| Japanese Journal of Clinical Oncology | Pages |
Letters
The "Sufficiency Principle" from the Perspective of Cancer Prevention
To the Editor:
The 27th International Symposium of the Princess Takamatsu Cancer Research Fund brought together scientists from several countries to present their work related to the title "Fundamentals of Cancer Prevention". The recently published proceedings from that symposium (1) included introductory remarks in which Dr T. Sugimura discussed the "Sufficiency Principle", citing Rothman's paper (2), for the multi-factorial nature of gastric cancer (3). Figure 1A in that paper shows how various carcinogenic factors cause sufficient genetic damage to convert normal cells into cancer cells, Fig.1B indicates the reduction of carcinogenic risk factors, and Fig.1C represents the summation of reductions, leading to "insufficiency" of genetic alterations (3, 4, 5).
Because of the subject matter of the proceedings, it struck me that the Sufficiency Principle might be viewed from the opposite direction, i.e. from the perspective of the preventive agent rather than the carcinogenic risk factors. Thus, in reference (3), Fig. 1A might define the "Sufficiency of Protection" required to give complete coverage, via a combination of preventive measures acting by multiple mechanisms and covering all stages of carcinogenesis (a-h). The preventive measures would include exposure to "blocking agents" during the initiation phase and "suppressing agents" for the post-initiation and progression phases of carcinogenesis, as defined by Wattenberg (6). Avoidance strategies also would be included, based on the "Twelve Points for Cancer Prevention" (7, 8), such as cessation of cigarette smoking and reducing the intake of charred foods and excess calories (9, 10, 11). If Fig. 1A in reference (3) defines the Sufficiency of Protection, Fig. 1B represents the "Insufficiency of Preventive Measures". The net result of this lowered protection would be to allow multiple genetic changes to occur by exposure to endogenous and external factors (white areas in Fig. 1B). As a consequence, mutations accumulate in various genes (a',c', d',e',f',h' in Fig.1C), and convert a normal cell to a cancer cell.
Figure 1. (A) "Sufficiency Principle" in the context of cancer prevention: various anticarcinogenic factors (a-h) provide complete protection during the initiation and post-initiation phases of carcinogenesis. (B) "Insufficiency Principle": reduced cancer preventive measures (white areas) provide a window for genetic alterations to occur in cells, and for pre-initiated cells to progress to later stages. (C) Accumulation of Hits: the number of genetic changes accumulates to the extent that normal cells are converted to cancer cells.
One might further choose to illustrate these ideas in the context
of colorectal carcinogenesis, with reference to the findings
reported in the proceedings (1). To provide the coverage required
by the Sufficiency Principle for the multifactorial nature of colon
cancer inhibition (Fig. 1A), an individual would be exposed to a
combination of preventive agents and measures, including the
following (though not necessarily in order of priority): (a)
arachadonic acid cascade inhibitors, (b) polyphenols, (c)
flavonoids, (d) organosulfur compounds, (e) trace elements, (f)
conjugated linoleic and docosa-hexaenoic acids, (g)
xanthophylls, chlorophylls, and carotenoids, and (h) low fat and
caloric intake, and dietary restriction (1). An insufficiency of
(a)-(h) would allow multiple genetic hits to occur in key genes
(Fig.1B, white areas). In the example of colorectal cancer, the key
genes might include several of the following: (a') APC, (c')
CTNNB1 (d') Ki-ras (e') DCC, (f') P53, and (h') BAX (Fig.1C)
(12, 13, 14, 15).
As defined here, the Insufficiency Principle represents one of
the "Fundamentals of Cancer Prevention", since it describes the
loss of protective agents and measures to such an extent that
genetic alterations accumulate and normal cells develop into
cancer cells.
Roderick H. Dashwood
To the Editor:
British surgeons have long been criticised for their poor quality
research and reliance on historical reviews of their own personal
series. A brief read of any surgical journal over the last five years
will seldom reveal a randomised surgical trial, a point noted by
Richard Horton (Editor of The Lancet) when he described British
surgical research as comic opera (1).
When British surgeons compare their own results for gastric
cancer surgery with those of Japanese surgeons, two excuses are
offered; firstly gastric cancer in Japan is a different disease than
in the West and secondly Japanese surgeons refuse to test their
hypotheses in randomised trials. I have recently had the
opportunity to visit the National Cancer Center Hospital (NCCH)
in Tokyo and feel that after such a thorough introduction to
Japanese gastric surgical practice I can address these two
misconceptions.
The gastric surgery division of the NCCH, in conjunction with
the endoscopy division, will treat approximately 430 gastric
cancer cases per year. Approximately 60% of these will be early
gastric cancer (limited to the mucosa and submucosa only)
whereas the proportion of early cases in the UK is nearer to 20%
(2). The incidence of gastric cancer in Japan however, is
approximately five times that in the UK. The Japanese
government established a screening programme 30 years ago and
this, in conjunction with greater population awareness has lead to
the greater proportion of early disease being treated. In 1996, 40%
of gastric cancer patients treated by the gastric surgery division
underwent either total or proximal gastrectomy, while in the
recent MRC randomised controlled trial, 56% of patients
underwent a total gastrectomy (2). The incidence of proximal
tumours is certainly increasing in the UK but the differences
between the UK and Japan are only slight. In my two-month stay
at the NCCH, I reviewed the radiology and witnessed the
treatment of all stages of gastric cancer. There is no doubt in my
mind that, apart from the proportion of early stage disease, gastric
cancer in Japan appears both macroscopically and
microscopically to be exactly the same as gastric cancer in the
UK.
The standard gastrectomy in Japan is a D2 resection and this is
performed with almost no mortality and minimal morbidity. It is
true that Japanese surgeons are not prepared to test their standard
resection against the British D1 resection. The surgical mortality
rates at the NCCH are under 1%, when this is compared to the
6.5% mortality rate in the D1 resection group in the MRC trial and
the fact that the NCCH can achieve an overall five-year survival
rate of 71.8% (all stages), who can blame them (2, 3).
Japanese surgeons, like surgeons all over the world, are
constantly looking at methods of improving their survival rates
and so the D4 resection was devised. A D4 dissection can now be
performed with no increased mortality over a D2 dissection, with
only a slightly longer post-operative stay and a slightly higher
morbidity. The safety and tolerability of the treatment has
therefore, been established. It is at this point that the British
surgical community would expect their Japanese colleagues to
amass a large personal series and present and publish their data
recommending this procedure as the cure for gastric cancer. This
approach may have been true in the past but it is no longer the
case.
The Japanese Clinical Oncology Group (JCOG) consists of
major oncology centres (both public and private) around Japan
who co-operate in clinical trials (4). Study number JCOG 9501 is
one of five current studies in gastric cancer, four of which are run
by JCOG. This study is designed to compare the standard D2
dissection with a D4 dissection in patients with advanced gastric
cancer. The hypothesis is that patients with a locally advanced
tumour, i.e. at least involvement of the subserosal layer but
without evidence of distant or peritoneal disease, will benefit
from an extended lymphadenectomy. The eligibility criteria are
strict, to ensure that only the correct sub-groups are included and
the patients are randomised during the operation. Recruitment
started 18 months ago and 155 patients have been recruited to date
with a total of 404 needed to complete the study.
Study number JCOG 9502 is a randomised trial in patients with
tumours of the cardia encroaching on the oesophagus. Patients are
randomised to either an abdominal approach or to a
thoraco-abdominal approach, which may allow a more radical
lymphadenectomy at the expense of a higher operative mortality.
Two randomised studies of adjuvant chemotherapy are currently
recruiting; one in patients with positive peritoneal cytology
(JCOG 9701) and a second in patients with pT2 disease and
lymph node metastases (NSAS-GC). A randomised study of
adjuvant chemotherapy in tumours without serosal involvement
(JCOG 9206-1) has recently finished recruiting and a study of
adjuvant chemotherapy in locally advanced tumours (JCOG
9206-2) is due to complete recruitment in March 1998.
It appears that Japanese surgeons are willing to test their
hypotheses in randomised clinical trials and that Japanese patients
will consent to such trials when appropriately counselled. Perhaps
of more importance is that, unlike British surgeons, the leading
Japanese surgeons will not adopt new surgical practice as routine
until it has been tested to their own satisfaction in a randomised
controlled trial.
This only leaves one question unanswered. Why are the
Japanese results for gastric cancer surgery, stage for stage, so
superior to those in the UK? I believe that the reasons are now
clearer. The higher operative mortality amongst UK patients is
partly related to the slightly older patient group and to the higher
incidence of ischaemic heart disease and chronic pulmonary
disease seen within the UK population. The most important
factors however, which lead to both a lower operative mortality
and improved survival, in stage matched patients, were neatly
summarised by R Welbourn (1997) when he wrote that Japanese
surgeons achieve gentleness, haemostasis, minimal trauma and
meticulous accuracy (5). We can now add that as well as being
master craftsmen, the leading Japanese surgeons base their
surgical judgement on sound science.
I would like to thank the Foundation for Promotion of Cancer
Research and the British Council of Japan for their generous
support and the surgeons of the gastric division of the NCCH for
allowing me to witness at first hand how cancer surgery can and
should be practised. This experience should allow me to change
my personal practice and perhaps help to change some of the
misconceptions amongst British surgeons.
SR Bramhall
References
The Linus Pauling Institute
Oregon State University
Corvallis, OR, USA
Abbreviations: APC, adenomatous polyposis coli gene; CTNNBI, [beta]-catenin gene
The author is the recipient of a Foreign Research Fellowship of the Foundation for Promotion of Cancer Research, Tokyo and is supported in part by NIH Grant CA 65525.
The Pre-conceived British Beliefs of Gastric Cancer in Japan Need to be Changed
References
Department of Surgery
Queen Elizabeth Hospital
United Kingdom
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Last modification: 24 Jul 1998
Copyright©Japanese Journal of Clinical Oncology, 1998.
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