Epidemiology of Stage IV Colorectal Cancer: Trends in the Incidence, Prevalence, Age Distribution, and Impact on Life Span

Abstract

Colorectal cancer is a common malignancy in men and women. Historically, stage IV colorectal cancer has 10 to 15% five-year survival. Developments in the management of colorectal metastatic disease have helped improve the overall survival of stage IV colorectal cancers from 12 to 30 months with some patients achieving disease-free survival.

Globally, colorectal cancer (CRC) is the third most diagnosed cancer in men and the second most in women according to the GLOBOCAN database. ^{1 2} In 2020, CRC accounted for 10% of global cancer incidence and 9.4% of cancer deaths with the global prediction of 3.2 million new CRC cases in 2040. ³ Significant regional differences are also noted in the incidence of colorectal across the world with higher incidences in Australia, Europe, and North America compared to south-central Asia and Africa. In the United States, CRC is the third most common cancer diagnosed with estimated 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer for 2022. The average lifetime risk of CRC is approximately 4% in the United States with annually more than 52,580 Americans die of CRC, accounting for nearly 8% of all cancer deaths. Metastases are the leading cause of cancer-related mortality in CRC. The overall survival (OS) at 5 years from initial diagnosis for stage I and II CRC ranges from 87 to 90%, stage III ranges from 68 to 72%, and significantly lower around 11 to 14% for stage IV metastatic CRCs. ²

Investigating the epidemiology of metastatic disease from colon and rectal cancer is challenging due to cancer registries not recording the metastatic sites regularly. Some studies have shown that up to 70% of patients will eventually develop metastatic disease or relapse, including up to 50% of synchronous or metachronous liver metastases. ^{4 5 6 7 8} Autopsy studies of patients who died from CRCs showed right-sided colon cancers (RCCs) to show evidence of local and distant spread in 90% and distant sites alone in 10%. Also, rectal tumors spread locally in 25% of cases, distant sites alone in another 25%, and both distant and local in 50% of cases. Two-thirds of the patients with RCC died of liver metastatic disease and 75% of rectal cancer died from metastatic disease. ⁹ But European epidemiological studies show both synchronous and metastatic liver metastases to be around 25%, with synchronous liver metastases ranging from 14 to 17% while the rate of metachronous liver metastases from 7 to 15%. ¹⁰ The differences in the definition used for metachronous metastases were touted as partly the reason for the differences seen in various studies. Surveillance programs with regular carcinoembryonic antigen (CEA) or computed tomography scan expectedly increase the likelihood of identifying metastatic liver lesions early.

The majority of CRC-related death is attributed to metastatic disease with 22% of such patients presenting with metastatic disease at the time of diagnosis. The outcome of patients diagnosed with stage IV CRC is poor with a 5-year survival of 14% compared to 71% for regional disease and 90% for localized CRC. But the outcomes are improving with significant evolution in the management options available for such patients. In fact, 64% of CRC patients who were diagnosed between 2012 and 2018 had not died from their cancer 5 years later. Also, epidemiological studies have shown that in general, incidence and mortality are substantially higher in men than in women with 25% higher risk in men and 20% higher risk in African Americans compared to white Americans. ^{10 11 12}

Developments in the management of colorectal metastatic disease like oligometastatic resection, combination chemotherapies, targeted therapies, monoclonal antibodies, and immunotherapies have helped improve the OS of stage IV CRCs from 12 to 30 months. ^{3 4 5 6 8 13}

The understanding of the pathophysiology, metastatic characteristics, and prognostic value of the various variables are improving which lead to the changes introduced in the eighth edition of the TNM for CRC with modification to the M category involving the peritoneal metastases based on the evidence that it is an indicator of poor prognosis. ⁸ However, the current M category still includes multiple heterogeneous groups of metastatic CRCs with varied outcomes and different treatment options.

Tumor location has been identified as an independent prognostic factor for survival after diagnosis of CRC. Patients with metastatic RCC have been shown to have a lower 1-year relative survival of 40% compared with more than 50% for patients with left colon cancer (LCC) and rectal cancer. And this has been attributed to the prognostic impact of the primary cancer location in metastatic colon cancer. ¹⁴ The seed-and-soil hypothesis states that tumor metastases prefer specific organs based on interactions between tumor cells and their microenvironment involving metastatic gene signatures and tumor-stroma interactions at a molecular level. ^{15 16} Mucinous adenocarcinoma and signet ring cell cancers are uncommon histological subtypes of CRC with different clinical profiles and are associated with poor prognosis compared to non-mucinous histological types. Mucinous and signet ring cell variants are also associated with a higher predilection for RCCs, peritoneal metastases, and advanced stage at the time of presentation and this is likely to be the cause of poor prognosis with RCC compared to rectal and LCCs along with possible differences in the response to chemotherapy. ¹⁷

In patients who present with solitary metastasis, lung-only metastasis is shown to have a better prognostic indicator of OS and disease-specific survival compared with liver-only metastasis. Also, in patients with liver-only metastasis and lung-only metastasis, a strong survival benefit was seen with surgery for the primary site and chemotherapy with studies arguing for more widespread use of surgical resection of primary tumor and chemotherapy in patients with stage IV disease. ¹⁷

Liver Metastases

The liver is the most common site of metastasis from CRC with approximately 25% of CRC patients developing metastatic lesions in the liver during the course of the disease. ^{10 18 19} The liver is the sole organ with metastatic disease in 33% of patients and prognosis depends on the disease burden and resectability of the lesion with only 20% of the patients with liver metastases being resectable at the time of diagnosis. ²⁰ Retrospective studies on CRC patients with liver-only metastases showed a median OS of 22.8 months. ²¹ Patients who successfully undergo resection of liver metastases have been shown to have 5-, 10-, and 20-year survival of 25 to 58%, 17 to 28%, and 17%, respectively. ^{22 23 24 25 26} A significant number of patients with 5-year survival still progress to cancer-related death but patients who survive 10 years are considered cured. ^{26 27 28} Liver metastases occur more frequently in male patients and in patients with LCC and are related to the embryological origin of the primary tumor. With regards to metachronous disease, most recurrences occur early in follow-up with the majority (76–85.3%) occurring within a year and 83 to 97.5% within 3 years, with 30 to 40% of patients having disease confined to the liver. Approximately 2% of patients will develop liver metastases between 5 and 10 years after resection of the primary tumor. ^{10 13 19 29 30} Distal colon primary tumors are shown to have a higher predilection for metastatic liver disease compared to proximal colon primaries. ³¹

Studies evaluating the prognostic value of synchronous and metachronous liver metastases show significant variation due to the cutoff used for defining synchronous and metachronous detection. Despite the differences in the timing of the presentation, synchronous and metachronous metastasis is likely to be from the same underlying mechanism. The mechanism of colorectal liver metastasis is likely due to tumor cells entering the liver either via the portal vein or hepatic artery, with the common point of entry being touted to be the sinusoidal space. The development of liver metastasis in the transplanted liver in the absence of other metastatic diseases suggests the presence of viable tumor cells in the circulation after the resection of the primary tumor or previously undiagnosed lung or lymph node metastases could be the source of metastases. ³²

Metastatic sites also differed based on primary tumor locations with lung cancers seen more with rectal cancer patients than in patients with colon cancer. Peritoneal metastasis is seen more in the right colon (15%) and left colon (9%) than in rectal cancer (4%).

Among patients with solitary hepatic metastatic disease, 1-year relative survival was 43, 57, and 60% for RCC, LCC, and rectal cancer, respectively. Also, among patients with extraregional lymph nodes as solitary metastases, rectal cancer patients had poor relative survival compared to others. But the differences in survival are less pronounced among patients with peritoneal or pulmonary metastases. ¹⁴

Pulmonary Metastases

The lungs are the second most common site for distant colorectal metastases and previous studies have shown about 10 to 15% incidence of pulmonary metastases during the course of the disease. ^{33 34 35 36 37} Rectal cancer has been shown to have a higher predilection for synchronous and metachronous lung metastases. This is believed to be due to the direct spread of rectal cancer through hemorrhoidal veins into the systemic veins. Isolated lung metastases are shown to be less common with two studies showing 2.8 and 7.4% incidence. Patients with lung-only disease are shown to have significantly better prognoses compared to single organ metastases to another organ. ²¹ A single pulmonary lesion, absence of thoracic lymph node involvement, prolonged disease-free survival from primary diagnosis to metastatic spread, and lower CEA levels have been shown to have better prognostic value. Unfortunately, in most colorectal patients with pulmonary metastases, the lesions are not resectable. Palliative chemotherapy has been shown to have reported 3-year survival rates of 14.4 and 15.3% for metachronous and synchronous metastatic disease and 5-year survival of 0 and 8.4%, respectively.

Peritoneal Metastases

Studies show the incidence of peritoneal metastases to be between 4 and 13% with peritoneal as the only site of metastasis in about 4% of patients. ^{38 39 40 41} Risks factors for peritoneal metastases include RCC, advanced T-stage, advanced N-stage, poorly differentiated tumors, mucinous adenocarcinoma and younger age at the time of diagnosis. Peritoneal carcinomatosis is associated with a poor prognosis with a median survival of 6 to 8 months. ^{42 43} Cytoreductive surgery with intraperitoneal chemotherapy for CRC with peritoneal involvement as the sole metastatic site has been shown to have higher survival rates with 1-, 3-, and 5-year survival rates of 81, 41, and 27%, respectively, and median survival was 30.1 months. ⁴⁴ Rectal cancers are shown to have a higher incidence of synchronous and metachronous pulmonary metastatic disease and are more likely to present with simultaneous metastatic disease in the lungs and liver. The spread of metastatic rectal cancer to lungs either in isolation or as part of several distant metastatic diseases is likely through systemic venous spread via middle and inferior rectal veins. ⁴⁵

Brain Metastases

The occurrence of brain metastases in patients with CRC is rare with studies showing 1 to 3% with other studies showing incidences varying from < 1 to 8.8%. Two previous autopsy studies from 1944 to 1984 showed a 2.5 to 5% incidence of brain metastases, and these predate modern chemotherapy. The major limitation of these studies is that it reports only symptomatic brain metastatic disease as routine brain surveillance is not performed. Screening studies on patients with metastatic CRC with regular screening brain imaging showed a higher incidence of 14.6% with 76% being asymptomatic brain metastasis and 3.5% symptomatic brain metastasis. Although no regular screening for brain metastasis is recommended, patients with metastatic CRC who have been treated with multiple lines of chemotherapy may benefit from surveillance imaging. ⁴⁶

Bone Metastases

Historically, the incidence of bone metastases from CRC is around 6% although retrospective studies have shown the rates to be around 10.4% due to improved survival from CRC increasing longevity and increased risk for metastatic disease including bone metastasis. Autopsy studies have shown a higher incidence of bone metastases, approximately 10 to 24%. ⁴⁷ The median time to detection of bone metastases is 21 months and all patients have visceral metastases at the time of diagnosis of bone metastatic disease. The median survival time is 17.8 months with a 5-year survival rate of 5.7%. ^{48 49}

Coronavirus Disease-Related Issues

As with nearly every aspect of health care, CRC management was also significantly affected by the coronavirus disease (COVID) pandemic. Multiple studies have shown the adverse impact of the COVID pandemic on CRC screening programs across the world including in western countries including the United States. ⁵⁰ Decreased screening and attended delayed diagnosis has led to disease progression, delayed treatment, increased urgent referrals, and increased mortality as well. Studies show an increased incidence of late-stage CRCs in 2020 compared to 2019. Numerous studies from the U.K. and Netherlands also showed an 11.9 to 62% reduction in the diagnosis of new cases of colon and rectal cancer as well. A higher percentage of patients were diagnosed in emergency situations (36.0% vs. 28.6%; p  = 0.03), and higher stages of diagnosis (T4) during 2020 were higher than in 2018 to 2019 (34.5% vs. 27.1%; p  = 0.03). Also, colon obstruction increased from 4.3% in 2019 and 2018 to 8.6% in 2020 ( p  = 0.01), and colon cancer presenting with perforation from 3.3% in 2018 to 2019 to 4.1% in 2020. ^{51 52 53} Some studies also reported changes in treatment plans including from chemotherapy to surgery, long-term radiation therapy to short-term radiation, and elective to emergency surgery as well. ^{54 55 56 57 58}

Colorectal Cancers in Octogenarians

CRC is predominantly a disease of the elderly with an increasing incidence with age. The median age of diagnosis of CRC is 68 and 35% of patients diagnosed are above the age of 75 years. With increasing longevity, the incidence of CRC in octogenarians is expected to increase in the coming years. ⁵⁹ Octogenarians with CRCs were shown to have had a predominance of Ashkenazi ethnicity, a higher rate of a personal history of other malignancies, and a lower rate of family history of any cancer or of CRC. Octogenarians were also found to have a predilection for RCCs, had a higher perforation rate at the time of diagnosis, and had a higher rate of microsatellite instability-high tumors. Well-differentiated tumors were less prevalent among octogenarians with comparable tumor stages at the time of the diagnosis. Octogenarians are shown to receive less aggressive treatment (chemotherapy and surgery) and worse outcomes. ⁶⁰