J R Soc Med 2002;95:587-590
doi:10.1258/jrsm.95.12.587
© 2002 Royal Society of Medicine
Advances in the management of rectal cancer
D Lawes MB FRCS
P B Boulos MS FRCS
Academic Division of Surgical Specialties, Royal Free and University
College Medical School, Charles Bell House, 67-73 Riding House Street, London
W1W 7EJ, UK
Correspondence to: Professor P B Boulos E-mail:
e.collins{at}ucl.ac.uk
 |
INTRODUCTION
|
|---|
Colorectal cancer is the second most common malignancy in the
western
world. In the UK 32 000 new cases are diagnosed annually,
of which
approximately 45% occur in the rectum and rectosigmoid.
Although the
management of colonic malignancies has not altered
greatly in recent years
this is not true of rectal cancer: advances
in surgical technique, molecular
biology, radiological imaging
and adjuvant therapy have dramatically altered
the way patients
are treated. This review gives a brief overview of these
changes.
|
MOLECULAR PATHOLOGY
|
|---|
Since 1932 when Sir Cuthbert Dukes described his system for
staging cancers
of the rectum, attempts have been made to identify
other factors that affect
outcome in the hope that management
can be tailored accordingly. Until
recently, little progress
had been made, but the advent of new genetic and
molecular pathology
techniques including DNA chip technology, in which
numerous
DNA sequences, can be analysed simultaneously, yielded much
new
information on the biology of malignancy.
Germline mutations responsible for inherited conditions that predispose to
the development of colorectal cancers, such as the APC gene in
familial adenomatous polyposis coli (FAP) and the mismatch repair genes in
hereditary non-polyposis colon cancer (HNPCC), have been known for some time,
allowing mutation carriers to be identified; these individuals are either
enrolled into a surveillance programme or offered prophylactic surgery before
malignancy develops. But FAP and HNPCC account for only about 5% of all
colorectal cancers, and the identification of genetic polymorphisms that
predispose to the development of colorectal cancer may be more important in
the population as a whole. Polymorphisms are normally functioning genes that
contain a region slightly different in sequence from that found in the
majority of the population. A polymorphism is commonly identified in the
APC gene of Ashkenazi Jews and increases the risk of colorectal
cancer by 1.5-1.7
times1. The
identification of other similar polymorphisms may be hastened by DNA chip
technology.
Molecular techniques have been employed in the diagnosis of colorectal
cancer, and mutated copies of the APC, K-ras and P53 genes
have been detected in the stools of patients with malignancies as have DNA
sequences demonstrating microsatellite
instability2. To
date this remains a research tool but has the potential to be employed for
population screening.
The ability to predict the response of a tumour to chemotherapy or
radiotherapy may also be governed by its molecular pathology. Rectal cancers
expressing the mutant P53 protein tend to be resistant to radiotherapy, whilst
those expressing the p21 gene seem more sensitive to its
effects3. Cancers
that express high levels of the enzyme thymidylate synthase show resistance to
5-fluorouracil4
whilst those demonstrating microsatellite instability seem to respond well to
5-fluorouracil5. The
prognostic value of identifying different genetic mutations has been widely
studied but its importance remains controversial. Cancers with mutations of
the K-ras, DCC and p53 genes tend to have a poor
prognosis6,7,8.
Microsatellite instability or reduced expression of
COX-29,10
correlate with better survival. In the future, a knowledge of the underlying
genetic and molecular abnormalities in each cancer should allow treatment to
be targeted specifically.
|
IMAGING
|
|---|
Preoperative evaluation of rectal cancer has become increasingly
important,
to identify patients with locally advanced disease
who may benefit from
neoadjuvant chemoradiotherapy and those
suitable for local resection.
Endoscopic rectal ultrasound (ERUS)
accurately indicates the extent of tumour
spread through the
wall of the rectum in over 90% of cases (T stage) and the
involvement
of perirectal lymph nodes in up to 80% (N
stage)
11,12.
It is
an essential investigation for those being considered for local
resection.
Currently, examination by ERUS is limited to tumours within
the
distal rectum but the recent development of colonoscopic
ultrasound may prove
useful to evaluate more proximal disease.
However, CT and MRI define the
extent of local spread, tissue
infiltration and lymph node involvement better
than ERUS. The
detection of recurrent disease by CT or MRI is highly effective
for
hepatic and extrahepatic disease, but changes in tissue appearances
on CT
scans following irradiation are similar to those seen
with recurrent tumour
and can lead to diagnostic uncertainty,
particularly within the pelvis. The
use of positron emission
tomography with fluorine-18-labelled deoxyglucose (a
glucose
substitute preferentially taken up by cancer cells) is more
sensitive
than CT scanning for the detection of both hepatic
and extrahepatic disease
including pelvic
recurrence
13,14
and
even identifies previously unsuspected metastasis.
|
SURGICAL TECHNIQUES
|
|---|
In the past, cancers of the distal rectum were treated by abdominoperineal
excision
of the rectum, but recently ‘low’ cancers have been
treated
increasingly by anterior resection, which avoids the need for
a
permanent stoma. The old concept that the distal resection
margin must be at
least 5 cm clear of the cancer has been discredited.
Unless the tumour is
poorly differentiated a 2 cm clearance
margin below the tumour edge is
adequate since distal intramural
spread seldom exceeds a few millimetres and
distal lymphatic
spread is rare. Tumours with intramural spread extending >
1
cm beyond the tumour are almost always advanced, with distant
metastasis
15,16.
This
change in approach, and the availability of stapling devices,
allows
restorative resection for well to moderately differentiated
cancers only 2-3
cm above the anal sphincters without compromising
oncological principles.
While low colorectal or coloanal anastomoses
avoid the need for a permanent
stoma this method does result
in increased frequency of bowel action, faecal
urgency and incontinence
(the anterior resection syndrome). The fashioning of
a short
5-7 cm colon J pouch (similar in principle to the ileal pouch
used in
ulcerative colitis) improves the functional outcome
of a low anastomosis
without added
morbidity
17.
Alternatively
a coloplasty pouch, created by making an 8-10 cm longitudinal
colostomy
4-6 cm above the anastomosis and closed transversely with two
layers
of sutures, has been advocated to improve the functional
outcome following a
low
anastomosis
18.
A major advance in surgical technique has been attention to cancer
clearance. The mesorectum consists of fatty tissue surrounding the rectum and
contains the lymphatics that drain the rectum. Isolated deposits of tumour can
be found within the mesorectum up to 3 cm distal to the main
tumour19. Total
mesorectal excision has reduced local recurrence following surgery to less
than
10%20,21
although anastomotic dehiscence rates as high as 19% have been
reported22.
Dehiscence is related to devascularization of the rectal stump, and a
temporary defunctioning stoma (usually a loop ileostomy) is frequently
employed for low resections to minimize the morbidity caused by a leak.
Failure to remove tumour that has extended into the pararectal tissue gives
rise to high rates of local recurrence (78%), and clearance at the
circumferential resection margins is another crucial component of rectal
excision23. Pelvic
lymphadenectomy, practised in Japan, offers no clear survival advantage over
total mesorectal excision: it results in a high incidence of bladder and
sexual dysfunction and has not been widely advocated in the
West24.
In carefully selected patients, particularly the elderly or those with
severe co-morbidity, local excision is a reasonable option. Tumours less than
10 cm from the dentate line may be resected under direct vision whilst more
proximal lesions can be treated by transanal endoscopic microsurgery. The
microsurgery is performed via a rectoscope in a manner similar to laparoscopic
surgery, with the rectum insufflated with carbon dioxide. The lesions should
be mobile on digital examination, less than 5 cm in diameter and of favourable
differentiation. Endorectal ultrasound and CT scanning should be available to
determine the depth of bowel wall involvement and local lymph node status.
Local resection should be limited to T1 and T2 tumours. Recurrence rates
following local excision are related to the tumour stage: 9.7% for T1, 25% for
T2 and 38% for T3 tumours; with postoperative chemoradiotherapy the local
recurrence rates are reduced to 9.5% for T1, 13.6% for T2 and 13.8% for
T325. The role of
prospective chemoradiotherapy has yet to be fully evaluated. Complication
rates tend to be low but include local sepsis, rectovaginal fistula, faecal
incontinence and urinary retention and infections. When pathological criteria
are unfavourable because of poor differentiation or inadequate clearance,
adjuvant chemoradiotherapy is essential and formal resection should be
considered. Salvage surgery for local recurrence can be life-saving if
performed
early26.
The place of laparoscopic surgery in colorectal cancer is dubious because
of concerns about intraperitoneal spread of malignant cells associated with
pneumoperitoneum, malignant recurrence at port sites and the adequacy of
resection. Results of studies have been inconsistent and large-scale trials
are now underway.
The sentinel lymph node is the first node that receives lymph from a
primary tumour and is thought to be the node most likely to contain metastatic
cells. The sentinel node in rectal cancer can be accurately identified in up
to 99%27 of cases.
Theoretically examination of this node, possibly with molecular techniques,
could improve the detection of micro-metastasis but experience with breast
cancer and melanoma indicates that this is unlikely to have an important
bearing on surgical technique for cancer clearance.
|
HEPATIC METASTASES
|
|---|
The prognosis for patients with hepatic metastasis is bleak.
The median
survival is 6-9 months and may increase to 12 months
with 5-fluorouracil
chemotherapy
28.
Although newer agents such
as irinotecan and oxaliplatin may improve survival
slightly,
chemotherapy remains a palliative treatment.
Surgical resection offers the only hope of a cure although the proportion
of patients with resectable disease is
10%29. The presence
of diffuse disease or tumour that invades vital structures such as the porta
hepatis is a contraindication to surgery.
With improved understanding of hepatic anatomy and better surgical and
anaesthetic techniques, perioperative mortality is now as low as
2%30,31.
The liver consists of eight segments each with its own bile duct, portal vein
and hepatic blood supply; thus each segment can be resected individually.
Blood loss is reduced by the use of ultrasound parenchymal dissectors, argon
diathermy and controlled anaesthesia in which the central venous pressure is
lowered; sometimes blood transfusion can be avoided.
The 5-year survival rates after liver resection for metastatic colorectal
cancer are around 30-50%, depending upon selection
criteria32,33,34.
Resection was previously limited to less than four metastases in a single
lobe, but it is now apparent that the number of metastases is less important
than the ability to excise them completely with a 1 cm margin of clearance.
Ideally two disease-free segments, preferably in continuity, should be
preserved. Other factors that influence prognosis after hepatic resection are
the stage of the primary tumour, the disease-free interval before hepatic
metastasis is recognized and the level of carcinoembryonic antigen.
Adjuvant chemotherapy in combination with liver resection seems to improve
the results. Hepatic arterial infusion together with systemic chemotherapy
gave better 2-year survival than surgical resection
alone34. Systemic
chemotherapy reduces the volume of metastatic disease, rendering inoperable
tumours amenable to surgery in 16% of cases with subsequent 5-year survival
comparable with that of patients undergoing a standard
resection29.
Currently a European Organization for Research and Treatment of Cancer (EORTC)
trial is evaluating the role of preoperative and postoperative chemotherapy in
patients with resectable hepatic metastases.
Newer modalities such as cryotherapy and radio-frequency ablation may be of
value. Cryotherapy, in which cancer tissue is destroyed by repeated cycles of
freezing and thawing, can be used to treat tumours of up to 8 cm in size
including those located near major structures; however, the drawbacks include
major haemorrhage, systemic responses to thermal injury and residual necrotic
tissue. Radio-frequency ablation, in which radiofrequency radiation is used to
produce heat in a local area of tissue, yields fewer complications than
cryotherapy although the volume of tumour that can be destroyed is limited.
Both techniques are capable of destroying cancer tissue but their impact on
long-term survival remains
controversial35.
|
CHEMOTHERAPY AND RADIOTHERAPY
|
|---|
In addition to their standard adjuvant role in Dukes stage C
disease,
chemotherapy and radiotherapy have been used in rectal
cancer to reduce local
recurrence, improve operability and allow
anal sphincter preservation. The
addition of preoperative radiotherapy
can reduce the rate of local recurrence
after surgery from 27%
to 11% and improves long-term survival from 48% to
58%
36. When
used in
combination with total mesorectal excision, preoperative
radiotherapy may
reduce the incidence of local recurrence to
as little as
2%
37. Preoperative
radiotherapy is safe: although
it tends to delay perineal wound healing and
causes sexual dysfunction,
it does not predispose to anastomotic dehiscence.
Postoperative
radiotherapy also reduces local recurrence, although it does
not
seem to improve long-term survival and is associated with
more complications,
particularly small-bowel obstruction and
late-onset diarrhoea due to radiation
enteritis
38. An
advantage
of postoperative radiotherapy is that it is can be reserved
for
patients with unfavourable operative or pathological findings.
Combined chemotherapy and radiotherapy (chemoradiotherapy) is being used
more widely in both the preoperative and postoperative management of rectal
cancer. Cancer cells are sensitized to the effect of radiotherapy by
5-fluorouracil, and combined therapy achieves a greater reduction in local
recurrence and better survival than seen with radiotherapy
alone39. The US
National Institutes of Health consensus recommends chemoradiotherapy for all
stage II and III rectal
cancers40.
Preoperative chemoradiotherapy is particularly indicated for locally advanced
or inoperable rectal cancers (T3 or T4). Although in the various studies
selection criteria and treatment regimens have differed widely, over 70% of
unresectable and locally advanced rectal cancers are ‘downstaged’,
allowing
excision41, and
pathologists are commonly unable to demonstrate residual cancer tissue after
chemoradiation. Patients with rectal cancers that respond to preoperative
chemoradiotherapy have better 5-year survival, with lower local recurrence
rates, than those in whom the tumour does not
respond42.
|
Acknowledgments
|
|---|
This review is based on a joint meeting at which the principal
speakers
were Dr Rob Glynne Jones (Neoadjuvant chemoirradiation
for T3, T4 rectal
cancer), Dr Harpreet Wassan (Molecular predictors
of treatment response), Mr
Paul Finan (Surgical technique and
outcome of rectal cancer), Dr Tim Maugham
(Chemotherapy before
or after liver metastasis resection), Mr Mike Thompson
(Early
diagnosis and identification of increased risk of colorectal
cancer),
and Professor Mike Richards (Bowel cancer and the National
Cancer Plan).
|
REFERENCES
|
|---|
- Laken SJ, Petersen GM, Gruber SB, et al. Familial
colorectal cancer in Ashkenazim due to a hypermutable tract in APC.
Nat Genet1997; 17:79
-83[Medline]
- Ahlquist DA, Skoletsky JE, Boynton KA, et al. Colorectal
cancer screening by detection of altered human DNA in stool: feasibility of a
multitarget assay panel. Gastroenterology2000; 119:1219
-27[Medline]
- Qiu H, Sirivongs P, Rothenberger M, Rothenberger DA, Garcia-Aguilar
J. Molecular prognostic factors in rectal cancer treated by radiation and
surgery. Dis Colon Rectum2000; 43:451
-9[Medline]
- Edler D, Hallstrom M, Johnston PG, Magnusson I, Raguhammar P,
Blomgren H. Thymidylate synthase expression: an independent prognostic factor
for local recurrence, distant metastasis, disease-free and overall survival in
rectal cancer. Clin Cancer Res2000; 6:1378
-84[Abstract/Free Full Text]
- Elsaleh H, Joseph D, Grien F, Zeps N, Spry N, lacopetta B.
Association of tumour site and sex with survival benefit from adjuvant
chemotherapy in colorectal cancer. Lancet2000; 355:1745
-50[Medline]
- Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten
ras mutations in patients with colorectal cancer: the multicenter
‘RASCAL’ study. J Natl Cancer Inst1998; 90:675
-84[Abstract/Free Full Text]
- Kahlenberg MS, Stober DL, Rodriguez-Bigas MA, et al. p53
tumor suppressor gene mutations predict decreased survival of patients with
sporadic colorectal carcinoma. Cancer2000; 88:1814
-19[Medline]
- Martinez-Lopez E, Abad A, Font A, et al. Allelic loss of
chromosome 18q as a prognostic marker in stage II colorectal cancer.
Gastroenterology1998; 114:1180
-7[Medline]
- Wright CM, Dent OF, Barker M, et al. Prognostic
significance of extensive microsatellite instability in sporadic
clinicopathological stage C colorectal cancer. Br J
Surg 2000;87:1197
-202[Medline]
- Sheehan KM, Sheehan K, O'Donoghue DP, et al. The
relationship between cyclooxygenase-2 expression and colorectal cancer.
JAMA1999; 282:1254
-7[Abstract/Free Full Text]
- Massari M, De Simone M, Cioffi U, Rosso L, Chiarelli M, Gabrielli
F. Value and limits of endorectal ultrasonography for preoperative staging of
rectal carcinoma. Surg Laparosc Endosc1998; 8:438
-44[Medline]
- Katsura Y, Yamada K, Ishizawa T, Yoshinaka H, Shimazu H. Endorectal
ultrasonography for the assessment of wall invasion and lymph node metastasis
in rectal cancer. Dis Colon Rectum1992; 35:362
-8[Medline]
- Johnson K, Bakhsh A, Young D, Martin TE Jr, Arnold M. Correlating
computed tomography and positron emission tomography scan with operative
findings in metastatic colorectal cancer. Dis Colon
Rectum 2001;44:354
-7[Medline]
- Schiepers C, Penninckx F, De Vadder N, et al. Contribution
of PET in the diagnosis of recurrent colorectal cancer: comparison with
conventional imaging. Eur J Surg Oncol1995; 21:517
-22[Medline]
- Pollett WG, Nicholls RJ. The relationship between the extent of
distal clearance and survival and local recurrence rates after curative
anterior resection for carcinoma of the rectum. Ann
Surg 1983;198:159
-63[Medline]
- Williams NS, Dixon MF, Johnston D. Reappraisal of the 5 centimetre
rule of distal excision for carcinoma of the rectum: a study of distal
intramural spread and of patients' survival. Br J Surg1983; 70:150
-4[Medline]
- Lazorthes F, Fages P, Chiotasso P, Lemozy J, Bloom E. Resection of
the rectum with construction of a colonic and colo-anal anastomosis for
carcinoma of the rectum. Br J Surg1986; 73:136
-8[Medline]
- Z'graggen K, Maurer CA, Birrer S, Giachino D, Kern B, Buchler MW. A
new surgical concept for rectal replacement after low anterior resection: the
transverse coloplasty pouch. Ann Surg2001; 234:780
-5[Medline]
- Scott N, Jackson P, al-Jaberi T, Dixon MF, Quirke P, Finan PJ.
Total mesorectal excision and local recurrence: a study of tumour spread in
the mesorectum distal to rectal cancer. Br J Surg1995; 82:1031
-3[Medline]
- MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal
cancer. Lancet1993; 341:457
-60[Medline]
- Enker WE, Thaler HT, Cranor ML, Polyak T. Total mesorectal excision
in the operative treatment of carcinoma of the rectum. J Am Coll
Surg 1995;181:335
-46[Medline]
- Hainsworth PJ, Egan MJ, Cunliffe WJ. Evaluation of a policy of
total mesorectal excision for rectal and rectosigmoid cancers. Br J
Surg 1997;84:652
-6[Medline]
- Adam IJ, Mohamdee MO, Marten IG, et al. Role of
circumferential margin involvement in the local recurrence of rectal cancer.
Lancet1994; 344:707
-11[Medline]
- Maas CP, Moriya Y, Steup WH, Kiebert GH, Kranenberg WM, van de
Velde GJ. Radical and nerve-preserving surgery for rectal cancer in The
Netherlands: a prospective study on morbidity and functional outcome.
Br J Surg1998; 85:92
-7[Medline]
- Sengupta S, Tjandra JJ. Local excision of rectal cancer: what is
the evidence? Dis Colon Rectum2001; 44:1345
-61[Medline]
- Mellgren A, Sirivongs P, Rothenberger DA, Madoff RD, Garcia-Aguilar
J. Is local excision adequate therapy for early rectal cancer? Dis
Colon Rectum 2000;43:1064
-71[Medline]
- Saha S, Nora D, Wong JH, Weise D. Sentinel lymph node mapping in
colorectal cancer—a review. Surg Clin North Am2000; 80:1811
-19[Medline]
- Simmonds PC. Palliative chemotherapy for advanced colorectal
cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative
Group. BMJ2000; 321:531
-5[Abstract/Free Full Text]
- Bismuth H, Adam R, Levi F, et al. Resection of
nonresectable liver metastases from colorectal cancer after neoadjuvant
chemotherapy. Ann Surg1996; 224:509
-20[Medline]
- Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty hepatic
resections: evolution of technique towards bloodless surgery. Br J
Surg 1996;83:1526
-9[Medline]
- Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score
for predicting recurrence after hepatic resection for metastatic colorectal
cancer: analysis of 1001 consecutive cases. Ann Surg1999; 230:309
-18[Medline]
- Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from
colorectal carcinoma: impact of surgical resection on the natural history.
Br J Surg1990; 77:1241
-6[Medline]
- Ohlsson B, Stenram U, Tranberg KG. Resection of colorectal liver
metastases: 25-year experience. World J Surg1998; 22:268
-76[Medline]
- Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial
infusion of chemotherapy after resection of hepatic metastases from colorectal
cancer. N Engl J Med1999; 341:2039
-48[Abstract/Free Full Text]
- Malafosse R, Penna C, Sa CA, Nordlinger B. Surgical management of
hepatic metastases from colorectal malignancies. Ann
Oncol 2001;12:887
-94[Abstract/Free Full Text]
- Swedish Rectal Cancer Trial. Improved survival with preoperative
radiotherapy in respectable rectal cancer. N Engl J
Med 2002;336:980
-7[Abstract/Free Full Text]
- Kapiteijn E, Marijnen CA, Nagtegaal ID, et al.
Preoperative radiotherapy combined with total mesorectal excision for
resectable rectal cancer. N Engl J Med2001; 345:638
-46[Abstract/Free Full Text]
- Frykholm GJ, Glimelius B, Pahlman L. Preoperative or postoperative
irradiation in adenocarcinoma of the rectum: final treatment results of a
randomized trial and an evaluation of late secondary effects. Dis
Colon Rectum 1993;36:564
-72[Medline]
- Krook JE, Moertel CG, Gunderson LL, et al. Effective
surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J
Med 1991;324:709
-15[Abstract]
- NIH consensus conference. Adjuvant therapy for patients with colon
and rectal cancer. JAMA1990; 264:1444
-50[Abstract/Free Full Text]
- Frykholm G, Glimelius B, Pahlman L. Preoperative irradiation with
and without chemotherapy (MFL) in the treatment of primarily non-resectable
adenocarcinoma of the rectum. Results from two consecutive studies.
Eur J Cancer Clin Oncol1989; 25:1535
-41[Medline]
- Janjan NA, Abbruzzese J, Pazdur R, et al. Prognostic
implications of response to preoperative infusional chemoradiation in locally
advanced rectal cancer. Radiother Oncol1999; 51:153
-60[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
TOP
INTRODUCTION
MOLECULAR PATHOLOGY
