Overview
If you're in your late 40's or early 50's or have a family history and your doctor recommends a colorectal exam, like many people, you'll think I'm fine; this is unnecessary.
The hard reality is, colorectal cancer is often a quiet growing cancer until it has metastasized and spread. When your doctor recommends a screening, don't hesitate and book an appointment.
I hope this article will show you why getting screened for colorectal cancer is essential and could save your life or the life of a loved one.
What you will read below is not conjecture or theory.
These facts are based on scientific data and supported with clinical research and data that explains the signs and symptoms, known causes, incident rate, stages of CRC cancer, and treatment options.
Hearing that you have cancer is nerve-racking. You immediately jump to worst-case scenarios, however with early treatment, you can look forward to a full and active life.
Colorectal cancer occurs in the colon and rectum. The colon is the large intestine, and the rectum is the passageway that connects the colon to the anus. Early prevention by removing polyp or growths inside the colon or rectum can and does prevent colorectal cancer.
The key is early detection and prevention, so when your doctor recommends a screening, don't hesitate to schedule the appointment.
What are the Early Signs of Colorectal Cancer (CRC)
- Blood in or on your stool.
- Chronic diarrhea, constipation, or feeling that the intestine does not empty all the way.
- Abdominal pain, aches, or ongoing cramps.
- Losing weight with no clear explanation or attempt.
What Causes Colorectal Cancer (CRC)?
Risk factors include:
- A family history (in a close family relative) parent, sibling, or child.
- Personal health history of cancer of the colon, rectum, or ovaries.
- Personal history of high-risk colorectal polyps that have abnormal pathology.
- Long-standing personal health history of chronic colitis or Chron's disease.
- Inherited or familial changes in specific genes increase the risk of FAP (familial adenomatous polyposis or Lynch syndrome (nonpolyposis colorectal cancer that is hereditary).
- Drinking three or more alcoholic drinks per day.
- Smoking.
- Diet - there is convincing evidence of an association between lower CRC risk with higher dietary fiber intake, dietary calcium, yogurt, and lower intakes of alcohol and red meat.
- African American heritage.
- Carrying excessive weight.
- Age, being older is a risk factor for most cancers. The odds of getting cancer increase as you age.
- Physically inactive increases the risk of developing CRC
What is the Incidence Rate of Colorectal Cancer (CRC)?
118 million new CRC cases arose, and 881,000 deaths were reported in 2018, which represents nearly 10% of new cancer cases and deaths worldwide,1
According to statistics in the USA, the death rate declined by ~50% in 2016 (13.7 per 10,000 patients) compared with 1970 (29.2 per 10,000 patients) because of the rapid development of screening methods and improved treatment methods. However, this trend seems to be observed only in highly developed countries.2
Cancers of the colorectal system represent 7.5% of all new cancer diagnoses; it is the 4th leading cancer diagnosed each year.
The cancer death rates increase with age and are the second leading cause of cancer death in the United States. The highest death rate is in people between ages 65–74.
How Is Colorectal Cancer (CRC) Diagnosed?
If your doctor recommends screening for colorectal cancer, tests can range from a simple stool test to a colonoscopy. Below are brief descriptions of each screening test:
- Fecal occult blood test: A test to check stool for microscopic blood in the stool. Blood in your stool can be a sign of colon polyps that need further investigation.
- Barium enema: This is a series of X-rays of the lower GI. A barium liquid is injected into the rectum to coat the lower GI tract to make polyps and other abnormalities visible.
- Sigmoidoscopy: a thin, tubular instrument with a light and camera with tools to safely remove polyps and tissue samples for biopsies.
- Colonoscopy: A colonoscope is a thin, tubular instrument with a light and a lens to view and capture images of polyps and your colon, and has tools to take tissue samples for biopsies and remove polyps that are checked in a lab for signs of cancer.
So, You were Diagnosed with Cancer. Now What?
With a colon or rectal cancer diagnosis, you immediately want to know what stage the cancer is. This will determine your treatment options, odds of remission, and cure. Your doctor will order additional tests from CAT, PET scans, MRIs, more blood work to determine if cancer has spread.
Each stage of cancer offers different treatment options.
- Stage 0 is where a cancerous polyp can be removed by a simple polypectomy, usually during a colonoscopy. In a more advanced stage where the polyp is too large to remove with a polypectomy, resection can be done, this is where the cancerous section is cut out, and healthy tissue is reconnected.
- Stage 1 and 2 typically require a resection, where the cancerous section is cut out and healthy tissue is reconnected.
- Stage 3 cancer has spread from the original tumor site and requires resection and chemotherapy.
Today, chemotherapy ranges from pill form to IV therapy and can include targeted therapy. Targeted chemotherapy drugs work differently on colorectal cancer than traditional chemotherapy drugs. As a result, targeted therapy has less severe side effects.
Targeted monoclonal antibodies target the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). We will cover this in more detail below.
Stage III colon cancer is divided into stages IIIA, IIIB, and IIIC.
Stage IIIA has spread:
- Through the innermost layer of the colon wall to the tissue layer near the mucosa (innermost layer of the colon). Or the muscle layer of the colon wall. Cancer has spread to one to three nearby lymph nodes, or cancer cells have formed in tissue near the lymph nodes, or
- Through the mucosa layer of the colon wall to the submucosa (layer of tissue next to the mucosa). Cancer has spread to four to six nearby lymph nodes.
Stage IIIB has spread:
- Through the muscle layer of the colon wall to the outermost layer of the colon called the serosa or has spread through the serosa to the tissue that lines the organs in the abdomen. One to three lymph nodes are involved, or cancer cells have formed in tissue near the lymph nodes; or
- To the muscle layer or the serosa (outermost layer) of the colon wall. Cancer has spread to four to six nearby lymph nodes; or
- The mucosa of the colon wall, to the layer of tissue next to the mucosa, is called the submucosa. Or to the muscle layer of the colon wall. Cancer has spread to seven or more nearby lymph nodes.
- Stage IIIC has spread:
- Through the serosa of the colon wall to the tissue that lines the organs in the abdomen. Cancer has spread to four to six nearby lymph nodes, or
- Through the muscle layer of the colon wall to the serosa (outermost layer) of the colon wall, or has spread through the serosa to the tissue that lines the organs in the abdomen (visceral peritoneum). Cancer has spread to seven or more nearby lymph nodes; or
- Through the serosa (outermost layer) of the colon wall to nearby organs. Cancer has spread to one or more nearby lymph nodes, or cancer cells have formed in tissue near the lymph nodes.
- Stage 4 CRC is divided into stages IVA, IVB, and IVC.
In stage IVA, cancer spreads to an area or organ not close to the colon and/or rectum, such as the liver, lung, ovary, or a distant lymph node.
In stage IVB, cancer has spread to more than one site or organ not close to the colon and/or rectum, such as the liver, lung, ovary, or a distant lymph node.
In stage IVC, cancer has spread to the tissue lining the abdominal wall and may have spread to other areas or organs.
Treatments for CRC
Today, there are seven different treatment that is used depending on the stage of CRC cancer:
- Surgery
- Radiofrequency ablation
- Cryosurgery
- Chemotherapy
- Radiation therapy
- Targeted therapy
- Immunotherapy
Let's start with an overview of Targeted Therapy:
Targeted therapy is precision medicine; it targets proteins that control how cancer cells grow, divide, and spread.
Targeted therapy is either delivered by:
- Small-molecule drugs can enter cells, so they are used for cancer cells inside cell membranes.
- Monoclonal antibodies, or therapeutic antibodies, are proteins produced in the lab.
These proteins attach to specific targets found on cancer cells. Some monoclonal antibodies mark cancer cells to be better seen and destroyed by the immune system.
Some monoclonal antibodies directly stop cancer cells from growing or cause them to self-destruct.
While others carry toxins to cancer cells.
Think of Covid19, and monoclonal antibodies used to mimic the immune system's ability to fight off the viruses known as SARS-CoV-2.
The idea of targeted therapy has a relatively long history. The concept of a chemical that explicitly targets a microorganism was first proposed in the early 1900s. This expanded to cancer treatment in 1988,3, and this concept was renewed and has flourished in the past 20 years.4
Targeted therapies can block cell proliferation, differentiation, and migration. The tumor's microenvironment, including local blood vessels and immune cells, could be altered by drugs to impede tumor growth.
Monoclonal antibodies are small molecules that are significant players in targeted therapies. Small molecules enter cells, act to inactivate selected enzymes in cells, impair the growth of tumor cells and even cause the death of cancerous cells.
A few examples are Carfilzomib for multiple myeloma, ribociclib for metastatic breast cancer, and rucaparib for BRCA-positive ovarian cancer.5
The first targeted agent for CRC the FDA approved was cetuximab in 2004, followed by bevacizumab in late 2004. More FDA-approved targeted drugs for CRC have been brought to market successively since then, with more on the horizon.
VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; EGFR: epidermal growth factor receptor.
Targeted Therapy targets overactive cells
This approach is more specific to cells where pathways, such as epidermal growth factor receptor (EGFR), are overactive. This contrasts with the relatively indiscriminate mechanism by which cytotoxic chemotherapy affects rapidly dividing cells, regardless of their role.
Unique factors to a given patient, like the presence of mutations that confer resistance or the location of the primary tumor (sidedness), may limit the effectiveness of these drugs. Targeted therapies are now standard in the treatment paradigm for metastatic colorectal cancer—resulting in enhanced survival outcomes that have significantly improved.
Targeting cancer cells with EGFR changes
Epidermal growth factor receptors (EGFR) are proteins that help cancer cells grow. Pharmaceuticals and biotech drugs targeting EGFR are used to treat some advanced retail and colon.
A few are:
Cetuximab (Erbitux)
Panitumumab (Vectibix)
These drugs are given by IV, either once a week or twice a month.
A drawback is that these drugs typically don't work as monotherapy in colorectal cancers with gene mutations (defects) in the BRAF, NRAS, or KRAS genes.
Doctors routinely complete gene tumor tests for gene changes before starting treatment and only use these drugs in people who don't have these gene mutations.
The exception to this is when cetuximab is combined with the BRAF inhibitor encorafenib. Combining these two drugs appears to help people with advanced colorectal cancer live longer, even with one of these mutations.
Target cells with BRAF gene changes
Less than 10% of all colorectal cancers have BRAF gene mutations. Colorectal cancer tumor cells with these changes make an abnormal BRAF protein that helps cancer grow and spread. Today, some drugs target this abnormal BRAF protein.
If your CRC has spread, you will probably be tested to see if you carry an abnormal BRAF gene. Drugs targeting abnormal BRAF protein (BRAF inhibitors) aren't likely to work on colorectal cancers with a normal BRAF gene.
Bevacizumab - Targeting Angiogenesis
Angiogenesis, which creates networks of blood vessels, is a wondrous biological process that promotes the growth and survival of normal, healthy cells.
This also supports the growth and survival of cancer cells and facilitates the metastasis of cancer.
This is of critical importance in treating different cancers.
Familial renal cell cancer is dependent on angiogenesis, for example. Still, in mCRC and most other cancers, new blood vessels (angiogenesis) do not determine cancer progression.
A balance mediates angiogenesis between pro-angiogenic and anti-angiogenic factors and receptors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor, and fibroblast (cells in connective tissue that produce collagen and other fibers growth factor.
Bevacizumab is a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) directed against VEGF-A. That can be used as a single agent or combination therapy.
Its potential mechanisms of action are thought to include the depletion of tumor vasculature (meaning the tumor cannot grow blood vessels). And the temporary normalization of the crazy-quilt pattern of tumor vasculature to enhance chemotherapy delivery.
Bevacizumab is most often used as combination therapy with oxaliplatin-based as a first-line for patients with mCRC.
Second Line CAC Targeted Therapies
Bevacizumab enhances the effects of second-line treatments.
The real benefit of continuing bevacizumab beyond the first-line progression in the Bevacizumab Regimens: Investigation of Treatment Effects and Safety (BRiTE) registry, cohort study conducted from 2004 to 2005, suggested a mean survival rate of 31.8 months in the bevacizumab-continuation group versus 19.9 months.
Other Anti-Angiogenesis Agents
Some other drugs targeting angiogenesis are available for second-and subsequent-line treatment of mCRC. Although none are used nearly as commonly used as bevacizumab.
Ziv-aflibercept is a fully-humanized, soluble recombinant fusion protein that targets angiogenesis by blocking VEGF-A, VEGF-B, and placental growth factors. It has a higher binding affinity for VEGF-A than bevacizumab.
No data supports the use of ziv-aflibercept as monotherapy and not in combination with another agent.
Ramucirumab is a fully human IgG1 mAb targeting the vascular endothelial growth factor receptor 2 extracellular domain.
Ziv-aflibercept like ramucirumab is also approved for use in the second line in combination with FOLFIRI or irinotecan. There are no data to support the use of ramucirumab monotherapy for mCRC.
Although bevacizumab, ziv-aflibercept, and ramucirumab have all demonstrated efficacy and are approved in the second line (in combination with FOLFIRI or irinotecan). Bevacizumab is still widely used. It is a preferred agent primarily because of the higher costs and toxicities associated with the others.
Immunotherapy
Immunotherapy boosts the body's natural defenses to fight cancer.
It is made from substances similar to what your body produces naturally or is made in a laboratory to boost your immune system works to find and destroy cancer cells.
Your immune system detects and destroys abnormal cells and most likely prevents or limits the growth of many cancers.
Common immunotherapy drugs are:
- Monoclonal antibodies like tumor-agnostic treatments, such as checkpoint inhibitors, are made in a laboratory to boost your body's natural antibodies.
- Oncolytic virus therapy utilizes lab-developed viruses that have been altered in a laboratory to destroy cancer cells.
- T-cell therapy: as the world learned with COVID19, T cells are immune cells that fight infection from viruses, bacteria, and more. The T-cell treatment removes T cells from your blood, then enhanced in a laboratory where specific proteins called receptors to the cells are added. The receptors allow T cells to recognize and kill cancer cells.
- Cancer vaccines are used to help your immune system learn to fight off a foreign protein called an antigen. This triggers vaccine teaches the immune system to recognize and destroy that antigen or related substances. There are 2 types of cancer vaccines: prevention and treatment vaccines.
- Interferons are proteins produced by your immune system to alert your body that a pathogen is typically a virus in your body.
- Interleukins, which help cells talk to each other and kick off an immune system response.
Radiofrequency ablation
Ablation techniques destroy small (less than 4 cm across) tumors instead of removing them with surgery. There are several different types of ablation techniques. They are used to treat tumors throughout the human body.
Radiofrequency ablation is the most common method to treat cancer that has spread to the liver. High-energy radio waves are used to kill cancer cells. A CT scan or ultrasound guides a thin probe through the skin and into the tumor. It uses an electric current sent to the probe's tip, releasing high-frequency radio waves that heat the tumor and destroy cancer cells.
Cryosurgery
Cryosurgery destroys tumors by freezing using a very thin probe. Using ultrasound, the probe is guided through the skin and into the tumor. Icy gas is passed through the probe to freeze the tumor, killing cancer cells. Cryosurgery is used to treat larger tumors than the other ablation techniques, with general anesthesia if needed. This treatment can be repeated as necessary to kill any remaining cancer cells.
5 Year Survival Rate of CRC -
Colon Cancer has a super high survival rate if caught early
The survival rate of all colorectal cancer stages:
- 64.4% is the five-year relative survival rate of colon cancer. For every 100 people diagnosed with colon cancer, 64 of them are expected to be alive five years after diagnosis.
- 67% is the five-year relative survival rate of rectal cancer.
Thanks to increased screening and advanced treatment options, relative survival rates of colorectal cancer are rising. In 1975, the rate was only 50%.
Stages I and II- Localized cancer:
Localized colorectal cancer is the most treatable and curable and is caught with colorectal screening.
- Early screening is critical as 39% of all colorectal cancer cases are localized.
- 89.9% is the five-year relative survival rate
Stage III
Cancer cells were also found in the tissue surrounding the tumor and nearby lymph nodes.
- Waiting for a colorectal screening could put you in the Stage III group, 35% of all colorectal cancer cases with metastasis to local tissues and multiple lymph nodes.
- 71.3% is the five-year relative survival rate
Distant Cancer: Stage IV
Metastatic colorectal cancer (mCRC) is distant cancer. This means cancer has metastasized beyond the colon or rectum. At this point, colon and rectum cancer has metastasized to the liver, lungs, or other organs.
- 22% of all colorectal cancer cases are distant
- 14.2% five-year relative survival rate
Survival Rates by Age
Studies have shown that age may play a factor in a metastatic patient's prognosis.
"Younger and older age are associated with poorer Overall Survival and Progression-Free Survival among treated patients with mCRC. Younger and older patients may represent higher-risk populations, and additional studies are warranted."
Source: Journal of Clinical Oncology, "Association of Age With Survival in Patients With Metastatic Colorectal Cancer: Analysis From the ARCAD Clinical Trials Program" (2014)
Survival Rate by Stage at Diagnosis
Stage
The 5-year relative survival rate
Localized
91%
Regional
72%
Distant
14%
All stages combined
63%
References:
- Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
- Dekker, E., Tanis, P. J., Vleugels, J. L. A., Kasi, P. M. & Wallace, M. B. Colorectal cancer. Lancet 394, 1467–1480 (2019).
- Brodsky, F. M. Monoclonal antibodies as magic bullets. Pharm. Res. 5, 1–9 (1988).
- Lee, Y. T., Tan, Y. J. & Oon, C. E. Molecular targeted therapy: treating cancer with specificity. Eur. J. Pharm. 834, 188–196 (2018).
- Ibid
- Arteaga, C. L. & Engelman, J. A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25, 282–303 (2014).
- Hsu, J. L. & Hung, M. C. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 35, 575–588 (2016).
- Rotow, J. & Bivona, T. G. Understanding and targeting resistance mechanisms in NSCLC. Nat. Rev. Cancer 17, 637–658 (2017).
- Roskoski, R. Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharm. Res. 79, 34–74 (2014).