State of the Art Oncology in EuropeFont: aaa

Colon Cancer


1. GENERAL INFORMATION

1.1 Epidemiological data

1.1.1 Incidence

Cancers of the colon and rectum are the third most common type worldwide (Parkin 2002; Ferlay 2004). 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 (Figure 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 (Parkin 2002).

Figura 1

tumore del colon_figure1

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 (Parkin 2001).
In Italy (Grande 2007), the annual incidence rates were estimated to increase throughout the period 1970-2010 for men from 30 to 70 per 100,000, and to stabilise 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) (Parkin 2001) (Figure 2).

Figura 2

tumore del colon_figure2

1.1.2 Survival

In Europe, the relative survival for adults diagnosed with colon cancer during 1995-99 was 72% at one year and 54% at five years (Berrino 2007). 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, one year survival rose by 6%, and the gain in five-year survival was 9% (Coleman 2003). Survival is higher in most nordic and western European countries, but even in the countries with the highest survival rates, five-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 (Engholm 2006). In the USA, survival for patients diagnosed with colorectal cancer, in 2000-2002, was 65.5%, while in Europe the figure was 56.2% (Verdecchia 2007). Colon cancer is characterised 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) (Grande 2007).

1.2 Aetiological and risk factors

1.2.1 Risk factors

Colorectal cancer most commonly occurs sporadically and it is inherited in only 5% of cases (Kwak 2007). 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 (Tomatis 1990). 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 (WCRF&AICR 2007) 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 30 g 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 (Stewart 2003). 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 (Giovannucci 2001). 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 randomised 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 ( Asano 2004). 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 percent confidence interval, 1.5-4.4) (von Roon 2007). The meta-analysis by Eaden and Colleagues (Eaden 2001) , 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 (Cali 1993). 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 (Ahmed 2006). 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 (Cleboswski 2004).

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 (Stewart 2003). 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% (Aarnio 1999).

1.3 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 (Stewart 2003). 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 randomised trials to reduce mortality from colorectal cancer by up to 25% among those attending at least one round of screening (Cochrane Database 2007). 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 ( Hakama 2008).  The Council of Europe recommends faecal occult blood screening for colorectal cancer in men and women aged 50–74 (ACCP 2000). 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 (Winawer 2005). 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 (Hakama 2008).

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

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 (Bodmer 1987). 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 (Vogelstein 1988). Frequent mutations have been found in the K-ras using RNAse protection assay (Forrester 1987) 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 and Colleagues 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 (Kinzler 1991).2.2 Histological types2.2.1 Histotypes

The major histological type of large bowel cancer is adenocarcinoma, which accounts for 90% to 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 Grading2.3.1 Clinical implications

In the Broders’ system four grades based on the percentage of differentiated tumour cells are described (Broders 1925). Well differentiated meant well formed glands resembling adenomas. Broders included the mucinous carcinomas in his system, whereas Dukes considered mucinous carcinomas separately (Dukes 1932). 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 (Qizilbash 1982). Jass and colleagues use seven parameters in their grading criteria: histologic type, overall differentiation, nuclear polarity, tubule configuration, pattern of growth, lymphocytic infiltration and amount of fibrosis (Jass 1986).2.4 Particular histological types considered elsewhere2.4.1 Rare 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. DIAGNOSIS

3.1 Signs and symptoms

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 Diagnostic strategy3.2.1 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 and colleagues ( Vining 1994). 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 (Pickhardt 2003; Cotton 2004)), 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 ( Luboldt 2000; Hartmann 2006; Leung 2004). 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 (Bresalier 1989). 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 (Fletcher 1986). 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 Stage I and Stage II lesions is 36%, compared with 74% for Stage III and 83% for Stage IV 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 ( Bresalier 1989). Their effectiveness for screening remains to be determined.

4. STAGING

4.1 Stage classifications

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 (Cohen 1993). Stages should preferably be defined by the TNM classification (UICC 2009) TNM 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.4.1.2 TNM Classification (UICC 2009)

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 **, ***
T4a: Tumour perforates visceral peritoneum
T4b: Tumour directly invades other organs or structures **, ****

Note: Tis includes cancer cells confined within the glandular basement membrane (intra-epithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

**Note: Direct invasion in T4b  includes invasion of other organs or segments of the colorectum by way of the serosa, as confirmed on microscopic examination, or for tumours in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (e.g. mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix or vagina).

***Note: Tumor that is adherent to other organs or structures, macroscopically, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1-4a, depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN site-specific factor should be used for perineural invasion.

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
N1a: Metastasis in 1 regional lymph node
N1b: Metastasis in 2-3 regional lymph nodes
N1c: Tumour deposit(s), i.e., satellites*, in the subserosa, or in non-peritonealized pericolic or perirectal soft tissue without regional lymph node metastasis
N2a: Metastasis in 4-6 regional lymph nodes
N2b: Metastasis in 7 or more regional lymph nodes

*Note: Tumour deposits (satellites), i.e., macroscopic or microscopic  nests or nodules, in the pericolorectal adipose tissue’s lymph drainage area of a primary carcinoma without histological evidence of residual lymph node in the nodule, may represent discontinuous spread, venous invasion with extra vascular spread (V1/2) or a totally replaced lymph node (N1/2). If such deposits are observed with lesions that would otherwise be classified as T1 or T2, then the T classification is not changed, but the nodule(s) is recorded as N1c. If a nodule is considered by the pathologist to be a totally replaced lymph node (generally having a smooth contour), it should be recorded as a positive lymph node and not as a satellite, and each nodule should be counted separately as a lymph node in the final pN determination.

Distant metastasis (M)*
M0: No distant metastasis
M1: Distant metastasis
M1a: Metastasis confined to one organ (liver, lung, ovary, non-regional lymph node(s))
M1b: Metastasis in more than one organ or the peritoneum

*Note: The Mx category is considered to be inappropriate as clinical assessment of metastasis can be based on physical examination alone. (The use of Mx may result in exclusion from staging)

4.1.3 Stage grouping
Stage grouping
Stage 0

 

Tis, N0, M0
Stage I T1, N0, M0
T2, N0, M0
Stage II T3 N0, M0
T4, N0, M0
Stage IIA T3, N0, M0

 

Stage IIB T4a, N0, M0

 

Stage IIC T4b, N0, M0

 

Stage III Any T, N1, M0
Any T, N2, M0
Stage IIIA T1, N1, M0
T2, N1, M0
T1, N2a, M0
Stage IIIB T3, N1, M0
T4a, N1, M0
T2, N2a, M0
T3, N2a, M0
T1, N2b; M0
T2, N2b, M0
Stage IIIC T4a, N2a, M0
T3, N2b, M0
T4a, N2b, M0
T4b, N1, M0
T4b, N2, M0
Stage IVA

 

Any T, Any N, M1a
Stage IVB

 

Any T, Any N, M1b

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 (Stage IIA) and worse (Stage IIB and IIC) prognostic groups as is Dukes’ C (Stage IIIA better, Stage IIIB intermediate, Stage IIIC worse).

4.2 Staging procedures

4.2.1 Preoperative staging: standard and optional procedures (Cohen 1993; Newland 1981; Olson 1980)

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

History: In addition to the personal medical history, the family history of colorectal cancer, polyps and other cancers should be obtained.

Physical examination: Check for hepatomegaly, ascites and lymphadenopathy. In women, rule out synchronous ovarian pathology, breast, ovarian and endometrial cancer.

Laboratory Data: Blood count, CEA, and liver chemistries.

Intestinal evaluation: Full colonoscopy or proctosigmoidoscopy and air-contrast barium enema (in the absence of obstruction or perforation). CT- and MR- colonography have a role in diagnosis and staging only in centers with elevated experience. Echo-endoscopy has a major role in rectal cancer for determining trans-mural penetration (as good as computed tomograpy) while no current techniques reliably detect lymph node spread: a frequent overstatement of the depth of penetration has been described, and only 50-60% of T4 cases showed a histological crossing of the organ borders (Dershaw 1990).

Instrumental work-up: A pre-operative chest radiograph and CT scan is appropriate. Nuclear magnetic resonance tomography (NMR) may be useful for locally advanced cases but its relative role is not be really determined (Butch 1986; Guinet 1990) . Positron emission tomography (PET) and immunoscintigraphy are methods under evaluation and currently proposed for differentiating scar and tumour tissue after surgery and/or radiotherapy.

 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 (VanCutsem 2002; Compton 2003). 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 (Tepper 2001 ). 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 ( Holscher 1995). 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. PROGNOSIS

5.1 Prognosis of operable disease

5.1.1 Prognostic and risk factors

Cancer of the colon is a highly treatable and often curable disease when localised 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 ( Eisenberg 1982 ; Olson 1980 ) . 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 (Steinberg 1986 ). Additional relevant parameters are grading, angio- or venous invasion (Sternberg 1999) 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 (Deans 1992; Olson 1980; Steinberg 1986 ) . 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 (Arbman 1996 ). Tumor location proved to be a strong prognostic discriminant. Lesions located in the left colon demonstrated the most favorable 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 ( Wolmark 1983). Also perforation is a clinical indicator of a poor prognosis (Steinberg 1986). Elevated pre-treatment serum levels of carcinoembryonic antigen (CEA) and of carbohydrate antigen 19-9 (CA 19-9) have a negative prognostic significance (Filella 1992). 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 (Fitzgerald 1993). Some retrospective studies suggest that perioperative blood transfusions impair the prognosis of patients with colorectal cancer ( Stephenson 1988; Voogt 1987 ). A small, single-institution, prospective randomised trial found that the need for allogeneic transfusions following resection of colorectal cancer was an independent predictor of tumour recurrence ()Heiss 1994). This finding was not confirmed by a large, multi-institutional, prospective randomised trial which demonstrated no benefit for autologous blood transfusions when compared to allogeneic transfusions (Busch 1993). 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 (Donohue 1995).

5.2 Prognosis of advanced or metastatic disease

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 to 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

•    Age by itself is not a predictor of tumour response to treatment.
•    Gender has an impact on overall prognosis of this disease in that females have longer median survival times than males, but this criterion is not a predictor of responsiveness to treatment.
•    The performance status of the patient strongly influences treatment outcome (Köhne 2002). In most recent studies the response rate for any of the commonly used chemotherapeutic regimens is in the range of 40 to 50% for patients with an ECOG performance status of 0-1, and 30% for those with an ECOG performance status of 2 (Sargent 2009).
•    Presence of tumour-related symptoms: asymptomatic patients live longer and respond to chemotherapy more frequently than symptomatic patients.

5.2.3 Factors related to the disease

•    The extent of the disease correlates with the probability of response and survival (Köhne 2002). Disease extent can be assessed in terms of number of metastatic sites, number of lesions within each metastatic site, percent liver involvement or, indirectly, by baseline LDH and WBC values.
•    Tumour grading correlates with the overall patient survival but data are insufficient to conclude that it is a predictor of response to chemotherapy.
•    The clinical use of plasma CEA levels in the post-operative setting for predicting recurrence, may be of benefit in patients due to the potential advantage of resection of liver metastases that results in a survival gain. Randomised, well-designed and adequately statistically powered trials on CEA monitoring are warranted. When CEA is monitored in metastatic conditions its modifications are predictive of failure or response to medical treatment: currently no data have been reported on its impact on survival.

5.2.4 Factors related to the treatment

•    Prior chemotherapy for advanced disease clearly introduces resistance to second-line treatment.
•    Prior adjuvant treatment clearly influences treatment outcome in advanced disease. In general, prior adjuvant treatment is not a criterion for exclusion from investigational trials provided that the treatment has been completed longer than 6 months before the diagnosis of metastatic disease. However, the lower response rates to chemotherapy reported in the last two years compared with those of the early 90′s may suggest clinical resistance to the same agents used in adjuvant setting.
•    Response to chemotherapy: in almost all studies, survival analysis of responding vs non-responding patients favours the former group.
•    Response appears to be an independent prognostic factor for survival (Buyse 2000). Nevertheless other factors besides tumour response may contribute substantially to the final outcome.

6. TREATMENT

6.1 Overall treatment strategy

Surgery is the primary treatment for patients affected with potentially curable colorectal cancer.
Adjuvant therapy is a systemic treatment administered with the intention of reduce  the risk of relapse and death. The recurrence rate can be predicted by pathological staging ( UICC 2009 ). Adjuvant chemotherapy is a standard of care in stage III patients while its role is less well estabilished in stage II. In metastatic disease chemotherapy represents the first treatment with the goal of prolonging survival, improving and mantaining quality of life.

6.1.1 Criteria for suggesting an adjuvant treatment

Adjuvant treatment is recommended for stage III and  high-risk stage II patients (Stage IIB, Stage IIC, or Vascular invasion, G3, perforation or obstruction, high preoperatory CEA level). 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 (Douillard 2005; Wils 2007).
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, stage I and IIA can be  considered low risk while stage IIB, IIC 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 to 75% and 11 to 56% in grade 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 (Wang 2004) 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:
a) the life expectancy of a 70 year old otherwise healthy individual is approximately 8 years for men and 14 years for women on a type C basis;
b) toxicity of chemotherapy is similar below and above age 70 on type 2 level of evidence and
c) the efficacy of adjuvant treatments is similar in elderly people compared to that in the general population on type 2 level of evidence.
d) recently nomograms have been developed and are available for colorectal cancer. These statistically based tools attempetd to provide all proven prognostic factors and to quantify the risk of 5 and 10 years death as precisely as possible (www.nomograms.org; Weiser 2008).

 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 (Buyse 2000; Chiara 1998; NGTATG 1992; Scheithauer 1993). Similar quantitative and qualitative toxic effects of therapeutic interventions have been observed for patients of all ages ( Goldberg 1997).

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 Treatment of localized disease

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 5 cm 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 (Dwight 1969; Grinnell 1965).

STAGE O COLON CANCER (TisN0M0)
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:
1. Local excision or simple polypectomy.
2. Segmentary resection for larger lesions not amenable to local excision.

STAGE I COLON CANCER (T1N0M0, 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:
1. Wide surgical resection and anastomosis.

STAGE II COLON CANCER (T3N0M0, T4N0M0)
Stage II (old staging: Dukes’ B or Modified Astler-Coller B2 and B3).
Standard treatment options:
1. Wide surgical resection and anastomosis.
2. Following surgery, in high-risk patients (IIB, IIC or who present almost one of the previously mentioned features 6.1.1) adjuvant therapy could be considered.
All patients can be considered for entry into controlled clinical trials evaluating adjuvant treatment.

STAGE III COLON CANCER (anyT, N1M0, any T, N2M0)
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 to 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 on a type 1 level of evidence .
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 ( O’Connell 1997; Haller 1992).
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 (Saini 2003; Andre 2003).
The benefit of the doublet schedule with oxaliplatin and 5FU/LV has been demonstrated in two recent trials. In the MOSAIC study (Andre 2004), 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 (Andre 2009) with extended 5-years DFS and 6-years OS follow-up confirmed the benefit of FOLFOX4. Data reported an overall relative risk reductions of 20% for recurrence and 16% for death in favor 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 (Kuebler 2007).Spectrum of toxicity between MOSAIC eand NSABP-C07 was different: grade 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 (Allegra 2009; Wolmark 2009) 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 (Cassidy 2004) showed that capecitabine is an active agent with a favorable 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 (Twelves 2005) .
Capecitabine and Oxaliplatin in combination have been tested in a range of different administration schedules and doses. XELOXA international phase III study (Schmoll 2007)
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 (Wolmark 2004) 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 ( Salz 2004) 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 (Van Cutsem 2009) 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 grade 3 to 4 gastrointestinal events and neutropenia.
In adjuvant setting several questions are still unanswered:
1.    the role of targeted agents associated to chemotherapy: the italian TOSCA study is investigating about the duration of chemotherapy and the role of bevacizumab in association to FOLFOX4 in patients with stage III.
2.    the “optimal duration” of adjuvant treatment: 3 or  6 months?  The Italian TOSCA trial  is investigating if three months of FOLFOX4 treatment is not inferior  to a six months  with the same schedule in terms of relapse free survival in stage II and III colon cancer patients. The same question is under scrutiny in a large international project (IDEA) which will compare american and  european trialsinvestigating the optimal duration of chemotherapy in  stage III patients.

Standard treatment options:
1. Wide surgical resection and anastomosis. For patients who are not candidates for clinical trials, postoperative chemotherapy is indicated. Standard treatment is 5-FU/leucovorin/oxaliplatin (FOLFOX) for 6 months.
2. Eligible patients should be considered for entry into controlled clinical trials comparing various postoperative chemotherapy regimens, or biological therapy, alone or in combination.

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/IIC/III):
1. Infusional FU/LV and oxaliplatin (FOLFOX-4). Modified or subsequent  FOLFOX regimens have not been compared to FOLFOX4 and probably never will be, but it is likely that they are equally effective.
2. Infusional 5-FU/LV alone may be considered in patients who can not tolerate oxaliplatin or for other reasons are not suited for FOLFOX. Suitable for individualised clinical use, on a type 2 level of evidence.
3. Capecitabine alone may be considered for patients not suited for FOLFOX.
4. Capecitabine /oxaliplatin (CAPOX) may be utilized instead of FOLFOX.

6.3 Treatment of metastatic disease

6.3.0 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:
1. Surgical resection of primary tumor/anastomosis or bypass of obstructing lesions in selected cases.
2. Treatment of isolated metastases (liver, lung, ovaries) (Adam 2000 ; Adson 1984; Coppa 1985; Scheele 1990; Scheele 1991; Wagman 1990).
3. Palliative chemotherapy (Douillart 2000; de Gramont 2000; Giacchetti 2000; Goldberg 2002; Grothey 2002; Kohne 2003
4. Biological therapy (Cunningham 2004; Hurwitz 2004; Kabbinavar 2003).
5. Radiation therapy to the primary tumour to palliate bleeding, obstruction, or pain. Palliative radiation therapy may also be targeted to other sites of metastases for similar indications.

6.3.1 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 (Scheer 2008), 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.

6.3.2 Treatment of isolated metastases (Stage IVA)

a. Surgery of liver metastases
The most common site of distant metastases from colorectal cancer is the liver. Synchronous metastases to the liver are evident at initial presentation in 10 to 25 per cent of cases of large bowel cancer, and 40 to 70 per cent of those whose cancers disseminate will have hepatic involvement (Daly 1986; Ridge 1985).
Seventy to 80 per cent of hepatic metastases appear within two years following primary resection (Ridge 1985; Butler 1986). The uniformly poor prognosis in patients with untreated hepatic metastases (Daly 1986; Ekberg 1986; Wagner 1984] underlies an aggressive approach. Local regional approaches to treating liver metastases include hepatic resection and/or chemotherapy delivered via hepatic arterial infusion or destructive therapies such as radiofrequency ablation. Candidates for resection of hepatic lesions are those in whom the primary tumour has been resected with curative intent and in whom there is no evidence of extra hepatic disease. Classic contraindications for surgery, such as more than four metastases have been revised in recent years. A margin of 1 cm around the tumors has been recommended for along time ( Barbare 1999). However, recent reports show that the width of the resection margin does not influence the recurrence rate or pattern of recurrence, but only the histological liver margin involvement is a significant predictor of survival and disease free-survival after surgery (Hamady 2006). The absolute contraindications should include unresectable extra hepatic disease, >70% liver involvement (six segments), liver failure, and insufficient fitness to undergo surgery (Poston 2005). Following a recent consensus conference, a definition of resectability was proposed that included the ability to achieve complete resection (negative margin), preserve two contiguous liver segments with adequate vascular inflow and outflow, and preserve an adequate future liver remnant (>20% healthy liver) (Charnsangavej 2006).
The percentage of “resectable” liver metastases therefore varies in different series ranging from 10 to 20% per cent ( Adam 2000; Adam 2001; Adam 2003). Modern techniques of anatomic dissection and haemostasis have resulted in improved operative survival (Butler 1986; Afortner 1984) with an operative mortality of about 2 per cent in highly trained hands. Overall five year survival rates range from 30 to 40% in selected patients (Scheele 1990). Long-term survival in patients who undergo surgical resection of hepatic metastases depends on the absence of extra hepatic disease and adequate surgical margins (Ekberg 1986; Wagner 1984). In about half of all resected patients recurrence is already evidenced within 18 months after resection and in 30%-50% of cases it is isolated to the liver. Even if repeat liver resections are technically more demanding and difficult, most series reported comparable morbidity, mortality and overall similar long-term survival rates to that of first hepatectomy ( Adam 1997; Nordlinger 1994; Petrowsky 2002). Similarly, in few series, a third hepatectomy offered the same survival benefit as first or second hepatectomy (Adam 2003; Morise 2003).
Even though eligibility for liver surgery continues to expand, 80% of patients with metastatic disease remain unresectable at presentation. The recent development of more effective chemotherapeutic agents such as oxaliplatin and irinotecan are capable of inducing significant shrinkage, prolong survival in non-operable disease and also appear to allow an additional 10% to 20% of patients thought to be initially unresectable for cure to undergo metastasectomy. A large number of studies, with different combination regimens’, have addressed this question suggesting a 40% to 50% 5-year survival in patients with macroscopically complete resection of colorectal metastasis following neoadjuvant chemotherapy (Oxaliplatin-based chemotherapy: Adam 2001; Alberts 2003; Giacchetti 1999; Tournigand 2004), Irinotecan-based chemotherapy: Tournigand 2004; Pozzo 2004; Oxaliplatin-Irinotecan combination chemotherapy: Falcone 2007; Quenet 2004). Patient selection and efficacy of pre-operative chemotherapy, in terms of response rate, are strong predictors for resecability of liver metastases (Folprecht 2005).
Recently some data are emerging with using target therapy. Kesmodel (Kesmodel 2008), in a retrospective analysis, suggested that the combination of bevacizumab with neoadjuvant chemotherapy in patients who have liver metastases does not increase surgical complications. The results were confirmed in a single-centre, nonrandomized phase II trial (Gruenberger 2008) and in 39 patients treated with preoperative irinotecan and oxaliplatin with concurrent bevacizumab ( Reddy 2008). These data are limited and preliminary, they need to be confirmed by prospective studies.

b. Chemotherapy after liver surgery
The benefit from additional systemic therapy after potentially curative resection of colorectal metastases has never been demonstrated, because despite the several decades of advance in surgery, few large prospective or randomized trials of “adjuvant” chemotherapy has been undertaken in this group of patients.
Two small phase III trials, with a very similar design, comparing systemic chemotherapy after surgery to surgery alone, were reported. In both studies enrollement was suspended before to have reached the sample sizes planned due to slow accrual, lacking the statistical power to demonstrate any significant difference in survival. The ENG study, which randomized 129 patients, reported only a trend in disease free-survival for patients treating after metastases resection (Langer 2002 ). The second more recent trial enrolled 173 patients of the planned 200 patients over a period of 10 years. Using disease free-survival as the predefined end point, patients receiving postoperative systemic fluorouracil (5-FU) plus folinic acid (LV) showed a significantly improvement than those receiving surgery alone (24.4 months versus 17.6 months, respectively). There was also a trend toward benefit in overall survival, though this has not reached a level of statistical significance (Portier 2006). A pooled analysis based on individual data from these two trials, showed a no significant trend toward a longer median PFS duration among patients who received adjuvant chemotherapy (2.20 years versus 1.55 years, respectively), but no significant difference in OS (5.09 years versus 3.91 years (Mitry 2008). An ongoing phase III trial is evaluating adjuvant oxaliplatin plus capecitabine and bevacizumab versus oxaliplatin plus capecitabine alone (NCT00394992).
There is a sound rationale for giving “adjuvant” intra-arterial chemotherapy after radical liver surgery (direct delivery to tumour bearing liver, high dose to liver and lower peripheral tissues distribution with lower systemic toxicity). However, because of the study design, the higher response rates, compared with systemic approaches, are difficult to correlate with improved survival. A phase III trial of oxaliplatin plus capecitabine with hepatic arterial infusion (HAI) of floxuridine versus oxaliplatin plus capecitabine in patients with resected or ablated liver metastases failed to accrue sufficient patients and was closed recently (NSABP C-09; NCT00268463).
The rationale underlying HAI is the maximization of exposure of hepatic metastases to high target concentrations of cytotoxic drugs by localized infusion. Most randomized studies have shown higher response rates for HAI when compared with systemic chemotherapy, but the impact of HAI on survival is unclear, particularly when compared with optimal systemic regimens. A recent meta-analysis of seven randomized controlled trials in 1,098 patients showed median OS durations of 16.04 months and 12.64 months (p = .3) for HAI and systemic chemotherapy, respectively, in patients with unresectable liver metastases ( Mocellin 2007).
A trial of hepatic arterial floxuridine plus systemic fluorouracil (5-FU) plus leucovorin was shown to result in improved 2-year disease-free and overall survival (86% versus 72%, p=0.0 3), but did not show a significant statistical difference in median survival, compared with systemic 5-FU therapy alone (Kemeny 1999). Long-term follow-up has confirmed superior progression-free survival and a trend to improved overall survival for the combination arm (Kemeny 2005). However, the chemotherapy used in all these trials is now considered inferior to currently available regimens. Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced a higher overall response rate but no consistent improvement in survival (Chang 1987; Kemeny 1987; Rougier 1992) when compared to systemic chemotherapy (Wagman 1990; Chang 1987; Kemeny 1987; Rougier 1992; Kemeny 1993; MACG 1996). Several studies show increased local toxicity, including liver function abnormalities and fatal biliary sclerosis. The use of the combination of intra-arterial chemotherapy with hepatic irradiation, especially employing focal radiation of metastatic lesions, was evaluated in a phase I (dawson 2000) and in a phase II study (Ben Josef 2005) reporting a high response rate, prolonged intrahepatic control and survival improvement, with acceptable toxicity.
Results of a large phase III trial (EORTC 40983 study (Nordlinger 2008), evaluating the benefit of peri-operative FOLFOX4 chemotherapy in patients with resectable liver metastases, were recently reported: completely resected patients in chemotherapy arm showed an improvement in progression free-survival in comparison to patients in the surgery alone arm. Data are too early to determine whether this more effective strategy may provide also improvement in survival and it is not possible to determine if the advantage derived from adjuvant ore neo-adjuvant chemotherapy. The results of ongoing two large phase III trial of adjuvant chemotherapy for patients with resected or ablated liver metastases in both North America (NSABP C-09) and Europe (EORTC study 40004) might clarify this issue. At present the EORTC 40051 BOS (Biologics, Oxaliplatin and Surgery) trial is assessing perioperative chemotherapy with FOLFOX6 and cetuximab with or without bevacizumab in patients with resectable hepatic metastases from colorectal cancer.

c. Ablative therapies for liver lesions
For those patients with hepatic metastases deemed unresectable (due to factors such as location, distribution, excessive number), local ablative techniques for elimination of liver metastases have been used, including cryosurgery, embolization, ultrasound, and interstitial radiotherapy on a type 3 level of evidence (Thomas 1993; Berber 2005; McKay 2006). These approaches are not curative and their role in treating colorectal metastases has to be evaluated in randomised trials and compared with liver surgery and with different modalities of chemotherapy (for example, the EORTC 40004 or CLOCC trial compares radiofrequency ablation plus chemotherapy with chemotherapy alone). In a recent Cochrane review, the authors concluded that: there is currently insufficient evidence to support a single approach, either surgical or non-surgical, for the management of colorectal liver metastases; therefore, treatment decisions should continue to be based on individual circumstances and clinician’s experience ( Al-Asfoor 2008).

d. Surgery of lung metastases
Lung metastases are seen in 10%–20% of patients with colorectal cancer. In properly selected cases surgical resection of pulmonary metastases may be a reasonable option. The overall 5-year survival after metastasectomy ranged from 25 to 40% in a small series of cases. The results of the International Registry of Lung Metastases show that among 653 patients treated with radical surgery the overall survival was 37% at 5 year and 22% at 10 years with median survival of 41 months. At multivariate analysis the disease free interval (> versus < 36 months) and number of metastases (single versus multiple) were significant independent prognostic factors (Girard 1996; McAfee 1992; Okumura 1996; Pfannschmidt 2003; Saito 2002; Vogelsand 2004).
Surgical resection of combined hepatic and pulmonary metastases remains controversial in light of limited supportive evidence.

6.3.3 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 (Schmoll 2000). Weekly 24-48 hours infusion or biweekly 48 hours 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 (Cassidy 2002; Hoff 1999; Saif 2005; Twelves 2002). 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 ( Saltz 2000) . The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression (7.0 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) ( Douillard 2000). 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 (Saltz 2000). 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 ( Kohne 2005). 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 (Giacchetti 2000; Andre 1999; Bleiberg 1998; Cvitkovic 1999; de Gramont 1997 ). The use of oxaliplatin in combination has been studied in a randomised trial in which it was compared with 5-FU and leucovorin alone in the treatment of chemotherapy-naïve patients (de Gramont 2000). 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 U.S.A. ( Goldberg 2004). 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 (Sanoff 2007).
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 ( Sargent 2001). 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 ( Rothenberg 2001). 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 (Colucci 2005).

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 (Tournigand 2004) . 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 (Grothey 2004). 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) (Grothey 2005) Of 5,768 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 ( Falcone 2007). 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 (Seymour 2005). 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 ( Punt 2007). 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 ( Tournigand 2006). 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 ( Maindrault-Goebel 2007). 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 ( Labianca 2006).

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 (Massuti 2006). Similar results were reported in an AIO trial (Arkenau 2005). 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 ( Cassidy 2007). 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 ( Rea 2005). 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 (Fuchs 2007). 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 (Aust 2006). Therefore the combination of CPT-11 and capecitabine can not be recommended .

a. Treatment vs Supportive Care
In general, patients, with a large tumor bulk with several metastatic sites and an ECOG performance status of 2 or greater, have a lower chance of response. This makes attendance or supportive care as needed a recommended treatment choice for many of these patients. Conversely, patients who are in a good general condition with a small tumor bulk, and who have not previously been exposed to chemotherapy, have a response rate to modern chemotherapy of approximately 50%. For these patients, as long as there are no other factors that contraindicate treatment, chemotherapy should be recommended. More debatable is the issue of the non-symptomatic patient. Since the endpoint of treatment is palliation, should we wait until symptoms develop (so that there is something to palliate) or should treatment be instituted right away? Some randomized studies have addressed this issue. The answer is that patients who are treated at diagnosis of metastatic disease with conventional 5-FU-based regimens live significantly longer (by 5 months) than patients in whom chemotherapy is delayed until symptoms develop on a type 1 level of evidence. At this time, there is a role for combination chemotherapy as first-line treatment in these patients. In most patients chemotherapy is also indicated for second- and, in some cases, third-line therapy.

b. Treatment and Quality of Life
The subjective response to biochemically modulated 5-FU in 10 randomized trials involving over 1500 patients with advanced colorectal cancer was around 50% – twice as much the overall objective response rate in the same studies. This by itself gives a measure of the symptomatic improvement afforded by chemotherapy. Four large randomized trials have addressed the issue of quality of life (NGTATG 1992; Scheithauer 1993; Allen-Mersh 1994; Glimelius 1994). The comparisons have been made between modulated 5-FU and either un-modulated 5-FU or best supportive care. Both comparisons have favoured the patients who received chemotherapy. We can thus conclude that even if the overall response rate to standard chemotherapeutic regimens is low in unselected patients with advanced colorectal cancer, the subjective benefit is substantial. Quality of life in patients with advanced colorectal cancer treated in second-line with cetuximab alone or in combination with irinotecan was evaluated in two large phase III studies ( Eng 2007; Au 2007). Cetuximab therapy seems to provide better palliation of symptoms, less deterioration in global health status scores, delaying detriment in Quality of Life.

6.3.4 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 (Kabbinavar 2003); 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) ( Hurwitz 2004). 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) ) (Giantonio 2007). 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 (Saltz 2007 ). 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) (Fuchs 2007). 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 ( Hochster 2006). 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% to 19% response rate and a 27% to 35% stable disease rate in metastatic colorectal cancer patients’ whose disease was refractory to irinotecan and oxaliplatin (Saltz 2004; Lenz 2004). 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) (Cunningham 2004) 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 ( Eng 2007). 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 (Folprecht 2004; Hohler 2004; Rosenberg 2002; Rougier 2004; van Cutsem 2007). 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 ( Bokemeyer 2007). The results confirmed that the addition of cetuximab increased the response rate of FOLFOX-4 in first-line treatment of metastatic colorectal cancer. Grade 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% ) (van Cutsem 2007).

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 ( Hecht 2004). 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) (van Cutsem 2007). 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 . 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.

(Amado 2008).
The same data emerged about cetuximab (Scartozzi 2004; van Cutsem 2004; Chung 2005). 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%) (Lievre 2006). 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 ( Lievre 2008). The same data were confirmed by Karapetis 2008 (Karapetis 2008). Also for patients randomised in CRYSTAL trail, KRAS status was analyzed (van Cutsem 2008). 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 (Bokemeyer 2008). 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 ( Di Nicolantonio 2008).

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 (Saltz 2005). 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 (Punt 2008). 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 1,000 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 ( Hecht 2008).  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.

COMBINATION SCHEDULES
A. Oxaliplatin 85 mg/sqm day 1, leucovorin 200 mg/sqm in two hours day 1-2, Bolus 5-FU 400 mg/sqm day 1-2, 22 hours continuous infusion 5-FU 600 mg/sqm day 1-2. every two weeks (FOLFOX-4). This combination can be used also with a “simplified” regimen of 5-FU/leucovorin: leucovorin 400 mg/sqm day 1, bolus 5-FU 400 mg/sqm day 1, continuous infusion 46 hours 5-FU 2400 mg/sqm day 1 every two 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 50 mg/sqm, leucovorin 500 mg/sqm 5-FU continuous infusion 24 hours 2000 mg/sqm day 1,8,15,22 every 5 weeks (FUFOX).

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

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

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

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

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

INFUSIONAL SCHEDULES

A. Protracted continuous infusion 5-FU. Unmodulated 5-FU is effective if given by continuous infusion. The dose of 5-FU is 225-300 mg/sqm/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 200 mg/sqm/day. LV is given at 20 mg/sqm/weekly. The toxicity is similar to that of the previous regimen.

C. Infusional 5-FU administered over 24-48 hours, weekly. The dose is 2600 mg/sqm of 5-FU + LV 500 mg/sqm (AIO or German regimen) in 24 hours or 3000-3500 mg/sqm of 5-FU (TTD or Spanish regimen) in 48 hours. 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 200 mg/sqm in two hours day 1-2, Bolus 5-FU 400 mg/sqm day 1-2, 22 hours continuous infusion 5-FU 600 mg/sqm day 1-2 every two weeks. This combination can be used also with a simplified regimen of 5-FU/leucovorin: leucovorin 400 mg/sqm day 1, bolus 5-FU 400 mg/sqm day 1, continuous infusion 46 hours 5-FU 2400 mg/sqm day 1 every two weeks .

6.3.5 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.

7. LATE SEQUELAE

7.1 Late sequelae

There are no relevant late sequelae of surgery or chemotherapy in colon cancer. In particular, up to date, there are no final data excluding the association between adjuvant FOLFOX regimen and late sequelae.

8. FOLLOW-UP

8.1 Objectives and frequency of post surgical follow up

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 (Taylor 1995).

8.2 Suggested protocols

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 (Martin 1985). 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 (Moertel 1993; Safi 1993). Postoperative monitoring should be reserved primarily for detection of asymptomatic recurrences that can be curatively resected and for early detection of metachronous tumours (Bruinvels 1994).

INDEX

 

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Dr. Giordano Beretta (Author)
Ospedale Sant’Orsola-Fatebenefratelli – Brescia, Italy
mail: beregd@iol.it

Dr. Filippo de Braud (Editor)
START Clinical Editor – European Institute of Oncology – Milan, Italy
mail: filippo.de-braud@ieo.it

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Dr. Basem Kildani (Author)
Ospedale Sant’Orsola-Fatebenefratelli – Brescia, Italy.
mail:

Prof. Roberto Labianca (Associate Editor)
Ospedali Riuniti – Bergamo, Italy
mail: rlabian@tin.it

Dr. Federica Merlin (Author)
Ospedale Sant’Orsola-Fatebenefratelli – Brescia, Italy.
mail:

Dr.ssa Laura Milesi (Author)
Ospedali Riuniti – Bergamo
mail: lauramilesi@hotmail.com

Dr. Stefania Mosconi (Author)
Ospedali Riuniti – Bergamo, Italy
mail: s.mosconi@tin.it

Dr. M. Adelaide Pessi (Author)
Ospedali Riuniti, Bergamo – Italy
mail:

Dr. Tiziana Prochilo (Author)
Ospedale Sant’Orsola-Fatebenefratelli – Brescia, Italy.
mail:

Dr. Antonello Quadri (Author)
Ospedali Riuniti, Bergamo – Italy
mail:

Prof. Jacques Wils (Reviewer)
Laurentius Hospital – Roermond, The Netherlands
mail: wils@cobweb.nl