After completing this module, students should be able to:
There are two possible goals for treatment: cure and palliation. Curative treatment is considered to engender a small degree of risk of significant side effects for the possibility of cure. On the other hand, palliative care is considered to alleviate symptoms when the risks of significant side effects outweigh the benefit of possible cure.
Curative treatment is indicated when a curative technique (usually surgery) is available, patient factors are favourable (eg. lack of comorbid illnesses), and the disease progression is localized. If a patient does not have metastases, corresponding to a lower stage tumour, curative treatment is usually possible.
Palliative care is usually the goal when there is metastatic disease, and patient factors are unfavourable (eg. presence of comorbid illnesses).
In order to make decisions about curative or palliative treatment, tumour, treatment and patient factors are considered. Tumour factors relate to tumour stage and tumour type. Treatment factors include the type of treatment being considered, availability of treatment and efficacy of treatment. Patient factors include personal choice and age, and most importantly, the patient’s status. For example, a “young 65 year old” may be a better surgical candidate than a “tired-appearing 55 year old”. When thinking about treatment for a patient, their physical condition or ability to withstand and recover from any given treatment, is of paramount importance. In order to assess a patient’s performance status and effectively communicate this in a consistent way with colleagues, physicians use a performance grade developed by the Eastern Cooperative Oncology Group, called the ECOG performance status. The ECOG performance status is graded by asking the patient a series of questions during the history-taking process. The various grades are described below.
Health care providers who may be involved in the care of cancer patients include:
Cancer treatment can be curative, if the disease has a chance of being completely eradicated by treatment. Palliative care is used to alleviate symptoms when the disease is not curative. Patient, tumour, and treatment factors guide the management of cancer patients which is provided by a multi-disciplinary team of health care professionals.
One in 250 females and one in 98 males are expected to develop esophageal cancer during their lifetime. In BC, the incidence rates of esophageal cancers diagnosed is 9.6 males per 100,000, and 3.7 females per 100,000 per year. It was responsible for 2,200 deaths in Canada in 2017 owing to the advanced stage at which most are diagnosed . It is less common in the West compared to globally where is ranks 9th in incidence and 6th in mortality among cancers .
Many esophageal cancer risks depend on the subtype of cancer, for example esophageal adenocarcinoma (EAC) vs. esophageal squamous cell carcinoma (ESCC). There is a trend toward higher incidence rates of EAC and lower incidence rates of ESCC in high-income Western countries and this can be attributed to increasing rates of obesity and GERD, which are strongly associated with EAC, and decreasing rates of smoking, a leading cause of ESCC [9, 10].
In general, esophageal cancer affects men 3-4 times more than women. African-americans are twice as likely to develop esophageal cancer than caucasian people. Smoking, alcohol-intake, obesity, and lower esophageal irritation (GERD, Barrett’s esophagus) are major risk factors for esophageal cancers overall.
A summary of risk factors for ESCC and EAC is below in Table 1. Esophageal cancer is relatively rare, so the risk of developing esophageal cancer in most patients with these risk factors remains low. The next section will cover prevention and screening. Please see the expandable section below for details and evidence regarding specific risk factors.
//Expandable header// Risk Factors
We will cover in more detail the specific risk factors for esophageal cancer as outlined in Table 1.
There is a strong relationship between smoking and the risk of developing ESCC and EAC . Tobacco and alcohol consumption appear to have a synergistic effect on the risk of ESCC .
Heavy alcohol consumption has been found to increase the risk of developing ESCC but not EAC . Alcohol and tobacco smoking synergistically increase the risk of ESCC .
Overweight and obese patients are at increase risk of developing EAC, possibly as a result of increased GERD . In contrast, elevated BMI appears to have a protective effect in ESCC .
Patients with GERD are at a markedly higher risk of developing EAC. Prolonged, more frequent, and more severe reflux symptoms confers additional risk .
Barrett’s esophagus has a 1-7% general population prevalence and 5-15% in patients with GERD. It is believed to be a precursor to most cases of EAC , and patients with Barrett’s esophagus are estimated to have a 0.5% annual risk of developing EAC.
Diets rich in meat, particularly red, increase the risk of EAC. Alternatively, fruits and vegetable consumption may have a protective role in EAC . There is evidence that nutritional deficiences in riboflavin, nicotinic acid, magnesium, and zinc account for increased risk of ESCC observed in high-risk regions .
Achalasia dramatically increases the risk of ESCC and, to a lesser extent, EAC . It is worth noting that obstruction by lower esophageal cancer can resemble achalasia, leading to misdiagnosis. As a result, the risk of esophageal cancer is especially high in the first year following the diagnosis of achalasia.
When adjusting for age, men are around 4x more likely to develop esophageal cancer .
The incidence rate of esophageal cancer increases with age. Among those newly diagnosed with esophageal cancer in the US, 98% are at least 45 years old .
Geographically, the incidence of esophageal cancer is highest in East Asia, followed by Southern Africa, Eastern Africa, and Northern Europe . While most esophageal cancers diagnosed in these high-incidence regions at ESCC, their etiology is less clear than those diagnosed in the West . Possible culprits include HPV infection and dietary deficiencies, but a causal link has not been established .
In the US, Caucasians have higher incidence rates of esophageal cancer than Asians, Hispanics, American Indians, and Blacks. Caucasians are at particular risk for EAC, while Blacks and Asians more commonly develop ESCC .
Prevention includes primarily the avoidance of environmental triggers including quitting smoking or avoiding exposure to tobacco and cigarette smoke. Avoid excessive alcohol use with complete avoiding reducing your cancer risk the most. The American Institute for Cancer Research advises less than two drinks a day for men and one per day for women. Healthy eating and regular physical exercise to maintain a healthy BMI can lower risk for esophageal cancer.
For patients with Barrett’s Esophagus, it is recommended that they receive appropriate treatment and follow their surveillance schedule (see below).
Currently no effective screening program exists for esophageal cancer in any Western organization. There is, however, interest in screening patients with reflux which has been described by the American College of Physicians, the American College of Gastroenterology, and the American Society of Gastrointestinal Endoscopy [25-27].
//Expandable section on Reflux investigations///
Guidelines agree that upper endoscopy is indicated in patients presenting with GERD and concomitant warning symptoms described below [25-27]. The ACP and ASGE recommend investigating reflux symptoms that are refractory to treatment. Endoscopy may also be appropriate in patients with longstanding or severe reflux symptoms and multiple additional risk factors including:
Patients who do not have any evidence of EAC or Barrett’s esophagus on screening endoscopy do not need repeat endoscopy. On the other hand, patients found to have Barrett’s esophagus should consider endoscopic surveillance and treatment of dysplasia.
People with known Barrett’s esophagus have specific screening recommendations (see below).
Severe caustic injury is associated with ESCC, allegedly increasing risk by a thousandfold. There is, on average, a 40-year latency between the time of injury and the development of esophageal cancer. The ASGE recommends beginning endoscopic surveillance 15-20 years after injury .
Achalasia increases the risk of developing esophageal cancer (1 in 300 patient-years). However, the number of endoscopies needed for each early diagnosis (400) and poor prognosis in this patient group has led the ACG and ASGE to withhold their endorsement, and practice within the field varies .
Hereditary cancer syndromes can be considered case-by-case for screening owing to their heterogeneity. The NCCN provides screening recommendations for some genetic conditions implicated in esophageal cancer: https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf.
Inflammation of esophagus is called esophagitis. There are many causes of esophagitis; in North America, the most common cause is regurgitation of gastric contents through the lower esophageal sphincter (Gastro-Esophageal Reflux Disease (GERD)). The acid gastric contents irritate the esophagus squamous mucosa causing inflammation. In some individuals, persistent reflux may cause squamous mucosa to undergo metaplastic transformation into glandular epithelium which is then called Barrett’s esophagus. The risk of progression to adenocarcinoma of the esophagus depends on factors including the length of Barrett’s (short vs. long segment), and the grade of dysplasia (low vs. high-grade dysplasia).
Table 2. Grade of Barrett's Esophagus and recommended surveillance and treatment
Symptoms depend on location of tumor. Early esophageal cancer is usually asymptomatic. Overall, dysphagia and weight loss are the most common symptoms at time of diagnosis, presenting in 74% and 57% of patients respectively .
Diagnosis includes a full detailed history and physical examination. Esophageal cancer specific history questions and physical exam findings are detailed below.
The normal thyroid gland is composed histologically of two main parenchymal cell types: follicular epithelial cells and C or parafollicular cells . Most thyroid cancers are derived from the follicular cells which give rise to both well-differentiated cancers (papillary, follicular) and anaplastic thyroid cancers. In the young (under 40 years of age), thyroid cancer is usually well-differentiated and the overall prognosis is excellent. On the other hand, anaplastic carcinomas (15%), particularly in older patients, have a significantly poorer prognosis and are rarely cured. From C or parafollicular cells arise medullary thyroid carcinoma (MTC).
Papillary carcinoma is the most common form of thyroid cancer in Canada compromising over 80% of all diagnosed thyroid Cancers. It is a slow growing subtype and survival rates are high if diagnosed early. It is often single lobular. Metastases most commonly involve cervical lymph nodes and, less commonly, the lungs .
Follicular carcinoma is the second most common type of thyroid cancer after papillary carcinoma. It arises from follicular cells responsible for thyroid hormone production. It is slow growing and survival rates are high if diagnosed early. Follicular carcinoma is often treated with radioactive iodine since this tumor is most likely to capture radioactive iodine. When metastasized, however, follicular thyroid cancers tend to metastasize hematogenously to distant sites, in particular, to lung and bones.
Anaplastic carcinoma is the least common type of cancer (<1%) and occurs more often in middle ages and elderly patients . It is the most aggressive type and is fast growing with early spread. A metastatic work-up often reveals locoregional disease and distant metastases, most commonly to the lungs followed by bones and brain. Anaplastic thyroid cancer often arises from and can coexist with differentiated thyroid cancer, but can also occur de novo. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with symptoms such as hoarseness, dysphagia, and dyspnea. It is often too advanced to surgically resect at diagnosis and therefore treated with radiation therapy alone. The cure rate of anaplastic carcinoma is very low.
On presentation, most patients with anaplastic thyroid cancer have a large, firm palpable mass in the thyroid with or without cervical adenopathy, and patients often develop hoarseness, dysphagia, and dyspnea. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with the aforementioned symptoms. 
Medullary carcinoma arises from parafollicular neuroendocrine cells of the thyroid - C-cells which are responsible for the production of calcitonin. It is uncommon and constitutes 1-2% of thyroid cancers . It is slow growing and survival rates are high if diagnosed early. It may spread to lymph nodes or metastasize elsewhere. It generally occurs on one side of the thyroid only. MTC is the most prominent clinical diagnosis in multiple endocrine neoplasia (MEN) 2A and MEN 2B - a quarter of medullary thyroid cancer cases occur in patients with an inherited MEN syndrome.
The American Joint Committee on Cancer (AJCC) uses different tumor-node-metastasis (TNM) classification for differentiated and anaplastic thyroid cancer, and for medullary thyroid cancer. For the purposes and level of this module we will provide the staging for only the differentiated and anaplastic thyroid cancers below in Figure 2. For specific staging guidelines, see AJCC 8th edition TNM classification :
There are additionally separate stage groupings based on AJCC 8th edition staging guidelines for differentiated, medullary, and anaplastic carcinomas seen in Table 2.
Table 2. AJCC 8th edition specific stage groupings for differentiated, anaplastic, and medullary carcinoma
Management of thyroid cancer can be highly individualized and treatment may differ depending on patient, center, or physician factors. The details of management decision is beyond the scope of this module, however, general approaches and treatment options will be briefly reviewed.
The pathological assessment of the thyroid tumor is of paramount importance as it will not only give the degree of differentiation of the tumor but will assess multicentricity, the extent and site of nodal involvement and the completeness of the surgical resection. Overall, surgery is the mainstay of the majority of thyroid subtype treatments.
Surgery is the primary mode of therapy for patients with differentiated thyroid cancer and should be performed by an experienced thyroid surgeon to minimize the risk of hypoparathyroidism and recurrent laryngeal nerve (RLN) injury.
Operative management can include either a thyroid lobectomy or a total thyroidectomy. The choice to pursue either depends on extent of disease, patient factors, and presence of comorbid conditions:
Post-operative thyroid hormone is generally not started for patients who received a lobectomy, however, is started for patients who received a total thyroidectomy.
Intra-operatively, careful search for lymph nodes in the area must be made and all obvious nodes removed. More extensive resection is required for different types and sizes of tumors and its spread to surrounding lymph nodes .
131-Iodine ablation may be used adjuvantly after surgery to target remaining thyroid tissue where recurrence may occur, or to treat already recurring or metastasized disease. In studies showing a benefit with 131-I ablation, patients with larger tumors, multifocality, residual disease, and nodal metastasis seem to benefit from treatment . Therefore, the recent treatment guidelines recommend consideration of adjuvant 131-Iodine ablation in postoperative findings of :
Only papillary and follicular cancers will take up iodine, and only 50% of less of these tumors are able to take up enough iodine for it to be therapeutic.
Treatment with thyroxine is important in management of patients with thyroid carcinoma. The aim of such treatment is to suppress TSH stimulation of the thyroid which can be achieved by maintaining the serum T4 at the upper limit of normal. The starting dose of thyroxine is 1 mcg/lb/day. The level will equilibrate in one month and then the T4 and TSH can be checked. The dosage can then be altered to achieve the desired level.
External irradiation has a definite role as an adjuvant to surgery or as treatment in the following circumstances:
The role of chemotherapy in thyroid cancer is limited. The single chemotherapeutic agent most commonly used for thyroid cancer is doxorubicin (Adriamycin) with partial response rates of 30% and up to 45% in some series. For surgically unresectable local disease that has not responded to radioiodine, the best treatment may be a combination of hyperfractionated radiation treatments plus Adriamycin. Response rates of more than 80% have been reported using this regimen, but even in this situation, complete responses are rare and limited in duration.
Initial follow-up is generally undertaken by an endocrinologist, surgeon, or at a cancer centre. Thereafter, most patients are referred back to the care of their family physician .
The follow-up is variable from centre to centre and from patient to patient, however, generally it is recommended a visit every 3 to 4 months for the first two years. If there is no evidence of recurrence after 2 years then visits should be every 6 months for the next two years, with annual visits thereafter.
Initial investigations may include neck ultrasonography (every 6 - 12 months), TSH levels, and serum thyroglobulin (Tg) levels on thyroid hormone suppression (every 3 to 6 months for the first year). Iodine scanning is typically continued until there is no evidence of uptake in the neck or elsewhere and only repeated if the thyroglobulin starts to rise of recurrence or metastasis is clinically detected.
If a patient is high risk and demonstrate either a biochemical or structural incomplete response to therapy, additional imaging can be considered, including MRI, CT, and FDG-PET. Gross residual disease in cervical lymph nodes identified by physical examination or ultrasonography should be confirmed by FNA and surgical resection considered. Diagnostic whole-body radioiodine scanning may have a role in the follow-up of patients with high or intermediate risk.
Most recurrences of differentiated thyroid cancer occur within the first five years after initial treatment, however, recurrences may occur many years or even decades later, particularly in patients with papillary cancer. Therefore, ongoing follow-up after one year post-treatment is guided by individual assessment of the patient’s response to therapy during the first year of follow-up .