Medical Progress

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Peer-reviewed CME Journal
June 2012 VOL. 39 NO. 6
Global Summaries
In Focus:
Clinical Review
Golorectal Cancer
A Middle-aged Woman With Morbid Obesity How to Treat?

In Focus
Colorectal Cancer: Prevention & Early Diagnosis Colorectal Cancer: Features & Investigation Can Metastatic Colorectal Cancer Be Cured?
Continuing Medical Education
Functional Bowel Disorders and FODMAPs Low Back Pain Management: Approaches to Treatment
eDItoRIAL BoARD
Director:
Assoc Prof Gerald KOH, National University of Singapore, Singapore

Deputy Director:
Dr Adrian WU, Private Practice, HKSAR, China

Anaesthesia & Intensive Care Medicine Nephrology
Prof Gavin JOYNT

The Chinese University of Hong Kong, HKSAR, China
Andrology
Prof Philip KT LI
Prince of Wales Hospital, HKSAR, China
June 2012 VOL. 39 NO. 6
Prof Wiguno PRODJOSUDJADI

The University of Indonesia, Indonesia
Neurology
Prof Wimpie PANGKAHILA

Udayana University, Indonesia
Cardiology
Prof Raymond TF CHEUNG

The University of Hong Kong, HKSAR, China
Emeritus Prof Ramon F ABARQUEZ

University of the Philippines, Philippines
Dr Gardian CY FONG
ContentS
261-264 261

Prof Boon-Lock CHIA

National University of Singapore, Singapore
Dr Chen-Ya HUANG
Dr Anna Maria CHOY

Ninewells Hospital and Medical School, UK
Dr Venketasubramanian RAMANI
National University Hospital, Singapore
Global Summaries
Cardiology
Rivaroxaban after acute coronary syndrome Vorapaxar in acute coronary syndromes Stroke risk with sub-clinical atrial fibrillation
Prof Harmani KALIM

University of Indonesia, Indonesia
Prof Hasan SJAHRIR

Universitas Sumatera Utara, Indonesia
Dr Anwar SANTOSO
Udayana University, Indonesia
Clinical Pharmacology
Prof Lawrence KS WONG

Occupation Medicine & Public Health
Prof Bernard CHEUNG

University of Hong Kong, HKSAR, China
Diabetes 262
Diabetes risk models and scores Intensive glucose control to preserve renal function
Prof Chay-Hoon TAN

Dermatology
Prof David KOH

Dr Judy SNG
Ophthalmology
Gastroenterology
New drugs for chronic HCV genotype 1
Dr Adrian YP FUNG
Private Practice, HKSAR, China
General Medicine 263

Gene therapy for haemophilia B Catheter-directed thrombolysis for acute ileofemoral DVT Management of diabetes and hypertension by rural health care workers in Iran
Dr Yoke Chin GIAM

National Skin Centre, Singapore
Endocrinology
Dr Michael SH LAW
Private Practice, Malaysia
Orthopaedics & Orthopaedic Surgery
Dr Norman CHAN
Prof David SK CHOON

University Malaya Medical Centre, Malaysia
Prof Siew-Pheng CHAN

University of Malaya, Malaysia
Dr Daniel KH YIP
264

Oncology
Gene changes and resistance of colorectal cancer to chemotherapy Denosumab for prostate cancer Prostate cancer gene mutation
Dr Ma Teresa P QUE
Philippine Diabetes Association, Philippines
Adj Asst Prof Eugene WONG

Perdana University Graduate School of Medicine, Malaysia
Otorhinolaryngology
Prof Sidartawan SOEGONDO

Family Medicine
Prof Cindy LK LAM

Gastroenterology & Hepatology
Prof Dato Balwant Singh GENDEH

The National University Hospital Malaysia, Malaysia
265-268
Clinical Review
GENERAL MEDICINE
Prof Khean-Lee GOH

University of Malaya, Malaysia
Prof William I WEI

Queen Mary Hospital, HKSAR, China
Pharmacy
Prof George KK LAU


Sharon Marks
Prof HA Aziz RANI

Prof Vincent HL LEE

Psychiatry
Prof Benjamin CY WONG

Geriatric Medicine
Dr Eric YH CHEN
Dr Leung-Wing CHU
Haematology & Oncology
Dr M Parameshvara DEVA
KPJ Selangor Specialist Hospital, Malaysia
Respiratory & Critical Care Medicine
Prof Raymond LIANG

Prof Menaldi RASMIN

Dr Raymond WONG
Prince of Wales Hospital, HKSAR, China
Infectious Disease
Assoc Prof Dessmon YH TAI

Tan Tock Seng Hospital, Singapore
Dr Kenneth WT TSANG
Rheumatology & Immunology
Dr Christopher LEE
Hospital Sungai Buluh, Malaysia
Prof Amorn LEELARASAMEE

Siriraj Hospital, Thailand
Prof Handono KALIM

Brawijaya University, Indonesia
262
264
Prof Ron HH NELWAN

Dr Swan-Sim YEAP
Private Practice, Malaysia
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ContentS
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PUBLISHeR: Medical Progress is published 12 times a year by UBM Medica, a division of United Business Media. CIRCULATION: Medical Progress is on controlled circulation to medical practitioners in Asia. It is also available on subscription to members of allied professions. SUBSCRIPTION: The price per annum is US$60 (surface mail, students US$30) and US$72 (overseas airmail, students US$36); back issues US$6 per copy. eDITORIAL MATTeR published herein has been prepared by professional editorial staff and by honorary specialist consultants from all fields of medicine. Views expressed are not necessarily those of UBM Medica. Although great effort has been made in compiling and checking the information given in this publication to ensure that it is accurate, the authors, the publisher and their servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions or inaccuracies in this publication whether arising from negligence or otherwise howsoever, or for any consequences arising therefrom. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields. The information contained within should not be relied upon solely for final treatment decisions. COPYRIGHT 2012 UBM Medica. All rights reserved. No part of this publication may be reproduced in any language, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), without the written consent of the copyright owner. Permission to reprint must be obtained from the publisher. ADVeRTISeMeNTS are subject to editorial acceptance and have no influence on editorial content or presentation. UBM Medica does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature. Philippine edition: entered as second-class mail at the Makati Central Post Office under Permit No. PS-326-01 NCR, dated 9 Feb 2001. Printed by Fortune Printing International Ltd, 3rd Floor, Chung On Industrial Building, 28 Lee Chung Street, Chai Wan, Hong Kong.
In Focus: Colorectal Cancer

Colorectal Cancer: Prevention and Early Diagnosis
Robert Dennis, Samson Tou, Richard Miller
Philippines Philip Katipunan Tel: (63 2) 886 0333 Email: enquiry.ph@ubmmedica.com Singapore Jason Bernstein, Carrie Ong, Elijah Lee, Reem Soliman Tel: (65) 6223 3788 Email: enquiry.sg@ubmmedica.com Thailand Wipa Sriwijitchok Tel: (66 2) 741 5354 Email: enquiry.th@ubmmedica.com Vietnam Nguyen Thi Lan Huong, Nguyen Thi My Dung Tel: (84 8) 3829 7923 Email: enquiry.vn@ubmmedica.com Europe/USA Kristina Lo-Kurtz, Tel: (852) 2116 4352 Email: enquiry.hk@ubmmedica.com
Colorectal Cancer: Features and Investigation

Nigel Hall
Can Metastatic Colorectal Cancer Be Cured?

David L Bartlett, edward Chu
293-296 293
Drug Profile
RoflumilastLast But Not Least?
Tan Tze Lee, Ong Kian Chung
270
279
283
ii
June 2012 VOL. 39 NO. 6
ContentS
The Cover: Colorectal Cancer Rowena Sim, Art Director Mark Foo, Illustrator
297-312 297
Continuing Medical education

Functional Bowel Disorders and FODMAPs
emma Halmos, Jane Muir, Sue Shepherd, Peter Gibson
305
Low Back Pain Management: Approaches to Treatment

Gerard A Malanga, Kevin R Dunn
Medical Progress contains articles under license from UBM Medica LLC. The articles appearing on pages 283293 and 305311 are from Oncology and The Journal of Musculoskeletal Medicine, respectively. Copyright 2010, 2012 UBM Medica LLC.
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Assessment and Diagnosis of the Poisoned Patient Low-toxicity Ingestions Management of Poisoning: Initial Management and Need for Admission
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Global Summaries
Synopses of major trials from leading international journals
Peer Reviewed
CARDIOLOGY Rivaroxaban after acute coronary syndrome

Rivaroxaban is a direct, selective inhibitor of factor Xa. A preliminary trial showed that rivaroxaban therapy reduced the risk of death, myocardial infarction, or stroke in patients who had recently had an acute coronary syndrome. Now, a phase III trial has been reported. At 766 sites in 44 countries, a total of 15,526 patients were randomized, within 7 days of hospital admission for myocardial infarction (ST-segment elevation or non-STsegment elevation) or unstable angina, to rivaroxaban 2.5 mg twice daily, rivaroxaban 5 mg twice daily, or placebo, for up to 31 months (mean, 13 months). The rate of the primary efficacy end point (cardiovascular death, myocardial infarction, or stroke) was 9.1% (2.5 mg dose), 8.8% (5 mg dose), and 10.7% (placebo), a significant reduction at either dose compared with placebo. The lower dose, but not the higher dose, reduced all-cause and cardiovascular mortality. Rivaroxaban was associated with significantly increased rates of noncoronary-artery-bypass-grafting-associated major bleeding (2.1% vs 0.6%) and intracranial haemorrhage (0.6% vs 0.2%), but not of fatal bleeding (0.3% vs 0.2%). There were fewer fatal bleeds with the lower dose (0.1%) than the higher dose (0.4%). Rivaroxaban reduced the cardiovascular risk but increased the risk of major bleeding but not of fatal bleeding.
Mega JL et al. Rivaroxaban in patients with a recent acute coronary syndrome. NEJM 2012; 366: 919; Roe MT, Ohman EM. A new era in secondary prevention after acute coronary syndrome. Ibid: 8587 (editorial).
366: 2033.
Stroke risk with sub-clinical atrial fibrillation

About 15% of strokes are attributed to known atrial fibrillation (AF), but AF may be asymptomatic and undetected. In about 25% of cases of ischaemic stroke, the cause remains unknown. The results of a multinational study have suggested that in some of these cases, the cause may be undetected AF. The study, in 23 countries, included 2,580 patients aged 65 years or older with hypertension and no history of AF. They had all recently received an implanted pacemaker or defibrillator. Patients were monitored for 3 months for episodes of subclinical atrial tachyarrhythmia (atrial rate >190 beats per minute for > 6 minutes) indicative of AF. Mean follow-up was for 2.5 years. At 3 months, subclinical atrial tachycardia had occurred in 261 patients (10%). The occurrence of subclinical atrial tachyarrhythmia was associated with a 5.6-fold increase in risk of clinical AF and a 2.5-fold increase in risk of ischaemic stroke or systemic embolism. Fifty-one patients had an ischaemic stroke or systemic embolism, and 11 of them had had subclinical atrial tachyarrhythmia on monitoring in the first 3 months. None had had clinical AF during that time. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmia was 13%. Subclinical AF may explain many strokes of which the cause is not apparent.
Healey JS et al. Subclinical atrial fibrillation and the risk of stroke. NEJM 2012; 366: 120129; Lamas G. How much atrial fibrillation is too much atrial fibrillation? Ibid: 178180 (editorial).
Vorapaxar in acute coronary syndromes

Vorapaxar is an oral drug that inhibits thrombin-induced platelet aggregation by acting as an antagonist of protease-
activated receptor 1, an activator of such platelet aggregation. It has been compared with placebo in patients with acute non-STsegment-elevation coronary syndromes in a multinational trial. A total of 12,944 patients with a non-ST-segment-elevation acute coronary syndrome were randomized at 818 sites in 37 countries to vorapaxar (40 mg loading dose, then 2.5 mg daily) or placebo, in addition to standard therapy. The trial was stopped early after a safety review. After an average follow-up of 502 days, the rate of the primary end point (cardiovascular death, myocardial infarction, stroke, rehospitalization for recurrent ischaemia, or urgent coronary revascularization) was 1,031/6,473 (16%) in the vorapaxar group and 1,102/6,471 (17%) in the placebo group, with KaplanMeier 2-year rates of 18.5% vs 19.9%, a non-significant difference. The composite outcome of cardiovascular death, myocardial infarction, or stroke occurred in 14.7% vs 16.4%, a significant 11% reduction in the vorapaxar group. There was a highly significant increase of 35% in moderate or severe bleeding in the vorapaxar group compared with the placebo group. There was a 3.4-fold increase in risk of intracranial haemorrhage in the vorapaxar group. The addition of vorapaxar to standard therapy increased the risk of major bleeding and did not reduce the rate of the primary end point significantly.
Tricoci P et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. NEJM 2012;
DIABETES Diabetes risk models and scores

A systematic review has assessed risk models and scores for the prediction of risk of type 2 diabetes.
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Global Summaries
The review included 43 papers with details of the development and/or validation of 145 models and scores, of which 94 were assessed in detail. They had been based on data from almost 7 million people with follow-up for up to 28 years. Meta-analysis was not possible because of the heterogeneity of the data. The mean number of components per score was 8 (314), and some, but not all, models and scores were statistically robust and had been externally validated on a different population. Seven risk scores were chosen as having a high potential for use in practice, and ten mechanisms were outlined whereby the assessment of risk of type 2 diabetes might lead to improvement in outcomes. There are many risk scores for the development of type 2 diabetes, but few are used routinely. Seven risk scores were considered to be highly suitable for clinical use.
Noble D et al. Risk models and scores for type 2 diabetes: systematic review. BMJ 2011; 343: 1243 (d7163).
(intensive group) versus 46 (conventional group), a significant 50% risk reduction with intensive therapy. End-stage renal disease occurred in eight patients vs 16. Intensive therapy slowed the rate of decrease in eGFR. The effect on eGFR was fully explained by the control of diabetes (glycated haemoglobin levels) and of proteinuria. Intensive glucose control preserves renal function in type 1 diabetes.
The DCCT/EDIC research group. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. NEJM 2011; 365: 23662376.
GASTROENTEROLOGY New drugs for chronic HCV genotype 1
and ribavirin for 12 weeks. Randomization was to daclatasvir plus asunaprevir with (DAPR) or without (DA) peginterferon plus ribavirin. In the DA group, four of 11 patients achieved a sustained virological response at 12 and 24 weeks after treatment. In the DAPR group, all 10 patients had a sustained virological response at 12 weeks and nine at 24 weeks. In the DA group, six patients had viral breakthrough on treatment, and in all six cases there were resistance mutations to both daclatasvir and asunaprevir. Diarrhoea was common in both groups, and six patients had transient rises in alanine aminotransferase levels. Adding daclatasvir and asunaprevir to peginterferon and ribavirin achieved sustained virological response in patients who had not responded initially to peginterferon and ribavirin alone.
Lok AS et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. NEJM 2012; 366: 216224; Chung RT. A watershed moment in the treatment of hepatitis C. Ibid: 273275 (editorial).
Intensive glucose control to preserve renal function

An impaired glomerular filtration rate (GFR) increases the risk of end-stage renal disease in patients with diabetes. Intensive blood glucose control reduced the risk of developing both microalbuminuria and macroalbuminuria in patients with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT) reported in 1993. Now, 22-year follow-up data from that trial have been used to assess the effect of intensive glucose control on glomerular filtration rate deterioration. A total of 1,441 patients aged 1339 with type 1 diabetes were randomized in the DCCT to intensive diabetes therapy (target glycated haemoglobin, < 6.05%) or conventional therapy for 6.5 years. Over a median of 22 years, impaired GFR (estimated GFR [eGFR] < 60 mLmin/1.73 m2 on two successive visits) occurred in 24 patients
GENERAL MEDICINE Gene therapy for haemophilia B

Treatment of chronic hepatitis C virus (HCV) infection with pegylated interferon (peginterferon) alpha and ribavirin for 48 weeks achieves a sustained virological response at 24 weeks after stopping treatment in 4050% of patients. Adding a protease inhibitor to treatment for nonresponders after 12 weeks of treatment produces a sustained virological response in 1433%. Now, a multicentre phase II study in the USA has shown that the use of two new antiviral agents may improve results. Daclatasvir is an HCVNS5A replication complex inhibitor and asunaprevir is an HCV NS3 protease inhibitor. The trial included 21 patients with chronic HCV genotype 1 infection unresponsive to treatment with peginterferon Haemophilia B (Christmas disease) results from a mutation in the gene for coagulation factor IX (FIX). In severe haemophilia B, functional FIX levels are < 1% of normal. Current therapy with FIX protein concentrate is not curative, and it is associated with inhibitor formation as well as being expensive. Gene therapy offers the prospect of a cure. Researchers in the UK and the USA have assessed a new gene therapya serotype-8-pseudotyped, selfcomplementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (sc AAV2/8LP1-hFIXco) given intravenously. Six patients with severe haemophilia B received a single gene therapy dose via a peripheral vein: two given a high dose, two
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an intermediate dose, and two a low dose. Follow-up was for 616 months. All patients benefitted: the two given the low dose were able to increase the intervals between injections of FIX and the other four were able to stop FIX prophylaxis and remained free of spontaneous bleeding. One patient who received the high dose had a transient asymptomatic increase in serum aminotransferase levels with detection of AAV8-capsid-specific T cells in peripheral blood. The other high-dose patient had a transient increase in aminotransferase. Both had normal aminotransferase levels after a course of steroids. Their FIX levels were 311% of normal values. This gene therapy at intermediate or high dosage was successful in raising FIX levels sufficiently to stop spontaneous bleeding without prophylactic FIX. The investigators express concern about immune-mediated clearance of AAV-transduced hepatocytes but point out that the process can be controlled with a short course of steroid without loss of transgene expression.
Nathwani AC et al. Adenovirus-associated virus vector-mediated gene transfer in haemophilia B. NEJM 2011; 365: 23572365; Ponder KP. Merry Christmas for patients with haemophilia B. Ibid: 24242425 (editorial).
treatment is needed. Systemic thrombolysis is effective but associated with a high risk of bleeding. A multicentre trial in Norway has shown that local delivery of the thrombolytic agent into the clot via a catheter is effective with less risk. At 20 hospitals in southeast Norway, a total of 209 patients aged 1875 with a first iliofemoral DVT were randomized within 21 days of symptom onset to conventional treatment with or without catheter-directed thrombolysis (CDT). Data were analysed from 189 patients. At 24 months, PTS had occurred in 41% (CDT) vs 56% (controls), a significant difference with an absolute reduction in risk of PTS of 14% and a number-needed-to-treat of seven. After 6 months, the rate of iliofemoral patency was 66% vs 47%. Among the 90 patients in the CDT group, there were 20 bleeding complications related to the CDT, with three major and five clinically relevant bleeds. These researchers conclude that additional CDT should be considered in patients with a high proximal DVT and low risk of bleeding.
Enden T et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVen T study): a randomised controlled trial. Lancet 2012; 379: 3138; The Lancet; ibid: 1 (editorial); Hofmann LV, Kuo WT. Catheter-directed thrombolysis for acute DVT. Ibid: 34 (comment).
Catheter-directed thrombolysis for acute ileofemoral DVT

The incidence of acute deep vein thrombosis (DVT) in the legs is about 1 in 1,000 people per year. Anticoagulant therapy prevents extension of the thrombus, recurrence and pulmonary embolism, and reduces mortality. It does not, however, dissolve the clot, and patients may develop post-thrombotic syndrome (PTS) with pain, swelling, a feeling of heaviness, oedema, skin pigmentation, and, in severe cases, venous ulcers. In most cases of symptomatic DVT, the thrombus is in the popliteal and more proximal veins. The risk of PTS can be halved by daily use of compression stockings, but more effective initial
Management of diabetes and hypertension by rural health-care workers in Iran

In high-income countries, the incidence of cardiovascular and some other noncommunicable diseases has decreased after population ageing has been accounted for. Dietary and lifestyle interventions, decrease in smoking, and better control of blood pressure and cholesterol levels may have played a considerable part. The prevalence of cardiovascular risk factors has changed little, however, in low- and middle-income countries. Little is known about optimal method of providing primary care, especially
in rural areas, and its influence on noncommunicable disease in poorer countries. A rural primary care system in Iran, the Behvarz system, has been assessed. In the Behvarz system, rural primary care is provided by community health workers, who are community members who, having been educated to at least a primary level, are given 2 years of medical education after passing an entrance examination. Survey and census data for 2005 and 2006 were used to assess the contribution of Behvarz workers (BWs) to diabetes and hypertension control. From the Non-communicable Disease Surveillance Survey (NCDSS) of 2005, data for systolic blood pressure (SBP) were available for 64,694 adults (11,521 in rural areas) and for fasting plasma glucose (FPG) for 50,202 (9,337 in rural areas). Overall, 39% of people with diabetes and 36% with hypertension were receiving treatment (more likely in women and in urban areas). On average, treatment in rural areas lowered FPG by 1.34 mmol/L and SBP by 2.5 mm Hg. In urban areas, the corresponding reductions were 0.21 mmol/L and 3.8 mm Hg. A single additional BW per 1,000 adults was associated with a significant 0.09 mmol/L lowering of district-level average FPG but did not reduce SBP significantly. These researchers conclude that primary care systems with trained community health-care workers and well-established guidelines can be effective in non-communicable disease prevention and management.
Farzadfar F et al. Effectiveness of diabetes and
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Global Summaries
hypertension management by rural primary healthcare workers (Behvarz workers) in Iran: a nationally representative observational study. Lancet 2012; 379: 4554; Habibzadeh F. The control of noncommunicable diseases in Iran. Ibid: 67 (comment).
ONCOLOGY Gene changes and resistance of colorectal cancer to chemotherapy
of key regulatory cancer gene mutations, microsatellite instability, and other genes affecting fluorouracil metabolism. Hypermethylation of TFAP2E is associated with chemotherapy resistance in patients with colorectal cancer, and this resistance is mediated through DKK4. Targeting of DKK4 could potentially reverse this resistance.
Ebert MPA et al. TFAP2E-DKK4 and chemoresistance in colorectal cancer. NEJM 2012; 366: 4453.
prostate cancer. The optimal clinical use of denosumab has yet to be determined.
Smith MR et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebocontrolled trial. Lancet 2012; 379: 3946; Logothetis CJ. Treatment of prostate cancer metastases: more than semantics. Ibid: 46 (comment).
Prostate cancer gene mutation

Prostate cancer may be familial, but the genetic basis is unclear. Genome-wide association studies have identified > 30 single nucleotide polymorphisms associated with increased risk, but the increase in risk from each of them has been low. An intensely studied locus has been at chromosome 17q21-22. Now, a US study has identified a new variant in the gene HOXB13 that is associated with increased risk of hereditary prostate cancer. More than 200 genes in the 17q21-22 region were screened by sequencing germline DNA from 94 unrelated patients with prostate cancer from families with familial prostate cancer linked to the 17q21-22 region. Four of these subjects had a mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene important in prostate development. In these four families, there were 18 men with prostate cancer and available DNA, and all of them carried the mutation. This mutation was present in 72 of 5,083 unrelated men of European descent with prostate cancer (1.4%) and 1 of 1,401 controls without prostate cancer (0.1%), a highly significant difference. It was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in men with late-onset non-familial prostate cancer (0.6%). The new variant accounts for a small proportion of prostate cancers but may provide increased understanding of the disease.
Ewing CM et al. Germline mutations in HOXB13 and prostate-cancer risk. NEJM 2012; 366: 141149.
Denosumab for prostate cancer

Bone metastases are common in prostate cancer. Tumour cells in bone secrete growth factors that induce RANKL production by stromal cells and osteoblasts, and RANKL induces osteoclastic activity. Such activity is suspected to promote the establishment of metastases. Prostate cancer cells might themselves express RANKL and that too might increase the likelihood of metastases in bone. Denosumab is a human monoclonal antibody that inactivates RANKL. It has been shown to be better than zoledronic acid in the prevention of bony metastases in breast or prostate cancer. Now, a multinational trial has shown that denosumab delays the development of bone metastases in men with prostate cancer. At 319 centres in 30 countries, a total of 1,432 men with castration-resistant prostate cancer but without, though at high risk of, bone metastases were randomized to subcutaneous denosumab 120 mg, or placebo, every 4 weeks. Median bonemetastasis-free survival was 29.5 months (denosumab) vs 25.2 months (placebo), a significant difference. Time to first bone metastasis was 33.2 vs 29.5 months. There was no significant difference in overall survival (43.9 vs 44.8 months). Osteonecrosis of the jaw occurred in 33 patients (5%) in the denosumab group but in none of the placebo group. Hypocalcaemia occurred in 12 (2%) vs 2 (< 1%). Denosumab may delay the development of bone metastases in men with high-risk
Gene alterations, both genomic and epigenetic, are common in human cancers, and some of them may affect response to chemotherapy. Researchers in Germany have concentrated on the gene encoding transcription factor AP-2 epsilon (TFAP2E) and its potential downstream target, DKK4, the gene encoding Dickkopf homologue 4 protein. Tumour samples were obtained from 74 patients treated for colorectal cancer and, later, another four cohorts (total, 220 patients) undergoing chemotherapy with or without radiotherapy. The expression, methylation, and function of TFAP2E was analysed in colorectal cancer cell lines in vitro and in patients with colorectal cancer. The gene was hypermethylated in 38 of the initial 74 samples, and this was associated with decreased gene expression. Cancer cell lines with overexpression of DKK4 had increased resistance to fluorouracil but not to irinotecan or oxaliplatin. In the four later cohorts, hypermethylation of TFAP2E was significantly associated with resistance to chemotherapy. Hypomethylation was associated with a sixfold increase in likelihood of chemotherapy responsiveness. Epigenetic alterations in TFAP2E were independent
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General Medicine
Peer Reviewed

Sharon Marks, MB BS, FRACP
An individual approach should be taken when treating morbidly obese patients, with multidisciplinary input.
Extreme morbid obesity is difficult to treat and requires specialist intervention.
Case Scenario
hirley is 41 years of age and has presented in despair about her huge weight gain since the birth of her sixth child, who is now 10 years old. She is 165 cm tall and weighs 179 kg. She is dyspnoeic on even minimal exertion, has painful knees and has recently developed a large inguinal hernia. She reports that she is uncomfortable in bed at night and sleeps poorly. A full blood check finds no major problems, although she reports a very strong family history of diabetes (she is of South Sea Island descent).
Shirley enjoys all the cooking she does for her large extended family and reports eating frequently and voraciously. What strategies or treatments would have the best chance of success for a patient with this level of morbid obesity?
Commentary
This level of obesity (body mass index [BMI] of 65.7 kg/m2) is referred to as extreme morbid obesity or super obese (BMI of more than 50 kg/m2) and is difficult to treat. In most cases, specialist intervention is required because
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General Medicine
many GP offices are not adequately equipped. Many patients (and their GPs) are unable to find scales to give an accurate weight, and hospital clinics need industrial type scales. (Some patients use weighbridges to weigh themselves.) Waiting room chairs as well as examination couches need to be able to support extremes of body weight. The problems for this particular patient are not so much the metabolic disorders that are usually connected with obesity, but more the physical effects of her extreme body weight hindering mobility through breathlessness and joint problems. However, Shirleys family history suggests an increased risk of diabetes. She needs initial rapid and substantial weight loss prior to the initiation of an exercise routine. Starting exercise too early can lead to further joint damage and thus limit ongoing weight maintenance. It is important to exclude any other factors that may be contributing to immobility, such as obstructive sleep apnoea, which is commonly seen in this group of patients. A sleep study is essential, particularly if excessive tiredness limits weight loss attempts or increases snacking behaviour. Nightly use of a continuous positive airway pressure pump should be considered if the patient has periods of hypoxaemia overnight or if the obstructive sleep apnoea is considered to be moderate to severe. Another issue to consider is the medications the patient is taking. Diabetic medications such as insulin, sulfonylureas and glitazones can contribute to increasing body weight and may need to be altered or ceased. Other medications, particularly high-dose corticosteroids and some of the antipsychotic and antiepileptic treatments, can markedly increase appetite. Although the patient in this scenario is taking no
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medications, she is the exception rather than the rule. Patients should also be assessed for depression and obsessivecompulsive behaviour as these conditions can contribute to increased snacking behaviour.
Treatment
The energy required for initial weight loss in this situation usually needs to be achieved by calorie restriction rather than by increasing physical activity. More substantial weight loss can be achieved and maintained by introducing a very-low-calorie diet. Once weight loss (even a small amount) has occurred, increased incidental activity such as walking can help potentiate further weight loss. Surgical intervention may give the best outcome for patients who have little chance of long-term maintenance. Medications Some of the selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine and sertraline) and some of the serotonin and noradrenaline reuptake inhibitors (SNRIs; eg, duloxetine and reboxetine) used to treat depressive and obsessive compulsive disorders have effects on satiety. The balance between increased satiety and overstimulation (insomnia and anxiety) needs to be found. These medications are not weight-loss drugs in their own right (and are not Therapeutic Goods Administration [TGA]-approved for the management of obesity), but they can be helpful if a patient is demotivated and struggling with frustration about their weight. It should also be noted that many patients find long-term diets to be very depriving and actually show signs of depression and anger if food is restricted. These patients benefit from being primed prior to altering their food intake.
Until recently, it was possible to use sibutramine to induce satiety and help patients eat smaller portions while maintaining a higher metabolic rate. However, sibutramine was withdrawn from sale in mid-October 2010 and is no longer an option. The recently published SCOUT study showed an increased risk of non-fatal cardiac events in high-risk patients, most of whom were treated off-licence.1 Most of the patients recruited had type 2 diabetes and had known cardiovascular disease with either a previous myocardial infarction or episodes of angina and so were at high risk of recurrent cardiac events. The weight loss achieved in the study group did not meet the minimum (5% of initial body weight) set by the Food and Drug Administration for a weight loss product. However, sibutramines efficacy and safety in a low-risk population was not evaluated. In some individuals, sibutramine was an effective medication that enabled greater adherence to a long-term diet, and in patients with morbid obesity it was possible to see significant weight losses in responders, although not in all cases. There is very little to use in its place as, apart from orlistat (discussed later), the only other drug approved by the TGA for the management of obesity is phentermine. This medication has been around for many years and has not undergone a similar rigorous study to prove efficacy and safety in this group of patients. It is approved only for short-term weight loss (less than 3 months) and has a very limited role in the management of extreme morbid obesity, which requires a long-term approach. Orlistat is a lipase inhibitor that may be of some benefit in producing a weight loss effect as it reduces the absorption of about 30% of ingested dietary fat. In the diet-nave patient,
General Medicine
who may not have a good comprehension of the fat content of food, it can help identify high-fat foods. The medication causes diarrhoea, abdominal pain and oil incontinence if a high-fat diet is consumed, thus encouraging adherence to a low-fat diet. Orlistat may help commence the weight loss process but is unlikely to cause substantial weight loss (ie, of more than 12 to 20 kg) in this group of patients. It may also have a place in the ongoing management of obesity because it can be used intermittently and has few side effects other than the effect of the drug to cause fat malabsorption. Supplementation with fat-soluble vitamins is not usually required unless the patient has a nutrient-poor diet overall. The cost of this over-the-counter treatment, about A$120 for a packet of 84 capsules (1 months supply) or A$70 for 42 capsules, needs to be placed in perspective with the outcome of the intervention. It is not available on the Pharmaceutical Benefits Scheme but is available on the Repatriation Pharmaceutical Benefits Scheme on authority for a once per lifetime treatment of obesity (BMI of 30 kg/m2 or greater with specified comorbidities, including type 2 diabetes, or BMI of 35 kg/m2 or greater without associated problems). Diet In patients with extreme morbid obesity, an energy-restricted diet should be used in the first instance. Some patients do respond to a wellbalanced, low-fat, calorie-reduced diet, particularly if satiety is increased. Thus, initial substantial weight loss can be seen with the use of low glycaemic foods and regular meal times plus the altering of other factors such as tiredness (related to obstructive sleep apnoea) or medications causing
An energy-restricted diet should be used in the first instance for patients with extreme morbid obesity.
increased appetite. The assistance of a qualified dietitian can be of great benefit, and weight losses of up to about 20 kg can occur fairly rapidly using a food-based dietary approach. In patients who are unable to modify their food intake because of excessive appetite or uncontrollable snacking behaviour, a very-low-calorie diet (VLCD) programme can achieve an energy deficit even in those with extreme immobility. Once weight loss has occurred, the patient can become more mobile as joint pain and obstructive sleep apnoea benefit greatly from relatively small weight losses. A VLCD programme (a diet of 800 calories [about 3,350 kJ] per day or less) can be expected to achieve a weight loss of 15 to 30 kg in the first 3 months, with ongoing weight loss if the intensive programme is continued. Patients need blood tests including liver and renal function testing as well as a lipid profile and diabetes screening before starting a ketogenic programme. Other investigations should include thyroid function test and a full blood count as well as iron studies. Medications such as insulin, sulfonylureas and glitazones may need to be adjusted or ceased during the weight loss phase to avoid episodes of hypoglycaemia, which may prevent the patient adhering to the strict ketone-inducing
regimen. Blood pressure medications may also need to be reduced to avoid hypotension. If a diuretic is being used, electrolytes should be monitored on a regular basis as weight loss occurs. I encourage all patients to follow the intensive regimen using the VLCD as a complete three-meal per day replacement for at least the first 2 weeks. During this initial phase, only a large bowl of steamed low-starch vegetables is allowed in addition to the three meal replacements. Once ketone bodies are produced, appetite usually reduces dramatically, which enables the continuation of the intensive programme (ie, three meals per day) for at least 3 months. Some people are able to continue further, particularly if motivated by initial weight loss. A gradual reintroduction of a low-fat and carbohydrate-reduced diet together with increasing exercise tolerance helps with ongoing weight maintenance. It is not unusual to see some weight regain when normal meals are introduced as the low carbohydrate content of the intensive phase contributes to an early diuresis. It is almost inevitable that some fluid regain will occur, and so it helps if the patient is prewarned. Weight maintenance needs to be encouraged although there should be a low threshold to returning to the intensive phase (replacing three meals
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General Medicine
a day) if needed. Patients need to be encouraged to be proactive with regard to weight regain and not see it as a failure of a particular programme. Regular follow-up is essential during the VLCD programme. Other health professionals, such as clinical psychologists, dietitians and exercise physiologists, can help lighten the load as it is fairly time-intensive to monitor these patients. A multidisciplinary team approach is of great value with regard to goal setting and provides useful feedback as many patients with extreme morbid obesity cannot weigh themselves at home or be weighed at the local doctors surgery. Surgery For some patients, the task of initiating and then continuing weight loss is overwhelming. Those with severe sleep apnoea (and associated tiredness) as well as those with debilitating joint disease may achieve initial weight loss but have little chance of maintaining the loss in the long term. A surgical intervention may give the best outcome in these patients. Laparoscopic gastric banding has become the most common bariatric surgery procedure in Australia as it is relatively non-invasive and adjustable and provides a long-term weight maintenance strategy. Other options include the gastric sleeve procedure and the Roux-en-Y gastric bypass. These procedures have their own complications, including risk of nutritional inadequacy and wound breakdown, but their suitability must be assessed in the light of the severity of the obesity and its complications. For instance, a patient with an insatiable appetite or a sweet tooth may be a poor candidate for a lap band, which requires food restriction. These patients may take in excess energy in the form of frequent small portions or by drinking high-calorie drinks that
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may pass around the band. Gastric bypass, which causes malabsorption by reducing the absorptive area of the small bowel, may be the best option to achieve significant weight loss even though life-long monitoring of nutritional indices is required. Generally, any intervention will be most successful if it reduces appetite and increases satiety. The gastric sleeve procedure is thought to achieve this by removing the portion of the stomach that produces ghrelin, the hormone that stimulates appetite. Long-term data is not yet available for this procedure. With the lap band, however, weight losses of more than 50% of excess body weight have been maintained over a 5-year period. Again, patients who have had lap bands need lifelong monitoring to ensure ongoing compliance and weight maintenance.
Summary
Successful treatment of patients with extreme morbid obesity is very complex. Patients vary greatly in their expectations and in their physical ability. It is imperative that an individual approach is taken with as much input from a multidisciplinary team as possible. Often the simple problem of weighing a patient who is more than 150 kg means that the treatment cannot be undertaken by the local doctor alone. Access to public hospital bariatric clinics is severely limited, with waiting lists of up to 12 months for initial assessment. The opportunity to obtain a lap band or gastric bypass procedure is similarly problematic, with even longer waiting lists. Those patients with private health insurance fare better although the out-of pocket expenses are sometimes prohibitive. Although there is much discussion about the obesity epidemic and the need for better bariatric assessment clinics with greater access to surgery,
very little has changed in this regard over the past 10 years. For the individual patient presenting at this level of obesity, the first interaction with a doctor will often dictate the long-term outcome. First attempts at long-term weight loss and maintenance are often unsuccessful, and the doctor needs to avoid expressing disappointment because it will only confirm the patients belief that the problem is insurmountable. A positive approach, balanced by a clear understanding of the physical and emotional barriers inherent in patients with extreme morbid obesity, will at least facilitate compliance. Obviously, the prevention of weight gain in at-risk patients is a vital component as it is easier to treat obesity in a mobile patient than in one unable to be active due to osteoarthritis, breathlessness or obstructive sleep apnoea.
Declaration of Interests
Dr Marks has been a member of medical advisory boards for Optifast, sibutramine and orlistat and has been involved in clinical trials of these products. She has also received honoraria from Nestle, Abbott and Roche for talks on obesity management.
Reference
1. James WPT, Caterson ID, Coutinho W, et al.; for the SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010;363:905917.
2010 Medicine Today Pty Ltd. Initially published in Medicine Today November 2010;11(11):7476. Reprinted with permission.
About the Author Dr Marks is a Consultant Physician in Clinical Nutrition at Monash Medical Centre, Melbourne, Victoria, Australia.
In focus
Colorectal Cancer
Reviews Colorectal Cancer: Prevention and Early Diagnosis Colorectal Cancer: Features and Investigation Can Metastatic Colorectal Cancer Be Cured?
Colorectal cancer is one of the most common cancers worldwide and is a disease of Westernized populations. With early detection, diagnosis and treatment, the morbidity and mortality associated with this cancer can be prevented.
How much do you know about colorectal cancer?

True 1. It is estimated that among those with colorectal polyps, 95% will develop invasive colorectal cancer (CRC). 2. Central obesity is a risk factor for CRC. 3. Colonoscopy is the gold standard investigation for CRC and polyps. 4. The liver is the most common metastatic site. 5. Metastatic CRC is potentially incurable, even when limited to a specific organ site. False
See page 292 for answers
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In focus
Peer Reviewed
Colorectal Cancer: Prevention and Early Diagnosis

Robert Dennis, MSc, FRCS; Samson Tou, MSc, FRCS; Richard Miller, MSc, FRCS
Colorectal cancer (CRC) is a curable disease; over 90% of patients who have surgical resection of a Dukes A tumour will still be alive after 5 years. This is direct evidence that an early diagnosis will reduce mortality from CRC. Despite this, CRC is the second most common cause of cancer-related death in the UK. The discrepancy suggests that outcomes can be improved by a better understanding of the causes of the disease and its early detection and treatment. In this article, prevention and early diagnosis are discussed.
olorectal cancer (CRC) is a major cause of cancer morbidity in the UK, and in 2006 there were more than 37,500 new cases and 16,000 deaths from the disease. After lung cancer, it is the second most common cause of cancer-related death.1
Pathogenesis
The pathogenesis of the majority of CRC is well understood in terms of the adenomacarcinoma sequence. This describes the progression of CRC as an accumulation of mutations in key genes, for example, tumour suppressor genes, such as the adenomatous polyposis coli (APC) and TP53 genes, and in proto-oncogenes such as K-ras. In macroscopic terms, these molecular changes contribute to the development of polypoid lesions and, later, invasive carcinoma. In polyps, the normal architecture of colonic crypts is disrupted by disturbances in the sequence of basal proliferation, migration, and differentiation. Many individuals have polyps, but it is
Many individuals have colorectal polyps, but it is estimated that only 5% will develop invasive cancer.
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In focus
What's new?
The US NIH AARP diet and health study An analysis within the EPIC study examining 25(OH)-vitamin D concentration and the incidence colorectal cancer Swedish study examining physical activity and risk of colorectal cancer Evidence for the dose and duration of aspirin associated with a reduction in the risk of colorectal cancer The NHS Bowel Cancer Screening Programme UK randomized trial of flexible sigmoidoscopy as a screening tool for colorectal cancer
estimated that only 5% will develop invasive cancer. Prevention of colorectal cancer, therefore, depends on early elimination of these polyps and/or the factors that predispose the colonic epithelium to become transformed.
PeutzJeghers syndrome, and juvenile polyposis) have germ-line mutations that predispose the epithelium to develop multiple polyps. A germ-line mutation of APC is responsible for the colorectal polyps that develop in FAP, whereas mutations in mismatch repair genes, which usually detect, excise and replace any inadvertent nucleotide mismatches during DNA replication, result in HNPCC. Compared with the large number of polyps in FAP, there are markedly fewer polyps in HNPCC. The HNPCC polyps are predominantly located in the right side of the colon, but their rate of transformation is high compared with FAP (see Figure). In IBD, such as ulcerative colitis and colonic Crohns disease, the predisposition to CRC arises from the increased proliferation of colonic epithelium during inflammatory episodes. Polyp formation in sporadic disease is not well understood; consequently, numerous studies on external factors such as diet, obesity and other lifestyle parameters have been and are
being undertaken to identify causal relationships with CRC. Some of these studies are discussed below and are an important source of evidence-based preventative measures.
Prevention
Diet
In the 1960s, Burkitt proposed that the relationship between diet and bowel disease should be investigated. His hypothesis was that low-fibre diets slowed colonic transit and thereby increased the opportunity of carcinogens, generated by bacterial activity on faecal constituents, to exert their effect on the colonic epithelium. The effect of diet (as well as metabolic, genetic and environmental factors) on the development of cancer is now being explored in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. EPIC is the worlds largest prospective study and involves over half a million people recruited from 23 different regions of 10 European
Aetiology
Eighty-five percent of CRC cases fall into the category of sporadic disease, where the primary cause of polyp formation is unknown. The remaining 15% of cases are accounted for by less common causes of CRC, for example familial CRC (ie, where one first-degree relative aged < 45 years old is affected by CRC or there are two affected first-degree relatives), dominantly inherited CRC syndromes and inflammatory bowel disease (IBD). In the latter two groups, the molecular events of polyp formation are understood. The hereditary CRC syndromes (eg, hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP),
Figure. Photograph of a resection specimen of colon for polyposis syndrome.
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In focus
Not all studies have demonstrated that a high-fibre diet reduces the risk of colorectal cancer.
countries. The advantage of obtaining data from multiple regions is that a clearer relationship between different dietary habits and the development of cancer may be seen.2 The first completed data sets from the ongoing EPIC study have now been analysed; these show that dietary patterns are regional and that diet does have an impact on the development of CRC. For example, it has been demonstrated that dietary fibre is likely to be protective against colorectal cancer; comparison between the lowest daily fibre intake of 12 g and the highest intake of 30 g showed a 40% reduction in the risk for CRC after calibration.3 The source of fibre was not significant.3 As a result, it has been suggested that about eight portions of fruit and vegetables and the equivalent of five slices of wholemeal bread should be eaten daily if the benefits of dietary fibre are to be realized. 2 Linked studies have also shown that a high intake of red or processed meat is associated with a 35% increase in
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colorectal cancer if more than 160 g are consumed per day (two or more portions) when compared to less than one portion per week. 4 In contrast, a high fish consumption of 80 g or more is protective. 4 The increased risk of CRC with a high consumption of red and processed meat may be related to the association of these foodstuffs with increased amounts of N-nitrosocompounds in the faeces. These compounds bind to the epithelial DNA and may act as mutagens to initiate the adenoma carcinoma sequence. The US prospective National Institutes of HealthAARP Diet and Health Study5 analysed 293,615 men and 198,767 women aged 5071 years with self-administered foodfrequency questionnaire at baseline in 19951996 and then 5 years of follow-up. Men with high scores on the fruit and vegetable factor were at decreased risk of colorectal cancer (relative risk, RR, 0.81; 95% confidence interval, CI, 0.700.93; P for
trend = 0.004). High scores on the red meat factor were associated with increased risk (RR, 1.17; 95% CI, 1.021.35; P for trend = 0.14 for men; and RR, 1.48; 95% CI, 1.201.83; P for trend = 0.0002 for women). Not all studies have demonstrated that a high-fibre diet reduces the risk of CRC. A pooled analysis of 13 prospective cohort studies 6 found that dietary fibre was not associated with a reduced risk of colorectal cancer after adjusting for other dietary risk factors. A Cochrane collaboration systematic review 7 has analysed five studies of over 4,000 subjects for the effect of intervention with soluble and insoluble dietary fibre or a comprehensive dietary intervention with high-fibre whole food sources. Over the 2- to 4-year period of the studies, combined data showed no outcome difference between the intervention and control groups in the number of subjects with at least one adenoma or a new diagnosis of colorectal cancer. A more recent analysis within the EPIC study has shown a possible relationship between pre-diagnostic, serum 25(OH)-vitamin D concentration and risk of colorectal cancer.8 After correcting for dietary and other possible confounding factors, serum 25(OH)-vitamin D concentration showed a strong inverse linear doseresponse association with risk of colorectal cancer (P for trend < 0.001), although subgroup analyses showed this association for colon but not rectal cancer (P for hetero geneity = 0.048). Greater dietary intake of calcium was also associated with a lower colorectal cancer risk. The authors noted that further randomized trials are needed to assess whether increases in circulating serum 25(OH)-vitamin D concentration can effectively decrease the risk of colorectal cancer.
In focus
Obesity and Exercise

There is accumulating epidemiological evidence that central obesity is a risk factor for CRC. The biological mechanisms still need to be elucidated, but hyperinsulinaemia appears to play a role. With further research, it may emerge that weight loss is an important preventative measure against CRC, as it is against endometrial cancer, heart disease, and type 2 diabetes mellitus. Regular exercise also protects against CRC. 9,10 Furthermore, there is evidence that CRC patients have an absolute improvement of 14% in their 5-year survival if they had active lifestyles before presenting with symptoms of CRC.9 An active patient is defined as someone who exercises vigorously for 20 minutes at least once a week or participates in weekly general health and fitness.9 The Swedish study showed differing distributions of colon cancer between the sexes, and no association between physical activity and rectal cancer.10
Patient Education
Table 1. Recommendations to reduce risk of developing colorectal cancer
Diet contains high fibre/fruit and vegetables/fish Reduce intake of red or processed meat Stop smoking and reduce alcohol consumption Reduce obesity Regular exercise Patient education/screening
Alcohol and Smoking

The link between alcohol and CRC remains equivocal. Some evidence suggests that there is a doserisk relationship that is particularly pertinent to rectal cancer. The evidence for tobacco is slightly stronger in rectal cancer, with a relationship to smoking even after adjustment for alcohol.11 This epidemiological evidence is also supported by other studies that have shown that smokers have a higher incidence of colorectal polyps.
Chemoprevention
Non-steroidal anti-inflammatory drugs may inhibit progression and development of CRC. A recent Cochrane meta-analysis analysed four randomized controlled trials that compared aspirin with a placebo in
average-risk populations.12 No significant reduction in the incidence of adenomas was noted in the primary prevention trial, but data from the three secondary prevention trials showed a statistically significant reduction in the recurrence of sporadic adenomas in the treatment groups. The overall results (which included trials treating FAP patients with aspirin) showed a trend in favour of treating with aspirin to prevent colorectal adenomas.12 However, this may be a type I error, since the subgroup taking 325 mg of aspirin did not see the benefit of the subgroup receiving 81 mg.13 A prospective study of 47,363 male health professionals aged 4075 years followed up for 18 years showed that men who regularly used aspirin ( 2 times/week) had a multivariate RR for colorectal cancer of 0.79 (95% CI, 0.690.90), compared with non-regular users. 14 However, this potential benefit necessitates at least 6 years of consistent use with maximal risk reduction at doses greater than 14 tablets/week. As noted by the authors, the risks of gastrointestinal bleeding and haemorrhagic stroke must be weighed against the benefit of treatment.
Symptoms of CRC include a change in bowel habit (particularly loose stools for more than 6 weeks) and rectal bleeding (characteristically, dark blood that may or may not be mixed with stool). Bright red rectal blood in the absence of other anal disease (eg, haemorrhoids, tags and fissures) is also a high-risk symptom. Efforts to educate patients about the importance of these symptoms, together with information about screening programmes, are likely to lead to earlier patient presentation, particularly as there is evidence that patients do ignore symptoms (for years in some cases), and express fears about unpleasant examinations and not wanting to waste the doctors time. A summary of the recommendations to reduce the risk of developing colorectal cancer is shown in Table 1.
Early Diagnosis Through Screening

There is evidence that polypectomy reduces the incidence of CRC.15,16 Population screening for premalignant or early disease in the form of polypoid lesions is, therefore, likely to reduce the incidence of sporadic CRC in the longer term. For an average-risk individual (eg, no family or personal history of CRC), the lifetime cumulative incidence of CRC is 6%,17 but the risk of developing sporadic CRC doubles every 10 years after 40 years of age.17 To achieve the maximum benefits of a screening test, it should be undertaken when the patient is most likely to have pre-invasive or very early invasive disease. Since the average age of patients who receive a diagnosis of adenomatous polyps is around 60 years, the Department of Health guidelines in the UK advise that biennial screening should be offered to everyone between
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In focus
Table 2. Definitions of sensitivity and specificity

sensitivity Definition: probability of a positive test when the disease is present Application: if the test has a high sensitivity, it will identify patients with the disease, and therefore a negative result indicates that the patient does not have the disease specificity Definition: probability of a negative test when the disease is absent Application: if the test has a high specificity, a negative result identifies people who do not have the disease, and therefore a positive result indicates that the patient has the disease
60 and 69 years of age and extended to 75 years from 2010 (http://www.cancer screening.nhs.uk/bowel/index.html). Initial screening is performed using the faecal occult blood test (FOBT). Patients with positive tests are offered colonoscopy in quality-assured centres. Using this test fits the World Health Organization criteria for screening: a screening test should be inexpensive, rapid, and simple, and is not intended to be diagnostic; those with positive tests require further evaluation.18
respectively (see Table 2 for definitions). Estimates of the sensitivity for CRC range from 12.9%19 to 50%,20 and for large adenomas are as low as 12%.19 The English Bowel Cancer Screening Pilot invited 480,250 individuals to take part in FOBT screening. There was a 56.8% uptake with an overall positive test rate of 1.9%. The cancer detection rate was 1.62/1,000 individuals screened. This gave a positive predictive value of 10.9% for cancer and 35.0% for adenomas.16 It is predicted that for every 1,000 individuals screened in the National Health Service (NHS) Bowel Cancer Screening programme, approximately 20 will be offered colonoscopy, 16 of whom will take up the offer. Half of these colonoscopies are expected to be normal, six are expected to detect adenomas, and two to detect cancer. The normal colonoscopies are the most significant cost to screening. They impose a financial burden to patients and the health service as well as the associated morbidity and mortality rates of the procedure, even though these are low.21 Despite the criticisms, FOBT
is still a viable screening test; it is non-invasive and cheap, but more importantly it reduces mortality from CRC. Several trials have independently shown a significant reduction in mortality from CRC in the individuals randomized to undergo FOBT.20,22,23 In the FOB-tested groups, the reduction in mortality was 1518% 20,23 for biennial screening and 33% for annual screening.22 Furthermore, 18 years of follow-up from the Minnesota trial has demonstrated a significant reduction in the incidence of CRC in patients randomized to FOBT.
Flexible Sigmoidoscopy
A large, multicentre, randomized, controlled trial has recently been published assessing once-only flexible sigmoidoscopy in people aged from 55 to 64 years as an effective means for the prevention of colorectal cancer.24 The rationale for this screening tool is that approximately two-thirds of colorectal cancers are located in the rectum and sigmoid colon, and most have arisen from adenomas. In
Faecal Occult Blood Test

The principle behind FOBT is that polyps and malignant lesions bleed, and blood from these lesions is shed into the faecal stream. The guaiacimpregnated test cards detect the peroxidase activity of haem. However, not all colonic lesions bleed, and the principal criticism of FOBT is its low sensitivity and inadequate specificity, which can translate into high false-negative and false-positive rates,
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Faecal occult blood test is a viable screening test for colorectal cancer.
In focus
Table 3. Summary of the guidelines on colonic surveillance programmes for patients at increased risk of CRC
Disease HNPCC
28
Risk 80% for CRC (1320% for gastric cancer and 40% for endometrial cancer)
colonic surveillance/surgery (guidelines) (i) Biennial colonoscopy from 20 to 25 years old, or 5 years before the age of diagnosis of the youngest affected relative. Continue until 75 years old. If CRC diagnosed: surgical resection and prophylactic surgery (high risk of metachronous CRC) (ii) If documented mismatch repair gene mutation: consider prophylactic surgery with endoscopic surveillance if the rectum is retained because the risk of rectal cancer is 3% every 3 years for the first 12 years (i) If patient is from a FAP family, but there is no documented mutation: annual flexible sigmoidoscopy (F/S) from puberty until 30 years old. Attenuated forms of the disease exist, therefore F/S every 35 years from 3060 years of age (ii) If documented APC mutation or 100 adenomatous polyps: prophylactic surgery. If the rectum is retained, annual endoscopic review (risk of cancer in the retained rectal stump is 1229%) Total colonic evaluation either after first consultation on family history or between 35 and 40 years old (whichever is later) to identify patients with adenomas/CRC. If no adenoma/CRC at first colonoscopy, repeat surveillance at 55 years old If no adenomas at 55 years of age, patients degree of risk is probably equivalent to that of the general population (i) First surveillance colonoscopy 810 years after the onset of disease; surveillance every 3 years for next 10 years (ii) Biennial colonoscopy for patients with a 2030-year history, and annual colonoscopy if > 30 years history 80% of recurrences within 2 years, therefore close follow-up in this period. CT, CEA and patient symptoms are the principal means of detecting recurrence. Current guidelines suggest liver imaging for asymptomatic patients at least once within 2 years of resection. CRC patients are predisposed to further adenomas and metachronous cancers, therefore surveillance colonoscopy, repeated every 35 years depending on local guidelines, is recommended.
FAP28
CRC almost certain without prophylactic surgery
Familial CRC30
1:6 if two affected first-degree relatives, 1:10 if one < 45 years old 58% after 20 years, 18% after 30 years 50% recurrence
IBD29
CRC34
small polyps and referral for colonoscopy if they had polyps meeting the following criteria: 1-cm diameter or larger; three or more adenomas; tubulovillous or villous histology; severe dysplasia or malignant disease; or 20 or more hyperplastic polyps above the distal rectum. Those with low-risk polyps were discharged from further follow-up. In the screened group, colorectal cancer incidence was reduced by 33% for all colorectal cancer sites and by 50% for the distal colon. Mortality from colorectal cancer was reduced by 31%. The authors estimated that 191 patients needed to be screened to prevent one colorectal cancer diagnosis over the course of the study. The authors concluded that flexible sigmoidoscopy is a safe and practical test, and provides substantial benefit when offered once only for patients aged between 55 and 64 years. At odds with these findings of the UK trial, the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, assessing the effects of once-only flexible sigmoidoscopy in 5564year-olds, has reported no reduction in colorectal cancer incidence at 7 years.25 The Italian SCORE trial (similar protocol to the UK trial) and US PLCO trial (screening every 35 years between ages 55 and 74) are due to be reported soon.
For HNPCC and FAP, families are advised also to register with the Regional Clinical Genetics Centre. APC = adenomatous polyposis coli; CEA = carcinoembryonic antigen; CRC = colorectal cancer; FAP = familial adenomatous polyposis; HNPCC = hereditary non-polyposis colorectal cancer; IBD = inflammatory bowel disease.
CRC Prevention Through the Surveillance of Screened Patients With Early Disease
The number of patients found to have adenomas and early CRC will increase as a result of the screening programme. These patients need regular follow-up or surveillance because of their increased risk of recurrent adenomas. The interval between surveillance colonoscopies is timed to balance the risk of repeat colonoscopies against the
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the majority of cases, people who develop a distal colon cancer will have developed an adenoma by 60 years of age, so removal of adenomas by sigmoidoscopy would provide long-term protection against the development of distal colorectal cancer. Recruitment and screening were
started in 1994 and completed in 1999. An initial 170,432 patients were randomized to either flexible sigmoidoscopy (40,621 screened) or a control group (112,939 analysed) and followed up for a median of 11.2 years. Participants underwent flexible sigmoidoscopy with polypectomy for
In focus
"The number and size of the adenomas often predict the polyp findings at subsequent follow-up colonoscopies"
CRC27 associated with this syndrome. Furthermore, surveillance frequency for HNPCC is based on the early age of presentation with the disease (median age, 4045 years) and the likelihood that progression from adenoma to invasive carcinoma is more rapid than sporadic CRC sometimes within 3 years of a clear colonoscopy. In contrast to HNPCC, the disease profiles and risks for FAP, IBD and familial CRC are all different, and so different surveillance guidelines are required.2830 These guidelines are summarized in Table 3, but they remain flexible and practice standards will evolve as new data are published.
need to diagnose and treat any further neoplasia and/or CRC before it causes significant morbidity. Initially, a 3-year interval was proposed based on the data from the US National Polyp Study, but further studies have modified this recommendation. It has been shown that if adenomas are found, the number and size of the adenomas often predict the polyp findings at subsequent follow-up colonoscopies. As a result, patients can be risk-stratified according to the number and size of the adenomas found at initial colonoscopy.26 At the next follow-up, the patient is re-stratified according to the new colonoscopic findings.
Prevention and Early Diagnosis Through UK Government Initiatives

The NHS Cancer Plan, introduced to reform cancer services, directed that by 2005, the time from GP referral to treatment for all cancers should be a maximum of 62 days. The initiative introduced the 2-week wait rule (TWR) and the two-week wait clinics. An implicit benefit of the rule is the earlier diagnosis and treatment of CRC and, therefore, better survival rates for patients. However, although 99.5% of patients referred via the TWR are seen within the specified time, a recent study has shown that less than 25% of CRC cases were diagnosed through these clinics.31 Most CRC patients still present through the emergency services and other routes (eg, general medical or surgical outpatients). This suggests that for most CRC patients the TWR has had little impact. To optimize the benefits of the TWR, factors that inhibit its efficiency need to be explored. The reasons for delays are multiple and include patient and primary and secondary care factors. In the primary care setting, early referral via the TWR is available
for patients with at risk symptoms/ signs, but delays still exist where, for example, the doctor gets locked into the wrong diagnosis or makes a routine referral because TWR criteria are either not met or not included.32 In practice, therefore, it may be necessary for all patients with suspicious symptoms, not just those who meet TWR criteria, to have rapid investigation. This could be via GP direct-access colonoscopy or the direct to test approach, where a consultant receives a referral and arranges investigation before a clinic visit. Clearly, this would require a significant improvement in colonoscopy services, especially since hospital waiting times, particularly for colonoscopy and computed tomographic scans, are significant in many units. The common factor to improve the efficiency of the TWR is rapid access to high-quality colonoscopy, the current gold-standard investigation.
Prevention and Early Diagnosis The Future

Screening promises to improve the detection of early CRC and ultimately contribute to its prevention. The value of FOBT as a single test is currently limited because of its low sensitivity and inadequate specificity, but if FOBT were complemented by another non-invasive test, sensitivity could be significantly improved. Various potential complementary non-invasive tests are currently being developed, such as faecal DNA tests and molecular tests on isolated colonocytes.33 However, the availability of these tests for clinical investigation is still in the future. Consequently, continuing patient education about lifestyle, symptoms of CRC and screening, as well as promoting and funding initiatives to expedite diagnosis, staging and treatment of
Prevention Through Surveillance of Patients at Above-average Risk of CRC

For patients with a higher risk of CRC compared with the general population (eg, inherited CRC syndromes and IBD), early detection of CRC depends on appropriate surveillance programmes. Strong evidence (level II) has shown that surveillance of HNPCC patients reduces both the incidence of CRC and the risk of mortality from
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CRC, are vital to help prevent the mortality and morbidity associated with the disease.
14. Chan AT, Giovannucci EL, Meyerhardt JA. Aspirin dose and duration of use and risk of colorectal cancer. Gastroenterology 2008;134:2128. 15. Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 1992;326:658662. 16. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:19771981. 17. Nicholson FB, Barro JL, AtkinW, et al. Review article: population screening for colorectal cancer. Aliment Pharmacol Ther 2005;22:10691077. 18. Wilson JMG, Jungner G. Principles and Practice of Screening for Disease. Public Health Papers No. 34. Geneva: World Health Organization; 1968. 19. Imperiale TF, Ransohoff DF, Itzkowitz SH, Turnbull BA, Ross ME. Fecal DNA versus fecal occult blood for colorectalcancer screening in an average-risk population. N Engl J Med 2004;351:27042714. 20. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348:14721477. 21. NHS Bowel Cancer Screening Programme. Evaluation of English Bowel Screening Pilot. Available at: http://www .cancerscreening.nhs.uk/bowel/pilot-2nd-round-evaluation .pdf (accessed 16 Jul 2010). 22. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993;328:13651371. 23. Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996;348:14671471. 24. Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:16241633. 25. Hoff Geir, Grotmol Tom, Skovlund Eva, Bretthauer Michael; Norwegian Colorectal Cancer Prevention Study Group. Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomized controlled trial. BMJ 2009;338:b1846. 26. Atkin WS, Saunders BP. Surveillance guidelines after removal of colorectal adenomatous polyps. Gut 2002;51(suppl 5):V6 V9. 27. Jarvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary non-polyposis colorectal cancer. Gastroenterology 2000;118:829834. 28. Dunlop MG. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adeno-
matous polypolis, juvenile polyposis, and PeutzJeghers syndrome. Gut 2002;51(suppl 5):V21V27. 29. Eaden JA, Mayberry JF. Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease. Gut 2002;51(suppl 5):V10 V12. 30. Dunlop MG. Guidance on large bowel surveillance for people with two first degree relatives with colorectal cancer or one first degree relative diagnosed with colorectal cancer under 45 years. Gut 2002;51(suppl 5):V17 V20. 31. Thorne K, Hutchings HA, Elwyn G. The effects of the TwoWeek Rule on NHS colorectal cancer diagnostic services: a systematic literature review. BMC Health Serv Res 2006;6:43. 32. Flashman K, OLeary DP, Senapati A, Thompson MR. The Department of Healths two week standard for bowel cancer: is it working? Gut 2004;53:387391. 33. Davies RJ, Freeman A, Morris LS, et al. Analysis of minichromosome maintenance proteins as a novel method for detection of colorectal cancer in stool. Lancet 2002;359:19171919. 34. Scholefield JH, Steele RJ. Guidelines for follow up after resection of colorectal cancer. Gut 2002;51(suppl 5):V3 V5.
None.
References
1. Cancer Research UK. UK bowel cancer statistics. Available at: http://info.cancerresearchuk.org/cancerstats/types/bowel/ (accessed 16 Jul 2010). 2. Bingham S, Riboli E. Diet and cancer the European Prospective Investigation into Cancer and Nutrition. Nat Rev Cancer 2004;4:206215. 3. Bingham SA, Day NE, Luben R, et al. Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study. Lancet 2003;361:14961501. 4. Norat T, Bingham S, Ferrari P, et al. Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst 2005;97:906916. 5. Flood A, Rastogi T, Wirflt E, et al. Dietary patterns as identified by factor analysis and colorectal cancer among middle aged. Americans Am J Clin Nutr 2008;88:176184. 6. Park Y, Hunter DJ, Spiegelman D, et al. Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies. JAMA 2005;294:28492857. 7. Asano T, McLeod RS. Dietary fibre for the prevention of colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2002;(2):CD003430. 8. Jenab M, Bueno-de-Mesquita HB, Ferrari P. Association between prediagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ 2010;340:b5500. 9. Haydon AM, Macinnis RJ, English DR, Giles GG. Effect of physical activity and body size on survival after diagnosis with colorectal cancer. Gut 2006;55:6267. 10. Moradi T, Gridley G, Bjrk J, et al. Occupational physical activity and risk for cancer of the colon and rectum in Sweden among men and women by anatomic subsite. Eur J Cancer Prev 2008;17:201208. 11. Doll R, Peto R, Boreham J, Sutherland I. Mortality from cancer in relation to smoking: 50 years observations on British doctors. Br J Cancer 2005;92:426429. 12. Asano TK, McLeod RS. Non steroidal anti-inflammatory drugs (NSAID) and aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2004;(2):CD004079. 13. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891899.
Further Reading
Cappell M. Colon cancer screening, surveillance, prevention and treatment: conventional and novel technologies. Med Clin N Am 2005;89:1217. Steele RJC. Module 14 Disorders of the colon and rectum. In: Cuschieri A, Steele RJC, Moosa AR, eds. Essential Surgi cal Practice: Higher Surgical Training in General Surgery. 4th ed. London: Arnold; 2002. National bowel cancer audit 2009. http://www.ic.nhs .uk/webfiles/Services/NCASP/audits%20and%20reports /National%20Bowel%20Cancer%20Audit%202009%20 Interactive%20for%20web.pdf
2011 Elsevier Ltd. Initially published in Medicine 2011;39(5):243249.
About the Authors Robert Dennis is a Specialist Registrar at the Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Samson Tou is Laparoscopic Colorectal Fellow, The Queen Elizabeth Hospital, Australia. Richard Miller is a Consultant Colorectal Surgeon at the Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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Peer Reviewed
Colorectal Cancer: Features and Investigation

Nigel Hall, BA, DM, FRCS
Colorectal cancer, also known as bowel cancer, is a common malignancy and is common in Westernized populations, owing largely to dietary factors. Bowel cancers are thought to arise through a combination of hereditary predisposition, exposure to environmental agents (eg, diet), lifestyle, and chance.
Colorectal cancer is generally a disease of advancing age.
olorectal cancer, often known simply as bowel cancer, is a common solid organ malignancy affecting 35,000 patients a year in the UK,1 about half of whom will die from it. At all ages, it is more common in males (especially rectal cancer), but because of the greater longevity of women the overall sex distribution is equal. It is generally a disease of advancing years, with a peak age at diagnosis of 70 years; the lifetime risk by the age of 80 years is about 510%.
Epidemiology
Colorectal cancer is common in Westernized populations, probably owing largely to dietary
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factors. Europe, the USA and Japan have high rates compared with Africa and Asia. Bowel cancers are thought to arise through a combination of hereditary predisposition, exposure to environmental agents (eg, diet), lifestyle, and chance. Dominantly inherited strongly penetrant syndromes, such as familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (Lynch syndrome), are responsible for a small percentage of colorectal cancers, often developing before the age of 40 years.2 A much greater proportion may be the result of weakly penetrant but more common susceptibility genes, which are yet to be identified.3 Other known risk factors include diets high in red meat and low in
In focus
What's new?
Screening programmes are increasing the numbers of polyp cancers Genetic analysis of individual tumours is feasible and will impact on future therapy
Practice points
Colorectal cancer is common; the majority are distal and may be within the reach of the examining finger or rigid sigmoidoscope Typical symptoms include rectal bleeding and a looser or more frequent bowel habit Right-sided cancers are a common cause of iron-deficiency anaemia Staging of most bowel cancers is best provided by computed tomography scans of chest, abdomen and pelvis along with a colonoscopy. Barium enema is becoming obsolete Pelvic magnetic resonance imaging is useful for staging rectal cancers and is used to direct preoperative therapy
carcinogenesis in many other malignancies.7 There are two common molecular pathways the classical or chromosomal instability pathway and the microsatellite instability pathway. The majority of sporadic cancers follow the classical pathway in which large segments or whole chromosomes may be lost or duplicated; but about 15% follow the other pathway in which small changes in DNA, often at repeated nucleotide sequences (microsatellites), result in cancer-causing genetic mutations. These pathways have their counterparts in hereditary syndromes FAP cancer follows the classical pathway whereas Lynch syndrome follows the microsatellite instability pathway.8,9 Detailed genetic analysis of individual tumours is becoming a reality with ever-decreasing costs and improved technology. This will help to predict behaviour and response to therapy. The large majority of colorectal cancers are adenocarcinomas arising from the mucosa. Rare tumours include
carcinoids, lymphoma, and melanoma.
Distribution
About two-thirds of sporadic cancers arise distal to the splenic flexure, with about 40% arising in the rectum. In patients with Lynch syndrome, this proportion is reversed with caecal cancer being the most common site.10
Spread
Like many cancers, colorectal carcinoma spreads locally, via lymphatics and through the bloodstream. The liver is the most common metastatic site, via the portal venous system, followed next by pulmonary seedlings. Rarer sites include the skin, brain, and bone. Trans-coelomic spread leads to the development of multiple peritoneal nodules, though ascites is usually minimal.
Pathological Staging
Histological staging of colorectal cancers is performed postoperatively. Dukes and TNM staging (Figure 1) are widely used to inform decisions about
Figure 1. Histological staging of colorectal cancers.

fibre, lack of exercise, obesity, alcohol and (probably) smoking, personal history of adenomatous polyps or previous colorectal cancer, and longstanding colonic inflammatory bowel disease.4,5 Aspirin and non-steroidal anti-inflammatory drugs are thought to be protective against polyps and cancer, but their use as chemopreventative agents is not currently recommended.6 A Muscularis mucosa Muscularis propria Peritoneum N1: 1-3 nodes N2: 4+ nodes C2 'D' M1 T1 T2 B
T3
T4
C1
Distant disease
Pathology and Pathogenesis

AdenomaCarcinoma Sequence
Analysis of the histological and molecular changes of colorectal polyps and malignancies has led to the adenomacarcinoma hypothesis that now underpins our understanding of
This illustrates the two common staging methods Dukes (stage A to D) and TNM (T1-4, N0-2, M0-1). T1 and T2 are Dukes A cancers and do not invade past the muscularis propria. T3 and T4 are Dukes B tumours: they penetrate the muscularis and T4 disease extends either beyond the peritoneum or into adjacent organs. N status depends on the number of involved lymph nodes as shown.
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Table 1. Criteria for referral to fast track colorectal clinic

A change in bowel habit (looser and/ or more frequent stools) persisting > 6 weeks without rectal bleeding in a person aged 60 years or older Rectal bleeding persisting > 6 weeks without a change in bowel habit and without anal symptoms, in a person aged 60 years or older Rectal bleeding with a change of bowel habit towards looser stools and/or increased stool frequency persisting for 6 weeks or more, in a person aged 40 years or older A palpable right lower abdominal mass or a palpable rectal mass (intraluminal and not pelvic) Iron-deficiency anaemia with a haemoglobin of 11 g/dL or less in a man, or of 10 g/dL or less in a nonmenstruating woman
classifications, is helpful in judging the risk of lymph node metastasis and thus in deciding whether a formal resection is indicated. Circumferential margin: for surgery to be potentially curative, especially for rectal cancers, it is important to remove a margin of normal tissue around a cancer. Measurement of whether the circumferential resection margin is involved with cancer can be a very useful predictor of local and even distant recurrence.14,15
Diagnosis
Symptoms
Gastrointestinal symptoms are common, even in the absence of pathology, and there is a wide overlap of symptomatology for malignant and benign causes. Based on a large clinical database in Portsmouth, referral criteria have been developed that identify patients with colorectal cancer most reliably (Table 1),16 but only about 1014% of patients meeting such criteria harbour a malignancy. Obstructive symptoms: as tumours enlarge, they tend to narrow the bowel lumen. This commonly leads to a looser more frequent stool rather than constipation, although any persistent change in bowel habit should be investigated. Distal tumours are more likely than proximal tumours to lead to an alteration in bowel habit, as the stool consistency is more solid. Proximal tumours may produce no symptoms at all until they obstruct completely. In the rectum, the mass effect of a cancer leads to tenesmus (a feeling of incomplete evacuation). Bleeding: rectal bleeding, especially if associated with a change in bowel habit, is a worrying symptom. Low rectal tumours can bleed bright blood just like haemorrhoids; bleeding from left-sided tumours may be darker
red and mixed in with the stool. Although right-sided tumours bleed, this is not visible in the stools, and so these cancers classically present with iron-deficiency anaemia because there is no warning sign to the patient. Symptoms not usually associated with colorectal malignancy: bowel cancers are biologically inert and do not display paraneoplastic features. Weight loss and anorexia are very uncommon unless there is widespread metastatic disease. Pain is also unusual unless a tumour is so advanced that it is nearly obstructing the bowel lumen or invading bone or nerves. Acute presentation: about 20% of patients with colorectal cancer present as emergencies usually with obstruction but occasionally with perforation or abscess formation. Most of these will require emergency surgery.
Signs
Patients with symptoms suggestive of colorectal pathology should undergo abdominal examination, rectal examination and a rigid sigmoidoscopy in the clinic. Palpable mass: many colorectal cancers are palpable typically, a right colon cancer gives rise to a firm mass in the right iliac fossa. Rectal cancers can often be felt on digital examination, and a rolled edge or circumferential nature can easily be appreciated. If a tumour is found, the surgeon will be greatly helped by information about the height of tumour from the anal verge, whether it is mobile, tethered, or fixed, and which quadrants are involved. Sigmoidoscopic findings: a rigid sigmoidoscope will be able to examine most of the rectum and sometimes the distal sigmoid, so it can easily identify rectal tumours in the clinic. Equally important, it may reveal bleeding and inflamed mucosa from inflammatory
adjuvant therapy. Dukes staging: node-negative tumours are staged A if they have not penetrated the muscularis propria, B if they have. If there is lymph node spread, the tumour is automatically a Dukes C.11 A C2 tumour is one in which there is lymphatic invasion at the node furthest away from the tumour at the high tie. Although not described by Dukes, it is now conventional to label any metastatic spread as stage D. TNM staging is more precise than Dukes staging but clinically less useful because there are so many subgroups. Malignant polyps: with the advent of screening programmes, earlier detection of cancers has led to an increased detection of polyp cancers, which are T1 lesions. Many of these are cured by polypectomy alone. Use of other staging methods that take into account the depth of penetration, such as the Haggitt 12 and Kikuchi 13
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Figure 2. a b c
a, b. This polyp in the descending colon was removed by endoscopic mucosal excision after raising it off the muscularis propria by injecting succinylated gelatin and methylene blue in the submucosal plane. c. The site of the polyp was marked with a black tattoo ink on either side of the polyp. Histological analysis revealed it to be a malignant polyp, and the patient subsequently underwent a laparoscopic colectomy; the tattoo was essential for the surgeon to know exactly which part of the colon to remove.
bowel disease as an alternative explanation of the patients symptoms. The presence of streaks of blood in the lumen of the rectum is strongly indicative of pathology in the sigmoid above the reach of the rigid scope usually a large polyp or cancer.
Differential Diagnosis
There is a wide differential diagnosis: alteration in bowel habit may be caused by irritable bowel syndrome, diverticular disease, infections, thyroid dysfunction, coeliac disease or inflammatory bowel disease; rectal bleeding may be caused by haemorrhoids, anal fissure, inflammatory bowel disease or polyps; iron-deficiency anaemia may be caused by gastric or small bowel pathology, poor diet, celiac disease or bleeding from other organ systems (eg, renal or genital tract).
cinoembryonic antigen is commonly assayed, its value is more in follow-up than diagnosis. Faecal occult blood testing is a screening tool and is not indicated in persons with colorectal symptoms such individuals need full colonic evaluation as described below. Colonoscopy: it is the gold standard investigation for colorectal cancer and polyps. Completion rates
should be over 90% in good centres with a perforation rate less than 0.1%. Colonoscopy will identify cancers and enable biopsy, and has therapeutic potential for removing polyps distant from the cancer to prevent metachronous malignancy developing during follow-up. A tattoo can be placed to allow the site of a tumour to be recognized at subsequent lapa-
Figure 3. Magnetic resonance imaging of a locally advanced rectal cancer.
Bladder Mesorectal fascia Rectal tumour encroaching mesorectal fascia Lumen of rectum Lymph node Sacrum
Investigations
Diagnosis
Biochemical tests: no blood test will confirm or refute the diagnosis of colorectal cancer. A full blood count is useful to detect anaemia. Although carMedical Progress June 2012
This transverse section clearly demonstrates the mesorectal fascial envelope, which is the boundary of surgical excision. The tumour is extending through the full thickness of the bowel wall and is very close to the edge of the mesorectum. One of many enlarged lymph nodes is shown on this image. This patient had preoperative chemoradiotherapy to downstage the tumour and then underwent a potentially curative resection of his rectal carcinoma.
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roscopic resection (Figure 2). Even if a rectal cancer is diagnosed in the clinic, luminal imaging is still required to rule out synchronous disease. Barium enema is rapidly and rightly becoming obsolete because it is inaccurate and consistently both over-diagnoses and misses cancers.17 Computed tomography (CT) scans: particularly for elderly patients, a CT of the abdomen and pelvis is a useful diagnostic tool and is noninvasive. 18 Occasionally, spasm on the right side of the abdomen can mimic the appearances of cancer on CT: if there is no clinically palpable mass in this situation, a colonoscopy is required to visualize the right colon and corroborate the CT findings. CT colography: with multislice volume acquisition CT, excellent views can be obtained by insufflating air into a prepared colon. CT colonography is almost as accurate as colonoscopy and can visualize bowel proximal to an obstructing tumour.19 Biopsy: all rectal cancers require biopsy proof of malignancy before treatment is decided. For colonic disease, this is less important as the endoscopic appearances usually indicate the need for surgery.
can accurately stage bowel wall invasion but is less good at detecting lymph node involvement.20 Magnetic resonance imaging is probably the most useful method for determining tumour invasion and nodal status (Figure 3). More importantly, it is the best way of assessing whether the tumour is close to the edge of the mesorectal envelope: this has implications for the surgeon and informs decisions regarding pre-operative chemoradiotherapy.21
implications for lesions removed by endoscopic polypectomy. Gastroenterology 1985;89:328336. 13. Kikuchi R, Takano M, Takagi K, et al. Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 1995;38:12861295. 14. Adam IJ, Mohamdee MO, Martin IG, et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994;344:707711. 15. West NP, Hohenberger W, Weber K, Perrakis A, Finan PJ, Quirke P. Complete mesocolic excision with central vascular ligation produces an oncologically superior specimen compared with standard surgery for carcinoma of the colon. J Clin Oncol 2010;28:272278. 16. Thompson MR. Referral guidelines for colorectal cancer. Colorectal Dis 2002;4:287297. 17. Winawer SJ, Stewart ET, Zauber AG, et al. A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. National Polyp Study Work Group. N Eng J Med 2000;342:17661772. 18. Fink M, Freeman AH, Dixon AK, et al. Computed tomography of the colon in elderly people. Br Med J 1994;308:1018. 19. Halligan S, Altman DG, Taylor SA, et al. CT colonography in the detection of colorectal polyps and cancer: systematic review, meta-analysis, and proposed minimum data set for study level reporting. Radiology 2005;237:893904. 20. Brown G, Davies S, Williams GT, et al. Effectiveness of preoperative staging in rectal cancer: digital rectal examination, endoluminal ultrasound or magnetic resonance imaging? Br J Cancer 2004;91:2329. 21. Brown G, Radcliffe AG, Newcombe RG, Dallimore NS, Bourne MW, Williams GT. Preoperative assessment of prognostic factors in rectal cancer using high resolution magnetic resonance imaging. Br J Surg 2003;90:355364.
Declaration of Interest
None.
References
1. Toms JR, ed. CancerStats monograph 2004. London: Cancer Research UK; 2004. 2. Fearnhead NS, Wilding JL, Bodmer WF. Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull 2002;64:2743. 3. Bodmer WF. Cancer genetics: colorectal cancer as a model. J Hum Genet 2006;51:391396. 4. Bingham SA, Day NE, Luben R, et al. Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study. Lancet 2003;361:14961501. 5. Boyle P, Langman JS. ABC of colorectal cancer: epidemiology. Br Med J 2000;321:805808. 6. Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin, salicylates, and cancer. Lancet 2009;373:1301 1309. 7. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759767. 8. Hall NR, Madoff RD. Genetics and the polyp-cancer sequence. In: Edelstein PS, ed. Colon and Rectal Cancer. Wilmington, DE: Wiley-Liss, 2000. 9. Hardy RG, Meltzer SJ, Jankowski JA. ABC of colorectal cancer: molecular basis for risk factors. Br Med J 2000;321:886889. 10. Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009;76:118. 11. Dukes CE. The classification of cancer of the rectum. J Pathol Bacteriol 1932;35:323332. 12. Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic factors in colorectal carcinomas arising in adenomas:
Pre-operative Clinical Staging

Once a colorectal cancer has been diagnosed, clinical staging investigations should be performed to detect synchronous polyps and cancer, local spread, and metastatic disease. CT of the chest, abdomen and pelvis is used for all patients to detect distant spread. Rectal cancers should be discussed at a multidisciplinary meeting before surgery; all tumours are discussed postoperatively. Rectal cancer: the extent of local spread determines pre-operative therapy, and so pelvic imaging is very important. Transrectal ultrasound
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Further Reading
Cunningham D, Atkin W, Lenz HJ, et al. Colorectal cancer. Lancet 2010;375:10301047. National Institute for Health and Clinical Excellence. Guid ance on Cancer Services: Improving Outcomes in Colorectal Cancers Manual Update. London:NICE; 2004.
2011 Elsevier Ltd. Initially published in Medicine 2011;39(5):250-253
About the Authors Nigel Hall is Consultant Colorectal Surgeon at Addenbrookes Hospital, Cambridge, UK.
In focus
Peer Reviewed
Can Metastatic Colorectal Cancer Be Cured?

David L Bartlett, MD; Edward Chu, MD
Significant advances have been made in the treatment of metastatic colorectal cancer. Development of the targeted biologic agents and their integration with cytotoxic chemotherapy regimens has led to improvements in clinical efficacy. A multimodality team-based approach involving medical oncologists, surgical oncologists, radiologists, and other health-care providers is absolutely critical for the success of this therapeutic approach. This article reviews the main issues that must be considered from the surgical oncology and medical oncology perspectives, respectively.
In patients who present initially with early-stage colorectal cancer, up to 50% will eventually develop metastatic disease.
Introduction
I
n 2012, colorectal cancer (CRC) continues to be a major public health problem. In the United States this year, there will be an estimated 147,000 new cases diagnosed and nearly 50,000 deaths resulting from this disease.1 Worldwide, approximately 1 million new cases of CRC are diagnosed each year, with nearly 500,000 deaths attributed to this disease annually. About 25% of patients present
with metastatic disease, and of this group, 50% to 75% will have disease confined to the liver.24 In patients who present initially with early-stage disease, up to 50% will eventually develop metastatic disease, with the liver being the most common site. Another 10% to 20% of patients will present with disease involving the lung and other less common sites of metastatic involvement, including the peritoneum, ovaries, adrenal glands, bone, and brain.5,6 When metastatic disease is limited to an
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In focus
organ-specific site, an important consideration is whether the disease is resectable at the time of initial diagnosis or whether it is initially deemed to be unresectable but may become resectable with the up-front use of chemotherapy. With the integration of chemotherapy and surgical resection, overall 5-year survival rates on the order of 30% to 40% can now be achieved. A multidisciplinary, team-based approach involving surgeons, medical oncologists, radiologists, and other health-care professionals is required to determine the optimal timing and sequence of surgery and chemotherapy. This article reviews the multidisciplinary approach to patients who have organ-limited metastatic CRC (mCRC), with the main focus being on liver-limited disease. In particular, the surgical and chemotherapy aspects of disease management will be discussed.
Table 1. Prognostic factors for cure after surgical resection

category Primary tumour characteristics Liver metastatic burden factors reported in multivariate analyses Tumour grade Lymph node involvement Tumour-free interval Tumour size (> 5 cm) Tumour number (> 3) Preoperative CEA (> 60) Extrahepatic disease (including hepatic lymph nodes) Surgical factors Unilateral vs bilateral involvement Major resection Positive margin Blood transfusion Resection of adjacent structures Chemotherapy
CEA = carcinoembryonic antigen.
Postoperative morbidity Response to neoadjuvant/conversion chemotherapy
Surgical Considerations for Patients With Metastatic Disease

Historically, the setting of liver-limited metastases from CRC has been one of the few examples of curative metastasectomy in oncology. Even before the development of effective chemotherapy agents, surgical resection of limited hepatic metastases was associated with prolonged survival and cures.7 Several important prognostic factors, such as disease-free interval, number and size of metastases, presence of extrahepatic disease, and stage of the primary cancer, have all helped to define the expected cure rate for hepatic metastasectomy. For patients with metastases defined by the most favourable prognostic categories, cure rates of 24% have been achieved with surgery alone.8 The indications for surgical metastasectomy were for
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patients with disease limited to the liver, a total of four or fewer metastases, unilobar involvement, tumours of less than 5 cm in their greatest diameter, and a disease-free interval of at least 6 months.912 It is, therefore, not surprising that the development of more effective chemotherapy has led to a significant improvement in overall survival (OS) and cure rates, as well as an expansion of the indication for metastasectomy. This indication has evolved into resection of any disease that allows for adequate hepatic residual volume for liver regeneration and survival, assuming there has been a response to neoadjuvant chemotherapy.13 In the past, surgeons were appropriately concerned that resection of visible disease would be followed by rapid recurrence from microscopic metastases in the residual liver. However, incorporation of effective neoadjuvant and/or conversion chemotherapy, as will be discussed in this article, provides greater confidence
that micrometastatic disease can be eliminated and that removal of gross disease can lead to long-term cure. In addition, as hepatic surgery has become safer and easier for the patient, there is now wider acceptance of incorporating hepatic resection into a multimodality strategy to prolong survival. The options for local and regional treatment of hepatic metastases have become broad, and include surgical resection, local ablation therapy, hepatic arterial infusion therapy, transarterial chemoembolization, radiomicrosphere therapy, and isolated hepatic perfusion.14,15 Each of these approaches has been associated with long-term cures, although surgical resection and local ablation strategies have been the most effective. The goal for surgical resection is to achieve a negative microscopic margin. Given the concern about microscopic extension beyond the visible tumour, a 1-cm margin around the tumour is ideal. Numerous coaguMedical Progress June 2012
In focus
lation devices exist to enhance the safety of parenchymal transection by limiting blood loss. Minimally invasive approaches, such as laparoscopic and robotic assistance, have become commonplace, and they are associated with reduced blood loss, shortened hospital stay, and decreased narcotic usage postoperatively.16,17 For patients undergoing multimodality therapies, minimally invasive surgery may also improve quality of life during treatment and decrease the recovery time necessary before adjuvant chemotherapy is administered. The options for resection include extended lobectomy, lobectomy, segmentectomies, and non-anatomic wedge resections. Many surgeons remove the least amount of liver tissue feasible to preserve the anatomy for future resections, if necessary, while others prefer formal anatomic resections in order to provide the best chance of a negative margin. These two approaches have not been directly compared in a randomized trial; however, retrospective data suggest that the ability to achieve a negative margin, as opposed to the specific type of resection, determines long-term prognosis.18 Local ablative approaches have provided an alternative to surgical resection for patients with mCRC. These approaches include radiofrequency ablation (RFA), microwave ablation, cryotherapy, and focused r a d i o t h e r a py ( e g , u s i n g t h e CyberKnife). RFA is a reliable technique to ablate metastases up to 5 cm in size. However, it has limited efficacy in centrally located tumours in which proximity to the main portal triads or hepatic veins may cause bile duct injury, extensive hepatic necrosis, or inadequate tumour cell death adjacent to the vessels. The potential advantages of these local strategies over surgical resection include enhanced safety,
A patients risk for morbidity and mortality also plays a significant role in defining the eventual treatment strategy
outpatient percutaneous treatment options, and the ability to preserve hepatic parenchyma. The local recurrence rate after local ablative procedures is clearly higher than with surgical resection, with rates as high as 34% having been reported.19 The local recurrence rate at the site of ablation is influenced by the size and location of the metastatic lesions, as well as the use of percutaneous vs laparoscopic approaches. Although local recurrence can often be salvaged with repeat ablation or resection, for patients with limited comorbidities in whom the goal is curative intent, surgical resection is the preferred and most reliable method for actual cure. A metaanalysis of non-randomized studies comparing RFA with surgical resection demonstrated an improvement in 5-year survival for patients treated with hepatic resection.20 The curative potential of surgical resection for hepatic metastases from CRC varies depending on a number of important prognostic factors (Table 1). Nomograms for predicting cancer-related survival have been
developed and may be helpful when considering the utility of resection.21 A patients risk for morbidity and mortality also plays a significant role in defining the eventual treatment strategy. Surgical resection is still associated with a defined mortality rate of 2.8% (0% to 6.6%), which is influenced, in large part, by the health of the background liver.22,23 Liver failure is the most common cause of death after hepatectomy, and as discussed below, this complication is influenced by the specific type and cumulative dose of chemotherapy received. The indications for surgical resection are currently based on feasibility and safety in patients who have responded to chemotherapy. It is critically important for the surgical resection to leave 20% to 25% of functioning liver volume (future liver remnant) in patients with a normal background liver, and 40% of liver volume in patients whose background liver is diseased from previous chemotherapy.24 Preoperative planning computed tomography scans, including residual volume calculations, are essential when planning an extended or bilobar resection.25 To date, more than 750 series of hepatic metastasectomy for metastatic CRC have been reported in the literature. The actuarial 5-year survival rate for patients who underwent R0 resections (negative margins) was 30% when combining 16 well-reported series of more than 100 patients with follow-up greater than 2 years (15% to 67%).22 While 5-year survival was historically considered a cure for this disease, because of advances in systemic chemotherapy an increasing number of patients are now living with their disease beyond 5 years. A single-institution study of 455 patients revealed a median OS of 33 months, with 5- and 10-year actuarial survival
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rates of 34% and 25%, respectively.26 In that study, 124 patients were identified as actual 5-year survivors (27%), and of this group 59 were found to be 10-year survivors. This finding suggests ongoing disease-related mortality beyond the 5-year timeframe, with actual cure rates of 10% to 15%. Randomized clinical data suggest an improvement in disease-free survival (DFS) when systemic chemotherapy is incorporated as part of a combined neoadjuvant and postoperative adjuvant approach, as will be discussed in detail in this article. With the extended indications for hepatic metastasectomy in the presence of active systemic chemotherapy, larger resections can now be safely and effectively performed. Commonly used techniques include staged resections for bilobar disease and preoperative portal vein occlusion to achieve compensatory hypertrophy and safer extended resections.27,28 While there appear to be impressive actuarial 5-year survival rates in these series of extensive surgical resections, it is expected that the true cure rate will be much lower. When looking at patients with initially unresectable colorectal liver metastases who were treated with chemotherapy and then resected, 16% of this group were considered cured, with a disease-free interval of more than 5 years after metastasectomy.29 On multivariate analysis, the main predictors of cure included maximum size less than 3 cm, no more than three metastatic lesions, and complete pathologic response.
patients with metastatic CRC, during a median follow-up of 10.3 years, only six (0.24%) were found to be free of disease after having received chemotherapy alone.30 It is now well established that a multimodality strategy results in a much higher chance of long-term cure. In patients with organ-limited disease, chemotherapy is administered in three main settings, which include neoadjuvant therapy, conversion therapy, and adjuvant therapy. Neoadjuvant therapy refers to chemotherapy given to patients with potentially resectable disease, while conversion therapy refers to chemotherapy given to patients deemed to have initially unresectable disease. Adjuvant chemotherapy is use of chemotherapy following an R0 surgical resection, with the intent of preventing disease recurrence.
Neoadjuvant Chemotherapy
Up to 20% to 30% of patients with liver-limited mCRC may have potentially resectable disease at the time of initial presentation. However, because a large proportion of patients experience recurrence of their disease either in the liver or systemically, chemotherapy has been integrated in their up-front care to improve upon the potential benefit of surgery. Several clinical trials have specifically evaluated the role of neoadjuvant therapy for patients with potentially resectable liver metastases. In a single-arm trial involving 20 patients, neoadjuvant therapy with a weekly administration of FOLFOX (fluorouracil [5-FU], leucovorin/ folinic acid [LV], and oxaliplatin) resulted in a partial or complete response in all patients enrolled. 31 A total of 16 patients underwent a potentially curative resection, with seven developing recurrence during the median follow-up period
Systemic Chemotherapy
Long-term cures are exceedingly rare when patients with organ-limited mCRC are treated with chemotherapy alone. In a retrospective review of 2,751
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of 23 months. A phase II trial of neoadjuvant therapy investigated bevacizumab plus the combination of capecitabine and oxaliplatin.32 In this study, 56 patients received six cycles of therapy prior to surgical resection, and a remarkably high objective response rate of 73% was observed. A total of 52 of the 56 patients were able to undergo an R0 resection, with complete pathologic response occurring in nearly 10% of patients. Given concerns over the potential risks of bleeding or wound-healing complications, bevacizumab was not given with the last cycle of chemotherapy prior to surgery. This study is important as it showed that bevacizumab could be safely administered to patients with no increased risk of intraoperative bleeding or woundhealing complications. Moreover, it was estimated that normal liver regeneration occurred in all but one patient. The European Organisation for Research and Treatment of Cancer (EORTC) randomized phase III trial 40983 investigated use of perioperative FOLFOX4 chemotherapy in patients with up to four resectable liver metastases. In this study, patients were randomized to surgery alone or to receive six cycles of FOLFOX4 before surgery and six cycles of FOLFOX4 after surgery. 33 The overall response rate was 43% in patients receiving chemotherapy. Of note, surgery was performed in 83% of patients randomized to chemotherapy and in 84% of patients randomized to surgery alone, providing evidence that use of initial chemotherapy did not compromise the ability of patients to undergo surgical resection. While there was an increased risk of postoperative complications in patients receiving neoadjuvant chemotherapy, these events were reversible and not associated with an increased risk of
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Table 2. Select trials reporting conversion of unresectable metastatic CRC to resectable metastatic disease
n Adam (2004)
40
Regimen FOLFOX or FOLFIRI FOLFOX4 FOLFIRI FOLFIRI FOLFOXIRI FOLFIRI FOLFOXIRI FOLFOXIRI FOLFIRI FOLFIRI + cetuximab FOLFOX FOLFOX + cetuximab FOLFOX + cetuximab FOLFIRI + cetuximab
Response NR 25% 47.5% 34% 60% 33.6% 43% 70% 39% 47% 36% 46% 68% 57%
conversion 12.5% 40% 33% 12% 36% 4%a 10%a 24% 3.7%a 7%a NR NR NR NR
R0 rate 11.6% 33.3% 33% 12% 36% 3.4%a 8%a 19% 1.7%a 4.8%a 2.4%a 4.7%a 38% 30%
Disease-free survival 22% 5-year DFS 19 mo median DFS Median DFS > 5 years NR NR NR NR 29% 5-year DFS NR NR NR NR NR NR
110 4 42 40 122 122 283 196 599 599 168 169 56 55
Alberts (2005)42 Barone (2007)

43
Falcone (2007)44 Souglakos (2006)45 Masi (2009)46 Van Cutsem (2009)54 Bokemeyer (2009)55 Folprecht (2010)56
DFS = disease-free survival; FOLFIRI = folinic acid, fluorouracil (5-FU), irinotecan; FOLFOXIRI = folinic acid, 5-FU, oxaliplatin, irinotecan; NR = not reported.
a
Denominator is entire cohort of patients with metastatic colorectal cancer and not limited to only liver-limited disease.
mortality. When the entire group of randomized patients was considered, a 7.3% increase in progression-free survival (PFS) at 3 years was observed in patients receiving chemotherapy, although this difference did not reach statistical significance. However, in the group of patients who underwent surgical resection, a significant 9.2% improvement in 3-year PFS was, in fact, observed. Adam et al examined the influence of the response to neoadjuvant chemotherapy on the eventual outcome in patients following surgical resection of multiple liver metastases.34 In this retrospective analysis of 131 patients, 44% underwent hepatectomy after achieving an objective tumour response, 30% went to surgical resection after tumour stabilization, and 26% were surgically resected after tumour progression. Five-year
survival was significantly lower in the group of patients who had evidence of tumour progression, compared with patients who had evidence of tumour response (8% vs 37%). Of note, patients with stable disease on neoadjuvant chemotherapy had only a slightly worse prognosis with respect to 5-year survival, compared with responders (30% vs 37%). DFS in patients who progressed on neoadjuvant chemotherapy was only 3%, compared with rates of 21% and 20% for patients with tumour response or stable disease, respectively. Based on this study, it is clear that tumour progression before surgery is associated with extremely poor clinical outcome, and in this setting, hepatic resection should be avoided in patients who are deemed to be non-responders to preoperative chemotherapy. Neoadjuvant chemotherapy may
be associated with complete disappearance of some or all of the hepatic metastases on imaging studies (approximately 18% of tumours will disappear completely).35 Pathological complete response is associated with a high rate of long-term cure after surgical resection (5-year survival of 79%).36 Controversy exists regarding the need to resect patients with complete radiographic responses, to achieve long-term cure. Up to 70% of these sites of complete radiographic response are associated with pathologic complete response or failure to recur at these sites.36,37 The remaining 30% of patients are at risk of disease recurrence if resection is not performed. Thus, curative therapy should include resection of these regions, although the potential risk of disease recurrence at other sites must also be taken into consideration.
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Metastatic colorectal cancer is potentially curable when it is limited to a specific organ site.
Conversion Therapy
The majority of patients will present with liver metastases from CRC that are unresectable or not optimally resectable based on their size, number, or location at the time of initial assessment. In this setting, conversion therapy is used in appropriately selected patients. The primary focus, therefore, is on achieving downsizing of the metastatic disease that is sufficient to allow surgical resection to be performed, but not with the goal of achieving a complete or even maximal response. Adam and colleagues in France have had the largest experience in this area to date, and their work has provided important insights into the potential role of conversion therapy.3840 In their original series of 701 patients with initially unresectable liver metastases, treatment with oxaliplatin-based chemotherapy resulted in downsizing in nearly 15% of patients, and subsequent surgery. Based on 5-year follow-up after surgery, 22% of
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patients had no evidence of residual or recurrent disease. When stratified according to the underlying reasons for initial unresectability, the 5-year OS rates were 60% for patients with large tumours, 49% for those with poorly located tumours, and 34% for patients with multinodular tumours. In an expanded series of 1,439 patients treated with a broader range of cytotoxic chemotherapy, the conversion rate was 12.5%, with a 5-year survival rate of 33%. Fo l p r e c h t a n d c o l l e a g u e s 41 conducted an interesting analysis of all published/presented clinical trials and retrospective studies of the rate of objective response and the subsequent rate of resection of initially unresectable metastases. They observed a strong correlation (r = 0.96) between response rates and the subsequent resection rate in patients with isolated liver disease. Moreover, their analysis confirmed that patient selection and efficacy of preoperative chemotherapy were strong predictors of potential
resectability of liver metastases. Since this analysis, several prospective clinical trials incorporating systemic chemotherapy plus surgery have been performed. In these studies, use of oxaliplatin- vs irinotecan-based chemotherapy has shown similar clinical outcomes.42,43 Of note, approximately 20% to 30% of patients were able to undergo R0 surgical resection. Two trials have directly compared the clinical efficacy of FOLFOX plus irinotecan (FOLFOXIRI), an aggressive regimen that incorporates the three active cytotoxic agents, against that of FOLFIRI (5-FU, LV, irinotecan). Falcone et al randomized patients with mCRC to receive either FOLFOXIRI or FOLFIRI, and they reported a significant increase in R0 resection for the subgroup of patients with liver-only metastases who were randomized to the FOLFOXIRI arm.44 The R0 resection rate was 36% in the FOLFOXIRI arm vs 12% in the FOLFIRI arm (P = 0.017). Despite the increased clinical activity of FOLFOXIRI, patients receiving this regimen experienced a significantly higher incidence of grade 3/4 toxicity in the form of myelosuppression and neurotoxicity. In contrast to the positive findings of the Falcone study, Souglakos et al observed a non-significant increase in overall response rate (43% vs 33.6%), conversion rate (10% vs 3.4%), and R0 resection rate (8.8% vs 3.4%).45 A pooled analysis of the Falcone phase III study and two phase II studies reported an overall response rate of 70% with the FOLFOXIRI regimen and a 19% R0 resection rate. The 5-year DFS and OS were 29% and 42%, respectively.46 Is there an optimal cytotoxic chemotherapy regimen for conversion therapy? To date, there has been a significant absence of randomized trials directly comparing the various cheMedical Progress June 2012
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motherapy regimens in patients with liver-limited disease. In reviewing the literature, it appears that irinotecanand oxaliplatin-based regimens yield approximately the same rate of conversion, on the order of 20% to 30%. While FOLFOXIRI appears to result in higher conversion rates in the 40% to 60% range and higher R0 surgical resections, this treatment regimen is clearly associated with increased toxicity and should be used only in certain select patient populations. Upon review of the recent National Comprehensive Cancer Institute (NCCN) guidelines, several regimens are currently recommended, and they include FOLFIRI, FOLFOX, the combination of capecitabine and oxaliplatin, and FOLFOXIRI.47 The introduction of targeted therapies with either the antiangiogenic agent bevacizumab or the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab has improved the clinical efficacy of chemotherapy in patients with mCRC. As a result, combination regimens incorporating these agents have now been evaluated in clinical trials for patients with liverlimited metastases. The addition of the antivascular endothelial growth factor (VEGF) antibody bevacizumab to either FOLFOX or to capecitabine and oxaliplatin vs the cytotoxic chemotherapy regimens alone was investigated in a randomized phase III trial in advanced mCRC. 48 Unfortunately, there was only a slightly higher incidence of R0 surgical resection with bevacizumab (8.4%) vs chemotherapy alone (6.1%). The anti-EGFR antibodies cetuximab and panitumumab have been approved for use in patients with mCRC. 49 Subsequent studies have shown that these agents are active only in patients with wild-type KRAS
tumours. KRAS mutations occur in up to 30% to 40% of patients with CRC, and they typically involve codon 12 or 13. In general, KRAS mutations lead to resistance to antibody therapy. However, recent studies have suggested that the G13D mutation in codon 13 may still allow for sensitivity to anti-EGFR antibody therapy, in sharp contrast to mutations in codon 12. Retrospective analyses of clinical trials in mCRC have provided insights into the potential role of cetuximab in the treatment of liver-limited disease. In a phase II trial of FOLFOX plus cetuximab, 37 of the 43 patients enrolled had liver involvement, and in 17 of these patients, the liver was the only site of metastatic disease. 50 An objective response was seen in 34 of the 37 patients; 10 of these patients underwent surgical resection of their metastases, including eight patients with liver metastases. In a series of 151 patients with unresectable mCRC liver metastases refractory to systemic chemotherapy, the addition of cetuximab to combination chemotherapy allowed 27 patients to undergo surgical resection, and of this group, 25 underwent potentially curative hepatectomy. 51 Of note, this group included a majority of patients who were deemed to have either technically unresectable or marginally resectable disease. Moreover, the incorporation of cetuximab with chemotherapy conferred significant clinical benefit, with median PFS and OS of 13 and 20 months, respectively. Several single-arm phase II trials have investigated the combination of cetuximab with either irinotecan- or oxaliplatin-based regimens. Min et al reported a radiologic response rate of 39%, with 30% of patients treated with FOLFIRI plus cetuximab able to undergo resection of their liver metastases.52 Nearly identical results
were observed with the combination of FOLFOX and cetuximab, which yielded an R0 resection rate of 29%.53 Two recent randomized studies have investigated the safety and efficacy of cetuximab in combination with either FOLFIRI 54 or FOLFOX.55 The addition of cetuximab to FOLFIRI significantly increased the overall response rate (59% vs 43%; P = 0.004) in patients with wild-type KRAS when compared with FOLFIRI alone, and this resulted in a higher number of patients able to undergo R0 surgical resection (4.3% vs 1.5%). An exploratory analysis revealed a twofold higher rate of R0 surgical resection in patients with liver-limited disease (9.8% vs 4.5%). 54 Similar findings were reported by Bokemeyer et al 55 with the combination of cetuximab plus FOLFOX4. The overall response rate increased from 37% to 61% in patients with wild-type KRAS and in those treated with the combination vs FOLFOX4 alone. This improvement in response rate in patients treated with the combination was associated with an increase in the R0 resection rate from 2.4% to 4.7%. A trial of 114 patients with initially non-resectable liver-limited metastases randomized patients to receive cetuximab in combination with either FOLFOX6 or FOLFIRI. R0 resection rates of 38% and 30% were observed, respectively, with an overall R0 resection rate of 34%.56 In a retrospective analysis of response according to KRAS status with the two arms of the trial combined, the clinical response rate in patients with wild-type KRAS was 70% compared with 41% for those with mutant KRAS. This study provides further evidence of the strong association between high tumour response rate and increased rate of liver metastasectomy. PRIME (the Panitumumab
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Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) was designed to evaluate the efficacy and safety of panitumumab plus FOLFOX4 vs FOLFOX4 alone as initial treatment for mCRC. The addition of panitumumab to FOLFOX4 chemotherapy significantly improved the overall response rate (57% vs 48%; P = 0.02) and median PFS in patients with wild-type KRAS tumours (9.6 vs 8.0 months; P = 0.01), which translated into a non-significant increase in median OS from 19.7 to 23.9 months. In terms of surgical resection, metastasectomy of any site was attempted in 10.5% of patients treated with the combination regimen as opposed to 9.4% of patients treated with chemotherapy alone. However, the R0 resection rate was higher in patients with wild-type KRAS tumours and liver-limited disease (28% vs 18%) who were treated with panitumumab plus FOLFOX4. At the time of the most recent analysis, median OS had not been reached in patients who underwent R0 liver resection, in contrast to a median OS of 23.6 months in those who were unable to undergo complete surgical resection.57
Adjuvant Chemotherapy
To date, only a limited number of clinical trials have investigated the role of adjuvant chemotherapy following surgical resection of organ-limited metastases. Two randomized phase III trials were conducted to determine the potential role of adjuvant chemotherapy with 5-FU/ LV vs surgery alone.58,59 Both trials showed a nonsignificant trend for improvement in DFS. Unfortunately, both studies closed prematurely due to slow patient enrolment. As a result, neither study
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had sufficient statistical power to demonstrate the predefined difference in OS. A pooled analysis of the individual data from these two trials was subsequently conducted by Mitry et al to improve the statistical power of the survival analysis. This analysis showed a marginally significant trend toward improved PFS for patients receiving chemotherapy (27.9 vs 18.8 months).60 This study is important as it provides proof of concept for the potential role of adjuvant chemotherapy in patients who have undergone curative resection of liver or lung metastatic disease. Unfortunately, a randomized phase III trial was unable to document the benefit of the FOLFIRI regimen as adjuvant therapy following surgical resection of liver metastases when compared with infusional 5-FU/LV.61 What should the recommendations be for adjuvant chemotherapy following surgical resection? Although definitive clinical data are lacking, the current approach would be to offer adjuvant therapy with an oxaliplatinbased regimen, whether it be FOLFOX or XELOX, for a defined 3- to 4-month period. As is the case for the adjuvant treatment of early-stage colon cancer, there is presently no role for a biologic agent, such as bevacizumab or the anti-EGFR antibodies cetuximab and panitumumab, in oxaliplatin-based chemotherapy. Further support for this approach comes from the recently published NCCN clinical practice guidelines for adjuvant therapy of resected metastatic disease, which recommend a shortened course of cytotoxic chemotherapy, as would be offered for patients with resected stage III colon cancer.47
There is now a large body of evidence showing that systemic chemotherapy can result in non-alcoholic fatty liver disease and sinusoidal injury
Limitations of Chemotherapy
The role of chemotherapy is to enhance the outcomes of surgery and/or permit
potentially curative resection to be performed. Unfortunately, chemotherapy has potential disadvantages, which relate to direct toxic effects on the liver, leading to an increased risk of potential postoperative complications. There is now a large body of evidence showing that systemic chemotherapy can result in non-alcoholic fatty liver disease and sinusoidal injury. The chemotherapy-associated liver disease ranges from steatosis to steatohepatitis (CASH).62 Steatosis resulting from chemotherapy and/or any other etiology has been shown to lead to a higher rate of complications following hepatic resection. However, the development of CASH appears to hold greater significance.63 Of note, CASH appears to be more closely associated with the use of irinotecan-based chemotherapy and to occur more commonly in patients with higher body mass index.64 The development of CASH has been associated with a higher postoperative mortality rate related primarily to postoperative liver failure. In one series, the 90-day
In focus
mortality rate in patients with steatohepatitis was 14.7% vs 1.6% for those who did not have steatohepatitis.65 In contrast to treatment with irinotecan, oxaliplatin-based chemotherapy has been typically associated with liver sinusoidal injury.62,65,66 In more severe cases, perisinusoidal fibrosis, sinusoidal obstruction, and portal hypertension have been observed. In contrast to CASH, the development of sinusoidal dilation has not been associated with an increased risk of perioperative morbidity and mortality.67,68
Peritoneal Carcinomatosis
While this review has focused on liverlimited metastatic disease, cures have also been reported after pulmonary metastasectomy, isolated nodal recurrences, and ovarian metastases.6971 While these are highly selected cases, they are worthy of consideration for patients with favourable tumour biology and/or for those who are responsive to chemotherapy. A growing field of interest has been the surgical management of peritoneal metastases from CRC, using cytoreductive surgery and intraoperative chemoperfusion with mitomycin C or oxaliplatin, combined with hyperthermia (HIPEC).72,73 This interest stems from early randomized trials with this treatment strategy in gastric cancer and a randomized trial in mCRC from the Netherlands.74,75 This mCRC carcinomatosis trial demonstrated an improvement in median survival in patients receiving intraoperative HIPEC, compared with systemic 5-FU/LV (22.3 months vs 12.6 months). Patients whose tumours could be completely resected from the peritoneum followed by HIPEC had an actuarial 3-year survival of 95%. A follow-up report on this trial demonstrated an overall actual 5-year survival of 45% in the HIPEC arm for patients with
all disease resected.76 A recent report from France noted a 5-year survival of 26% in patients receiving HIPEC with oxaliplatin for colorectal peritoneal carcinomatosis.77 A number of series have compared surgical cytoreduction and HIPEC for peritoneal carcinomatosis vs surgical resection of hepatic metastases from mCRC, demonstrating similar survival curves.7880 This finding suggests that an aggressive combined-modality approach for peritoneal carcinomatosis may have a defined cure rate. Presently, most centres combine surgical cytoreduction and HIPEC with neoadjuvant and postoperative adjuvant systemic chemotherapy, such as has been described for liver-limited metastatic disease.
Conclusions
When limited to a specific organ site, mCRC is potentially curable. To date, nearly all of the clinical studies have focused on liver-limited disease, but similar results are now being reported for patients with disease limited to the lungs, ovaries, and peritoneum. It is clear that a multidisciplinary team-based approach is required for the optimal care of this particular subset of patients. The development of an individual treatment plan comes from a careful discussion and ongoing communication among a multidisciplinary team of specialists, including surgeons, medical oncologists, and radiologists. With the appropriate integration of chemotherapy plus biological agents and surgery, up to 30% to 40% of patients with organlimited metastatic disease can be cured. While the costs of the three biological agentscetuximab, panitumumab, and bevacizumabare not insignificant, the clinical evidence is now well-established that their incorporation with cytotoxic chemo-
therapy regimens in the neoadjuvant and conversion settings has greatly facilitated curative resection of liverlimited metastatic disease. However, further improvements are needed to enhance the clinical outcome of the remaining 60% to 70% of patients. Further refinements in whole-body and hepatic imaging should provide for a more accurate selection of the subset of patients who would benefit most from resection and would identify the presence of minimal residual disease following surgery. Finally, clinical trials are needed to develop novel cytotoxic agents and biologic/targeted agents that can be used in both the preoperative and postoperative settings to reduce the risk of local and systemic recurrence.
Declaration of Interest
None.
References
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tions for colorectal metastases in the Netherlands. A multiinstitutional 10-year study. Cancer 1992;70:2834. 10. Fortner JG, Silva JS, Golbey RB, et al. Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. I. Treatment by hepatic resection. Ann Surg 1984;199:306316. 11. Hugh TJ, Kinsella AR, Poston GJ. Management strategies for colorectal liver metastasesPart I. Surg Oncol 1997;6:1930. 12. Ekberg H, Tranberg KG, Andersson R et al. Determinants of survival in liver resection for colorectal secondaries. Br J Surg 1986;73:727731. 13. Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:12611268. 14. Pwint TP, Midgley R, Kerr DJ. Regional hepatic chemotherapies in the treatment of colorectal cancer metastases to the liver. Semin Oncol 2010;37:149159. 15. Alexander HR, Jr, Bartlett DL, Libutti SK, et al. Analysis of factors associated with outcome in patients undergoing isolated hepatic perfusion for unresectable liver metastases from colorectal center. Ann Surg Oncol 2009;16:18521859. 16. Idrees K, Bartlett DL. Robotic liver surgery. Surg Clin North Am 2010;90:761774. 17. Nguyen KT, Gamblin TC, Geller DA. World review of laparoscopic liver resection 2,804 patients. Ann Surg 2009;250:831841. 18. Sarpel U, Bonavia AS, Grucela A, et al. Does anatomic versus nonanatomic resection affect recurrence and survival in patients undergoing surgery for colorectal liver metastasis? Ann Surg Oncol 2009;16:379384. 19. Berber E, Siperstein A. Local recurrence after laparoscopic radiofrequency ablation of liver tumors: an analysis of 1032 tumors. Ann Surg Oncol 2008;15:27572764. 20. Wu YZ, Li B, Wang T, et al. Radiofrequency ablation vs hepatic resection for solitary colorectal liver metastasis: a meta-analysis. World J Gastroenterol 2011;17:4143 4148. 21. Gomez D, Cameron IC. Prognostic scores for colorectal liver metastasis: clinically important or an academic exercise? HPB (Oxford) 2010;12:227238. 22. Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006;94:982999. 23. Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008;247:125135.
24. Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:12611268. 25. Shoup M, Gonen M, DAngelica M, et al. Volumetric analysis predicts hepatic dysfunction in patients undergoing major liver resection. J Gastrointest Surg 2003;7:325330. 26. Chua TC, Saxena A, Chu F, et al. Predictors of cure after hepatic resection of colorectal liver metastases: an analysis of actual 5- and 10-year survivors. J Surg Oncol 2011;103:796800. 27. Hemming AW, Reed AI, Howard RJ, et al. Preoperative portal vein embolization for extended hepatectomy. Ann Surg 2003;237:686691. 28. Adam R, Laurent A, Azoulay D, et al. Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors. Ann Surg 2000;232:777785. 29. Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009;27:18291835. 30. Ferrarotto R, Pathak P, Maru D, et al. Durable complete responses in metastatic colorectal cancer treated with chemotherapy alone. Clin Colorectal Cancer 2011;10:178 182. 31. Wein A, Riedel C, Bruckl W, et al. Neoadjuvant treatment with weekly high-dose 5-fluorouracil as 24-hour infusion, folinic acid, and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer. Oncology 2003;64:131138. 32. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008;26:18301835. 33. Nordlinger B, Sorbye H, Glimelius B, et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:10071016. 34. Adam R, Pascal G, Castaing D, et al. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg 2004;240:10521061. 35. Tanaka K, Takakura H, Takeda K, et al. Importance of complete pathologic response to prehepatectomy chemotherapy in treating colorectal cancer metastases. Ann Surg 2009;250:935942. 36. Adam R, Wicherts DA, de Haas RJ, et al. Complete pathologic response after preoperative chemotherapy for colorectal liver metastases: myth or reality? J Clin Oncol 2008;26:16351641.
37. Auer RC, White RR, Kemeny NE et al. Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy. Cancer 2010;116:15021509. 38. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996;224:509520. 39. Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8:347 353. 40. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;240:644657. 41. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response rate and resections rates. Ann Oncol 2005;16:13111319. 42. Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol 2005;23:92439249. 43. Barone C, Nuzzo G, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Br J Cancer 2007;97:10351039. A complete list of references can be obtained upon request from the editor. 2012 UBM Medica LLC. Initially published in Oncology 2012;26(3):266275. Reprinted with permission.
About the Authors David L Bartlett is chief of the Division of Surgical Oncology, Department of Surgery, and staff investigator of the Molecular Therapeutics and Drug Discovery Research Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh. Edward Chu is chief of the Division of Hematology-Oncology, Department of Medicine and Pharmacology & Chemical Biology, and leader of the Molecular Therapeutics and Drug Discovery Research Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Answers to questions on page 269: 1. F, 2. T, 3. T, 4. T, 5. F
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Peer Reviewed
RoflumilastLast But Not Least?

Tan Tze Lee, MBChB(Edin), MRCP(UK), FRCP(Edin); Ong Kian Chung, MBBS, MRCP(UK), FRCP(Edin), FCCP(USA)
Roflumilast, a novel phosphodiesterase-4 inhibitor, has demonstrated efficacy in improving lung function in severe chronic obstructive pulmonary disease (COPD). Its anti-inflammatory properties appear to address COPDs underlying chronic inflammatory process, and it has been shown to improve the forced expiratory volume in the first second of expiration and quality of life, and reduce exacerbations, especially in the chronic bronchitis subgroup.
Introduction
hronic obstructive pulmonary disease (COPD) is an increasing problem in the world today, with an estimated 64 million having moderate to severe disease in 2004.1 By 2020, it is estimated to be ranked fifth worldwide in terms of burden of disease based on a World Bank/World Health Organization study, and is expected to become the third ranked cause of death by then.2 The predominant cause is cigarette smoking, although exposure to biomass and occupational pollution also play a role, in some cases significantly.3 This chronic inflammatory disease of the lungs and airways is a major cause of morbidity and mortality.4 It is well recognized to be a progressive chronic inflammatory disease, and early detection, smoking cessation and therapeutic intervention are key to optimizing COPD management.5
Chronic obstructive pulmonary disease is an increasing health problem, the predominant cause of which is cigarette smoking.
Until recently, there has been no available treatment that alter the progression of COPD, and current therapies have, to date, focused on symptom relief and improvement of quality of life (QOL). 6 Inhaled short-acting 2-agonists, long-acting
2 -agonists (LABA), short-acting muscarinic antagonists (SAMA), longacting muscarinic antagonists, and LABAinhaled corticosteroids (ICS) combinations have all been used to manage COPD. Theophylline has been used for
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over 100 years in clinical practice. Concerns about its narrow therapeutic window and drug interactions can limit its use in COPD.7 A weak bronchodilator, it nevertheless remains popular because it is inexpensive and widely available.
Figure. Chemical structure of roflumilast.
Cl
3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4(difluoromethoxy)benzamide; C17H14Cl2F2N2O3; Mr = 403.2
Pharmacology
PDE4 is a primary regulator in most inflammatory and immune cells. By inhibiting PDE4, various pro-inflammatory processes are suppressed, and this have shown, in some studies, to benefit animal models of pulmonary inflammation.811 PDE4 inhibitors have demonstrated many anti-inflammatory properties, including inhibition of inflammatory mediators and immune cell activation.12 Roflumilast, together with its active metabolite roflumilast N-oxide, is a potent PDE4 inhibitor (Figure).8 In both animal models and patients with COPD, roflumilast has been shown to suppress inflammatory mediator release, reduce airway inflammation, and reduce the neutrophil and eosinophil counts. These outcomes are very promising but did not always correlate with good clinical outcomes for all COPD patients. It would appear that the chronic bronchitis phenotypic group of COPD patients would tend to benefit the most.13
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Roflumilast is active orally and has been approved for the treatment of moderate to severe COPD. It is given orally, is highly bioavailable (f = 0.79), bounds extensively to plasma proteins (98.9%), achieves a steady state in 4 days (daily dosing regime), has an elimination half-life of 7 to 25 hours, and is subject to negligible first-past hepatic metabolism. The pharmacokinetic profile is linear and predictable over the dose ranges of 250 to 1,000 g. The major metabolite is roflumilast N-oxide by the N-oxidation pathway. This is primarily by the cytochrome P450 isozymes CYP3A4 and CYP1A2. The half-life of roflumilast N-oxide is considerably longer than that of its parent, at approximately 27 hours. This suggests that the pharmacological ability of roflumilast to produce a long-lasting, competitive, 24-hour inhibition of PDE4 is in fact through its metabolite. 1418 Roflumilast N-oxide is finally deactivated and excreted via the renal pathway. There are no specific contraindications except for specific allergy
to roflumilast or its excipients. Care should be taken in patients with moderate to severe hepatic impairment (Child-Pugh B or C) in view of the cytochrome P450 pathways. Data suggest that roflumilast has little adverse interaction with erythromycin, ketoconazole, montelukast, digoxin, warfarin, sildenafil, midazolam, and inhaled salbutamol, formoterol and budenoside. Oral magnesium hydroxide was also found not to affect the pharmacokinetics of roflumilast.1926 Inducers of the cytochrome P450, such as rifampicin, have been shown to significantly affect the efficacy of roflumilast.17 Strong inducers, such as carbamazepine, phenytoin and phenobarbital, could potentially limit the efficacy of roflumilast.
The Evidence
The early studies used forced expiratory volume in the first second of expiration (FEV1) and QOL as end points. Rabe et al and Calverley et al found roflumilast to be effective in moderate to severe
Cyclic adenosine monophosphate (cAMP) plays an important part in regulating inflammatory cell activity and is degraded by the phosphodiesterase enzymes. The phosphodiesterase 4 (PDE4) enzyme is the main cAMPmetabolizing enzyme in inflammatory cells, and its inhibition leads to accumulation of cAMP levels in the cell, which reduces the cells inflammatory activity.
Background
N H
Cl
COPD (M2-107 trial) and severe COPD (M2-112 trial), respectively.27,28 In the former study conducted over a treatment period of 24 weeks, significant improvements in postbronchodilator FEV 1 were found in subjects taking roflumilast 250 or 500 g as compared with placebo (difference, 74 mL for 250 g, and 97 mL for 500 g; P < 0.0001). QOL using the St Georges Respiratory Questionnaire total score was also found to be improved as compared with placebo (-1.6 for 250 g, and -1.7 for 500 g). The latter trial focused on subjects with severe COPD and studied the effect of roflumilast 500 g daily in these patients for a year. Concomitant ICS were permitted (60% of subjects). The results found improvements in post-bronchodilator FEV1 (39 mL; P = 0.001) and a non-significant reduction of moderate to severe exacerbations. Subsequent post hoc analysis of M2-112 and its replicate M2-111 demonstrated a significantly reduced exacerbation rate (14.3%; P = 0.026), with the following subgroup of patients benefitting the most: patients with chronic bronchitis (26.2%, P = 0.001), or with high cough (20.9%, P = 0.006) or sputum scores (17.8%, P = 0.03) prior to randomization, or patients receiving concomitant ICS or SAMAs (18.8%, P = 0.014). The finding that roflumilast preferentially reduced exacerbations in COPD patients who had characteristics of chronic bronchitis, with or without ICS, led the investigators to craft the design of the subsequent phase III studies to examine the effect of roflumilast on acute exacerbations of COPD.13 Two 12-month studies, M2-124 and M2-125, were pivotal in establishing the therapeutic benefits of roflumilast in severe COPD cases. They were of identical design and compared roflumilast 500 g daily with placebo, and were different
only in their study population ethnic composition. The subjects were not allowed ICS, and only half used longacting bronchodilators. There was improvement in pre-bronchodilator FEV1 of 48 mL (P < 0.0001) as well as post-bronchodilator FEV 1 of 55 mL (P < 0.0001). There was also a relative risk reduction of 17% in rate of exacerbations (P = 0.0003), which was greatest in moderate exacerbations. The pooled analyses of M2-124 and M2-125 by Calverley et al revealed that the mean rate of moderate and severe exacerbations were significantly lower in patients receiving roflumilast as compared with placebo, be it with concomitant inhaled LABA (20.7%, P = 0.011), SAMA (13.1%, P = 0.0458), or previous ICS (19.3%, P = 0.0038).29 Two further 6-month studies provided the evidence for roflumilast use as an add-on to long-acting bronchodilator therapy. M2-127 studied the concomitant use with salmeterol and M2-128 with tiotropium. The tiotropium subjects recruited were more symptomatic, and in both studies the subjects were randomized to roflumilast 500 g or placebo added on to inhaled salmeterol or tiotropium. The salmeterol group showed improved pre- and postbronchodilator FEV 1 of 49 mL and 60 mL (both P < 0.0001), respectively, whereas the tiotropium group similarly showed improvement for both pre- and post-bronchodilator FEV1 of 80 mL and 81 mL (both P < 0.0001), respectively.30
"The mainstay of the benefits from roflumilast use in COPD is through its unique anti-inflammatory effect"
the treatment and placebo groups in pooled safety studies, and there were 6% of roflumilast subjects exhibiting psychiatric disorders compared with 3% in those receiving placebo. There remain concerns about the incidence of completed suicides in the COPD safety pool, although none have been identified as being related to roflumilast.
Conclusion
COPD is a multiorgan and multisystem disease. It not only involves the airways and lung parenchyma but also has effects far removed from its origins in the respiratory system. The inflammatory process that accompanies COPD often progresses even when smoking has ceased, and therapies in the past were unable to address this. Historically, the drugs used to manage COPD have primarily been bronchodilators and, in cases of recurrent exacerbations, ICS. Prior to the arrival of roflumilast, these therapies did not adequately address the issue of inflammatory processes in
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Safety
The most common adverse effects encountered with roflumilast are gastrointestinal, with diarrhoea (9%) being the most common, followed by nausea (5%) and decreased appetite (3%). Weight loss (12%) was also commonly reported. The rates of cardiovascular events were similar in both
DRuG Profile
COPD. The mainstay of the benefits from roflumilast use in COPD is through its unique anti-inflammatory effect. Even though it does not have a direct bronchodilator effect, studies have shown that FEV 1 improves following regular administration of roflumilast. Many questions remain unanswered. Long-term survival studies are needed to address whether or not the benefits of roflumilast are only confined to the severe-stage chronic bronchitis phenotype cohort, or whether it extends to other phenotypes and severity stage and under what conditions. Would roflumilast be the panacea for COPD, by suppressing inflammation and reducing mortality as well as the rate of decline of FEV1, ie, lung function? Only time will tell.
Exp Ther 2001;297:280290. 10. Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 2005;172:848853. 11. Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62:10811087. 12. Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005;365:167275. 13. Rennard SI, Caverley PM, Goehring UM, Bredenbrker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast the importance of defining different subsets of patients with COPD. Respir Res 2011;12:18. 14. Bethke TD, Bhmer GM, Hermann R, et al. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J Clin Pharmacol 2007;47:2636. 15. Hauns B, Hermann R, Hnnemeyer A, et al. Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phospho-diesterase 4 inhibitor, in healthy subjects. J Clin Pharmacol 2006;46:11461153. 16. Neville KA, Szefler SJ, Abdel-Rahman SM, et al. Singledose pharmacokinetics of roflumilast in children and adolescents. J Clin Pharmacol 2008;48:978985. 17. Nassr N, Hennemeyer A, Herzog R, et al. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin Pharmacol 2009;68:580587. 18. David M, Zech K, Seiberling M, Weimar C, Bethke TD. Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability. J Allergy Clin Immunol 2004;113:S220S221 19. Lahu G, Hennemeyer A, von Richter O, et al. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J Clin Pharmacol 2008;48:13391349. 20. Nassr N, Lahu G, Hnnemeyer A, et al. Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast. J Clin Pharmacol 2007;47:660666. 21. Nassr N, Lahu G, von Richter O, et al. Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects. Br J Clin Pharmacol 2007;63:365370. 22. Bethke TD, Giessmann T, Westphal K, et al. Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects. Int J Clin Pharmacol Ther 2006;44:572579. About the Authors Dr Tan is General Practitioner and Principal Partner of a private practice; Honorary Treasurer of the College of Family Physicians Singapore; Visiting Consultant to the Department of Medicine at the National University Hospital; Vice-President of the Chronic Obstructive Pulmonary Disease Association (Singapore); and Clinical Preceptor and Adjunct Assistant Professor at the Duke-NUS Graduate Medical School, Singapore. Dr Ong is Specialist in respiratory medicine in private practice at the Mount Elizabeth Medical Centre; President of the Chronic Obstructive Pulmonary Disease Association (Singapore); and National Leader in Singapore of the Global Initiative for Chronic Obstructive Lung Disease. 23. Bhmer GM, Nassr N, Wenger M, et al. The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions. J Clin Pharmacol 2009;49:389397. 24. Hermann R, Siegmund W, Giessmann T, et al. The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide. J Clin Pharmacol 2007;47:10051013. 25. Lahu G, Hennemeyer A, Herzog R, et al. Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int J Clin Pharmacol Ther 2009;47:236245. 26. von Richter O, Lahu G, Hennemeyer A, Herzog R, Zech K, Hermann R. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin Pharmacokinet 2007;46:613622. 27. Rabe KF, Bateman ED, ODonnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilastan oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005;366:563571. 28. Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154161. 29. Calverley PMA, Rabe KF, Goehring U-M, et al; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685694. 30. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al; M2-127 and M2-128 study groups. Roflumilast in moderateto-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. Lancet 2009;374:695703.
References
1. World Health Organization. The Global Burden of Disease: 2004 Update. Geneva: World Health Organization; 2008. 2. Murray CJL, Lopez AD. The Global Burden of Disease. Cambridge, MA: Harvard University Press; 1996. 3. Salvi S, Barnes PJ. Is exposure to biomass smoke the biggest risk factor for COPD globally? Chest 2010;138;36. 4. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. http:// www.goldcopd.org/Guidelines/guidelines-resources.html. Accessed 30 March 2012. 5. Price D, Freeman D, Cleland J, Kaplan A, Cerasoli F. Earlier diagnosis of COPD in primary care and earlier treatment. Prim Care Resp J 2011;20:1522. 6. National Clinical Guideline Centre. (2010) Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary care and secondary care. London: National Clinical Guideline Centre. Available from: http://guidance.nice.org.uk/CG101 /Guidance/pdf/English. 7. Ramsdell J. Use of theophylline in the treatment of COPD. Chest 1995;107(5 Suppl):206S209S. 8. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001;297:267279. 9. Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol
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Take the challenge, test your knowledge
Peer-Reviewed
Functional Bowel Disorders and FODMAPs

Emma Halmos, BND, PGradDipBSc, APD; Jane Muir, BSc(Hons), PhD, PGradDip(Dietetics), APD; Sue Shepherd, PhD, BAppSci(Health Promotion), MND, AAPD; Peter Gibson, MD, FRACP
A diet that is low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) has been shown to be effective in reducing gastrointestinal symptoms in patients with functional gut disorders.
categories of irritable bowel syndrome, functional bloating, functional constipation and functional diarrhoea.
Why Should We Be Interested in FBD?

Reasons for being concerned about FBD include those listed below. FBD is very common, with a prevalence of 5% to 12% in Western countries.7,8 The various disorders are chronic conditions of unknown cause and cannot be cured. Approaches therefore need to focus on strategies to manage symptoms. Patients with FBD commonly seek attention from medical and other health professionals. FBD accounts for up to 10% of consultations for general practitioners and 50% of referrals to gastroenterologists.9 FBD can lead to substantial reduction in quality of life. The impact on quality of life is comparable with that of depression and of chronic renal failure and is associated with increased use of health-care resources.7,8,10 Treatment has had limited success. The therapeutic approach is palliative and, until recently, therapeutic interventions have been frustratingly unreliable and targeted at treating only one symptom. For example, a patient who has IBS with constipation as the predominant bowel function can be treated with laxatives, but this often has little effect on the bloating and abdominal discomfort that are
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Functional gastrointestinal symptoms are common and their management is often a difficult clinical problem. There is a link between food intake and symptom induction and it has been shown that restricting the intake of rapidly fermentable, short-chain carbohydrates (FODMAPs fermentable oligosaccharides, disaccharides, monosaccharides and polyols) reduces these symptoms. 1,2 FODMAPs are widespread in the diet and their ingestion results in delivery of readily fermentable substrate and more water to the distal small intestine and proximal colon, where this osmotic load and the gas produced are likely to induce luminal distension and functional gut symptoms.3,4 Dietary management strategies for functional bowel disorders have changed markedly since the recent introduction of the low FODMAP diet.
Functional Bowel Disorder

The term functional gastrointestinal disorder (FGID) refers to gastrointestinal symptoms in the absence
of a clear pathologically evident cause. Because FGID can originate from anywhere in the gastrointestinal tract, a symptom-based classification comprising eight categories, the Rome III classification, was developed by a consensus body.5 Categories include chronic symptoms derived from the proximal gut (functional heartburn and functional dyspepsia) and from the small and large intestine (irritable bowel syndrome, functional bloating, functional constipation and functional diarrhoea). Although this system is useful to ensure homogeneity in classifying patients for trials (particularly those that are multicentred), in clinical practice there is a large degree of overlap between categories, and it is not uncommon for patients to move from one category to another over time.6 The classification therefore has yet to be a good guide for therapeutic decision-making. This review will use the term functional bowel disorder (FBD) to cover symptoms originating from the intestine. The term includes the
commonly found in conjunction. Furthermore, benefit of therapeutic interventions is usually marginal, with some studies reflecting no efficacy over placebo.11
Understanding the Pathogenesis of FBD

Although the aetiologies of the various conditions included in FBD are not known, there is increasing understanding of the pathophysiological basis for the genesis of symptoms. A central underlying problem appears to reside in the enteric nervous system, which is estimated to have as many neurones and synapses as the brain and is arranged with immense complexity that includes complex reflex pathways and memory. The enteric nervous system has been called the gut brain. The two major characteristics of the enteric nervous system that are seen in patients with FBD are discussed below. V i s c e r a l h y p e r s e n s i t i v i t y. Patients with FBD have a low sensory threshold. This is best demonstrated by barostat studies where distension of the gut (of the rectum by a balloon, or the stomach by liquid) leads to the sensation of distension or pain.12 The sensory threshold of patients with FBD is often much lower than would usually be encountered. This might be due to sensitization of the stretch receptors of the gut, which provide a major sensory input, or from altered signalling from colonic mucosa to the enteric nervous system.12,13 The enteric nervous system may also be stimulated by bioactive molecules in the diet; this mechanism has been implicated in, for example, salicylate sensitivity. Immune stimulation in the gut in response to dietary proteins (allergic or hypersensitivity mechanisms) may also stimulate the enteric nervous system via, for example, serotonin or
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histamine release.14,15 Changed motility response to sensory stimulation. This has been best demonstrated by gas distension studies where some patients with FBD do not develop the normal propulsive response (hence expelling the gas) and the gas remains within the lumen.16 The enteric nervous system is connected to the central nervous system, suggesting the brain also plays a substantial role in the genesis of symptoms via the gutbrain axis. There is little doubt that the brain can influence motility patterns and visceral sensitivity, as shown by the commonly observed occurrence of diarrhoea and/ or abdominal pain in times of stress, such as sitting for an examination. There is also a large body of data indicating the brains involvement in the genesis of FBD symptoms. Information sent to the brain via the enteric nervous system will cause regional patterns of stimulation that are different in patients with FBD from those in healthy controls, leading to a different interpretation of the sensory input. Thus, in patients with FBD, a similar sensory input from the enteric nervous system may be interpreted as, for example, abdominal pain rather than mild discomfort. 17 Thus, the brain is an important modifying factor in symptom genesis and in symptom interpretation.
controlling FBD symptoms include the following: minimizing stimulation of the enteric nervous system: potential targets for therapy include stimuli that may be present in food (having effects either directly or secondarily) and possibly also in the gut microbiota treating specific symptoms: pharmacological or other approaches to deal with specific symptoms, such as analgesics for pain, laxatives and prokinetics for constipation, and hypomotility agents for diarrhoea managing the gutbrain axis: pharmacological and psychological therapies, such as anxiolytics, antidepressants, cognitive behaviour therapy and hypnotherapy, to modulate symptom perception and the distress it causes.
Dietary Change as a Therapeutic Tool in FBD

Until recently, dietary management of FBD has included reduction of fat (on the basis that fat influences motility); avoidance of caffeine (presumably related to its bioactive nature); alteration of dietary fibre intake (to improve the quality of colonic contents); and elimination of suspected dietary triggers such as milk and wheat, with a purely trialand-error approach.9,18,19 Many other dietary regimens, including low salicylate, gluten-free and very low carbohydrate diets, have been reported in the medical literature or are discussed on the internet. Although many of these diets may produce some improvement in symptoms, the evidence for efficacy is anecdotal only and there is no rational way of matching an appropriate dietary modification to individual patients. Another problem is that protocols using strict elimination diets followed by fixed rechallenges
Current Therapeutic Strategies for FBD

Ideally, the best way of dealing with FBD is to retune the enteric nervous system or the central nervous system, just as the best approach to food allergy or hypersensitivity is to stop the immune reaction to the inciting protein. The ability to do this is poor. Hence, other more palliative approaches to dealing with the symptoms are needed. Approaches to
are labour-intensive and require seriously devoted patients to carry them out. Such protocols also give no opportunity to assess dosing of dietary triggers in the induction of symptoms. Dietary management strategies for FBD have changed markedly since the recent introduction of the low FODMAP diet. This dietary approach is based on known and validated pathophysiological principles and has a high level of evidence for efficacy.2,4,20 Moreover, this treatment appears effective across many centres and is supported by detailed food composition analysis.21,22
Table 1. FODMAPs and gastrointestinal symptoms in patients with functional bowel disorders
Property of FODMAPs Poorly absorbed in the small intestine Outcome Delivery to the colon or fructans, galactooligosaccharides and polyols, and in some people, fructose and lactose A laxative effect by increasing liquidity in luminal contents, thereby affecting gut motility Production of gas causing luminal distension
Osmotically active Rapidly fermented by colonic bacteria
FODMAPs
The acronym FODMAPs refers to fermentable short-chain carbohydrates that are poorly absorbed and may then have effects on the gastrointestinal tract fermentable oligosaccharides, disaccharides, monosaccharides and polyols. 1 The specific carbohydrates are: o l i g o s a c c h a r i d e s : f r u c t a n s (including fructo-oligosaccharides [FOS] and insulin) and galactooligosaccharides (GOS) disaccharide: lactose monosaccharide: fructose (in excess of glucose, see later under Small intestinal absorption of FODMAPs) polyols: including sorbitol and mannitol. The effects of the various FODMAPs are additive and these carbohydrates should be viewed together as a group rather than individually. The concept of reducing dietary FODMAPs to control gastrointestinal symptoms in patients with FBD relates to their physiological effect. FODMAPs are poorly absorbed in the small intestine and have the same physiological effects in the distal
small bowel and proximal colon, namely luminal distension with solids, liquids and gas. FODMAPs contribute particularly to luminal distension by liquids and gases: liquids because of the large osmotic load they cause due to their small molecular size, and gases because of their rapid fermentation by intestinal bacteria (rapid due to their short chain length).4 They have a smaller contribution to the solids content, through their fibre content and the microbial mass expansion associated with their fermentation. The increased water content of the colon exerts a natural laxative effect, and the fermentation of the unabsorbed FODMAPs by intestinal bacteria leads to the production of short-chain fatty acids as well as gas. 3,4 In small amounts, some FODMAPs (fructans and GOS) may exert beneficial prebiotic effects by promoting differential expansion of bacterial populations, which will suppress potential colonic pathogens.23 Conversely, the increased water load and gas production caused by FODMAPs can lead to laxation and distension of the bowel that results in symptoms of bloating, pain and secondary motility disturbances. 4 Such effects are exaggerated in patients with FBD because of the presence of visceral hypersensitivity and abnormal
motility responses. This explains why FODMAPs exacerbate gastrointestinal symptoms in patients with FBD, with studies confirming this hypothesis.3,4 Furthermore, studies have shown that reducing the intake of dietary FODMAPs in this population group has been successful in reducing gastrointestinal symptoms. 2,20 The features unique to FODMAPs that explain this impact are listed in Table 1.
Small Intestinal Absorption of FODMAPs

The various FODMAPs are digested and adsorbed in the small intestine to differing extents. There are three patterns of digestion and absorption, as described below. Totally malabsorbed: the fructans and GOS. As the human body does not possess enzymes to hydrolyse these oligosaccharides, they cannot be absorbed and their fate is to be fermented by bacteria in the distal small intestine and, particularly, the colon.4,24 Partly malabsorbed in all people: the polyols. Absorption of polyols is considered to be by passive diffusion, which is inefficient (because of the presence of the attached alcohol group). Thus, there will usually be some malabsorption of polyols;
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indeed, on average, about 70% of sorbitol (the most commonly found dietary polyol) will be malabsorbed.25 Partly malabsorbed in only some people: fructose and lactose. In the presence of equimolar glucose, fructose is rapidly absorbed by the proximal small intestine due to glucose-mediated activation of a high capacity transporter. However, fructose in excess of glucose (free fructose) is transported by a slow and low capacity transporter that acts all along the small intestine.24 This transporter varies in its capacity across individuals and can be readily overloaded by too much free fructose or by too rapid a transit along the small intestine.24 Lactose, on the other hand, is a disaccharide (galactose plus glucose) and requires splitting into its component molecules (by lactase in the small intestinal brush border) to be absorbed. The activity of lactase varies across individuals according to ethnicity and other factors. Thus, only some people malabsorb fructose and/or lactose.
is from bacterial fermentation of carbohydrates in the intestine and that a rise in breath hydrogen following the ingestion of a specific carbohydrate implies malabsorption of that carbohydrate. A relatively large dose of lactose (50 g) or fructose (35 g) is generally given to determine whether complete absorption is achieved. Results showing absorption of the load given indicate that restriction of that particular short-chain carbohydrate is not necessary. Interpretation of the test can be improved by also performing a test with lactulose (15 g), which is not absorbed in anyone, as the control. Breath methane can also be measured, but results are not as easily interpreted as breath hydrogen responses and the test should only be used if there is a poor hydrogen response (often reflected in the lactulose control breath test).
After all, fructans and GOS, and to a lesser extent polyols, are malabsorbed by all people. Their restriction forms the core of the diet for symptomatic patients. The presence of malabsorption does not give an indication of the proportion of ingested sugar malabsorbed, so cannot be used to predict therapeutic reductions in food sources. It is difficult to interpret symptoms that are generated during (or after) breath testing because the predictive value of symptoms relates to usual intake of the sugar from dietary sources. Also, dietary FODMAPs are seldom consumed alone and different FODMAPs have additive effects on the bowel.
Instituting the Low FODMAP Diet

The low FODMAP diet is a dietitiantaught diet. As with all conditions requiring dietary restriction, nutritional adequacy and, therefore, degree and length of time of restriction are important in tailoring the low FODMAP diet to the individual patient. A dietitian with a good knowledge in implementing the low FODMAP diet will assess the patient and adapt the diet to accommodate the greatest possible food variety while achieving good symptom control, to improve the patients quality of life. This will often involve replacing foods rich in FODMAPs (high FODMAP foods) with appropriate alternatives that are poor in FODMAPs (low FODMAP foods). Detailed lists of foods are available in the article J Gastroenterol Hepatol 2010; 25: 252258 and in the literature available on the Monash University Eastern Health Clinical Schools website www.med.monash .edu.au/ehcs/research/index.html. 23 The most common high FODMAP
Interpreting Breath Hydrogen Tests

There has been a tendency to misinterpret or overinterpret the results of breath testing. Important points to note include those listed below. Carbohydrate malabsorption is present in all populations, not just those with FBD. It is physiologically normal to have fructose or lactose malabsorption, both of which occur with similar frequency in healthy individuals and patients with FBD.26 Therefore, breath testing does not indicate visceral hypersensitivity and is not a diagnostic test for FBD. Breath testing is therefore indicated only in symptomatic patients who would consider adopting dietary modification to treat their symptoms. Breath testing does not provide information as to whether the low FODMAP diet should be used; rather, it gives information on the design of the diet, tailoring it to the individual.
The Low FODMAP Diet Determining FODMAP Absorptive Capacity

As the aim of the low FODMAP diet is to restrict the intake of short-chain carbohydrates that are poorly absorbed and delivered to the colon, it would be helpful to know whether fructose and/ or lactose is completely absorbed in an individual because this may permit a less restrictive diet. Fructose and lactose absorption may be explored through dietary trials, but experience has shown the inaccuracy of this method. It is preferable to determine an individuals absorptive capacity by performing breath hydrogen tests. Breath hydrogen tests are based on the principles that the only source of hydrogen in the breath
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Table 2. Top eight sources of FODMAPs and their alternatives21,22

High FODMAP food Onions (all varieties) and garlic Wheat- and rye-based breads, pastas and cereals Legumes (eg, lentils, chickpeas, baked beans, kidney beans) Honey Apples and pears Stone fruit Mushrooms, cauliflower Milk, yoghurt, ice cream
GOS = galacto-oligosaccharides.
FODMAP present Fructans Fructans
Low FODMAP alternatives Chives, green section of spring onions, garlicinfused oils, ginger, chili, fresh herbs Rice, gluten-free breads and pastas, oats, cornflakes Tofu, eggs, meat, poultry, fish
Fructans and GOS
Fructose Fructose and sorbitol Sorbitol Mannitol Lactose
Golden syrup, maple syrup, sugar, jam (with no added fructose) Bananas, grapes, citrus fruits, strawberries Bananas, grapes, citrus fruits, strawberries Broccoli, green beans, capsicum, carrot, potato, pumpkin, spinach Lactose-free milks, yoghurts and cheese, rice milk
foods and suitable low FODMAP alternatives are shown in Table 2.25,26 The best procedure in finding this balance of food restriction and symptom control is to over-restrict all potential FODMAPs (while considering breath test results, if completed) until the best symptom control is achieved and maintained. This usually takes 6 to 12 weeks, depending on the patients dietary compliance and symptoms. Once symptom relief is achieved, controlled doses of foods are reintroduced to assess the patients absorptive capacity for the partly absorbed FODMAP (if breath testing has not been performed) as well as the amount of malabsorbed FODMAPs that may still be tolerated. Improvement of FBD symptoms is relatively rapid (some improvement is usually seen within days), but clinical improvement has been noted to occur over a few weeks, particularly in patients with constipationMedical Progress June 2012
predominant IBS who may require more time to rid the effects of luminal distension. On review, the dietitian will aim to widen the patients knowledge of the FODMAP-content of foods, so that the patient may best predict the role of FODMAPs in inducing symptoms. Dietary restriction may then be in the control of the patient, and be flexible enough to suit the patients lifestyle and preferred food choices. If there is no improvement in symptoms from the low FODMAP diet and adherence to the regimen is confirmed, another symptom management strategy must be considered. The flowchart on page 302 summarizes the diagnosis and management of patients with FBD.
involved. As such, the dietitian may use simplified versions or perhaps an adapted reduced FODMAP diet for patients with limited education or understanding or for those with English as a second language. Elderly patients, children or patients at risk of malnutrition may also require a less restrictive approach to ensure adequate intake from a greater variety of food sources. Furthermore, a patient with a diet history that is very high in FODMAPs may require only a reduction in the amount of FODMAPs in the diet, rather than a diet that is low in FODMAPs. Conversely, patients with extreme visceral hypersensitivity may require a very low FODMAP diet with strict ongoing adherence. Costs associated with implementing the strict low FODMAP diet are ideally short-term. Consultation with the dietitian usually only requires two consultations. Extra food costs mainly relate to specialty breads and pastas. Most low FODMAP alternatives are commonly found in the supermarket with no additional costs. Nonetheless, socioeconomic status and food availability should also be taken into account on assessment.
Success of the Low FODMAP Diet

In clinical practice, the low FODMAP diet is very successful in assisting the management of FBD. The diet is now widely practiced across Australia and New Zealand, in the United Kingdom and to a lesser extent in North America. Three out of four patients report significant reduction of symptoms and improvement in quality of life.2,20 Although patients with extreme v i s c e r a l hy p e r s e n s i t i v i t y m ay not achieve complete symptom resolution, improvement is usually enough to motivate continued
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Modified Approaches to the Low FODMAP Diet

Educating patients about the concept of the low FODMAP diet to reduce FBD symptoms can be quite
compliance. Combination therapy with pharmacological agents or psychological therapies may be advantageous in this select patient group.
Long-term Strategies of the Low FODMAP Diet

The most important aspect in restricting FODMAPs in patients with FBD is that there is a dose-dependent relation to symptom induction. Often small amounts of FODMAPs are well tolerated. Therefore, after symptom control is achieved, liberalization of the diet to the individual threshold of the patient is encouraged to gain the health benefits of FODMAPcontaining foods and to continue good food variety while still managing symptoms. Furthermore, the extent of dietary restriction should accommodate the individual patients satisfaction of symptom control, food knowledge, understanding of his or her condition and ability to interpret information.
intake may possibly improve general gastrointestinal health. FODMAPs may exert a prebiotic effect, with the putative health benefits of this. Because FODMAPs assist in laxation (as outlined above), they may play an important role in bowel function in patients with visceral sensitivity
or other physiological abnormalities associated with FBD. The fermentation of FODMAPs in the large bowel yields short-chain fatty acids that appear to be anticarcinogenic. For these reasons, a low FODMAP diet should not be considered a diet for good health, but rather a therapeutic diet for those
Diagnosis and management of patients with functional bowel disorders

Patient presents with functional gut symptoms Assess alarm features* Perform coeliac testing and other appropriate investigations Diagnosis of functional bowel disorder Is breath testing available? Yes Breath hydrogen (and methane) testing with fructose and lactose to assess absorptive capacity Core diet (restriction of fructans, galacto-oligosaccharides, polyols) No Complete FODMAP restriction (fructans, galacto-oligosaccharides, polyols, fructose, lactose) Liberalization of dietary FODMAPs to patients symptom threshold, lifestyle and preferred food choices Other diagnoses
Appropriate treatment
Other Uses for FODMAP Manipulations

In addition to reducing gastrointestinal symptoms in patients with FBD, reducing FODMAP ingestion also appears effective in other illness situations. It is effective in controlling functional gut symptoms in patients with quiescent inflammatory bowel disease and in reducing the frequency of bowel actions in patients with an ileal pouch. 27,28 It may be also be useful in decreasing effluent volume in patients with high output ileostomies, and the selecting of low FODMAP enteral solutions might be effective in preventing diarrhoea in patients receiving enteral nutrition.3,29 Conversely, increasing FODMAP
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If fructose malabsorption present, restriction of fructose Liberalization of dietary FODMAPs to patients symptom threshold, lifestyle and preferred food choices
If lactose malabsorption present, restriction of lactose Liberalization of dietary FODMAPs to patients symptom threshold, lifestyle and preferred food choices
* Alarm features include significant weight loss, family history of inflammatory bowel disease, coeliac disease or colorectal cancer, gastrointestinal blood loss, nocturnal symptoms, fever, steatorrhoea, severe pain, anaemia or iron deficiency, elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate), significant change in symptoms and new onset symptoms at age over 40 years.
individuals troubled by functional gut and possibly other symptoms.
Other Strategies for Treating FBD Symptoms

The low FODMAP diet is the first dietary approach proven to be successful in treating FBD symptoms.2 Unfortunately, well-designed clinical trials investigating other dietary approaches have not yet been completed. These other approaches are discussed below.
excluded. As a minimum, coeliac serology should be performed while the patient is on a gluten-containing diet. Ideally, all patients in whom coeliac disease is suspected should have a small bowel biopsy before adopting a gluten-free diet. HLA-D gene status can exclude coeliac disease if neither HLA-DQ2 nor HLA-DQ8 are present, but the presence of either or both does not make the diagnosis and so genetic testing is only useful for excluding the condition.
g u t sy m p t o m s a n d q u i e s c e n t inflammatory bowel disease. 27 It was found that the best predictors of improved response included the use of low FODMAP cookbooks, working less than or equal to 35 hours per week and having a post-secondary school qualification.27
Conclusion
FBDs are common conditions and until recently therapies have been largely unsuccessful. There is increasing evidence that the implementation of the low FODMAP diet offers a new and effective strategy to symptom management. Through dietetic guidance, an appropriate balance between maintainable dietary restriction and symptom management may be achieved in most patients.
Food Chemical Sensitivities

Salicylates, amines and glutamate are food chemicals hypothesized to induce gastrointestinal symptoms in some patients with food chemical sensitivities. Patients will often present with non-gastrointestinal symptoms as well, including skin, respiratory and systemic symptoms (eg, fuzzy head, extreme fatigue and headaches). As foods included in the low FODMAP diet are often still high in food chemicals, patients who are food chemical-sensitive can usually be identified. Currently, the protocol recommended for assessing food chemical sensitivities requires a very restrictive diet and must be carried out in conjunction with a dietitian.
Probiotics
There is a body of research on the role of probiotics in controlling symptoms in patients with FBD. Unfortunately, studies have not generally shown much benefit, although there have been some notable exceptions.31 It is clear, however, that results from one probiotic cannot be extrapolated to another. The recommending of probiotics generally has no negative implications, but their use should be ceased if symptoms remain unchanged.
Ms Halmos and Dr Muir: None. Dr Shepherd is the author of five low FODMAP cookbooks and a low FODMAP shopping guide. Dr Shepherd and Professor Gibson are co-owners of the FODMAP trademark.
Supportive Resources
Essential in the successful implementation of the low FODMAP diet is the provision of supporting written information, food lists, recipes and other advice such as suitable websites to access accurate information. Refer to www .med.monash.edu.au/ehcs, www .shepherdworks.com.au or www .dietsolutions.net.au for useful resources including information booklets, cookbooks, supportive journal articles, and dietitians specializing in FBD. The importance of good education resources, quantity of free-time and level of education was evident in a study of patients with functional
A complete list of references can be obtained upon request from the editor.
2011 Medicine Today Pty Ltd. Initially published in Medicine Today March 2011;12(3):2938.
Non-coeliac Gluten Intolerance

Gluten restriction to aid FBD symptoms in patients thought to be non-coeliac gluten intolerant is frequently promoted by naturopaths a n d o t h e r a l t e r n a t i ve h e a l t h practitioners. Evidence for its basis is presently being investigated30; while its existence is likely, how commonly it occurs and who should be offered a gluten-free diet, is unknown. Before recommending a gluten-free (or reduced gluten) diet, it is crucial that coeliac disease is properly
About the Author

Ms Halmos is an Accredited Practising Dietitian and PhD student, Dr Muir is an Accredited Practising Dietitian and Director of Research and Dr Shepherd is an Advanced Accredited Practising Dietitian and Senior Lecturer at the Eastern Health Clinical School of Monash University. Professor Gibson is a Gastroenterologist, and Professor of Medicine and Head of the Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.
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CME Questions
This continuing medical education service is brought to you by the Medical Progress Institute, an institute dedicated to CME learning. Read the article Functional Bowel Disorders and FODMAPs and answer the following questions. Answers are shown at the bottom of this page.
CME Article: Functional Bowel Disorders and FODMAPs Please answer True or False to the questions below.
1. The Rome III classification, developed to help classify functional gastrointestinal disorder patients for trials, consists of five categories. 2. Visceral hypersensitivity and changes in motility response to sensory stimulation are two major characteristics of the enteric nervous system seen in patients with functional bowel disorder (FBD). 3. The brain can influence motility patterns and visceral sensitivity in times of stress. 4. Many dietary regimens used in the past have been shown without doubt to be effective in the treatment of FBD. 5. FODMAPs refer to fermentable oligosaccharides, disaccharides, monosaccharides and polyols. 6. FODMAPs cause an increase in water content in the colon which exerts a constipative effect. 7. The various FODMAPs are digested and adsorbed in the small intestine to differing extents. 8. An individuals FODMAP absorptive capacity can be determined by performing breath hydrogen tests. 9. The low FODMAP diet is yet to be proven as an effective approach for treating FBD symptoms. 10. Salicylates, amines and glutamate are thought to induce gastrointestinal symptoms in some patients with food chemical sensitivities.
True False
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Answers: 1. F; 2. T; 3. T; 4. F; 5. T; 6. F; 7. T; 8. T; 9. F; 10. T
Take the challenge, test your knowledge
Peer-Reviewed
Low Back Pain Management: Approaches to Treatment

Gerard A Malanga, MD; Kevin R Dunn, MD
Management of low back pain includes a variety of approaches. These approaches include remaining active, use of lumbar traction and bracing, and treatment with acetaminophen, NSAIDs, muscle relaxants, opioid analgesics and oral corticosteroids.
that increase intradiskal pressure, such as sitting, bending, and lifting.
Traction
Lumbar traction has long been a preferred method for managing lumbar disk problems. About 1.5 times a patients body weight is required to develop distraction of the vertebral bodies. In a recent literature review, there was no evidence to support lumbar traction as a treatment.3 In fact, there was the suggestion that sustained traction might cause more harm than good. However, a randomized controlled trial conducted by Fritz and associates4 showed that there may be a subgroup of patients who may benefit from traction in the short term. This subgroup is characterized by the presence of leg symptoms, signs of nerve root compression, and either peripheralization with extension movements or a positive crossed straight-leg raising test result.
Management of low back pain (LBP) involves a multifaceted approach with the goals of relieving the patients pain and restoring normal function. With a detailed evaluation, clinicians may establish an appropriate diagnosis and formulate a targeted treatment plan. Approaches to treatment include lifestyle modification, medications, physical therapy and various modalities, psychological counseling and, where appropriate, interventional procedures. In this article, we provide an update on approaches to LBP management and explore the treatment options.
Discussion of the treatment plan should include a description and rationale for additional diagnostic testing, if necessary, and medications, therapeutic exercises, or interventional procedures (Figure). The patient should be encouraged to become an active participant in his or her treatment. The clinician can engage the patient in the discussion with a review of proper posture, spine biomechanics in activities of daily living, and simple methods to minimize symptoms.
Bed Rest
Historically, bed rest was the treatment for patients with LBP. Although some benefits may be gained from reducing intradiskal pressure while the patient is prone, bed rest has many deleterious effects on bone, connective tissue, muscle, and cardiovascular fitness. The proactive approach emphasizes activity modification rather than strictly bed rest. Remaining active is more effective than bed rest for patients who have acute or subacute LBP.1,2 The patient should be instructed to avoid activities
Lifestyle Modification Education

After a thorough history, physical examination, and review of diagnostic testing, the clinician should involve the patient in the discussion of the treatment plan. This is the appropriate time to review the pertinent anatomy, biomechanics, and underlying pain generators of the spine.
Lumbar Bracing
Braces have been used prophylactically to prevent injury to the lumbosacral spine, and they purportedly help manage existing pathology. The use of lumbar bracing has not demonstrated efficacy as a means to prevent LBP in the workplace.5 Lumbar supports are not more effective than other marginal therapies in reducing LBP, and there is minimal
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Figure. Low back pain diagnosis and treatment algorithm
Low back pain Rule out red flags Fevers/chills: infectious aetiology Night sweats, night pain, weight loss: metastatic process Bowel/bladder dysfunction, saddle anaesthesia: cauda equina syndrome
evidence to support their use.6 Lumbar bracing may help prevent reinjury by serving as a kinesthetic reminder for using proper biomechanics when lifting or bending, although this has not been demonstrated in the literature.
Perform detailed history and physical examination
Exercise
There is no good scientific evidence to support therapeutic exercise in acute LBP. In subacute back pain, however, an intensive interdisciplinary rehabilitation programme that includes physician consultation with psychological, physical therapy, and social/ vocational intervention has been shown to be moderately effective.7 In patients with chronic LBP, programmes that incorporate tailoring to individual needs, supervision, stretching, and strengthening are associated with the best outcomes.8 The overall goals of exercise programmes for LBP are to reduce pain, restore normal motion, and develop muscular strength of the trunk and spine sufficient to diminish stress to the intervertebral disk and static stabilizers of the spine. 9 In addition, therapy should be directed to the patient who demonstrates reasonable understanding of his pain and good technique in performing the exercises on his own and to implementation of an appropriate home exercise programme.
Assurance Patient education on pathophysiology, biomechanics Encourage patient to remain active and continue normal activities Education on self-care/home exercises, superficial heat/ice Avoid bed rest Consider short course of NSAIDs vs acetaminophen If indicated, consider muscle relaxant Consider spinal manipulation Initiate physical therapy
Requires immediate workup; if indicated, consider surgical consultation
Follow up after 4 weeks, assess response to treatment
Limited improvement; signs/symptoms of radiculopathy or spinal stenosis? Yes Consider referral to low back pain specialist vs obtaining diagnostic imaging Radiography MRI No Reassess risk factors, symptoms, diagnosis
Pain resolved, no functional deficits
Continue home exercise programme
Concordant nerve root impingement or stenosis Refer for evaluation and consideration of interventional procedure
Consider: Imaging Additional pharmacological therapy (eg, tramadol, opioid analgesics, tricyclic antidepressants, anticonvulsants) Referral for multidisciplinary treatment approach Additional therapy (eg, physical therapy, massage, manipulation, acupuncture, yoga, cognitive behavioural therapy, relaxation)
Manipulation
There is conflicting evidence about spinal manipulation and manual mobilization in the management of LBP, although recent clinical guidelines suggest that spinal manipulation in the hands of trained professionals provides a small to moderate short-term benefit in relieving pain.10 Moderate evidence
Follow up after 46 weeks
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suggests that the effect of manipulation in combination with strengthening exercise is similar to the effect of prescription NSAIDs with exercise in both the short and long terms.11 Spinal manipulation has not been found to be more effective than other treatments, such as analgesics, exercise, and physical therapy. However, there appears to be a subgroup of patients with LBP for whom spinal manipulation results in significant reductions in pain and disability.1214 Manipulation should be performed in conjunction with and to facilitate an active physical therapy programme.
there are contraindications to other medications. Prolonged use is contraindicated because of the potential for liver toxicity.
NSAIDs
These agents are a reasonable first-line treatment for acute LBP because of their combined analgesic and anti-inflammatory effects. Non-selective NSAIDs have been shown to be more effective for pain relief than acetaminophen.17 The dose needed to produce anti-inflammatory effects differs substantially from that for analgesic effects. These medications often are taken intermittently, and a significant level is not sustained to take advantage of the anti-inflammatory properties. Patients should be advised to take the medications at regular intervals to maximize both the analgesic and the anti-inflammatory effects. Not one NSAID has been shown to be more effective than the others in terms of pain relief for patients with LBP. In a systematic review, the selective cyclooxygenase-2 inhibitors showed fewer adverse effects than the traditional NSAIDs.18 The major adverse reactions to NSAIDs include gastrointestinal bleeding and renovascular damage. NSAIDs also have been shown to slow bone and tissue healing. 19 Prolonged use should be avoided to minimize the associated risks. The lowest effective dose is recommended for the shortest duration that is necessary.20
serotonin reuptake inhibitor class and trazodone have been shown to be no more effective than placebo.22,23 Antidepressants typically take up to 4 weeks to achieve effect, but whether the same time is required to achieve pain relief is unknown. 23 Of note, depression is a common problem in patients with chronic LBP, and it should be addressed appropriately.24
Muscle Relaxants
These often are prescribed in the management of acute LBP to relieve pain, improve range of motion, and interrupt the pain-spasm-pain cycle. They have been shown to be more effective when they are used in conjunction with NSAIDs.25 Tizanidine has been shown to be effective in the management of acute LBP.26 Other studies have not determined superiority for any particular muscle relaxant in terms of benefit or adverse effects. The most frequently reported effect of muscle relaxants is sedation; they usually are prescribed at bedtime to take advantage of this property.
Medications
Patients with LBP have been treated with medications in a number of classes, including acetaminophen, NSAIDs, muscle relaxants, opioid analgesics, and oral corticosteroids. Each agent has unique trade-offs between risk and anticipated benefits. Therefore, before prescribing a medication, the clinician should be aware of its contraindications, common adverse effects, and mechanism of action.
Acetaminophen
This para-aminophen derivative has analgesic and antipyretic effects equal to those of aspirin, but it has weak antiinflammatory effects. Acetaminophen is relatively inexpensive and is available without a prescription. It is effective for mild to moderate pain but lacks other desirable effects on inflammation and muscle spasm. In acute LBP, studies have shown no difference between acetaminophen and no treatment,15 and no clear difference was seen in pain relief between acetaminophen and NSAIDs.16,17 Acetaminophen generally is not a first-line medication for LBP unless
Opioid Analgesics
The use of opioid analgesics in the management of LBP should be limited to pain that is unresponsive to other treatments or when other medications are contraindicated. A careful riskbenefit analysis should be considered before starting these medications because of the potential risk of aberrant drug-related behaviours with long-term use in patients who have a history of or predilection to addiction or abuse. There is no evidence to support the use of one opioid versus another.27 Prolonged or repeated use of opioids is not necessary for most patients who have acute LBP.
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Antidepressants
There is good evidence to support the analgesic effect of tricyclic antidepressants in the treatment of patients with LBP. In a systematic review, tricyclic antidepressants were more effective than placebo in controlling pain.21 Other antidepressants in the selective
Tramadol
This centrally acting analgesic has a combined mechanism of binding to receptors and a mixed serotonin/ norepinephrine reuptake inhibitor. Although no studies have compared tramadol with acetaminophen, NSAIDs, or opioid analgesic monotherapy, there is evidence to suggest that tramadol is effective for short-term pain relief and improved function.28
Antiseizure Medications
Gabapentin, an antiepileptic medication widely used in the management of neuropathic pain, has been shown to provide short-term benefit in patients with radicular pain.29,30 The most frequently noted adverse effects include drowsiness, loss of energy, and dizziness. There is insufficient evidence for or against other antiepileptic medications in the management of LBP with or without radiculopathy.20
more effective than placebo.20,31-34 In a double-blind placebo-controlled trial, Holve and Barkan35 demonstrated that patients treated with a tapering course of prednisone have a more rapid return to baseline in pain, mental well-being, and disability scores and require fewer subsequent epidural injections. There was no difference in physical examination findings, the use of NSAIDs or other pain medications, or return to work. Better studies clearly are needed to determine the role and effectiveness of oral corticosteroids in LBP, particularly for lumbar radiculopathy.
Ultrasonography
This deep-heating modality has been shown to improve the distensibility of connective tissue and facilitate stretching.38 Ultrasonography is contraindicated in acute inflammatory conditions because it may exacerbate the inflammatory response. In addition, this modality is contraindicated over a previous laminectomy site. There is insufficient evidence for or against the use of ultrasonography in LBP.37 It may be best used to improve segmental limitations in range of motion by facilitating soft tissue mobilization and stretching with a skilled physical therapist.25
Modalities
Modalities offer an adjunct to evidencebased treatment in patients with LBP. However, the evidence to support their use is generally poor, despite their widespread use.
Superficial Heat
This modality produces effects to a depth of 1 to 2 cm and has been shown to reduce muscle spasm and pain. Heat packs often are used in combination with electrical stimulation therapy. Heat wrap therapy has been shown to be more effective than placebo in short-term pain relief and functional status.39 These effects typically last for less than 1 week and are not more effective than exercise.
Oral Corticosteroids
The use of oral corticosteroids in the management of LBP is unsupported in the literature, especially when there are radicular symptoms, because these agents have not been shown to be
Transcutaneous Electrical Nerve Stimulation (TENS)

TENS, the use of electrical impulses over surface electrodes to provide symptomatic relief by modifying pain perception, has not been shown to be effective for chronic LBP.20 In recently published American Academy of Neurology guidelines, TENS is not recommended for chronic LBP because it has not been shown to be more effective than placebo.36
Therapeutic Injections Trigger Point Injections

Myofascial trigger points are thought to be hyperirritable foci within muscles and fasciae that are associated with taut muscle bands. Trigger points are identified on palpation, which produces a focal twitch response and referred pain distal to the site of muscle irritability. Palpation examinations have poor inter-rater reliability.40 In an assessment of intra-rater reliability, local twitch response and referred pain varied from one session to the next; taut bands, tender points, and jump sign remained consistent.41
The proactive approach emphasizes activity modification rather than strictly bed rest
Electrical Stimulation
High-voltage pulsed galvanic stimulation has been used to reduce muscle spasm and oedema in patients with acute LBP. The use of electrical stimulation typically is limited to the initial stages of treatment to allow patients to progress to more active treatments in restoring normal range of motion and strength. There is insufficient scientific evidence for or against its use in patients who have LBP.37
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Proliferation therapy involves injection of solution into the tendons and ligaments to promote healing.
correlates well with radiographic evidence. To minimize the risks, they should be performed with fluoroscopic guidance and contrast enhancement. There is no indication for performing injections in series. Typically, one or two injections are sufficient to improve the radicular pain symptoms and facilitate a successful course of rehabilitation.
Facet Injections
Although lumbar facet joints are a potential source of LBP, there is a poor correlation between history and physical examination findings and true facet-mediated LBP. In addition, diagnostic imaging is unreliable for identifying underlying facet joint pathology. In spite of various attempts reported in the literature, an identifying clinical feature of facet-mediated pain has yet to be found. Thus, the only means of diagnosis is through facet joint blocks. Facet joint injections with corticosteroids have not been shown to be more effective than placebo in controlling pain. 45,46 Therefore, lumbar medial branch blocks or radiofrequency neurotomies remain a potential treatment, given an appropriate patient response to diagnostic blockade.46
Trigger points are managed initially with stretching; restoration of normal posture and biomechanics; and modalities, such as superficial heat or cryotherapy. Muscle relaxants also may be useful. Trigger point injections may be considered when more conservative measures have not succeeded. However, there is no evidence that injections of normal saline with corticosteroids are more effective than normal saline alone. The benefit may result from needling alone or from placebo or nonspecific effects. In one study, there was no difference among dry needling, injection with lidocaine, lidocaine with corticosteroid, and vasocoolant spray with acupressure.42,43 As a result, the type of injections, appropriate dosage, and interval are not known. Trigger point injections remain an option for myofascial-related LBP resistant to conservative treatments. They should be limited and used in
conjunction with an appropriate functional rehabilitation programme.
Epidural Corticosteroid Injections

These injections are a frequently performed interventional procedure aimed at reducing pain and inflammation resulting from disk herniation and subsequent nerve root irritation. The effectiveness of these injections is increased if they are used in the first weeks after the onset of pain and followed with an active exercise programme. Even though they are used widely, good scientific evidence for their use in the management of LBP is limited. In a multicenter randomized controlled trial, epidural corticosteroid injections offered transient benefit in symptoms at 3 weeks in patients with sciatica but no sustained benefits in terms of pain, function, or the need for surgery.44 Epidural injections should be used when clinical evidence based on the history and physical examination
Sacroiliac Joint Injections

The sacroiliac joint is a potential pain generator in the lumbar spine, with an overlapping referral pain pattern around the posterosuperior iliac spine. Sacroiliac jointmediated pain should be considered in patients for whom a comprehensive rehabilitation programme and a trial of NSAIDs, ice/ heat, and mobilization or manipulation have not succeeded. Injection should be considered for both diagnostic and therapeutic purposes; if the results are positive, it should
309
be followed with an active physical therapy programme.
Prolotherapy
This therapy involves injection of solution to promote healing of loose tissue, ligaments, tendons, and joint capsules. Prolotherapy remains poorly studied and validated in spite of a long history of use to manage various conditions thought to be the result of ligamentous instability. In the management of LBP, prolotherapy has been shown to be effective in combination with spinal manipulation therapy. 47,48 It has yet to be studied as a single treatment without co-interventions.
Acupuncture
This modality has been used to manage various conditions for more than 2,000 years. Evidence for the use of acupuncture in the management of acute LBP is sparse,49 but it has been shown to be effective in the management of chronic LBP.50,51 The literature on acupuncture is not of high quality.49
failed back surgery syndrome, complex regional pain syndrome, and chronic back pain. As the number of low back surgeries increases, so do the number and the use of spinal cord stimulation therapies.53 In a recent systematic review, Frey and associates 53 found strong evidence for the clinical use of spinal cord stimulation in failed back surgery syndrome in terms of pain relief and cost-effectiveness. Spinal cord stimulation does involve risk, which is estimated to exist in up to 43% of patients. The most common complications include electrode or lead problems, infection, generator problems, extension cable problems, and cerebrospinal fluid leakage.53
low-back pain and sciatica. Cochrane Database Syst Rev 2007;(2):CD003632. 3. Gay RE, Brault JS. Evidence-informed management of chronic low back pain with traction therapy. Spine J 2008;8:234242. 4. Fritz JM, Delitto A, Erhard RE. Comparison of classification based physical therapy with therapy based on clinical practice guidelines for patients with acute low back pain: a randomized clinical trial. Spine (Phila Pa 1976) 2003;28:13631372. 5. Woodhouse ML, McCoy RW, Redondo DR, Shall LM. Effects of back support on intra-abdominal pressure and lumbar kinetics during heavy lifting. Hum Factors 1995;37:582590. 6. Jellema P, van Tulder MW, van Poppel MN, et al. Lumbar supports for prevention and treatment of low back pain: a systematic review within the framework of the Cochrane Back Review Group. Spine (Phila Pa 1976) 2001;26:377 386. 7. Karjalainen K, Malmivaara A, van Tulder M, et al. Multidisciplinary biopsychosocial rehabilitation for subacute low back pain in working-age adults: a systematic review within the framework of the Cochrane Collaboration Back Review Group. Spine (Phila Pa 1976) 2001;26:262269. 8. Hayden JA, van Tulder MW, Tomlinson G. Systematic review: strategies for using exercise therapy to improve outcomes in chronic low back pain. Ann Intern Med 2005;142:776785. 9. Saal JA. Dynamic muscular stabilization in the nonoperative treatment of lumbar pain syndromes. Orthop Rev 1990;19:691700. 10. Assendelft WJ, Morton SC, Yu EI, et al. Spinal manipulative therapy for low back pain: a meta-analysis of effectiveness relative to other therapies. Ann Intern Med 2003;138:871881. 11. Bronfort G, Haas M, Evans R, et al. Evidence-informed management of chronic low back pain with spinal manipulation and mobilization. Spine J 2008;8:213225. 12. Flynn T, Fritz J, Whitman J, et al. A clinical prediction rule for classifying patients with low back pain who demonstrate short-term improvement with spinal manipulation. Spine (Phila Pa 1976) 2002;27:28352843. 13. Childs JD, Fritz JM, Flynn TW, et al. A clinical prediction rule to identify patients with low back pain most likely to benefit from spinal manipulation: a validation study. Ann Intern Med 2004;141:920928. 14. Cleland JA, Fritz JM, Kulig K, et al. Comparison of the effectiveness of three manual physical therapy techniques in a subgroup of patients with low back pain who satisfy a clinical prediction rule: a randomized clinical trial. Spine (Phila Pa 1976) 2009;34:27202729. 15. Milgrom C, Finestone A, Lev B, et al. Overexertional lumbar and thoracic back pain among recruits: a prospective study of risk factors and treatment regimens. J Spinal Disord
Conclusions
LBP is a frequently encountered complaint associated with great costs that continue to increase. Most patients improve with time if they remain active. Physicians need to have a clear understanding of the pertinent anatomy and physiology of the spine and correlate this with their findings in the history and on physical examination to develop a good differential diagnosis and a proper treatment plan. The literature may help guide the decision-making process, but much of the evidence is not well validated. The best evidence is for a short course of NSAIDs, active exercise and, as soon as possible, a return to normal activities. Physical therapy, injections, and other approaches to treatment may help in properly selected patients.
Psychological Counselling
Cognitive-behavioural therapy is an effective component in the treatment of patients who have chronic pain.52 However, it needs to be combined with other therapeutic components, such as physical therapy, to deal with physical deconditioning issues. Currently, there are no studies that directly address what combination of components might provide the best therapeutic outcomes for what type of chronic pain syndrome.52
References
1. Hagen KB, Hilde G, Jamtvedt G, Winnem M. Bed rest for acute low back pain and sciatica. Cochrane Database Sys Rev 2004;(4):CD001254. Article withdrawn June 16, 2010. 2. Hilde G, Hagen KB, Jamtvedt G, Winnem M. WITHDRAWN: advice to stay active as a single treatment for
Spinal Cord Stimulation

With this modality, an implantable device is used primarily to manage
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1993;6:187193. 16. van Tulder MW, Scholten RJ, Koes BW, Deyo RA. Non-steroidal anti-inflammatory drugs for low back pain [published updates appear in Cochrane Database Syst Rev 2008;(1):CD000396 and 2006;(2):CD000396]. Cochrane Database Syst Rev 2000;(2):CD000396. 17. van Tulder MW, Scholten RJ, Koes BW, Deyo RA. Nonsteroidal anti-inflammatory drugs for low back pain: a systematic review within the framework of the Cochrane Collaboration Back Review Group. Spine (Phila Pa 1976) 2000;25:25012513. 18. Roelofs PD, Deyo RA, Koes BW, et al. Non-steroidal antiinflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976) 2008;33:17661774. 19. Riew KD, Long J, Rhee J, et al. Time-dependent inhibitory effects of indomethacin on spinal fusion. J Bone Joint Surg 2003;85A:632634. 20. Chou R, Qaseem A, Snow V, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians; American College of Physicians; American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society [published correction appears in Ann Intern Med 2008;148:247-248]. Ann Intern Med 2007;147:478491. 21. Staiger TO, Gaster B, Sullivan MD, Deyo RA. Systematic review of antidepressants in the treatment of chronic low back pain. Spine (Phila Pa 1976) 2003;28:25402545. 22. Salerno SM, Browning R, Jackson JL. The effect of antidepressant treatment on chronic back pain: a meta-analysis. Arch Intern Med 2002;162:1924. 23. Malanga GA, Dennis RL. Use of medications in the treatment of acute low back pain. Clin Occup Environ Med 2006;5:643653, vii. 24. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med 2003;163:24332445. 25. Malanga GA, Nadler SF. Nonoperative treatment of low back pain. Mayo Clin Proc 1999;74:11351148. 26. van Tulder MW, Touray T, Furlan AD, et al; Cochrane Back Review Group. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the cochrane collaboration. Spine (Phila Pa 1976) 2003;28:19781992. 27. Chou R, Clark E, Helfand M. Comparative efficacy and safety of long-acting oral opioids for chronic noncancer pain: a systematic review. J Pain Symptom Manage 2003;26:10261048. 28. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. J Rheumatol 2000;27:772778.
29. McCleane GJ. Does gabapentin have an analgesic effect on background, movement and referred pain? A randomised, double-blind, placebo controlled study. Pain Clinic 2001;13:103107. 30. Yildirim K, Sisecioglu M, Karatay S, et al. The effectiveness of gabapentin in patients with chronic radiculopathy. Pain Clinic 2003;15:213218. 31. Finckh A, Zufferey P, Schurch MA, et al. Short-term efficacy of intravenous pulse glucocorticoids in acute discogenic sciatica: a randomized controlled trial. Spine (Phila Pa 1976) 2006;31:377381. 32. Friedman BW, Holden L, Esses D, et al. Parenteral corticosteroids for Emergency Department patients with nonradicular low back pain. J Emerg Med 2006;31:365370. 33. Haimovic IC, Beresford HR. Dexamethasone is not superior to placebo for treating lumbosacral radicular pain. Neurology 1986;36:15931594. 34. Porsman O, Friis H. Prolapsed lumbar disc treated with intramuscularly administered dexamethasonephosphate: a prospectively planned, double-blind, controlled clinical trial in 52 patients. Scand J Rheumatol 1979;8:142144. 35. Holve RL, Barkan H. Oral steroids in initial treatment of acute sciatica. J Am Board Fam Med 2008;21:469474. 36. Dubinsky RM, Miyasaki J. Assessment: efficacy of transcutaneous electric nerve stimulation in the treatment of pain in neurologic disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010;74:173176. 37. Poitras S, Brosseau L. Evidence-informed management of chronic low back pain with transcutaneous electrical nerve stimulation, interferential current, electrical muscle stimulation, ultrasound, and thermotherapy. Spine J 2008;8:226233. 38. Lehmann JF, Masock AJ, Warren CG, Koblanski JN. Effect of therapeutic temperatures on tissue extensibility. Arch Phys Med Rehabil 1970;51:481487. 39. French SD, Cameron M, Walker BF, et al. Superficial heat or cold for low back pain. Cochrane Database Syst Rev 2006;(1):CD004750. 40. Nice DA, Riddle DL, Lamb RL, et al. Intertester reliability of judgments of the presence of trigger points in patients with low back pain. Arch Phys Med Rehabil 1992;73:893898. 41. Al-Shenqiti AM, Oldham JA. Test-retest reliability of myofascial trigger point detection in patients with rotator cuff tendonitis. Clin Rehabil 2005;19:482487. 42. Malanga G, Wolff E. Evidence-informed management of chronic low back pain with trigger point injections. Spine J 2008;8:243252. 43. Garvey TA, Marks MR, Wiesel SW. A prospective, randomized, double-blind evaluation of trigger-point injec-
tion therapy for low back pain. Spine (Phila Pa 1976) 1989;14:962964. 44. Arden NK, Price C, Reading I, et al; WEST Study Group. A multicentre randomized controlled trial of epidural corticosteroid injections for sciatica: the WEST study. Rheumatology (Oxford) 2005;44:13991406. 45. Ogsbury JS 3rd, Simon RH, Lehman RA. Facet denervationin the treatment of low back syndrome. Pain 1977;3:257 263. 46. Bogduk N. Evidence-informed management of chronic low back pain with facet injections and radiofrequency neurotomy. Spine J 2008;8:5664. 47. Ongley MJ, Klein RG, Dorman TA, et al. A new approach to the treatment of chronic low back pain. Lancet 1987;2:143146. 48. Klein RG, Eek BC, DeLong WB, Mooney V. A randomized double-blind trial of dextrose-glycerin-phenol injections for chronic, low back pain. J Spinal Disord 1993;6:2333. 49. Ammendolia C, Furlan AD, Imamura M, et al. Evidenceinformed management of chronic low back pain with needle acupuncture. Spine J 2008;8:160172. 50. Furlan AD, van Tulder M, Cherkin D, et al. Acupuncture and dry-needling for low back pain: an updated systematic review within the framework of the cochrane collaboration. Spine (Phila Pa 1976) 2005;30:944963. 51. Manheimer E, White A, Berman B, et al. Meta-analysis: acupuncture for low back pain. Ann Intern Med 2005;142:651663. 52. Gatchel RJ, Rollings KH. Evidence-informed management of chronic low back pain with cognitive behavioral therapy. Spine J 2008;8:4044. 53. Frey ME, Manchikanti L, Benyamin RM, et al. Spinal cord stimulation for patients with failed back surgery syndrome: a systematic review. Pain Physician 2009;12:379397.
2010 UBM Medica LLC. Initially published in The Journal of Musculoskeletal Medicine 2010;27(8):305315. Reprinted with permission.
About the Authors

Dr Malanga is director of the PM&R Sports Medicine Fellowship and Dr Dunn is a PM&R sports medicine fellow at Atlantic Health System in Summit, New Jersey. Dr Malanga also is director of pain management at Overlook Hospital, also in Summit.
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CME Questions
This continuing medical education service is brought to you by the Medical Progress Institute, an institute dedicated to CME learning. Read the article Low Back Pain Management: Approaches to Treatment and answer the following questions. Answers are shown at the bottom of this page.
CME Article: Low Back Pain Management: Approaches to Treatment Please answer True or False to the questions below.
1. Bed rest used to be the treatment of choice for low back pain (LBP). 2. Lumbar bracing is effective in preventing LBP. 3. The goals of exercise programmes for LBP patients are to decrease pain, restore normal motion, and develop muscular strength of the trunk and spine. 4. Spinal manipulation has been demonstrated to be more effective than other treatments such as analgesics, exercise and physical therapy in the management of LBP. 5. The analgesic and antipyretic effects of acetaminophen are superior to those of aspirin. 6. Gastrointestinal bleeding, renovascular damage, and slow bone and tissue healing are some of the major adverse reactions to NSAIDs. 7. Studies have shown that tricyclic antidepressants are less effective than placebo in controlling LBP. 8. Tizanidine has not been demonstrated to be effective in the management of acute LBP. 9. Electrical stimulation reduces muscle spasm and oedema and restores normal range of motion and strength in patients with acute LBP. 10. One or two epidural corticosteroid injections are usually not sufficient to improve radicular pain symptoms.
True False
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Answers: 1. T; 2. F; 3. T; 4. F; 5. F; 6. T; 7. F; 8. F; 9. T; 10. F

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