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Clinical Diagnosis and
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Edited by
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Clinical Diagnosis and Therapy of
Colorectal Cancer
Edited by: Ralph Schneider
ISBN: 978-1-63278-054-6
DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
Published Date: September, 2015
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Preface
Colorectal Cancer (CRC), the most common malignancy in Europe, results as an interaction
of genetic and environmental factors. Three risk categories are known: sporadic, familial,
and hereditary.
Sporadic CRC originate from acquired somatic mutations over time, are associated with older
age and account for approximately 70% of all CRC. Familial CRC are based on polymorphisms
and low penetrance susceptibility loci combined with environmental factors and account for
approximately 20–30% of all CRC. Hereditary CRC account for approximately 5% of all CRC
and are characterized by inherited, highly penetrant mutations.
In this eBook we explain all interesting points of colorectal cancer. We focus on epidemiological
facts, risk factors for the development of CRC, the therapy of colon and rectal cancer but
also on the therapy of metastases. Additionally hereditary tumor syndromes are explained.
In this book you will find all facts you should know about CRC.
Thank You,
Ralph Schneider
II
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About Editor
PD Dr. Ralph Schneider is surgeon at the Center for Hereditary Tumor Syndromes“at the
HELIOS Klinikum Wuppertal in Germany, which is the University hospital of the University
Witten/Herdecke. His main clinical and research interests are hereditary tumor syndromes
like FAP, Lynch syndrome or Peutz-Jeghers-syndrome. Within the last years he published
several original papers and review in the field.
PD Dr. Schneider studied medicine at the University of Regensburg and worked at the
Military Hospital in Koblenz and at the Philipp’s University of Marburg. Since2014 he
works together with Professor Gabriela Möslein - one of the leading scientists in the field of
hereditary cancer worldwide.
III
eBooks
Acknowledgement
I like to thank all authors and co-authors who have written a chapter for this eBook for
the time and dedication. It is important to know as much as possible about CRC to initiate
an optimal treatment. I am sure, that many patients with CRC worldwide will profit from
this book.
I also like to thank all contributors of OMICS who were involved in the preparation of this
book.
IV
eBooks
Sl no
Chapter title
1
Colorectal Cancer Epidemiology
2
Colorectal Cancer: Risk Factors and Prevention, Detection of
Colorectal Cancer
3
Hereditary Colorectal Cancer Syndromes
4
Treatment of Colorectal Cancer Liver Metastases: Clinical and
Molecular Aspects
5
Treatment of Rectal Cancer
6
Familial colorectal cancer type X (FCCX)
7
Treatment of Colon Cancer
8
Treatment of colorectal cancer
Pulmonary Metastas
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eBooks
ISBN: 978-1-63278-054-6
DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
Chapter 1
Colorectal Cancer Epidemiology
Pedro J. Tarraga Lopez1*, Juan Solera Albero2 and Jose Antonio
Rodriguez Montes3
Pedro J Tarraga Lopez, Medical Director Integrated Management Universitario
Albacete, Spain-Associate Professor Medicine, UCLM, Spain
2
juan Solera Albero, Medical Coordinator EAP Albacete, Spain
3
jose Antonio Rodriguez Montes, Professor of Surgery UAM. Head Surgery
Department University Hospital of La Paz Madrid, Spain
1
*
Corresponding author: Pedro J. Tarraga Lopez, Medical Director Integrated
Management Universitario Albacete, Spain-Associate Professor Medicine, UCLM,
Spain, E-mail: [email protected]; Telephone: 91 7277197; Fax: 91 2071064
Colorectal Cancer: Descriptive Epidemiology and Mortality
Cancer is a worldwide full-scale problem as it will affect one in three men and one in four
women during their lifetime [1]. Nowadays, cancer represents one in eight deaths around
the world. The global cancer rate has doubled in the last 30 years of the 20th century, and
will almost triple by 2030, a year in which it is foreseen that 20.3 million people will be
diagnosed cancer and 13.2 million will die as a result of this disease [2].
Colorectal Cancer (CRC) is the third most frequent cancer in men, after lung and
prostate cancer, and is the second most frequent cancer in women after breast cancer. It
is also the third cause of death in men and women respectively, and is the second most
frequent cause of death by cancer if both genders are considered together. CRC represents
approximately 10% of deaths by cancer. The incidence of CRC is low up to the age of 45-50
years, but progressively increases with age, and men are at more risk than women. In the
USA, 135.260 people were diagnosed with CRC in 2011; of these, 70.099 were men and
65.161 were women, and it has been estimated that 142,820 adults will be diagnosed with
CRC in 2013. These figures include 102,480 new cases of colon cancer and 40,340 new
cases of rectal cancer [3]. In 2011, 51.783 people died from CRC, of whom 26.804 were
men and 24.979 were women, and it is calculated that there will be 50,830 deaths by this
pathology in 2013 (26,300 men and 24,530 women)[3]. In Europe, CRC is the second most
common cause of death from all cancer types in both men and women. In 2012, 447,000
new cases of CRC causing 215,000 deaths were estimated [4] (Table 1).
Around the world, especially in more industrialised countries, high CRC rates continue,
whereas they are lower in Eastern Europe, Asia, Africa and South America. In 2008, the
highest incidence rates were found in Australia and New Zealand, Europe and North
America, whereas the lowest incidence rates were recorded in Africa and Central Asia;
CRC rates were also markedly higher in men than in women [5]. The incidence of CRC
has increased in several geographical areas where its incidence has been traditionally low:
Spain (29,000 new cases every year), and countries of East Asia and Central and East
Europe [6­,7] Slovakia (92 cases per 100.000), Hungary (87 cases) and the Czech Republic
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
1
(81 cases) in men, and in Norway (54 cases), Denmark (53 cases) and Holland (50 cases)
in women, with lower rates in the Balkan countries of Bosnia and Herzegovina (30 cases
in men, 19 cases in women), Greece (25 and 17 cases, respectively) and Albania (13 and
11 cases, respectively). Mortality partly follows the geography of incidence, but is also high
in some countries with a relatively low incidence (Moldavia, Russia, Montenegro, Poland
and Lithuania) [4]. Interestingly, the rates found for women from the Czech Republic and
Japan have exceeded the incidence peak observed in the USA, Canada and Australia, where
these rates are diminishing or becoming stable [6,7]. This unfavourable trend reflects a
combination of factors, which include changes in diet, obesity and heavier smoking [7,8].
The USA is the only country where the incidence of CRC has lowered significantly in both
men and women during the 1975-2006 [9] period, due to the beneficial effect of early diagnosis
and exeresis of precancerous lesions by CRC screening [7,9]. Although CRC mortality rates have
lowered in several western countries thanks to improved treatments and early detection, rates
continue to increase in other countries with fewer economic resources and limited healthcare
infrastructures, particularly in South and Central America, and East Europe.
Modifiable risk factors of CRC include smoking habit, physical inactivity, being overweight
and obesity, eating processed meat and drinking alcohol excessively [10-12]. Studies done
on Japanese immigrants in the USA, Asian Jewish immigrants to Israel and East European
immigrants in Australia have revealed that they acquire the common CRC rates in the
country of their adoption [13]. There is no doubt whatsoever which environmental factors,
probably diet [14], may account for these cancer rates. Excessive alcohol consumption and
cholesterol-rich diet are associated with a high risk of colon cancer [15,16]. A diet poor
in folic acid, vitamin B6 and other vitamins like E, specially D and even A, C or K2 is also
associated with a higher risk of developing colon cancer with an overexpression of p53 [17]
related bcl-2 family proteins activity (regulation of apoptosis). Eating pulses at least 3 times
a week lowers the risk of developing colon cancer by 33%, after eating less meat, while
eating brown rice at least once a week cuts the risk of CRC by 40%. These associations
suggest a dose-response effect. Frequently dairyproducts has been associated with a lower
risk of colorectal polyps [18]. High calcium intake offers a protective effect against distal
colon and rectal tumours as compared with the proximal colon. Higher intake of dairy
products and calcium reduces the risk of colon cancer [19]. Taking an aspirin regularly after
being diagnosed with colon cancer is associated with less risk of dying from this cancer,
especially among people who have tumours with COX-2 overexpression [20]. Nonetheless,
these data do not contradict the data obtained on a possible genetic predisposition, even in
sporadic or non-hereditary CRC.
CRC screening programmes are possible only in economically developed countries. However,
attention should be paid in the future to those geographical areas with ageing populations and
a western lifestyle [21,22]. Sigmoidoscopy screening done with people aged 55-64 years has
been demonstrated to reduce the incidence of CRC by 33% and mortality by CRC by 43% [23].
Screening programs with colonoscopy, FOB tests or tumor M2-PK test, which are easy to use
by patients, are also demostrated to incease detectability of CRC. Moreover, virtual colonoscopy
or capsules with camera are effective in decreasing mortality by CRC.
The vast majority of CRCs are sporadic and the rest occur in patients who are considered
to be at high risk. Some patients are predisposed to develop CRC, including patients with
hereditary afflictions, such as Familial Adenomatous Polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and ulcerative colitis [24]. The presence of polyps
considerably increases the risk of CRC (generally 2,5 polyps/1000 ones wich ungergo
malignant transformation), which depends on the size, histology and degree of dysplasia;
almost half of polyps of >2 cm present malignant degeneration, while 5% of tubular
adenomas become malignant as opposed to 40% of the villous types and 20% of those
with mixed forms. FAP patients have an almost 100% risk of developing CRC. Ulcerative
colitis and Crohn’s disease also raise the risk of CRC, with a risk of between 5 and 11 times
2
higher than the general population for the former, and of 20 times higher for the latter.
Approximately 20-30% of CRCs occur among the patient’s first-degree family members;
indeed several studies have demonstrated the high risk that first-degree family members of
patients diagnosed with CRC and adenomas have [25-27]. Between 5% and 10% of CRCs
occur in people with genetic syndromes, such as FAP and the syndromes of Gardner, Turcot
and Lynch. Furthermore, radiotherapy, former abdominal surgery and having a personal
medical background of CRC can also increase the frequency of CRC. Patients with PeutzJegher syndrome or juvenile polyposis coli are not at a particularly high risk of CRC [24].
Occupational exposure to asbestos triples the risk of colon cancer if compared to the rest of
the general population.
Being diagnosed with colon cancer is almost 3 times more frequent than rectal cancer.
Total incidence and colon cancer mortality rates have lowered in both men and women
since the mid-1980s [28], unlike previous decades. This lower mortality rate is probably
due to the better treatments currently available and diagnosis being made generally earlier
as survival depends basically on tumour stage at time of diagnosis. Notwithstanding, the
accumulated risk during one’s lifetime of developing colon cancer in the USA is 5.1%, and
this risk is lower in women than in men. However it is 3.5%, for example, in Spain. The
possibility of developing this disease clearly increases with age. In the USA, 1.40% of men
who are now 60 years of age will contract CRC at some time over the next 10 years; this
means that 1 or 2 per 100 men who are now 60 years of age will develop CRC by the
time they are 70. Save some hereditary forms, onset of this disease before the age of 40
is not a frequent occurrence, so it is advisable to start screening in people as of 50 years.
When CRC is diagnosed, the disease is localised in 37% of patients, 37% have CRC with
regional extension, 20% present distance metastasis and 6% have not been staged. The 5
year survival rate for local, regional and distance neoplastic colon disease is 90%, 70% and
12%, respectively [29]. Thus early colon cancer diagnosis is important as it offers a high
cure rate (60%) when localised in the intestine alone. However in patients with only one or
some tumours that have disseminated from the colon to lungs or liver, the surgical removal
of these tumours can eliminate the cancer, which notably improves survival rates.
Care must be taken when interpreting CRC survival statistics because estimations are
based on data that originate from thousands of people with this cancer type in only the USA
each year for instance, while a given individual’s actual risk can vary. It is impossible to tell
people how long they will live with CRC. As survival statistics measure in 5 year intervals,
it is quite possible that they do not represent the advances made in treating or diagnosing
this cancer type [3].
References
1. Siegel R, Ward E, Brawley O, Jemal (2011) A: Cancer statistics,The impact of eliminating socioeconomic and
racial disparities on premature cancer deaths. CA Cancer J Clinic 61: 212-236.
2. Bray F, Jemal A, Grey N, Ferlay J, Forman D et al.(2012) Global cancer transition according to the Human
Development Index (2008-2030): a population-based study. Lancet Oncol 13: 790-781.
3. American Cancer Society. Cancer Facts & Figures, (2013) Atlanta. Ga. American Cancer Society 2013.
Available on line. Last accessed 1: 1-64.
4. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coeberg JWW, et al. (2013) Cancer incidence and
mortality patterns in Europe: Estimated for 40 countries in 2012. European J Cancer 49:1374-1403.
5. Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al.(2011) Forman D: Global cancer statistics. CA Cancer J
Clin 61:69-90.
6. Center MM, Jemal A (2009) Ward E: International trends in colorectal cancer incidence rates. Cancer Epidemiol
Biomarkers Prev 18: 1688-1694.
7. Center MM, Jemal A, Smith RA, Ward E et al (2009) Ward E: Worldwide variatios in colorectal cancer. CA
Cancer J Clin 59:366-378.
3
8. Boffetta P, Hazelton WD, Chen Y, Sinha R, Inoue M, et al (2012) Body mass, tobacco smoking, alcohol
drinkings and risk of cancer of the small intestine-a pooled analysis of over 500.000 subjects in the Asia Cohort
Consortium. Ann Oncol 23: 1894-1898.
9. Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, et al. (2010) Annual Report to the nation on the status
of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening,
and treatment) to reduce future rates. Cancer 116: 544-573.
10. Ferrari P, Jenab M, Novat T, Moskal A, Slimani N, et al. (2007) Lifetime and baseline alcohol intake and risk
of colon and rectal cancer in the European prospective investigations into cancer and nutrition (EPIC). Int J
Cancer 121: 2065-2072.
11. Boyle P, Levin B eds (2008) World Cancer Report Lyon, France. World Health Organization. International
Agency for Research on Cancer.
12. Center MM, Jemal A, Ward E (2009) Ward E: International trends in colorectal cancer incidence rates. Cancer
Epidemiology Biomarkers Prev 18: 1688-1694.
13. Posner M, Steeke G, Mayer R: Adenocarcinoma del colon y del recto. Cirugía del Aparato Digestivo. Madrid.
Editorial Panamericana 2005:251.
14. Vargas AJ, Thompson PA (2012) Diet and nutrient factors in colorectal cancer risk. Nutr Clin Pract 27: 613-623.
15. Su L J, Arab L (2004) Alcohol consumption and risk of colon cancer: evidence from the National Health and
Nutrition Examination Survey I Epidemiologic Follow-up study. Nutr Cancer 50: 111-119.
16. Hu J, La Vecchia C, de Groh M, Negri E, Morrison H, et al. (2012) Dietary cholesterol intake and cancer. Ann
Oncol 23: 491-500.
17. Schernhamer ES, Ogino S (2008) Fuch CS: Folate and vitamin B6 intake and risk of colon cancer in relation
to p53 expression. Gastroenterology 135:770-780.
18. Tantamango YM, Knutsen SF, Beeson WL, Fraser G, Sabate J (2011) Foods and food groups associated with
the incidence of colorectal polyps: the Adventist Health Study. Nutr Cancer 63: 565-572.
19. Huncharek M, Muscat J, Kupelnick B (2009) Colorectal cancer risk and dietary intake of calcium, vitamin D,
and dairy products: a meta-analysis of 26.335 cases from 60 observational studies. Nutr Cancer 61: 47-69.
20. Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Wu K, et al.(2008) Aspirin dose and duration of
use and risk of colorectal cancer in men. Gastroenterology 134: 21-28.
21. Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, et al. (1993) Reducing mortality from colorectal
cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 328: 13651371.
22. Muller AD, Sonnenberg A (1995) Preventioon of colorectal cancer by flexible endoscopy and polypectomy. A
case-control study of 32.702 veterans. Ann Intern Med 123: 904-910.
23. Atkin Ws, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, et al. (2010) UK Flexible Sigmoidoscopy Trial
Investigators, Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre
randomized controlled trial. Lancet 375: 1624-1633.
24. Weitz J, Koch M, Debus J, Hôhler T, Gall PR (2005): Colorectal cancer. Lancet 365: 153-165.
25. Winawer SJ, Zauber AG, Verdes H, O´Brien MJ, Gottlieb LS, et al. (1996) Risk of colorectal cancer in the
families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med 334: 82-87.
26. Johns LE, Houlston RS (2001) A systematic review and meta-analysis of familial colorectal cancer risk. Am J
Gastroenterol 96: 2992-3003.
27. Lynch KL, Ahnen DJ, Byers T, Weiss DG, Lieberman DA, et al. (2003) First-degree relatives of patients with
advanced colorectal adenomas have an increased prevalence of colorectal cancer. Clinical Gastroenterology
& Hepatology 1: 96-102.
28. Wingo PA, Jamison PM, Hiatt RA, Weir HK, Gargiullo PM, Hutton M, et al. (2003) Building the infrastructure for
nationwide cancer surveillance and control-a comparison between the National Program of Cancer Registries
(NPGR) and the Survelillance, Epidemiology, and End Results (SEER) Program (United States). Cancer
Causes Control 14: 175-193.
29. Feig B, Berger D, Furham G: Oncología quirúrgica. Madrid. Editorial Marbán Libros SL, 2005:212.
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DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
Chapter 2
Colorectal Cancer: Risk Factors and Prevention,
Detection of Colorectal Cancer
Pedro J. Tarraga Lopez1*, Juan Solera Albero2 and Jose Antonio
Rodriguez Montes3
Pedro J Tarraga Lopez, Medical Director Integrated Management Universitario
Albacete, Spain-Associate Professor Medicine, UCLM, Spain
2
juan Solera Albero, Medical Coordinator EAP Albacete, Spain
3
jose Antonio Rodriguez Montes, Professor of Surgery UAM. Head Surgery
Department University Hospital of La Paz Madrid, Spain
1
*
Corresponding author: Pedro J. Tarraga Lopez, Medical Director Integrated
Management Universitario Albacete, Spain-Associate Professor Medicine, UCLM,
Spain, E-mail: [email protected]; Telephone: 91 7277197; Fax: 91 2071064
Colorectal Cancer: Risk Factors and Prevention
Epidemiology studies, especially chose of time trends and migrations studies, confirm the
importance of envirommental factors in the etiology of colorectal cancer. Thus, corrections
of these may reduce its incidence. These factors can be studied by the descompositional
approach by looking at specific nutrients or by the integrative approach by considering
the effects of whole foods or dietary patterns. Because colorectal cancer is a relatively rare
disease, intervention studies with cancer endpoints require large numbers of participans
folowed for many years. Therefore, other surrogate markers, such as measurements of
epithelial proliferations (intermediate biomarkers) or adenoma recurrence, have been used.
Although the validity of cell proliferation endpoints is unclear at present, strong inferences
to colorectal cancer are reasonably made from results of adenoma recurrence trials. Results
from such adenoma trials are reviewed in this chapter. To date, these are only limited
evidence that dietary modification can influence colorectal neoplasia. A number of larger
adenoma recurrences now being carried out in several countries should yield more definitive
informations on the relations of dietary change to colorectal neoplasia.
Many factors may influence the appearance of CRC. Although it is not possible to
accurately determine the exact foods or nutrients that are the main causes of it, we can take
an approach, and even offer a list of these factors which, according to studies, influence
CRC:
-High fat content in food
-High calorie intake
-High raw meat intake
-Very low fibre intake
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
5
-Very little vitamin C
-Low calcium content
-Low selenium content
-High alcohol content and smokers
-Very little salt, among others.
Macronutrients
An excessive intake of the various macronutrients making up a diet can increase the
risk of CRC. Nonetheless, there are studies which present limitations because isolating
different diet components is not easy. The food type that independently contributes to the
risk of CRC, or whether there is a relation between it and excessive dietary intake of several
macronutrients, is also unknown [1-3].
Fats
Observational studies offer contradictory results of the effect that a low-fat diet has on
the risk of CRC. The Randomised Clinical Trial (RCT) of the Women’s Health Initiative (WHI)
(48,835 postmenopausal women aged 50-75 years, selected between 1993 and 1998) does
not reveal that low-fat diet cuts the risk of CRC after an 8-year follow-up [3].
In an at-risk population, the ECA Polyp Prevention RCT (2,079 men and women aged
over 35 years with a background of colorectal adenomas) does not reveal that low-fat, highfibre diet with fruit and vegetables modifies the recurrence rate of colorectal adenomas
after an 8 year follow-up (relative risk (RR)=0.98; 95% Confidence Interval (CI): 0.881.09). Nevertheless, the study design does not definitely conclude that changes in diet are
ineffective to lower the risk of CRC [3].
Meat
Observational studies present contradictory results on the effect of red meat as a factor
of CRC. However, several meta-analyses reveal that eating red meat and processed meat can
increase the risk of CRC [4-7].
The most recent review done, which included 15 cohort studies on eating red meat
(7,367 cases) and 14 observational studies on consuming processed meat (7,903 cases)
published up to 2006 show an RR of 1.28 (95% CI:1.15-1.42) for red meat and an RR of 1.20
(95% CI: 1.11-1.31) for processed meat [7].
Another review demonstrates a higher association with processed meat than with red
meat. Eating red and processed meats is positively associated with a high risk of developing
colon and rectal cancer. However, the association with red meat is higher for rectal cancer
[7].
Several pyrolysis products, such as heterocyclic amines, aromatic polycyclic
carbohydrates and nitro compounds, which form when meat is very well-done or come
into direct contact with flames, can increase the risk of CRC, especially in people who
are genetically predisposed to transform these components into more active intermediate
products. Genetic predisposition can also influence the risk associated with eating red or
processed meat [7].
Fibre, Vegetables and Fruit
Several studies conducted with cases and controls show an inverse association between
6
fibre intake and the risk of CRC, which most studies do not confirm. The result obtained in
a systematic review, which included 13 prospective studies (725,628 men and women) and
follow-ups of between 6 and 20 years, reveals that fibre intake is inversely associated with
the risk of CRC according to an analysis adjusted for age (RR=0.84; 95% CI: 0.77-0.92).
However, this protective effect disappears when other diet-related risk factors are taken into
account (RR=0.94; 95% CI: 0.86-1.03). Nonetheless, the prospective study done in the NIHAARP Diet and Health Study reveals that total dietary fibre is not associated with a change
in the risk of CRC, but with a slight reduction in this risk with cereals [8].
The result that a meta-analysis obtained, which included 14 prospective studies
(756,217 men and women) and with follow-ups lasting 6-20 years, shows that eating fruit
and vegetables is associated with a non-significant reduction in the risk of CRC: fruit and
vegetables (RR=0.91; 95% CI: 0.82-1.01), fruit (RR=0.93; 95% CI: 0.85- 1.02) and vegetables
(RR=0.94; 95% CI: 0.86-1.02) 24. Notwithstanding, when the analysis was done by taking
tumour location into account, eating fruit and vegetables is significantly associated with
a reduced risk of distal cancer (RR=0.74; 95% CI: 0.57-0.95), but not of proximal cancer
(RR=1.02; 95% CI: 0.82-1.27) [9].
In a high-risk population of a Cochrane review, which evaluated the effect of dietary fibre
on the incidence or recurrence of colorectal adenomas and the incidence of CRC (including
5 RCTs and 4,349 cases), greater dietary fibre intake does not lower the incidence or the
recurrence of adenomatous polyps over a period lasting 2-4 years (RR=1.04; 95% CI: 0.951.13) [10].
As mentioned earlier, the Polyp Prevention Trial does not demonstrate that low-fat; highfibre diet with fruit and vegetables modifies the recurrence of colorectal adenomas [11].
The combined analysis of the Wheat BranFiber Trial and the Polyp Prevention Trial reveals
that this risk lowers significantly among men (RR=0.81; 95% CI: 0.67-0.98), but not among
women [12-16].
Milk and Other Dairy Products
Case-control studies do not show that milk and dairy products protect against the risk of
CRC, although cohort studies do [16,17]. The result of a systematic review, which included
10 prospective studies (534,536 cases), shows a protector effect for consumption that
exceeds 250 g/day (RR=0.86; 95% CI: 0.78-0.94), but in relation only to neoplasias located
in the distal colon [17].
Micronutrients
Several studies have evaluated the effect of administering folate, calcium and vitamin D
supplements, among others, to prevent CRC.
Folate Acid
The potencial of folic acid as a chemopreventive agent is suggested by its importance
in maintaining normal cellular methylation levels and in gene expression, as well as
epidemiologic evidence associating folate deficiency with carcinogenesis.
The epidemiologic evidence of folic acid´s inhibition of colorectal adenomas and cancer
is more compelling. Inverse correlations of dietary folate intake to incidence of colorectal
adenoma was found in subjects from the Women´s Health Study and the Physicians study
who had undergone sigmoidoscopy or colonoscopy, as well as in a case-control study of 101
patients with colorectal adenomas and 242 controls. Also, the ocurrence of colonic neoplasm
was 2.5times greather in patients with ulcerative colitis who did not take supplemental
folate than in those who did.
7
The result of a systematic review, including seven prospective studies and nine casecontrol studies, shows that the association between folic acid intake in diet and CRC
(RR=0.75; 95% CI: 0.64-0.89) is stronger than dietary folic acid plus folic acid supplements
(RR=0.95; 95% CI: 0.81-1.11) [18].
In people with a previous history of adenoma, the United Kingdom Colorectal Adenoma
Prevention RCT does not reveal that administering folic acid supplements (0.5 mg/day)
amends the risk of recurrent adenoma (RR=1:07; 95% CI: 0.85-1.34) [19].
Similarly in the Aspirin/Folate Polyp Prevention Study RCT, administering folic acid
supplements (1 mg/day) does not reduce the risk of colorectal adenomas recurring
(RR=1.04; 95% CI: 0.90-1.20), and an increase in this risk was even detected in relation to
pre-neoplastic lesions after a 3-5 year follow-up [20].
Calcium
The result obtained with a systematic review including 10 prospective studies (534,536
cases) reveals a protector effect of dietary calcium consumption (RR=0.86; 95% CI: 0.780.95) and of dietary calcium intake plus supplements (RR=0.69; 95% CI: 0.69-0.88) [17].
Nonetheless, this review does not differentiate the independent effect of diet and calcium.
A preliminary analysis of the Women’s Health Initiative (WHI) RCT does not reveal that
calcium supplements cut the risk of CRC after a 7-year follow-up [2]. Yet a re-evaluation
of these data consistently shows an interaction with oestrogens, to the extent that calcium
modifies the effect on the relation with a risk of CRC depending on whether oestrogens are
administered concomitantly or not [18-20].
The Cochrane review, which included two TCTs (1,346 subjects), shows that in those
people with a history of adenomas, taking calcium supplements can have a protector effect
on the development of colorectal adenomas (RR=0.74; 95% CI:0.58-0.95) [18].
Vitamin D
Two meta-analysis of observational studies show that taking high vitamin D doses
(1,000-2,000 U/day) cuts the risk of CRC, but also indicate that taking low doses (200-400
U/day) may not suffice to appreciate such benefits, particularly if sun exposure is low[1922]. A preliminary analysis of the Women’s Health Initiative (WHI) RCT does not indicate
that vitamin D supplements reduce the risk of CRC after a 7 year follow-up period [22].
A re-evaluation of these data consistently shows an interaction with oestrogens, to the
extent that vitamin D amends the effect in relation to the CRC risk depending on whether
oestrogens were administered concomitantly or not [23].
Antioxidants
The results of a recently updated Cochrane review, which included 20 RCTs and 211,818
participants, shows that administering antioxidants, as compared to placebos, does not
modify the incidence of CRC (RR=0.91; 95% CI: 0.80-1.03). Similar results were obtained for
different antioxidants, administered either separately or combined, after a 2-12-year followup period: beta-carotenes (RR=1.09; 95% CI: 0.79-1.51), vitamin E (RR=1.10; 95%CI: 0.871.9), selenium (RR=0.8; 95% CI: 0.22-1.05), beta-carotene+vitamin A (RR=0.97; 95% CI:
0.76-1.25), beta-carotene+vitamin E (RR=1.20; 95%CI: 0.89-1.63), beta-carotene+vitamins
C and E (RR=0.84; 95%CI: 0.65-1.07), beta-carotene+vitamins C and E+selenium (RR=0.88;
95% CI: 0.49-1.58) [24].
The results of a recent meta-analysis, which included 11 cohort studies (702,647
participants with follow-up lasting 6-20 years, on carotenes also confirm that carotenes do
not modify the risk of CRC (RR=1.04; 95%CI: 0.84-1.00) [25].
8
The results of another meta-analysis indicate that antioxidants do not seem to have a
beneficial effect on preventing the recurrence of colorectal adenomas [26].
Others Factors
Several risk factors related with lifestyle and economic development in western countries
is associated with a higher incidence of CRC.
Physical, Activity, Obesity and Energy Balance
More than 50 observational studies estimate that regular physical exercise cuts the risk
of CRC by around 40%, independently of body mass index (BMI) l [27]. The level of activity,
intensity, frequency and duration of physical activity, and maintaining this activity over
time, seem to be associated with a greater reduction in this risk. The results of a systematic
review reveal a significant reduction in this risk in men as regards both occupational
(RR=0.79; 95% CI: 0.72-0.87) and recreational (RR=0.78; 95% CI: 0.68-0.91), activity, but
only for recreational activities in women (RR=0.71; 95% CI: 0.57-0.88) [28].
Cohort and case-control studies have shown an association between body fat content
and the risk of CRC41. The results of a meta-analysis, which included 23 cohort studies
and eight case-control studies, show that obesity, when comparing people with a BMI of >30
with those who have a BMI=20-25, presents a direct and independent association with the
risk of CRC, be it weaker than previously assumed (RR=1.19; 95%CI: 1.11-129). The risk
for men is higher (RR=1.41; 95% CI: 1.30-1.54) than for women (RR=1.08; 95% CI: 0.981.18) [29]. Three other meta-analyses confirm that the association between BMI and CRC
is higher in men [27-30]. The European Prospective Investigation into Cancer and Nutrition
Study shows the distribution of the waist-hip index and waste perimeter as indicators of
abdominal obesity, both associated with the risk of CRC in both genders [31]. Another metaanalysis confirms this association [32].
The consistency of the results obtained about diet, obesity, central obesity and physical
inactivity, and the risk of CRC, corroborates the hypothesis that high concentrations of
circulating insulin are a risk factor. In a meta-analysis of cohort studies, an excessive risk
of CRC is shown to be associated with high C-peptide, circulating insulin and blood sugar
marker values [33,34].
Alcohol
In a joint analysis of eight cohort studies, a positive association is revealed between
drinking alcohol and developing CRC [35], showing that the more alcohol drunk, the greater
the association. Alcohol intake of 30-45 g/day inplies a risk of 1.16 (95% CI: 0.99-1.36),
and a risk of 1.41 (95% CI: 1.16- 1.72) for >45 g/day. Nevertheless, it is important to point
out that the results of these studies are inconsistent due to their different study designs
and possible confounding factors (diet, gender). A more recent meta-analysis, based on data
from 16 cohort studies, alcohol intake is associated with both the risk of developing colon
cancer (RR=1.50; 95% CI: 1.25-1.79) and rectal cancer (RR=1.63; 95% CI: 1.35-1.97) [3639].
Smoking
In the various reviews that have been conducted [40,41] on studies done before the
1970s, no association is found between smoking and CRC. However, the more long-term
follow-up of some these studies (30 and 40 years) reveal an increased risk of CRC. The
results of a meta-analysis, which included [42] observational studies, unveils an association
between cigarette smoking and developing colorectal adenomas, with differentiated risks for
9
active smokers (RR=2.14; 95% CI: 1.86-2.46), former smokers (RR=1.47; 95% CI: 1.29-1.67)
and occasional smokers (RR=1.82; 95% CI: 1.55-2.01) [43]. Some recent studies show that
active smokers are at higher risk of rectal cancer (RR=1.95; 95% CI: 1.10-3.47), but not for
colon cancer [44].
Evidence of Chemoprevention
Several case-control and cohort studies, and phase II/III RCTs have been done to evaluate
the potential use of various chemoprevention agents.
These include Aspirin (ASA), NSAIDs, five aminosalicylates, 5-ASAs, statins and
ursodeoxycholic acid, as well as vitamins and micronutrients (calcium, selenium, folic acid,
etc.), which have all been reviewed in other sections.
Acetysalicyclic Acid and Non-Steroidal Anti-Inflammatory Drugs
The results of a Cochrane review, which included 3 RCTs, showed that ASA
significantly lowers the recurrence of adenomas after a 3-year follow-up (RR=0.77; 95%
CI: 0.61-0.96) [45]. The joint analysis of the British Doctors Aspirin Trial and the UKTIA Aspirin Trial indicates that taking ASA in doses of ≥ 300 mg/day for at least 5 years
is an effective primary prevention method against CRC with a 10-year latency period
[46]. The same authors did a systematic review, which included 19 case-control studies
(20,815 cases) and 11 cohort studies (1,136,110 individuals), demonstrates that regular
use of ASA and NSAIDs is associated with a reduced risk of CRC, particularly after 10
years or more. However, it is noted that this association is consistent only for ASA taken
in doses of ≥ 300 mg/day, and this association decreases and is more inconsistent with
lower doses if not taken on a daily basis [47]. This association has also been found in a
recent observational prospective study, which included men treated with a dose of 325
mg/day for at least 6 years [48].
The results of two systematic reviews of RCTs on the role of NSAIDs to prevent colorectal
adenomas in patients with FAP show that, in the short term, treatment with sulindac
or celecoxib favours the regression of adenomas, but not their elimination or prevention
[47,48]. Subsequent RCTs confirm that selective inhibitors of cyclo-oxygenase-2, celecoxib
[49,50] and rofecoxib [51] help reduce the recurrence of colorectal adenomas [52].
Statins
The results of a meta-analysis with six RCTs (RR=0.95; 95% CI: 0.80-1.13) and three
cohort studies (RR=0.96; 95% CI: 0.84-1.11) reveal that statins have no significant beneficial
effect on preventing CRC, although nine case-control studies do (RR=0.91; 95% CI: 0.870.96) [53].
Hormone Treatment in Postmenopausal Women
Several observational meta-analysis studies show an inverse association between
hormone treatment and the risk of CRC in postmenopausal women. Nonetheless, RCTs
that have evaluated the incidence of cancer as a secondary variable do not confirm a
protector effect. The preliminary results of the Women’s Health Initiative indicate this
association (RR=0.63; 95% CI: 0.43-0.92), which is not statistically significant, after
adjusting (RR=0.63; 95% CI: 0.32-1.24) [54]. A more recent analysis reveals that this
effect disappears 3 years after dropping off treatment, and that the incidence of colorectal
adenomas and the risk of CRC even increase [55]. The results of the Heart and Estrogen/
Progestin Replacement Study show a non-significant protector effect (RR=0.81; 95% CI:
0.46-1.45) [56-61].
10
Factor
Evidence Prevención o no
fat
+
meat
++
Fiber, fruit and vegetables
++
Protector milk
++
Folate protector
+
Calcium Protector
+
High dose vitamin D
+
Antioxidants
No evidence
Physical Activity
++
Obesity
++
Alcohol
++
Tobaco
++
age
+++
Acetylsalicylic
++
NSAIDs
++
statins
No evidence
Hormone Therapy
+
other
+
(+) mild relationship, (++) moderate relationship, (+++) intense relationship
Table 1: Relationship factors of diet and exercise with Colorectal Cancer
Colorectal Cancer: Detection of colorectal cancer
CRC is susceptible to screening because it is a serious health problem given its high
incidence and its associated high morbidity/mortality. Its natural history is known, there
are screening tests that allow the disease to be detected at early stages, and treatment is
more effective when the lesion is diagnosed early. The aim of CRC screening is to reduce its
incidence (by detecting and resectioning precursor lesions, basically colorectal adenomas)
and mortality by this cause.
Different screening strategies exist for the medium-risk population (individuals aged ≥
50 years with no other risk factors for developing CRC). Traditional CRC screening tests
include the detection of Faecal Occult Blood (FOB) using the guaiac test, sigmoidoscopy and
colonoscopy. The new screening tests include immunological FOB detection, a foecal DNA
analysis and virtual colonoscopy.
The various tests were evaluated and compared in intervention efficiency terms (lower
morbidity/mortality) after considering risks and adverse factors. Validity, acceptability and
the participation rate were evaluated for all the tests.
Screenings with Faecal Occult Blood Tests by the Guaiac Method
The meta-analysis of four RCTs, which examined screening by FOB detection with
Hemoccult II,® reveals reduced mortality by CRC, and included 327,043 participants in
Denmark (Funen), Sweden (Gothenburg), the USA (Minnesota) and the UK (Nottingham). A
recently updated Cochrane review estimates a reduction in the mortality of the intervention
group of 16% (RR=0.84; 95% CI: 0.78-0.90). In the three RCTs which used a 2 yearly
detection system (Funen, Minnesota, Nottingham), the reduction in the risk of death by
CRC was 15% (RR=0.85; 95% CI: 0.78-0.92) [62]. The reduction in estimated mortality rises
to 25% (RR=0.75; 95% CI: 0.66-0.84) when adjusting for participation in at least one round.
No differences were found in either overall mortality (RR=1.00; 95% CI: 0.99-1.02) or overall
mortality with CRC excluded (RR=1.01; 95% CI: 1.00-1.03) [62,63].
11
In the Minnesota RCT, which included a group examined after a 1-year interval and
another after a 2 year interval, initially finds no significant reduction in mortality in the
group which was submitted to a 2-year examination, but a significant reduction was seen
after an 18 year follow-up (RR=0.79; 95% CI: 0.62-0.97) [64].
The Minnesota RCT used the FOB test with faecal rehydration, and shows a 33%
reduction in mortality (RR=0.67; 95% CI: 0.50-0.87).
The Minnesota RCT results also indicate a reduction in the incidence of CRC of 20%
with annual screening (RR=0.80; 95% CI: 0.70-0.90) and of 17% with 2 yearly screening
(RR=0.83; 95% CI: 0.73-0.94) [65].
The sensitivity of the FOB tests to detect any colorectal neoplasia (9 cohort studies) was
6-46% (with specificity at 80-89%) for Hemoccult II® and 43% (with specificity at 91%) for
Hemoccult Sensa®. When comparing the rehydrated vs. the non-rehydrated FOB studies,
sensitivity was 10-14% (with specificity at 90-94%) for rehydrated samples and 6-45% (with
specificity at 94-98%) for non-rehydrated samples [65].
Sensitivity to detect adenomas of ≥ 10 mm (7 cohort studies) was estimated to be 1633% (with specificity at 94-98%) for Hemoccult II® and 21-27% (with specificity at 90-99%)
for Hemoccult Sensa®. Sensitivity was greater for CRC detection (19 cohort studies) [66],
which were estimated at 25-96% (with specificity at 80-99%) for Hemoccult II® and at 6279% (with specificity at 87-96%) for Hemoccult Sensa®. When comparing the rehydrated
and non-rehydrated FOB studies done, sensitivity was 25-89% (with specificity at 80-99%)
for rehydrated samples and 25-89% (with specificity at 92-96%) for non-rehydrated samples
[67].
The systematic review carried out by the US Preventive Services Task Force (USPSTF),[66]
which included studies until 2007, and based on two cohort studies (106,107 cases), point
out that the sensitivity of Hemoccult Sensa® was higher for CRC than Hemoccult II® (6480%), but specificity was lower (87-90%). Nonetheless, both the systematic CRC review
and the USPSTF show that reference Hemoccult Sensa® data are scarce [66,67]. When
specificity lowers, there are more false positives, which increase the risk of having to do
further research (colonoscopy).
Immunological Faecal Occult Blood detection tests
No RCT has been performed to evaluate the efficacy of FOB tests in terms of incidence or
mortality, but some have assessed them in terms of intermediate results (rate of detecting
colorectal neoplasias). One RCT compared FOB (Hemoccult II®) with iFOB (OC-Sensor® test)
in a population sample of 20,623 individuals in the 50-75 year age group. It reveals that
the latter is significantly more efficacious than the former to detect CRC and advanced
adenomas; although its specificity is lower [68,69]. In this study, participation in and
fulfilment of the iFOB test are significantly higher (a 12.7% increase) than those obtained
with the FOB test [70].
In the systematic CRD review on the diagnostic validity of qualitative iFOB tests, which
included studies done until December 2004 (more than 50% of them were case-control
studies), it is estimated that the sensitivity of these tests to detect colorectal neoplasias (6
cohort studies) is 5-63%, while their specificity is 89-99% [71,72]. Moreover, their sensitivity
to detect: CRC (15 cohort studies) is 2-98%; any adenoma (5 cohort studies) is 4-63%;
adenomas of >1 cm (4 cohort studies) are 28-67%. Specificity is estimated at: 89-99% to
detect CRC; 89-98% to detect any adenoma; 93-97% to detect advanced adenomas [73].
The systematic review done by the USPSTF, which included studies done until 2007,
12
centres on nine cohort studies. It concludes that the iFOB test is more sensitive to detect
CRC (61-69%) than Hemoccult II® for a FOB test with non-rehydrated samples (25-38%),
and that it is less specific (91-98% as opposed to 98-99%, respectively) [72-74].
Faecal DNA Detection
By analysing foecal DNA, it is possible to identify the molecular alterations present in
cells of adenomas and CRC [75-77]. No RCT has been done to evaluate the efficacy of a
foecal DNA analysis in CRC screening in terms of incidence or mortality [75-77].
A multicentre cohort study done in a medium-risk population, made up of 5,486
individuals aged over 50 years, shows that a multitarget foecal DNA test, which included
the detection of 21 mutations in genes TP53, KRAS and APC, these being markers of the
instability of microsatellites and the analysis of DNA integrity, offers higher sensitivity
than the FOB test to detect CRC (52% vs. 13%), CRC and adenomas with a high degree of
dysplasia (41% vs. 14%), as well as advanced colorectal neoplasias (18% vs. 11%), but their
specificity is similar (94% vs. 95%) [78].
Other studies done with less objectivable reference standards, in several age groups, and
using various molecular markers, show that the validity of the foecal DNA test is lower than
that of colonoscopy. These studies estimate that FOB DNA test sensitivity and specificity to
detect CRC are 52-91% and 82-97%, respectively and that its sensitivity to detect adenomas
is lower (15-82%) [76,77].
The FOB DNA test is not invasive and entails no adverse effects, no restrictions to diet or
medicine, or colon preparation. Its acceptability is greater than that of other CRC screening
techniques and is just as acceptable as a guaiac-based (gFOB) test [76-79]. The clinical
relevance of a positive result obtained in a patient with a negative colonoscopy is currently
unknown. However, its high cost and low cost-effective ratio, as compared with other
screening strategies, limits is applicability [80-82]. Finally, scientific tests to determine the
suitable interval between performing two determinations are not available.
Sigmoydoscopy
Flexible sigmoidoscopy is done using an endoscope which allows the examination of
the mucous surface up to 60 cm from the anal verge (rectum, sigmoid colon and part
of the descending colon). This examination is done before colon lavage using enema or
administering laxatives, and sedation is not necessary. The procedure lasts 10-15 min. A
positive result means having to completely examine the colon by colonoscopy.
Nowadays, three RCTs are underway: two European ones, the UK Flexible Sigmoidoscopy
Screening Trial [83] and the Italian SCORE Trial [84], which evaluate the efficiency of
performing a single sigmoidoscopy in people in the 55-64 age group with 170,432 and
34,292 people randomly selected, respectively. The US RCT, called the PLCO Cancer
Screening Trial, assesses the efficacy of sigmoidoscopy done in 5 year intervals (with 3 year
intervals between the first two sigmoidoscopies), with 154,000 people aged 55-74 years. The
mortality data of the European RCTs are still not available, and those of the US RCT go up
to 2010-2012.
The detection rate in these RCTs for CRC (0.3-0.5%) and distal adenomas (7.2-12.1%)
in the first screening round is higher than that obtained in the RCTs done on gFOB-based
detection (0.2% and 8%, respectively) [85-87]. Nonetheless, the detection of advanced
adenomas performed by sigmoidoscopy screening is significantly lower than that observed
in colonoscopy screening [88].
13
A Norwegian non-randomised controlled study-the Telemark Polyp Study-assessed the
effect of polypectomy on the incidence of CRC in a screening programme context, with
400 people (50-59 years) that formed a study group, and 399 controls. It shows that
sigmoidoscopy reduces the incidence of CRC, adenomas of ≥ 5 mm (RR=0.7; 95% CI: 0.50.95), and high-risk adenomas (RR=0.6; 95% CI: 0.3-1.0) after a 13-year follow-up [87,88].
Sigmoidoscopy sensitivity for CRC is estimated to be 58-75% for small-sized lesions and
72-86% for more advanced neoplasias. These variations are likely accounted for by the
differences in examiners’ experience and skills and by the risk of proximal lesions in the
unexplored colon [88].
When sigmoidoscopy detects a carcinoma or an adenoma of ≥ 10 mm, conducting a
complete study of the colon is mandatory given the major incidence of synchronic lesions
proximal to the tract explored. It has been estimated that 5-16% of colonoscopies are
performed after sigmoidoscopy [89-91].
In the clinical practice, there is some controversy as to the need to explore the whole
colon when distal lesions of < 10mm have been detected. A meta-analysis estimates that the
RR of presenting a proximal neoplasia is 2.68 (95% CI: 1.93-3.73) for any distal adenoma,
and of 2.36 (95% CI: 1.30-4.29) for adenomas of <10 mm. The meta-analysis that evaluated
the meaning of distal hyperplasic polyps offers a series of estimations. One meta-analysis
reveals that these polyps are associated with the presence of a proximal neoplasia (RR=1.44;
95% CI: 0.79-2.62), but are not statistically significant. Another meta-analysis indicates
that distal hyperplasic polyps are associated non-significantly with the presence of a
proximal neoplasia (RR=1.3; 95% CI: 0.9-1.8), but significantly with an advanced proximal
neoplasia (RR=2.6; 95% CI: 1.1-5.9). Another more recent meta-analysis shows that the RR
of proximal neoplasia for patients with distal hyperplasic polyps is 1.81 (95% CI: 1.20-2.73).
However when including only quality studies, this increased risk disappears. In this metaanalysis, distal hyperplasic polyps present an RR of proximal neoplasia of 0.69 (95% CI:
0.60-0.80) [91-93] as compared with distal adenomas.
Case-control studies estimate that sigmoidoscopy has a protector effect over a period
lasting 9-10 years [93]. Based on this, a 5-year interval between screening sigmoidoscopies
was conservatively established [94-103]. This interval is shorter than that employed in
colonoscopy screening because sigmoidoscopy sensitivity is lower owing to the technique
itself, to colon preparation and to variability in examiners’ experience [98].
The results available to date reveal that sigmoidoscopy is well-accepted by the general
public, and is feasible and safe [104-107]. Compared to colonoscopy, sigmoidoscopy is a
safer test, although it is not completely risk-free. According to some estimation made in the
UK Flexible Sigmoidoscopy RCT, 0.3 cases of haemorrhages associated with sigmoidoscopy,
0.15 perforations and 0.025 deaths per 1,000 examinations occur. The results of an RCT
indicate that 14% of individuals complain of pain (which is strong in 1%) after having been
submitted to sigmoidoscopy. If we compare it to colonoscopy, lack of sedation is associated
with more discomfort and less adhesion to future sigmoidoscopies [108].
Faecal Occult Blood Detection and Sigmoidoscopy
The combination of two screening tests can overcome the limitations that each has
separately. No RCT has been found which evaluates the efficacy of the screening strategy in
terms of reduced mortality by CRC [108-110].
The Danish Funen-2 RCT provides limited data about the incidence and mortality of
CRC. It included 5,495 people to whom it offered a FOB test and a single sigmoidoscopy,
and 5,483 people were invited to undergo only a FOB test [108,111]. An RCT done in Norway
evaluated this same intervention in 20,780 men and women in the 50-64 age group, but
it also provides limited data. Both studies conclude that the combination of FOB and
14
sigmoidoscopy does not exceed sigmoidoscopy in terms of the number of CRC and advanced
adenomas identified [108-111].
The sensitivity of the combined strategy does not improve that of sigmoidoscopy. Thus
in one study with a large number of individuals, the rehydrated FOB and sigmoidocopy
combination gives sensitivity of 76%, which is similar to that achieved with sigmoidoscopy
alone. Indeed the positive predictive value of the combined strategy (2.8%) is lower than that
of the FOB (5.4%) [112].
The adverse effects of the combined strategy are the sum of those derived from each
strategy separately. These drawbacks may condition their acceptability. Along these lines,
one study reveals that adhesion to the combined strategy is less than that to each separate
test (47% with sigmoidoscopy, 32% with gFOB and 30% for the combination). In the RCTs
of Norway and Demark, participation was higher in the sigmoidoscopy or the gFOB groups
than it was for the combined strategy [113-118].
Colonoscopy
Colonoscopy is done using an endoscope which allows an examination of the mucous
surface of the whole colon. For it to be considered complete, it must reach the blind gut
(by visualising the ileocecal valve or appendicular orifice), which is done in 80-95% of
explorations [112]. Colonoscopy must be done under sedation using intraveous drugs. It
also requires being on a low-residue diet on the days before the test, antegrade colon lavage,
administrating laxatives and drinking plenty of water. A thorough exploration must be done
during withdrawal, which must last at least 6-8 min. This examination takes between 20
and 40 min. Most people fully recover after a 1-hour rest.
No RCT has evaluated the efficacy of colonoscopy in CRC screening in reduced mortality
terms. Howevever, several studies indirectly corroborate its efficiency and show that this
test not only favours CRC detection in early stages, but also reduces the incidence of CRC
as it identifies and resects polyps. Therefore in the Minnesota detection FOB RCT, the major
reduction in mortality as compared with the European RCTs is attributed to the fact that
more colonoscopies were performed113-114. Likewise, several cohort studies demonstrate that
polyp removal lowers the incidence of CRC by between 76% andl 90%, and that colonoscopy
detects the majority of these lesions [114].
Colonoscopy could be an advantage over other non-invasive tests like FOB and iFOB.
Currently some RCTs are underway and are evaluating if colonoscopy is superior to the FOB
test in CRC screening. The National Cancer Institute of the United States began a multicentre
RCT in May 2000, and it invited 5,000 healthy people aged 40-69 years to participate.
The Spanish Gastroenterology Association (AEG, in Spanish) set up a multicentre RCT in
a medium-risk population to be carried out in eight Spanish Autonomous Communities
(Aragon, Canary Islands, Catalonia, the Valencian Community, the Basque Country,
Galicia, Madrid and Murcia) to assess the efficiency of colonoscopy as compared to the
iFOB detection test.
As it is a reference test, colonoscopy validity is difficult to analyse. The results of a metaanalysis (9 studies), which compared conventional colonoscopy and virtual colonoscopy,
estimates greater sensitivity for the virutal test, 98% (95%CI: 96-100%) for polyps of ≥ 10
mm, and 97% (95% CI: 94-100%) for polyps of ≥ 5 mm [115].
Narrow band colonoscopy imaging, which allows images of submucous vascularisation
by a digital chromoendoscopy technique, does not appear to significantly improve the rate of
adenomas detected by conventional colonoscopy. However, the available RCTs do not offer
consistent scientific tests [116,117].
15
The colonoscopy employed in screening imposes the risk of adverse effects for healthy
patients. The mortality associated with colonoscopy is 0.3 cases per 1,000 examinations.
The rate of interstinal perforation or haemorrhaging is 1-5 cases per 1,000 examinations
[116-118].
Other described complications include infections and those relating to sedation,
particularly among the elderly with cardiovascular problems. Nonetheless, the results
obtained with a systematic review, which included 36 studies and 3,918 patients; reveal
that superficial sedation provides a high degree of patient and doctor satisfaction, with a
low risk of adverse effects [117]. Complications basically occur when therapeutic procedures
are carried out.
Computed Tomography Colonography
Computed Tomography (CT) colonography or virtual colonoscopy consists in obtaining
tomographical images after colon insufflation using air or carbon dioxide, and their
subsequent 2D or 3D construction in a computer. This test requires the same preparation
required for a colonoscopy, but without sedation [115-117]. Currently, the efficiency of
performing CT colonography, without colon lavage, but with foecal marking using an oral
contrast is being evaluated. Images can be captured in 5-10 min, although a further period
lasting 20-30 min is required to reconstruct and interpret them. If the result is positive,
performing a colonoscopy is mandatory, ideally on the same day or the next day in order to
avoid further intestinal preparation [114-116].
No RCT has been done to assess the efficacy of screening by CT colonography in terms
of the incidence of or mortality by CRC.
The efficacy of detecting adenomas and CRC has been evaluated in several comparative
studies. In them, CT colonography reveals a similar rate for detecting polyps of ≥ 10 mm and
advanced neoplasias to that of colonoscopy [112].
The systematic review done by the US Prevention Services Task Force concludes that
variations in the validity parameters of CT colonography can be attributed to not only the
size, but also to the shape, of the lesion (polypoid vs. flat), and also to the radiologist’s
experience, the technique being used and colon preparation.
CT colonography is a non-invasive test and barely entails serious complications. The
rate of symtomatic colon perforations is 0.05%, which lowers if carbon dioxide is employed
instead of air. Patients complain about abdominal discomfort when the colon is insufflated.
The potential risks of periodical exposure to low radiation doses are not clear. Another
CT colonography value is the detection of significant extracolon disease in 4.5-16% of all
assessed individuals. However, its consequences in terms of potential benefits, risks and
costs remain unknown. There are no scientific tests available on determing the suitable
internval between screening CR colonographies.
Screening
Evidence
Cost/ effectiveness
Guaiac Fecal Occult Blood
++
++++
Immunological FOB
++
++
ADN fecal
+++
+
Sigmoidoscopy
+++
+++
FOB+Sigmoidoscopy
+++
++++
Colonoscopy
++++
+
CT colonography
+++
++
+Slight++moderate+++high++++very high.
Table 2: Relatión screening with evidence and Cost/ effectiveness.
16
Cost-Effectivenees of Colorectal Cancer Screening
The results of two systematic reviews [104] reveal that CRC screening is cost-effective
when compared to no screening.
In the US, the cost-effective ratio of the various screening strategies available ranges
between 10,000 and 25,000 dollars per life gained.
One or 2 year screening with FOB offers the most consistent and favourable scientific
tests on the cost-effectiveness ratio, as well as information about costs obtained directly
from RCTs. The limited information available on the effectiveness and costs of screening
with iFOB or sigmoidoscopy means that it is difficult to consistently establish which strategy
offers the best cost-effective ratio and the optimum age to start and finish screening [105-107].
Cost-effectiveness studies must be valued in each context and merely represent
approaches to the clinical practice in each setting. In Spain, a Markov decision model
and some conservative assumptions conclude that CRC screening is cost-effective and
that the screening strategy with a better cost-effective ratio is an iFOB done yearly, with
an incremental cost of 2,154 euros per year of life adjusted by quality gained. Yet other
screening strategies present similar incremental costs: 1 yearly FOB, 2,211 euros; 2 yearly
FOB, 2,322 euros; 2 yearly iFOB, 2,233 euros; 5 yearly sigmoscopy, 2,305 euros, and 10
yearly colonoscopy, 2.369 euros, per per year of life adjusted by quality gained [108-110].
Other Aspects Related With Colorectal Cancer Screening
In some health systems, primary care doctors actively participate in CRC screening
programmes. An RCT conducted in Italy shows that if primary care doctors actively participate
in screening programmes, the aim of this practice is significantly enhanced. In the UK,
preparing informative materials for primary care doctors has become a priority, as have
regular information exchanges to guarantee their support. The results of a recent narrative
review assign several possible roles to primary care doctors in screening programmes,
such as facilitators, advisors and educators. In these roles, communication among primary
care and specialist care, if a consultation is located in an urban or rural area, and other
individual factors, are all influences [111].
Some studies have evaluated other strategies to raise participation rates. A descriptive
study done in Australia indicates a statistically significant increase when FOB tests are
collected in chemists.
Other experiments performed in France reveal that the participation rates increase when
there is coordination between all health areas, including primary care and chemists. Finally,
an RCT evaluated the effect of two different contact methods with the target population and
shows that the direct contact made by a trained non-healthcare professional was much
more effective than sending a letter of invitation [112-116].
A study done in Albacete (Spain) in 1996 (Tarraga et al) [118] shows that participation
rose to almost 76% after sending a letter of invitation and running an awareness campaign.
Populational Colorectal Cancer Screening Strategies and Implementation In
Our Setting
Despite scientific tests indicating that CRC screening lowers the incidence of and
mortality by this neoplasia; these measures have been poorly introduced into usual clinical
practice. This is most probably due to the characteristics of the screening test, the fact that
it is barely perceived as being beneficial and its low social pressure.
17
Doctors should be familiar with the various screening options available and know their
potential risks, offer them to partipants, and identify those individuals who belong to highrisk CRC groups, who can benefit from screening or specific monitoring measures.
Despite there being no gold-standard screening test, any one of them is much better
than none at all. Although the FOB detection test is not ideal, it is justified by the scientific
tests resulting from RCTs, and for their cost-effective ratio and greater feasibility as far
as resources is concerned. iFOB detection methods avoid drawbacks relating to dietary
and pharmacological restrictions, and improve fulfillment, favour better standardisation
and quality control of the process, and allow a more efficient foecal haemoglobin detection
cut-off point to be selected in accordance with the resources available. Colonoscopy is
the most sensitive and specific test, but is associated with a higher rate of complications,
requires more resources (trained staff and suitable facilities), and is not as well-accepted
by the population as FOB or sigmoidoscopy detection. Flexible sigmoidoscopy seems to
be more effective than FOB and must be considered an alternative. It is also safer than a
colonoscopy, patient preparation is easier, and requires neither sedation nor monitoring.
Applied as a screening method, it involves considerable investments in facilities and training
professionals. CT colonography efficacy is similar to that of colonoscopy to detect advanced
neoplasias, but entails milder adverse effects, but its application as a screening test requires
better quality and consistent scientific tests, as well as considerable technological resources
and specialised professionals. Foecal DNA tests are not currently backed by direct scientific
tests to confirm their efficiency, and they are still expensive.
In 2003, the International Colorectal Cancer Screening Network (ICRCSN) was created
for the purpose of promoting quality CRC screening programmes. This international group
did a descriptive survey-based study of the various initiatives there were before 2004 to
identify, share and promote the best strategies to carry out screening programmes. In all,
35 screening initiatives in 17 countries were identified: 10 were populational screening
programmes, 9 were pilot-phase programmes and 16 were research projects. The most
widely employed screening test was FOB, although one programme included colonoscopy.
Most invited people aged 50-64 years to participate, although some included patients as of
40 years of age, while others did not set an age limit.
European Union Council Directives, the NHS Cancer Strategy, and various Health
Plans of Spanish Autonomous Communities (SACs) recommend applying populational
CRC screening with FOB in men and women within the 50 to 69-74 age range. Nowadays,
only three SACs (Catalonia, Murcia and the Valencian Community) have a CRC screening
programme, although most SACs are proposing them. Indeed, the Interterritorial Board of
the Spanish Ministry of Health has approved CR screening.
The participation and follow-up rates of the programmes that are underway are low
and lower than those of other cancer prevention programmes. The NHS Cancer Strategy
establishes the need to conduct preliminary population pilot studies that evaluate all
these aspects, particularly the acceptance of the various strategies by the population,
their effectiveness, the human and material resouces required for screening, diagnosis and
treatment in any detected cases, and the cost-effective ratio in our setting. The efforts made
to reduce mortality by CRC must concentrate on developing programmes that maximise
participation. For this purpose, when setting up a population programme, it is essential to
run awareness campaigns for the general population and health professionals about the
benefits, risks and limitations of CRC screening to control this disease.
A population screening programme will be beneficial if it is systematically applied, covers
the whole target population and is of good quality. To set it up, organising an adequate
18
summoning system is essential and one that provides a suitable diagnosis, treatment and
follow-up for patients. Managing a screening programme means that information systems
that include the target population and data on screening tests, evaluation and diagnostics
must be available. A quality programme includes an analysis of the process and its
results, and also notifying them quickly. A screening programme evaluation is easier if the
programe’s database is linked to cancer and mortality registries. The European Guidelines
for Quality Assurance of Colorectal Cancer Screening are being prepared in Europe. These
guidelines will cover the entire screening process, from inviting participants to treating
detected lesions, and will include a series of recommendations on standardising processes,
programme follow-up, programme evaluation and future CRC screening perspectives.
The various experiments and accomplishments to reduce mortality by breast cancer must
serve as experience in implementing CRC screening in forthcoming years. Primary care and
specialised care professionals must be a clear reference for the population. Coordination and
team work among SACs are essential to design and organise such programmes.Screening
alternatives may vary in the future if the RCTs underway that evaluate colonoscopy efficiency
confirm a reduction in the incidence of and/or mortality by CRC.
E. Quintero et als refered In his prospective randomized trial involving first-degree
relatives of sporadic CRC index cases, repeated FIT screening detected all CRC and 61%
of advanced adenomas, proving equivalent to one-time colonoscopy screening in terms of
diagnostic yield and tumor staging. However, colonoscopy was superior to the FIT strategy
for the detection of any neoplasm. The study also revealed that the number of subjects
requiring colonoscopy to detect one advanced neoplasm was 4 times less in first-degree
relatives screened by FIT than in those screened by colonoscopy. This finding indicates that
FIT screening may save a large amount of unnecessary colonoscopies in this population
[119,120].
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a prospective study of 1000 colonoscopies in the UK. Lancet. 355: 1211-1214.
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112. Inoue T, Murano M, Murano N, Kuramoto T, Kawakami K, et al. (2008) Comparative study of conventional
colonoscopy and pan-colonic narrow-band imaging system in the detection of neoplastic colonic polyps: a
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study on narrow-band imaging versus conventional colonoscopy for adenoma detection: does narrow-band
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114. Kaltenbach T, Friedland S, Soetikno R (2008) A randomised tandem colonoscopy trial of narrow band imaging
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117. Brenner H, Chang-Claude J, Seiler CM, Sturmer T, Hoffmeister M, et al,(2006) Does a negative screening
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25
eBooks
ISBN: 978-1-63278-054-6
DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
Chapter 3
Hereditary Colorectal Cancer Syndromes
Taina T Nieminen1*, Satu Valo1,2 and Noora Porkka1
Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki,
Finland
*
Corresponding author: Taina T Nieminen, Department of Medical and Clinical
Genetics, University of Helsinki, Helsinki, Finland
1
2
Colorectal Cancer (CRC) is among the three most common cancers worldwide. While
majority of cases are sporadic, 5-15 % have been estimated to have a hereditary background
[1]. Hereditary CRC syndromes are divided to polyposis syndromes, characterized by the
development of multiple colorectal polyps, and non-polyposis syndromes where only few or
no polyps occur. Classification and diagnosis are done based on genetic, pathological and
clinical features of each syndrome. The most common forms of hereditary CRC syndromes
are described in this chapter (Figure 1).
Figure 1: Scheme of Colon Cancer Syndromes. Modified from Lindor et al. 2005.
Hereditary Non-polyposis Colorectal Cancer (HNPCC)
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is the most prevalent form of
hereditary CRC with a share of 3–5 % of all CRCs. It is transmitted in autosomal dominant
manner. Hereditary CRC occurs at a younger age (~45 years) when compared to sporadic
CRC (~70 years). The lifetime risk for CRC in predisposed individuals is high, approximately
70–80 % [2,3]. For males the risk for CRC is higher (80 %) when compared to females (40 %)
[4]. In addition to CRC, the syndrome is characterized by the development of endometrial,
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
26
urinary tract, gastric, small bowel and other extra colonic tumors [5].
HNPCC was first described approximately a hundred years ago [6]. Before the genetic
basis of the syndrome was revealed, an international collaborative group of researchers set
up the Amsterdam Criteria (AC) I and II, to further define the disease [7,8], (Table 1). For
screening purposes, the Revised Bethesda Guidelines were established [9] (Table 2).
I
At least three relatives who have diagnosed CRC and all above mentioned Criteria Should be present
One relative Should be a first-degree the other Two
Affection of two Successive Generations
At least One CRC at young age at onset (< 50 years)
Exclusion Of familial Adenomatous Polyposis
Pathological Verification Of Tumor
II
At least Three Relatives Should found who have diagnosed HNPCC-related cancer (CRC ,endometrium,cancer,small
bowel,ureter,renal pelvis)
One relative should be a first-degree the other two
Affection of two Successive Generations
At least one should be diagnosed at young age at onset (< 50 years)
Exclusion of Familial Adenomatous polyposis (FAP)CRC cases
Pathological Verification of Tumor
Table 1: Amsterdam criteria I and II
B1: CRC Diagnosed before 50 years of age
B2:Extracolonic Lynch syndrome tumors or metachronous or synchronous CRC diagnosed at any age
B3:MSI-high CRC diagnosed < 60 years of age
B4: CRC diagnosed in at least two first degree relatives with LS related cancer of which one diagnosed < 50 years of age
B5: CRC diagnosed in at least two first or second degree relatives with LS
Table 2: Revised Bethesda (B1-B5)Guidelines.
When the Human Mismatch Repair (MMR) genes were identified in the 1990s, HNPCC
was divided in to two separate categories: Lynch Syndrome (LS), caused by pathogenic
germline mutations in MMR genes, and to Familial Colorectal Cancer Type X (FCCX), where
no MMR mutations were detected [10].
Lynch syndrome (LS)
Lynch syndrome is caused by a defect in one of the MMR genes: MLH1, MSH2, MSH6
or PMS2 [2,11-14]. MMR mechanism recognizes and corrects errors that arise during
DNA replication. MMR defects can be detected in tandemly repeated sequences scattered
throughout the genome called the microsatellites. Microsatellites are polymorphic, but in
each individual they are similar in length [15]. Microsatellites may consist of mono-, di-,
tri- or tetranucleotide repeats. Microsatellite instability (MSI) can be defined as emergence
of an extra allele, or multiple alleles, in tumor DNA compared to matching normal DNA [1618]. MSI was first discovered as mutations in CA- dinucleotide sequences in CRC specimens
[19]. It represents a hallmark for LS CRC, and MSI analysis is commonly used as a screening
method to distinguish LS CRC [20].
The average age of CRC diagnosis in LS patients is approximately 44 years [21]. In
majority of the cases (60-80%) tumors tend to arise on the right side of the colon, and
multiple tumors in the same individual are frequent. Villous adenomas are the most common
precancerous lesions in the colorectum of LS patients. The progression sequence from polyps
to carcinomas is accelerated in LS patients (under 2 years of time) compared to sporadic
CRC (over 10 years of time) due to defective MMR-gene function and hence accumulation
27
of genomic mutations that most probably cause additional alterations in oncogenes and
Tumor Suppressor Genes (TSGs) [22]. Histologically tumors are characterized as poorly
differentiated; despite the fact that the survival rate is better than in sporadic colon cancer
cases [23]. Early recognition of LS mutation carriers is essential in order to reduce CRC
mortality. Intensive colonoscopy surveillances are recommended for LS patients starting at
the age of 25, with a 2 year interval [22].
Approximately 70 % of mutations are found in MLH1 and MSH2 genes. Loss of function
of a MMR gene occurs when the wild type allele becomes somatically inactivated through
deletions, point mutations or CpG island hypermethylation. Somatic inactivation by
hypermethylation primarily occurs in the promoter of the MLH1 gene [24-26]. Large genomic
rearrangements of MLH1 and MSH2 genes have also been reported to cause deficient MMR
function and LS phenotype in patients that lack MMR gene mutations [27]. Age of onset
and the risk of developing various types of cancer vary depending on which MMR gene is
mutated [28-30]. Patients with MLH1 and MSH2 mutations have similarly increased risk
for the whole spectrum of LS associated cancers with the distinction that MSH2 mutation
carriers seem to have a more prominent risk for urinary tract cancer in both sexes and
prostate cancer in males [28,31].
Loss of MSH2 expression is most often caused by defects in MSH2 gene, but in 10 %
of cases germline deletion of the 3’ end of EPCAM gene, located upstream of MSH2, is
known to results in hypermethylation and inactivation of the MSH2 gene promoter [3234]. The clinical phenotype of patients with MSH2 and EPCAM mutations is similar, with a
distinction of a lower lifetime risk (12 % by the age of 70) for endometrial cancer in patients
with EPCAM mutations (compared to 20–50 % risk in MSH2 mutation carriers) [35].
Patients with MSH6 mutations have later age of onset and substantially lower lifetime
risk for CRC (10–22 %) as well as to other cancers associated with LS, compared to patients
bearing mutations in other MMR genes. Although, female MSH6 mutation carriers have
been suggested to have a higher risk for endometrial cancer [30]. MSH6 deficient tumors
show consistent MSI only in association with mononucleotide repeat sequences [36].
After identification of the PMS2 gene, increasing number of individuals with mutations
in this gene have been identified. The risk of developing CRC, endometrial and other LS
associated cancers seems to be lower (~20 % and ~15 % for CRC and endometrial cancer,
respectively) in PMS2 mutation carriers [37].
In addition to genetic mutations, germline epimutations have been reported in a small
number of individuals meeting the clinical criteria of LS [38].
Familial colorectal cancer type X (FCCX)
Recent clinical and molecular studies have revealed that not all HNPCC cases are caused
by defects of the MMR genes. The clinical phenotype of FCCX patients often fulfill the
Amsterdam Criteria I (AC I), or at least the Revised Bethesda Guidelines B1-B5 (Tables 1
and 2) with a slightly higher age of onset (~ 60 years) but lack the evidence of MMR defects
[10]. FCCX patients have an increased risk of CRC, but usually no extra colonic tumors.
Surveillance guidelines for FCCX patients are the same as for LS patients. In comparison to
LS, colorectal tumors in FCCX occur more frequently in the sigmoid colon and rectum and
they are mostly microsatellite stable (MSS) [39].
Germline mutation and promoter hypermethylation of APC tumor suppressor gene
contribute in the formation of Western sporadic microsatellite stable CRC, which usually
develops from tubular adenoma (a form of precancerous lesions of CRC), followed by p53
mutation and/or Chromosomal Instability (CIN) [40]. Similarly, FCCX related CRCs seem
to develop via similar CIN pathway [39]. CIN is described as increased loss or accumulation
of chromosomal material that leads to polyploidy or aneuploidy (imbalance of chromosome
28
number) [41,42]. CIN can occur at any point in carcinogenesis and it can cause aneuploidy
as well as Loss of Heterozygosity (LOH) [43].
LOH can cause the inactivation of TSGs by somatic loss of chromosomal material, ranging
from the loss of a chromosome sub band to loss of the whole chromosome [43]. LOH can
be measured by comparing the tumor tissue to a normal tissue (e.g. blood leukocytes) from
the same individual by different methods (e.g. using fragment analysis). If LOH is present in
a particular tumor, then one allele is missing or has decreased in intensity. These missing
or attenuated alleles frequently contain TSGs. In many common cancers, multiple regions
of chromosomal losses have been identified by LOH analysis [41]. The number of TSGs
that have been recognized based on LOH is low if a somatic mutation must be seen in the
remaining allele [45].
TSGs are genes that provide a cell with the capability to accept and process growth
suppression signals from its environment. They are also key players in the intracellular
signaling cascade. TSG inactivation by mutation or methylation is linked to carcinogenesis
[46]. TSGs control versatile cellular activities; responses to cell cycle checkpoints, as
well as perceiving and repairing of DNA damage. In addition, protein degradation and
ubiquitination, tumor angiogenesis, cell movement and differentiation, cell definition and
mitogenic signaling belong to TSGs duties [47]. TSGs can be divided into gatekeepers
and caretakers. The gatekeepers are genes that function actively in cell proliferation, and
mutations in these genes frequently lead to the conversion from normal to neoplastic cells.
The caretaker genes’ function is to maintain cell genome integrity [48,49].
It has been hypothesized that cancers occur in FCCX patients only by chance, or that
these families share the same environmental circumstances. However, there may still be
a yet unknown common genetic factor behind this syndrome [10]. Linkage analyses, Next
Generation Sequencing (NGS) and association studies have been conducted to discover
predisposing genes for FCCX.
Until recently, the genetic background of FCCX has remained unknown. Few predisposing
germline candidate mutations have been identified for FCCX in Europe. Two novel germline
mutations in the gene encoding a BMPR1A were identified in two out of 18 (11%) Finnish FCCX
families. These findings were the first to report germline alterations in a high-penetrance
susceptibility gene in FCCX, and the first to link mutations in BMPR1A gene to FCCX [50].
BMPR1A belongs to BMP signaling cascade and it phosphorylates different SMAD proteins,
which then form a composition with SMAD4 protein [51,52]. This composition migrates to
the nuclei and regulates the transcription of other genes [53].
A novel germline mutation (c. 147 dupA) in the RPS20 gene, encoding a component
(S20) of the small ribosomal subunit, was found from seven CRC affected patients in one
Finnish FCCX family. The mutation leads to frameshift and premature protein truncation
(p.Val50SerfsX23). The product of RPS20 is required during the late steps of 18S ribosomal
RNA (rRNA) formation. Ribosomes are the organelles that catalyze protein synthesis, and
they consist of a small 40S and a large 60S subunit. RPS20 encodes a ribosomal protein
that is a component of the 40S subunit [54]. When RPS20 function is normal, it can bind to
Mdm2 and activate p53 tumor suppressor proteins [55].
Three different missense type mutations (p.Val78Met, p.Gly484Ala, and p.Ser326Phe)
in the SEMA4A gene were identified in three FCCX families from Germany and Austria
[56]. Semaphorins have role in physiological and developmental processes; additionally
semaphorins and their receptors have been connected to malignant disorders [57,58]. It
has been proposed that semaphorins act in protumoral as well as anti-tumoral manner,
depending on the context of the tumor and on the semaphorin in question. Never the less
semaphorins may have a role in angiogenesis, evading apoptosis, cell proliferation and
metastasis as well as in other tumorigenic properties [56].
29
The findings mentioned above were the first to report germline alterations in highpenetrance susceptibility genes in FCCX, and the first studies to link mutations in BMPR1A,
SEMA4A or RPS20 to FCCX, or to any other human disease in the case of RPS20 gene [56,
59,60]. Based on these findings, it is reasonable to conclude that FCCX is a genetically
heterogeneous disease, and it is probably explained by many different gene mutations. All
of these above mention candidate mutations need to be confirmed in the global context.
Familial Adenomatous Polyposis Syndrome (FAP)
Familial adenomatous polyposis syndrome (FAP) is the second most common CRC
predisposition condition after LS, and the most common polyposis syndrome [61,62]. FAP
syndromes can be divided to two slightly different conditions: classic FAP and attenuated
FAP. Both of the syndromes are caused by germline mutation occurrence in the APC
gene, although mainly different parts of the gene, and both are inherited in an autosomaldominant manner [63].
Classic FAP
FAP syndrome was identified in 1991 and for the cause of it, germline mutations in
the APC gene were described [64, 65]. The manifestation of the disease is multiple, even
hundreds or thousands of colonic adenomas (adenomatous polyps), and if untreated, CRC
develops in 40–100 % of cases. The average age of CRC onset is 39 years in FAP patients
[61]. FAP accounts less than 1 % of all CRC cases, and the incidence rate is 1/10000 [62].
Approximately in 50 % of the FAP patient’s, adenomas are detected by the age of 15,
and 95 % of patients have developed adenomas by the age of 35 [66, 67]. Adenomas are
located throughout the colon with slightly higher incidence in the distal part. Majority of the
adenomas in the FAP patient’s colon are very small, less than 0,5 cm in diameter, and only
very few (less than 1 %) are over 1 cm in diameter [68]. In the histopathology point of view,
the tubular adenomas are the most common in FAP patients. Tubulovillous and villous
adenomas are also detected, representing mainly the large adenomatous polyps [69].
APC gene is located in the q21-22 of chromosome 5. It consists of 15 protein coding exons,
from which exon 15 is the largest comprising more than half of the protein coding part. Exon
15 is also the most common location for somatic and germline mutation occurrence [70].
The 310 kDa APC protein consist of 2843 aminoacids and it has an important role in the
WNT-signaling cascade. APC protein regulates β-catenin oncoprotein in a negative manner
by degradation and ubiquitination of β-catenin. When APC protein is absent, β-catenin
assembles in the nucleus and influences components that are involved in up-regulating the
transcription of genes that participate in cell proliferation, migration, apoptosis, cell cycle
entry and cell differentiation [71]. APC protein is also necessary to stabilize microtubules
to maintain chromosomal stability [72]. Aberrant mitosis and insufficient chromosome
segregation might be the consequence of inactive APC protein function [73].
At present over 1100 APC mutations and over 3000 APC variants are known, all together.
Most of the mutations are damaging germline mutations: small deletions, insertions or
nonsense mutations that cause truncation of the protein [74,75]. Codons 1061 and 1309 in
the 5´part of the exon 15 comprise the mutational hotspots of the APC gene. These codons
form approximately 11 % and 17 % of the germline mutations in the APC gene, respectively.
Second hit character depends on type of the germline mutation in the APC gene. Allelic
loss of APC gene as a second hit exists if the mutation can be found from the codon 1194
to 1392. If the germline mutation locates between codons 1250-1464, called the mutation
cluster region (MCR), the second hit probably causes protein truncation [76,77]. After the
second hit has occurred in the APC gene, its carcinogenic route resembles the sporadic
event, where the accumulation of mutations in the K-ras or p53 gene is a very common
phenomena [78].
30
For Classic FAP patients, biannual sigmoidoscopy screenings are recommended starting
at the age of 12–14. Annual colonoscopy screening is recommended if any adenomas are
found until colectomy is performed [79].
Attenuated FAP
A less severe form of FAP syndrome is Attenuated FAP (AFAP), where affected individuals
usually bear less colonic adenomas than in classic FAP (0-100+). The age of CRC onset is higher
in AFAP compared to FAP [61]. In AFAP the lifetime risk for CRC is 70% [60]. When the number
of usually right sided colon adenomas is 10-99, the examination of family members can be used
to verify the AFAP diagnose [80]. In the AFAP patients the risk of extracolonic tumor occurrence
is also evident: duodenal and gastric polyps, desmoid tumors, osteomas, brain and thyroidal
tumors as well as other malignancies are detected, although relatively rarely [81].
The APC gene mutations in AFAP are mainly detected upstream of the codon 157 or
downstream of codon 1595, but in some cases also between codons 213 and 412 of exon
9, which is the alternatively spliced region [82-84]. The surveillance guidelines recommend
biannual colonoscopy starting from the age of 18–20. If any adenomas are found, endoscopical
removal of adenomas and annual colonoscopy screenings are recommended thereafter [85].
MUTYH-Associated Polyposis (MAP)
MUTYH-Associated Polyposis (MAP) syndrome was discovered in 2002 [86]. MAP
syndrome resembles AFAP and it can be associated with numerous (15-100) polyps in the
colorectum. This syndrome is caused by biallelic mutations in the MY, or better known as the
MUTYH gene, thus MAP is inherited as an autosomal-recessive manner [87]. MAP syndrome
patients have a 80 % lifetime risk for CRC [63].The age at onset of CRC in MAP syndrome is
approximately 40 years, although some individuals tend to manifest the disease at younger
age [88]. In MAP patients, CRC occur evenly in the distal and proximal part of the colon [89].
The MUTYH gene is located in chromosome 1p34.3-32.1 and it constitutes of 16 exons
which form a 535 aminoacid long protein [90]. MUTYH gene is involved in the base-excision
repair system (BER), which repairs mutations caused by cells’ internal metabolism (eg.
reactive oxygen species arisen from metabolic action) [91]. BER is activated through DNA
glycosylases, which are a class of enzymes that recognize chemically modified bases. DNA
damage causes stable 8-oxo-7, 8-dihydro-2’-deoxogyanosine (8-oxoG) lesion in which
8-oxoG mispairs with adenine causing a transversion mutations, eg. G:C to T:A [92]. The
main duty of MUTYH protein is to remove mispaired adenines-8-oxoG bases [93-95]. When
a biallelic mutation occurs in the MUTYH gene, MUTYH protein is no longer able to remove
these mispaired bases and hence G:C to T:A transversion mutations occur in the following
replication round. This phenomena is frequently detected in somatic mutations of APC or
KRAS genes in MAP-adenoma or tumor tissues [86, 96]. Somatic mutations in APC gene are
probably one explanation of the similar phenotype in MAP and AFAP [97].
More than 80 damaging mutations have been found in the MUTYH gene [74]. Minority of
the mutations are truncating or splice site mutations, whereas the missense substitutions
are more common [83]. Mutations have been discovered in all exons except exons 1 and
2. Two hotspot missense mutations are predominantly seen especially in the Europeans:
p.Y179C and p.G396D in exons 7 and 13, respectively. These mutations cover 70 to 80 % of
all mutations in MAP detected in Europe [96].
Lifelong biannual colonoscopy screening program is recommended for MAP patients starting
from the 18–20 years of age. Screening recommendations are the same as for AFAP [67].
Polymerase Proofreading-Associated Polyposis (PPAP)
Polymerase Proofreading-Associated Polyposis (PPAP) is the most recently described
31
syndrome that predisposes to endometrial cancer and CRC [98]. PPAP penetrance is high
and it is inherited dominantly [99]. Endometrial cancer in PPAP patients has been linked
to germline mutations in POLD1 gene, and germline mutations in POLE gene are associated
with CRC. Chromosomal instability has been discovered to be the carcinogenic mechanism
behind PPAP. PPAP tumors are microsatellite stable, and K-ras and APC mutations are often
detected [100]. Typically the age of onset in PPAP seems to be less than 40 years. Multiple
large colonic adenomas (>5) are detected, resembling phenotypically MAP or AFAP [101].
POLE mutation carriers are also associated with other malignancies, including ovarian,
pancreatic, stomach, brain and small intestine cancers [102]. POLE and POLD1 are DNA
polymerase enzymes that are involved in the DNA replication. Inactivation of POLE and
POLD1 exonuclease proofreading domains creates mutations all over the genome and
results in tumor formation [103]. All of the mutations identified in POLE and POLD1 genes
so far are of missense type [101-103]. PPAP syndrome is lacking the surveillance program
recommendation due to the novelty of the disease. However similar surveillance program as
in FAP syndrome is suggested [101].
Hamartomatous Polyposis Syndrome
Hamartomatous polyposis syndromes consist of variety of hereditary conditions that
exhibit hamartomatous polyp histology [104]. The conditions include Peutz-Jegherssyndrome, Juvenile polyposis syndrome, PTEN hamartoma syndrome and GREM1 mixed
polyposis syndrome. These syndromes cause distribution of polyps in gastrointestinal
tissues, benign extra-intestinal findings, increased risk for gastrointestinal (GI) cancers,
such as CRC and small bowel cancers as well as increased risk for other malignancies.
Hamartomatous polyposis syndromes are very rare conditions and account only to less
than 1 % of all CRC cases. However the transition of polyps to cancer remains still to
be fully delineated [104,105]. Early identification of the individuals at risk is critical for
appropriate surveillance and management plan [106]. The focus of this chapter will be on
Peutz-Jeghers- and Juvenile polyposis syndromes, which are the two most common types.
Peutz-Jeghers Syndrome (PJS)
Peutz-Jeghers Syndrome (PJS) is an autosomal dominantly inherited syndrome in which
the diagnosis can be made when a patient meets at least two of the following three features:
occurrence of hamartomatous polyps, most frequently in the small intestine but also in
colon and stomach; occurrence of mucocutaneous hyperpigmentation around and inside
the perianal region and mouth; and family history of the disease [107]. Extraintestinal
hamartomatous polyps may also occur for example in uterus, nasal cavity, lungs and
bladder [105].
The first symptoms of PJS, usually arising in early teenage years, comprise gastrointestinal bleeding and possibly anemia. Peutz-Jeghers polyps are mostly found in the small
intestine and colon and might cause painful obstructions, intussusceptions and puncture
of the intestines [104,108]. PJS patients have an increased risk for several cancer types
including CRC (39 %), breast (45–50 %), small intestine (13 %), gastric (29 %), pancreatic (11–
36 %), ovarian (18–21 %) and lung (15–17 %) cancers [109-111]. Lifetime risk for all cancers
in PJS patients is estimated to be 81–93 % [109,110,112]. Also risk for benign neoplasm of
the ovaries and adenoma malignum of the cervix in females, and large calcifying sertoli cell
tumors of the testes in males is elevated. Sertoli cell tumors might cause gynaecomastia,
a condition characterized by short stature and advanced skeletal age, due to oestrogen
secreted by the tumor cells [108,113].
PJS is caused by germline mutations in STK11 gene (also known as LKB1) in
chromosome 19p13.3 [114,115]. STK11 is a TSG, a serine-threonine protein kinase, and
its functions involved various cellular processes such as apoptosis, DNA-damage responses
32
and metabolism [108]. Depending of the methods used, it is estimated that 50–90 % of PJS
patients carry a mutation in this gene. Most of the mutations are missense or truncating
mutations that cause elimination of the kinase function, but also large deletions have been
detected [104,116].
PJS incidence is estimated to be 1/200 000 births but also other estimates exist [117,118].
The mean age of PJS patients developing malignancies is 42 years [117]. Current treatment
is endoscopic polypectomy to reduce the risk of obstructions and intussusceptions, and the
risk of cancer later in life. Surveillance recommendations vary from starting the endoscopic
screening at the age of 8 or at the age of 18, and there after every 2–5 years, depending on
the specialist [108,119].
Juvenile Polyposis Syndrome (JPS)
Juvenile Polyposis Syndrome (JPS) causes appearance of multiple (>1) juvenile polyps
in GI tissues, most frequently in the colon and rectum, but also in the small intestine and
stomach [120,121]. Juvenile polyps can appear at any age and, hence the presence of these
polyps is relatively common (~ 2 % of children under 10 years of age) the JPS diagnosis can
be made when a patient meets the following three criteria: occurrence of ~ 5 colorectum
associated juvenile polyps, juvenile polyps all over the GI tract, and any juvenile polyps
found in an individual who has a positive family history of the syndrome [121]. Diagnosis of
JPS is usually made before the age of 20 years hence the appearance of the first symptoms
might come as early as the first or second decade of life [122,123]. The symptoms include
rectal bleeding that may cause anemia, abdominal pain, obstructions and, rarely, rectal
prolapse of polyps [124]. JPS patients have increased risk for cancers in GI tract, CRC being
the most common form (39 %) and gastric, small bowel and possibly pancreatic cancers less
common. [123,63].
Germline mutations in two primary genes, BMPR1A and SMAD4 are associated to JPS.
Both genes encodes proteins involved in Transforming Growth Factor (TGF) -β pathway
which is involved in regulation of cell differentiation and proliferation, especially in colonic
cells, and also inflammation, hematopoiesis, wound repair and skeletal development.
SMAD4 mediates its downstream signaling transduction [123,125]. Features of BMPR1A are
described previously in chapter Familial Colorectal Cancer type X. Defects in these genes
account for equal parts of JPS, approximately in 20 % of cases. [117, 126]. It has been
suggested that the BMPR1A mutation carriers has lower risk of gastric cancer than SMAD4
mutation carriers [117,126].
JPS incidence is between 1/100 000 to 1/160 000 births [121]. Currently international
guidelines for treatment considering prophylactic surgery are missing and the surveillance
program varies depending on country of question. Those patients with positive family history
of JPS prophylactic colectomy should be considered [127-129]. In Britain colonoscopy
surveillance is suggested once a year or biannually starting from age 15 or 18 and continuing
to age 70 [129].
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eBooks
ISBN: 978-1-63278-054-6
DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
Chapter 4
Treatment of Colorectal Cancer Liver
Metastases: Clinical and Molecular Aspects
Esin ECE1, Saadettin KILIÇKAP1,Aykut ÖZGÜR2, Yusuf TUTAR3*
University of Hacettepe, Institute of Cancer, Department of Medical Oncology,Ankara,
Turkey
2
Gaziosmanpaşa University, Faculty of Natural Sciences and Engineering, Department
of Bioengineering, Tokat, Turkey
3
Cumhuriyet University, Faculty of Pharmacy, Department of Basic Sciences, Division
of Biochemistry, Sivas, Turkey
1
*
Corresponding author: Yusuf TUTAR, Professor at Cumhuriyet University, Faculty
of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry,
Sivas,Turkey, Phone: +90 346-219-1010 ext. 3907 E-mail: [email protected]
or [email protected]
Abstract
Colorectal Cancer (CRC) is one of the common cancer types and a great proportion of
the CRC patients develop metastasis to liver. Innovative treatment methods for liver
CRC metastasis (mCRC) have improved the patients’ survival rate and quality of life.
Modern treatment of CRC employs combination of surgery, ablative therapies, and (neo)
adjuvant chemotherapy. This review discusses recent developments in the treatment of
mCRC in terms of ablation, drug therapy and surgery with an general overview of the
recent literatureg.
Keywords: Chemotherapy, Colorectal Cancer, Liver metastases, Molecular mechanism,
Radiotherapy, surgery.
Introduction
Colorectal Carcinoma (CRC) is the third most common cancer in the Western World
and CRC has the second most common cause of cancer related mortality after lung cancer
in North America1. An annual new cases of 130.000 colorectal cancer and nearly 50.000
cases of death due to CRC were estimated for 2015 [1]. In the last decade, a significant
improvement has achieved in the management of CRC patients with improvements in
screening strategies, diagnostic methods, and implementation of novel chemotherapeutics
with biological agents. The 10-year survival rate is 90% in early stage disease but is lower
than 5% in patients with inoperable metastatic stage [2].
Liver is known to be the most common metastasis site for CRC. More than 50% of
patients with CRC will develop liver metastases during their life (metachronous liver
metastasis) [3]. At the time of diagnosis, 25% of CRC patients have already hepatic metastasis
(synchronous liver metastasis) [4]. One third of the patients with liver metastases have an
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
40
isolated metastatic site limited to the liver and the survival of this specific population is
directly related to biological behavior and number of hepatic lesions. Hepatic metastasis
accounts for more than half of colorectal cancer deaths which emphasize the importance of
effective managements strategies of liver metastasis [5]. Nowadays, especially in liver-only
metastatic disease the 5-year Overall Survival (OS) rate has increased up to 35-58% [6,7].
The multidisciplinary therapeutic approach can be classified into three parts; i. new and
more effective chemotherapeutic agents administered as a single agent or in combination
with other anti-cancer agents (Table 1), ii. An advanced role of interventional radiology and
nuclear medicine iii. New strategies and techniques for hepatic resections for CRC and mCRC
patients. These therapeutic strategies improved resectability rate of metastases and increased
the survival rate, as a result the unresectable cases decreased approximately to 20-30%.
Surgery is the bony frame in the management of any stage CRC. In metastatic setting,
surgery still remains the only curative option for patients. Historically, only 5-10% of
hepatic lesions were reported to be resectable. With advances in diagnostic methods,
new staging systems for resections and new therapies resectability have increase up to
25%. [8]. Emerging strategies that increase the potential for resection are neo-adjuvant
chemotherapy, preoperative portal vein occlusion and the two-stage resection approaches.
In this manuscript, the treatment modalities for liver metastatic colorectal carcinoma along
with molecular perspectives will be outlined.
Treatment Methods of Mcrc
Surgical resection
In patients with limited liver CRC metastasis, hepatic resection is the gold standard
approach for curative treatment. Nowadays, the most common indication for hepatectomy
in western countries is metastatic CRC (mCRC) [9]. Surgery increases the cure rate to 2050% and gives long-term survival chance for patients after complete R0 hepatic resection
[10]. Generally, limited liver mCRC cases can be categorized into three groups: resectable,
potentially resectable, and definitely unresectable.
The criteria for resectability of liver lesions were defined as having less than three lesions
(an estimated resection margin of more than one cm), absence of extrahepatic disease, and
expected sufficient postoperative liver volume. This definition limits the curability option of
more than 70-80% of mCRC patients. Recent debates enabled substantial data to change
the resectability criteria. Malik et al. reported that liver resection still have a favorable
outcome in patients with 4 to 7 hepatic lesions or even more than 7 lesions [11]. Several
studies have indicated that actual surgical margin after possible R0 resection did not affect
survival rates [12,13]. The presence of extrahepatic disease is no longer considered an
absolute contraindication for liver resection. The requirements for remaining sufficient liver
volume after surgery can be different. In a healthy liver at least 20% of liver volume should
be preserved but this proportion may increase due to underlying liver damage and/ or
chemotherapy associated liver injury [14,15].
The optimal timing of surgery in patients with synchronous liver metastasis is
controversial. There are three options for surgical treatment of primary and metastatic
tumors: 1) simultaneous resection of both the primary and liver metastasis 2) primary tumor
resection followed by hepatic resection and 3) upfront hepatectomy approach. The decision
of choice lies behind a thought of surgical complexity, patient characteristics, biological
behavior and genetic status of the disease and surgeon expertise [16,17]. In the past, due
to high mortality and morbidity, simultaneous surgical approach was not widely accepted.
However, more recently, with improved techniques and improved postoperative care of
patients, simultaneous resection is more widely adopted. In a systemic analysis which
includes trials that compared the two approaches, no significant difference had been found
in 5-year overall survival [18]. However, preoperatively planned extend of liver resection is
41
important. Major hepatectomy (i.e. resection of three or more hepatic segments) have still
a significantly higher mortality and morbidity [16,19]. A new paradigm called “liver first
strategy” is introduced due to the potential risk of significantly increased complications.
This method includes primary liver resection without neo-adjuvant chemotherapy, after
surgery chemotherapy and finally primary tumor resection. This method is more suitable
for patients with potentially resectable liver metastasis, but can be applied also to resectable
metastatic disease. A potential detrimental effect of this approach can be progression of
primary tumor and requiring an emergency surgery. Hence, for locally advanced stage
tumors or urgent surgery requiring patients, upfront liver strategy is not suitable.
Liver mCRC cases may be initially unresectable. However, there might be a potential for
future resection option by the aid of chemotherapy, interventional radiology, and nuclear
medicine therapeutic strategies. The chemotherapy approach that enables an initially
unresectable metastatic liver lesion to be removed is called “conversion chemotherapy”.
This phenomenon has been known for two decades and improved with introduced biological
molecularly targeted agents. This topic will be discussed separately in chemotherapy section.
It is well known that liver is a metamorphic organ that can replace itself to some extent.
Preserving sufficient liver volume after liver resection is a major obstacle for especially
extensive liver metastatic cases. In the situation, Portal Vein Embolization (PVE) can help to
increase the remnant contralateral liver volume to fulfill the resectability criterion. The right
liver lobe volume is generally sufficient as a remnant when left hepatectomy is planned. PVE
is usually necessary when extensive right lobe resection is required.
A single hepatectomy session might not be enough for complete resection of all metastasis
even with neoadjuvant chemotherapy or PVE. In that circumstance “two stage hepatectomy”
may be planned. This approach resulted better for unresectable metastatic cases when
compared to palliative chemotherapy only. Usually 4-6 cycles of chemotherapy is applied
initially and in accordance with response in diagnostic imaging techniques, first stage
hepatectomy is done. After the healing period, chemotherapy is continued with achieved
response criteria and the patient is prepared for a second stage hepatectomy. Often PVE
may be necessary before the second stage. Adam et al. conducted a study that involves
this strategy in 2000 [20]. The updated results showed that 5-year OS was a 42% but more
than 30% of the patients were not completed a second hepatectomy session due to higher
postoperative morbidity and mortality. It is important to consider the future morbidity of
first stage hepatectomy. The survival results of this approach is a reflection of both the
intrinsic biology of tumor and overall complete resection of metastasis. Hence, case selection
is important when considering a two-stage hepatectomy.
Ablative therapies
Interventional radiology plays an important role in management of liver mCRC. Ablation
therapies include Radiofrequency Ablation (RFA), Microwave Ablation (MWA), cryoablation,
radioembolization, and chemoembolization. Thermal ablation results in delivering extreme
temperatures to neoplastic tissue to cause immediate cell death and tumor necrosis
[21]. Thermal ablation techniques have a low morbidity, allow for future adjunct therapy
approaches and resections and do not to damage the liver parenchyma extensively.
Radiofrequency ablation is the most commonly used approach. An electrode is
placed
and high frequency alternating current causes thermal damage and coagulation necrosis.
Open surgical approach, laparoscopic or percutaneous techniques are possible for RFA. The
reported local recurrence rate varies from 17% to 46% [22-24] . In circumstances when a
liver resection is planned, RFA can be done intraoperatively. RFA is generally recommended
for lesions less than 3 cm since for bigger lesions recurrence rates increases dramatically
[22]. RFA has some limitations. There is a risk of heat transfer via blood vessels (heat sink
phenomenon) and increasing the damage area and further there is a risk of biliary damage.
42
The median survival rate after RFA ranges from 24 to 45.3 months [25-28] . Previously,
RFA was found to be inferior to liver resection for mCRC due to high local recurrence rate
[25,29]. However, RFA not alone but combined with liver resection can be helpful in cases
with extensive liver metastasis and/or inadequate remnant liver volume. The use of RFA may
obviate the need for a two-stage hepatectomy. The CLOOC (EORTC 40004) trial addressed
this question [27]. In this study, the 5-year OS was reported as 56%. The CLOOC trial
also compared the RFA with chemotherapy vs. chemotherapy alone. Although RFA alone
arm had better PFS results (16.8 months vs. 9.9 months) it was not ultimately powered to
evaluate the OS.
Microwave ablation is a thermal ablation technique in which the electrode generates
a rapid heat source with microwave energy. Rapid oscillation of water molecules creates
coagulation necrosis. MWA is advantages over RFA in way that it is more rapid, safer to
administrate with lower recurrence rate [30].
Cryoablation involves rapid nitrogen or argon gas being delivered to tumor tissue by the
guidance of ultrasound. It causes freezing of tissue below the degrees of survival and cause
necrosis. It has more complication and recurrence rates hence it has fallen out of favor
[31,32].
Chemoembolization is not a thermal ablative approach rather than a local ablative
technique that involves either emulsions of ethiodized oil or drug eluting beads. The median
duration of response was reported as 6 months with median survival of 25 months [33].
There is a risk of post-embolization syndrome characterized with right upper quadrant pain,
fever, nausea and increase in transaminases.
Radioembolization (RE) is the best known local ablative technique for liver adverse effects
are lung and Gastrointestinal (GI) toxicity. They occur as the microspheres go through
the vessels of lung and major GI organs. The vasculature diversity should be known well
before the application of this technique. A Lung Shunt Fraction (LSF) is calculated based
on imaging and dose reductions can be made accordingly if LFS is between 10-20%. The
response rate varies between 12.9-35.5% [34-36]. The median OS following RE is 10.2-12.6
months [36].
For the majority of patients with hepatic metastasis there are no curative option rather
than a significant benefit in OS and quality of life can be achieved. Palliative surgery of
primary tumor is indicated for symptomatic patients or in emergent cases related to intestinal
obstruction or partial mechanical ileus, intractable bleeding, anemia or perforation. The
value of primary tumor resection for asymptomatic patients with unresectable metastasis
is still vague. There will be a risk for future emergent conditions related to primary tumor
progression during palliative chemotherapy which may increase the mortality and morbidity
of compulsory surgery. In previous series, Cook et al. reported that 66% of patients received
primary tumor resection [37]. The Memorial Sloan-Kettering Cancer Center reported that
only 7% of patients recommended after surgery during treatment [38]. Thus, US National
Comprehensive Cancer Network (NCCN) recommends beginning chemotherapy with primary
tumor unresected. Besides the role of surgery, palliative chemotherapy with/ without
ablation techniques plays an important role for unresectable metastatic cases and this will
be discussed in the following sections.
Chemotherapy
Molecular mechanism of clinically used mcrc drugs
5-Fluorouracil, capecitabine, oxaliplatin, cetuximab, bevacizumab, and panitumumab
are FDA approved anticancer drugs that are clinically used in advanced chemotherapy for
mCRC patients (Table-1).
43
DRUG
TARGET
ADMINISTRATION TYPE
BRAND NAME
COMPANY
Adria
Sanofi
Tobishi
Valeant
Meda
Valeant
Aqua
Verofarm
5-fluorouracil
Thymidylate synthase
Intravenous
Adrucil®
Carac®
Carzonal®
Efudex®
Efudix®
Efurix®
Fluoroplex®
Ftoruracil®
Capecitabine
Thymidylate synthase
Oral
Xeloda®
Roche
YakultHonsha Co. Ltd.
Pfizer
Irinotecan
Topoisomerase I
Intravenous
Campto®
Camptosar®
Oxaliplatin
DNA synthesis and
transcription
Intravenous
Eloxatin®
Sanofi-Aventis
Cetuximab
Epidermal growth factor
receptor (EGFR)
Intravenous
Erbitux®
ImClone Systems Inc.
Bevacizumab
Vascular endothelial growth
Intravenous
factor-A (VEGF-A)
Avastin®
Altuzan®
Genentech Inc.
Roche
Panitumumab
Epidermal growth factor
receptor (EGFR)
Vectibix®
Amgen
Intravenous
Table 1: FDA approved anticancer drugs in treatment of mCRC.
Especially, the combination of 5-fluorouracil, irinotecan and leucovorin (FOLFIRI),
5-fluorouracil, oxaliplatin and leucovorin (FOLFOX) and capecitabine with oxaliplatin
(XELOX) are increased therapeutic efficiency in these patients. Recently, target specific
monoclonal antibodies (cetuximab, bevacizumab and panitumumab) have been included in
these drug combinations in order to achieve successful treatment results [39-41].
5-Fluorouracil and capecitabine
5-Fluorouracil (also known as 5-FU or 5-fluoro-2,4-pyrimidinedione) is pyrimidine analog
which is still a widely used anticancer drug for the treatment of various cancer types (colon,
rectum, breast, head and neck, pancreas, skin, stomach and esophagus) as an anticancer
agent over the past 40 years [42,43].
For most mCRC patients, 5-FU is the first line treatment drug; however, 5-FU is used in
combination with oxaliplatin, irinotecan and leucovorin in advanced stages of metastasis
[39,40]. Due to its chemical structure, 5-FU interacts with DNA and leads to irreversible
inhibition of thymidylate synthase (Figure-1) [42,44]. .
5-fluorouracil
FUH2
FUPA
FBAL
(Urine)
FdUrd
dUMP
FdUMP
INHIBITION
Thymidylate
Synthetase
dTMP
Figure 1: Mechanism and metabolic pathway of 5-FU. FUH2(5-Fluorodihydrouracil), FUPA (5-Fluoroureidopropionic
Acid), FBAL (α-fluoro-β-alanine), FdUrd (5-Fluorodeoxyuridine), FdUMP (5-Fluorodeoxyuridine Monophosphate), dUMP
(Deoxyuridine Monophosphate) and dTMP (Deoxythymidine Monophosphate) (Redrawn from Ref. 47)
Thymidylate synthetase (EC 2.1.1.45) is an essential precursor for DNA biosynthesis,
44
and catalyzes the methylation of Deoxyuridine Monophosphate (dUMP) to deoxythymidine
monophosphate (dTMP). This reaction is necessary for DNA biosynthesis and repair
processes. 5-FU is metabolized to form active FdUMP (fluorodeoxyuridine monophosphate)
metabolite that binds covalently to the nucleotide-binding site of thymidylate synthase.
Consequently, this interaction blocks binding of the dUMP and interferes with dTMP
synthesis in cancer cells [45,47]. Therefore, thymidylate synthase has been accepted as a
critical target in cancer drug design studies.
Apart from these advantages, drug resistance and poor bioavailability reveal some
limitations to the clinical use of 5-FU. 5-FU has a short biological life (0,4-2,1 hours) due
to rapid metabolism and its non-oral form administration. Further, 5-FU shows toxic side
effects especially on bone marrow, gastrointestinal tract and unselective effect on normal
healthy cells [42,48-49]. To resolve all these limitations, capecitabine was designed and
approved by FDA. Capecitabine is an orally-administered pro-anticancer drug which is
converted to 5-FU via three-step enzymatic cascade. Oral administration provides rapid
absorption of the capecitabine through the gastrointestinal wall and prevents direct contact
of 5-FU with intestinal tissue [50-52].
Formation of rapid 5-FU resistance is important limiting factor for clinical efficiency.
Multiple factors may contribute to 5-FU resistance in cancer cells. According to the
experimental studies, overexpression of thymidylate synthetase is the main reason for
the resistance development of 5-FU. Further, increased expression level of multidrug
resistance-associated protein 2 and increased glutathione S-transferase activity generate
drug resistance against 5-FU activity in mCRC patients [48,53].
Irinotecan
Irinotecan is a water-soluble and semi-synthetic camptothecin derivate which is mainly
used against colorectal cancer and its metastases as first and second-line chemotherapeutic.
It is used in treatment of advanced CRC and liver metastases with 5-FU and leucovorin.
Further, irinotecan shows anticancer activity in advanced non-small cell lung cancer, either
alone or in combination with cisplatin. Irinotecan inhibits the action of topoisomerase
1 enzyme in cancer cells [47,54-56]. Topoisomerase 1 (EC 5.99.1.3) is ubiquitous and
abundant enzyme in eukaryotic cells and plays critical role in DNA replication, transcription,
translation, and repair processes. Topoisomerase 1 is highly expressed in CRC tissues, and
therefore inhibition of topoisomerase 1 is the significant therapeutic aspect in treatment
of CRC and liver metastases.. Double strand structure of DNA exist in supercoil state and
it is tightly packed into chromatin in normal cellular conditions. During transcription and
DNA replication processes, DNA must be in unwound state. Topoisomerase 1 binds to
the double strand DNA and catalyzes breaking of the phosphodiester bonds between
nucleotides in DNA replication process [57,60].
After administration, irinotecan is converted to SN-38 by catalysis of the carboxylesterase
2 (CES2) enzyme in the liver. SN-38 is active metabolite of irinotecan and metabolized by
uridine diphosphate glucuronosyltransferase (UGT1A1) enzyme. SN-38 is 1000 times more
active than irinotecan. SN-38 binds to the topoisomerase DNA complex in order to prevent
breaking of the single strand of DNA (Figure-2).
INHIBITION
Irinotecan
SN-38
APC/NPC
(Urine)
SN-38G
(Urine)
Topoisomerase-1
Figure 2: Mechanism and metabolism pathway of irinotecan. APC (7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin), NPC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecin, SN-38G (SN-38
glucuronide). (Redrawn from Ref. 47)
45
As a result, DNA replication and transcription mechanisms are inhibited and blocked, and
they ultimately lead to cancer cell death [47,58-61].
Oxaliplatin
Platinum-based anticancer agents (for example: cisplatin, carboplatin, and oxaliplatin)
have been extensively used in treatment of cancer for a long time [62,63]. Oxaliplatin is
a third-generation platinum-based antineoplastic agent which is extensively used in
treatment of first line advanced CRC and liver metastases along with 5-FU, leucovorin,
and capecitabine. Oxaliplatin demonstrate well aqueous solubility, less drug resistance and
significant antitumor activity than cisplatin and carboplatin. Like other platinum-based
compounds, the anticancer action of oxaliplatin is based on formation of DNA damage in
cancer cells. Oxaliplatin causes breaking of the DNA strand and inhibition of DNA replication
unselectively [47,64,65].
Oxaliplatin has planar structure and consists of a central platinum atom (Pt), a
1,2diaminocyclohexane group (DACH) and a bidentate oxalate ligand. Pro-drug oxaliplatin
is converted to highly reactive dichloro, monoaquo, and diaquocomplexes by non-enzymatic
hydrolysis (Figure-3).
NH
Cl
Pt
Cl
NH
NH
O
O
NH
Pt
NH
Pt(DACH)
dicloro complex
O
Cl
Pt
O
+
OH 2
NH
Oxaliplatin
Pt(DACH)oxalate
Pt(DACH)
monoaqua complex
NH
+
OH 2
Pt
+
NH
OH 2
diaqua complex
Pt(DACH)
Figure 3: Bioactive derivatives of oxaliplatin.
These complexes covalently bind to sulphur and amino groups of DNA, RNA, and
proteins. Particularly, its anticancer feature is formed by formation of oxaliplatin-DNA
interaction. Oxaliplatin binds to the guanine and cytosine moieties of DNA and causes
cross-linking of DNA. As a result DNA synthesizes and transcription is inhibited and cancer
cell proliferation is interrupted unspecifically [47,66,67].
Cetuximab and Panitumumab
Cetuximab and panitumumab are monoclonal antibodies which are clinically used
in treatment of a wide spectrum of human malignancies including metastatic colorectal
cancer, non-small cell lung cancer, and head and neck cancer. Cetuximab is a chimeric
(mouse/human) monoclonal antibody; however, panitumumab is a fully human monoclonal
antibody. Especially, cetuximab and panitumumab are used as first-line therapeutics
for the treatment of patients with Epidermal Growth Factor Receptor (EGFR)-expressing,
46
ras wild-type metastatic colorectal cancer in combination with FOLFOX and FOLFIRI
[68-70].
EGFR is the transmembrane receptor which is member of the Erb-B/ HER tyrosine
kinase receptors family. EGFR is involved in the pathogenesis and progression (cancer cell
proliferation, survival, migration, apoptosis, and differentiation) of different cancer types.
Therefore, aberrant expression of EGFR is to be a significant prognostic feature for many
tumor types, especially for CRC and liver metastases. EGFR is activated by binding of several
specific ligands: Epidermal Growth Factor (EGF), Transforming Growth Factor α (TGFα),
and heparin-binding EGF (HB-EGF). Numerous oncogenic signaling pathways (JAK-STAT,
PI3K/AKT/mTOR, MAPK/ERK, and PLC-Ɣ signaling pathways) are stimulated by EGFR. These
pathways lead to the inhibition of apoptosis and activation of metastases, cell proliferation,
angiogenesis, cell migration, adhesion and invasion in tumor pathogenesis (Figure-4).
Ligand (EGF, TGF-α)
INHIBITION
Ligand binding
Cetixumab
Panitumomab
EGFR
Ligand binding domain
CELL MEMBRANE
P
CYTOPLASM
P
EGFR
PHOSPHORYLATION
JAK/SRC
PI3K
Ras/Raf/
MEK
PLC
DAG
STAT
Akt
Erk
PKC
Inhibition of Apoptosis
Angiogenesis
Cell Proliferation
Migration, Adhesion, Invasion
Metastases
Figure 4: Mechanism pathway of cetuximab and panitumumab (Redrawn from Ref. 74).
Cetuximab and panitumumab bind specifically to the ligand binding domain of EGFR
as competitive inhibitors of the EGF and TGFα. These interactions support internalization
of the EGFR from cell surface to cytoplasm. Therefore, inhibition of EGFR has become
important therapeutic strategy in oncology [71-74].
47
Bevacizumab
Bevacizumab is a recombinant humanized monoclonal antibody that is known as the
first FDA approved angiogenesis inhibitor in treatment of mCRC, HER2-negative metastatic
breast cancer, and advanced non-squamous non-small cell lung cancer. Angiogenesis is
an essential process for the development and progression of cancer. Bevacizumab inhibits
Vascular Endothelial Growth Factor A (VEGF-A), and blocks prevents and/or reduces the
formation of blood vessels (angiogenesis) in cancer cells. Therefore, bevacizumab is more
effective on metastatic solid tumors [75-77].
The VEGF family consists of six members: VEGF-A, VEGF-B, VEGF-C, VEGF-D,
VEGF-E, and placenta induced growth factor. Especially, VEGF-A comes to the forefront
in angiogenesis pathways. VEGF-A is a dimeric glycoprotein and it is involved in vascular
development and blood-vessel formation. VEGF-A is the key pro-angiogenic factor that
stimulates tumor angiogenesis and the survival of tumor endothelial cells. VEGF-A is
overexpressed in almost all cancer tissues and it is induced by Hypoxia-Inducible Factor
1 (HIF-1); Platelet Derived Growth Factor (PDGF), Tumor Necrosis Factor A (TNF-a), and
transforming growth factor-b (TGF-b) and by inactivation of the von Hippel-Lindau (vHL)
gene. RAS/RAF/MEK/ERK (MAPK) and PI3K/PTEN/AKT (AKT) are two major signaling
pathways and are related with angiogenesis. Bevacizumab binds to the VEGFR-1 and
VEGFR-2, and this interaction inhibits angiogenesis process [78-82].
Clinical applications of drugs in mcrc treatment
Historically, the first line combined chemotherapy for mCRC was 5-FU and leucovorin
(5-FU-Lv). Over the past decade, addition of oxaliplatin and irinotecan lead to improvement in
treatment of patients. More recently, insights of pathophysiologic mechanism of metastasis
have been highlighted and therefore, biologic mechanisms of CRC tumors were targeted
with bevacizumab, cetuximab, and panitumumab (Table-2).
Author
Phase
De Gramont [39]
III
Arms
Sample size
(n)
LV5FU2
420
FOLFOX
Saltz [40]
III
LV5FU2
683
FOLFIRI
Douillard [41]
III
LV5FU2
387
FOLFIRI
Tournigard [42]
III
FOLFIRI/FOLFOX
220
FOLFOX/FOLFIRI
Hurwitz [43]
III
IFL
813
IFL+Bevasizumab
Salt z [46]
III
FOLFOX/XELOX
1401
FOLFOX/XELOX +
Bevacizumab
Van Cutsem [47]
III
FOLFIRI
1198
FOLFIRI + Cetuximab
Bokemeyer [48]
II
FOLFOX
315
FOLFOX+ cetuximab
Douillard [49]
III
FOLFOX
FOLFOX+ panitumomab
1183
ORR
PFS
OS
(%)
(months)
(months)
Resectability
rate (%)
22.3
6.2
14.7
3.3
50.7
9.0
16.2
6.7
NA
28
8.7
12.6
50
9.2
14.8
41
4.4
14.1
69
6.7
17.4
NA
56
21.5
9
54
20.6
22
NA
34.8
6.2
15.6
44.8
10.6
20.3
38
8.0
19.9
6.0
38
9.4
21.3
8.4
38.7
8.0
18.6
1.7
46.9
8.9
19.9
4.8
36
7.2
18
3*
46
7.2
18.3
12*
48*
8.6*
19.7*
18**
57
10.0
23.9
28
Table 2: Clinical trials in metastatic colorectal cancer .
ORR: Overall response rate PFS: Progression free survival OS: Overall survival
*KRAS wild type, ** Only cases with liver metastasis
48
Oxaliplatin in addition with 5-FU-Lv regimen (FOLFOX) was compared with 5-FU-Lv
alone in a randomized controlled trial [83]. The addition of oxaliplatin improved Progression
Free Survival (PFS) by 2.7 months (9.0 months vs. 6.3 months, p=0.0001). In this study,
6.7% of the patients who received FOLFOX regimen were able to get their liver metastasis
resected. In contrary, 5-FU-Lv group had only 3.3% of liver metastasis resection. The most
common grade 3-4 side effects of oxaliplatin containing chemotherapy were neutropenia
and neurosensory toxicity.
Saltz et al. compared irinotecan, irinotecan with 5-FU-Lv combination (IFL) and 5-FULv combination alone in patients with Mcrc [84]. The Objective Response Rate (ORR) was
higher with IFL than that of FU-Lv (p<0.001; 50% vs 28%, respectively). The combination
therapy with irinotecan was shown to be superior FU-Lv regimen in terms of PFS, response
rate, and OS times. PFS was 7.0 months in the arm of IFL vs. 4.3 months in FU-Lv arm.
Median OS was 14.8 and 12.6 months, respectively (P=0.04).
In another study, Douillard et al. had similar results [85]. In their study, ORR, PFS,
and OS were superior with irinotecan compared to non-irinotecan combined chemotherapy
(ORR: 69% vs. 41%; PFS: 6.7 vs. 4.4 months; OS: 17.4 vs. 14.1 months). Metastasectomy
was not a study end point for both of these trials. Diarrhea, neutropenia, mucositis were the
most common side effects observed during the treatment.
In GERCOR study, the authors compared oxaliplatin- (FOLFOX) and irinotecan plus
5-FU+Lv (FOLFIRI) combination regimens [86]. FOLFOX regimen was compared initially
with irinotecan+ 5-FU-Lv (FOLFIRI) regimen in this study [86]. In the first-line, while PFS
was 8.5 months with FOLFIRI and 8.0 months with FOLFOX, PFS was 4.2 and 2.5 months
in the second line, respectively. FOLFOX had a similar therapeutic benefit to FOLFIRI with
less gastrointestinal adverse effects and neutropenia at a cost of more neuropathy. However,
metastasectomy rate was 22% for FOLFOX and 9% for FOLFIRI (p=0.02).
In 2004, in a German study, addition of bevacizumab to IFL regimen resulted in 4.9
months increase in OS [87]. The median OS was 20.3 months in the arm of bevacizumab
and 15.6 in the arm of IFL. The PFS and response rates were superior in bevacizumab added
arm (10.6 and 6.2 months, respectively). The ORR was superior in the experimental arm
compared to the control (44.8% vs. 34.8%). Newer infusional irinotecan-5-FU-Lv regimens
were not inferior to IFL regimen [88,89].
Capecitabine is a 5-FU analog used alone or in combination with oxaliplatin and/or
irinotecan including regimens. The addition of bevacizumab to FOLFOX or capecitabineOxaliplatin Regimen (XELOX) was tested by Saltz et al [90]. The only statistical difference
was shown in PFS (9.4 months vs. 8.0 months, p=0.0023). There was no difference in either
OS duration or response rates (DFS: 38% vs. 38% and OS: 19.9 vs. 21.3 months). Of 1401
patients recruited in that study, 8.4% in bevacizumab arm and 6.0% in chemotherapy only
arm had the chance of curative metastasectomy.
CRYSTAL study was published in 2009 in which addition of cetuximab to irinotecan based
protocol was tested [91]. Cetuximab with FOLFIRI had resulted in better PFS (8.9 vs. 8.0 months)
and ORR (47% vs. 39%), but no difference in OS (19.9 vs. 18.6 months). There was another
endpoint of study that showed a higher rate of R0 liver resection in cetuximab arm (4.8% vs.
1.7%, p=0.0002). Subgroup analysis yielded that KRAS status is the determinant of efficacy of
cetuximab and also in FOLFIRI only arm KRAS wild type tumors were more prevalent (66.9%
vs. 62.1%). However, the difference surgery rate according to KRAS status was not reported.
KRAS status was tested for cetuximab efficacy in OPUS study [92]. OPUS study was a
phase II study which enrolled patients in FOLFOX 4 and FOLFOX4-cetuximab arms. ORR
was higher in cetuximab arm (46% vs. 36%; p=0.064). But, PFS and OS were similar in the
study groups. Further, the patients were tested for KRAS status and Wild Type (WT) tumor
harboring patients had better survival results with cetuximab. However, in patients with
KRAS wild-type, ORR and PFS improved with cetuximab (ORR: 57% vs. 34% and PFS 8.3
49
vs. 7.2 months). The addition of cetuximab to KRAS WT patients also led to increased liver
surgery rates (12% vs. 3%, p=0.242).
A phase 3 multicenter trial, the Panitumumab Randomized Trial in Combination
with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME), was
investigated panitumumab in combination with FOLFOX4 chemotherapy as first-line
treatment for patients with mCRC [93]. In patients with KRAS WT, ORR was significantly
higher in the panitumumab arm compared to the control group (57% vs. 48%; p=0.02).
Also, PFS improved in the arm of panitumumab-FOLFOX4 than the control group (10.0
vs. 8.6 months; p=0.01). However, in patients with KRAS mutation, the treatment effect of
panitumumab was found inferior. The median OS was superior in the combination group
than the control group, but the difference was no significant (23.9 vs. 19.7 months; p=0.17).
The complete resection rate in patients with KRAS WT mCRC was similar in the groups
(10% vs. 8%). In patients with KRAS WT mCRC with baseline metastasis in the liver, the rate
was higher in the experimental arm than the FOLFOX4 alone arm (28% vs. 18%).
The results of subset analyses of these trials suggested that KRAS was a well-established
biomarker predictive of anti-EGFR monoclonal antibody efficacy in patients with mCRC.
Wild type KRAS is an obligatory biomarker for patients to get benefit from anti-EGFR
targeted therapy. (Table 3).
CRYSTAL
Arms
Cetuximab +
KRAS Exon FOLFIRI
2 WT
FOLFIRI
Cetuximab +
KRAS Exon FOLFIRI
2 MT
FOLFIRI
RAS wild
OPUS
PRIME
PFS
OS
Arms
PFS
OS
Arms
PFS
OS
9.9
23.5
Cetuximab
+FOLFOX-4
8.3
22.8
Panitumumab +
FOLFOX-4
10.0
23.9
8.4
20.0
FOLFOX-4
7.2
18.5
FOLFOX-4
8.6
19.7
7.4
16.2
Cetuximab +
FOLFOX-4
5.5
13.4
Panitumumab +
FOLFOX-4
7.4
15.5
7.7
16.7
FOLFOX-4
8.6
17.5
FOLFOX-4
9.2
19.2
12.0
20.7
Panitumumab +
FOLFOX-4
10.1
25.8
5.8
17.8
FOLFOX-4
7.9
20.2
Cetuximab +
FOLFIRI
11.4
28.4
Cetuximab +
FOLFOX-4
FOLFIRI
8.4
20.2
FOLFOX-4
Table 3: The outcomes of anti-EGFR therapies in patients with metastatic colorectal cancer according to KRAS mutation.
Given these findings, it can be interpreted that a proportion of patients with initially
unresectable liver disease may have a chance in future with careful patient selection and
proper chemotherapy implementation. However, in the studies that are described latter,
the primary end point was not resectability nor the patients were defined as potentially
resectable in the initial recruitment. Therefore, the results should be carefully investigated.
The role of chemotherapy for patients with initially resectable disease is controversial.
The aims of neoadjuvant chemotherapy in this setting are: i) to eradicate micrometastasis
that already exists in the initial diagnosis and may progress during the surgery period, ii) to
evaluate the chemosensitivity and biologic behavior of tumor and, iii) to decrease the size of
liver metastasis in order to have a low surgical morbidity.
Neoadjuvant chemotherapy response can be a selection criterion for further surgery
and treatment modalities. This hypothesis has been tested since 2004. In a French study,
the patients who had progressive disease during neo-adjuvant therapy course had a lower
5-year OS probability [94]. Allen et al. had a similar result showing that progressive disease
is a negative prognostic factor [95]. However, if the patient remained resectable despite the
disease progression, than the surgery is still beneficial. The 5-year OS rate for which the
surgery was offered was better than for patients who were withheld from surgery.
EORTC 40983 trial addressed the same question of real evidence for neo adjuvant
chemotherapy [96]. An upfront surgery arm was compared with pre- and post-operative
chemotherapy (FOLFOX4) + surgery arm. The median PFS durations were not statistically
50
significant between the two arms (11.7 months vs. 18.7 months, p=0.058). Seventeen
percent of the patients were excluded from analysis since they were found to have more
extensive state of the disease. After the exclusion, the 3-year PFS was found to be 36.2%
for combination modality arm and 28.1% for surgery alone arm which was statistically
significant (p=0.025). Forty-four percent of the patients could not complete postoperative 6
cycles of chemotherapy whereas 79% of the patients completed preoperative chemotherapy
cycles. Chemotherapy resulted in high but reversible postoperative complication rate.
Adam et al. showed that with better case selection neoadjuvant chemotherapy can be
more beneficial. They retrospectively analyzed the data from Liver Met Survey International
Registry [97]. In patients with >5 cm liver lesion, neoadjuvant chemotherapy has resulted in
better 5-year OS rate (58% vs. 33%, p<0.01).
A recent systematic review summarized the evidence on the beneficence of neoadjuvant
chemotherapy for patients with initially resectable live metastasis [98]. Eight retrospective
studies were included. The 5-year OS rate for neoadjuvant chemotherapy received patients
ranged from 38.9 % to 74%. For the surgery patients, the range was from 20.7% to 56%.
No statistically significant difference between the groups was found in 7 of 8 studies. The
authors concluded that there is no clear evidence on the role of neoadjuvant chemotherapy
for resectable liver lesions.
The role of adjuvant chemotherapy after the liver resection is also not clear. According
to results of MOSAIC trial, FOLFOX was superior to FU-Lv in terms of 5-year disease free
survival in patients with stage III, resected liver lesions. Irinotecan has not been shown
superior over 5-FU-Lv in adjuvant setting [99]. A meta-analysis of four studies of perioperative
chemotherapy found no OS benefit but did find a 25% PFS benefit [100]. The addition of
bevacizumab to FOLFOX6 or cetuximab to FOLFOX6 in KRAS WT tumors have not been
clearly shown adding benefit in adjuvant setting for resected stage III mCRC.(Figure 5)
VEGF-A
INHIBITION
Ligand binding
Bevacizumab
VEGFR-2
VEGFR-1
CELL MEMBRANE
CYTOPLASM
PI3K
p38MAPK
Ras/Raf/
MEK
Akt
Erk
ANGIOGENESIS
Figure 5: Mechanism pathway of bevacizumab (Redrawn from Ref. 82).
51
Herein, we described latest advancement in mCRC treatment by surgical and oncological
approaches. Specially, combined drug therapy improves the life quality of mCRC patients
and help surgical treatments
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96. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, et al. (2008) Perioperative chemotherapy with
FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC
Intergroup trial 40983): a randomised controlled trial. See comment in PubMed Commons below Lancet 371:
1007-1016.
56
97. Adam R, Bhangui P, Poston G, Mirza D, Nuzzo G, et al. (2010) Is perioperative chemotherapy useful for
solitary, metachronous, colorectal liver metastases? See comment in PubMed Commons below Ann Surg
252: 774-787.
98. Nigri G, Petrucciani N, Ferla F, La Torre M, Aurello P, et al. (2015) Neoadjuvant chemotherapy for resectable
colorectal liver metastases: what is the evidence? Results of a systematic review of comparative studies. See
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99. Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, et al. (2009) Randomized phase III trial comparing
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57
eBooks
ISBN: 978-1-63278-054-6
DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
Chapter 5
Treatment of Rectal Cancer
Ahmed M El-Sharkawy1*
Biochemistry department, Faculty of Science, Alexandria University, Alexandria,
Egypt
*
Corresponding author: Ahmed M El-Sharkawy, Biochemistry department, Faculty
of Science, Alexandria University, Alexandria, Egypt,Tel:+201000512872; E-mail:
[email protected]
1
Introduction
Globally, rectal cancer is a major health problem with increasing incidence. In the United
States, 40 340 new cases were estimated to be diagnosed with rectal cancer in 2005 [1].
The treatment goals of patients with rectal cancer can be summarized into 4 main goals:
(1) local control; (2) long-term survival; (3) preservation of sexual functions, bladder and
anal sphincter and (4) improving life quality of rectal cancer patients. These goals can be
achieved through a multi-modality approach carried out by a multi-disciplinary team. In
this chapter, some of the important surgical issues aiming at the management of patients
with early (T1/T2 and N0), as well as locally advanced (T3/T4 and/or N1) rectal cancer.
Preoperative Staging
When planning a curative rectal cancer resection, it is important to take into considerations
the following factors: (1) tumor penetration through the rectal wall; (2) involvement of
lymph nodes and (3) the presence of metastatic disease. The importance of preoperative
staging is to determine the indication for neoadjuvant therapy and to determine whether
radical resection or local cancer excision would result in optimum surgical treatment.
There are several imaging techniques currently used in the preoperative staging of rectal
cancer, the most common of which are: (1) Positron Emission Tomography (PET) scan, (2)
Magnetic Resonance Imaging (MRI), (3) Computed Tomography (CT) scan and (4) Endorectal
Ultrasound (ERUS).
ERUS
ERUS is considered as an accurate imaging technique to stage rectal cancer preoperatively.
It has 2 advantages: (1) can be performed with minimal preparation at the time of patient
evaluation and (2) performed with patient discomfort. ERUS is used to determine the tumor
(T) and lymph node (N) stage of rectal cancer (figure 1). ERUS is 62% to 92 % accurate for
T-staging and 64% to 88% accurate for N-staging [2,3] according to the currently available
data. Although, ERUS is currently considered the most accurate method of rectal cancer
local staging, it is limited by operator variability, its steep learning curve and limitations
for staging near-obstructing tumors and downstaged tumors after chemoradiation therapy.
An analysis of 4118 subjects reported an overall mean T-staging accuracy of 85% (median,
88%) and N-staging accuracy of 75% (median, 76%). With the lowest rates reported in more
recent literature, Both T-staging and N-staging accuracy rates declined over time [4].
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
58
Figure 1: Rectal wall anatomy. A: Schematic diagram of ERUS image; B: Actual image of normal ERUS [3].
CT
In an effort to identify intra-abdominal metastatic disease prior to a curative or radical
resection, the vast majority of patients with clinically localized rectal cancer have an
abdominopelvic CT prior to surgical resection. However, the role of CT in the preoperative
locoregional staging of rectal cancer is much more limited. The accuracy of CT for T-stage (53%
to 94%) and N-stage (54% to 70%), are substantially lower overall than that of ERUS [2].
MRI
ERUS is considered more accurate than traditional body-coil MRI and that’s why MRI is
rarely used for locoregional staging of rectal cancer. However, newer techniques of endorectal
coil MRI and phased-array MRI has an accurate percentage of 66% to 92% in determining
T-stage, and can determine extent of tumor mesorectal involvement up to 100% of cases
[2,5,6]. Although MRI is limited by its relatively small field of view, expense and patient
intolerance, it is promising in the preoperative staging of rectal cancer. Restaging patients
treated with preoperative chemoradiation using MRI does not appear to be as accurate,
similar to ERUS. MRI had the accuracy of 52% in T stage and 68% in N stage [7] in a study of 50
patients. Overstaging was the causative factor in most of the inaccuracy in both T and N stages,
this was due to the inability of MRI to differentiate treatment induced fibrosis from the viable
tumors. In the future, MRI may play a fundamental role in determining whether the mesorectal
fascia has been breached by tumor preoperatively, and thus optimize patient selection for
neoadjuvant therapy. The results of an ongoing prospective, multicenter trial should better
define the role of MRI in the preoperative staging of patients with rectal cancer (Figure 2).
Figure 2: Treatment algorithm for patients with rectal cancer and no evidence of distant metastases. LE: local excision; CRT:
chemoradiation therapy. Observation following a LE of a T1 adenocarcinoma, even with good pathological features, may
result in 20% local recurrence at 10 years.
59
PET
PET scanning has been used in the postoperative evaluation of potential recurrences after
a curative resection of rectal cancer. This is often initiated by a rising CEA level. However,
preliminary data from a prospective trial conducted at our institution suggests that PET
may have a role in determining locally advanced rectal cancer response to neoadjuvant
chemoradiation [8]. As such, PET can potentially guide changes to the type of neoadjuvant
chemoradiation to increase tumor response, as well as guide extent of subsequent surgical
therapy. An ongoing, large, prospective study aims to confirm these encouraging results.
Selection of Curative Resection
Local excision is likely to be curative in patients with a primary tumor which is limited
to the submucosa (T1N0M0), without high-risk features (i.e., poorly differentiated, vascular
and neural invasion) and in the absence of metastatic disease. However, recent retrospective
series with long-term follow-up suggest that even T1 rectal cancers without high-risk
features have higher recurrence rates than expected [9-12]. Therefore, an increasing
percentage of these patients are undergoing radical rectal resection. The decision to pursue
a radical resection versus a local excision for an early staged rectal cancer is most difficult
when the radical resection would require a permanent colostomy. Careful discussion of
risks and benefits with the patient is particularly essential in this circumstance. Once the
tumor invades the muscularis propria (T2), radical rectal resection in acceptable operative
candidates is recommended. In patients with transmural and/or node positive disease
(T3/T4 and/or N1) with no distant metastases, preoperative chemoradiation followed by
radical resection according to the principles of TME has become widely accepted (Figure
2). In patients with metastatic disease, complex and interrelated variables such as patient
co-morbidities, patient expectations, and resectability of metastases must be considered
when planning surgical therapy. For patients with unresectable distant metastatic disease,
surgical excision of the primary rectal cancer may still be considered when palliation of
symptoms is anticipated.
Chemo radiation Therapy
The use of perioperative Chemoradiation Therapy (CRT) for rectal cancer continues to
evolve. Based largely on the results of two multicenter trials, the 1990 NIH Consensus
Conference on rectal cancer recommended postoperative chemoradiation for patients with
trans mural and/or node positive rectal cancer [13]. Although postoperative therapy for stage
II/III rectal cancer remains a reasonable option, many centers have adopted a treatment
strategy of using preoperative chemoradiation therapy. The benefits of neoadjuvant
chemoradiation therapy have been well documented, and include tumor regression and
downstaging associated with increased tumor resectability and a higher rate of sphincter
preservation [14-18]. Moreover, complete pathologic response rates up to 10% to 25%
can be achieved [18-25]. The German Rectal Cancer Study Group recently completed a
large, prospective, randomized trial that compared preoperative versus postoperative
chemoradiation in the treatment of clinical stage II and III rectal cancer [26]. They concluded
that, although there was no difference in overall survival between the two groups, there was
a significant reduction both in local recurrence rate (6% vs 13%, P = 0.006) and treatment
toxicity in the preoperative group. Although the quality of life for patients treated with
preoperative CRT may transiently decrease, this finding is counterbalanced, in large part,
by the potential for improved oncologic outcome in properly selected patients [27]. Current
studies evaluating treatment outcomes in rectal cancer patients with a complete or near
complete response to neoadjuvant chemoradiation have demonstrated improved survival
compared to partial responders or nonresponders [14,18]. In one report, patients with a
complete pathological response had a 5 year disease-free survival of 95.2% compared to
55.4% for those with a partial or no pathological response (P = 0.03)[14]. In a recent report
60
from MSKCC, 297 patients with locally advanced (T3-4 and/or N1) rectal cancer were treated
with preoperative chemoradiation therapy followed by TME [28]. Patients who achieved >
95% pathological response from preoperative CRT had a significantly improved 10 year OS
and RFS rates, when compared to those patients with a < 95% pathological response [28].
In light of the significant response rates that can be achieved with preoperative therapy,
some have suggested limiting further surgical therapy to transanal excision alone [29,30]
or observation[31,32] for patients with a complete response. This approach is limited by
the difficulty in precisely determining tumor response to chemoradiation and assessing
residual mesorectal lymph node involvement. Currently, assessment of tumor response is
determined postoperatively by objective measurements of tumor volume in the surgical
specimen compared to preoperative clinical staging; however, preoperative staging is based
on subjective evaluation and, with current methods and technology, remains unreliable
following chemoradiation. ERUS is considered the most accurate way to stage rectal cancer.
But after radiation therapy, it is diffi cult to distinguish between residual tumor and radiation
fi brosis and accuracy decreases to 47%-58% [33-37]. Similarly, restaging patients treated
with preoperative chemoradiation using MRI does not appear to be accurate [7]. As discussed
earlier, a preliminary report from MSKCC showed response assessment may be improved
with the use of FDG-PET scanning [8]. In a series of 15 patients, FDG-PET scanning was
able to more accurately assess treatment responses; confirmation with a large, prospective
study is ongoing. In patients that undergo transanal local excision, there is a risk of leaving
residual disease in the mesorectum, even after combined preoperative chemoradiation
therapy. Many studies have reported 1.8% to 16% of patients with lymph node involvement
despite a complete pathological response in the primary tumor [38-40]. Given the inability
of existing imaging modalities to reliably confirm the eradication of mesorectal nodal
metastases, patients undergoing TAE alone following preoperative CRT are at risk for local
failure due to residual nodal disease.Currently, there are no data to support the routine
use of TAE in these patients, and definitive treatment should continue to be rectal resection
with TME. These data strongly support the need for prospective clinical trials designed
to optimize the combination and sequencing of multidisciplinary neoadjuvant therapy in
order to maximize survival and locoregional control rates in rectal cancer patients. If the
response rate can be enhanced, it may permit less radical surgery in patients with complete
responses to preoperative therapy and adjust the dose intensity or duration of postoperative
chemotherapy. Ultimately, the aim of this approach is to be able to individualize or customize
a patient’s treatment based upon expression of molecular markers, genetic signatures
using gene arrays and response to systemic therapy preoperatively. In patients treated with
preoperative chemoradiation, surgical resection is generally deferred until 6 to 8 weeks
following completion of therapy in order to allow maximal tumor response, as well as patient
recuperation from the toxicities sometimes associated with chemoradiation. Although the
benefit of a prolonged interval from completion of chemoradiation to surgery is unclear,
when clinically necessary it does not appear to increase the operative blood loss, operative
time, and positive margin rate [41].
Early Rectal Cancer (T1/T2 and N0)
Local Excision
Transanal Local Excision (LE) for T1 rectal cancer offers minimal morbidity and minimal
long-term functional problems compared to radical resection (i.e., APR or LAR). On the other
hand, recent evidence suggests that patients treated with LE have higher local recurrent
rates than those treated with radical resection [10-12,42]. Preoperative staging is relatively
inaccurate and rates of LR vary widely from 7% to 40% after LE for T1 tumors [10-12,4245]. Based on more recent, larger studies with longer follow-up, the LR rate appears to
be approximately 10% to 25%. In those patients that recur after LE, only 50% or less will
ultimately be cured by radical resection for salvage [46]. Because local excision does not
61
remove the lymph node bearing tissue of the rectum (mesorectum), optimal patient selection
is imperative in order to diminish the likelihood of offering this procedure to a patient whose
rectal cancer might have lymph node metastases. The risk of lymph node involvement
is 0%-12% for T1 cancers, 12%-28% for T2 cancers, and 36%-79% for T3 cancers [47].
Features associated with a significantly increased risk of lymph node metastases include
poor differentiation, lymphovascular invasion, and size greater than 3 centimeters [48,49].
It is therefore not surprising that, following local excision, local regional recurrence rates
can be as high as 11%-29% for T1 tumors, 25%-62% for T2 tumors, and > 40% for T3
tumors [10,11,47]. Overall survival has been reported from 70% to 89% in recent series
of properly selected patients (Table 1) [10-12,43,44]. However, most studies on transanal
excision have followup data of less than 5 years and a relatively small sample size. This,
in addition to the long natural history of the disease, makes conclusions on long term
efficacy difficult. In 67 T1 patients treated by LE, a study at Memorial Sloan Kettering
Cancer Center reported a 74% 10 year DSS [10]. In patients who develop a locoregional
recurrence following local excision of rectal cancer, salvage with a radical resection is
possible, with several small series reporting a 50% to 88% Disease-Free Survival (DFS)
[44,50]. After final pathology is available from a LE, consideration should be given to
immediate radical resection (i.e., within 30 d). Thus, high-risk tumor characteristics and
a location or size that does not enable a re-excision with clear margins warrants radical
salvage surgery in order to achieve maximum local disease control. In one report of 21
patients at MSKCC, immediate radical surgery in stage I patients with adverse features
was superior to those treated initially with LE followed by salvage surgery at the time
of local recurrence; 94% DFS was noted in the group treated with immediate radical
resection for adverse pathology versus 55% in the cohort treated with radical surgery
after LR was documented [51]. A recent report from the Mayo clinic also showed that
LE followed by radical surgery within 30 d does not compromise outcome compared
with primary radical surgery. In the largest series published to date, 49 patients who
underwent successful surgical salvage of local recurrence after LE of T1 rectal cancer,
55% required an extended pelvic dissection with en bloc resection of adjacent pelvic
organs [46]. Despite the fact that 47 of 49 patients had complete resection of their pelvic
disease, 58% had recurred or died of disease within 33 mo.
Five year DSS was 53% [46]. Currently, local excision for cure is recommended only for
carefully selected T1 tumors without high-risk features [9,10]. Patients must be followed
closely and for a long period, since almost a third of local recurrences after TAE of early
stage rectal cancer occur 5 years or more after local excision [10]. The role of adjuvant
chemotherapy and radiation after LE is not defined at this time. Local excision is also an
option for palliation in patients with locally advanced rectal cancer or stage IV patients
unsuitable for radical resection [52].
Study (yr)
n
Tayler et al (1998)
[45]
24
Follow – up (n10)
Local Recurrence (%)
Overall survival (%)
52
T1:40
T2:50
67
66
Chakaravati et al(1994)[44]
52
52
T1:11
T2:62
Steel et al (1999)[43]
1101
48
T1:7
T1:20
T1:87
T2:85
Mellgreen et al (2000)[42]
108
53
T1:17
T2:46
69
Paty et al(2002)[10]
125
80
T1:17
T2:26
T1:74
T2:72
Endreseth et al (2005)[11]
35
24-97
T1:12
T1:70
Madbouly et al (2005)[11]
52
55
T1:29
T1:89
Table1: Patients with T2 cancers on pathology were treated with postoperative chemo radiation.
62
Figure 3: Specialized equipment in use for the performance of TEM[90].
Trans anal Endoscopic Microsurgery (TEM)
TEM is an option for excising rectal cancers that are otherwise inaccessible by
standard transanal excision [53]. Using a specially designed 40 millimeter diameter and 25
centimeter long operating endoscope, tumors located as high as 10 centimeters anteriorly,
15 centimeters laterally, and 20 centimeters posteriorly can be excised under direct vision
(Figure 3). TEM provides a technique for full thickness excision of both benign and properly
selected malignant lesions (i.e. T1 with no high risk features) that are too high for Trans anal
excision and would otherwise require radical resection [53]. It is imperative to keep in mind
that the selection criteria for TEM are the same as those for local excision (described above)
[54]. When used on appropriately selected early-stage lesions, TEM can achieve oncologic
results similar to those of radical resection, while limiting morbidity and mortality [54].
Locally Advanced Rectal Cancer (T3/T4 And/Or N1)
During the planning and conduct of a radical operation for a locally advanced rectal
cancer, a number of surgical management issues are considered, including: (1) Total
Mesorectal Excision (TME); (2) Autonomic Nerve Preservation (ANP); (3) Circumferential
Resection Margin (CRM); (4) Distal Resection Margin; (5) sphincter preservation and options
for restoration of bowel continuity; (6) laparoscopic approaches; and (7) postoperative quality
of life. The sections that follow examine each of these issues.
Total Mesorectal Excision (TME)
TME is a technique which requires precise dissection in an areolar plane between the
visceral fascia that envelops the rectum and mesorectum and the parietal fascia overlying
the pelvic wall structures. The end result of this procedure, when performed properly, is
an intact mesorectum containing the draining lymph nodes of the rectum. This technique
also facilitates pelvic autonomic nerve preservation. TME emphasizes the achievement of
negative CRM and distal margins, thus optimizing the oncologic outcome for the patient.
TME has been shown to achieve a negative CRM in up to 96% of resected specimens [55].
Most importantly, large series from surgical teams worldwide using TME techniques have
reported local failure rates as low as 3% and overall 5-year survival of up to 80% (Table 2)
[55-59]. This compares favorably with large reviews of standard surgery that reported local
recurrence rates of 15% to 19%, with some studies reporting local failure as high as 48%
[60,61]. In fact, in studies comparing rectal resection according to the principles of TME
to historical controls of standard, blunt mesorectal dissection, the patients treated with
TME consistently have lower local recurrence rates [55,62-64]. Currently, TME should be
63
considered an integral aspect of the optimal surgical management of the patient with locally
advanced rectal cancer.
Autonomic Nerve Preservation
The sympathetic nerves of the pelvis originate from the T12 to L3 ventral nerve roots,
ultimately forming the preaortic superior hypogastric plexus (Figure 4) [65]. Distal to the
aortic bifurcation, the superior hypogastric plexus forms the hypogastric nerve, which may
be intimately associated with the visceral fascia of the mesorectum. Injury to the hypogastric
sympathetic nerve trunks results in increased bladder tone with reduced bladder capacity,
voiding difficulty, impaired ejaculation in men, and loss of vaginal lubrication and dyspareunia
in women. The parasympathetic nerves of the pelvis (nervi erigentes), arising from the S2 to
S4 ventral nerve roots, join the hypogastric nerves (sympathetic) on the pelvic sidewall to
form the inferior hypogastric plexus (pelvic autonomic nerve plexus) (Figure 4) [65]. Damage
to the parasympathetic nerves leads to erectile dysfunction, impaired vaginal lubrication,
and voiding difficulty. Truncal ANP is defined as preservation of the anterior nerve roots
of S2, S3, and S4, the superior hypogastric nerves, and the pelvic autonomic nerve plexus
[57]. With careful autonomic nerve preservation, postoperative genitourinary and sexual
dysfunction can be reduced from 25% to 75% to as low as 10% to 28% [66]. More specifically,
neurogenic bladder can be reduced from 9% to 40% with conventional rectal resection to
as low as 0% to 11% with TME and ANP [66-68]. The rate of sexual dysfunction may be
further reduced by using intraoperative nerve stimulators to help identify and preserve the
pelvic autonomic nerves [69]. It must be emphasized, however, that factors other than ANP,
such as history of chemoradiation, patient co-morbidities (i.e. -atherosclerosis, diabetes
mellitus, hypertension), medications (i.e. beta-blockers), and alcohol use may contribute to
genitourinary and sexual dysfunction following radical rectal resection.
LN: Lymph node; DFS: Disease free survival
Figure 4: Diagram of pelvic autonomic nerve anatomy [70].
Circumferential Resection Margin (CRM)
The importance of the CRM in minimizing local recurrence of rectal cancer was first reported
in 1986 (Figure 5). A recent series of 686 patients with rectal cancer treated with TME after a
median follow-up of 29 mo documented a 5% local recurrence rate for patients with CRM > 1
millimeter and a 20% local recurrence rate for a CRM ≤ 1 millimeter [58]. Obtaining a negative
CRM is likely to result in decreased rates of local recurrence, distant metastases, and death. In
order to provide an optimal oncologic outcome, the surgeon must make all efforts to obtain a
negative CRM, including en bloc resection of contiguous structures.
64
Figure 5: MRI of rectal cancer with demonstration of circumferential resection margin (CRM) [6]; Black arrows: rectal cancer;
White arrows: mesorectal fascia; Dashed line: CRM, which is defined as the shortest distance from rectal cancer to the
lateral resection margin of the mesorectum.
Distal Resection Margin
Distal spread greater than 1 centimeter beyond the mucosal edge of rectal cancer
has been documented in only 10% of cases, all in poorly differentiated, node-positive
lesions [70-73]. Recent data support this fi nding, suggesting that margins as small as
1 centimeter may provide acceptable oncologic results. In a series from our institution,
the recurrence-free survival and local recurrence rates with 3 years of follow up after
preoperative Combined Modality Therapy (CMT) and TME-based resection were not
significantly different in patients when margins less than or equal to 1 centimeter were
compared to those greater than 1 centimeter. Thus, although we advocate striving for a
2-centimeter distal resection margin when feasible, acceptable oncologic results may
be achieved with margins of at least 1 centimeter, especially when resection follows
CRT.
Sphincter Preservation and Restorative Options
In patients with acceptable preoperative an rectal function, ideal body habitus and
pelvic anatomy, sphincter preservation is usually possible for rectal cancer located greater
than one centimeter above the upper portion of the anorectal ring. Generally, slender
patients with a wide pelvis are more appropriate for sphincter preserving resection of distal
rectal cancer than obese patients with a narrow pelvis [66,73]. Male patients with a long,
narrow pelvis and/or enlarged prostate present a technical challenge that may preclude a
restorative procedure [73]. Finally, patients with impaired preoperative anorectal function
may be better treated with radical resection and permanent
Colostomy, thus avoiding substantial postoperative perineal morbidity [73]. Hence, it
is imperative that the surgeon exercise sound clinical judgment when selecting patients
for restorative rectal resection. Classically, bowel continuity following Low Anterior
Resection (LAR) was restored with a straight colorectal or clonal anastomosis. In
1986, J-pouch clonal anastomosis was developed in order to increase colonic reservoir
function and improve quality of life following an LAR that required clonal anastomosis for
restoration of bowel continuity (Figure 6)[74]. A prospective, randomized trial comparing
patients with a straight CAA and a clonal J-pouch anastomosis using the European
65
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ C-38
demonstrated an improved postoperative quality of life in the patients reconstructed
with a J-pouch [74]. Randomized studies have demonstrated the superiority of a 6 to 8
cm clonal J-pouch anastomosis relative to a straight clonal anastomosis, particularly
during the first year following surgery [75]. There is a significant reduction in the
postoperative anastomotic leak rate, number of stools per day, and improved quality
of life in patients with a J-pouch versus those with a straight clonal anastomosis
after LAR [76]. One disadvantage of the colonic J-pouch is that up to 25% of patients
treated with an LAR are not candidates for the procedure, due in large part to the
somewhat bulky size of the pouch [77]. In 1997, an alternative procedure, known
as the transverse coloplasty, was introduced in an attempt to create a distal colonic
reservoir (Figure 7) [78]. A recent randomized trial demonstrated comparable
functional results, with improved neorectal sensitivity, when patients undergoing
transverse coloplasty-anal anastomoses were compared to those reconstructed with a
J-pouch [77]. However, another trial documented increased leak rates with transverse
coloplasty and no differences in bowel function, when compared to a colonic J-pouch
[79]. Therefore, colonic J-pouch provides optimal postoperative bowel function with
lower morbidity than transverse coloplasty and in most cases should be the primary
method of bowel reconstruction when a coloanal anastomosis is required following
an LAR [74,79]. However, when reconstruction with a J-pouch is not technically
feasible, transverse coloplasty-anal anastomosis provides a reasonable option for
bowel reconstruction.
Figure 6: Illustrated comparison of a straight coloanal anastomosis and a coloanal anastomosis with a colonic J-pouch [74].
Laparoscopic Approaches
Data from small, non-randomized studies evaluating laparoscopic-assisted rectal
cancer resection suggest that laparoscopic-assisted TME is feasible when performed by
experienced surgeons [80]. From these non-randomized reports, oncologic outcome does
not appear to be impaired by laparoscopic rectal cancer resection [81-83]. In addition,
short-term morbidity may be reduced in the laparoscopic group, while oncologic
outcome is not compromised [81-83]. However, pending prospective, randomized trials
focusing on laparoscopic resection of rectal cancer need to be concluded before definitive
recommendations can be made concerning the safety and oncologic efficacy of these
procedures.
66
Figure 7: Technique of construction of a stapled coloanal anastomosis with a transverse coloplasty pouch. Alternatively, the
pouch may be hand-sewn to the anal canal [77].
Quality of life Following Radical Resection
Although improved outcome is the ultimate goal for the surgical treatment of rectal
cancer, there has recently been increased interest in the quality of life of patients following
radical rectal resection. As previously discussed, performing a rectal resection according
to the principals of TME with ANP substantially reduces the incidence of postoperative
genitourinary and sexual dysfunction. In fact, a recent series reported that even in the
face of postoperative fecal incontinence, genitourinary dysfunction, and sexual dysfunction,
patients were satisfied with their quality of life following rectal resection [84]. A recent 4-year
prospective study of 329 patients with rectal cancer reported the quality of life following
radical resection [85]. Using the EORTC QLQ-30 and CR-38 questionnaires, they report
that patients undergoing LAR have improved quality of life when compared to patients
undergoing APR.
In addition, patients who had no stoma, or had their stoma reversed, reported a
substantially improved postoperative quality of life compared to patients with a permanent
stoma [85]. Another large series with 2 years of follow-up, using the EORTC QLQ-C30 and
QLQCR-38 questionnaire, reported opposite results. Patients with a permanent stoma
reported significantly better social function (P = 0.005), less anxiety (P = 0.008), and higher
self-esteem (P =0.0002) than patients who underwent restoration of bowel continuity [86].
These findings have been supported by others in the literature [87]. In addition, others
have reported that postoperative quality of life improves with time, and should therefore
be evaluated in a dynamic fashion [88]. To add further complexity to this issue, patients
who are treated with a very low colorectal or coloanal anastomosis may have a decreased
postoperative quality of life than patients treated with APR and permanent stoma [89]. It is
clear that postoperative quality of life is dependent upon the interaction of patient factors
(i.e. co-morbidities and preoperative anorectal function), tumor factors (i.e. extent of local
invasion, distance from the anal verge), and surgical factors (i.e. level of the anastomosis).
However, the conflicting data in the literature concerning quality of life evaluation for patients
with resected rectal cancer underscore the importance of the development of more sensitive,
validated instruments. In conclusion, surgery for rectal cancer continues to develop towards
the ultimate goals of improving local control and overall survival, maintaining quality of
life, and preserving sphincter, genitourinary, and sexual function. In appropriate patients,
minimally invasive procedures, such as local excision, TEM, and laparoscopic resection
allow for improved patient comfort, shorter hospital stays, and earlier return to preoperative
activity level. Currently, local excision for cure is recommended only for carefully selected T1
tumors without high-risk features. Recent studies suggest that in patients with resectable
rectal cancer, a response to preoperative chemoradiation is predictive of decreased local
recurrence and improved survival. As response rates to neoadjuvant therapy continue to
improve, it will enable more patients to
undergo sphincter-sparing surgery, and will additionally provide a guide to postoperative
67
chemotherapy regimens. However, at this time the existing imaging modalities are
limited by their inability to confi rm eradication of mesorectal nodal metastases; thus,
patients undergoing TAE alone following preoperative chemoradiation therapy are at
risk for local failure due to unidentifi ed residual nodal disease. Currently, there are
no data to support the routine use of TAE in these patients, and defi nitive treatment
should continue to be rectal resection with TME. By strictly adhering to the principles
of TME with autonomic nerve preservation, maintenance of urinary and sexual function
can be achieved in the majority of patients undergoing a curative radical rectal cancer
resection. The ultimate goal is for physicians to be able to individualize a patient’s
treatment based upon expression of molecular markers, genetic signatures using gene
arrays and response to systemic therapy preoperatively, optimizing the combination and
sequencing of multidisciplinary neoadjuvant therapy in order to maximize survival and
locoregional control rates.
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71
ISBN: 978-1-63278-054-6
DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
eBooks
Chapter 6
Familial colorectal cancer type X (FCCX)
Taina T Nieminen1
1
Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
Corresponding author: Taina T Nieminen, Department of Medical and Clinical
Genetics, University of Helsinki, Helsinki, Finland
*
Hereditary Colorectal Cancer Syndromes
Colorectal Cancer (CRC) is among the three most common cancers worldwide. While a
majority of cases are sporadic, 5-15% have been estimated to have a hereditary background [1].
Hereditary colorectal cancer syndromes are divided into polyposis syndromes characterized
by the development of multiple colorectal polyps, and non-polyposis syndromes where only
few or no polyps occur. Classification and diagnosis are done based on genetic, pathological
and clinical features of each syndrome. The most common forms of hereditary colorectal
cancer syndromes are described in this chapter (Figure 1).
Figure 1: Scheme of Colon Cancer Syndromes. Modified from Lindor et al. 2005
Hereditary Non-polyposis Colorectal Cancer (HNPCC)
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is the most prevalent form of
hereditary CRC with a share of 3-5 % of all CRCs and an autosomal dominant transmission
pattern. Hereditary CRC occurs at a younger age (~45 years) when compared to sporadic
CRC (~70 years). The lifetime risk for CRC in predisposed individuals is high, approximately
70-80% [2,3]. Among males the risk for CRC is higher (80%) when compared to females (40%)
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
72
[4]. In addition to CRC, the syndrome is characterized by the development of endometrial,
urinary tract, gastric, small bowel and other extra colonic tumors [5].
HNPCC was first described a hundred years ago [6]. Before the genetic basis of the
syndrome became known, an international collaborative group of researchers set up the
Amsterdam Criteria (AC) I and II, to further define the disease [7,8] (Table 1) For screening
purposes, the Revised Bethesda Guidelines were set up [9] (Table 2).
When the human mismatch repair (MMR) genes were identified in the 1990s, HNPCC
was divided into two separate categories, Lynch syndrome, caused by pathogenic germline
mutations in MMR genes, and later on Familial Colorectal Cancer Type X (FCCX), where no
MMR mutations are detected [10].
Lynch syndrome (LS)
Lynch syndrome is caused by a defect in one of the MMR genes: MLH1, MSH2, MSH6
or PMS2 [2,11-14]. MMR mechanism recognizes and corrects errors that arise during
DNA replication. MMR defects can be detected in tandemly repeated sequences scattered
throughout the genome called the microsatellites. Microsatellites are polymorphic, but in
each individual they are similar in length [15]. Microsatellites may consist of mono-, di-,
tri- or tetranucleotide repeats. Microsatellite instability (MSI) can be defined as emergence
of an extra allele/s in tumor DNA compared to matching normal DNA [16-18]. MSI was
first discovered as mutations in CA dinucleotide sequences in CRC specimens [19]. MSI
represents a hallmark for LS CRC [20]. MSI analysis is commonly used as a screening
method to distinguish LS CRC.
The average age of CRC diagnosis in LS is approximately 44 years [21]. Tumors tend to
arise on the right side of the colon in majority of the cases (60-80%), and multiple tumors
in the same individual are frequent. Villous adenomas are the most common precancerous
lesions in the colorectum of LS patients. The progression sequence from polyps to carcinomas
is accelerated in LS (<2 years) compared to sporadic CRC (>10 years) due to defective MMR
and accumulation of genomic mutations that probably cause additional alterations in
oncogenes and tumor suppressor genes [22]. Histologically tumors are characterized as
poorly differentiated; despite the fact that the survival rate is better than in sporadic colon
cancer cases [23]. Early recognition of LS mutation carriers is essential to reduce CRC
mortality. Intensive colonoscopy surveillances are recommended for LS patients starting at
the age 25 with a 2 year interval [22].
Approximately 70% of mutations are found in MLH1 and MSH2 genes. Loss of function
of a MMR gene occurs when the wild type allele becomes somatically inactivated through
deletions, point mutations or CpG island hypermethylation. Somatic inactivation by
hypermethylation primarily occurs in the promoter of the MLH1 gene [24-26]. Large genomic
rearrangements of MLH1 and MSH2 genes have also been reported to cause deficient MMR
and LS phenotype in patients that lack MMR gene mutations [27]. Age of onset and the risk
of developing various types of cancer vary depending on which MMR gene is mutated [2830]. Patients with MLH1 and MSH2 mutations have similarly increased risk for the whole
spectrum of LS associated cancers with the distinction that MSH2 mutation carriers seem
to have a more prominent risk for urinary tract cancer in both sexes and prostate cancer in
males [28,31].
Loss of MSH2 expression is most often caused by defects in MSH2 gene, but in 10% of
cases germline deletion of the 3’ end of EPCAM gene located upstream of MSH2 is known
to results in hypermethylation and inactivation of the MSH2 promoter [32-34]. The clinical
phenotype of patients with MSH2 and EPCAM mutations is similar with a distinction of a
lower lifetime risk (12% by the age of 70) for endometrial cancer in patients with EPCAM
mutations (compared to 20-50% risk in MSH2 mutation carriers) [35].
73
Patients with MSH6 mutations have later age of onset and substantially lower lifetime
risk for CRC (10-22%) as well as other cancers associated with LS, compared to patients
bearing mutations in other MMR genes. Although, female MSH6 mutation carriers have
been suggested to have a higher risk for endometrial cancer [30]. MSH6 deficient tumors
show consistent MSI only in association with mononucleotide repeat sequences [36].
After identification of the PMS2 gene, increasing number of individuals with mutations
in this gene has been identified. The risk of developing CRC, endometrial and other LS
associated cancers seems to be low (~20% and ~15%, for CRC and endometrial cancer,
respectively) in PMS2 mutation carriers [37].
In addition to genetic mutation, germline epimutations have been reported in a small
number of individuals meeting the clinical criteria of LS [38].
Familial Colorectal Cancer Type X (FCCX)
Recent clinical and molecular studies have revealed that not all HNPCC cases are caused
by defects of the MMR genes. The clinical phenotype of FCCX patients often fulfill the
Amsterdam Criteria I (AC-I), or at least the Revised Bethesda Guidelines I-IV (Tables 1 and
2), with a slightly higher age of onset (approximately 60 years) but lack the evidence of MMR
defects [10]. FCCX patients have increased risk of CRC, but usually no extra colonic tumors.
A surveillance guideline is the same than in Lynch syndrome. FCCX colorectal tumors occur
more frequently in the sigmoid colon and rectum [39]. In FCCX patients tumors are Mostly
Microsatellite Stable (MSS).
Germline mutation and promoter hypermethylation of APC tumorsuppressor gene
contribute in the formation of Western Sporadic Microsatellite Stable (MSS) CRC, which
usually develops from tubular adenoma (a form of precancerous lesions of CRC), followed
by p53 mutation and/or Chromosomal Instability (CIN) [40]. Similarly, FCCX related
colorectal cancer seems to develop via similar CIN pathway [39]. Chromosomal Instability
(CIN) is described as increased loss or accumulation of chromosomal material that leads to
polyploidy or aneuploidy [41,42]. CIN can occur at any time during carcinogenesis and it
can cause aneuploidy (imbalance of chromosome number) but also Loss of Heterozygosity
(LOH) [43].
I
•
At least three relatives who have diagnosed CRC and all the above mention criteria should be present
•
One relative should be a first-degree the other two
•
Affection of two successive generations
•
At least one CRC at young age at onset (<50 years)
•
Exclusion of familial adenomatous polyposis
•
Pathological verification of tumor
II
•
At least three relatives should found who have diagnosed HNPCC-related cancer
(CRC, EC, small bowel, ureter, renal pelvis)
•
One relative should be a first-degree the other two
•
Affection of two successive generations
•
At least one should be diagnosed at young age at onset (<50 years)
•
Exclusion of Familial adenomatous polyposis (FAP) CRC cases
•
Pathological verification of tumor
Table 1: Amsterdam criteria I and II.
LOH can cause the inactivation of tumor suppressor genes [43] by somatic loss of
chromosomal material, ranging from the loss of a chromosome sub band to the whole
chromosome. LOH can be measured by comparing the tumor tissue to the normal tissue
74
(e.g. blood leukocytes) from the same individual by different methods (e.g. using fragment
analysis). If LOH is present in a particular tumor, then one allele is missing or has decreased
in intensity. These missing or attenuated alleles frequently contain Tumor Suppressor
Genes (TSGs). In many common cancers, multiple regions of chromosomal losses have been
identified by LOH analysis [41]. Still the number of TSGs that have been recognized based
on LOH remains low; if it is required that a somatic mutation must be seen in the remaining
allele [45].
Tumor Suppressor Genes (TSG) is genes that provide a cell with the capability to accept
and process growth suppression signals from its environment. They are also key players
in the intracellular signaling cascade. Tumor suppressor gene inactivation by mutation
or methylation is linked to carcinogenesis [46]. TSG controls versatile cellular activities;
responses to cell cycle checkpoints, as well as perceiving and repairing of DNA damage. In
addition, protein degradation and ubiquitination, tumor angiogenesis, cells movement and
differentiation, cell definition and mitogenic signaling belong to TSGs duties [47]. TSGs can
be divided into gatekeepers and caretakers. The gatekeepers are genes that function actively
in cell proliferation [48]. Mutations in caretaker genes frequently lead to the conversion from
normal cells to neoplastic cells. The caretaker genes’ function is to maintain cell genome
integrity [49].
It has been hypothesized that cancers occur in FCCX patients only by chance, or that
these families share the same environmental circumstances. However, there may still be a
yet unknown common genetic factor behind of this syndrome [10]. Linkage, Next Generation
Sequencing (NGS) and association studies have been conducted to discover predisposing
genes behind FCCX.
Until recently, the genetic background of the FCCX patients has remained unknown.
Few predisposing germline candidate mutations have been identified for FCCX in Europe.
Two novel germ line mutations in the gene encoding a type I Bone Morphogenetic Protein
Receptor (BMPR1A) were identified in 2/18 (11%) of Finnish FCCX families. Those findings
were the first to report germline alterations in a high-penetrance susceptibility BMP gene in
FCCX and the first to link mutations in BMPR1A to FCCX [50]. BMPR1A belongs to signaling
cascade and it phosphorylates different SMAD-proteins which then form a composition with
SMAD4 protein [51,52]. This composition migrates to the nuclei and regulates other genes
transcription [53].
A novel germline mutation (c. 147 dupA) in the RPS20 gene, encoding a component (S20)
of the small ribosomal subunit, was found from seven CRC-affected patients from Finland
in the one FCCX family. The mutation leads to frameshift and premature protein truncation
(p.Val50SerfsX23). The product of RPS20 is required during the late steps of 18S ribosomal
RNA (rRNA) formation. Ribosomes are the organelles that catalyze protein synthesis, and
they consist of a small 40S subunit and a large 60S subunit. RPS20 encodes a ribosomal
protein that is a component of the 40S subunit [54]. When RPS20 is function normally it
can bind to Mdm2 and activate p53 tumors suppressor protein [55].
Three different missense type mutations in the SEMA4A gene from Germany and Austria
were identified in three FCCX families. These SEMA4A gene mutations identified in the CRC
patients were p.Val78Met, p.Gly484Ala, and p.Ser326Phe [56]. Semaphorins have role in
physiological and developmental processes; additionally semaphorins and their receptors
have been connected to malignant disorders as well [57,58]. It has been proposed that
semaphorins act as protumoral as well as an anti-tumoral manner, depending on the
context of the tumor and which semaphoring is in question. Never the less semaphorins
might have a role in angiogenesis, evading apoptosis, cell proliferation and metastasis as
well as other tumorigenic properties [56].
Above mentioned findings were the first to report germline alterations in high-penetrance
susceptibility genes in FCCX and the first to link mutations in BMPR1A, SEMA4A or RPS20 to
75
FCCX, or any other human disease in the case of RPS20 gene [56, 59,60]. Based on findings
described above, it is reasonable to conclude that FCCX is a genetically heterogeneous
disease, which is probably explained by many different gene mutations. All of these above
mention candidate mutations need to be confirmed in the global context.
Familial Adenomatous Polyposis Syndrome
Familial Adenomatous Polyposis Syndrome (FAP) is the second most common colon
cancer predisposing condition after Lynch syndrome [61] and the most common polyposis
syndrome [62]. FAP syndromes can be divided by two slightly different conditions; classic
FAP and attenuated FAP. The cause of both of these syndromes is germline mutation
occurrence in the APC gene, but mainly different part of it. Both of the syndromes are
inherited in an autosomal-dominant manner [63].
Classic FAP
FAP syndrome identified in 1991 and for the cause of it a germline mutation in the APC
gene was described [64,65]. FAP individuals suffer from even hundreds or thousands of
colon adenomas and if untreated, CRC develops in 40-100% of cases. The average age at
onset of CRC is 39 years [61]. When all CRC cases account FAP includes less than 1% of
them and the incidence rate is 1/10000 [62].
Approximately 50 % of the FAP patient’s adenomas are seen by age 15 and by age 35,
95% have developed adenomas [66, 67]. Adenomas are located throughout the colon with
slightly more in the distal part. Majority of the adenomatous polyps in the FAP patient colon
are very small, less than 0,5 cm in diameter and only very few (less than 1 %) are over 1 cm
in diameter [68]. In the histopathology point of view, the tubular adenomas are the most
commonly seen in FAP patients and tubulovillous and villous adenomas are also seen, but
mainly in the large ones [69].
Tumor-suppressor gene APC locates in the q21-22 on chromosome 5. APC consist of 15
protein coding exons and the exon 15 is the largest one, comprising more than half of the
protein coding part. Exon 15 is also the most common location for somatic and germline
mutation occurrence [70]. The 310 kDa APC protein consist of 2843 aminoacids and it
has an important role in the WNT-signaling cascade. APC protein normal function is to
regulate β-catenin oncoprotein in negative manner by degradation and ubiquitination of
β-catenin. When APC protein is absence β-catenin assemble in the nucleus and influence
to components that are needed for up-regulating the transcription of genes that participates
in cell proliferation, migration, apoptosis, cell cycle entry, differentiation and progression
[71]. APC protein is also needed to stabilize microtubules achieving to chromosomal stability
[72]. Aberrant mitosis and insufficient chromosome segregation might be the consequence
of inactive APC protein function [73].
Now a day’s over 1100 APC, most likely damaging germline mutations and over 3000
APC variants all together are known [74]. Most of the germline mutations are protein
truncating; small deletions, insertions or nonsense [75]. Codons 1061 and 1309 in the
5´part of the exon 15 comprise the mutational hotspots of the APC gene. These codons
form approximately 11% and 17%, respectively of the germline mutations in the APC gene.
Second hit character depends on type of the germline mutation in the APC gene. Allelic
loss of APC as the second hit exists if the mutation can be found from the codon 1194 to
1392. If the germline mutation locates between codons 1250-1464, which is also called
Mutation Cluster Region (MCR) [76], the second hit probably achieve a protein truncating
event in MCR [77]. After the second hit has occurred in the APC gene, it´s carcinogenic route
resembles sporadic event, where accumulation of mutations in the K-ras or p53 gene is very
common phenomena [78].
Biannually sigmoidoscopy screenings are recommends starting at age 12-14 for FAP
76
patients. When adenomas are found yearly colonoscopy screening are recommended until
colectomy is performed [79].
Attenuated FAP
A less severe form of FAP disease is Attenuated FAP (AFAP), where individuals suffer from
much fewer colon adenomas (0-100+) and the age at CRC onset is higher [61]. In attenuated
FAP the lifetime risk for CRC is 70% [60]. When the number of usually right sided colon
adenomas is 10-99 the examinations of other family member can verify AFAP diagnose
[80]. In the AFAP patients the risk of extracolonic occurrence is also evident. Duodenal and
Gastric polyps, desmoid tumors, osteomas, brain and thyroidal tumors among others, are
seen, even though rarely [81].
The APC gene mutations in AFAP are mainly seen before the codon 157 or after
codon 1595, but some cases also between codons 213 and 412 in the exon 9, which is
the alternatively spliced region [82-84].The surveillance guidelines recommend biannual
colonoscopy starting from age 18-20. If adenomas are found removing them by endoscopically
and annual colonoscopy screening is recommended [85].
MUTYH-Associated Polyposis
MUTYH-Associated Polyposis (MAP) syndrome was depicting in 2002 [86]. MAP syndrome
resembles attenuated FAP and it can be associated with numerous (15-100) polyps in an
individual’s colorectum. This syndrome is produced by biallelic mutations in the MY, or
better known as the MUTYH, gene [87], so MAP is inherited as an autosomal-recessive
manner. In MAP individuals the lifetime risk for CRC is 80% [63].The age at onset of CRC in
MAP is around 40 years, although younger age at onset is also seen [88]. MAP patients CRC
locates evenly in the distal and proximal part of the colon [89].
The MUTYH gene locates on chromosome 1p34.3-32.1 and it constitute of 16 exons,
which form a 535 aminoacid protein [90]. MUTYH gene is involved in the base-excision
repair system. Mutations caused by cells’ internal metabolism, eg. reactive oxygen species,
are repaired by Base-Excision Repair (BER) [91].The starting point for BER occurs through
DNA glycosylases, which are a class of enzymes, which recognize chemically modified bases.
A stable 8-oxo-7, 8-dihydro-2’-deoxogyanosine (8-oxoG) is produced by DNA damage. A
stable 8-oxoG mispairs with adenine and lead to transversion mutations, eg. G:C to T:A
[92] and MUTYH main duty is to remove mispaired adenines with 8-oxoG [93-95]. When
MUTYH is unable to remove mispaired adenines with 8-oxoG, due to biallelic mutations
in the MUTYH gene, G:C to T:A transversion mutations occur in the following replication
round. This previous phenomena is frequently seen in somatic mutations of APC or KRAS
genes in MAP-adenomas or tumors [86,96]. Somatic mutations in APC gene are probably
one explanation of the similar phenotype in MAP and AFAP [97].
More than 80 damaging mutations have been found in the MUTYH gene [74]. Minorities
of the mutations are truncating or splice site, whereas the missense substitutions consist
large part of the mutation spectrum [83]. Mutations have been discovered all exons except 1
and 2. Two hotspot missense mutations are predominantly seen especially in the Europeans:
p.Y179C and p.G396D in exons 7 and 13, respectively. These mutations cover 70 to 80 %
of all in Europe [96].
Starting from age 18-20 MAP patients could participate in biannual colonoscopy
screening program. Participating should continue lifelong. Screening protocol is the same
as in the AFAP recommendations [67].
Polymerase Proofreading-Associated Polyposis (PPAP)
Polymerase Proofreading-Associated Polyposis (PPAP) is recently described syndrome
which predispose to endometrial and colorectal cancer [98]. PPAP penetrance is high and
77
this syndrome is dominantly inherited [99]. Endometrial cancer has been linked to germline
mutations in POLD1 gene and germline mutations in POLE gene are associated with
colorectal cancer. Carcinogenic mechanism behind PPAP is chromosomal instability. PPAP
tumors are microsatellite stable and often K-ras and APC somatic mutations are involved
in PPAP patient’s tumor [100]. Typically the age at onset in PPAP seems to be less than 40
years. Multiple large adenomas (more than 5) are seen in PPAP patient’s colon, resembling
phenotypically MAP or AFAP [101].
POLE mutation carriers are possibly associated also with other malignancies, including
ovary, pancreas, stomach, brain and small intestine cancer [102]. POLE and POLD1 are
DNA polymerases that are involved in the DNA replication. Inactivation of POLE and POLD1
exonuclease, proofreading domains creates mutations all over the genome and end result is
cancer [103]. All of the mutations identified in POLE and POLD1, so far, are missense type
[101-103]. PPAP syndrome is lacking the surveillance program recommendation due to the
novelty of the disease. However similar surveillance program like FAP is suggested [101].
Hamartomatous Polyposis Syndrome
Hamartomatous polyposis syndromes consist of variety of hereditary conditions that
exhibit hamartomatous polyp histology [104]. The conditions include Peutz-Jegherssyndrome, Juvenile polyposis syndrome, PTEN hamartoma syndrome and GREM1 mixed
polyposis syndrome. These syndromes cause distribution of polyps in gastrointestinal
tissues, benign extra-intestinal findings, increased risk for gastrointestinal (GI) cancers,
such as colorectal (CRC) and small intestine cancers as well as increased risk for other
malignancies. Hamartomatous polyposis syndromes are very rare conditions and account
only to less than 1 % of all CRC cases. However the transition of polyps to cancer remains
still to be fully delineated. [104,105]. Early identification of the individuals at risk is critical
for appropriate surveillance and management plan [106]. The focus of this chapter will be on
Peutz-Jeghers- and Juvenile polyposis syndromes, which are the two most common types.
Peutz-Jeghers syndrome
Peutz-Jeghers Syndrome (PJS) is an autosomal dominantly inherited syndrome in which
the diagnosis can be made when a patient meets at least two of the following three features:
hamartomatous polyps, most frequently in the small intestine but also in colon and stomach,
mucocutaneous hyperpigmentation around and inside the perianal region and mouth, and
family history of the disease [107]. Extraintestinal hamartomatous polyps may also occur
in for example uterus, nasal cavity, lungs and bladder [105]. The first symptoms of PJS,
usually arising in early teenage years, comprise gastro-intestinal bleeding and possibly
anemia. Peutz-Jeghers polyps are mostly found in the small intestine and colon and might
cause painful obstructions, intussusceptions and puncture of the intestines. [104,108].
PJS patients have an increased risk for several cancer types including CRC (39 %), breast
(45-50 %), small intestine (13 %), gastric (29 %), pancreatic (11–36 %), ovarian (18–21 %) and
lung (15–17 %) cancers [109-111]. Lifetime risk for all cancers in PJS patients is estimated to be
81–93 % [109,110,112]. Also risk for benign neoplasm of the ovaries and adenoma malignum
of the cervix in females, and large calcifying sertoli cell tumors of the testes in males is elevated.
Sertoli cell tumors might cause gynaecomastia, a condition characterized by short stature and
advanced skeletal age, due to oestrogen secreted by the tumor cells. [108,113].
PJS is caused by germline mutations in STK11 gene (also known as LKB1) on chromosome
19p13.3 [114,115]. STK11 is a tumor suppressor gene, a serine-threonine protein kinase,
and its functions involved various cellular processes such as apoptosis, DNA-damage
responses and metabolism [108]. Depending of the methods used, it is estimated that 50–90
% of PJS patients carry a mutation in this gene. Most of the mutations are missense or
truncating causing elimination of the kinase function, but also large deletions have been
detected. [104,116].
78
PJS incidence is estimated to be 1/200 000 births but also other estimates exist [117,118].
The mean age of PJS patients developing malignancies is 42 years [117]. Current treatment
is endoscopic polypectomy to reduce the risk of obstructions and intussusceptions, and the
risk of cancer later in life. Surveillance recommendations vary from starting the endoscopic
screening at the age of 8 or at the age of 18, and there after every 2–5 years, depending on
the specialist [108,119].
Juvenile Polyposis Syndrome
Juvenile Polyposis Syndrome (JPS) causes appearance of multiple (>1)any juvenile
polyps in GI tissues, most frequently in the colon and rectum, but also in the small intestine
and stomach [120,121]. Juvenile polyps can appear at any age and, hence the presence
of these polyps is relatively common (~ 2 % of children under 10 years of age) the JPS
diagnosis can be made when a patient meets the following three criteria: ~ 5 colorectum
associated juvenile polyps, juvenile polyps all over the GI tract, and any juvenile polyps
found in an individual who has a positive family history of the syndrome [121]. Diagnosis
of JPS is usually made before the age of 20 hence the appearance of the first symptoms
might come as early as the first or second decade of life [122,123]. The symptoms include
rectal bleeding that may cause anemia, abdominal pain, obstructions and, rarely, rectal
prolapse of polyps [124]. JPS patients have increased risk for cancers in GI tract, CRC being
the most common form (39 %) and gastric, small intestine and possibly pancreatic cancers
less common. [123,63]. Germline mutations in two primary genes, BMPR1A and SMAD4
are associated to JPS. Both genes encodes proteins involved in transforming growth factor
(TGF) -β pathway which is involved in regulation of cell differentiation and proliferation,
especially in colonic cells, and also inflammation, hematopoiesis, wound repair and skeletal
development. SMAD4 mediates its downstream signaling transduction. [123,125]. Features
of BMPR1A are described previously in chapter Familial Colorectal Cancer type X. Defects
in these genes account for equal parts of JPS, approximately in 20 % of cases. [117, 126].
It has been suggested that the BMPR1A mutation carriers has lower risk of gastric cancer
than SMAD4 mutation carriers [117,126]. JPS incidence is between 1/100 000 to 1/160
000 births [121]. Currently international guidelines on treatment considering prophylactic
surgery are missing and the surveillance program varies depending on country of question.
Those patients with positive family history of JPS prophylactic colectomy should be
considered [127-129]. In Britain colonoscopy surveillance is suggested once a year or
biannually starting from age 15 or 18 and continuing to age 70 [129].
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eBooks
ISBN: 978-1-63278-054-6
DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055
Chapter 7
Treatment of Colon Cancer
Mehmet TOPÇUL1*, İdil ÇETİN2
Istanbul University, Faculty of Science, Department of Biology, Istanbul/Turkey
Istanbul University, Institute of Science, Department of Radiobiology, Istanbul/
Turkey
1
2
*
Corresponding author: Mehmet TOPÇUL, Istanbul University, Faculty of Science,
Department of Biology, Istanbul/Turkey, Tel: +90 212 455 5700/15097; Fax: +90 212
528 05 27; E-mail: [email protected]
Abstract
Surgery, radiotherapy and chemotherapy are conventional methods used in colorectal
cancer as with other types of cancers. These therapies can be used alone or together.
However, it is difficult to cure the disease completely. In order to increase the efficacy of
treatment novel approaches are being developed day by day.
Introduction
Colorectal Cancer (CRC) is the second most commonly diagnosed cancer in Europe,
with an annual incidence of 400.000 cases and an annual mortality of more than 200.000
patients [1]. Over the past 10 years of data (2000-2009), the largest annual declines in death
rate for colorectal cancer was 3.0% [2]. As for deaths, CRC is the third most common cause
of death from malignancy in males after pulmonary and prostatic cancer and in females the
second most common after breast cancer [3].
Recent studies suggest that the risk of colon cancer for people with İnflammatory Bowel
Disease (IBD) increases by 0.5-1.0% yearly, 8-10 years after diagnosis. The magnitude of
CRC risk increases with early age at IBD diagnosis, longer duration of symptoms, and
extent of the disease, with pancolitis having a more severe inflammation burden and risk of
the dysplasia-carcinoma cascade [4]. Crohn Disease (CD) is a common inflammatory bowel
disease, in which nonpathogenic, commensal intestinal bacteria are thought to trigger a
chronic dysregulated immune response against the mucosal barrier function [5,6]. Patients
diagnosed with Crohn Disease (CD) are known to be at an increased risk of colon cancer [7].
There are two main clinical types of genetically determined predisposition to CRC:
intestinal polyposis syndromes and Hereditary Non-Polyposis CRC (HNPCC) [8,9]. The most
frequent site of metastases of CRC is the liver. Almost 70% of CRC patients develop liver
metastases during the course of disease [10].
Colorectal cancer has four stages, based on the location of the tumor. In stage 0, the
cancer is found only in the inner most lining of the colon or rectum. Carcinoma in situ is
another name for stage 0 colorectal cancer. In stage I, the tumor has grown into the inner
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
86
wall of the colon or rectum. In stage II, the tumor extends more deeply into or through the
wall of the colon or rectum. It may have invaded nearby tissue, but does not extend to the
lymph nodes. In stage III, the cancer has spread to nearby lymph nodes, but not to other
parts of the body. In stage IV, the cancer has spread to other parts of the body, such as the
liver or [11].
Stage is the strongest predictor of survival for patients with colorectal cancer. Accurate
staging also is critical for appropriate patient management and meaningful clinical research
[12] Large differences exist in survival, according to the stage of disease [13].
Treatment options for patients vary and are assessed taking into account tumour size,
stage of diagnosis, location of the tumour in the colon or rectum, risk of the cancer returning,
physical health of the patient The introduction of several effective cytotoxic and targeting
agents, in combination with surgical treatment, has extended survival [14].
Treatment Options for Colorectal Cancer
Surgery
Surgery is the only curative treatment for colorectal cancer. The surgical approach
for colorectal cancer is affected by tumour stage and localization [15]. In the surgial
approach of colon cancer, the basic principle is to remove the primary tumor and regional
lymphatics with clear surgical margins (radical resection). Because of lymphatic and
arteries of the column are parallel, when determining resection margins, vessels supplying
the corresponding columns segment also must be considered as well as localization of the
tumor and regional lymph drainage. Also if the involvement of tumor-adjacent tissues and
organs is concerned they also should be tried to removed with the primary tumor (en block
resection). The tumor can not be removed surgically exactly, in oder to avoid to relieve
symptoms and potential complications, more limited resections such as colostomy and
ileostomy or palliative surgical procedures such as “by pass” can be performed [16-18].
Surgical procedures can be performed conventional (open) or laparoscopically. After
resection gastrointestinal continuity is performed with the anastomosis of proximal and
distal intestinal segment [19]. Laparoscopic colorectal operations have many advantages
over conventional open operations. The benefits in terms of short term outcomes are well
established and include shorter hospital stay, faster return to work, better cosmesis, less
post operative pain, less risk of bleeding and ileus. Long term outcomes including cancer
specific and disease free survival have been subject of many well-designed trials. In the
long-term, there has been no difference in morbidity, the rates of recurrence or cancerrelated mortality between laparoscopic and open surgery [20-25].
Radiotherapy
Radiotherapy can be used for different purposes at different stages of colorectal cancer.
In order to down-size and down-stage advanced tumours and subsequently to prevent local
recurrence radiotherapy is used before surgery far more frequently than after surgery. It is
used for shrinking tumors before surgery, for the destruction of cancer cells that might be
remain after the surgery and as palliative at advanced cancers.
In general, complete surgical resection of the tumour offers the best chance of cure for
non metastatic colorectal cancer. Radiotherapy serves as adjunctive treatment to reduce
local and regional recurrence. In situations when patient cannot undergo operation or the
tumour is unresectable, radiotherapy with/without chemotherapy can be considered as
definitive treatment. For colon cancer, there is no need to offer radiotherapy before or after
87
complete surgical resection of tumour. Radiotherapy can be considered after operation to
reduce local recurrence if the colon cancer is not completely removed. For rectal cancer,
because of the higher chance of relapse even after complete surgical resection, post‐
operative radiotherapy are usually given aiming to reduce local and regional recurrence
Two treatment regimens have been proposed: short schedule radiotherapy (25 Gy in five
fractions), followed by surgery within a week (the Swedish study) [27,28]and long schedule
radiotherapy (50.4 Gy divided in 5 weeks) with surgery performed after 5-6 weeks (the Polish
study) [29].
The target irradiation volume should include the corresponding lymphatic drainage areas
for the invaded organs: the upper pelvirectal space, the ischio-rectals fossa, the seminal
vesicles and the prostate for men and the posterior vagina wall for women. For the lower
rectal tumor, the internal iliac lymph nodes should be included in the CTV[30].
Preoperative radiotherapy decreases the local recurrence rate and is used in combination
with chemotherapy to treat locally advanced rectal cancer [31,32].
The technology of radiation oncology is evolving at a rapid rate, primarily as a result of
the evolution of computer applications and their integration into diagnostic imaging and
radiation therapy dose delivery equipment [33]. In this context there are various radiation
therapies such as Intensity Modulated Radiation Therapy (IMRT), Intraoperative Radiation
Therapy (IORT), TomoTherapy, CyberKnife for colorectal cancer.
Intensity-Modulated Radiotherapy (IMRT) differs from standard external radiotherapy
techniques as it provides the ability to more accurately irradiate the cancerous tissues. It
allows sparing of organs at risk that are surrounded by targets with concave surfaces. In
IMRT this is achieved by controlling or modulating the intensity of the subcomponents of
each radiation beam. IMRT can be produced through numerous delivery methods. Moving
gantry with the treatment beam on, using an arcing or tomotherapy (serial or spiral delivery)
method with dynamic collimation [34].
In case of tomotherapy the user has three options if leakage radiation is higher than
the desired value: limit the number of sweeps of the gantry, using a larger tomotherapy
aperture, or using an IMRT dose delivery technique that is more monitor unit efficient [35].
Intraoperative Radiotherapy (IORT) allows precise application of a high radiation dose
with minimal exposure of surrounding organs at the time of an operation [36,37]. A high
local control rate can be achieved by using IORT, especially in patients with primary or
recurrent tumors that are difficult to resect due to severe invasion into adjacent organs
[38-45].
Cyberknife® is a dedicated stereotactic radiotherapy device. This new technology permits
precise delivery of high dose gradient radiation therapy while sparing the surrounding
organs at risk [46].
Chemotherapy
Despite recent advances in chemotherapeutic treatment, great numbers of deaths occur
each year from the disease as well as due to the adverse effects of anticancer drugs. There
are enough data regarding the efficacy of various regimens, used in different stages of
colorectal carcinoma among western population [47,48].
The Fluoropyrimidine 5-Fluorouracil (5-FU) is an antimetabolite drug that is widely used
for the treatment of cancer, particularly for colorectal cancer. 5-FU exerts its anticancer
effects through inhibition of Thymidylate Synthase (TS) and incorporation of its metabolites
88
into RNA and DNA [49]. 5-FU is considered to be purely an S phase active chemotherapeutic
agent, with no activity when cells are in G0 or G1 [50].
The drug needs to be converted to the nucleotide level in order to exert its effect. It
can be incorporated into RNA leading to interference with the maturation of nuclear
RNA. However, its conversion to 5-Fluoro-2’deoxy-5’ Monophosphate (FdUMP) leading to
inhibition of Thymidylate Synthase (TS) and subsequently of DNA synthesis, is considered
to be its main mechanism of action [51]. It is well-established that treatment of cells with
5-FU causes DNA damage, specifically double strand (and single-strand) breaks, during S
phase due to the misincorporation of FdUTP into DNA [52,53]. However, damage to DNA
can occur in all cell cycle phases in proliferating cells, and the repair mechanisms involved
vary in the different phases of the cell [54]. DNA damage checkpoint pathways in G1, S, and
G2 couple DNA damage detection to inhibition of cell cycle progression, activation of DNA
repair, maintenance of genomic stability, and when damage is beyond repair, to initiation
of cellular senescence [55]. 5-FU is generally believed to induce G1-S-phase arrest, and its
cytotoxic effects are attributed to apoptosis, via a p53-dependent pathway [56].
Addition of folinic acid to chemotherapy increases and prolongs the inhibition of the target
enzyme (thymidylate synthase) and seems to confer improved clinical outcome compared
with fluorouracil alone in advanced disease and when used in adjuvant therapy [57].
Capecitabine (Xeloda®; Hoffmann-LaRoche Inc., Nutley, NJ) is currently registered
for monotherapy in the first line of treatment of advanced colorectal cancer and adjuvant
treatment of patients with stage III colon cancer [58]. Capecitabine is a pre-prodrug of
5-FU and is rapidly converted to 5-FU in tumor tissue. Thymidylate synthase inhibition
and incorporation into RNA and DNA are the most important mechanisms of action of
capecitabine[59].
In patients who develop metastatic colorectal cancer oxaliplatin is the most extensively
used treatment [60]. It is an alkylating agent that inhibits DNA synthesis and replication
by generating DNA damage. Apoptosis of cancer cells can be caused by formation of DNA
lesions, arrest of DNA synthesis, inhibition of RNA synthesis, and triggering of immunologic
reactions [61,62].
Oxaliplatin is an anticancer agent that acts by formation of Platinum-DNA (Pt-DNA)
adducts resulting in DNA-strand breaks, and is used for the treatment of colorectal cancer.
Oxaliplatin has distinct biochemical, pharmacological and cytotoxic properties compared to
the related platinum compounds cisplatin and carboplatin, and shows no crossresistance
[63].
Various mechanisms of action are ascribed to oxaliplatin. Like other platinum-based
compounds, oxaliplatin exerts its cytotoxic effect mostly through DNA damage. Apoptosis of
cancer cells can be caused by formation of dna lesions, arrest of DNA synthesis, inhibition of
RNA synthesis, and triggering of immunologic reactions. Oxaliplatin also exhibits synergism
with other cytotoxic drugs, but the underlying mechanisms of those effects are less well
understood [62].
In patients who develop recurrent or metastatic CRC, oxaliplatin and 5-Fluorouracil
(5-FU) combined are the most extensively used first line treatment, with a response in
approximately half of patients [60].
Irinotecan is the second line chemotherapy for advanced stage Colorectal Cancer (CRC) after
failure of first line chemotherapy with oxaliplatin and 5-fluorouracil [64]. It is a chemotherapy agent
that causes S-phase-specific cell killing by Poisoning Topoisomerase I (Topo I) in the cell [65].
89
Irinotecan interacts with cellular Topo I–DNA complexes and has S-phase-specific
cytotoxicity Topoisomerases reduce DNA twisting and supercoiling that occur in selected
regions of DNA as a result of essential cellular processes such as transcription, replication
and repair recombination. They cleave and reseal the phosphodiester backbone of DNA,
and form a covalent enzyme-DNA linkage, which allows the passage of another single- or
double-stranded DNA through the nicked DNA. Topo I binds to single-strand DNA breaks,
and the reversible Topo I-irinotecan-DNA cleavable complex is not lethal to the cells by
itself. However, upon their collisions with the advancing replication forks, the formation
of a doublestrand DNA break occurs, leading to irreversible arrest of the replication fork
and cell death [66]. The collision of the irinotecan-Topo I complex with the replication fork
also results in G2 arrest/delay by signaling the presence of DNA damage to an S-phase
checkpoint mechanism [67]. At higher concentrations of irinotecan, non-S-phase cells
can also be killed. The mechanism of non-S-phase cell killing appears to be related to
transcriptionally mediated DNA damage, and through the mechanism of apoptosis [68].
When offering multiple chemotherapy drugs to patients with advanced and metastatic
colorectal cancer, consider one of the following sequences of chemotherapy unless they
are contraindicated: FOLFOX (Folinic Acid Plus Fluorouracil Plus Oxaliplatin) as first-line
treatment then single agent irinotecan as second-line treatment or FOLFOX as first-line
treatment then FOLFIRI (Folinic Acid Plus Fluorouracil Plus İrinotecan1) as second-line
treatment or XELOX (capecitabine plus oxaliplatin) as first-line treatment then FOLFIRI
(Folinic Acid Plus Fluorouracil Plus İrinotecan1) as second-line treatment [69].
Immunotherapy for colorectal cancer
Biological therapy has only recently been introduced [70]. This includes the use of agents
that interfere with growth factors for malignant cells, and block tumor neovascularization
[71]. Among the Monoclonal Antibodies (mAbs) that have been approved for cancer treatment,
most operate via indirect mechanisms, and only a minority target natural or artificial
mechanisms of cell destruction Systemic treatment with agonist anti-CD137 monoclonal
antibodies eradicates transplanted murine colon cancers [72].
Cytotoxic T-Lymphocytes (CTLs), Natural killer (NK) cells, γδT cells and antibodies
efficiently recognize and target colorectal Cancer Stem-Like Cells (CSCs)/ Cancer-İnitiating
Cells (CICs). NK cells and γδT cells are non-specific effectors, and these effectors should
recognize both colorectal CSCs/CICs and non CSCs/CICs. Therefore, NK cells and γδT cells
might be good candidates to treat evident tumor, since a tumor is composed of a large
proportion of non-CSCs/CICs and a small proportion of CSCs/CICs [73].
To incorporate cytokines into vaccine therapy has been to transfect tumor cells or
Dendritic Cell (DC) used in vaccination with the gene for cytokines such as İnterleukin-2
(IL-2) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) to localize the
cytokine effects to the sites of tumor and T cell activation. For this purpose the results
recently obtained in murine colon carcinoma are most impressive, where murine DCs of an
established JAWS II cell line were transduced with a retroviral vector carrying murine IL-2
gene (JAWS II/IL-2). JAWS II/IL-2 cells demonstrated slightly decreased Tumor Antigen
(Tag) uptake [74].
Targeted therapies for colorectal cancer
Surgery, radiotherapy and chemotherapy are conventional methods used in cancer
treatment. Because these methods have some limitations, it is difficult to cure the disease
completely. In recent years, to overcome these limitations and also to increase the efficiency
of the therapies, new methods are being developed [75]. In this context, targeted therapy is a
90
promising approach. Targeted therapy refers to a new generation of anticancer drugs that are
designed to interfere with a specific molecular target, usually a protein with a critical role in
tumor growth or progression. This approach differs from the more empirical approach used
in conventional cytotoxic chemotherapy, which has remained the mainstay of anticancer
drug use over the past several decades [76]. Targeted agents have dramatically improved and
enriched the therapeutical choices for patients with Metastatic Colorectal Cancer (mCRC)
[77]. As a consequence of improved understanding of the molecular pathology of cancer,
a number of targeted agents have been developed which have demonstrated improved
outcome in Metastatic CRC (mCRC) patients, with combination chemotherapy [78].
Vascular endothelial growth factor (vegf) targeted therapies
Angiogenesis is the production by a tumor of a new blood vessel system for the purpose
of providing nutrients to the tumor [79]. Vascular Endothelial Growth Factor (VEGF) is
an approximately 45-kD proangiogenic homodimeric glycoprotein that functions as a
major contributor in stimulating pathologic angiogenesis [80]. VEGF is a proangiogenic
factor known to play a central role in tumor angiogenesis and has, therefore, emerged as a
promising target for therapeutic intervention [81]. The VEGF family currently includes six
known members: VEGF, placenta growth factor, VEGF-B, VEGF-C, VEGF-D, and VEGF-E
[82-84]. VEGF expression is increased in the majority of cancers including colon and rectal
cancer [85,86]. As anticancer strategy, targeting tumor associated vascular endothelial cells
instead of tumor itself has several theoretical advantages over common cytotoxic regimes
(e.g. 5-Fluorouracil (5-FU), oxaliplatin) [87].
Potential approaches for blocking VEGF action include inhibiting secretion of endogenous
tumor VEGF, neutralizing VEGF in the microcirculation, and preventing VEGF binding
and subsequent signal transduction. A number of these strategies for inhibiting tumor
angiogenesis by selectively targeting the VEGF signaling pathway are currently being tested
in early phase I/II clinical trials [80].
Targeting of tumor expressed VEGF is highly attractive approach to the treatment of
human cancer. Bevacizumab, a humanized murine monoclonal antibody directed at VEGF,
has shown promising efficacy in the treatment of colorectal cancer. The results of ongoing
phase III trials are eagerly awaited to help determine whether and when bevacizumab
therapy will become a standard entry in the armamentarium against this disease [88].
Bevacizumab is a recombinant humanised monoclonal antibody that specifically targets
VEGF-A, which is synthesised during tumour growth. Bevacizumab is thus defined as an
anti-angiogenic drug due to its ability to prevent VEGF from interacting with appropriate
receptors in vascular endothelial cells. As a result, cell signalling pathways that enhance
angiogenesis, and thus the blood supply for tumours, are diminished. Bevacizumab is
commonly used in combination with standard chemotherapeutic agents (e.g. 5-FU) as a
first line treatment for patients with mCRC and improves the Overall Survival (OS) of these
patients by approximately 5 months [89,90].
In addition, several investigational angiogenesis inhibitors are currently under
development and may soon expand the armamentarium of vascular-disrupting agents
available for the treatment of mCRC. As treatment options for CRC continue to expand, it
will become increasingly important to establish molecular diagnostics to identify the subsets
of patients who are most likely to benefit from specific treatment approaches [91].
Epidermal growth factor receptor (EGFR) targeted therapies
Elevated levels of Epidermal Growth Factor Receptor (EGFR) expression have been
found in a variety of epithelial tumors including colorectal cancer [92]. The EGFR signaling
91
pathway has been the focus of new drug development for colorectal cancer because it is
overexpressed in approximately 80% of colorectal carcinomas [93]. EGFR expression was
reported to be correlated with more aggressive disease [94], increased risk of metastases
[95], advanced tumor stage [96]and higher rates of mesenteric lymph-node involvement
[97]. Inhibiting of EGFR causes cell cycle arrest, potentiation of apoptosis, inhibition of
angiogenesis, inhibition of tumor cell invasion and metastasis and augmentation of the
anti-tumor effects of chemotherapy and radiation therapy [98].
Convincing preclinical and clinical studies have already demonstrated the efficacy
of EGFR inhibitors in advanced colorectal carcinomas and their potential synergistic
combinations with chemo- and radiation therapy [99].
Cetuximab is a chimeric IgG1 Monoclonal Antibody (mAb) that binds to the extracellular
domain of the EGFR, and was the first biologic agent to receive approval in 2004 by Food
and Drugs Administration (FDA) in the United States (US) for use in combination with
irinotecan for the treatment of EGFR expressing irinotecan refractory mCRC patients and
as single agent in those intolerant to irinotecan-based chemotherapy [100].
Panitumumab is the first fully monoclonal antibody that binds EGFR approved by
Food and Drugs Administration for the treatment of EGFR expressing CRC patients with
disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan containing
chemotherapy regimens based on improvement in progression free survival and response
rate [101].
When epidermal growth factor, as well as several other ligands, occupies the EGFR, it
activates a signaling pathway cascade through the downstream effectors of the mitogenactivated protein kinases (MAPK) pathway. These effectors (KRAS, BRAF, ERK, and MAPK)
influence cellular proliferation, adhesion, angiogenesis, migration, and survival. Other
EGFR-mediated pathways include (1) the signal transducer and activator of transcription
and (2) the phosphoinositide-3-kinase (P13k)/ AKT Signaling Pathway (STAT) [102]. Blocking
EGFR with cetuximab or panitumumab blocks all downstream effects of this receptor and is
the basis of these therapeutic agents [103].
Oncogenic activation of signaling pathways downstream of the EGFR, such as mutation
of KRAS, BRAF or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene
is central to the progression of colorectal cancer. Tumor KRAS mutations, which may be
present in 35%-45% of patients with colorectal cancer, have emerged as an important
predictive marker of resistance to panitumumab or cetuximab treatment. In addition,
among colorectal tumors carrying wild-type KRAS , mutation of BRAF or PIK3CA or loss
of PTEN expression may be associated with resistance to EGFR-targeted monoclonal
antibody treatment, although these additional biomarkers require further validation before
incorporation into clinical practice [104].
Conclusion
Surgical and technological advances offer opportunity to realize minimally invasive
method for complicated surgery to surgeon. Shortened duration of stay in hospital,
decreased morbidity and rapid recovery time provide many advantages to patients. Advances
in radiation therapy increased the quality and accuracy of treatment. Using targeted and
immunotherapeutic drugs alone or in combination with conventional drugs increases
chemotherapeutic effectiveness.
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eBooks
ISBN: 978-1-63278-054-6
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Chapter 8
Treatment of colorectal cancer
Pulmonary Metastas
Tony Ibrahim
M.D, M.Sc. Hematology-Oncology Department, Faculty of Medicine Saint Joseph
University, Beirut, Lebanon
Corresponding author: Tony Ibrahim, Hematology Oncology Department, Faculty of
Medicine Saint Joseph University, Beirut, Lebanon.E-mail: [email protected];
Phone number: +96170 971758
*
Abstract
The lung is the second most common site of colorectal cancer metastasis. Treatment
is based mainly on systemic therapy which has largely evolved lately but outcome is still
relatively poor. Ablative techniques including surgery, radiation therapy and radiofrequency
ablation is being used lately with encouraging results. Patient selection along with complete
resection of all metastasis and conservation of good pulmonary function are the main
principles behind the efficacy of local therapy. Randomized trials are still needed.
Introduction
The lung is the second most common site of colorectal cancer (CRC) metastasis after
the liver. In fact during the course of the disease, nearly 15% of diagnosed patients will
eventually develop Lung Metastasis (LM) and less than 5% remain alive after 5 years if
left untreated [1-6]. Their median survival does not surpass 1 year [7,8]. Even though the
treatment of Metastatic Colorectal Cancer (mCRC) is based mainly on systemic therapy
(chemotherapy and or targeted therapy), ablative techniques including surgery, radiation
therapy and radiofrequency ablation are being used commonly in recent years. This is
done only in selected patients despite the doubts about the effect of locoregional therapy in
systemic diseases [9-16]. In this chapter the author reviews the therapeutic strategies for
pulmonary metastasis and discuss its’ effectiveness.
Systemic Therapy
Systemic therapy for mCRC has largely evolved in the last 10 years which led to a
doubling of the median overall survival (12 months in the era of Solitary 5-Fluorouracil (FU)
therapy versus 2 years in the modern era of new active agents) [17] . Seven different classes
of drugs with proven anti-tumor activity are actually available: the first three belong to
cytotoxic chemotherapies (Fluoropyrimidines, Irinotecan and Oxaliplatin) and the remaining
four to targeted therapies (Cetuximab/Panitumumab, Bevacizumab, Aflibercept and
Regorafenib) [17,18]. Several combinations are actually recommended to treat disseminated
CRC regardless of metastatic location [18]. Even though some authors have proposed that
CRC cells could respond differently to chemotherapy according to their sites [19,20], actual
Clinical Diagnosis and Therapy of Colorectal Cancer
Edited by: Ralph Schneider
98
recommended regimens do not take this factor into consideration. Thus patients with lung
only metastasis are treated similarly to patients with other metastatic sites [17,18].
Surgery
Since Blalock first described resection of CRC pulmonary metastases in 1944 [21],
numerous other studies have been conducted suggesting better survival rates in patients
treated with Pulmonary Metastasectomy (PM) compared with palliative chemotherapy
[22,23]. This has led to the establishment of The International Registry of Lung Metastases
by the European Society of Thoracic Surgeons (ESTS), in order to conduct large multicentric studies [13]. The role of surgery, however, remained controversial due to the lack
of prospective randomized controlled trials [24]. In fact, only suitable candidates with good
prognostic factors are selected for metastasectomy in retrospective and non-comparative
studies. The beneficial outcome might therefore be attributed to patient selection rather
than surgical resection of pulmonary metastasis per se [25,26]. Instead, the rationale for
surgery is supported by multi-centric prospective studies, systematic literature reviews and
meta-analysis of non-randomized or non-comparative studies, regrouping large numbers
of patients. For example, a prospective study including 5206 patients who underwent
surgery at 18 sites in Europe and North America (United States and Canada), demonstrated
a 5 year survival rate of 36% in patients undergoing complete resection of all pulmonary
metastasis [13]. Several authors have also conducted systematic reviews and meta-analyses
to overcome limitations of retrospective studies. They are summarized in Table 1.
Thus, surgery for pulmonary metastasis of CRC has become widely accepted with a
curative intent [5,27]. Careful patient selection, however, remains a key to insure a
successful outcome. The National Comprehensive Cancer Network (NCCN) established
current guidelines for PM as follows: the primary tumor must have been resected for cure
(R0) and maintenance of adequate pulmonary function is required after complete resection
of all metastasis [18,28-31]. Hence, the presence of resectable extrapulmonary metastases
do not preclude resection [32-35]; in such cases, all metastases could be either resected
synchronously or using a staged approach [18].
Authors and year of
publication
Involved patients and studies
5 years overall survival
rate
1870 patients from 20 published studies between 1995 and 2006
41 to 56%
Gonzalez et al. [11]
2925 patients from 25 studies between 2000 and 2011
27 to 68%
Salah et al. 2013 [50]
927 patients between 1983 and 2008
Pfannschmidt et al. [14]
54.3%
Table1: list of meta-analysis studying the efficacy of surgical resection of pulmonary metastasis.
Pre-Operative Imaging Tests
Before considering the surgical option in the management of LM, physicians should
search for unrecognized unrespectable metastatic lesions that would preclude the possibility
of this approach. This could be done by mean of a Positron Emission Tomography (PET)-CT
scan [18]. In addition thin-section (1-2 mm) image reconstruction techniques along with
appropriate exposure factor are recommended in order to evaluate for possibility of complete
resection [18,36,37]. It should be noted however that not all lung lesions detected by high
sensitive CT scans are certainly metastatic disease in nature. In fact a systematic review
of 12 studies including a total of 5873 patients with CRC undergoing chest CT for initial
staging has shown indeterminate pulmonary nodules in up to 9% of subjects, among which
only 10.8% turned out to be metastases at follow up [38]. The presence of calcification
indicated benign lesions whereas regional lymph nodes enlargement along with multiple
nodules was predictive of malignancy. Therefore the detection of indeterminate pulmonary
nodules on high resolution chest CT should not contraindicate nor delay surgery with
curative intent [38].
99
Surgical Techniques
Completeness of resection along with preservation of as much healthy lung parenchyma
as possible are the two major principles that can never be compromised no matter
what surgical approach is used [5]. Open procedures, either by thoracotomy or median
sternotomy, are the most commonly used [39]. However, the high sensitivity of helical CT
in detecting small pulmonary nodules along with the improvement of minimally invasive
techniques, have encouraged surgeons all over the world to apply the video-assisted thoracic
surgery VATS technique in pulmonary metastasectomy. This later approach offers less postoperative pain, morbidity and reduces duration of hospital stay and should be considered if
complete resection can be guaranteed [40-43].
Perioperative Chemotherapy
In contrast to liver metastasis, no prospective study comparing patients undergoing
surgical metastasectomy with and without neoadjuvant chemotherapy for LM is available.
Concerning the addition of targeted therapy to chemotherapy regimens after complete
resection of metastatic disease is still a matter of debate. According to the NCCN panel,
FOLFOX (5-FU, Leucovorin, Oxaliplatine) or CapeOx (capecitabine, oxaliplatine) regimens
are recommended alone without Cetuximab, neither Panitumumab nor Bevacizumab, as
the systemic treatment is not considered for metastatic disease but as adjuvant therapy
[18].
Repeated Resection
Even though re-resection is considered unfavorable for most surgeons, the NCCN panel
suggests that it could be considered in selected patients [18,44]; in fact some authors have
tried this approach and reported safe effective results [45-49]. Recently, a pooled analysis
of seven published retrospective series was conducted by Salah et al including 148 patients
undergoing repeated PM, have shown a 5 years survival rate of 57.9%. Results of this study
should be interpreted with caution with patient selection being a major bias [50].
Prognostic Factors
Several factors have been proposed to be of prognostic significance in deciding surgical
removal of pulmonary metastasis, including Carcinoembryonic Antigen (CEA), number and
location of lesions in the lung, and mediastinal lymph node metastasis [5]. This later was
shown to be of poor outcome in the meta-analysis of Gonzales et al.,[11] and several authors
have suggested the need to consider mediastinoscopy in order to assess histologically lymph
node metastasis when suspected by imaging before surgery [5,11].
Other Ablative Techniques
If complete surgical resection is not feasible other ablative techniques could be considered
in highly selected cases, in the setting of a clinical trial or as palliative care interventions
(NCC). Options include radiotherapy (3D conformal radiation therapy, IMRT, or Stereotactic
Body Radiation Therapy (SBRT)), brachytherapy and radiofrequency ablation depending on
the size and location of metastasis [9,18,51-57]. The later approach has gained popularity
recently and is discussed below.
Radiofrequency Ablation
Radiofrequency ablation is considered a minimally invasive percutaneous approach
using only local anesthesia [51]. It causes focal coagulation necrosis in tumor tissue by
mean of an alternating electrical current heating cancer cells to more than 50 degree
Celsius [58]. Several authors have studied its efficacy in treating pulmonary metastasis less
than 3 cm with curative intent [59-66]. Although tumor progression after the procedure is
around 10%, 1 and 3 years survival rates is approximately 90 and 50%, respectively. Even
100
though mortality rate related directly to the procedure is very low, nearly 50% develop
pneumothorax with or without the need of a chest tube placement [51]. Repeatability with
minimal influence on pulmonary function is one of the major advantages of RFA which
should be considered in patients unfit for surgery or refusing invasive interventions [51,
67].
Conclusion and Future Perspectives
Treatment of PM should always be based on a multidisciplinary approach. Although
systemic therapy is still the cornerstone of mCRC treatment, ablative techniques should
also be considered as an adjunct that would be beneficial in highly selected patients.
Finally, randomized studies are still needed to confirm the efficacy of local therapy
and determine selection factors for patients who would benefit from this approach like
the PulMiCC trial which results are still attended [26].
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