Esophageal Cancer Treatment & Management

Nonoperative therapy is usually reserved for patients who have esophageal carcinoma and are not candidates for surgery due to clinical conditions or advanced disease. The goal of therapy for these patients is palliation of dysphagia, allowing them to eat. A single best method of palliation cannot be applied to every situation. Most patients require more than one palliative method to sustain lumen patency during the course of their disease.

The most appropriate method to control dysphagia should be tailored for each patient individually, depending on tumor characteristics, patient preference, and the specific expertise of the physician. The following treatment modalities are available to help achieve this goal:

Chemotherapy as a single modality has limited use. Only a few patients achieve a modest and short-lived response.

Radiation therapy is successful in relieving dysphagia in approximately 50% of patients. In patients with advanced esophageal cancer, the preoperative combination of chemotherapy and radiotherapy has shown good results. In a large multicenter study, Herskovich and colleagues reported a 2-year survival rate of 38%, with a median survival of 12.5 months.^[13] See the practice guideline Combined Modality Radiotherapy and Chemotherapy in Nonsurgical Management of Localized Carcinoma of the Esophagus.^[14]

Laser therapy (Nd:YAG laser) can help achieve temporary relief of dysphagia in as many as 70% of patients. Multiple sessions are usually required to keep the esophageal lumen patent.

Patients may be intubated with expandable metallic stents, which can be deployed by endoscopy under fluoroscopic guidance and can keep the esophageal lumen patent. They are particularly useful when a tracheoesophageal fistula is present.

In 2006, a Cochrane review tried to assess the effectiveness of chemotherapy versus best supportive care or different chemotherapy regimens against each other, in metastatic esophageal carcinoma. The authors found that there was no consistent benefit of any specific chemotherapy regimen.^[15] Chemotherapy agents with promising response rates and tolerable toxicity are cisplatin, 5-fluorouracil (5-FU), paclitaxel, and anthracyclines. Future trials comparing palliative treatment modalities should assess quality of life with validated quality of life measures.

Photodynamic therapy (PDT) offers an interesting nonsurgical form of therapy. PDT refers to the administration of photosensitizing chromophores, which are selectively retained by dysplastic malignant tissue. Light is delivered in the area where the photons are absorbed by the photosensitizer. The photosensitizer becomes photoexcited and transfers its energy to a chemical substrate that causes biologic damage to the abnormal tissue.

Recent studies have demonstrated that PDT alone or with Nd:YAG laser thermal ablation combined with long-term acid inhibition provides an effective endoscopic therapy to (1) eliminate Barrett mucosal dysplasia and superficial esophageal cancer and (2) reduce the extent of and, in some cases, eliminate Barrett mucosa. A drawback of PDT is the formation of esophageal strictures in 34% of patients. Therefore, even though the initial results are encouraging, this form of treatment is still considered experimental.

See related CME at Highlights in Head and Neck Cancer.

Because most patients undergo surgery when lymph node metastases are already present, the 5-year survival rate for this disease remains quite low. Chemotherapy and radiotherapy (alone or in combination) have been used before or after surgery in the attempt to improve survival.

The aims of preoperative (neoadjuvant) chemotherapy are to reduce the bulk of the primary tumor before surgery to facilitate higher curative resection rates and to eliminate or delay the appearance of distant metastases. Note that chemotherapy concurrently administered with radiotherapy has demonstrated a pathologic response rate of as high as 30% but has been associated with increased operative morbidity and mortality. While chemotherapeutic management of squamous cell malignancies is generally based on cisplatin use, the chemotherapeutic choices in esophageal adenocarcinoma have been extrapolated from the chemotherapy experience in patients with adenocarcinoma of the stomach.

Previous reports of induction chemotherapy in esophageal cancer often are difficult to interpret because of varying definitions of response (eg, symptomatic improvement, decrease in tumor length after barium esophagram, subjective determination of improvement at endoscopy or CT scan). Even the complete response, often defined as endoscopic biopsies or cytologies with negative findings, is hampered by the inability to assess the true extent of the transmural disease. Not surprisingly, reported responses are quite variable, ranging from 20-65%, with clinical complete responses in as many as 40% of patients.

Neoadjuvant therapy consists of a combination of radiotherapy (approximately 45 Gy) and chemotherapy (cisplatin and 5-fluorouracil).

While the radiotherapy acts locally at the tumor site, the chemotherapy acts on tumor cells that have already spread. This combination therapy is usually administered over a 45-day period and is followed by esophageal resection after an interval of approximately 4 weeks.

The results of many studies suggest that approximately 15-20% of patients have a complete response to therapy because no tumor is found in the specimen by the pathologists; these patients have a definite improvement in survival. The remaining patients, in whom a partial response or no response has occurred, have no benefit.

A randomized trial conducted by Urba that compared preoperative chemoradiation (ie, cisplatin, fluorouracil, and vinblastine) versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

Walsh conducted a prospective randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery and reported that patients who received induction chemotherapy (ie, 2 courses of cisplatin and fluorouracil, 1 course of radiotherapy at 40 Gy) followed by surgery had improved survival compared to those who had surgery alone. Of the patients who underwent surgery after multimodal therapy, 25% had complete responses as determined pathologically. Their median survival was 16 months, as compared with 11 months for those assigned to surgery alone. The survival advantage was even more evident at 3 years (32% vs 6%, P = .01).^[16]

Bosset treated patients with induction chemoradiotherapy (ie, cisplatin and 18.5 Gy) and surgery and with surgery alone, reporting that in patients with squamous cell carcinoma of the esophagus, preoperative chemoradiotherapy did not improve overall survival, but it did prolong disease-free survival and survival deemed free of local disease.^[17]

Herskovic reported that combined therapy increased the survival of patients with squamous cell carcinoma or adenocarcinoma of the esophagus, stages T1-3 N0-1 M0, compared with radiotherapy alone.^[13]

A meta-analysis of randomized trial data identified 10 randomized comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209) and 8 trials of neoadjuvant chemotherapy versus surgery alone (n=1724) in patients with local operable esophageal carcinoma. The authors found that the hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0.81 (95% CI 0.70-0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histological tumor types: 0.84 (0.71-0.99; p=0.04) for squamous-cell carcinoma (SCC), and 0.75 (0.59-0.95; p=0.02) for adenocarcinoma. The hazard ratio for neoadjuvant chemotherapy was 0.90 (0.81-1.00; p=0.05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with SCC (hazard ratio 0.88 [0.75-1.03]; p=0.12), although there was a significant benefit for those withadenocarcinoma(0.78[0.64-0.95];p=0.014).

The authors concluded that significant survival benefit was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the esophagus.

The goal for the future is to identify patients who are likely to benefit from neoadjuvant therapy.

An article from Scheer et al described the benefit of a pathologic complete response after neoadjuvant chemoradiotherapy in the treatment of esophageal and gastroesophageal cancer.^[18] Pathologic complete response significantly increases overall survival, as patients with pathologic complete response are 2-3 times more likely to survive than those with residual tumor at esophagectomy. Furthermore, 33-36% more patients survive when pathologic complete response is achieved.

Adjuvant therapy does not appear to improve survival. No survival benefit is obtained when radiation and chemotherapy are administered postoperatively.

A study by Rao et al identified groups of tumors with distinct gene expression profiles, which may allow for tailored treatment protocols with further study.^[19]

Esophageal resection (esophagectomy) remains a crucial part of the treatment of esophageal cancer. It is used in patients who are considered candidates for surgery. It no longer is used for palliation of symptoms because other treatment modalities are now available for relieving dysphagia (see Medical Care). An esophagectomy can be performed by using an abdominal and a cervical incision with blunt mediastinal dissection through the esophageal hiatus (ie, transhiatal esophagectomy [THE]) or by using an abdominal and a right thoracic incision (ie, transthoracic esophagectomy [TTE]).

THE offers the advantage of avoiding a chest incision, which can be a prolonged cause of discomfort and can further aggravate the condition of patients with compromised respiratory function. After removal of the esophagus, continuity of the gastrointestinal tract is usually reestablished using the stomach.

Some authors have questioned the validity of THE as a cancer operation because part of the operation is not performed under direct vision and fewer lymph nodes are removed compared to TTE. However, many retrospective and 2 prospective studies have shown no difference in survival between the operations, suggesting that the type of operation is not the factor influencing survival but, rather, the stage of the cancer at the time the operation is performed.

The morbidity associated with the operation is due mostly to cardiac, respiratory, and septic complications. As with other complex operations (eg, cardiac operations, resection of the pancreas or liver), a low mortality rate is achieved in centers with personnel who have more clinical experience (ie, those in high-volume centers). The better results (as compared to low-volume centers) are due to a team approach, during which expert surgeons work with intensivists, cardiologists, pulmonologists, radiologists, and nurses who have experience and expertise. For instance, in California from 1990-1994, only 5 centers had a mortality rate of 5% or less for esophageal resection for cancer, while the average mortality rate in the state was approximately 18%.

A study by Nederlof et al found that single-layered, hand-sewn, cervical end-to-side (ETS) anastomosis has a lower anastomotic stricture rate than end-to-end (ETE) anastomosis. However, ETS was associated with increased anastomotic leakage and longer in-hospital stay.^[20]

Relevant anatomy includes the following:

• The esophagus is a muscular tube that extends from the level of the 7th cervical vertebra to the 11th thoracic vertebra. The esophagus can be divided into 3 anatomic parts: the cervical esophagus, the thoracic esophagus, and the abdominal esophagus.
• The blood supply of the cervical esophagus is derived from the inferior thyroid artery, while the blood supply for the thoracic esophagus comes from the bronchial arteries and the aorta. The abdominal esophagus is supplied by branches of the left gastric artery and inferior phrenic artery.
• Venous drainage of the cervical esophagus is through the inferior thyroid vein, while the thoracic esophagus drains via the azygous vein, the hemiazygous vein, or the bronchial veins. The abdominal esophagus drains through the coronary vein.
• The esophagus is characterized by a rich network of lymphatic channels in the submucosa that can facilitate the longitudinal spread of neoplastic cells along the esophageal wall. Lymphatic drainage is to cervical nodes, tracheobronchial and mediastinal nodes, and gastric and celiac nodes.

Indications for surgery include the following:

• Diagnosis of esophageal cancer must be made in a patient who is a candidate for surgery.
• Surgery is indicated when high-grade dysplasia is present in a patient with Barrett esophagus. As many as 50-70% of such patients are found to have cancer when the esophagus is resected.

Contraindications to surgery include the following:

• Metastasis to N2 nodes (ie, celiac, cervical, or supraclavicular lymph nodes) or solid organs (eg, liver, lungs) is a contraindication.
• Invasion of adjacent structures (eg, recurrent laryngeal nerve, tracheobronchial tree, aorta, pericardium) is a contraindication.
• Severe associated comorbid conditions (eg, cardiovascular disease, respiratory disease) can decrease a patient's chances of surviving an esophageal resection.
• Cardiac function and respiratory function are carefully evaluated preoperatively. A forced expiratory volume in 1 second of less than 1.2 L and a left ventricular ejection fraction of less than 0.4 are relative contraindications to the operation.

TTE involves the following:

• The patient is placed supine on the operating room table. An arterial line, a central venous catheter, a Foley catheter, and a dual-lumen endotracheal tube are placed. Preoperative antibiotics are administered. An upper midline incision is made.
• After exploring the peritoneal cavity for metastatic disease (if metastases are found, the operation is not continued), the stomach is mobilized. The right gastric and the right gastroepiploic arteries are preserved, while the short gastric vessels and the left gastric artery are divided.
• Next, the gastroesophageal junction is mobilized, and the esophageal hiatus is enlarged. A pyloromyotomy is performed, and a feeding jejunostomy is placed for postoperative nutritional support.
• After closure of the abdominal incision, the patient is repositioned in the left lateral decubitus position and a right posterolateral thoracotomy is performed in the fifth intercostal space.
• The azygos vein is divided to allow full mobilization of the esophagus. The stomach is delivered into the chest through the hiatus and is then divided approximately 5 cm below the gastroesophageal junction.
• An anastomosis (hand-sewn or stapled) is performed between the esophagus and the stomach at the apex of the right chest cavity. Then, the chest incision is closed.

THE involves the following:

• Preoperative details are similar to those of TTE, with the exception of a single rather than a double-lumen endotracheal tube. The neck is prepared in the operative field.
• The abdominal part of the operation is identical to the TTE; however, dissection of the esophagus is performed through the enlarged esophageal hiatus without opening the right chest. The esophagus is mobilized in this fashion all the way to the thoracic inlet.
• Then, a 6-cm incision is made in the left side of the neck. The internal jugular vein and carotid artery are retracted laterally, and the esophagus is identified and isolated posterior to the airway. To prevent injury to the left recurrent laryngeal nerve, no mechanical retractors are used to retract the trachea.
• Next, after resection of the proximal stomach and thoracic esophagus, the remaining stomach is pulled up through the posterior mediastinum until it reaches the remaining esophagus at the cervical level.
• Then, a hand-sewn anastomosis is performed, and a small drain is placed in the neck alongside the anastomosis. The abdominal and neck incisions are closed.

Advantages of minimally invasive surgery include the following:

• The use of laparoscopic or thoracoscopic techniques has revolutionized the treatment of benign esophageal disorders such as achalasia and GERD.
• When compared to open surgery, the hospital stay is shorter, the postoperative discomfort is reduced, and the recovery time is much faster. In the near future, these techniques might find a place in the treatment of esophageal cancer, reducing the morbidity due to cardiac and respiratory complications.

A study by Uenosono et al found that sentinel node mapping can be applied to patients with cT1 and cN0 esophageal cancer and may facilitate less invasive surgery with reduction of lymphadenectomy.^[21]

Endoscopic mucosal resection (EMR) is a modern, attractive option for the treatment of superficial esophageal cancers. High-grade dysplasia and mucosa-limited neoplasms are candidates for EMR due to the low risk of node metastasis.

In 2011, Professor Alex Seifalian et al of the University College of London produced the first completely synthetic trachea. Made of nanocomposite material, the synthetic trachea was transplanted into a patient whose own windpipe was damaged by cancer. The operation was performed in Sweden at the Karolinska University Hospital in conjunction with the Karolinska Institute.^[22]

The synthetic windpipe's wide and porous surface area allowed the stem cells taken from the patient's bone marrow and lining cells from the nose to be seeded with the patient's tissue. Within days, a synthetic windpipe, which essentially was the patient's own, was created in a revolving bioreactor and then transplanted into the patient. This technique allows the patient to provide the stem cells to create the new trachea, avoiding a long waiting period to find a donor and eliminating the need for antirejection drugs that other transplant patients must take.

A study by Fogh et al examined the use of induction chemoradiotherapy followed by surgery a strategy that is widely used in treating esophageal cancer. The study compared the perioperative morbidity and mortality of patients aged 70 years or older with those of patients younger than 70 years who underwent chemoradiotherapy followed by esophagectomy. The study found no significant differences in mortality or morbidity in elderly patients. Thus, the authors suggest using this strategy in elderly patients.^[23]