Colon cancer

1.1.1. Incidence 

Cancers of the colon and rectum are the third most common type worldwide [1], [2]. Cancer of the colon is more frequent than rectal cancer: in industialized countries, the ratio of colon to rectum cases is 2:1 or more (rather more in females) while in non-industrialized countries rates are generally similar. In Europe around 250,000 new colon cases are diagnosed each year, accounting for around 9% of all the malignancies. Rates of this cancer increase with industrialization and urbanisation. It has been much more common in high income countries but it is now increasing in middle- and low-income countries. It remains relatively uncommon in Africa and much of Asia (Fig. 1). The incidence is slightly higher in Western and Northern Europe than in Southern and Eastern Europe. Other high risk areas include North America, Europe and Australia. Central and South America, Asia and Africa are areas of low risk [1].

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Fig. 1. Incidence rates of colon cancer in the world. Source: Ref. [1].

In general, there have been increases in incidence in countries where the overall risk of large bowel was low, while in countries with high incidence rates there have been either stabilitations or decreases in incidence, particularly in younger age groups. For colon cancer, the greatest increases in incidence are observed in Asia, as well as in countries of Eastern Europe. In Western Europe and Oceania, the overall (age-adjusted) rates have remained fairly constant. In the USA, since the mid-1980s there has been a decline in incidence in both sexes, while there has been no similar decline in the black population [3]. In Italy [4], the annual incidence rates were estimated to increase throughout the period 1970–2010 for men from 30 to 70 per 100,000, and to stabilize from the end of the 1990s for women at around 38 per 100,000. The estimated numbers of annual new diagnosis and deaths, for the year 2005, were 46,000 and 16,000 respectively; 58% of both were related to men. About 70% of patients with colon cancer are over 65 years of age. Colon cancer is rare under the age of 45 years (2 per 100,000/year). In the age group 45–54 years colon cancer incidence is about 20 per 100,000/year and thereafter it increases at a much higher rate (55 per 100,000/year for aged 55–64, 150 for aged 65–74 and >250 per 100,000/year for those older than 75 years of age) [3] (Fig. 2).

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Fig. 2. Incidence rates of colon cancer by age in the UK. Source: Ref. [1].

1.1.2. Survival 

In Europe, the relative survival for adults diagnosed with colon cancer during 1995–1999 was 72% at 1 year and 54% at 5 years [5]. Five-year relative survival decreased with age from 63% to 49% from the youngest (15–45 years) to the oldest age group of patients (75 years and over). There have been large improvements in survival since the late 1970s in both sexes and in all regions of Europe. In Europe as a whole, 1-year survival rose by 6%, and the gain in 5-year survival was 9% [6]. Survival is higher in most nordic and western European countries, but even in the countries with the highest survival rates, 5-year survival is still less than 60%. Detailed studies suggest that variations among countries were bigger in the first half year following diagnosis than in the interval 0.5–5 years, with about 30% higher risk in the UK and Denmark. Patient's management, diagnostics, and comorbidity likely explain the excess deaths in the UK and Denmark during the first 6 months [7]. In the USA, survival for patients diagnosed with colorectal cancer, in 2000–2002, was 65.5%, while in Europe the figure was 56.2% [8]. Colon cancer is characterized by a much better response when treated at an early stage, and the large survival differences may therefore reflect the fact that more healthy Americans than Europeans undergo early diagnostic procedures.

1.1.3. Prevalence 

About 267,000 prevalent cases for colorectal cancer are estimated in Italy for the year 2008; 53% of prevalent cases related to men. The proportion in Northern Italian regions proved to be 2-fold that in the Southern regions (580 vs. 295 for men and 447 vs. 225 per 100,000 for women) [4].

1.2.1. Risk factors 

Colorectal cancer most commonly occurs sporadically and it is inherited in only 5% of cases [9]. Migrant studies indicate that when populations move from a low-risk area (e.g. Japan) to a high-risk area (e.g. the USA), the incidence of colorectal cancer increases rapidly within the first generation of migrants, and Japanese born in the USA have a higher risk than the white population [10]. Diet is definitely the most important exogenous factor identified so far in the etiology of colorectal cancer. Recently, the World Cancer Research Fund and the American Institute for Cancer Research [11] in their extensive report on the scientific literature on diet, physical activity and prevention of cancer, have concluded that colorectal cancer is mostly preventable by appropriate diets and associated factors. After a systematic literature review of 752 publications a panel of experts made the following conclusions. The evidence that physical activity protects against colorectal cancer is convincing, although the evidence is stronger for colon than for rectum cancer. The evidence that red meat, processed meat, substantial consumption (more than about 30g per day ethanol) of alcoholic drinks (by men, and probably by women), body fatness and abdominal fatness, and the factors that lead to greater adult attained height, or its consequences, are causes of colorectal cancer, is convincing. Foods containing dietary fibre, as well as garlic, milk, and calcium, probably protect against this cancer. There is limited evidence suggesting that non-starchy vegetables, fruits, foods containing folate, as well as fish, foods containing vitamin D, and also selenium and foods containing it, protect against colorectal cancer, and that foods containing iron, and also cheese, foods containing animal fats, and foods containing sugars are causes of this cancer.

1.2.2. Non-dietary factors 

Established non-dietary risk factors of colon cancer include smoking tobacco, chronic use of non-steroidal antiinflammatory drugs (NSAIDs) and aspirin and some conditions such as a few colorectal diseases, genetic predispositions and the metabolic syndrome [12]. Smoking has consistently been positively associated with large colorectal adenomas, which are generally accepted as being precursor lesions for colorectal cancer. Thus exposure to tobacco constituents may be an initiating factor for colorectal carcinogenesis [13]. An updated review suggested a temporal pattern consistent with an induction period of three to four decades between genotoxic exposure and colorectal cancer diagnosis. In the USA one in five colorectal cancers may be potentially attributable to tobacco use.

A systematic review was conducted to determine the effect of nonsteroidal anti-inflammatory drugs for the prevention or regression of colorectal adenomas and cancer. The reviewers’ conclusions were that there is evidence from three randomized trials that aspirin significantly reduces the recurrence of sporadic adenomatous polyps. There was evidence from short-term trials to support regression, but not elimination or prevention, of colorectal polyps in familial adenomatous polyposis [14]. Inflammatory bowel disease (Crohn's disease and ulcerative colitis) increases the risk of colon cancer. A recent meta-analysis reported an increased risk to develop colon cancer in people affected by Crohn's disease (relative risk, 2.6; 95% confidence interval, 1.5–4.4) [15]. The meta-analysis by Eaden et al. [16], found a positive relationship between ulcerative colitis and colorectal cancer. The risk exists for ulcerative colitis by decade of disease and in pancolitics. Patients who have had previous malignant tumour are also at great risk of developing a second colorectal tumour [17]. The metabolic syndrome (≥3 of the following components: high blood pressure, increased waist circumference, hypertriglyceridemia, low levels of high density lipoprotein cholesterol, or diabetes/hyperglycemia) had a modest, positive association with colorectal cancer incidence in the ARIC cohort among men, but not among women; there was a dose response according to the number of components present [18]. Based on significant evidence, postmenopausal estrogen plus progesterone hormone use decreased the incidence of colorectal tumour, but non-comparable benefit was demonstrated for estrogen alone employment [19].

1.2.3. Genetic factors 

Genetic vulnerability to colon cancer has been attributed to either polyposis or nonpolyposis syndromes. The main polyposis syndrome is familiar adenomatous polyposis (FAP), which is associated with mutation or loss of FAP (also called the adenomatous polyposis coli (APC)) gene. Hereditary nonpolyposis colorectal cancer (often referred to as HNPCC) syndrome is associated with germline mutations in six DNA mismatch repair genes [12]. The incidence of colorectal cancer was determined in HNPCC-gene carriers up to age 70 years in the Finnish Cancer Registry. By age 70 years the cumulative colorectal cancer incidence was 82% [20].

1.3.1. Screening 

The identification of the adenomatous polyp as a well-determined premalignant lesion, together with the good survival associated with early disease, make colorectal cancer an ideal candidate for screening. The major aim of screening is to detect the 90% of sporadic cases of colorectal cancer, most of which occur in people above the age of 50 years [12]. Up to now two screening strategies are available: faecal occult blood test (FOBT) and endoscopy. The most extensively examined method, FOBT, has been shown in several randomized trials to reduce mortality from colorectal cancer by up to 25% among those attending at least one round of screening [21]. Screening colonoscopy has the advantage of visualising the entire colon, but the procedure is expensive, involves substantial discomfort, and has a risk of complications such as bowel perforation. No trials have evaluated the effectiveness of screening colonoscopy [22]. The Council of Europe recommends faecal occult blood screening for colorectal cancer in men and women aged 50–74 [23]. Colonoscopy should be used for the follow-up of test positive cases. Screening should be offered to men and women aged 50 years to approximately 74 years. The screening interval should be 1–2 years. The screening strategies should be implemented within organized programs, where possible, in order to stimulate an increased awareness among the public and providers of the burden of the disease and the potential to reduce this burden through effective screening, diagnosis and treatment [24]. At present, a national screening programme exists in Finland. In 2007, approximately a third of the Finnish population was covered. Regional initiatives have been implemented in several other European Union countries, including France, Italy, Poland, the Netherlands and the United Kingdom. Other screening modalities are also available, but evidence for their effectiveness is very limited [22].

2.1.1. Histogenesis 

The development of colorectal cancer is a multistep process that involves a successive loss of genes. Rapid advances in molecular biology techniques have allowed characterization of the genetic changes thought to be responsible for this multistep process. More definitive studies using genetic linkage were made possible when the locus for Familial Adenosis Polyposis (FAP) gene was discovered. Using RFLP analysis and in situ hybridization of DNA from 13 families of patients with FAP, the location of the FAP gene was found to be close to a marker at 5q21-q22 [25]. Colorectal cancer has provided a useful model for the understanding of the multistep process of carcinogenesis. The availability of numerous polymorphic DNA markers provides a means for the localization of other mutations associated with the somatic loss of heterozygosity in colon cancer and it suggests that other tumour suppressor genes may be involved in colorectal oncogenesis more downstream from the formation of a polyp. Vogelstein and Colleagues examined the genetic alterations in colorectal tumour specimens at various stages of the neoplastic development and found that changes in the 5q chromosome and the RAS oncogene tend to occur early in the pathway [26]. Frequent mutations have been found in the K-ras using RNAse protection assay [27] and DNA hybridization analysis. Further downstream in the progression to malignancy is the deletion of a region of chromosome 18. This region was frequently deleted in carcinomas and advanced adenomas but only occasionally in early adenomas. This gene has been named deleted in colon cancer (DCC) and the primary structure of its protein product is homologous to the neural cell adhesion molecule (N-CAM). Vogelstein et al. discovered a fourth tumour suppressor gene called mutated in colon cancer (MCC), also located at 5q21, that has loss of function mutations in sporadic colorectal cancer [28].

2.2.1. Histotypes 

The major histological type of large bowel cancer is adenocarcinoma, which accounts for 90–95% of all large bowel tumours. Colloid or mucinous adenocarcinomas represent about 17% of large bowel tumours. These adenocarcinomas are defined by the large amounts of extracellular mucin retained within the tumour. A separate classification is the rare signet-ring cell carcinoma (2–4% of mucinous carcinomas), which contains intracellular mucin pushing the nucleus to one side. Some signet ring tumours appear to form a linitis plastica-type tumour by spreading intramurally, usually not involving the mucosa. Other rare variants of epithelial tumours include squamous cell carcinomas and adenosquamous carcinomas, sometimes called adenoacanthomas. Finally there are the undifferentiated carcinomas, which contain no glandular structures or other features, such as mucous secretions. Other designations for undifferentiated carcinomas include carcinoma simplex, medullary carcinoma and trabecular carcinoma. Other types of tumours, that can be found in the large bowel, are carcinoid tumours and nonepithelial tumours, such as leiomyosarcomas, hematopoietic and lymphoid neoplasms and gastrointestinal stromal tumours (GISTs).

2.3.1. Clinical implications 

In the Broders’ system four grades based on the percentage of differentiated tumour cells are described [29]. Well differentiated meant well formed glands resembling adenomas. Broders included the mucinous carcinomas in his system, whereas Dukes considered mucinous carcinomas separately [30]. Because of the poor prognosis associated with mucinous carcinomas, other Authors group them with the most undifferentiated tumours. The Dukes’ grading system considered the arrangement of the cells rather than the percentage of the differentiated cells. The initial Dukes approach has evolved into the three-grade system that is now the most widely used. Grade 1 is the most differentiated, with well formed tubules and the least nuclear polymorphism and mitoses. Grade 3 is the least differentiated, with only occasional glandular structures, pleomorphic cells and a high incidence of mitoses. Grade 2 is intermediate between Grades 1 and 3 [31]. Jass et al. use seven parameters in their grading criteria: histologic type, overall differentiation, nuclear polarity, tubule configuration, pattern of growth, lymphocytic infiltration and amount of fibrosis [32].

2.4.1. Rarer tumours 

This chapter does not include management of rarer tumours that can occur in the large intestine, such as carcinoid tumours, leiomyosarcomas, haematopoietic and lymphoid neoplasms and gastrointestinal stromal tumours (GISTs).

3.1.1. Signs and symptoms 

Colorectal cancer may be diagnosed when a patient presents with symptoms or as the result of a screening programme. Except for patients with obstructing or perforating cancers, the duration of symptoms does not correlate with prognosis. Because early colorectal cancer produces no symptoms and because many of the symptoms of colorectal cancer are non-specific (change in bowel habits, general abdominal discomfort, weight loss with no apparent cause, constant tiredness), aggressive efforts at detection through screening programmes are essential. Symptoms of colorectal cancer – intermittent abdominal pain, nausea or vomiting – are secondary to bleeding, obstruction or perforation. A palpable mass is common with right colon cancer. Bleeding may be acute and most commonly appears as red blood mixed with stool. Dark blood is most commonly secondary to diverticular bleeding. Occasionally, melena may be associated with a right colon cancer. Chronic occult blood loss with iron deficiency anaemia occurs frequently. Such patients may present with weakness and high output congestive cardiac failure. Lesser degrees of bleeding may be detected as a part of a faecal occult blood test. Rectal bleeding associated with anticoagulant use should be investigated to rule out colon cancer. Malignant obstruction of the large bowel is most commonly associated with cancer of the sigmoid. If the ileocecal valve is competent, such obstructions manifest as acute abdominal illness. If the ileocecal valve is incompetent, the illness is more insidious, with increasing constipation and abdominal distension noticed over many days. The major differential diagnosis in such cancer includes diverticulitis. Tenesmus and even urinary symptoms or perineal pain may be present in locally advanced rectal tumours. A limited barium enema examination may yield only suggestive data, fiberoptic endoscopy may not be diagnostic if associated oedema precludes reaching the cancer with the endoscope. Cytology of a brush biopsy through the endoscope may be diagnostic. Perforation of colon cancer may be acute or chronic. The clinical picture of acute perforation may be identical to that of appendicitis or diverticulitis, with pain, fever, and a palpable mass. In the presence of obstruction, there may be a perforation through the tumour or through proximal non-tumourous colon. The distinction is important from a prognostic viewpoint. Chronic perforation with fistula formation into the bladder from sigmoid colon cancer is similar to diverticulitis. Gross pneumaturia may occur, or the patient may present with recurrent urinary tract infections only. The continued presence of cystitis with multiple enteric organisms on culture despite repeated treatment, mandates diagnostic studies. Bladder cytology, cystoscopy, brushing and biopsies may not lead to the correct diagnosis. Fibreoptic endoscopy of the colon is the most valuable diagnostic procedure.

3.2.1. Instrumental and pathologic assessment 

Endoscopy can be performed to varying lengths using either a sigmoidoscope or colonoscope. The fundamentals in the technique of colonoscopy include inflating the bowel as little as possible consistent with vision, while aspirating excess air. Biopsy specimens are taken with cupped forceps. Those with a central spike make it easier to take specimens from lesions which have to be approached tangentially. At least six good specimens should be taken from any lesion. When sampling proliferative tumours, it is wise to take several specimens from the same place to penetrate the outer necrotic layer. A larger final tumour biopsy may be obtained by grabbing a protuberant area and deliberately not pulling the forceps into the instrumentation channel but withdrawing the instrument with the specimen still at the tip.

3.2.2. Radiological techniques and their indication according to the diagnostic question 

Ideally one should attempt colonoscopy first in order to confirm histology of the lesion. However, a barium enema has a complementary investigative role to play in those with tortuous sigmoid colons. Colonoscopy is the method of choice for cancer surveillance examinations and follow-up. The only provision is that a few patients who are very difficult to colonoscope for anatomical reasons may be best examined by combining limited left sided colonoscopy (much more accurate than double contrast barium enema in the sigmoid colon) with barium enema to demonstrate the proximal colon. In a few very high-risk patients such as those with numerous adenomas, it may be justified to combine a double contrast barium enema with colonoscopy for extra accuracy. Limited examination by flexible sigmoidoscopy may have a major role to play in patients with left iliac fossa pain or altered bowel habit while the double contrast barium enema alone is safer and adequately effective in patients with constipation or others with minor functional symptoms where the result is expected to be normal or to show minor diverticular disease. Computed tomographic (CT) colonography, also referred to as virtual colonoscopy, was first introduced in 1994 by Vining et al. [33]. This technique acquires data using helical or spiral CT scanning and generates high-quality two-and three-dimensional images of the colon lumen using specialized post-processing software. It is a noninvasive procedure, allows scanning of the entire large intestine in a short time and provides additional information on other organs. Until recently, the use of CT-colonogrphy was limited to upper colon examinations for which CC is not available, although its use has gradually increased as a screening test for precancerous adenomas in adults without symptoms. Although several studies have compared CT-colonography and colonscopy in the diagnosis of precancerous polyps and colorectal cancers [34], [35], In recent years, several researchers have investigated the use of magnetic resonance (MR) colonography in symptomatic populations; most of these researchers concluded that MR colonography has diagnostic value [36], [37], [38]. These techniques should be you apply only in centers with heading experience.

3.2.3. Biological markers 

A great deal of effort has been spent in search of serological markers that would allow the early detection and diagnosis of colorectal cancer. A variety of proteins, glycoproteins and cellular and humoral substances have been studied as potential tumour markers, but none has been found to be specific for colorectal cancer [39]. The most widely studied marker, CEA, may be useful in the preoperative staging and postoperative follow-up of patients with large bowel cancer v but has a low predictive value for diagnosis in asymptomatic patient [40]. The test's relatively low sensitivity and specificity combine to make it unsuitable for screening large asymptomatic patients. Its lack of sensitivity in detecting early colorectal cancer makes CEA determination especially poor for screening. The sensitivity for Dukes’ A and B lesions is 36%, compared with 74% for Dukes’ C and 83% for Dukes’ D disease when 2.5mg/ml is used as the upper limits of normal. Several new carbohydrate antigens such as CA19-9 are being examined and may hold some promise in terms of specificity for preneoplastic and early neoplastic lesions in the colon [39]. Their effectiveness for screening remains to be determined.

4.1.1. Criteria for stage classification 

Treatment decisions are usually made in reference to the older Dukes or the Modified Astler-Coller (MAC) classification schema [41]. Stages should preferably be defined by the TNM classification [42], [43], [44], [45].

4.1.2. TNM classification (Table 1) 

TNM [46] is a dual system that includes a clinical (pretreatment) and a pathological (postsurgical histopathological) classification. It is imperative to differentiate between the two, since they are based on different methods of examination and serve different purposes. The clinical classification is designed cTNM, the pathological pTNM. When TNM is used without a prefix, it it implies the clinical classification. In general the cTNM is the basis for the choice of treatment and the pTNM is the basis for prognostic assessment.

Table 1. TNM classification.

	Primary tumour (T)
	TX: Primary tumour cannot be assessed
	T0: No evidence of primary tumour
	Tis: Carcinoma in situ: intraepithelial or invasion of the lamina propria*
	T1: Tumour invades submucosa
	T2: Tumour invades muscularis propria
	T3: Tumour invades through the muscularis propria into the subserosa, or into the nonperitonealized pericolic or perirectal tissues
	T4: Tumour directly invades other organs or structures and/or perforates the visceral peritoneum **,***
	Regional lymph nodes (N)
	NX: Regional nodes cannot be assessed
	N0: No regional lymph node metastasis
	N1: Metastasis in 1 to 3 regional lymph nodes
	N2: Metastasis in 4 or more regional lymph nodes
	Distant metastasis (M)
	MX: Presence of distant metastasis cannot be assessed
	M0: No distant metastasis
	M1: Distant metastasis

* Note: This includes cancer cells confined within the glandular basement membrane (intra-epithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. ** Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum. *** Tumor that is adherent to other organs or structures, macroscopically, is classified T4. However, if no tumor is present in the adhesion, microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion.

4.1.3. Stage grouping (Table 2) 

Stage I may be equivalent to Dukes’ A or MAC A or B1. Tumour is limited to bowel wall (mucosa, muscularis mucosae, submucosa, and muscularis propria). Stage II may be equivalent to Dukes’ B or MAC B2 or B3. Tumour has spread to extramural tissue. Stage III may be equivalent to Dukes’ C or MAC C1-C3. Regional nodes are involved. Note: Dukes’ B is a composite of better (T3, N0, M0) and worse (T4, N0, M0) prognostic groups as is Dukes’ C (any T, N1, M0 and any T, N2, M0).

Table 2. Stage grouping.

	Stage 0	Tis, N0, M0
	Stage I	T1, N0, M0
		T2, N0, M0
	Stage IIA	T3, N0, M0
	Stage IIB	T4, N0, M0
	Stage IIIA	T1-2, N1, M0
	Stage IIIB	T3-4, N1,M0
	Stage IIIC	Any T, N2, M0
	Stage IV	Any T, any N, M1

4.2.1. Preoperative staging: standard and optional procedures [41], [43], [44] 

The following are general guidelines for the staging of patients with potentially curable colorectal cancer:

4.2.2. Surgical staging 

Surgical staging of colorectal cancer includes an assessment of liver metastases, nodal spread of disease, and extension of tumour through the bowel wall and onto adjacent structures. For proper pN-staging at least 12 nodes should be removed [50], [51]. This is particularly important for stage II patients. It has been demonstated that in pN0 patients prognosis was much better if >14 nodes had been removed as opposed to patients with less nodes removed. It is not clear however if this is a surgical (resecting more nodes) or a pathological (finding more nodes) issue [52]. Intra-operative ultrasound is a more accurate assessment for liver metastases. Compared to preoperative ultrasound and computed tomography as well as intraoperative inspection and palpation, intraoperative ultrasonography has the highest sensitivity for the detection of liver metastases of colorectal carcinomas. With this method occult liver metastases can be found in 15% of patients; in 5% these are solitary metastases which could easily be resected [53]. During resection of liver tumours intra-operative ultrasonography can be used to exclude multifocal tumour development or satellite metastases; furthermore it is important for planning the plane of resection and the appropriate safety margin. Without intra-operative ultrasonography modern liver surgery cannot be performed. Laparoscopic ultrasonography is indicated for laparoscopic staging of colorectal tumours and also serves for the detection of occult liver metastases.

5.1.1. Prognostic and risk factors 

Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. It is the second most frequently diagnosed malignancy in the United States as well as the second most common cause of cancer death. Surgery is the primary treatment and results in cure in approximately 50% of patients [42], [44]. Recurrence following surgery is a major problem and is often the ultimate cause of death. The prognosis of colon cancer is clearly related to the degree of penetration of the tumour through the bowel wall and the presence or absence of nodal involvement. These two characteristics form the basis for all staging systems developed for this disease [54]. Additional relevant parameters are grading, angio- or venous-invasion [55] and perineural invasion, lymphoid inflammatory response and tumour involvement of resection margins that the Dukes and TNM classifications do not take into account. Also the number of involved nodes is relevant, although this is generally recognised it has not been adequately validated as a prognostic indicator. Many other prognostic factors such as p53, ki-ras and bcl-2 expression, TGF-alpha, EGF, proliferative index, and aneuploidy observed in tumour tissue are under evaluation for their single or combined predictive value in high risk conditions [44], [54], [56]. In rectal cancer the tumoral involvement of radial (lateral) margins and complete excision of the mesorectum in the middle and lower third segments have to be added as probable prognostic factors [57]. Tumor location proved to be a strong prognostic discriminant. Lesions located in the left colon demonstrated the most favourable prognosis. The presence of bowel obstruction also strongly influenced the prognostic outcome and the effect of bowel obstruction was influenced by the location of the tumor. The occurrence of bowel obstruction in the right colon was associated with a significantly diminished disease-free survival, whereas obstruction in the left colon demonstrated no such effect. This phenomenon was independent of nodal status [58]. Also perforation is a clinical indicator of a poor prognosis [54]. Elevated pre-treatment serum levels of carcinoembryonic antigen (CEA) and of carbohydrate antigen 19-9 (CA 19-9) have a negative prognostic significance [59]. An age of more than 70 years at presentation is not a contraindication to standard therapies; acceptable morbidity and mortality, as well as long-term survival, are achieved in this patient population [60]. Some retrospective studies suggest that perioperative blood transfusions impair the prognosis of patients with colorectal cancer [61], [62]. A small, single-institution, prospective randomized trial found that the need for allogeneic transfusions following resection of colorectal cancer was an independent predictor of tumour recurrence [63]. This finding was not confirmed by a large, multi-institutional, prospective randomized trial which demonstrated no benefit for autologous blood transfusions when compared to allogeneic transfusions [64]. Both studies established that patients who do not require any blood transfusion have a reduced risk of recurrence, but it would be premature to change transfusion procedures based on these results, as other studies have not confirmed this finding [65].

5.2.1. Survival and prognostic factors 

In general, the median survival time of patients with advanced colorectal cancer without treatment is around 5–6 months and with 5-fluorouracil (5-FU)-based chemotherapy around 10–12 months, with fewer than 5% alive at 5 years from the diagnosis. Presently 5-FU-based chemotherapy affords a 20–30% response rate (5% of them being complete responses), an additional 30% disease stabilization, a median duration of response of approximately 6 months and a median time to treatment failure of 4–5 months. Some data are actually available on the importance of immediate treatment of metastatic disease. With the advent of drugs such as CPT-11 and oxaliplatin the effectiveness of chemotherapy has clearly increased. Response rates have increased to 50% and survival to 18–24 months. There are factors that clearly influence treatment outcome and must therefore be taken into strong consideration in an individual patient's management as well as in the interpretation of clinical trials results. Factors predicting for treatment outcome, unless otherwise specified, can be divided as follows:

5.2.2. Factors related to the patient 

5.2.3. Factors related to the disease 

5.2.4. Factors related to the treatment 

6.1.1. Criteria for suggesting an adjuvant treatment 

Adjuvant treatment is recommended for stage III and high-risk stage II patients. The first issue is therefore defining the “risk”. The 5-year survival after surgical resection alone is: stages I 85–95%, stage II 60–80%, stage III 30–60%. The wide ranges reflect major differences in prognosis depending upon stage subset, tumour grading, and the other biological characteristics discussed in the next sections. The question therefore remains: who should be treated and by what. Therefore there is the need of parameters to define better which patients should be treated and which can avoid a toxic treatment [69], [70]. As it will be explained below, there are several options for colon cancer adjuvant therapy. Every treatment option, including only observation, need to be discussed with patients evaluating their characteristics (Performance Status, age, comorbidities and patient preference) and tumor features (pathological stage, grading, risk of relapse).

(A) Stage subset: Penetration of the neoplasm through the serosa of the bowel wall by itself is generally considered the cut off stage separating high versus low risk patients. In general, stages I and IIA can be considered low risk while stages IIB and III are widely felt to deserve adjuvant treatment; this means that high risk for relapse is defined as more than 30% on a type C basis. T4 lesions carry a much worse prognosis than T1 to T3 lesions; within the stage III groupe the 5-year survival drops to half if more than 4 (26%) lymph-nodes are involved.

(B) Tumour grading: Grade 1 carcinomas are less aggressive than the others and the 5-year survival ranges between 59 and 93%, while it drops to 33–75% and 11–56% in grades 2 and 3 tumours, respectively.

(C) Among the other biological characteristics, blood vessel invasion, microscopic tumour budding around the primary lesion, DNA content and thymidine labelling index are known parameters accounting for the different prognosis of patients with neoplasms at the same stage and of the same grade. Several newer predictors have been recently examined, including microsatellite instability (MSI), 18q delection, k-ras mutations, TP53, TGFBR2, DCC, and TS gene expression. The most promising candidate markers at present are allelic loss of chromosome 18q and MSI. Wang and colleagues [71] used microarray technology and gene-expression profiling to identify markers of risk of relapse in stage II. Nevertheless the practical value of these factors still needs confirmation by large-scale studies.

The general consensus suggests that patients with stage II are high-risk subjects if they present one of following: limphnode sampling <13; poorly differentiated tumor; vascular or limphatic or perineural invasion; tumor presentation with occlusion or tumor perforation and pT4 stage. During risk assessment one must integrate all known tumour-related prognostic factors starting from the stage and grade and derive a rough estimate of the chances of relapse. For example, a patient with a stage II adenocarcinoma, G3 with blood vessel invasion, presence of tumour budding and high thymidine labelling index, is likely to have more than 70% chances of relapse, much higher than those of another patient with a stage IIIA G1 lesion but with opposite pathological and biological parameters. The second problem is tailoring the decision to each individual patient's characteristics. In this context, the most debated issue is the impact of the patients’ age on the decision making. The median age of patients presenting with colorectal cancer is 72, however, the median age of patients in clinical trials of the adjuvant treatment of this disease is 63 years. Fewer than 10% of patients above age 70 are accrued in these clinical studies. When facing an elderly patient (above age 70) with a high risk colorectal cancer that has been radically resected one must remember the following:

6.1.2. Advanced disease 

Many chemotherapy trials, with 5-FU-based schedules, have demonstrated increased partial responses and time to progression of disease, as well as improved survival and quality of life for patients receiving chemotherapy compared to best supportive care on a type 1 level of evidence [68], [73], [74], [75]. Similar quantitative and qualitative toxic effects of therapeutic interventions have been observed for patients of all ages [76].

6.1.3. Treatment of malignant polyps or “early colorectal cancer” 

Complete endoscopic polypectomy should be performed whenever the morphologic structure of the polyp permits. The presence of invasive carcinoma in a neoplastic polyp requires a thorough review with the pathologist for histological features that are associated with an adverse outcome. Making the decision to undergo surgical resection for a neoplastic polyp that contains invasive carcinoma involves the uncertainties of predicting and balancing adverse disease outcome against operative risk. Unfavourable histological findings include lymphatic or venous invasion, grade 3 differentiation, level 4 invasion (invades the submucosa of the bowel wall below the polyp) or involved margins of excision. Although level 4 invasion and involved margins of excision are two of the most important prognostic factors, their absence does not necessarily preclude an adverse outcome. When unfavourable histological features are present in a polyp from a patient with an average operative risk, resection is recommended. The pedunculated polyp with invasive carcinoma confined to the head with no other unfavourable factors has a minimal risk for an adverse outcome. The consensus is that endoscopic polypectomy is adequate treatment with proper follow-up examination. Invasion of the stalk but with clear margins of excision and favourable histologic features may be treated with endoscopic polypectomy with a similar risk as level 2 invasion (invades the muscularis mucosa but is limited to the head and neck of the stalk). Pedunculated polypoid carcinomas can be treated using the same criteria as other pedunculated polyps with invasive carcinoma. Invasive carcinoma in a sessile polyp usually should be interpreted as having level 4 invasion. Consequently, standard surgical resection is recommended in patients with average operative risk.

6.2.1. Surgical treatment of localized disease 

The goal of surgery is a wide resection of the involved segment of bowel together with removal of its lymphatic drainage. The extent of the colonic resection is determined by the blood supply and distribution of regional lymph nodes. The resection should include a segment of colon of at least 5cm on either side of the tumour, although wider margins are often included because of obligatory ligation of the arterial blood supply. Extensive “super radical” colonic and lymph node resection does not increase survival over segmental resection [77], [78].

Stage 0 colon cancer (TisN0M0, T1N0M0)

Stage 0 colon cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, the surgical procedure may be limited.

Treatment options are:

Stage I colon cancer (T2N0M0)

Stage I (old staging: Dukes’ A or Modified Astler-Coller A and B1). Because of its localized nature, stage I has a high cure rate.

Standard treatment options:

Stage II colon cancer (T3N0M0, T4N0M0)

Stage II (old staging: Dukes’ B or Modified Astler-Coller B2 and B3).

Standard treatment options:

All patients can be considered for entry into controlled clinical trials evaluating adjuvant treatment.

Stage III colon cancer (anyT, N1M0, any T, N2,M0)

Stage III (old staging: Dukes’ C or Modified Astler-Coller C1–C3).

Stage III colon cancer denotes lymph node involvement. The number of lymph nodes involved is related to the prognosis: patients with 4 or more involved nodes have a significantly worse survival than those with 1–3 involved nodes.

The standard treatment option in this stage is a doublet schedule with oxaliplatin and 5FU/LV (FOLFOX4 or FLOX). In some circustances monotherapy with FU/LV mostly with infusional schedules (DeGramont, AIO regimes) or oral fluoropyrimidines (capecitabine or UFT) can be recommended (type 1).

In 1990s bolus 5-FU/LV has been the standard treatment on a type 1 level of evidence. 6 months of therapy was demonstrated to be equally to 12 months [79], [80].

Later, infusional 5-FU in different schedules have been assessed in several studies and resulted in equal activity as bolus 5-FU/LV with less toxicity, on a type 1 level of evidence [81], [82].

The benefit of the doublet schedule with oxaliplatin and 5FU/LV has been demonstrated in two recent trials. In the MOSAIC study [83], the addition of oxaliplatin to 5-FU/LV (FOLFOX schema), showed a significantly increased DFS at 3 years, with a reduction in the risk of recurrence of 23% compared to control arm (LV5FU2). The final analysis [84] with extended 5-year DFS and 6-year OS follow-up confirmed the benefit of FOLFOX4. Data reported an overall relative risk reductions of 20% for recurrence and 16% for death in favour of oxaliplatin.

The NSABPC 07 trial confirms and extends the result of the MOSAIC study. It compared the efficacy of bolus FU/LV+oxaliplatin (FLOX) with FU/LV alone (Roswell Park schedule); the overall DFS rates at 4 years were 67.0% for FULV and 73.2% for FLOX respectively [85]. Spectrum of toxicity between MOSAIC eand NSABP-C07 was different: grades 3–4 diarrhea resulted higher with FLOX than FOLFOX, while grade 3 sensory neuropathy was observed in 12% with FOLFOX and 8% with FLOX.

The NSABP C-08 [86], [87] was designed in order to test the potential benefit and safety associated with the addition of bevacizumab to the modified FOLFOX6 regimen. Toxicity profile resulted acceptable: no significant increase in GI perforations, hemorrhage, arterial or venous thrombotic events, or death was observed; hypertension and proteinuria occured at a significantly higher rate in the bevacizumab arm versus control. Unfortunately, no improvement in 3 years DFS was observed with the addition ogf bevacizumab.

As a result of these studies FOLFOX for 6 months has been adopted worldwide as the new standard of care in stage III colon cancer patients.

In special situations a monotherapy with capecitabine, UFT/LV, or 5-FU/LV in infusion can be an alternative strategy of adjuvant chemotherapy.

The X-Act trial [88] showed that capecitabine is an active agent with a favourable toxicity profile and may reduce overall costs compared with i.v. treatments (level 1). After 4.3 years of follow-up data still confirme the equivalence in terms of DFS between capecitabine and 5FU/LV [89].

Capecitabine and oxaliplatin in combination have been tested in a range of different administration schedules and doses. XELOXA international phase III study [90] evaluated the safety and efficacy of adjuvant capecitabine plus oxaliplatin (XELOX) versus bolus FU/LV (Mayo Clinic or Roswell Park regimen). Data of efficacy have been presented at ECCO-ESMO Meeting (Berlin, September 2009) while toxicity profile showed to be different: patients receiving XELOX experienced less all-grade diarrhea, alopecia, and more neurosensory toxicity, vomiting, and hand-foot syndrome than those patients receiving FU/LV. Treatment-related mortality within 28 days from the last study dose was 0.6% in the XELOX group and 0.6% in the FU/LV group.

Finally the NSABPC-06 [91] demonstrated the equivalence of UFT/LV to 5FU/LV in stage II/III colon cancer patients. Nevertheless UFT/LV is not approved in adjuvant setting.

Negative trials are related to Irinotecan is association to 5FU (bolus or infusional).

The CALGB-89803 trial [92] compared 5-FU/LV+irinotecan (IFL) versus Roswell Park scheme in more than 1200 patients. The trial was prematurely closed because of an elevate rate of mortality of IFL group respect to FL regimen (2.2% versus 0.8%). Preliminary results indicated no improvement in terms of either overall survival or event free survival for IFL, as compared to FL. The PETACC-3 trial [93] sought to determine whether infused irinotecan/5FU/LV, which has improved survival in metastatic colorectal cancer, would also improve DFS in stage III compared with 5-FU/LV alone The addition of irinotecan failed to result in statistically significant improvement in DFS in patients with stage III colon cancer at a follow-up of 66.3 months: the primary end-point of this study was therefore not met. The adding of irinotecan was associated with an increased incidence of grades 3–4 gastrointestinal events and neutropenia.

In adjuvant setting several questions are still unanswered:

Standard treatment options:

6.2.2. Adjuvant chemotherapy 

Standard treatment for stage III colon cancer is 5-FU plus leucovorin plus oxaliplatin on a type 1 level of evidence. The following regimens may be considered adjuvant options for high-risk colon cancer patients (stage IIb/III):

6.3.1. Overall treatment strategy for stage IV 

Stage IV colon cancer denotes distant metastatic disease. About 25–30% of patients with colorectal cancer present with metastasis at the time of diagnosis. The main goal of therapy is to prolong survival and to maintain quality of life.

Standard treatment options are:

6.3.2. Surgical resection of primary tumor 

In patients with colorectal cancer, the primary tumour may be resected, even in the presence of distant metastases, in order to prevent complications such as intestinal obstruction, perforation or haemorrhage. Systemic chemotherapy is administered after resection of the primary tumor, for treatment of metastatic disease. However, resection of the primary tumour is associated with a high overall morbidity and chemotherapy needs to be postponed because of postoperative complications. For this reason, in asymptomatic patients, several institutions prefer a more conservative approach. Systemic chemotherapy is the first treatment and tumor resection is reserved for patients who develop symptomatic disease. Both strategies are practiced but there are no data to know which approach is evidence based. In a recent review [109], seven studies were analyzed and the results from meta-analysis suggest that for patients with stage IV colorectal cancer, resection of the asymptomatic primary tumor provides only minimal palliative benefit: the overall postoperative morbidity ranged from 18.8% to 47.0%. When leaving the primary tumor in situ, the mean complications were intestinal obstruction in 13.9% and haemorrhage in only 3.0%. The authors concluded that, with asymptomatic disease, initial chemotherapy should be started and resection of the primary tumor should be reserved for the small portion of patients who develop major complications from the primary tumor. On the other hand, when incurable stage IV disease is converted into potentially curative disease, combined resection of both the primary tumor and its metastases should be considered.

6.3.3. Treatment of isolated metastases 

6.3.4. Palliative chemotherapy 

The standard systemic chemotherapy for advanced colorectal cancer is the use of combination therapy with 5-FU/LV (preferably infusional 5-FU) with oxaliplatin or CPT-11 on a type 1 level of evidence. It is well established that these multiagent regimens are superior to 5-FU plus LV alone.

Only in some cases can 5-FU/leucovorin alone be considered the best choice. In general there is agreement that bolus 5-FU alone is ineffective and that biochemical modulation is needed for bolus 5-FU activity whereas it is not for protracted infusional 5-FU [160]. Weekly 24–48h infusion or biweekly 48h infusion is most frequently utilized. Capecitabine, an oral fluoropyrimidine carbamate, in first-line metastatic colorectal cancer is as active as bolus 5-FU/LV. Several controlled trials have compared directly capecitabine with 5-FU/LV; capecitabine showed a response rate higher than 5-FU plus leucovorin with similar survival, duration of response, and time-to-disease progression on a type 1 level of evidence [161], [162], [163], [164]. Toxic effects were less than 5-FU groups: there were less stomatitis, nausea, and neutropenia with neutropenic fever. In the capecitabine groups, hand-foot syndrome was more frequent and severe diarrhoea requiring hospitalization was increased. It may serve to substitute for 5-FU plus leucovorin as a less toxic single agent or in combinations.

Three phase III prospective randomized, controlled trials were designed to evaluate the combination of 5-FU, leucovorin, and CPT-11 to 5-FU and leucovorin alone in first-line therapy. The first of these trials compared the bolus 5-FU, leucovorin, and CPT-11 to bolus 5-FU and leucovorin alone and to CPT-11; the primary endpoint was progression-free survival [165]. The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression (7.0 months versus 4.3 months, p=.004) and overall survival (14.8 months vs 12.6 months, p=0.042) for the combination schedule. The second trial of combination chemotherapy with CPT-11 compared 2 different regimens of infusional 5-FU and folinic acid (either the AIO [Arbeitsgemeinschaft Internische Onkologie] or the deGramont regimen) [100]. CPT-11 was administered weekly or biweekly according to the schedule of the infusional 5-FU. Also in this trial there was an improvement in response rate, time-to-tumor progression and median survival. Combined analysis of pooled data confirmed the activity of this combination [166]. The third trial compared the association of CPT-11 and AIO regimen with the standard AIO regimen. Also in this study all efficacy parameters were in favour of CPT-11 combination arm [167]. Because the important gastrointestinal toxicity related to CPT-11 administration, in the most of studies dose reductions were required.

Oxaliplatin combined with 5-FU and leucovorin, has shown promising activity in previously treated and untreated patients with metastatic colorectal cancer and in patients with 5-FU refractory disease [102], [168], [169], [170], [171]. The use of oxaliplatin in combination has been studied in a randomized trial in which it was compared with 5-FU and leucovorin alone in the treatment of chemotherapy-naïve patients [101]. Response rates with the oxaliplatin-based regimen were essentially double that of the fluorouracil and leucovorin regimen, and progression-free survival was also statistically superior. Overall survival was not significantly different between the two groups. Furthermore, another randomized study, the U.S. N9741 study, showed that the FOLFOX-4 regimen was more active than CPT-11/5FUbolus/leucovorin (IFL) schedule, that was the standard regimen in the USA [172]. A recent update of results from the N9741 trial showed that patients receiving FOLFOX were significantly more likely to survive for 5 years than patients receiving either irinotecan combined with oxaliplatin (IROX) or IFL [173].

The data and safety monitoring committees of the cooperative groups conducting studies comparing the value of bolus 5-FU/leucovorin/CPT-11 with 5-FU/leucovorin in the adjuvant setting and to bolus 5-FU/leucovorin/oxaliplatin or bolus 5-FU/leucovorin/CPT-11 in the advanced disease setting have led to a temporarily suspended accrual to these trials and a subsequent dose attenuation due to an unexpectedly high death rate on the 5-FU/leucovorin/CPT-11 arms [174]. This 3 drug regimen appears to be more toxic than initially reported. For the present, the use of this regimen should be accompanied by careful attention to early signs of diarrhoea, dehydration, neutropenia, or other toxic effects, especially during the first chemotherapy cycle [175]. Because 5-FU/LV infusional plus either oxaliplatin or CPT-11 has shown to be much better tolerated and more efficacious than bolus regimens, infusional regimens evolved to become the preferred choice. Even in the US bolus 5-FU regimens are now hardly used, with FOLFIRI replacing IFL. Comparison of doublets containing oxaliplatin or CPT-11 with infusional fluorouracil was reported in a phase III GOIM study. In this study a total of 360 chemonaive patients were randomly assigned to receive FOLFIRI or FOLFOX-4. In both arms overall response rate, median time to progression and overall survival were similar, without any statistically significant difference [176].

In addition, a randomized study investigating different treatment sequences in first and second line therapy with CPT-11 and oxaliplatin combinations failed to prove superiority for either of these [128]. However this study provided the first evidence suggesting improvement in overall survival with sequential exposure to regimens that included the three key drugs. Treating patients sequentially with FOLFIRI followed by FOLFOX, or the inverse, resulted in median survival times of 21.5 months and 20.6 months, respectively. This was the first randomized trial to report median survival superior to 20 months for patients with metastatic colorectal cancer. The benefit of sequences of regimens was further supported in a combined analysis that examined recent phase III trials in this subset of patients [177]. This analysis showed that there was a positive connection between the proportion of patients receiving all available cytotoxic agents over the course of their disease and increased median survival, on a type 1 level of evidence. These initial findings were validated by an updated analysis that included further four phase III trials (for a total of 11 studies) [178]. Of 5768 metastatic colorectal patients’ for whom data on exposure to fluorouracil/leucovorin, irinotecan and oxaliplatin were available, patients receiving all three agents showed a significant correlation with reported overall survival. It is important to underline that when these studies were performed adjuvant FOLFOX was not in use. An interesting and recent alternative approach was reported in a randomized phase III Italian GONO trial in which the triplet combination irinotecan, oxaliplatin and fluorouracil (FOLFOXIRI) was demonstrated to be superior to FOLFIRI as first-line treatment of metastatic colorectal cancer, with a higher response rate (60% versus 34%, p<0.001), median survival of 23.6 months versus 16.7 months (p=0.042) and with 15% of patients versus 6% undergone to radical metastases resection [130]. Another question evaluated in randomized trials is whether first-line use of combination chemotherapy is superior to the use of these same agents sequentially. The FOCUS trial (fluorouracil, oxaliplatin, CPT-11 use and sequencing), suggested a modest, but statistically significant, advantage of using combination chemotherapy, whether given 1st line or 2nd line, rather than using the same single agents in sequence. In the same trial there was no significant benefit when first line monochemiotherapy was followed by combination therapy respect combination up-front [179]. The Dutch study compared sequential 1st line capecitabine, 2nd line irinotecan and 3rd line CapOx with 1st line CapIri and 2nd line CapOx. In this study combination therapy does not significantly improve overall survival compared with sequential therapy [180]. A still open question is the duration of treatment. Several studies were performed to answer this question, in attempt to reduce duration of treatment and, consequently, incidence of cumulative toxicities, but preserving efficacy. The OPTIMOX1 initiated to try to limit the problem of peripheral neurotoxicity from FOLFOX. In OPTIMOX1 patients received FOLFOX 4 every 2 weeks until disease progression or FOLFOX7 for six cycles followed by 5-FU/LV alone for 12 cycles and reintroduction of FOLFOX7 upon progession. Median survival times were comparable in two arms of treatment and overall rates of any grade of neurotoxicity were approximately equal [181]. In OPTIMOX2 patients were randomized to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by 5-FU/LV until disease progression and reintroduction of mFOLFOX7 (such as OPTIMOX1 arm) or six cycles of mFOLFOX7 followed by cessation of chemotherapy and reintroduction of mFOLFOX7 before tumor progression had reached baseline measures (OPTIMOX2 arm). Median duration of the chemotherapy-free period in the OPTIMOX2 arm was 4.6 months. Median duration of disease control (progression-free survival from the first treatment plus progression-free survival from FOLFOX7 reintroduction), was 10.8 months in the OPTIMOX1 arm and 9.0 months in the OPTIMOX2 arm. Median overall survival was 24.6 months in the OPTIMOX1 and 18.9 months in OPTIMOX2 arm (p=.05). The authors concluded that a chemotherapy-free interval can be recommended only in selected patients without adverse prognostic factor [182]. Different results were reported in an Italian study of intermittent FOLFIRI (2 months on, 2 months off) versus continuous FOLFIRI administered until disease progression in patients with advanced colorectal cancer, median overall survival was found to be similar between the two groups [183].

The efficacy and safety of capecitabine as a replacement for 5-FU/LV in standard infusional combination regimens as FOLFOX has recently been suggested. In addition with oxaliplatin, in the schedule named XELOX or CAPOX, capecitabine was compared with oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) in the Spanish TTD Group study, suggesting a similar toxicity profile, response rate and time to progression [184]. Similar results were reported in an AIO trial [185]. Another international phase III trial (NO16966) was performed to demonstrate the non-inferiority of XELOX to FOLFOX4 for the first-line treatment of metastatic colorectal cancer. The efficacy data, in terms of progression free-survival and overall survival, showed that XELOX was not inferior to FOLFOX4 [186]. In association with CPT-11 results were controversial. In a phase I/II trial the combination of irinotecan and capecitabine as first-line therapy for metastatic colorectal cancer was well tolerated and with good activity [187]. In the BICC-C trial patients were randomized to receive FOLFIRI, IFL modified (mIFL) or Capecitabine/irinotecan (CapeIri arm) with or without celecoxib. Time to progression and overall survival were significantly better for the FOLFIRI arm than IFL modified or CapeIri arms. The addition of celecoxib not improved chemotherapy efficacy [188]. A phase III EORTC trial designed to compare capecitabine/irinotecan with FOLFIRI was suspended after enrollement of 85 patients due to occurrence of 8 treatment related deaths in the capecitabine/irinotecan arm [189]. Therefore the combination of CPT-11 and capecitabine cannot be recommended.

6.3.5. Biological therapy 

The introduction of novel targeted therapies, such as Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, and Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), increase the armamentarium in metastatic colorectal cancer. The addition of bevacizumab to 5-FU/LV-based therapy suggested prolonging overall survival [108]; toxicities correlated with bevacizumab administrations were hypertension, proteinuria, bleeding, thrombosis and same cases of bowel perforation. A phase III trial testing the addition of bevacizumab to irinotecan/5-FU chemotherapy (IFL), in chemonaive patients with metastatic colorectal cancer, reported a median duration of survival of 20.3 months for patients receiving IFL plus bevacizumab compared with 15.6 months for those receiving IFL alone (p<.001) [107]. Because bolus administration of 5-FU/LV is no longer considered optimal therapy, recent trials have combined bevacizumab with the infusional regimens FOLFOX and FOLFIRI. FOLFOX has also been studied in combination with bevacizumab in ECOG 3200 study as second-line therapy in 829 patients with metastatic colorectal cancer pre-treated and progressed after 5-FU/LV and irinotecan. A median overall survival time of 12.9 months was observed in patients receiving FOLFOX plus the antibody, compared with 10.8 months in the group treated with FOLFOX alone (p<.0011)) [194]. The trial NO16966 in August 2003 was amended by adding bevacizumab or placebo to XELOX and FOLFOX4. The efficacy data showed that bevacizumab/chemotherapy significantly prolonged progression free survival compared with placebo and chemotherapy (9.3 months versus 8.0 months, p=0.0023) without differences in overall survival and response rate [195]. These results were more modest than the authors hoped and the trial filed to demonstrate a clinical meaningful benefit for patients treated with in first line. The BICC-C trial was amended in April 2004 and bevacizumab was added to FOLFIRI and mIFL arm, whereas CapeIri arm was discontinued. Median progression-free survival was 11.2 months for FOLFIRI+Bevacizumab and 8.3 months for mIFL+Bevacizumab. Median overall survival was not reached for FOLFIRI+Bevacizumab arm but was 19.2 months for mIFL+Bevacizumab (p=0.007) [188]. The randomized trial Three Regimens of Eloxatin Evaluation (TREE-study) compared in first-line treatment 3 oxaliplatin-based regimens, with addition or not of bevacizumab. Overall response rate of 52% and median time to progression of 9.9 months was reported for patients treated with FOLFOX plus bevacizumab versus 41% and 8.7 months for patients treated with FOLFOX alone. Too, in this study capecitabine was combined successfully with oxaliplatin and bevacizumab, resulting in a 46% response rate and a 10.3-month median time-to-tumor progression versus 27% and 5.9 months of the association of capecitabine-oxaliplatin alone [196]. At present there are no sufficient data supporting the efficacy of continuing bevacizumab second-line in patients who have progressed following treatment with a bevacizumab-containing regimen first-line. A phase III trial to address this question is in development (BEBYP trial).

Cetuximab, as single agent, produced an 11–19% response rate and a 27–35% stable disease rate in metastatic colorectal cancer patients’ whose disease was refractory to irinotecan and oxaliplatin [197], [198]. In the BOND-1 study the addition of cetuximab to irinotecan, in patients refractory to prior irinotecan treatment, significantly prolongs progression-free survival compared with cetuximab alone (4.1 months versus 1.5 months, p<.001) [106]. In second-line treatment a phase III trial comparing cetuximab plus irinotecan to irinotecan alone, in patients who have failed prior oxaliplatin-based chemotherapy (EPIC study), showed a statistically significant improvement in response rate and progression-free survival in cetuximab/irinotecan arm (secondary and point of this study). Overall survival, that was the primary end-point, was comparable between the two arms, although the authors explained this data by subsequent use of cetuximab in 46% of patients progressed in the irinotecan alone arm [192]. Cetuximab has also been evaluated in patients with advanced colorectal cancer in first-line setting. There are some phase II studies and data from five trials suggest promising activity when cetuximab is combined with either irinotecan- or oxaliplatin-based chemotherapy [199], [200], [201], [202], [203]. In these studies the most frequent adverse events related to cetuximab were allergic reaction and skin toxicities. Retrospective analysis of the BOND data showed a clear association between higher grades of skin reaction and response rate and median time to progression disease. This was true also for overall survival, the median value rising from 3 months in patients with no skin rash to 14 months in those with rash of grade 3 severity. The association between rash severity and survival seems to be confirmed by retrospective analysis of the other clinical trials of cetuximab in colorectal cancer. An important phase II randomized, controlled study (OPUS) was conducted to compare response rate of FOLFOX-4+cetuximab vs. FOLFOX-4 [204]. The results confirmed that the addition of cetuximab increased the response rate of FOLFOX-4 in first-line treatment of metastatic colorectal cancer. Grades 3/4 adverse events, with the exception of skin rash, were not significantly more frequent in the cetuximab arm. Randomized phase III trials of cetuximab plus FOLFIRI versus FOLFIRI alone as first-line treatment for metastatic colorectal cancer (CRYSTAL study), reported a median progression-free survival significantly longer for cetuximab/FOLFIRI arm (8.9 months versus 8 months, p=0.036). This result could seem not so clinically meaningful, however, in patient treated with cetuximab, response rate and 1-year PFS were significantly increased (RR 46.9% versus 38.7%, 1-year PFS 34% vs. 23%) [205].

Another monoclonal antibody against EFGR with promising activity is Panitumumab. Panitumumab single agent produced a 10% response rate and 38% rate of stable disease in patients with disease resistant to irinotecan or oxaliplatin or both. The median duration of response was 5.2 months, median progression-free survival was 2.0 months and the median survival amounted to 7.9 months [206]. Toxicity drug-related was skin rash, in this study generally mild to moderate. There is also data showing good activity first-line when panitumumab is added to IFL. Of 19 patients 47% had a response rate and disease was stable in 32%. Recently data from a phase III trial of panitumumab plus best supportive care compared with best supportive care alone, in 463 pre-treated metastatic colorectal cancer patients, were reported. Progression-free survival, the first end point of the study, was significantly higher in the panitumumab arm (8 weeks versus 7.3 weeks, p<.0001) [207]. Though the absolute improvement in PFS was not clinically meaningful; panitumumab was approved in the USA for the treatment of metastatic colorectal cancer patients with EGFR-expressing tumors. However recently new data emerged about EGFR: in patients treated with EGFR inhibitors, the iperexpression of EGFR, determinated by immunohistochemistry, seems not to correlate with response rate, time to progression or survival, and response. Recent studies suggest that tumor KRAS mutational status affects response to panitumumab. In a trial of 463 patients evaluating the potential efficacy of panitumumab in last line therapy, 427 had available KRAS data, of whom 43% had mutated KRAS [208]. For patients with wild-type KRAS, 17% responded and 34% had stable disease, compared with zero responders and 12% with stable disease in the mutated KRAS group. When the treatment arms were combined, the OS time was longer in patients with wild-type KRAS than in patients with mutated KRAS. As a result of these new data, use of panitumumab was approved also by EMEA.

The same data emerged about cetuximab [209], [210], [211]. Cetuximab has now been found to bind to the EGFR with high specificity, blocking ligand-induced phosphorylation of the receptor, and hence preventing the activation of intracellular effectors involved in intracellular signaling pathways, such as the G protein KRAS. An activating KRAS mutation was significantly associated with resistance to cetuximab and a shorter OS duration. Those patients without KRAS mutations had a higher disease control rate than those patients with mutations (76% versus 31%) [212]. A retrospective, larger, multicenter study found KRAS status to be an independent prognostic factor associated with OS and PFS, confirming the high prognostic value of such mutations in response to cetuximab and survival in patients with treated with cetuximab [213]. The same data were confirmed by Karapetis et al. [214]. Also for patients randomized in CRYSTAL trail, KRAS status was analyzed [215]. A statistically significant difference in favour of cetuximab was seen in KRAS wild-type patients for PFS (p=0.0167) and overall response (p=0.0025). In KRAS wild-type subgroup, 1-year PFS was statistically different in patients treated with cetuximab (43% vs. 23%). In patients with KRAS mutation status, the study showed no significant differences for PFS and overall response between two groups of treatment. Also OPUS trial observed that the benefit from addition of cetuximab to standard treatment is higher for the population with wild-type KRAS and suggested a possible detrimental effect using cetuximab in patients with KRAS mutations [216]. The currently available information shows that approximately 40–45% of patients with advanced colorectal cancer have mutations within KRAS, making this a potential major determinant of treatment outcome for patients receiving EGFR inhibitors. Retrospective analyses of trials using either cetuximab or panitumumab have shown that there is essentially no response to treatment with one of these antibodies in patients with mutated KRAS, whereas those with wild-type KRAS are likely to respond. These agents should therefore be applied only in tumors with a wild-type status of the KRAS gene. Further parameters of resistance are lack of EGFR amplification, PTEN loss or BRAF mutation. However, they are less well studied or associated with less consistent data and therefore require prospective analyses before integration into clinical decision making. The serine-threonine kinase BRAF is the principal effector of KRAS. A recent study retrospectively analyzed objective tumor responses, time to progression, overall survival, and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic colorectal cancer patients. The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (p=.029). BRAF-mutated patients had significantly shorter progression-free survival (p=.011) and OS (p<.0001) than wild-type patients. The authors concluded that also BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment [217].

The association of bevacizumab and cetuximab, with or without irinotecan, has been evaluated in patients with irinotecan-refractory colorectal cancer, in a phase II trial (BOND-2 study). Response rates were 20% for cetuximab+bevacizumab arm versus 37% for cetuximab+bevacizumab+irinotecan arm and median progression-free survival was 5.6 months and 7.9 months, respectively [218]. Toxicities were as would have been expected from the single agents. At the 2008 Annual Meeting of the American Society of Clinical Oncology, Punt and colleagues presented the much-anticipated results of the CAIRO2 study [219]. This was a phase III trial that randomized patients with previously untreated metastatic colorectal cancer to receive CAPOX (capecitabine/oxaliplatin) and bevacizumab or the same combination regimen plus cetuximab. The primary endpoint of the CAIRO2 study was progression-free survival (PFS), with secondary endpoints being overall survival (OS), response rate (RR), and toxicity. The combination of both antibodies, cetuximab and bevacizumab, to CAPOX results in a significant decrease in PFS compared to bevacizumab and CAPOX. When patients were grouped according to KRAS status, patients with mutant KRAS who received CAPOX with the dual biologic agents experienced a significant 4-month reduction in median PFS compared with CAPOX plus bevacizumab. The findings from this study are disappointing because they clearly demonstrate that the use of bevacizumab plus cetuximab in combination with CAPOX chemotherapy in the first-line setting did not provide clinical benefit. Moreover, this study follows closely the negative results of the PACCE phase III trial, designed to assess bevacizumab with or without panitumumab in combination of oxaliplatin- or irinotecan-based chemotherapy. The study completed accrual of approximately 1000 patients; however, panitumumab therapy was discontinued following a review of the data after the first 231 PFS events. Analysis of the data for the oxaliplatin-based chemotherapy cohort (data cut-off, October 2006) showed median PFS durations of 8.8 months among patients receiving chemotherapy plus bevacizumab with panitumumab and 10.5 months among patients receiving chemotherapy plus bevacizumab alone (p=0.004). OS events were most common in the bevacizumab–panitumumab arm (20% versus 14%; HR, 1.56). Additional toxicity was also observed in the bevacizumab–panitumumab arm, with grade 4 events in 28% and 18% of patients, grade 5 events in 4% and 3% of patients, and any serious event in 56% and 37% of patients, respectively. These results suggest a lack of synergy and possibly even antagonism, between bevacizumab and panitumumab and that the toxicity of the individual agents may be increased in combination [220]. These negative results brought to close the phase III trial by the Cancer and Leukemia Group B and Southwest Oncology Group (80405 study), investigated the combination of cetuximab plus bevacizumab, versus each agent alone, as first-line treatment in combination with either FOLFOX or FOLFIRI chemotherapy. At the moment, it would be said that there are sufficient data to suggest that dual biologic combination does not have added clinical benefit and could indeed have negative effects.

6.3.5.1. Combination schedules 

A.Oxaliplatin 85mg/m2 day 1, leucovorin 200mg/m2 in 2h day 1–2, Bolus 5-FU 400mg/m2 day 1–2, 22h continuous infusion 5-FU 600mg/m2 day 1–2 every 2 weeks (FOLFOX-4). This combination can be used also with a “simplified” regimen of 5-FU/leucovorin: leucovorin 400mg/m2 day 1, bolus 5-FU 400mg/m2 day 1, continuous infusion 46h 5-FU 2400mg/m2 day 1 every 2 weeks. FOLFOX-6 utilizes a higher dose of oxaliplatin with the simplified FU/LV regimen. FOLFOX-7 does not includes bolus 5-FU.

B.Oxaliplatin 50mg/m2, leucovorin 500mg/m2 5-FU continuous infusion 24h 2000mg/m2 day 1, 8, 15, 22 every 5 weeks (FUFOX).

C.CPT-11 180mg/m2 day 1, leucovorin 200mg/m2 in 2h day 1–2, Bolus 5-FU 400mg/m2 day 1–2, 22h continuous infusion 5-FU 600mg/m2 day 1–2 every 2 weeks (FOLFIRI). This combination can be used also with a simplified regimen of 5-FU/leucovorin: leucovorin 400mg/m2 day 1, bolus 5-FU 400mg/m2 day 1, continuous infusion 46h 5-FU 2400mg/m2 day 1 every 2 weeks.

D.CPT-11 80mg/m2, leucovorin 500mg/m2, 5-FU continuous infusion 24h 2000mg/m2×6 weeks every 8 weeks (FUFIRI).

E.Capecitabine 1000mg/m2 bid day 1–14+oxaliplatin 130mg/m2 day 1 every 3 weeks (CAPOX or XELOX) (on a type 1 level of evidence).

F.Bevacizumab 5mg/kg day 1+FOLFIRI every 2 weeks (in selected patients, without predictive factor of high risk of adverse event).

G.Cetuximab 400mg/m2 (first dose) and sequently cetuximab 250mg/m2 weekly+CPT-11 180mg/m2 every 2 weeks (patients refractory to CPT-11).

6.3.5.2. Infusional schedules 

A.Protracted continuous infusion 5-FU. Unmodulated 5-FU is effective if given by continuous infusion. The dose of 5-FU is 225-300mg/m2/day for prolonged periods (generally 1 cycle is 8 weeks followed by a 2-week rest period). In general this regimen is less toxic than the previous ones. Myelosuppression is not usually seen and diarrhoea is rare, Grade 3 mucositis however develops in approximately one fourth of the patients and the hand foot syndrome in one third. The advantages of this different and milder toxicity must be weighed against the need of venous access for infusion and the inconvenience of carrying around an infusion pump.

B.Continuous infusion 5-FU with low dose weekly LV. This regimen is similar to. However the 5-FU dose should not exceed 200mg/m2/day. LV is given at 20mg/m2/weekly. The toxicity is similar to that of the previous regimen.

C.Infusional 5-FU administered over 24–48h, weekly. The dose is 2600mg/m2 of 5-FU+LV 500mg/m2 (AIO or German regimen) in 24h or 3000–3500mg/m2 of 5-FU (TTD or Spanish regimen) in 48h. The toxicity spectrum is similar to that of bolus 5-FU plus LV, but the severity is somewhat lower.

D.The deGramont schedule (LV5FU2): leucovorin 200mg/m2 in 2h day 1–2, Bolus 5-FU 400mg/m2 day 1–2, 22h continuous infusion 5-FU 600mg/m2 day 1–2 every 2 weeks. This combination can be used also with a simplified regimen of 5-FU/leucovorin: leucovorin 400mg/m2 day 1, bolus 5-FU 400mg/m2 day 1, continuous infusion 46h 5-FU 2400mg/m2 day 1 every 2 weeks.

6.3.6. Radiotherapy for metastatic disease 

Radiotherapy for distant metastases has a palliative intent, either relief of symptoms or arrest of tumour growth to delay the development of symptoms. No standard radiotherapy regimen exists in these cases and treatment decisions must consider the patient's general condition, life expectancy, toxicity of the therapy, severity of symptoms, presence of alternative therapies, etc. Often, a few, high dose fractions can be administered to patients with short life expectancy because their time in hospital should be as short as possible. Metastases to bowel, brain, skin, soft tissues and those causing compression of the spinal cord, trachea and oesophagus are the most suitable for radiotherapy.

8.1.1. When is follow-up necessary? 

There is no doubt that routine follow-up of patients treated for colorectal cancer is both time consuming and expensive. But does it benefit the patient? Most patients enjoy regular contact with the medical team and this has supportive benefits which should not be underestimated. Does earlier recognition of recurrence, however improve survival? If so, what ‘screening’ investigations should be routinely performed: CEA, CT or ultrasound scanning of the liver or colonoscopy? These matters have not been totally resolved and studies designed to assess the benefit of routine post-operative follow-up deserve consideration [221].

8.2.1. Suggested protocols 

Careful follow-up of high-risk populations (patients with panulcerative colitis, previous colon cancer, a family history of colon or female genital cancer, or of polyposis syndromes and previous history of sporadic colon polyps) should include periodic stool occult blood evaluation and appropriate radiologic and endoscopic studies. Following treatment for colon cancer, periodic determinations of serum CEA levels, radiographic and laboratory studies, and physical examination may lead to the earlier identification and management of recurrent disease [222]. The impact of such monitoring on overall mortality of patients with recurrent colon cancer is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, there have been no large-scale randomized trials documenting the efficacy of a standard, postoperative monitoring program [223], [224]. Postoperative monitoring should be reserved primarily for detection of asymptomatic recurrences that can be curatively resected and for early detection of metachronous tumours [225].