by Dr. C.H. Weaver M.D. updated 1/2023
Patients with stage IV esophageal cancer have metastatic cancer that has spread to distant sites. Optimal treatment of patients with stage IV esophageal cancer often requires more than one therapeutic approach. Thus, it is important for patients to be treated at a medical center that can offer multi-modality treatment involving medical oncologists, radiation oncologists, surgeons, gastroenterologists and nutritionists. Treatment approaches are primarily directed at controlling the symptoms of cancer and prolonging survival. A number of treatment options are currently utilized alone or in combination to achieve optimal results.
Current research suggests that combining immunotherapy with chemotherapy can reduced the risk of death by 27% compared to chemotherapy when used as the initial treatment of esophageal cancer. In addition there are specific treatments that can be administered that can result in short-term benefit and improvement in nutrition.1
Systemic Therapy & Minimal Residual Disease
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Many patients have small amounts of cancer that have spread away from their site of origin or remain after surgery. These cancer cells are difficult to detect and are referred to as micro-metastatic or minimal residual disease (MRD). Their presence is what causes a cancer recurrence following local treatment with surgery and/or radiation therapy. An effective systemic treatment is needed to cleanse the body of MRD to improve a patient’s duration of survival and potential for cure.
Systemic Therapy: Precision Cancer Medicines, Chemotherapy & Immunotherapy
Precision cancer medicines, chemotherapy and immunotherapy are all forms of systemic treatment that circulate in the blood and can destroy cancer cells throughout the body. Chemotherapy, once the only systemic therapy is increasingly being replaced by more targeted precision cancer medicines and immunotherapy. The use of precision medicines and immunotherapy is determined by performing biomarker tests that identify which therapy will be most effective. Cancer patients should undergo NGS testing to look for biomarkers that can be targeted with precision medicines. Precision cancer medicines and immunotherapies can be used both instead of and in addition to chemotherapy.
Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, and can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill. Chemotherapy is not “targeted” to the cancer and acts more generally in the body’s cells which can result in more side effects.
Single chemotherapy drugs such as the taxanes (paclitaxel and Taxotere®) may be the most active single chemotherapy drugs for the treatment of esophageal cancer, with complete remissions occurring in up to 15% of patients. Currently available combination chemotherapy treatment for stage IV cancer results in complete remission in up to 20% of patients, with average survival of 8-12 months. As newer drugs, such as the taxanes, Camptosar®, and Gemzar®, are incorporated into regimens, this may continue to improve.
Immunotherapy is also a standard treatment for cancer and can be used alone or in combination with other systemic therapies. Immunotherapy either works to stimulate your immune system to attach the cancer or remove obstacles that prevent your immune system from working normally.
Checkpoint Inhibitor Immunotherapy
Checkpoint Inhibitors are precision cancer immunotherapy drugs that help to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. Programmed death (PD)-1 and PD-L1 are proteins that inhibit certain types of immune responses that allow cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor blocks the PD-1 and PD-L1 pathway and restores an immune cells’ ability to recognize and fight the cancer cells. Checkpoint inhibitors are most effective when high levels of PD-L1 are present and in individuals with a high tumor mutational burden (TMB). A diagnostic test to measure the level of PD-L1 is available.
Data from Phase 3 clinical trials evaluating checkpoint inhibitors in combination with platinum-based chemotherapy for the first-line treatment of patients with locally advanced or metastatic esophageal and gastroesophageal junction (GEJ) cancer was featured during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Virtual Congress in 2020. The study found that checkpoint inhibitor immunotherapy when combined with chemotherapy improved the response to treatment, delayed cancer progression, and prolonged survival.7
KEYNOTE-590 is a Phase 3, randomized, double-blind clinical trial that enrolled 749 patients with locally advanced or metastatic esophageal carcinoma (including esophageal squamous cell carcinoma and adenocarcinoma of the esophagus) to compare treatment with Keytruda in combination with chemotherapy or chemotherapy alone regardless of histology or PD-L1 expression status.
At the first interim analysis, after a median follow-up of 10.8 months, Keytruda in combination with chemotherapy
- Produced an overall response to treatment of 45% versus 29.3% for chemotherapy.
- Demonstrated superior survival - the median survival duration was 12.4 months in the Keytruda combination arm versus 9.8 months for chemotherapy. In patients with ESCC whose tumors expressed PD-L1 (CPS ≥10), the median OS was 13.9 months in the Keytruda combination arm versus 8.8 months for chemotherapy alone.
- Delayed cancer progression reducing the risk of disease progression or death by 35% or more than a third.
- Treatment-related side effects led to discontinuation of treatment in 19.5% of patients in the Keytruda combination arm and 11.6% of patients in the chemotherapy arm.
Checkmate-649 compared Opdivo plus chemotherapy and Opdivo plus Yervoy (ipilimumab) to chemotherapy alone as the initial treatment for patients with previously untreated, non-HER2-positive, advanced or metastatic gastric cancer, GEJ cancer or esophageal adenocarcinoma in patients with a combined positive score (CPS) ≥ 5. The median survival duration was 14.4 months compared to 11.1 months for chemotherapy alone among PD-L1 positive patients with CPS ≥ 5.2,7
Precision Cancer Medicines
Not all cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing can be performed to test for certain genetic mutations or the proteins they produce, and the results can help identify newer precision cancer medicines that target cancer cells with specific genetic mutations.
The purpose of precision cancer medicine is to define the genomic alterations in the cancers DNA that are driving the growth of that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Several precision medicines been approved for the treatment of advanced esophageal cancer or are being developed in clinical trials. In order to identify which drugs can be used your physician needs to have NGS-biomarker testing performed on the cancer tissue or blood. The following are known targets for available precision cancer medicines.
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HER2: (human epidermal growth factor 2) is a receptor on the surface of cancer cells. When HER2 is "turned on" it causes the cells to grow and reproduce. Normal cells have 2 copies of the gene that makes HER2. In contrast to normal cells some have more than two HER2 genes and/or produce too much HER2. This results in more HER2 receptors - a condition doctors refer to as "over expression" Over expression of HER2 leads to increased cell production or cancer and can be targeted with precision medicines directed at HER2.3,4
TRK + Cancers: Tropomyosin receptor kinases (TRK) fusions are rare chromosomal abnormalities that occur when one of the NTRK genes becomes abnormally connected to another, unrelated gene and results in uncontrolled TRK signaling that can lead to cancer.5,6
Epidermal growth factor receptor: A mutation in the EGFR contributes to occurs in up to 1 in 6 individuals with esophageal cancer. EGFR is involved in cellular growth and replication and drugs that block the activity of EGFR slow cancer growth and prolong survival.
Surgery for Palliation
Patients with stage IV esophageal cancer often have widespread cancer at the time of diagnosis and cannot be cured with surgery. There is controversy over how best to treat patients who cannot undergo surgery with curative intent. In one clinical study, doctors compared the outcomes of 39 patients with stage IV esophageal cancer who underwent an esophagectomy for palliation with the outcomes of 49 patients with stage IV esophageal cancer who underwent more complete removal of cancer. Both groups of patients experienced significant improvement with regard to both the quantity and quality of food intake and a reduction in the severity of eating related symptoms. After 9 months, patients in the palliative group experienced more pain and a poorer quality of life, but there were no differences in sleep, leisure activity and performance scores when compared to the other group. This study suggests that palliative esophagectomy relieves symptoms in the majority of patients with inoperable esophageal cancer. It could also be argued that both groups had palliative surgery since the majority of patients who undergo surgery with curative intent have rapid recurrence of cancer in the first year or two after surgery.
- To learn more, go to Surgery and Cancer of the Esophagus.
Other Treatment Modalities
Many other treatment modalities are utilized to prolong survival and quality of life for patients with esophageal cancer.
Thermal laser: Thermal laser coagulation performed by endoscopy can provide temporary relief of dysphagia. Laser ablation appears to be most helpful for treating polypoid cancers that grow into the esophagus causing occlusion. Laser treatment is less effective for upper esophageal cancers or cancers of the gastroesophageal junction. A multi-center clinical trial has compared photodynamic laser therapy to thermal laser ablation for the palliation of patients with esophageal cancer who experience difficulty swallowing food. In general, photodynamic laser therapy was more effective than thermal laser treatment.
Photodynamic treatment: Photodynamic ablation has been used for the palliation of patients with esophageal cancer. Photodynamic treatment involves injection of a light sensitizer into a vein, which is then taken up by cells. A laser is then directed at the cancer cells. The reaction between the laser and the light sensitizer destroys the cells. The objective response rate at one month with this approach has been reported to be 32% for patients receiving photodynamic laser treatment, which compared favorably to the 20% reported for patients receiving thermal-laser treatment.
Esophageal dilatation: Frequently, after the administration of chemotherapy, radiation therapy, laser or photodynamic treatment, the area of the esophagus with cancer can be constricted or narrowed. Narrowing of the esophagus may be due to recurrent cancer or to treatment induced strictures or both. Relief of this constriction by dilation can temporarily improve swallowing. During esophageal dilation, a physician uses endoscopic or fluoroscopic guidance to pass flexible dilators (mercury filled rubber tubes) through the mouth. Increasing diameters of dilators, called bougies, are gradually introduced until the difficulty in swallowing resolves. One clinical study reported a 92% success rate for dilation. The duration of symptom relief after successful dilatation varies from days to weeks. One complication of esophageal dilation is the potential for perforation; however, this occurs only rarely. In a large study of 154 patients, a total of 3,140 dilators were passed before, during and after radiation therapy and resulted in only two perforations.
Esophageal stents or prostheses: Stents are rigid tubes that stay in the esophagus to keep it open. Recently, a clinical study evaluated the use of esophageal stents over a 4-year period for the management of patients with inoperable esophageal cancer. In a group of 160 patients with esophageal cancer,159 had stents placed successfully. In this study, a traditional rigid tube was placed in 84 patients and metallic self-expanding stents were placed in 75 patients. After placement of the stents, chemotherapy and/or radiation therapy was administered to 82 patients. The results indicated that 11% of patients had complications, including displacement of the stent, incomplete expansion of the stent, perforation of the esophagus or bleeding. Swallowing was improved in 97% of patients. These doctors concluded that placement of stents to improve swallowing was a relatively safe palliative procedure. Self-expanding metallic stents were thought to be preferable to rigid stents for maintaining an open esophagus.
Strategies to Improve Treatment
The progress that has been made in the treatment of esophageal cancer has resulted from improved patient and physician participation in clinical studies. Future progress in the treatment of esophageal cancer will result from continued participation in appropriate studies. Currently, there are several areas of active exploration aimed at improving the treatment of esophageal cancer.
New Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies is an active area of clinical research carried out in phase II clinical trials. These studies are performed in patients with stage IV or recurrent esophageal cancer.
Phase I Trials: New chemotherapy drugs or other anti-cancer therapies continue to be developed and evaluated in phase I clinical trials. The purpose of phase I trials is to evaluate new therapies in order to determine the best way of administering the drug and to determine whether the drug has any anti-cancer activity in patients with esophageal cancer. Patients with stage IV esophageal cancer should consider participation in phase I trials.
- https://www.businesswire.com/news/home/20200902005293/en/New-Scientific-Data-ESMO-Virtual-Congress-2020, Abstract #LBA51
- Presentation #LBA6_PR - featured in a Presidential Symposium at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 on September 21 from 18:30-18:42 CEST.
- Entrectinib Granted Priority Review by FDA for NTRK+ Tumors and ROS1+ NSCLC
- Entrectinib Granted Priority Review by FDA for NTRK+ Tumors and ROS1+ NSCLC
- Lancet Oncol. 2019 May 20. Epub ahead of print.
- Janjigian YY, Shitara K, Moehler MH, et al. Nivolumab (nivo) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJ/EAC): 3-year follow-up from CheckMate 649. Presented at: 2023