to prevent one death of 11. The benefit was similar across histologic subtypes (for SCC, the HR was 0.80, 95% CI 0.68-0.93; for ACs, the HR was 0.75, 95% CI 0.59-0.95). The potential benefit of neoadjuvant therapy was not offset by a higher postoperative mortality (in-hospital or 30-day postoperative death).

Older adults – Few data are available on the safety and efficacy of CRT in older adults. However, at least one report suggests that patients over age 70 tolerate cisplatin-based CRT without a major increase in adverse events and with outcomes that seem comparable with those achieved in younger individuals [59]. Patients with significant comorbidity (ie, Charlson score ≥1 (table 4)) did experience more severe toxicity and chemotherapy delays/dose reductions than those without comorbidity. (See "Comprehensive geriatric assessment for patients with cancer".)

Sequential chemoradiotherapy — In contrast to the data on concurrent CRT, at least three trials comparing sequentially administered chemotherapy and RT followed by surgery with surgery alone have failed to show any survival advantage to combined modality therapy [24,36,37].

Technique for preoperative RT — The degree of response of a tumor and normal tissues/organs to radiation depends upon several radiotherapeutic factors [60-62]:

Fraction size (standard fraction size, 1.8 Gy to 2 Gy) and interfractional intervals (standard interval, 24 hours)

Total dose (standard preoperative dose in once daily schedule, 41.4 to 50.4 Gy)

Duration of treatment (5 to 5.6 weeks for standard fractionation, without a rest during treatment)

The arrangement of radiation portals in a manner that achieves the maximum dose differential between tumor and adjacent vital organs

Significant deviations from standard techniques should be avoided in a potentially curative setting. Fraction sizes that are larger than 2.5 Gy, treatment breaks of longer than one week, split-course fractionation schedules [63], and suboptimal radiation plans with a potential for increased risk of injury to the lung, heart, and spinal cord should be avoided.

Conformal RT – Conformal therapy is a term that describes a strategy for matching ("conforming") the high-dose radiation region to the target volume while minimizing the radiation dose to normal tissues. This term is typically used when the target volumes are defined on a CT or other high-definition imaging study used during the treatment planning. (See "Radiation therapy techniques in cancer treatment", section on 'Conformal therapy'.)

3D-CRT is recommended over two-dimensional RT (2D-RT) for better coverage of the target volume while protecting the surrounding normal organs from excess RT dose. Conformal treatment planning also enables measurement of the dose of radiotherapy delivered to a volume of given organs, allowing more refined assessment of the interaction between radiotherapy dose and potential side effects.

3D-CRT uses four to eight beams if necessary to conform the distribution of radiation dose to the gross tumor volume (GTV), clinical tumor volume (CTV), and planning tumor volume (PTV), while the surrounding normal structures are protected from excessive radiation dose to the greatest extent possible. 3D-CRT plan provides a dose-volume histogram for GTV, CTV, and PTV as well as for normal organs at risk for complications. Thus, it is feasible to formulate a radiation dose schedule for the desired level of tumor control probability that is balanced with an acceptable level of toxicities. However, such risk assessment is not feasible with 2D-RT.

IMRT is an advanced radiation modality. Unlike 2D and even standard 3D-CRT, it uses inverse treatment planning to deliver highly conformal RT plans, enabling increased sparing of normal structures while still delivering the same dose of radiotherapy to the GTV, CTV, and PTV. As a result, the volume of normal tissue in the high radiation dose region (40 to 60 Gy) is smaller with IMRT than with 3D-CRT while the volume of normal tissue in the low-dose region (5 to 10 Gy) is larger with IMRT than with 3D-CRT. It may be expected (though not yet proven) that treatment with IMRT will result in fewer side effects than 3D-CRT [64-66].

Target volume – The target volume consists of the GTV with a margin of clinically uninvolved tissue but potentially harboring microscopic tumor tissue CTV. The CTV should include 4 to 5 cm margins beyond the radiographic tumor extent in the cephalad-caudad direction and 2 to 2.5 cm beyond the radial border of GTV (defined by barium esophagogram or CT scan). For lesions of the lower third of the esophagus and EGJ, the caudal extension CTV beyond GTV includes a 3 to 4 cm margin of gastric cardia below the lower border of GTV. CTV for regional lymph nodes includes the celiac, gastric, and gastrohepatic lymph node groups for primary tumors at the EGJ. For primary tumors involving the upper two-thirds of the thoracic or the cervical esophagus, CTV includes both supraclavicular regions. It is necessary to add another 0.5 to 0.7 cm beyond CTV as the PTV in order to compensate for daily set-up error and respiratory tumor motion.

Esophageal cancers that are located at the EGJ can have a significant degree of tumor motion associated with respiration. We reported peak-to-peak motion of the primary tumor in 10 patients (9 near the EGJ with their involved lymph nodes at the celiac region) [67]. The peak-to-peak tumor motion in craniocaudal directions ranged from 0.6 cm to 4.8 cm for the primary tumor and from 1.2 cm to 4.4 cm for the involved lymph nodes. To avoid geographic miss in some of these patients when using 3D-CRT, four-dimensional CT (4D-CT) treatment planning and delivery of 3D-CRT has a significant advantage for optimum coverage of the target volume over 3D-CRT planned with the conventional helical CT.

Optimal dose and fractionation schedules – Tumor size and radiation dose are important considerations for local-regional tumor control. RT alone with curative intent requires a total dose of 60 to 66.6 Gy in 30 to 37 daily fractions using 1.8 to 2 Gy daily fractions, five fractions per week. Small daily fractions (ie, 1.8 to 2 Gy instead of 2.5 to 3 Gy) reduce the likelihood of late toxicity [60,61].

The optimal radiation dose for preoperative CRT regimens is not well defined, although a total dose of 41.4 to 50.4 Gy administered in daily 1.8 Gy fractions, five days per week, results in reasonable results with acceptable toxicity [42,53,68,69].

Altered fractionation schedules such as accelerated schedules (45 Gy in 30 fractions over three weeks using twice daily 1.5 Gy fractions) or hybrid schedules using twice daily radiation during chemotherapy and once daily treatment between chemotherapy cycles (45 Gy in 25 fractions over five weeks to CTV, and 58.5 Gy in 34 fractions over five weeks to GTV, respectively) are tolerable, with encouraging tumor response, high pCR rates, and survival [35,70].

Patients judged inoperable because of either comorbidities or the presence of distant metastases can be treated by hypofractionated schedules to reduce overall treatment time. A total dose of 40 to 45 Gy at 2.5 Gy daily fractions five days a week is a reasonable schedule for patients who require palliation of esophageal obstruction.

Intensification of preoperative therapy — A consistent finding in many studies is that response to preoperative therapy, particularly the absence of residual disease in the surgical specimen, is an indicator of better disease-free and overall survival [35,71-82]. In a comprehensive literature review of 22 studies in which patients with esophageal or EGJ cancer underwent esophagectomy after neoadjuvant CRT, patients with a pCR were two- to threefold more likely to survive, as were those with residual disease in the esophagectomy specimen [81]. These benefits translate into a 33 to 36 percent mean absolute survival benefit when a pCR is achieved than when it is not.

These results provide the rationale for intensification of preoperative treatment through adding several cycles of induction chemotherapy prior to preoperative chemoradiation, or increasing the number of cytotoxic agents administered concurrent with RT.

Several groups have reported their experience with sequential induction chemotherapy followed by CRT [83-88].

While no randomized trials have compared this sequential induction chemotherapy followed by CRT with standard CRT, only one published trial, the German POET trial, has compared this approach with induction chemotherapy alone followed by surgery.

In the German POET trial, 126 patients with EGJ AC were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus leucovorin and short-term infusional FU) versus 12 weeks of the same chemotherapy regimen followed by low-dose RT concurrent with cisplatin and etoposide; both groups underwent subsequent surgical resection [86]. The pCR rate was significantly higher after induction chemotherapy followed by CRT, and there was a nonsignificant trend towards better median and three-year survival (47 versus 28 percent, p = 0.07) in this group as well. Whether these results can be extrapolated to SCC of the thoracic esophagus is uncertain. This trial and the implication of its findings for treatment of EGJ cancers are discussed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Neoadjuvant CRT versus chemotherapy alone'.)

Although early results from many trials evaluating intensified chemotherapy during RT are encouraging [89-94], whether the added toxicity of any of these approaches is counterbalanced by substantial survival gains is unclear. Phase III trials are needed to confirm the benefit of these more toxic approaches over concurrent cisplatin/FU.

Necessity for surgery

Chemoradiotherapy responders — For patients with clinically resectable AC, we suggest inclusion of surgery rather than definitive CRT alone. We also suggest inclusion of surgery rather than definitive CRT for SCC. However, nonoperative management is an option for those who have an endoscopic complete response, balancing the risks of surgical mortality versus improved locoregional control. Regardless of histology, definitive CRT is a reasonable approach for patients who are not surgical candidates.

Approximately 50 percent of patients with SCC and 25 percent of those with AC have a pCR after neoadjuvant CRT [53]. The necessity of resection for these patients is controversial. Whether there is a survival benefit for trimodality therapy (which included post-RT or post-CRT esophagectomy) over definitive RT or CRT alone has been addressed in two meta-analysis, which came to opposite conclusions:

One meta-analysis included data from eight studies (16,647 patients), only one of which was a randomized controlled trial [95]. Overall survival was improved with neoadjuvant CRT as compared with definitive CRT in combined populations (HR for death 0.55, 95% CI 0.49-0.62), and the benefit was seen in both the AC and SCC subgroups. The authors did not address the impact of treatment response on outcomes.

On the other hand, a year 2016 Cochrane review of eight randomized trials concluded that there was no difference in long-term mortality between definitive and neoadjuvant CRT (HR 0.88, 95% CI 0.76-1.03; 602 participants; four studies; low-quality evidence), and no difference in long-term recurrence between nonsurgical treatment and surgery (HR 0.96, 95% CI 0.80-1.16; 349 participants; two studies; low-quality evidence) [96]. The difference between nonsurgical and surgical treatment was imprecise for short-term mortality (risk ratio [RR] 0.39, 95% CI 0.11-1.35; 689 participants; five studies; very-low quality evidence), and the risk for local recurrence at maximal follow-up (RR 0.89, 95% CI 0.70-1.12; 449 participants; three studies; very-low quality evidence) [96].

An important point is that the optimal way to define "complete CRT responders" is not established. At some institutions, an EUS-guided FNA biopsy is routinely undertaken [15,16], but others (including the NCCN [17]) advise only upper endoscopy with biopsy if avoidance of surgery is being considered. The role of FDG-PET/CT to evaluate the local response to therapy as a means of selecting patients for whom surgery might be avoided is controversial and discussed below. (See 'Utility of postinduction therapy PET scans' below.)

There are much more data on definitive CRT in SCC as compared with ACs.

Squamous cell carcinoma – In contemporary series, definitive CRT provides long-term survival in up to 27 percent of patients with SCC [42,45,63,68,97], a result that is not dissimilar to that achieved with preoperative CRT followed by surgery [21,35,39], neoadjuvant chemotherapy and surgery (see 'Neoadjuvant chemotherapy' below) [23,98], and surgery alone [23,24]. However, nearly all reports note a higher rate of locally persistent/recurrent disease when surgery is not a component of treatment [42,63,97].

At least two randomized trials directly comparing CRT alone with trimodality therapy (CRT followed by surgery) have failed to demonstrate better survival, although both show better locoregional control and a lesser need for palliative procedures when surgery is a component of multimodality treatment [99,100]. The patient populations in both were either exclusively or predominantly SCC. A Cochrane analysis of these two trials [101] came to the following conclusions:

There was high-quality evidence that the addition of esophagectomy had no significant impact on survival (HR 0.99, 95% CI 0.79-1.24).

There was moderate-quality evidence that the addition of esophagectomy improved freedom from locoregional relapse (HR 0.55, 95% CI 0.39-0.76), but low-quality evidence suggested that it increases the risk of treatment-related mortality (risk ratio [RR] 5.11, 95% CI 1.74-15.02) [100,102,103].

All other endpoints (quality of life, treatment-related toxicity, use of salvage procedures for dysphagia) were only reported in one trial, which found only very-low-quality evidence that surgery reduced the use of salvage procedures for dysphagia (HR 0.52, 95% CI 0.36-0.75).

Another meta-analysis by the American Society of Clinical Oncology (ASCO) came to similar conclusions, although they considered the evidence of a lack of survival benefit from resection to represent moderate quality evidence [18].

If definitive CRT is chosen, the chemotherapy regimen can be either cisplatin/FU or paclitaxel/FU [42,97]. (See 'Concurrent chemoradiotherapy' above.)

Adenocarcinoma – In contrast to SCC, there are no randomized trials directly comparing trimodality versus bimodality (CRT alone) therapy in ACs. Some data from retrospective analyses suggest inferior outcomes in this group with nonsurgical management [104-107]. As examples:

One of the largest series of nonsurgical management of AC comes from a retrospective analysis of 276 patients treated with definitive CRT at the University of Texas MD Anderson Cancer Center for esophageal cancer, 215 of whom had AC [105]. RT was planned and delivered using modern techniques (4D-CT and IMRT), and a moderate-dose (50.4 Gy in 28 fractions) was combined with chemotherapy. The majority of patients had T3 (83 percent), N1 (69 percent), and M0 (87 percent) disease. Nearly all (98 percent) received concurrent chemotherapy, and 37 percent also received induction chemotherapy prior to CRT. At a median follow-up of 54 months, 140 (51 percent) had experienced a local recurrence, while 144 (52 percent) encountered distant failure with or without a locoregional recurrence, and 92 (33 percent) had no evidence of disease at last follow-up.

In a second retrospective series of 154 patients with esophageal AC treated at a single center over an 11-year period, 60 were treated without surgery while the remainder received trimodality therapy [106]. Despite the fact that the surgically-treated patients had more advanced disease stage, survival was significantly better in this group (median survival 4.6 versus 1.9 years; five-year overall survival 44 versus 36 percent, p = 0.007).

The specificity of clinical complete response (cCR) for ACs is too low to be used for clinical decision-making for delaying or avoiding surgery. In one series of 284 esophageal/EGJ cancers (92 percent ACs), 218 (77 percent) achieved a cCR (as defined by endoscopic biopsy negative for cancer and FDG-PET showing only physiologic uptake) after CRT, but only 67 (31 percent) were true pCRs [108].

It is likely that some of these patients have a high risk for early disease recurrence within one year of completing treatment, and in this group, the benefit of surgery might not outweigh its potential side effects. Investigators at MD Anderson Cancer Center used data from 568 consecutive patients with potentially resectable esophageal ACs who underwent CRT at MD Anderson Cancer Center over a 10-year period to construct a preoperative nomogram to risk stratify patients for the benefit of trimodality therapy in esophageal AC [107]. In the entire cohort, 373 underwent esophagectomy, while 195 did not; median follow-up was 62 months. Five-year overall survival in the trimodality and bimodality groups was 56.3 percent (95% CI 47.9-64.7) versus 36.9 percent (95% CI 31.4-42.4). However, when stratified according to risk factors (histologic grade, signet ring cell morphology, clinical nodal stage, intensity of FDG uptake) and balanced with propensity score matching, the survival benefit of trimodality therapy was much less pronounced in the high-risk cohort (five-year overall survival 32 versus 21 percent) compared with the low-risk group (five-year overall survival 66 versus 46 percent). Importantly, this nomogram did not identify a population for whom there was no benefit from resection. Furthermore, although propensity score matching was used to improve the comparability between the two treatment groups, unknown confounding factors may have influenced the outcomes. This model requires external validation.

Utility of postinduction therapy PET scans — Until further data are available, we do not use postinduction therapy PET scanning to select patients for nonsurgical therapy.

Postinduction therapy FDG-PET provides information about metabolic response in the primary tumor that may be clinically useful for selection of subsequent therapy. In particular, some retrospective data suggest that post-CRT FDG-PET scanning may serve to identify those patients for whom surgery might be avoided. One series included 105 patients with stage I to IVA esophageal cancer (75 percent AC) who were evaluable for a post-CRT PET response, 50 of whom received CRT alone [109]. In this cohort, those whose PET response was characterized by a post-treatment maximum standard uptake value (SUVmax) ≤3 in the tumor (n = 19, 38 percent) had an excellent outcome without resection (two-year overall survival 71 versus 11 percent for those with a post-treatment tumoral SUVmax ≥3.1; the corresponding two-year rates of freedom from local failure were 75 versus 28 percent). By contrast, those patients undergoing trimodality therapy (n = 55) showed no difference in outcome according to the post-CRT PET findings, probably because those patients who had residual disease underwent resection.

However, others have failed to find a correlation between the post-CRT SUV on PET and pathologic response at the time of resection. A systematic review of 13 studies, totaling 697 patients, concluded that the available data are too contradictory to conclude that interim PET-directed therapy for esophageal cancer can be considered a standard approach [110]. A major issue is that the best method to quantify FDG uptake for clinical use in esophageal cancer remains to be determined. A later systematic review and meta-analysis concluded that even when combined with endoscopic biopsies and EUS, FDG-PET/CT was insufficiently accurate for detecting residual disease after induction therapy for esophageal cancer [111].

The main use of PET in esophageal cancer may be to recognize which patients are not responding to induction chemotherapy prior to CRT, administered prior to resection. This subject is discussed elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'PET-directed therapy'.)

Nonresponders — For CRT nonresponders, surgery should be considered for those who remain operable.

Timing of surgery after chemoradiotherapy — For most patients, a five- to seven-week interval between completion of CRT and surgery is preferred. For those who need extra time to recuperate from CRT, surgery can be delayed.

The optimal timing between completion of neoadjuvant CRT and resection is not established. The typical interval, four to seven weeks, is arbitrary, with the intent of allowing resolution of acute inflammation and for tumor regression while minimizing chronic fibrotic changes in the surgical field. Most tumors regress slowly after RT because one of the ways in which the cells die is through mitotic death that occurs only during cell division. Increasing the interval between treatment completion and attempted resection may allow the tumor to continue to regress, thereby improving resectability, and increase the chance of observing a pCR. Studies have shown that pCRs in patients undergoing trimodality treatment for esophageal cancer predict decreased local and distant recurrence and improved survival [73,76,86]. There are some data demonstrating higher pCR rates for patients who delay surgery for 64 or more days after the completion of CRT (relative to those undergoing surgery at 45 to 63 days, pCR rates were 41 versus 13 to 23 percent), with no significant increase in surgical morbidity [112]. However, despite the higher pCR rates, delaying surgery has not translated into an improvement in overall survival [78,112-114]. Furthermore, delaying surgery beyond six to seven weeks might negatively impact the clinical outcomes of those who have residual cancer after neoadjuvant therapy, but the available data on this point are mixed. At least one analysis from the National Cancer Database suggests inferior 90-day mortality and long-term survival rates in patients who wait 65 days or longer between CRT and surgery [115].

We prefer that surgery be performed within five to seven weeks of completing CRT. Postoperative complications increase if it is done sooner than four weeks, and the risk for distant metastasis from remaining cancer increases as surgery is delayed longer than seven weeks.

Neoadjuvant chemotherapy — Multiple randomized trials have evaluated the benefit of chemotherapy administered prior to resection in patients with esophageal cancer limited to the primary and regional nodes by clinical assessment [23,72,98,116-119]. Four trials with a surgery-alone control arm are negative, including the US Intergroup 0113 trial [23,72,116,120], while five others (including the MRC OE2 trial, the UK MAGIC trial, and the French FNLCC/FFCD trial), demonstrate a survival benefit compared with resection alone [98,117,118,121,122].

Meta-analyses — A survival benefit for neoadjuvant chemotherapy relative to surgery alone has been shown in four meta-analyses [18,57,123,124]; in one of these, the survival benefit was limited to the subgroup of patients with SCC, not all patients with resectable esophageal cancer. In the year 2015 meta-analysis that included 10 randomized comparisons of preoperative (only) chemotherapy versus surgery alone for esophageal or EGJ cancers (the MAGIC trial [117] was excluded because it also included gastric cancer) the HR for all-cause mortality for neoadjuvant chemotherapy was 0.88 (95% CI 0.80-0.96) [123]. There was no significant difference in the rate of R0 resections with neoadjuvant chemotherapy (relative risk [RR] 1.11, 95% CI 1.03-1.19) or, curiously, in the risk of a distant recurrence (RR 0.94, 95% CI 0.78-1.13). The potential benefit of neoadjuvant therapy was not offset by higher postoperative mortality or morbidity rates.

Chemotherapy versus chemoradiotherapy — Although randomized trials (and at least three meta-analyses [18,58,125]) have failed to demonstrate a survival advantage for preoperative CRT over chemotherapy alone, at least one network meta-analysis concluded that there is a survival benefit for neoadjuvant CRT over neoadjuvant chemotherapy [34], and we consider CRT to be a preferred strategy due to higher rates of pCRs and R0 resections.

At least three trials have directly compared neoadjuvant chemotherapy with CRT, and all have come to remarkably similar conclusions; all were conducted exclusively or predominantly in patients with ACs:

Chemotherapy was directly compared with CRT in a randomized phase II Australian trial involving 75 patients with AC of the esophagus or EGJ [126]. Although the histopathologic response rate and rate of margin-negative resections favored CRT, median overall survival was not significantly better (32 versus 29 months).

In the multicenter phase III German POET trial, 126 patients with EGJ ACs were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus short-term infusional FU plus leucovorin) versus 12 weeks of the same chemotherapy regimen followed by low-dose RT concurrent with cisplatin and etoposide; both groups underwent subsequent surgical resection [86]. The pCR rate was significantly higher after induction chemotherapy followed by CRT (16 versus 2 percent), and there was a nonsignificant trend towards better median and three-year survival in this group as well (47 versus 28 percent, p = 0.07). These data, which are discussed in more detail elsewhere, support the view that CRT is a preferred strategy rather than induction chemotherapy alone for patients with EGJ ACs.

Similar conclusions were reached in a multicenter phase III Swedish trial, in which 181 patients with cancer of the esophagus or EGJ (73 percent ACs) were randomly assigned to chemotherapy (three 21-day courses of cisplatin [100 mg/m2 on day 1] plus FU [750 mg/m2 over 24 hours per day, days 1 to 5]) with or without RT (40 Gy in daily 2 Gy fractions, administered concomitant with cycle 2 and 3 of chemotherapy) [127]. All patients underwent surgical resection four to six weeks after completing neoadjuvant therapy. CRT was associated with significantly higher rates of pCR (28 versus 9 percent) and R0 resection (87 versus 74 percent), and a lower rate of positive lymph nodes (35 versus 62 percent). However, these differences did not translate into significant better three-year overall (47 versus 49 percent) or progression-free survival (44 percent in both groups).

Of note, two of these three trials were closed prematurely [86,126] and, therefore, were underpowered to show a survival advantage. These trials and the two meta-analyses are discussed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Neoadjuvant CRT versus chemotherapy alone'.)

A network meta-analysis that included these three trials plus one other concluded that there was an overall survival benefit for neoadjuvant CRT over neoadjuvant chemotherapy alone (HR for death 0.83, 95% CI 0.70-0.96) [34]. However, the risk of postoperative mortality was also higher with CRT (HR 1.58, 95% CI 1.00-2.49).

Similar safety, comparable survival, and better histopathologic outcomes (pCR 36 versus 4 percent) with CRT were noted in a fourth trial directly comparing neoadjuvant chemotherapy versus CRT prior to minimally invasive esophagectomy in 264 patients with esophageal SCC [128]. However, interpretation of this result is hampered by the use of a nonstandard neoadjuvant chemotherapy regimen (two-three week courses of paclitaxel plus cisplatin), that preoperative staging endoscopic ultrasound was not performed in all cases, and a higher than expected perioperative morbidity rate in both groups.

Neoadjuvant versus postoperative chemotherapy — The superiority of neoadjuvant as compared with postoperative adjuvant chemotherapy was shown in a Japanese trial (JCOG9907) in which 330 patients with clinical stage II or III SCC of the thoracic esophagus were randomly assigned to surgery preceded or followed by two 21-day courses of cisplatin (80 mg/m2 on day 1) plus infusional FU (800 mg/m2 daily for five days) [119]. Five-year overall survival was significantly higher in the group receiving preoperative chemotherapy (55 versus 43 percent, p = 0.04).

Impact of preoperative treatment on local control — Although most trials focus upon survival as a primary endpoint, local-regional control is also important when selecting among treatment options. Local failures can be defined as recurrent local disease following a margin-negative esophagectomy or after a margin-negative or margin-positive resection. Using either definition, the frequency of local failure appears to be higher in trials in which patients were treated with surgery alone or definitive CRT alone as compared with those receiving CRT followed by surgery [23,24,35,63,129,130]. (See 'Patterns of failure' below.)

As examples:

In a combined analysis of the Dutch CROSS trial (described above) in conjunction with data from the preceding phase II trial investigating the same preoperative regimen followed by surgery, there were 374 patients who underwent resection, 49 percent allocated to surgery and 51 percent to CRT followed by surgery [130]. At a minimum follow-up of 24 months, patients undergoing preoperative CRT had significantly lower rates of recurrent disease overall (35 versus 57 percent), locoregional recurrence (14 versus 34 percent), and isolated locoregional recurrence (3.3 versus 9.3 percent). (See 'Concurrent chemoradiotherapy' above.)

In the previously described meta-analysis of trials comparing preoperative CRT with surgery alone [129], the odds ratio (OR) for local-regional recurrences was significantly lower with preoperative therapy (OR for local recurrence 0.38, 95% CI 0.23-0.63). (See 'Concurrent chemoradiotherapy' above.)

Whether local recurrence rates are lower in patients treated with neoadjuvant chemotherapy alone as compared with surgery is uncertain; the following data are available (see 'Neoadjuvant chemotherapy' above):

In the MAGIC trial, local failure was confirmed before death in fewer patients in the chemotherapy group as compared with surgery alone (14 versus 20 percent), but the p value for the comparison was not reported [117].

In the MRC trial, the local failure rates were nearly identical in the chemotherapy and surgery groups (12 and 11 percent, respectively) [98]. The meta-analysis of preoperative chemotherapy versus surgery alone did not address the issue of locoregional control [131]. (See 'Meta-analyses' above.)

Clinical T1N0 disease — Initial resection, rather than trimodality treatment, is preferred for patients with clinical stage T1N0 esophageal cancer (table 1) as assessed by EUS. This recommendation is consistent with consensus-based guidelines from the NCCN [17] and the European Society for Medical Oncology (ESMO) [132]. Endoscopic resection alone may be adequate treatment for selected patients. This subject is addressed elsewhere. (See "Management of superficial esophageal cancer" and "Endoscopic ultrasound in esophageal cancer", section on 'Preoperative staging'.)

Clinical T2N0 disease — The optimal approach to clinical T2N0 disease is debated, and guidelines from expert groups differ. Some suggest initial chemoradiotherapy for SCC, and either neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinomas of the distal esophagus or EGJ [132]. Others, including the NCCN [17], suggest initial resection for clinical T2N0 adenocarcinomas or SCCs as long as they are <3 cm and well differentiated, but initial chemoradiotherapy for others with either histology who have high-risk disease. Year 2020 ASCO guidelines also state that initial surgery may be more appropriate for patients with low-risk clinical T2N0 lesions (ie, well-differentiated, <2 cm) [18]. We follow the NCCN and ASCO guidelines.

The contribution of neoadjuvant CRT to outcomes in clinical T2N0 thoracic esophageal cancer is uncertain. These patients were included in the three positive trials examining the benefit of preoperative CRT, although the actual representation is only known for CALGB 9781 (3 of the total 56 enrolled patients) [39,40,53]. None of the trials stratified outcomes according to histologic stage.

As noted above, the French FFCD 9901 trial failed to show a benefit for preoperative CRT compared with surgery alone in 195 patients with stage I or II esophageal or EGJ cancer (table 5) [52]. Thirty-seven of the enrolled patients (19 percent) had clinical stage I disease. It is possible that the study was underpowered to show a significant survival benefit, if one was present [133]. (See 'Concurrent chemoradiotherapy' above.)

Although several retrospective studies and a systematic review of several of these studies have examined whether surgical resection or neoadjuvant therapy provides better outcomes for these patients, they have come to disparate conclusions, and there is no consensus as to the best approach [134-139]. Guidelines from the NCCN suggest that patients with clinical T2N0 esophageal cancer be approached similarly to those with more advanced stage potentially resectable disease (ie, with initial CRT preferred) [17]. However, a major problem is the accuracy of preoperative staging. In one report of 499 patients with clinical T2N0 esophageal cancer, preoperative staging was accurate in only 14 percent, and patients were both understaged (50 percent) and overstaged (36 percent) [140]. There is a need for better clinical staging modalities. Increasingly, endoscopic resection is being pursued in this patient population to improve the selection of patients who need surgery [141]. (See "Endoscopic ultrasound in esophageal cancer".)

Role of postoperative adjuvant therapy

After preoperative therapy — For patients with residual disease in the esophagectomy specimen after initial CRT, we suggest adjuvant nivolumab. For patients without access to nivolumab, the optimal approach is undefined, and management must be individualized based on the clinical circumstances. One approach is to attempt to administer adjuvant chemotherapy with different agents than those given preoperatively.

Nivolumab – Benefit for nivolumab was shown in the CheckMate 577 trial, in which 794 patients who had received neoadjuvant CRT for esophageal or EGJ cancer (70 percent AC) and had residual pathologic disease at the time of surgery were randomly assigned to nivolumab (240 mg) or placebo every 2 weeks for 16 weeks followed by nivolumab 480 mg or placebo every 4 weeks; the maximum treatment duration was one year [142]. Enrollment was irrespective of programmed death receptor-1 ligand 1 (PD-L1) overexpression. Tumor site was esophagus in 60 percent and EGJ in 40 percent; histology was AC in 71 percent and SCC in 29 percent. At a median follow-up of 24.4 months, median disease-free survival, the primary endpoint, was twice as long with nivolumab (22.4 versus 11 months, HR for disease progression or death was 0.69, 95% CI 0.56-0.86), and the benefits were seen across all patient subgroups (histology, location, initial and post-treatment disease stage, PD-L1 overexpression or not). Overall survival data were not mature. Although treatment-related adverse effects were frequent, most were grade 1 or 2 and only 9 percent of patients discontinued adjuvant nivolumab because of adverse effects. The benefits were gained without any significant decline in patient-reported health-related quality of life over the year of nivolumab treatment.

Based on these results, the US Food and Drug Administration has approved nivolumab as adjuvant therapy for patients who previously received neoadjuvant CRT following complete resection of esophageal or gastroesophageal junction cancer with residual pathologic disease. This approach was also endorsed by a year 2021 updated ASCO guideline on the treatment of patients with locally advanced esophageal carcinoma [19].

Data are not available to support any recommendation for nivolumab following treatment with perioperative chemotherapy or in those undergoing definitive chemoradiotherapy. Whether a benefit for adjuvant checkpoint inhibitor immunotherapy will be seen in patients undergoing perioperative chemotherapy alone is under investigation in KEYNOTE trial 585. A separate trial is evaluating the benefit of immune checkpoint inhibitors after definitive CRT (KEYNOTE trial 975).

Cytotoxic chemotherapy – In the postoperative setting, there are concerns as to tolerability of further cytotoxic chemotherapy [43,117,143], but a potential survival benefit for adjuvant chemotherapy in patients with and without residual nodal disease following CRT was suggested in two retrospective analyses derived from the National Cancer Database of patients with esophageal cancer who were treated with neoadjuvant CRT followed by resection [144,145], and a meta-analysis of ten studies involving 6462 patients, nine of which were cohort studies; most utilized neoadjuvant CRT rather than induction chemotherapy [146]. When compared with neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups had a significantly lower mortality at both one-year (risk ratio [RR] 0.52, 95% CI 0.41-0.65) and five-year follow-up (RR 0.91, 95% CI 0.86-0.96).

Although the optimal regimen is not established, administering adjuvant chemotherapy with different agents than those given preoperatively is a reasonable approach.

No prior neoadjuvant therapy — For patients with completely resected node-positive or pathologic T3 or T4 node-negative esophageal ACs who have not received neoadjuvant therapy, we suggest some form of postoperative therapy in an attempt to improve outcomes. We also suggest some form of postoperative therapy for high-risk pathologic T2N0 ACs (ie, those that are poorly differentiated, have lymphovascular or perineural invasion, or arise in a patient under the age of 50). It is difficult to come to any conclusions as to whether there are specific advantages for adjuvant CRT over chemotherapy alone, and either approach is reasonable. Further confirmatory trials, particularly randomized trials, are necessary before specific recommendations can be made. For patients with resected SCC who have not received neoadjuvant therapy, we only offer postoperative therapy if the margins are positive.

These recommendations are in keeping with guidelines from the NCCN [17]. The issue of postoperative adjuvant therapy was not addressed in the year 2020 ASCO guideline [18].

Chemoradiotherapy — For patients with a node-positive AC of the EGJ, postoperative CRT is a standard approach, at least in the United States, based upon results from the US Intergroup trial. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Adjuvant CRT'.)

For other patients, particularly those with a thoracic esophageal SCC, the optimal approach is uncertain. Some uncontrolled trials and retrospective comparisons of patients treated with and without CRT suggest potential benefit for postoperative CRT. However, others do not, and there is only a single randomized trial demonstrating benefit of adjuvant therapy as compared with surgery alone:

In a retrospective report, outcomes of 38 patients with node-positive disease after esophagectomy alone who received postoperative CRT (concurrent or sequential RT plus cisplatin and FU with or without epirubicin) were compared with 28 similar patients who did not receive further therapy [147]. Local recurrence rates were lower in the group receiving postoperative therapy (35 versus 13 percent), and the median overall survival was longer (48 versus 14 months).

Mature data from a prospective phase II uncontrolled trial also support benefit for adjuvant CRT in this setting. In this trial, 50 patients with locally advanced esophageal cancer (90 percent T3, 81 percent node-positive, 13 percent with extraregional nodal metastases) received CRT (RT 50.4 to 59.4 Gy plus concurrent cisplatin and FU) after esophagectomy [148]. At a median follow-up of 47 months, four-year projected survival was 51 percent, a rate that is far higher than might be expected for this relatively poor prognosis cohort.

Benefit was also suggested in a small Chinese trial in which 172 patients with stage IIb-III esophageal SCC were randomly assigned to surgery alone (n = 54) or followed by postoperative RT alone (n = 54) or chemoradiotherapy (n = 64, concurrent chemotherapy was with paclitaxel plus cisplatin or nedaplatin [149]. When both postoperative groups were combined, postoperative therapy was associated with a significantly improved three-year disease-free (53.8 versus 36.7 percent) and overall survival (63.9 versus 48 percent).

Benefit for CRT over RT alone was suggested in a retrospective review of 304 patients with thoracic SCC who had undergone upfront esophagectomy with a three-field lymph node dissection and determined to have lymph node but not distant metastases [150]. Postoperative chemotherapy (cisplatin plus paclitaxel) plus RT (50 Gy) was administered to 164, while 140 underwent postoperative RT alone (50 Gy). Margin status was not addressed. Five-year overall survival rates were significantly better with CRT (47 versus 39 percent), and recurrence rates (including distant, combined regional and distant, and overall) were all significantly less with chemotherapy. Although early toxicity was significantly more common with CRT, there were no significant differences in late toxic effects between the two groups.

Chemotherapy alone — For patients with esophageal cancer who have not received preoperative chemotherapy or CRT, postoperative chemotherapy alone may be beneficial, although proof of a survival benefit from randomized trials with a surgery alone control group is scant [151-154].

The only randomized trial to compare surgery alone versus surgery followed by adjuvant chemotherapy (two courses of cisplatin 80 mg/m2 on day 1 and FU 800 mg/m2 daily for five days) included 242 patients with esophageal SCC recruited from 17 Japanese institutions [154]. The five-year disease-free survival rate (the primary endpoint) was significantly better with chemotherapy (55 versus 45 percent), but overall survival was not significantly different (61 versus 52 percent). The short duration of adjuvant chemotherapy, and the fact that 25 percent of the patients in the chemotherapy group did not receive both full courses of therapy, may have compromised the ability to document a survival difference.

Post-treatment cancer surveillance

Patterns of failure — The majority of recurrences develop within one year, and recurrences tend to develop earlier in patients treated with neoadjuvant therapy as compared with surgery alone. This was illustrated in a series of 590 patients who underwent esophagectomy for AC [155]. The peak interval for recurrence after esophagectomy alone was six to nine months, and more than 90 percent of the disease recurrences occurred by three years. By contrast, among patients treated with neoadjuvant CRT (ie, trimodality therapy), the peak time frame for recurrence was the first three months, and >90 percent of recurrences were evident by 21 months. The pattern of recurrence was distant, locoregional, or both in 60, 30, and 10 percent of patients, respectively, and did not differ in patients treated with surgery alone. Of note, these results may be impacted by selection bias, as patients with more advanced tumors likely had an increased likelihood of receiving neoadjuvant therapy. A similar distribution of recurrences (distant, locoregional, or both in 55, 28, and 17 percent) have been reported by others following trimodality therapy [156].

On the other hand, isolated local recurrences are more frequent after definitive CRT, and salvage surgery may benefit a greater number of these patients. This was shown in a retrospective analysis of 276 patients with esophageal cancer (78 percent AC) who were treated with definitive CRT at MD Anderson Cancer Center over a nine-year period (2002 to 2011) [105]. The site of first failure was local only in 64 (23 percent); and 23 (36 percent, 8 percent of the entire cohort) of these were amenable to salvage surgery. At a median follow-up of 54 months for the entire cohort, the estimated three- and five-year overall survival rates for those undergoing salvage surgery were 61 and 45 percent, respectively. Ninety-one percent of the local recurrences developed within two years, suggesting that vigilant surveillance is more important in this time frame. (See 'Impact of preoperative treatment on local control' above and 'Necessity for surgery' above.)

Surveillance strategy — There are no randomized trials to guide the postoperative surveillance strategy and no data that demonstrate improvement in quality of life or longevity from earlier detection of asymptomatic recurrences. At our institutions, we perform history, physical examination, and targeted blood work (for a symptomatic patient, or if there was a serum tumor marker that was elevated preoperatively) every four months for the first three years and also perform restaging CT scans of the chest and abdomen at four-month intervals. We do not carry out surveillance endoscopy unless there was a preoperative history of Barrett's esophagus, a questionable margin at the time of surgery, or if the patient has a recalcitrant stricture that is worrisome for an occult local recurrence. More vigilant surveillance in the first two years after treatment may be warranted in patients who underwent definitive CRT.

The primary purpose of post-treatment surveillance is to implement a potentially beneficial salvage therapy in cases of locoregional failure. However, the incidence of locoregional failure is low, particularly after trimodality therapy, and the number of potentially curable recurrences that will be detected by intensive post-treatment surveillance is small.

This was demonstrated in a report of 518 patients with esophageal AC who were treated with preoperative CRT and followed for a median of 29.3 months [157]. The post-treatment surveillance strategy included CT or PET-CT every three months for the first year, every six months for two additional years, then annually for at least five years. Endoscopic examination was performed every six months for 18 months, then annually. Isolated locoregional failure developed in 27 (5 percent), only 11 of which were intraluminal. By contrast, distant metastases developed in 188 (36 percent). Twelve patients with locoregional failure had salvage CRT, and four underwent salvage surgery (three of whom later developed metastatic disease). Overall, only 10 of the 27 patients with a locoregional failure survived longer than 10 years. Thus, only 2 percent of the 518 patients benefited from post-treatment surveillance.

Consensus-based guidelines from the NCCN suggest the following [17]:

History and physical examination every three to six months for one to three years, then every six months for years 4 and 5, then annually

Complete blood count (CBC) and chemistry profile, as clinically indicated

Radiologic imaging and upper gastrointestinal (GI) endoscopy, as clinically indicated

Dilation for anastomotic stenosis

Nutritional counseling

By contrast, consensus-based guidelines from the ESMO emphasize the lack of evidence that regular follow-up after initial therapy has an impact on survival outcomes, with the possible exception of patients who might be potential candidates for endoscopic reintervention or early "salvage surgery" after failing definitive CRT [132]. They advise that follow-up visits concentrate on symptoms, nutrition, and psychosocial support. In the case of a complete response to CRT and no surgery, a three-month follow-up based on endoscopy, biopsy, and CT scan may be recommended to detect early recurrence, leading to a discussion about salvage surgery. (See 'Patterns of failure' above.)

Long-term follow-up is needed to address treatment-related late complications associated with high-dose radiation therapy (RT).

When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)

CERVICAL ESOPHAGUS TUMORS — Squamous cell carcinoma (SCC) of the cervical esophagus presents a unique management situation. If surgery is performed, it usually requires removal of portions of the pharynx, the larynx, the thyroid gland, and portions of the proximal esophagus. In addition, radical neck dissections are usually carried out; as such, the management is more closely related to SCC of the head and neck than for malignancies involving the more distal portions of the esophagus. In general, radiation therapy (RT) combined with chemotherapy is preferred over surgery for proximal esophageal cancers where laryngectomy would be necessary for a good cancer operation since survival appears to be comparable and major morbidity is avoided in most [158]. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Cervical esophageal cancer resection' and "Management of locally advanced, unresectable and inoperable esophageal cancer", section on 'Cervical esophageal tumors'.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from delaying diagnostic evaluation and cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited health care resources. Specific guidance for decision-making for upper gastrointestinal cancers is available from the Society for Surgical Oncology, European Society for Medical Oncology, and others. A discussion of COVID-19 risks in patients with cancer, clinical presentation of COVID-19, approach to testing for the SARS-CoV-2 virus, and general recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Esophageal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Esophageal cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

Thoracic esophageal cancer

Initial therapy

-We recommend combined modality therapy, rather than surgery alone, for patients with T3N0, T4aN0, and clinically node-positive thoracic esophageal cancer, regardless of histology (table 1) (Grade 1B). We suggest concurrent chemoradiotherapy (CRT) instead of chemotherapy alone for neoadjuvant therapy (Grade 2B). (See 'Clinical T3-4 or node-positive disease' above.)

The benefit of preoperative CRT for patients with clinical stage T2N0 tumors is less clear. Nevertheless, we suggest combined modality therapy rather than resection alone for patients with an adenocarcinoma (AC) (Grade 2C). Initial resection is an option for T2N0 squamous cell carcinomas (SCCs), especially if well-differentiated and <2 cm in size. (See 'Clinical T2N0 disease' above.)

For patients with T1N0 esophageal or esophagogastric junction AC or SCC, we suggest surgery or endoscopic resection rather than initial chemotherapy or CRT (Grade 2C). Definitive CRT is a reasonable approach for patients who are not surgical or endoscopic resection candidates. (See 'Clinical T1N0 disease' above.)

-The optimal type, dose, combination, and schedule of drugs has not been definitively established for neoadjuvant CRT. For most patients, we suggest low-dose weekly carboplatin plus paclitaxel (table 3) as was used in the Dutch CROSS trial rather than two courses of cisplatin plus fluorouracil (FU) (Grade 2C). (See 'Concurrent chemoradiotherapy' above and "Treatment protocols for esophagogastric cancer".)

Role of surgery

-For patients with clinically resectable AC, we suggest inclusion of surgery rather than definitive CRT alone (Grade 2C). (See 'Necessity for surgery' above.)

We also suggest inclusion of surgery rather than definitive CRT for SCC (Grade 2C). However, nonoperative management is an option for those who have an endoscopic complete response, balancing the risks of surgical mortality versus improved locoregional control. (See 'Chemoradiotherapy responders' above.)

For CRT nonresponders, surgery is an important component of therapy for those who are still operable after CRT, regardless of histology. (See 'Nonresponders' above.)

-We do not use post-CRT fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning to evaluate the local response to therapy as a means of selecting those patients for whom surgery might be avoided. (See 'Utility of postinduction therapy PET scans' above.)

Postoperative therapy

-For patients with completely resected esophageal cancer who have not received neoadjuvant therapy, we suggest postoperative adjuvant therapy for patients with node-positive or pathologic T3 or pT4 N0 AC (Grade 2C). We also suggest adjuvant therapy for selected patients with high-risk (poorly differentiated histology, lymphovascular or perineural invasion, or patients younger than age 50), resected pathologic T2N0 AC (Grade 2C).

In these settings, chemotherapy alone and CRT are both reasonable options. We only offer postoperative therapy to patients with SCC if the resection margins are positive. (See 'No prior neoadjuvant therapy' above.)

-For patients with residual disease after preoperative CRT we suggest nivolumab for up to one year (Grade 2B). For patients with residual nodal disease after neoadjuvant CRT who lack access to nivolumab, treatment must be individualized. One approach is to administer adjuvant chemotherapy with different agents than those given preoperatively (eg, FOLFOX (table 6) if the initial CRT regimen included only paclitaxel and carboplatin). (See 'After preoperative therapy' above.)

Post-treatment surveillance

-There are no randomized trials to guide the postoperative surveillance strategy and no data that demonstrate improvement in quality of life or longevity from earlier detection of asymptomatic recurrences. We perform history, physical examination, targeted blood work, and CT of the chest and abdomen every four months for the first three years.

We do not carry out surveillance endoscopy unless there was a preoperative history of Barrett's esophagus, a questionable margin at the time of surgery, or if the patient has a recalcitrant stricture that is worrisome for an occult local recurrence. (See 'Surveillance strategy' above.)

Cervical esophageal cancer

Management of carcinoma arising in the cervical esophagus is more closely related to SCC of the head and neck than for malignancies involving the more distal portions of the esophagus. In general, radiation combined with chemotherapy is preferred over surgery since survival appears to be the same and major morbidity is avoided in most. (See 'Cervical esophagus tumors' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Noah C Choi, MD, who contributed to an earlier version of this topic review.

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Topic 2478 Version 98.0

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