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3. Rectal Carcinoma and the Role of Radiotherapy
Data from Europe indicates that the 5-year survival rate for rectal cancer
improved from 40% to 48% during the period from 1977–1989. This was
mainly due to increased curative resections, fewer advanced cases, and
decreased postoperative mortality. Despite potentially curative surgery, the
5-year survival rates are approximately 60%, varying from about 80% in
patients with stage I disease to 30% in those with stage III disease, thus
indicating that resection alone is adequate treatment only for patients with
early disease [37]. Recurrence will occur locally within the pelvis in 50% of
cases and radiotherapy has therefore formed the mainstay of treatment.
Radiotherapy is also important in the symptomatic treatment of advanced
rectal cancer, and can improve pain, haemorrhage, and tenesmus. In addi-
tion, one large study has demonstrated that radiotherapy can convert
35%–75% of locally advanced inoperable tumours to resectability [38].
Four randomised trials have assessed the role of adjuvant radiotherapy
preoperatively. The largest trial administered 25Gy in 5 fractions and
demonstrated a significant improvement in overall survival (58% vs 48%)
by a relative reduction in local recurrence rate of 61% [39]. The other 3
trials have also revealed significant decreases in the local recurrence rates
of between 50%–63% [40–42]. The main disadvantage of preoperative
radiotherapy compared to postoperative treatment is that there is possibly
a group of patients, usually those patients with stage T1/2, N0, M0 disease
who do not require any adjuvant treatment and who are therefore being
overtreated. However, advantages of preoperative treatment include
decreased tumour seeding at the time of surgery, increased radiosensitivity
compared to postoperative fibrous wound areas, and improved rates of
sphincter-sparing surgery. Currently, preoperative radiotherapy is recom-
mended for patients with T3 or resectable T4 rectal cancer.
Postoperative radiotherapy even at higher doses has been shown to be
less effective than preoperative treatment, possibly due to rapid tumour-
cell repopulation after surgery and wound hypoxia reducing radiosensitiv-
ity. However, 3 trials have demonstrated that 40–50Gy postoperatively
significantly reduced rates of local failure compared to surgery alone
[43–45]. The dose of radiation is important as dose response in radiation
therapy follows a sigmoidal distribution and therefore a small decrease in
dose can result in a large difference in local control. Of the 3 randomised
trials, the National Surgical Adjuvant Bowel and Breast Project (NSABP)
is the only trial to confirm that postoperative radiation therapy decreases
local failure and it is the only trial which administered continuous course,
full-dose therapy with modern techniques. A MRC study has also shown
lower recurrence rates for radiotherapy after surgery than for surgery only
(hazard ratio 0.54 [95% CI, 0.38–0.66], P = .001) [46].
There has only been one randomised trial comparing preoperative versus
postoperative radiotherapy in patients with rectal cancer. The dose of radi-
10. The Role of the Oncologist in the Treatment of Colorectal Cancer 201
ation postoperatively was significantly higher, 60 Gy compared to 25 Gy
presurgery, and despite this the study demonstrated a significantly lower
rate of recurrence in patients treated preoperatively (12% vs 21%, P < .02)
[47]. However, the results of this trial must be interpreted with caution as
the local failure rates with surgery alone were higher than accepted rates
in the United Kingdom and the United States.
In an attempt to reduce the frequency of inappropriate radiotherapy
administration to patients with early stage disease, the CRO7 trial is ran-
domising rectal cancer patients to either preoperative radiotherapy (25 Gy)
or selective postoperative radiotherapy (45 Gy) if the circumferential resec-
tion margins are involved on histological inspection. Postoperative patients
will receive chemoradiotherapy (Figure 10.6).
Animal studies have suggested that 5FU has the capacity to prime rectal-
cancer cells and sensitise them to subsequent radiation. Indeed, one study
has demonstrated a significant benefit for patients treated with a combina-
tion of 5FU chemotherapy and radiation compared with the cohort treated
with radiotherapy alone [48]. However, only results of CRO7 and other
trials will demonstrate whether or not a combination of chemotherapy and
radiotherapy is both effective and safe in this setting and this combination
can not be condoned as standard therapy at present.
4. New Approaches to the Treatment of
Colorectal Cancer
4.1. Immunotherapy
Several immunotherapeutic techniques have been suggested for use in col-
orectal cancer. These include antibody-mediated therapies and immune-
cellular–mediated therapies such as peptide vaccination with mutated ras
peptides and dendritic-cell vaccination.
Over the past 10 years several clinical trials have assessed monoclonal
antibodies as therapeutic agents for advanced solid tumours, and demon-
strated no significant benefits. Explanations for the failures have included
antigenic heterogeneity and poor accessibility of cells in advanced tumours.
However, there seems to be more promise in the adjuvant setting. In a ran-
domised trial, 189 patients with Dukes C colorectal cancer were assigned
to receive either a monoclonal antibody, 17-1A, that binds a tumour-
specific cell surface glycoprotein (17-1A) or observation only. Survival was
significantly lengthened in the antibody treated group, with 5-year survival
rates of 51% vs 36% (P = .025). Side effects included mild constitutional
and gastrointestinal symptoms [49]. This antibody is currently being tested
as a single agent in patients with Dukes B colorectal cancer and also in com-
bination with 5FU/FA in Dukes C colorectal cancer following curative
resection.
202 S. Nicum et al.
4.1.2. Recombinant Virus Vaccines
CEA is a 180 kd cell-surface glycoprotein that appears to be involved in cel-
lular adhesion, cell-to-cell interactions, and possibly glandular differentia-
tion. It is a member of a family of glycoproteins that are expressed in the
tumour cells of 85% of patients with colorectal cancer. A direct immuno-
10. The Role of the Oncologist in the Treatment of Colorectal Cancer 203
CRO7
Randomisation of operable
rectal adenocarcinoma
Selective post-operative
radiotherapy
Pre-operative
radiotherapy
DXT 25Gy
Surgery
Pathology
assessment
Adjuvant
chemotherapy
Surgery
Pathology
assessment
Involved
margins-chemoradiothe
rapy
Figure 10.6. Schematic representation of the CRO7 trial.
logic approach to carcinoembryonic-antigen (CEA)–bearing tumours has
been developed using inoculation with a recombinant vaccinia virus which
expresses the human CEA gene. Vaccinia virus is a member of the DNA
containing Poxviridae family of viruses. These viruses replicate within the
host cell’s cytoplasm and can elicit both humoral and cell-mediated immune
responses, therefore copresentation of human protein products with vac-
cinia may enhance immunogenicity to the protein and thus start or augment
tumour rejection [50].
In a phase I study, 26 patients with advanced gastrointestinal, breast, and
lung adenocarcinoma were administered with escalating doses of recombi-
nant vaccinia–CEA vaccine. There was no serious toxicity and although a
therapeutic immune response was not demonstrated, these patients gener-
ated cytotoxic T lymphocytes specific for CEA which would be expected to
have a significant role in rejection of tumour cells positive for CEA [50].
4.2. Gene Therapy
Gene therapy encompasses various techniques in which viral and nonviral
vectors are used to deliver to tumour cells, genes that encode cytokines,
tumour-suppressor proteins, and proteins that sensitise cells to chemother-
apy (such as p53). Following successful completion of phase I trials of ade-
novirus delivered p53 tumour-suppressor genes via the hepatic artery, phase
II studies combining the virus with 5FU are now in progress [51].
Phase I trials of virus-directed enzyme prodrug therapy (VDEPT) are
currently in progress. This novel technique involves insertion of genes into
cells that transcribe enzymes capable of metabolising prodrugs into potent
cytotoxic species. Adenoviral vectors that link the carcinoembryonic
antigen (CEA) promoter to the structural gene for the bacterial enzyme
cytosine deaminase have been developed [52]. Cytosine deaminase meta-
bolises the prodrug 5-fluorocytosine to 5FU. Transduction of the gene hybrid
should theoretically only occur in cells expressing CEA thus conferring
tumour selectivity on the cytotoxic agent. This permits a 1000-fold higher
concentration of 5FU in the tumour and the neighbouring cells (the
bystander effect) than in the systemic circulation. This technique is cur-
rently being assessed in patients with advanced colorectal cancer, and if
found to be efficacious it will be tried in the adjuvant setting.
Acknowledgments. The support of Cancer Research UK and the
Medical Research Council is gratefully acknowledged.
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11
Investigation of Functional
Bowel Disorders
Ponnandai J. A rumugam,John Beynon, and Bharat Patel
1. Introduction
Functional bowel disorders present a management challenge to coloproc-
tologists, therefore, careful history taking, recording of symptomatology,
and clinical assessment are essential in the evaluation of these patients
(Table 11.1).
Patients may present with symptoms of rectal bleeding and tenesmus
and it is vitally important that colorectal malignancy is excluded before
attributing the patient’s symptoms to functional disorders. This will entail
an endoscopic or a contrast study of the colorectum before proceeding to
comprehensive assessment of the clinical problem.
As patients with functional bowel disorders present with a variety of
symptoms, it is important to be as objective as possible in documenting the
symptoms that may be complemented by the use of specifically modified
and validated quality-of-life questionnaires, in addition to those used to
assess specific problems such as continence (e.g., Cleveland continence
score). This role can be performed by a specialist colorectal nurse who is
able to document the presenting complaints and has contact with patients
following surgery or biofeedback.
Assessment is completed by a thorough clinical examination of the
abdomen and anorectum. Anal tone and squeeze should be evaluated and
gluteal recruitment, if present, is recorded as is the presence of rectocoele,
external prolapse, and solitary rectal ulcer.
Pelvic-floor dysfunction is assessed routinely by evacuatory proctogra-
phy, anal manometry, and endo–anal ultrasound (EAUS) [1,2]. Other com-
plementary investigations such as magnetic resonance imaging (MRI) of
the pelvic floor, electromyography (EMG), pudendal nerve terminal motor
latency (PNTML), and colonic transit studies are useful. Although careful
and thorough clinical examination can detect the majority of defects, the
above investigations play an important role in determining the appropriate
management for symptomatic patients.
209
2. Evacuatory Proctography
Evacuatory proctography was first described by Burhenne in 1964 but was
not widely used clinically for nearly 20 years [3]. This is a dynamic assess-
ment of defaecation and can provide information on function of the pelvic-
floor muscles and the rectum. A wide overlap exists in normal findings in
asymptomatic subjects and different groups of symptomatic patients [4].
Further, it is difficult to differentiate controls from symptomatic patients
based on proctographic findings alone [5,6]. Abnormalities demonstrated
on the proctogram correlate poorly with symptomatology and manometric
assessment, and the majority of radiologists rely on time taken to evacuate
and completeness of evacuation [6,7]. Evacuatory proctography does,
however, provide an understanding of pelvic-floor pathophysiology but this
must be interpreted cautiously. A decision to proceed with surgery rather
than conservative management must not be based on radiographic diagno-
sis alone but must include consideration of patient symptoms, clinical find-
ings, and the results of other appropriate complementary investigations.
Karasick et al., in their study on the role of parity and hysterectomy,
believed evacuatory proctography to be a useful tool in assessing pelvic-
floor disorders,while Klauser et al. showed a good interobserver agreement
in assessing rectocoele on proctography [8,9]. Mahieu et al. described vari-
ations in the technique while Bernier et al. and Ginai et al. contributed
towards designing the commode used in this investigation [10–12].
Indications for evacuatory proctography for the assessment of functional
disorders include (a) obstructed defaecation/incomplete evacuation, (b)
constipation, (c) solitary rectal ulcer, (d) rectal prolapse or intussusception,
and (e) anal incontinence.
The barium paste used is readily available commercially but can also be
prepared from barium powder and potato/corn starch. This paste is usually
delivered into the rectum by a commercially available gun. Most centers
now use liquid barium to coat the lining of the rectum prior to injection of
the thick viscous barium paste, which simulates stools. This examination
does not provide the ideal natural environment to assess an individual’s
210 P.J. Arumugam et al.
Table 11.1. History and record of symptomatology.
Inquire about
• Presence of rectal bleeding, mucous discharge, or perineal pressure
• Type of incontinence: solid, liquid, or flatus
• Impact of symptoms: need for a pad, restriction of daily or sexual function
• Awareness of need to defaecate
• Presence/absence of obstructed defaecation/incomplete evacuation
• Need for digitation vaginally or rectally to evacuate
• Previous anal surgery: haemorrhoidectomy, sphincterotomy, or fistula surgery
• Anoreceptive Intercourse
• Urinary and sexual history
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