Management of locally advanced unresectable or inoperable esophageal cancer

INTRODUCTION — 

Some patients with locally advanced esophageal cancer and no distant metastases may have disease that is unresectable based on specific surgical criteria or inoperable (ie, not amenable to surgery because the patient is a poor surgical candidate or declines surgery). For such patients, the goals of treatment are generally palliative and not curative, and quality of life generally takes precedence. The major goals of therapy are restoration and/or maintenance of the ability to swallow, management of pain, and prevention of bleeding.

Treatments include radiation therapy (RT) alone, chemoradiation (CRT), and endoscopic therapies, among others. Most patients can achieve improvements in quality of life and sustained relief of dysphagia with these interventions, but the durable symptom palliation is variable. A minority of treated patients may achieve a small but real chance of prolonged progression-free survival (PFS) and, potentially, overall survival (OS).

The management of locally advanced esophageal cancer that is either unresectable or inoperable is presented here. Other treatment approaches for esophageal cancer are discussed separately.

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

●(See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer".)

●(See "Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma".)

●(See "Initial systemic therapy for metastatic esophageal and gastric cancer".)

PRETREATMENT EVALUATION

Pretreatment evaluation — Patients with esophageal cancer should undergo a pretreatment staging evaluation (including biopsies, imaging studies, and possibly diagnostic surgical exploration) to determine if the tumor is resectable. Patients should also be evaluated for Eastern Cooperative Oncology Group performance status (table 1) and comorbidities to determine their fitness for surgery. Patients should also be asked about their preferences for therapy, including surgical resection. Further details on pretreatment staging evaluation are discussed separately. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Pretreatment staging evaluation' and "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Fitness for surgery'.)

Staging system — Esophageal cancer is staged using the eighth edition combined American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging system (table 2). (See "Clinical manifestations, diagnosis, and staging of esophageal cancer".)

Regardless of histology, esophageal tumors that involve the cervical, thoracic, or abdominal esophagus, and those that involve the gastroesophageal junction (GEJ) (which can also be called the esophagogastric junction [EGJ]) that have an epicenter within 2 cm of the GEJ (table 3) share the same criteria for tumor (T), node (N), and metastasis (M) staging (table 2). By contrast, GEJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach (gastric) cancers, as are all cardia cancers not involving the GEJ, even if they are within 2 cm of the GEJ (table 4). (See "Clinical presentation, diagnosis, and staging of gastric cancer", section on 'Staging systems'.)

Criteria for unresectable disease — Esophageal cancers that meet the following criteria are generally classified as unresectable disease. Such criteria may vary according to the institution and the individual surgeon.

Distant metastases — Patients with esophageal cancer and distant metastatic disease such as peritoneal, lung, bone, adrenal, brain, or liver metastases, or extraregional lymph node spread (eg, paraaortic, mesenteric, or supraclavicular lymphadenopathy) precludes resection. Such patients should be treated with palliative systemic therapy. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Local versus metastatic disease' and "Initial systemic therapy for metastatic esophageal and gastric cancer".)

Unresectable primary disease

Thoracic or abdominal esophageal tumors — Based on the eighth edition AJCC TNM staging criteria, thoracic or abdominal esophageal tumors that are classified as T4a disease (invasion of the pleura, pericardium, azygos vein, peritoneum, or diaphragm) are potentially resectable [1]. By contrast, tumors that are classified as T4b disease (invasion of other adjacent structures, including the aorta, trachea, or vertebral body) constitute unresectable disease (table 2 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 computed tomography (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 [2,3]. 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 — Tumors of the cervical esophagus (which extends from the hypopharynx to the sternal notch (figure 1)) are proximal to major organs such as the larynx, pharynx, and thyroid. These tumors are rarely resected due to the resultant functional deficits and impairment of quality of life. Regardless of whether the tumors are resectable or not, ear, nose, and throat (ENT) surgeons are often involved in the multidisciplinary care of these patients as these tumors may involve the hypopharynx. Nevertheless, for cervical esophageal tumors, findings that preclude surgery include 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. Management of cervical esophageal tumors is discussed separately. (See 'Cervical esophageal cancer' below.)

Grading dysphagia severity — Dysphagia is a subjective term that encompasses any difficulty in swallowing food, liquids, or oral secretions [4]. Dysphagia can be caused by benign or malignant disorders of the oral cavity, oropharynx, or esophagus. Dysphagia may also be caused by structural and/or functional diseases. (See "Oropharyngeal dysphagia: Etiology and pathogenesis" and "Approach to the evaluation of dysphagia in adults".)

In patients with esophageal cancer, the severity of dysphagia can be graded using the following criteria:

●RTOG/EORTC dysphagia grading scale – A standardized grading scale for dysphagia is available from the Radiation Therapy Oncology Group (RTOG) and the European Organisation for Research and Treatment of Cancer (EORTC) (table 5) [5]. These criteria for dysphagia were developed to describe the late effects of radiation therapy (RT) and are especially useful for radiation-induced benign strictures.

●CTCAE dysphagia grading scale – The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) provides separate grading scales for dysphagia (table 6) and long-term stricture/stenosis. (See "Common terminology criteria for adverse events".)

THORACIC OR ABDOMINAL ESOPHAGEAL CANCER

Definitive chemoradiation — For patients with locally advanced unresectable or inoperable thoracic or abdominal esophageal cancer (squamous cell carcinoma [SCC] or adenocarcinoma) with good Eastern Cooperative Oncology Group performance status (table 1) and minimal or well-controlled comorbidities, we suggest definitive chemoradiation (CRT) rather than radiation therapy (RT) alone, as this approach improves overall survival (OS) and palliates symptoms of dysphagia. (See 'Benefits' below.)

Some patients with severe dysphagia at presentation may be candidates for endoscopic interventions for symptomatic relief, in addition to definitive CRT. (See 'Endoscopic interventions' below.)

Benefits — In most randomized trials of patients with locally advanced unresectable thoracic or abdominal esophageal cancer, definitive CRT improved OS compared with RT alone [6-8]. In a phase III trial (Radiation Therapy Oncology Group [RTOG] 85-01), 123 patients with locoregional (T1-3, N0-1, M0) thoracic esophageal cancer (approximately 90 percent with SCC) were randomly assigned to definitive CRT (infusional fluorouracil [FU] plus cisplatin administered concurrently with RT at 50 Gy in 25 fractions over five weeks) or definitive RT alone (64 Gy in 32 fractions over 6.5 weeks) [6,7]. Patients with T4 disease and high nodal burden were not included in this study. Surgical resectability was not an inclusion criterion. Patients treated with CRT also received two additional cycles of chemotherapy, three weeks apart, after RT.

In extended follow-up (minimum of five years), definitive CRT improved OS relative to RT alone (median OS 14 versus 9 months, five-year OS 27 versus 0 percent) [7]. In an analysis of first treatment failure, definitive CRT also reduced the rate of persistent disease (25 versus 37 percent) and the rate of distant metastases only (8 versus 15 percent), with a similar rate of locoregional disease only (15 versus 18 percent) relative to RT alone. Systemic side effects (nausea, vomiting, kidney dysfunction, and myelosuppression), were more frequent with definitive CRT compared with RT alone, while local side effects were similar in both treatment arms. The trial was closed early for clinical benefit with CRT. As a result of this trial, definitive CRT became the accepted standard of care for patients with unresectable or inoperable esophageal cancer. Further details of this trial are discussed separately. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Concurrent chemoradiation'.)

Definitive CRT also provides long-lasting palliation of dysphagia in most patients with unresectable disease [9-12]. As an example, one observational study described posttreatment swallowing function in 120 patients with esophageal cancer who were treated with CRT [9]. Most patients noted improvement in dysphagia within a median time of two weeks (88 percent), with maximal benefit seen by four weeks. At this time point, all but two patients 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.

Selection of radiosensitizing chemotherapy — For patients with locally advanced unresectable or inoperable thoracic or abdominal esophageal cancer (either adenocarcinoma or SCC) who plan to receive definitive CRT, we suggest concurrent radiosensitization with low-dose weekly carboplatin plus paclitaxel (table 7) rather than other systemic regimens due to better tolerance and ease of administration. FOLFOX is an acceptable alternative that is effective and well-tolerated but requires the use of a continuous infusional FU pump.

Carboplatin plus paclitaxel — The use of low-dose weekly carboplatin plus paclitaxel (table 7) for locally advanced unresectable or inoperable esophageal cancer is extrapolated from a phase III trial (CROSS) conducted in patients with potentially resectable distal esophageal or gastroesophageal junction (GEJ) cancer [13-15]. Although this study was performed in a different patient population (those with potentially resectable disease) and included surgery in both treatment arms, it demonstrated that the addition of neoadjuvant CRT with weekly carboplatin plus paclitaxel to surgery resulted in high pathologic complete response (pCR) rates (23 percent for those with adenocarcinoma, 49 percent for those with SCC) improved OS, and was well-tolerated. Further details of this study are discussed separately. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma", section on 'Carboplatin plus paclitaxel'.)

FOLFOX — For patients with locoregionally advanced unresectable or inoperable esophageal cancer receiving definitive CRT, FOLFOX is an appropriate alternative radiosensitizing regimen [16-20]. Studies suggest it is effective and generally well-tolerated (particularly with respect to less mucositis, kidney toxicity, and alopecia compared with cisplatin plus FU) [18]. Patients who receive this regimen are required to carry a continuous infusional FU pump for 46 hours, which may be less convenient for some patients compared with other regimens (eg, low-dose weekly carboplatin plus paclitaxel, which is completely administered in the infusion clinic and does not require the patient to take home any chemotherapy).

In an open-label phase II/III trial (PRODIGE5/ACCORD17), 267 patients with stage I-IVA esophageal cancer (85 percent with SCC; 14 percent with adenocarcinoma; 1 percent with adenosquamous carcinoma) were randomly assigned to treatment with definitive CRT using radiosensitization with either six cycles of FOLFOX (bolus FU 400 mg/m², infusional FU 1600 mg/m² over 46 hours, oxaliplatin 85 mg/m², leucovorin 200 mg/m²) or four cycles of FU (1000 mg/m² per day for four days) plus cisplatin (75 mg/m² on day 1) [18]. All patients also received RT at 50 Gy in 25 daily fractions of 2 Gy each (five fractions per week). At a median follow-up of 25 months, median progression-free survival (PFS) was similar between the two treatment arms (median 9.7 versus 9.4 months, hazard ratio [HR] 0.93, 95% CI 0.70-1.24). Any grade toxicities that were more frequent with cisplatin plus FU than FOLFOX were mucositis (32 versus 27 percent), increases in serum creatinine (12 versus 3 percent), and alopecia (9 versus 2 percent) whereas toxicities that were more frequent with FOLFOX than FU plus cisplatin were paresthesias (47 versus 2 percent), sensory neuropathy (18 versus 1 percent), and increases in alanine aminotransferase (ALT; 8 versus 2 percent) and aspartate aminotransferase (AST; 11 versus 2 percent).

Regimens not used — In patients with locoregionally advanced unresectable or inoperable thoracic or abdominal esophageal cancer, we do not offer cisplatin plus FU as a concurrent radiosensitizing regimen for definitive CRT. Although the definitive CRT with cisplatin plus FU to improve OS relative to RT alone in this population [6,7], this regimen causes more toxicity (ie, mucositis, cytopenias, alopecia, kidney toxicity) compared with other regimens such as FOLFOX [18] or carboplatin plus paclitaxel [13]. This regimen is also more complex to administer and less convenient since it requires the patient to carry a continuous infusional FU pump for 96 hours. (See 'Benefits' above.)

Other radiosensitizing chemotherapy regimens or targeted agents either remain investigational or are not used with definitive CRT due to lack of clinical benefit or significant toxicity. These include taxanes-containing regimens [21-24], irinotecan-containing regimens [25], CAPOX [26], S-1 [27], the addition of cetuximab to definitive CRT [28-30], and the addition of human epidermal growth factor receptor 2 (HER2)-targeted therapy to definitive CRT in esophageal adenocarcinoma. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma", section on 'HER2-targeted therapy for HER2+ adenocarcinomas'.)

Radiation therapy dosing — For patients with locally advanced unresectable or inoperable thoracic or abdominal esophageal cancer who are receiving definitive CRT, we suggest standard-fractionation RT (50.4 to 54 Gy total dose in daily 1.8 to 2 Gy fractions) rather than higher RT doses. In randomized trials, dose-escalation of RT failed to improve OS or local control compared with standard fractionation of RT and is more toxic [31-33]. Data are as follows:

●In a randomized trial (US Intergroup 0123/RTOG 94-05), 236 patients with clinical stage T1 to 4, NX, M0 (table 2) esophageal cancer (SCC or adenocarcinoma) were randomly assigned to definitive CRT using either high-dose RT (64.8 Gy) or standard-dose RT (50.4 Gy), both with concurrent cisplatin plus infusional FU [31]. Two additional cycles of chemotherapy were repeated four weeks after the completion of RT. Surgical resectability was not an inclusion criterion. At a median follow-up of 16 months, relative to standard-dose RT, high-dose RT failed to improve OS (median OS 13 [95% CI 11-19] versus 18 [95% CI 15-23] months, two-year OS 31 versus 40 percent) with a similar incidence of locoregional persistent or recurrent disease (56 versus 52 percent). The rate of treatment-related deaths was increased with high-dose compared with standard-dose RT (10 versus 2 percent), although most of the deaths occurred before reaching the escalated RT dose. The trial was closed early due to the lack of benefit with higher-dose RT. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Concurrent chemoradiation'.)

●In a randomized trial (ARTDECO), 260 patients with medically inoperable or unresectable SCC (61 percent) or adenocarcinoma (39 percent) were randomly assigned to concurrent CRT using either standard-dose RT (50.4 Gy over 5.5 weeks) or high-dose RT (61.6 Gy), both with concurrent carboplatin plus paclitaxel [33]. Compared with standard dose of RT, high-dose RT did not improve local or locoregional PFS for either adenocarcinoma or SCC. Similar results were seen in another randomized trial of patients with inoperable esophageal SCC, which used high-dose RT (60 Gy) versus standard-dose RT (50 Gy), both with weekly cisplatin plus docetaxel [32].

We also do not routinely offer brachytherapy in combination with definitive CRT. There are limited high-quality data to support this approach [34-37], and some studies have demonstrated significant toxicity, including the potential for fistula formation [38-40].

Complications of radiation therapy — Patients with esophageal cancer who undergo definitive CRT are at risk for developing a tracheoesophageal fistula and esophageal strictures. Other toxicities related to RT are discussed separately. (See "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects'.)

●Post-RT tracheoesophageal fistula – A tracheoesophageal fistula, a pathologic connection between the esophagus and the trachea, may develop in the setting of a locally advanced tumor or as a complication of RT or CRT (image 1). In our experience, tracheoesophageal fistulas occur more frequently with esophageal SCC than adenocarcinoma, as esophageal SCCs tend to lie closer to the airways.

Tracheoesophageal fistulas are uncommon during RT or CRT for esophageal cancer. In one observational study, the incidence of a tracheoesophageal fistula during CRT was 6 percent and accounted for one-half of all fistulas that developed in patients with esophageal cancer [41]. The others presented before the initiation of therapy; in this cohort, spontaneous closure of the fistula after completion of CRT was seen in 70 percent.

Esophageal stenting is a risk factor for a post-RT tracheoesophageal fistula. In an observational study of 208 patients who underwent stent placement with or without palliative RT for inoperable, locally advanced esophageal cancer, 18 patients developed a tracheoesophageal fistula, 17 of whom had received RT (9 percent) [42]. The risk of a tracheoesophageal fistula was higher among patients who received stent placement followed by RT rather than those who received RT followed by stent placement.

For patients with a persistent tracheoesophageal fistula after the completion of treatment, options for symptomatic management include airway stents or esophageal stents (picture 1). In most cases, such stenting can result in symptomatic treatment and closure of the fistula. (See "Tracheo- and broncho-esophageal fistulas in adults", section on 'Malignant lesions (palliative therapy)' and "Endoscopic stenting for palliation of malignant esophageal obstruction", section on 'Patients with tracheoesophageal fistula' and "Airway stents".)

Alternatives to stenting include esophageal exclusion with cervical esophagostomy, gastrostomy, and placement of a jejunostomy feeding tube (although a feeding tube does not prevent aspiration via the fistula). Surgical interventions (eg, esophageal bypass, palliative resection) are not typically performed because it carries a very high risk of morbidity and mortality [43].

●Post-RT strictures – Post-RT strictures may be either benign or malignant and may lead to recurrent dysphagia. In one observational study, the prevalence of malignant and nonmalignant post-RT strictures was similar [44]. 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 [44]. (See "Endoscopic interventions for nonmalignant esophageal strictures in adults".)

Management after definitive chemoradiation — For patients with locally advanced unresectable esophageal cancer who complete definitive CRT, management is evolving. Most of these patients are not candidates for (or would not benefit from) surgical resection. There are limited data to guide the optimal treatment approach, and clinical trials are encouraged, where available. Our approach to management following definitive CRT is as follows.

Posttreatment evaluation — Patients who complete definitive CRT are evaluated for treatment response with a history and physical examination, fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT (obtained at least five to eight weeks after completion of CRT to avoid false-positive findings due to treatment-related inflammation), and esophagogastroduodenoscopy (EGD) with endoscopic ultrasound (EUS) with biopsy of any suspicious mucosal findings and/or lymph nodes.

A clinical complete response (cCR) is defined as no clinical or histopathologic evidence of tumor on physical examination, PET-CT, and EGD and EUS with biopsies [45-47]. The PET-CT should show a maximum standardized uptake value in the primary tumor region at a normal physiologic level or distributed in an esophagitis pattern. The EGD should show no lesions, budding, or ulceration. If any ambiguous findings are present, the patient should be observed and re-evaluated within six weeks [47].

Patients with a complete clinical response — For patients with locally advanced unresectable or inoperable thoracic or abdominal esophageal cancer who complete definitive CRT and demonstrate a complete clinical response (ie, no clinical or histopathologic evidence of disease), we suggest posttreatment surveillance rather than surgery [46]. This approach is extrapolated from a randomized trial (SANO) conducted in patients with potentially resectable esophageal cancer treated with neoadjuvant CRT, which demonstrated noninferior OS for subsequent surveillance relative to immediate surgery. In addition, most patients who initially present with locally advanced technically unresectable esophageal cancer are not typically rendered resectable with definitive CRT alone. Posttreatment surveillance schedules in patients with treated esophageal cancer are discussed separately. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Post-treatment cancer surveillance'.)

There are no randomized trials to guide subsequent management (eg, surveillance versus surgery versus other strategies) in patients with locally advanced unresectable esophageal cancer who successfully complete definitive CRT. In this population, management is generally extrapolated from data in individuals with potentially resectable esophageal cancer treated with neoadjuvant CRT.

●Some patients with resectable disease demonstrate a pCR after neoadjuvant CRT and surgery, which is thought to be a surrogate marker for OS. In a randomized trial (CROSS), higher pCR rates were seen in esophageal SCC than adenocarcinoma [13]. In patients with resectable esophageal SCC initially treated with neoadjuvant CRT, a cCR, which is assessed prior to surgery, is frequently associated with pCR (up to 73 percent in one observational study [48]). These data, and others, have led to the question of whether surgery is necessary in patients with locally advanced esophageal cancer and a cCR to initial CRT. The necessity for surgery in patients with resectable esophageal cancer (both SCC and adenocarcinoma) treated with neoadjuvant CRT is discussed separately. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Necessity for surgery' and "Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma", section on 'Necessity for surgery'.)

●An initial prospective cohort study (preSANO) of patients with potentially curable locally advanced esophageal cancer established the accuracy of using a cCR to detect locoregional residual disease [45]. Subsequently, a stepped wedge, cluster randomization, noninferiority phase III trial (SANO) was conducted in the Netherlands in 309 patients with locally advanced potentially resectable esophageal cancer (75 percent adenocarcinoma, 22 percent SCC, and 3 percent other histology) who were treated with neoadjuvant CRT using weekly carboplatin plus paclitaxel [46]. Most patients had tumors in the middle or distal third of the esophagus or the GEJ; only seven patients (3 percent) had disease in the proximal third of the esophagus (cervical esophagus). Patients with a cCR to neoadjuvant CRT (ie, no tumor detected on endoscopic biopsies, ultrasound, or PET-CT) were randomly assigned to either active surveillance or standard surgery (esophagectomy). At a median follow-up of 38 months, active surveillance resulted in noninferior OS compared with immediate surgery (two-year OS 75 versus 70 percent, HR 0.83, 95% CI 0.53-1.31), which met the prespecified noninferiority difference of 15 percent or less. Patients who underwent active surveillance followed by postponed surgery demonstrated a similar frequency of postoperative complications (82 versus 84 percent) and postoperative mortality (4 versus 5 percent) compared with those who underwent immediate standard surgery.

Patients without a complete clinical response — For patients who are treated with definitive CRT but do not achieve a cCR soon after completing therapy (ie, persistent disease) or achieve a cCR but later develop disease (ie, recurrent disease), the optimal treatment approach is not established, and further randomized trials are necessary.

Persistent or recurrent localized disease — For patients treated with definitive CRT who have persistent or recurrent localized disease (limited to the esophagus without regional lymph node involvement or distant metastases), options include endoscopic therapies (eg, esophageal stenting, dilation, or ablation), palliative systemic therapy using the same treatment approach as those with metastatic esophageal cancer, or evaluation for clinical trials. Surveillance with best supportive care is an option for patients who are unable to tolerate (or decline) further therapy. Salvage esophagectomy is a less preferred option. Most of these patients will remain nonsurgical candidates following definitive CRT, and they are at high risk for developing metastatic disease. In addition, definitive CRT followed by salvage esophagectomy is associated with significant morbidity and mortality. (See 'Endoscopic interventions' below and "Initial systemic therapy for metastatic esophageal and gastric cancer" and "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Post-treatment cancer surveillance'.)

Patients with persistent or recurrent localized disease (ie, on EGD/EUS, biopsy, and/or PET-CT imaging) following definitive CRT likely have a poor prognosis, and most are not good candidates for surgical resection. These patients have disease that is likely CRT-resistant, and they are more likely to die from metastatic disease than locoregionally recurrent disease [49]. Some of these patients may also have concurrent metastatic disease, which can be detected on posttreatment PET-CT imaging [50] and is a contraindication to surgery. Such patients are more likely to benefit from alternative approaches, such as endoscopic therapies such as esophageal stenting, dilation, or ablation (which could definitively treat local disease in some cases), systemic therapy for metastatic disease, or even best supportive care if they are unable to tolerate aggressive therapy. (See 'Endoscopic interventions' below and "Initial systemic therapy for metastatic esophageal and gastric cancer".)

For patients with locally advanced unresectable or borderline resectable esophageal cancer, an important question is whether definitive CRT can successfully reduce tumor burden to the point where it is potentially resectable with salvage esophagectomy. In our view, definitive CRT followed by salvage esophagectomy is a less preferred option. There are no randomized trials evaluating this approach in unresectable esophageal cancer. Most patients treated with definitive CRT will either remain as nonsurgical candidates or will not clinically benefit from esophagectomy following CRT. However, some patients with initially unresectable or borderline resectable disease (ie, limited T4 tumors) might achieve a sufficient response from definitive CRT such that potentially curative resection becomes feasible [51,52]. Such patients interested in salvage esophagectomy should be evaluated by an experienced thoracic surgeon and offered a discussion of the risks and benefits. Although some studies suggest that definitive CRT followed by resection results in long-term disease control in a few patients (particularly those with SCC [53,54]), this is rare and most patients eventually develop relapsed or metastatic disease. In addition, definitive CRT followed by salvage esophagectomy is associated with more morbidity (eg, anastomotic leak rates due to poorer healing of the radiated tissue, pulmonary complications, and wound healing issues) and mortality than either primary esophagectomy alone or neoadjuvant CRT followed immediately by a planned esophagectomy with curative intent [53,55-64]. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Persistent or recurrent disease after chemoradiation'.)

Persistent or recurrent locoregionally advanced or metastatic disease — For patients treated with definitive CRT who have persistent or recurrent disease that is locoregionally advanced or metastatic, we evaluate for palliative systemic therapy. Further details are discussed separately. (See "Initial systemic therapy for metastatic esophageal and gastric cancer".)

Investigational approaches

Induction chemotherapy followed by definitive CRT — In patients with locally advanced unresectable or inoperable esophageal cancer, there is no established role for induction chemotherapy followed by definitive chemoradiation (CRT), as data suggest limited additional clinical benefit and significant toxicity with this approach [65]. The rationale for this approach is that many such patients may ultimately develop locoregional recurrence or distant metastases despite definitive CRT alone and thus require additional chemotherapy. However, no randomized trials have compared induction chemotherapy followed by definitive CRT versus definitive CRT alone in this population. In addition, most clinical trials evaluating induction chemotherapy followed by CRT have only been conducted in the preoperative setting for patients with locally advanced but potentially resectable disease who subsequently go on to surgery. These studies are described separately. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma", section on 'No role for adding neoadjuvant CRT to perioperative chemotherapy' and "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Intensification of preoperative therapy'.)

In a randomized phase II trial, 84 patients with nonmetastatic esophageal cancer (25 with SCC, 47 with adenocarcinoma) whose disease was technically unresectable or were unwilling or medically unfit for surgery were randomly assigned to induction chemotherapy with either FU, cisplatin, and paclitaxel or cisplatin plus paclitaxel, both followed by definitive CRT (50.4 Gy; concurrent FU plus paclitaxel for the first group and concurrent cisplatin plus paclitaxel for the second group). The study did not meet its prespecified one-year survival endpoint (one-year OS for the induction FU/cisplatin/paclitaxel group was 76 percent, goal one-year OS of 77.5 percent). Two-year OS were 56 versus 37 percent, respectively. Treatment-related toxicity rates were high in both groups (grade 3 toxicity rate of 54 versus 40 percent; grade 4 toxicity rate of 27 versus 40 percent). Both approaches were deemed toxic and OS outcomes were not sufficiently superior to historical results from other trials of definitive CRT (Intergroup 0123) [31]. (See 'Radiation therapy dosing' above.)

Immunotherapy plus definitive CRT — In patients with locally advanced unresectable or inoperable esophageal cancer, the addition of immunotherapy to definitive chemoradiation (CRT) has been evaluated in initial clinical trials [66-68]. This approach remains investigational and further randomized studies are needed.

Ineligible for definitive chemoradiation — Some patients with locally advanced unresectable or inoperable esophageal cancer may be unable to tolerate definitive CRT or their estimated life expectancy may be too short (ie, six months or less) to obtain any clinically significant benefit from such therapy. Even in patients who are candidates for CRT, improvements in swallowing may not occur for several weeks. In the interim, these patients can suffer with symptoms of esophageal obstruction, fistulae, dysphagia, odynophagia, aspiration, poor nutrition, and weight loss.

Symptomatic patients who are ineligible for or unable to tolerate definitive CRT, may benefit from alternative treatment options such as RT alone, endoscopic interventions (stenting, dilation, or ablation), or brachytherapy. The goals of such therapies are palliative and not curative, with a focus on treating tumor-related dysphagia and pain.

Radiation therapy alone — A short course of RT alone is an option for patients who are ineligible for or unable to tolerate definitive CRT and whose treatment goal is palliation of dysphagia only. For patients receiving short-course RT for esophageal cancer, the standard RT dose is a total of 30 Gy in 10 fractions [69]. Another short-course RT dosing strategy is a total of 12 Gy in four fractions (one fraction twice a day for two days) [70]. Although RT alone may successfully palliate dysphagia, it rarely achieves sustained remission or long-term OS benefit [6-8,71-73].

Endoscopic interventions

Indications for esophageal cancer — Endoscopic interventions may be appropriate to palliatively treat advanced esophageal cancer in the following settings:

●Patients for whom definitive management is planned, but severe dysphagia at presentation requires intervention prior to therapy

●Those who are poor candidates for chemotherapy, RT, or both

In addition, endoscopic interventions can be used following initial therapy for patients with:

●Failure to achieve adequate palliation of dysphagia

●Persistent or recurrent localized disease

●Recurrent dysphagia due to persistent or recurrent locoregional disease

●Recurrent dysphagia due to benign strictures after being successfully treated with RT or CRT

There are several endoscopic approaches to providing palliation from malignant dysphagia:

●Esophageal stenting – (See 'Esophageal stenting' below.)

●Esophageal dilation – (See 'Esophageal dilation' below.)

●Endoscopic mucosal resection – (See "Overview of endoscopic resection of gastrointestinal lesions", section on 'Endoscopic mucosal resection'.)

●Esophageal ablation (eg, photodynamic therapy [PDT], argon plasma coagulation [APC], cryospray ablation) – (See 'Esophageal ablation techniques' below.)

Esophageal stenting — For patients with advanced esophageal cancer or those who are poor candidates for surgery or CRT, esophageal stenting is the most commonly used palliative endoscopic treatment for dysphagia [74] Stenting can also be used for palliation of patients with postoperative tumor recurrence [75]. This topic is discussed in detail separately. (See "Endoscopic stenting for palliation of malignant esophageal obstruction".)

Stenting is also preferred for patients with a malignant stricture and/or fistula (image 1). In the absence of a fistula, optimal therapy remains controversial. In a systematic review of interventions for palliation of dysphagia associated with locally advanced esophageal cancer, insertion of a self-expanding metal stent (SEMS) was safe and provided rapid relief of dysphagia, while thermal and chemical ablative therapy provided comparable dysphagia palliation but were more likely to have adverse effects and require reintervention [76].

Esophageal dilation — Esophageal dilatation can provide temporary relief of dysphagia until more definitive treatment can be accomplished. However, in clinical practice, dilation of malignant esophageal strictures is uncommonly performed given the short-term benefit, the need for repeated procedures, and the associated risks such as perforation. (See "Adverse events related to endoscopic dilation of esophageal strictures".)

Esophageal dilation can be accomplished with either through-the-scope balloon or wire-guided polyvinyl bougies. Many malignant strictures can be safely dilated to 16 or 17 mm in several sessions [77]. However, repeat dilatation is usually required every two to four weeks. Esophageal dilation is also associated with risk of perforation, especially if performed using blind Maloney dilation during radiotherapy [78-81].

Esophageal ablation techniques — Esophageal ablation techniques such as PDT, APC, and cryotherapy are available but not commonly used to treat esophageal cancer. Their use is limited to tertiary care institutions and clinicians with appropriate expertise in such interventions.

Photodynamic therapy — PDT, a tissue ablative technique, uses a photosensitizing agent in combination with endoscopic low-power laser exposure. Only one photosensitizing agent, porfimer sodium (Photofrin), is available in the United States. Porfimer sodium is a hematoporphyrin derivative, which is approved for the palliation of esophageal cancer. PDT with porfimer sodium is thought to have a direct toxic effect on malignant cells via the production of singlet oxygen, which damages the microvasculature of the tumor and renders it ischemic causing tumor necrosis [82]. (See "Endobronchial photodynamic therapy in the management of airway disease in adults", section on 'Principles of photodynamic therapy'.)

Porfimer sodium accumulates in malignant tissue after intravenous injection, and the area is then exposed to an endoscopically placed low-power laser diffuser with monochrome light (630 nm), which initiates a photochemical reaction that results in tumor necrosis. The malignant tissue can be repeatedly treated in order to provide optimal tissue ablation.

●Advanced disease – PDT is less commonly used to palliate malignant dysphagia due to the widespread availability of SEMS for esophageal cancer, the high cost of photosensitizers, and side effects including photosensitivity. For patients with SEMS, PDT can be used to treat stent occlusion related to tissue ingrowth or overgrowth. (See "Endoscopic stenting for palliation of malignant esophageal obstruction", section on 'Stent occlusion'.)

PDT has also been studied in combination with APC. (See 'Argon plasma coagulation' below.)

Studies suggest that PDT provides palliation from dysphagia for patients with advanced esophageal cancer and that PDT with a second-generation photosensitizer has shown promise for patients with local failure after chemoradiotherapy [83-86]. In an observational study including 121 patients with esophageal cancer and local failure following chemoradiotherapy, salvage PDT using talaporfin sodium was associated with higher rates of local complete response compared with PDT using porfimer sodium (69 versus 58 percent) [85]. Adverse events including skin phototoxicity, esophageal stricture, and esophageal fistula were less common in the talaporfin sodium group.

In prior studies, other adverse events reported with PDT were chest pain and worsening dysphagia [82,87]. Although porfimer sodium is cleared from a variety of tissues within 40 to 72 hours after injection, tumors, the skin, and some organs (ie, liver, spleen) retain the drug for a longer period. Skin photosensitivity may persist for four to six weeks after the treatment; sunscreens are ineffective since they do not block visible light. After undergoing PDT, patients are advised to avoid sunlight for four to six weeks. Agents with less phototoxicity (eg, talaporfin sodium) may be the future of PDT therapy [84,85].

●Early-stage inoperable disease – Another potential use of PDT is for patients with early-stage disease who pose a high surgical risk or those who decline surgery [88,89]. In an observational series of 123 such patients who were recommended for nonoperative treatment, the complete response rate at six months was 87 percent with PDT alone or as a component of multimodality therapy, and the five-year disease-specific survival rate was 74 percent [88].

Argon plasma coagulation — APC is a technique of monopolar, noncontact, high-frequency electrocautery that uses ionized, electrically charged argon gas to cause tissue coagulation and tumor destruction. The advantages of APC are that it is widely available and easy to use. However, efficacy is limited due to the relatively superficial depth of tumor destruction, and multiple treatment sessions are required. APC has been used to palliate tumors in a variety of gastrointestinal lumens [90]. (See "Argon plasma coagulation in the gastrointestinal tract".)

Outcome data for APC compared with endoscopic stent placement are limited [91]. APC has also been studied alone in combination with brachytherapy and PDT. In on randomized trial, patients with malignant dysphagia who were treated with APC alone had shorter median times to first dysphagia recurrence compared with those who also received APC with brachytherapy or APC with PDT (35 versus 88 and 59 days, respectively) [92]. There were no differences in OS.

Cryospray ablation — Cryospray ablation (cryotherapy) is a low-pressure, noncontact method that uses supercooling (temperatures with nitrogen reaching -196°C) to cause cryonecrosis and has been used to palliate esophageal cancer [93-96]. Cryotherapy involves freezing and thawing cycles. The degree of tissue injury induced by cryotherapy varies depending on the rate and duration of cooling, the number of freeze-thaw cycles, and the distance from the target tissue to the origin of the spray. Studies have suggested that endoscopic cryotherapy using liquid nitrogen spray improved dysphagia in patients with inoperable esophageal cancer [94,97].

Brachytherapy — Brachytherapy is not a commonly used technique, and its use is limited to institutions and clinicians with appropriate expertise in this intervention. Brachytherapy permits treatment of a localized area of the esophagus with high radiation doses with relative sparing of surrounding structures. Brachytherapy does not require endoscopic guidance. It is 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 8A-B) [98]. 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 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 [99]. 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 [100-104]. In one clinical trial, 209 patients with obstruction from esophageal or GEJ 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 [103]. 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.

No role for palliative surgery — Palliative resection is not an option for patients with locally advanced disease or distant metastases due to their short life expectancy (usually less than six months). Palliative resection is also no longer a valid concept for patients with locally advanced nonmetastatic 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 with other less invasive procedures, such as endoluminal stents. (See 'Endoscopic interventions' above.)

Like palliative esophagectomy, surgical bypass provides limited benefit and is associated with substantial morbidity in patients with clearly unresectable disease [2,3,105-107]. Although these palliative bypasses relieve symptoms, complication rates usually exceed 50 to 60 percent, and mortality rates are between 5 and 10 percent [3,105-107]. As a result, these procedures are now rarely attempted. Instead, the preferred treatment for patients with inoperable local tumor invasion of the airway or aorta, or extraregional abdominal metastases is endoscopic therapy, stent placement, RT, or CRT.

CERVICAL ESOPHAGEAL CANCER — 

For most patients with locally advanced cervical esophageal squamous cell carcinoma (SCC), we suggest definitive chemoradiation (CRT) rather than surgery, as this approach preserves major proximal organs (eg, larynx, pharynx, thyroid) and is associated with similar locoregional recurrence and overall survival (OS) benefit. For patients who are ineligible for or unable to tolerate CRT, alternative options include radiation therapy (RT) or endoscopic interventions. (See 'Radiation therapy alone' above and 'Endoscopic interventions' above.)

When administering CRT for cervical esophageal SCC, we suggest concurrent chemotherapy with carboplatin plus paclitaxel rather than other systemic regimens. This regimen is effective, based on data in locally advanced thoracic and abdominal esophageal cancer, relatively easy to administer, and is better tolerated than other available regimens. An alternative approach is concurrent cisplatin-based CRT, using the same treatment regimens for patients with head and neck SCC. (See 'Carboplatin plus paclitaxel' above and "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Concurrent chemotherapy'.)

Among patients with esophageal cancer, approximately 5 and 6 percent have disease arising 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) [108]. Cervical esophageal cancer is almost exclusively of SCC histology, and most patients present with locally advanced disease at the time of diagnosis [109].

Cervical esophageal 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. Surgery 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'.)

As such, treatment is more closely related to SCC of the head and neck than to thoracic esophageal cancer [110]. As with SCCs of the oropharynx, hypopharynx, and larynx, definitive CRT is preferred over initial surgery because it contributes to organ preservation (ie, avoidance of a laryngopharyngectomy). In observational studies, OS, local failure-free survival (FFS), and distant FFS are the same, and major morbidity is avoided in most patients [110-120]. As examples:

●In a retrospective series of 224 patients with cervical esophageal cancer, 161 patients were treated with RT or CRT with or without subsequent surgery and 63 patients were treated with primary surgery with or without subsequent RT [115]. At a median follow-up of 15 months, patients treated with primary RT or CRT demonstrated similar local FFS (69 percent each), distant FSS (74 versus 63 percent), and OS (49 versus 51 percent) compared with those treated with primary surgery. However, surgery was associated with higher treatment-related mortality relative to primary RT or CRT (13 versus 4 percent).

●In a systematic review and meta-analysis of 22 retrospective studies of 1222 patients with cervical esophageal cancer were treated with definitive CRT [119]. The estimated pooled one-year, three-year, and five-year OS rates were 78, 48, and 35 percent, respectively. The estimated one-year, three-year, and five-year progression-free survival (PFS) rates were 64, 38, and 30 percent, respectively.

For patients with residual or recurrent disease following definitive CRT, options include surgical resection, re-irradiation, or systemic therapy using the same approach as those with metastatic disease. (See "Initial systemic therapy for metastatic esophageal and gastric cancer".)

SPECIAL CONSIDERATIONS

Malignant tracheoesophageal fistula (non-treatment related) — Patients with previously untreated locoregionally advanced esophageal cancer who present with a malignant tracheoesophageal fistula are typically treated with esophageal stenting. Tracheoesophageal fistulas are a relative contraindication for radiation therapy (RT) or chemoradiation (CRT) because of the high rates of perforation [121]. The management of patients with malignant tracheoesophageal fistula using esophageal stenting is discussed separately. (See "Endoscopic stenting for palliation of malignant esophageal obstruction", section on 'Patients with tracheoesophageal fistula'.)

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 5^th to 6^th 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 10^th to 12^th 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

●General principles – Some patients with locally advanced esophageal cancer and no distant metastases may have disease that is unresectable based on specific surgical criteria or inoperable (ie, not amenable to surgery because the patient is a poor surgical candidate or declines surgery). For such patients, the goals of treatment are generally palliative and not curative. (See 'Introduction' above.)

●Pretreatment evaluation – Patients with esophageal cancer should undergo a pretreatment staging evaluation (including biopsies, imaging studies, and possibly diagnostic surgical exploration) to determine if the tumor is resectable. Patients should also be evaluated for Eastern Cooperative Oncology Group performance status (table 1), comorbidities to determine their fitness for surgery, and asked about their preferences for therapy, including surgical resection. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Pretreatment staging evaluation' and "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Fitness for surgery'.)

●Criteria for unresectable disease – Esophageal cancers that meet the following criteria are generally classified as unresectable disease (see 'Criteria for unresectable disease' above):

•Distant metastatic disease – Such patients are treated with palliative systemic therapy. (See "Initial systemic therapy for metastatic esophageal and gastric cancer".)

•T4b disease (primary tumor invasion of other adjacent structures, including the aorta, trachea, or vertebral body) (table 2).

•Cervical esophageal tumors – Cervical esophageal tumors are proximal to major organs (larynx, pharynx, and thyroid) and are rarely resected due to the resultant functional deficits and impairment of quality of life. (See 'Cervical esophageal tumors' above.)

●Management of thoracic or abdominal esophageal cancer – For patients with locally advanced unresectable or inoperable thoracic or abdominal esophageal cancer (squamous cell carcinoma [SCC] or adenocarcinoma) with good Eastern Cooperative Oncology Group performance status (table 1) and minimal or well-controlled comorbidities, we suggest definitive chemoradiation (CRT) rather than radiation therapy (RT) alone (Grade 2C), as this approach improves overall survival (OS) and palliates symptoms of dysphagia. (See 'Thoracic or abdominal esophageal cancer' above.)

Some patients with severe dysphagia at presentation may be candidates for endoscopic interventions for symptomatic relief, in addition to definitive CRT. (See 'Endoscopic interventions' above.)

•Selection of radiosensitizing chemotherapy – For patients who plan to receive definitive CRT, we suggest concurrent radiosensitization with low-dose weekly carboplatin plus paclitaxel (table 7) rather than other systemic regimens (Grade 2C) due to better tolerance and ease of administration. FOLFOX is an acceptable alternative that is effective and well-tolerated but requires the use of a continuous infusional fluorouracil (FU) pump. (See 'Selection of radiosensitizing chemotherapy' above.)

•Assessing clinical response to definitive CRT – Patients who complete definitive CRT are evaluated for treatment response with a history and physical examination, fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT (obtained at least five to eight weeks after completion of CRT), and esophagogastroduodenoscopy (EGD) with endoscopic ultrasound (EUS) with biopsy of any suspicious mucosal findings and/or lymph nodes. A clinical complete response (cCR) is defined as no clinical or histopathologic evidence of tumor on physical examination, PET-CT, and EGD with EUS with biopsies. (See 'Posttreatment evaluation' above.)

-Complete clinical response – For patients who demonstrate a cCR, we suggest posttreatment surveillance rather than immediate surgery (Grade 2B). (See 'Patients with a complete clinical response' above.)

-Persistent or recurrent localized disease – For patients with persistent or recurrent localized disease (limited to the esophagus without regional lymph node involvement or distant metastases), options include endoscopic therapies (eg, esophageal stenting, dilation, or ablation), palliative systemic therapy, or evaluation for clinical trials. Surveillance with best supportive care is an option for patients who are unable to tolerate (or decline) further therapy. Salvage esophagectomy is a less-preferred option as most patients remain nonsurgical candidates following definitive CRT, they are at high risk for metastatic disease, and definitive CRT followed by salvage surgery is associated with significant morbidity and mortality. (See 'Persistent or recurrent localized disease' above and 'Endoscopic interventions' above and "Initial systemic therapy for metastatic esophageal and gastric cancer".)

-Persistent or recurrent locoregionally advanced or metastatic disease – For patients treated with definitive CRT who have persistent or recurrent disease that is locoregionally advanced or metastatic, we evaluate for palliative systemic therapy. (See "Initial systemic therapy for metastatic esophageal and gastric cancer".)

•Ineligible for definitive CRT – For patients who are ineligible for or unable to tolerate definitive CRT, alternative treatment options include RT alone, endoscopic interventions (esophageal stenting, dilation, or ablation), or brachytherapy. (See 'Ineligible for definitive chemoradiation' above.)

●Management of cervical esophageal cancer – For most patients with locally advanced cervical esophageal SCC, we suggest definitive CRT rather than surgery (Grade 2C), as this approach preserves major proximal organs (eg, larynx, pharynx, thyroid) and is associated with similar locoregional recurrence and OS benefit. For patients who are ineligible for or unable to tolerate definitive CRT, alternative options include RT alone or endoscopic interventions. (See 'Cervical esophageal cancer' above.)

•Selection of radiosensitizing chemotherapy – When administering CRT for cervical esophageal SCC, we suggest concurrent chemotherapy with carboplatin plus paclitaxel rather than other systemic regimens (Grade 2C). An alternative approach is concurrent cisplatin-based CRT, using the same treatment regimens for patients with head and neck SCC. (See 'Carboplatin plus paclitaxel' above and "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Concurrent chemotherapy'.)