Contemporary Management of Metastatic Colorectal Cancer: A Precision Medicine Approach

Contemporary Management of Metastatic Colorectal Cancer: A Precision Medicine Approach summarizes current knowledge and provides evidenced-based practice recommendations on how to treat patients with metastatic colorectal cancer. The book presents topics such as pre-operating imaging, the use of molecular markers in treatment decisions, neoadjuvant therapy, synchronous colorectal liver metastasis, and minimally invasive approaches. In addition, it discusses immunotherapy, targeted therapies and survivorship. This is a valuable resource for practitioners, cancer researchers, oncologists, graduate students and members of biomedical research who need to understand more about novel treatments for colorectal cancer metastasis.

• Summarizes contemporary data in the workup and treatment of patients with metastatic colorectal cancer
• Discusses novel patient-centric personalized approaches surrounding the management of such cancer types
• Presents evidenced-based recommendations for precision care among patients with metastatic colorectal cancer

• Language: English
• Publisher: Academic Press
• Release date: Jun 23, 2022
• ISBN: 9780323985680

Book preview

Preface

Hepatic Colorectal Metastases: A Story of Potential Cure for a Stage Four Cancer

Colorectal carcinoma is the third most common cancer in humans. Yearly, over 2 million people worldwide will be diagnosed with this cancer. Nearly a million people will die of colorectal cancer this year. The liver is the most frequent site of hematogenous metastases from colorectal cancer, and the site most responsible for death from this common cancer (Stewart et al., 2018).

Until the late 20th century, metastatic colorectal cancer was thought to be uniformly fatal. Then, observation in autopsy studies and in radiologic studies using CAT scanners invented in the 1970s that metastatic disease can be isolated to the liver encouraged early pioneers to resect liver metastases. Bold pioneers such as Joseph Fortner, Kevin Hughes, James Foster, and Martin Adson performed and reported data to establish such liver resections of metastatic disease as rational practice (Hughes et al., 1988).

By the end of the 20th century, resection of hepatic colorectal metastases was an established field. We knew from the work of Joseph Fortner, with actual 25-year follow-up, that surgical resection alone can result in cure in 25% of patients (Fortner and Fong, 2009). We knew from the work of many including the famed trialist Bernard Nordlinger (Nordlinger et al., 1996) that liver resection at major centers is safe, with mortality less than 5%, and result in 5-year survival of greater than 40 months. The progress in chemotherapy was also remarkable. In 1996, Henri Bismuth reported that 15% of nonresectable cases could be converted to resectable with chemotherapy and result in long-term survival and potential cure (Bismuth et al., 1996).

The progress in the first quarter of the 21st century has also been notable. The current status of the field is well summarized in the current book edited by Dr. Pawlik and Dr. Ejaz. They have included chapters on our current scientific knowledge of epidemiology, molecular pathogenesis, tumor microenvironment, and promising therapeutic targets including immunotherapy. Radiologic and molecular staging have been summarized as relevant for patient selection, surgical planning, and long-term follow-up. Treatment options of resection, ablation, regional chemotherapy, radiation therapy, and minimally invasive approaches are discussed in the context of optimizing patient outcome. Included are also important methods of making more patients eligible for resection by portal vein embolization, two-stage resections, and ALPPS. A number of important special topics are discussed including disappearing metastases, management of synchronous metastasis, and management of recurrences. This is a comprehensive handbook for this field intended for all levels and all disciplines of medical professionals treating patients with metastatic colorectal cancer.

It is gratifying for all of us who have spent a lifetime treating this disease that patients with this stage 4 disease are now provided with an opportunity to survive their disease and live full lives. However, it must be noted that less than 10% of patients with hepatic colorectal metastases are offered liver resection, when 30–50% are eligible (Raoof et al., 2020). As we go forward, the biggest challenge remains to educate all physicians and oncologist surgical resection is the standard of care. Works such as this book by Pawlik and Ejaz will be important for such educational efforts. It is also sobering that access to lifesaving liver surgery is determined by ethnicity (Thornblade et al., 2020) and health insurance coverage (Raoof et al., 2021).

The progress in treatment of patients with metastatic colorectal cancer has been remarkable. Over 50% of patients are now 5-year survivors, and over one-third cured. Now, it is our job not only to continue the great scientific and clinical progress, but also to make social progress to ensure more eligible patients are offered and receive such treatment, regardless of race, ethnicity, or economic resources.

Yuman Fong

Sangiacomo Chair and Chairman

Department of Surgery

City of Hope Medical Center

References

Bismuth, H., et al., Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann. Surg., 1996. 224(4): p. 509–520.

Fortner, J.G. and Y. Fong, Twenty-five-year follow-up for liver resection: the personal series of Dr. Joseph G. Fortner. Ann. Surg., 2009. 250(6): p. 908–13.

Hughes, K.S., et al., Resection of the liver for colorectal carcinoma metastases. A multi-institutional study of long-term survivors. Dis. Colon. Rectum., 1988. 31: p. 1–4.

Nordlinger, B., et al., Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer, 1996. 77(7): p. 1254–1262.

Raoof, M., et al., Systematic failure to operate on colorectal cancer liver metastases in California. Cancer Med., 2020. 9(17): p. 6256–67.

Raoof, M., G. Jacobson, and Y. Fong, Medicare advantage networks and access to high-volume cancer surgery hospitals. Ann. Surg., 2021. 274(4): p. e315-e319.

Stewart, C.L., et al., Cytoreduction for colorectal metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When does it palliate, prolong survival, and potentially cure?Curr. Probl. Surg., 2018. 55(9): p. 330–379.

Thornblade, L.W., et al., Association of race/ethnicity with overall survival among patients with colorectal liver metastasis. JAMA Netw. Open, 2020. 3(9): p. e2016019.

Chapter 1

Epidemiology and risk factors for metastatic colorectal disease

Erin P Ward, MDa, Callisia N Clarke, MD, MSb

aAssistant Professor of Surgery, Division of Surgical Oncology, 8701, W. Watertown Plank Road, Milwaukee, WI, 53226

bMedical College of Wisconsin, CGSO Fellow, Surgical Oncology, Milwaukee, WI, United States

Colorectal cancer incidence and survival

In the United States, colorectal cancer (CRC) is the third leading cause of cancer-related deaths for both women and men. It accounts for 7.9 percent of all new cancer diagnoses each year and 8.7 percent of all cancer deaths (Siegel et al., 2020). The majority of patients diagnosed with CRC are over the age of 50; however, 12 percent of all new CRC cases are diagnosed in patients younger than 50 (Siegel et al., 2020). Although improved screening efforts have led to an overall decrease in incidence in CRC diagnoses since 2000, incidence in young adults under the age of 50 has increased since the 1990s. By 2030, current projections of CRC incidence predict that while the overall rates will decrease, rates of CRC in those between age 35–49 will increase by 27 percent for colon cancer and 46 percent for rectal and rectosigmoid cancer (Bailey et al., 2015).

The American Cancer Society (ACS) estimates the lifetime risk of CRC to be 1 in 23 for men and 1 in 25 for women (American Cancer Society: About Colorectal Cancer., 2021). The Surveillance, Epidemiology, and End Results (SEER) Program data shows that at the time of diagnosis, 38 percent of patients have localized disease, 35 percent have regional disease, 21 percent have distant disease and 7 percent are unstaged. Overall, the rates of localized CRC have decreased since 2007, likely attributable to increased surveillance with colonoscopies and other screening modalities including fecal occult blood tests. For all patients, the annual incidence of localized disease has dropped by 4.2 percent from 2007 to 2016.

The 5-year survival for all patients with CRC is 64.7 percent. When broken down by stage, the 5-year survival for localized disease is 91 percent, 72 percent for regional disease and 15 percent for distant disease. For distant disease, the 5-year survival for patients varies based on age and race. The 5-year survival for patients under 50 with distant disease is 23 percent compared to 11 percent for those over 65. The 5-year survival for distant disease in black patients is 12 percent compared to 25 percent for white patients (including Hispanics).

Risk factors for colorectal cancer

Environmental/Diet and Lifestyle

The majority of CRCs are sporadic; only a small subset are related to germline mutations or found in the setting of a significant family history (Jasperson, Tuohy, Neklason, and Burt, 2010). Variation in CRC risks across the globe and the observation that younger generations are at increased risk of CRC in westernized countries has further solidified the influence of environmental exposures. Significant research has gone into identifying and trying to quantify the environmental and lifestyle-based risk factors associated with CRC. Global studies document a 45-fold difference in age-standardized incidence for CRC across the world (Keum and Giovannucci, 2019; Cancer Fact Sheets — Colorectal Cancer, 2018). The lowest rates of CRC are observed in Gambia and other non-industrialized countries, while the highest rates are observed in westernized countries. Over time, rates of CRC within a country are found to increase as a country industrializes and begins to adopt a westernized diet and lifestyle (Arnold et al., 2017). Migration studies also document that over time, an individual's risk of cancer will shift towards their host country's risk profile for CRC (Mousavi, Fallah, Sundquist, and Hemminki, 2012). For example, men who migrate to Sweden from low risk countries are observed to have increased trends of CRC compared to their home countries' population. The global variations in CRC incidence and migration studies support that variations in diet, environment and lifestyle play a significant role in CRC risk.

Some specific environmental risk factors for CRC have been well established and include smoking, alcohol, diets heavy in processed meats and diets low in fiber (Table 1.1).

Table 1.1

FAP, MAP, HNPCC

Smoking increases the risks of both colorectal adenomas and serrated polyps (Figueiredo et al., 2015). Large observation studies show that increased rates of CRC are observed with more pack-years (Liang, Chen, and Giovannucci, 2009). Recent studies suggest that smoking disproportionally increases rates of rectal and proximal CRC and is associated with BRAF-mutant cancers, but only weakly associated with microsatellite instable (MSI)-high tumors. Similarly, alcohol consumption is a well-established risk factor for CRC, and recent pooled studies have shown that even light alcohol intake is associated with an increased risk of developing CRC (Choi, Myung, and Lee, 2018).

Figure 1.1 Three molecular pathways for colorectal carcinogenesis. There are three molecular pathways proposed for colorectal carcinogenesis, the chromosomal instable (CIN) or classic pathway, the micro-satellite instability (MIS) pathway and the serrated pathway.

A diet low in fiber, fruits, and vegetables and high in processed meats, sugary beverages, and refined grains, i.e. a westernized diet, is correlated with higher rates of CRC. It has proven difficult to tease out exactly all that contributes to the increased risk of CRC in a westernized diet. It is likely that several aspects of this diet contribute to the higher incidence of CRC. Studies consistently find that diets high in processed and red meat are associated with increased risks of CRC. A recent meta-analysis of 111 studies including 400 patients reported a 12 percent increase in CRC incidence for each 100 g of red and processed meat intake (Vieira et al., 2017). The authors also found that increased intake of whole grains was overall protective against CRC. Currently, the American Institute for Cancer Research (AICR) recommends a diet low in processed and red meats and high in whole grains containing fiber to reduce the risk of developing CRC.

Multiple studies have demonstrated that obesity and reduced physical activity are associated with increased risk of CRC (Keum and Giovannucci, 2019). Excess body fat, most commonly measured with BMI and waist circumference, are consistently found to be associated with CRC (Dong et al., 2017; Harriss et al., 2009). Sedentary behavior including prolonged sitting or TV watching is also associated with increased risk of CRC (Ma, Yao, Sun, Dai, and Zhou, 2017). Most of the studies validating obesity and low physical activity to be risk factors for CRC have been completed in populations over 50. The increasing burden of young-onset CRC within industrialized countries, like the US, has prompted renewed interest in trying to define the influence of obesity and physical activity on rates of early-onset CRC. Recently, two studies were published using the Nurses' Health Study II, a long-term prospective cohort study of nurses, enrolled between the ages of 25 to 42, to evaluate the impact of obesity and sedentary lifestyle on early-onset CRC (before the age of 50). Liu et al. found that both a higher BMI at age 18 and greater weight gain during the study period contributed to higher rates of early-onset CRC (Liu et al., 2019). The second study observed that increased sedentary activity, primarily estimated by self-reported hours watching TV per week, correlated with higher rates of early-onset CRC (Nguyen et al., 2018). These and other studies support the recommendations from the ACS and other cancer societies that increased physical activity and a healthy weight are important for reducing the risk of CRC.

Polyps

The majority of CRC arise from a benign precursor polyp. As such, a significant personal or family history of high-risk polyps puts patients at increased risk for colorectal cancer. There are several types of polyps, some of which are non-neoplastic (hyperplastic, mucosal, inflammatory and harmatomatous polyps). The remainder, adenomatous polyps and serrated polyps, have malignant potential. The vast majority of sporadic CRCs develop from adenomatous polyps. In the United States, it is estimated that about 1/3 of adults will have a polyp by age 50 (Reinhart et al., 2013). The majority of these, however, will not progress to CRC. Polyps that are > 1 cm, have villous histology or high-grade dysplasia have an increased propensity to progress to CRC. Although less common, serrated polyps are thought to be precursors for up to 10–15 percent of sporadic CRCs.

There are three molecular pathways proposed for colorectal carcinogenesis, two of which revolve around the neoplastic progression of polyps (Fig. 1.1). The classic pathway describes progression of normal cells to adenomas and ultimately to carcinomas over an extended period (Adenoma-Carcinoma sequence). This is predominately associated with development of chromosomal instable (CIN) tumors and accounts for 85–90 percent of all sporadic CRC (Malki et al., 2021; Keum and Giovannucci, 2019). It is typically associated with an early APC gene mutation, an activation of KRAS or BRAF oncogenes which promote growth, and subsequent mutations that leads progression to carcinoma. The CpG island methylator phenotype (CIMP)/serrated pathway accounts for about 10–15 percent of sporadic CRCs (Malki et al., 2021). Many genes are silenced secondary to these alterations in the methylation of promoter regions of genes and overall hypomethylation. These tumors have often have early BRAFV600E mutations which lead to the activation of the MAPK pathway and formation of hyperplastic polyps (Clarke and Kopetz, 2015). The third pathway is the MSI-high pathway. This is the prominent cancer pathway for patients with Lynch Syndrome and constitutes over 95 percent of associated cancers. MSI is rarely found outside of Lynch Syndrome and is driven by the loss of DNA mismatch repair genes that ultimately leads to altered DNA sequences.

Overall, about 8–25 percent of polyps that harbor invasive carcinoma will metastasize to regional lymph nodes. Polyps that are poorly differentiated, have vascular or lymphatic invasion, have invasion into the submucosa or have positive resection margins are at increased risk to have disease that spreads to the regional lymph nodes. Polyps that are unable to be removed with a 1–2 mm margin are also at higher risk for metastatic spread to regional lymph nodes. Given the propensity for cancer to develop from polyps, all polyps that are found during screening should be removed via colonoscopy when possible, and all patients who are found to have a polyp via sigmoidoscopy need a completion colonoscopy to rule out other polyps. For polyps that cannot be removed via colonoscopy or have high risk features for invasive carcinoma, surgery should be recommended. The exact type of surgical intervention will depend on the location of the polyp but should include regional lymphadenectomy to allow for adequate staging.

Hereditary risk factors

The hereditary component of CRC is estimated at 35–40 percent, with 25 percent of CRCs related to a family history without a clear syndrome and about 5 percent attributed by hereditary cancer syndromes (Graff et al., 2017; Jasperson et al., 2010). The most common hereditary cancer syndromes include Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome), familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). The most common inherited CRC syndrome is Lynch syndrome, which accounts for about 2–4 percent of all colorectal cancers (Keum and Giovannucci, 2019). For patients under age 50 years at the time of CRC diagnosis, it is estimated that 16 percent have a hereditary syndrome and 8 percent have Lynch syndrome (Pearlman et al., 2017). Patients with Lynch syndrome are at risk for several other cancers, including endometrium, ovary, stomach, small bowel, hepatobiliary tract, pancreas, ureter, and renal pelvis cancers (Win et al., 2012). The genetic mutations that lead to Lynch syndrome are in DNA mismatch repair genes hMLH1, hMSH2, hMSH6 and hPMS2. These patients have a 5–85 percent lifetime risk of developing CRC. Although these patients are more likely to be diagnosed at a younger age, around 45, they are more likely to have better survival. They also have increased rates of right-sided CRC and metachronous or synchronous tumors. A significant proportion of patients with Lynch are not diagnosed; thus, a high index of suspicion is needed even in the setting of no significant family history. The Amsterdam criteria can be used to help identify high-risk families and individuals (Umar et al., 2004).

The second most common inherited colorectal cancer syndrome is FAP and accounts for about 1 percent of CRCs (Talseth-Palmer, 2017). FAP is secondary to a germ line mutation in the APC gene, which results in a truncated APC protein. It is inherited in an autosomal dominant fashion with a 90 percent inheritance. These patients develop thousands of polyps throughout the gastrointestinal tract, with the majority in the colon. Without prophylactic colectomy, CRC will develop in all affected patients with FAP by the third or fourth decade. These patients are also at risk for other extracolonic cancers including duodenal adenomas and carcinomas, desmoid tumors, thyroid cancer, and mandibular osteomas. Early screening is necessary for effected individuals and should start around age 10 to 12.

There are additional polyposis syndromes that increase patients' risk of CRC. These include MAP, which is associated with a mutation in the MUTYH gene and is inherited in a recessive manner (Talseth-Palmer, 2017). This accounts for less than 1 percent of CRC, but patients with MAP have an estimated 43–100 percent lifetime risk of CRC. Other polyposis syndromes with an increased CRC risk include serrated polyposis syndrome, Peutz-Jeghers syndrome and juvenile polyposis syndrome. These are all rare syndromes that account for less than 1 percent of CRC incidence together.

Patients with a history of inflammatory bowel disorders have an increased risk of CRC. Specifically, those with chronic ulcerative colitis have a risk for CRC 30 times higher than the general population. Chronic inflammation in the setting of ulcerative colitis is associated with a 0.5 to 1 percent increased risk of cancer. The tumors that do arise in these settings tend to have early mutations in p53 and are less often associated with mutations in KRAS or APC genes. The cancer also tends to more often be multiple, broadly infiltrating and poorly differentiated. The risk of cancer seems to be directly related to the duration and amount of inflammation, and surveillance is recommended to start 8 years after diagnosis to identify cancer or high grade dysplasia early.

Beyond family history, other non-modifiable risk factors for CRC include race, age, and sex. Overall, male patients have a higher risk for CRC than females; the theories behind this include that women tend to have relatively less visceral fat and benefit from overall protective nature of estrogen against CRC. In addition, men have potentially increased exposure to environmental factors, including alcohol, smoking and poor diets, and are less likely to pursue screening. In the US, population studies show that African Americans have a 11 percent higher incidence of CRC than white Americans, while Asian Americans have the lowest risk of CRC. The reasons behind these discrepancies are likely multi-factorial and based on environmental exposures, access to care issues and reduced screening (Augustus and Ellis, 2018; Siegel et al., 2020). In general, CRC is a disease of older patients; although, as alluded to before, the rates of CRC are decreasing in the over-50 population, whereas the risk of CRC (and rectal cancer in particular) continues to rise in the less-than-50 population. Recent trends suggest that by the year 2030, the rates of rectal cancer will increase by 124 percent for patients aged 20–34 and by 90 percent for colon cancer (Bailey et al., 2015). These trends have promoted a change in the screening recommendations by the major institutions.

Screening guidelines

Beyond a healthy diet, physical activity, and avoiding alcohol and tobacco, appropriate screening remains critical for reducing CRC incidence and morbidity. Up until 2018, all of the major organizations recommended starting CRC screening for average-risk patients at age 50. The increasing rates of CRC diagnosis among patients under 50 prompted the ACS to reduce the recommended age of initial screening from 50 to 45 in 2018 (Wolf et al., 2018). This recommendation was made after an extensive review of the potential risks and benefits of earlier screening. Age 45 was chosen because approximately half of patients diagnosed before age 50 are between the age of 45 and 49, and most of these patients are considered of average risk. In 2018, the U.S. Preventive Services Task Force (USPSTF) reviewed the same evidence and simulation models used to guide the ACS recommendations, but it was not until 2021 that the UPSTF changed the initial screening age from 50 to 45 (Force, n.d.). The UPSTF cites that models from the Cancer Intervention and Surveillance Modeling Network support the notion that beginning screening at 45 will lead to an increase in life years gained and a decrease in cancer cases and deaths from CRC. Current UPSTF screening guidelines describe several accepted screening regimens. These include a colonoscopy every 10 years, flexible sigmoidoscopy every 5 years or a stool-based study every 1 year for average risk patients; the alternative methods are outlined in Table 1.2.

Table 1.2

FAP, MAP, HNPCC

For patients with higher-than-average risk for CRC, screening is recommended to start before age 45. The US Multi-Society Task Force of Colorectal Cancer and National Comprehensive Cancer Network outline recommendations for patients with a family history of cancer or advanced adenomas (Provenzale et al., 2020; Rex et al., 2017). Overall, all patients with first or second degree relatives with a diagnosis of either CRC or an advanced adenoma before age 60 are recommended to start screening at least by age 40. Patients with a first degree relative with CRC or advanced adenoma are to start screening 10 years earlier than the age of diagnosis in the first degree relative with a colonoscopy and then to repeat a colonoscopy every 5 years. Patients with FAP, Lynch or IBD have disease-specific recommendations for screening. Patients with FAP are to start screening at age 10–12 with an annual colonoscopy until colectomy. Lynch patients are to start screening with a colonoscopy every 1–2 years starting at age 20–25, unless a family member was diagnosed before age 25; then, they are to start screening 5 years younger than that family member's age at diagnosis. Patients with IBD are to start screening with colonoscopy every 1–3 years, 8 years after their IBD diagnosis.

Metastatic CRC epidemiology

Current data supports that about 15−20 percent of patients will present with metastatic disease at time of diagnosis (Adam et al., 2015; Elferink, de Jong, Klaase, Siemerink, and de Wilt, 2015; Siegel et al., 2020). The annual incidence of Stage IV disease has decreased by 1.1 percent, although rates of Stage IV disease at presentation varies by age and race. Overall, the survival for those who have distant disease is 14 percent at 5 years, and studies show that the survival for patients with lung- or liver-only metastases is improving over time (Siegel et al., 2020; van der Geest et al., 2015).

Risk factors for presenting with late-stage disease include age less than 50 years (young patients) at the time of diagnosis (Andrew et al., 2018). In young patients, the annual incidence of distant CRC has increased by 2.5 percent from 2012 to 2016. About 26 percent of patients under 50 years present with advanced disease, compared to just 23 percent of patients between 50 and 64 years and 19 percent of patients over age 65 years. There are likely multiple contributing factors to the higher rates of advanced CRC in the early-onset population. The majority of these patients fall outside of standard screening recommendations, and the majority (86 percent) of early-onset CRCs are not diagnosed until symptoms from the disease develop (Dozois et al., 2008). Studies also show that these patients are slower to present for evaluation and often experience diagnostic delays, as their symptoms are more likely to be attributed to other benign disease processes such as hemorrhoids (Scott, Rangel, Osler, and Hyman, 2016; You, Lee, Deschner, and Shibata, 2020).

Race, gender and location of primary tumor also seem to influence the incidence of metastatic disease at diagnosis. Black patients are more likely to be diagnosed with stage IV CRC compared to non-Hispanic Whites: 25 percent vs. 20 percent (Siegel et al., 2020). Lower rates of CRC screening and advanced symptoms at diagnosis are also believed to contribute to these disparities. However, the overall incidence and later stage at diagnosis for CRC is higher at any age in Black patients, suggesting other underlying biological drivers (Augustus and Ellis, 2018). In the Netherlands, male patients have also been found to be more likely to present with distant disease than women (van der Geest et al., 2015). In addition, patients with colon cancer are at increased risk to present with advanced disease compared to those with rectal cancer. This is likely secondary to the earlier symptoms associated with rectal cancer.

Specific metastatic site epidemiology and risk factors

The liver is the most common site for distant metastasis, followed by the peritoneum and lungs (van der Geest et al., 2015). About 15–25 percent of patients will develop liver metastasis within 5 years of diagnosis (Engstrand, Nilsson, Strömberg, Jonas, and Freedman, 2018; Manfredi et al., 2006). Patients with synchronous liver metastases have worse outcomes than those patients that have metachronous liver metastases (Adam et al., 2015). About 20–30 percent of patients with liver metastases present with resectable disease, and those treated with a curative operation have up to a 50 percent 5-year survival. While the ability to resect liver metastasis contributes significantly to improved survival, tumor biology and response to systemic therapy also play a critical role. Recently BRAF mutations have been found to be associated with worse outcomes in patients with liver CRC metastasis (Clarke and Kopetz, 2015; Pikoulis et al., 2016).

Up to 8 percent of patients with CRC will present with synchronous peritoneal disease, although the true incidence is likely underestimated; detection with current cross-sectional imaging is limited to identification of only larger metastatic deposits (Kranenburg, Speeten, and Hingh, 2021). Approximately 19 percent of patients will develop peritoneal metastasis (PM) during the course of their disease, and up to 80 percent of patients with CRC will have PM at the time of autopsy (Koppe, Boerman, Oyen, and Bleichrodt, 2006; Kranenburg et al., 2021). Patients with isolated PMs have overall worse prognoses compared to those with other isolated single-organ metastases (Kranenburg et al., 2021; Franko et al., 2016). Patients with T4 tumors, node-positive disease, proximal colon cancers, BRAF mutation, mucinous or signet histology or a CMS4 molecular subtype are more likely to develop PM during their cancer course (Fig. 1.2) (Kranenburg et al., 2021; Ubink et al.,