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Chemotherapy and Radiotherapy As Primary Treatment of Esophageal Cancer

Geoffrey Y. Ku, David H. Ilson
Chemotherapy and Radiotherapy As Primary Treatment of Esophageal Cancer is a topic covered in the Pearson's General Thoracic.

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Key Points

  • In esophageal and gastroesophageal junction cancer, single-agent chemotherapy achieves responses in 10-20% of patients and combination chemotherapy in 35-45% of patients, with a median survival of 10-12 months.
  • The addition of trastuzumab, a monoclonal antibody against Her2, to first-line chemotherapy with a fluoropyrimidine/platinum doublet is standard for Her2 positive tumors. In the second-line setting, the anti-vascular endothelial growth factor receptor-2 antibody ramucirumab is active as monotherapy or when combined with paclitaxel chemotherapy.
  • Immune checkpoint inhibitors are undergoing intensive evaluation. To-date, one phase III study in East Asian chemorefractory patients has shown benefit for nivolumab, an anti-programmed death-1 antibody. These drugs have the potential to transform the treatment of this disease.
  • The addition of docetaxel to cisplatin and fluorouracil offers marginal improvement in survival, at the expense of significant additional hematologic toxicity. Although epirubicin is routinely added to a fluoropyrimidine/platinum doublet, there are no randomized data to indicate a benefit.
  • In locally advanced esophageal cancer, primary concurrent chemoradiation achieves curative potential in patients with squamous cell carcinoma and long-term disease control is also achieved with chemoradiation in a proportion of patients with adenocarcinoma.
  • The addition of surgery to primary chemoradiation reduces local recurrence without a clear impact on survival in squamous cell carcinoma patients. Because of lower pathologic complete response to chemoradiation in adenocarcinoma of the esophagus, surgery is more often considered as part of primary management.
  • Although uncertainty remains about the preferred pre-operative therapy in esophageal cancer, pre-operative chemoradiation may offer benefits over pre-operative chemotherapy.
  • Higher radiation therapy doses above conventional 5,040 cGy or the addition of induction chemotherapy before radiation, do not appear to improve treatment outcome.
  • The use of PET scan to guide the choice of chemotherapy with radiation appears to be a promising approach.

Esophageal cancer, an uncommon but highly virulent malignancy in the United States, will be responsible for 15,690 deaths in 2017.[1] The majority of patients who have esophageal cancer die of the disease, which represents the seventh leading cause of cancer death in American men. Although esophageal cancer remains relatively uncommon in the United States, it is a major cause of cancer worldwide, especially in East Asia and other developing countries. Particularly high incidence is observed in northern China[2], the Caspian littoral[3] and the Transkei province of South Africa.[4] The epidemiologic factors responsible for the geographic variability in incidence of esophageal cancer, including potential dietary and environmental carcinogens, remain under active investigation. While other etiologic factors remain unclarified, an association with the abuse of tobacco and alcohol and the development of squamous cell carcinoma (SCC) of the esophagus has been clearly established.[5] Human papilloma virus infection, which is increasingly linked to SCCs of the oropharynx, has not been clearly linked to esophageal SCC.[6]

SCC and adenocarcinoma account for 98% of all cases of esophageal cancer. SCCs typically occur in the proximal two-thirds of the esophagus while adenocarcinomas are found in the distal third and at the gastroesophageal junction (GEJ). While cases of SCC have steadily declined in the U.S. because of a decrease in tobacco and alcohol abuse[5], the incidence of adenocarcinoma of the distal esophagus, GEJ and gastric cardia has increased 4% to 10% per year among U.S. men since 1976 so that it now comprises 75% of all esophageal tumors.[7],[8]

Changing epidemiologic factors account for the increasing incidence of adenocarcinomas, which are now more common because of an increased incidence of gastroesophageal reflux disease (GERD)[9] and obesity.[10] Helicobacter pylori, implicated in peptic ulcer disease and associated with an increased risk of gastric cancer, has not been implicated in the pathogenesis of esophageal adenocarcinoma. In fact, because infection with H. pylori may lead to a reduction in gastric acidity in association with atrophic gastritis, there has been speculation that a decline in the prevalence of H. pylori infection may predispose to an increase in GERD and, therefore, in the incidence of GEJ adenocarcinomas.[11],[12]

For locally advanced esophageal cancer, surgery remains the mainstay of treatment. Various reviews have reported 5-year overall survival (OS) rates from 10% up to 30% to 40% with surgical resection alone.[13],[14] Numerous studies – that have included both adenocarcinoma and SCC histologies and focused on tumors from the esophagus/GEJ and/or stomach – have evaluated pre- and post-operative strategies for locally advanced disease, including chemotherapy or chemoradiation. As a whole, these studies show that some treatment in addition to surgery clearly improves outcomes.

Approximately 50% of patients with a diagnosis of esophageal cancer present with overt metastatic disease, and chemotherapy is the mainstay of palliation in this setting. With the high likelihood of the development of metastatic disease in patients with initial locoregional cancer, systemic chemotherapy is ultimately required in the majority of patients. This chapter focuses on the use of systemic chemotherapy in the treatment of esophageal cancer and of radiation-based therapy in the primary management of locally advanced esophageal cancer.

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Key Points

  • In esophageal and gastroesophageal junction cancer, single-agent chemotherapy achieves responses in 10-20% of patients and combination chemotherapy in 35-45% of patients, with a median survival of 10-12 months.
  • The addition of trastuzumab, a monoclonal antibody against Her2, to first-line chemotherapy with a fluoropyrimidine/platinum doublet is standard for Her2 positive tumors. In the second-line setting, the anti-vascular endothelial growth factor receptor-2 antibody ramucirumab is active as monotherapy or when combined with paclitaxel chemotherapy.
  • Immune checkpoint inhibitors are undergoing intensive evaluation. To-date, one phase III study in East Asian chemorefractory patients has shown benefit for nivolumab, an anti-programmed death-1 antibody. These drugs have the potential to transform the treatment of this disease.
  • The addition of docetaxel to cisplatin and fluorouracil offers marginal improvement in survival, at the expense of significant additional hematologic toxicity. Although epirubicin is routinely added to a fluoropyrimidine/platinum doublet, there are no randomized data to indicate a benefit.
  • In locally advanced esophageal cancer, primary concurrent chemoradiation achieves curative potential in patients with squamous cell carcinoma and long-term disease control is also achieved with chemoradiation in a proportion of patients with adenocarcinoma.
  • The addition of surgery to primary chemoradiation reduces local recurrence without a clear impact on survival in squamous cell carcinoma patients. Because of lower pathologic complete response to chemoradiation in adenocarcinoma of the esophagus, surgery is more often considered as part of primary management.
  • Although uncertainty remains about the preferred pre-operative therapy in esophageal cancer, pre-operative chemoradiation may offer benefits over pre-operative chemotherapy.
  • Higher radiation therapy doses above conventional 5,040 cGy or the addition of induction chemotherapy before radiation, do not appear to improve treatment outcome.
  • The use of PET scan to guide the choice of chemotherapy with radiation appears to be a promising approach.

Esophageal cancer, an uncommon but highly virulent malignancy in the United States, will be responsible for 15,690 deaths in 2017.[1] The majority of patients who have esophageal cancer die of the disease, which represents the seventh leading cause of cancer death in American men. Although esophageal cancer remains relatively uncommon in the United States, it is a major cause of cancer worldwide, especially in East Asia and other developing countries. Particularly high incidence is observed in northern China[2], the Caspian littoral[3] and the Transkei province of South Africa.[4] The epidemiologic factors responsible for the geographic variability in incidence of esophageal cancer, including potential dietary and environmental carcinogens, remain under active investigation. While other etiologic factors remain unclarified, an association with the abuse of tobacco and alcohol and the development of squamous cell carcinoma (SCC) of the esophagus has been clearly established.[5] Human papilloma virus infection, which is increasingly linked to SCCs of the oropharynx, has not been clearly linked to esophageal SCC.[6]

SCC and adenocarcinoma account for 98% of all cases of esophageal cancer. SCCs typically occur in the proximal two-thirds of the esophagus while adenocarcinomas are found in the distal third and at the gastroesophageal junction (GEJ). While cases of SCC have steadily declined in the U.S. because of a decrease in tobacco and alcohol abuse[5], the incidence of adenocarcinoma of the distal esophagus, GEJ and gastric cardia has increased 4% to 10% per year among U.S. men since 1976 so that it now comprises 75% of all esophageal tumors.[7],[8]

Changing epidemiologic factors account for the increasing incidence of adenocarcinomas, which are now more common because of an increased incidence of gastroesophageal reflux disease (GERD)[9] and obesity.[10] Helicobacter pylori, implicated in peptic ulcer disease and associated with an increased risk of gastric cancer, has not been implicated in the pathogenesis of esophageal adenocarcinoma. In fact, because infection with H. pylori may lead to a reduction in gastric acidity in association with atrophic gastritis, there has been speculation that a decline in the prevalence of H. pylori infection may predispose to an increase in GERD and, therefore, in the incidence of GEJ adenocarcinomas.[11],[12]

For locally advanced esophageal cancer, surgery remains the mainstay of treatment. Various reviews have reported 5-year overall survival (OS) rates from 10% up to 30% to 40% with surgical resection alone.[13],[14] Numerous studies – that have included both adenocarcinoma and SCC histologies and focused on tumors from the esophagus/GEJ and/or stomach – have evaluated pre- and post-operative strategies for locally advanced disease, including chemotherapy or chemoradiation. As a whole, these studies show that some treatment in addition to surgery clearly improves outcomes.

Approximately 50% of patients with a diagnosis of esophageal cancer present with overt metastatic disease, and chemotherapy is the mainstay of palliation in this setting. With the high likelihood of the development of metastatic disease in patients with initial locoregional cancer, systemic chemotherapy is ultimately required in the majority of patients. This chapter focuses on the use of systemic chemotherapy in the treatment of esophageal cancer and of radiation-based therapy in the primary management of locally advanced esophageal cancer.

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Last updated: January 9, 2020