Elsevier

The Lancet

Volume 375, Issue 9719, 20–26 March 2010, Pages 1030-1047
The Lancet

Seminar
Colorectal cancer

https://doi.org/10.1016/S0140-6736(10)60353-4Get rights and content

Summary

Substantial progress has been made in colorectal cancer in the past decade. Screening, used to identify individuals at an early stage, has improved outcome. There is greater understanding of the genetic basis of inherited colorectal cancer and identification of patients at risk. Optimisation of surgery for patients with localised disease has had a major effect on survival at 5 years and 10 years. For rectal cancer, identification of patients at greatest risk of local failure is important in the selection of patients for preoperative chemoradiation, a strategy proven to improve outcomes in these patients. Stringent postoperative follow-up helps the early identification of potentially radically treatable oligometastatic disease and improves long-term survival. Treatment with adjuvant fluoropyrimidine for colon and rectal cancers further improves survival, more so in stage III than in stage II disease, and oxaliplatin-based combination chemotherapy is now routinely used for stage III disease, although efficacy must be carefully balanced against toxicity. In stage II disease, molecular markers such as microsatellite instability might help select patients for treatment. The integration of targeted treatments with conventional cytotoxic drugs has expanded the treatment of metastatic disease resulting in incremental survival gains. However, biomarker development is essential to aid selection of patients likely to respond to therapy, thereby rationalising treatments and improving outcomes.

Introduction

Worldwide, every year, more than 1 million individuals will develop colorectal cancer,1 and the disease-specific mortality rate is nearly 33% in the developed world. Here we summarise some of the important developments and advances in molecular carcinogenesis, prognostic and predictive molecular markers, hereditary predispositions, screening, diagnosis, and treatment during the past 5 years.

Section snippets

Molecular carcinogenesis

The classic description of colorectal carcinogenesis is the adenoma-carcinoma sequence and multistep tumourigenesis that is determined by gatekeeper and caretaker molecular pathways, which takes years to decades.2 Colorectal cancer is increasingly classified into specific phenotypes on the basis of molecular profiles (table 1), two of which represent genetic instability classes. Most sporadic cases (about 85%) have chromosomal instability, an allelic imbalance at several chromosomal loci

Risk factors

Most cases of colorectal cancer arise sporadically. Risk factors include increasing age, male sex, previous colonic polyps, or previous colorectal cancer, and environmental factors (eg, red meat, high-fat diet, inadequate intake of fibre, obesity, sedentary lifestyle, diabetes mellitus, smoking, and high consumption of alcohol).16 Inflammatory bowel disease (ulcerative colitis and Crohn's disease) accounts for roughly two-thirds of the incidence,17, 18 and the risk increases with duration of

Screening of colorectal cancer

Survival rates in individuals with colorectal cancer have increased substantially in the past few years, possibly as a result of early diagnosis and improved treatment. Although substantial information about risk factors exists, about 75% of diagnoses are in patients with no apparent risk factors other than older age.48 5-year survival is still less than 60% in most European countries.49 Population screening therefore continues to offer the best prospects for reduction in mortality rates.

The

Diagnosis and staging

Colorectal cancer is diagnosed on the basis of the results of colonoscopy or sigmoidoscopy with tumour biopsy. Treatment strategy is guided by adequate staging. The pretreatment workup of a newly diagnosed cancer includes physical examination, a complete colonoscopy to rule out metachronous tumour, and CT of the chest, abdomen, and pelvis to identify metastatic disease.79

CT colonography is valuable for precise localisation of the tumour and can help surgical approaches, especially in patients

Surgery

For colon cancer, total resection of the tumour should be done with adequate margins, and lymphadenectomy. Distal margins of 5 cm or more are recommended. At least 12 lymph nodes should be taken and analysed to allow appropriate nodal staging;93, 94, 95 analysis of fewer than ten nodes might understage the tumour.12 En-bloc resection of invaded adjacent organs might be needed for T4 tumours to obtain R0 resection (no evidence of microscopic cancer at the margins). Surgical resection of the

Radiation treatment for rectal cancer

The risk of local failure in treatment of rectal cancer is affected by involvement of the circumferential resection margin, lymph-node status, and extramural venous invasion.84 Since a significantly lower incidence of local recurrence and toxicity, and a higher incidence of sphincter preservation were reported with preoperative than with postoperative chemoradiation in the German CAO/ARO/AIO 94 trial,117 the conventional treatment for clinical stage T3 (cT3) or node-positive rectal cancer is

Adjuvant treatment for early stage disease

Surgery is the cornerstone for cure in localised colorectal cancer. In node-positive (stage III) disease, administration of adjuvant fluorouracil for 6 months reduces the risk of death by 30%, which is equivalent to an additional 10–15% survival gain.140 The alternative oral fluoropyrimidine, capecitabine, has shown similar efficacy to fluorouracil alone.141 The establishment of 3-year disease-free survival as a validated surrogate for 5-year overall survival142, 143 and primary endpoint has

Treatment of metastatic disease

Palliative chemotherapy for metastatic colorectal cancer can improve survival, lessen symptoms, improve quality of life, and downsize liver-only or lung-only metastases in patients with potentially resectable disease. Survival has increased from 12 months with fluorouracil monotherapy to roughly 2 years with the addition of irinotecan, oxaliplatin, and targeted drugs. The use of infused fluorouracil added to oxaliplatin and to irinotecan has reduced toxicity and is commonly used.163

Prognostic and predictive molecular markers

Prognostic biomarkers are associated with survival that is independent of the treatment effect. Predictive biomarkers indicate likely benefit of treatment. Markers can be prognostic and predictive. The most important development in molecular markers for metastatic colorectal cancer has been the validation of KRAS mutation status as predictive of non-response to EGFR-targeted drugs. In the adjuvant setting, prognostic and predictive molecular markers (microsatellite instability and 18q

Conclusions

There have been considerable advances in understanding the molecular pathogenesis, in diagnosis (hereditary and sporadic), and in treatment of colorectal cancer. Despite the use of active targeted drugs for treatment of metastatic colorectal cancer in the past decade, and improvement of overall survival to nearly 2 years for non-resectable disease, cure rates remain low. Parallel development of predictive molecular and clinical markers is paramount to achieve the best outcomes from targeted

Search strategy and selection criteria

We searched Medline, PubMed, ASCO abstracts, ESMO abstracts, and the Cochrane database, between 2004 and 2009, for papers published in English. We used the search terms “colorectal cancer”, “colon cancer”, “rectal cancer”, “carcinogenesis”, “epidemiology”, “genetics”, “screening”, “diagnosis”, “staging”, “surgery”, “radiation therapy”, “chemotherapy” (“adjuvant”, “metastatic”, and “neoadjuvant”), and “molecular prognostic and predictive markers”. We cross-checked reference lists we found,

References (216)

  • P Quirke et al.

    Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial

    Lancet

    (2009)
  • DM Parkin et al.

    Global cancer statistics, 2002

    CA Cancer J Clin

    (2005)
  • B Vogelstein et al.

    Genetic alterations during colorectal-tumor development

    N Engl J Med

    (1988)
  • AE Noffsinger

    Serrated polyps and colorectal cancer: new pathway to malignancy

    Annu Rev Pathol

    (2009)
  • C Lengauer et al.

    Genetic instabilities in human cancers

    Nature

    (1998)
  • RA Lothe et al.

    Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history

    Cancer Res

    (1993)
  • B Vogelstein et al.

    Genetic alterations during colorectal-tumor development

    N Engl J Med

    (1988)
  • B Vogelstein et al.

    Allelotype of colorectal carcinomas

    Science

    (1989)
  • LA Aaltonen et al.

    Clues to the pathogenesis of familial colorectal cancer

    Science

    (1993)
  • Y Ionov et al.

    Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis

    Nature

    (1993)
  • P Peltomaki

    Role of DNA mismatch repair defects in the pathogenesis of human cancer

    J Clin Oncol

    (2003)
  • MF Kane et al.

    Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines

    Cancer Res

    (1997)
  • JM Cunningham et al.

    Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability

    Cancer Res

    (1998)
  • M Toyota et al.

    CpG island methylator phenotype in colorectal cancer

    Proc Natl Acad Sci USA

    (1999)
  • L Shen et al.

    Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer

    Proc Natl Acad Sci USA

    (2007)
  • J Young et al.

    Serrated pathway colorectal cancer in the population: genetic consideration

    Gut

    (2007)

  • Colorectal cancer risk factors

  • AC von Roon et al.

    The risk of cancer in patients with Crohn's disease

    Dis Colon Rectum

    (2007)
  • JA Eaden et al.

    The risk of colorectal cancer in ulcerative colitis: a meta-analysis

    Gut

    (2001)
  • JK Triantafillidis et al.

    Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies

    Anticancer Res

    (2009)
  • H Hampel et al.

    Feasibility of screening for Lynch syndrome among patients with colorectal cancer

    J Clin Oncol

    (2008)
  • P Watson et al.

    The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome

    Int J Cancer

    (2008)
  • E Barrow et al.

    Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations

    Clin Genet

    (2009)
  • H Bussey

    Familial polyposis coli: Family studies, histopathology, differential diagnosis, and results of treatment

    (1975)
  • S Bulow et al.

    The incidence rate of familial adenomatous polyposis. Results from the Danish Polyposis Register

    Int J Colorectal Dis

    (1996)
  • NM Lindor et al.

    Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X

    JAMA

    (2005)
  • X Llor et al.

    Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway

    Clin Cancer Res

    (2005)
  • A Umar et al.

    Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability

    J Natl Cancer Inst

    (2004)
  • HT Lynch et al.

    Who should be sent for genetic testing in hereditary colorectal cancer syndromes?

    J Clin Oncol

    (2007)
  • C Engel et al.

    Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

    Int J Cancer

    (2006)
  • HT Lynch et al.

    Toward a consensus in molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome)

    J Natl Cancer Inst

    (2007)
  • L Senter et al.

    The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations

    Gastroenterology

    (2008)
  • J Gerard et al.

    Randomized multicenter phase III trial comparing two neoadjuvant chemoradiotherapy (CT-RT) regimens (RT45-Cap versus RT50-Capox) in patients (pts) with locally advanced rectal cancer (LARC): Results of the ACCORD 12/0405 PRODIGE 2

    Proc ASCO Meeting Abstracts

    (2009)
  • C Aschele et al.

    Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial

    Proc ASCO Meeting Abstracts

    (2009)
  • CH Crane et al.

    Phase II trial of neoadjuvant bevacizumab (BEV), capecitabine (CAP), and radiotherapy (XRT) for locally advanced rectal cancer

    Proc ASCO Meeting Abstracts

    (2008)
  • CG Willett et al.

    Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study

    J Clin Oncol

    (2009)
  • M Mohiuddin et al.

    Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012

    J Clin Oncol

    (2006)
  • SJ Wong et al.

    RTOG 0247: A randomized phase II study of neoadjuvant capecitabine and irinotecan versus capecitabine and oxaliplatin with concurrent radiation therapy for locally advanced rectal cancer

    Proc ASCO Meeting Abstracts

    (2008)
  • C Fernández-Martos et al.

    Multicenter randomized phase II study of chemoradiation (CRT) followed by surgery (S) and chemotherapy (CT) versus induction CT followed by CRT and S in high-risk rectal cancer: GCR-3 final efficacy and safety results

    Proc ASCO Meeting Abstracts

    (2009)

  • Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives

    Genet Med

    (2009)

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