Colon And Rectal Cancer

Michael D. Hellinger, M.D., F.A.C.S., F.A.S.C.R.S
Associate Professor of Clinical Surgery
Chief, Division of Colon and Rectal Surgery
DeWitt Daughtry Family Department of Surgery
University of Miami/Sylvester Comprehensive Cancer Center

To produce an extensive discussion on the topic of carcinoma of the colon and rectum would require an entire textbook. Therefore, the focus of what follows is to provide an overview of the topic and an update of advances since the last Core subject review on this topic in 1998. For details, I would refer you to a standard textbook of colon and rectal surgery or to any of the references listed at the end of this manuscript.

Incidence

Carcinoma of the colon and rectum (CRC) remains the fourth leading cancer in the United States and the second leading cause of cancer death. It follows lung, breast, and prostate cancer in incidence, and lung cancer in mortality. The American Cancer Society (ACS) estimates that for the year 2003 there will be 147,500 new cases and 57,100 deaths from CRC. However, recent trends reveal a slight decrease in both the incidence of and mortality from CRC. This is assumed to be secondary to increased screening rates leading to polypectomy and the diagnosis of cancers at an earlier stage. Still the lifetime risk approaches 6%.

Etiology

While the vast majority of cases of CRC are still considered to be sporadic, genetic causes or predispositions are more commonly sited as risk factors. It is still assumed, however, that upwards of 70% of all CRCs are sporadic in nature. A variety of risk factors are listed in table 1.

Table 1: Risk Factors

Genetics

Whether secondary to an inheritable abnormality or due to environmental exposure, CRC is a genetic disorder. That is to say that the transformation of a normal cell to a neoplastic one occurs through an orderly step-wise accumulation of genetic alterations as established in the adenoma to carcinoma sequence. The probability that this will occur is extremely low. Not only are mutational events extremely rare, but also most mutations are not advantageous to the cell. They are either silent and cause no effect or are lethal to the cell. In most circumstances, DNA damage will result in cessation of replication in order to complete a reparative process, or if the damage were severe enough the cell would signal its own destruction (apoptosis). The accumulation of the correct set of advantageous mutations in the appropriate order, known as genetic instability is therefore extremely unlikely to occur.

Several different events are necessary to complete the transformation to malignancy. Mutational events may lead to activation of oncogenes or inactivation of tumor suppressor genes, which facilitate cellular growth and proliferation. The final key to the pathway is the mutation of the mismatch repair genes, which are responsible for identifying and repairing mismatched base pairs during the replication process. Failure of this system will predispose to the development of mutations. Inactivation of the mismatch repair genes leads to what has been termed microsatellite instability. This concept refers to new short segments of DNA found within a tumor that is not present in the normal tissue. A combination of these mutational events will lead to successful selection of a growth advantage and progression to malignancy.

Screening and prevention

Primary prevention of CRC includes lifestyle changes as well as medical intervention. Since the majority of cases of colorectal cancer are felt to be sporadic in nature, changes in diet and lifestyle may very well contribute to a diminished risk. Although still controversial, in the low risk individual moderate physical activity and a diet high in consumption of vegetable fiber and low in red meats and animal fats may be protective. In addition, recent evidence indicates that daily aspirin, dietary calcium, and a multivitamin containing folate may also be protective. In the higher risk population, use of antioxidants and NSAIDs may also be advantageous.

Multiple studies have shown the benefits of screening utilizing the different available tools. Current guidelines are listed in table 2. Low or average risk individuals should begin screening at age 50. Despite these established guidelines, less than 40% of the US population has ever had any form of CRC screening. While colonoscopy is felt to be the best option, there is insufficient evidence to recommend one test over another. Therefore, a menu approach has been adopted to allow choice of a screening method that is best for the patient. The combination of flexible sigmoidoscopy and FOBT is felt to be the second best approach. However, recent data has shown that a single FOBT and flexible sigmoidoscopy may miss up to 30-40% of all significant neoplasms proximal to the splenic flexure. Individuals at increased or high risk should undergo more rigorous surveillance, and have recommendations tailored to their specific risk.

Table 2: Screening guidelines

Several emerging technologies hold future promise as screening tools. However, limited evidence precludes their use a screening tools at the present time. CT or MRI colonography utilizes high-resolution scans to render both 2 and 3 dimensional reconstructions of the colon. In the hands of highly trained individuals the accuracy for detecting polyps greater than 10 mm. approaches 90%, while that of smaller lesions falls to 50% or less. Although this test has several potential advantages, it is the most expensive of all the available screening tools, it still requires bowel prep, and colonoscopy must be performed to confirm a positive test. Although this test shows promise, especially in patients with obstructing lesions, it has not yet been studied sufficiently in a screening population to make recommendations regarding its use. For this test to receive widespread acceptability, it must be accurate enough to correctly identify patients with lesions who need to undergo colonoscopy or surgery as a therapeutic intervention.

A new immunochemical FOBT and a stool-based DNA test have recently been introduced. Although both have been shown to have sensitivities and specificities in the 80-90% range in individuals with know polyps and cancers, they have not been tested as screening tools. While the immunochemical FOBT may be easier and more accurate to use than current FOBT testing, DNA stool testing may very well prove to be a more advantageous approach. DNA is stable in the stool and shed continuously. It can be detected in trace amounts and is neoplasm specific. Therefore false positives should be low. Current ongoing trials may lead to new screening recommendations utilizing these agents in the future.

Several studies have looked at barriers to screening. The most frequently sited reason for not having undergone screening is that the primary care physician (PCP) never recommended it. Other reasons for not undergoing screening are a fear of pain, embarrassment or the preparation process, cost and reimbursement related issues, lack of a perceived need, and lack of access. Predictors of screening are a college education, a family history of cancer, participation in other screening exams and regular annual physicals, and Medicare vs. private insurance. In fact when PCPs are surveyed regarding screening, reasons for low screening rate sited are lack of awareness of the guidelines and benefits of screening, lack of a practice system to discuss screening in the context of a standard office visit and to track compliance, and a belief that patients do not want to be screened or to talk about CRC.

Future strategies will focus on awareness, increasing screening rates, and development of screening tools that are highly accurate and more acceptable to the patients and physicians. These tools must be noninvasive, convenient, and cost-effective alternatives in order to effectively increase acceptability.

PET Imaging

Positron emission tomography (PET) utilizing fluor-deoxy-D-glucose (FDG) has recently been shown to be a beneficial adjunct in the evaluation of colon and rectal cancer patients. This method takes advantage of the increased glucose metabolism of most malignancies to obtain functional imaging. FDG is accumulated and trapped within malignant cells allowing rapid whole body imaging.

Studies have shown that FDG-PET is more accurate in delineating metastatic disease from post-surgical changes. In studies comparing CT scanning and FDG-PET imaging for recurrent rectal cancer, FDG-PET has shown superior results for liver metastases as well as intra-abdominal and pelvic disease. While the sensitivity and specificity for CT scanning ranges from 40-80% for all sites, that for FDG-PET ranges from 70-100%. One study actually showed a survival benefit in FDG-PET staged patients over CT scan staging after surgical resection of liver metastases. The overall 3-year survival in FDG-PET imaged patients was 77% vs. 40% in those undergoing conventional imaging. In fact studies have reported a change in management in 20-60% of patients. FDG-PET may therefore be a cost-effective tool in the evaluation of patients with suspected recurrent or metastatic disease. It's superiority to conventional imaging techniques may make this the first study of choice in evaluating patients with a rising CEA, with CT or MRI reserved for evaluation of positive findings. Additionally FDG-PET has been shown to be instrumental in differentiating equivocal findings seen on conventional scans.

Sentinel Lymph Node mapping

The ability to accurately identify metastatic lymph nodes in resected colonic specimens translates into more accurate staging and treatment with postoperative chemotherapy. Since lymph node status is the most sensitive predictor of long-term survival in CRC and adjuvant chemotherapy has been shown to prolong survival in stage 3 disease, more accurate diagnosis of node positive disease is crucial if we are able to improve a patient's chances of cure.

The clinical utility in sentinel lymph node (SLN) mapping has already been determined in both carcinoma of the breast and malignant melanoma. However, the utility of this technique has not been proven in colorectal malignancies. In fact, regardless of whether or not lymphazurin blue dye or Technetium colloidal is utilized, the results are highly variable. Studies have shown that identification of one or more SLNs occurs in 55-90% of patients. The diagnostic accuracy ranges from 30-90%, while the false negative rate is more highly variable (4-60%). There also tends to be poor concordance between blue staining and radioactive lymph nodes.

What can be concluded from this early data is that the SLN does not accurately predict the total nodal status and SLN mapping in its current state is of little clinical value. For this SLN mapping to become effective, it must accurately stage the patient based on the targeted nodes. Accuracy may be increased by using immunohistochemistry, step sectioning techniques, or detection of specific markers by reverse-transcriptase analysis. However, the clinical relevance of micrometastases in these SLN is of unknown clinical relevance. It is possible that these tumor cells would not survive an attack by the body's immune system. Therefore, further studies are clearly warranted before any clear recommendations can be made regarding this technique

Local Excision of Rectal Carcinomas

Local excision (LE) of early stage rectal carcinoma is a reasonable alternative to radical resection on a select group of patients. Current staging tools can fairly accurately identify these stage 1 lesions that may be amenable to LE. Contrary to older data, recent literature has shown a rather high recurrence rate for LE of T1 and T2 lesions. Local recurrence rates after LE of stage 1 lesions ranges from 0-28%. That for T1 tumors is in the range of 5-18%, while for T2 lesions the recurrence rates are as high as 47%. The most important issue is the presence of metastatic lymph nodes. Studies have confirmed a risk of lymphatic metastases in 5-20% of T1 and 10-30% of T2 tumors. Tumors with high-risk features carry the greatest risk of nodal metastases. Addition of postoperative chemoradiation to LE of T2 lesions has recently been shown to diminish the local recurrence rate in these T2 and other high-risk lesions. The ultimate endpoint for these trials is overall survival, which ranges from 69-73%. Survival for T1 tumors (72-90%) was clearly better than that for T2 tumors (55-78%). Addition of chemoradiation improves overall survival, especially in the patients with T2 tumors (75-94%).

A recent trial comparing radical to LE revealed an overall 5-year recurrence rate of 28% in the LE group vs. 4% in the radical resection group. No patient recurred after radical resection of a T1 lesion, while 6% of the T2 lesions recurred after this mode of therapy. In the LE group recurrence for T1 tumors was 18% while that of T2 tumors was 477%. There was also a difference in long-term survival (69% for LE and 82% for radical resection). This difference reached significance only for the T2 tumors (65% VS. 81%). Studies Have also shown that 50% of patients who experience a recurrence after LE are amenable to curative surgery.

Several authors have recently reported the importance of the depth of submucosal invasion in T1 CRCs. The submucosa has been categorized into upper, middle, and lower thirds (sm1, sm2, sm3). Depth of invasion into level sm3 has been shown to be a significant predictor of nodal metastases and recurrent disease. Therefore, these higher risk lesion should be considered for either adjuvant chemoradiation or radical resection.

It there becomes even more important for us to accurately stage and carefully select our patients preoperatively prior to embarking on LE. Those that are found to have T2 or otherwise high-risk lesions should undergo postoperative chemoradiation to diminish the risk of recurrence. However, to date there has been no prospective randomized trials comparing LE with or without chemoradiation to radical resection in patients with T1 and/or T2 rectal tumors.

Neoadjuvant chemoradiation trials have demonstrated a significant rate of tumor down-staging, improved local control and lesser rates of lymph node metastases. Several authors have recently reported the use of LE after down-staging to clinical T0 or T1 lesions. In cases of T0 tumors the scar is excised while in T2 lesions the residual disease is excised with a clear margin. Any patient with positive margins or disease greater than T1 is counseled to then undergo radical resection. Although this represents a small percentage of our patient population, reported low recurrence and excellent survival rates in these initial reports are encouraging and warrant further trials.

Laparoscopic Colectomy for Cancer

Ten years after early data determined the feasibility of laparoscopic resection for selected CRCs, we are no closer to determining the long-term outcome. Early studies have clearly documented benefits in the short term. Reports indicate that laparoscopic resection results in less postoperative pain, a quicker return of bowel function, diminished infectious complications, and therefore a shorter overall hospital stay and earlier return to pre-surgical activities. Obviously, in some patients cosmesis is also an important issue.

Several small prospective randomized single institution trials have been completed which show acceptable mid and long-term data. Although oncological outcome is clearly the most crucial factor, other issues remain important. There is data to support that a greater percentage of elderly patients return to their preoperative state of independence after a laparoscopic resection. In addition, a lower rate of adhesions has been demonstrated. This may translate into a decreased incidence of small bowel obstruction, and therefore less hospitalizations and re-operations. Oncological results are measured in the long-term by survival and recurrence. In the short term, we measure margins and lymphovascular clearance. These two factors have been shown to be equivalent to open surgical techniques. Initial concerns regarding wound and port site recurrences are currently less concerning. Recent reports from larger series indicate the rate of recurrence, in the wound or port sites, is between 0 and 2.5%. This is not statistically different from that of open surgical procedures. It has been assumed therefore that these recurrences are most likely due to inadequate surgical technique. No study has shown a detrimental effect on survival. In fact, the published data documents equivalent or slightly better outcomes in the laparoscopic group. However, the results of ongoing large prospective randomized trials are needed to ultimately answer the question of oncological equivalency or superiority.

Adjuvant Chemotherapy

For the past decade, 5-FU based therapy in combination with Levamisole or Leukovorin has been the standard of care for stage 3 CRC. Long-term data has shown a 40% decreased recurrence rate and a 33% improved survival. However, a substantial group of patients are still succumbing to CRC. Recent advances in chemotherapeutics have led to further combinations as first and second line alternatives. Newer agents have recently entered the field, including Irinotecan and Oxaliplatin. Results of randomized trials reveal increased response rates and prolonged survival using 3 drug combinations. In addition, an oral form fluoropyridine is now available, which has been shown to have equivalent results to infusional 5-FU. Further trials are ongoing to determine the optimal combination and sequence of these agents.

Various other trials are investigating the utility of targeted biological therapy. These agents include inhibitors of the epidermal growth factor receptor, tyrosine kinase, and tumor angiogenesis, as well as vaccines, gene therapies, and chemopreventative agents. These investigations and advancements will hopefully lead to further decreased recurrences, improved long-term survival, and a better quality of life in CRC patients.

Metastatic Disease

30-70% of all CRC patients will develop metastatic disease, the vast majority of which occur in the liver or lungs. If left untreated the 5-year survival is less than 5%. Highly selected patients with liver or lung metastases are candidates for further curative surgery. Curative resection of liver disease results in a 22-49% 5-year survival. For lung metastases, the 5-year survival ranges from 14-78%. However, re-recurrences occur in 50-70% of these patients. In addition concurrent or sequential liver and lung resections are possible with a 5-yeaer survival approaching 30%. Other then systemic chemotherapy, alternative therapies for liver metastases include hepatic artery infusion, portal vein embolization, and local destruction utilizing cryosurgical techniques or Radiofrequency ablation. Although short term data is encouraging, there is no long-term data available on any of these alternatives.

Rectal Cancer - Locally Advanced or Recurrent

Locally advanced and recurrent rectal carcinoma represents an extremely difficult clinical dilemma. Results of surgical intervention have been mixed. Reports of high recurrence rates and poor long-term survival have led to a multimodal approach to these tumors. Based on results of trials revealing improved local control and prolonged survival, the NIH published a consensus statement recommending the use of post-operative chemoradiation in patients with stage 2 and 3 rectal cancer. However, recent trends have advocated the use of pre-operative chemoradiation. The primary advantages of pre-operative vs. post-operative therapy are enhanced sphincter salvage rates and diminished complications. There is also a reported complete response rate of 10-30%. In comparison, although pre-operative therapy results in a higher rate of sphincter preservation and possibly a lower local recurrence rate than post-operative therapy, a clear survival advantage has not been proven. Several recent studies investigating the use of both pre-operative and intra-operative radiation therapy have documented an improvement in local control and over all survival over pre-operative radiation therapy alone.

In addition, the importance of total mesorectal excision (TME) cannot be over looked. The adaptation of TME has resulted in lower recurrence rates without the use of adjuvant therapy. Several advocates of TME contend therefore that radiation therapy is not necessary in patients who undergo resection utilizing this technique. However, instead of considering TME as a competitor to adjuvant therapy, this meticulous surgical technique should be considered central to the successful management of rectal cancer and a crucial component of the ultimate therapy.

Post-operative Surveillance

The aim of post-operative surveillance is early detection of recurrent disease or identification of a new primary malignancy, as well as measuring the efficacy of the original treatment. Components of this evaluation are history and physical examination, endoscopic evaluation, serum tumor markers, and diagnostic imaging. Since the vast majority of recurrences occur with in the first 2 years following resection (60-80%), intensive early follow up may be beneficial. In meta-analysis of trials comparing intensive to routinely followed patients, recurrence rates were similar. However, recurrence was more often diagnosed at an earlier, often asymptomatic, stage. However, although nonrandomized trials revealed a survival advantage in the intensely followed group, randomized trials did not.

Although guidelines on the frequency and type of evaluation remain to be clearly determined, the American Society of Clinical Oncology (ASCO) published their recommendations based on a 20 year review of the medical literature. Their recommendations include a history and physical every 3-6 months for the first 3 years and a CEA level every 2-3 months for patients with stage 2 and 3 disease for at least 2 years. In addition, they recommend colonoscopy every 3-5 years. Other directed evaluations are recommended for symptoms or an elevated CEA.

References

1. American Cancer Society Guidelines for Early Detection of Cancer, 2003; Cancer Statistics, 2003; Merging Technologies in Screening for Colorectal Cancer. CA: A Cancer Journal for Clinicians 2003;53(1).
2. Blumberg D, Paty PB, Guillem JG, et. al. All Patients with Small Intramural Rectal Cancers are at Risk for Lymph Node Metastasis. Dis Colon Rectum 1999;42:881-885.
3. Esser S, Reilly WT, Riley LB, et. al. The Role of Sentinel Lymph Node Mapping in the Staging of Colon and Rectal Cancer. Dis Colon Rectum 2001;44:850-856.
4. Farouk R, Nelson H, Gunderson LL. Aggressive Multimodal Treatment for Locally Advanced Irresectable Rectal Cancer. BJS 1997;84:741-749.
5. Johnson K, Bakhsh A, Young D, et. al. Correlating Computed Tomography and Positron Emission Tomography Scan with Operative Findings in Metastatic Colorectal Cancer. Dis Colon Rectum 2001;44:354-357.
6. Joosten JJA, Strobbe LJA, Wauters CAP, et. al. Intraoperative Lymphatic Mapping and the Sentinel Node Concept in Colorectal Carcinoma. BJS 1999;86:482-486.
7. Kemeny, MM editor. Chemotherapy for Colorectal Cancer. Seminars in Colon and Rectal Surgery 2002;13(4).
8. Kitagawa Y, Watanabe M, Hasegawa, H, et. al. Sentinel Node Mapping for Colorectal Cancer with Radioactive Tracer. Dis Colon Rectum 2002;45:1476-1480.
9. Lechauz D, Trebuchet G, Le Calve JL. Five-Year Results of 206 Laparoscopic Left Colectomies for Cancer. Surg Endosc 2002;16:1409-1412.
10. Lujan HJ, Plasencia G, Jacobs M, et. al. Long-Term Survival After Laparoscopic Colon Resection for Cancer. Dis Colon Rectum 2002;45:491-501.
11. Mellgren A, Sirivongs P, Rothenberger DA, et al. Is Local excision Adequate Therapy for Early Rectal Cancer. Dis Colon Rectum 2000;43:1064-1074.
12. Merrie AE, van Rij AM, Phillips LV, et al. Diagnostic use of the Sentinel Node in Colon Cancer. Dis Colon Rectum 2001;44:410-417.
13. Minsky, BD editor. Radiation Therapy for Colorectal Cancer. Seminars in Colon and Rectal Surgery 2001;12(4).
14. Ratto C, Valentini V, Morganti AG, et. al. Combined-Modality Therapy in Locally Advanced Primary Rectal Cancer. Dis Colon Rectum 2003;46:59-67.
15. Read, T editor. Advanced Imaging In Colon and Rectal Surgery. Seminars in Colon and Rectal Surgery 2002;13(2).
16. Schell SR, Zlotecki RA, Mendenhall WM, et. al. Transanal Excision of Locally Advanced Rectal Cancers Downstaged Using Neoadjuvant Chemoradiotherapy. J Am Coll Surg 2002;194:584-591.
17. Colorectal Cancer. Guillem JG, Sigurdson ER, Ed. Surgical Clinics of North America 2002;82(5).
18. Weinstein LS, Timmcke AE. Future Technology: Colography and the Wireless Capsule. Clinics in Colon and Rectal Surgery 2001;14:393-399.
19. Wright CM, Dent OF, Barker M, et. al. Prognostic Significance of Extensive Microsatellite Instability in Sporadic Clinicopathological Stage C Colorectal Cancer. BJS 2000;87:1197-1202.
20. Young-Fadok TM, Talac R, Nelson H. Laparoscopic Colectomy for Cancer: The Need for trials. Seminars in Colon and Rectal Surgery 1999;10:94-101.