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Colon cancer: diagnosis, treatment, and emerging frontiers

Oncology
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Introduction

Colorectal cancer (CRC) is currently the third leading cause of cancer-related deaths, among men and women, in the United States[1]. 104,610 new cases of colon cancer are expected in the United States in the year 2020[1]. The World Health Organization Global Cancer Observatory provides detailed region-by-region cancer statistics around the globe. 
In the past two decades, the median age of diagnosis for colon cancer has been gradually decreasing (69 years of age in 2015-2016)[1]. Perhaps even more concerning than the decreasing age at diagnosis is the seeming reversal in the decline of new colon cancer cases. For more than two decades, colon cancer incidence and mortality have been slowly declining in the United States and other developed countries. However, this trend appears to be slowing or even reversing, driven largely by younger patients. During the 2000’s, CRC incidence among people 50-64 years-old declined by 2-3% per year, but rates increased by 1% per year between 2011 – 2016[1]. Between 2008 and 2017, death rate from CRC declined by 3% per year in patients older than 65 years of age, but increased by 1.3% per year in patients younger than 50[1].
This alarming trend among younger patients is an area of intense research. More than half of all cases and deaths are attributable to potentially modifiable risk factors, chief among them are smoking, poor diet, obesity, and sedentary lifestyle[2]. This is believed to play a role in young-onset colon cancer, but the complete biologic reason remains elusive. 
While this trend of younger diagnosis is alarming and perplexing, in general, colon cancer remains an elderly disease with approximately 21% of patients diagnosed before age 55[3]. When diagnosed early, colon cancer is immensely treatable with generally good outcome. However, most patients do not experience signs or symptoms of colon cancer until more advanced stages. In the ensuing sections, we will broadly highlight the latest evidence-based approaches on the detection, diagnosis, and treatment of colon cancer. This chapter will primarily focus on colon cancer. The management of rectal cancer is often different and will be discussed separately. 

Symptoms

Early-stage colon cancer often does not produce appreciable symptoms. As the tumor progresses, subtle symptoms will begin to emerge. The precise symptoms and signs of colon cancer depend on the location and size of the tumor. Tumors confined to the left colon tend to have higher risk of obstructive symptoms owing to the descending colon’s narrower lumen and the more solid consistency of the transiting stool[4]. These symptoms may include bloating, changes in bowel habits, constipation, decrease in stool caliber, nausea, and abdominal pain. If unattended to, late stage disease could present with perforation or complete obstruction. 
Right-sided tumors tend to have more occult bleeding. Because of the longer transit distance from the right colon, subtle bleeding can be difficult to appreciate as it mixes with colonic content[5]. Occult bleeding can often result in iron deficiency anemia which could present as fatigue, pallor, and overall weakness. Abdominal pain can also be present as the tumor enlarges. 
In general, the most common symptoms in patients with newly diagnosed colon cancer are abdominal pain, change in bowel habit, hematochezia or melena, weakness or fatigue, and unexpected weight loss[5]. Colon cancer does not tend to produce overt clinical signs until more advanced stages[5]. Late signs of colon cancer most often result from tumor enlargement and invasion, they include: perforation, tumor-viscera fistula, or frank bleeding. Signs and symptoms that most often prompt diagnostic colonoscopy are blood per rectum, abdominal pain, and anemia[6]. 

Screening

Most colon cancers develop from precursor lesions (adenoma) via a complex multistep molecular pathway known as the adenoma-carcinoma sequence[5]. This process involves the accumulation of multiple mutations and often takes many years. This process of carcinogenesis offers a unique window of opportunity where precursor adenomas (polyps) can be detected and removed. Unfortunately, nearly 90% of CRC are still diagnosed only after symptoms develop or prompted by laboratory or radiographic abnormalities[6]. In fact, more than 26% of patients diagnosed with CRC at the time of emergent surgery have never had a screening colonoscopy[6]. However, there are encouraging signs that increased public awareness is translating into greater action. Among adults over 50 years-old, the prevalence of screening colonoscopy has tripled from 20% in 2000 to approximately 60% in 2018[1]
Multiple relevant societies have published their own guidelines on the methods and interval of colon cancer screening. They generally share similarities with the official guidelines set forth by the United States Preventative Service Taskforce (USPSTF)[7]. For the general population, USPSTF recommend start screening at 45 years of age and continue until 75. Until 2020, the USPSTF recommended screening initiation at age 50. While it remains a Class A recommendation to screen all patients between age 50 – 70, USPSTF now recommend screening to start at 45 years-old (Class B recommendation). Screening for individuals between 76 and 85 years-old should be individualized (Class C recommendation). The “general population” include patients without personal history of CRC or certain types of polyps, familial history of CRC, personal history of inflammatory bowel disease, hereditary CRC syndromes, or personal history of abdominal or pelvic radiation. Table 1 lists the most commonly available methods of colon cancer screening as well as their recommended frequencies.  
Table1. Common methods of colon cancer screening
MethodFrequencyConsideration
ColonoscopyEvery 10 yearsLess frequent interval
Diagnostic and therapeutic
Requires bowel preparation
Flexible
Sigmoidoscopy		Every 5 yearsLess extensive than colonoscopy
Limited anatomic coverage
Requires bowel preparation
Availability has declined in USA
CT ColonographyEvery 5 yearsMinimal procedural risk
No anesthesia/sedation
Not diagnostic nor therapeutic
Requires bowel preparation
Guaiac-based
Fecal Occult Blood
Test		Every yearNo bowel preparation
No procedural/anesthesia risk
Easy to perform at home
Not diagnostic nor therapeutic
Fecal
Immunochemical
Test		Every yearNo bowel preparation
No procedural/anesthesia risk
Easy to perform at home
Not diagnostic nor therapeutic
Data taken from USPSTF[7].
Patients with high risk for colon cancer should adhere to a modified screening schedule. 
  • Certain high-risk polyps[8]: 
    • Small hyperplastic polyps (<10mm): 10 years
    • 1-2 tubular adenoma (<10mm): 5-10 years
    • 3-10 tubular adenoma: 3 years
    • >10 adenoma: <3 years
    • ≥1 tubular adenoma ≥10mm: 3 years 
  • Family history of CRC: Center for Disease Control and Prevention recommends starting screening colonoscopy at age 40 or 10 years before the age of immediate family member’s CRC diagnosis
  • Hereditary syndromes[9]:
    • Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome): screening colonoscopy starting 20-25 years-old, repeat every 1-2 years
    • Familial adenomatous polyposis (FAP): screening colonoscopy starting 10-12 years-old, repeat every 1-2 years. Once adenomatous polyps form, screening frequency should be reduced to yearly.
  • Inflammatory bowel disease: colonoscopy with staging biopsy starting 8 years after onset of disease. Repeat every 1-5 years based on individual risk factors[10].

Diagnosis

Diagnosis of colon cancer should start with a complete history and physical. Emphasis should be placed on recent changes in weight, bowel habits, stool characteristic, and personal risk factors. In addition, a thorough family history is also mandatory. Routine laboratory tests should include complete blood count, basic chemistries, and liver function test. 
Tissue diagnosis of colon cancer should be obtained whenever possible. Colonoscopy remains the mainstay diagnostic modality for suspected colon cancer. Flexible sigmoidoscopy is generally not useful for the diagnosis of colon cancer given its limited anatomic reach.
CT colonography is a non-invasive diagnostic modality for colon cancer that could be considered. In the SIGGAR trial, a randomized control trial of 1610 patient comparing colonoscopy with CT colonography, the detection rate for CRC or large polyps were similar for both modalities, around 11%[11].
CT colonography missed 1/29 CRC and colonoscopy missed 0/55 CRC. It is important to note that 30% of patients in the CT colonography group underwent additional colonic investigations compared to 8.2% in the colonoscopy group. 
Early diagnosis affords the patient with the greatest chance for cure. In a series of 394 patients, Moreno et al reported that among patients whose initial tissue diagnosis of CRC were made during screening colonoscopy, 38.5% were stage 1[6]. That number drops to 7.2% for diagnostic colonoscopy, and no stage 1 tumors were diagnosed at emergent surgery. Despite this knowledge for the importance of early diagnosis, approximately 15% of CRC patients still present as surgical emergencies, and nearly half of those patients will have metastatic disease at the time of their diagnosis[6,12]. 
For tissue diagnoses of colon cancer, the most common histologic type is adenocarcinoma, accounting for >80% of colon cancer diagnoses[6]. This is followed by mucinous adenocarcinoma (~10%), adenocarcinoma with signet ring (~1.2%), adenocarcinoma with signet ring and mucinous features (1%), and neuroendocrine tumors (~1%). 6% of metastatic disease with unknown primary will ultimately turn out to be CRC[13]. ~4% of CRC are diagnosed with synchronous lesions, which highlights the importance of a full colonoscopy as part of an adequate evaluation[14]. 
Serum biomarkers are generally not helpful for the initial diagnosis of primary colon cancer. No serum markers have demonstrated sufficient diagnostic ability to warrant their routine use, including carcinoembryonic antigen (CEA)[15]. CEA does play an important role in prognosis and surveillance, which will be addressed later[16]. 

Staging

Accurate staging of newly diagnosed colon cancer is critical for optimal management and should be achieved whenever possible. Staging begins with a full colonoscopy if it has not already been performed during diagnosis. Imaging studies should include CT of the chest, abdomen, and pelvis to assess locoregional tumor burden as well as potential distant metastasis to the thorax, liver, lymphatics, and peritoneal cavity[17]. If liver lesions are detected, MRI of the liver should be considered to better evaluate the liver parenchyma[17]. Otherwise, routine use of MRI of the abdomen and pelvis or PET/CT are not indicated for colon cancer staging[17]. 
In addition to imaging, pathologic staging is critical for the management of colon cancer. Complete pathologic staging is made after surgical resection. The most commonly used staging system is the American Joint Committee on Cancer (AJCC) TNM system, currently in its 8th edition. In colon cancer, the tumor (T) stage is determined by the depth of invasion rather than size of the lesion. Both the AJCC and the College of American Pathologists recommend a minimum of 12 regional lymph nodes for adequate N stage[18].
Table 2 and 3 outline the TNM stages for colon cancer as espoused by the AJCC 8th edition[19]. Tumor tissue should be tested for mismatch repair (MMR) and microsatellite stability (MSI) status whenever possible[17]. RAS and BRAF mutations should be tested in all metastatic CRC[17].  
Table 2. TNM classification for primary colon cancer 
Tumor (T)Lymph Nodes (N)Metastasis (M)
Tx: tumor cannot be assessed
T0: no evidence of tumor
Tis: carcinoma in situ
T1: invasion into submucosa
T2: invasion into mucularis propria
T3: invasion through muscularis propria into adjacent tissue
T4a: invasion through visceral peritoneum
T4b: invasion or adherence to adjacent organs		Nx: lymph nodes cannot be assessed
N0: no regional lymph node involvement
N1a: 1 positive regional lymph node
N1b: 2 or 3 positive regional lymph nodes
N1c: tumor deposits in subserosa, mesentery, nonperitonealized pericolic tissue
N2a: 4-6 positive regional lymph nodes
N2b: ≥7 positive regional lymph nodes 
M0: no distant metastasis
M1a: one metastatic site without peritoneal metastasis
M1b: ≥2 metastatic sites without peritoneal metastasis
M1c: peritoneal surface metastasis 
Information taken from American Joint Committee on cancer Staging Manual, 8th Edition 
Table 3. AJCC staging for primary colon cancer
AJCC StageTNM Grouping
0TisN0M0
IT1 or T2N0M0
IIAT3N0M0
IIBT4aN0M0
IICT4bN0M0
IIIAT1 or T2
T1		N1/N1c
N2a		M0
M0
IIIBT3 or T4a
T2 or T3
T1 or T2		N1/N1c
N2a
N2b		M0
M0
M0
IIICT4a
T3 or T4a
T4b		N2a
N2b
N1 or N2		M0
M0
M0
IVAAny TAny NM1a
IVBAny TAny NM1b
IVCAny TAny NM1c
Information taken from American Joint Committee on cancer Staging Manual, 8th Edition 

Treatment

Treatment for primary colon cancer depends on the stage of the disease. 
Localized Disease
For resectable and non-obstructing tumors in medically operable patients, upfront colectomy should be offered, which includes en bloc resection of regional lymph nodes[17]. Proximal and distal resection margins should be ≥5cm[20]. Laparoscopic colectomy has become the mainstay approach in the United States. In a multicenter randomized controlled trial (COST), 872 patients with colon adenocarcinoma were randomized to either open or laparoscopic colectomy[21]. At 3 years, the recurrence rate and overall survival were similar for both groups while the laparoscopic group experienced a shortened hospital stay by 1 day.
When undergoing radical resection for primary colon cancer, the importance of adequate lymph node sampling cannot be overstated. As noted above, both AJCC and the College of American Pathologists recommend a minimum of 12 regional lymph nodes for adequate N staging. In the event that <12 lymph nodes are harvested, the specimen should be resubmitted for further processing with the goal of identifying additional lymph nodes. In a standard lymphadenectomy for primary colon cancer, the segmental mesentery is resected down to the origin of the named primary feeding vessel[22]. An alternative approach involves more extensive dissection beyond the primary feeding vessels[23].
This approach has been variably referred to as “high ligation, “central vascular ligation,” “complete mesocolic excision,” or as “D3” lymphadenectomy, contrasting it to the standard “D2” dissection[22]. Regardless of terminology, this approach typically involves dissecting beyond the central lymph nodes along the primary feeding vessel. In a right sided colon tumor, this will involve dissecting close to the origin of the superior mesenteric vessels. In a left sided colon tumor, dissection will extend to the origin of the inferior mesenteric vessels. 
While some studies have suggested a potential survival benefit with a “high ligation” approach, robust evidence from randomized studies remains wanting[24]. The COLD trial is a randomized controlled trial comparing D2 or D3 lymphadenectomies in patients with resectable primary colon cancer[25].
In their short-term results published in 2019, they enrolled 100 patients, and found no difference in 30-day postoperative morbidity, postoperative recovery, or readmission between the two groups. The mean lymph node yield was also similar (26.6 in D2 versus 27.8 in D3). They did find that N-positive status was more common in D3 patients, suggesting a potentially improved N staging with the extended approach. At present, the American Society of Colon and Rectal Surgeons (ASCRS) does not recommend the routine performance of extended lymphadenectomy, except where suspicious or bulky lymphadenopathy beyond the standard field of resection is present[22].
Selected stage 1 disease may be amendable to endoscopic mucosal resection (EMR). EMR is generally reserved for patients with pedunculated or sessile malignant polyps that can be removed in one piece[26]. EMR is contraindicated for patient with high risk features including poorly differentiated tumors, lymphovascular invasion, positive margins, T1 lesions invading into the lower third of the submucosa or through the muscularis propria[26].  
Neoadjuvant chemotherapy should be considered for bulky nodal disease or clinical T4b disease[17]. The standard regimens are FOLFOX or CAPEOX. The PRODIG 22 trial was a phase 2 randomized controlled trail in resectable high-risk T3, T4, and/or N2 colon cancer comparing 6 months of adjuvant FOLFOX (control) versus 4 cycles of preoperative FOLFOX followed by 8 postoperative cycles (peri-op)[27]. It found that peri-op FOLFOX was feasible and induced pathological regression and downstaging of the disease. Although it was not associated with increased major pathological response rate. Another larger randomized controlled trial of 1053 patients with T3-4 N0-2 M0 colon cancer is underway comparing 6 weeks of pre- and post-operative FOLFOX versus postoperative FOLFOX (FoxTROT trial). Preliminary results reported in 2019 showed histological downstaging after neoadjuvant FOLFOX with 3.8% achieving pathological complete response[28]. Neoadjuvant FOLFOX also decreased incomplete resection rate (4.8% vs 9.1%). There was also a trend towards less recurrence within 2 years. 
Adjuvant chemotherapy is recommended for all ≥stage 3 (node-positive) disease[17]. Preferred regimens include CAPEOX for 3 months (low risk, T1-3, N1) to 6 months (high risk, T4, N1-2; any T, N2) or FOLFOX for 6 months. Additional options include capecitabine for 6 months or 5-FU for 6 months. Adjuvant chemotherapy is not indicated for stage 0 or stage 1 colon cancer[17]. For individuals with stage 2 disease, the evidence remains unclear, and the decision should be individualized17. Adjuvant radiation is not routinely used in colon cancer. 
Metastatic Disease
Management and prognosis of newly diagnosed metastatic colon cancer depends on the location and extent of spread as well as the patient’s preference and baseline physical status. The current National Comprehensive Cancer Network (NCCN) guideline organizes metastatic colon cancer management into three broad categories[17]. 
Isolated liver and/or lung metastases: synchronous or staged colectomy with liver/lung metastasectomy followed by adjuvant chemotherapy. Alternatively, patients can be treated with neoadjuvant FOLFOX or CAPEOX for 2-3 months followed by synchronous or staged resection. Lastly, upfront colectomy can be followed by FOLFOX or CAPEOX for 2-3 months, then followed by metastasectomy. 
Unresectable liver/lung metastases: these patients should be treated with systemic therapy and re-evaluated every 2 months to determine resectability. Preferred regimens include FOLFIRI or FOLFOX or CAPEOX or FOLFOXIRI ± bevacizumab or FOLFOXIRI ± panitumumab.   
Synchronous abdominal/peritoneal metastases or unresectable metastases to other sites: these patients should be treated with systemic therapy. 
Palliative surgical diversion or resection could be considered for obstruction or bleeding. 
A Note on Immunotherapy
While significant progress has been made in advanced/metastatic CRC using multimodal therapy and improvements in chemotherapy, survival remains poor. Immunotherapy is the latest frontier in systemic therapy for colon cancer. At present, checkpoint blockade is the most well studied immunotherapy in colon cancer. Monoclonal antibodies to programed death 1 (PD-1) have been well studied in colon cancer.
Currently, both pembrolizumab and nivolumab are approved for MMR-deficient/MSI-high metastatic CRC[29]. Cellular therapy such as chimeric antigen receptor T cell (CAR-T) therapy in colon cancer remains investigational with several early phase studies ongoing[29].  

Surveillance

Proper surveillance following upfront treatment is critical for long-term survival in colon cancer. The precise frequency and evaluation depend on the stage of the initial disease. 
Stage 1: colonoscopy at 1 year following surgery. If advanced adenoma is detected, repeat colonoscopy in 1 year. If no advanced adenoma, repeat in 3 years then every 5 years[17].
Stage 2/3: history and physical every 3-6 months for 2 years, then every 6 months for total of 5 years. CEA every 3-6 months for 2 years, then every 6 months for total of 5 years[17]. CT chest/abdomen/pelvis every 6-12 months for total of 5 years[17]. Colonoscopy 1 year after surgery. If advanced adenoma is detected, repeat colonoscopy in 1 year. If no advanced adenoma, repeat in 3 years then every 5 years[17]. PET/CT or MRI are not routinely indicated for surveillance in colon cancer. 
Several studies have examined whether a more frequent surveillance regimen would be beneficial. The COLOFOL trial randomized 2509 patients with stage 2 or 3 CRC to either CT and CEA at 6, 12, 18, 24, and 36 months after surgery (high frequency) or at 12 and 36 months after surgery (low frequency)[30]. They found no significant reduction in 5-year overall mortality or CRC-specific mortality in the high frequency group. 

Controversies

As outlined in the introduction, a major new challenge confronting us is the rising rate of early-onset (<50 years-old) colon cancer. We still do not fully understand the drivers behind this alarming trend, but it is likely multifactorial[31]. One of the potential drivers is the increasing consumption of diets high in processed meats, high-fructose corn syrup, fat, and synthetic dyes[31]. This dietary pattern combined with a rising prevalence of obesity and physical inactivity likely fuel some of the growth in early-onset colon cancer[32]. 
A major controversy is the role of weight loss surgery vis-à-vis obesity and colon cancer. Although it has been repeatedly shown that obesity is an independent risk factor for the development of colon cancer, it remains unclear whether weight loss surgery would be beneficial in reducing that risk[33]. Several large human studies have attempted to answer this question with mixed results. Some studies have found that weight loss surgery significantly decreases the risk of developing CRC in obese individuals[34]. However, similar studies have suggested that weight loss surgery is associated with increased risk of colon cancer development[35]. 
This perplexing reality likely reflect the complex environmental and molecular processes involved in colon carcinogenesis. The colon occupies a unique environment with constant and direct exposure to the gut microbiome. Both the gut microbiome and several specific bacteria have been linked to colon cancer[36–38]. Obesity and weight loss surgery both profoundly affect the microbiome[39]. Emerging evidence is suggesting that because of this unique environmental reality, the effect of weight loss surgery on colon cancer development likely extends beyond simple weight reduction alone. Intense efforts are underway to address this critical question in the attempt to help stem the tide of young-onset colon cancer. 

Summary and Recommendations

  • Colon cancer is the third leading cause of cancer-related death in the United States. 
  • The recent trend of declining incidence appears to be reversing, fueled largely by an alarming rise in early-onset colon cancer. 
  • Screening and early diagnosis remain the key for long-term survival and potential cure. 
  • Management of colon cancer is guided by the stage of the disease. For early disease, upfront surgery should be pursued. For locally advanced disease, neoadjuvant chemotherapy should be considered. 
  • Immunotherapy is showing early promise in colon cancer in the form of PD-1 blockade. The use of cellular therapy in colon cancer remains investigational. 
  • Proper surveillance following initial treatment is critical for long-term survival and should be individualized based on disease stage and risk factors. 
  • The role of obesity and weight loss surgery in colon cancer development is a major area of ongoing research. Early results suggest the microbiome likely plays a key mediating role in this process.     

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