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212
S. Jamdar et al.
demonstrated in a survival curve from a Japanese cohort [ 20 ] . The key fi nding in
both these reports is that up to 20% of patients undergoing liver resection for col-
orectal hepatic metastases will survive for up to 10 years.
15.8 Conclusion
Liver resection for colorectal metastases is an important part of the contemporary
management of patients with bowel cancer. Colorectal and hepatobiliary surgical
teams must work closely together to identify appropriate patients and to ensure
optimal follow-up. The principles of staging are clearly defi ned and seek to identify
those patients who will gain most benefi t from resection. Future trends in the use of
biologic agents for adjuvant therapy, laparoscopic techniques for resection, and
improved understanding of the biology of colorectal cancer suggest that this is a
steadily evolving fi eld with outcomes likely to continue to improve.
References
1. Rudmick LR, Magliocco AM. Molecular mechanisms of hepatic metastasis in colorectal can-
cer. J Surg Oncol. 2005;92:347–59.
2. Cancer Research UK Information Resource Centre. Cancer Stats. 2003.
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searchuk.org/cancerstats
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3. Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of hepatic metastases from
colorectal cancer: a systematic review of published studies. Br J Cancer. 2006;94:982–99.
4. Treasure T. Pulmonary metastasectomy: a common practice based on weak evidence. Ann R
Coll Surg Engl. 2007;89:744–8.
5. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma:
impact of surgical resection on the natural history. Br J Surg. 1990;77:1241–6.
Key Points
There is ample evidence that liver resection can lead to survival •
advantage.
Resection involves•
Careful staging –
Assessment of comorbidity –
Resection planning –
In a fi t person, up to 75% of the liver can be resected. •
Detailed anatomical knowledge is necessary in order to leave a functioning •
remnant.
Preresection strategies include neoadjuvant chemotherapy and PVE. •
For those deemed to be appropriate for resection, 5-year survival of 34% •
can be achieved.
213
15 Colorectal Liver Metastases
6. Renehan AG, Egger M, Saunders MP, O’Dwyer ST. Impact on survival of intensive follow up
after curative resection for colorectal cancer: systematic review and meta-analysis of ran-
domised trials. BMJ. 2002;324:813.
7. Gomez D, Sangha VK, Morris-Stiff G, et al. Outcomes of intensive surveillance after resection
of hepatic colorectal metastases. Br J Surg. 2010;97:1552–60.
8. 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.
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9. Junejo M, Foster P, Moore J, et al. Cardiopulmonary exercise testing for risk assessment prior
to hepatectomy. HPB. 2011; 13: Suppl 2 p84.
10. Valls C, Martίnez L, Ruiz S, Alba E. Radiological imaging of liver metastases. In: Vauthey
J-N, Hoff PM, Audisio R, Poston GJ, editors. Liver metastases. London: Springer; 2009. p.
1–15.
11. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and
surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC
Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007–16.
12. Belgihiti J, Clavien PA, Gadzijev, et al. The Brisbane 2000 terminology of liver anatomy and
resections. HPB. 2000;2:333–9.
13. Hamady ZZ, Cameron IC, Wyatt J, et al. Resection margin in patients undergoing hepatectomy
for colorectal liver metastasis: a critical appraisal of the 1 cm rule. Eur J Surg Oncol.
2006;32:557–63.
14. Buell JF, Cherqui D, Geller DA, et al. The international position on laparoscopic liver surgery:
the Louisville Statement, 2008. Ann Surg. 2009;250:825–30.
15. Sebag-Montefi ore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective
postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG
C016): a multicentre, randomised trial. Lancet. 2009;373:811–20.
16. Bosset J-F, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal
cancer. N Engl J Med. 2006;355:1114–23.
17. Allen PJ, Kemeny N, Jarnagin W, et al. Importance of response to neoadjuvant chemotherapy
in patients undergoing resection of synchronous colorectal liver metastases. J Gastrointest
Surg. 2003;7:109–15.
18. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver metastases from colorectal
cancer after neoadjuvant chemotherapy. Ann Surg. 1996;224:509–22.
19. Chua TC, Saxena A, Chu F, Zhao J, Morris DL. Predictors of cure after hepatic resection of
colorectal liver metastases: an analysis of actual 5- and 10-year survivors. J Surg Oncol. 2011.
doi: 10.1002/jso.21864 (Epub ahead of print).
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215
S.R. Brown et al. (eds.), Contemporary Coloproctology,
DOI 10.1007/978-0-85729-889-8_16, © Springer-Verlag London Limited 2012
Anal cancer comprises 1% of lower gastrointestinal tract cancers with approxi-
mately 800 reported new cases per year in the UK. Nearly all cases are of epider-
moid type (squamous, basaloid, or cloacogenic); malignant melanoma, and other
primary malignancies are very rare and respond poorly to any treatment modality.
Anal canal lesions are twice as common as margin cancers; canal lesions are twice
as common in women with the reverse ratio for margin lesions. The distinction
between the two lesion sites is clinically important for two reasons: fi rstly, that canal
lesions can invade adjacent organs (vagina, urethra, prostate, and bladder) and may
require different treatment strategies and, secondly, that T1 margin lesions can be
excised locally. Presenting symptoms include pain (49%), bleeding (44%), change
in bowel habit (34%), a mass (24%), and pruritus/discharge (23%) [ 1 ] .
Until the 1980s, standard treatment for anal canal cancer consisted of anorectal
excision with or without inguinal lymph node dissection and 5-year survival rates of
38–71% were achieved [ 2– 4 ] . In the 1970s, Norman Nigro in North America intro-
duced combined chemotherapy and radiotherapy in an attempt to downstage patients
with advanced anal cancer. To their surprise, they found that resection specimens
contained no residual tumor. Chemoradiotherapy (CMT) became their standard
treatment and 5-year survival rates of 80% were achieved. Anorectal excision was
abandoned unless residual tumor was present 6–8 weeks after initial treatment [ 5 ] .
The benefi ts of chemoradiotherapy were confi rmed in three recently reported
European randomized trials. Treatment involved two phases of treatment with a gap
between the two phases. The median phase 1 dose of radiotherapy (given to the
primary tumor and lymph nodes) was 39.6 Gy with a median phase 2 dose of
J. Hill, M.B.Ch.B., M.Ch., FRCS
Department of Surgery , Manchester Royal Infi rmary ,
Oxford Rd. , Manchester , M13 9WL , UK
e-mail: james.hill@cmft.nhs.uk
Chapter 16
Anal Cancer
Jim Hill
216
J. Hill
14.4 Gy. The median overall radiotherapy treatment time was 52 days. Concurrent
standard chemotherapy with 5-fl uorouracil and mitomycin C was administered. The
reported 3–5-year survival rates were between 56% and 76% and colostomy-free
survival rates were 75–91% [
6– 8 ] . In the UKCCCR trial, for every 100 patients
treated with CMT, there were 25.3 fewer patients with locoregional relapse and 12.5
fewer anal cancer deaths compared with radiotherapy treatment alone [
9 ] .
A follow-up trial in the UK, the ACT II anal cancer trial was designed to address two
questions: fi rstly whether replacing mitomycin C with cisplatin would improve the
complete response rate, and secondly whether two cycles of maintenance chemother-
apy after chemoradiotherapy would reduce recurrence [ 10 ] . Between 2001 and 2008,
940 patients were recruited to this randomized trial. Patients received 50 Gy radio-
therapy in 28 fractions without a gap in the radiotherapy schedule. The chemotherapy
used was 5-FU and either mitomycin C or cisplatin. Patients were also randomized to
receive maintenance therapy 4 weeks after chemoradiotherapy (two cycles of cisplatin
and 5-FU for weeks 11 and 14) or no maintenance. The complete response rate was
94% mitomycin C and 95% cisplatin. The high complete response rate in the ACT II
study (95%) compares favorably with the complete response rates reported in the three
earlier European trials and may have been infl uenced by the absence of a gap in the
radiotherapy schedule. In addition, a recurrence-free survival (75% at 3 years) was
achieved. There was no difference in complete response rates between mitomycin C
and cisplatin nor in recurrence-free survival rates with or without maintenance chemo-
therapy. Thus, 5-FU and mitomycin C with radiotherapy remains the standard of care
for squamous cancer of the anal canal and margin. Quality of life studies for CMT treat-
ment are acceptable overall, but poor sexual function is common [ 11 ] .
Introduction of chemoradiotherapy treatment as standard care has reduced the
requirement for salvage surgery. The disease prevalence itself will also be infl u-
enced, albeit not for some considerable time, by the recent introduction of an HPV
immunization program for teenage girls in the UK.
16.1 Initial Assessment
Standard assessment at initial presentation consists of PR examination and palpa-
tion of inguinal lymph nodes. Biopsy proof of malignancy usually performed
under general anesthesia is required in all cases. The size of the lesion is usually
assessed clinically. The current staging system by necessity uses size criteria (T1–
3) for the primary tumor, rather than depth of invasion (Table
16.1 ). Staging accu-
racy may be improved by measurement of the primary tumor with endoanal
ultrasound or MRI.
Assessment of lymph node status is made using a combination of clinical, radio-
logical, and pathological assessments (FNA, Tru-cut, or formal biopsy). No radio-
logical method (CT, PET/CT, or MRI) is accurate enough to allow selective
radiotherapy of nodal groups. Histological proof of lymph node involvement is
more important in suspected recurrence as the inguinal, mesorectal, and internal
iliac nodes are included in the radiation fi elds when the primary tumor is treated.
217
16 Anal Cancer
16.2 Role of Surgery (Box 16.1 )
16.2.1 Local Excision
For T1 anal margin tumors (<2 cm) where local excision achieves survival and local
control rates approaching 100% [ 12 ] .
16.2.2 Stoma Formation
Patients who have tumors with extensive involvement of the anal sphincters may present
with incontinence. Radiation therapy is likely to exacerbate this symptom as it produces
Table 16.1 AJCC/UICC staging of anal canal cancer
Primary tumor (T)
Tx – Tumor cannot be assessed
T0 – No evidence of tumor
Tis – Carcinoma in situ
T1 – <2 cm in greatest dimension
T2 – >2 and <5 cm in greatest dimension
T3 – >5 cm in greatest dimension
T4 – Any size with invasion of adjacent organ(s) (vagina, urethra, bladder)
Lymph nodes
Nx – Lymph nodes cannot be assessed
N0 – No regional lymph node metastases
N1 – Perirectal lymph nodes
N2 – Unilateral internal iliac and or inguinal LN
N3 – N1 and N2 and/or bilateral internal iliac and/or inguinal LN
Distant metastases (M)
Mx – Metastases cannot be assessed
M0 – No distant metastases
M1 – Distant metastases
Staging
Stage 0 – TisN0M0
Stage 1 – T1N0M0
Stage 2 – T2,3N0M0
Stage 3a – T1–3N1M0, T4N0M0
Stage3b – T4N1M0, any TN2M0, any TN3M0
Stage 4 – Any T, any NM1
Box 16.1: Role of the Surgeon
Diagnosis and biopsy of primary lesion
Excision of T1 margin lesions
Diverting stoma for incontinence or complications of treatment
Diagnosis and biopsy of recurrence
Salvage surgery
218
J. Hill
varying degrees of proctitis with diarrhea, rectal bleeding, and mucous discharge. A loop
colostomy may be necessary to control incontinence and protect the perianal skin during
CMT. Even after successful treatment, reversal of the stoma is often not possible due to
residual sphincter defi ciency; sphincter repair is unlikely to be rewarding.
CMT for anteriorly placed lesions involving the rectovaginal septum or anal
canal carries the risk of rectovaginal fi stula after tumor shrinkage. Repair is usually
unsuccessful; if attempted, the repair needs to be protected with a covering stoma.
Although rare, radionecrosis of perianal tissue does occur, and pain and persistent
ulceration may necessitate a permanent colostomy.
16.2.3 Diagnosis of Recurrence
The full effect of CMT is seen 6–8 weeks after the treatment has been completed. If
there is any suspicious residual palpable abnormality after that time, examination
under anesthesia and biopsy should be performed.
When local treatment failure occurs, the vast majority of recurrences do so
within 18 months of starting treatment. Locally recurrent disease is almost uni-
versally found at the anal margin or within the lumen of the anal canal or rectum.
Such lesions are almost always palpable digitally and may thus be detected before
becoming symptomatic, therefore regular outpatient follow-up with a high index
of suspicion is recommended. Clinically, differentiation between radiation effect
and recurrence can be very diffi cult, especially if there is residual ulceration at
the site of the original cancer following chemoradiotherapy (Fig. 16.1 ). If recur-
rent disease is suspected, examination under anesthesia and biopsy are required.
PET/CT scanning has a potential role in detecting recurrent disease, but its value
is not yet proven.
16.2.4 Salvage Surgery (Box 16.2 )
Once a diagnosis of recurrence has been made, the patient should be considered for
salvage surgery. Patients need to be fi t enough to withstand a major procedure and
have metastatic disease excluded by CT scanning of the thorax, abdomen, and pel-
vis. If there are suspicious enlarged nodes, every effort should be made to obtain
tissue for histological analysis. The chances of curative surgery in patient with met-
astatic disease in the inguinal or iliac nodes are remote.
Irradiated tissues are typically indurated and fi brotic; this makes accurate assess-
ment of the extent of local recurrence extremely diffi cult. The diffi culties are demon-
strated by the fact that involved resection margins are found in around one-third of
resected anal cancer specimens, a much higher rate than for rectal cancer specimens.
Preoperative MR scanning may aid assessment of the degree of radial invasion
beyond the anal canal, but its accuracy is also reduced post chemoradiotherapy.
219
16 Anal Cancer
For the surgery itself, lateral excision margins must be as wide as possible. For
anal margin cancers and anal canal lesions extending to the anal margin, the skin
incision should be at least 2 cm lateral to the tumor. The posterior vaginal wall
should be included in the excision if it is involved. As invasion into the ischiorectal
and perirectal fat carries a poor prognosis, radical excision of the ischiorectal fat
should be performed with detachment of the levator muscles from the pelvic side
walls. It is important to recognize that in a previously radiated fi eld, normal tissue
Fig. 16.1 Ulcer following
chemoradiotherapy. Is this a
therapy effect or is it residual
cancer?
Box 16.2: The Problems with Salvage Surgery for Anal Cancer
Effect of chemoradiotherapy
Assessment of tumor extent less accurate
Loss of normal tissue planes
Increased risk of bleeding
Impaired healing
220
J. Hill
planes may be more diffi cult to identify, tissues may be more friable, healing likely
to be compromised, and the risk of bleeding increased.
Despite the fact that the current TNM staging of anal cancers is not appropriate
for resected specimens, there is currently no agreed pathological staging system for
salvage surgery of anal cancer. Histopathological reports should include statements
about the anatomical extent of local invasion and the lateral excision margins.
Most reported series have described high rates of delayed and nonhealing wounds
when primary closure is performed. Even if wounds do heal, this can take many
months. Radice et al. compared complications of primary skin closure, primary skin
and omental transposition into the pelvis, and immediate myocutaneous fl ap closure
(using rectus abdominis) in patients undergoing extended resections for locally
advanced primary malignancy or locally recurrent anorectal cancer [ 13 ] . Overall,
the use of a myocutaneous fl ap was associated with a reduction in serious wound
complications without an increase in operating time or length of stay.
Depending on the volume to be fi lled, either rectus abdominis or gracilis muscles
can be used to fi ll a defect with well-vascularized tissue [ 14, 15 ] . Where the perineal
skin has been widely excised, a myocutaneous fl ap is required. The inferiorly based
rectus abdominis fl ap works well in this situation, the rectus muscle is wide, and the
skin fl ap is reliable and can carry enough skin to resurface the whole of the perineum.
The inferior epigastric artery and the full width of the fascia under the skin fl ap must
be preserved. The skin fascia and rectus muscle are rotated behind the bladder. Mobility
is such that the fl ap can be sutured to the perineal skin without tension (Fig. 16.2 ).
In the UKCCCR trial (ACT 1) of radiotherapy alone versus radiotherapy, 5-fl uo-
rouracil, and mitomycin (CMT), there were 265 (47%) local treatment failures; 143
patients underwent anorectal excision (ARE), 44% developed further pelvic disease
post-ARE, and in 67 patients, 50% died of anal cancer. Other studies have shown that
approximately 50% of patients undergoing salvage anorectal excision will survive
Fig. 16.2 Rectus abdominis
fl a p
221
16 Anal Cancer
3–5 years after surgery (Table 16.2 ) [ 16– 25 ] . All the reported case series describe
high rates of further locoregional recurrence. Risk factors for treatment failure
include fi xation of tumor to the pelvic side wall and invasion into the perirectal fat,
involved resection margins, and involvement of an adjacent organ. Stage of the pri-
mary tumor, mesorectal nodal involvement, and tumor differentiation do not appear
to affect recurrence. Patients should be specifi cally counseled about the high risk of
further recurrent disease and the risk of delayed or failed perineal wound healing.
The poor results of salvage surgery have led to the suggestion that patients should
be given additional postoperative chemotherapy following salvage anorectal exci-
sion. Further pelvic disease following salvage is unlikely to be amenable to further
pelvic surgery. Palliative chemotherapy should be discussed with the patients’
oncologist. Should the patient develop an isolated inguinal lymph node recurrence,
inguinal lymphadenectomy can avoid the pain, ulceration, and discharge of uncon-
trolled malignancy (Box 16.3 ) .
Table 16.2 Results of salvage anorectal excision following failed radiation with or without che-
motherapy for anal cancer
Author Number
Mean follow-up
months Survival (%)
Zelnick [
16 ] 25 20
29 (3 years)
Tanum [
17 ] 9 36 67
Ellenhorn [
18 ] 38 47 44 (5 years)
Longo [
19 ] 14 18 57
Pocard [
20 ] 21 58 (3 years)
UKCCCR 2003 [
25 ] 133 3.3 50
Ghouti [
21 ] 36 67 69 (5 years)
Papaconstantinou [
22 ] 19 14 40
Schiller [
23 ] 40 18 39 (5 years)
Mullen [
24 ] 31 29 64 (5 years)
Box 16.3: Recommendations for the Surgical Management
of Anal Cancer Following Failure of Chemoradiation
Multidisciplinary Team
In order to manage patients with anal cancer following failed chemoradiation,
the multidisciplinary team should include two colorectal surgeons, a plastic
surgeon, urologist, oncologist, GI radiologist, colorectal cancer nurse special-
ist, and stoma therapist. High dependency and ICU care should be available
postoperatively where required. Patients developing further recurrence should
have access to a palliative care team.
Assessment
Standard investigations to determine fi tness for surgery
Local Disease
Examination under anesthetic, biopsy (recurrence must be confi rmed histo-
logically), MRI scan, transanal ultrasound scanning
222
J. Hill
16.3 Anal Intraepithelial Neoplasia
There is clear evidence of an association of HPV infection with cervical, vulval,
vaginal, and anal intraepithelial neoplasia and anal cancer. Human papillomavirus
(HPV) is the most common sexually transmitted infection in the world; individuals
are typically infected with several different types of HPV at the same time. Both the
anal and cervical regions are frequent sites of HPV infection. High-risk HPV types
may be associated with cancer of the anus (HPV 16 and 18). There are as yet no
clear guidelines for the management of AIN. Active management and monitoring is
most often carried out for high-grade (AIN3) lesions. AIN1 and 2 lesions can resolve
spontaneously.
In North America, around 7% of HIV-negative gay or bisexual men have AIN,
and around one-third of HIV-positive gay or bisexual men have AIN. Anal cancer is
thought to be more common in HIV-positive than HIV-negative men, and HIV-
positive men may respond less well to treatment and have greater treatment-related
side effects than anal cancer in HIV-negative men. Testing for oncogenic HPV
strains allows selective screening of at-risk individuals as it may predict the devel-
opment of high-grade dysplasia [ 26 ] . Other immunocompromised patients are also
at increased risk of AIN.
Metastatic Disease
Lymph node fi ne needle aspiration or biopsy for clinically suspicious groin
nodes, CT scan of abdomen and chest
Treatment
This should be based on the extent of disease. In the absence of metastatic
disease, anorectal excision is the standard procedure. The operative technique
should include wide excision of the anal canal and circumrectal tissue also
ensuring the widest pelvic fl oor clearance. As both the abdominal and perineal
part of the operation may be technically diffi cult, two colorectal surgeons
working synchronously would be advantageous. Where preoperative investi-
gations have shown evidence of invasion of adjacent organs and surgical care
still possible, anorectal excision with en bloc excision of the involved struc-
tures should be performed with the assistance of appropriate surgical
specialists.
Reconstruction
In view of the high rates of perineal wound breakdown and the long time to
perineal wound healing in many patients, a rectus abdominis fl ap is generally
necessary unless the tissues are very favorable at the examination under
anesthetic.
Histopathological Reporting
Following histopathological review, all cases should be discussed at a multi-
disciplinary meeting to consider further adjuvant therapies.
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