State of the Art Oncology in EuropeFont: aaa

Rectal cancer

1. GENERAL INFORMATION

1.1 Epidemiological data

1.1.1 Incidence

Cancer of the rectum is less frequent than colon cancer, accounting for 5% of malignant tumours, and ranks as the the fifth most common cancer in adults (Parkin 2002; Ferlay 2004). About 140,000 new cases are diagnosed in Europe each year, with about 20-50% more cases in men than women in most populations (Parkin 2002; Ferlay 2004). The incidence (age-adjusted) of rectal cancer is most frequent in Japan, Eastern Europe, Northern Europe (¡Ý15 cases/100,000/year) (Figure 1) (Parkin 2002). Incidence is low in Africa and Asia but is increasing in several populations previously at low risk (Parkin 2001). In general, there have been increases in incidence in countries where the overall risk of large bowel was low, while in high-risk countries there have been either stabilitations or decreases in incidence, particularly in younger age groups. For rectal cancers, the countries with the largest increase are in Eastern Europe and Japan. For mortality, the pattern is similar, with an increase for countries with a low initial rate (Eastern Europe, Japan and Singapore), small increases or stable rates in countries with moderate rates, and a decrease for high-rate populations (Western Europe and North America) (Parkin 2001). In Italy (Crocetti 2004), incident rates of colorectal cancer statistically increased in both men (mean annual increase of +1.7%) and women (+0.6%). Mortality rates showed a statistically significant decrease, in both sexes, of -0.7%/year among males and -0.9% among women.

Figure 1. Incidence rates of rectal cancer in the world

tumore del retto_figure1

1.1.2 Survival

In Europe, the relative survival for adults diagnosed with rectal cancer during 1995-99 was 78% at one year and 54% at five years (Berrino 2007). Five-year relative survival decreased with age from 60% in the youngest (15-45 years) to 46% in the the oldest age group of patients (75 years and over). The survival curves for rectal cancer differ in shape from those for colon cancer. One-year survival from rectal cancer is higher than colon cancer (73 vs. 78%), but five-year survival is equal (54%), because substantial excess mortality from rectal cancer persists well beyond the first year after diagnosis. The survival curves for colon cancer approach a plateau earlier. There are major between-country differences in survival for European patients with rectal cancer (Berrino 2007). Survival from cancer of the rectal in eastern European countries, Denmark and the UK is lower than the European average. 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 variation between countries were bigger in the first half year following diagnosis than in the interval 0.5-5 years with about 30% higher risk in UK and Denmark. Patients management, diagnostics, and comorbidity likely explain the excess deaths in UK and Denmark during the first 6 months (Engholm 2006).

1.1.3 Prevalence

Prevalence of cancer is the number of people living with a diagnosis of cancer. In Europe for both sexes colorectal cancer accounts for 5% of total cancer prevalence (Micheli 2002). About 267,000 prevalent cases are estimated in Italy for the year 2005. The prevalence proportion in northern regions proved to be 2-fold that in southern regions (580 vs 295 per 100,000 for men and 477 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 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 (Shimizu 1987). Diet is definitely the most important exogenous factor identified up to now in the aetiology of colorectal cancer. It has been estimated that 70% of colorectal cancers could be prevented by nutritional intervention (Stewart 2003); various promoting and protective factors have been identified in prospective and case-control studies. Evidence that diets rich in vegetable protect against colorectal cancer is substantial. Among subgroups of vegetables, green leafy vegetables were associated with a lower risk of colorectal cancer for men while intake of fruits was not related to risk of colorectal cancer in men or women (WCRF&AICR 1997; Park 2007). Vegetables contain a large array of substances – both micronutrients, such as carotenoids, folate and ascorbate; and bioactive compounds, such as phenols, flavonoids, isothiocyanates, and indoles – with anticarcinogenic properties. Vegetables are also rich in fiber. Consumption of non-digestible fructo-oligosaccharides may selectively promote the growth and activity of potentially beneficial bacteria, such as Bifidobacterium and Lactobacillus (WCRF&AICR 1997). An expert meeting held at International Agency for the Research on Cancer in 2003 in the frame of the Handbook of Cancer Prevention program concluded with a less optimistic judgement of the protective effect of fruit and vegetables consumption (IARC Working Group 2003). Whether the intake of dietary fibre can protect against colorectal cancer is a long-standing question of considerable public health import, but the epidemiologic evidence has been inconsistent. The role of fibre as a protective factor for colorectal cancer was determined in a large cohort European study on diet (Bingham 2003). In populations with a low average intake of dietary fibre, an approximate doubling of total fibre intake from food could reduce the risk of colorectal cancer by 40%. While in a recent large prospective cohort study, a total dietary fibre intake was not associated with colorectal cancer risk, whereas whole-grain consumption was associated with a modest reduced risk (Schatzkin 2007). In 1997 the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research in their extensive report on the scientific literature on diet and cancer, concluding that high alcohol consumption probably increases the risk of colorectal cancer (WCRF&AICR 1997). Among the most important publications that followed the 1997 WCRF report, a major contribution came from the large European Prospective Investigation into Cancer and Nutrition (the EPIC cohort) (Ferrari 2007) that have recently confirmed the association. An inceased risk from lifetime alcohol intake (HR=1.12, 95%CI=1.06-1.18 for 15 g/day increase), with higher cancer risks observed in the rectum (HR=1.12, than distal colon (HR=1.08, 95%CI=1.01-1.16), and proximal colon (HR=1.02, 95%CI=0.92-1.12) was reported. Several epidemiological studies have examined meat intake and the risk of colorectal cancer. The mechanisms by which red meat and processed meat may increase the risk of colorectal cancer include the facilitating effect of fat on bile acid production, and the formation of carcinogens when meat is cooked or processed. Processed meats may contribute to the production of nitrosamines. The evidence shows that red meat probably and processed meat possibly increases risk of colorectal cancer (WCRF&AICR 1997; Gonzales 2006). A substantial number of other dietary factors, and factors related to diet, possibly modify the risk of colorectal cancer. These factors are diets high in starch, non-starch polysaccharides (fibre) and carotenoids, all of which are found in foods of plant origin, and possibly decrease the risk (WCRF&AICR 1997). Greater adult height, frequent eating, and diets high in sugar, total and satured fat, and eggs, all possibly increase risk (WCRF&AICR 1997; Gonzales 2006).

1.2.2 Non dietary factors

Established non-dietary factors of colorectal cancer include smoking tobacco, infestation with Schistosoma sinensis, radiation, chronic use of non-steroidal antiinflammatory drugs (NSAIDs) and aspirin and some conditions and genetic predispositions (Stewart 2003). Smoking has consistently been associated with large colorectal adenoma, 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 2002). An updated review suggested a temporal pattern consisten with an induction period of three to four decades between genotoxic exposure and the diagnosis of colorectal cancer. In the US one in five colorectal cancers may be potentially attributable to tobacco use. Baxter at al showed that prostate irradiation is associated with an increased risk of rectal cancer. They found an adjusted hazards ratio for rectal cancer of 1.7 (95%CI, 1.4-2.2) in men surviving more than 5 years after radiation treatment of the prostate cancer compared with men with prostate cancer treated with surgery alone (Baxter 2005). Conditions that predispose to the development of colorectal cancer include inflammatory bowel disease and Crohn’s disease (Stewart 2003). The metabolic syndrome (¡Ý3 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).

1.3 Screening and case finding

1.3.1 Screening programme

Colorectal cancer screening is now proposed for healthy people with a view to cancer secondary prevention, that is prevention by detection of preclinical lesions. The major aim of the screening is to detect the 90% of sporadic cases of colorectal cancer, most of which occur in people over the age of 50 years (Stewart 2003). A study on screening in people 40-49 years old confirmed that colorectal cancers are uncommon in this age group, supporting the recommendation that screening in average risk people begins at age 50 (Imperiale 2002). 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 three randomised trials to reduce mortality from colorectal cancer by up to 20% if offered biennally (Mandel 1999). The sensitivity of the test is around 50% for cancer (of all screened persons who have cancer, 50% will be detected) (Stewart 2003; Winawer 2003). For polyps it is lower, at around 10%. The predictive value of a positive test is around 10% for cancer (out of every ten persons detected as positive, nine will not have cancer). An immunological FOBT for haemoglobin is on trial; it is proving more specific, but more costly. One study showed that 1 in 3 people with a positive FOBT currently undergoes colonoscopy, they should therefore be in a position to benefit fully from screening (Lurie 1999). Screening by endoscopy (flexible sigmoidoscopy or colonoscope) is the best method of detecting colorectal cancer and polyps. However, its application at population level is limited by cost and availability of qualified specialists. A major advantage of endoscopy is in the possibility for performing interventional procedures immediately and the potential for tissue sampling. Population-based eradication of adenomatous polyps may reduce cancer incidence (Stewart 2003). Computed tomography colonography (CTC), also known as ‘virtual colonoscopy’, is a noninvasive method of imaging the colon using helical CT. Although CTC has been shown to be useful for certain clinical indications, it has not yet been endorsed as a colorectal cancer screening test. When screening by sigmoidoscopy has been evaluated, case-control studies have reported that sigmoidoscopy was associated with reduced mortality for colorectal cancer. The study with the best results described a mortality reduction of two thirds for lesions within reach of the sigmoidoscope (Selby 1992). A 10-year interval seems adequate when the examination is performed by well-trained examiner, in a patient who is well prepared and has been examined up to or near the splenic flexure (Winawer 2003). The decision to perform colonoscopy after the detection of a neoplasm on sigmoidoscopy is controversial. In one randomised control trial, screening sigmoidoscopy followed by colonoscopy when polyps were detected was associated with an 80% reduction in colorectal cancer incidence (Lieberman 2000). Within the recommendations on cancer screening in the European Union (ACCP 2000), the Advisory Committee on Cancer Prevention has suggested that if screening programmes for colorectal cancer are implemented they should use the faecal occult blood screening test. Colonoscopy should be used for the follow-up of 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.

1.3.2 Screening and case finding for people at increased risk

The updated guidelines by the American Gastroenterology Associations make the following recommendations for people at increased risk (Winawer 2003).

  • People with a family history of colorectal cancer or adenomatous polyps.People with a first-degree relative (parent, sibling, or child) with colorectal cancer or adenomatous polyps diagnosed at age < = 60 years or two first degree relatives diagnosed with colorectal cancer at any age should be advised to have screening colonoscopy starting at age 40 years or 10 years younger than the earliest diagnosis in their family, whichever comes first, and repeated every 5 years. Mortality reduction studies directed at screening persons with a family history of colorectal cancer or adenomatous polyps are not yet available. The screening recommendations given for this group must therefore be considered provisional.
  • Familial adenomatous polyposis.People who have a genetic diagnosis of familial adenomatous polyposis (FAP), or are at risk of having FAP but in whom genetic testing has not been performed or is not feasible, should have annual sigmoidoscopy, beginning at age 10-12 years, to determine if they are expressing the genetic abnormality. Genetic testing should be considered in patients with FAP who have relatives at risk. Genetic counseling should guide genetic testing and considerations of colectomy. The colorectal cancer mortality rate is lower in FAP patients who choose to be screened compared with those who present with symptoms (Green 2002). The benefit of genetic testing in FAP is presumed but has not been proven.
  • Hereditary nonpolyposis colorectal cancer. People with a genetic or clinical diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) or who are at increased risk for HNPCC should have colonoscopy every 1-2 years beginning at age 20-25 years, or 10 years earlier than the youngest age of colorectal cancer diagnosis in the family?{whichever comes first. Genetic testing for HNPCC should be offered to first-degree relatives of persons with a known inherited mismatch repair (MMR) gene mutation. A prospective Finnish study on the endoscopic detection of neoplasia in families fulfilling the Amsterdam criteria for hereditary nonpolyposis colorectal cancer has suggested efficacy of colonoscopy in reducing the risk and mortality from colorectal cancer (Heiskanen 2000).
  • Surveillance of people at increased risk. People with history of adenomatous polyps.Patients who have had one or more adenomatous polyps removed at colonoscopy should be managed according to the findings on that colonoscopy. They should have their first subsequent colonoscopy in 3-5 years depending on the pathology and the number of adenomas detected. Evidence is still accumulating regarding the appropriate timing of subsequent colonoscopy. Future evidence may clarify the intervals more precisely.
  • People with a history of colorectal cancer. Patients with colorectal cancer that has been surgically resected with curative intent should have a colonoscopy around the time of diagnosis to rule out synchronous neoplasms. If the colorectum is obstructed preoperatively, colonoscopy can be performed approximately 6 months after surgery. If this, or a complete preoperative examination is normal, subsequent colonoscopy should be offered at 3 years, and then, if normal, every 5 years. In a follow-up study, the incidence of secondary colorectal cancers was increased despite intensive surveillance (Jarvinen 2000). A randomised controlled trial compared the effects of annual colonoscopy, liver and chest examinations, carcinoembryonic antigen (CEA) plus regular history, and physical examination with the effect of history, examination, and CEA alone. The study indicated that the value colonoscopy is confined to detection of metachronous adenomas and not recurrent intraluminal cancer (Schoemaker 1998).
  • People with inflammatory bowel disease. In patients with long-standing, extensive inflammatory bowel disease, surveillance colonoscopy with systematic biopsies should be considered. This applies to both ulcerative colitis and Crohn’s colitis because the cancer risk is similar in both diseases. There are no randomised controlled trials of surveillance colonoscopy in patients with ulcerative colitis or Crohn’s colitis. A case control study has found better survival in ulcerative colitis patients in surveillance programmes (Choi 1993). Observational studies (Engelsgjerd 1999; Rubin 1999) suggest that tubular adenomas with only low-grade dysplasia in flat mucosa are not markers of cancer risk over short interval. Such lesions can be considered sporadic adenomas, and, if other indications for colectomy are absent, surveillance can be continued.

1.4 Referral

It is recommended that all suspected cases of colorectal cancer are referred to specialized institutions

2. PATHOLOGY AND BIOLOGY

2.1 Biological Data

2.1.1

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 localization of other mutations associated with the somatic loss of heterozygosity in colon cancer, and 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 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 deleted frequently 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 types

2.2.1

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.

  • Epithelial tumours M-80103
    Adenocarcinoma M-81403
    Mucinous adenocarcinoma M-84803
    Signet ring adenocarcinoma M-84903
    Squamous cell carcinoma M-80703
    Adenosquamous carcinoma M-85603
    Undifferentiated carcinoma M-80203
    Unclassified carcinoma M-80003
  • Carcinoid tumours (Appendix M-82401, Others M-82403)
    Argentaffin M-82413
    Nonargentaffin M-82403
    Composite M-82433
  • Nonepithelial tumours M-88003
    Leiomyosarcomas M-88903
    Others
  • Hematopoietic and lymphoid neoplasms M-98003/ M-95903
  • Unclassified M-80003

2.3 Grading

2.3.1

In 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, others 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 elsewhere

2.4.1

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.

3. DIAGNOSIS

3.1 Signs and symptoms

3.1.1

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, 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 intestinal wall. 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. Endoscopy of the colon-rectum is the most valuable diagnostic procedure.

3.2 Diagnostic strategy

3.2.1 Laboratory markers

A great deal of effort has beenspent 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 (Moertel 1986) but has a low predictive value for diagnosis in asymptomatic patients ((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 Dukes’ A and B lesions is 36%, compared with 74% for Dukes’ C and 83% for Dukes’ D disease when 2.5mg/ml is used as the upper limits of normal. Several new carbohydrate antigens such as CA19-9 are being examined and may hold some promise in terms of specificity for preneoplastic and early neoplastic lesions in the colon (Bresalier 1984). Their effectiveness for screening remains to be determined.

3.2.2 Endoscopy and biopsy technique

Endoscopy can be performed to varying lengths uing 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 at every opportunity. The endoscopist should be gentle – and avoid forming unnecessary loops – by pushing as little as possible. The colonoscope should be pulled back to shorten the colon at every opportunity. The distance the colonoscope is inserted should be kept appropriate to the anatomic location and great care should be given to patient discomfort which indicates excessive looping or insufflation. 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.

3.2.3 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 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.

4. STAGING

4.1 Stage classifications

4.1.1

Treatment decisions are usually made in reference to the older Dukes or the Modified Astler-Coller (MAC) classification scheme (Cohen 1993). Stages should preferably be defined by the TNM classification (Eisenberg 1982; Newland 1981; Olson 1980; Olson 1980; UICC 2002; Zinkin 1983).
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.

TNM definitions:
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 **, ***

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

**Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum.

*** Tumor that is adherent to other organs or structures, macroscopically, is classified T4. However, if no tumor is present in the adhesion, microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion.

Regional lymph nodes (N)
NX: Regional nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in 1 to 3 regional lymph nodes
N2: Metastasis in 4 or more regional lymph nodes

Distant metastasis (M)
MX: Presence of distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
Stage 0 Stage 0 is defined as the following TNM grouping:

Tis, N0, M0: (carcinoma in situ)

Stage I Stage I is defined as any of the following TNM groupings:
T1, N0, M0
T2, N0, M0

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 IIA Stage IIA is defined as any of the following TNM groupings:
T3, N0, M0

Stage IIB Stage IIB is defined as any of the following TNM groupings:
T4, N0, M0

Stage II may be equivalent to Dukes’ B or MAC B2 or B3. Tumour has spread to extramural tissue.

Stage III (A,B,C) Stage III is defined as any of the following TNM groupings:
any T1-2, N1, M0 (IIIA)
any T3-4, N1, M0 (IIIB)
any T, N2, M0 (IIIC)

Stage III may be equivalent to Dukes’ C or MAC C1-C3. Regional nodes are involved.

Stage IV Stage IV is defined as the following TNM grouping:
any T, any N, M1

Note: Dukes’ B is a composite of better (T3, N0, M0) and worse (T4, N0, M0) prognostic groups as is Dukes’ C (any T, N1, M0 and any T, N2, M0).

4.2 Staging procedures

4.2.1 Preoperative staging: standard and optional procedures

The following are general guidelines for the staging of patients with potentially curable rectal 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.

Rectal examination: Intestinal evaluation is performed with digital rectal examination (DRE), full colonoscopy (for evaluation of multifocal neoplasm) or proctoscopy (for obstructive tumours) with biopsy. Echo-endoscopy has a major role in rectal cancer with up to 95% accuracy for determining trans-mural penetration and up to 74% accuracy for determining perirectal node status, while no current techniques reliably detect lymph-node spread (Snady 1998). 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 is appropriate. Colon cancer patients may benefit from a peri-operative computed tomography (CT) (9) scan or ultrasound study of their liver as a baseline. Only a small subset of patients have an intrahepatic tumour not recognizable at laparotomy that will not impact on the operative procedure. Although preferable, this study need not be performed preoperatively if liver function tests are normal and hepatomegaly is not present (Butch 1986; Guinet 1990). MR imaging (MRI) is mandatory for proper staging of rectal cancer because it is the best method for visualizing the mesorectal fascia, and the circumferential margin (CRM) for a TME resection can be accurately predicted. By doing so the optimal treatment can be defined, i.e. preoperative radio(chemo)therapy or primary surgery (Beets-Tan 2001; Mercury Study 2007).
Recent role of positron emission tomography (PET) has been investigated: frequently yields additional staging information in patients with low rectal cancer. Improved accuracy of pretreatment imaging with FDG-PET/CT will allow for more appropriate stage-specific therapy (Gearhart 2006).

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. 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 (Guinet 1990). During resection of liver tumours intraoperative ultrasonography can be used to exclude multifocal tumour development or satellite metastases; furthermore it is important for establishing the plane of resection and the appropriate safety margin. Without intraoperative 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. During this procedure focal liver lesions can be biopsied under combined laparoscopic and sonographic view (Guinet 1990).

5. PROGNOSIS

5.1 Prognosis of operable disease

5.1.1

Rectal cancer is still one of the most frequent tumours in developed countries and affects men and women almost equally. There is a consistent variation in incidence and mortality rates of colorectal cancer in Europe with an overall tendency for rates of rectal to follow those of colon cancer. The highest rate of incidence of rectal cancer has been reported in Czechoslovakia with 24.2/100,000 (Levi 1998).
Recent data has shown steady decreases in mortality of intestinal cancers and if recent trends are maintained, colorectal cancer mortality is likely to decline further in Europe in the current decade (Fernandez 2005). Cancer of the rectum is often curable when is localised to the bowel. Radical resection represent the first option 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 rectal cancer is clearly related to the degree of penetration of the tumour through the bowel wall, the presence or absence of nodal involvement and the presence or absence of systemic metastases. The staging systems in common use reflect these characteristics (Steinberg 1986).
Additional relevant parameters are grading, angio- or venous invasion and perineural invasion, lymphoid inflammatory response and tumour involvement of resection margins that the Dukes and TNM classifications do not take into account (Hermanek 1990). 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, EGFR, proliferative index, and aneuploidy observed in tumour tissue are under evaluation for their single or combined predictive value in high risk conditions (Bell 1993; Deans 1992; Eisenberg 1982; Olson 1980; Steinberg 1986; Watson 1996). In rectal cancer the tumour involvement of radial (lateral) margins and complete excision of the mesorectum in the middle and lower third segments may predict local recurrence (Arbman 1996; de Haas-Kock 1996). A positive circumferential resection margin is associated with a high risk of local recurrence and distant metastasis after total mesorectal excision for rectal cancer. The mesorectum is thinner anteriorly than posteriorly, and the risk of a positive resection margin may be higher for anterior than for posterior tumors. Anterior tumors tend to be more advanced and, at least in male patients, has a higher risk of recurrence and death than tumors in other locations (Lee 2005). Bowel obstruction and perforation are clinical indicators of 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; Lorchel 2007). Some retrospective studies suggest that perioperative blood transfusions impair the prognosis of patients with colorectal cancer and that number of perioperative blood units is associated with postoperative mortality and overall survival (Stephenson 1988; Voogt 1987). In addition, allogenic perioperative blood transfusion has been postulated to produce host immunosuppression and has been reported to result in adverse outcome in patients with colorectal cancer. Autologous blood transfusion might improve results compared with allogenic transfusion. 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; Jagoditsch 2006).

5.2 Prognosis of Advanced Disease

5.2.1

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.
Currently, 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 4-8 months. With the advent of new drugs such as CPT-11 and oxaliplatin the efficacy of chemotherapy has clearly increased. Response rates have increased to 50% and survival to 18-24 months. Factors predicting for treatment outcome on a type C basis, unless otherwise specified, can be divided as follows:

Factors related to the patient:

  • Age by itself is not a predictor of outcome.
  • 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 (Kohne 2002). In most recent studies the response rate for any of the commonly used chemotherapeutic regimens is in the range of 30 to 60% for patients with an ECOG performance status of 0, and 10 to 30% and 0 to 10% for those with an ECOG performance status of 1 and 2, respectively.
  • Presence of tumour-related symptoms: asymptomatic patients live longer and respond to chemotherapy more frequently than symptomatic patients.Factors related to the disease:
  • The extent of the disease correlates with the probability of response and survival (Kohne 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. Locally advanced, inoperable rectal carcinoma constitutes a tremendous challenge for the oncologist. In fact the prognosis of these patients is particularly poor: not so much in terms of survival, as in terms of quality of life. Objective responses to chemotherapy alone are extremely rare but an aggressive multidisciplinary approach (external beam RT, brachytherapy, laser therapy with early pain management) may produce downstaging with subsequent potential for resection and/or afford an acceptable quality of life for prolonged periods of time.
  • Tumour grading correlates with the overall patient survival, but data are insufficient to conclude that it is a predictor of response to chemotherapy.
  • CEA (carcinoembryonic antigen): 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 (Kemeny 1995). Randomised, well-designed and adequately statistically powered trials on CEA monitoring are warranted. In recent observation patients with a failed conversion of abnormal preoperative value to normal postoperative concentration were found to have the worst overall survival rate. Abnormal pre- and postoperative serum CEA levels might represent single independent predictors for survival and postoperative relapse, respectively (Wang 2007). 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.
  • Other prognostic factors: recent trials have regarded increasingly the role of tumor cells in peripheral blood detected by molecular methods as a clinically relevant prognostic factor after resection of colorectal tumour (Allen-Mersh 2006). The cytokeratins, particularly cytokeratin 19 and cytokeratin 20 used for the detection of circulating tumor cells in the peripheral blood, are the most investigated prognostic markers, but even for these questions remain about their clinical value, and hence most recent studies are utilizing a combination of factors. There is the necessity to standardize isolation and analysis techniques to be adopted thus allowing large-scale, appropriately controlled, multicenter trials to be undertaken on the most promising candidate markers (Khair 2007). Furthermore, the prognostic value of molecular biomarkers, such as thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), all of which are involved in the FU metabolism, or as p53, p21, and Epidermal Growth factor Receptor (EGFR) over expressed in 70-80% of colorectal cancer, is debated and deserves future large observations. Retrospective evaluation of surgical specimens of patients affected by locally advanced rectal cancer and treated with neoadjuvant chemo-radiotherapy, showed that it could be a correlation between tumor regression assessment and outcome. In particular grade of regression (GR) according to Dworak system (GR0=absence of regression to GR4=complete regression) correlate with disease free-survival (Dworak 1997; Jacob 2006).Factors related to the treatment:
  • Prior adjuvant treatment is a more debated issue: it is too early to draw conclusions about the influence of six or more months of fluoropyrimidine-based regimens given adjuvantly on the outcome of chemotherapy given as palliative treatment of advanced disease. In general, prior adjuvant treatment is not a criterion of exclusion from investigational trials provided that the treatment has been completed longer than at least six months before the diagnosis of metastatic disease.
  • Response to chemotherapy: in almost all studies, survival analysis of responding vs non-responding patients favours the former group. Response is an independent prognostic factor for survival (Buyse 2000). Nevertheless other factors besides tumour response may contribute substantially to the final outcome. Data from NSABP R03 and the CAO/ARO/AIO-94 trial were intriguing, showing that patients with a complete response to preoperative radiochemotherapy had an improved survival as compared to other patients (Roh 2004; Rodel 2005).Whether the response to therapy is altering the course of the disease or merely serving as a predictor of biology is unclear.
  • Prior radiotherapy: local relapse not suitable for radical surgery is a difficult challenge for cure due to vascular injury and fibrosis induced by radiotherapy. Systemic treatment have improbable therapeutic effects and reirradiation is expected to be associated with a high risk of late toxicity.

6. TREATMENT

6.1 Stage 0 rectal cancer

Stage 0 rectal cancer is characterised by superficial lesions limited to the mucosa without invasion of the lamina propria.
Treatment options:
1. Local excision or simple polypectomy.
2. Transanal or transcoccygeal rectal resection for larger lesions not amenable to local excision.
3. Endocavitary irradiation.
4. Local radiation therapy.
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. The decision to undergo operative 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 histologic features are present in a polyp from a patient with an average operative risk, resection is recommended (Stein 1993).
The pedunculated polyp with invasive carcinoma confined to the head, and 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 histological 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 (Stein 1993).

6.2 Surgical treatment of localised disease

The TME (total mesorectal excision) technique is standard for all rectal cancers on a type C basis, only in selected, very early, cases can local excision be performed. From a surgical point of view the rectum is divided into three regions: upper, middle and lower thirds, each one being approximately 5 cm in length. The approach towards rectal cancers depends on location of the lesion. For lesions of the rectosigmoid and upper rectum a low anterior resection can be performed through an abdominal incision and primary anastomosis accomplished. Even for middle and lower rectal (extra-peritoneal tract) lesions a sphincter saving resection with total mesorectum excision represents the gold standard surgery, providing a minimum distance of at least 1 cm between the lower edge of the tumour and the dentate line is detected. In such circumstances the distance from the anal verge should be at least 3.5-4 cm. Increased recurrence or attenuated survival is not associated with sphincter saving resections for rectal cancer when compared with abdominoperineal resection if a 1.5-2 cm distal margin is preserved (Heimann 1986; Williams 1984; Wolmark 1986). In about 5-10% of middle third and 30-40% of lower rectum tumours, the inability to obtain an adequate distal margin, the presence of a large bulky tumour deep within the pelvis, extensive local spread of local cancer, and a poorly differentiated morphology all dictate the need for an abdominoperineal resection. Here the distal sigmoid, rectosigmoid, rectum and anus are removed through a combined abdominal and perineal approach, and a permanent sigmoid colostomy is established. Generally 90% of cases can be treated with radical surgery and operative mortality is about 5%, with no apparent differences being seen between the sphincter preservation technique and the abdominoperineal approach. Colo-anal reconstruction with staples or suture is a recent surgical technique that permits an intestinal continuity through the anastomosis of colon to the level of anus and dentate line, in tumours occurring 2-5 cm from the anal verge. The most frequent causes of recurrence are T3 stage, low grade of differentiation, positive margins, mesenteric and perineural involvement (Grotz 1995; Paty 1994). Pre- or postoperative radiotherapy may reduce the incidence of these events (Wagman 1998).
Several authors propose conservative approaches in selected conditions:
1. local excision is possible in cases of T1 lesions that are easily accessible by digital examination, <3 cm and grade 1 or 2 without suspicious adenopathies in the mesorectum by echoendoscopy. In case of T2 tumours, that are grade 1 or 2, discussion remains open (Billingham 1992; DeCosse 1989);
2. local resection plus radiotherapy: some experiences of this combination has been obtainedbut the role of postoperative radiotherapy is not yet clarified (Bailey 1992);
3. contact or endocavitary radiotherapy: may be used in case of elderly patients who present contraindications for surgery (Papillon 1992).

6.2.1 Stage 1 rectal cancer

Stage I or Dukes’ A or Modified Astler-Coller A and B1, is a localised disease with a high cure rate. Treatment options:
1. Wide surgical resection and anastomosis: low anterior resection (LAR) or colo-anal anastomosis when normal rectal tissue is sufficient or abdominoperineal resection (APR) for distal lesions not manageable with more limited approach.

2. Local excision: in case of pathological T1 with diameter <4 cm, G 1-2 (risk of positive lymph nodes is about 3%) without venous or perineural extension, local excision without any additional treatment is indicated. Patients with T2 tumour have a risk of loco-regional lymph-node involvement of about 18%, 26% and 40% for G1,G2 and G3, respectively and require adjuvant chemo- and radiotherapy or standard surgical resection (Bailey 1992; Russell 2000; Sitzler 1997; Willett 1994). No randomized trials are available to compare local excision with or without chemoradiation treatments to wide surgical resection (LAR and APR). One prospective multicenter phase II study and several larger retrospective series suggest that well-staged patients with small (<4 centimeters) tumors with good hystologic prognostic features (well-moderately-differentiated adenocarcinomas), mobile and no lymphatic, venous or perineural invasion, trated with full-thickness local excision that results in negative margins may have outcome equivalent to APR or LAR with the selective post-operative use chemoradiation therapy (Willett 1994; Russell 2000; Steele 1999).

3. Endocavitary radiotherapy: in cases of tumours with diameter <3 cm, G1-2, without deep ulceration, tumour fixation and suspicious palpable lymph nodes endocavitary treatment may be proposed in selected institutions (Kodner 1993; Papillon 1992; Maingon 1998; Gerard 2004). Special expertice is essential for achieving results equivalent to surgery. Currently no data are available on advantage of additional medical treatment.

6.2.2 Stage II rectal cancer

Stage II or Dukes’ B or Modified Astler-Coller B2 and B3.
Treatment options:
1. Wide surgical resection (TME) and anastomosis (low anterior resection with colo-rectal or colo-anal anastomosis; abdominoperineal resection; partial or total pelvic exenteration) followed by postoperative radiotherapy and chemotherapy especially in stage IIb.

2. Preoperative chemo-radiotherapy followed by surgery with an attempt to preserve sphincter function. Randomized trials have strongly suggested that preoperative radiotherapy is superior to postoperative therapy and is now generally viewed as the standard of care. Some patients with stage IIa with high rectal tumors may not need adjuvant treatment (Tepper 2007):

3.Intraoperative electron beam radiation therapy (IORT) to the sites of residulal microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate equipment is available. When combine d with external beam radiation therapy and chemotherapy in highly selected patients, IORT with or without 5FU has resulted in improved local control in single institution experiences (Gunderson 1997; Nakfoor 1998). obstruction. The pattern of recurrence of colon and rectal cancers differs substantially. The former recurs most frequently in the liver, the latter, locally. This different pattern of failure accounts for different strategies for patient management and conduction of clinical trials in this area. Local recurrence of rectal cancer is always incurable. Moreover it causes severe symptoms that strongly affect the quality of life of these patients. This is the reason why, at the 1990 the Consensus Conference sponsored by USA National Institute of Health, aside from disease free survival and overall survival, local control of this disease was included among the primary objectives of trials on the adjuvant treatment of rectal cancer with recurrence high risk. For patients with stage II and III disease postoperative radiotherapy in combination with chemotherapy was recommended (NIH 1990).

The standard surgical treatment for rectal cancer is total mesorectal excision. Studies in Europe and the US have demonstrated that pre-or postoperative radiotherapy can improve outcome. In Europe there has been a greater enthusiasm for the preoperative approach but also in US preoperative treatment is now considered as standard approach (Tepper 2007). Two types are used: high-dose or long term with 45-55 Gy in 1.8 Gy fractions in 4-6 weeks and short term, 25 Gy in 5 fractions (advocated by Swedish and Dutch groups). Potential advantages of the long regimen include more downstaging and more sphincter saving surgery. The optimal chemotherapy to be combined with radiotherapy is under evaluation. This technique requires radiosensitizing agents with a long half-life. An intergroup study has demonstrated 10% improved survival with 5-FU given as continuous infusion concomitantly with radiotherapy compared with the same agent used as bolus injection (O’Connell 1994). These data support the use of FU as prolonged infusion in conjunction with radiotherapy. High-dose, short duration, preoperative radiotherapy as described by the Swedish Rectal Cancer Group has confirmed a reduction in the local recurrence rate compared with that previously obtained using postoperative radiation. It also showed a significant improvement in overall survival with the disadvantage of more chronic intestinal dysfunction; therefore, it is suitable for individual clinical use on a type 2 level of evidence (SRCT 1997). Currently no other experiences with preoperative irradiation alone have produceed favourable survival results. Short term preoperative radiotherapy also significantly reduced local recurrence rates in the Dutch trial (Kapiteijn 2001) without an impact on survival.
A prospectively randomized clinical trial comparing preoperative vs postoperative combined-modality therapy was reported at the 2003 meeting of the American Society of Therapeutic Radiology by the German Rectal Cancer Group (Sauer 2004). This study demonstrated a significant reduction in local tumor relapse and less toxicity from preoperative combined modality therapy as compared to similar treatment given postoperatively. These data provide a strong rationale to consider sequencing radiation prior to surgery for operable T3 or T4 rectal cancer.

6.3 Adjuvant treatments

Different strategies for the treatment of rectal cancer
Colon and rectal cancer are usually considered one disease in the advanced setting, because the prognosis and sensitivity to anti-neoplastic agents is largely similar for neoplasms originating from different portions of the large bowel. However, the pattern of recurrence of colon and rectal cancers differ substantially. The final outcome of rectal cancer depends far more upon the skills of the surgeon than for colon cancer. Chemotherapy is given with adjuvant intent to high-risk patients with both neoplasms, but in general, radiation therapy is also necessary in rectal cancer while it is not in colon cancer.

Definition of patients with high risk of recurrence
By stage, the survival of patients with rectal cancer is similar to that of colon cancer. The 5-year survival for Dukes’ stages A, B and C is 85% (range 75-100%), 65% (range 40 to 80%) and 40% (range 15 to 60%). The wide ranges reflect major differences in prognosis depending upon stage subset, tumour grading, and the other biologic al characteristics discussed in the previous sections.
a) Stage subset: T4 lesions, corresponding to Dukes’ stages B3 or C3 carry a much worse prognosis than T1 to T3 lesions; within the C stage grouping the 5-year survival drops to half if more than 4 (26%) lymph nodes are involved compared with an involvement of 1-3 lymph-nodes (56%).
b) Tumour grading: Grade 1 carcinomas are more superficial 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. Nevertheless, the practical value of these features still needs confirmation by large-scale studies.

6.3.1 Criteria for suggesting an adjuvant treatment

As with any adjuvant therapy, it appears clear that a large proportion of patients do not need additional treatment. Patients who would be cured without adjuvant therapy and patients who die despite adjuvant therapy are individuals who do not need it. Therefore adjuvant treatment is recommended for high-risk patients. The first problem is, therefore, defining what high-risk is. Penetration of the neoplasm through the serosa of the bowel wall is by itself generally considered the cut-off stage separating high vs low risk patients. In general Dukes’ B1 lesions are considered low risk while B2 ones are widely felt to deserve adjuvant treatment; this means that high risk for relapse is defined as more than 30%. During risk assessment all known tumour-related prognostic factors must be integrated starting from the stage and grade to derive a rough estimate of the chances of relapse. For example, a patient with a Dukes’ B1 G3 adenocarcinoma with blood vessel invasion, presence of tumour budding and high thymidine labelling index is likely to have more than 70% chance of relapse – much higher than those of another patient with a C2 G1 lesion but with the opposite pathological and biological parameters. Defining high-risk is gtradually becoming more sophisticated and with the advent of molecular prognostic and predictive factors this will even become more complex. The second problem is tailoring the decision to each individual patient’s characteristics. In this context, the most debated issue is the impact of patients’ age in the decision making. The median age of patients presenting with colorectal cancer is 72, however, the median age of patients in clinical trials of 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;
b) toxicity of chemotherapy is similar below and above age 70 and
c) the efficacy of adjuvant treatment is similar in elderly people compared to that in the general population.

6.3.2 Adjuvant Chemotherapy

The standard treatment for Dukes’ B2 and C rectal cancer is RT plus fluorouracil. Despite well-recognised standard adjuvant programmes, a recent survey of the implementation of these guidelines in 73 American centers showed that fewer than 5% of patients receive the recommended schedules of combined chemo-radiation reported below. The reasons for this are 1) complexity and 2) toxicity. The recommended adjuvant regimen for Dukes’ B2 and C rectal cancer is the following: 5-FU 500 mg/sqm day 1-5 and 36-40 then RT (4500 cGy) day 63-107 with continuous infusion 5-FU at 225 mg/sqm/day, then 5-FU 450 mg/sqm day 134-138 and 169-173.

6.3.3 Post-operative radiotherapy

The standard adjuvant treatment is preoperative chemoirradiation. Postoperative chemo-irradiation should be applicated in patients considered to have a high risk of local relapse following surgery, if adequate pre-operative radiotherapy has not been given. This includes patients with remaining microscopic disease after the operation. Patients with locally advanced disease (T3-4) and local relapses should receive preoperative and not postoperative radiotherapy as described previously. Patients with stage III tumours, whether or not they underwent total mesorectal excision surgery, should be given postoperative radiotherapy as standard treatment if adequate preoperative chemo-irradiation has not been given. Patients who did not receive preoperative radiotherapy and have a CRM of < or 0 1mm at pathology report should receive postoperative (chemo)radiotherapy. Treatment volumes and the doses are similar to preoperative radiotherapy (45-55 Gy in 4-6 weeks). Post-operative radiotherapy should also be given when tumour cells are spilled in the operation field during surgery.

6.3.4 Combined chemo-radiotherapy

Several cytotoxic agents act as radiosensitizers, and hence increase the cytotoxic effect of radiotherapy. When used as adjuvant treatment, combined chemo-radiotherapy reduces the local recurrence rate and improves survival compared with radiotherapy alone. Moreover, chemotherapy may also have an effect on micrometastases and thereby reduce the frequency of distant metastases. However, cytotoxic agents also increase the side effects of radiotherapy, especially regarding the small bowel. Several drugs are being used, but 5-FU is the main component. The cytotoxic agents are given concurrently with radiotherapy but the optimal time schedules have not yet been defined. In this respect, continuous 5-FU infusion has been shown to be more effective than bolus 5-FU (O’Connell 1994). The results of a trial (INT 0144) evaluating the benefit of continuous infusion 5- FU during the entire 6 months adjuvant program vs continuous infusion 5-FU only during the period of radiotherapy do not show relevant differences between the three arms of the study (Smalley 2003). Furthermore there is no advantage of leucovorin- or levamisol-containing regimens over bolus 5-FU alone when combined with irradiation. An open question has been if radiochemotherapy is better when administered as adjuvant or neoadjuvant modality: two trials in North America were conducted with the aim of evaluating the role of integrated strategy but were closed because of poor patient accrual. The preliminary results of NSABP R03 trial and the German study strongly suggested a benefit for the preoperative approach: neoadjuvant integrated strategy was more active and demonstrated less risk for acute and late morbidity (Roh 2001; Sauer 2004).

6.3.5 Preoperative radiotherapy

The potential advantages of a preoperative approach over a postoperative one are: decreased tumour seeding during the operation, less acute and late toxicity, increased efficacy of radiotherapy and, for patients who receive a conventional long-course of radiotherapy, an increased rate of sphincter preservation (Bosset 2000). It is accepted that long-course radiation regimens can down-size a rectal cancer, whereas short-course radiation regimens do not induce down-sizing of the tumour. The long-course radiation regimens might therefore be more suitable for locally more advanced cancers. The disadvantage is the potential overtreating patients with early stage or undetected metastatic disease. The standard approach (>3 fields, computerised plan and customised blocking; 45-55 Gy, delivered in 4-6 weeks followed by surgery 6-8 weeks later) has the potential objective of inducing down-staging in locally advanced tumours and permiting radical surgery with preservation of sphincter function (Minsky 1994; Minsky 1993). Based on a series of experiences the optimal time of surgery is about 4-6 weeks after radiotherapy for obtaining the maximum therapeutic effect with lower postoperative complications. A different approach in irradiation techniques has been evaluated by a Swedish Group with high-dose short-course treatments (5 Gy daily for 5 days followed by surgery 1 week later): favourable results on pathological responses and overall survival have been reported, but also long-term bowel dysfunction (SRCT 1997). The Dutch trial using preoperative radiotherapy combined with total mesorectal excision showed a reduction of local recurrence rates from 8% to 2% without impact on survival (Kapiteijn 2001).

6.3.6 Preoperative radio-chemotherapy

Fluorouracil-based schemes in combination with preoperative irradiation are employed with the aim of improving local control and reducing distant recurrence rates. The recent randomized trial conducted by German Rectal Cancer Study on this issue, described an improved local control and reduced toxicity obtained by pre-operative chemoradiotherapy compared to post-, but failed to demonstrate significant difference in terms of incidence of distant recurrence, disease-free or overall survival (Sauer 2004). Currently, in locally advanced rectal cancer conventional preoperative radiation is based on the dose and the techniques used in postoperative approaches. Chemotherapy is delivered concomitantly with 6 weeks of radiotherapy and is administered for at least 4 months after surgery. Pathological complete response rates have been observed in 10-30% with toxicity > grade 3 (WHO or NCI) in 20-25% and an incidence of local failure of < 5% (Chari 1995; Grann 1997; Rich 1995). In 75% of patients sphincter-sparing surgery is performed. New chemotherapy agents with a high therapeutic index and possibly reduced toxic profile are being evaluated for increasing pathological remission, for limiting local and systemic side-effects and for increasing patient compliance.

6.4 Stage III or Dukes’ C or Modified Astler-Coller C1-C3

Treatment options:

1. Wide surgical resection (TME) and anastomosis (low anterior resection with colo-rectal or colo-anal anastomosis; abdominoperineal resection; partial or total pelvic exenteration) followed by postoperative radiotherapy and chemotherapy.

2. Preoperative chemo-radiotherapy followed by surgery with an attempt to preserve sphincter function. Randomized trials have strongly suggested that preoperative radiotherapy is superior to postoperative therapy and is now generally viewed as the standard of care (see above).

3. Intraoperative electron beam radiation therapy (IORT) to the sites of residual microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate team is available. When combined with external beam radiation therapy and chemotherapy in highly selected patients, IORt with or without 5FU has resulted in improved local control in single institution experiences (Gunderson 1997).

4. Palliative chemo-radiotherapy in case of surgical contraindications.

Stage III rectal cancer is characterised by regional lymph node involvement. The number of lymph nodes involved correlates with prognosis: patients with 1-3 involved nodes have a significantly better survival than those with 4 or more involved nodes. On the basis of a series of American experiences, and in line with the Consensus Conference sponsored by USA National Institute of Health, radiotherapy combined with chemotherapy for patients with stage II and III postoperative was recommended on a type 1 level of evidence (NIH 1990).

Currently preoperative chemoradiotherapy is considered treatment of choice for stage IIb/III rectal cancer. Radiotherapy is delivered at high-dose: 45-55 Gy in 4-6 weeks.

Preoperative approaches in rectal cancers have the same object of controlling micrometastases as postoperative strategies in resectable cases and of permitting radical excision with potential sphincter-preservation in fixed tumours. High dose short duration preoperative radiotherapy as described by the Swedish Rectal Cancer Group has confirmed the reduction in local recurrence rates previously obtained by postoperative radiation and showed a significant improvement in overall survival with the disadvantage of more chronic intestinal dysfunction; therefore, it is suitable for individual clinical use on a type 2 level of evidence (SRCT 1997). Currently no other experiences with preoperative irradiation alone have reproduced these favourable results on survival. Recently capecitabine, an oral 5-FU prodrug, demonstrated similar activity compared to protracted infusion 5-FU in clinical trial in metastatic setting and was investigated in a series of studies in the preoperative setting (Sawada 1999). A recent trial compared preoperative capecitabine to continuous infusion 5-fluorouracil in combination with radiotherapy: more favorable results was obtained by capecitabine due to its reduced toxicity and higher down-staging rates (Glynne-Jones 2006). The addition of oxaliplatin to 5-FU confers a significant clinical benefit in metastatic disease and was well tolerated when of administered concomitantly to radiotherapy in locally advanced rectal cancer. Its role in adjuvant setting is approved for stage III colon cancer but is under investigation in case of rectal cancer. The combination of oxaliplatin and capecitabine has shown significant anti-tumor activity in a similar range of combinations of oxaliplatin and leucoverin-modulated 5-fluorouracil (Cassidy 2004). In addition twice-daily dosing of oral capecitabine obviates the drawbacks of prolonged infusions of 5-fluorouracil and makes therapy more convenient for patients. For those reasons, the integration of capecitabine and oxaliplatin in concomitant administration with radiation has been extensively evaluated in patients with locally advanced rectal cancer in clinical trials (Glynne-Jones 2006; Machiels 2005; Chau 2006). It is anticipated that capecitabine will replace FU/LV in combination with radiotherapy in the treatment of rectal cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is evaluating neo-adjuvant,capecitabine-based chemoradiation in a randomized, phase III trial (NSABP R-04). A recent phase I-II trial has demonstrated that preoperative capecitabine plus oxaliplatin (XELOX) combined to radioterapy is a feasible and well tolerated treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based therapy with XELOX chemoradiotherapy (Rodel 2003). Other combinations with capecitabine plus irinotecan or bevacizumab or plus targeted agents are under investigation.

6.5 Stage IV rectal cancer

Standard treatment options are:
1. Surgical resection/anastomosis or bypass of obstructing lesions in selected cases.
2. Surgical resection 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. Palliative chemotherapy and 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. Stage IV colon cancer denotes distant metastatic disease. The most frequent site of metastases is liver. 15-25% of patients present liver metastases at diagnosis and 45-50% of patients develop liver metastases at different intervals of their clinical history. 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. Evidence suggests that resection of limited hepatic metastases may enhance survival in some patients if resection results in no clinically apparent residual tumour (Pedersen 1994; Scheele 1990; Scheele 1991; Steele 1991). For patients with limited (3 4 or less) hepatic metastases, resection may be considered with 5-year survival rates of 20% to 40% on a type 3 level of evidence (Fong 1997; Fong 1999; Hamady 2006; Harmon 1999; Pawlik 2005; Pedersen 1994; Scheele 1990; Scheele 1991; Steele 1991). 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 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 2006). Such as for liver metastases, in recent years aggressive surgical resection of lung metastases has become increasingly common with the recognition that this offers the best chance of long-term cure. Some series of cases reported a favourable outcome in selected patient, with 5-year survival rate ranging from 27 to 40.5% (Girard 1996; McAfee 1992; Okumura 1996; Pfannschmidt 2003; Saito 2002; Vogelsang 2004). Limited pulmonary metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients (Girard 1996; McAfee 1992). The benefit from additional systemic therapy after potentially curative resection of colorectal metastases has never been demonstred, 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 suspendend 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 randomized 129 patients to receive chemotherapy after liver or lung metastasectomy versus chemotherapy at progressive disease. Only a trend in disease free-survival was reported in this study 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 an 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). At the ASCO 2006 has been reported a pooled analysis based on individual data from these two trials. The meta-analysis showed an improvement in median progression free-survival statistically significant for patients receiving postoperative chemotherapy versus patients receiving surgery alone. No differences statistically significant in median overall survival were reported. Since about 60% recurrences after hepatic metastases resection are seen in the residual liver, seemed to be rationale the use of regional hepatic arterial infusion chemotherapy. 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. Results of a large phase III trial (EORTC 40983 study), evaluating the benefit of peri-operative FOLFOX4 chemotherapy in patients with resectable liver metastases, were reported at the ASCO 2007 meeting: completely resected patients in chemotherapy arm showed an improvement in progression free-survival in comparison to patients in the surgery alone arm (Nordlinger 2007). Data are too early to determine whether these more effective strategy may provide also improvement in survival. 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. 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). 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 (Chang 1987; Kemeny 1987; Kemeny 1993; MAGC 1996; Rougier 1992; Wagman 1990). Several studies show increased local toxicity, including liver function abnormalities and fatal biliary sclerosis. The use of the combination of intraarterial 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. In stage IV colon cancer, chemotherapy has been used for palliation, with 5-FU-based treatment considered as standard. In Europe as well as in the US infusional 5-FU/LV is now considered the best choice. 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 at least active as bolus 5-FU. Several controlled trials have compared directly capecitabine with 5-FU; 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 2000a). The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumour progression, and overall survival for the combination schedule. The combination treatment showed highly significant benefit (confirmed responses in 39% of patients, compared with 21% in patients treated with 5-FU and leucovorin alone and 18% in patients treated with CPT-11). In addition, time-to-tumour progression was significantly prolonged with the combination (7.0 versus 4.3 months, P=.004). Median survival was also improved with the combination (14.8 months for patients on the combination arm and 12.6 months for patients on the 5-FU and leucovorin arm, p=0.042). 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. In this trial there was also improvement in response rate, time-to-tumour progression, and median survival. For the most important endpoint, median survival, the combination arm was associated with a median survival of 17.4 months, compared with 14.1 months for the 5-FU and folinic acid arm (P=0.032). Combined analysis of pooled data confirmed the activity of this combination (Saltz 2000b). 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 (Köhne 2005). Because the important gastrointestinal toxicity related to CPT-11 administration, in the most of studies dose reductions were required. Oxaliplatin, a new platinum derivative, 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 (Andre 1999; Bleiberg 1998; Cvitkovic 1999; de Gramont 1997; Giacchetti 2000). 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). This could be related to the use of different ways of 5-FU administration (continuous and bolus) and differences in second-line treatment, rather than different efficacy between CPT-11 and oxaliplatin. 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. The majority of deaths in both studies were observed in the first 60 days, usually during the first chemotherapy cycle. 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 preffered 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’s. 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). Therefore, combination chemotherapy with 5-FU/LV/irinotecan or 5-FU/LV/oxaliplatin are considered standard option for patients with stage IV disease, on a type 1 level of evidence. 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 sequencial exposure to regimens that included the three key drugs. Treating patients sequentially with FOLFIRI followed by FOLFOX, or the inversal, 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 (Seymour 2005). In contrast the results of a Dutch study that 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 perfomed to answer this question, in attempt to reduce duration of treatment and, consequently, incidence of cumulative toxicities, but preserving efficacy such as in continuous 2 trials were initiated to try to limit the problem?chemotherapy. The OPTIMOX1 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. Median survival times were comparable in two arms of treatment and overall rates of any grade of neurotoxicity were approximately equal (Tournigard 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 mon ths in OPTIMOX2 arm (p=.05). The autors concluded that a combination free-interval can be recommended only in selected patients without adverse prognostic factor (Maindrault-Gœbel 2007). Different results were reported in a 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: 16.9 months for the intermittent arm versus 17.6 months for the continuous therapy arm arm (Labianca 2006). This strategy appear reasoneable for patients with “good” tumor biology. The oral 5-FU prodrugs such as capecitabine and UFT/leucovorin mimic infusional 5-FU and may replace infusional 5-FU/LV in the near future. Capecitabine, as mentioned above, provides identical survival but less toxic effects compared with bolus 5-FU/LV. 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 a AIO trial (Arkenau 2005). Another international phase III trial (NO16966) was performerd to demostrate 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 as effective as 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 occurence of 8 treatment related deaths in the capecitabine/irinotecan arm (Aust 2006). Therefore the combination of CPT-11 and capecitabine can not be recommended. 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 exact mechanism of action of bevacizumab in colorectal cancer remains unknown. The addition of bevacizumab to 5-FU/LV-based therapy suggested to prolong overall survival (Kabbinavar 2003); toxicities correlated with bevacizumab administration’s 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 pretreated 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 (pooled with XELOX or FOLFOX) significantly prolonged progression free survival compared with placebo and chemotherapy (9.3 months versus 8.0 months, p=0.0023) (Saltz 2007). Also 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 regimen, 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 single agents produced a 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. Overall survival 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 only relatively small phase II studies, but data from five trials suggest promising activity when cetuximab is combined with either irinotecan- or oxaliplatin-based chemotherapy (Folprecht 2004; Höler 2004; Rosenberg 2002; Rougier 2004; Van Cutsem 2004). 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. Further, the iperexpression of EGFR determinated by immunohistochemistry, seems not to correlate with response rate, time to progression or survival, and response to cetuximab were seen in patients identified as negative for EGFR (Scartozzi 2004; Chung 2005). 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); also response rate was significantly increased by cetuximab (46.9% versus 38.7%, p=0,005) (Van Cutsem 2007a). Another phase III trial comparing first-line FOLFOX plus cetuximab versus FOLFOX alone (COIN study) is ongoing. In addition, a current phase III trial by the Cancer and Leukemia Group B and Southwest Oncology Group (80405 study) is investigating the combination of cetuximab plus bevacizumab, versus each agent alone, as first-line treatment in combination with either FOLFOX or FOLFIRI chemotherapy. The association of bevacizumab and cetuximab, with or without irinotecan, has been already 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). Another monoclonal antibody against EFGR under evaluation in colorectal cancer and 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 are also data showing good activity first-line when panitumumab is added to IFL. Of 19 patients 47% had an 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 pretreated 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 2007b).

6.6 Surgical treatment of metastatic disease

There is now an increasing interest in the combination of neoadjuvant chemotherapy and surgery. Non-randomized studies have suggested a 40% 5-year survival in patients with non-resectable liver metastases that became resectable after chemotherapy (Adam 2000). It is likely that the benefit of the combined approach will be validated by randomized studies such as an ongoing EORTC Intergroup trial (40986). The separation of resectable and unresectable liver metastases may become obsolete with the emergence of a group of patients with “unresectable” metastases which become resectable after responding to chemotherapy.

6.6.1 Ablative therapies for liver lesions

Several ablative methods (cryoablation, alcohol ablation, radiofrequency ablation, embolization) are currently available for treating small liver lesions in cases where there are systemic contraindications to surgery, where there is bilobar involvement or in patients previously treated with surgery. Prognostic factors correlated with outcome of ablative treatments are similar to the variables associated with hepatic resection on a type 3 level of evidence: low CEA values, negative margins, negative involvement of regional lymph nodes at the primary site. They are standard on a type 3 level of evidence. These approaches are not curative and their role in colo-rectal metastases has to be evaluated in randomized trials compared with liver surgery and with different modalities of chemotherapy (Livraghi 1993; Morris 1993; Solbiati 1997). An example of such is study is EORTC 40004 or CLOCC trial that compares radiofrequency ablation plus chemotherapy with chemotherapy alone.

6.6.2 Chemotherapy after liver surgery

The role of systemic 5-FU-based chemotherapy administered after radical hepatic colorectal resection is a matter of current debate: 4 published studies have reported contradictory results (Butler 1986; Fortner 1984; Hughes 1988; Pagana 1986).
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 (Chang 1987; Kemeny 1987; Rougier 1992).
“Adjuvant” intra-arterial and intravenous chemotherapy is beneficial when administered postoperatively (Kemeny 2002), but to date insufficient evidence is available and randomized studies are encouraged.

6.6.3 Surgery of lung metastases

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 (McAfee 1992; Wilking 1985). 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. On multivariate analysis the disease free interval (> versus < 36 months) and number of metastases (single versus multiple) were significant independent prognostic factors (IRLM 1997).

6.6.4 Treatment of local recurrence

Recurrence after limited local therapy requires radical surgery that in 25-50% of cases represents salvage treatment (Pihl 1981; Suzuki 1996). Local relapse after radical resection may be treated with combined chemo-radiotherapy in selected patients who have not been previously treated with these approaches with the aim of performing adequate surgery (repeated anterior resection or an abdomino-perineal resection). The role of regional chemotherapy in combination with hyperthermia or intraoperative radiotherapy are under evaluation in clinical trials. However, local failure after radical resection is often associated with distant tumour spread and the disease is so not curable. Palliative treatments include wide local excision, local radiotherapy, or photodynamic therapy; each has a different impact on quality of life.

6.7 Chemotherapy for metastatic disease

6.7.1 Chemotherapy for metastatic disease: Treatment vs Supportive Care

In general, patients with a large tumour bulk with several metastatic sites and an ECOG performance status of 2 or greater have a lower chance of response to chemotherapy. This makes attendance or supportive care as needed the recommended treatment choice for many of these patients. On the other hand, patients who are in a good general condition with a small tumour bulk, and who have not previously been exposed to chemotherapy, have response rates to modern chemotherapy of approximately 50%. For these patients, as long as there are no other factors that contraindicate treatment chemotherapy should be recommended for approximately 2 months and then their outcome must be evaluated. If the treatment is fairly well tolerated and there is at least a stabilization of the disease chemotherapy should be continued.br> The cases in-between the two conditions described are more difficult to manage and the approach must be individualized. If the patient is very old, his general condition is not so good or he doesn’t seek particular medical attention, it is reasonable to wait a month or two, check the rate of disease progression and withhold treatment until later in the course.
More debateable is the issue of treatment 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? Five Phase III studies addressed this issue (NHS 1997). The answer is that patients who are treated at diagnosis of metastatic disease with conventional 5-FU based-regimens live significantly longer (by 3-6 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 fit patients. In these patients chemotherapy is also indicated for second-, and in some cases third-, line therapy.

6.7.2 Chemotherapy for metastatic disease: Locoregional vs Systemic Treatment

It is well established that the hepatic arterial infusion of fluoropyrimidines produces a higher response rate than systemic administration. Randomised comparisons do not show consistent prolongation of survival. This treatment modality is controversial (Cohen 1996) and nowadays almost completely abandoned.

6.7.3 Chemotherapy for metastatic disease: suggested schedules

Standard systemic chemotherapy for advanced colorectal cancer is the use of combination therapy with oxaliplatin or CPT-11 on a type 1 level of evidence. Only in some cases can 5-FU/leucovorin 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. Biochemical modulation is also required when using intermittent high-dose infusional 5-FU (Schmoll 2000). The major distinctive features of each regimen are summarized below.

INFUSIONAL SCHEDULES

A. Protracted Continuous infusion 5-FU. Unmodulated 5-FU is effective if given by continuous infusion. The dose of 5-FU is 300 mg/sqm/day for prolonged periods of times (generally 1 cycle is made up of 8 weeks followed by a 2-week rest period). In general this regimen is less toxic than the previous ones. No myelosuppression is generally seen and diarrhoea is rare. Grade 3 mucositis however develops in approximately one fourth of the patients and hand foot syndrome in one third. The advantages of a different and milder toxicity is counterbalanced by the need of a 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 #5. 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 in 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. deGramont schedule (LV 5-FU2): 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 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.

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 “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.

B. Oxaliplatin 50 mg/sqm , leucovorin 500 mg/sqm 5-FU continuous infusion 24 hours 2000 mg/sqm days 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 also be used 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. Oral 5-FU prodrugs alone or in combination may play a role in the near future as part of chemo-radiotherapy or as chemotheraly alone on a type 2 level of evidence.

F. Avastin 5 mg/kg day 1 plus 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 also be used 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.

G. Cetuximab 250 mg/mq (400 mg/mq at first infusion) every weeks plus CPT11 100 mg/sqm or 180 mg/sqm every weeks or two weeks.

TARGET THERAPY

A. Avastin (bevacizumab): 5 mg/kg administered every two weeks in combination with folinic acid and infusional fluorouracil or irinotecan combinations.

B. Cetuximab: 400mg/sqm in 120’ at first dose, then 250 mg/sqm at subsequent doses in 60’ in combination with irinotecan.

6.7.4 Chemotherapy and Quality of Life
The subjective response rate to biochemically modulated 5-FU in 10 randomized trials on 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 recent large randomized trials have addressed the issue of quality of life. The comparisons have been made between modulated 5-FU and either unmodulated 5-FU or best supportive care. Both comparisons have favoured the patients treated with one of the regimens mentioned in the previous section.
We can thus conclude that even if overall response rate to standard chemotherapeutic regimens is low in unselected patients with advanced colorectal cancer, the subjective benefit is substantial.

6.8 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 for these cases and treatment must be balanced against the patient’s general condition, life expectancy, toxicity of the therapy, entity of symptoms, presence of alternative therapies, etc (Montague 1995). Often, few, large fractions can be administered in patients with short life expectancy because 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 effects and sequelae related to radiotherapy

About 10-20% of patients exhibit chronic treatment-related symptoms after radiotherapy to the pelvis. Radiotherapy induces more sequelae if large treatment volumes or high daily doses (> 2Gy) are given, and if additional, parallel chemotherapy is administered. Injury to the small intestines is the most serious sequela, including intestinal obstruction, chronic diarrhoea and fistulae. These patients have a poor quality of life and often have to undergo several surgical interventions. Anorectal and bladder dysfunction are occasionally observed because of radiation injury to the sacral nerve plexus or spinal nerves. Chronic pelvic pain may develop about one year after radiotherapy because of multiple microfractures in sacral bowel. Pain lasts for 1-2 years until it spontaneously regresses.

8. FOLLOW-UP

8.1 Objectives and frequency of post surgical follow up

There is no doubt that routine follow-up of patients treated for colorectal cancer is both time consuming and expensive. Most patients enjoy regular contact with the medical team and this has supportive benefits which should not be underestimated. Earlier recognition of recurrence, however, did not produce improved survival: 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

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 programme (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; Lautenbach 1994).

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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

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

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

Dr. Maria Giulia Zampino (Author)
European Institute of Oncology – Milan, Italy
mail: maria.zampino@ieo.it