a multidisciplinary approach to the treatment of early colorectal cancer, cmp medica, 2007

8/12/2019 A Multidisciplinary Approach to the Treatment of Early Colorectal Cancer, CMP Medica, 2007

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New Treatment Paradigms

A Multidisciplinary ApproTreatment of Early Colorec

Including a Clinical Discussion on

Edited by

Edward Chu, MD Yale Cancer Center

Yale University School of Medicine


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Note to the reader

The information in this book has been carefully reviewed for accuracindications. Before prescribing any drug, however, the clinician shomanufacturers current package labeling for accepted indications, arecommendations, and other information pertinent to the safe and effecproduct described. This is especially important when drugs are given inas an adjunct to other forms of therapy. Furthermore, some of the medicaherein, as well as some of the indications mentioned, may not have been US Food and Drug Administration at the time of publication. This possborne in mind before prescribing or recommending any drug or regime

Educational activities in the form of monographs, audio programs, suother formats are sent to the readership of ONCOLOGY on a regularof the journal can opt out of receiving it and accompanying educationaltime by contacting our circulation department at CMPMedica, phone: or by e-mail: [email protected].

Copyright 2007 by CMP Healthcare Media LLC. All rights reserprotected by copyright. No part of it may be reproduced in any manner oelectronic or mechanical, without the written permission of the publish

Library of Congress Catalog Card Number 2007-929229

ISBN 978-1-891483-54-7

Single copies of this book are available for $24.95 each. For informatiadditional copies, contact the publisher, CMPMedica, The OncoloCommunity Drive, Manhasset, New York 11030. Telephone (212) 600600-3050.

Cover image courtesy of Getty Images.


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New Treatment Paradigm

Contributing Authors

Charles Cha, MD Assistant Professor of Surgery Gastrointestinal Surgery andSurgical Oncology

Yale University School of MedicineNew Haven, Connecticut

Edward Chu, MDProfessor of Medicine and Pharmacology Chief, Section of Medical Oncology Deputy Director, Yale Cancer Center


Jose Costa, MDProfessor of Pathology & Medicine(Medical Oncology)Director of Anatomical Pathology

Vice Chairman, Department of Pathology Yale University School of MedicineNew Haven, Connecticut

Andrew J. Duffy, MD, FACS Assistant Professor of Surgery Department of Surgery


Walter E. Longo, MDProfessor of Surgery Chief of GastrointestinDirector of Colon and Program Director in S

Yale University SchooNew Haven, Connecti

M. Wasif Saif, MD, M Associate Professor ofSection of Medical On


Margit McGowan, DClinical FellowSection of Medical OnDepartment of Interna

Yale Cancer CenterNew Haven, Connecti

Zenta Walther, MD, P

Assistant ProfessorDepartment of Patholo



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XX New Treatment Paradigms in Lung Cancer

Monograph Contents

Contributing Authors

Roundtable Participants

Roundtable Contents

Continuing Medical Education

Introduction Edward Chu, MD

Chapter 1: Early Colorectal Cancer: Nodal Evaluation andSentinel Lymph Node Mapping Charles Cha, MD

Chapter 2: The Role of Minimally Invasive Surgery in Colon Cancer ResectionAndrew J. Duffy, MD , FACS

Chapter 3: Surgical Management of Rectal Cancer and Its VariantsWalter E. Longo, MD


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Chapter 4: Pathologic Staging of Colorectal CancerZenta Walther, MD , P h D , and Jose Costa, MD

Chapter 5: Role of Prognostic and Predictive Markersin Pathologic Assessment

Zenta Walther, MD , P h D , and Jose Costa, MD

Chapter 6: Adjuvant Chemotherapy of Colon CancerM. Wasif Saif, MD , MBBS

Chapter 7: Biologic Agents in the Adjuvant Treatment of Colon C James J. LeeMD , P h D , and Edward Chu, MD

Chapter 8: Combined-Modality Chemoradiotherapy Approachesfor Locally Advanced Rectal CancerMargit McGowan, DO , Edward Chu, MD , and James J. Lee, MD , P h D

CME Post-Test Questions

Index

Monograph Contentscontd


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Roundtable Participant

MODERATOR Edward Chu, MDProfessor of Medicine and Pharmacology Chief, Section of Medical Oncology Deputy Director, Yale Cancer Center


FACULTY

Jose Costa, MDProfessor of Pathology & Medicine(Medical Oncology)Director of Anatomical Pathology

Vice Chairman, Department of Pathology


Walter E. Longo, MDProfessor of Surgery Chief of Gastrointestinal Surgery Director of Colon and Rectal Surgery

Program Director in Surgery Yale University School of MedicineNew Haven, Connecticut

M. Wasif Saif, MD, MBBS Associate Professor of Medicine


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Roundtable Contents

Clinical Discussion on Audio CDRoundtable ParticipantsEdward Chu,MD (Moderator)

Jose Costa,MD Walter E. Longo,MD M. Wasif Saif,MD , MBBS Track 1 Surgical Management Track 2 Open vs Laparoscopic Surgery Track 3 Collection and Evaluation of Lymph Nodes Track 4 Palliative Surgery for Advanced Disease

Track 5 Preoperative Chemoradiotherapy in Rectal Cancer Track 6 Pathologic Evaluation and Workup Track 7 Prognostic Indicators Track 8 Multimodality Treatment Track 9 Adjuvant Therapy Options for Colon Cancer

Track 10 Role of Targeted Therapies in the Standards of Care Track 11 Post-Treatment Surveillance Protocols Track 12 Adjuvant Therapy Options for Rectal Cancer


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An Open Invitation to the Readers of

ONCOLOGY , Oncology News International , and COAB

Dear Colleague,

The Oncology Group and Beam Institute invite you to participate in a costutilizing the exciting new AMA/PRA-accredited performance improvprogram.

It is consistent with the self-assessment, performance improvement activiby your professional certication and accreditation organizations. In addit

you a stress-free opportunity to practice your skills in responding to pay-for-requirements.

To begin the process, please go to our website at www.beaminstituenroll in the activity, A Multidisciplinary Approach to the Treatment of E

Cancer , based on this monograph and audio CD edited by Edward Chu, then be instructed how to send your rst e-mail to Beam Institute, describing improvement plan based upon what youve learned from reading the monogralistening to the audio CD.

If you should have any questions before you begin or during your participoffer, please feel free to call me at 212-600-3195 or e-mail me at spu

I look forward to working with you on this exciting project.Regards,


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Continuing Medical Ed

Continuing Medical Educ

Monograph Activity release date: September 1, 2007

Activity expiration date: September 1, 2008

About the Activity

The CME activity is based on the information learned from the bookA Multidisciplinary Approach to the Treatment of Early Colorectal Clinical Discussion on Audio CD . It was developed from an identied eduinformation about practical management issues in the practice of medicaradiation oncology.

This activity has been developed and approved under the direction of B

Activity Learning Objectives After reading A Multidisciplinary Approach to the Treatment of Earlparticipants should be able to:

Assess protocols to harvest and analyze lymph nodes and othe viduals suspected of having colon cancer to accurately stage dismaximal benet of therapy.

Describe various surgical techniques used to resect colorectaconsider their advantages and disadvantages, and understandmorbidities related to their use.

Compare clinical results of current surgical, chemotherapeutic, peutic methods to treat colorectal cancer and its recurrence.


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Continuing Medical Educationx

Credit Designation

Beam Institute designates this educational activity for a maximum Category 1 Credit(s) . Physicians should only claim credit commensutent of their participation in the activity. Physicians not licensed in th

who participate in this CME activity are eligible for AMA PRA C

Financial Disclosure

Dr. Chu is a consultant for Bristol-Myers Squibb/ImClone, Roch Aventis; he receives grants/research support from Bristol-Myers SqGenentech, Pzer, Roche, and Sano-Aventis. Dr. Saif receives granport from Avalon, Biogen, Bristol-Myers Squibb/ImClone, Roche

Taiho; he serves on the speakers bureau for Amgen, Genentech, PzSano-Aventis. Drs. Cha, Costa, Duffy, Lee, Longo, McGowan, and dicated they have no nancial relationships with any manufacturer

Roundtable on Audio CD Activity release date: September 1, 2007

Activity expiration date: September 1, 2008

About the Activity

The CME activity is based on the information learned from the audio po

tidisciplinary Approach to the Treatment of Early Colorectal Cancer. It wasidentied educational need for information about practical managemenpractice of medical, surgical, and radiation oncology.

This activity has been developed and approved under the direction of Be

Activity Learning Objectives


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Continuing Medical Ed

Assess protocols to harvest and analyze malignant tumor tissue andindividuals suspected of having new or recurrent colorectal cancer.

Describe the advantages and disadvantages of surgical techniquecolorectal cancer lesions.

Review the staging of colorectal tumors, considering the utility of imm

istry and of prognostic and predictive markers of the disease. Examine current standards of treatment and controversies concer

treatment of colorectal cancer.

Credit Designation

Beam Institute designates this educational activity for a maximumCategory 1 Credit(s) . Physicians should only claim credit commensuraof their participation in the activity. Physicians not licensed in the Unparticipate in this CME activity are eligible for AMA PRA Category 1

Financial Disclosure

Dr. Chu is a consultant for Bristol-Myers Squibb/ImClone, Roche, andhe receives grants/research support from Bristol-Myers Squibb/ImClonPzer, Roche, and Sano-Aventis. Dr. Saif receives grants/research suppo

Biogen, Bristol-Myers Squibb/ImClone, Roche, Samyang, and Taiho; hspeakers bureau for Amgen, Genentech, Pzer, Roche, and Sano-Avand Longo have indicated they have no nancial relationships with anyor providers.

Target Audience

This activity targets physicians in the elds of oncology and hematology

AccreditationThis activity has been planned and implemented in accordance with the and policies of the Accreditation Council for Continuing Medical Educati

joint sponsorship of Beam Institute and The Oncology Group. Beam Instituby the ACCME to provide continuing medical education for physicians


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Continuing Medical Educationxii

Compliance Statement

This activity is an independent educational activity under the direction of The activity was planned and implemented in accordance with the Essepolicies of the ACCME, the Ethical Opinions/Guidelines of the AMA, thand the PhRMA Code on Interactions with Healthcare Professionals, th

highest degree of independence, fair balance, scientic rigor, and objectBeam Institute, the Grantor, and CMPMedica shall in no way be liable fof information or for any errors, omissions, or inaccuracies in the activconcerning drugs, dosages, and procedures may reect the clinical expauthor(s), or they may be derived from the professional literature or othmay suggest uses that are investigational in nature and are not approvindications. Activity participants are encouraged to refer to primary refer

full prescribing information resources. The opinions and recommendatiherein are those of the author(s) and do not necessarily reect the views oor producer.

Copyright

Copyrights owned by Beam Institute, a division of CME LLC. Copyrigh

Contact Information

We would like to hear your comments regarding this or other activities prInstitute. In addition, suggestions for future programming are welcome.

Address : Director of Continuing Education Beam Institute 11 West 19th Street, 3rd Floor New York, NY 10011-4280Phone : 888-618-5781


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Introduction

Colorectal cancer (CRC) is a major public health problem in the Unitedthroughout the world. Each year, this disease affects nearly 150,000 new patithe second leading cause of mortality, accounting for almost 50,000 deaths inStates. Worldwide, CRC aficts nearly 800,000 individuals and is associate

deaths. Over the past 10 years, signicant advances have been made in the sand early detection of CRC as well as in the different treatment approachessurgery, radiation therapy, and chemotherapythat are now available for pearly-stage CRC and more advanced stages of the disease. Without question, Cbecome a highly preventable and curable disease through regular screeningdetection, and highly treatable when diagnosed at an even more advanced s

In this book, we have condensed and summarized a wealth of essential infthe multidisciplinary treatment approach for patients with early-stage CRC, anit in a practical and readable format. It is critical that a team of physicians fspecialtiesincluding surgery, radiation oncology, medical oncology, pathodiologyprovide their particular expertise in developing individual treatmepatients with CRC. With this in mind, the rst three chapters review variourelating to the surgical management of patients with CRC. The subsequent tware focused on pathologic staging and the role of prognostic and predictive in pathologic assessment. The nal three chapters are devoted to an update oof adjuvant chemotherapy for colon cancer, the integration of biologic agents treatment regimens, and the combined-modality approach to treating rectal

My hope is that this book will serve as a source of practical informatiod b h i i d th h lth f i l ti l i l d i


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2


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Nodal Evaluation and Sentinel L

Chapter 1: Early ColorectaNodal Evaluation and Sentinel Lym

Charles Cha, MD

As is the case with a growing number of malignancies, the quantof lymph node retrieval has become a topic of much debate for patients cancer (CRC). Colorectal cancer is the most common malignancy of the tract, with an estimated 153,000 new cases expected to be diagnosed in thin 2007.[1] Nearly all patients with early CRC will undergo resection foran adequate lymph node assessment is critical to provide both accurate smaximal therapeutic benet. It has therefore been the goal of numerouto evaluate whether the traditional resection of the node-bearing mesent

the colorectal surgical specimen is sufcient. If so, how much of the mbe removed and how many lymph nodes must be assessed? Furthermtechnologies such as sentinel lymph node mapping, immunohistochemispolymerase chain reaction (PCR) of any added benet to our standard te

Adequate lymph node analysis is a critical factor for making a therin CRC; the presence or absence of nodal metastases will predict long-tpatients more accurately than any other prognostic factor. Because of t

recurrence, adjuvant chemotherapy is recommended for all patients wimetastases (stage III). Furthermore, even in node-negative stage II pof developing recurrent disease remains in the range of 20% to 30%.selected patients with stage II disease and adverse histologic features w

vant chemotherapy.[3] Will better sampling or improved analysis of ly


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4 Nodal Evaluation and Sentinel Lymph Node Mapping

survival in stage II and III colon cancer patients.[4] It is unclear whether tha true therapeutic benet or rather more accurate staging with concomitantion (also known as the Will Rogers effect). In either case, what is clearstaging is a crucial component determining both therapy and prognosis.

History of Nodal Staging in ColorectMuch of our knowledge about the nodal spread of colorectal canc

anatomic studies of Cuthbert Dukes, a pathologist at St. Marks Hospital tor of the Dukes staging classication, in 1932. Recognizing the patholof lymphatic spread, Dukes created a system where involvement of regio

was designated stage C, regardless of depth of tumor invasion into the bsystem was further modied into the Astler-Coller modied Dukes sys

ed node-positive patients according to depth of tumor penetration in 19The TNM system in use today was rst introduced in 1953 and is

the Dukes staging system with varying degrees of modications. The currsystem for colorectal cancer was jointly developed by the American JoinCancer (AJCC) and the International Union Against Cancer (UICC).[6change in the most recent sixth edition of the AJCC Cancer Staging Mcation of stage III into IIIa (T1/2, N1), IIIb (T3/4, N1), and IIIc (N2), asferences in survival were seen among node-positive patients who were pretogether into a single group in the fth edition (T, any N1, M0).[7]

Although the current staging system has been validated by a numbcluding two that analyze over 56,000 colorectal cancer patients with stagesome inconsistencies have arisen, highlighting the problem of undedisease. In a study of the Surveillance, Epidemiology and End Results (

OConnell et al compared survival using the sixth edition of theManual .[10] In their analysis, they found that survival in patients with sM0) disease was actually worse than in those presenting with stage IIIadisease. Furthermore, a recent population-based analysis found that only receive adequate lymph node evaluation.[11] These ndings suggest that g IIb di ith i d t l t g d th t th b t


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Surgical Management of Rectal Cancer and Its Variants). The importancelymph node retrieval has become increasingly apparent, and current guidthat at least 12 nodes be assessed in order to consider a patient truly noderecommendation was established by a number of governing bodies, incluthe UICC, the World Congress of Gastroenterology, and a National C(NCI)-sponsored panel of experts specically gathered to ensure adequaassessment.[12-15] However, it should be noted that this nal recommenover time and is based on numerous studies that have suggested that as fewas 40 nodes were an ideal minimum obtained during resection.[16-18]

Early studies of patients with stage II disease found that those with sinodes assessed had a lower survival than patients with more than six removal of only six nodes was eventually determined to be inadequate for

by Caplin et al.[19] A report by Wong et al[17] analyzing the National Cconcluded that a minimum of 14 nodes would lead to accurate staging for Another group studied 2,427 patients with T3 tumors and found a 75.8%survival when 17 nodes were assessed compared to 62.2% for those within their surgical specimen.[20,21] Some authors utilized mathematical mthe Poisson paradigm and the Bayes theorem to mathematically conrmnegative patients were adequately staged.[22]

Eventually, an international consensus of a minimum of 12 lymph noon, though interestingly, none of the available trials at the time used 12off. Subsequent analysis of actual lymph node retrieval noted that in thethe median number of lymph nodes recovered following colorectal res9, and that only 37% of patients actually had 12 or more nodes recoverepercentage improved to 44% of patients who were adequately staged wlymph nodes.[11] These results were not unique to the United States, atrials from the Netherlands, Canada, France, and Sweden found the medlymph nodes examined at surgery to be seven to nine.[23-25] It is signicthe assessment of at least 12 lymph nodes is one of the quality measuretargeted by the NCI-sponsored National Quality Forum on colorectal cancof the American College of Surgeons quality assurance program, the nu


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Surgical FactorsThe rst variable that must be considered is the quality of surgica

surgeon must provide an adequate specimen that is composed of the secontaining the tumor and its associated mesentery to the level of theing vessels. Long-term survival and local failure rates after surgical treatm

cancer and other malignancies

have been associated with surgeon andsuggesting that surgeon or hospital volume may be a surrogate indicatoity.[27-29] Surgeons performing a high volume of colorectal resections ming a more complete resection of the primary tumor with a more complethe lymph nodecontaining mesentery. In fact, surgeon volume has been lymph node recovery as well.[30] Furthermore, resections occurring in teahave been observed to have a higher recovery of lymph nodes as wel

hospital volume is also associated with an increased number of lymph nand reects inuences by both the surgeon and pathologist.[34] Patients hospitals were more likely to have fewer than seven lymph nodes evato have positive lymph nodes detected.

Pathologist-Related Factors

High hospital volume also leads to increased experience and experof the pathologist. Much like the surgeon who specializes in colorectal dgists who develop a special interest in colorectal cancer will identify of lymph nodes in a given specimen. In a multicenter trial from the Neadjustments for relevant factors such as stage and adjuvant therapy, there patient survival between departments of pathology, based on the ability tonodes.[35] As evidence that pathologic assessment was as important a

Dutch study, there was no difference in the number of lymph nodes recohospitals that were covered by the same department of pathology. Furthercovered by two separate pathology groups had lymph node recovery rpathology group rather than surgeon. These results suggest that pathologsurgical practice patterns may be more important in lymph node recover


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have been shown to be important in lymph node recovery after adjustinand tumor-related factors.[30,38] Thus, both surgeon and pathologist f

with lymph node recovery may inuence the relationship between hcolon cancer outcome.

Patient FactorsThere are a number of patient-related factors that can inuence the nurecovered following surgery. A brotic response occurs in patients whpreoperative chemoradiotherapy, making it difcult to identify nodesevaluation; the size of both normal and involved lymph nodes decreasaverage lymph node harvest for patients following preoperative therapylower, the AJCC has concluded that a pathologic N0 designation was justifollowing chemoradiation even when the optimum number of 12 nodesable for analysis.[6]

Another patient factor that affects lymph node recovery is the anatoresection. Right hemicolectomy and subtotal colectomy appear to give thelymph nodes compared to transverse colectomy and abdominal-perineal rea 33% to 48% reduction in the number of lymph nodes is seen.[39] Other

include older age and obesity, which decrease lymph node recovery (a 6.8lymph node recovery for every 10-year increase in age).[11,32,40] Howevemay perform less extensive or palliative operations on older patients, whthe association between age and the number of lymph nodes recovered.

Increasing the Sensitivity of Detecting Lym A more thorough scrutiny, as well as a more sensitive analysis, of l

are recovered with surgical resection of colorectal cancer represent straaccurately stage a patient. The standard assessment of lymph nodes is to bieach half of all identied nodes larger than 2 mm in size. Simply increasof sections taken of individual nodes could increase the sensitivity of detemetastases. However, this approach would also increase the workload


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The use of immunohistochemical evaluation of lymph nodes usingantibodies can also detect micrometastasis with greater sensitivity thanevaluation of lymph nodes. At this time, however, the clinical signicanstatic disease that is not detectable by conventional means is unclear.[4tion that patients with node-negative disease have a signicantly pooremicrometastatic disease detected by IHC is a matter of debate. Some in

identied a higher risk of recurrence as well as adverse outcome with micthe regional lymph nodes and have recommended the routine IHC evaluapatients,[43] though other authors have suggested there is little to no clinicto micrometastases.[44,45] Given the increased workload and lack of croutine immunohistochemistry is not recommended on all lymph nodes used selectively.

An even more sensitive test for micrometastases is using reverse tramerase chain reaction (RT-PCR) to detect three epithelial markers (carcantigen, guanylyl cyclase, and cytokeratin 20) in histologically node-nReverse transcriptasepolymerase chain reaction is highly sensitive at metastases in 24.5% of patients previously categorized as node-negativthe detection rate of micrometastases in lymph nodes by a reported 66%.to the results of IHC, the clinical value of PCR-positive micrometastases

and its use in routine practice is not currently recommended.

Sentinel Lymph Node BiopsyGiven the success of sentinel lymph node (SLN) biopsy techniques

and melanoma, a signicant amount of research has been directed towaapplicability and usefulness in colorectal cancer. Unlike breast cancer a

sentinel node biopsy in colorectal cancer does not reduce the extent of surgbut instead allows for a more focused analysis of a few lymph nodes, ofRT-PCR techniques. Furthermore, SLN may identify unusual or unconvnode drainage patterns and allow these areas to be removed with the surgThough uncommon, direct drainage into the para-aortic basin or oppos

l h b d [48 49]


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of the sentinel node. Timing of dissection is not standardized, but appro60 seconds following injection, dissection of the mesentery is performblue lymphatic path to the blue-stained SLN. A gamma probe may be udissection if 99mTc is used.[50]

An alternative ex vivo method has been proposed by Wong et al.[5resection, the surgical specimen is placed on a back table and 1 to 2 mL odye is injected into the subserosa around the tumor. Again, ex vivo, the lycarefully dissected to the sentinel node which is marked for further patholotechnique has demonstrated success both as a primary means of identifyinalso as salvage when in vivo mapping is unsuccessful. However, ex vivo mdoes not allow for the identication of atypical lymphatic drainage patte

The initial results of SLN biopsy for colon cancer demonstrated a h

of identifying sentinel nodes and good accuracy in predicting nodal disal reported results of a phase II multicenter trial where SLN were identhe time with an 88% sensitivity.[53] Of note, 24% of patients with stagupstaged by SLN biopsy and IHC.

In contrast, Bertagnolli et al reported on the results of a prospectivmulticenter trial of SLN biopsy for colon cancer and found a 92% locaaccuracy of 80%, but a high false-negative rate of 58% using standard H&authors then reanalyzed the data using IHC and improved their false-negatiusing a denition of a positive single tumor cell seen on IHC. Using thisof node-negative patients were upstaged to have nodal diseasea far grethan the 25% recurrence rate typically seen in stage II patients.[54,55] Gchemotherapy to this entire cohort of patients with a single positive lymph nodes would likely overtreat this group of patients. Clearly, a bstruck between sensitivity and accuracy of SLN biopsy and what is conrelevant in colon cancer.

Rectal cancer SLN biopsy is technically more difcult than colon SLthe inability to access tumors that are not visible from the peritoneal side

A posterior tumor could only be visualized by disrupting the mesocolo


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modality of endorectal ultrasound in rectal cancer dictating neoadjuvant SLN biopsy for rectal cancer is likely to be limited.

Alhough SLN biopsy for colon cancer appears to be of reasonable actions are twofold. First, it does not change the morbidity of nodal dissectechnique in terms of excision of local tumor or nodal drainage, except iof atypical nodal basins. Second, the true impact of SLN biopsy will not bmicrometastatic disease, as detected by PCR or IHC, is demonstrated tosignicancethen the detection of micrometastases to the lymph nodes, dbiopsy in node-negative patients, will be much more useful. The current litthat micrometastases contribute to a slightly poorer prognosis than node-nbut is not quite equivalent to true node-positive disease. Initial results cancer and melanoma SLN biopsy were less than ideal as well; perhaps ative data are accumulated and surgical technique improves, SLN biopsy f

will slowly be adopted. For now, it is a technique that provides a modicinformation compared to a standard resection with adequate nodal samp

SummaryThe number of lymph nodes recovered from a patient with colon

identied as a potentially important measure of the quality of cancer care b

College of Surgeons, the American Society of Clinical Oncology, thhensive Cancer Network, the National Quality Forum, and health in

The recovery of at least 12 lymph nodes has become the international stanpatients with colorectal cancer. Based on the literature, it is clear that inanode recovery leads to poorer outcome due to a missed opportunity totherapy to a patient who actually has node-positive disease, as well the theof leaving gross disease behind that could progress.

Since the institution of the 12 lymph node standard, an additional clhas arisen: what to do with colorectal cancer patients who are clearly usignicantly less than 12 nodes assessed and no evidence of nodal diseasepatients should receive adjuvant therapy is a matter of ongoing debate; tfurther addressed in chapter 6 of this book


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It remains to be determined whether obtaining substantially more nodes is benecial, or what signicance a single cell found by IHC in a lymsents. As molecular proling of tumors with gene and protein microarrayscommonplace in predicting and directing treatment options for individual of these issues and technologies may become obsolete.[57] Until then,continue to use technology that has not changed for decades, namely, lig

with the precise counting and staining of nodes.

References1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 52. Sobrero A, Kohne CH: Should adjuvant chemotherapy become standard treatm

with stage II colon cancer? Lancet Oncol 7:515-517, 2006.

3. Engstrom PF, Benson AB, III, Chen YJ, et al: Colon cancer clinical practice guid J Natl Compr Canc Netw 3:468-491, 2005.4. Chang GJ, Rodriguez-Bigas MA, Skibber JM, et al: Lymph node evaluation andtive resection of colon cancer: Systematic review. J Natl Cancer Inst 99:433-445. Astler VB, Coller FA: The prognostic signicance of direct extension of carciand rectum. Ann Surg 139:846-852, 1954.6. Greene FL, Page DL, Morrow M, et al: AJCC Cancer Staging Manual . New Y

7. Merkel S, Mansmann U, Papadopoulos T, et al: The prognostic inhomogeneity cinomas stage III: A proposal for subdivision of stage III. Cancer 92:2754-2758. Greene FL, Stewart AK, Norton HJ, et al: A new TNM staging strategy for nodecolon cancer: An analysis of 50,042 patients. Ann Surg 236:416-421, 2002.9. Greene FL, Stewart AK, Norton HJ: New tumor-node-metastasis staging strateg(stage III) rectal cancer: An analysis. J Clin Oncol 22:1778-1784, 2004.10. OConnell JB, Maggard MA, Ko CY: Colon cancer survival rates with the nCommittee on Cancer sixth edition staging. J Natl Cancer Inst 96(19):1420-1411. Baxter NN, Virnig DJ, Rothenberger DA, et al: Lymph node evaluation in patients: A population-based study. J Natl Cancer Inst 97:219-225, 2005.12. Nelson H, Petrelli N, Carlin A, et al: Guidelines 2000 for colon and rectal can


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for pNO. Cancer 92:452, 2001.16. Hernanz F, Revuelta S, Redondo C, et al: Colorectal adenocarcinomaQualityof lymph-node metastases. Dis Colon Rectum 37:373-376, 1994.17. Wong JH, Severino R, Honnebier MB, et al: Number of nodes examined andin colorectal carcinoma. J Clin Oncol 17:2896-2900, 1999.18. Esser S, Reilly WT, Riley LB, et al: The role of sentinel lymph node mapping and rectal cancer. Dis Colon Rectum 44:850-854, 2001.19. Caplin S, Cerottini JP, Bosman FT, et al: For patients with Dukes B (TNM Scarcinoma, examination of six or fewer lymph nodes is related to poor prognos672, 1998.20. Goldstein NS, Sanford W, Coffey M, et al: Lymph node recovery from cspecimens removed for adenocarcinomaTrends over time and a recommendationnumber of lymph nodes to be recovered. Am J Clin Pathol 106:209-216, 199621. Berberoglu U: Prognostic signicance of total lymph node number in patientcolorectal cancer. Hepatogastroenterology 51:1689-1693, 2004.22. Turner JW, Vollmer RT: Impact of Bayes theorem and Poisson paradigm on onegative colorectal cancer patients after surgical resection. Mod Pathol 18:1223. Lemmens VE, van Lijnschoten I, Janssen-Heijnen ML, et al: Pathology praclymph node evaluation and outcome of colon cancer: A population-based study.

1809, 2006.24. Maurel J, Launoy G, Grosclaude P, et al: Lymph node harvest reporting in patienof the large bowelA French population-based study. Cancer 82:1482-1486, 25. Jestin P, Pahlman L, Glimelius B, et al: Cancer staging and survival in colon caon the quality of the pathologists specimen examination. Eur J Cancer 41:2026. Commission on Cancer, eQuIP. American College of Surgeons Website: httpNCIC/BMARKS/colorecdata/ColoRec_eQuIP_Overview.pdf

27. Harmon JW, Tang DG, Gordon TA, et al: Hospital volume can serve as a surr volume for achieving excellent outcomes in colorectal resection. Ann Surg 228. Ko CY, Chang JT, Chaudhry S, et al: Are high-volume surgeons and hospitals tpredictors of inhospital outcome for colon cancer resection? Surgery 132:2629 P KS S h D Ri d l E t l Th ff t f l t i f t


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32. Wright FC, Law CHL, Last L, et al: Lymph node retrieval and assessment incancer: A population-based study. Ann Surg Oncol 10:903-909, 2003.33. Pheby DFH, Levine DF, Pitcher RW, et al: Lymph node harvests directly inuecolorectal cancer: Evidence from a regional audit. J Clin Pathol 57:43-47, 20034. Miller EA, Woosley J, Martin CF, et al: Hospital-to-hospital variation in lymafter colorectal resection. Cancer 101:1065-1071, 2004.

35. Lemmens VE, van Lijnschoten I, Janssen-Heijnen ML, et al: Pathology praclymph node evaluation and outcome of colon cancer: A population-based study.1809, 2006.36. Compton CC: Updated protocol for the examination of specimens from patientsof the colon and rectum, excluding carcinoid tumors, lymphomas, sarcomas, an

vermiform appendixA basis for checklists. Arch Pathol Lab Med 124:1016-137. Cohen SM, Wexner SD, Schmitt SL, et al: Effect of xylene clearance of mesenof lymph-nodes after colonic resection. Eur J Surg 160:693-697, 1994.38. Ratto C, Sofo L, Ippoliti M, et al: Accurate lymph-node detection in colorectal sfor cancer is of prognostic signicance. Dis Colon Rectum 42:143-154, 1999.39. Tekkis PP, Kinsman R, Thompson MR, et al: The association of coloproctology oIreland study of large bowel obstruction caused by colorectal cancer. Ann Su40. Gorog N, Nagy P, Peter A, et al: Inuence of obesity on lymph node recovery

tion specimens. Pathol Oncol Res 9:180-183, 2003.41. Verrill C, Carr NJ, Wilkinson-Smith E, et al: Histopathological assessment colorectal carcinoma: Does triple levelling detect signicantly more metastases?1167, 2004.42. Greenson JK, Isenhart CE, Rice R, et al: Identication of occult micrometalymph-nodes of Dukes-B colorectal cancer patients using monoclonal antibodies aand Cc49Correlation with long-term survival. Cancer 73:563-569, 1994.

43. Sasaki M, Watanabe H, Jass JR, et al: Occult lymph node metastases detecimmunohistochemistry predict recurrence in node-negative colorectal canc32:758-764, 1997.44. Cutait R, Alves VAF, Lopes LC, et al: Restaging of colorectal-cancer based oof lymph-node micrometastases through immunoperoxidase staining of CEA and


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48. Yamamoto Y, Takahashi K, Yasuno M, et al: Clinicopathological characteristicnode metastases in patients with colorectal cancer. Jpn J Clin Oncol 28:378-3849. Bilchik AJ, Saha S, Tsioulias GJ, et al: Aberrant drainage and missed micromeof lymphatic mapping and focused analysis of sentinel lymph nodes in gastrointeAnn Surg Oncol 8:82S-85S, 2001.50. Saha S, Dan AG, Viehl CT, et al: Sentinel lymph node mapping in colon and

impact on staging, limitations, and pitfalls. Cancer Treat Res 127:105-122, 20051. Wong JH, Johnson DS, Namiki T, et al: Validation of ex vivo lymphatic mappineosin node-negative carcinoma of the colon and rectum. Ann Surg Oncol 11:52. Wong JH, Steineman S, Calderia C, et al: Ex vivo sentinel node mapping incolon and rectum. Ann Surg 233:515-521, 2001.53. Bilchik AJ, DiNome M, Saha S, et al: Prospective multicenter trial of stagingcancer: Preliminary results. Arch Surg 141:527-534, 2006.54. Redston M, Compton CC, Miedema BW, et al: Analysis of micrometastaticlymph nodes from resectable colon cancer: Results of Cancer and Leukemia Gro

J Clin Oncol 24:878-883, 2006.55. Bertagnolli MM, Redston M, Miedema B, et al: Sentinel node staging of resectResults of CALGB 80001. J Clin Oncol 22:246S, 2004.56. Braat AE, Oosterhuis JWA, Moll FCP, et al: Sentinel node detection after preoperadiotherapy in rectal carcinoma is not reliable. Br J Surg 92:1533-1538, 200557. Sticca RP: Is there clinical value to sentinel lymph node sampling in colon c24:841-842, 2006.


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Minimally Invasive Colo

Chapter 2: The Role of Minimallin Colon Cancer Resect

Andrew J. Duffy, MD, FACS

Surgical removal of a primary colon tumor is essential for treatmeintent. The importance of successful surgery in colon cancer outcome m

variations in surgical techniques or treatment plan must be at least eqhistorical standards of care.

There is now increasing patient and physician emphasis on minimain some cases, endoscopic therapies for malignancy and complicated disease. These treatment modalities have been and are currently undergclinical trials to ensure that any perceived patient benet is not at the exp

oncologic principles. These studies are carefully evaluating laparoscopiccolon cancer with regard to standard endpoints such as disease-free surviconcerns about tumor recurrence at surgical wounds and metastatic potentiof pneumoperitoneum are also being examined. Increasingly, attention ison the extent of the mesenteric lymphadenectomy during colon cancer sscopic or open, and their respective prognostic and potential curative va

TerminologyThere are a number of variations of the technique of laparoscopic

several terms are used with, at times, subtle distinctions:

Laparoscopic colectomy refers to complete mobilization of the coloh d i l i f h b l Th i


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16 Minimally Invasive Colon Cancer Resection

mesenteric attachments are divided through the extraction incision. The constructed extracorporeally.

Hand-assisted laparoscopic colectomy is a hybrid procedure that invotion of one of the surgeons hands through a gas-tight seal. The intracorused to assist in retraction and mobilization of the colon. The introducthand is used, with its accompanying wound barrier, as the extraction sitehand incision is generally related to the size of the surgeons hand and win the largest incision of the three variations of this procedure.

Operative Technique and ConsideraFor most patients with colon cancer, the diagnosis is established

usually with a tissue diagnosis from colonoscopy. One of the most imp

operatively for laparoscopic colon surgery is to ensure the location of thThis is particularly true in cases where cancer was detected in a polyp tor completely resected endoscopically. Except in hand-assisted laparoscois not able to directly palpate the bowel to locate lesions. When tumors operatively, it is essential for the endoscopist to ensure the location is Endoscopic tattooing of the area in multiple locations around the circumbowel is the most effective method. For polyps at clear landmarks, such as

orice or ileocecal valve, endoscopic marking is not required if adequate of the lesions position is provided. If a tattoo mark is not visible at thedespite careful inspection of the entire colon, intraoperative colonoscopy tool. Inability to locate the lesion may result in conversion to a hand-assiprocedure for full manual palpation of the bowel.

Any abdominal cancer operation includes a complete inspection of tand the liver. Again, as in most laparoscopic procedures, the liver cannotpated. A preoperative abdominal and pelvic CT scan is routine for colon undergoing laparoscopic resection to help direct the intra-abdominal visIntraoperative ultrasound with a laparoscopic ultrasound probe is also evaluate suspicious liver lesions.


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this pressure, most patients require 2 to 3 L of gas insufation. COused because it is noncombustible and rapidly absorbed into the bloodstrecharacteristic speeds absorption at the conclusion of the procedure and hpatient discomfort from residual gas.

The absorbed CO 2 is solubilized in the bloodstream. The increaserected, will result in acidosis, with the accompanying physiologic deranesthesiologist compensates for the CO 2 absorption by increasing the during the period of insufation. Patients with signicant pulmonary dretention at baseline may not tolerate prolonged pneumoperitoneum.

The positive intra-abdominal pressure required to complete the procent some challenges for perioperative uid management. Especially inresection where a preoperative bowel preparation is used, many patien

dehydrated at the onset of the procedure. If the abdominal pressure is signithan the central venous pressure, venous return to the heart and cardiac fuimpeded. Careful pre- and intraoperative hydration usually counteracts t

Intraoperative and postoperative uid requirements for laparoscosurgery are signicantly lower than those for open surgery. This is relafactors including decreased evaporative losses during the procedure andas further discussed below.

The space realized by insufation is adequate for most procedures iOnly in rare cases of extreme bowel distention is abdominal exposurefeasible. Obesity and prior surgery are not contraindications to laparoscop

TABLE 1. Indications and contraindications for laparoscopic colon resectio

for cancerIndications Contraindications

Same as for open Inability to tolerate general anesthespneumoperitoneum


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laparoscopic bowel resection, although both can present technical challeng

FIGURE 1. This intraoperative laparoscopic view for a right hemicolectomy demosure that can be obtained with careful bed positioning. In this case, the Trendelenbethe bed rolled to the patients left side is used. The third portion of the duodenumthrough the right colon mesentery. The liver (L), right colon (RC), and transverseas shown. The ileocolic artery (IA) label is at its origin off the superior mesenteri


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5-mm incisions, and most techniques of laparoscopic colon resection resions. Incisions of 12 mm in size are generally required for most staplin

In place of standard retractors to maneuver the bowel, bed positioningis critical. Positioning the patient in the Trendelenberg position helps kintestine out of the surgical eld for pelvic and lower abdominal procthe patient to the right and left side down positions, similarly, assists in manual and mechanical retraction would be used in open procedures. Ducases, the bed may be repositioned several times during the course of the cexposure for various areas of the abdominal cavity (Figure 1).

During cases when a specimen is to be extracted, it can either be withan existing port, or directly through one of the small incisions. For proccolectomy, one incision needs to be enlarged to accommodate the cross-s

the specimen. Most colon specimens require either enlarging an existing ining a separate incision for specimen extraction. For example, for a left csurgeons will perform a left lower quadrant, muscle-splitting incision thperform the extraction.[1] This incision is usually between 2.5 and 6 cmnow the standard of care to exclude the specimen from the wound, either a wound protector or a specimen retrieval bag, as seen in Figure 2.[2] Tr


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tion of specimens may also be performed during left colon surgery and recThis technique eliminates the need for abdominal incision expansion.

Evolution of Laparoscopic Surgery for CThe widespread use of laparoscopic techniques for abdominal surge

late 1980s. Gynecologic procedures were a starting point, but the techniquto common general surgical procedures, including cholecystectomy and aLaparoscopic cholecystectomy is now considered the standard of caresurgery by patients and physicians alike. The benets to the patient are ininclude shorter hospital stays, less postoperative pain, and faster return tactivity.

The lessons learned from the development of laparoscopic cholec

been applied to more complex abdominal and gastrointestinal procedulaparoscopic variations of procedures for colon diseases, reux, achalasiorgan disease, and morbid obesity.

As of 2007, most open abdominal procedures have a laparoscopic aroscopic techniques are increasingly commonplace for malignant disease iand rectal cancer, gastric cancer, and early-stage esophageal cancer. Tratechniques is widely sought after by surgeons in training and is an essenof premier minimally invasive, colorectal, and surgical oncology fellow

The rst laparoscopic colon procedures were performed in 1990. DeMoises Jacobs, individually, published their initial experiences in the sa

journal Surgical Laparoscopy and Endoscopy in September 1991.[1,3] Thestrated that laparoscopic techniques could be safely applied to colonic reseleft-[1,3] and right-sided diseases.[3] The development of colon surgery

with other advanced laparoscopic surgery procedures, was very dependeopment of novel technology to facilitate the safe completion of these pro

Specically, laparoscopic analogs of open surgical stapling devicesto ensure reliable, reproducible ligation and division of the mesenteric vaand to transect the bowel specimen. Other devices have subsequently reac


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Potential Advantages of the Laparoscopic ApproachIn addition to demonstrating that laparoscopic colon surgery is f

Jacobs, and others have gone on to demonstrate that the benets to the proscopy can be applied to major bowel resections. These benets comeof increased operative and anesthesia time in all major reports on laparesection.

Some of the potential benets for patients are hard to quantify, su wound cosmesis and less adhesion formation. The latter may translate into rates of bowel obstruction, but signicant data to support this are lackipotential advantages of the laparoscopic approach are enumerated below

Postoperative PainMultiple authors have attempted to quantify postoperative pain aft

colectomy with Visual Analog Scores (VAS) and tracking of narcotic reresults have consistently demonstrated an signicant overall reductioncompared to patients who have undergone an open colectomy.[2,4,5] Irequirements are similar for the rst 12 hours after surgery, but rapidlyrst postoperative day. Over the subsequent hospital stay, narcotic re

roughly half of that required following open colectomy.[4] In addition to ton patient comfort, minimizing postoperative narcotic requirements mayfaster return of bowel function and shorter length of stay (LOS).

Length of StayMultiple authors have commented on the duration of stay after lapa

resection, for both benign and malignant disease. Hospital LOS is usthe time to return of bowel function and ability to tolerate a diet. Practicbetween Europe and the United States but multiple prospective studiesignicantly shorter stays following laparoscopic surgery.[6-8] The lrigorously constructed multicenter, prospective trials comparing laparos


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Return to WorkThis outcome measure is harder to accurately quantify than LOS but

important to the patient and the employer. Any analysis of the costs of sulost worker productivity, will be incomplete without assessing this relevaIn a nonrandomized fashion, Fowler and Franklin have reported an aver

weeks for patients return to work after surgery.[8,12] This timeline comage of 7 weeks after open resection in Franklins 1996 series.[8] These daa one-third to one-half reduction in the time to return to full duty.

Blood LossReduced intraoperative blood loss is an often overlooked benet

surgery. For many operations performed laparoscopically, there is signicloss than the equivalent open procedure. As demonstrated in the COLOR trthere is signicantly less blood loss in laparoscopic colon surgery.[9]

A surgeons ability to successfully perform laparoscopic surgery is liity of the view and the contrast between tissue planes. Even small amount

will signicantly impair the surgical exposure. As a result, very meticurequired to minimize tissue trauma and bleeding. The pneumoperitone

by helping to tamponade small, low-pressure bleeding sources. An abdo with the accompanying abdominal wall injury, is often the signicant soerative blood loss during open procedures and is generally minimized witechniques.

Port Site Recurrence

The early reports of technical feasibility, combined with favorable shodata in the early and mid-1990s, encouraged the application of laparoscopithe treatment of colon cancer. Indeed, many publications at that time inc

who underwent surgery for benign or malignant disease.[3,7,12] Howevcerns were raised about tumor recurrence at the surgical port sites at rat


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site wound recurrences has been reported between 0%[15] and 21%.[16]about port site metastasis have led to further basic science research anphasis on prospective, randomized clinical data on short- and long-terthese procedures.

Several studies have been performed in animal models evaluating thtreatment at the time of surgery of port sites. Numerous substances havincluding chemotherapeutic agents such as oxaliplatin (Eloxatin). Althodecreased tumor implants at port sites has been noted with oxaliplatin istatistical signicance was not obtained.

Perhaps the most interesting nding of this and other similar studieimmunocompromised rat model, peritoneal injection of colon cancer ceence of unprotected wounds and positive pressure pneumoperitoneum res

rate of tumor implantation in controls.[17] This model highlights the neesurgical technique including trocar site protection, careful venting of inand careful handling of the tumor specimen.

Effects of Pneumoperitoneum and OncoloMetastatic spreadlocally throughout the peritoneum or distant via

or lymphatic channelsis a primary concern in colon cancer diagnosis

Mechanical factors from tissue handling, spillage of luminal contents, orthe tumor can lead to exfoliated cells in the bowel lumen and free cells incavity. The no touch technique of cancer surgery has long been esponcologic principle. This dictum emphasizes minimizing direct mechathe tissues, especially the areas containing a malignancy. As such, this isimportant in laparoscopy than open surgery given the inherent limitations oinstrumentation and the loss of direct tactile feedback from the operative

On a cellular level, any effects of direct manipulation of the tumexfoliated cells may be magnied by some of the effects of the CO 2 pLocal effects of increased pressure, acidosis, and hypoxia have been daffect the adhesion molecules expressed in human colon cancer cell lines


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in the immediate postoperative period in patients who have undergonsurgery when compared to equivalent open procedures.[20-23] In thedegree of surgical trauma and incision length correlated with the degreeof the T-cellmediated responses.

Cellular immunity is affected in other ways. Surgery-related deprekiller cell function is less marked in laparoscopy. Neutrophil and lymphocis less inhibited and monocytes are more responsive to subsequent stantigen presenting cell HLA-DR expression is better preserved followprocedures.

All signicant surgery triggers a systemic inammatory response, woften being signicant postoperative immunosuppression. In contrast laparoscopy results in smaller postoperative increases in serum levels ofIL-6 and IL-1, tumor necrosis factoralpha (TNF- ), C-reactive

vascular endothelial growth factor (VEGF).

VEGF is a potent inducer of angiogenesis and helps support tumor line, preoperatively, VEGF levels are higher in patients with colon cancerless additional elevation was noted in laparoscopic patients.[24] The higheincreases seen in open surgery may constitute a detrimental oncologic laparotomy but this effect requires more study.

The upregulation of many inammatory mediators also correlates wserum decrease of insulin-like growth factorbinding protein-3 (IGFBP-3)patients, when compared with matched laparoscopic patients.[25] IGFBsuppressor effects. Plasma from patients who undergo major open surginduces signicant in vitro tumor growth when compared to the same ppreoperatively.[26] The combined effects of variations in serum proteinsmediators, and immune cell function may have signicant effects on theoperative patients to respond to infections, eliminate micrometastatic tuon their overall recovery after surgery. Possible oncologic benets of laparequire further exploration.


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this series. Oncologic outcomes over the study duration were equivalent

In 2002, Lacy published a single-institution, randomized proslaparoscopic colon cancer surgery. This study included 219 patients. Thconversion rate to open surgery in the laparoscopic group. The patients alaparoscopic arm required shorter length of stay and had faster return of bpostoperatively. There was an overall lower complication rate in this grou

ingly, a survival advantage was noted in stage III patients who underwsurgery. The authors concluded that laparoscopic colectomy conferred ansurvival advantage over open surgery for colon cancer.[27]

To date, the effects noted for stage III patients in the Lacy trial have duced and this study has been criticized for yielding suboptimal lymph for analysis, a mean of 11.1 in both the open and laparoscopic arms.

A number of case series and prospective trials have since been publfactory results and equivalency to open surgery have been universally rOne recently reported study, a prospective randomized trial from Taiwanto investigate possible long-term clinical advantages for patients with stacolon cancers. All patients underwent a formal left hemicolectomy withmobilization. Patients with unsuspected metastatic disease discovered excluded from the nal analysis. In this study, lymph node retrieval was s

the open and laparoscopic groups, 15.6 and 16.0, respectively. There wsion rate to open surgery in the laparoscopic groups. These patients wethe laparoscopic group for the statistical analysis. With a median follow-usurvival and recurrence rates were equivalent in both groups.[30]

While these results have been reassuring, most surgeons who perfocolon surgery for cancer have been awaiting the results of the largest Nand European randomized, prospective trials. The results that have beedate are summarized below and are outlined in Table 2.

The COST Trial


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48 institutions in North America. Patients were randomized into laparotreatment paths. Throughout this study, there was a 21% conversion ratscopic to open surgery. For the purposes of the study, these patients were laparoscopy arm of this intention-to-treat analysis.

At the participating institutions, 66 surgeons were enrolled as providein technique is considered the most likely contributing factor to port sit

strict technical requirements were implemented for the duration of the tributing surgeons were required to document a minimum of 20 laparoscresections. In addition, an expert panel reviewed representative case each surgeons adherence to oncologic techniques. Throughout the studparticipants were subject to a random audit of case video and pathologicadequacy of bowel margins.

The oncologic techniques required for certication for the study includabdominal exploration, identication of critical adjacent structures suchand major vessels, avoidance of direct tumor manipulation, and a high leve

vessel ligation. High ligation of the mesenteric pedicle is necessary to elymphadenectomy during the procedure.

The short-term outcome data from the COST trial was published ining many of the ndings regarding the patient benets of laparoscopy d

postoperative period.[9] The long-term data and conclusions were publis England Journal of Medicine in 2004. With a median follow-up of 4.4 yearsno differences in recurrence rate, survival, or the rate of wound recurrthe laparoscopic and open arms. Patients with lymph nodepositive caequivalent survival between the groups.[2] In both the open and laparoscthis trial, the median number of lymph nodes harvested and analyzed wa

This study concluded that laparoscopic colectomy is equivalent to the hands of appropriately trained and experienced surgeons for the treatmcancer.

The MRC-CLASICC and COLOR Trials


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abdominal perineal resections. The mean number of lymph nodes obtainearm was 13.5 vs 12 in the laparoscopic group. This nding suggests thalogic resection can be obtained in both groups.

The long-term data from this trial were published in July 2007.[34rate of positive circumferential margins for laparoscopic low anterior rescorrelate with increased local recurrence rates. The overall long-term outc

were equivalent between the open and laparoscopic groups. Further trialaparoscopy in rectal cancer are required and are ongoing.

The COlon cancer Laparoscopic or Open Resection study group (COLits short-term outcomes in July 2005. This trial does not include rectal but, unlike the COST trial, did include hand-assisted laparoscopic casesshort-term differences in outcome, length of stay, blood loss, and posscores were decreased in the laparoscopic arm.[5] The extent of lymph nthis trial is somewhat less than the other major studies at a median of 10 the study. Long-term outcome data are pending.

In March 2007, the authors of COST, COLOR, and CLASICC trialsa meta-analysis of the available 3-year follow-up data. Cumulatively, included in the laparoscopic arm of the analysis, 740 in the open arm. Thrmed the independent ndings of the COST and CLASICC trials in th

and open colectomy are equivalent in long-term outcomes for colon canIn an interesting offshoot from the COLOR trial, the Swedish con

cohort was independently analyzed for cost differences between the opscopic approaches. Although laparoscopic resection resulted in increashealth-care system, this difference was recouped by 12 weeks from profrom earlier returns to work. There was no signicant societal cost diffaspects were considered.[36]

Numerous other reports are now available reporting on case series follow-up, including a number or retrospective series with 5-year folloThe reports to date demonstrate similar short- and long-term outcomeprospective randomized trials.[38]


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of conversion to open surgery, perioperative complications, and cancer rThe authors concluded that patients who undergo laparoscopic resectioncolon cancers will have equivalent oncologic outcomes and will benetterm advantages of laparoscopy.

The Role of LymphadenectomyIn 2000, a National Cancer Institute (NCI) consensus conference m

of recommendation regarding standards for colon cancer surgery. Threinforced key oncologic principles such as high ligation of the primaryat its origin with accompanying removal of the associated lymph nodessuspicious lymph nodes should also be removed.[40] Specimen analysis suite was also emphasized. Meticulous examination, with fat-removal techniques is mandated.

This emphasis on lymph node retrieval by surgeons and identicatiby pathologists is required to maximize the number of excised and exapotential nodal metastasis. A minimum target number of lymph nodes

was set at 12 for a colon resection. This number confers a greater thanin lymph node and overall tumor staging. If fewer than 12 lymph nodes referral to a medical oncologist is recommended.[41] More recent data s

number of lymph nodes retrieved during colectomy may impart more of just more accurate staging. Retrieval of greater than 18 lymph nodes at susurvival in some analyses.[42] Lymph node retrieval is clearly a key beguide subsequent treatment, and the same high standards should be maintathe colectomy is performed open or laparoscopically.

The Learning CurveIn 1991, it was projected that laparoscopic colectomy would rapidly

uitous as laparoscopic cholecystectomy through a combination of patiand surgeon ability and availability. The initial projections, as with otcomplex laparoscopic procedures, were overstated. Complex laparoscoare technically more complex than the equivalent open procedures and


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surgeon has been reported in a number of publications. Patient outcomes, otherwise, are emphasized as key bench marks of skill development. Foinitial series of 60 patients that LOS, operating room time, and complicatiodramatically with experience. He concludes that there is a steep learning culaparoscopic colectomy.[12] Wishner noted in 1995 that operative times fcolectomy dropped to a mean of 150 minutes per case after an initial expe

50 cases. After 50 cases, the operative time plateaued at 140 minutes.[44In 2007, Kang described a single-surgeon, hand-assisted experien

between 21 and 25 cases to traverse the learning curve. The endpoints of otime, return of bowel function, intraoperative blood loss, and LOS all lecase range.[45]

Based on this experience, the most recent revision of NCI guidelinecancer surgery, published in November 2006, mandates a requirement laparoscopic colorectal resections be successfully completed by an indeither during training, by proctoring, or for benign disease before proceroscopic colorectal resection for cancer.[41] This recommendation is mthat surgeon experience and skill do not negatively impact the oncologpatients with potentially curable colorectal malignancies.

Surgeon CredentialingSurgeon credentialing is becoming an increasingly important topic atices become more specialized. Hospitals and surgical facilities have evopatients increasingly inquire about surgeon experience, and major insuranbecoming more inquisitive about individual surgeon outcome data.

Current guidelines on credentialing surgeons for advanced laparoscoin general and specically for laparoscopic colorectal surgery are deconsensus guidelines of major surgical organizations. The experience anpractice required for admittance to the COST trial is the basis for these glong-term outcome data of this trial supports the conclusion that with tenforced, oncologic outcomes of laparoscopy are equivalent to open p


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metastatic cancer (noncurative intent) with anastomosis should be comgranting of privileges for potentially curative colorectal cancer excision

ConclusionsThe COST trial and other studies have established the effectivene

laparoscopic colectomy for colon cancer. Since the development of the t

equipment that enable laparoscopic colon surgery, signicant insight hainto the skills required, the standards to be set, and the surgical principlesto for safe and effective resections for curable colon cancer. Appropriaexperience is required to achieve oncologically appropriate patient otechnical difculty of the procedure with the concomitant rigid oncolrequire thoughtful surgeon operative credentialing at institutional levels national standards.

Continued efforts are required to maximize disease-free survival, winclude ongoing and future medical and surgical clinical trials, continued for excellence in training surgical residents and fellows, and close monitoriand quality markers to standardize care among practitioners and centers. Sof technical evaluation need to be applied to rectal cancer and other gmalignancies. The continued emphasis on a coordinated multidisciplithat emphasizes early detection through colon cancer screening programin surgical management, rigorous pathologic evaluation, and adjuvant trappropriate, will help ensure continued progress and uniformity in improvoutcomes and survival.

References1. Fowler DL, White SA: Laparoscopy-assisted sigmoid resection. Surg Laparo

1991.2. Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoand open colectomy for colon cancer. N Engl J Med 350(20):2050-2059, 20043. Jacobs M, Verdeja JC, Goldstein HS: Minimally invasive colon resection (laparoSurg Laparosc Endosc 1(3):144 150 1991


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688 (discussion 688-689), 1997.7. Ramos JM, Beart RW, Jr, Goes R, et al: Role of laparoscopy in colorectal surevaluation of 200 cases. Dis Colon Rectum 38(5):494-501, 1995.8. Franklin ME, Jr, Rosenthal D, Abrego-Medina D, et al: Prospective comparison scopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39(109. Weeks JC, Nelson H, Gelber S, et al: Short-term quality-of-life outcomes follo

assisted colectomy vs open colectomy for colon cancer: A randomized trial.2002.10. Stead ML, Brown JM, Bosanquet N, et al: Assessing the relative costs of standalaparoscopic surgery in colorectal cancer in a randomised controlled trial in the UCrit Rev Oncol Hematol 33(2):99-103, 2000.11. Guillou PJ, Quirke P, Thorpe H, et al: Short-term endpoints of conventional verassisted surgery in patients with colorectal cancer (MRC CLASICC trial): Multic

controlled trial. Lancet 365(9472):1718-1726, 2005.12. Fowler DL, White SA, Anderson CA: Laparoscopic colon resection: 60 cases.5(6):468-471, 1995.13. Nduka CC, Monson JR, Menzies-Gow N, et al: Abdominal wall metastases foBr J Surg 81(5):648-652, 1994.14. Ramos JM, Gupta S, Anthone GJ, et al: Laparoscopy and colon cancer. Is the preliminary report. Arch Surg 129(9):897-899; discussion 900, 1994.15. Curet MJ, Putrakul K, Pitcher DE, et al: Laparoscopically assisted colon resecinoma: Perioperative results and long-term outcome. Surg Endosc 14(11):1016. Berends FJ, Kazemier G, Bonjer HJ, et al: Subcutaneous metastases after laparoLancet 344(8914):58, 1994.17. Tai YS, Abente FC, Assalia A, et al: Topical treatment with oxaliplatin for the site metastases in laparoscopic surgery for colorectal cancer. JSLS 10(2):160-

18. Paraskeva PA, Ridgway PF, Olsen S, et al: A surgically induced hypoxic environmin the metastatic behaviour of tumours in vitro. Clin Exp Metastasis 23(2):14919. Basson MD, Yu CF, Herden-Kirchoff O, et al: Effects of increased ambient cancer cell adhesion. J Cell Biochem 78(1):47-61, 2000.20 Whelan RL Franklin M Holubar SD et al: Postoperative cell mediated im


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23. Trokel MJ, Bessler M, Treat MR, et al: Preservation of immune response afte Endosc 8(12):1385-1387 (discussion 1387-1388), 1994.24. Belizon A, Balik E, Feingold DL, et al: Major abdominal surgery increases plasmendothelial growth factor: Open more so than minimally invasive methods.798, 2006.25. Kirman I, Cekic V, Poltoratskaia N, et al: Open surgery induces a dramatic deing intact IGFBP-3 in patients with colorectal cancer not seen with laparoscopic su19(1):55-59, 2005.26. Kirman I, Cekic V, Poltaratskaia N, et al: Plasma from patients undergoing mstimulates in vitro tumor growth: Lower insulin-like growth factor binding protepart, account for this change. Surgery 132(2):186-192, 2002.27. Lacy AM, Garcia-Valdecasas JC, Delgado S, et al: Laparoscopy-assisted cocolectomy for treatment of non-metastatic colon cancer: A randomised trial.2229, 2002.28. Kaiser AM, Kang JC, Chan LS, et al: Laparoscopic-assisted vs. open colectom

A prospective randomized trial. J Laparoendosc Adv Surg Tech A 14(6):329-33429. Anderson CA, Kennedy FR, Potter M, et al: Results of laparoscopically assisfor carcinoma. Surg Endosc 16(4):607-610, 2002.30. Liang JT, Huang KC, Lai HS, et al: Oncologic results of laparoscopic versus surgery for stage II or III left-sided colon cancers: A randomized controlled tria

14(1):109-117, 2007.31. Lezoche E, Guerrieri M, De Sanctis A, et al: Long-term results of laparoscolorectal resections for cancer in 235 patients with a minimum follow-up of 5 20(4):546-553, 2006.32. Kitano S, Kitajima M, Konishi F, et al: A multicenter study on laparoscopic sucancer in Japan. Surg Endosc 20(9):1348-1352, 2006.33. DAnnibale A, Morpurgo E, Fiscon V, et al: Minimally invasive resection foPerioperative and medium-term results in an unselected patient group at a singleColoproctol 10(4):303-307, 2006.34. Jayne DG, Guillou PJ, Thorpe H, et al: Randomized trial of laparoscopic-ascolorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J 3068 2007

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38. Law WL, Lee YM, Choi HK, et al: Impact of laparoscopic resection for cooperative outcomes and survival. Ann Surg 245(1):1-7, 2007.39. Schlachta CM, Mamazza J, Poulin EC: Are transverse colon cancers suitabresection? Surg Endosc 21(3):396-399, 2007.40. Nelson H, Petrelli N, Carlin A, et al: Guidelines 2000 for colon and rectal canCancer Inst 93(8):583-596, 2001.

41. McGory ML, Shekelle PG, Ko CY: Development of quality indicators for pcolorectal cancer surgery. J Natl Cancer Inst 98(22):1623-1633, 2006.42. Prandi M, Lionetto R, Bini A, et al: Prognostic evaluation of stage B colonimproved by an adequate lymphadenectomy: Results of a secondary analysis of a ltrial. Ann Surg 235(4):458-463, 2002.43. Figert PL, Park AE, Witzke DB, et al: Transfer of training in acquiring laparoColl Surg 193(5):533-537, 2001.

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45. Kang JC, Jao SW, Chung MH, et al: The learning curve for hand-assisted lapar A single surgeons experience. Surg Endosc 21(2):234-237, 2007.

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Chapter 3: Surgical ManagRectal Cancer and Its Va

Walter E. Longo, MD

John of Arderne, the 14th century surgeon, is credited with the recsigns, symptoms, and natural history of rectal cancer. However, no fo

surgery was performed for nearly the next 400 years. The surgical trecancer has evolved signicantly over the past 250 years, paralleling theart and science of surgery. The rst procedures were local excisions aalways palliative in nature. The earliest radical procedures were essenttion of the anus and distal rectum with an incontinent perineal anus.[1]these procedures were associated with substantial morbidity, and mordue to sepsis. Improvements in anesthesia and antisepsis allowed the d

radical extirpative procedures done with curative intent. Perineal appsacral resections, and abdominal sacral resections were in vogue as rabut again, complications were frequent (more than 50%), and just as impof life (QOL) was poor.

In the current modern era of rectal cancer treatment, the managecancer has progressed tremendously over the past 80 years. Due to aderstanding of the pathology and natural history of the disease, surgicaincludes a spectrum of operative procedures ranging from radical operattive sphincter-preserving techniques including local therapy.[2]

Today, physicians managing this condition have a number of peoperative techniques at their disposal for the better treatment of these p

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perianal suturing techniques, all of which have improved oncologic outcoof life in patients with early (T1/T2 and N0) as well as locally advancedN1) rectal cancer. The use of sentinel lymph node mapping and the role are discussed in other chapters in this book.

Preoperative StagingInformation regarding the depth of tumor penetration through th

lymph node involvement, and the presence of distant metastatic disease planning rectal cancer treatment. A number of rectal tumors can be deterectal examination. Results are often reported as mobile, tethered, otumors are obviously beyond the reach of the nger, making clinical stagCurrent imaging modalities are superior to that of digital examinatioultrasound (ERUS) is currently a well-established method and appears standard for the preoperative assessment of most rectal cancers. Currentof ERUS in evaluating perirectal neoplastic inltration varies between 81%the accuracy in demonstrating perirectal lymph node involvement rangeand 83%.[4] High rectal tumors, lesions close to the anal verge and bulktumor hamper accurate placement of the probe and diminish accuracy. TERUS is also affected by tumor stage where early lesions are often overstlymph node staging is less accurate than perirectal wall inltration. When tmetastatic lymph nodes are typically hypoechoic, usually comparatively lamatory nodes (frequently 4 mm in diameter), and irregular with sharply deTechnical improvements to increase accuracy have employed endoluminacolor Doppler imaging and the use of water enema transvaginal ultrasou

Magnetic resonance (MR) imaging, initially popularized in the late 19into a useful tool in an effort to stage rectal cancer accurately. Initial stud

accuracy rates similar to those obtained with ERUS and signicantly b with standard MRI, CT, and clinical assessment. The traditional body-ccurate than ERUS and is rarely used for locoregional staging of rectal caMR imaging employing an endorectal surface coil has been extensivelyassessment of rectal cancer, and is becoming the preferred modality for th

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this staging evaluation can help to assess the local extent of the tumor, aof regional lymph nodes, and any local extension into surrounding strucCT scans can detect the presence of metastatic disease outside the local primary tumor. However, it is important to emphasize that the accuracy in local staging is inferior to that of ERUS or MR. As such, the primaryning is to determine if the primary tumor has metastasized to the liver,

ovaries, kidneys, or lungs. The accuracy of detection of liver metastasesemission tomography scanning is often used in the postoperative evalurent disease. Its role in determining response to neoadjuvant therapy is cinvestigation.[7]

Curative Treatment of Rectal CanThere are many factors involved in determining the optimal treatm

with potentially curable rectal cancer. Factors such as stage of diseasetumor from the anal verge, age and preoperative continence, the potentpermanent colostomy, the role for preoperative neoadjuvant therapy, andpatients wishes and expectations, are all crucial. A thorough and detailedall options including morbidity and quality of life are paramount. This iif a patient chooses an option that deviates from the standard of care or th

with a poor oncologic outcome.

Today, the majority of patients are treated with one form of radicaother. However, prior to embarking on this form of operative endeavor, to whether to employ preoperative neoadjuvant therapy is routinely discthe results of preoperative local staging. This combined-modality approoptimized surgery, has dramatically improved outcomes of patients wThe benets of preoperative chemoradiation have evolved from the resu

multicenter trials that demonstrated that postoperative chemoradiation for patients with transmural or node-positive rectal cancer.[8] Many centpreoperative chemoradiation to enhance chances of tumor resectability, recurrence, increase rate of sphincter preservation, and diminish treatment tients treated with preoperative neoadjuvant therapy, they are often restag



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Treatment of Early Rectal CanceTreatment of rectal cancer determined to be early upon preope

remains a controversial issue. For the most part, T1/T2, N0 proximal thcurately staged, often undergo immediate sphincter-sparing proctosigmocolorectal anastomosis. This approach is often taken of true T1 middHowever, in centers utilizing transanal endoscopic microsurgery (TEM)

peranal modality has been used for proximal and middle third T1 lesionslocal excision of early distal third rectal cancer is attractive in that it ca

with minimal morbidity and satisfactory functional results. It obviatessphincter preservation, but its oncologic benet continues to be broughtThis is especially true in high-risk lesions that are poorly differentiatadverse histopathologic features. It must be kept in mind and completthat recent evidence suggests that patients treated with local therapy harecurrence rates than those treated with radical resection. Because locanot remove the lymph nodebearing tissue of the mesorectum, accurresection may be, at best, speculative. Local recurrence rates vary betwefollowing local excision for rectal cancer. This rather wide range in locdue to the fact that lymph node involvement is 0% to 12% for T1 tumofor T2 tumors, and 36% to 79% for T3 tumors. Overall survival has bee70% to 89% in properly selected patients.[9] However, most reported sesmall sample size and follow-up of often less than 5 years.

Patient Selection for Local TherapyIdeally, tumors that are suitable for local treatment are less than 4 c

mobile on digital rectal examination, located within 7 cm from the analess than 30% of the rectal circumference, have no associated palpable pnodes, and have favorable histology. Either ERUS or MR imaging can assin selecting patients for local therapy. Regardless, patients often weighdecision, especially when local therapy is utilized for nonideal tumorThere are situations when adjuvant chemotherapy and radiation are ad

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defect in the rectal wall is either left open or closed with absorbable suturesis carefully pinned on a piece of cardboard and marked for orientation. A

with the pathologist is highly recommended for orientation and clinical cprocedure carries a low morbidity, with the most frequent complications bhematoma, urinary retention, and transient defecatory disability. Althoug

were quite encouraging, local recurrence rates, even in the setting of Tranged between 10% and 25%.[9,11,12]

Transanal Endoscopic MicrosurgeryTransanal endoscopic microsurgery was developed and populariz

1980s. Patient selection is nearly identical to local excision barring distan verge. It may be utilized for tumors located 10 cm anteriorly, 15 cm late

posteriorly. It employs a highly sophisticated 40-mm-diameter ectoscopchannels allowing the use of

a multidisciplinary approach to the treatment of early colorectal cancer, cmp medica, 2007

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