Oxygen-Derived Free-Radical Scavengers Prolong Survival in Gastric Cancer

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Steven Powers MD.

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Sunday, April 21, 2002 11:05 AM

Oxygen-Derived Free-Radical Scavengers Prolong

Survival in Gastric Cancer

 

- http://www.dmso.org/articles/cancer/gastrcan.htm -

 

Oxygen-Derived Free-Radical Scavengers Prolong Survival in Gastric Cancer

Aws S. Salim

University Department of Surgery

Medical City, Baghdad, Iraq

 

 

 

Abstract

 

The influence of oxygen-derived free radical scavengers on survival in

gastric cancer, with serosal invasion and metastases to the lymph nodes

surrounding the stomach, was assessed in a prospective randomized controlled

double-blind trial conducted for 5 years. To this end, allopurinol (inhibits the

enzyme xanthine oxidase which is responsible for the formation of superoxide

radicals and scavenges hydroxyl radicals) and dimethyl sulphoxide (DMSO;

scavenges hydroxyl radicals) were used. Following potentially curative distal

two-thirds partial gastrectomy, 228 patients making an uneventful recovery from

surgery were randomized to the control group or to receive allopurinol (50 mg by

mouth 4 times a day) or DMSO (500 mg by mouth 4 times a day). In 160 fully

evaluable patients who were studied for 5 years, allopurinol and DMSO incurred a

significant (p <l 0.01) survival advantage over the whole period of study. The

similarity in efficacy between allopurinol and DMSO and the fact that the only

action they share is scavenging oxyradicals suggest that these radicals mediate

the aggressiveness of gastric cancer by producing tissue damage, thus allowing

the cancer to spread. Consequently, oxygen-derived free radicals are implicated

in the mechanism of gastric cancer, and removing them provides patients with a

survival advantage.

 

 

Introduction

 

The majority of gastric cancer patients have widespread disease at the

time of diagnosis. consequently in a considerable proportion surgery is often

palliative.1 The overall 5-year survival of patients with gastric cancer is

approximately 5%.2 The early stages of this disease, defined as tumor limited to

the mucosa and submucosa with or without lymph node metastases3 have a 5-year

survival following surgical resection of 70-90%, compared with 30-40% in locally

advanced stages.4-6After almost all non-curative, gastrectomies and some

curative ones, gastric cancer recurs. Over half of the patients show peritoneal

dissemination followed in order of importance by distant metastases via

lymphatic and/or haematogenous spread, and reappearance of the cancer at

anastomotic stomata.2, 3-5 Recently,7 it has been clearly shown that the 5-year

survival rate in gastric cancer patients is inversely related to the degree of

serosal invasion and that patients with this invasion at resection will develop

disease recurrence. Furthermore, the presence of lymph node metastases in

conjunction with serosal invasion had poor prognosis causing intraperitoneal

dissemination followed by death of most of the patients within 2 years of their

operation.7The results of adjuvant chemotherapy trials in gastric cancer are

less favorable in European and Anglo-American countries than in Japan.8 The

majority of findings in Western countries leads to the conclusion that the

routine application of adjuvant chemotherapy for gastric cancer cannot be

recommended.8 On the other hand, intraoperative radiotherapy has been shown to

improve the survival only in patients with locally advanced gastric

carcinoma.9Oxygen-derived free radicals are cytotoxic and play a key role in the

mechanism of tissue injury.10-12 Studies in the rat (to be published)

demonstrated that these radicals are permissive for gastro-intestinal

carcinogenesis. Exposure to doses of carcinogenics that are capable of producing

gastrointestinal cancer failed to exhibit any carcinogenic activity when the rat

was treated with radical scavengers. Conversely, the doses of these

carcinogenics which do not produce cancer under normal circumstances were

allowed to do so when the overall pool of oxygen-derived free radicals was

increased. It was also noted that in the rat bearing gastrointestinal cancer

scavenging oxygen-derived free radicals delays hepatic metastases and prolongs

survival. These studies propose that oxyradicals are implicated in the mechanism

of gastrointestinal cancer in the rat and mediate its aggressiveness probably by

producing the destruction of tissues associated with this cancer and which, in

turn, allows it to spread. The present investigation was, therefore, designed to

examine whether removing oxygen-derived free radicals incurs any survival

advantages in patients with carcinoma of the stomach.

 

 

Patients and Methods

 

Drugs

 

A 1% solution of allopurinol (Burroughs Wellcome Co, Research Triangle

Park. N.C., USA) was prepared by dissolving the powder in double-distilled water

containing the molar equivalent of 0.1 M NaOH. A 10% solution of dimethyl

sulphoxide (DMSO; Sigma. St. Louis, MO, USA) was prepared by diluting the stock

solution with double-distilled water. The vehicle solution of allopurinol was

given to controls. Solutions were placed in 600-ml capacity dark-colored glass

bottles of identical appearance. The patients were issued a fresh supply of

solutions every 30 days and were treated with identical volumes of solution

throughout the 5-year period of the study.

 

Study Design

 

This was a prospective randomized controlled double-blind trial conducted

for 5 years on consecutive patients making an uneventful recovery from a

'potentially' curative distal two-thirds partial gastrectomy for carcinoma of

the distal third of the stomach. Randomization was carried out by drawing sealed

envelopes. Treatment started on the 5th postoperative day and continued to the

end of the study (5 years).

 

Recruitment Criteria

 

Patients were considered to be suitable for the study if all the following

conditions applied:

 

1.. The carcinoma had invaded the serosa but not any contiguous

structures.

2.. The gastrectomy specimen showed tumour-free proximal resection lines

(within 5 mm from resection lines) for at least 2 cm.

3.. Complete excision of all the regional lymph nodes of the stomach

according to the location of cancer, i.e. lymph nodes along the greater and

lesser curvatures, the supra- and subpyloric nodes, the right paracardial lymph

nodes and the lymph nodes along the course of the left gastric, the common

hepatic and around the coeliac arteries.

4.. There were metastases to the lymph nodes surrounding the stomach but

no metastases to the nodes along the main arteries including the coeliac axis.

5.. The lymph, node metastases were in the form of cancer cells within

the lymph node system but without extension beyond the node into the perinodal

fatty tissues.

6.. No macroscopically evident peritonea dissemination and no free

cancer cells within the peritoneal cavity immediately after the gastrectomy (the

peritoneal cavity was washed with 100 ml of physiological saline at 37°C

immediately after the gastrectomy, then 50 ml of this fluid was centrifuged,

stained and examined as described in detail elsewhere.13

7.. No evidence of hepatic or distant metastases. This means that the

stage of the patients studied was S2 N1 P0 according to the Japanese Research

Society for Gastric Cancer.

Patients were not recruited into the trial if one or more of the following

were present:

 

1.. age over 80 years

2.. risk factors (adenomatous polyp(s) removed]

3.. admission as an emergency failing to respond to conservative

treatment or septicaemia or peritonitis on presentation

4.. pregnancy

5.. alcoholism

6.. taking prohibited drugs or regularly taking any form of medication

(to avoid unknown therapeutic effects and drug interactions)

7.. hypertension

8.. diabetes

9.. hepatic (including cirrhosis) or renal disorders

10.. serious underlying disease (for example: cardiorespiratory

problems)

11.. rheumatoid arthritis or any form of collagen diseases

12.. Zollinger-Ellison syndrome or other gastrointestinal disorders like

the irritable-bowel syndrome which would make it difficult to assess patients

and the significance of their signs and symptoms

13.. previous gastrointestinal surgery

14.. history of radiotherapy, chemotherapy or any malignancy

15.. synchronous carcinomas

16.. invasion of the abdominal wall or any adjacent organs or structures

found during laparotomy

17.. postoperative complications (cardiovascular, pulmonary -- pneumonia

or atelectasis --, hepatic, wound infection or dehiscence, gastrointestinal

hemorrhage, anastomotic failure, ileus, significant reflux esophagitis or

psychiatric problems)

18.. cases with hypersensitivity to penicillin and its derivatives.

Survival was measured from the time of tumor resection until death from

any cause. Postoperative deaths (mortality from any cause during hospital stay

irrespective of its duration) were not included in the study. Survival

calculations were only carried out on patients who had died from tumor

recurrence, and those dying from other causes (e.g.cerebrovascular accidents,

myocardial infarction, bronchopneumonia) were excluded.

 

Clinical Management

 

Gastric carcinoma was diagnosed from the history, physical examination,

endoscopy with biopsies and a barium meal. Other investigations were undertaken

to determine the extent of the disease or to serve as a baseline for future

reference, and these included: standard haematology, biochemistry measurements,

urine examination, chest X-rays and liver ultrasonography. Once the diagnosis of

gastric carcinoma had been made, patients were admitted to hospital and prepared

for surgery; correction of any anemia or hypoproteinaemia, and chest and lower

limb's physiotherapy. At induction of anesthesia the patients were given

intravenous chemoprophylaxis, 500 mg of ampicillin and 80 mg of gentamicin, and

prophylaxis against deep-vein thrombosis was by peri-operative pneumatic

compression leggings. In all cases the abdomen was opened by an upper midline

incision, the liver was palpated for any metastases, the various lymph node

groups (surrounding the stomach, in the hepatoduodenal ligament, in the

retropancreatic area, in the mesenteric root, around the left gastric, common

hepatic, coeliac and middle colic arteries, and around the abdominal aorta) were

carefully examined and the peritoneum was inspected for evident dissemination.

At least a 2-cm tumor-free proximal resection line was achieved, excision of all

the regional lymph nodes as detailed above was carried out, gastric

reconstruction was by a Roux-en-Y gastrojejunostomy, all the anastomoses were

performed by double-layer continuous suturing with 2/0 polyglycolic material

(Dexon), and the peritoneal cavity was examined for free cancer cell as stated

above. Post-operatively patients were hydrated intravenously for at least 3 days

during which period their oral intake of fluids was gradually increased. The

return to solid food was not permitted before the 4th postoperative day. The

patients were supplied with special charts to mark their compliance with the

therapeutic regimen and to record all adverse events.Following discharge from

hospital, the patients were reviewed every 3 months on an out-patient basis. At

each visit a detailed assessment of any symptoms and possible adverse events

coupled with a full physical examination, endoscopy with biopsies of any

suspicious gastric mucosa, full blood counts, liver function tests and a liver

ultrasound scan were performed. A chest X-ray was taken annually, unless

indicated earlier.

 

Ethical Considerations

 

This study was approved by the Ethical Committee on Human Experimentation

of the hospital, and every patient gave written informed consent.

 

Study Groups

 

Two hundred and twenty-eight consecutive patients with an uneventful

recovery from a distal two-thirds partial gastrectomy for carcinoma of the

stomach were allocated to one of three groups and treated for 5 years. In the

first group patients were given the vehicle solution of allopurinol by mouth, 5

ml 4 times a day (controls). In the second group patients were given allopurinol

by mouth, 5 ml (50: mg) 4 times a day. In the third group patients were

similarly treated with 5 ml DMSO (500 mg) 4 times a day.

 

Exclusion Criteria

 

Exclusion of patients from evaluability was based on the following rules:

 

1.. Significant adverse events to the therapeutic regimen.

2.. Intolerance of this regimen.

3.. Failure to comply with the regimen.

4.. Concomitant treatment during the study with medicines.

5.. Postoperative complications or mortality occurring after

randomization of the patients an the 5th post-operative day.

6.. Missed synchronous malignant tumours (detected up to 6 months after

surgery) or occurrence of metachronous malignant tumours.

7.. Death from other than tumour-related causes.

8.. Failure to attend for or lost to follow-up.

The decision to regard patients as nonusable for analysis was undertaken

before breaking the treatment code.

 

Statistical Analysis

 

A sample size of 150 patients with 50 patients in each group was chosen

initially. Based on a two-tailed test, such a size will detect a significant

difference of 30% between active and no therapy (p <0.05) with a probability of

80% for the overall sample. Because of the anticipated problems of

non-evaluability of a proportion of patients inherent in a long-term study which

could weaken any conclusions drawn, the aim was to enter at least 75 patients in

each group. Results are expressed as percentages or the mean ±SEM unless stated

otherwise. The statistical significance (p < 0.05) of observed differences in

percentage values was assessed using the 2 test with Yates' correction. and the

Mann-Whitney U test for non-parametric data was employed to examine whether

differences in mean values were significant. Kaplan-Meier's product limit

methodwas used to estimate the survivor functions for the three study groups.

The difference between these functions was assessed using the Mantel-Cox

statistics. Proportional hazard models were then used to investigate the effect

of treatment on survival when account was taken of the other patient factors as

covariates. Additional intention-to-treat analyses were carried out re-including

the patients who were excluded from the study and using various theoretically

possible outcomes to assess any influence their exclusion might have had on the

conclusions of the study.

 

 

Results

 

Patient Characteristics

 

Seventy-seven patients (30 women and 47 men with an age range of 41-79

years, mean 59) were randomized to the control group. Seventy-five patients (30

women and 45 men with an age range of 44-78 years, mean 58) were randomized to

the allopurinol group. Seventy-six patients (27 women and 49 men with an age

range of years, mean 61) were randomized to the DMSO group. The patients

excluded from evaluability are presented in table 1, and the characteristics of

those remaining shown in table 2. The three groups were well matched for age and

sex, for duration of symptoms before presentation, type of presentation, weight

loss, and for tumor differentiation.

 

General Observations

 

Seventeen controls (31%), 20 patients in the allopurinol group (39%) and

16 patients in the DMSO group (30%) were smokers, and all the men studied were

social drinkers who did not indulge heavily. Ten patients in the control group

(18.2%; 6 vomiting and 4 acute gastrointestinal haemorrhage), 8 patients in the

allopurinol group (16%; 3 vomiting and 5 acute gastro-intestinal hemorrhage) and

11 patients in the DMSO group (20.4%; 6 vomiting, 1acute epigastric pain, 4

acute gastro-intestinal hemorrhage) presented as an emergency which settled with

conservative treatment. The remaining cases presented with one or more of

abdominal pain, dyspepsia, anorexia, or signs and symptoms of iron deficiency

anemia, and the frequency of these symptoms was similar among the three groups.

The mean length of symptoms for the emergency and non-emergency cases was

comparable among the groups. In the non-emergency cases, iron deficiency anemia

was seen in 10 controls, in 8 members of the allopurinol group, and in 11

members of the DMSO group. Of these patients, 5 controls, 4 members of the

allopurinol group, and 6 members of the DMSO group were given pre-operative

blood transfusions, whereas the remaining patients were given oral ferrous

sulphate. Consequently, the total number of patients in each group who received

pre-operative blood transfusions were 9 controls (16.4%), 9 patients in the

allopurinol group (17.6%), and 10 patients in the DMSO group (18.5%). During

surgery, 10 patients in the control group (18.2%), 12 patients in the

allopurinol group of (23.5%), and 11 patients in the DMSO group (20.4%) received

blood transfusions.The overall operative mortality (death from any cause during

hospital stay irrespective of its duration) was 3.1%. Of these patients 1

control died because of myocardial infarction, and 1 patient in the DMSO group

died because of bronchopneumonia after randomization.

 

 

Table 1.

 

Evaluability of patients

 

Control Allopurinol DMSO

Total entered 77 75 76

Fully evaluable 55 51 54

Not evaluable because of:

Intolerance 0 2 1

Adverse events 2 2 1

Non-compliant 3 3 2

Prohibited drugs used 0 0 1

Failure to attend for follow-up 5 4 5

Metachronous malignancy 0 1 0

Synchronous carcinoma 0 1 0

Postoperative complications 1 3 2

Postoperative mortality 1 0 1

Died from non-cancer-related causes 10 8 10

Total not evaluable 22 24 23

 

One patient in the control group (bronchopneumonia), 3 patients in the

allopurinol group (1 deep-vein thrombosis and 2 wound infections) and 2 patients

in the DMSO group (1 wound infection and 1 anastomotic failure) developed

postoperative complications after entry into the study. One patient given DMSO

and 2 patients given allopurinol were intolerant to their therapeutic regimen.

Four patients given the vehicle solution of allopurinol and 5 patients in each

of the remaining groups reported drug-related side-effects consisting of

headache, nausea and general malaise. In addition, allopurinol treatment caused

skin hypersensitivity and allergic reactions. However, these effects were severe

enough to warrant cessation of treatment only in 2 controls, in 2 patients

treated with allopurinol and in 1 patient treated with DMSO.

 

 

Table 2.

 

Patient details

 

Control Allopurinol DMSO

n 55 51 54

Age, years, n

Mean 57 59 58

Range 42-77 44-77 48-78

Women, n 20 17 17

Men, n 35 34 37

Emergency Cases, n 10 8 11

Symptoms (mean), months

Emergency cases 1.7 2.1 1.9

Non-emergency cases 6.1 5.8 6.3

Weight loss, n

< 5% 31 25 26

5-10% 15 20 18

> 10% 9 6 10

Patients given pre-operative blood transfusion, n 9 9 10

Patients given peri-operative blood transfusion, n 10 12 11

Patients given post-operative blood transfusion, n 3 3 3

Tumor location, n

Antrum and pylorus 42 (76.4%) 40 (78.4%) 44 (81.5%)

Gastric stump 13 (23.6%) 11 (21.6%) 10 (18.5%)

Tumur differentiation, n

Good 14 9 15

Moderate 15 19 12

Poor 6 7 10

Undifferentiated 16 13 14

Signet ring cell 2 1 0

Mucinous 2 2 3

Lauren's classification, %

Intestinal 58 59 61

Diffuse 29 25 26

Mixed 13 16 13

Lymph nodes resected per specimen (mean) 28.2 32.5 30.7

 

Tumor Characteristic

 

Pre-operative histologic diagnosis of gastric cancer was achieved in every

patient. The tumor location, its degree of differentiation, its histologic

grade, and the number of lymph nodes resected per specimen were comparable among

the study groups. The majority of the gastric cancers studied were located in

the antrum or pylorus and were differentiated adenocarcinomas (table 2).

 

Recurrence

 

All patients who developed a recurrence subsequently died of their

disease. Over half of the patients who died in each group developed peritoneal

dissemination (26 controls, 53.1%; 18 patients in the allopurinol group, 51.4%;

20 patients in the DMSO group, 55.6%), whereas distant metastases to the liver

and/or lung were less common (13 controls, 26.5%; 10 patients in the allopurinol

group, 28.6% 9 patients in the DMSO group, 25 %), and local recurrence at the

anastomotic stoma was the least common (10 controls, 20.4%; 7 patients in the

allopurinol group, 20%; 7 patients in the DMSO group, 19.4%).

 

Survival

 

In all groups, most of the deaths occured during the first 3 years

following the gastrectomy (table 3). In the control group the number of patients

who were alive after 1 year, (33, 60%) was significantly (p < 0.01) less than

that at the start of the study. Similarly, the number of control patients who

remained alive after 2 and 3 years was significantly (p < 0.01) less than their

corresponding number a year earlier. This significance in observed differences

of survival was lost at later time periods in the study (table 3). At the end of

each of the first 5 years of the study, the number of patients remaining alive

in each of the allopurinol and DMSO groups was similar but significantly (p <

0.01) larger than their corresponding control number (table 3). Death was due to

disease recurrence in 49 of 55 patients (89%) in the control group, in 35 of 51

patients (68.6%) in the allopurinol group, and in 36 of 54 patients (66.7%) in

the DMSO group. Survivor functions were estimated for the three study groups,

and the differences between those for the control and allopurinol or DMSO

groups, were significant (p < 0.01). There was, however, no significant

difference between the survivor functions for the allopurinal and DMSO groups.A

series of Cox proportional hazard models was fitted using, as covariates, all

factors other than treatment to acquire a group of patients and postoperative

factors that independently and significantly affect survival.

 

Treatment with allopurinol and DMSO was then added as separate covariates.

This showed that age over 70 years, the male sex, decreasing duration of

symptoms, emergency presentation with vomiting and/or acute gastro-intestinal

haemorrhage, blood transfusions immediately before, during or just after

surgery, and tumor dedifferentiation an had a significantly (p < 0.001)

detrimental effect on survival at the 5% level. When these and all the

non-significant variables (table 1) were allowed for, treatment with allopurinol

or DMSO continued to exert a significant survival advantage (p < 0.01).

 

 

Table 3.

 

Patient survival

 

Time (years) Control Allopurinol DMSO

n % n % n %

0 55 100 51 100 54 100

1 33 60 41 80.4 44 81.5

2 22 40 32 62.8 33 61.1

3 15 27.3 24 47.1 26 48.2

4 6 11 16 31.4 18 33.3

n = Number of patients alive.

 

The influence of method of analysis on survival was studied.

Intention-to-treat analyses were carried out to determine what might have

happened if all patients had been evaluable or had died of cancer-related

causes. This required postulating that some patients would have survived and

others would have died at various time periods. When all the deaths excluded

from the study (the postoperative cases and those who died from other than

cancer-related causes) were assumed to have been cancer related, both

allopurinol and DMSO continued to offer a survival advantage (p < 0.05). This

advantage was maintained when only the control deaths were assumed to have been

either cancer related (p <0.01) or non-cancer related (p < 0.05). When all the

patients who were excluded while still alive were assumed to have died during

the study because of their gastric cancer, both allopurinol and DMSO continued

to offer a survival advantage (p < 0.05). This advantage was maintained when

only the patients excluded from the control group were assumed to have died

because of their gastric cancer during the study period (p < 0.01) but lost when

the assumption was that only the patients excluded from the allopurinol or DMSO

groups died because of their gastric cancer during the same period.

 

 

Discussion

 

The variables considered to be directly implicated in influencing the

prognosis of patients with gastric cancer have been critically assessed.

Maruyama2 analysed 25 variables in patients with this cancer by multivariate

analysis and identified the following factors to be especially important: depth

of invasion, lymph node metastases, cancer type, location and histologic

character. In the studies of Curtis et al.,14 11 variables were analysed, and of

these the depth-invasion, lymph node metastases, and distant metastases were

most significant. On the other hand, the multivariate analysis studies of

Nakazato et al.15 identified serosal involvement, lymph node metastases, and

distant metastases to be prognostically most important in gastric cancer. It,

thus, appears that of the many factors relevant to survival after curative

gastrectomy, the most important are the presence of serosal invasion, lymph node

metatases with invasion of the perinodal fatty tissue, and peritoneal

dissemination, while hepatic metastasis is irrelevant.2, 7In patients with

serosal invasion survival is lower in those who have peritoneal dissemination

than in those without it.7 This dissemination is largely produced by cancer

infiltration from the serosa leading to free cancer cells within the peritoneal

cavity and by invasion of the perinodal fat tissues by the cancer cells that

have metastasized into regional lymph nodes.7 It, thus, follows that having

carried out a gastrectomy for cancer with serosal invasion, an attack on the

lymph nodes and peritoneal free cancer cells may contribute to prolonging

survival. However, in relation to this point adjuvant chemotherapy in gastric

cancer has failed to keep up to expectations,8 and the free cancer cells in the

peritoneal cavity of patients with this cancer may retain their viability even

after intraperitoneal mitomycin C.16 With these facts and the knowledge that

radiotherapy has only influenced survival when applied intraoperatively for

locally advanced disease,9 the search continues for more effective, yet safe,

carcinostatic treatments for the prevention of intraperitoneal dissemination of

gastric cancer.The present study was, therefore, conducted on gastric cancer

patients with serosal invasion and metastases to the surrounding lymph nodes,

who had no free cancer cells in their peritoneal cavity, because following

gastrectomy they remain at risk of developing peritoneal recurrence and

compromising their survival.7 Such patients may, thus, be a valuable means for

studying any influence scavengers of oxygen-derived free radicals might have on

the survival of gastric cancer patients. The poor prognosis of patients with

advanced gastric cancer might overshadow any effects afforded by radical

scavengers on the rate of survival and this rate might not be influenced in

patients with early gastric cancer where 90% or more have a 5-year survival

rate.5, 6No general agreement seems to have been reached on the concept of

curative resection. Soga et al.17 identified curative resection on the basis of

the following conditions: no grossly visible tumour left behind, histologic

confirmation that resection margins (within 5 mm from resection lines) are free

from cancer invasion, and exclusion of any cases with remote cancer involvement

although successfully removed. These authors argue that such a concept follows

along the lines of the definition of curability widely employed in Japan but

occasionally results in cases which actually belong to the non-curative group

since there is a possibility of residual neoplastic tissue at the histologic

level being left behind.17 Consequently, the term 'potentially curative

gastrectomy' was employed in this study to encompass the objective of the

surgical approach at the time of the operation while accounting for the

possibility of residual disease being left behind perhaps in the lymph

nodes.DMSO and allopurinol scavenge hydroxyl radicals,11, 12 and the latter

agent also inhibits the enzyme xanthine oxidase which is responsible for the

formation of superoxide radicals. These agents were equally effective in

incurring a significant survival advantage in patients with carcinoma of the

stomach over 5 years ( Table 3). The similarity in efficacy between allopurinol

and DMSO (Table 3) and the fact that the only action they share is scavenging

free radical-suggest that the activities attributed to them in the present study

were achieved by this scavenging. The knowledge that oxygen-derived free

radicals are directly responsible for producing injury and damage of normal

tissues10-12 suggests that the tissue destruction associated with malignancy is

caused by these radicals. It follows that oxygen-derived free radicals are

implicated in the mechanism of gastric cancer and mediate its aggressiveness by

producing the tissue damage which allows it to spread. Scavenging oxyradicals

impairs this spread by sustaining the integrity of biological tissues, thus

incurring a significant survival advantage. This advantage has also been noted

in patients bearing colonic carcinoma treated with the same radical scavengers

used in this study.18The survival rates noted in the present study (Table 3) are

similar to those reported by others,7 an observation which excludes the

possibility that the survival advantage afforded by the radical scavengers might

have been an experimental error or occurring in a heteroeneous group of patients

of abnormally low survival. This investigation excluded patients with risk

factors, those with a history of previous malignancy, those having synchronous

or developing metachronous tumors, or those dying from non-cancer-related causes

so that as near a cancer-specific survival as possible, without the influence of

any aggravating factors, could be calculated. Consequently, the survival

advantages provided by removing oxy-radicals were achieved by acting on

cancer-related mechanisms rather than on non-cancer-related factors of a

possible bearing on survival. Over the 5-year period of study, all patients who

developed tumor recurrence subsequently died of their disease. The pattern of

recurrence was similar in each of the three groups with peritoneal dissemination

being the commonest. The use of computed tomography might have strengthened the

study in terms of detection of distant tumor recurrences.Although DMSO can be

smelt in the breath, this was never a significant inconvenience to any patient.

Furthermore, it could not be seen as a source of bias in favour of any group,

since the major parameters of assessment were objective ones.

 

 

Acknowledgment

 

I am very grateful to Dr. S.H. Alwash for giving me the opportunity to

undertake this work at the Medical City, and I thank Mrs. Moira Caimey and Mrs.

Jutta Gaskill for their skillful secretarial work.

 

 

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Source:

 

Chemotherapy 1992.38:135-144. DMSO Organization wishes to thank the

publisher of Chemotherapy for allowing this article to be placed on our World

Wide Web site. The publisher retains all copyright. To copy or reprint any

portion of this article, permission must be obtained from the publisher.

 

 

 

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