COLORECTAL CANCER



Overview
The patient, Morrie, is a 55 year old white male. Morrie has three children and is happily married. He has worked as a businessman in positions such as consultant and CEO. He does not have any family history of colon cancer and is of Irish descent. Morrie is 5’10” tall and 190 pounds. He has a relatively average American diet composed of heavy meat and dairy consumption along with some fruits, vegetables, grains, and sweets. Morrie consumes alcohol almost daily, yet not to excess and is not a smoker or a diabetic. He exercises several times per week and enjoys hiking and the outdoors. Morrie has a medical history of diverticulitis and a sensitive stomach. Diverticulitis is an inflammation or infection of pouches in the intestines and symptoms include abdominal pain, diarrhea, and blood in stool. Upon examination, he has reported feelings of fatigue, blood in stool, irregular bowel movements consisting of diarrhea, as well as abdominal cramps.

Morrie has colon cancer and his profile places him at an increased risk of colon cancer in several areas. Colon cancer is much more common among men around the age of 50. His diet also places him at an increased risk. Diets high in meat and dairy consumption are directly associated with an increased risk of colon cancer[1]. In addition, the medical history of diverticulitis is related to an increased risk of colon cancer[2]. The blood in Morrie's stool could be attributed to both a tumor growth within the colon or the diverticulitis. This tumor could be damaged with the passing of stool, releasing blood into the passing stool. If the patient is experiencing large amounts of blood in the stool, the weakness and fatigue that the patient is experiencing is likely due to the anemia caused by loss of blood in the stool. The weakness and fatigue could also be caused by the immune response.


external image NCI_Digestive_torso_large.jpg

http://www.nlm.nih.gov/medlineplus/magazine/issues/spring09/images/NCI_Digestive_torso_large.jpg


Most specifically, Morrie has a mucinous adenocarcinoma located in the sigmoid colon, which is the section of the large intestine located between the descending colon and the rectum. Mucinous adenocarcinomas are characterized by having >50% of the tumor volume composed of extracellular mucin[3]. Mucin is a protein that has many functions such as immune suppression and lubrication and is produced by goblet cells found in and around gastrointestinal epithelial cells[4]. Given these properties, an increased proliferation of mucin can protect the tumor from the immune response, allowing the tumor to grow rapidly. This over-proliferation of mucin could also account for Morrie's reported diarrhea because mucin is a lubricating agent and could expedite stool passage. In addition, since the tumor resides in the colon and is a growth of epithelial cells, the tumor could be limiting the reabsorption of water that takes place in the large intestine. This lack of reabsorption could also contribute to Morrie's diarrhea. Excess mucin is normally taken up through the lymphatic system. When the mucin is in contact with the tumor cells, it can have the potential to transfer cancerous cells into the lymphatic system and then on to the rest of the body because the lymphatic system circulates lymph throughout the body[5]. This property makes mucinous adenocarcinoma more dangerous because it can easily become invasive. Morrie will continue to be closely monitored due to the dangerously invasive nature of this cancer.

Cancer Staging Criteria

To determine the stage that the cancer is in, the AJCC (American Joint Committee on Cancer) has devised a system that describes the different areas of cancer growth[6]. The T score tells which tissue the primary tumor has grown. In this patient, the cancer has grown into the fourth layer of the colon wall and is thus given the score of T3. The N score reflects the spread of cancer within neighboring lymph nodes. The patient exhibits N1a which means that the cancer has spread to one nearby lymph node. The M score reflects whether the cancer has spread to different sites or not. This patient scores an M0 which means that the cancer has not spread to distant sites. The combination of these scores places the patient in the stage IIIB group. There are five stages ranging from stage 0 to stage IV[7].

external image winslow_rm_illustration_of_colorectal_cancer_stages.jpg
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Treatment

In stage IIIB colon cancer, the cancer has managed to spread to neighboring lymph nodes, but has not spread to other parts of the body[8]. Cancers in this stage have grown through the colon wall and affected nearby tissues. To determine the stage of cancer, several diagnostic tools are used. A flexible sigmoidoscopy is used as a screening tool to visualize areas of the sigmoid colon and is done every 5 years. A total colonoscopy is used to allow the doctor to examine the entire large intestine in order to investigate any polyps or diseases and is done every 10 years. Imaging tests, most often CT (computed tomography) scans are also performed to allow doctors to determine the size, growth, and spread of the cancer and are done every 5 years[9]. In addition, laboratory tests such as guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and stool DNA test are done.

external image Colonoscopy-Preparation.jpg
http://yourgreatestmoms.com/files/2011/03/Colonoscopy-Preparation.jpg

Given the stage of cancer, the standard of care in this case is a partial colectomy of the section containing cancer as well as surgical removal of nearby lymph nodes. In order to prepare for surgery, Morrie will have to eat less, change to a liquid diet, or use enemas/laxatives to empty the colon for surgery[11]. Surgery is then followed by adjuvant chemotherapy, which is essentially just therapy following surgery to reduce the risk of cancer returning. Most often, the regimen used is a 6-month FOLFOX (5-FU, leucovorin, and oxaliplatin) regimen[12]. 5-FU is an antimetabolite pyrimidine antagonist which means that it interrupts the action of thymidylate synthase which is required for DNA replication[13]. Leucovorin is a medication which aids in 5-FU action as well as reducing the negative side effects of 5-FU[14]. Oxaliplatin is a metal salt alkylating agent and acts through non-targeted cytotoxic effects by inhibiting DNA synthesis in the cell cycle. It inhibits DNA synthesis by forming both inter- and intra-strand cross-links in DNA which prevents transcription[15]. The alternate treatment is CapeOx which is a combination of capecitabine plus oxaliplatin which provides an equal survival benefit. Capecitabine is enzymatically converted to 5-FU once inside the body[16]. If the doctor thinks that all of the cancer cells were not destroyed by this treatment, the doctor will often advise radiation therapy. The patient in this case is healthy enough for surgery and should opt for it. There was found to be no difference in efficacy rates when comparing age in colon cancer adjuvant treatments[17].


Patients given the 6-month FOLFOX regimen experienced a cancer related event in 21.1% of cases. After three years, the rate of disease-free survival was 78.2%[18]. There are novel treatment strategies being developed that the patient could opt for. There are targeted therapies such as bevacizumab which targets vascular endothelial growth factors (VEGFs), cetuximab and panitumumab which target epidermal growth factor receptors (EGFRs) that are mostly used in stage IV cancers that are being considered for use in conjunction with chemotherapy[19]. In addition, Morrie could consider using vaccines to treat the cancer or prevent it from coming back after treatment by boosting the immune reaction to fight the cancer more effectively[20][15]. Cancer vaccines work by targeting infectious agents that aid in the development of cancer. The vaccines target these causative agents by introducing the proper antigens into the body that correspond to the target cells. Morrie could participate in a clinical trial called “Redefining Adjuvant Therapy for Stage III Resected Colon Cancer”. Unfortunately, FOLFOX causes negative side effects. The most harmful side effects include anemia, diarrhea, loss of fertility, and hair thinning[21]. To limit the toxicity associated with FOLFOX, the trial will determine whether a 3 month course of FOLFOX treatment is as effective as a 6 month course in preventing recurrence of colon cancer. The trial stated that they have not seen any disturbing trends in the 1,700 patients enrolled since 2010[22]. The decision to participate in this trial is not a harmful or risky decision. Given this, I would recommend that Morrie should participate in this trial in order to avoid negative side effects.



Molecular Basis


Colorectal cancer exhibits several hallmarks of cancer that Morrie should be aware of. The hallmark that will be most important to focus on will be the proliferative signaling hallmark because the patient presents with two problems that exhibit this hallmark. The first mutation that Morrie presents with is the KRAS oncogenic mutation. This mutation occurs in 30-50% of colorectal cancers[23]. The KRAS oncogene encodes a small protein that normally acts to turn of signaling pathways involved in cell growth. KRAS is activated by epidermal growth factor receptors (EGFRs) in cells. When EGFRs are stimulated, cell growth and proliferation occurs. When KRAS is turned on, the cell is encouraged to grow. In the KRAS pathway, KRAS binds to GTP and converts it to GDP using GTPase which then turns off KRAS, inhibiting uncontrolled cell growth[24]. The KRAS mutations most frequently observed in cancers are a G to A transition and a G to T transition[25]. These mutations ensure that KRAS is constitutively on by inhibiting its ability to hydrolyze GTP by producing a protein with impaired GTPase enzymes. When KRAS cannot hydrolyze GTP, it is then unable to turn itself off. This results in a sustained proliferative signal for cell growth and increases the chance of tumorigenesis.



Another mechanism by which colorectal cancers work through sustaining proliferative cell signaling is through mammalian target of rapamycin (mTOR). mTOR is a protein kinase encoded by the MTOR gene. The mTOR protein is activated by the PI3K/Atk pathway which leads to protein synthesis and cell proliferation[26]. PI3K is activated by factors such as EGFR and insulin. PI3K phosphorylates Atk and localizes it to the plasma membrane of cells. Atk then activates mTOR which leads to proliferative cell growth. Over-activation of this pathway leads to sustained proliferative cell signaling. Over-activation is predicted to be caused by problems upstream of mTOR. Nearly 40% of carcinomas of the colorectum exhibit problems within the mTOR pathway[27]. Morrie exhibits this issue and mTOR aberration is playing a role in the patient’s tumor progression.



A particularly effective new targeted therapy is a drug called cetuximab. This drug is monoclonal antibody and an epidermal growth factor receptor inhibitor that works against the proliferative cell signaling hallmark of cancer. By inhibiting EGFRs in colorectal cancer, the drug can decrease tumor growth and size and improve patient outcome. However, the drug only works on patients who do not have the KRAS oncogene mutation. Patients with this mutation are not susceptible to cetuximab and other epithelial growth factor receptor inhibitor drugs[28]. The reasons for this resistance are unknown. Fortunately, there are KRAS genetic tests that can be done to determine if patients will respond to these drugs or not and whether use of cetuximab is necessary at all. This mutational analysis is very important because around 65% of colorectal cancer patients do not possess the KRAS mutation and would benefit from this drug[29]. Unfortunately, the patient in this case exhibits a KRAS mutation and would not benefit from the cetuximab treatment regimen. New strategies are being developed to combat this mutation; however there is currently no confirmed treatment. Proposed treatments include blocking downstream targets in the KRAS pathway. Unfortunately individual targeting has been found to be ineffective because the pathway involves many branching pathways within the pathway. A multi-targeted strategy may be more efficient but has yet to be confirmed in trials[30].



Given that Morrie would not benefit from cetuximab treatment since he has the KRAS mutation, other treatment options must be considered. The previously mentioned FOLFOX treatment is recommended in combination with the chemotherapy drug rapamycin. Rapamycin is a product of bacteria that is able to inactivate mTOR by associating with its intracellular receptor FKBP12[31]. This FKBP12-rapamycin complex binds to mTOR and inhibits its activity. This inhibition down-regulates protein synthesis and cell growth and decreases the chances of tumorigenesis and colorectal cancer[32].


Conclusion

Morrie can expect to have a 69% chance of survival with his stage IIIB colorectal cancer[33]. He has a long road ahead, but the treatment will most likely be effective and he has a good prognosis. The FOLFOX and rapamycin treatment will be used for Morrie in order to inactivate mTOR to combat his specific mutations. I hope that Morrie will opt for the clinical trial treatment option and do everything he can to make it through this. Morrie's cancer is a disease mainly caused by the choices that he made in his life. Should he survive, which I believe he will, it is my hope that he is able to learn from the poor lifestyle and diet related decisions that he made and begin a new and healthier life moving forward. This disease gives those who survive an opportunity to make a real change in their lives and develop habits that decrease their chances of developing the cancer again. Changes that Morrie can make include adopting a healthier, perhaps vegetarian, diet made of mostly fruits, vegetables, whole grains, and dairy in addition to a more intensive exercise plan and a professional life that is less stressful.

Apercu

The insight that I gained most from investigating this cancer is that colon cancer in particular is a result of poor lifestyle choices. This cancer is very preventable. The disease gives those who survive an opportunity to make a real and lasting change in their lives and improve their quality of life moving forward.


[1]"Colon and Rectal Cancer Key Statistics." Colon/Rectal Cancer. Web 16 Apr 2015.

http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-key-statistics
[2] Ibid.
[3] Fleming, Matthew et al. “Colorectal Carcinoma: Pathologic Aspects.” Journal of Gastrointestinal Oncology 3.3 (2012): 153–173.PMC. Web. 8 Apr. 2015.<http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418538/>
[4] Ibid.
[5] Leonie J.M. Mekenkamp, Karin J. Heesterbeek, Miriam Koopman, Jolien Tol, Steven Teerenstra, Sabine Venderbosch, Cornelis J.A. Punt, Iris D. Nagtegaal, Mucinous adenocarcinomas: Poor prognosis in metastatic colorectal cancer, European Journal of Cancer, Volume 48, Issue 4, March 2012, Pages 501-509, ISSN 0959-8049, http://www.sciencedirect.com/science/article/pii/S095980491101029X
[6] “NCCN Guidelines for Patients” Colon Cancer. Web. 23 Apr 2015. <http://www.nccn.org/patients/guidelines/colon/index.html#26>
[7] Ibid.
[8] “Colorectal Cancer: Treating by Stage” Colon/Rectum Cancer. Web. 23 Apr 2015. <http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-treating-by-stage-colon>

[9] “NCCN Guidelines for Patients” Colon Cancer. Web. 23 Apr 2015. <http://www.nccn.org/patients/guidelines/colon/index.html#26>
[10] “Colorectal Cancer Screening Tests” Colorectal Cancer and Early Detection. Web 30 Apr 2015. http://www.cancer.org/cancer/colonandrectumcancer/moreinformation/colonandrectumcancerearlydetection/colorectal-cancer-early-detection-screening-tests-used
[11] Lee, D-W et al. “Prognostic Implication of Mucinous Histology in Colorectal Cancer Patients Treated with Adjuvant FOLFOX Chemotherapy.” //British Journal of Cancer// 108.10 (2013): 1978–1984. //PMC//. Web. 24 Apr. 2015.
[12] Ibid.
[13] “Fluorouracil” Chemotherapy Drug Info. Web. 30 Apr 2015. <http://www.chemocare.com/chemotherapy/drug-info/fluorouracil.aspx.>
[14] “Leucovorin” Chemotherapy Drug Info. Web 30 Apr 2015. <http://chemocare.com/chemotherapy/drug-info/Leucovorin.aspx>
[15] “Oxaliplatin” Chemotherapy Drug Info. Web 30 Apr 2015.< http://chemocare.com/chemotherapy/drug-info/Oxaliplatin.aspx>
[16] “Cape/Ox is Non-inferior to FOLFOX for Colon Cancer” Pharmacy Practice News. O’Rourke, Kate. Web 30 Apr 2015.http://www.pharmacypracticenews.com/ViewArticle.aspx?d=Clinical&d_id=50&i=December%2B2006&i_id=207&a_id=6263

[17] D. G. Haller, M. J. O'Connell, T. H. Cartwright, C.J. Twelves, E. F. McKenna, W. Sun, M. W. Saif, S. Lee, G. Yothers, and H.-J. Schmoll
“Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: a pooled analysis of individual patient data from four randomized controlled trials”. Web. 23 Apr 2015. http://www.ncbi.nlm.nih.gov/pubmed/25595934
[18] Thierry André, M.D., Corrado Boni, M.D., Lamia Mounedji-Boudiaf, M.D., Matilde Navarro, M.D., Josep Tabernero, M.D., Tamas Hickish, M.D., Clare Topham, M.D., Marta Zaninelli, M.D., Philip Clingan, M.D., John Bridgewater, M.D., Isabelle Tabah-Fisch, M.D., and Aimery de Gramont, M.D. Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. Web. 23 Apr 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa032709
[19] “What’s new in colorectal cancer research and treatment?” Colorectal Cancer. Web. 23 Apr 2015. http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-new-research
[20] Ibid.
[21] “FOLFOX” Treatment/Cancer Drugs. Web 30 Apr 2015. http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/cancer-drugs/folfox
[22] “Redefining Adjuvant Therapy for Stage III Resected Colon Cancer” Colorectal Cancer. Web. 23 Apr 2015. http://www.cancer.gov/cancertopics/types/colorectal/research/folfox-celecoxib

[23] Liu, Xiuli “KRAS gene Mutation in Colorectal Cancer is Correlated with increased Proliferation and Spontaneous Apoptosis” American Journal of Clinical Pathology; 135: 245-252. <http://www.medscape.com/viewarticle/736647>
[24] Ibid.
[25] Ibid.
[26] Wagner, Marcus. “Effective Treatment of Advanced Colorectal Cancer by Rapamycin and 5-FU/Oxaliplatin Monitored by TIMP-1” Journal of Gastrointestinal Surgery. <http://link.springer.com/article/10.1007/s11605-009-0948-x/fulltext.html>
[27] Ibid.
[28] Pearson, R.k. "Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer." Yearbook of Gastroenterology: 91-93. http://www.nejm.org/doi/full/10.1056/NEJMoa0805019#t=article
[29] Ibid.
[30] Prenen, Hans. “New Strategies for Treatment of KRAS Mutant Metastatic Colorectal Cancer” Clinical Cancer Research. <http://clincancerres.aacrjournals.org/content/16/11/2921.long>
[31] Wagner, Marcus. “Effective Treatment of Advanced Colorectal Cancer by Rapamycin and 5-FU/Oxaliplatin Monitored by TIMP-1” Journal of Gastrointestinal Surgery. <http://link.springer.com/article/10.1007/s11605-009-0948-x/fulltext.html>
[32] Ibid.
[33] “What are the survival rates for colorectal cancer by stage?” Colorectal Cancer. http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-survival-rates