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Clinical Diagnosis and Therapy of Colorectal Cancer www.esciencecentral.org/ebooks I Edited by Dr. Ralph Schneider eBooks 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 Printed Version: September, 2015 Published by OMICS Group eBooks 731 Gull Ave, Foster City, CA 94404, USA. Copyright © 2015 OMICS Group All book chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. However, users who aim to disseminate and distribute copies of this book as a whole must not seek monetary compensation for such service (excluded OMICS Group representatives and agreed collaborations). After this work has been published by OMICS Group, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. Notice: Statements and opinions expressed in the book are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. A free online edition of this book is available at www.esciencecentral.org/ebooks Additional hard copies can be obtained from orders @ www.esciencecentral.org/ebooks I eBooks 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 eBooks 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 V Page no 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. 4 eBooks ISBN: 978-1-63278-054-6 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. 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(2012) Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening N Engl J Med, 366: 697-706. 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]. 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Gut. 59: 666-689. 39 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 References 1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. See comment in PubMed Commons below CA Cancer J Clin 65: 5-29. 2. Van den Eynde M, Hendlisz A (2009) Treatment of colorectal liver metastases: a review. See comment in PubMed Commons below Rev Recent Clin Trials 4: 56-62. 3. Adam R, De Gramont A, Figueras J,Guthrie A, Kokudo N, et al. 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See comment in PubMed Commons below BMC Cancer 10: 309. 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. 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Br J Surg 88: 1617-1622. 89. Grumann MM, Noack EM, Hoffmann IA, Schlag PM (2001) Comparison of quality of life in patients undergoing abdominoperineal extirpation or anterior resection for rectal cancer. Ann Surg 233: 149-156. 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]. 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Gut. 59: 666-689. 85 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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Nat Rev Cancer 5: 341-354. 103.Monzon FA, Ogino S, Hammond ME, Halling KC, Bloom KJ, et al. (2009) The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med 133: 1600-1606. 104.Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A (2009) Biomarkers predicting clinical outcome of epidermal growth factor receptor -targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst 101: 1308-1324. 97 eBooks ISBN: 978-1-63278-054-6 DOI: http://dx.doi.org/10.4172/978-1-63278-054-6-055 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. 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