Download Anti-adenoma therapy in FAP: Robin Phillips

A NTI-ADENOMA THERAPY IN FAP
polyp regression. Sulindac might affect very small duodenal
6)
polyps but has generally been disappointing in the
RKS, 'Randomised controlled trial of the effect of sulindac
duodenum (8).
on duodenal and rectal polyposis and cell proliferation in
patients with familial adenomatous polyposis'. Br J Surg.
Robin Phillips
Celecoxib is a COX2 inhibitor shown in a randomised
Professor of Colorectal Surgery and Dean, St Mark's Hospital, UK
80, (1993), 1618-1619.
controlled trial significantly to reduce large bowel polyps
7)
in FAP by 28% which is now licensed in the USA and a
BACKGROUND
Familial adenomatous polyposis is caused by a germline
mutation on chromosome 5q 21 leading to the development
colectomised patients with familial adenomatous polyposis:
prophylactic pylorus preserving and pancreas preserving
as an adjunct to normal patient management (9). It does
duodenectomy seems a therapy too far. Not all cases with
clinical results of a dose-finding study on rectal sulindac
seem to have a duodenal effect (10). A new study will test
administration. Int J Colorect Dis 1993; 8: 13-17.
an ileorectal anastomosis and advanced rectal polyposis
celexocib along with difluormethylornithine.
8)
are suited to pouch conversion. Some even cannot have
of multiple colorectal and upper gastrointestinal adenomas
and an almost certain large bowel cancer risk if left
untreated, the average age for cancer development in
untreated patients being aged 39 years.
Modern surgical treatment of the large bowel component
or to perform a pouch. With the former the rectal remnant
needs to be kept under surveillance every six months
because of the cancer risk which seems to be age
dependent. In one study about 8% of patients developed
cancer in the rectum by the age of 50, rising to 29% by
The sulfone derivative of sulindac has also been tested in
RKS. 'The effect of sulindac on small polyps in familial
disease. All of these patients are suitable for trials of anti-
a large randomised controlled trial in FAP patients. Whereas
adenomatous polyposis', Lancet. 345, (1995), 855-6.
adenoma therapy.
the primary end point in terms of polyp regression was not
9)
Gordon GB, Wakabayashi N, Saunders B, Shen Y, Li-Kuo S,
efficacy, particularly on longer term therapy.
F u g i m u r a T, L e v i n B .
There are many ways to reduce the adenoma burden:
Finally, experimentally liposome-mediated APC gene
physical, pharmacological/nutrient, photodynamic and
therapy has been tested in MIN mice and has produced
e x p e r i m e n t a l g e n e t h e r a p y t o n a m e b u t a f e w.
a 25% reduction in polyp burden. Locally applied as an
Straightforward polyp fulguration can be time consuming,
enema this might also prove an interesting, albeit currently
but we have found argon plasma coagulation to be safe,
futuristic, way forward in man.
within the thin-walled duodenum is limited not only by
The alternative pouch operation is not itself without risk
worries of perforation but also by the high argon gas flow
of adenoma development. In our own series at St Mark's
rates leading to marked bloating and discomfort.
Hospital 58% of our pouch patients have pouch adenomas
polyposis. New Engl J Med 2000; 342 (26): 1946-1958.
10) Phillips RKS, Wallace, MH, Lynch P, Hawk E, Gordon GB,
Saunders B, Wakabayashi N, Shen Y, Zimmerman S, Godio
L, Rodrigues-Bigas M, Li-Kuo S, Sherman J, Kelloff G, Levin
B, Steinbach G. A randomised double blind placebo
controlled study of celecoxib, a selective cyclooxygenase-
1)
to light of a particular wavelength, the depth of necrosis
Two of our pouch patients have had
advanced pouch polyps of large size and villous histology.
I am personally aware of three cases of actual pouch cancer
2 inhibitor, on duodenal polyposis in familial adenomatous
polyposis. Gut 2001 (in press).
Nugent KP, Phillips RKS, 'Rectal cancer risk in older patients
with familial adenomatous polyposis and an ileorectal
anastomosis: a cause for concern'. Br J Surg. 79, (1992),
1204-1206.
disappointing as each polyp requires prolonged exposure
of cancer is hard to quantify at this early stage of pouch
2)
Nugent KP, Spigelman AD, Phillips RKS, 'Life expectancy
is very superficial, and patients can become markedly
after colectomy and ileorectal anastomosis for familial
sensitive to sunlight for a prolonged period (3).
adenomatous polyposis'. Dis Colon Rectum. 36, (1993),
1059-1062.
in FAP patients (that is to say, not cancer arising from
Dietary/nutrient trials have focussed on added calcium (4),
islands of mucosa left behind after mucosectomy or at the
Vitamin C (5) and resistant fibre (the latter being in the
anal component of a stapled anastomosis).
CAPP -Concerted Action in Polyposis Prevention - study).
3)
'Photodynamic therapy for polyps in familial adenomatous
polyposis - a pilot study'. Eur J Cancer. 31a, (1995), 1160-
calcium and Vitamin C have been disappointing.
one of the foremost causes of death (2). In our recent
Mlkvy P, Messman H, Debinski H, Regula J, Conio M,
MacRobert A, Spigelman A, Phillips RKS, Bown SG.
The CAPP study has not yet reported and the effect of
In treated FAP patients, upper gastrointestinal cancer is
1165.
experience, about one third of our patients with advanced
Until the emergence of COX2 inhibitors, sulindac was the
(Spigelman stage IV) duodenal disease went on to develop
drug of choice to treat rectal stump polyps, either orally
Long term effects of dietary calcium on risk markers for
duodenal adenocarcinoma and die from their disease over
in a standard dose or as a rectal suppository at a much
colon cancer in patients with familial polyposis. Gut 1990;
a ten year period. In the same period only 2% of patients
lower dose of 25mg daily (6, 7). But combined COX1/COX2
108: 528-33.
with Stages III and II disease developed cancer respectively.
drugs suffer the side-effects of their COX1 component,
Presently we do not know what to do about pouch polyps.
Except in the most advanced stages of duodenal polyposis,
P.4
The effect of celecoxib, a
cyclooxygenase-2 inhibitor, in familial adenomatous
REFERENCES
Early experience with photodynamic therapy was
and the risk is increased with patients' age. The later risk
Steinbach G, Lynch P, Phillips RKS, Wallace M, Hawk E,
seen in this study, there are tantalising suggestions of
effective and well tolerated in the rectum. Experience
the age of 60 (1).
Debinski H, Trojan J, Nugent KP, Spigelman AD, Phillips
the rectum removed because of coincidental desmoid
TECHNIQUES OF ANTI-ADENOMA THERAPY
is either to perform colectomy and ileorectal anastomosis
Winde G, Gumninger HG, Osswald H, Kemper F, Bunte H.
The NSAID sulindac reverses rectal adenomas in
number of other countries, including Australia and Israel,
surgery in FAP.
Nugent KP, Farmer KCR, Spigelman AD, Williams CB, Phillips
4)
5)
Stern HS, Gregoire RC, Kashtan H, Stadler J, Bruce RW.
Bussey HJR, DeCosse JJ, Deschner EE et al. A randomised
being gastrointestinal ulceration and platelet dysfunction,
trial of ascorbic acid in polyposis coli. Cancer 1982; 50:
and rectal cancer has been reported, despite apparent
1434-9.
P.5
A NTI-ADENOMA THERAPY IN FAP
polyp regression. Sulindac might affect very small duodenal
6)
polyps but has generally been disappointing in the
RKS, 'Randomised controlled trial of the effect of sulindac
duodenum (8).
on duodenal and rectal polyposis and cell proliferation in
patients with familial adenomatous polyposis'. Br J Surg.
Robin Phillips
Celecoxib is a COX2 inhibitor shown in a randomised
Professor of Colorectal Surgery and Dean, St Mark's Hospital, UK
80, (1993), 1618-1619.
controlled trial significantly to reduce large bowel polyps
7)
in FAP by 28% which is now licensed in the USA and a
BACKGROUND
Familial adenomatous polyposis is caused by a germline
mutation on chromosome 5q 21 leading to the development
colectomised patients with familial adenomatous polyposis:
prophylactic pylorus preserving and pancreas preserving
as an adjunct to normal patient management (9). It does
duodenectomy seems a therapy too far. Not all cases with
clinical results of a dose-finding study on rectal sulindac
seem to have a duodenal effect (10). A new study will test
administration. Int J Colorect Dis 1993; 8: 13-17.
an ileorectal anastomosis and advanced rectal polyposis
celexocib along with difluormethylornithine.
8)
are suited to pouch conversion. Some even cannot have
of multiple colorectal and upper gastrointestinal adenomas
and an almost certain large bowel cancer risk if left
untreated, the average age for cancer development in
untreated patients being aged 39 years.
Modern surgical treatment of the large bowel component
or to perform a pouch. With the former the rectal remnant
needs to be kept under surveillance every six months
because of the cancer risk which seems to be age
dependent. In one study about 8% of patients developed
cancer in the rectum by the age of 50, rising to 29% by
The sulfone derivative of sulindac has also been tested in
RKS. 'The effect of sulindac on small polyps in familial
disease. All of these patients are suitable for trials of anti-
a large randomised controlled trial in FAP patients. Whereas
adenomatous polyposis', Lancet. 345, (1995), 855-6.
adenoma therapy.
the primary end point in terms of polyp regression was not
9)
Gordon GB, Wakabayashi N, Saunders B, Shen Y, Li-Kuo S,
efficacy, particularly on longer term therapy.
F u g i m u r a T, L e v i n B .
There are many ways to reduce the adenoma burden:
Finally, experimentally liposome-mediated APC gene
physical, pharmacological/nutrient, photodynamic and
therapy has been tested in MIN mice and has produced
e x p e r i m e n t a l g e n e t h e r a p y t o n a m e b u t a f e w.
a 25% reduction in polyp burden. Locally applied as an
Straightforward polyp fulguration can be time consuming,
enema this might also prove an interesting, albeit currently
but we have found argon plasma coagulation to be safe,
futuristic, way forward in man.
within the thin-walled duodenum is limited not only by
The alternative pouch operation is not itself without risk
worries of perforation but also by the high argon gas flow
of adenoma development. In our own series at St Mark's
rates leading to marked bloating and discomfort.
Hospital 58% of our pouch patients have pouch adenomas
polyposis. New Engl J Med 2000; 342 (26): 1946-1958.
10) Phillips RKS, Wallace, MH, Lynch P, Hawk E, Gordon GB,
Saunders B, Wakabayashi N, Shen Y, Zimmerman S, Godio
L, Rodrigues-Bigas M, Li-Kuo S, Sherman J, Kelloff G, Levin
B, Steinbach G. A randomised double blind placebo
controlled study of celecoxib, a selective cyclooxygenase-
1)
to light of a particular wavelength, the depth of necrosis
Two of our pouch patients have had
advanced pouch polyps of large size and villous histology.
I am personally aware of three cases of actual pouch cancer
2 inhibitor, on duodenal polyposis in familial adenomatous
polyposis. Gut 2001 (in press).
Nugent KP, Phillips RKS, 'Rectal cancer risk in older patients
with familial adenomatous polyposis and an ileorectal
anastomosis: a cause for concern'. Br J Surg. 79, (1992),
1204-1206.
disappointing as each polyp requires prolonged exposure
of cancer is hard to quantify at this early stage of pouch
2)
Nugent KP, Spigelman AD, Phillips RKS, 'Life expectancy
is very superficial, and patients can become markedly
after colectomy and ileorectal anastomosis for familial
sensitive to sunlight for a prolonged period (3).
adenomatous polyposis'. Dis Colon Rectum. 36, (1993),
1059-1062.
in FAP patients (that is to say, not cancer arising from
Dietary/nutrient trials have focussed on added calcium (4),
islands of mucosa left behind after mucosectomy or at the
Vitamin C (5) and resistant fibre (the latter being in the
anal component of a stapled anastomosis).
CAPP -Concerted Action in Polyposis Prevention - study).
3)
'Photodynamic therapy for polyps in familial adenomatous
polyposis - a pilot study'. Eur J Cancer. 31a, (1995), 1160-
calcium and Vitamin C have been disappointing.
one of the foremost causes of death (2). In our recent
Mlkvy P, Messman H, Debinski H, Regula J, Conio M,
MacRobert A, Spigelman A, Phillips RKS, Bown SG.
The CAPP study has not yet reported and the effect of
In treated FAP patients, upper gastrointestinal cancer is
1165.
experience, about one third of our patients with advanced
Until the emergence of COX2 inhibitors, sulindac was the
(Spigelman stage IV) duodenal disease went on to develop
drug of choice to treat rectal stump polyps, either orally
Long term effects of dietary calcium on risk markers for
duodenal adenocarcinoma and die from their disease over
in a standard dose or as a rectal suppository at a much
colon cancer in patients with familial polyposis. Gut 1990;
a ten year period. In the same period only 2% of patients
lower dose of 25mg daily (6, 7). But combined COX1/COX2
108: 528-33.
with Stages III and II disease developed cancer respectively.
drugs suffer the side-effects of their COX1 component,
Presently we do not know what to do about pouch polyps.
Except in the most advanced stages of duodenal polyposis,
P.4
The effect of celecoxib, a
cyclooxygenase-2 inhibitor, in familial adenomatous
REFERENCES
Early experience with photodynamic therapy was
and the risk is increased with patients' age. The later risk
Steinbach G, Lynch P, Phillips RKS, Wallace M, Hawk E,
seen in this study, there are tantalising suggestions of
effective and well tolerated in the rectum. Experience
the age of 60 (1).
Debinski H, Trojan J, Nugent KP, Spigelman AD, Phillips
the rectum removed because of coincidental desmoid
TECHNIQUES OF ANTI-ADENOMA THERAPY
is either to perform colectomy and ileorectal anastomosis
Winde G, Gumninger HG, Osswald H, Kemper F, Bunte H.
The NSAID sulindac reverses rectal adenomas in
number of other countries, including Australia and Israel,
surgery in FAP.
Nugent KP, Farmer KCR, Spigelman AD, Williams CB, Phillips
4)
5)
Stern HS, Gregoire RC, Kashtan H, Stadler J, Bruce RW.
Bussey HJR, DeCosse JJ, Deschner EE et al. A randomised
being gastrointestinal ulceration and platelet dysfunction,
trial of ascorbic acid in polyposis coli. Cancer 1982; 50:
and rectal cancer has been reported, despite apparent
1434-9.
P.5