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INTRODUCTION — Cancer of the esophagus is a highly lethal malignancy. There are approximately 16,940 people diagnosed with esophageal cancer each year in the United States and 15,690 deaths from the disease . 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 edition of the tumor, node, metastasis (TNM) staging manual (seventh edition, 2010), tumors arising at the EGJ or in the cardia of the stomach within 5 cm of the EGJ that extend into the EGJ or esophagus are staged as esophageal rather than stomach cancers, while those that arise within 5 cm of the EGJ without extension into the esophagus are still staged as gastric cancers . However, these definitions have changed in the most recent (2017, eighth edition) revision of the American Joint Committee on Cancer (AJCC) staging classification, which is scheduled to go into effect in the United States on January 1, 2018 . Tumors involving the EGJ with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal cancers, 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 1). Outside of the United States, the Union for International Cancer Control (UICC) has implemented the eighth edition changes as of January 1, 2017. (See "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 adjuvant and neoadjuvant chemotherapy for gastric cancer, and institutional practice varies. Management of EGJ and gastric cardia tumors is discussed in detail separately. (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.
SQUAMOUS CELL VERSUS ADENOCARCINOMA — There are two major histologies of esophageal cancer: squamous cell cancer (SCC) and adenocarcinoma. 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 acknowledgement of these differences, the current 2010 tumor, node, metastasis (TNM) staging system provides separate stage groupings (but similar definitions for T, N, M, and grade [G] categories) for SCCs and adenocarcinomas of the esophagus and esophagogastric junction (EGJ) (table 2 and table 3) . In addition, tumor location (for SCCs only) is incorporated into stage grouping. These prognostic stage groupings have been further refined in the most recent (eighth edition, 2017) revision of the TNM classification, which is scheduled to go into effect in the United States on January 1, 2018 (table 4) . Outside of the United States, the Union for International Cancer Control (UICC) has implemented the eighth edition changes as of January 1, 2017. (See "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, and if an endoscopic complete response is achieved, non-operative management is an option following initial chemoradiotherapy. By contrast, few data exist on the adequacy of nonoperative management for adenocarcinomas, and most patients are recommended to undergo surgery after upfront chemoradiotherapy. (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 adenocarcinomas differ in terms of pathogenesis, epidemiology, tumor biology, and prognosis:
●The incidence of SCC is declining in the United States while that of adenocarcinoma has increased markedly over the last 20 years, suggesting underlying etiologic differences. SCC is almost always the result of tobacco and/or alcohol abuse while adenocarcinomas are associated with gastroesophageal reflux disease (GERD) and high body mass. (See "Epidemiology, pathobiology, and clinical manifestations of esophageal cancer".)
●The precursor lesion of SCC is epithelial dysplasia, which progresses in sequence to carcinoma in situ, and finally to invasive carcinoma . In contrast, adenocarcinomas usually arise as a consequence of persistent GERD, in which the mucosa of the distal esophagus undergoes intestinal metaplasia. 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 arising from Barrett's'.)
●Although SCCs tend to arise 10 years earlier, on average, than adenocarcinomas, perioperative mortality is higher for SCC than for a Barrett's adenocarcinoma, likely related to associated comorbidity and tumor location [7,8]. 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. In contrast, 65 percent of SCCs are located above this location . Tumors located in the upper third of the esophagus have significantly higher rates of postoperative death. (See "Surgical management of resectable esophageal and esophagogastric junction cancers" and "Epidemiology, pathobiology, and clinical manifestations 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 adenocarcinomas more commonly recur with distant dissemination.
Despite these data, many (but not all ) contemporary series suggest that the prognosis of adenocarcinoma is better than that of SCC, particularly in early stage disease [4,10-15]. One reason may be the lower prevalence of lymphatic spread for Barrett's-associated cancer than for SCCs [4,10].
It has been proposed that the difference in tumor location also has implications for the choice of therapy. Some suggest that induction chemotherapy alone may suffice for adenocarcinomas, while results are superior with chemoradiotherapy for SCCs because of the greater need for tumor downsizing to achieve a complete radical resection . However, there are few data to support 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 adenocarcinomas. (See 'Necessity for surgery' below.)
THORACIC ESOPHAGUS TUMORS
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 esophageal cancer. Its utility as monotherapy has been challenged [16,17]. Data from contemporary surgical series report five-year survival rates of 15 to 20 percent for surgery alone [18-22]. In an analysis of 4627 patients with esophageal cancer who were treated with surgery alone, without adjuvant or neoadjuvant therapy, five-year survival rates were <50 percent for all disease stages except T1N0 cases (table 4), and they were 15 percent for any patient with node-positive disease .
This 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'.)
RT alone — Before the era of modern chemotherapy and combined chemoradiotherapy, radiation therapy (RT) alone (60 to 66 Gy over a period of six to seven weeks) was associated with five-year survival rates of 5 to 21 percent, depending upon tumor extent [24-27].
Modern techniques (eg, three-dimensional conformal RT [3D-CRT], intensity-modulated RT [IMRT]) are associated with more favorable toxicity profiles than those associated with the lower-energy units 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 squamous cell cancer (SCC) . 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 adenocarcinoma.
Although these data are encouraging, the role of RT alone has been supplanted by combined chemoradiotherapy in the majority of patients because of significantly better outcomes , despite a higher rate of treatment-related toxicity.
Preoperative chemoradiotherapy — Several trials and meta-analyses have demonstrated better survival with preoperative concurrent chemoradiation as compared to local therapy, and this approach is generally preferred for potentially resectable stage II or III localized cancer of the thoracic esophagus. However, the optimal regimen is not established. Whether this approach should also be applied to patients with clinical T2N0 tumors is also uncertain. This subject is discussed below. (See 'Patients with T1-2N0 disease' below.)
The poor long-term survival associated with surgery alone and the radiosensitizing effect of concurrent chemotherapy provided the impetus to evaluate preoperative chemoradiotherapy. At least seven trials have directly compared surgery with or without preoperative chemoradiotherapy for patients with potentially resectable esophageal carcinoma [19,30-35]. Two demonstrate a significant survival benefit from combined modality therapy, both using a concurrent rather than sequential approach [34,35].
Versus RT alone — In randomized trials, the addition of cisplatin-based chemotherapy to RT significantly improves survival over RT alone [36-38]. However, the available data are almost exclusively in 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 chemoradiotherapy (two cycles of infusional 5-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 . Patients were required to have no evidence of spread beyond mediastinal and supraclavicular lymph nodes; 90 percent had SCC. The chemoradiotherapy group received two additional chemotherapy courses, 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 chemoradiotherapy (five-year survival 27 versus 0 percent) . Analysis of failure patterns showed a significant reduction in both locoregional and distant failure for chemoradiotherapy. However, despite this benefit, 46 percent of patients in the chemoradiotherapy 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 chemoradiotherapy 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.
Intergroup 0123 — In the US Intergroup Study 0123 (INT 0123), 236 patients with nonmetastatic esophageal SCC or adenocarcinoma received concurrent cisplatin and 5-FU (as in RTOG 85-01), but they 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) . Higher RT doses were not associated with a higher median (13 versus 18 months) or two-year survival (31 versus 40 percent), or 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 Gy of RT plus concurrent cisplatin and 5-FU remains a standard approach.
More recent studies are investigating the role of newer chemotherapy regimens combined with RT (eg, FOLFOX  or weekly carboplatin plus paclitaxel as was used in the CROSS trial ). (See 'CROSS trial' below.)
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 [42-44]. At least one Chinese trial of 170 patients with locally advanced esophageal cancer suggests that definitive chemoradiotherapy using the combination of IMRT plus concurrent cisplatin plus docetaxel improves local control and prolongs survival over IMRT alone, but side effects were more prominent . 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 five completed randomized trials that compared preoperative concurrent chemoradiotherapy versus surgery alone, only two show a statistically significant survival benefit for chemoradiotherapy [34,45]; three others do not, two of which were underpowered [30,35,46]. Of these, the two most important are the Dutch CROSS trial and CALGB 9781.
CROSS trial — Dutch investigators randomly assigned 363 patients with potentially resectable esophageal or esophagogastric junction (EGJ) cancer (86 SCC, 273 adenocarcinoma, 4 other; majority distal esophageal, 11 percent EGJ) to preoperative chemoradiotherapy 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 . Preoperative chemoradiotherapy 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 complete (R0) resection rate was higher with chemoradiotherapy (92 versus 69 percent), and 29 percent of those treated with chemoradiotherapy had a pathologic complete response (pCR). At a median follow-up of 32 months, median overall survival was significantly better with preoperative chemoradiotherapy (hazard ratio [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 (median 84-month) follow-up (five-year survival 47 versus 33 percent, HR for death 0.67, 95% CI 0.51-0.87) .
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 endoscopic ultrasound (EUS) and thoracoscopy/laparoscopy were encouraged. Due to poor accrual, the study was closed prematurely with only 56 patients enrolled (42 adenocarcinomas, 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 . Five-year survival was 39 versus 16 percent in favor of trimodality therapy, although the difference was not statistically significant.
FFCD 9901 — The benefit of preoperative chemoradiotherapy in smaller resectable tumors was directly addressed in the French FFCD 9901 trial, which randomly assigned 195 patients with stage I or II esophageal or EGJ cancer (T1N0/N+, T2 N0/N+, or T3N0, (table 3)) to preoperative chemoradiotherapy (two courses of infusional 5-fluorouracil [5-FU] 800 mg/m2 daily days 1 to 4 and 29 to 32 plus cisplatin 75 mg/m2 on day 1 or 2 of each course and concurrent RT [45 Gy]) versus surgery alone . At a median follow-up of 94 months, neoadjuvant chemoradiotherapy did not improve three-year overall survival (47.5 versus 53 percent, HR 0.99, 95% CI 0.69-1.40), did not improve the complete (R0) resection rate, and it was associated with a significantly higher rate of perioperative mortality (11.1 versus 3.4 percent). There were no subgroups (eg, node-positive, stage II/IIIA, adenocarcinoma versus squamous cell) for which a survival benefit of initial chemoradiotherapy could be shown. While it is possible that patients with early stage, potentially resectable disease derive minimal to no benefit from trimodality therapy, it is also likely that study was underpowered to show a significant survival benefit, if one was present .
Meta-analyses — Several meta-analyses have addressed the benefit of trimodality therapy over surgery alone for esophageal cancer [50,51]. One of the most recent and largest of these included 12 randomized comparisons of neoadjuvant chemoradiotherapy (either concurrent or sequential) versus surgery alone for esophageal or EGJ cancer, including the FFCD 9901, CALGB 9781, and CROSS trials . The HR for all-cause mortality for neoadjuvant chemoradiotherapy 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 adenocarcinomas, 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).
Sequential chemoradiotherapy — In contrast to the data on concurrent chemoradiotherapy, 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 [19,31,32].
Technique for preoperative RT — The degree of response of a tumor and normal tissues/organs to radiation depends upon several radiotherapeutic factors [52-54]:
●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, 45 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 , 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. In this regard, IMRT provides a better RT plan than 3D-CRT.
Target volume — The target volume consists of gross tumor volume (GTV) with a margin of clinically uninvolved tissue but potentially harboring microscopic tumor tissue (clinical target volume [CTV]). The CTV should include 4 to 5 cm margins beyond the radiographic tumor extent (GTV) 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 (planning target volume) 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) . 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 [52,53].
The optimal radiation dose for preoperative chemoradiotherapy 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 [36,47,57,58].
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 [30,59].
Patients judged inoperable because of either poor general condition or the presence of distant metastases can be treated by rapid fractionation schedules. 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.
3D-CRT uses four to eight beams if necessary to conform the distribution of radiation dose to the GTV and 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 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 that delivers 3D-CRT. Unlike 2D and even standard 3D-CRT, it uses inverse treatment planning to deliver highly conformal RT. 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 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 [60-62].
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 [30,63-74]. In a comprehensive literature review of 22 studies in which patients with esophageal or EGJ cancer underwent esophagectomy after neoadjuvant chemoradiotherapy, patients with a pCR were two- to threefold more likely to survive, as were those with residual disease in the esophagectomy specimen . 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 chemoradiotherapy [75-80].
While no randomized trials have compared this sequential induction chemotherapy followed by chemoradiotherapy with standard chemoradiotherapy, 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 adenocarcinoma were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus leucovorin and short-term infusional 5-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 . The pCR rate was significantly higher after induction chemotherapy followed by chemoradiotherapy, 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 chemoradiotherapy versus chemotherapy alone'.)
Although early results from many trials evaluating intensified chemotherapy during RT are encouraging [81-86], 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/5-FU.
Necessity for surgery — We suggest resection for all patients with adenocarcinoma and for patients with SCC who have less than an endoscopic complete response to chemoradiotherapy. For patients with SCC who have an endoscopic complete response, nonoperative management is an option balancing the risks of surgical mortality versus improved locoregional control.
The necessity of resection in patients who have a response to chemoradiotherapy is controversial. A survival benefit for trimodality therapy (which included post-RT or postchemoradiotherapy esophagectomy) over definitive RT or chemoradiotherapy alone has been suggested in national surveys of patients with thoracic adenocarcinoma or SCC who were treated in the 1990s [87-89], in an analysis of data from a the National Cancer Database of patients with esophageal cancer who were treated between 2004 and 2011 , and in an analysis of 3123 patients with thoracic esophageal SCC derived from the Taiwan Cancer Registry database who were treated with modern RT and chemoradiotherapy techniques between 2006 and 2014 . However, others have questioned the necessity of surgery in chemotherapy responders [16,17].
In contemporary series, definitive chemoradiotherapy provides long-term survival in up to 27 percent of patients with SCC [36,39,55,57], a result that is not dissimilar to that achieved with preoperative chemoradiotherapy followed by surgery [16,30,34], neoadjuvant chemotherapy and surgery (see 'Neoadjuvant chemotherapy' below) [18,92], and surgery alone [18,19]. Nearly all reports note a higher rate of locally persistent/recurrent disease when surgery is not a component of treatment [36,55]. In general, there is a lack of data on nonsurgical management for patients with adenocarcinoma, and at least some retrospective series suggest inferior outcomes in this group when treated with nonsurgical therapy .
At least two randomized trials directly comparing chemoradiotherapy alone with trimodality therapy (chemoradiotherapy 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 [94,95]. The patient populations in both were either exclusively or predominantly SCC:
●In one trial, 172 patients (all with esophageal SCC) were randomly assigned to three cycles of induction 5-FU, leucovorin, etoposide, and cisplatin followed by concomitant chemoradiotherapy (cisplatin plus etoposide on days 2 and 8 only, and 40 Gy external beam RT) and then resection, or the same chemotherapy followed by concomitant chemoradiotherapy (chemotherapy on days 2 and 8 only) with an additional 20 Gy of RT added instead of surgery . Treatment-related mortality was higher in the trimodality arm (12.8 versus 3.5 percent). The surgically treated patients had significantly better local control (two-year local progression-free survival 64 versus 41 percent), but this did not translate into significantly better overall survival at three (31 versus 24 percent), five (28 versus 17 percent), or 10 years (19 versus 12 percent) .
Of note, in comparison with other trials using concomitant chemoradiotherapy alone  or followed by surgery , RT doses and the intensity of chemotherapy were lower in this study. This may in part explain the lower survival rate in the nonsurgically treated patients when compared with the results of RTOG 85-01. (See 'RTOG 85-01' above.)
●In the French trial FFCD 9102, 444 patients with potentially resectable T3, N0-1, M0 esophageal SCC (89 percent) or adenocarcinoma (11 percent) received induction chemoradiotherapy with either protracted (46 Gy in 4.5 weeks) or split course (2 X 15 Gy, days 1 to 5 and 22 to 26) RT concurrent with two courses of 5-FU and cisplatin chemotherapy . Patients with at least a partial response and who had no contraindication to surgery (n = 259) were then randomly assigned to continue chemoradiotherapy (three more cycles of chemotherapy with either 20 Gy [protracted] or 15 Gy [split course] RT) or to undergo surgery.
At a median follow-up of 47 months, the surgically treated patients had similar two-year (34 versus 40 percent) and median survival (17.7 versus 19.3 months) as compared with those assigned to continue chemoradiotherapy. Surgically treated patients had significantly lower rates of locoregional recurrence (34 versus 43 percent) and were significantly less likely to require palliative intervention for dysphagia (24 versus 46 percent). There were no differences in longitudinal quality of life among survivors with two years of follow-up .
A later report included 192 patients who were not randomized to surgery, including 111 who were clinical non-responders . Among the 111 non-responders, median survival was significantly longer for those who underwent surgery compared with those who did not (17 versus 5.5 months). For chemoradiotherapy nonresponders, surgery should be considered for those who are still operable.
The contribution of surgery was further explored in a Cochrane analysis of these two trials, plus three others: two comparing chemoradiotherapy alone versus surgery alone [99-101], one of which  was only reported in abstract form, and one  comparing chemoradiotherapy with surgery plus chemotherapy . The bulk of the patients enrolled on all of these trials had SCC, and the conclusions about surgical versus nonsurgical therapy were considered applicable to this subgroup alone:
●There was no statistically significant difference in long-term mortality in the chemoradiotherapy group compared with the surgery group (HR 0.88, 95% CI 0.76-1.03).
●In an analysis of two chemoradiotherapy trials [95,100] and one additional trial, which compared RT alone with surgery alone , there was no significant difference in local recurrence in the nonsurgically treated patients (risk ratio [RR] 0.89, 95% CI 0.70-1.12).
●The proportion of patients with dysphagia at last follow-up was significantly higher with definitive chemoradiotherapy compared with surgical treatment (RR 1.48, 95% CI 1.101-2.19), but this analysis was derived only from one study , and the impact of dysphagia on quality of life could not be assessed.
●The evidence was considered low- or very low-quality, and all included trials had a high risk of bias.
The available data on non-surgical management of adenocarcinoma are more limited:
●The largest series of nonsurgical management of adenocarcinoma comes from a retrospective analysis of 276 patients treated with definitive chemoradiotherapy at MD Anderson for esophageal cancer, 215 of whom had adenocarcinoma . 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 chemoradiotherapy. 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 adenocarcinoma treated at a single center over an 11-year period, 60 were treated without surgery while the remainder received trimodality therapy . Despite the fact that the surgically-treated patients surgery 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).
Taken together, these data suggest that patients who undergo surgery after chemoradiotherapy appear to have better locoregional control and similar quality of life. Thus, inclusion of surgery remains the preferred treatment approach for clinically resectable esophageal cancer, particularly for adenocarcinoma since there are few data on nonsurgical management, and the rate of pCR is relatively low as compared with SCC. Furthermore, the specificity of clinical complete response (cCR) 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 adenocarcinomas), 218 (77 percent) achieved a cCR (as defined by endoscopic biopsy negative for cancer and 18-F-deoxyglucose [FDG] positron emission tomography [PET] showing only physiologic uptake) after chemoradiotherapy, but only 67 (31 percent) were true pCR .
Patients with SCC who have a clinical complete response to CRT — For patients with SCC who have an endoscopically-documented complete response, definitive chemoradiotherapy is an option. Although nonoperative management avoids the risks of surgical morbidity and mortality, this benefit must be weighed against the lower likelihood of locoregional control without resection. Resection is preferred for patients who have potentially resectable disease and who are reasonable surgical candidates.
Definitive chemoradiotherapy is a reasonable approach for patients who are not surgical candidates. Concurrent chemoradiotherapy permits maximal tumor control because the combined local antitumor effect is more than additive (a therapeutic advantage termed radiation sensitization), and chemotherapy provides the opportunity for control of micrometastatic disease [108-110]. The data supporting benefit from definitive chemoradiotherapy in SCC are discussed above. (See 'Versus RT alone' above.)
Elderly patients — Few data are available on the safety and efficacy of chemoradiotherapy in the elderly. However, at least one report suggests that patients over age 70 tolerate cisplatin-based chemoradiotherapy without a major increase in adverse events and with outcomes that seem comparable to those achieved in younger individuals . Patients with significant comorbidity (ie, Charlson score ≥1, (table 5)) did experience more severe toxicity and chemotherapy delays/dose reductions than those without comorbidity. (See "Comprehensive geriatric assessment for patients with cancer".)
Whether results with definitive chemoradiotherapy are as good as can be obtained with esophagectomy in elderly patients with early stage esophageal cancer is unclear .
Utility of postinduction therapy PET scans — 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 postchemoradiotherapy 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 adenocarcinoma) who were evaluable for a postchemoradiotherapy PET response, 50 of whom received chemoradiotherapy alone . In this cohort, those whose PET response was characterized by a posttreatment 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 posttreatment tumoral SUVmax ≥3.1; the corresponding two-year rates of freedom from local failure were 75 versus 28 percent). In contrast, those patients undergoing trimodality therapy (n = 55) showed no difference in outcome according to the postchemoradiotherapy PET findings, probably because those patients who had residual disease underwent resection.
However, others have failed to find a correlation between the postchemoradiotherapy SUV on PET and pathologic response at the time of resection [114,115]. Thus, these data need to be confirmed and validated in a prospective trial before PET-directed therapy for esophageal cancer can be considered a standard approach. Furthermore, the best method to quantify FDG-PET for clinical use in esophageal cancer remains to be determined.
The main use of PET in esophageal cancer may be to recognize which patients are not responding to induction chemotherapy prior to chemoradiotherapy, administered prior to resection. This subject is discussed elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Use of PET and PET-CT during treatment'.)
Patients with T1-2N0 disease — Initial resection, rather than trimodality treatment, is preferred for patients with clinical stage T1N0 esophageal cancer (table 2) as assessed by EUS. This recommendation is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) . 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 carcinoma", section on 'Preoperative staging'.)
cT2N0 tumors — The benefit of preoperative chemoradiotherapy for patients with clinical stage T2N0 tumors is controversial. Although others disagree [116,117], we concur with consensus-based guidelines from the NCCN, preferring initial chemoradiotherapy rather than resection in this subgroup.
The contribution of neoadjuvant chemoradiotherapy to outcomes in clinical stage T2N0 (cT2N0) thoracic esophageal cancer is uncertain. These patients were included in the three positive trials examining the benefit of preoperative chemoradiotherapy, although the actual representation is only known for CALGB 9781 (3 of the total 56 enrolled patients) [34,35,47]. 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 chemoradiotherapy compared to surgery alone in 195 patients with stage I or II esophageal or EGJ cancer (table 3) . 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 . (See 'FFCD 9901' above.)
Although several retrospective studies have examined whether surgical resection versus neoadjuvant therapy provides better outcomes for these patients, they have come to disparate conclusions, and there is no consensus as to the best approach [118-122]. Guidelines from the NCCN suggest that patients with cT2N0 esophageal cancer be approached similarly to those with more advanced stage, potentially resectable disease (ie, with initial chemoradiotherapy preferred). However, a major problem is the accuracy of preoperative staging, with at least one study suggesting that as many as 49 percent of patients undergoing initial surgery are understaged by EUS, especially those with poorly-differentiated tumors, and 42 percent were overstaged . There is a need for better clinical staging modalities in this patient population. (See "Endoscopic ultrasound in esophageal carcinoma".)
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 [18,64,92,124-127]. Four trials with a surgery-alone control arm are negative, including the US Intergroup 0113 trial [18,64,124,128], 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 [92,125,126,129,130].
Meta-analyses — A survival benefit for neoadjuvant chemotherapy relative to surgery alone has been shown in two meta-analyses [50,131]; 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  was excluded because it also included gastric cancer) the hazard ratio for all-cause mortality for neoadjuvant chemotherapy was 0.88 (95% CI 0.80-0.96) . There was no significant difference in the rate of complete (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 no randomized trial (and at least two meta-analyses [51,132]) has concluded that there is no survival advantage for preoperative chemoradiotherapy over chemotherapy alone, chemoradiotherapy is a preferred strategy due to higher rates of pCRs and complete (R0) resections. At least three trials have directly compared neoadjuvant chemotherapy with chemoradiotherapy, and all have come to remarkably similar conclusions; all were conducted exclusively or predominantly in adenocarcinomas:
●Chemotherapy was directly compared with chemoradiotherapy in a randomized phase II Australian trial involving 75 patients with adenocarcinoma of the esophagus or EGJ . Although the histopathologic response rate and rate of margin-negative resections favored chemoradiotherapy, median overall survival was not significantly better (32 versus 29 months).
●In the multicenter phase III German POET trial, 126 patients with EGJ adenocarcinoma 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 . The pCR rate was significantly higher after induction chemotherapy followed by chemoradiotherapy (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 chemoradiotherapy is a preferred strategy rather than induction chemotherapy alone for patients with EGJ adenocarcinomas.
●Similar conclusions were reached in a multicenter phase III Swedish trial, in which 181 patients with cancer of the esophagus or EGJ (73 percent adenocarcinoma) 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) . All patients underwent surgical resection four to six weeks after completing neoadjuvant therapy. Chemoradiotherapy was associated with significantly higher rates of pCR (28 versus 9 percent) and complete (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 [78,133] 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 chemoradiotherapy versus chemotherapy alone'.)
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 5-FU (800 mg/m2 daily for five days) . 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 chemoradiotherapy alone as compared with those receiving chemoradiotherapy followed by surgery [18,19,30,55,135,136]. (See 'Patterns of failure' below.)
●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 chemoradiotherapy followed by surgery . At a minimum follow-up of 24 months, patients undergoing preoperative chemoradiotherapy 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 'CROSS trial' above.)
●In the previously described meta-analysis of trials comparing preoperative chemoradiotherapy with surgery alone , 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 .
●In the MRC trial, the local failure rates were nearly identical in the chemotherapy and surgery groups (12 and 11 percent, respectively) . The meta-analysis of preoperative chemotherapy versus surgery alone did not address the issue of locoregional control . (See 'Meta-analyses' above.)
Timing of surgery after chemoradiotherapy — For most patients, a five to seven-week interval between completion of chemoradiotherapy and surgery is preferred. For those who need extra time to recuperate from chemoradiotherapy, surgery can be delayed.
The optimal timing between completion of neoadjuvant chemoradiotherapy and resection is not established. The typical interval, four to seven weeks, is arbitrary, with the intent of allowing resolution of acute inflammation and allowing for tumor regression while minimizing the 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 [65,68,78]. There are some data demonstrating higher pCR rates for patients who delay surgery for 64+ days after the completion of chemoradiotherapy (relative to those undergoing surgery at 45 to 63 days, 41 versus 13 to 23 percent pCR rate) with no significant increasing surgical morbidity . However, delaying surgery did not translate into an improvement in overall survival. Delaying surgery beyond six to seven weeks would likely impact the clinical outcome negatively of those who have residual cancer after neoadjuvant therapy. Others have failed to demonstrate any correlation between delayed surgery and improved outcomes [70,139,140].
We prefer that surgery be performed within five to seven weeks of completing chemoradiotherapy. 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.
Postoperative adjuvant therapy — For patients with completely resected node-positive or T4 esophageal cancer who have not received neoadjuvant therapy, we suggest some form of postoperative therapy in an attempt to improve outcomes . It is difficult to come to any conclusions as to whether there are specific advantages for adjuvant chemoradiotherapy over chemotherapy alone, and either approach is reasonable. Further confirmatory trials, particularly randomized trials, are necessary before specific recommendations can be made.
Chemoradiotherapy — For patients with a node-positive adenocarcinoma of the EGJ, postoperative chemoradiotherapy 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 chemoradiotherapy'.)
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 chemoradiotherapy suggest potential benefit for postoperative chemoradiotherapy. However, others do not, and there are no randomized trials proving benefit as compared with surgery alone:
●In a retrospective report, outcomes of 38 patients with node-positive disease after esophagectomy alone who received postoperative chemoradiotherapy (concurrent or sequential RT plus cisplatin and 5-FU with or without epirubicin) were compared with 28 similar patients who did not receive further therapy . 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 chemoradiotherapy 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 chemoradiotherapy (RT 50.4 to 59.4 Gy plus concurrent cisplatin and 5-FU) after esophagectomy . 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 for chemoradiotherapy 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 . 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 chemoradiotherapy (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 chemoradiotherapy, there were no significant differences in late toxic effects between the two groups.
●On the other hand, a lack of benefit from RT was suggested by a randomized trial comparing postoperative chemotherapy (five weeks of cisplatin plus 5-FU) alone versus the same chemotherapy regimen with RT (50 Gy over five weeks) in 45 patients undergoing potentially curative resection for SCC of the thoracic esophagus who did not receive preoperative therapy . There was no significant benefit from the addition of RT to chemotherapy in terms of five-year survival (50 versus 38 percent), and locoregional control rates were also not better in this group.
Chemotherapy alone — For patients with esophageal cancer who have not received preoperative chemotherapy or chemoradiotherapy, postoperative chemotherapy alone may be beneficial, although proof of a survival benefit from randomized trials with a surgery alone control group is lacking [146-148]:
●Benefit for adjuvant chemotherapy alone was suggested in an uncontrolled trial conducted by the Eastern Cooperative Oncology Group (ECOG) that included patients with distal esophageal (n = 9), EGJ (n = 34), or gastric cardia (n = 12) tumors . Eligible patients had either T2N1-2 or T3/4 disease that was completely resected with negative margins; 49 (89 percent) were node positive. Treatment consisted of four three-week cycles of paclitaxel (175 mg/m2) followed by cisplatin (75 mg/m2). With a median follow-up of four years, the two- and three-year survival rates were 60 and 44 percent, respectively. The lack of a surgery alone control group precludes interpretation of these data.
●Benefit for chemotherapy but not RT in conjunction with chemotherapy was suggested in an analysis of data on 1694 patients derived from the National Cancer Database who underwent esophagectomy for a node-positive esophageal cancer from 2003 to 2011 without induction therapy . Adjuvant chemotherapy was administered to 874 patients, 618 of whom also received RT. Patients who received adjuvant chemotherapy had a better five-year survival compared with those not receiving it (24 versus 15 percent). RT did not improve survival over chemotherapy alone.
●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 5-FU 800 mg/m2 daily for five days) included 242 patients with esophageal SCC recruited from 17 Japanese institutions . 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.
POSTTREATMENT CANCER SURVEILLANCE
Patterns of failure — The majority of recurrences develop within one year, and recurrences tend to develop earlier in patients treatment with neoadjuvant therapy as compared with surgery alone. This was illustrated in a series of 590 patients who underwent esophagectomy for adenocarcinoma . 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. In contrast, among patients treated with neoadjuvant chemoradiotherapy (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. A similar distribution of recurrences (distant, locoregional, or both in 55, 28, and 17 percent) have been reported by others following trimodality therapy .
On the other hand, isolated local recurrences are more frequent after definitive chemoradiotherapy, 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 adenocarcinoma) who were treated with definitive chemoradiotherapy at MD Anderson Cancer Center over a nine-year period (2002 to 2011) . 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 'Patients with SCC who have a clinical complete response to CRT' above and 'Impact of preoperative treatment on local control' 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. The primary purpose of posttreatment 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 posttreatment surveillance is small.
This was shown in a report of 518 patients with esophageal adenocarcinoma who were treated with preoperative chemoradiotherapy and followed for a median of 29.3 months . The posttreatment surveillance strategy included computed tomography (CT) or positron emission tomography (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. In contrast, distant metastases developed in 188 (36 percent). Twelve patients with locoregional failure had salvage chemoradiotherapy, 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 posttreatment surveillance.
Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following:
●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
In contrast, consensus-based guidelines from the European Society for Medical Oncology (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 early "salvage surgery" after failing definitive chemoradiotherapy . They advise that follow-up visits concentrate on symptoms, nutrition, and psychosocial support. In the case of a complete response to chemoradiotherapy 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.
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 chemoradiotherapy. (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 posttreatment 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 studies".)
CERVICAL ESOPHAGUS TUMORS — Squamous cell cancer (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 [152-154]. (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'.)
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
●The management of local-regional cancer of the esophagus and esophagogastric junction (EGJ) has undergone a major evolution over the past 15 years. The majority of patients now undergo some form of combined modality therapy rather than local therapy alone. However, the optimal management of these patients remains controversial. (See 'Introduction' above.)
●There are two major histologies of esophageal cancer: squamous cell cancer (SCC) and adenocarcinoma. Although most clinical studies have not differentiated between these two tumor entities, an increasing amount of evidence supports the view that they differ in terms of their pathogenesis, epidemiology, tumor biology, and prognosis. In recognition of these differences, the current 2010 edition of the tumor, node, metastasis (TNM) staging criteria provides separate stage groupings for SCC and adenocarcinomas of the esophagus and EGJ (table 3 and table 2) . These prognostic stage groupings have been further refined in the most recent (eighth edition, 2017) TNM classification, which is scheduled to go into effect in the United States on January 1, 2018 (table 4) . Outside of the United States, the Union for International Cancer Control (UICC) has implemented the eighth edition changes as of January 1, 2017.
However, it remains unclear whether and how histology should be used to select the treatment 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. (See 'Squamous cell versus adenocarcinoma' above.)
Thoracic esophageal cancer — The following conclusions regarding therapy for thoracic esophageal cancers can be derived from phase III studies comparing definitive chemoradiotherapy with radiotherapy alone, and preoperative chemoradiotherapy or preoperative chemotherapy with surgery alone for patients with esophageal or EGJ cancer that is localized to the primary site and regional nodes:
●Several trials and meta-analyses support the view that a concurrent trimodality approach (concomitant chemoradiotherapy followed by surgery) provides a survival benefit compared with surgery alone. Furthermore, local failure rates appear to be lower in patients treated with chemoradiotherapy followed by surgery compared with those treated by surgery alone. (See 'Concurrent chemoradiotherapy' above and 'Impact of preoperative treatment on local control' above.)
Induction chemotherapy without radiation therapy (RT) also provides a significant survival benefit over surgery alone, and this approach has been adopted in the United Kingdom based upon the results of several neoadjuvant trials, including the MAGIC trial. However, whether preoperative chemotherapy improves local control over surgery alone remains unclear, and whether these results can be extrapolated to the setting of esophageal SCCs is uncertain. (See 'Meta-analyses' above and 'Impact of preoperative treatment on local control' above.)
As a result of these issues, 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 3 and table 2) (Grade 1A). For these patients, we suggest concurrent chemoradiotherapy instead of chemotherapy alone for neoadjuvant therapy (Grade 2B).
The benefit of preoperative chemoradiotherapy for patients with clinical stage T2N0 tumors is less clear. Nevertheless, these patients were included in three trials that demonstrated a survival benefit for neoadjuvant chemoradiotherapy, and we suggest combined modality therapy rather than resection alone for these patients as well (Grade 2B). (See 'Patients with T1-2N0 disease' above.)
For patients with T1N0 esophageal or EGJ adenocarcinoma or SCC, we recommend surgery alone (Grade 1B). Definitive chemoradiotherapy is a reasonable approach for patients who are not surgical candidates. (See 'Patients with T1-2N0 disease' above.)
●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 6) as was used in the Dutch CROSS trial rather than two courses of cisplatin plus 5-fluorouracil (5-FU) as was used in CALGB 9781 (Grade 2B). (See 'CROSS trial' above and 'CALGB 9781' above and "Treatment protocols for esophagogastric cancer".)
Issues related to carboplatin dosing (ie, estimation of glomerular filtration rate [GFR], appropriate weight to use in the calculation of drug dose according to the Calvert formula) are discussed elsewhere. (See "Dosing of anticancer agents in adults", section on 'Carboplatin'.)
●The optimal dose-fractionation RT schedule for concurrent chemoradiotherapy regimens remains to be determined. However, three-dimensional conformal techniques should be used for modern treatment planning to minimize toxicities to adjacent vital organs (ie, heart, lung, spinal cord, or liver). Even though the Dutch CROSS trial used a lower dose (41.4 Gy), the standard dose of RT for patients treated with concurrent chemotherapy remains 50.4 Gy administered in 28 daily fractions, as was used in CALGB 9781 and RTOG 85-01. (See 'Optimal dose and fractionation schedules' above and 'CROSS trial' above and 'CALGB 9781' above.)
●Definitive chemoradiotherapy is a reasonable approach for patients who are not surgical candidates. For patients who are potential surgical candidates who have SCC and an endoscopically-documented complete response, definitive chemoradiotherapy is also an option. However, while nonoperative management avoids the risks of surgical morbidity and mortality, this benefit must be weighed against the lower likelihood of locoregional control without resection. Given the higher rate of locally persistent/recurrent disease after chemoradiotherapy alone and a lack of data on nonsurgical management of patients with adenocarcinoma, who have a low rate of pathologic complete response (pCR) after chemoradiotherapy, inclusion of surgery is preferred for clinically resectable esophageal cancer, particularly for adenocarcinoma. (See 'Necessity for surgery' above.)
●For patients with completely resected node-positive esophageal cancer who have not received neoadjuvant therapy, we suggest postoperative adjuvant therapy (Grade 2C). Chemotherapy alone or chemoradiotherapy are both reasonable options. (See 'Postoperative adjuvant therapy' above.)
EGJ cancers — Most clinicians now treat EGJ and proximal gastric (ie, cardia, (figure 1)) cancers as esophageal cancers with preoperative chemoradiotherapy. However, these tumors have been included in many of the trials examining the benefit of adjuvant and neoadjuvant chemotherapy for gastric cancer, and institutional practice varies. The therapeutic approach to tumors of the EGJ is addressed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)
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 for these patients since survival appears to be the same and major morbidity is avoided in most. (See 'Cervical esophagus tumors' above.)
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