Esophageal Cancer
Esophageal cancers account for a small percentage of cancers in the US. However, it is not insignificant. According to the American Cancer Society as there will be 22,000 new cases and 16,000 deaths this year from the disease. It predominates in men, with less than one quarter of new cases and deaths occurring in women. Treatment is often delayed until later stages of disease, as there are few early symptoms, which accounts for the bleak overall five -year survival of 10%. If early surgical intervention can be achieved, indicating an earlier diagnosis, the five- year survival is still only 20-40%.
Introduction
Esophageal cancer is predominately one of two types, and together they account for greater than 90% of all disease.
Squamous cell cancer (SCC) occurs in the outer epithelial lining cells.
Historically, in the early twentieth century, in the US, three quarters of esophageal cancers were squamous cell, with disease occurring in the upper and middle parts of the esophagus. and was occurring four times more commonly in black males, than in white males. Today, again in the US the prevalence of squamous cell is declining while adenocarcinoma is becoming the prevalent form of cancer. But worldwide, squamous cell still represents 80% of esophageal cancer. It is seen more commonly in southeast Asia, and areas of Africa
Adenocarcinoma (AC) originates from the glandular mucous producing cells.
Since the 1970’s, in the US, esophageal cancer has shifted to become predominately adenocarcinoma, involving either the lower esophagus or the area where the stomach and esophagus meet and connect, the gastroesophageal junction. While the stomach and lower esophagus are different organs, there behavior in cancer resemble each other closely, and their treatments have become similar.
And the demographic for adenocarcinoma has now reversed with 4x as many white males as black males being diagnosed, with this form representing 60% of esophageal cancer.
Adenocarcinoma occurs commonly at the gastroesophageal junction and is associated with chronic reflux causing Barrett’s esophagus. This is a condition in which the cells change from a normal appearance to abnormal precancerous cells called esophageal or intestinal metaplasia.
Barrett’s esophagus is primarily discovered, in middle aged adults, during an endoscopy, for upper abdominal complaints such as heartburn or pain. Acid reflux injury to the esophagus, called gastroesophageal reflux disease, GERD can range from mild inflammation to severe lower esophageal inflammation called erosive esophagitis. Risk for AC occurs in the lower esophagus from longstanding GERD after many years. Having Barrett’s confers between 1-2% annual risk of cancer, which is many times greater than the general population.
GERD and secondary Barrett’s esophagus are both issues that have treatments.
Most GI specialists recommend reducing acid that inflames the esophagus and prescribe acid blockers, especially PPI’s or proton pump inhibitors for long extended periods of time. This is to reduce reflux of irritative acid from the stomach, but studies show that many people still get reflux but without symptoms.
An important concept that is unfamiliar to most western physicians, but can successfully improve GERD in many older adults, suggests that GERD and reflux rather than being too much acid is really a symptom of a lack of stomach acid.
The problem that often occurs with advancing age is that the stomach is unable to produce adequate amounts of hydrochloric acid for digestion, which is necessary to activate another enzyme, pepsin, which together breakdown protein amino acids. Stomach acid also destroys many pathogens entering the digestive tract and acts to stimulate small intestine digestion and closes the stomach esophageal sphincter reducing reflux. With reduced acid food remains much longer in the stomach allowing enough acid resulting in, distention and often reflux. So, some reflux is not due to overproduction of acid but diminished acid, which can be compounded by acid blockers.
With persistent reflux, endoscopy, or the insertion of a fiberoptic camera is used to evaluate the esophagus for degrees of inflammation often prompting biopsies to determine the degree of inflammation or if there are precancerous tissue changes.
The cellular histology is graded as:
No dysplasia, or having no cellular abnormality
Low grade dysplasia shows a small number of mildly abnormal looking cells, but they are precancerous. Endoscopy is performed again at 6 months then every 6-12 months and medical treatment, see below, is an recommended.
High grade dysplasia indicates markedly abnormal cells and are at risk of becoming cancer.
Superficial cancer on the outer esophageal surface.
In high grade dysplasia and superficial carcinoma treatment is performed
using thermal or radiofrequency energy or cryosurgery(cold). By destroying the abnormal cells, the goal is to allow normal healing of these tissues.
In situations of severe dysplasia or early superficial cancer the recommendation may instead be to remove the diseased section of the esophagus and reconnecting it to the stomach.
In situations with Barrett’s, regular follow up for endoscopy is continued, as other areas can develop Barrett’s and surveillance is key to early diagnosis. Your physician will also offer medical treatment and suggest lifestyle modifications.
Risks for Developing Esophageal Cancer, Squamous Cell Carcinoma (SCC) and Adenocarcinomas (AC)
The risks include:
Tobacco, both
Alcohol, both
Opium, SCC
Hot drinks, SCC
Obesity, with a BMI > 30. There is a slight increase in risk for both
Hiatal Hernia
Infection with Heliobacter Pylori (H. Pylori), decreases risk in AC
Family History-approximately ¼ of adults with significant GERD have a family member with similar symptoms.
Using biomass fuels, coal for example and kerosene, both
Unpiped water, SCC
Poor dental hygiene and tooth loss, both
High fat intake, AC
Many of these risk factors have the potential for modification but are associated with lower socioeconomic status making changes difficult.
Other Associated Risk Factors:
Nutrition: Low intake of fruits and vegetables and many associated vitamins and minerals. These include selenium, zinc, and folate which if ingested in adequate doses reduces risk. Red meat, Pickled and preserved foods increase squamous cell risk.
Age: middle and older age are associated with the greatest risk, age mid-forties to seventies.
Alcohol: Inhibits DNA repair, and one of the associations of squamous cell cancer in Asia and China is a link to aldehyde dehydrogenase deficiency and the ability to process alcohol. It is why some people, and many Asians get flushed and red faced when drinking alcohol. It can be moderated with adequate selenium intake.
In the US, perhaps the health hazards of smoking have decreased it as a risk factor, and in past decades alcohol intake was greater, but with stricter DUI laws perhaps there is moderation, again lowering risk.
Preexisting Esophageal Damage
Strictures from poisoning, such as ingestion of drain cleaners or other products with Lye.
Achalasia, failure of the muscles of the lower esophagus to relax, esophageal spasm, preventing food passage and allowing food to stagnate and cause inflammation.
These both pose increased risk of squamous cell esophageal cancer
HPV Virus: Recent studies indicate that HPV is detectable in 20% of esophageal cancers worldwide but more studies are needed to determine its prognostic significance Most experts believe it is rarely associated with esophageal cancer.
Squamous cell and adenocarcinoma are both causes of esophageal cancer with similar evaluations to confirm disease status. However, their risk factors and location are different as are risk of progression and survival. While chemotherapy was the only option in the past, today each type can receive additional therapy, with squamous cell cancer being treated with immunotherapies and adenocarcinoma utilizing molecular targeted therapies.
Diagnosis
Diagnosis is made by tissue biopsy through an endoscopy (scoping) and the histology or appearance under the microscope. For the most accurate confirmation several biopsies are performed.
Following the determination of disease, evaluation of the extent of disease and its staging will provide information as to the extent of disease, the prognosis, and type of treatments that are indicated.
Endoscopic Ultrasound (US)- Using US in the esophagus provides information on local disease and the region around it. Looking at the esophagus and surrounding tissues presents images showing circular patterns, like a tube, and the US can reveal distortions in the circle pattern indicating disease.
The US images seen in early cancer are superficial plaques or ulcerations while advanced disease is seen as a narrowing, from stricture, ulcerated masses, or masses that surround the esophagus. It also can show the different layers of tissue the circle the esophgus. Accuracy in diagnosing cancer with non- invasive US approximates 70%.
Lymph Node Assessment - In performing endoscopic US, local regional lymph nodes can be assessed. There images are distinct for suggestion of benign versus malignant appearing nodes. Benign nodes can be described as elongated, size is <10mm and are irregular, while in cancer abnormalities reveal nodes >10mm, round shape without any vascularity, which isn’t seen in a normal node requiring the transport of nutrients and immune products. The tissue also appears fluid filled or solid.
The assessment of lymph nodes previously was based on their location, but current guidelines consider the number of nodes instead as a better prognostic indicator.
Bronchoscopy- can be performed for thoracic disease to see if there is extension into the bronchi of the lung.
Laryngoscopy- also is commonly performed as sometimes a head and neck cancer is present at the same time.
CT/PET Scan-of the head, neck, chest, and abdomen is performed. These together are the most sensitive method for finding metastasis which is important to prevent surgery if cancer has already spread and cannot be cured by surgery.
Signs and Symptoms
Difficulty swallowing -occurs with narrowing of the diameter of the esophagus tube and is a sign of advanced disease. Early on, someone may feel food is sticking, but overcome with smaller pieces of food chewed well. Later people will change to more soft foods or liquids. Many fail to realize its significance.
Weight Loss- can result from changes in the types and amount of food being eaten and/or from cancer causing anorexia or loss of appetite contributing to weight reduction.
Indigestion, chronic
Vomiting – sometimes even spitting up saliva
Pain- in the chest along the sternum or throat pain
Anemia- secondary to slow blood loss which is often unrecognized as there is no blood in the stool or blood if vomiting or regurgitation of food
Hoarseness
Staging of the Primary Tumor
Stage 0
T0 – No evidence of primary tumor
Tis- High grade dysplasia confined to the epithelium.
Stage 1
T1-Invasion of either the:
The lamina propria, which is a thin layer of connective tissue which forms a part of mucosal lining of the esophagus.
The muscularis mucosa, just beneath the lamina propria
The submucosa, the supportive layer for the mucosal lining
T1A -Invasion of lamina propria or muscularis muscle
T1B- Invasion of the submucosa
Stage T2
Tumor invades deeper into the muscularis propria or the muscular layer of the esophagus
Stage T3
Tumor invades the outer connective tissue layer around the esophagus
Stage T4
Tumor invades adjacent structures
T4A-Invasion of the pleura, pericardium, azygos vein, diaphragm, or peritoneum
T4B-invasion of other structures, the aorta, vertebral body, or airway
Disease grade
Grade 1 cells are well differentiated and appear to closely resemble normal cells
Grade 2 cells are moderately differentiated
Grade 3 cells are poorly differentiated or undifferentiated cells that don’t look at all like normal cells.
Treatments
Treatment of Esophageal Cancers That Can Be Removed Using Surgery
Esophageal cancer that is confined to the esophagus itself occurs in approximately one fifth of people making them potential candidates for surgery. Removal of the portion that is in the upper cervical area is often not an option as it requires partial removal of the larynx, pharynx, and thyroid. Surgery and radiation are the general treatment.
If it is in the middle or lower esophagus, but not the junction with the stomach, the entire esophagus is removed as there are often lesions that involve multiple other areas. Cancer at the gastroesophageal junction require removal of the cancer with areas 4-cm away from the cancer, as well as multiple lymph nodes.
Initial surgical treatment can be considered for people with:
T1 disease involving the lamina propria, muscularis mucosa, or submucosa without evidence of involvement of nodes or distant spread.
and
In some centers, T2 disease, invasion of the muscularis propria, is considered an operable situation.
Surgery is done after preoperative (called neoadjuvant) chemotherapy, or both chemotherapy and radiotherapy in people with:
Thoracic esophageal cancer or cancer of the gastroesophageal junction, without lymph node involvement
T3 disease extending throughout the esophagus but no nodal involvement
But in order to consider surgery, it is necessary to consider if there is advanced age which is not just a chronologic age but the level of energy and constitutional strength at that age. A young 80-year-old or old 80-year-old are different surgical risks but also underlying chronic problems as having medical issues poses a risk of post op complications.
Removing the esophagus surgically is technically difficult to perform based on the location and related other anatomic organs as well as creating a functioning tube to connect the mouth to the rest of the GI system.
With the completion of surgery, feeding is through a tube that has been placed commonly in the small intestine to provide nutrition. it is started a couple days after surgery with the volume of food increased slowly over several days. A barium swallow is done after several days to check that there is no leakage at the incision sites and to evaluate the swallowing mechanism.
Even with successful surgery, recovery takes optimistically 12-24 months, but many take three years. Also, there are other can be residual issues with reflux, difficulty and pain with eating and swallowing and feeling short of breath.
Decisions as to Who Would Not Qualify for Surgery include:
Distant Metastasis in major organs such as the liver, lung, bone, or brain eliminate surgery as a choice
Inoperable Esophageal Cancer Treatments and Palliative Care
People that present with Stage 4 cancer, invasion of structures adjacent to the esophagus, are in a situation that surgery and potential cure are beyond reach. It means there is not distant spread of disease, but treatment is still essential to reduce tumor burden, alleviate pain, maintain swallowing, and reduce potential bleeding from tissue damage in the esophagus from the cancer.
These are all considered under the context of palliative care, an often-misunderstood concept.
Palliative care is designed to assist and act as a resource for a person or family unit that is in a situation of a chronic illness. It might be cancer, but it is also accessible for other illnesses such as chronic lung disease, heart failure.
Palliative care is a medical model of care provided by knowledgeable specialized providers ranging from physicians to nutritionists, to social workers, physical, occupational, mental health, and spiritual representatives. Palliative care interventions are extremely important therapeutic tool for these patients to support and treat systemic symptoms such as pain, sleep disorders and fatigue. Also, with difficulty swallowing (dysphagia) malnutrition is of critical concern which can lead to decreased survival.
Interestingly, but expected, in situations where people receive this type of intervention connection and help especially for situations of depression and anxiety associated with their disease, survival is definitely improved.
While the goal is to provide relief of symptoms, and assistance with life transitions, as important is allowing the individual to understand and decide their available choices and discuss other needs, they may have or anticipate.
This is not end of life care. It is an approach to allow each individual their highest quality of life with the time available to them. Something everyone should aspire too, both the healthy and the ill.
Also, cancer treatments can be continued, and new available therapies should be continually explored. There is often coverage for some services by insurance, and the VA has its own palliative model.
Treatment of Disease That Is Locally Advanced and Non-Operable
Cervical Area Cancer of the Esophagus -occurs in approximately 1 in 20 esophageal cancers and is usually already advanced. This area of squamous cell cancer is anatomically from the back of the throat to the sternal notch, and is in close proximity to the throat, larynx, trachea, and surrounding nerves which poses high risks of complications, so surgery is not done. Squamous cell esophageal cancer is very close to the type of squamous cell cancer seen in head and neck cancer, so treatment is similar involving external beam radiation and chemotherapy.
Thoracic and Abdominal Esophageal Cancer-that are locally advanced and inoperable are treated with a combination of external beam radiation and chemotherapy. Both squamous cell and adenocarcinoma are treated similarly with chemotherapy. These are then offered if the physician feels that a person can tolerate this intensity of treatment. Even after treatment, with complete response, surgery is not considered to offer benefit as even though cancer may appear resolved very few truly are. Also, combined therapy rather than radiotherapy alone offers significant benefits for survival, and combination therapy also offers a longer sustained response to problems associated with difficulty swallowing
Chemotherapy Treatment for Locally Advanced Disease
The two chemotherapy protocols are used, combining:
5 FU (Fluorouracil)
Cisplatin
or
Carboplatin
Paclitaxel
And these drugs are used in both Cervical and Thoracic/Abdominal disease
Platinum Drugs- These drugs activate inside the cancer cell and binds to DNA linkages, causing damage to the DNA and inducing self-destruction and cell death.
The two used are:
There are other side effects that should be discussed with your oncologist
Cisplatin
Major Side effects include:
>40% up to 80% peripheral neuropathy, drug manufacture sites 0%
28% Kidney dysfunction
31% Hearing loss
30% Marrow suppression
or
Carboplatin
Major side effects include:
5% Peripheral neuropathy
10% Nephrotoxicity
93% Nausea
84% Vomiting
44% Pain
Taxane Drugs-These drugs interfere with normal cell division inducing death
The two used are:
Taxol (Paclitaxel)
Major side effects include:
90% Low white count
87% Hair Loss
78% Anemia
60% Peripheral Neuropathy and Muscle Pain
58% nausea and Vomiting
5FU (5-Flurouricil) interferes with DNA and protein synthesis, and RNA processing
Major side effects include:
It is interesting that this drug has been available and used for years yet specific percentages of side effects are vague
All listed are 10% or greater:
Suppression of bone marrow, white cells, and platelets
Inflammation, of mucous membrane of mouth, throat and esophagus
Spasm of airways
Abnormal EKG s representing diminished coronary blood flow
Radiotherapy while of benefit, in combination with chemotherapy it has its own potential complications. Two significant ones include tracheoesophageal fistula (TE), damage to the tissues that allow the trachea and esophagus to connect rather having separate tubes. Also, after radiation therapy there can be the development of scar tissue that can narrow the esophageal tube causing the return of difficulty swallowing.
Treatment for Advanced or Metastatic Esophageal Cancer
In earlier decades, treatment protocols were different for adeno and squamous esophageal cancers. Studies have confirmed that similar chemotherapies for either type results in the same response rate and length of survival. However, there is now a divergence in available additional treatments.
Changes have occurred that send each type of cancer on a different trajectory as therapies that are now being utilized have combined multiple combinations of chemotherapy to molecular targeted therapies, for adenocarcinoma and immunotherapies, for squamous cell cancer.
In squamous cell cancer treatments now use Immune checkpoint inhibitors as a standard combination treatment with chemotherapy.
Chemotherapy utilizes:
Cisplatin and 5 Fluorouracil, as they are the safest for patients in situations of progressive disease
combined with
Pembrolizumab or Nivolumab (PD-L1) checkpoint inhibitors
In the immune system, activated T cells are a lymphocyte white blood cell that regulates and coordinates our response to infections, allergens, cancer, and any foreign threatening appearing cells. They can allow normal immune actions, but they also have the PD-1 receptor on their surface which can allow them to act to slow or stop immune responses, as an inhibitor of immune function. This design allows an intervention to prevent overactivity that might cause an excessive inflammatory response or potential autoimmune disease. They do this by binding to a receptor, a PD-L1 receptor on the front-line cells that initiate the immune activation cascade, the macrophages, and dendritic cells.
When the PD-1 receptor on T cells combine with the PD-L1 receptor on our immune initiators this interaction dampens down the immune response pumping the brakes on the immune system, when needed, and maintains balanced immune responses.
Cancer cells are capable of intervening on their own behalf to control this system and maintain this damping down effect on immune activity to prevent the necessary increased immune attack that is required to actively target and destroy them.
Immunotherapies are now available that can be measured for therapy in squamous cell esophageal cancer which are PD-L1 inhibitors that allow specific types of T cells, CD 4 helper immune cells and our CD 8 natural killer cells to have their restraints taken off and amplify their attack on cancer cells.
Two of these therapies are the PD-L1 checkpoint inhibitors, pembrolizumab or nivolumab either of which is combined with the chemotherapy combination of cisplatin and 5-flurouricil in squamous cell esophageal cancer.
Even in people without a PD-L1 marker, these checkpoint drugs are used as studies show while the survival benefit is less than when a receptor is present, it still offers improved survival over chemotherapy alone.
Keytruda (Pembrolizumab) a PDL-1 (Programmed Cell Death Ligand) drugs, Checkpoint Inhibitors. These drugs take the brakes off of the immune system and allow it to more actively engage in fighting the cancer
Major Side effects listed as up to:
92% Anemia
71% Rash or elevated liver functions
80% Elevated blood sugar
61% Alopecia
62% Enteritis
70% Fatigue
48% Weight loss
Potential autoimmune disease
Nivolumab
Major side effects include:
49% Fatigue
32% Musculoskeletal pain
28% Elevated liver Testing/ Loss of Appetite
21% Rash or Itching
20% Joint pain
In Adenocarcinoma of the Esophagus
Chemotherapy is the primary treatment utilizing a fluoropyridine derivative such as:
Fluorouracil or capecitabin
combined with
Oxaliplatin.
In addition, targeted therapies based on the presence or absence of Epidermal Growth Factor Receptor (EGFR) called HER-2 are now the standard of treatment.
HER2+ Treatment:
Having this receptor tends to make these cancers grow and spread more aggressively than patients who lack this receptor. Treatment to stop the amplification of growth rely primarily on the manufactured monoclonal antibodies, Herceptin (Trastuzumab). It is surmised that they bind to the receptors to fight tumor growth by signaling the cell to stop growing or signaling the immune system to destroy the cell.
Major Side effects of Herceptin (Trastuzumab)
47%, pain
36%, chills and fever
22%, abdominal or back pain
25%, vomiting or diarrhea
26%, cough
18%, rash
HER 2 – Treatment
Implies there is no receptor to inhibit growth and in these situations
The addition of the Checkpoint Inhibitor is used, either:
Keytruda (Pembrolizumab)
Or
Nivolumab
Integrative and Supportive Care
The information gained from research testing is designed to encourage larger scientific studies to determine the possibilities and potential application of both natural substances and drugs in clinical situations for patients.
The following is some of the research in esophageal cancer treatments. It often uses multiple esophageal cancer cell subtypes that can be grown and used in laboratory situations for research, while some of the information is also from clinical data on patients.
Also, in patients with difficulty swallowing care should be taken when using supplement pills or capsules.
Utilizing a semisynthetic artemisinin, in the lab, it was shown that it could inhibit esophageal cancer by causing diminished proliferation via cell cycle arrest as well as increase apoptosis, cell death. The researchers felt it was worth pursuing with further testing as a promising intervention in esophageal cancer.
Artemisinin is the Chinese herb, Qing Hao that has been used for thousands of years for treating malaria and parasites. It also has antibiotic and antihypertensive effects.
Quercetin has been shown when combined with 5-Flurouracil can enhance the growth of cancer cells and increase cell death in esophageal cancer. It inhibits NF-kappa B one whose functions is to control cell replication and survival.
A study looking at the composition of the bacteria in the gut, the microbiome, showed variations in the types and amounts of bacteria seen in esophageal cancer patients versus controls. It would suggest that manipulating the microbiome, as our understanding becomes deeper, offers the possibility of an aspect of potential prevention through diet and supplementation.
A study from 2018 looked at the effects, in esophageal cancer, of optimizing a patient’s nutritional status prior to surgery and post operatively. There were treated patients and a control group. The finding revealed in the treated group, that albumin levels were higher, their immune response was better, and ultimately their length of hospital stay was reduced, with less cost.
Albumin, produced in the liver is a simple protein and comprises 60% of body’s protein. It is water soluble and essential to carry hormones and nutrients in the blood.
A study in esophageal cancer showed that the combination of EGCG, curcumin (see our monographs) and a statin, lovastatin, suppressed growth of esophageal cancer cells in a mouse model. They acted to block cellular growth by inhibiting kinase signaling in the cancer nucleus for replication.
Under conditions mimicking a low glucose environment, which is seen in many cancers, the addition of metformin, a diabetic drug with several anticancer characteristics, to cisplatin chemotherapy augmented cell destruction in squamous cell esophageal cancer.
Squamous cell esophageal cancer is the leading cause of death in Taiwan. A clinical study of stage 4 patients, followed for five years or until death occurred, from 2002-2018 added Chinese herbal formulas (CHF) to a group of patients, as part of their treatment. The results showed a greater number those on CHF had a higher 5 year survival, 19% versus 6% and overall median survival was 7 months longer.