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223
16 Anal Cancer
The rate of progression to invasive carcinoma is unknown, and while efforts to
identify and treat high-grade anal intraepithelial neoplasia to prevent anal cancer
may be justifi ed, the effi cacy of such a policy is unknown.
If there is a suspicion of AIN, a biopsy should be performed using high-resolu-
tion anoscopy under general anesthesia. For patients with AIN3, it is reasonable to
follow up patients every 6 months with either repeat anoscopy or liquid-based anal
cytology. Patients who smoke may be a greater risk of malignant transformation of
their AIN. The most commonly used treatments are local excision or ablation of the
affected skin or application of topical agents such as 5-fl uorouracil cream.
HPV infections are a common cause of anal warts. When treated surgically, they
should be sent for histological assessment. Recognition of giant condyloma (or
Buschke-Lowenstein tumor) is important. This lesion of the anal margin resembles
a condyloma macroscopically but is much larger and requires urgent surgical exci-
sion. Around 50% of these lesions will eventually undergo malignant transforma-
tion (see Chap. 8 ).
16.4 Anal Cancer in Crohn’s Disease
This is a rare, but well-described complication of long-standing fi stulae in this con-
dition. Because symptoms from the cancer are similar to those seen in Crohn’s fi s-
tulae, diagnosis is often delayed. Increased and persistent pain, swelling, and the
development of a mass in a patient with long-standing Crohn’s disease related fi stu-
lae should raise suspicion and biopsy under anesthesia performed.
References
1. Wolfe HR, Bussey HJ. Squamous-cell carcinoma of the anus. Br J Surg. 1968;55:295–301.
2. O’Brien PH, Jenrette JM, Wallace KM, et al. Epidermoid cancer of the anus. Surg Gynecol
Obstet. 1982;155:745–51.
3. Hardcastle JD, Bussey HJR. Results of surgical treatment of squamous cell carcinoma of the
anal canal and anal margin seen at St. Mark’s Hospital 1928–1966. Proc R Soc Med.
1968;61:629–30.
4. Boman BM, Moertel CG, O’Connell MJ, et al. Carcinoma of the anal canal: a clinical and
pathological study of 188 cases. Cancer. 1984;54:114–25.
Key Points
Most anal carcinomas are of the epidermoid type •
First line treatment is chemoradiotherapy and achieves a complete response •
is around 90% of cases
Recurrence is most likely to occur within 18 months of initial treatment•
Salvage anorectal excision achieves cure rates of 50%•
Perineal wound healing is improved with the use of myocutaneous fl aps •
224
J. Hill
5. Nigro ND. An evaluation of combined therapy for squamous cell cancer of the anal canal. Dis
Colon Rectum. 1984;27:763–6.
6. Flam M, Madhu J, Pajak TF, et al. Role of mitomycin in combination with fl uorouracil and
radiotherapy and of salvage chemoradiation in the defi nitive nonsurgical treatment of epider-
moid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin
Oncol. 1996;14:2527–39.
7. Bartelink H, Roelofsen F, Eschwege R, et al. Concomitant radiotherapy and chemotherapy
superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a
phase III randomized trial of the EORTC Radiotherapy and Gastrointestinal Cooperative
Groups. J Clin Oncol. 1997;15:1040–9.
8. UKCCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: results from the
UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fl uorouracil, and
mitomycin. Lancet. 1996;348:1049–54.
9. Northover J, Glynne-Jones R, Sebag-Montefi ore D, et al. Chemoradiation for the treatment of
epidermoid anal cancer: 13 year follow-up of the fi rst randomised UKCCCR Anal Cancer
Trial (ACT 1). Br J Cancer. 2010;30:1123–8.
10. James R, Wan S, Glynne-Jones R, et al. A randomized trial of chemoradiation using mitomy-
cin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the
anus (ACT II). J Clin Oncol. 2009;27:18 (suppl; abstr LBA4009).
11. Das P, Cantor SB, Zampieri JB, et al. Long term quality of life after radiotherapy for the treat-
ment of anal cancer. Cancer. 2010;116:822–9.
12. Mendenhall WM, Zlotecki RA, Vauthey J-N, et al. Squamous cell carcinoma of the anal mar-
gin. Oncology. 1996;10:1843–54.
13. Radice E, Nelson H, Mercill S, et al. Primary myocutaneous fl ap closure following resection
of locally advanced pelvic malignancies. Br J Surg. 1999;86:349–54.
14. Mann CV, Springall R. The use of a muscle graft for unhealed perineal sinus. Br J Surg.
1986;73:1000–1.
15. Brough WA, Schofi eld PF. The value of the rectus abdominis myocutaneous fl ap in the treat-
ment of complex perineal fi stula. Dis Colon Rectum. 1991;34:148–50.
16. Zelnick RS, Haas PA, Ajlouni M, Szilagyi E, Fox TA. Results of abdominoperineal resections
for failures after combination chemotherapy and radiation therapy for anal canal cancers. Dis
Colon Rectum. 1992;35:574–8.
17. Tanum G. Treatment of relapsing anal carcinoma. Acta Oncol. 1993;32:33–5.
18. Ellenhorn JD, Enker WE, Quan SH. Salvage abdominoperineal resection following combined
chemotherapy and radiotherapy for epidermoid carcinoma of the anus. Ann Surg Oncol.
1994;2:105–10.
19. Longo WE, Veranva III AM, Wade TP, et al. Recurrent squamous cell carcinoma of the anal
canal. Predictors of initial treatment failure and results of salvage surgery. Ann Surg.
1994;220:40–9.
20. Pocard M, Tiret E, Nugent K, Dehni N, Parc R. Results of salvage abdominoperineal resection
for anal cancer after radiotherapy. Dis Colon Rectum. 1998;4:1488–93.
21. Ghouti L, Houvenaeghel G, Moutardier V. Salvage abdominoperineal resection after failure of
conservative treatment in anal epidermoid cancer. Dis Colon Rectum. 2005;48:16–22.
22. Papaconstantinou HT, Bullard K, Rothenberger DA, Modoff RD. Salvage abdominoperineal
resection after failed Nigro protocol: modest success, major morbidity. Colorectal Dis.
2006;8(2):124–9.
23. Schiller DE, Cummings BJ, Rai S. Outcomes of salvage surgery for squamous cell carcinoma
of the anal canal. Ann Surg Oncol. 2007;14:2780–9.
24. Mullen JT, Rodriquez-Bigas MA, Chang GJ. Results of surgical salvage after failed chemora-
diation therapy for epidermoid carcinoma of the anal canal. Ann Surg Oncol.
2007;14:478–83.
25. Hill J, Meadows H, et al. Pathological staging of epidermoid anal carcinoma for the new era.
Colorectal Dis. 2003;5(3):206–13.
26. Goldstone SE, Moshier E. Detection of oncogenic human papillomavirus impacts anal screen-
ing guidelines in men who have sex with men. Dis Colon Rectum. 2010;53:1135–42.
225
S.R. Brown et al. (eds.), Contemporary Coloproctology,
DOI 10.1007/978-0-85729-889-8_17, © Springer-Verlag London Limited 2012
17.1 Epidemiology
Ulcerative colitis (UC) affects about 1 in 400 of the UK population, with a stable
incidence in the last few decades. The peak age of onset of disease is around
30 years, but onset of disease can occur at any age, though it is rare after 70 years
[ 1 ] . The strongest risk factor for developing UC is a family history of infl ammatory
bowel disease (IBD) (either UC or Crohn’s disease); however, the risk of monozy-
gotic twins developing UC is lower than for Crohn’s disease (10% versus 38%)
broadly suggesting that UC is less “genetic” than CD [ 1 ] .
P. Flanagan • K. Leiper (*)
Link 5Z , Royal Liverpool University Hospital ,
Prescot Street , Liverpool , L7 8XP , UK
e-mail: paulfl anagan@nhs.net ; keith.leiper@rlbuht.nhs.uk
Chapter 17
Medical Management of Ulcerative Colitis
Paul Flanagan and Keith Leiper
In Memoriam: Keith Leiper 1967–2011
Dr. Keith Leiper, universally loved by his patients and by all the staff with whom he worked, all of
whom he treated as his friends, died from cancer on Friday, October 21, 2011. Keith had been the
Leslie Parrott Research Fellow of Crohn’s and Colitis UK and completed his M.D. on the patho-
genesis and treatment of infl ammatory bowel disease before going on to be a consultant with a
passionate interest in clinical research. On a national level, his outstanding work as the fi rst lead
for the UK Infl ammatory Bowel Disease Audit has led to a marked improvement in standards of
IBD care, an achievement brought about through his close collaboration with patient organiza-
tions, particularly Crohn’s and Colitis UK for whom Keith acted as a regional medical advisor. But
far more than his (formidable) list of achievements can attest, Keith was an inspiration to all who
met him: exceptionally widely read, possessing a phenomenal grasp of the medical literature, an
enthusiastic and much loved teacher and trainer, and immensely benefi cial to the care of IBD
patients locally; his personality, enormous kindness, selfl ess generosity, integrity, and constant
good humor will be particularly remembered. He was unfailingly fun to be with, even when he
became ill, and was constantly prioritizing others above himself. He is survived by his wife Libby,
also a doctor, and by their children Cameron, Mirren, and Ailish to whom our thoughts go.
226
P. Flanagan and K. Leiper
There is an intriguing negative association with smoking. Fewer than 5% of UC
patients smoke compared with 60% with CD. The risk of developing UC is highest
in the fi rst year after stopping smoking, and smoking is associated with fewer fl are-
ups. The mechanism of the protective effect is not clear but is unlikely to be due to
nicotine. There is evidence that carbon monoxide has anti-infl ammatory effects.
Advising smoking to control disease is however not wise counsel as people with UC
have a normal life expectancy whereas smokers do not.
A further intriguing negative association is with appendicectomy for appendici-
tis. The effect is strongest for those with appendicectomy for appendicitis below the
age of 20, with no apparent effect on reducing the chance of developing UC after
this age. The reason for this effect is likely to be that genes which increase the risk
of early appendicitis in some way reduce the risk of UC or vice versa. However, it
is not known which genes these may be.
The colectomy rate is 24% at 10 years. In the 3–7 years after diagnosis, each year,
50% are in remission at any time, 25% of patients are in long-term remission, 18% had
activity every year, and 57% had intermittent relapses [
2 ] . The extent of colitis can vary
so that >50% with left-sided colitis will progress proximally during 25 years, and 75%
extensive colitis will regress. Overall, UC patients have a normal life expectancy.
17.2 Pathophysiology
17.2.1 Genetics
Fundamentally, UC seems to be an inappropriate infl ammatory response to the
intestinal microbiota in genetically susceptible individuals. There is as yet no single
gene defect strongly associated with UC. Twelve genome-wide association studies
have identifi ed 9 loci associated with IBD (IBD1–9) of which 5 show a strong asso-
ciation. Some of these are associated with UC and CD (chromosomes 2q, 3q, 5q, 7q,
and 16) and one (2q) for UC alone. IBD 2 (Ch 12) is linked with extensive UC,
though a disease-associated gene has not yet been identifi ed.
Case Scenario
A 35-year-old nurse presents to outpatients with increased stool frequency
and blood and mucous in her stools. Colonoscopy shows friable mucosa with
ulceration and contact bleeding to the proximal sigmoid colon; the colon is
normal above this point – except for an isolated patch of infl ammation in the
cecum. All of the following are TRUE except:
(a) CRP is a useful test to monitor infl ammation.
(b) Appendicectomy before 20 years protects against ulcerative colitis.
(c) Rectal ASA might be considered as fi rst-line therapy.
(d) An isolated patch of infl ammation in the cecum strongly suggests Crohn’s
disease.
(e) CMV inclusions may be found in CUC biopsies.
227
17 Medical Management of Ulcerative Colitis
Apart from negative associations with smoking and appendicectomy, there are
few other defi nite environmental associations. High-fat and, in particular, high-red-
meat diets are associated with UC and with increased fl are-up rates.
17.2.2 Diagnosis of UC
The diagnosis of UC is usually straightforward: bloody diarrhea or blood per rectum,
confl uent infl ammation endoscopically, and typical histological features. Details of the
diagnosis of UC are detailed in recent ECCO guidelines [ 1 ] . The primary presenting
symptom of ulcerative colitis is visible blood in the stools. Symptoms depend on extent
and severity of disease consisting of bloody diarrhea (often nocturnal), rectal bleeding,
mucus (pus) per rectum, crampy predefecation pain, and/or rectal urgency. Severe
attacks cause malaise, anorexia, and weight loss. The onset of UC is usually insidious
and symptoms which last more than a few weeks differentiate UC from infective coli-
tis (Table 17.1 ). Extraintestinal manifestations, especially an axial or peripheral
arthropathy, episcleritis, and erythema nodosum, may accompany the presentation in
about 10% and rarely precede intestinal symptoms.
Endosocopy is key in making a defi nitive diagnosis. Flexible sigmoidoscopy is
adequate as an initial investigation as preparation is often not needed. No endoscopic
feature is specifi c for UC. However characteristic features of UC are continuous and
confl uent colonic involvement with clear demarcation of infl ammation and rectal
involvement. However, it needs to be remembered that UC can be patchy especially
in children and in partially treated disease. A patch of infl ammation in the cecum or
around the appendiceal orifi ce is seen in about 30% of patients with left-sided UC.
Endoscopic severity of UC is assessed by mucosal friability, spontaneous bleeding,
and deep ulceration (Fig. 17.1 ). Histologically, characteristic features are basal plas-
macytosis (defi ned as the presence of plasma cells around the deep part of the lamina
propria or below the crypts); heavy, diffuse transmucosal lamina propria cell increase;
and widespread mucosal or crypt architectural distortion. General or widespread
crypt epithelial neutrophils (cryptitis and crypt abscesses) favor ulcerative colitis.
17.3 Management of Mild to Moderate UC
17.3.1 General Principles
Outpatient management of active UC consists of assessing the extent, severity, and
pattern of disease. Extent can be inferred from symptoms – distal disease presents
with predominantly blood and mucus (pus) per rectum, while more extensive dis-
ease presents with diarrhea or bloody diarrhea. The practical implication is that
distal disease can be treated with per rectal therapy while more extensive disease
requires oral therapy as well as rectal therapy. The most important aspect is the abil-
ity to identify acute severe colitis and the simplest system is that of Truelove and
228
P. Flanagan and K. Leiper
Witts (Table 17.2 ). Plain AXR is useful for estimating the extent of disease [mucosal
edema and presence of stool indicates areas free of severe infl ammation (Fig. 17.2 )]
and toxic dilatation. Patients with severe disease require hospital admission, while
those with mild/moderate disease can generally be managed as outpatients.
For any fl are-up, stool should be sent for microbiology including CDT and blood
to check U&Es, FBC, CRP, and albumin. Nonsteroidal anti-infl ammatory drugs
should be avoided particularly in active disease as they can cause worsening of UC
and also a specifi c drug-induced colitis. Opiates and loperamide should be avoided
particularly in severely active UC as they are associated with colonic dilatation.
Drugs used to treat UC are outlined below. As a general rule, about 30–45% of
patients are nonadherent to regular medication with the highest rates of nonadher-
ence in unmarried males, younger patients, and those with psychological distress.
Table 17.1 Differential diagnosis of UC and distinguishing features
Diagnosis Diagnostic clues
Investigation
Infections
Campylobacter Acute onset, severe abdominal pain,
rectal bleeding rare, and recent
foreign travel
Stool culture
Salmonella Endoscopy often mild
changes
Shigella
Yersinia
E . coli 0571:H7 Hemolytic uremic syndrome
Clostridium diffi cile Recent antibiotics or chemotherapy,
rectal bleeding less common
Pseudomembranes at
endoscopy
CD toxin
PCR of rectal biopies
CMV Immunodefi ciency Inclusion bodies on
histology
Entamoeba histolytica Recent foreign travel Large, numerous ulcers at
endoscopy
Stool microscopy
Serology
Ischemic colitis Thromboembolic risk factors (age,
diabetes, atrial fi brillation, IHD,
smoking)
Endoscopy: rectal sparing
CT: segmental changes
Drug-induced colitis History of NSAID, mycophenalate,
cocaine, and amphetamine use
Endoscopy: patchy changes
Bechet’s disease Orogenital ulceration, prominent
arthralgia/arthritis, pathergy,
rashes, and neurological signs
Endoscopy: often rectal
sparing, deep ulcers, and
vasculitic features on
biopsies
Vasculitis Clinical features of rheumatoid
disease, SLE, etc.
Autoantibodies: ANA,
ANCA
Vasculitis on deep colonic
biopsies
Crohn’s disease Smoker, perianal disease, prominent
abdominal pain, and small bowel
disease
Patchy endoscopic changes,
granulomas on biopsies
229
17 Medical Management of Ulcerative Colitis
a
b
Fig. 17.1 Endoscopic
images of active ulcerative
colitis ( a ) shows severely
active disease with superfi cial
ulcers and spontaneous
bleeding and ( b ) shows
moderate infl ammation and
contact bleeding
Table 17.2 Assessment of severity of UC
Mild Moderate
Severe
No bloody stools <4 4 or more if
³ 6
Pulse (bpm) <90 £ 90 >90
Temperature (°C) <37.5 £ 37.8 >37.8
Hemoglobin (g/dl) >11.5 ³ 10.5 <10.5
ESR (mmh
−1
) or <20 £ 30 >30
CRP (mg/l) <5 <30 >30
230
P. Flanagan and K. Leiper
17.4 Drugs
17.4.1 5-Aminosalicylates
Meta-analysis shows rectal 5-ASAs to be superior to placebo in active distal colitis
[ 3 ] . Remission was achieved in around two-thirds of patients treated with rectal
5-ASA. Combination with oral 5-ASAs achieves higher mucosal drug concentra-
tions and should be used for active left-sided or extensive disease.
Because oral unbound 5-ASA is rapidly absorbed in the proximal small bowel,
there are several systems which deliver oral 5-ASA to the colon: pH-dependent,
dependent on colonic bacterial or deliver 5-ASA throughout the large and small
bowel. There is no evidence of any difference in effi cacy between different 5-ASA
formulations, and there is no evidence that high-dose 5-ASA are superior to stan-
dard doses. A reasonable dose for active disease is 2.4 g oral mesalazine or 6.75 g
balsalazide [ 1 ] . Sulfasalazine is generally avoided because of higher risk of adverse
effects (nausea, hemolytic anemia, and reversible oligospermia).Once daily prepa-
rations may be more convenient for some patients. All 5-ASAs have a small risk of
nephrotoxicity which is idiosyncratic. The recommendation is to check renal func-
tion 3 months after starting and thereafter yearly. A curious, uncommon side effect
of oral 5-ASA is diarrhea and should be remembered as a cause of “diffi cult colitis.”
The clue is normal or near normal endoscopic fi ndings.
Fig. 17.2 Abdominal x-ray
in severely active UC
showing mucosal edema
( arrows ) and dilatation of
cecum
231
17 Medical Management of Ulcerative Colitis
17.4.2 Steroids in UC
Oral prednisolone is a highly effective therapy for moderately active UC. The start-
ing dose should be 40 mg, and high dose should be continued for 1 month followed
by a tapering dose for the second month. A dose of 40 mg is as effective as 60 mg,
has fewer side effects, and is more effective than 20 mg. This dose induces remis-
sion in about 80% of cases. Combination with rectal 5-ASA is more effective than
monotherapy and should always be coprescribed with oral steroids. Common errors
made are starting on too low a dose of prednisolone which is ineffective or tapering
too rapidly which is associated with high relapse rates. Another common error is to
use oral steroids as maintenance therapy. There is no evidence that long-term ste-
roids are effective in maintaining remission in UC and use for over 3 months should
be avoided and is an indication for a step-up in medical therapy or referral for sur-
gery. A commonly used regime is 40 mg for 2 weeks, 30 mg for 2 weeks, and
20 mg for 1 week, reducing by 5 mg/week. Bone protection agents should be copre-
scribed to reduce the risk of osteoporosis – calcium and vitamin D for low risk and
bisphosphonate for high risk (age >65 years, known osteoporosis) [
4 ] .
Side effects of systemic steroids affect up to 50% of patients. Patients need to
receive an information booklet outlining side effects, e.g., important short-term effects
are weight gain, mood changes, diabetes, increased risk of infections, and avascular
necrosis of the hip. Because of the fi rst two, many patients with UC are reluctant to
start oral prednisolone. Alternative oral steroids are budesonide (colonic release prep-
aration) and oral beclomethasone which achieved remission rates of 75% in one small
study [ 5 ] . In general, these alternatives have fewer side effects but are less effective.
However they are useful where side effects of prednisolone are unacceptable.
17.4.3 Thiopurines (Azathioprine and Mercaptopurine)
Thiopurines (azathioprine or mercaptopurine) are indicated as steroid-sparing
agents for patients with a severe relapse, more than two courses of steroids in
12 months, for steroid dependent patients or those relapsing within 3 months of an
oral steroid course. There is no strong evidence of a dose response, but normal prac-
tice is to use a maintenance dose of azathioprine of 2–2.5 mg/kg/day or mercap-
topurine 0.75–1 mg/kg/day (in the absence of leucopenia) [ 6 ] . Prior to starting
therapy, blood thiopurine methyltransferase levels (TPMT) should be measured.
TPMT is one of the main enzymes which metabolizes thiopurines, and 1 in 400
people have no TPMT activity, and 20% have low levels. Administration of thiopu-
rine in a patient with no functional TPMT can lead to fatal myelosuppression. It is
also recommended that prior to starting immunosuppressant agents, varicella zoster
(VZV) and hepatitis B and C serologies are checked. Those negative for VZV and
hepatitis B should be vaccinated [
7 ] . Azathioprine is mainly used to maintain remis-
sion although the data are of generally poor quality. The mean effi cacy of thiopurine
is 65% for induction and 76% for maintenance of the remission [ 6 ] . The number
232
P. Flanagan and K. Leiper
needed to treat was 5 and an absolute risk reduction of 23% compared to placebo. It
is recommended that regular blood counts are performed. There are no guidelines
available at present but common practice is to perform a full blood count every
2–4 weeks for 2 months and then every 4–8 weeks. About 5–10% of patients are
intolerant of thiopurines predominantly due to nausea, but also due to pancreatitis,
hepatitis, myelosuppression, and hair loss. Long term, there seems to be conclusive
evidence for an increased risk of lymphoma in patients continuing on thiopurines
though the absolute risk is low and benefi ts outweigh risks [
8 ] .
17.4.4 Methotrexate
The evidence base for the use of methotrexate is poor, but it used as an alternative to
thiopurines for steroid resistant UC. A single RCT of low-dose therapy showed no
effect; however, observational data suggest effi cacy of 60% in patients with UC intol-
erant of thiopurines [ 9 ] . It is important to recognize that dosing once a week (orally,
intramuscularly, or subcutaneously) reduces side effects. For instance folic acid is
also given once a week (but not on the day methotrexate is given). Side effects are rare
though. They include nausea, myelosuppression, pulmonary fi brosis, and hepatitis.
17.4.5 Anti-TNFs
Infl iximab is the only agent for which there is RCT evidence in ulcerative colitis.
Meta-analysis shows that IFX (three intravenous infusions at 0, 2, and 6 weeks) was
more effective than placebo in inducing clinical remission (odds ratio 3.22, 95% CI
2.18–4.76), endoscopic remission (odds ratio 1.88, 95% CI 1.54–2.28), and clinical
response (odds ratio 1.99, 95% CI 1.65–2.41) at 8 weeks [ 10 ] . However, despite
these positive fi ndings, in the largest trial of infl iximab use in chronic active UC
(ACT-1), only 20.9% were in corticosteroid-free remission at 1 year follow-up. On
the other hand, cumulative incidence of colectomy is signifi cantly reduced at 1 year
(10% for infl iximab and 17% for placebo ( P = .02)) as are hospitalizations and sur-
geries/procedures per 100 patient years [ 11 ] . NICE has not approved infl iximab for
treatment of subacute UC (defi ned as outpatient basis) based on the lack of cost-
effectiveness [ 12 ] .
17.5 Management of UC
17.5.1 Active Left-Sided or Extensive UC
This is defi ned as disease extending beyond the rectosigmoid. For mild relapses,
oral 5-ASA can be used together with rectal 5-ASA. The combination is better than
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