Эпидемиология колоректального рака
Колоректальный рак (CRC), который включает первичные злокачественные образования толстой и прямой кишки, является третьим по распространенности раком у мужчин и вторым у женщин в мире согласно GLOBOCAN статистике за 2012 год . Это составляет 1,36 миллиона новых случаев CRC в год и 694 000 смертей, ассоциированных с этим заболеванием.
При сравнении развитых и развивающихся регионов согласно критериям ООН, возраст-стандартизированная частота (age standardized rates, ASR) на 100,000 для CRC инцидента составила 36.3 у мужчин из развитых регионов и 13,6 из развивающихся. Паттерны женщин были сходными с 23,6 в развитых регионах и 9,8 в развивающихся регионах. Особенно высокая заболеваемость наблюдается в Австралии и Новой Зеландии, Южной и Западной Европе и Северной Америке. Заболеваемость выше у мужчин относительно женщин (по соотношению полов от ASR 1,4: 1) .
Риск развития CRC повышается с возрастом, и, вероятно, распределение инцидентов в колоректуме становится более проксимальным [2-4]. Возраст, видимо, являлся способствующим фактором в этом наблюдении , также как женский пол  и возможное использование скрининга, который может обнаруживать больше повреждений левой части толстой кишки. Недавние данные о распространенности рака толстой кишки из Surveillance, Epidemiology and End Results (SEER) в США показывают, что 67% были правосторонними поражениями  в соответствии с более ранними исследованиями. Однако с середины 1980-х годов в США наблюдается снижение числа CRC случаев; возможно, это может быть частично результатом скрининга на CRC, в частности, с появлением эндоскопического скрининга . Примечательно, однако, что снижение заболеваемости началось до широкого внедрения эндоскопического скрининга в США, что свидетельствует об альтернативных объяснениях. Наблюдалось снижение CRC-ассоциированной смертности в США за аналогичный период времени . Выживаемость за год и пять лет после CRC терапии составляет 83,2% и 64,3% соответственно . Это поднимает вопрос о выживании, о чем будет сказано ниже в этой главе. Оценки превалирования CRC выживших в США в 2012 году, делают CRC вторым по распространенности диагнозом рака среди выживших, 9% для мужчин и 8% женщин .
Факторы риска для CRC
Хроническое воспаление/воспалительное заболевание кишечника
Хроническое воспаление играет решающую роль в инициировании, поддержании и продвижении роста опухоли. Хроническое воспаление изменяет микроокружение растворимыми медиаторами (цитокиновыми сетями) путем задействования клеток, которые стимулируют рост опухоли. Продукция реактивных кислородных и азотных форм провоспалительными клетками может привести к ДНК повреждению в эпителиальных клетках, что может активировать онкогены и инактивировать гены-супрессоры опухолей. Действительно, эти кислородные формы уменьшают экспрессию и активность протеинов мисматч-репарации, включая MLH1, MSH2 и MSH6, путем прямого энзимного повреждения, смещения факторов транскрипции или повышения регуляции ДНК-метилтрансферазы. Структурное ДНК повреждение в виде разрывов нитей и поперечных сшивок, например, может вести к хромосомной нестабильности. Кроме того повышенное метилирование и аберрантная экспрессия microRNA наблюдается при хронических воспалительных состояниях. Воспаление также может «поставлять» биологически активные молекулы в микроокружение опухоли. Наряду с локальными эффектами, хроническое воспаление может вызвать генотоксичность, влияющую преимущественно на лейкоциты, которые могут снижать противоопухолевую активность. Несколько генетических и эпигенетических изменений в эпителиальных клетках были описаны при язвенном колите, которые могут быть причиной канцерогенеза толстой кишки. Ранние шаги в колит- ассоциированном канцерогенезе часто включают микросателлитную нестабильность (microsatellite instability, MSI) и p53 мутацию, которые уже присутствуют в недиспластической, хронически воспаленной ткани. Ускоренное старение толстого кишечника, видимо, вносит большой вклад в повышение риска развития рака у пациентов с язвенным колитом, вследствие преждевременного сокращения теломер и повышенного возраст-ассоциированного метилирования CpG-островков. Таким образом, и язвенный колит, и болезнь Крона являются значительным фактором риска развития CRC, после наследственных синдромов, таких как семейный аденоматозный полипоз (FAP) и синдром Линча с относительным риском 19x и 18x, соответственно. Для язвенного колита существуют кумулятивные вероятности 8% через 20 лет и 18% через 30 лет (без наблюдения или химиопрофилактики), а для болезни Крона существует кумулятивный риск CRC ~7% через 20 лет, и они, как правило, связаны до степени поражения толстой кишки. Хотя редко, после продолжения воспаления карман-ассоциированные карциномы наблюдаются у пациентов с воспалительным заболеванием кишечника. Растущие опухоли, скорее всего, являются хорошо дифференцированными аденокарциномами муцинозного или перстневидно-кольцевидно- клеточного типа по сравнению со спорадическим CRC и могут демонстрировать различия в молекулярных характеристиках.
Радиация-индуцированная неоплазия является хорошо известным следствием солнечной инсоляции, ионизирующего излучения или излучения частиц. Различные ткани отличительно реагируют на эти типы излучения и, несмотря на сильные острые эффекты излучения, желудочно-кишечный тракт довольно устойчив к радиация-индуцированной неоплазии, как показывают редкие вторичные опухоли, которые развиваются после лечения предстательной железы, шейки матки и мочевого пузыря.
Питание и образ жизни
Существует обширная литература об ассоциации диетических и диетических компонентов с риском развития CRC. По оценкам, роль диеты в качестве фактора, способствующего развитию CRC, достигает 50% для спорадического CRC [11, 13].
В 1971 году Burkitt сообщил об ассоциации CRC с потреблением клетчатки, что объясняет более низкий уровень заболеваемости у африканцев вследствие диеты с высоким содержанием клетчатки . С того времени было проведено несколько исследований, в которых изучалось влияние пищевых волокон на частоту развития CRC. Исследования по контролю над заболеванием заключили об умеренном защитном эффекте [13, 14], но результаты когортных исследований были неоднозначными [15-17] с сообщениями о влиянии на результаты стиля жизни и безволокнистой пищи , которые не учитывались в более ранних исследованиях. Было высказано предположение, что защитный эффект пищевых волокон может обуславливаться специфическими подтипами волокон, таких как зерновое волокно , что может объяснять некоторые смешанные результаты в исследованиях, которые группировали все типы волокон.
Потребление красного мяса или обработанного мяса и содержание жира в пище считались связанными с риском развития CRC [20-23]. Willet et al. сообщил, что диета с высоким содержанием животного жира высоко ассоциирована с повышенным риском CRC . Однако первоначальные позитивные ассоциации между этими рационами и риском CRC поставлены под сомнение, и согласно другим проспективным исследованиям и крупным метаанализам величина риска также сомнительна [24-26].
Несколько гипотез связывают питание продуктами с высоким содержанием животных жиров и риском CRC. Одна механистическая связь включает повышенную экспозицию толстого кишечника желчным кислотам, которая действует как мутаген или канцероген [27-29]. Имеются сообщения об увеличении уровня выделяемых желчных кислот в популяциях, которые подвержены повышенному риску CRC [30, 31]. Одна из преобладающих теорий заключает, что бактериальная флора в толстом кишечнике может продуцировать канцерогены из животного жира или из желчных кислот . Также были высказаны предположения о бактериальных или вирусных эффектах, которые могут способствовать риску CRC через множественные механизмы, но с участием эпителиального воспаления .
Lifestyle often confounds analysis of studies investigating diet and CRC risk. There have been attempts to clarify the role of lifestyle in the risk for CRC. A recent large prospective cohort trial in Denmark addressed this issue and suggested adherence to recommendations for physical activity, waist circumference, smoking, alcohol intake, and diet may reduce the risk of CRC by up to 23% . This is compelling data that a significant proportion of CRC risk can be modified by lifestyle measures.
On the balance of evidence it would appear that lifestyle and certain dietary modification may be benefi al in reducing the risk of CRC, but the degree of benefit remains to be determined. Given the negligible health risks of such positive lifestyle changes, it makes practical sense for health professionals to advocate these changes for those deemed to be at risk of CRC. The data on specific diets remains inconclusive, particularly with respect to red meat and dietary fibre. However, a number of studies and at least one large meta-analysis have suggested Vitamin D intake and blood 25(OH)D levels were inversely associated with the risk of CRC . The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing randomized clinical trial in 25,875 US men and women investigating whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 g) reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses (NLM Identifier NCT01169259).
Another link to the role of bile acids and CRC comes from observational data suggesting an association of cholecystectomy and risk of developing CRC . Two meta-analyses of predominantly case-control studies suggested an increased risk of CRC in the proximal colon [37, 38] and both raised concerns about the quality of the data.
A relatively recent study from Sweden suggested a higher-than-expected incidence of proximal CRC and proximal carcinoids . A concern with these data was raised in earlier studies suggesting that there was more enriched risk after 15 years post-cholecystectomy . The Swedish study measured potential latency and found the majority of cases of CRC occurred earlier than 15 years, which is contrary to earlier studies. They concluded that the risk of CRC post-cholecystectomy is low.
Диабет, ожирение и резистентность к инсулину
There is consistent evidence of an association of obesity [40, 41] and type II diabetes mellitus and risk of CRC [42–44]. Early studies were small and difficult to interpret the risk of type II diabetes mellitus in the context of confounders such as BMI and physical inactivity [45, 46].
Prospective studies showed an independent association between type II diabetes mellitus and onset of CRC in men and women [44, 47]. Other studies have found the same trend in increased risk in both males and females, but the result did not reach statistical significance in women . In an analysis of the Nurses Health Study, adult onset type II diabetes mellitus was also found to be a risk factor for the development of CRC  with a multivariate adjusted relative risk of 1.30 (95% CI 1.20–1.40). This relative risk is consistent with the risk for men. A Japanese prospective cohort study of more than 90,000 individuals also made an association of diabetes mellitus and colon cancer with an adjusted relative risk of 1.36 (95% CI 1.00–1.85). However, when they excluded diagnoses of colon cancer within five years, which may have antedated the diagnosis of diabetes mellitus, the risk for CRC was not significant 1.14 (95% CI 0.74–1.75) .
There are a number of hypotheses posed for the mechanism of type II diabetes mellitus accounting for an increased risk of CRC. There is data suggesting a causal role of hyperinsulinaemia and insulin-like growth factors (IGF) in colorectal carcinogenesis. Colorectal cancer cells are found to express insulin and IGF-1 receptors [51, 52] and there is animal data implicating insulin as a promoter of growth of aberrant crypt foci which are thought to be the earliest precursor lesion of CRC . Indeed, high endogenous insulin has been suggested as a risk factor for CRC when levels of C-peptide are measured in high-risk populations [54, 55].
There is a suggestion that exogenous insulin therapy may also lead to higher risk of CRC  although data are conflicting, with the association of type II diabetes probably accounting for the excess risk rather than insulin therapy .
As yet, screening guidelines have not specifically targeted individuals with diabetes mellitus for more intensive screening interventions, but this may be a consideration in populations with endemic obesity and increasing prevalence of type II diabetes mellitus.
A meta-analysis of observational data  has found those individuals that have ever smoked have a relative risk of 1.18 (95% CI 1.11–1.25) of developing CRC over those individuals who have never smoked. This study found an equally significant increase in mortality from CRC in smokers. Previous studies also made the association between cigarette smoking and CRC incidence .
The association between alcohol consumption and CRC risk has been made in a number of studies. A recent meta-analysis summarizes the potential risk for moderate to heavy consumers up to a relative risk (RR) of 1.52; 95% CI 1.27–1.81 for persons consuming more than four standard drinks per day . In support of no association with low alcohol intake, a study investigating consumption of up to 30 g alcohol per day (one standard drink) in the UK Dietary Cohort Consortium found no association with CRC . There are ongoing studies investigating the potential beneficial role of specific types of alcoholic beverages and the risk of CRC. Red wine has been postulated to lower the risk of CRC due to its content of polyphenols but this work needs further study.
The practice of ureterosigmoidostomy has been reported to increase the risk of CRC at the anastomosis. This is an uncommon complication of an uncommon procedure and has a long latency [61–63].
Генетические факторы риска
There are a number of dominant and recessively inherited predispositions for CRC. These will be covered in the section ‘Molecular biology’.
There are now well-established guidelines that address screening issues for patients deemed at average or population-level risk and those at high risk due to high penetrance genetic syndromes through many gastroenterological associations (the American Gastroenterological Association, the British Society of Gastroenterologists, and Australian National Health and Medical Research Council are some examples).
As mentioned earlier, the incidence of CRC in the US has been declining over the last three decades [9, 64]. Screening has been determined as a factor accounting for up to 50% of the decreasing incidence using microsimulation modelling methods, particularly with the removal of adenomatous polyps . Screening may also have contributed to the reduction in mortality due to earlier diagnosis and management of CRC.
Risk factors that are considered in the allocation of appropriate screening recommendations include: (1) genetic risk such as Lynch syndrome or FAP mutation carriers; (2) personal history of colorectal carcinoma or adenomatous polyps of the colon; (3) inflammatory bowel disease with colonic involvement for over eight years; (4) family history of CRC but not meeting criteria for a diagnosis of a known genetic syndrome; and (5) demographic and clinical risk factors that are known to attribute higher risk for CRC. These have included race/ethnicity in the US, where black persons have highest incidence and mortality from CRC .
While recommendations vary slightly according to country, average risk persons are advised to consider a number of options for screening strategies as outlined in greater detail in Chapter 30, ‘Population cancer screening’:
- Фекальный иммунохимический тест (FIT), который, в значительной степени, заменил гвайак-базисную фекальную пробу на скрытое кровотечение (gFOBT) ежегодно или каждые два года.
- Фекальный ДНК анализ.
- Гибкая сигмоидоскопия.
- CT колонография (хотя еще широко не используется).
Аспирин и NSAID
Epidemiological associations of a negative correlation with CRC incidence and regular use of aspirin [66, 67] stimulated significant research into its use as a potential chemoprevention agent.
These initial studies led to intervention studies into aspirin as a chemoprevention for CRC. A systematic review of the literature prepared for the US Preventive Services Taskforce  suggested regular aspirin use reduces the incidence of CRC with a pooled relative risk reduction of 22%, especially with longer duration of therapy and at relatively high dosage. The study did acknowledge the potential harms of aspirin when given at dosage above 200 mg/ day with an approximate gastrointestinal bleed rate of 2.69% per year. This study acknowledged a discrepancy in data from randomized controlled studies that did not show as significant an effect as observational studies.
Another meta-analysis of radiochemotherapy (RCT) data suggested the effect of aspirin was seen in the first 12 months after the intervention . There have also been mixed effects on the incidence of colonic adenoma with studies suggesting a reduction in incidence of new adenomas in patients with a prior CRC or adenoma that was treated with regular aspirin [70, 71].
Follow-up data from British-led intervention trials of aspirin have been analysed suggesting a reduction in the incidence of CRC of approximately 24% in patients taking aspirin . This also led to improved prognosis.
A randomized control trial of daily aspirin in Lynch syndrome patients has shown a reduction in incidence of CRC after a treatment period of at least two years’ duration . The initial analysis of this data did not show a significant difference at one year . A peculiarity of this data was that there was no difference in the incidence of adenomas between the control group and treatment group during the follow-up period.
Studies have also shown that NSAID drugs reduce the burden of colorectal adenomas in familial adenomatous polyposis (FAP) patients, with sulindac being the best studied, showing up to 40% reduction in polyp burden [75–77]. Although there is benefit from COX2 selective inhibitors, their potential cardiovascular toxicity at high dose has caused concern. Generally, NSAID drugs are advocated to delay definitive colectomy in FAP patients but do not replace prophylactic surgery .
Молекулярная биология и патология CRC
Genomic integrity in normal cells is maintained by a comprehensive array of DNA repair machinery. However, mutations in genes coding for elements in the different repair pathways leads to genomic instability, the ‘mutator’ phenotype, which facilitates the development of cancers. There are three main molecular pathways [79–80] leading to genomic instability in CRC development. First, the conventional adenoma-carcinoma sequence characterized by chromosomal instability (CIN), as reported by Vogelstein et al.  which accounts for ~60% of colorectal carcinoma. Second, defects in DNA repair that accounts for ~5% and lead to the microsatellite instability pathway (as seen in the prototypical HNPCC/Lynch syndrome) and third, aberrant DNA methylation that leads to the so-called CpG island methylated phenotype (CIMP+), which accounts for the remaining ~35% [82–84]. Since there is no consensus on the precise criteria of these pathways they are not mutually exclusive.
Хромосомная нестабильность (CIN)
This is characterized by large and frequent changes in chromosomal copy number and structure that result in inactivation of tumour suppressor genes (the so-called suppressor pathway) . The tumour karyotype is complex with numerous chromosomal gains and losses that differ between tumour cells. The defi tion of CIN has not been standardized, with many different methodologies and criteria being used such as karyotyping, FISH, LOH, array CGH, and more recently next-generation sequencing. Indeed, some authors have suggested that there are sub-categories within CIN with low and high subtypes that may be prognostic [86, 87].
There are many proposed mechanisms that could be responsible for the CIN phenotype . See Figure 39.1. The aneuploidy could result from chromosomal segregation disorders from perturbations in the spindle assembly that control the mitotic checkpoint or centrosomes and anchor the microtubules [88–91]. Other potential causes of CIN include telomere dysfunction through shortening, resulting in repetitive breakage–fusion–bridge cycles, amplification of DNA sequences genomic alteration  and abnormalities in the DNA damage response . All these processes, therefore, lead to unbalanced structural rearrangements leading to the numerous mutations in CRC demonstrating CIN; however, only a small proportion will be driver mutations, with the majority being passenger mutations .
Аномалии ДНК репарации
Cells have developed a vast array of different mechanisms of DNA repair to ensure genomic integrity [90, 95]. Indeed, ~30% of the genes in the human genome encode for proteins that regulate DNA fidelity . One such DNA repair apparatus is the mismatch repair pathway, which removes replication errors in a strand-specific manner, to remove mismatched nucleotides from the newly replicated strand of DNA. The major proteins involved in this process are MLH1, MSH2, MSH6, PMS2, which form functional heterodimers [97, 98]. Mutations in these genes lead to loss of function leading to strand slippage or looping in repetitive regions present in introns, untranslated terminal regions, and the coding exons throughout the genome . This results in increases in sequence length in daughter cells during DNA synthesis or shortening if there is slippage during DNA replication. This can be assessed in the pathology laboratory using MSI testing (see Figure 39.2) [99, 100]. The degree of MSI can be categorized as high MSI (MSI-H) when two or more panel markers are involved, low MSI (MSI-L) if only one marker is involved, and microsatellite stable (MSS) if none [101, 102]. The value of a MSI-L category remains questionable  since the clinical presentation of MSI-L tumours has yet to be fully determined.
Fig. 39.1. CIRCOS plot demonstrating inherent difference between the two broad molecular subtypes of CRC: MSI-H and CIN. While CIN tumours are characterized by genome-wide copy number aberrations, MSI-H tumours remain largely chromosomally stable (inner circles represent the proportion of tumours with copy number gain/ loss at a given chromosomal location). Conversely, MSI-H tumours exhibit elevated number of non-synonymous mutations (both single nucleotide polymorphisms and indels, especially around simple sequence repeats), when compared to CIN tumours (outer circle represents proportion of samples with a non-synonymous mutation at a given gene).
Since there are repetitive sequences in a number of oncogenes including growth factor receptors (EGFR, TGFβ type II), cell cycle and apoptosis (BAX, caspase-5), and DNA repair (CHK1, MLH3, MSH3) subsequent alterations in these genes lead to further accumulation of genetic changes .
The preferred test for MMR deficiency is the combination of MSI testing with immunohistochemistry to MMR proteins (see Figure 39.3), since this can identify the likely candidate gene for subsequent germline testing which testing for MSI cannot. MLH1 methylation can be responsible for aberrant MLH1 staining and
MSI (~15% of all MSI tumours and >80% of sporadic MSI CRCs) with similar morphology as the other MSI tumours and a good prognosis [102, 103].
A further DNA repair pathway mechanism of CRC development results from mutation in the Mut Y homolog (MUTYH) gene (see section on MUTYH below).
Аберрантное ДНК метилирование
DNA methylation is more frequent in tumorigenesis than DNA mutation . Although aberrant methylation occurs throughout the genome, methylation that leads to transcriptional silencing occurs preferentially at CpG islands present in up to 60% of the 5’ promoter region. There is a group of ~35% CRCs that become aberrantly and extensively methylated that have been termed CpG island methylator phenotype (CIMP) [84, 105]. Methylation appears to occur early in CRC development as it is identified in adenomas [106–110]. The precise definition of this group is unclear with different classification schemes using different markers for CIMP . It is also unclear whether such CRC are a true molecular subtype or represent the end of a spectrum of methylation.
Fig. 39.2. Microsatellite electropherograms following multiplex PCR amplification of fluoresceinated microsatellite markers from a microsatellite stable (A) and unstable (B) CRC. Normal and tumour DNA product from the same individual are amplified for each microsatellite marker and the product lengths are compared to determine MSI status. Amplification normally gives rise to a central peak plus a Gaussian distribution of stuttering peaks from slippage of the polymerase during the amplification reaction. The appearance of additional shorter peaks from shortening of the repeats occurs in the tumour cells. Residual normal peaks are often present in the tumour electropherogram due to contamination of non-neoplastic cells within the tumour sample.
Nevertheless, there are data to suggest that there are qualitative as well as quantitative differences within CIMP that are determined by the molecular pathway of tumourigenesis, either the traditional adenoma-carcinoma or serrated adenoma-carcinoma [84, 111–113]. Thus, CIMP1 is predominantly associated with methylation of multiple genes including MLH1 through the increased susceptibility to methylation from a BRAF mutation, which results in MSI. CIMP2, another category, is characterized by KRAS and is associated with methylation of a restricted number of genes including the DNA repair gene, O-6-methylguanine DNA methyltransferase (MGMT) that results in base excision and repair defects leading to the observed chromosomal instability and LOH; these are MSI-low. The third CIMP negative category is rarely methylated but demonstrates p53 mutation . The CIMP1 and CIMP2 categories are proposed to arise from an alternative serrated adenoma pathway. The BRAF serrated pathway is better defined than the KRAS mediated pathway.
Ключевые гены, вовлеченные в CRC
In CRC, the presence of repeating molecular aberrations in copy number, expression profile, methylation patterns, and mutations support a common underlying biology. Several pathways are central to CRC carcinogenesis, the Wnt signalling pathways being the most important . The tumour suppressor gene APC is frequently mutated, in a minority of cases β catenin is mutated, and in rare cases, functional analogues of APC like AXIN 1 and 2, and NKD1 are the first step towards CRC. Consecutive steps towards tumour development are the inactivation of additional tumour suppression genes in the p53 and TGFβ pathways. Activation of oncogenes such as KRAS, BRAF, and PI3CKA are necessary for the development of the tumour. When DNA repair defects are the initial step for carcinogenesis, the sequence of events can be modified and frequencies of affected genes are different. Recent data from massive parallel sequencing demonstrate that by including these commonly affected genes and pathways a total number of 24 genes are repeatedly mutated in CRC  but the frequency may differ between primary and metastases .
Наследственные аспекты колоректальной карциномы
Approximately 25% of all colorectal carcinoma is estimated to have an hereditary element (see Figure 39.4). The major CRC genetic syndromes that account for ~5% of the hereditary effect and include FAP, attenuated FAP (AFAP), MUTYH-associated polyposis (MAP), and Lynch syndrome (hereditary nonpolyposis CRC, HNPCC) . Rarer syndromes include hamartomatous polyposis conditions (Peutz–Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and others) [119–121] and hyperplastic polyposis ; they contribute a further small proportion of cases together with a number of genetic syndromes including Li–Fraumeni (p53)  and Bloom’s (BLM)  that are associated with multiple tumour types and sites, including the colon. Additionally, familial CRCs that do not meet the clinical criteria for a diagnosis of known hereditary CRC syndromes have up to a sixfold increased risk that is dependent on the age and number of affected family members. A component of this increased risk is likely to be due to a number of low-penetrance risk genes that account for ~10% of the familial association have been identified using genome wide association studies [125, 126] which might also act as modifiers of other more penetrant genes.
Фиг. 39.3. Иммуногистохимия мисматч-репарации. Иммуногистохимия для MSH6. One of the mismatch repair proteins, showing the loss of staining for protein in the tumour cells (large arrow) with retention of expression in the non-neoplastic elements including normal intestinal crypts, stromal cells (thin arrow) and lymphocytes.
Основные наследственные синдромы
Семейный аденоматозный полипоз (familial adenomatous polyposis, FAP)
FAP is an autosomal dominantly transmitted disease caused by a mutation of the APC gene located on 5q21, which is a negative regulator of the Wnt pathway [127–129]. Most mutations are nonsense type, leading to the formation of a truncated protein. FAP is characterized by up to thousands of adenomatous polyps in the large intestine that develop in childhood and inevitably transform to CRC by 40 years of age . However, there are FAP variants that depend on the region and the type of mutation (i.e. frameshift mutation versus missense mutation) in the APC gene. These include (1) attenuated FAP, a variant that has a later presentation with polyps that are fewer in number compared with conventional FAP (up to 100 polyps), and a lower (~70%) lifetime risk of CRC ; (2) Gardner’s syndrome, in which individuals also develop extracolonic tumours including upper GI polyps, small intestinal tumours, desmoid tumours, osteomas, and cysts; and (3) one form of Turcot’s syndrome in which patients develop CRC and medulloblastoma [132–134]. Thus, for example, a mutation between codons 1250–1464 is associated with usual-type FAP whereas mutations at the 3’ end are associated with desmoid tumours [130, 133].
MUTYH is located on chromosome 1p, and encodes a protein of the DNA base excision repair (BER) pathway, mutations of which predispose to the development of CRC . The BER system is responsible for repairing one of the most stable deleterious products of oxidative DNA damage, that of 8-oxo-7,8-dihydro-2-deoxyguanosine. Formation of such damaged DNA predisposes to point mutations particularly increased G:C to T:A transversions , but even though the genomic instability effects individual base pairs the tumours demonstrate CIN . MUTYH polyposis is autosomal recessive and is associated with variable adenomatous polyposis from only a few to several hundred that can mimic FAP; it has a significant increase in susceptibility to CRC that approaches 100% by the age of 60 years [137–139]. Two common variants have been reported—Tyr165Cys and Gly382Asp, which account for ~80% of cases. Affected individuals also have an increased incidence of developing other tumour types .
Синдром Линча (Lynch)
Lynch syndrome is an autosomally dominant disease characterized by colorectal, endometrial, ureteric, gastric, ovarian, biliary, urinary tract, small bowel, brain, and pancreatic carcinomas that result from germline inactivation of DNA mismatch repair genes (see Chapter 31, ‘Familial cancer syndromes and genetic counselling’). Lynch syndrome is largely (~80%) due to mutations in MLH1 and MSH2 with alterations in MSH6 (10%), PMS2, and MLH3 accounting for the remainder. A rare germline deletion in TACSTD1, resulting in TACSTD1/MSH2 fusion transcripts generation with epigenetic inactivation of the corresponding MSH2 allele, also causes Lynch syndrome. The overall lifetime risk of CRC is 80%, but risks vary depending on the gene affected (e.g., PMS2 has only a 15–20% risk for CRC). Although mutations can be identified spanning these genes, founder mutations have been identified, accounting for up to 10% of all Lynch syndrome patients. Variants of Lynch syndrome include (1) Turcot syndrome, the result of mutation in the mismatch repair genes hMLH1 or hPMS2 characterized by CRC and glioblastoma and (2) Muir–Torre syndrome, which results from mutations in MLH1 and MSH2 and is characterized by the presence of sebaceous gland neoplasms and visceral malignancies, usually CRC. Screening for Lynch syndrome includes using immunohistochemistry for MMR proteins on CRC or endometrial carcinomas (other Lynch-associated tumours have low specificity and sensitivity) for absence of staining and MSI . Since absent staining of MLH1 protein might be due to methylation, BRAF mutation status by mutational analysis or use of mutation-specific antibodies may be required. If negative, directed germline mutation analysis can be performed; in the future, clinical massive parallel sequencing may alter this testing algorithm.
Фиг. 39.4. Частота наследственного CRC. The majority of CRC have a sporadic origin (75%), 15% of cases have an increased risk of CRC (familial CRC), but no defined underlying gene mutation. The remaining 10% of cases originate from patients with a known hereditary cancer syndrome, of which Lynch syndrome is the most frequent (5%).
Синдромы гамартоматозного полипоза
Синдром Пейтца-Егерса (Peutz-Jeghers)
Peutz-Jeghers syndrome is an autosomal dominant disorder that presents in childhood, characterized by mucocutaneous pigmented lesions around and within the mouth, and hamartomatous polyps in the gastrointestinal tract, particularly the small bowel . Most patients have a germline truncation or missense mutation in the tumour suppressor STK11 gene, located at 19p13.3 that encodes a serine threonine kinase (STK) protein , although other genes may be implicated (e.g., MYH11 ). Mutation results in tumour suppressor activity as LKB1-AMPK signalling negatively regulates the mTOR pathway . Activation of mTOR signalling leads to hamartoma formation, which predisposes to a number of malignancies in the gastrointestinal tract and other organs including pancreatic, lung, breast, uterine, ovarian, and testicular tumours [143, 144].
Juvenile polyposis is rare and has three main subtypes comprising juvenile polyposis of infancy, juvenile polyposis of the colon, and generalized juvenile polyposis, all of which have different modes of presentation [119, 120]. Patients with juvenile polyposis of infancy have no family history and present with diffuse gastrointestinal polyposis that is associated with macrocephaly, digital clubbing, and hypotonia. Individuals usually die from non-neoplastic complications of the condition such as haemorrhage, malnutrition, or and intussusception before the age of 2 years.
Juvenile polyposis of the colon and generalized juvenile polyposis usually present by the age of 10 with acute or chronic gastrointestinal haemorrhage, anaemia, and polyps that can number in the hundreds. Patients have a cumulative life-time risk for CRC of 39–68% and an increased risk of other intestinal tumours, dependent on the location of the polyps. They are associated in 50–60% with an inherited or new mutation (usually point mutations or small deletions but also large deletions in 5–15%) in SMAD4 and BMPR1A. Mutations of PTEN, the gene responsible for Cowden syndrome, have also been reported, and some individuals with SMAD4 germline mutations have hereditary haemorrhagic telangiectasia . All these genes encode proteins in the TGFβ signalling pathway and thus might represent be a spectrum of phenotypes.
Смешанный полипозный синдром
Mixed polyposis syndrome is a relatively recent recognized entity, without any clear definition, caused by a mutation in BMPR1A and thus, might be part of the spectrum of TGFβ-pathway-associated polyposes. This mutation shows an autosomal dominant inheritance and carriers have an increased risk of CRC [146, 147] on a background of adenomas and hyperplastic and juvenile polyps.
Polyps closely resembling juvenile polyps are found in other conditions such as Cowden disease, an autosomal dominant condition of the phosphatase and tensin homolog (PTEN) gene or rarely SDHB. However, although polyps are identified in the gastrointestinal tract in ~80% there is no apparent cancer risk . Bannayan–Riley–Ruvalcaba syndrome, characterized by juvenile polyps, mental retardation, macrocephaly, lipomatosis, haemangiomas, and genital pigmentation was originally thought to be a distinct entity but also harbour a PTEN mutation in 60% of individuals. Thus, an aggregate term of PTEN hamartoma syndrome has been suggested , the phenotypic differences being due to ascertainment bias. Cronkhite–Canada syndrome is a further gastrointestinal polyposis of unknown aetiology but is non-hereditary .
Синдром гиперпластического полипоза
Hereditary non-polyposis colon cancer/hyperplastic polyposis is a rare condition defined by arbitrary criteria that are likely to represent a spectrum of conditions. They are characterized by the WHO as having (1) at least five histologically diagnosed hyperplastic polyps proximal to the sigmoid colon of which two are greater than 10 mm in diameter; (2) any number of hyperplastic polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with hyperplastic polyposis; or (3) more than 30 hyperplastic polyps of any size, but distributed throughout the colon [150–152]. Individuals develop CRC (baseline 25–37% of patients [150, 153]) on a background of hyperplastic polyps, other serrated adenomas, and even traditional adenomas. The molecular genetics of this condition(s) is unknown.
Патология колоректальной карциномы
Прекурсорные поражения CRC
Аберрантные фокусы крипт (aberrant crypt foci, ACF)
ACF are microscopic mucosal abnormalities , some of which may be precursors to CRC . ACF are most frequent in the rectum, descending and sigmoid colon and microscopically have the morphology of dysplastic microadenomas (single crypt adenomas) or hyperplastic crypts with or without a serrated luminal pattern. Although reported in FAP and sporadic CRC they are also identified in ~40% of patients with benign colonic diseases such as diverticular disease, rectal prolapse, and volvulus . The number of ACF increases with age and correlate with the presence of adenomas. The adenomas that form from ACF in the context of FAP have APC mutations, whereas those in the sporadic setting harbour KRAS mutations (and lack of methylation). The non-dysplastic ACF might be precursors of CRC through the alternate serrated adenoma pathway associated with BRAF and occasionally KRAS mutations [156, 157].
These are largely polypoid neoplasms characterized by dysplastic large intestinal-type epithelium, although some show a flat or sessile configuration. They can show a tubular, villous, or mixed architecture and most are <10mm. Villous adenomas >10mm with severe dysplasia are associated with synchronous or metachronous carcinoma associated with the CIN pathway. The pathology is similar whether the patient has FAP or its variants, with MUTYH-associated polyposis or sporadic. KRAS rather than BRAF mutations are associated with adenomas.
Serrated polyps [84, 113] are a heterogeneous collection of lesions characterized by serrated epithelium and account for a ~40% of colorectal polyps. There are many forms, some forms of which, through genetic and epigenetic changes akin to the traditional adenoma-carcinoma sequence, progress along a ‘serrated pathway’ as an alternate mechanism of CRC development.
These are malformations of the mucosa, lamina propria, and sometimes muscularis propria that form a polyp. They have varied morphologies depending on the underlying pathogenesis but include polyps with a central smooth muscle core that arborizes and is covered by mucosa with a villous pattern, as in Peutz–Jegher, to simple tags and mixtures of connective tissue with oedematous stroma, cystic gland formation, variable inflammation, lobulation, and branching.
The histological biopsy forms the basis for therapeutic decisions for the patient and, for rectal cancer, is a requirement for the commencement of neoadjuvant therapy. After surgery, pathological evaluation  of the characteristics of the primary tumour, the presence of lymph node metastases, and the evaluation of treatment (surgery and neoadjuvant therapy) form the basis for subsequent adjuvant therapy. Primary tumour characteristics that are suggestive of hereditary cancer syndromes might necessitate additional testing, such as MSI testing and MMR immunohistochemistry. In case of advanced or metastatic disease, additional molecular testing can be performed in order to test suitability for targeted therapies (e.g., RAS testing) .
The macroscopic appearances of CRC are varied with tumours having an appearance that is endophytic, exophytic, or annular with or without ulceration or a combination; a rare form of diffuse infiltration has also been described. The presence of carcinoma is defined as invasion through the muscularis mucosa to the submucosa. Histological classification follows the World Health Organization. There are also other non-epithelial tumour types, which might be encountered in the colon and rectum: lymphomas, sarcomas, and melanomas .
Particular histological tumour types are associated with particular molecular characteristics. For example MSI-H tumours, whether Lynch or sporadic, tend to be well circumscribed, proximally located, and demonstrate two patterns: (1) well-differentiated mucinous and (2) poorly-differentiated with tumour-infiltrating lymphocytes, a Crohn’s-like reaction (also classified as medullary carcinoma), which despite their poor differentiation have a good prognosis.
The majority of CRCs are located in the distal colon and rectum, although the frequencies at different sites depend on the underlying molecular genetics. Thus, tumours demonstrating MSI or CIMP are generally right-sided (caecum, ascending and transverse colon) whereas CIMP-positive and MSS cancers occur on right and left; MSS without CIMP are located mainly in the left colon. Although location has been used to aid classification of the underlying pathogenesis of CRC, recent data suggests that non-MSI tumours are similar irrespective of their origin, whereas a continuum model may apply for MSI tumours as frequencies of CIMP, MSI, and BRAF mutation increase in a linear manner distal to proximal .
Патологические прогностические маркеры
The staging system of choice is the TNM or AJCC classification [162, 163]. The three pillars of this system are depth of Tumour penetration (TNM I and II), presence of lymph Node metastases (TNM III) and distant Metastases (TNM IV). This system can adequately predict local recurrence, distant metastases, and survival rates, although stage II patients do show a large variation in prognosis. A special high-risk stage II group has been defined, characterized by the presence of perforation, T4, obstruction, less than ten examined lymph nodes, extramural vascular invasion, or poor differentiation .
Груз лимфатических узлов
One of the most important factors in patients’ prognosis is the presence of nodal metastases. Approximately ~70% of the patients with no lymph node metastases are alive five years after surgery, while those with metastases have a five-year survival rate of 40%. Standard guidelines are provided for the number and location of the examined lymph nodes, but ideally 12 lymph nodes should be examined before a patient can be classified as N0. Nevertheless, in daily practice, even 12 lymph nodes can be challenging to acquire, as the number of nodes is influenced by preoperative radiotherapy and in the type of resection performed, as well as variation between patients . Differences in the quality of pathological examination using a combination of visual inspection, palpation, and dissection is another important factor determining the yield of lymph nodes isolated from the perirectal fat.
Ранний CRC канцер
With the widespread introduction of population screening for CRC, the number of early CRCs is expected to increase from the ~25% that currently present with early disease (stage I). Local excision is an attractive option for early disease in both colon and rectal cancer, since it is associated with considerably less surgery-related morbidity and almost no post-operative mortality compared with colectomy and total mesorectal excision (TME) (mortality rates of 1.9–6.5% (rectum) and 3.2–9.8% (colon) have been reported). Patient selection through careful histological analysis of local excision specimens can be very useful to avoid overand under-treatment. Several pathologic features of the primary tumour have been associated with presence of LNM, such as poor differentiation, tumour budding, presence of lymphatic or vascular invasion, and submucosal invasion depth.
Гистологические прогностические факторы
Mucinous carcinomas have a slightly poorer prognosis than adenocarcinomas, mainly from presentation at advanced stage. Signet-ring-cell carcinomas, as well as mucinous carcinomas with signet ring cells, are associated with poor prognosis. In contrast, medullary carcinomas have a very good prognosis. Histological grading of cancer though the assessment of tumour differentiation is used as a surrogate for tumour aggressiveness. There are a variety of systems  but the majority of studies use a two-tiered stratifi ation. Growth pattern is another feature that has prognostic value in CRC. The circumscript/pushing confi tion is associated with a good prognosis, while diffuse infiltration is associated with a poor prognosis . A closely-associated feature is the presence of tumour budding , where tumour cells at the invasive front of CRC detach into single cells or clusters of up to five cells. The presence of budding is associated with lymph node metastases and metastatic disease. Other histological features that have prognostic relevance are (1) lymphatic invasion (tumour cells in the submucosal lymphatic vessels), which is mainly related to the risk of lymph node metastases; (2) extramural vascular invasion (tumour cells in the subserosal blood vessels), which is associated with the development of blood-borne distant metastases; and (3) perineural invasion (tumour cells in and around nerves), which is associated with local as well as distant recurrence .
Регрессия опухоли, оцениваемая после неоадъювантной терапии
Various methods have been developed to grade tumour regression to assess neoadjuvant treatment, and although using differing criteria, each generally show increased regression is associated with a prolonged survival. However, the lack of standardization of grading together with interand intra-observer variation make regression grading a less reliable indication of tumour response such that other factors, such as circumferential radial margin involvement, are more important . Nevertheless, although response grading is of some utility, the main purpose of neoadjuvant therapy is downstaging of the tumour, facilitating surgical excision.
Другие прогностические маркеры
Despite the numerous publications about prognostic markers in CRC, few are used in practice such as an inflammatory infiltrate in and around the tumour . Recent developments have standardized this analysis in the Immunoscore® , which is currently under investigation in a multicentre study. There is consistent evidence for the favourable prognosis of MSI tumours  whereas BRAF mutation is associated with a poor prognosis .
The presence of MSI has previously been considered a contraindication for 5-FU-based therapy, although again conflicting studies have been published. In a meta-analysis  no clear conclusion could be drawn about the effects of MSI on 5-FU response, due to significant inter-study heterogeneity. However, with the relative good prognosis of these tumours, the potential for beneficial effects is small. For targeted therapy, the predictive marker is KRAS mutation. In the presence of an activating KRAS mutation, inhibition of the EGF receptor does not have the desired effect on tumour cells and thus there is no indication for this therapy. It is expected that the increased use of targeted drugs will lead to the identification of additional predictive markers.
Surgery is the mainstay of treatment for colon cancer. If a patient is fit enough to undergo surgery, resection of the primary tumour with excision of the draining lymph nodes provides the only option for cure, with around two-thirds of the patients disease-free at five years , and recurrence after this time is rare. The introduction of laparoscopic colorectal surgery over the last decade has reduced the traumatic impact of surgical resection, improving patient recovery. Advanced colonoscopic techniques such as endoscopic mucosal resection have facilitated removal of adenomas that would previously have required surgical resection. These are being identified more frequently with the advent of national bowel cancer screening programs.
Survival rates following surgery remained static for some time, but the introduction of adjuvant chemotherapy has resulted in an improvement in survival and a reduction in the development of metastatic disease. The surgical approach to metastatic disease, either metachronous or synchronous, has evolved to become increasingly proactive. Resection of liver, lung, and peritoneal metastases can be curative and improve survival outcomes. The increased survival of patients with stage IV disease through improvements in chemotherapy has also led to an increased role for surgery to control palliative symptoms.
Colonoscopy is the gold standard diagnostic test for colon cancer, with a sensitivity of 95% . Cancers can be visually assessed and biopsied to provide tissue for histological diagnosis. Histology may be inconclusive due to sampling of tumour slough and inflammation or if a malignant core is surrounded by adenoma. If further biopsies are inconclusive or the lesion is not reachable endoscopically, it should be considered to be malignant. CT pneumocolonography provides a diagnostic alternative to endoscopy. The sensitivity for cancers is equal to that of colonoscopy ; however, identified abnormalities need endoscopic evaluation.
With the increase in minimally invasive surgery, lesions should be marked at their distal border with Indian or carbon particle suspension ‘ink’. Lesions impassable with an endoscope are at risk of obstruction and early surgery or colonic stenting should be considered. If there is an impassable lesion, the remainder of the colon should be examined for synchronous lesions by CT pneumocolonography.
This aims to identify metastatic spread and local invasion. The mainstay of staging in colonic cancer is high-resolution CT scanning. This should include the chest, abdomen, and pelvis. The two commonest sites of haematogenous spread are to the liver and the lungs. Incidental liver lesions may cause diagnostic uncertainty and further imaging with ultrasound or MRI may be required. FDG-PET scanning is being used more frequently, as it has a higher sensitivity for recurrent and metastatic disease than CT . It can also help differentiate between benign and malignant lesions seen on standard CT. In patients with metastatic disease being considered for curative resection, it may identify otherwise occult metastases.
Identifi ation of locally advanced disease allows planning of en-bloc resection of the invaded organ along with the primary tumour, if the patient is fit enough. In colon cancer, the proximity of the small bowel and the mobility of the colon make the use of neoadjuvant chemoradiotherapy mostly impractical.
Prior to elective cancer resection there is a window to investigate the patient’s general health. The stress of abdominal surgery places the patient at risk of ischaemic vascular events, thromboembolism, and hypostatic and invasive-line-related infections. Preoperative assessment aims to find unidentified or undertreated medical conditions and assess the likelihood of surviving the procedure. This is usually started with a pre-anaesthetic assessment and may then be aided by a number of objective measures of patient ‘fitness’.
Ischaemic and valvular heart disease, respiratory conditions, hypertension, and diabetes mellitus should be optimally medically managed prior to surgery. Medical conditions such as cardiac ischaemia, which would normally require intervention, should be treated and surgery delayed to allow this .
An objective measure of risk can be gained with scores such as the acute physiology and chronic health evaluation score or physiological testing such as cardio-pulmonary exercise testing. These can help to identify patients who require more aggressive and invasive perioperative care . They can also identify patients in whom surgery has a high risk of complications or death. If patients are found to have poor performance with physiological testing, then preoperative optimization of haematinics, nutrition, and exercise programmes may improve their outcome .
Once diagnostic, staging, and preoperative assessment have taken place, cases should be presented to a CRC multidisciplinary team. These groups review the radiology and histology, ensuring quality control and allowing a consensus opinion on the appropriate management of individual cases.
Colonic cancer surgery has led the way in the healthcare trend towards early mobilization and reduced inpatient stay. The work by Kehlet  in open intestinal surgery has become the cornerstone of enhanced recovery programmes. These are often combined with the reduced surgical stress of minimally invasive techniques to facilitate early discharge.
Perioperative care should start prior to admission. Consent is best gained away from the stress of the surgical environment. Patients can meet stoma therapists, nurse specialists, and enhanced recovery coordinators prior to their stay. Education on thromboembolic prevention, physiotherapy, and pain control can be provided. Bowel preparation and preoperative nutritional supplements can all be taken at home prior to admission. In most cases, it is safe for patients to be admitted on the morning of surgery .
Enhanced recovery tries to facilitate the normal return of gut and motor function. This combines early feeding and mobilization with reduced opiates and nauseating anaesthetic agents. Pain control with local or regional anaesthetic blocks and non-steroidal anti-inflammatories are combined to reduce opiates. Tubes which reduce mobility such as abdominal drains, nasogastric and urinary
catheters are avoided or used for short periods. Intravenous fluid replacement is ‘targeted’  intraoperatively and in the post-operative period replaced at maintenance volumes only, until full oral nutrition has returned. Enteral nutrition is encouraged from day one in the post-operative period.
Thromboprophylaxis is particularly important in patients with a cancer diagnosis and undergoing abdominal surgery. Anti-thromboembolism stockings, pneumatic compression devices, and early low-molecular-weight heparin should all be utilized if possible, aided by early return to mobility.
Резекция толстой кишки (colonic)
The underlying principle of surgery for colon cancer is resection of the bowel where the tumour has originated along with the lymph nodes draining that area. The two ends of bowel are then joined together with an anastomosis to restore bowel ‘continuity’. Lymph node involvement is usually unknown until the resected specimen is reviewed by the pathologist. Hence, the extent of resection is determined by the lymphatic anatomy of the colon. Lymphatic colonic drainage channels follow the arterial blood supply. By ligating and dividing the relevant artery close to its origin, ‘high ligation’, removal of the draining lymph nodes is ensured. Turnbull proposed a ‘no-touch technique’ , where ligation of the feeding vessels is undertaken prior to mobilization of the tumour, reducing tumour spread. In fact, this was a surrogate for ‘proper’ high arterial ligation and adequate resection of the lymph node containing colonic mesentery. See Figure 39.5.
Division of the artery will defi e an area of colon which will become ischaemic. This should contain the tumour and margins of ‘normal’ colon of at least 5 cm proximally and distally. The two ends of intestine should have adequate blood supply from the adjacent arterial vessels via the marginal artery to allow healing. The marginal artery runs around the length of the colon and is supplied by branches of both the superior mesenteric and inferior mesenteric arteries. The blood flow in this artery is determined by the distance from the feeding vessel and the quality of those vessels. This is affected by factors such as atherosclerosis, hypotension, vasoconstriction, and cardiac output. The quality of blood flow in the marginal artery can be demonstrated by pulsatile flow on division of the vessel . If the blood supply is poor, further resection of colon may be required. Other factors influencing anastomotic healing include tension across the anastomosis, radiotherapy, or bowel disease. Healing is also influenced by global patient factors such as poor nutrition, immunosuppression, and concurrent illness. Despite this, most colonic surgery can be anastomosed safely. In obstructed or severely malnourished patients a de-functioning or temporary-end ileostomy can be life-saving. In most cases, the risk of anastomotic leaks is not enough to warrant their formation.
When performing a right hemicolectomy, the ileocolic artery is high ligated, along with the right colic artery which is present in 10% of patients. This resection will allow removal of caecal, ascending colon, and hepatic flexure tumours. For tumours of the descending and sigmoid colon high ligation of the inferior mesenteric artery is performed as part of a left hemicolectomy or high anterior resection. Tumours of the transverse colon are predominantly supplied by the middle colic artery but may include supply from the ileocolic vessels. These tumours are removed with an extended right hemicolectomy, where ligation of the middle colic is added to that of the ileocolic artery. Transverse colon resections are rarely performed as they may compromise the oncological resection and have been associated with a higher anastomotic leak rate .
Fig. 39.5. Quality of surgery and relation to the circumferential resection margin. (A)–(B) Good quality of surgery, the plane of resection is on the mesorectal fascia, the CRM is free. (C)–(D) The plane of surgery is on the muscularis propria, the CRM is threatened.
The steps required to undertake a colonic resection remain fairly constant. The right and left colon are retroperitoneal with their vessel containing mesentery draped over the retroperitoneal structures, whilst the transverse and sigmoid colon are freely mobile on their respective mesenteries. The right and left colon are mobilized by division of their peritoneal attachments. Once mobilized, the supplying vascular pedicle is divided high and the mesentery divided up to the points on the bowel appropriate for the resection. After resection, the bowel is usually reanastomosed using one of a number of configurations. These include end-to-end, end-to-side, and side-to-side anastomoses, all of which can be performed using hand-sewn or stapled techniques.
Treatment of splenic flexure tumours
The surgical management of tumours near the splenic fl xure remains diffi ult. This area is a watershed between the middle colic and left colic artery and branches of both will supply most of these tumours. If the inferior mesenteric artery is taken high then the whole of the left colon needs to be resected unless one relies on marginal artery supply to maintain the remaining left colon. The alternative is to perform an extended right hemicolectomy and anastomose the ileum to the left colon. This doesn’t take as much of the left-sided lymphatic drainage but replaces poorly vascularized left colon with ileum to form an anastomosis. There remains no good evidence to favour one approach, and surgeons commonly make the decision based on the position of the tumour intraoperatively.
Laparoscopic colonic resection
The advent of laparoscopic or minimally invasive approaches has been the major change in surgery for CRC over the last ten years. There remains a spectrum of uptake for these techniques. The fundamental steps and principles of colonic resection are the same as for open surgery but are performed via small incisions in the abdominal wall through which 5 mm or 10 mm ‘ports’ are inserted. The laparoscopic instruments are then inserted through these ports. Division of the mesentery can be undertaken intraor extra-corporally. The bowel division and subsequent anastomosis may also be undertaken intraor extra-corporally, the mobilized specimen being delivered through a small incision using a wound protector to minimize wound or port site implantation. The end result is the same operation as an open resection but with a reduction in iatrogenic trauma to the patient.
Initially, there were concerns of an inferior oncological outcome for laparoscopic resection as well as fears of implantation of tumour cells at port sites. A number of multicentre randomized trials of laparoscopic versus open resection for colon cancer were completed and published early in the millennium. These include the CLASSIC , COST , and COLOR  trials. These have demonstrated oncological equivalence and no significant risk of port site metastasis. Patient recovery is quicker following laparoscopic resection as measured by reduction in analgesic requirements and reduced time to bowel function. There is also a reduction in length of inpatient stay, increased by combining minimally invasive surgery with enhanced recovery programmes. There is a learning curve for attaining laparoscopic skills and laparoscopic colonic resection. Even in experienced hands there remain limits on what is possible. Conversion rates to open surgery are around 10%, and relative contraindications such as previous laparotomy, emergency cases, or bowel obstruction make laparoscopic surgery challenging. For the majority of elective colonic resections a laparoscopic approach should be considered the approach of choice.
Рак толстого кишечника и воспалительное заболевание кишечника
Colitis due to Crohn’s disease and ulcerative colitis predisposes to the development of colonic cancer. In patients with pancolitis who develop an adenocarcinoma or area of dysplasia there may be a field change in the colon. These patients have a high risk of further tumours or dysplasia developing or already being present. In this situation it is safest to remove the whole colon and rectum . In ulcerative colitis the patient can be left with either an end ileostomy or a restorative ileoanal pouch.
If the patient has segmental colitis then a balance needs to be struck between segmental resection and colectomy. In patients with mild, burnt-out, or very limited disease it may be possible to perform a standard segmental resection. Prior to this, careful evaluation of patients’ symptoms and endoscopic evaluation of the mucosa is essential. Patients with limited disease but troublesome urgency and frequency will have a poor functional result with a segmental resection. For these patients an end stoma or pouch may well give a better quality of life.
Рак толстого кишечника и полипоз или HNPCC
Patients with familial adenomatous polyposis coli should be managed in specialist centres. Following a period of endoscopic surveillance started in their late teens, they should have a colectomy and pouch or ileoanal anastomosis formed in their twenties prophylactically.
Patients with hereditary non-polyposis coli are best treated with a subtotal colectomy and ileorectal or ileosigmoid anastomosis . The remainder of the colon should then be regularly examined with flexible sigmoidoscopy to prevent metachronous disease developing.
Рак толстого кишечника, представленный критическим состоянием
Undergoing emergency surgery for colonic cancer is an independent poor prognostic factor . In patients with malignant perforation the aim should be to treat the emergency expediently to reduce peritoneal contamination time. The aim should be to allow the patient to receive adjuvant chemotherapy, if required, soon after surgery to improve its efficacy. It may be more sensible to perform a Hartmann’s, removing the attendant risks of anastomotic leak and reducing operative time. This can be reversed once the patient has completed chemotherapy.
Patients presenting with obstructing tumours may be treated with surgery or stenting. Right-sided tumours should be treated with a right hemicolectomy. Although this is considered a low-morbidity procedure, the complications rates are higher than the elective setting, with anastomotic leak rates as high as 10% and a mortality of 17% . In patients who are unfit for surgery or are palliative, stenting provides an alternative treatment . The use of stenting in patients who have metastatic disease or as a bridge to surgery in obstruction is still being evaluated with prospective trials, but has been shown to be safe in retrospective studies . Stents should be placed using a combination of endoscopy and radiological guidance. Results are best when stents are placed in short left-sided strictures. In acute obstruction, delay waiting for stenting must be avoided as there is a risk of perforation and caecal ischaemia. If stenting is not available or appropriate then emergency resection should be undertaken. If the caecum is not viable then a subtotal colectomy should be performed. This is a safe operation but an ileorectal anastomosis as a single or two-stage operation can lead to troublesome loose motions and nocturnal call to stool. If the remainder of the colon is viable, a Hartmann’s or segmental resection can be used. Studies have shown that segmental resection and primary anastomosis is a safe operation in the emergency setting .
Лечение полипа или ранних карцином
Improvements in endoscopic polypectomy techniques have allowed bigger polyps to be excised. Early cancers or ‘polyp’ cancers (stage 1 or T1/T2) are being found more commonly in these resected polyps. Early cancers that have not already been excised at colonoscopy should be treated with standard resection techniques.
Colonic adenomas are polyps with areas of cellular dysplasia. They have a risk of malignancy broadly related to size, with polyps smaller than 1 cm having less than a 1% chance of containing a malignant focus . All polyps larger than 1 cm and those with suspicious features should be tattooed prior to polypectomy or tattooed and biopsied if not excisable. Polypectomy can be performed using endoscopic mucosal resection, where the polyp is lifted away from the submucosa with saline/gelatine or hyaluronate solution. The polyp is then excised with a diathermy snare. Endoscopic submucosal dissection is a modification using an endoscopic diathermy knife to resect the lesion en bloc, which can reduce recurrence [198, 199].
Resected polyp cancers cannot be fully staged. To determine if further resection is required, features that increase the risk of lymph node spread or local recurrence are identified. If the polyp cancer is incompletely excised or within 1–2 mm of the diathermy margin, further excision should be undertaken. The risk of spread or invasion is also related to the levels of invasion towards the base of the polyp: see Haggitt  for stalked and Kikuchi  for flat polyps. If the patient is unfit for surgery, then endoscopic surveillance can be used. Features which suggest more aggressive cancer types with a greater likelihood of metastasis are high grade, lymphovascular invasion, budding, and cribriform cellular pattern, which are shown in Table 39.1.
Table 39.1. Risk factors for lymph node positivity in early CRCs : high-grade, lymphovascular invasion, budding, cribriform cellular pattern
|Факторы риска||Метастаз в лимфатический узел||Микрометы в «негативном» узле|
Метастазы в печень и легкие
There has been a change in the philosophy of metastatic colon cancer management over the last 20 years. The two most common sites of metastasis, liver and lungs, can now be treated curatively with resection. Improvements in imaging have allowed metastases to be identified earlier and improvements in surgical technique and haemostatic technology have reduced the physiological insult of the surgery. Liver resection has now become the standard of care for hepatic metastasis, with five-year disease free survival of 26–34% . Whilst hepatic resection was initially limited to one to three metastatic deposits, the indications for resection are now much broader. Hepatic resection can be considered if the metastatic disease can be resected with clear margins, leaving enough functional liver—around 30%—for survival. Factors such as the volume of metastatic disease and time of recurrence are predictive of long-term outcome .
Patients who present with liver metastasis and a primary colon tumour may undergo synchronous resection or have their liver metastasis resected in a separate operation. Synchronous resection is usually reserved for patients having a simple colonic resection and a simple liver resection. The morbidity with simultaneous resection can be significantly increased, with higher rates of anastomotic leaks making complex resections unsafe .
Strategies have also developed to address initially unresectable hepatic disease. Chemotherapy may downstage unresectable disease to resectable disease. A recent European Organisation for Research and Treatment of Cancer (EORTC) randomized trial has demonstrated the benefit in progression-free survival of preoperative chemotherapy in the majority of resectable cases . Lack of adequate functional liver post resection can be addressed by staged liver resection. This can be combined with portal vein embolization to generate hypertrophy of one side of the liver, increasing residual liver volume. Even unresectable liver deposits can be controlled by radiofrequency or microwave ablation.
Pulmonary resection of colorectal metastatic disease is a more recent development but has also demonstrated survival benefits. This has been facilitated by the advent of improved imaging and surveillance leading to higher detection rates and the use of minimally invasive thoracoscopic techniques, reducing the morbidity of pulmonary resection .
Up to 10% of colon cancer cases have peritoneal spread at the time of presentation, and its treatment remains one of the challenges in colon cancer management. Cytoreductive surgery and perioperative intraperitoneal hyperthermic chemotherapy (HIPEC) has provided a treatment option for these patients . The principle is to surgically resect the macroscopic peritoneal disease leaving microscopic or minimal visible disease only. Heated intraperitoneal chemotherapy, either oxaliplatin or mitomycin C, is then added to the abdominal cavity to control any remaining malignant cells. Patient selection is important as the surgery can be extensive, involving resection of a number of organs and stripping of large areas of peritoneum. It is usually reserved for patients with good performance status and low volumes of disease. A single randomized trial demonstrated a survival advantage, with a median survival of 22 months . This data is being increasingly supported by large cohort studies .
Результаты хирургии и лечения рака толстого кишечника
Elective colon cancer surgery is considered to have a low mortality and morbidity, with good postoperative quality of life. Results from large prospective multicentre trials show mortality figures of 1–4%, and morbidity of 1–20% [210, 211]. The surgery still has significant risks of adverse events. This is in part because even very elderly patients and those with multiple comorbidities will be offered surgical treatment. The quality of life following surgery is excellent, even in older populations, often with scores as good as or better than before surgery .
The results of colon cancer treatment have been improving steadily over the last 30 years, with 22% five-year survival for colon cancer in 1971–1975 compared with 51% in 2001–2006 . Outcomes in the UK are not as good as for those with equivalent disease in the rest of Western Europe. The reasons for this remain poorly understood [214, 215]. The main determinant of survival is still cancer stage (Table 39.2); other independent poor prognostic features include presentation as an emergency and poor socioeconomic groups , and cancer features associated with more aggressive phenotypes such as lymphovascular and perineural invasion, tumour budding, mucinous, and poorly differentiated cell types.
Table 39.2. Percentage of cases and five-year relative survival (%) by stage at diagnosis, CRC patients diagnosed 1996–2002, England 
|AJCC/Dukes’ стадия||Процент случаев||Пятилетняя выживаемость|
Медицинский менеджмент болезни на ранней стадии
See Chapter 38 for the management of stage IV disease. Approximately 70–80% of newly diagnosed cases of CRC undergo curative resection; however, 40% of these develop incurable recurrent disease due to undetected micrometastases [217, 218]. Patients with stage III (A (T1, 2N1M0), B (T3, 4N1M0), C (T x N2M0) or Dukes’ C) disease have a five-year survival rate from 83% to 44%, respectively, with three-year disease-free survival (DFS) ranging from 45% to 52%. Those with stage II (A (T3N0M0) or B (T4N0M0)) colon cancer after surgical resection have a five-year survival rate of 45–60% and 64–75%, respectively [217, 219]. The inability to cure all such patients is a direct consequence of residual occult disease.
Adjuvant chemotherapy is offered to such high-risk patients with the aim of decreasing relapse and improving overall survival (OS) by attempting to eliminate microscopic residual disease. It is offered where the benefits outweigh the risks from chemotherapy-related toxicities. Adjuvant therapy has been offered to patients with stage III disease as standard therapy for over two decades , a practice strongly reinforced by two recent meta-analyses [221, 222].
In the case of patients with stage II disease, the role of adjuvant therapy is controversial given the difficulty in identifying patients at the highest of risk who would benefit the most from adjuvant therapy . The recognized clinical/pathological poor prognostic markers for patients with stage II disease include (1) poorly differentiated histology , obstruction or perforation at presentation , lymphovascular invasion ; (2) fewer than 12 lymph nodes retrieved during primary resection [225, 227, 228]; and (3) tumoural stage, including T4 disease (with invasion into adjacent organs) [224, 229]. From the SEER database, it was observed that the five-year OS rates between T3N0 and T4N0 patients was 87.5%±0.4% versus 71.5%±0.8% and between T4a (penetration through visceral peritoneum) and T4b (penetration of other organs or structures) 79.6%±1% versus 58.4%±1.3%, respectively . These high-risk factors have not been evaluated in prospective trials in which such patients were randomized to treatment versus no treatment .
Адъювантная химиотерапия для болезни III стадии (T1-4, N1-2M0)
Adjuvant chemotherapy has been the standard of care for stage III disease for the last two decades. Initial efforts concentrated on the evaluation of 5-fluorouracil (5-FU)-based regimens and 5FU biochemical modulation. With the advances in the treatment of metastatic disease including oral 5-FU prodrugs, oxaliplatin, irinotecan, and the biologicals (including EGFR and anti-vascular endothelial growth factor (VEGF) monoclonal antibodies), these agents have also been evaluated and—in some cases—are now standard of care in patients with stage III disease. These new agents either provided a more favourable administration or toxicity profile (as in the case of the oral 5-FU prodrugs) or increase in DFS or OS (in the case of oxaliplatin).
During this time, three-year DFS rate has been validated as an appropriate endpoint for adjuvant trials given its strong correlation with five-year OS (correlation coefficient 0.86, HR = 0.91) . On a subsequent analysis of six additional phase III trials, the twoor three-year DFS HRs were highly predictive of fiveand six-year OS HRs in stage III, but not stage II patients. In all patients, the DFS/ OS association is stronger for six-year OS; thus at least six years’ follow-up was recommended to assess OS benefit . However, extended survival after recurrence reduces the association between treatment effects on thee-year DFS and five-year OS, particularly in stage II patients . In modern adjuvant trials, six or seven years may now be required to demonstrate OS improvements .
The major advances in adjuvant chemotherapy for resected CRC were made in the early 1990s, with the biochemical modulation of 5-FU with either levamisole (Lev) or LV. Two recent meta-analyses have shown that the reduction in mortality by modulation of 5-FU by LV or Lev (29%, P < 0.007; 22%, P < 0.01, respectively) was significantly larger than that for unmodulated 5-FU (6%, P < 0.11) [221, 222].
The NCCTG study demonstrated the benefit of 5-FU-Lev relative to observation or Lev alone in reducing tumour recurrence and improving OS in patients with Dukes’ C disease . The IMPACT, NSABP-C03, and NCCTG trials have all demonstrated the advantage of 5-FU-LV relative to their respective control arms [235–237]. Since then, several large multicentre randomized trials have been performed to define the optimal 5-FU-based regimen: that is, the combination with highor low-dose LV (HDLV, LDLV, respectively) and/or Lev in patients with stage III colon cancer. One of the largest was the Intergroup-0089 trial, a four-arm trial involving 3760 patients with high-risk stage II/III disease . The other large trial, the QUASAR study, evaluated the role of Lev (versus placebo) and LV dose (175 mg versus 25 mg) in stage I–III CRC [239–240]. These large studies demonstrated the following: (1) 5-FU/HDLV is equivalent to 5-FU/LDLV at least as administered in the daily by 5, four-weekly regimen; (2) the weekly regimen of 5-FU-LV is equivalent but less toxic compared with a four-weekly regimen; (3) the addition of Lev provided no additional survival benefit [237–241]; and (4) the efficacy of adjuvant chemotherapy for 12 months provided no further benefit compared with six months.
The effi acy of 5-FU-LV or -Lev in the adjuvant setting has been evaluated specifically in terms of the elderly with stage III disease [242–244]. The lack of significant interaction between age and treatment efficacy has been demonstrated by the results of a meta-analysis (seven trials involving 3351 patients) , a population analysis using NCI SEER and the US Medicare database , and a prospective analysis of 85,934 patients from 1990 to 2002 .
Пероральные 5-FU пролекарства
The most widely available is capecitabine, a prodrug that undergoes final conversion to 5-FU through tumoural thymidine phosphorylase. In terms of adjuvant therapy, capecitabine (24 weeks, 1250 mg/m2 twice daily, day 1–14, one week rest) was compared to the six-months’ bolus 5-FU-LV as adjuvant therapy for stage III colon cancer in the randomized phase III X-ACT trial . The DFS (primary study endpoint) in the capecitabine arm was at least equivalent to that in the 5-FU-LV arm (HR = 086, P = 0.04); the upper limit of the HR was significantly (P < 0.001) below the predefined margins for non-inferiority. Capecitabine was also associated with significantly fewer 5-FU-related grade 3/4 adverse events (AEs; P < 0.001) and fewer adverse-event (AE)-related hospital admissions. Pharmacoeconomic analyses performed in several countries showed that the savings in direct costs (drug administration and AE-related costs) associated with capecitabine versus 5-FU-LV offset the drug acquisition costs . A follow-up report with a median follow-up of 6.9 years again confirmed these earlier results with regards to DFS .
Оксалиплатин и 5-FU или капецитабин
The efficacy of oxaliplatin plus 5-FU in the adjuvant setting was demonstrated by two pivotal trials: the MOSAIC  and the NSABP C07 trials. In the MOSAIC trial, 2246 patients who had stage II or III colon cancer were randomized to receive a combined bolus and infusional 5-FU regimen (LV5-FU2) alone or with oxaliplatin (FOLFOX4) for six months. The primary endpoint was 3year DFS . A total of 1123 patients were randomly assigned to each group. The rate of DFS at three years was 78.2% in the group given FOLFOX4 versus 72.9% in the LV5-FU2 group (P = 0.002). In the group given FOLFOX4, the incidence of grade 3 sensory neuropathy was 12.4% during treatment, decreasing to 1.1% at one year of follow-up .
With longer follow-up, the final results of the study, including six-year OS and five-year updated DFS were reported . The five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5-FU2 groups, respectively (HR = 0.80; P = 0.003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 versus LV5-FU2 groups, respectively (HR = 0.84; P = 0.046). The corresponding six-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR = 0.80; P = 0.023). Of note was that no difference in OS was seen in the stage II population .
In the NSABP C07 trial, 2492 patients with stage II and III colon cancer were randomly assigned to either 5-FU 500 mg/m2 bolus weekly for six weeks plus LV 500 mg/m2 IV weekly for six weeks during each eight-week cycle (Roswell Park regimen) for three cycles (5-FU-LV), or the same 5-FU-LV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each eight-week cycle for three cycles (FLOX) . The DFS hazard ratio (FLOX versus 5-FU-LV) was 0.80 (P <0.004). The four-year DFS rates were 67.0% for 5-FU-LV and 73.2% for FLOX, respectively. In terms of stage II and III patients: for stage II the four-year DFS was 81% versus 84.2%, and stage III 61.1% versus 68.9% for 5-FU-LV and FLOX, respectively .
A subsequent trial compared capecitabine plus oxaliplatin (XELOX; oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1 to 14, every three weeks for 24 weeks) with bolus 5-FU-LV (Mayo Clinic for 24 weeks or Roswell Park for 32 weeks) as adjuvant therapy for patients with stage III colon cancer . The primary study endpoint was DFS. After 57 months of follow-up, the three-year DFS rate was 70.9% with XELOX and 66.5% with 5-FU-LV (HR = 0.80, P = 0.0045). The HR for OS for XELOX compared to 5-FU-LV was 0.87 (P = 0.1486). The five-year OS for XELOX and 5-FU-LV were 77.6% and 74.2%, respectively. It was thus concluded that the addition of oxaliplatin to capecitabine improves DFS in patients with stage III colon cancer. XELOX is thus considered an additional adjuvant treatment option for these patients .
The efficacy of adjuvant oxaliplatin therapy has also been confirmed, albeit inconsistently, in the elderly. Subgroup analyses of DFS of the NO1968 trial comparing XELOX to 5-FU-LV, demonstrated reduced risk of recurrence in all subgroups receiving oxaliplatin including patients <65 years of age and those =65 years of age; however, in the latter group the trend was not significant . A post hoc analysis of the effect of oxaliplatin in the NSABP CO7 trials did vary by age for OS (younger than age 70 versus 70+, interaction P = 0.039), with a similar trend for DFS (interaction P = 0.073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; P = 0.013), but no positive effect was evident in older patients .
An analysis of the ACCENT database, derived from six phase III adjuvant trials comparing IV 5-FU to combinations with irinotecan, oxaliplatin, or oral FU in stage II/III colon cancer, evaluated data from 10,499 patients younger than 70 and 2170 patients =70 years. OS, DFS, and TTR were not significantly improved for those patients older than 70 years of age in the experimental versus control arms. The interaction between age and treatment was statistically significant for all endpoints (P = 0.01 for OS, DFS, and TTR) . A further analysis evaluated the benefit of the oxaliplatin combination in patients above and below 70 years of age (overall, 3742 patients; 614 ≥70 years of age) from four clinical trials in the adjuvant and metastatic setting . OS and DFS rates did not differ by age, though data from patients older than 80 was sparse .
Иринотекан и 5-FU
Despite the activity of irinotecan in the treatment of advanced CRC, randomized phase III trials in the adjuvant setting (including CALBG 89803, PETACC3, ACCORD 2 trials) have failed to demonstrate an added benefit relative to 5-FU-LV alone [254–256]. Further trials evaluating this agent in this setting have not progressed.
Биологические агенты и комбинированная химиотерапия
In the metastatic setting the antiangiogenic agent, bevacizumab, a monoclonal antibody to VEGF, and the anti-EGFR monoclonal antibodies cetuximab and panitumumab have shown added benefit when added to conventional chemotherapy backbones, whether oxaliplatinor irinotecan-based or 5-FU-LV . However, recent phase III trials in the adjuvant setting have demonstrated that these biological agents provide no additional benefit and may actually be detrimental when added to a chemotherapy backbone, usually oxaliplatin-5-FU.
In the case of bevacizumab, the NSABP C08  and the AVANT trials  have shown no additional benefit. In the former trial, 2672 patients with stage II/III disease were randomized to mFOLFOX6 for six months versus the same regimen with 12 months of bevacizumab. The primary endpoint of three-year DFS was 75.5% versus 77.4% for the control and experimental arms, respectively (HR = 0.89, P = 0.15). There was a transient effect of bevacizumab during treatment whereby the impact on DFS was significant before versus after a 15-month landmark: HR = 0.61 (P < 0.001) and HR = 1.22 (P = 0.076), respectively . The reason for this transient benefit of bevacizumab is unclear [258, 260].
The lack of benefit with bevacizumab was, however, confirmed by the AVANT trial, in which high-risk stage II/III patients were randomized to FOLFOX4 for six months ± bevacizumab for 48 weeks or XELOX for six months ± bevacizumab for 48 weeks . The addition of bevacizumab did not prolong DFS or OS in stage III patients, with efficacy favouring the chemotherapy-alone arm . Two other large relevant trials are yet to be reported. These include the QUASAR 2 study, randomizing patients to capecitabine ± bevacizumab, and ECOG E5202 .
In terms of cetuximab, the NCCTG-N0147 trial randomized patients with stage III KRAS wild-type disease to six month of mFOLFOX6 ± cetuximab . Three-year DFS for mFOLFOX6 alone was 74.6% versus 71.5% with the addition of cetuximab (HR = 1.21; P = 0.08), with no significant benefit in any subgroups assessed . The PETTAC8 trial was of similar design: a pre-specified interim analysis did not support a benefit in DFS for patients given cetuximab plus FOLFOX-4 compared with patients treated with FOLFOX-4 alone. The FoxTROT trial evaluating FOLFOX or XELOX ± panitumumab is yet to be reported .
The mechanisms for this lack of synergy with chemotherapy and the biological agents in this setting as compared to advanced disease are not clear but may be explained by the induction of compensatory/alternate mechanisms and pro-survival pathway activation by VEGF or EGFR inhibition, which have been discussed elsewhere .
Адъювантная терапия пациентов с резецированным раком толстого кишечника стадии II
Случай за и против
In the case of patients with stage II disease the role of adjuvant therapy is controversial given the difficulty in identifying patients at the highest risk who would benefit the most from adjuvant therapy whilst avoiding potential toxicity in patients who would not benefit .
The effi acy of systemic adjuvant chemotherapy for patients with stage II cancer has still not been confi med. A pooled analysis of 1016 patients with B2 colon cancer from the IMPACT trial, in which patients were randomized to 5-FU-LV versus observation, found chemotherapy did not provide a significant advantage in terms of event-free survival (EFS) (82% versus 80%, respectively) or OS (76% versus 73%, respectively) after a median follow-up of 5.75 years . However, in contrast, when the results from the NSABP C01–4 trials were pooled to compare the effi acy of chemotherapy in 1565 patients with Dukes’ B relative to Dukes’ C disease, regardless of stage, there was a reduction in mortality, DFS, and recurrence after chemotherapy. The reduction for Dukes’ B was of a similar magnitude to that seen for Dukes’ C disease .
The large phase III QUASAR trial randomized 6668 patients with resected stage II and III colon cancer to 5-FU (370 mg/m2) with HD (175 mg) or LD (25 mg), LV and either Lev or placebo. The primary outcome was all-cause mortality [239–240]. Overall, 28% of the patients entered had stage B (or stage II) disease, selected for high risk features, such as T4, obstruction, and perforation. The relative risk of recurrence for colon cancer was reduced with an HR of 0.78 (P = 0.004), and the relative risk for cancer-related death was also reduced, HR = 0.84 (P = 0.06). Treatment efficacy did not differ significantly by tumour site, stage, sex, age, or chemotherapy schedule [239–240].
In terms of modern combination therapy there is relevant data from the MOSAIC and the NSABP C07 trials in patients with stage II disease. In terms of the MOSAIC trial, 899 patients with stage II disease were randomized between LV5U2 versus oxaliplatin-LV5U2. With a median follow-up of 6.8 years: five-year DFS was 79.9% versus 83.7% (HR = 0.84, P = 0.258) and the six-year OS 86.8% versus 86.9% (P = 0.986), respectively . For the NSABP CO7 trial, 29% overall had resected stage II disease; the four-year DFS was 81% versus 84.2% in favour of FLOX . A recent Cochrane analysis considered all randomized trials or meta-analyses containing data on stage II colon cancer patients undergoing adjuvant therapy versus surgery alone; overall 8642 patients were considered . In terms of the effect of adjuvant therapy on stage II colon cancer, the pooled relative risk ratio for OS was 0.96 (95% CI 0.88–1.05), and for DFS 0.83 (95% CI 0.75–0.92).
Hence the benefit was in terms of DFS only. The authors concluded that it was reasonable to discuss the benefits of adjuvant systemic chemotherapy with those stage II patients who have high-risk features. The comorbidities and likelihood of tolerating adjuvant systemic chemotherapy should be considered as well .
Идентификация пациентов II стадии с высоким риском
Given the modest benefit for adjuvant therapy in patients with resected stage II disease, there is thus an urgent need to better characterize high-risk patients who would gain the greatest benefit. At present, the identifiers of high risk relate to the tumour as well as clinical factors, albeit inconsistently . Considerable effort has been directed to identify molecular prognostic and predictive factors; however, as expected, there is considerable heterogeneity in terms of the cohorts evaluated, prospective versus retrospective analyses, and analytical methodology.
The markers evaluated thus far include aneuploidy/tetraploidy DNA, 18q allelic loss, as well as microsatellite status (MS), p53, KRAS, BRAF, and thymidylate synthase [230, 277–270]. A detailed review of these molecular factors with regard to stage II disease has been published recently . These factors, however, may not be mutually exclusive: for example, the molecular analysis of the PETACC-3 study found that in stage II–III colon cancer, KRAS mutation status did not have major prognostic value, but BRAF was prognostic for OS in MS-L/MSS tumours .
Микросателлитная нестабильность (MSI)
The assessment of MSI, which serves as a marker for DNA mismatch repair (MMR) system function, has emerged as a useful tool for risk stratification of patients with stage II colon cancer. It seems clear, from retrospective studies and meta-analyses, that patients with stage II and III tumours classified as MSI-H (or defective MMR (dMMR)) have a better prognosis, independent of adjuvant therapy, relative to MSS tumours [272–274].
Whilst the prognostic importance of MSI has been confirmed, however, its importance in predicting response to adjuvant chemotherapy is unclear . It appears that patients with dMMR do not benefit from adjuvant 5-FU therapy [275, 276]. The largest study involved 457 patients who were previously randomized to 5-FU-based therapy adjuvant therapy (n = 229) versus no post-surgical treatment (n = 228) . Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (HR = 0.67; P = 0.02) in patients with preserved MMR tumours. Patients with dMMR tumours receiving 5-FU had no improvement in DFS (HR = 1.10; P = 0.85) compared to surgery alone. A parallel analysis of a pooled data set of 1027 patients confirmed these findings .
The data thus far support MMR status assessment for patients being considered for 5-FU therapy alone. Based on the body of current data, with the caveat that MSI status is still to be validated prospectively as a predictive biomarker, the current NCCN guidelines recommend that where adjuvant therapy is being considered in patients with stage II disease, MSI status must be assessed; those with MSI-H tumours should not be offered 5-FU-based therapy [225, 260].
It is unclear whether this also applies to oxaliplatin-5-FU adjuvant regimens. A recent study investigated the clinical implication of MSI-H/dMMR and p53 expression in resected colon cancer patients who received post-operative FOLFOX therapy . Overall, in 135 patients there were 13 (9.6%) patients with stage II disease and 108 (80%) patients with stage III. MMR status was not significantly associated with DFS or OS in patients receiving adjuvant FOLFOX. It was concluded, albeit in this small heterogeneous study, that adding oxaliplatin to adjuvant chemotherapy may overcome the negative impact of 5-FU on colon cancers with MSI-H/dMMR .
18q аллельный дисбаланс (18qAI)
The chromosome 18q contains the tumour suppressor genes deleted in colon cancer (DCC) and the SMAD4 gene, which are lost in the oncogenic development of CRC . The allelic loss of 18q is manifested as a loss of heterozygosity (LOH). The 18qLOH or 18 allelic imbalance (18qAI) have been correlated with a poorer prognosis in patients with stage II and III disease, albeit inconsistently [279, 280].
In a landmark study, LOH from chromosomes 18q, 17p, and 8p, cellular levels of p53 and p21 (WAF1/CIP1) proteins, TGF-β1 type II receptor gene mutation, and MSI status were analysed in 460 patients with stage III and high-risk stage II colon cancer who had been treated with 5-FU-based therapy . Among patients with MSS stage III cancer, five-year OS after 5-FU-based chemotherapy was 74% in those whose cancer retained 18q alleles and 50% in those with 18q LOH (RR for death with 18q LOH was 2.75; P = 0.006). The five-year OS among patients whose cancer had MSI-H was 74% in the presence of a mutated gene for the TGF-β1 type II receptor and 46% if the tumour did not have this mutation (RR of death, 2.90; P = 0.03). It was concluded in this retrospective study that retention of 18q alleles in MSS cancers and TGF-β1 type II receptor gene mutation in cancers with high levels of MSI-H point to a favourable outcome with 5-FU-based regimens for stage III colon cancer .
The recently closed ECOG E5202 study is also relevant in this regard. It assigned stage II patients, stratified by MSI status and 18q allele imbalance, to observation for low-risk patients (MSS or MSI-L with retention of 18q or MSI-H) and high-risk patients (MSS/18qLOH or MSI-L/18qLOH) to FOLFOX4 +/ bevacizumab. It was closed early following the reports of the AVANT and NSABP C08 trials that demonstrated the lack of benefit of bevacizumab in the adjuvant setting .
Подходы экспрессии генов
Quantitative gene expression assays have been evaluated to assess recurrence risk, though with less utility for the benefits from chemotherapy in patients with stage II disease. There are at present two commercially available gene expression classifiers (ColoPrint® and Oncotype DX®) that have been developed and are being subsequently validated prognostically to classify patients with early-stage colon cancer at high risk of relapse, rather than to determine their predictive ability in terms of outcomes from adjuvant chemotherapy [281, 282]. Others have also been reported and are being validated [283, 284].
ColoPrint® is an 18-gene prognostic classifi that was developed to predict disease relapse in patients with early-stage CRC. It was derived from fresh frozen tumour tissue from 188 patients with stage I to IV CRC undergoing surgery, whereby the majority (83.6%) did not receive adjuvant chemotherapy, and were analysed using Agilent 44K oligonucleotide arrays . The classifier components were identified for their association with five-year distant metastasis-free survival. The classifier was validated on an independent set of 206 samples from patients with stages I–III CRC, whereby the signature classifi d 60% of patients as low risk and 40% as high risk. Five-year relapse-free survival (RFS) rates were 87.6% and 67.2% for lowand high-risk patients, respectively, with a HR of 2.5 (P = 0.005). In a multivariate analysis, including pathological stage and MSI status, the signature remained one of the most significant prognostic factors, with a HR of 2.69 (P = 0.003). In patients with stage II CRC, the signature had an HR of 3.34 (P = 0.017). Thus, ColoPrint® significantly improved the prognostic accuracy of pathologic factors and MSI in patients with stage II and III CRC and may identify patients with stage II disease who may be managed without chemotherapy .
ColoPrint® has subsequently been validated in an independent dataset, comprising of 320 stage II patients, 227 of which were T3/MSS . In the analysis of all stage II patients, ColoPrint® classified two-thirds of stage II patients as being at lower risk. The three-year RFS was 91% for low risk and 74% for patients at higher risk, HR of 2.9 (P = 0.001). Standard poor prognostic clinicopathological parameters did not predict a differential outcome for high-risk patients (P <0.20). In the subgroup of patients with T3 and MSS phenotype, ColoPrint® classified 61% of patients at lower risk with a three-year RFS of 91% and 39% of patients at higher risk with a three-year RFS of 73% (P = 0.002) .
The second type of commercial assay is the Oncotype DX®. It was developed to quantify the risk of recurrence, as well as the likelihood of differential treatment benefit, of 5-FU/LV adjuvant chemotherapy for patients with resected stage II and III disease . Fixed, paraffi bedded tumour blocks were analysed from 1086 patients with stage II or III colon cancer treated as part of the NSABP C-01, -02, -04, and -06 trials. In its final development, the assay comprised of an 18-gene panel that included seven genes for RFS prognosis in colon cancer to yield a prognostic recurrence score (RS), six genes to predict response to 5-FU/LV chemotherapy to yield a predictive treatment score (TS), and five reference genes. Subsequent algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from 5-FU/LV .
Oncotype DX® has been subsequently validated in the stage II CRC dataset from the QUASAR study . RNA was extracted from fixed paraffin-embedded primary colon tumour blocks from 1436 patients. Both RS and TS were calculated from gene expression levels of the 13 cancer-related genes described previously. The risk of recurrence was significantly associated with RS: recurrence risks at 3 years were 12%, 18%, and 22% for predefined low-, intermediate-, and high-recurrence risk groups, respectively. T stage (HR 1.94; P
<0.001) and MMR status (HR 0.31; P <0.001) were the strongest histopathologic prognostic factors. There was no trend for increased benefit from chemotherapy at higher RS (P = 0.95). It was concluded that this continuous 12-gene RS provided prognostic value that complements T stage and MMR. The TS was not predictive of chemotherapy benefit . The Oncotype DX® assay has also been validated in the dataset derived from the PETACC-3 trial .
In conclusion, adjuvant therapy is recommended for patients with resected stage III colon cancer. Patients, based on fitness and preference, with completely resected stage III cancer should be offered six months of adjuvant chemotherapy, which optimally should start within eight weeks of surgery. The optimal regimen is oxaliplatin in combination with 5-FU-LV or capecitabine, based on relevant consideration of the therapeutic ratio, especially in regard to neurotoxicity. Patients not considered suitable for oxaliplatin should be offered 5-FU-LV (weekly bolus, or Roswell Park regimen, or LV5-FU2 bolus-infusional regimen) or capecitabine . Patient compliance in terms of cumulative toxicity and the differing toxicity profile for capecitabine must be carefully considered. Current trials are now investigating the optimal length of therapy, i.e. three versus six months (IDEA trial, multinational intergroup trial) and the SCOT (Short Course Oncology Therapy), a study of adjuvant chemotherapy in colorectal cancer by the CACTUS and QUASAR 3 Groups, and the additional benefit of the EGFR monoclonal antibody panitumumab (the FOxTROT trial), which is also testing the role of neoadjuvant therapy .
In terms of patients with resected stage II disease, adjuvant chemotherapy may be discussed with patients at high risk of disease relapse, based upon clinicopathological factors discussed above and whilst considering the patients’ comorbidities, age, as well as the risk of therapy-related adverse events. MSI status must be assessed for those patients being considered for adjuvant therapy, and those with an MSI-H tumour should not be offered 5-FU-based therapy alone [225, 260]. The utility of oxaliplatin-based therapy in this setting is controversial, given the marginal benefit and greater risk of toxicity. Where available, commercial gene expression classifiers may also be considered to further classify patients based on risk of relapse. However, at his stage they cannot predict which patients are likely to respond to therapy.
Лучевая терапия рака толстого кишечника
In contrast to rectal cancer, the role of adjuvant radiotherapy is not well established in the management of colon cancer. The colon is a much longer structure than the rectum. It begins with the caecum in the right iliac fossa, and continues as the ascending colon in the retroperitoneal region on the right side of abdomen. It then becomes the transverse colon with its mesentery attached to the posterior abdominal wall, running from the right side to the left side of the abdomen. It runs further as the descending colon in the retroperitoneal position on the left side of the abdomen, and then as the sigmoid colon with its mesentery in the lower abdomen.
Colon cancer may recur locally in several different ways: anastomotic recurrence, tumour bed recurrence, and nodal recurrence . The risk of local recurrence is, however, lower compared with rectal cancer. Anastomotic recurrence is not common, possibly because, at surgery, wide proximal and distal resection margins are achievable in most situations. The extent of proximal and distal resection margins is determined not only by the tumour extent, but also by the amount of vascular supply of the colon that is resected during clearance of the lymphatic drainage.
The risk of tumour bed recurrence varies for different parts of the colon. The high-risk portion is the immobile part of the colon in the retroperitoneal position—the ascending colon and the descending colon. The risk is particularly high when the tumour involves the posterolateral wall of the colon where the serosa is lacking. The low-risk portion is the mobile part of the colon with complete peritoneal covering attached to the posterior abdominal wall with its mesentery, the transverse colon, and the sigmoid colon. Wide circumferential margins are achievable in these areas. The risk of local recurrence also depends on whether the adjacent organs, when invaded by the tumour, can be sacrificed for an extended resection.
Adjuvant radiotherapy was found to decrease local recurrence for locally advanced tumours . It was found to be beneficial for patients with T4 lesions, tumours associated with abscess or fistula formation, and residual local disease after subtotal resection . It was also found in a retrospective study that post-operative radiotherapy decreased the risk of local recurrence in patients with T3–4 tumours of the caecum, ascending colon, or descending colon . In view of the high risk of local recurrence in the autopsy and reoperation series, a randomized controlled study was performed to evaluate the benefit of adjuvant radiation in addition to adjuvant chemotherapy after complete resection of the colon cancer . Patients suitable for the Intergroup Protocol 0130 were those with resected colon cancer where there was tumour adherence or invasion to the surrounding structures and with T3N1 or T3N2 tumours of the ascending or descending colon. The experimental arm included treatment with radiation to a total dose of 45 to 50.4 Gy in 1.8 Gy per fraction, in addition to adjuvant chemotherapy consisting of 5-FU and levamisole. This study was terminated because of slow accrual after the enrolment of 222 patients, which was less than a third of the accrual target. Data from assessable patients (n = 187) showed that patients who received chemotherapy or chemoradiation had similar overall survival and disease-free survival rates. Toxicity was higher among chemoradiation patients. These results, however, must be interpreted with caution because of the high number of ineligible patients and the limited power of the study to detect potentially meaningful differences.
Several deficiencies in the study methodology were subsequently identified. Radio-opaque surgical clips for guiding the radiation field were used only in a minor proportion of patients. Preoperative imaging was not available for most patients. The completeness of the resection could not be confirmed because of the lack of information about the radial margins. It highlights the importance of close cooperation among surgeons, radiation and medical oncologists, pathologists, and radiologists in selection of patients for adjuvant radiotherapy.
In order to evaluate the area at risk for adjuvant radiotherapy planning, availability of a preoperative CT scan, operation notes, and pathology report are essential. In addition, surgeons can assist in localization of the tumour bed by inserting radio-opaque surgical clips at the time of surgery. Accurate localization of the tumour bed improves tumour control by reducing the risk of marginal miss. It also limits unnecessary radiation exposure to the nearby critical structures at low risk for involvement.
The organs that limit radiation dose vary according to the location of the colon cancer. These organs include small intestine, liver, kidneys, spinal cord, urinary bladder, and gynaecological structures. Improvement of radiotherapy technique allows treatment to be delivered safely. Radiation side effects have been significantly reduced with conformal radiotherapy and intensity-modulated radiation therapy (IMRT).
Adjuvant chemoradiation is to be considered for selected patients with T4 disease penetrating to a fixed structure or for patients with recurrent disease. Preoperative chemoradiation is also a consideration for patients with clinical T4 or recurrent disease to increase the chance of complete resection. In addition, highly selected cases of T3 cancers on the posterolateral wall of the ascending and descending colon, where wide resection margins cannot be achieved, are to be considered. The common dose regimen for adjuvant chemoradiation is 45–50.4 Gy in 1.8 Gy per fraction over 5–5.5 weeks with concurrent infusion chemotherapy 5-FU. The radiotherapy target volume includes the primary tumour bed with a margin. There is no evidence that enlarging the radiotherapy target volume to include the regional lymph nodes improves outcomes . Radiation can also be delivered intraoperatively in specialized centres after resection of the colon cancer . Intraoperative radiation therapy (IORT) is a highly conformal form of radiotherapy. Special equipment and dedicated operation theatres are necessary for this procedure. Two forms of IORT are available. One form of delivery is with electrons from a dedicated linear accelerator located in a shielded theatre. IORT can also be delivered by brachytherapy with the flap technique. Brachytherapy is a form of radiotherapy where a radiation source is placed inside or next to the area requiring treatment. The radiation target volume is tailored according to the area at risk at the time of surgery. Side effects are kept to a minimum by displacing normal organs away from the radiation field during treatment. In addition, lead shields are used to protect tissue close to the radiation target. The effective depth of radiation is approximately 1 cm. It is reserved for situations where a wide circumferential resection margin is not achievable. In order to select suitable cases for IORT, thorough preoperative workup is necessary.
Whole abdominal radiation therapy (WART) has also been attempted to reduce the risk of intra-abdominal recurrence. A pilot clinical study of WART was performed in patients with locally advanced colon cancer, in view of the high incidence of peritoneal metastasis in this group of patients . The inclusion criteria of the Southwest Oncology Group study were patients with completely resected T3Nl–2M0 colon cancer. Infusion chemotherapy 5-FU was administered with concomitant 30 Gy of WART in 1 Gy per fraction. An additional 16 Gy boost to the tumour bed was administered in 1.6 Gy per fraction. There were no treatment-related fatalities but 17% of patients had severe toxicity and 7% had life-threatening toxicity of any kind. Its efficacy has not been confirmed in randomized studies.
Лучевая терапия метастаза в печень
In a selected group of patients, resection of liver metastasis provides long-term tumour control and improved survival . Recently, high-dose radiotherapy has been used to eradicate liver metastasis; this is a treatment option available in specialized centres. Technological improvements in radiation delivery have allowed liver irradiation to be delivered safely up to doses of 90 Gy in 1.5 Gy per fractions .
Stereotactic body radiotherapy (SBRT) is an emerging technique employed in the treatment of liver metastasis. It delivers high doses of radiation to the liver metastasis with multiple fields, resulting in highly conformal dose gradients that can spare normal structures from high risk of toxicity. High accuracy and precision of treatment is ensured by use of image-guided radiotherapy at every treatment course (usually one to six treatments). Insertion of radio-opaque markers in the liver can facilitate localization of the metastasis at every treatment. 4-dimensional CT imaging is used in planning the position of the metastasis during different phases of the respiratory cycle. Accordingly, internal motion of the lesion can be accounted for in the radiotherapy plan. Various methods to control respiratory motion are used. Abdominal compression is used to reduce abdominal movement during the respiratory cycle. Active or voluntary breathholding during simulation and treatment allows treatment to be delivered at either an inhale or exhale phase of breathing. Gated radiotherapy can be performed by obtaining a respiratory signal or position of the tumour by use of either an internal or external fiducial marker. These methods allow smaller margins to be used in radiotherapy delivery and hence reduce rates of normal tissue toxicity while obtaining ablative doses of radiotherapy to the tumour.
In a multi-institutional phase I/II study, patients with one to three hepatic lesions and maximum individual tumour diameters less than 6 cm were included. Radiation dose was escalated from 36 Gy to 60 Gy, in three fractions, in increments of 6 Gy, during phase I study. The phase II dose was 60 Gy in three fractions. Thirteen patients were treated to a dose less than 60 Gy, and 36 patients received 60 Gy. Forty-seven patients with 63 lesions were treated. Grade 3 or higher toxicity was 2%. Actuarial in-field local control rates at one and two years after SBRT were 95% and 92%, respectively. Among lesions with maximal diameter of 3 cm or less, two-year local control was 100%. Median survival was 20.5 months .
A different approach is individualizing total radiation dose according to the normal tissue tolerance of the liver. In a phase I study, 68 patients with inoperable liver metastases were treated with individualized SBRT. Median radiation dose was 41.8 Gy (range 27.7 to 60 Gy) in six fractions over two weeks. Median tumour volume was 75.2 ml (range 1.19 to 3,090 ml). Two grade 3 liver toxicity enzyme changes occurred, but no radiation-induced liver disease or other grade 3 or higher liver toxicity. The one-year local control rate was 71% (95 CI, 58% to 85%) .
New treatment strategies are being explored. A dose-escalating phase I study is being performed to investigate the maximum tolerated dose of single-fraction SBRT (NCT01162278). A phase I/II trial combines liver SBRT with sorafenib (NCT00892424). Proton beam SBRT is being investigated in treating liver metastasis (NCT01239381). Proton beam radiation uses tiny particles to deliver radiation to tumours. A phase II with individualized SBRT for liver tumours is being conducted with patients who have had previous liver treatment (NCT01522937). The development of SBRT for liver metastasis has been promising. Conformal external beam radiotherapy can be considered in highly selected cases or in the setting of a clinical trial but it should not be used indiscriminately in patients who are potentially surgically resectable.
Мультидисциплинарное лечение рака толстого кишечника ранней стадии
Введение в мультидисциплинарное лечение
As management strategies for colon cancer become increasingly refined and personalized medicine becomes the rule rather than the exception, complexity arises when optimizing the treatment for individuals. The treatment of colon cancer has evolved over the last several decades from what was originally primarily a surgical disease, to one where it is expected that doctors and allied health professionals from several disciplines will be involved in patient management from the outset. A multidisciplinary approach is essential from the point of diagnosis, through treatment, and beyond. While the role of multidisciplinary involvement is most obvious in challenging and complex scenarios, every patient in fact requires expertise from several medical and allied health disciplines—a biopsychosocial approach for optimal outcomes after the diagnosis of colon cancer. Many (over 60%) are cured from their colon cancer, and thus surveillance and survivorship issues are particularly pertinent in the setting of colon cancer.
This section will outline the multidisciplinary nature of early-stage colon cancer care. As several aspects of such care are addressed in other chapters within this textbook, a general overview will be presented in these circumstances.
Роль междисциплинарных встреч и командный менеджмент — консенсус и противоречия
Multidisciplinary team meetings and strategies have been implemented in many cancer centres throughout the world. Multiple doctors are involved in an individual’s care; a prior UK study of 50 cancer patients found that within the first year of diagnosis, patients saw an average of 28 doctors . Clearly, communication between these doctors is of critical importance. A multidisciplinary approach can help to streamline a patient’s personal navigation through the system of colonoscopies, blood work, radiological investigation, surgery with or without perioperative chemotherapy or radiotherapy, stomal care, and timely post-operative oncological review, and appropriate follow-up. Aside from the ‘physical’ aspects of multidisciplinary care, the involvement of a multidisciplinary team can also identify potential psychosocial or comorbidity-related issues which may need to be considered and addressed during the patient’s care. Finally and most importantly, discussion in a multidisciplinary context may help to identify patients who are suitable for clinical trials .
A more formalized approach to multidisciplinary care, including multidisciplinary team meetings, documentation, and care planning, is a concept increasingly embraced worldwide. The UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend that patients with CRC should be treated by a multidisciplinary team . Effective, coordinated, universal multidisciplinary care, although desirable, is not as prevalent in some centres as others .
The literature regarding the effectiveness of a formalized multidisciplinary approach is largely supportive , but while this is certainly felt to improve timeliness of referral, communication between specialists, and quality of patient care, it has been more diffi ult to demonstrate objective evidence that the multidisciplinary team improves patient outcome, especially in the context of changing and improving proposed therapies. An international literature review in 2010 of 21 studies investigating the impact of multidisciplinary care on patient survival could not demonstrate a positive relationship between the two, largely due to significant heterogeneity in the definition of multidisciplinary care, but noted that 12 of the studies did report a statistically significant association between multidisciplinary care and patient survival . Specifically for CRC, a single-centre study from China comparing outcomes before and after the introduction of an MDT concluded that MDT discussion was an independent variable associated with improved overall survival . Similarly, a single-surgeon audit from the UK of cases before and after the implementation of an MDT meeting reported a significant association between MDT status and survival, as well as a prognostic indicator of chemotherapy prescription .
Where possible, all patients with newly diagnosed CRC should be discussed and managed in a formalized multidisciplinary setting, while nevertheless recognizing that hospitals and centres may have differing capacities for multidisciplinary care depending on location and resources. A good outline of the ‘ideal’ MDT system is provided in the NICE guidelines.
Мультидисциплинарный менеджмент рака толстого кишечника в специальных группах
The current consensus is that the management of older cancer patients needs to be multidisciplinary—and ideally involves a geriatrician, where possible, as well as the patient’s community doctor. A formalized comprehensive geriatric assessment is ideal, but may be resource intensive [305, 306]. Even without the resources to implement a comprehensive geriatric assessment, the role of social work, physiotherapy, and occupational therapy practitioners is clearly of value when assessing the ability of an older person to live well in the community. A decision about adjuvant chemotherapy must be made with this in mind, being aware that the balance between recurrence risk and quality of life is perhaps a more delicate one in the very old.
Two to three percent of CRC is diagnosed in individuals less than 40 years of age. A diagnosis of any malignancy in a young person is associated with specific issues—in particular fertility and the possibility of a genetic cause or familial cancer. Concurrent illness such as inflammatory bowel disease, known to be associated with increased risk of CRC, may be present and need treatment, usually by a gastroenterologist. Concomitant immunosuppressive drugs used to treat inflammatory bowel disease may increase the risk of chemotherapy-associated myelosuppression. Additionally, many young people are working rather than retired at the time of diagnosis—thus the need for social work involvement with respect to the economic consequences of being away from the workplace during treatment. Disability-adjusted life years are rarely accounted for when considering the cost of CRC to the community, but are pertinent in this patient group.
There is ongoing dissent in the literature regarding whether young age at diagnosis is a poor prognostic factor itself in CRC. One American study utilizing a prospective clinical database concluded that patients under 40 did not have inferior DFS, but were more likely to have higher surgical lymph node yield and receive adjuvant chemotherapy; the authors postulated that more aggressive management may result in similar survival outcomes . A UK retrospective review of young patients found that although no differences in survival overall was seen, younger patients had a higher rate of T4 disease and vascular invasion, both of which led to inferior outcomes . A study from Scotland reported on ten-year survival outcomes for over 2000 patients, concluding that young age did not have an adverse impact on cancer-specific survival . A Canadian retrospective study over 20 years, however, concluded that young patients with early-stage CRC had survival outcomes inferior to expectation . Similarly, a Taiwanese study found inferior survival outcomes in young patients with CRC . It may be stage at diagnosis rather than age itself that may contribute to what may appear to be worse overall outcomes in young patients with CRC.
Fertility may be affected by surgery, radiotherapy, and chemotherapy. While radiotherapy is generally not a consideration for early-stage colon cancer, chemotherapy in many cases will be considered in particular in a young person where much is at stake. The implications of fluoropyrimidines on gonadal function are thought to be minimal; however, oxaliplatin may be moderately gonadotoxic [312, 313]. Pregnancy should be avoided during chemotherapy and for several months afterwards. In male patients who are considering having children, the option of sperm collection and storage prior to chemotherapy must be discussed. In female patients, there are several options to consider for oocyte or ovarian preservation [312–314]. Expedited referral to a fertility expert is essential if fertility preservation is desired in young women diagnosed with CRC. The timing of fertility preservation techniques must be balanced with the need to commence adjuvant chemotherapy ideally within six to eight weeks of surgery.
Роль союзных медицинских команд и факторов образа жизни в мультидисциплинарном менеджменте
With the advent of screening faecal occult blood tests, and the universal recognition that CRC screening reduces mortality from the disease, comes the ever-increasing need for endoscopists to perform diagnostic lower gastrointestinal endoscopy. To this end, nurse practitioners have been involved in some centres for several years [315, 316]. A more recent randomized controlled trial comparing screening colonoscopy performed by nurse practitioners (n = 50) or gastroenterologists (n = 100) found that the nurse practitioner group were as safe and accurate as the gastroenterologist group . The use of nurse practitioners for this purpose has been advocated by many as a way of safely, efficiently, and effectively addressing the need for endoscopic services . Nurse practitioners are also involved in follow-up clinics after CRC diagnosis in some centres, again addressing the demand for timely and appropriate follow-up methods given the high prevalence of survivors . Since the advent of capecitabine, an oral 5-FU analogue, for the management of both early-stage and metastatic CRC, nurse-led hospital and home-based care has been shown to be effective in monitoring and delivering oral chemotherapy safely [320, 321].
Depending on the type of bowel surgery required, a temporary or permanent stoma may be necessary for individuals undergoing resection of colon or rectal cancer. A stoma may have significant adverse effects on patient quality of life and body image [322, 323], although an earlier Cochrane review did not conclude firmly that quality of life with a stoma was significantly inferior . Where possible, preoperative assessment and education by a stomal therapist is ideal. A study across 12 colorectal surgical units in Spain showed that patients who did see a therapist preoperatively had significantly less stoma complications and anxiety than those who did not . Ongoing physical and psychological support from a stomal therapist while a stoma is present is appropriate.
Weight loss is significantly associated with decreased survival in colon cancer. Conversely, obesity places a person at increased risk of not only developing CRC but also having inferior outcomes [326–332]. The role of a dietician in the management of early-stage colon cancer is important at three steps: the acute phase of perioperative care and surgical recovery, the medium-term phase during adjuvant chemotherapy treatment, and the longer-term phase of healthy eating to maintain a healthy weight range. In the metastatic setting, managing cancer-related cachexia also requires the expertise of a dietician.
To demonstrate a positive association between particular dietary constituents and cancer incidence requires large cohort studies over long periods of time, and defi tive evidence may remain elusive. Meat consumption, in particular processed meats, has been associated with increased risk of colon cancer in one meta-analysis . A high-fibre diet was shown to be protective in the EPIC prospective cohort study, involving over 510,000 people . A prospective observational study of over 1000 patients enrolled in an adjuvant stage III colon cancer trial found that a Western-pattern diet was associated with higher recurrence and mortality compared with a prudent dietary pattern, as has low levels of vitamin D . It is important to be aware of these and other similar studies, in order comprehensively to advise patients on strategies to reduce their risk of CRC development and recurrence.
Exercise is protective against the development of colon cancer . Greater levels of exercise both preand post-diagnosis of CRC have been positively associated with improved survival in several observational studies. The Melbourne Collaborative Cohort Study, involving over 41,000 Australians, found that of the 528 people diagnosed with CRC over the follow-up period, those who exercised regularly had significantly improved disease-specific survival, in particular for stage II–III cancers, where the HR for DFS was
0.49 (P = 0.01) . This finding, if related to a new anti-cancer agent, would be practice-changing if confirmed in a prospective study, which is understandably difficult to achieve in an intervention such as exercise, although intervention trials are underway. Nevertheless, exercising more and maintaining a healthy body weight are most likely the two most influential lifestyle modifications an individual can address in order to reduce their lifetime risk of CRC; and at least in the case of exercise, to reduce the risk of recurrence and death from their disease.
An oncologist, surgeon, or family practitioner alone can only partly influence an individual’s decision to address issues such as weight loss and exercise, Similarly to the anti-smoking message and campaign, a multidisciplinary approach will surely be required to help effect the increasing body of evidence regarding the adverse effects of obesity and lack of exercise in the risk of CRC and other malignancies. A team effort, including government and non-government as well as doctors, dieticians, physiotherapists, and exercise physiologists will be required. Importantly, strategies are needed for the purposes of prevention as well as post-diagnosis health and, as such, addressing these risk factors is a large-scale effort and extends well beyond the individual and into the realms of public health and health policy.
Непосредственное и отдаленное наблюдение — междисциплинарный путь
The aim of surveillance after curative-intent treatment of early-stage colon cancer is to improve survival by detecting early (curable) recurrence or small-volume asymptomatic metastatic disease that may be amenable to curative-intent resection. Additionally, colonoscopic surveillance for precancerous adenomas and polyps can reduce the risk of a second primary malignancy developing. As the majority of recurrences will recur within three to five years, this is when surveillance is most beneficial.
Several systematic reviews or meta-analyses, including a Cochrane review, have demonstrated significantly improved overall survival for patients who have more intensive post-surgical follow up for early-stage CRC, although, notably, not all randomized trials comparing ‘intensive’ with ‘minimal’ surveillance have shown a survival advantage for the ‘intensive’ arm [336–339]. Interestingly, the optimal methods or timings of surveillance investigations are not definitively established. A more recent systematic review of 15 studies comparing different surveillance programmes was inconclusive, largely due to the heterogeneity of surveillance programmes among studies, and recommended future randomized trials with larger sample sizes to help establish the best surveillance practices . In fact, ‘intensive’ surveillance in one study may be akin to ‘minimal’ surveillance in another; hence, the difficulty when attempting to ascertain which practice is optimal. Several such trials are currently underway at the time of writing including the GILDA, FACS, and COLOFOL randomized studies.
As such, to date, clinical practice guidelines for optimal surveillance vary somewhat between countries. Surveillance generally includes clinical examination, colonoscopic surveillance, imaging (most commonly CT), and testing of serum carcino-embryonic antigen (CEA) . FDG-PET imaging is currently not used as a surveillance tool, but rather when investigating suspected recurrence, for example in the setting of an increased CEA without CT changes. A randomized trial of 130 patients from France comparing PET with conventional surveillance found that recurrences were found after a shorter time in the PET group, and these were more frequently cured by surgery . Another single-arm European surveillance study in 132 patients found that CT/PET had the highest sensitivity and specificity for detection of recurrence . However, from a practical and financial perspective, PET is unlikely to be part of routine surveillance in most centres and is not currently recommended as part of evidence-based guidelines .
By nature of the methods of regular surveillance recommended, multidisciplinary involvement already exists in that surgeons and radiologists are involved; not uncommonly, a medical oncologist will also continue to follow the patient, especially if adjuvant chemotherapy has been administered. In some models of care, a family physician, general practitioner, or nurse specialist may assume a dominant role in overseeing patient follow-up [319, 344]; in others, this rests with the patient’s primary specialist centre.
A number of guidelines are now available, each based on a literature review and expert opinion. It should be noted that these guidelines are for standard-risk patients; higher-risk patients such as those with a familial cancer syndrome or inflammatory bowel disease should have more frequent colonoscopic surveillance, again available using the various guidelines [345, 346–349].
За границами физического: многодисциплинарный подход к психосоциальным последствиям и выживанию
The majority of patients diagnosed with early-stage colon cancer will survive the disease. Stage I and II disease have a 90% five-year survival rate and stage III up to 70% . Even in metastatic disease, a small percentage of patients are alive years later due to the aggressive surgical management of oligometastatic disease and improved drug strategies. Overall, close to 65% of patients with CRC are considered ‘cured’ after five to ten years . As such, there are tens of thousands of colon cancer survivors in the community, and this number is sure to increase given, firstly, advances in CRC screening and, secondly, improved survival outcomes for those diagnosed with the disease. However, the term ‘management’ should not extend only to the duration of adjuvant chemotherapy or the completion of recommended surveillance tests. Colonoscopies, serum CEA tests, and CT scans are only one (physical) component of the ongoing patient management after a diagnosis of colon cancer. To be diagnosed with any malignancy is understandably challenging for an individual and their family, and both symptom management and psychological support both during and after the diagnosis should be, in ideal circumstances, readily available. A systematic review of ten studies detailing long-term quality of life in CRC survivors (more than five years) concluded that overall quality of life was good, although depression scores were worse than the general population and ongoing bowel symptoms and cancer-related distress remained prominent . A five-year prospective study of quality of life in CRC survivors found that although quality of life measures improved with increasing time from diagnosis, psychological distress measures remained static . Ongoing healthcare provision for CRC survivors should continue to be addressed . Aside from standard surveillance strategies, a more holistic approach to CRC survivorship should ideally address the role of diet, exercise, and maintaining a healthy body weight, as, in particular for exercise and body mass index, evidence indicates maintaining a healthy weight range and exercising regularly may reduce the risk of cancer recurrence or even second primary cancers [355, 356].
The management of early-stage colon cancer continues to evolve as science and medicine grow a deeper appreciation of not only the molecular, cellular, and genetic aspects of this disease, but also its effect on the individual, the family, the medical system, and society as a whole. Colorectal cancer will continue to be one of the most common malignancies in the developed world and increasingly in the developing world, and due to significant advances in screening, diagnosis, and management over the last several decades, there are increasing numbers of people surviving or living with the disease, rather than dying from it. These promising advances necessitate a multidisciplinary approach to CRC across the spectrum from prevention, through diagnosis and treatment, to palliative care. We need to encompass appreciation of the genetic makeup of a single cell from an individual’s tumour, but also understand the impact of CRC from a global public health perspective, and everything in between these two extremes. Multidisciplinary management is the way forward in the optimal management of CRC.
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