Esophageal cancer stage 4

Science Surgery: ‘How quickly do tumours develop?’

Lung cancer cells under a microscope. Credit: LRI EM Unit

Our Science Surgery series answers your cancer science questions.

Kathryn asked: “How quickly do tumours develop?”

The short answer is it varies from tumour to tumour. But overall, it’s slower than you might expect.

According to Professor Trevor Graham, a Cancer Research UK-funded cancer evolution expert, the best evidence for the fact that most cancers grow slowly comes from screening. The screening programmes we have in the UK work “because there’s a long period of time when a tumour may have started to develop but it’s not become dangerous yet”, he says.

Take bowel screening for example. For every cancer that’s picked up during bowel cancer screening, 4 early tumours called adenomas are detected. Although most will never go on to become cancer, some will.

“It seems that tumour growth is started in lots of people, but it never quite makes it to the cancer stage,” says Graham. “That really points to growth often being slow.”

And this doesn’t just apply to bowel cancer. Similar trends are seen in breast cancer, where 1 in 4 breast cancers picked up during screening would never have caused any problems, which points to them being slow growing.

And even with cancers that often seem to be fast growing and aggressive, such as pancreatic cancer, Graham says this could just be down to the point at which they’re detected.

“We think that pancreatic cancers are often detected quite late, so they’ve been growing and evolving for a while. There might be a long and fairly slow development phase, but the first part is just invisible to us,” he says.

But like all good rules of thumb, there are exceptions. Graham works with people with inflammatory bowel disease, who have a higher risk of bowel cancer and are offered more regular bowel screening. This gives researchers a better idea of when tumours have begun to grow.

“Around 1 in 6 cancers develop in the 3 years between screens,” he says. “They won’t be there the first time we test, but they’ll develop before the second time. So they’ve developed relatively quickly.”

The question then becomes: what decides how quickly a tumour develops?

Turning back the clock

There’s a crucial set of ingredients needed for a cell to turn cancerous, which we’ve blogged about before.

A cell accumulates mistakes in its DNA, which cause a gene or a set of genes to go awry. And because cells have safety mechanisms that work to stop cells growing and dividing more than they should, multiple faults need to appear before a cell tips over the edge and becomes cancerous.

How quickly these faults appear, and what types of faults appear, could help to determine how fast a tumour develops.

Cancer Research UK-funded scientists have found that kidney cancer generally fall into one of 3 categories, based on the amount, type and variety of genetic damage the cancer cells have. And this is linked to how the cancers behave.

Some kidney cancers don’t have much genetic damage, producing slow-growing tumours that are unlikely to spread. At the other end of the spectrum were the aggressive, fast-growing tumours, which typically have lots of genetic changes inside the cells that push them to grow quickly and spread early on in their development.

Reading a cancer’s DNA can help us to understand when it started to develop.

By reading a cancer’s DNA, scientists can wind back the clock to its beginnings.

“Scientists can estimate how old cancers are using something called the ‘molecular clock’,” says Graham. “They can estimate how often random DNA faults occur and then compare that with how many faults are found in a particular tumour – and that can give them an estimate of how old the tumour is.”

Scientists have found that for most breast and bowel cancers, the tumours begin to grow around ten years before they’re detected. And for prostate cancer, tumours can be many decades old.

“They’ve estimated that one tumour was 40 years old. Sometimes the growth can be really slow,” says Graham.

So what can we do with this information?

Knowledge is power

For Graham, studying cancers’ clocks could help diagnose more tumours earlier.

“If we know how long a tumour takes to develop and when it’s likely to begin, then we know when to start looking in people for early signs of cancer. It could help us to design better screening programmes.”

This type of research could also help to personalise treatment. Using a cancer’s DNA code to predict how it might behave would give doctors an opportunity to tailor each person’s treatment. And also decide when treatment isn’t necessary.

We’re not there yet, but Graham’s team are working to make predictions like these a reality.

“It would help us to get diagnosis and treatment right and reduce the number of people whose cancers aren’t treated aggressively enough. But, equally as important, it would reduce the number of people who are overdiagnosed and overtreated for a slow-growing cancer that would never cause harm.”

Katie

We’d like to thank Kathryn for asking this question. If you’d like to ask us something, post a comment below or email [email protected] with your question and first name.

Breast cancer: How fast does it spread?

Share on PinterestMetastasis occurs when breast cancer cells begin to grow in another body part.

It is hard to say exactly how quickly breast cancer can grow, including the timeframe, as the disease affects each person differently.

Cancer occurs due to mutations in human cells. Mutations do not follow normal, predictable patterns of cell division, so it is difficult to predict the progression.

Tumors appear when damaged cells replicate over and over to form a clump of abnormal cells. Breast cancer cells can break off and move through the lymph or blood vessels to other areas of the body.

If breast cancer cells begin to grow in another body part, this is called metastasis. Breast cancer is most likely to metastasize to the lymph nodes, lungs, and bones.

Regardless of the location of the new tumor, doctors still consider it to be breast cancer.

Breast cancer growth and its chances of spreading depend on the following:

Type of breast cancer

Breast cancer can be invasive or noninvasive:

  • Noninvasive breast cancer will not spread beyond the ducts or lobules.
  • Invasive breast cancer can spread to the surrounding connective tissue, the lymph nodes, and other areas of the body.

Grade (1–3)

A doctor will grade breast cancer (1–3) based on how much the cancer cells look like normal breast cells:

  • grade 1 is a slower-growing cancer
  • grade 3 is a faster-growing cancer

A higher grade means that a cancer is more likely to grow faster and to spread to other areas of the breast or body.

Stage (0–4)

Healthcare professionals describe the extent of breast cancer progression in stages. This information is incredibly important when making decisions regarding treatment.

The stages of breast cancer are as follows:

  • Stage 0. Doctors consider breast cancer at this stage noninvasive, and it is only present in the ducts or the lobules. Ductal carcinoma in situ is a form of stage 0 breast cancer.
  • Stage 1. Breast cancer at this stage is invasive, but it remains small and near the primary site. Stage 1A involves tumors that are 2 centimeters or smaller and have not reached the lymph nodes. At stage 1B, the cancer has reached the lymph nodes.
  • Stage 2. Stage 2 breast cancer is invasive, tumors may be larger than in stage 1, and the cancer may have spread to the lymph nodes.
  • Stage 3. Stage 3 breast cancer is invasive, tumors may be larger, and cancer has spread to the lymph nodes, possibly to several. Breast cancer at this stage has not spread to other organs.
  • Stage 4. Breast cancer has developed in other areas of the body outside the breast and lymph nodes, often in the bones, lungs, brain, or liver. Treatment at this stage focuses on controlling the cancer and preventing it from spreading any farther.

Cancer that has already spread to other areas of the body, or stage 4 cancer, is more likely to spread further.

Although it is difficult to assess the progress of cancer over the course of 1 year, the American Cancer Society provide estimates about the 5-year survival rates for people at different stages of breast cancer.

The 5-year survival rate refers to the number of people who will live for 5 years after finding out that they have breast cancer:

  • close to 100 percent for stages 0 and 1
  • 93 percent for stage 2
  • 72 percent for stage 3
  • 22 percent for stage 4

These figures are population estimates. Each person’s individual survival rate varies depending on a wide range of factors.

Personal factors

Growth or spread within a year will often depend on personal factors, including:

  • age at diagnosis
  • hormone status, such as pre- or postmenopause
  • family history of breast cancer
  • exposure to alcohol, cigarettes, or pollution
  • previous history of cancer

Response to treatment

A doctor may also take how a person responds to previous or current treatment into account when working out the likely change or progression of cancer.

Understanding Advanced Cancer, Metastatic Cancer, and Bone Metastasis

If the cells travel through the lymph system, they could end up in nearby lymph nodes (small, bean-sized collections of immune cells) or they could spread to other organs. More often, cancer cells that break off from the main tumor travel through the bloodstream. Once in the blood, they can go to any part of the body. Many of these cells die, but some may settle in a new area, start to grow, and form new tumors. This spread of cancer to a new part of the body is called metastasis.

Cancer cells have to go through several steps to spread to new parts of the body:

  • They have to be able to break away from the original tumor and enter the bloodstream or lymph system, which can carry them to another part of the body.
  • They need to attach to the wall of a blood or lymph vessel and move through it into a new organ.
  • They need to be able to grow and thrive in their new location.
  • They need to be able to avoid attacks from the body’s immune system.

Going through all these steps means the cells that start new tumors may no longer be exactly the same as the ones in the tumor they started in. This might make them harder to treat.

Even when cancer has spread to a new area, it’s still named after the part of the body where it started. For instance, breast cancer that has spread to the lungs is called “metastatic breast cancer to the lungs” – it’s not lung cancer. Treatment is also based on where the cancer started. If prostate cancer spreads to the bones, it’s still prostate cancer (not bone cancer), and the doctor will recommend treatments that have been shown to help against metastatic prostate cancer. Likewise, colon cancer that has spread to the liver is treated as metastatic colon cancer, not liver cancer.

Sometimes the metastatic tumors have already begun to grow when the cancer is first found and diagnosed. And in some cases, a metastasis may be found before the original (primary) tumor is found. If a cancer has already spread to many places when it’s found, it may be very hard to figure out where it started. If this happens the cancer is called cancer of unknown primary.

Why cancer cells tend to spread to certain parts of the body

Where a cancer starts is linked to where it will spread. Most cancer cells that break free from the original tumor are carried in the blood or lymph system until they get trapped in the next “downstream” organ or set of lymph nodes. Once the cells are there, they can start to grow and form new tumors. This explains why breast cancer often spreads to underarm lymph nodes, but rarely to lymph nodes in the groin. Likewise, there are many cancers that commonly spread to the lungs. This is because the heart pumps blood from the rest of the body through the lungs’ blood vessels before sending it elsewhere.

What is bone metastasis?

A bone metastasis is an area of bone that contains cancer that spread there from somewhere else.

Cancer can spread to any bone in the body, but metastases are most often found in bones near the center of the body. The spine is the most common site. Other common sites are the hip bone (pelvis), upper leg bone (femur), upper arm bone (humerus), ribs, and the skull.

Once cancer has spread to the bones or to other parts of the body it’s rarely able to be cured. Still, it often can be treated to shrink, stop, or slow its growth. Even if a cure is no longer possible, treating the cancer may be able to help you live longer and feel better.

How does bone metastasis cause bone changes and other problems?

Bone is the supporting framework of the body. Bones are made of a network of fibrous tissue called matrix, minerals such as calcium that attach to the matrix and give the bone its strength and hardness, and 2 main kinds of bone cells are osteoblasts and osteoclasts.

Knowing a little about these 2 kinds of cells can help you understand how bone metastases grow, and how some medicines work to treat bone metastases. The osteoblast is the cell that forms new bone, and the osteoclast is the cell that dissolves old bone. When these cells are both working right, new bone is always forming while old bone is dissolving. This helps keep the bones strong.

Cancer cells can affect the bones by interfering with osteoblasts and osteoclasts:

  • Often, the cancer cells make substances that turn on the osteoclasts. This leads to bone being broken down without new bone being made. This weakens the bones. The holes that develop when parts of bones dissolve are called osteolytic or lytic lesions. Lytic lesions are so weak that they can cause the bone to easily break.
  • Sometimes, the cancer cells release substances that turn on the osteoblasts. This leads to new bone being made without breaking down the old bone broken down first. This makes areas of the bones harder, a condition called sclerosis. The areas of bone where this occurs are called osteoblastic or blastic lesions. Although these blastic areas are harder, the structure of the bone is not normal and these areas actually break more easily than normal bone.

Bone metastasis can cause other problems as well:

  • When cancer spreads to the bones of the spine, it can press on the spinal cord. This can cause nerve damage that may even lead to paralysis if not treated.
  • As cancer cells damage the bones, calcium from the bones is released into the blood. This can lead to problems caused by high blood calcium levels (hypercalcemia).

Why do cancers metastasize to bones?

For cancer cells to spread to other parts of the body, they have to go through many changes:

  • They have to be able to break away from the original (primary) tumor and get into the bloodstream or lymph system, which can carry them to another part of the body.
  • At some point they need to attach to the wall of a blood or lymph vessel and move through it, out into a new organ.
  • They then need to be able to grow and thrive in their new location.

All the while, the cancer cells need to be able to avoid attacks from the body’s immune system. Going through all these steps means the cells that start new tumors may no longer be exactly the same as the ones in the tumor where they started, but they will still be called the same name. For instance, breast cancer that spreads to the bone is called metastatic breast cancer, not bone cancer.

What’s the difference between primary bone cancer and bone metastasis?

Some cancers start in the bone, rather than spreading to the bones from somewhere else. Cancers that start in the bone are called primary bone cancers. These cancers are very different from bone metastases. Bone metastasis is much more common than primary bone cancers, especially in adults.

Information on different types of primary bone cancers can be found in Bone Cancer, Osteosarcoma, and Ewing Family of Tumors.

Survival Rates for Esophageal Cancer

Survival rates can give you an idea of what percentage of people with the same type and stage of cancer are still alive a certain amount of time (usually 5 years) after they were diagnosed. They can’t tell you how long you will live, but they may help give you a better understanding of how likely it is that your treatment will be successful.

Keep in mind that survival rates are estimates and are often based on previous outcomes of large numbers of people who had a specific cancer, but they can’t predict what will happen in any particular person’s case. These statistics can be confusing and may lead you to have more questions. Talk with your doctor about how these numbers may apply to you, as he or she is familiar with your situation.

What is a 5-year relative survival rate?

A relative survival rate compares people with the same stage of esophageal cancer to people in the overall population. For example, if the 5-year relative survival rate for a specific stage of esophageal cancer is 60%, it means that people who have that cancer are, on average, about 60% as likely as people who don’t have that cancer to live for at least 5 years after being diagnosed.

Where do these numbers come from?

The American Cancer Society relies on information from the SEER* database, maintained by the National Cancer Institute (NCI), to provide survival statistics for different types of cancer. The SEER database tracks 5-year relative survival rates for esophageal cancer in the United States, based on how far the cancer has spread. The SEER database, however, does not group cancers by AJCC TNM stages (stage 1, stage 2, stage 3, etc.). Instead, it groups cancers into localized, regional, and distant stages:

  • Localized means that the cancer is only growing in the esophagus.
  • Regional means that the cancer has spread to nearby lymph nodes or tissues.
  • Distant means that the cancer has spread to organs or lymph nodes away from the main tumor.

5-year relative survival rates for esophageal cancer

These numbers are based on people diagnosed with esophageal cancer between 2009 and 2015.

Stage

5-Year Relative Survival Rate

Localized

47%

Regional

25%

Distant

5%

All SEER stages combined

20%

These survival rates do not separate squamous cell carcinomas from adenocarcinomas, although people with adenocarcinomas are generally thought to have a slightly better prognosis (outlook) overall.

Understanding the numbers

  • People now being diagnosed with esophageal cancer may have a better outlook than these numbers show. Treatments improve over time, and these numbers are based on people who were diagnosed and treated at least five years earlier.
  • These numbers apply only to the stage of the cancer when it is first diagnosed. They do not apply later on if the cancer grows, spreads, or comes back after treatment.
  • These numbers don’t take everything into account. Survival rates are grouped based on how far the cancer has spread, but your age, overall health, how well the cancer responds to treatment, and other factors will also affect your outlook.

*SEER = Surveillance, Epidemiology, and End Results

PMC

DISCUSSION

The overall prognosis in stage IV esophageal adenocarcinoma remains poor. The estimated 5-year mortality for stage IV disease exceeds 85% to 90% . Following diagnosis, many patients suffer significant comorbidities and require interventions such as esophageal stenting and feeding tube placement. A significant factor in improving survival after chemoradiation involves local disease control . The present case demonstrates the long-term safety and efficacy of adjunctive cryoablation in combination with concurrent chemoradiotherapy for local control of recurrent esophageal cancer. Over the treatment course, the primary tumor increased slowly in length; however, chemo-cryo-radiotherapy appeared to maintain disease control. The patient remained asymptomatic, without requiring nutritional support, and had an ECOG performance status of 0–1 for 7 years following initial diagnosis.

Cryotherapy for esophageal cancer has been found to be effective for local tumor eradication . In a 2010 multicenter, retrospective study, 79 patients with esophageal carcinoma underwent cryotherapy, and had biopsy-confirmed, complete eradication of luminal cancer. Of 49 patients, 30 (61%) demonstrated a complete response to cryotherapy. Among those with early tumors, 72.2% with T1 stage disease had complete endoscopic response. In safety analysis, no serious adverse events were reported. Benign strictures occurred in 13% of the patients .

This patient underwent concomitant chemoradiation therapy, which also likely augmented disease control. He received a standard platinum- and fluorouracil-based regimen for esophageal adenocarcinoma . He was initially treated with FOLFIRI which has been studied in gastroesophageal junction cancer, and has a response rate, time to progression, and median survival similar to those of platinum and 5- fluorouracil-based regimens . He was subsequently changed to FOLFOX. He underwent standard external beam radiation of 50.4 total Gy, with 36 fractions of 1.8 Gy per fraction over 2 months. The chemotherapy and radiation conformed to standard regimens, with the addition of serial cryoablation. We believe that cryoablation may have a synergistic effect in combination with chemoradiotherapy, and that the effects of combination treatment likely contributed to the favorable disease course and long-term survival,

Long-term follow-up allowed for longitudinal evaluation of the safety profile of cryotherapy ablation. After 18 treatments, the patient has not experienced any side effects. When comparing spray cryotherapy to other endoscopic treatments for esophageal adenocarcinoma, there appears to be a very low adverse event rate. Salvage photodynamic therapy after chemoradiation has side effects including esophageal stenosis (23%–100% of patients), cutaneous phototoxicity, perforation, mediastinitis, and pleural effusion. Endoscopic mucosal resection is an excellent therapeutic approach for high-grade dysplasia and early T-stage tumors, but does not play a role in the treatment of T2-T4 cancers .

The findings in this case suggest that cryotherapy is a safe adjunct and viable long-term addition for local control of recurrent esophageal cancer in combination with concurrent chemoradiation, and may offer palliative benefit. The patient in this case remained free of obstruction and did not require a feeding tube or stent placement. It is not yet clear whether the addition of routine cryotherapy to standard chemoradiation yields a survival benefit; however, cryotherapy it is a potential additional measure which could be offered and studied in a cohort of patients with an otherwise poor long-term prognosis.

Understanding the Progression of Esophageal Cancer

In the earliest stages, when it’s easiest to treat, esophageal cancer has very few symptoms, so unfortunately it’s rarely caught early. As esophageal cancer begins to progress and advance to the later stages, symptoms become more apparent, and the cancer becomes more difficult to treat.

Esophageal Cancer: Stages and Survival Rates

The esophagus is a long, muscular tube that joins your mouth to your stomach. Esophageal cancer is classified into four stages, 0 through IV. In the earliest stage of esophageal cancer, the cancer affects only the lining of the esophagus. At this point, it is generally easy to treat and survival rates are high. But as cancerous cells grow and spread, a larger tumor forms in the esophagus, and often spreads to nearby lymph nodes, tissues, and eventually to other organs in the body. The following is a breakdown of the stages of esophageal cancer:

  • Stage 0. This is the best-case scenario for a person diagnosed with esophageal cancer; in this stage of cancer, the disease has just begun to develop and has not spread beyond the lining of the esophagus. There are typically very few or no symptoms in this stage. Between 80 and 90 percent of esophageal cancer patients diagnosed in stage 0 can expect to survive five years following their treatment.
  • Stage I. At this stage of esophageal cancer, the disease has spread deeper into the tissues of the esophagus, but has not yet affected nearby lymph nodes or organs. The five-year survival rate for people diagnosed with esophageal cancer during this stage is 34 percent.
  • Stage II. By this stage, the cancer has moved into the deeper tissues of the esophageal wall and may now affect lymph nodes near the esophagus. The five-year rate of survival is 17 percent when esophageal cancer is diagnosed at stage II.
  • Stage III. In stage III, the cancer has progressed beyond the wall of the esophagus and nearby lymph nodes to surrounding tissues, but other organs are not yet affected. At this stage, people often complain of throat pain and difficulty swallowing. Twenty to 30 percent of patients in stage III who receive both chemotherapy and radiation are likely to survive between three and five years.
  • Stage IV. In stage IV, the cancer has metastasized, or spread, to other parts of the body. The five-year rate of survival for esophageal cancer patients diagnosed during stage IV drops to 2.8 percent.

Esophageal cancer

Esophageal cancer stages

Making an educated esophageal cancer treatment decision begins with determining the stage, or progression, of the disease. The stage of esophageal cancer is one of the most important factors in evaluating treatment options.

Our cancer doctors use a variety of diagnostic tests to evaluate esophageal cancer and develop an individualized treatment plan. If you have been recently diagnosed, we will review your pathology to confirm you have received the correct diagnosis and staging information and develop a personalized treatment plan. If you have a recurrence, we will perform comprehensive testing and identify a treatment approach tailored to your needs.

It’s also important to understand that the stage of your cancer may change. Your care team will let you know if your staging information is affected by the progression, or regression, of your disease.

The stages of esophageal cancer are assigned based on the American Joint Committee on Cancer’s (AJCC) TNM system, a commonly accepted method based on three key components:

T (tumor): This describes the size of the original tumor.

N (node): This indicates whether the cancer is present in the lymph nodes.

M (metastasis): This refers to whether cancer has spread to other parts of the body.

A number (0-4) or the letter X is assigned to each factor. In esophageal cancer staging, as in all cancer staging, a higher number indicates increasing severity. For instance, a T1 score indicates a smaller tumor than a T2 score. The letter X means the information could not be assessed.

Once the T, N and M scores have been assigned, one of these overall stages is assigned:

Stage I (stage 1 esophageal cancer): A stage I esophageal cancer tumor is small (7 cm or less across) and limited to the esophagus.

Stage II (stage 2 esophageal cancer): A stage II esophageal cancer tumor has grown larger but still remains within the esophagus. In this stage of the disease, there is no evidence of spread to lymph nodes or distant sites.

Stage III (stage 3 esophageal cancer): A stage III esophageal cancer tumor has grown beyond the esophagus and may now extend into nearby tissues or organs. The cancer may or may not have spread to nearby lymph nodes.

Stage IV (stage 4 esophageal cancer): A stage IV esophageal cancer tumor may be any size and has grown beyond the esophagus. In this stage of esophageal cancer, the disease may have spread to lymph nodes or distant sites like the liver or abdominal cavity.

Next topic: How is esophageal cancer diagnosed?

Sites of metastasis and overall survival in esophageal cancer: a population-based study

Introduction

Metastasis to distant organs is the leading cause of cancer-related deaths.1–4 Esophageal cancer (EC) is a highly lethal malignant tumor. The incidence of EC, especially the rate of esophageal adenocarcinoma (AC) in Western countries has gradually increased in recent decades.5–7 Approximately 50% of patients present with metastases to distant lymph nodes or organs at initial diagnosis.8,9 The prognosis of metastatic EC is poor, and the five-year survival rate is less than 5%.10,11 Although the major mechanisms that regulate metastasis have been identified, limited advances have been made in our understanding of the epidemiology of cancer metastasis.

EC most commonly spreads to the liver, followed by lung, bone, and brain.12–15 Therefore, knowledge of the patterns of distant metastasis (DM) is crucial to improve patient treatment and follow-up. Population-based cancer registries provide an excellent opportunity to investigate the relationship between the patterns of DM and prognosis in metastatic cancer. However, such data are rarely recorded. The purpose of this study was to assess the site-specific patterns of DM and survival outcomes of metastatic EC using the surveillance, epidemiology, and end results (SEER) database.

Methods

Data were obtained from the recent SEER-18 database, which is maintained by the National Cancer Institute and represents approximately 28% of the population of the United States.16 We limited this study to patients diagnosed between 2010 and 2014 as detailed information about site-specific metastasis was not recorded before 2010. We identified patients with de novo stage IV esophageal squamous cell carcinoma (SCC) or AC. Patients for whom EC was not the first tumor or for whom data on sites of DM were not available were excluded. Approval for this study was obtained from the Institutional Review Board of the First Affiliated Hospital of Xiamen University.

We assessed the effect of potential demographic and clinicopathological variables (age, sex, race/ethnicity, tumor location, histological subtype, tumor grade, tumor classification, nodal classification, treatment, and sites and the number of DM) on patient survival. The sites of DM were classified as distant lymph node, bone, brain, liver, and lung. Due to the moderate sensitivity and high specificity of the radiotherapy and chemotherapy data, radiotherapy and chemotherapy are classified as “yes” or “no/unknown” in the current SEER custom database.17 Survival time from initial diagnosis (months), specific cause of death, and vital status were also extracted from the dataset. The primary end point of this study was overall survival (OS).

Independent predictors of OS in de novo stage IV EC were assessed using a Cox proportional model. Kaplan–Meier analysis and log-rank testing were used to compare OS. p<0.05 was considered statistically significant. All calculations were performed using SPSS statistical software (version 21.0; IBM Corporation, Armonk, NY, USA).

Results

Characteristics of the patients

Table 1 Characteristics of the 3218 patients with stage IV esophageal cancer

Abbreviations: AC, adenocarcinoma; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; G4, undifferentiated; N, node; SCC, squamous cell carcinoma; T, tumor.

Sites of distant metastases

Table 2 Patterns of distant metastases for the 3218 patients with stage IV esophageal cancer

Treatment

Survival outcomes and prognostic analysis

Median OS was 6 and 5 months for patients with a single site of DM and multiple sites of DM, respectively. Median OS for patients with liver, distant lymph node, lung, bone, and brain metastases was 5, 10, 6, 4, and 6 months, respectively (p<0.001).

In patients with a single site of DM (n = 1885), univariate analysis indicated that age, nodal classification, surgery, radiotherapy, chemotherapy, and site of DM were associated with OS (Table 3). In the entire cohort (n = 3218), age, sex, race/ethnicity, tumor location, histological subtype, nodal classification, surgery, radiotherapy, chemotherapy, and the number of DM sites were prognostic factors for OS (Table 3).

Table 3 Univariate Cox regression analysis of prognostic factors for overall survival in stage IV esophageal cancer

Note: “–” indicates no data.

Abbreviations: AC, adenocarcinoma; CI, confidence interval; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; G4, undifferentiated; HR, hazard ratio; N, node; SCC, squamous cell carcinoma; T, tumor.

Multivariate analysis of patients with a single site of DM revealed that the site of DM was an independent prognostic factor affecting OS (Table 4). Using liver metastases as the reference, DM to bone was associated with poorer OS (hazard ratio 1.211, 95% confidence interval 1.023–1.434, p=0.026), while DM to distant lymph nodes was associated with better OS (HR 0.829, 95% CI 0.722–0.953, p=0.008). Brain (HR 1.077, 95% CI 0.779–1.490, p=0.653) and lung (HR 0.865, 95% CI 0.736–1.018, p=0.081) metastases were associated with similar OS compared to liver metastases. The corresponding survival curves are shown in Figure 1. In the entire cohort, the number of DM was an independent prognostic factor for OS; multiple sites of DM were associated with poorer OS (HR 1.388, 95% CI 1.269–1.518, p<0.001). In addition, surgery, radiotherapy, and chemotherapy were associated with better OS in multivariate prognostic models of patients with single or multiple sites of DM.

Figure 1 Kaplan–Meier survival curves for patients with metastatic esophageal cancer stratified by sites of distant metastases.

Table 4 Multivariate Cox regression analysis of prognostic factors for overall survival in stage IV esophageal cancer

Note: “–” indicates no data.

Abbreviations: AC, adenocarcinoma; CI, confidence interval; HR, hazard ratio; N, node; SCC, squamous cell carcinoma.

Figure 2 Kaplan–Meier survival curves for patients with metastatic esophageal squamous cell carcinoma (A) and adenocarcinoma (B) stratified by sites of distant metastases.

Discussion

This population-based study indicates that the prognosis of patients with metastatic EC differs according to the site of DM, and also that multimodality treatment may improve OS in metastatic EC.

Similarly to previous retrospective reports and autopsy studies of patients with metastatic EC,12–15 the most common sites of DM in this study were the liver, followed by distant lymph nodes, lung, bone, and brain. Notably, this study was based on a much larger sample size than the previous studies. Moreover, our analysis provides additional information on the prognostic impact of site-specific DM in metastatic EC.

There are limited studies on the effect of the site of DM on survival in metastatic EC. Chen et al found that DM (not including DM to distant lymph nodes) was not associated with OS in metastatic esophageal SCC.13 Tanaka et al also observed no significant difference in median survival for different sites of DM, including liver, bone, and lung (p=0.8786).10 The study by Blank et al included patients with metastatic esophagogastric AC, and found that localization (distant hematogenous vs. peritoneal carcinomatosis vs. distant lymph nodes, p=0.631) and the number (p=0.754) of metastases were not significant prognostic factors for survival;18 however, they did not further analyze the effect of site-specific DM on survival. In this study, patients with distant lymph node metastases had better OS than patients with liver metastases, while bone metastases were associated with poorer OS compared to liver metastases, especially in esophageal AC. We also observed similar OS rates for patients with liver, bone, or lung metastases in esophageal SCC. Therefore, patients with stage IV EC represent a heterogeneous group that could potentially be classified by site-specific metastasis. In addition, the number of DM was also an independent prognostic factor for OS. These observations may help physicians more accurately assess the prognosis of patients with metastatic EC.

In this study, patients with distant lymph node metastases had significantly longer OS (median, 10 months) than patients with DM to other sites. Chao et al reported a similar median OS duration of 14.2 months for patients with non-regional lymph node metastases after chemoradiotherapy.19 Therefore, combined modality treatment may yield reasonable survival outcomes for patients with EC who have distant lymph node metastases.

In breast cancer, patients with bone metastases achieve significantly better survival than patients with metastasis to other sites.20,21 However, in this study, patients with bone metastases had significantly poorer OS (median, 4 months) than those with metastasis to other sites. Bone metastases were also associated with poor survival in a population-based study of metastatic lung cancer.22 The mechanism by which bone metastases lead to poorer survival compared to other sites of DM in metastatic EC is not known. Overexpression of parathyroid hormone-related protein (PTHrP) is associated with increased risk of bone metastases in small cell lung cancer.23 Osteolytic bone metastases often overproduce PTHrP.1 Bone metastases in EC was associated with humoral hypercalcemia and leukocytosis, which may promote rapid disease progression.24–26

There is no consensus on whether palliative radiotherapy or surgery is of value in metastatic EC. Several retrospective and prospective studies have suggested that palliative radiotherapy could improve survival in metastatic EC.27–29 In addition, several recent retrospective studies found that resection of primary tumors may be considered for a select group of patients with stage IV EC who achieve a favorable response to systemic chemotherapy.18,19,30 Our previous study of the SEER database also found that surgery and preoperative radiotherapy were associated with better survival in metastatic EC.11 Furthermore, lymph node dissection is associated with better survival.31 In the present study, most of patients who underwent esophagectomy also received radiotherapy and chemotherapy, and surgery. Radiotherapy and chemotherapy were independent favorable prognostic factors for OS, similarly to results in metastatic breast cancer, colorectal cancer, and renal cell carcinoma.32–36 However, the numbers of patients who underwent surgical resection of the primary tumor in the aforementioned studies were not large enough to reach definite conclusions. In addition, these retrospective studies possess methodological defects. Therefore, further studies are required to identify the subgroups of patients who may benefit from aggressive multimodality therapy.

We should acknowledge that this study has several limitations. First, retrospective analyses may be inherently biased. Second, the SEER database lacks detailed information on comorbidities, which could lead to potential selection bias towards patients receiving a specific treatment. In addition, the SEER program only included five site-specific DM at the initial diagnosis, and we could not obtain further details concerning the other sites of DM. Third, the findings of this study can only be generalized to the United States population and are not representative of the global population, especially in endemic areas such as People’s Republic of China. Moreover, the overall sensitivity of the radiotherapy and chemotherapy data in the current SEER database was 80% and 68%, respectively. However, the radiotherapy and chemotherapy data had a high specificity.17

Conclusion

In conclusion, in advanced EC, patients with bone metastases seem to have the poorest OS, while patients with distant lymph node metastases have the best OS. This study suggests that increased attention should be paid to the mechanisms and prognostic value of site-specific metastases. Furthermore, additional studies are required to identify the subset(s) of patients with advanced EC who may benefit from primary local treatment.

Disclosure

The authors report no conflicts of interest in this work.

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