Esophageal Cancer

Etiology

Esophageal Squamous Cell Carcinoma

In the US, smoking, alcohol consumption, and a diet low in fruits and vegetables are the main risk factors for esophageal SCC. Poor nutrition, low fruit and vegetable intake, and drinking hot beverages may increase the risk in developing countries. Other factors associated with esophageal SCC include human papillomavirus (HPV) infection, preexisting anatomical diseases, previous SCC of the aerodigestive tract, and genetic syndromes (eg, tylosis, Bloom syndrome, and Fanconi anemia). Some studies have also linked oral bisphosphonates to esophageal SCC and adenocarcinoma.

Esophageal Adenocarcinoma 

Esophageal adenocarcinoma in the US often arises from Barrett metaplasia, with risk factors including smoking, high body mass index, gastroesophageal reflux disease (GERD), and a diet low in fruits and vegetables. Alcohol intake is not associated with adenocarcinoma. Some studies have linked Barrett esophagus to epidermal growth factor polymorphisms as well as conditions that increase esophageal acid exposure, including Zollinger-Ellison syndrome, scleroderma, lower esophageal sphincter relaxing drugs, and bariatric procedures. Familial Barrett esophagus may be associated with rare autosomal inherited dominant susceptible alleles. Protective factors against Barrett esophagus and esophageal adenocarcinoma include a high-fiber diet, antioxidants, fruits and vegetables, folate, vitamin C, proton-pump inhibitors, and NSAIDs. However, none have been confirmed as preventative interventions.

Epidemiology

In the US, esophageal cancers represent the sixth most common gastrointestinal cancer, with 20,640 new cases per year, and are the eighth most common cancer worldwide. The highest-risk area, called the “esophageal cancer belt,” includes portions of northern Iran, southern Russia, central Asian countries, and northern China, where SCC dominates all cases by 90%. In this risk area, esophageal cancer is the fourth most common cause of cancer.

In recent decades, particularly in Western countries, including the US, the incidence of esophageal SCC has decreased. Conversely, the incidence of esophageal adenocarcinoma has rapidly increased during the same period in the Western world, paralleling the rise of GERD in the general population, with a notable association for patients with a high body mass index.[3][4]

Esophageal SCC is associated with low economic status and lack of refrigeration. As global economies have become wealthier, the adoption of refrigeration for meat storage has increased, while the use of meat curing and associated nitrosamine exposure has decreased. This shift has contributed to a reduced incidence of esophageal SCC worldwide.

Esophageal SCC is more likely to occur in Black patients. The primary risk factors include cigarette smoking and excessive alcohol consumption, as well as achalasia, caustic injury, tylosis, and Plummer-Vinson syndrome. Additionally, HPV has been correlated with an increased incidence of SCC in the upper cervical esophagus.[5] Patients with esophageal SCC are at risk for synchronous or metachronous head and neck or lung SCC.

Pathophysiology

The pathophysiology of esophageal SCC consists of a complex interaction between genetic, environmental, and lifestyle factors. Chronic irritation and inflammation caused by smoking, alcohol consumption, hot beverages, and poor nutrition can damage the esophageal mucosa. This chronic inflammation, along with exposure to carcinogens, can lead to genetic alterations, such as mutations in tumor suppressor genes (eg, p53) and oncogenes (eg, cyclin D1), disrupting normal cell cycle regulation and promoting uncontrolled cell growth. As genetic alterations accumulate, the esophageal epithelium develops dysplastic changes, characterized by abnormal cell morphology and disorganized tissue architecture. Dysplasia is classified as low-grade or high-grade based on the extent of cellular abnormalities. High-grade dysplasia may progress to carcinoma in situ, where cancer cells are confined to the epithelial layer. Eventually, cancer cells breach the basement membrane and invade the underlying layers of the esophageal wall (eg, submucosa and muscularis propria), enabling the tumor to grow and spread to adjacent structures. Cancer cells may enter the lymphatic system or bloodstream as the tumor grows, allowing them to metastasize to regional lymph nodes and distant organs, including the liver, lungs, and bones.

In contrast, the pathophysiologic mechanism of esophageal adenocarcinoma is repeated exposure of the lower esophagus to stomach acid secondary to chronic GERD, which leads to the replacement of the normal squamous epithelium with metaplastic columnar epithelium (ie, Barrett esophagus). The metaplastic epithelium may progressively undergo dysplastic changes, classified as low-grade or high-grade dysplasia, based on the degree of cellular abnormalities. High-grade dysplasia can progress to invasive adenocarcinoma, where cancer cells invade the underlying layers of the esophageal wall.

Histopathology

For esophageal SCC, the squamous epithelium undergoes dysplastic changes, including nuclear enlargement, hyperchromasia, and loss of polarity. Dysplasia is categorized as either low-grade or high-grade, depending on the degree of these abnormal changes. The dysplastic changes affect the entire thickness of the epithelium, but the basement membrane remains intact. As the tumor progresses, the cancer cells breach the basement membrane and invade the underlying layers of the esophageal wall. The tumor cells are organized in sheets, nests, or individual cells, exhibiting varying degrees of keratinization. Esophageal SCC is graded based on the level of keratinization, nuclear pleomorphism, and mitotic activity. Well-differentiated tumors display abundant keratinization and low mitotic activity, while poorly differentiated tumors show minimal keratinization and high mitotic activity.

Esophageal adenocarcinoma usually develops in the metaplastic epithelium, a condition called Barrett esophagus. This premalignant condition occurs when the stratified squamous epithelium is replaced by columnar epithelium due to chronic GERD. Patients with Barrett esophagus are typically monitored through upper endoscopy and biopsy to check for dysplasia.[6] If high-grade dysplasia is found, more aggressive treatment, such as surgical resection, may be necessary.[7][8] 

Histopathological features that help to assess disease prognosis include:

• Malignant cells within lymphatic or blood vessels (suggests a higher risk of metastasis)
• Malignant cells infiltrating the space surrounding nerve fibers (associated with a poorer prognosis)
• Lymphocytes within the tumor (may indicate an immune response against the cancer cells)
• Surgical resection margin status (positive or negative margins are a crucial prognostic factor)

Toxicokinetics

Carcinogens can enter the body through various routes, including the ingestion of food, drinks, or other substances that come into contact with the esophageal lining. Factors that increase the permeability of the esophageal mucosa (eg, alcohol) can facilitate the absorption of carcinogens. Once absorbed, carcinogens spread throughout the body via the bloodstream or lymphatic system; some may accumulate in specific tissues, such as the esophageal mucosa, resulting in prolonged exposure and an increased cancer risk.

The body eliminates carcinogens and their metabolites through various routes, including urine, feces, or sweat, and the efficiency of this elimination process influences the duration and extent of carcinogen exposure. Several factors, including age, gender, and genetics, impact the toxicokinetics of carcinogens in the body. Furthermore, chronic conditions (eg, obesity or liver disease) and lifestyle factors (eg, smoking and alcohol consumption) can alter the metabolism and elimination of carcinogens, elevating the risk of esophageal cancer.

History and Physical

Early-stage esophageal cancer may present with nonspecific symptoms and no significant physical findings. As the disease progresses, the signs and symptoms typically become more apparent. Therefore, a thorough history, physical examination, and appropriate diagnostic tests (eg, endoscopy, biopsy, and imaging studies) are crucial for timely diagnosis and accurate staging of esophageal cancer.

Clinical History

Esophageal cancer presents with a range of symptoms that often reflect the progressive nature of the disease. One of the most common initial complaints is progressive dysphagia. This difficulty in swallowing typically starts with solid foods and progresses to liquids as the tumor enlarges, narrowing the esophageal lumen. Unintentional weight loss is another significant symptom, often due to the reduced ability to eat and the increased metabolic demands of the growing tumor. Some patients also report odynophagia, which can be quite distressing. Chest pain or discomfort, particularly when the tumor is situated in the mid or lower esophagus, may also be reported. In cases where the tumor invades the recurrent laryngeal nerve, hoarseness can develop, a sign that is often concerning for more advanced disease. When taking the patient's history, esophageal cancer risk factors, including smoking, alcohol consumption, chronic GERD, and a family history of esophageal cancer, are essential to identify as these are suggestive of the underlying etiology and help guide diagnostic studies.

Physical Examination

On physical examination, patients with esophageal cancer may appear cachectic or malnourished due to significant weight loss. Vital signs might reveal signs of anemia, such as tachycardia or pallor, which can result from chronic blood loss caused by the tumor. During the neck examination, cervical or supraclavicular lymphadenopathy can indicate metastatic spread, an essential consideration in disease staging. Although rare, a palpable mass in the chest wall may be detected if the tumor has invaded through the esophageal wall. Abdominal examination findings of hepatomegaly or a palpable left upper quadrant mass are suggestive of liver metastases or a large, locally advanced tumor. Additionally, a hoarse or weak voice secondary to vocal cord paralysis may be observed on neurological examination if the tumor affects the recurrent laryngeal nerve. Finally, laboratory findings often show iron deficiency anemia, which can be attributed to chronic blood loss from the tumor, further complicating the patient's condition.

Evaluation

Esophageal cancer is diagnosed through histologic evaluation of biopsy specimens (Please refer to the Histopathology section for more information on the histologic features of esophageal cancer). However, imaging studies are essential for assessing the disease stage. Biopsies are typically obtained with upper endoscopy. Diffuse-type gastric adenocarcinoma may necessitate repeated endoscopy examinations and specialized techniques.

Computed tomography (CT) imaging of the chest, abdomen, and pelvis is frequently performed to evaluate the extent of disease and potential metastases. Endoscopic ultrasound (EUS) for patients without obvious metastatic disease may be performed to determine the depth of invasion and biopsy suspicious lymph nodes as part of disease staging. Positron emission tomography may also be utilized to assess lymph node status and detect occult metastases for staging. Diagnostic laparoscopy may be considered for patients with distal GEJ adenocarcinomas, gastric adenocarcinomas, or proximal gastric cardia with ≥ Stage III or lymph node-positive disease to identify occult peritoneal metastases.

Staging for gastroesophageal cancers follows the American Joint Committee on Cancer (AJCC) manual, with distinct systems for esophageal SCC and esophageal and EGJ adenocarcinomas. The eighth edition of the AJCC manual incorporates clinical staging at diagnosis (clinical stage), pathologic stage after neoadjuvant therapy (yp stage), and pathologic stage in those without neoadjuvant therapy (p stage), along with prognostic estimates for each scenario.[9][10] Please refer to the Staging section for more information.

Treatment / Management

Accurate preoperative staging will guide the most appropriate treatment selection.[11][12][13] The general recommendations are as follows:

• Endoscopic resection for superficial, limited mucosa disease (less than T1a or, in some cases, superficial cT1b)
• Esophagectomy with lymphadenectomy for lesions penetrating the submucosa with negative lymph nodes (cT1bN0, low risk, well-differentiated, and <3 cm)
• Neoadjuvant chemoradiation of resectable lesions cT2, high risk-cT4a, and all lymph node-positive
• Definitive chemoradiation for some T4a or T4b or in patients who decline surgery
• Palliative systemic therapy for metastatic disease

Endoscopic Resection

Routine endoscopic surveillance has contributed to an increase in the incidence of superficial esophageal cancer. Lesions limited to the lamina propria or muscularis mucosae may be candidates for endoscopic resection. Patients who have invasion into the submucosa or muscularis mucosa with lymphovascular invasion are not candidates for endoscopic resection due to an increased risk of lymph node metastases. Alternative endoscopic resection techniques include endoscopic mucosal resection, endoscopic submucosal dissection, or endoscopic ablation (eg, cryoablation, radiofrequency ablation, and photodynamic therapy), though no randomized clinical trial has compared these techniques. Endoscopic resection is reserved for centers with experience in this technique, patients with an interest in pursuing esophagus-sparing techniques, high-risk surgical candidates, or elderly patients with multiple comorbid medical conditions. Other esophageal factors that preclude patients from endoscopic resection are large-size lesions (>2 cm), the presence and magnitude of Barrett's esophagus, and other esophageal diseases, for example, varices. Patients who undergo endoscopic resection require extended and close follow-up. Patients who are not endoscopic resection candidates but are medically fit should be offered esophagectomy. Chemotherapy and radiation may be therapeutic options for those who are not surgical candidates.

Surgical Resection

Localized resectable esophageal cancers comprise approximately 22% of all cases, and those presenting with regional lymph node spread comprise another 30%. The goal of surgical resection is curative. The first-line esophagectomy is offered to T1N0M0 (ie, not an endoscopic resection candidate) and selected T2N0M0. Neoadjuvant chemoradiation therapy followed by esophagectomy is offered to T2 with positive disease node, T3, and selected T4a disease without metastasis. Relative exclusion criteria for esophagectomy include elderly patients, though offered to selected patients, and high-risk patients with comorbid medical conditions. The presence of metastatic disease to other organs or extra-regional lymph nodes is an absolute contraindication to esophagectomy.

Surgical procedures are divided according to the anatomical position of esophageal cancer. Cervical esophageal cancer usually requires resectioning portions of the larynx, pharynx, thyroid, and proximal esophagus with lower esophagus preservation. Thoracic esophageal cancer will include a total esophagectomy (cervical esophagogastrostomy) with radical 2-field lymph node dissection and jejunostomy feeding tube placement. EGJ cancer will involve total esophagectomy and partial or extended gastrectomy. Thoracic cancer resection for the middle to lower esophagus can be divided into 3 primary techniques in the US: transhiatal, transthoracic (Ivor-Lewis), and tri-incisional esophagectomy.

Esophagectomy guidelines recommend resection of at least 15 lymph nodes for adequate staging as this is associated with a significant reduction in mortality (5-year disease-specific survival; 55% less than 11 resected nodes, 66% for 11 to 17 resected nodes, and 75% more than 18 resected nodes). A positive circumferential resection margin has higher overall mortality compared to the negative (OR 4.02, 2.25 to 7.20, P < .001). Surgery mortality rates are reported to be <5% and the 5-year survival rate ranges from 5% to 34%. Thoracic, minimally invasive esophagectomy with abdominal laparoscopic intervention offers a surgical recovery advantage with promising better oncologic outcomes over an open thoracotomy and abdominal laparotomy procedure with an experienced surgeon at a center of excellence. Patients' nutritional status on esophageal cancer complicated by dysphagia before and after surgery should be monitored and should be palliated with esophageal stents, laser therapy, endoscopic dilation, and gastric/jejunal feeding tube when necessary and feasible.

Neoadjuvant Therapy

In the setting of disease localized to the primary site and regional nodes, chemotherapy or radiation therapy alone has significantly improved outcomes. Radiation therapy, before or after surgery, has been associated with tumor cytoreduction, improved swallowing, and local-regional tumor control, but the combination did not improve survival over surgery alone. Neoadjuvant chemotherapy (without radiation therapy) provides a significant survival benefit over surgery alone; however, it has an uncertain benefit on local control, and results are extrapolated mainly from data. Tri-modality treatment, which is concomitant chemotherapy and radiation therapy followed by surgery, provides a survival benefit compared with surgery alone. The addition of chemotherapy is designed to treat micrometastases and enhance the local effects of radiation, providing better surgical outcomes as measured by pathological complete response (pCR) and complete resections (R0).

RTOG 85-01 was an original landmark clinical trial performed by Herskovic and was the first to demonstrate the benefit of chemoradiation therapy, which is currently the standard of care. Patients with locoregional thoracic esophageal cancer (90% SCC histology; T1-3, N0-1, M0) were randomly assigned to receive either radiation therapy alone (64 Gy in 32 fractions over 6.5 weeks) or chemoradiation therapy (2 cycles of infusional 5-FU [1000 mg/m² per day, days 1 to 4, weeks 1 and 5] plus cisplatin [75 mg/m² day 1 of weeks 1 and 5] and radiation therapy [50 Gy in 25 fractions over 5 weeks]). RTGO was closed prematurely after an interim analysis showed 27% of patients were alive at 5 years in the group that received chemoradiation therapy, and none of the patients who received radiation therapy alone were alive at 5 years. Further analysis showed that 46% of patients in chemoradiation therapy had no recurrence at 12 months. The study's results led to chemoradiation therapy becoming the standard of care for unresectable disease or in patients who cannot undergo surgery. RTOG 85-01 led to a series of trials designed to confirm this positive result. INT 0123 trial was the follow-up trial to RTGO 85-01, which compared a higher radiation therapy dose (64.8 Gy) to the standard dose (50.4 Gy), plus 5-FU/CIS in both arms, found no significant difference in median overall survival (mOS).

The Dutch CROSS phase 3 trial confirmed the superiority of a neoadjuvant chemoradiation therapy approach compared with surgery alone for patients with localized esophageal cancer. The study included 368 patients (23% SCC, 75% adenocarcinoma, 2% other; T2-3, N0-1, M0; majority distal esophageal, 11% EGJ) who were randomly assigned to receive preoperative chemoradiation therapy with weekly paclitaxel 50 mg/m² plus carboplatin AUC of 2 plus concurrent radiation therapy (41.4 Gy over 5 weeks) or surgery alone. The neoadjuvant chemoradiation therapy led to an R0 of 92% and a pCR rate of 29%. At a median follow-up of 32 months, mOS was significantly better in the chemoradiation therapy arm (HR, 0.657; 95% CI; 0.50, 0.87 [P = .003]). The mOS was 49 months in the chemoradiation therapy arm versus 24 months in the surgery alone arm. The 5-year survival rate was 47% in the tri-modality arm and 34% in the surgery-alone arm. Notably, the results appeared more convincing in SCC (pCR 49%) than in adenocarcinoma (23%). Chemoradiation therapy was well tolerated, with a grade of more than 3 in 7% of patients with <13% for hematologic and nonhematologic toxicities. In contrast, the FFCD 9901 trial failed to show the benefits of 5-FU/CIS with surgery; rather, a significant increase in postoperative mortality was seen compared to surgery alone. CALGB 9781 trial was a prospective randomized trial that would have favored tri-modality therapy (5-Fu/CIS followed by surgery) versus surgery alone but failed to enroll patients. The largest meta-analysis involved 12 randomized clinical trials, including the FFCD 9901, CALGB 9781, and CROSS trials that provided strong evidence for a survival benefit of neoadjuvant chemoradiation therapy (either concurrent or sequential) over surgery alone for esophageal or EGJ cancer across histologic subtypes.

The advantage of neoadjuvant chemoradiation therapy over neoadjuvant chemotherapy has not been established, possibly due to a majority of patients enrolled in comparative trials had SCC histology that is known to be more sensitive to chemoradiation therapy than adenocarcinoma. However, the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, which compared perioperative chemotherapy (consisted of 3 preoperative and 3 postoperative cycles of intravenous epirubicin [E: 50 mg per square meter of body-surface area] and cisplatin [C: 60 mg per square meter] on day 1, and a continuous intravenous infusion of fluorouracil [F: 200 mg per square meter per day] for 21 days) with surgery alone for patients with adenocarcinoma of gastric, GEJ and esophageal cancers, significantly improved mOS (HR, 0.75; 95% CI; 0.60, 0.93 [P = .009]) and progression-free survival (HR, 0.66; 95% CI; 0.53, 0.81 [P = < .001]) for patients who received perioperative ECF. Twenty-six percent of patients in this trial had esophageal, and GEJ cancers and multivariate subgroup analyses indicated a survival benefit from perioperative chemotherapy, at least for GEJ cancers. Thus, perioperative chemotherapy with ECF should be considered for patients with GEJ cancers who are not optimal candidates for chemoradiation therapy. In the absence of medical contraindications, most patients in the US with localized esophageal cancers are receiving neoadjuvant chemoradiation therapy followed by surgery. This practice is so prevalent that clinical trials that try to enroll patients in a surgery-alone arm or compare optimized perioperative chemotherapy with neoadjuvant chemoradiation therapy have major accrual problems.[14][15][16](A1)

Adjuvant Therapy

As neoadjuvant therapy has become the standard of care, few patients who have not received it are identified. However, patients with R0 resection of node-positive or T4 esophageal cancers who have not received neoadjuvant therapy are routinely offered adjuvant chemotherapy or chemoradiation therapy since no randomized trial data support or refute either approach. Adjuvant chemoradiation therapy for GEJ has become a standard based on significantly better overall survival of 36 months compared to the observation of 27 months from the SWOG9008/INT 0116 trial (20% GEJ adenocarcinoma). 

Systemic Treatment 

The treatment goals for metastatic esophageal cancer are symptom palliation, improved quality of life, and prolonged survival. Symptom burden, performance status, comorbidities, histologic type, tumor-targeted biology, and patient preference guide therapy. Several chemotherapy agents have demonstrated some activity against esophageal cancer, including fluoropyrimidines (fluorouracil and capecitabine), platinum agents (cisplatin and oxaliplatin), taxanes (paclitaxel, docetaxel), irinotecan, irinotecan, mitomycin-C, anthracyclines, and, to a lesser extent, methotrexate, vinorelbine, and gemcitabine. Treatment commonly involves a combination of 2 or 3 drugs with a response rate as high as 65%, modestly translating to survival of weeks to a few months or, less frequently, as single-agent therapy ranging from 10% to 40%, typically with survival of fewer than 6 months. Palliation therapy may include local interventions (eg, esophageal stent) and radiation therapy with or without chemotherapy, particularly in scenarios such as dysphagia or bleeding. If available, enrollment in clinical trials is preferred.

All patients with esophageal adenocarcinoma who are chemotherapy candidates should have their tumor assayed for HER2 overexpression. HER2-positive adenocarcinoma can have trastuzumab added to a cytotoxic chemotherapy doublet backbone (most commonly fluoropyrimidine plus platinum). Non-HER2 or SCC fit patients can be offered doublet therapy (eg, oxaliplatin plus leucovorin and infusional fluorouracil [FOLFOX], oxaliplatin plus capecitabine [XELOX], irinotecan plus leucovorin and fluorouracil [FOLFIRI] or fluorouracil plus cisplatin) over triplet regimen (eg, epirubicin plus cisplatin and infusional fluorouracil [ECF], epirubicin, cisplatin and capecitabine [ECX], epirubicin plus cisplatin and capecitabine [EOX], docetaxel, cisplatin, infusional fluorouracil [DCF] or modified DCF) due to treatment toxicities. Poor performance or elderly patients may be appropriate for single agents (eg, leucovorin-modulated fluorouracil alone, single-agent capecitabine, single-agent irinotecan, or low-dose weekly taxanes). Docetaxel and irinotecan have shown a survival benefit for second-line chemotherapy. Nevertheless, there is no optimal standard of care.

The REAL-2 trial compared 4 triplet regimens (ECF, ECX, EOF, or EOX), and results showed outcomes were comparable when capecitabine was substituted for infusional fluorouracil and EOX. This was preferred due to a longer mOS of 11.2 months compared to 9.9 months with ECF (HR, 0.80; 95% CI; 0.66, 0.97 [P = .02]). Patients on oral capecitabine should not take proton pump inhibitors due to inferior absorption on less acid gastric pH. A multinational TAX-325 trial compared DCF (or taxane cisplatin fluorouracil [TCF]) with cisplatin and fluorouracil, favoring docetaxel addition for a significant response rate (37% versus 25%), time to progression (5.6 versus 3.7 months), and 2-year survival (18% versus 9%). However, higher toxicity rates requiring supportive granulocyte-colony stimulating factor were seen.

Different targeted agents added to cytotoxic backbone have been investigated in clinical trials with unfavorable results in first-line therapy. Bevacizumab failed to improve overall survival, epidermal growth factor receptor monoclonal antibodies exhibited a detrimental effect, and ramucirumab had no significant impact. Trastuzumab was added to standard chemotherapy in HER2-overexpressing gastric and GEJ cancers and showed improved overall and progression-free survival compared with chemotherapy alone. The ToGA was a phase 3 trial that compared 6 courses of cisplatin plus either infusional fluorouracil or capecitabine with and without trastuzumab. Patients received trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 3 weeks until disease progression on HER2-positive either by IHC 3+ or FISH+ on a majority gastric adenocarcinoma (80%). The primary endpoint of mOS was significantly better with trastuzumab 13.8 versus 11.1 months (P = .046). Trastuzumab, in combination with chemotherapy, became a new standard of care for patients with HER2-positive advanced or metastatic GEJ and gastric. A higher trastuzumab dose (10 mg/kg) did not improve efficacy in a phase 3 HELOISE trial. Trastuzumab candidates should be evaluated for cardiac eligibility criteria before invasive procedures or starting treatment.

The vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab dosed at 8 mg/kg intravenously (IV) every 2 weeks showed a modest survival benefit of 9.6 months when combined with paclitaxel versus paclitaxel alone dosed at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle alone (7.4 months), RAINBOW trial. Ramucirumab also showed a modest survival benefit in the REGARD trial when used as a single agent (5.2 months) versus best supportive care (3.8 months). The 2 trials mentioned above were both phase 3 clinical trials in patients with advanced gastroesophageal cancers who progressed first-line chemotherapy on a fluoropyrimidine and platinum agent. Other second-line targeted therapy agents with clinical improvement in survival outcomes in clinical trials are apatinib (an oral VEGFR-2 inhibitor with a median of 6.5 versus 4.7 months with placebo), regorafenib (an oral multikinase inhibitor with a median of 5.8 versus 4.5 months with placebo). Bevacizumab, sunitinib, sorafenib, aflibercept, gefitinib, and everolimus had no significant overall survival benefit with other secondary outcome improvements.

Another clinical trial studying patients with low expression of ataxia telangiectasia protein showed a significant survival benefit from paclitaxel plus olaparib, an oral active poly-ADP ribose polymerase inhibitor, with a mOS not reached compared to paclitaxel plus placebo, which had a mOS of 8.2 months; a phase 3 trial is ongoing. A 2017 study hypothesized that microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) tumors might be susceptible to immune checkpoint inhibition. The frequency of dMMR or MSI-H has been reported as high as 7% for esophageal/GEJ adenocarcinoma. Eighty-six selected dMMR patients with 12 different tumor types, including refractory advanced or metastatic esophageal carcinoma, who received pembrolizumab achieved 53% objective response and 21% complete response, with subsequent FDA approval for all solid tumors with those characteristics.[17][18] In 2021, the FDA approved the antibody-drug conjugate fam-trastuzumab deruxtecan for the treatment of advanced HER2-positive gastric or GEJ adenocarcinoma after prior trastuzumab-containing chemotherapy.[19](A1)

Differential Diagnosis

Several diseases and conditions can present with symptoms similar to esophageal cancer, making it crucial to rule them out during the diagnostic process, including:

• Gastroesophageal reflux disease 
  • Symptoms such as heartburn, regurgitation, and difficulty swallowing can mimic esophageal cancer.
  • GERD can lead to Barrett's esophagus, a precancerous condition that increases the risk of esophageal adenocarcinoma.
  • Endoscopy and biopsy can help differentiate between GERD and esophageal cancer.
• Eosinophilic esophagitis
  • This is an inflammatory condition characterized by eosinophilic infiltration of the esophageal mucosa.
  • Symptoms include dysphagia, food impaction, and chest pain, which can resemble esophageal cancer.
  • Endoscopy with biopsy is necessary to confirm the diagnosis and rule out malignancy.
• Esophageal motility disorders
  • Conditions such as achalasia, diffuse esophageal spasm, and nutcracker esophagus can cause dysphagia and chest pain.
  • These disorders are characterized by abnormal esophageal muscle function, leading to impaired peristalsis.
  • Esophageal manometry and endoscopy can help differentiate motility disorders from esophageal cancer.
• Esophageal strictures
  • Benign strictures can develop due to long-standing GERD, radiation therapy, or caustic ingestion.
  • Symptoms include progressive dysphagia and weight loss, similar to esophageal cancer.
  • Endoscopy with biopsy can help distinguish benign strictures from malignant lesions.
• Infectious esophagitis
  • Viral (eg, herpes simplex virus, cytomegalovirus), fungal (eg, candidiasis), or bacterial infections can cause esophageal inflammation and ulceration.
  • Symptoms may include odynophagia, dysphagia, and chest pain, mimicking esophageal cancer.
  • Endoscopy with biopsy and microbiological studies can help establish the diagnosis and guide appropriate treatment.
• Esophageal tuberculosis
  • This is a rare condition that can present with dysphagia, odynophagia, and weight loss, similar to esophageal cancer.
  • Endoscopic findings may include ulcers, strictures, or fistulae.
  • Biopsy and microbiological studies, including acid-fast bacilli staining and culture, can confirm the diagnosis.
• Esophageal leiomyoma
  • A benign tumor arising from smooth muscle cells in the esophageal wall.
  • Symptoms, when present, may include dysphagia and chest pain resembling esophageal cancer.
  • EUS can help characterize the lesion, and a biopsy can confirm the diagnosis.
• Esophageal diverticula
  • Outpouchings of the esophageal wall can cause dysphagia, regurgitation, and halitosis.
  • Symptoms may be confused with those of esophageal cancer.
  • Barium swallow studies and endoscopy can help diagnose diverticula and rule out malignancy.

Surgical Oncology

Surgery Evaluation

The evaluation process for surgery in esophageal cancer patients involves a thorough preoperative assessment, which includes staging investigations such as endoscopy, EUS, CT, and positron emission tomography (PET)/CT scans. These tests help determine the extent of the disease and evaluate the patient's overall fitness for surgery. Patients with early-stage esophageal cancer, classified as T1-2, N0, may be candidates for upfront surgical intervention. For those with locally advanced disease, characterized by T3 to T4 tumors or positive lymph nodes (N+), neoadjuvant chemoradiotherapy followed by surgery is often recommended to improve outcomes.

Surgical Techniques

The primary surgical treatment for esophageal cancer is esophagectomy, which can be performed using various techniques depending on the tumor's location and the patient's condition. These techniques include transhiatal esophagectomy, transthoracic esophagectomy (Ivor Lewis procedure), and minimally invasive esophagectomy (MIE). During the surgery, lymph node dissection is typically performed to remove potential metastatic nodes and enhance staging accuracy. Following tumor removal, reconstruction is necessary to restore gastrointestinal continuity, usually achieved by creating a gastric conduit or performing colonic interposition.

Pertinent Studies and Ongoing Trials

Several significant studies and ongoing trials have shaped the current approach to esophageal cancer treatment, including:

• CROSS trial: Demonstrated improved overall survival with neoadjuvant chemoradiotherapy (carboplatin, paclitaxel, and 41.4 Gy radiotherapy) followed by surgery compared to surgery alone in patients with esophageal or junctional cancer.
• FLOT4 trial: Showed improved overall survival with perioperative FLOT chemotherapy (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) compared to ECF/ECX (epirubicin, cisplatin, and 5-fluorouracil or capecitabine) in patients with resectable gastric or gastroesophageal junction adenocarcinoma.
• CheckMate 577 trial: Demonstrated improved disease-free survival with adjuvant nivolumab (an immune checkpoint inhibitor) in patients with resected esophageal or gastroesophageal junction cancer who had residual pathologic disease following neoadjuvant chemoradiotherapy.
• RTOG 0436 trial: Investigated the addition of cetuximab (an anti-EGFR monoclonal antibody) to concurrent chemoradiotherapy in patients with unresectable esophageal cancer.

Adverse Effects and Complications of Surgery

Despite the potential benefits, esophagectomy is associated with several postoperative complications and long-term adverse effects, including:

•  Pulmonary complications
  • Atelectasis, pneumonia, and acute respiratory distress syndrome (ARDS) are common due to the proximity of the surgery to the lungs and the potential for aspiration.
  • Management includes aggressive pulmonary toilet, incentive spirometry, early ambulation, and prompt treatment of infections with antibiotics.
  • Mechanical ventilation may be necessary for severe cases of ARDS.
• Anastomotic leaks
  • Leaks at the anastomosis between the esophagus and the gastric conduit can occur in 5% to 20% of cases, leading to mediastinitis, sepsis, and prolonged hospitalization.
  • Diagnosis is made through clinical suspicion, imaging (eg, CT with oral contrast), and endoscopy.
  • Management depends on the severity and location of the leak, ranging from conservative measures (eg, antibiotics, drainage, nil-per-os) to surgical repair or revision of the anastomosis.
• Cardiac complications
  • Arrhythmias, particularly atrial fibrillation, can occur due to the proximity of the surgery to the heart and the associated inflammation.
  • Myocardial infarction and heart failure are less common but can be life-threatening.
  • Management includes electrocardiographic monitoring, correction of electrolyte imbalances, and pharmacologic treatment (eg, beta-blockers and antiarrhythmics) as needed.
• Chylothorax
  • Injury to the thoracic duct during lymph node dissection can lead to chyle leak into the chest cavity.
  • Diagnosis is made by analysis of the pleural fluid, which appears milky and has a high triglyceride content.
  • Management includes drainage of the chyle, nil-per-os or a low-fat diet, and sometimes octreotide to reduce chyle flow. Surgical ligation of the thoracic duct may be necessary for persistent leaks.
• Recurrent laryngeal nerve injury
  • During surgery, injury to the recurrent laryngeal nerve can cause vocal cord paralysis and hoarseness.
  • Management includes speech therapy and, in some cases, vocal cord injection or medialization procedures.
• Dysphagia and strictures
  • Difficulty swallowing can occur due to anastomotic strictures or impaired motility of the gastric conduit.
  • Diagnosis is made through endoscopy and barium swallow studies.
  • Management includes endoscopic dilation for strictures and, in some cases, stent placement or surgical revision.
• Reflux and dumping syndrome
  • The altered anatomy after esophagectomy can lead to reflux of gastric contents and rapid emptying of the gastric conduit (dumping syndrome), causing symptoms such as heartburn, regurgitation, and diarrhea.
  • Management includes dietary modifications (eg, small, frequent meals and avoidance of simple sugars), antacids, and prokinetic agents. Surgical fundoplication may be considered for severe, refractory cases.
• Nutritional deficiencies
  • The altered anatomy and reduced stomach capacity can lead to malnutrition, vitamin deficiencies, and weight loss.
  • Management includes regular nutritional assessment, dietary counseling, and supplemental vitamins and minerals as needed. Enteral feeding through a jejunostomy tube may be necessary for some patients.
• Psychological and quality of life issues
  • Esophagectomy can have a significant impact on patients' emotional well-being and quality of life, with issues such as anxiety, depression, and impaired social functioning.
  • Management includes psychosocial support, counseling, and participation in support groups. Regular follow-up with the interprofessional team can help address ongoing concerns and facilitate adaptation to the new normal.

Radiation Oncology

Radiation oncology is a crucial component in the treatment of esophageal cancer, serving both in the definitive management of unresectable tumors and as a neoadjuvant therapy to improve surgical outcomes in locally advanced disease. For patients with tumors that cannot be surgically removed or for those who are not candidates for surgery due to other health issues, definitive chemoradiotherapy is considered the standard treatment. In this approach, radiation doses typically range from 50.4 to 60 Gy, administered in daily fractions of 1.8 to 2 Gy over a period of 5 to 6 weeks. The radiation is combined with concurrent chemotherapy, often involving cisplatin and 5-fluorouracil (5-FU) or carboplatin and paclitaxel, to enhance the therapeutic effect.

For patients with locally advanced esophageal cancer, characterized by T3 to T4 tumors or positive lymph nodes (N+), neoadjuvant chemoradiotherapy followed by surgery is commonly recommended. This approach involves delivering radiation doses typically ranging from 41.4 to 50.4 Gy in daily fractions of 1.8 to 2 Gy over 4 to 5 weeks, similar to the definitive treatment but adjusted for the preoperative setting. The concurrent chemotherapy regimens used in this context generally include carboplatin and paclitaxel or 5-FU and oxaliplatin, with capecitabine sometimes substituted for 5-FU. Alternative regimens may also incorporate cisplatin and 5-FU, depending on the patient's specific medical condition and the tumor's characteristics. This combined modality approach aims to shrink the tumor and improve surgical resectability, ultimately enhancing overall treatment outcomes.

Pertinent Studies and Ongoing Trials

Radiation therapy plays a crucial role in the management of esophageal cancer, both as a component of definitive chemoradiotherapy for unresectable tumors and as neoadjuvant therapy before surgery for locally advanced disease. Several pivotal studies have established the benefits of radiation therapy in esophageal cancer, and ongoing trials continue to refine treatment strategies and explore novel approaches. Pertinent studies and ongoing trials include:

• CROSS trial: Demonstrated improved overall survival with neoadjuvant chemoradiotherapy (carboplatin, paclitaxel, and 41.4 Gy radiotherapy) followed by surgery compared to surgery alone in patients with esophageal or junctional cancer.[20]
• RTOG 0436 trial: Investigated the addition of cetuximab (an anti-EGFR monoclonal antibody) to concurrent chemoradiotherapy in patients with unresectable esophageal cancer. The addition of cetuximab did not improve overall survival.[21]
• PROTECT-1402 trial: Evaluating the safety and efficacy of preoperative chemoradiation for resectable esophageal and junctional cancer and will compare preoperative FOLFOX and carboplatin-paclitaxel.[22]
• NRG-GI006 trial: Comparing Proton Beam Therapy (PBT) versus Intensity Modulated Photon Radiotherapy (iMRT ) in patients with locally advanced esophageal adenocarcinoma.[23]

Treatment Planning

In radiation therapy for esophageal cancer, precise targeting and dosing are crucial to maximize tumor control while minimizing damage to surrounding healthy tissues. The radiation prescription begins with defining the Gross Tumor Volume (GTV), which includes the primary tumor and any involved lymph nodes identified through diagnostic tools such as endoscopy, EUS, CT, and PET/CT. The next step involves establishing the Clinical Target Volume (CTV), which encompasses the GTV along with a margin to account for potential microscopic disease spread. Typically, this includes a 3- to 4-cm longitudinal margin and a 1-cm radial margin around the primary tumor, as well as the inclusion of elective regional lymph node regions. The Planning Target Volume (PTV) is then determined by adding an additional margin to the CTV to compensate for uncertainties in patient setup and organ motion, with a common margin range of 0.5 to 1 cm.

The primary dosimetric goal in radiation therapy is to deliver the prescribed radiation dose to the PTV while minimizing exposure to critical structures such as the lungs, heart, and spinal cord. These dose constraints vary depending on the prescribed radiation dose and the fractionation schedule being used. To achieve this dosimetric goal, various radiation techniques are employed. Three-dimensional conformal radiation therapy (3D-CRT) uses multiple-shaped beams to conform the radiation dose to the target volume, sparing adjacent normal tissues as much as possible. Intensity-modulated radiation therapy (IMRT) offers even greater precision, allowing for modulation of the intensity of each beam to further spare normal tissues while delivering a high dose to the tumor. Volumetric-modulated arc therapy (VMAT), a form of IMRT, continuously delivers radiation as the machine's gantry rotates around the patient, which can reduce treatment time. Proton beam therapy is another advanced technique that utilizes protons instead of photons, taking advantage of protons' unique dose deposition properties to potentially reduce the radiation dose to normal tissues surrounding the tumor, thus lowering the risk of treatment-related side effects.

Toxicity and Adverse Effect Management

The management of adverse effects and complications from radiation therapy in esophageal cancer is essential for patient comfort and long-term outcomes. Acute esophagitis is a common side effect characterized by inflammation of the esophagus, leading to pain and difficulty swallowing. Management involves the use of analgesics to control pain, antacids to reduce acid irritation, and dietary modifications such as soft and bland foods to minimize discomfort. Topical anesthetics and coating agents may also provide symptomatic relief. In severe cases where oral intake is significantly impaired, the temporary placement of a feeding tube might be necessary to ensure adequate nutrition.

Radiation dermatitis, another frequent side effect, manifests as skin irritation or burns in the area exposed to radiation. This condition can be managed by applying topical emollients to soothe the skin and mild steroids to reduce inflammation. Proper wound care is crucial to prevent infection, and patients are advised to avoid tight clothing and irritants that could exacerbate the condition.

Fatigue is a common systemic side effect during radiation therapy. Patients are encouraged to rest and adopt energy conservation strategies to manage fatigue effectively. Maintaining adequate hydration and proper nutrition is also critical to supporting the body’s energy levels and overall health during treatment.

Late complications from radiation therapy, such as strictures, perforation, and fistula formation, require more intensive interventions. Strictures, or narrowing of the esophagus, may be treated with endoscopic dilation to widen the passage or the placement of a stent to keep the esophagus open. Perforations or fistulas, which are abnormal connections that can form between the esophagus and other structures, may necessitate surgical repair depending on their severity and location.

Radiation can also lead to pulmonary complications such as radiation pneumonitis and fibrosis. Acute pneumonitis, an inflammatory condition of the lungs, may require treatment with steroids to reduce inflammation and oxygen support to assist with breathing. For long-term complications like pulmonary fibrosis, which involves the scarring of lung tissue, pulmonary rehabilitation, and ongoing monitoring are essential to manage symptoms and maintain lung function.

Medical Oncology

Neoadjuvant Therapy

Medical oncology plays a critical role in the management of esophageal cancer, with systemic therapy being a cornerstone of treatment across various stages of the disease. For patients with locally advanced esophageal cancer, characterized by tumor invasion into deeper layers (T2-4a) or involvement of regional lymph nodes (N+), neoadjuvant therapy is recommended to enhance surgical outcomes and improve overall survival. This typically involves neoadjuvant chemoradiotherapy, where chemotherapy (such as carboplatin and paclitaxel) is administered alongside concurrent radiation therapy. In cases of gastroesophageal junction (GEJ) adenocarcinoma, perioperative chemotherapy with the FLOT regimen—comprising fluorouracil, leucovorin, oxaliplatin, and docetaxel—can also be considered, although its use in pure esophageal cancer is less common.

Definitive Chemoradiotherapy

For patients with unresectable or medically inoperable esophageal cancer, definitive chemoradiotherapy serves as the primary treatment modality. This approach combines radiation therapy with concurrent chemotherapy to achieve local control of the tumor. The chemotherapy regimens commonly used in this setting include carboplatin with paclitaxel, or a combination of 5-fluorouracil (5-FU) and oxaliplatin. Capecitabine, an oral fluoropyrimidine, may be an alternative to 5-FU. Other chemotherapeutic options include cisplatin and 5-FU, which may be selected based on patient-specific factors and tolerance.

Palliative Systemic Therapy

In cases of metastatic or recurrent esophageal cancer, where the disease has spread beyond the esophagus or returned after initial treatment, palliative systemic therapy is the mainstay of care. The goal of this therapy is to prolong survival and improve the patient's quality of life. First-line treatment typically involves a combination of a fluoropyrimidine (such as 5-FU or capecitabine) and a platinum-based drug (cisplatin or oxaliplatin). For patients with HER2-positive tumors, trastuzumab, a targeted therapy, may be added to the regimen to enhance efficacy. In the second-line setting, after the disease progresses despite initial treatment, options include taxanes like paclitaxel or docetaxel, irinotecan, or ramucirumab, an anti-VEGFR2 monoclonal antibody. The choice of second-line therapy depends on factors such as the patient's prior treatment history and overall performance status.

Additionally, immunotherapy has emerged as a promising option for certain patients with advanced esophageal cancer. Checkpoint inhibitors, such as pembrolizumab and nivolumab, can be considered for tumors that exhibit high expression of programmed death-ligand 1 (PD-L1) or possess microsatellite instability-high (MSI-H) status. These agents enhance the body's immune response against cancer cells, offering a novel approach to treatment in this challenging disease.

Pertinent Studies and Ongoing Trials

Current therapies still being investigated include:

1. FLOT4 trial (Al-Batran et al, 2019)
   • A randomized trial comparing perioperative FLOT chemotherapy (5-FU, leucovorin, oxaliplatin, and docetaxel) versus ECF/ECX (epirubicin, cisplatin, and 5-FU or capecitabine) in patients with resectable gastric or gastroesophageal junction adenocarcinoma.
   • FLOT significantly improved overall survival (50 months versus 35 months) and progression-free survival compared to ECF/ECX.[24]
2. CheckMate 648 trial (NCT03143153)
   • A phase 3 trial comparing first-line chemotherapy (cisplatin and 5-FU) with or without nivolumab, or nivolumab plus ipilimumab, in patients with unresectable advanced, recurrent, or metastatic esophageal SCC.
   • The combination of nivolumab plus chemotherapy or nivolumab plus ipilimumab improved survival compared with chemotherapy in patients with tumor cell PD-L1 expression >1% or the overall population. 
   • The FDA approved nivolumab for the first-line treatment of patients with metastatic esophageal SCC in combination with fluoropyrimidine fluoropyrimidine- and platinum-based chemotherapy or in combination with ipilimumab on May 27, 2023.[25]
3. KEYNOTE-590 trial (NCT03189719)
   • A phase 3 trial comparing first-line chemotherapy (cisplatin and 5-FU) with or without pembrolizumab in patients with locally advanced or metastatic esophageal or gastroesophageal junction carcinoma.
   • The primary endpoints are overall survival and progression-free survival.
   • It demonstrated an overall survival benefit in the pembrolizumab arm, most pronounced in tumors with a combined positive score (CPS) >10. Pembrolizumab is currently listed in the National Comprehensive Cancer Network (NCCN) guidelines for use in CPS >10 tumors (both SCC and adenocarcinoma) in this setting, in combination with platinum and 5-FU; the FDA-approved pembrolizumab for all tumors irrespective of histology or programmed death ligand 1 (PD-L1) level on March 22, 2021.[26]

Evaluation of Systemic Therapy

The evaluation of systemic therapy in esophageal cancer involves continuous assessment of the patient's response to treatment and vigilant monitoring for potential toxicities. Periodic radiographic imaging (eg, CT scans or PET/CT) combined with endoscopic evaluation is essential to assess how well the tumor is responding to therapy. These assessments guide ongoing disease management, helping to determine whether the current treatment regimen should be continued, modified, or changed altogether.

Adverse Effect and Complication Management

Monitoring treatment-related toxicities is equally critical to ensure patient safety and optimize therapeutic outcomes. Hematologic toxicities, for example, require regular monitoring of blood counts. In cases of neutropenia (a dangerous drop in white blood cells), growth factors such as granulocyte colony-stimulating factor (G-CSF) may be administered to stimulate the production of white blood cells. Gastrointestinal toxicities, which are common with chemotherapy, necessitate a comprehensive approach to symptom management. This includes using antiemetics to control nausea and vomiting, antidiarrheals for diarrhea, and supportive care measures to address mucositis (inflammation of the mucous membranes). Neurologic toxicities, particularly peripheral neuropathy associated with taxanes and platinum-based agents, require close monitoring; dose adjustments may be necessary to prevent long-term damage.

Special attention must be paid to immune-related adverse events (irAEs) when treating patients with immunotherapy, which can affect various organ systems. These events result from the immune system becoming overactive and attacking healthy tissues. Prompt recognition and management of irAEs are crucial to prevent serious complications. Treatment strategies for irAEs may include the administration of corticosteroids to reduce inflammation, immunosuppressive agents to calm the immune response, and other supportive care measures tailored to the specific organ system involved. The severity of the irAE and the particular organ affected dictate the intensity and type of treatment required.

Staging

Esophageal cancer staging is crucial for determining prognosis and guiding treatment decisions. The most widely used staging system is the TNM (Tumor, Node, Metastasis) classification developed by the American Joint Committee on Cancer (AJCC). The current 8th edition of the AJCC staging system for esophageal and esophagogastric junction cancers incorporates both clinical (cTNM) and pathologic (pTNM) staging. The staging components are as follows:

• Tumor (T) stage
  • Tis: High-grade dysplasia
  • T1: Tumor invades the lamina propria, muscularis mucosae, or submucosa
    • T1a: Tumor invades the lamina propria or muscularis mucosae
    • T1b: Tumor invades the submucosa
  • T2: Tumor invades the muscularis propria
  • T3: Tumor invades the adventitia
  • T4: Tumor invades adjacent structures
    • T4a: Tumor invades the pleura, pericardium, azygos vein, diaphragm, or peritoneum
    • T4b: Tumor invades other adjacent structures such as the aorta, vertebral body, or trachea
• Node (N) stage
  • N0: No regional lymph node metastasis
  • N1: Metastasis in 1-2 regional lymph nodes
  • N2: Metastasis in 3-6 regional lymph nodes
  • N3: Metastasis in 7 or more regional lymph nodes
• Metastasis (M) stage
  • M0: No distant metastasis
  • M1: Distant metastasis

The overall stage grouping for esophageal cancer, based on the TNM classification, is as follows:

• Stage 0: Tis N0 M0
• Stage I: T1 N0-1 M0
• Stage II: T2 N0-1 M0 or T3 N0 M0
• Stage III: T1-2 N2 M0, T3 N1-2 M0, or T4a N0-2 M0
• Stage IVA: T4b Any N M0 or Any T N3 M0
• Stage IVB: Any T Any N M1

In addition to the TNM staging, other factors that influence prognosis and treatment decisions include:

• Histologic subtype
  • SCC
  • Adenocarcinoma
  • Other rare subtypes (eg, adenosquamous carcinoma, small cell carcinoma)
• Grade (G)
  • G1: Well-differentiated
  • G2: Moderately differentiated
  • G3: Poorly differentiated
  • G4: Undifferentiated
• Location
  • Cervical esophagus
  • Upper thoracic esophagus
  • Middle thoracic esophagus
  • Lower thoracic esophagus
  • Esophagogastric junction (Siewert types I, II, and III)

Prognosis

The prognosis of esophageal cancer depends on various factors, including the stage at diagnosis, histologic subtype, grade, and patient characteristics such as age and overall health. Despite advances in treatment, the overall prognosis for esophageal cancer remains poor, with a 5-year survival rate of about 20% for all stages combined.[27] However, prognosis varies widely based on the stage at diagnosis and other prognostic factors, including:

• Stage at diagnosis
  • Localized (Stage 0-I): 5-year survival rate of 45% to 50%
  • Regional (Stage II-III): 5-year survival rate of 20% to 30%
  • Distant (Stage IV): 5-year survival rate of <5% [28][27]
• Histologic subtype
  • Squamous cell carcinoma: Generally has a worse prognosis compared to adenocarcinoma, particularly in Western countries, due to the higher likelihood of presenting at an advanced stage and the association with smoking and alcohol consumption.
  • Adenocarcinoma: Has a slightly better prognosis compared to SCC, particularly when diagnosed at an early stage. However, the incidence of adenocarcinoma has been rising in recent years, and it now accounts for the majority of esophageal cancer cases in Western countries.
• Grade
  • Well-differentiated (G1) tumors generally have a better prognosis compared to poorly differentiated (G3) or undifferentiated (G4) tumors.
• Location
  • Tumors in the upper and middle thirds of the esophagus tend to have a worse prognosis compared to those in the lower third or esophagogastric junction due to the greater likelihood of presenting at an advanced stage and the technical challenges associated with surgical resection.
• Treatment response
  • Patients who achieve a complete pathologic response (no residual tumor) after neoadjuvant chemoradiotherapy have a significantly better prognosis compared to those with residual disease.
  • Patients who undergo a complete (R0) surgical resection have a better prognosis compared to those with microscopic (R1) or macroscopic (R2) residual disease.
• Patient factors
  • Older age, male gender, and the presence of comorbidities such as cardiovascular disease, pulmonary disease, and liver disease are associated with a worse prognosis.
  • Performance status and nutritional status also influence prognosis, with better outcomes observed in patients with good performance status and adequate nutritional intake.
• Molecular markers
  • Specific molecular markers, including HER2 overexpression (in adenocarcinoma) and PD-L1 expression, may influence prognosis and response to targeted therapies or immunotherapy.
  • Although rare in esophageal cancer, microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status is associated with a better prognosis and response to immunotherapy.

Complications

Esophageal cancer can lead to numerous complications that profoundly affect both the quality of life and survival of patients. These complications can arise from the primary tumor's growth, the spread of metastatic disease, or as a consequence of the various treatments administered to manage the cancer.

Obstruction

One of the most common complications is obstruction. As the tumor enlarges, it can progressively narrow the esophageal lumen, making it increasingly difficult for patients to swallow. This dysphagia often starts with difficulty swallowing solid foods and can advance to a point where even liquids are challenging to ingest. In severe cases, complete obstruction can occur, necessitating nutritional support through feeding tubes or parenteral nutrition to ensure the patient receives adequate nourishment. Interventions such as esophageal stents or endoscopic dilation may be required to restore some degree of patency in the esophagus to alleviate the symptoms of obstruction.

Aspiration

Another serious complication is aspiration, which occurs when the obstruction or impaired motility of the esophagus leads to the inadvertent inhalation of food or liquids into the lungs. This can result in aspiration pneumonia, the formation of lung abscesses, or acute respiratory distress syndrome (ARDS), all of which are potentially life-threatening and require prompt medical attention.

Bleeding

Bleeding is another major concern in patients with esophageal cancer. Tumors can invade and erode nearby blood vessels, leading to significant bleeding manifested as hematemesis (vomiting blood) or melena (black, tarry stools). Massive bleeding episodes can precipitate hypovolemic shock, a critical condition that may necessitate urgent endoscopic intervention or even surgical management to control the bleeding.

Fistula Formation

Fistula formation is a severe complication that can occur when advanced tumors invade adjacent structures, such as the trachea or bronchi. This invasion can create tracheoesophageal or bronchoesophageal fistulae, leading to recurrent aspiration pneumonia, lung abscesses, or sepsis, all of which are difficult to manage and may require endoscopic or surgical repair to prevent further complications.

Perforation

Esophageal perforation is another life-threatening issue that can arise due to tumor erosion or iatrogenic injury during endoscopic procedures. If the esophagus perforates, it can lead to mediastinitis (inflammation of the chest cavity), sepsis, or death if not rapidly recognized and treated. Perforation management typically involves administering antibiotics and often requires surgical intervention to repair the defect.

Metastatic Complications

Metastatic complications are also common in esophageal cancer, as the disease can spread to distant organs such as the lungs, liver, bones, and brain. These metastases can lead to a variety of organ-specific symptoms, including cough and difficulty breathing in cases of lung metastases, abdominal pain and jaundice with liver involvement, bone pain and fractures when the bones are affected, and neurological deficits if the cancer spreads to the brain.

Treatment-Related Complications

The treatment of esophageal cancer itself can lead to a range of complications. Surgical interventions, for example, can result in postoperative issues such as anastomotic leaks, pulmonary complications, cardiac arrhythmias, and chylothorax. Long-term surgical complications include persistent dysphagia, gastroesophageal reflux, dumping syndrome (rapid gastric emptying), and nutritional deficiencies due to the altered anatomy and function of the digestive tract.

Chemotherapy, a common component of treatment, is associated with several adverse effects. Myelosuppression can lead to reduced levels of blood cells, increasing the risk of infection, anemia, and bleeding. Nausea, vomiting, and diarrhea are also frequent side effects, contributing to dehydration and electrolyte imbalances. Peripheral neuropathy, characterized by tingling, numbness, or pain in the hands and feet, is another potential complication, particularly with certain chemotherapeutic agents. Additionally, specific drugs like 5-fluorouracil can cause cardiac toxicity, leading to complications such as angina or arrhythmias, while cisplatin is known for its potential to cause renal toxicity and ototoxicity.

Radiation therapy, another critical modality in the treatment of esophageal cancer, also presents its own set of challenges. During treatment, patients may experience acute complications such as esophagitis, leading to pain and difficulty swallowing. Mucositis and skin reactions are also common. Over time, late complications can develop, including the formation of esophageal strictures that further impede swallowing. More severe late-stage complications may involve perforation and fistula formation.

Nutritional Complications

Nutritional complications are a significant concern for patients with esophageal cancer. Dysphagia, anorexia, and cachexia can lead to profound malnutrition. This malnutrition can weaken the immune system, impair wound healing, and reduce the patient's ability to tolerate ongoing cancer treatments. In cases where swallowing becomes too difficult, feeding tubes may be necessary to ensure adequate nutrition. However, it is crucial to avoid placing gastric tubes before surgery, and the decision on the type of feeding tube should be made in consultation with the treating surgeon. Jejunostomy tubes are often preferred for long-term nutritional support in these patients.

Psychological Complications

Psychological complications are also prevalent among patients with esophageal cancer. The diagnosis, along with the demanding treatment and the uncertain prognosis, can lead to significant emotional distress. Anxiety and depression are common, impacting the patient's mental health and overall well-being. To address these concerns, psychosocial support and counseling are essential components of care. Palliative care also plays a crucial role in improving the quality of life for these patients, helping them cope with the challenges they face throughout their treatment journey.