INTRODUCTION — Management of patients with unresectable or inoperable but non-metastatic esophageal cancer is challenging and requires a multimodality approach. This is a heterogeneous group that includes patients with potentially resectable (T4a (table 1)) and unresectable (T4b) primary disease, poor surgical candidates, and those who decline surgery. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'TNM staging criteria'.)
Prolonged progression-free survival (PFS) is possible in a minority of these patients; however, control (which we herein label as "palliation," or "palliative" modalities) rather than cure of the cancer is the treatment goal for the majority, and quality of life (QOL) issues generally take precedence. Major goals of therapy are restoration and/or maintenance of the ability to swallow, management of pain, and prevention of bleeding. To achieve these goals, a variety of therapies may be used, including external beam radiation therapy with or without chemotherapy, esophageal dilatation and/or stenting, photodynamic therapy (PDT), laser ablation, chemical ablation, and palliative surgery.
Optimal palliation usually requires the integration of two or more of these modalities, either concurrently or sequentially. While combined modality therapy offers a small but real chance of prolonged PFS and, potentially, prolonged overall survival, improvement in QOL and sustained relief of dysphagia can be achieved in the majority of patients. However, the durability of symptom palliation is variable.
This topic focuses on locoregional therapy for locally advanced, inoperable, but non-metastatic esophageal cancer. The roles of palliative surgery and radiation therapy without or with concurrent chemotherapy will be covered, as well as an overview of endoscopic procedures for palliation of swallowing (dilation, stenting, PDT, and laser ablation). Other approaches to localized esophageal cancer and metastatic disease, as well as a more detailed discussion of endoscopic palliation, are provided in other topic reviews. (See "Surgical management of resectable esophageal and esophagogastric junction cancers" and "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas" and "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer" and "Endoscopic palliation of esophageal cancer" and "Endoscopic stenting for palliation of malignant esophageal obstruction", section on 'Efficacy'.)
GRADING THE SEVERITY OF DYSPHAGIA — Dysphagia is a subjective term that encompasses any difficulty in swallowing food, liquids, or oral secretions [1]. Dysphagia can be caused by benign or malignant disorders of the oral cavity, oropharynx, or esophagus. (See "Oropharyngeal dysphagia: Etiology and pathogenesis" and "Approach to the evaluation of dysphagia in adults".)
Due to the lack of standardization for grading the severity of dysphagia, published reports vary in how they quantify or characterize dysphagia. The Radiation Therapy Oncology Group (RTOG) and the European Organisation for Research and Treatment of Cancer (EORTC) developed a grading scale for late effects of radiation therapy, which helps standardize the evaluation of dysphagia (table 2) [2]. These criteria are especially useful for radiation-induced benign strictures. The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) provides separate grading scales for dysphagia (table 3) and long-term stricture/stenosis.
STAGING EVALUATION — The Tumor, Node, Metastasis (TNM) staging system of the combined American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) is used universally. Regardless of histology, esophageal tumors arising in the cervical, thoracic, or abdominal esophagus, and those involving the esophagogastric junction (EGJ) that have an epicenter within 2 cm of the EGJ (table 4) share the same criteria for T stage, N stage, and M stage designation (table 1). By contrast, 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 5).
Staging and evaluation for resectability require endoscopic ultrasound (EUS) for T staging (focusing on the possibility of T4 disease) and for staging and evaluation of lymph nodes, computed tomography (CT), and fluorodeoxyglucose positron emission tomography (FDG-PET), which is often integrated with CT (PET/CT). For squamous cell cancers (SCCs) located at or above the carina, bronchoscopy is indicated to rule out tracheoesophageal fistula. For cervical SCCs, flexible laryngoscopy to assess local disease spread and exclude a synchronous malignancy of the head and neck is generally recommended. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer".)
Criteria for unresectability — Although criteria vary according to institution and individual surgeon, the presence of any of the following is generally considered to preclude resection:
Distant metastases — The presence of peritoneal, lung, bone, adrenal, brain, or liver metastases or extraregional lymph node spread (eg, paraaortic or mesenteric lymphadenopathy) precludes an attempt at resection.
The finding of a malignant node in the celiac area remote from the primary tumor (eg, for a SCC in the upper or middle thoracic esophagus) was previously thought to be a sign of unresectability and was considered metastatic disease [3]. However, celiac nodal metastases are scored as regional nodal disease in the current TNM staging system, regardless of the primary tumor location or histology, and they no longer carry the connotation of distant metastatic disease [4].
Nevertheless, prognosis is poor in such cases, even if the primary tumor is located in the distal esophagus or EGJ [5,6]. In one series, the two-year survival rate of patients with celiac node involvement who underwent surgery as a component of therapy was approximately 10 percent [6].
Unresectable primary disease
Thoracic or abdominal esophagus — In the current TNM staging criteria, invasion of the pleura, pericardium, azygos vein, peritoneum, or diaphragm is classified as T4a disease and considered potentially resectable [4]. By contrast, invasion of other adjacent structures, including the aorta, trachea, or vertebral body, constitutes unresectable (T4b) disease (table 1 and image 1).
A thorough evaluation of the airway is mandatory for all esophageal cancers at or above the carina, including those involving the middle third of the esophagus (figure 1). Meticulous attention should be paid to the preservation or obliteration of fat planes between the esophagus and adjacent structures on chest CT. In general, preservation of fat planes implies no direct tumor invasion and suggests potential resectability.
On the other hand, obliteration of the fat plane does not necessarily indicate direct tumor invasion and unresectability. In normal patients, fat may be absent between an esophageal carcinoma and the aorta, trachea, left main bronchus, or pericardium, thus complicating the differentiation between an abutting tumor and true invasion. Fat planes may also be absent in cachectic patients who do not have evidence of tumor invasion.
If the tumor abuts the aorta with obliteration of the normal adventitial plane, there will likely be a positive radial margin, but this finding does not preclude exploration if there are no other findings to indicate unresectability [7,8]. Invasion of the aorta (and thus, unresectable disease) is suggested by an arc of contact between the tumor and the aorta that is more than 90 degrees, although this is not absolute confirmation of an unresectable T4b tumor.
Cervical esophageal tumors — For tumors of the cervical esophagus (which extends from the hypopharynx to the sternal notch (figure 1)), infiltration into the prevertebral fascia or posterior larynx, invasion of the membranous trachea to the level of the carina, or significant bilateral encasement of major neurovascular structures precludes surgical resection. Regardless of apparent resectability, however, tumors of the cervical esophagus are rarely resected, due to the resultant functional deficits and impairment of quality of life. They are more often treated in a similar manner to head and neck SCCs. (See 'Treatment of cervical tumors' below.)
TREATMENT OF THORACOABDOMINAL TUMORS — External beam radiation therapy (RT) with concurrent chemotherapy is a standard approach for patients with locally advanced, unresectable or inoperable, thoracic and abdominal esophageal cancer who are medically able to tolerate chemotherapy and radiation. The optimal type, dose, combination, and schedule of drugs have not been definitively established. In general, similar chemotherapy regimens are used for squamous cell cancers (SCCs) and adenocarcinomas. (See 'Conventional chemoradiotherapy' below.)
Patients who are fit for combined modality therapy — For inoperable or unresectable esophageal SCC or adenocarcinoma, we recommend concurrent chemoradiotherapy (CRT) rather than RT alone for patients who are able to tolerate this approach and who have an estimated life expectancy of greater than a few weeks.
Choice of treatment — The optimal type, dose, combination, and schedule of drugs have not been definitively established. For patients with categorically inoperable esophageal SCC who are planned for definitive CRT, we suggest the concurrent CRT regimen that was used in the Radiation Therapy Oncology Group (RTOG) 85-01 and the US Intergroup 0123 trials [9,10] (see 'Impact on survival' below):
●Infusional fluorouracil (FU) 1000 mg/m2 per day for 96 hours during weeks 1 and 5 of external beam RT
●Cisplatin 75 mg/m2 on day 1 during weeks 1 and 5 of external beam RT
For other patients, including those with inoperable adenocarcinomas, we suggest CRT as was used in the Dutch CROSS trial [11], rather than cisplatin plus FU (see 'Impact on survival' below). The chemotherapy regimen during RT consists of:
●Carboplatin dosed at an area under the curve of concentration X time (AUC) 2, weekly for five weeks
●Paclitaxel 50 mg/m2 weekly for five weeks
The great majority of patients treated with palliative CRT will not benefit from post-CRT esophagectomy. Rarely, patients with initially unresectable disease will have a sufficient disease response to warrant subsequent surgical consideration. However, particularly for SCCs, the benefit of post-CRT surgery is debated, even in those with initially localized potentially resectable disease. In our view, definitive CRT is appropriate for patients with locoregionally advanced esophageal SCC. For patients with adenocarcinoma, the role of nonoperative treatment remains poorly defined. (See 'Role of postchemoradiotherapy surgery' below.)
Historically, external beam RT played an important role in the management of unresectable esophageal cancer, both for palliation of dysphagia and for maintenance of long-term locoregional disease control. Although RT alone may successfully palliate dysphagia, sustained remission and long-term survival are rarely achieved [9,12-16]. Most experts consider combined CRT to provide superior palliation and the potential for long-term progression-free survival (PFS). It is the preferred approach for patients who are suitably fit for combined therapy.
Conventional chemoradiotherapy
Impact on survival — Many randomized controlled trials have compared CRT with RT alone for definitive treatment of esophageal cancer. Some show a significant survival advantage for the addition of chemotherapy to RT [9,14,16], but results are not consistent [17]. Most of these studies were flawed because of suboptimal doses of RT or chemotherapy, or the sequential, rather than concurrent, delivery of chemotherapy and RT. Sequential administration is now recognized as inferior to concurrent use of chemotherapy and RT. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Sequential chemoradiotherapy'.)
●Chemoradiotherapy versus RT alone: RTOG 85-01 – The only randomized trial that used adequate RT doses and modern concurrent chemotherapy, the landmark RTOG 85-01 trial, demonstrated that the addition of concurrent cisplatin-based chemotherapy to conventional fractionation RT provided a significant survival benefit compared with treatment with RT alone [9,14]. Patients with locoregional (T1 to 3, N0 to 1, M0) esophageal cancer were randomly assigned to CRT (two cycles of infusional FU [1000 mg/m2 per day, days 1 to 4, weeks 1 and 5] plus cisplatin [75 mg/m2 on day 1 of weeks 1 and 5] plus RT [50 Gy in 25 fractions over five weeks]) or RT alone (64 Gy). CRT was associated with significantly better median survival (14 versus 9 months) and five-year survival (27 versus 0 percent). These data resulted in the widespread adoption of CRT, rather than RT alone, as the definitive nonoperative treatment of locoregional esophageal cancer.
Patients with T4 disease and high nodal burden were not included in this study. Because the inclusion criteria did not require surgical unresectability or initial endoscopic ultrasound (EUS) to assess local tumor extent, the study group likely represents, on average, a prognostically more favorable population than those with unresectable, locally advanced disease. Furthermore, 85 percent of the study group had SCC. Nevertheless, these data are widely considered to provide support for the superiority of CRT over RT in patients with unresectable, locally advanced esophageal SCC or adenocarcinoma.
●Dutch CROSS trial – An alternative regimen to that used in RTOG 85-01 was used in the Dutch CROSS trial, in which 363 patients with potentially resectable esophageal or esophagogastric junction (EGJ) cancer (273 adenocarcinoma, the majority distal esophageal) were randomly assigned 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 to surgery alone [11]. As with RTOG 85-01, patients with T4 disease were not included in this study.
Preoperative CRT was well tolerated, with grade 3 or worse hematologic toxicity in 7 percent and grade 3 or higher nonhematologic toxicity in <13 percent. The complete (R0) resection rate was higher with CRT (92 versus 69 percent), and 29 percent of those treated with CRT had a pathologic complete response (pCR). Median overall survival was significantly better with CRT (median 49.4 versus 24 months, hazard ratio 0.657, 95% CI 0.495-0.871) [11].
In the latest report with long-term follow-up, preoperative CRT achieved a median overall survival of 48.6 months, versus 24 months for surgery alone. Patients with SCCs had a median overall survival of 81.6 months, while those with adenocarcinoma had a median overall survival of 43.2 months when treated with preoperative CRT, as compared with 21.1 and 27.1 months in the surgery-alone arms, respectively [18].
Palliation of dysphagia — Combined CRT provides long-lasting palliation of dysphagia in most patients with unresectable disease [19-22]. As an example, one report described post-treatment swallowing function in 120 patients who were treated with different combination regimens [19]. The majority of evaluable patients (88 percent) noted improvement in dysphagia within an average of two weeks. Benefit was maximal by four weeks in 86 percent of responding patients. At this time point, all but two could swallow at least soft or solid food without dysphagia. Two-thirds of the patients treated with palliative intent had no significant dysphagia until death or last follow-up examination.
Alternative methods for palliation of dysphagia in patients with esophageal cancer, including the use of expandable stents, are summarized below and discussed in detail elsewhere. (See 'Endoscopic interventions' below and "Endoscopic palliation of esophageal cancer" and "Endoscopic stenting for palliation of malignant esophageal obstruction".)
Complications — Patients who undergo RT are at risk for an esophagorespiratory fistula (eg, a tracheoesophageal [TE] fistula) and postradiotherapy esophageal strictures.
●TE fistula – A TE fistula may develop in the setting of a locally advanced tumor or as a complication of RT or CRT (image 1). Combined modality therapy for patients who present with a TE fistula in the setting of locally advanced disease is addressed below. (See 'Patients presenting with a malignant fistula' below.)
TE fistulas are uncommon during RT or CRT for esophageal cancer. The incidence of a TE fistula during CRT was 6 percent in one series and accounted for one-half of all fistulas that developed in patients with esophageal cancer [23]. The others presented before the initiation of therapy; in this cohort, spontaneous closure of the fistula after completion of CRT was noted in 70 percent.
Esophageal stenting is a risk factor for a post-RT TE fistula. In a report of 208 patients who underwent stent placement with or without palliative RT for inoperable, locally advanced esophageal cancer, 18 developed a TE fistula, 17 of whom had received RT [24]. The risk of a TE fistula was higher among patients who received RT after stent placement compared with those who received it beforehand. In our own experience, TE fistulas occur more often with SCC than with adenocarcinoma due to proximity to the airways.
For patients with a persistent TE fistula after the completion of treatment, options for symptomatic management include airway stents, esophageal stents (picture 1), or surgery. In most cases, symptomatic treatment and closure of the fistula are achieved with stenting; dual stenting appears to work better than single prosthesis, both for palliation and safety [25]. (See "Airway stents" and "Endoscopic stenting for palliation of malignant esophageal obstruction".)
Alternatives to stenting include esophageal exclusion with cervical esophagostomy, gastrostomy, and placement of a jejunostomy feeding tube. Surgical intervention (eg, esophageal bypass, palliative resection) is justified in very few cases and carries very high morbidity and mortality [26].
●Strictures – Post-RT strictures may be either benign or malignant and may lead to recurrent dysphagia. The prevalence of malignant and non-malignant post-RT strictures was approximately equal in one series [27]. The majority of patients with benign strictures were successfully dilated and had a 12-month survival rate of 88 percent, compared with 19 percent for those with malignant strictures [27].
Patients presenting with a malignant fistula — The presence of a malignant TE fistula in patients with locoregionally advanced esophageal cancer was historically considered a relative contraindication for RT or CRT because of the high rate of perforation [28]. However, at least some data support the view that selected patients who have a previously unirradiated T4 lesion with a malignant fistula can be safely treated with CRT, with some achieving at least transient closure of the fistula and, occasionally, long-term survival [5,29]. Toxicity may be prominent, and most patients fail to achieve long-term local control. The best way to select those patients who might benefit from CRT versus placement of stents is uncertain.
Treatment intensification — Intensification of the different components of the CRT regimen has been explored in an attempt to improve outcomes in patients with unresectable or inoperable esophageal cancer. However, to date, none has been shown to definitively improve outcomes, and toxicity may be worse. None of these approaches can be recommended outside of the context of a clinical trial.
RTOG protocol 85-01 clearly demonstrated that patients with locally advanced esophageal cancer (mostly SCC) can be cured without surgery [9,14]. However, the local failure rate (persistent and recurrent disease) of approximately 45 percent in patients treated with definitive CRT (as has been seen in other trials as well [10,30]) leaves much room for improvement. (See 'Impact on survival' above.)
Radiation therapy dose intensification — The available options for intensification of RT include higher radiation doses, accelerated fractionation RT, and the addition of brachytherapy to RT. At present, none of these approaches has been shown to improve outcomes, and none can be recommended over standard fractionation RT (50.4 to 54 Gy total dose in daily 1.8 to 2 Gy fractions) for patients with locally advanced esophageal cancers.
Several trials have explored RT dose escalation as a means of improving outcomes, none of which have demonstrated improved cancer outcomes from this approach, and most show prohibitive toxicity. As examples:
●US Intergroup trial 0123 compared high-dose external beam RT (64.8 Gy) with the previous standard (50.4 Gy), with both schedules being administered with concurrent chemotherapy (cisplatin plus infusional FU) in 236 patients with clinical stage T1 to 4, NX, M0 (table 1) esophageal cancer [10]. Two additional chemotherapy courses were repeated four weeks after the completion of RT. The trial was closed early because there was no demonstrable survival or local control advantage from higher-dose RT, although most of the deaths occurred before reaching escalated doses. Furthermore, there was a higher rate of toxic deaths (9 versus 2 percent) with the higher RT dose. One- and two-year survival rates were 66 and 40 percent, respectively.
A similar negative result was obtained in the ARTDECO study in which 260 patients with locally advanced unresectable esophageal cancer (adenocarcinoma or SCC) were randomly assigned to RT at 50.4 Gy (SD) or up to 61.6 Gy (HD) concurrent with weekly carboplatin plus paclitaxel (the CROSS CRT regimen) [31], and in a Chinese study comparing 60 Gy versus 50 Gy concurrent with weekly cisplatin and docetaxel for inoperable SCC [32]. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'CROSS trial'.)
●Another approach to RT dose intensification is the addition of brachytherapy to external beam RT and chemotherapy. Brachytherapy permits treatment of a localized area of the esophagus to high radiation doses with relative sparing of surrounding structures. It can be administered using two general methods: low dose rate brachytherapy (LDRB) and high dose rate brachytherapy (HDRB). Modern HDRB equipment delivers radiation at a high dose rate, permitting the delivery of a planned dose within minutes, compared with LDRB sources, which require many hours or days. Because of this high dose rate, fractionation is necessary; typically, two to four fractions are administered for treatment of esophageal cancer. (See "Radiation therapy techniques in cancer treatment", section on 'Brachytherapy'.)
The combination of CRT with a brachytherapy boost has been investigated in patients ineligible for surgical resection. However, randomized trials comparing this approach with CRT alone are not currently available, and the results of uncontrolled trials are mixed. While encouraging results are reported by some [33-36], others demonstrate prohibitive toxicity [37-39].
Consensus guidelines for brachytherapy in the treatment of esophageal cancer from the American Brachytherapy Society are presented in the tables (table 6A-B) [40]. However, given the potential for treatment-related toxicity, we recommend that if brachytherapy is given as a component of treatment for locally advanced esophageal cancer, chemotherapy not be administered concurrently with brachytherapy. Furthermore, brachytherapy should be used with extreme caution in the setting of a local recurrence after prior CRT because of the risk of fistula formation.
Chemotherapy intensification — Others have explored the use of novel combinations, targeted agents, or alternative radiation sensitizers (eg, taxanes, oxaliplatin) during RT [41-52]. Although results from phase II trials are encouraging, particularly for adenocarcinomas [50], at least one randomized phase II/III trial conducted in 134 patients who were "unsuitable for surgery" failed to show improved outcomes from the use of oxaliplatin plus short-term infusional FU and leucovorin (the FOLFOX regimen) during definitive concurrent CRT compared with conventional concurrent cisplatin and FU both during and following RT [49]. Approximately 85 percent of the enrolled patients had SCCs. Benefit has also not been shown for the addition of cetuximab, an inhibitor of the epidermal growth factor receptor (EGFR), to standard cytotoxic chemotherapy [48,51,52].
Other studies are evaluating combinations of cytotoxic chemotherapy with agents targeting the human epidermal growth factor receptor 2 (HER2) for HER2-overexpressing esophageal adenocarcinomas. These trials are addressed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'HER2-targeted therapy for HER2+ adenocarcinomas'.)
These and other approaches to chemotherapy intensification are discussed in more detail elsewhere. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)
Induction plus concurrent chemoradiotherapy — Up to 75 percent of patients diagnosed with locally advanced disease will ultimately develop distant metastases, providing the rationale for studying induction systemic chemotherapy prior to CRT. While phase I/II studies have shown that this approach is feasible and provides significant relief of dysphagia in up to 90 percent of patients, no trials have compared this approach with concurrent CRT alone, and it remains uncertain whether induction chemotherapy followed by concurrent CRT is superior to concurrent CRT alone for locally advanced esophageal cancer.
Most of the trials evaluating this approach have been conducted in patients with locally advanced but potentially resectable disease, and are described elsewhere. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)
Two of the only trials to include patients with T4 disease are described below:
●One randomized trial included 172 patients with T3 to 4, N0 to 1, M0 SCC (29 with EUS-staged T4 disease) [30]. The treatment groups were induction chemotherapy (three 21-day courses of bolus FU, leucovorin, etoposide, and cisplatin on days 1 to 3) followed by CRT (40 Gy RT with concurrent cisplatin and etoposide on days 2 through 8) and then surgery, or the same induction chemotherapy followed by CRT (RT dose at least 65 Gy) without surgery.
Only 62 of the 86 patients in the surgery arm underwent surgery, and this number was not broken down according to the initial EUS T stage. Overall survival was similar in both groups, although two-year PFS significantly favored the surgery arm (64 versus 41 percent). Treatment-related mortality was also significantly higher in this group (13 versus 4 percent). Tumor response to induction chemotherapy identified a prognostically favorable group within both treatment arms. The major criticisms of this study were its small size and the relatively low RT dose in the surgery arm.
●The RTOG conducted a multi-institutional phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by CRT in patients with non-metastatic esophageal cancer (25 SCC, 47 adenocarcinoma) who were technically unresectable or unwilling/medically unfit for surgery [53]. One group received FU-based induction chemotherapy (FU, cisplatin, and paclitaxel followed by RT [50.4 Gy] concurrent with paclitaxel and FU; arm A), while the other received non-fluoropyrimidine-based therapy (induction paclitaxel plus cisplatin followed by the same regimen concurrent with 50.4 Gy RT; arm B).
Treatment-related morbidity was prominent in both groups; grade 3 toxicity developed in 54 and 40 percent of patients in arms A and B, respectively, while the corresponding rates of grade 4 toxicity were 27 and 40 percent, respectively. The rate of gastrointestinal grade 3 or 4 toxicity was similar in both groups (54 and 60 percent in arms A and B). There was one treatment-related death in arm A and two in arm B.
At one and two years, 76 and 56 percent of the patients in arm A were alive, respectively, while the corresponding rates in arm B were 69 and 37 percent, respectively. The authors concluded that both approaches were toxic and neither was sufficiently superior to historical results from Intergroup 0123/RTOG 94-05 (one- and two-year survival of 66 and 40 percent in the standard RT dose arm) to justify their selection over standard cisplatin and FU-based CRT. (See 'Radiation therapy dose intensification' above.)
Role of postchemoradiotherapy surgery — The great majority of patients treated with palliative CRT will not benefit from esophagectomy following CRT. However, some patients with initially unresectable or borderline resectable limited disease (ie, limited T4 tumors) might achieve a sufficient response from preoperative CRT such that potentially curative resection becomes feasible [54,55]. This decision must be individualized and made on a case-by-case basis.
The benefit of surgery following CRT among patients who present with locoregionally advanced esophageal cancer is an area of major controversy, even among those who present with potentially resectable disease. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Necessity for surgery'.)
The key question for locally advanced, unresectable or borderline resectable disease is whether neoadjuvant concurrent CRT can successfully downstage these patients to the point where they are potentially resectable. There are no randomized trials that included patients with initially unresectable or borderline resectable disease. The only two randomized trials to address the benefit of post-CRT surgery were conducted predominantly in patients with T3, N0 to 1, M0 SCC, and both concluded that definitive CRT alone and CRT followed by surgery were equivalent in terms of two-year survival and quality of life [30,56]. CRT alone, however, was associated with more local failures (40 to 50 percent) and a greater need for later endoscopic intervention for relief of dysphagia. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Necessity for surgery'.)
These data have led some to conclude that definitive CRT is a reasonable option for patients with locoregionally advanced, potentially resectable esophageal SCC who respond to initial therapy; others disagree, arguing that successful downstaging that leads to an R0 resection improves overall and disease-free survival, especially for those who achieve a pCR from neoadjuvant therapy [57,58]. The role of nonoperative treatment for adenocarcinomas remains poorly defined. These issues are discussed in detail elsewhere. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Necessity for surgery'.)
An important point is that if post-CRT surgery is considered, a through restaging to include positron emission tomography (PET) prior to planned esophagectomy is useful to detect interval metastases (which were found in 8 percent of such patients in one study [59]) and, thus, avoid an unnecessary operation.
Salvage esophagectomy for locoregionally recurrent or persistent disease — Although rarely used, salvage esophagectomy is a feasible therapeutic option for carefully selected patients who have a limited volume of recurrent disease following definitive CRT. Surgery should only be attempted if an R0 resection is technically feasible and after distant metastatic disease has been carefully ruled out. Although there is no consensus as to which patients are appropriate candidates, we typically reserve salvage esophagectomy for patients with early stage recurrent disease (ie, node negative, T1 to 2 disease) (table 1).
A decision to pursue salvage surgery for patients with disease persistence after definitive CRT, particularly with adenocarcinomas, is more difficult. Persistent disease likely represents a more aggressive phenotype than recurrent disease, and outcomes with salvage surgery are poorer [60]. Distant metastatic disease is the cause of death in the majority of such patients, and esophagectomy is unlikely to improve survival.
While long-term disease control has been achieved in a few patients (particularly those with SCC [61,62]), there is little doubt that salvage esophagectomy is a more morbid operation than either primary esophagectomy or planned esophagectomy after neoadjuvant CRT [61,63-71].
The feasibility of salvage esophagectomy for persistent or recurrent disease following definitive CRT relates to two major issues: meticulous selection of candidates who are appropriate for salvage surgery (true local failures without metastatic disease), and experienced surgical skills in performing esophagectomy with measured and acceptable operative mortality.
A major problem is the difficulty in diagnosing recurrent or persistent local disease. In contrast to the primary diagnosis of esophageal cancer, which is usually straightforward, EUS and CT are of limited utility for assessing locoregional therapeutic response; furthermore, endoscopic biopsies are sometimes negative despite the presence of viable tumor in deeper layers of the esophagus [59]. PET-CT may offer some advantages over conventional anatomic imaging; however, it too suffers from false-positive and false-negative results in patients with prior interventions such as stent placement. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'PET restaging after induction therapy' and "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'CT, PET, and integrated PET/CT'.)
A persistent stricture may be the only clue that malignant disease is present; confirmation is often difficult, but it is essential if salvage esophagectomy is being considered. A lack of tumor in the resected esophagectomy specimen represents a diagnostic failure and a particularly difficult situation should the patient die (disease free) after surgery. Conclusive evidence of a local failure on a biopsy specimen and absence of metastases (distant failure) on a restaging PET scan should be obtained before embarking on salvage esophagectomy for locally recurrent disease.
A locoregional failure following CRT may manifest as persistent disease at the completion of the planned definitive therapy (primary failure) or as recurrent disease months later (secondary failure). Although surgery may be easier to perform in the setting of a primary failure, these patients are CRT nonresponders, and their anticipated survival is poor. As a group, they are more likely to die from metastatic than locoregionally recurrent disease. On the other hand, a carefully selected patient with a late recurrence may have a better cancer prognosis, but the potential for long-term survival must be balanced against the technical difficulty and greater morbidity of salvage esophagectomy in this setting.
Thus, salvage esophagectomy can be performed with acceptable mortality in selected patients in the hands of experienced surgeons [72]. The best way to select patients for this approach is not established.
A substantial number of patients, particularly those with SCC, have a pCR after CRT (eg, in the CROSS trial, 49 percent of patients with SCC and 23 percent of patients with adenocarcinoma achieved pCRs [11]), and these patients may not benefit from surgery. A clinical complete response has been associated with rates of pCR in up to 73 percent [73]. Clinically complete responses have been identified as being more likely in women, squamous cell tumors, and tumors with lower T stages and poor differentiation [74]. A multicenter trial is planned to evaluate a "surgery as needed" protocol with active surveillance following the completion of CRT for patients with both SCC and adenocarcinoma who have a clinical complete response to CRT [75].
Patients who are unable to tolerate initial chemoradiotherapy — For patients who are unable to tolerate initial CRT or who have a short estimated life expectancy (ie, six months or less), we suggest alternative approaches to palliation of dysphagia, such as endoscopic therapy (stenting, laser resection, photodynamic therapy, etc) or brachytherapy, rather than concurrent CRT.
Endoscopic interventions — Endoscopic interventions may be appropriate for palliation of dysphagia in patients who have advanced esophageal cancer in the following settings:
●Patients for whom definitive management is planned, but who have severe dysphagia at presentation requiring intervention prior to therapy
●Failure to achieve adequate palliation of dysphagia with initial therapy
●Recurrent dysphagia due to locoregional failure
●Recurrent dysphagia due to benign strictures in patients who are successfully treated with RT
●Patients are poor candidates for either chemotherapy or RT
In addition to brachytherapy, which doesn't require endoscopic guidance, there are several endoscopic approaches to providing palliation from malignant dysphagia:
●Placement of a prosthetic self-expanding metal stent (SEMS)
●Dilation
●Endoscopic mucosal resection
●Photodynamic therapy
Stenting is preferred for patients with a malignant stricture and/or fistula (image 1). In the absence of a fistula, optimal therapy remains controversial. A systematic review of interventions for palliation of dysphagia associated with locally advanced esophageal cancer concluded that insertion of an SEMS is safe and provides rapid relief of dysphagia, while thermal and chemical ablative therapy provided comparable dysphagia palliation but with an increased requirement for reintervention and adverse effects [76]. Brachytherapy is a suitable alternative that may be associated with improved survival and quality of life.
Endoscopic approaches to palliation in esophageal cancer are discussed in detail elsewhere. (See "Endoscopic palliation of esophageal cancer" and "Endoscopic stenting for palliation of malignant esophageal obstruction".)
Brachytherapy — Brachytherapy permits treatment of a localized area of the esophagus with high radiation doses with relative sparing of surrounding structures. It should be considered an alternative to stent placement for palliation of dysphagia, particularly when the extent of extraluminal disease is limited, and long-term palliation is likely. Although stenting has the advantage of palliating dysphagia immediately, the palliative effect of brachytherapy is frequently more durable.
Consensus guidelines for brachytherapy in the treatment of esophageal cancer from the American Brachytherapy Society are presented in the tables (table 6A-B) [40]. However:
●Although brachytherapy can successfully palliate dysphagia, as monotherapy, its use should be restricted to patients with a short life expectancy (less than six months). For patients who are expected to live less than three months, short-term palliation of swallowing may be better achieved with endoscopic stent placement. (See 'Endoscopic interventions' above and "Endoscopic palliation of esophageal cancer" and "Endoscopic stenting for palliation of malignant esophageal obstruction", section on 'Efficacy'.)
A simple score to identify patients with a poor prognosis in whom stent placement may be preferable to brachytherapy has been developed [77]. However, this prognostic model has not been independently validated, and further study, particularly of long-term outcomes, is needed.
●Brachytherapy should be used with extreme caution in the setting of a local recurrence after prior CRT because of the risk of fistula formation.
Brachytherapy alone can provide successful long-term palliation of dysphagia in patients with unresectable and/or advanced esophageal cancer [78-82]. In a trial in which 209 patients with obstruction from esophageal or gastroesophageal junction tumors were randomly assigned to brachytherapy alone (12 Gy) or to endoscopic placement of a metal stent, the stented group had more rapid improvement within 30 days of the procedure [81]. However, at later time points, brachytherapy was associated with significantly lower dysphagia severity scores and a significantly greater number of days with almost no dysphagia (115 versus 82 days). The brachytherapy group also had a significantly lower complication rate, as well as better quality of life scores, and they were no more likely to require retreatment for recurrent or persistent dysphagia than the stented group.
Surgical palliation — Palliative resection is usually not considered for patients with locally advanced disease and distant metastases due to their short life expectancy (usually less than six months). Palliative resection is also no longer considered a valid concept for patients with locally advanced non-metastatic esophageal cancer. Perioperative morbidity and mortality rates are high, and the opportunity for potentially curative alternatives, such as definitive CRT, may be lost. Furthermore, although palliative resection can relieve dysphagia, restoration of the ability to swallow can now be accomplished successfully nonsurgically in the majority of patients and is most commonly achieved by the placement of an endoluminal stent. (See 'Endoscopic interventions' above and "Endoscopic palliation of esophageal cancer".)
Like palliative esophagectomy, surgical bypass provides limited benefit and is associated with substantial morbidity in patients with clearly unresectable disease [7,8,83-85]. Although these palliative bypasses relieve symptoms, complication rates usually exceed 50 to 60 percent, and mortality rates are between 5 and 10 percent [8,83-85]. As a result, these procedures are now rarely attempted. Instead, the recommended treatment for inoperable patients with local tumor invasion of the airway or aorta, or extraregional abdominal metastases, is endoscopic therapy, stent placement, RT, or combined chemotherapy and radiation. (See 'Palliation of dysphagia' above.)
TREATMENT OF CERVICAL TUMORS — We suggest radiation therapy (RT) combined with concurrent chemotherapy rather than surgery for most patients with locally advanced tumors of the cervical esophagus.
Between 5 and 6 percent of esophageal cancers arise in the cervical portion of the esophagus, which is 6 to 8 cm long and extends from the hypopharynx to the thoracic inlet (suprasternal notch) (figure 1) [86]. Locally advanced disease is usually present at the time of diagnosis [87].
Cervical esophageal squamous cell cancers (SCCs) present a unique management challenge. Surgery is usually not possible or highly morbid due to the very close relationship to other organs, such as the larynx and trachea. As such, treatment is more closely related to SCC of the head and neck than to thoracic esophageal cancer [88].
As with SCCs of the oropharynx, hypopharynx, and larynx, RT combined with chemotherapy is preferred over initial surgery because it contributes to organ preservation; overall survival, local failure-free survival (FFS), and distant FFS are the same; major morbidity is avoided in most [88-97]:
●The largest retrospective series included 224 patients with cervical esophageal cancer, 161 treated with RT (either RT alone or concomitant chemoradiotherapy) with or without subsequent surgery and 63 with primary surgery with or without subsequent RT [93]. At a median follow-up of 15.1 months, rates of overall two-year local FFS, distant FFS, and overall survival for patients undergoing primary RT versus primary surgery were 69.9 versus 68.6, 74.3 versus 62.5, and 49.3 versus 50.7 percent, respectively (all with p values >0.05). Treatment-related mortality was significantly greater in the surgery group (12.8 versus 3.5 percent).
●The best data on oncologic outcomes of definitive chemoradiotherapy come from a systematic review and meta-analysis of 1222 patients derived from 22 retrospective studies [97]. Estimated pooled overall survival rates at one, three, and five years were 78, 48, and 35 percent, respectively, and the corresponding PFS rates were 64, 38, and 30 percent, respectively.
Cisplatin-based chemotherapy concurrent with RT is usually chosen. Specific regimens as are appropriate for patients with head and neck cancer are discussed in detail elsewhere. (See "Overview of treatment for head and neck cancer", section on 'Locoregionally advanced disease'.)
Surgery may be considered for selected patients, mainly those with earlier stage disease. If surgery is performed, it usually requires removal of portions of the pharynx, the larynx, the thyroid gland, and the proximal esophagus or the entire esophagus (pharyngo-laryngo-esophagectomy [PLE]). This one-stage, three-phase operation requires cervical, abdominal, and thoracic incisions and a permanent terminal tracheostomy. Restoration of gastrointestinal tract continuity can be accomplished with a gastric pull-up and anastomosis to the pharynx. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Cervical esophageal cancer resection'.)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues 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. 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
●Pretreatment considerations
•Locally advanced, unresectable or inoperable esophageal cancer is incurable in the majority of patients. A major goal of treatment is improvement in quality of life by restoring and/or maintaining the ability to swallow. (See 'Introduction' above.)
•Evaluation for resectability requires endoscopic ultrasound (EUS), computed tomography (CT), and integrated fluorodeoxyglucose positron emission tomography (FDG-PET)/CT. For squamous cell cancers (SCCs) located at or above the carina, bronchoscopy is indicated to rule out tracheoesophageal fistula. For cervical SCCs, flexible laryngoscopy to assess local disease spread and exclude a synchronous malignancy of the head and neck is generally recommended. (See 'Staging evaluation' above.)
In general, the finding of unresectable T4b disease (table 1), the presence of a tracheoesophageal fistula (image 1), or distant metastases precludes curative surgical resection. (See 'Criteria for unresectability' above.)
●Treatment for thoracoabdominal tumors
•For most patients with non-metastatic, inoperable or unresectable esophageal SCC or adenocarcinoma who are able to tolerate it and have an estimated life expectancy of greater than a few weeks, we recommend concurrent chemoradiotherapy (CRT) rather than radiation therapy (RT) alone (Grade 1B). (See 'Patients who are fit for combined modality therapy' above.)
•For most patients with SCC who are undergoing definitive CRT, we suggest concurrent cisplatin and fluorouracil (FU) during RT, as was used in the Radiation Therapy Oncology Group (RTOG) 85-01 and the US Intergroup 0123 trials rather than a different regimen (Grade 2B). (See 'Impact on survival' above.)
For patients with adenocarcinoma, we suggest the low-dose weekly carboplatin plus paclitaxel regimen (table 7) concurrent with RT, as was used in the Dutch CROSS trial, rather cisplatin plus FU (Grade 2B). (See 'Impact on survival' above and "Treatment protocols for esophagogastric cancer" and "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Concurrent chemoradiotherapy'.)
Modern three-dimensional (3-D) conformal techniques should be used for treatment planning to minimize toxicities to adjacent vital organs. Even though the Dutch CROSS trial used a lower dose (41.4 Gy), the standard dose of RT for patients treated with concurrent CRT for esophageal cancer remains 50.4 Gy administered in 28 daily fractions, as was used in RTOG 85-01. (See 'Impact on survival' above and "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Technique for preoperative RT'.)
•The great majority of patients will not benefit from esophagectomy following CRT. However, selected patients with initially unresectable or borderline resectable disease (ie, limited T4 disease) might achieve a sufficient response from preoperative CRT such that potentially curative resection becomes feasible. (See 'Role of postchemoradiotherapy surgery' above.)
For patients whose disease recurs after initial definitive CRT, the decision to pursue salvage esophagectomy must be made on a case-by-case basis. The best candidates are those who have early stage (ie, node negative, T1 to 2 tumors (table 1)) recurrent, rather than persistent, disease. Definitive pathologic evidence of an isolated local failure with the absence of metastatic disease should be established using integrated PET/CT and diagnostic laparoscopy (for distal adenocarcinomas) prior to salvage esophagectomy. (See 'Salvage esophagectomy for locoregionally recurrent or persistent disease' above.)
•For patients who are unable to tolerate initial CRT or who have a short estimated life expectancy, we suggest alternative approaches to palliation of swallowing, such as endoscopic therapy or brachytherapy, rather than concurrent CRT (Grade 2C). (See 'Endoscopic interventions' above and 'Brachytherapy' above.)
Endoscopic interventions (dilation, placement of an endoluminal stent, laser and photodynamic therapy) are appropriate for palliation of dysphagia in the following settings (see "Endoscopic palliation of esophageal cancer" and "Endoscopic interventions for nonmalignant esophageal strictures in adults" and "Endoscopic stenting for palliation of malignant esophageal obstruction", section on 'Efficacy'):
-Patients for whom definitive management with CRT is planned, but who have severe dysphagia at presentation requiring intervention prior to therapy
-A failure to achieve adequate palliation of dysphagia with initial therapy
-Recurrent dysphagia due to locoregional failure
-Recurrent dysphagia due to benign strictures in patients who are successfully treated with RT
-Patients who are poor candidates for either chemotherapy or RT
-Dysphagia associated with a tracheoesophageal fistula
Brachytherapy is an alternative to endoscopic therapy for palliation of dysphagia, particularly when the extent of extraluminal disease is limited, and long-term palliation is likely to be needed. Although stenting has the advantage of immediate palliation of dysphagia, the benefit of brachytherapy is frequently more durable. (See 'Brachytherapy' above.)
•The preferred treatment for inoperable patients with local tumor invasion of the airway or aorta, or extraregional abdominal metastases, is endoscopic therapy, stent placement, RT, or concurrent CRT rather than surgical palliation. (See 'Surgical palliation' above.)
●Cervical tumors – We suggest RT combined with concurrent chemotherapy rather than RT alone or surgery for most patients with locally advanced tumors of the cervical esophagus (Grade 2C). (See 'Treatment of cervical tumors' above.)
