Gastric adenocarcinoma

GASTRIC ADENOCARCINOMA BENTON J.~DUPONT,,/JR., M.D. ISlDORE COHN, JR., M.D.

0147-0272/80/08001-46505.00 O 1980)Year Book Medical Publishers, Inc.

TABLE OF CONTENTS SELF-AssESSMENT QUEST:ONS INTrCODL'CTI~:'; EPIDEMIOLOGY

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DIAG~,~OS]S

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PA'rHOLOGY

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HISTORICAL

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TREATMENT

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T W E N T Y - F I v E - Y E A R EXPERIENCE WITI-i GASTRIC CANCER-1 4 9 7 CASES .

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PALLIATTON FOR UNRESECTABLE GASTRIC CANCER

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SUMMARY . . . . . . . . . . . . . . . . . . . . .

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SELF-ASSESSMENT QUESTIONS 1. What is the Laur6n classification of gastric adenocarcinoma and its importance to epidemiologic research? 2. What precursor lesions of the gastric mucosa are associated with the development of gastric adenocarcinoma? 3. What dietary carcinogens possibly explain the geographic distribution and incidence of gastric cancer? 4. What is the potential benefit of a diet high in fresh fruit and vegetable content? 5. What types of gastric polyps are associated with gastric adenocarcinoma? 6. What survival rates are associated with the early diagnosis and t r e a t m e n t of gastric cancer? 7. What diagnostic accuracy is to be expected from the use of radiographic studies, endoscopy and biopsy or cytology? What percent of cases will be a diagnostic problem? 8. What factors have contributed to the failure of operative staging by the surgeon to document the actual extent of disease? 9. What evidence exists from necropsy analysis of patients with gastric adenocarcinoma that an adjuvant form of treatment might be of benefit in the surgical t r e a t m e n t of gastric cancer? 10. Who performed the first gastrectomy in a human? The first gastrectomy with survival? The first successful total gastrectomy? 11. What is the currently preferred curative treatment for gastric adenocarcinoma involving the distal h a l f o f t h e stomach? What are the indications for total gastrectomy? 12. What is the 5-year survival after radical subtotal gastrectomy versus subtotal gastrectomy for Hoerr stage A and B lesions? 13. What is the theoretical basis of adjuvant therapy in the treatment of malignant disease? 14. What procedure has been shown to be effectively palliative in patients with incurable gastric adenocarcinoma in terms of survival and quality of life? 15. What is the overall 5-year survival of patients with gastric adenocarcinoma?

Answers appear on t he following pages. 1. 2. 3. 4. 5. 6. 7. 8.

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pp. 8 - 9 pp. 1 2 - 1 4 pp. 9 - 1 2 pp. 1 0 - 1 2 p. 13 p. 14 pp. 1 7 - 1 9 p. 20

9. pp. 23 - 25 p. 26 p. 28 p. 33 pp. 3 5 - 3 6 p. 3 7 p. 42

10. 11. 12. 13. 14. 15.

is a graduate of the Louisiana State Medical Center. His postgraduate training has consisted of a one year rotating surgical internship at Grady Memorial ttospital in Atlanta, Georgia, a four-year general surgical residency on the 9 L.S.U. Surgical Service, Charity Hospital, New Orleans, and a one-year Fellowship in Surgical Oncology at the M.D. Anderson Tumor Institute, Houston. As the primary author, Dr. Dupont submitted and presented several cancer-related papers at national surgical society meetings. In 1979, he was awarded but did not accept the American Cancer Society Junior Faculty Clinical Fellowship Award due to the fact that he entered private practice in Lafayette, Louisiana. During the preparation of this manuscript, he served as Chief Administrative Resident of the L.S.U. Surgical Service at Charity Hospital, New Orleans.

received his M.D. and D.Sc. (Med.) degrees from the University of Pennsylvania. He completed his internship and surgical residency at the Graduate Hospital of the University of Pennsylvania and joined the faculty at Louisiana State University School of Medicine in 1952, becoming Chairman of the Department of Surgery in 1962. Dr. Cohn's primary interests include gastrointestinal cancer, antibiotics, and intestinal obstruction.

INTRODUCTION On J a n u a r y 29, 1881, T h e o d o r e Billroth r e s e c t e d a m u c i n o u s a d e n o c a r c i n o m a of the pylorus and achieved t h e first survival in a p a t i e n t w h o had u n d e r g o n e g a s t r e c t o m y . I Since then, the surgical t r e a t m e n t of gastric c a n c e r has varied, m a i n l y in the e x t e n t of resection, all t h e way from p a r t i a l to e x t e n d e d total gastrectomy. 5

In spite of these surgical advances, the prognosis ofgastric adenocarcinoma remains poor. The operative results as well as the survival rates have shown little change over the last 50 years. Diagnosis frequently is not made until advanced stages ofdisease are present. There are 2 reasons for this: one is the aggressive nature of this type of cancer and the other, the fact that the symptoms, which are frequently of an obstructive nature do not become manifest until the large gastric lumen has been replaced by tumor. Consequently, many patients are denied the benefit of a curative gastric resection because of advanced stages of disease and diagnosis late in their disease process. Goldsmith and Ghosh have observed: "If we are going to do anything to improve survival in gastric cancer, the disease must be diagnosed prior to gastric symptoms.''2 The progress in methods of early diagnosis of gastric carcinoma developed by the Japanese is noteworthy. These procedures involve double contrast roentgenographic techniques, gastrocamera, fiberoptic gastroscopy, gastric cytology and photofluorographic studies. Although these efforts have achieved clearly lower rates of death due to gastric cancer in mass surveyed populations, the demonstrated value of these methods is limited, as evidenced by the 0.15% diagnostic yield in 90,557 examinations reported by Kaneko et al.a Encouraging epidemiologic data on gastric carcinoma collected over the past decade have revealed several interesting aspects of geographic distribution and possible etiology. There are good reasons for accepting the hypothesis that geographic as well as dietary factors have influenced the worldwide incidence and prevalence ofgastric cancer. Despite its declining incidence observed in s o m e countries and the encouraging reports on the identification of environmental and dietary etiologic factors, gastric carcinoma presents a challenging and complex problem to the physician.

EPIDEMIOLOGY AND ETIOLOGY During the past 50 years, little attention has been directed to the epidemiology of gastric cancer. The major medical literature on gastric carcinoma has consisted primarily of improved surgical techniques, as well as methods of earlier diagnosis and identification of high-risk groups. The decreasing incidence of gastric cancer in several countries, particularly the U.S., is well documented, but little knowledge is available to explain this decline. Epidemiologic investigation over the past decade in countries with a high prevalence of the disease has produced several interesting findings as to etiology and incidence in these endemic areas.

TABLE 1.-NONSPECIFIC MORTALITY RATES DUE TO GASTRIC ADENOCARCINOMA PER 100,000 (1968-1969)

Japan Chile Poland Austria Finland Venezuela Germany Italy Norway England France Denmark U.S.A. (white) (nonwhite)

MALE

FEMALE

65.8 59.4 40.4 38.0 36.9 34.3 33.1 30.7 24.6 21.7 19.3 17.7 14.7 10.7

34.4 35.6 18.8 20.6 13.6 21.1 17.9 15.8 13.1 10.6 9.2 9.8 7.0 6.7

GEOGRAPIIIC DISTRIBUTION Considerable variation in the geographic distribution of gastric adenocarcinoma has been well documented worldwide by several investigators (Table 1). Segi et a l . / B j e l k e , s and Wynder and coworkers 6 dem ons t r a t e d a high mortality rate due to gastric cancer in J a p a n , Korea, Chile, Finland, Poland, Austria, Yugoslavia, and Costa Rica as well as in the U.S.S.R., w here gastric cancer is considered the most common malignant t u m o r of the gastrointestinal tract. On the other hand, several countries were found to have low m or t a l i t y rates associated with gastric cancer, most notably t he U.S., where the age-adjusted m o r t a l i t y rate due to gastric carcinoma declined from 28.8/100,000 in 1930 to 8.5/100,000 in 1968J. " The reason for this phenomenon is not well understood. In 1964, the World Organization of Gastroenterology defined the then undisputed epidemiologic characteristics of gastric cancer. ~These facts were summarized as follows: 1. T h e r e was a marked inter-country variation in stomach cancer mortality, the rates in high-risk countries being approximately 5 times those in low-risk areas. 2. The inter-country variation was accompanied by variation within countries, the general rule being t h a t nort hern and/or colder regions had the higher risks. Several well-known examples consist of the high rates of gastric cancer in the mountainous region of Slovenia (Yugoslavia) and the A n d e a n region of South America (Colombia, Peru and Costa Rica) compared to the lower risk along the Adriatic Yugoslavian Coast and the tropical coastal zones of Central AmericaY, 8 7

3. A stable male-female ratio of risks apparently prevailed in all populations: the female rate was one-half to two-thirds that among males. 4. An inverse socioeconomic gradient in risk was a prominent finding; the risk among lower classes was roughly 2.5 times that of the higher socioeconomic classes. 5. No consistent urban-rural gradient w a s demonstrable. 6. In the U.S., foreign-born individuals displayed a h i g h e r mortality rate than those native born and the rate was the highest among those immigrants from high-risk countries such as J a p a n and certain European countries. 7. For m a n y years, a steady decline in stomach cancer mortality has been documented in the U.S. and also in several European countries. 8. The premalignant role of pernicious anemia in gastric cancer was firmly established. Environmental factors incriminated in the possible etiology of gastric cancer were thought to be related to diet. Haenszel s astutely observed that dietary factors of long-lasting effect may have occurred many years earlier, thereby creating inadequacies in the epidemiologic studies that depended on accurate recall by individuals. Three general classes of dietary effects were proposed, i.e., the presence of a carcinogen in the food, the introduction of carcinogens in food preparation and the absence of protective factors in some foods. Major advances have occurred over the past decade in the epidemiology of gastric carcinoma in m i g r a n t population studies in several areas of the world. Haenszel 9 documented that foreignborn U.S. immigrants from high-risk countries continued to have the same risk as the population of origin. The switch over to the risk characteristic of the U.S. population was delayed until the succeeding generation of the native-born offspring. A similar phenomenon was documented in Cali, Colombia, where the cancer registry has recorded a marked excess of stomach cancer among immigrants born in Narino, a mountainous region bordering Ecuador. 1~ The fact that the migrants retain the high risks associated with their birthplace suggests exposure early in life to an exogenous agent, possibly a dietary carcinogen or precarcinogen. Companion pathologic Studies performed in high-risk areas worldwide have provided further impetus to epidemiologists in identifying a common etiology of stomach cancer in endemic areas. In 1965, Laur6n H proposed two main types of gastric carcinoma after performing structural as well as histochemical studies on 1,344 surgical specimens. The "intestinal type carcinoma" accounted for 53% of all gastric carcinomas and the "diffuse type carcinoma" for 33%. He proposed that in addition to structural differences, different etiologic factors as well as a different patho8

genesis might account for his findings. Munoz et al. '2 applied Laurdn's classification of gastric carcinoma to Latin American populations at high risk for the disease. They found a greater proportion of cases in high-risk areas exhibiting the intestinaltype lesions described by Laurdn. In addition, Correa et al? ~ documented a high frequency of intestinal-type gastric carcinomas among the migrant subpopulation in Call, Colombia that accounted for the excess incidence of gastric cancer in that region. Collaborative studies involving the Miyagi Prefecture, Japan, and Hawaii have strongly substantiated the conjecture of Laur~n, and Munoz and co-workers by providing the most convincing evidence available on type-specific age and sex differences in incidence among populations at varying levels of risk. '3 The risk for the diffuse type of gastric lesion rises more slowly with age in both Japan and Hawaii than t h a t of the intestinal type, which definitely exhibits a higher risk with advancing age. This was also noted by Griffith, ~4who documented a 1.16 male-tofemale ratio at ages under 35, which reached a peak ofabout 2.23 at 55 and thereafter declined to 1.45 at the oldest ages. These studies m a y reflect either a later exposure to carcinogens or a longer latent period. Given the close link between intestinal metaplasia and the intestinal-type tumor, the latter appears more plausible. In Cali, Colombia, Correa et al. '~ demonstrated through necropsy studies a greater prevalence of intestinal metaplasia in migrants from the mountainous area of Narino. The prevalence of intestinal metaplasia appeared more closely correlated with the incidence of intest.inal-type stomach cancer than with the diffuse type. Retrospective necropsy analysis in several other localities have confirmed an excess of intestinal metaplasia in populations at high risk for gastric cancer. Stemmermann et al. 15 have provided further corroborative details implicating metaplasia as a precursor to gastric carcinoma. GEOCIIEMISTRY

The discovery of the mutagenic and carcinogenic properties of the nitroso compounds m a y have provided a major clue in the search for etiologic dietary factors contributing to the development of gastric cancer. Hill et al.le reported an association between high nitrate ingestion and high rates of gastric cancer in Warksop, England. This association is being investigated in Colombia (Narino) where nitrate and nitrite sampling in food and drinking supplies is analyzed. Pursuit of the nitrate compounds and their possible role in causation of gastric cancer is necessary since they offera plausible pathway for the production ofcarcinogens. Weisburger. and Raineri 17 have developed the working hypoth9

esis t h a t gastric cancer in man may result from the in vivo nitrosation of as y e t unknown substrates, with the production ofalkylnitrosamides. Sugimura and co-workers 's conducted feeding experiments with MNNG (N-methyl-N-nitro-N-nitrosoguanidine) in animal models and have made possible an epidemiologic-experimental approach to stomach cancer t h a t may shed new light on its carcinogenesis in high-risk areas. Endo and Takahashi '9 found t h a t intake in drinking water, food or by gavage of an alkylnitrosamide (MNNG), a compound present in several foods, readily induced cancer in the glandular tissues of the stomach in several species. Furthermore, MNNG was converted to a potent m u t a g e n after exposure to sodium n i t r a t e in a h u m a n gastric juice environment. Since it is now known t h a t nitrites can be converted to nitrosamines in the stomach of animals and man, examination o f t h e dietary environment for the presence of nitrite and the simultaneous presence o f a l k y l a m i d e s has begun in areas with populations at high risk for gastric cancer. Nitrite is a food additive used primarily to preserve meats and fish in various countries and to act as a color former in beef. As a preservative, it is necessary because it inhibits the spores of Clostridium botulinum. At the present time, the practice is to add 125-156 ppm nitrite to various types of meats, but data show t h a t the nitrite level at the time such meats are eaten is no higher t h a n 10 ppm. Mirvish 2~ has shown t h a t small amounts of nitrite would probably not lead to the formation of substantial amounts of carcinogenic nitrosamides. The practice of r e g u l a t e d nitrite addition to meats as a preservative is not a likely cause of gastric carcinoma. However, Binkerd and Kolari ~' have pointed out the historical changes in nitrate and nitrite use and showed t h a t there have been considerable alterations in the practice of nitrate addition to meats and fish in the U.S. Amounts as high as 5,000 ppm nitrate have been used as preservatives in the past. Weisburger and RainerW in their analysis of nitrosamide formation have documented several interesting aspects of this process, which m a y have further preventive epidemiologic implications. Using foods eaten by populations typical of high-risk situations for gastric cancer, they have demonstrated conversion of endogenous or added nitrate into substantial amounts of nitrite when food was stored at room temperature and not in the refrigerator. Mirvish et al3 ~,23 have demonstrated the inhibitory effect of ascorbic acid on the nitrosation o f m e t h y l u r e a as well as on the nitrosation ofalkylamines. Weisburger and Raineri also found t h a t less nitrite was formed in the presence of high amounts of ascorbic acid and less carcinogenic methylurea was formed in the presence of vitamin C. This study identifies a possible source of nitrite, n a m e l y the reduction of nitrate t h a t is deliberately added to food or is present as a result of agricultural practice, which underwrites the hypothesis t h a t gastric cancer in man may result from 10

the formation in the stomach of a locally active alkylnitrosamide. The apparently protective nature of ascorbic acid m a y also play an important role outside the laboratory since tumor induction in rats was inhibited despite the administration of nitrite and methylurea. In Japan, where there is the highest death rate due to gastric cancer (691100,000), a correlation has been made between the consumption of salted fish and the incidence of gastric carcinoma. 5 Theoretically, fish preserved by crude salt may contain nitrate, which m a y be reduced to nitrite. The high content of methylguanidine in fish, combined with nitrite, may result in the formation of methylnitrosocyanamide and methylnitrosourea. Both agents are potent mutagens and carcinogens. In Chile, which has the second highest death rate due to gastric cancer (58/100,000), Zaldivar and Robinson ~* have demonstrated large nitrate deposits and corresponding levels of nitrate in food and drinking water. A positive correlation between nitrates in soil and the incidence of gastric cancer has been established by Hawksworth et al. 25 Similar geologic features have also been documented by Correa et al. 26 in Colombia. The case controlled study of patients in the Department of Narino, Colombia, carried out by Cuello et alY 7 has indicated a general correlation among the following parameters: (1) gastric cancer risk; (2) prevalence of chronic atrophic gastritis and intestinal metaplasia; and (3) nitrate content of well waters and nitrate excretion by the population. These authors believe that the Narino data provide presumptive epidemiologic evidence for the etiologic role in stomach cancer of nitrate in drinking water. Poland, H u n g a r y and Czechoslovakia have, respectively, the 3d, 4th, and 5th highest death rates due to gastric cancer; their geographic proximity suggests a common etiologic factor. 5 Our current knowledge from epidemiologic studies, migrant population research, companion epidemiologic-pathologic analysis and experimental data supports the hypothesis of a possible dietary carcinogen or precarcinogen in producing gastric cancer. Preventive efforts in reducing the presence of nitrate and nitrite in food consumed by man might be recommended on the basis of this knowledge. Nitrite is an effective economic and preventive tool against botulism and the levels of nitrite needed for this purpose are lower than the amounts present in high-risk areas. The sizable amounts of nitrite required for nitrosation to produce sufficient amounts of gastric carcinogen m a y occur from two sources, i.e., the addition of large amounts of nitrate-nitrite mixtures that are used to preserve certain meats and fish, particularly pork, and the natural presence of high levels of nitrate locally, either due to geologic formations or to the addition of nitrates in agricultural practices as nitrate-containing fertilizers. The hazard arises when nitrates ingested as part of foodstuffs 11

are reduced to nitrite. This reaction does not occur at low temperatures and is significantly affected by ascorbic acid. Vitamin C neutralizes the nitrite and reduces the formation of carcinogenic nitrosoamines. As these encouraging findings clarify and delineate the complete carcinogenesis of gastric cancer, preventive measures may be exercised against this dreaded disease and at least reduce the high death rate due to gastric cancer in endemic areas. PRECURSOR LESIONSOF GASTRICADENOCARCINOMA One of the most controversial questions concerning the etiology of gastric carcinoma has been the relationship to other "benign" lesions of the gastric mucosa. Stemmermann and others'5 have identified intestinal metaplasia as a precursor lesion of stomach cancer by detecting a simultaneous high incidence of both cancer and intestinal metaplasia, as well as transitional zones between the two. In Colombia, Cuello et al.26identified intestinal metaplasia and/or chronic atrophic gastritis in 25% of those with stomach cancer in low-risk communities and close to 50% in high-risk areas. The excess prevalence of intestinal metaplasia persisted among individuals born in high-risk communities (i.e., Narino) who later moved to low-risk areas, reenforcing the important role ofcarcinogen exposure in early life. The consistencyof these survey findings and the earlier autopsy studies enhance the case for intestinal metaplasia and chronic atrophic gastritis as precursor lesions. It remains to be seen what percentage of these individuals actually developgastric carcinoma. Reynolds et al? 8have given some insight to the clinical implications of gastric intestinal metaplasia and chronic atrophic gastritis by analyzing 50 specimens with malignant lesions. Intestinal metaplasia was identified frequently in both groups, 62% with benign lesser curvature gastric ulcers and 80% with gastric adenocarcinomas. These findings are similar to those reported by DuPlessis/-9 Paulino and Roselli,"~~ Laur6n," and Morson.~' Further corroborating evidence has been provided by Munoz and Matko,~" and Suirala et al., ~3who found 9 carcinomas in 116 patients followed up for chronic atrophic gastritis. Confirmation of these findings in long-term studies might suggest a consideration for prophylactic surgery in those patients with a 10-yearhistory of chronic atrophic gastritis and intestinal metaplasia, just as in patients with ulcerative colitis. The relationship of benign gastric ulcer to carcinoma of the stomach has been controversial since 1900. This relationship has been documented only infrequently in several large series. Paulino and Roselli3~observedover a 30-year period 500 patients with gastric cancer of whom only an occasional patient had had a proved chronic benign gastric ulcer in the past. ReMine et al24 12

documented malignant gastric ulcers in 3% of benign gastric ulcers and 5% of all gastric cancers in the large Mayo Clinic series. Sakita et al. 3~ popularized the theory that carcinoma is the primary lesion and the mucosal ulceration associated with it m a y heal at times. It is generally accepted that a malignant gastric ulcer or a n y malignant gastric lesion is malignant from its beginning and that malignant degeneration of a benign gastric ulcer is exceedingly uncommon. This underlines the importance of maintaining an aggressive surgical approach to the nonhealing gastric ulcer if we are to diagnose gastric carcinoma at the earliest possible time. Gastric polyps and their association with achlorhydria and pernicious anemia have a statistical relationship to gastric adenocarcinoma (Table 2). Pernicious anemia predisposes 10% of these individuals to gastric cancer and is also known to coexist with gastric polyps in 5% of patients. Menetrier, 3Gin 1888, first described the origin of a carcinoma in a gastric polyp; since then the reported incidence of malignant transformation in gastric polyps has ranged from 0 - 5 0 % . Recently, Tomasulo 37 differentiated gastric polyps histologically into hyperplastic and adenomatous lesions. In the 76 hyperplastic lesions studied by Ming and Goldman, no malignant transformations occurred in this group. ~s Tomasulo found carcinoma solely in polyps of the adenomatous variety occurring in 22%. He observed adenomatous polyps coexistent with carcinoma of the stomach more frequently than hyperplastic polyps, 59 and 28%, respectively. Ming and Goldman found that 40% of adenomatous growths had'evidence of malignancy and an additional 30% coexisted with a cancer elsewhere in the stomach. Multiplicity of gastric polyps in both studies was a more common feature of hyperplastic lesions and they concluded that multiple polyps were less prone to show malignant change. Thus, the morphologic and statistical relationship between true adenomatous gastric polyps and carcinoma of the stomach is obvious, although this has been obscured by the presence of vastly more numerous hyperplastic lesions and confusing terminology. The size of gastric polyps is another important precancerous feature. H a y 39 and Eklof 4~ each described a definite relationship TABLE 2.-PRECURSOR LESIONS AND PREDISPOSING CONDITIONS TO GASTRIC CANCER PERCENT

Gastric polyps (> 2 cm) Gastric ulcer Pernicious anemia Achlorhydria Chronic atrophic gastritis Intestinal metaplasia

30 5 10 10 ? ? 13

between malignant change and the size of gastric polyps (greater than 2 cm in diameter) reporting a malignancy rate of 55% and 33%, respectively. Lesions less than 2 cm were malignant in less than 5% of the cases. Ming and Goldman3s and Tomasulo'~7documented a similar malignancy rate in adenomatous polyps greater than 2 cm in diameter (27% and 24%). Unfortunately, controlled studies are not available comparing operative and nonoperative treatment of gastric polyps based on endoscopic biopsy or other diagnostic techniques. Bone and McClelland~' have cautioned against the routine use of so-called medical management or observation in dealing with gastric polyps.

MODERN TRENDS IN DIAGNOSIS EARLY DIAGNOSIS The insidious presence of gastric cancer which is not manifest until far advanced has been reported throughout the medical literature. Paulino and Roselli3~reported the silent existenceof gastric cancer in 50% of their patients before advanced disease became obvious and was diagnosed. This has been a discouraging feature in many of the large series in the Western literature and has been reflected in operative resectability rates ranging from 49% reported by Lumpkin et al. 42 to 80% reported by Gilbertsen and. Hollenberg. 43 The early diagnosis of gastric cancer has been impaired by: (1) procrastination of patients and lack of diligence on the part of physicians to order appropriate diagnostic evaluations; (2) vagueness and lack of specific characteristics of the initial symptoms; (3) frequency of transient gastrointestinal complaints in the general population; and (4) the insidious onset and presentation of the disease in many cases. Because many of these patients are asymptomatic, identification of those who are likely to have demonstrable gastric pathology has been the crux of the early diagnosis problem. Gastric mass survey and screening programs undertaken most notably by the Japanese have failed in terms of the effort, the high cost, the number of people refusing examination and the low yield of actually diagnosed gastric cancers. Although most Western nations have abandoned the idea of mass cancer screening programs for gastric carcinoma, the efforts in Japan have led to improved modalities of diagnosis. These include fiberoptic endoscopy, endoscopically directed biopsy, gastric camera studies, and double contrast radiographic techniques. These efforts have led to the identification of the pathologic entity of "early gastric cancer" and have shown it to be definitely associated with a greater than 90% 5-year survival rate when adequately treated. Classification of "early gastric cancer" was established by the Japanese Society for Gastroenterological Endoscopy in 1962 (Fig 1). Although the 14

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Fig 1.-Microscopic (A) and macroscopic (B) classifications ol early gaslric adenocarcinoma.

diagnostic yield of mass survey programs is small, the encouraging epidemiologic data uncovered within the last decade, linking nitrate metabolism and gastric carcinogenesis in certain endemic areas, may better guide future efforts in mass screening programs. With the techniques developed by the Japanese, the diagnostic yield would justify the economic expense and effort if screening for precursor lesions as well as gastric cancer was done in these high risk geographic areas. Such programs coupled with lay population education in geographically endemic areas and an active environmental surveillance program may play a significant role in reducing mortality from gastric cancer. In addition, those patients with known precursor lesions of gastric carcinoma, namely, intestinal metaplasia and chronic atrophic gastritis, may be identified and selected for further evaluation. Identification of patient groups harboring precursor lesions, those with asymptomatic carcinoma, as well as those with "early gastric carcinoma" would increase the diagnostic yield, justifying programs of this magnitude. DIAGNOSIS OF THE SYMPTOMATIC PATIENT

Evaluation of the symptomatic patient with gastric cancer offers little challenge to the modern diagnostician. Definite histo15

logic preoperative diagnosis of gastric adenocarcinoma is essential since this carries serious and important implications in the proper operative treatment. An accurate preoperative evaluation of a suspicious gastric ulcer or mucosal lesion using the combined diagnostic modalities of radiographic studies, endoscopy with direct biopsy and cytology approaches a diagnostic accuracy of 100%.44, 45 The decision to operate on the basis of possible cancer only reflects a problem in diagnosis. N o l o n g e r is it acceptable for the surgeon to place himself in the predicament of deciding whether to reoperate when faced with a postoperative pathologic diagnosis of gastric carcinoma, after unsuspectingly resecting a "benign" gastric ulcer or mucosal lesion of the stomach. Significant differences in survival have been demonstrated by several investigators by analysis of the results of radical nodal dissections for malignancies of the stomach versus simple subtotal gastrectomy for gastric cancer. 46, 47 An established preoperative diagnosis is an obvious necessity. The diagnosis ofgastric cancer or the suspicion of a gastric malignancy is usually the result of an upper gastrointestinal (GI) x-ray study. Traditionally, this has been the initial investigative technique for the patient with GI complaints. Devotion to the "upper GI series" is well justified in the case of gastric cancer since a radiologic diagnosis of gastric carcinoma is about 90% accurate. In a cooperative international study on gastric cancer, Lundh et al. 4s documented an 85% diagnostic accuracy rate with barium studies of the stomach, a 12% incidence of suspicious lesions and a 3.5% incidence of "benign-appearing" lesions, later shown to be malignant histologically. The definitive radiologic diagnosis of gastric cancer is a justifiable indication for surgical exploration and treatment even without preoperative histologic evidence of cancer. The diagnostic problem with radiographic studies arises in differentiating the benign and malignant gastric ulcer. Experienced radiologists, internists and surgeons are well aware that a conclusive diagnosis of malignancy cannot be made in 10% of cases in which the ulcers are actually malignant. Since the opinion of the radiologist frequently influences the initial therapeutic course, the radiographic limitations should be understood. Classically, a positive "meniscus sign" has been a reliable indication of malignancy in a case of gastric ulcer. This sign suggests a peripheral neoplastic mass, described as a volcano with its peak pointing inward and the ulcer forming its crater. In contrast, a classical sign of benignancy is the presence of star-shaped folds radiating from the ulcer in otherwise normal-appearing mucosa. Site of the gastric ulcer is of limited help, b u t localization to the prepyloric and the distal third portions of the stomach should alert one to a possible malignant lesion. H a y e s 49 noted that both benign and malignant lesions had a predilection for the lesser t6

curvature and distal third portion of the stomach and found no significant difference in location between the two. Ulcer size is of limited help. Cohn and Sartin '~~reported on 35 ulcers that were larger t h a n 2.5 cm in diameter, only 3 of which were malignant. In their review of 613 cases with ulcers larger than 2 cm in diameter, the overall rate of malignancy was 29%. Kirsh, 5I Hayes/9 and Shoulders and Lischer~2 also emphasized t h a t the so-called giant gastric ulcer is usually benign. The gastric ulcer with residual "masked malignancy" referred to by Runyeon and Hoerr z3 is well documented. Ravdin and Horn} 4 Hayes 49 and Berry and Schmidt 55 found t h a t 8 - 1 7 % of gastric ulcers previously thought to be benign were in fact malignant. This finding led Hoerr to propose an aggressive approach in managing gastric ulcers, benign gastric ulcers or those in which the diagnostic findings are equivocal, if no sign of healing occurs on a medical regimen. Relatively few firm statistics exist on the diagnostic accuracy of x-ray studies in evaluating gastric ulcers histologically proved to be benign or m a l i g n a n t (Table 3). Elliot et al. 5" achieved an impressive accuracy of 93% in diagnosing m a l i g n a n t ulcers, but at the expense of misdiagnosing 21% of benign ulcers as malignant. Most other series have suffered due to lack of histologic proof or inability to extract actual numbers of exact radiologic diagnoses. More recently, additional radiologic criteria for evaluating gastric ulcers have been proposed by Schulman and Simpkins, 57 after 145 cases of gastric ulceration evaluated radiographically were reviewed and correlated with the histologic specimens. A correct diagnosis was made radiographically in 99.5% of the proved benign ulcers, but in only 68.6% of the proved malignant ulcers. This occurred primarily in those lesions arising on the basis of "preexisting benign" ulcers t h a t were wrongly diagnosed initially by x-ray examination. Assuming t h a t a f u n d a m e n t a l l y different radiographic appearance existed in the "secondarily malignant ulcers" from t h a t of primarily malignant ulcers, 3 categories were identified based on profile appearance: type I - p r o j e c t i n g into the TABLE 3.-PREVIOUS RADIOGRAPHIC STATISTICS BENIGN GASTRIC U L C E R S CORRECTLY DIAGNOSED

MALIGNANT GASTRIC ULCERS CORRECTLY DIAGNOSED

Smith and Jorden, 1948 Kirsch, 1955 83% (120) Elliot, et al., 1957 79% (121) Strandjard, et al., 1960 Schulman and Simpkins, 1975 99.5% (145) Numbers in parentheses represent numbersofpatients. (From Schulman,A., and Simpkins,K. C.s7Usedby permission.)

28% (22) 93% (70) 52% (27) 68% (145)

17

TABLE 4 . - A S S O C I A T I O N B E T W E E N RADIOLOGIC AND tIISTOLOGIC TYPES HISTOLOGIC TYPES Benign ulcers (89) Primarily m a l i g n a n t ulcers (33) Secondarily m a l i g n a n t ulcers (13)

RADIOLOGIC TYPES TYPE 1 TYPE 2 TYPE 3 (PROJECTING) (IN'TRALUMINAL) (VERYSIIALLOW) 88 6 11

1 16 1

0 11 1

(From Schulman, A., and Simpkins, K. C. ~7 Used by permission.)

gastric lumen; type II-nonprojecting, with most of the ulcer situated in the gastric lumen; and type I I I - a n ulcer so shallow that even on direct profile it was not convincingly projecting or intraluminal. Type II or III ulcers were almost certainly malignant and type I almost certainly benign (Table 4). Whether or not one adheres to.the philosophy of secondarily malignant ulcers arising from previously benign ulcers, these criteria yield further diagnostic insight toward evaluating the equivocal gastric ulcer. As pointed out by Schulman and Simpkins, type II and III corresponded well to the fundamental pathologic appearance of malignant gastric ulcers described by Morson and Dawson. ss Obviously, the small, shallow, nonpenetrating malignant gastric ulceration should be sought and managed aggressively. Type I ulcers are almost always benign but should be followed until healed because the rare secondarily malignant ulcers are of this type. ENDOSCOPY, ENDOSCOPIC BIOPSY AND CYTOLOGY

In experienced hands, endoscopy of the upper GI tract with biopsy and cytology under direct vision is extremely effective in differentiating between benign and malignant gastric lesions. A meticulous examination done with the proper endoscopic biopsy instruments leads to an accurate diagnosis of gastric cancer in almost 100% of the cases. Refinement of the fiberoptic endoscope developed by the Japanese afforded them the opportunity to define "early gastric cancer" as it appeared endoscopically and pathologically. In 1962, the Japanese Society for Gastroenterological Endoscopy classified "early gastric cancer" according to pathologic criteria and its macroscopic appearance and reported higher rates of early diagnosis than previously observed. The diagnostic approach to a patient with gastric symptoms should include a gastroscopic examination with visually directed biopsies, and even blind biopsies performed empirically in areas with no mucosal evidence of disease. This becomes even more important in the context of the suspected precursor lesions to gastric cancer, namely, intestinal metaplasia and chronic atrophic gastritis, 18

which are definitively diagnosed histologically and are essentially undiagnosable radiographically. This has been clearly pointed out by Fung and Lee 5~ in evaluating the worrisome distal third portion of the stomach and prepyloric areas. The importance of the site of gastroscopic biopsy has been emphasized by Y a m a k a w a et al.,6~ who reported a diagnostic accuracy rate in excess of 90% when the ulcer was biopsied at the rim as well as at the slough. This method eliminates the possibility of sampling normal gastric mucosa at the rim of the ulcer, which may be heaped over the adjacent submucosal extension of tumor, rendering it inaccessible to the biopsy forceps. In addition to endoscopy and biopsy, gastric lavage cytology is an extremely useful adjunctive measure to evaluate suspicious gastric ulcers. Winawer et al. 6' and others ~2reported on the use of endoscopically directed brush cytology to give improved diagnostic accuracy. They pointed out that endoscopic lavage and blind gastric tube lavage is less accurate than the brush technique because fewer extraneous cells are recovered and the cellular matter is better preserved. This technique is particularly useful in troublesome areas such as the incisura and the cardia or in evaluating infiltrative lesions. Winawer et al2' noted that combined endoscopic biopsy and brush cytology provided a 92% accuracy rate for exophytic lesions, whereas infiltrating lesions yielded only a 50% accuracy rate for an overall corrected diagnosis of 72%. In their series, endoscopic brush cytology was superior to endoscopic biopsy alone. The most troublesome lesions, as they point out, are antral or cardiac infiltrating lesions, notably those that are recurrent. Malignant cells that exfoliate will be recovered with cytologic washings. In a small n u m b e r of patients, falsenegative smears will appear, as in linitis plastica which does not invade the mucosa so malignant cells do not exfoliate.

MISCELLANEOUS DIAGNOSTIC MEASURES Analysis of the localimmune response ofthe host to malignant tissue has been the focal point in the developmentof specificserologic testing for malignancy. Levy eta]. ~3have evaluated secretory IgA levels in the serum and gastric aspirate ofpatients with benign and malignant gastric lesions. IgA, an immunoglobulin known to have antibacterial and antiviral neutralizing activity, was found in significantlyhigher titers among patients with malignant neoplasms than in those with benign lesions. The significance of secretory IgA and its response to malignant antigens is unknown, but Levy et al. have noted that this finding may be of value when used in conjunctionwith other diagnostic modalities. An immunologicdiagnostic tool would have a role in wide-scale screeningfor gastric cancer. 19

PATHOLOGY Pathologic staging Of gastric cancer and clinical staging at the operating table have been of little use in making prognoses and predicting the biologic behavior of the t u m o r or the efficacy of surgical treatment. Apparently curative procedures for gastric cancer followed by death of the patient, from abdominal carcinomatosis, often in a matter of weeks, has contributed to the frustration of surgeons and their efforts aimed at cure. The "secondlook" procedure of Wangensteen, 64 with t h e purpose of resecting any asymptomatic recurrences, and the extended node dissections proposed by Arhelger et al. 65 have been futile attempts to deal with this behavioral characteristic of recurrent gastric cancer. L u m p k i n et al. 42 noted at autopsy a comparatively greater frequency of carcinomatosis in a surgical group of 220 patients, half of whom had had surgical extirpation of the primary lesion. These authors suggested that spillage of tumor cells or incomplete excision of the tumor resulted in accelerated growth of the remaining cancer. In view of our present knowledge, few would refute that subclinical microscopic disease in nodal tissue, in distant visceral sites and within the peritoneal cavity logically and adequately explains the failure of surgical cures. Hoerr and Hodgman 66 concluded that "regional metastasis may be present in any of the structures about the stomach and this is the major stumbling block toward successful surgical removal of the growth." The failure of operative staging of gastric cancer to docu m e n t the actual extent of disease is apparent when one examines the survival figures of any large surgical series. Our experience at Charity Hospital of N e w Orleans, using conventional methods of operative and pathologic staging, was well documented in an l l - y e a r (1963-1973) retrospective analysis in 462 patients with histologically proved adenocarcinoma of the stomach. In 421 patients, the location of the primary tumor, the extent of disease and the degree of spread were recorded either from surgical or from autopsy data. The site of the primary tumor tended toward the distal gastric mucosa: 355 (76.8%) lesions involved the pylorus and antrum, 97 (27.0%) lesions were located in the body and 87 (18.4%) involved the cardia and fundus (Table 5). Predilection for the lesser curve and posterior gastric wall was TABLE &-REGIONAL GASTRIC INVOLVEMENT (462 PATIENTS, CHARITY HOSPITAL, 1963-1973) NO. (%) Pylorus and antrum Cardia and fundus Body All areas 20

355 (76.8) 87 (18.4) 97 (21.9) 14 (3.3)

documented as the site ofthe primary tumor in 134 (29%) and 102 (22.1%) patients, respectively. The greater curve was involved in 81 (17.8%) patients, whereas 100 (21.6%) patients had involvement of the anterior and posterior walls as well as the greater and lesser curvatures. The gross abdominal findings at operation or autopsy were recorded in each of 423 patients. The lesion was grossly limited to the stomach alone in 51 (11%) patients, whereas in 52 (11.1%) patients the only evidence of disease beyond the stomach were clinically positive nodes. Contiguous extension was documented in 123 (26.6%) patients and distant visceral metastatic disease was present in 144 (31.2%) patients. The overall incidence of histologically positive nodes was 52%. Although the incidence of nodal metastases was less than the 70% reported by Arhelger et al. G',, Coller et al. 67 have shown t h a t neither size nor location of the primary tumor had any significant bearing on where or how often lymph node metastasis occurred and t h a t a primary lesion on one side of the stomach could metastasize to nodes on the opposite side. The operating surgeon's accuracy or lack of accuracy in evaluating grossly the extent of abdominal disease can be appreciated easily by comparing the previous findings with the final pathologic staging done in each case according to Hoerr's criteria (Table 6). Other attempts to classify gastric carcinoma that would provide the surgeon with more predictable information about the disease are based on the microscopic characteristics described by Broders) ,~ The disadvantages of this staging system are that it fails to take into account the fact t h a t all histologic types of gastric malignancy can metastasize, t h a t the tumor can at some time be localized to the stomach and may possibly be cured by resection and t h a t any malignant lesion can exhibit various histologic features in its evolution. Borrmann's classic description 6~ of the gross gastroscopic appearance of the lesion has been more useful to clinicians, but only in t h a t a more favorable prognosis was associated with a grossly polypoid circumscribed growth t h a n with an ill-defined infiltrating lesion (Table 7). Application of the Borrmann criteria to the TABLE 6.-IIOERR CLASSIFICATION(462 PATIENTS, CHARITY HOSPITAL, 1963-1973) NO. (%) A. No metastasis B. Regionalmetastasis C. Distant metastasis I. Inner gastric layer involvement II. Serosal involvement III. Contiguousstructure involvement

58 (12.7) 182 (39.2) 164 (35.6) 52 (10.9) 75 (16.2) 258 (55.8) 21

TABLE 7.-BORRMANN'S MACROSCOPIC CLASSIFICATION OF STOMACH CANCERS A: Polypoidor fungating B. Ulcerated C. Infiltrating D. Ulceratedwith marginal protrusion and infiltration

462 patients in the Charity Hospital series who were autopsied or operated on revealed an ulcerating m a l i g n a n t lesion in 81 (17.5%) patients, a diffusely infiltrating tumor in 34 (7.4%) patients and a polypoid lesion in 252 (53.7%) patients. These findings differed somewhat from those in the series reported by Paulino and Roselli,3~ where ulcerated tumors were described in 59% of the cases, polypoid lesions in 11.5% and infiltrating cancers in 29.5% of the specimens evaluated. Hoerr 7~proposed the first combined surgical-pathologic classification based on (1) the invasion of the gastric wall layers and (2) the absence or presence of metastatic lesions and their accessibility at the time of definitive t r e a t m e n t (Table 8). This system has been popular since the 1950s and was used in the Charity Hospital analysis of 1,497 patients with gastric adenocarcinoma treated from 1948 to 1973. It provided a means of distinguishing lesions surgically incurable from those potentially curable, which is of some practical value in predicting prognosis. Laur~n's H 1965 classification has gained wide acceptance. Differences in tumor morphology and histology are closely related to the epidemiologic, etiologic and behavioral aspects of the cancer. According to Laur~n, there are two types of gastric cancer: "the intestinal type," or well-differentiated adenocarcinoma, and the "diffuse type," or undifferentiated adenocarcinoma. The intestinal type is more frequent in men and in older patients and is associated with a relatively better prognosis t h a n the diffuse type. The diffuse type has a poorer prognosis and occurs more frequently in younger people. The great e n t h u s i a s m among epidemiologists for the Laur6n classification arises from the fact t h a t the intestinal type of gastric cancer is the d o m i n a n t type in countries TABLE 8.-HOERR CLASSIFICATIONOF GASTRIC CANCER METASTASES

Stage A-no metastases Stage B-regional metastases (usually can be resected with the specimen) Stage C-distant metastases (surgically incurable) 22

Stage I-inner gastric layers Stage II-all gastric layers Stage III-extension to contiguousstructures Stage NX-Not explored

with a high incidence of stomach cancer. Evidence cited previously strongly suggests a direct link to dietary environmental etiologic factors, namely, high nitrogen content diets. In the prospective study of 200 surgical specimens, Paulino and Roselli 3o analyzed the incidence of gastritis and intestinal metaplasia associated with gastric cancer. They documented a higher incidence of intestinal metaplasia in the intestinal type of tumor described by Laur6n and a lower incidence in the diffuse type and in tumors that involve most of the stomach. Reynolds et a l Y documented similar findings of intestinal metaplasia associated with intestinal type gastric cancer in 86% of their cases. Munoz and Matko, 3'-' Walker et alY' and Siurala et al? 3 apparently have established the entity of intestinal metaplasia and chronic atrophic gastritis as precursor lesions of gastric adenocarcinoma. The importance of early diagnosis and of endoscopic and radiographic follow-up evaluation performed on a regular basis for these patient s is obvious. Ming ~2 proposed further refinement of the classification of gastric cancer to the expanding type and infiltrative type of gastric cancer. In general, these tumor types described by Laur6n and those of Ming correspond closely to each other.

NECROPSY SERIES--352 PATIENTS This analysis of the Charity Hospital experience with gastric cancer focuseson those patients with histologically proved adenocarcinoma of the stomach who died of their disease and were autopsied during the 25-year period 1948-1973. A total of 352 necropsies were performed during this period, 220 from 1948 to 1962 and 132 from 1963 to 1973. In view ofthe inadequacy ofoperative and pathologic staging to predict accurately the clinical course and prognosis, the autopsy records of these patients were reviewed to document causes of death and possiblyto identify as yet unrecognized factors contributing to long-term survival or early recurrences after surgical procedures. Operative complications were, as expected, the most common causes of death in 179 (51%) autopsied patients who had undergone an operation. Peritonitis was present in 13 of these patients as a sequela of suture ]ine failure, in contrast to peritonitis occurring only once in the nonoperative group, secondary to perforation of a carcinoma. This finding illustrated an interesting difference compared to the reports of WarwickTM and Ransom,TM who both indicated that peritonitis was the most common cause of death in their series. The most frequent postoperative complications contributing to death in the Charity Hospital series were pneumonia, pulmonary embolus, and sepsis. In the nonoperative group of patients, the most frequent causes of death were pneumonia, pulmonary embolus, carcinomatosis 23

and cachexia, all of which reflect the severely wasted, moribund condition of patients with terminal carcinoma. Most of these patients had their first histologic diagnosis at necropsy because they either refused surgery or were in terminal condition on admission. In many different respects, the necropsy series roughly paralleled the findings documented in all 1,497 patients treated at Charity Hospital during the 25-year period 1948-1973. This was most obvious when location of the tumor in the stomach and frequency oforgan involvement were considered. The origin of the primary tumor, documented in 215 patients, tended toward the distal half of the stomach in 70% of the cases from 1948 to 1962 and in 94% of the cases from 1948 to 1973. The frequency of involvement of various organs was almost identical in those patients who had had a previous operation and those who had not, and it therefore seems reasonable to conclude that the incidence oforgan involvement for the autopsy series can serve as a guide to the incidence of organ involvement in patients with cancer of the stomach (Table 9). This assumption is further confirmed by a study of the incidence of abdominal organ involvement in those patients who were operated on. The frequency and distribution of distant organ involvement was consistent in the present series with the reports of Clarke et TAB[,E 9 . - O R G A N INVOLVEMENT AT AUTOPSY (348 PATIENTS, CtIARITY HOSPITAL, 1948- 1973)

Liver Pancreas Omentum Peritoneum Lung Duodenum Colon Adrenals Spleen Small bowel Esophagus Diaphragm Biliary tree Kidney Urinary bladder Ovary Thyroid Skin

Bone Heart Brain Submaxillary gland

189

100 91 83 78 56 55 52 45 45 25 21 14 12 12 10 5 4 4 3 1 1

(From Dupont, J.B., et alY' used by permission.) 24

al., TM Warren TM and Warwick. 73 Although the adrenals were involved with tumor in 52 patients, only one patient with an adre: nal metastasis died from an Addisonian crisis. The spleen was involved microscopically in only 45 patients in this series. This finding, coupled with the fact that only 16 of our 111 five-year survivors and 8 of 58 five-year survivors reported by Brown et al. 77had a splenectomy at the time of the primary resection, suggests that splenectomy should not be routine in resection for carcinoma of the stomach, in contrast to its advocacy by Fly et al. TM The high incidence ofcarcinomatosis documented in the autopsy series and the more careful documentation of disseminated cancer found among 37 (27%) patients after recent operation was disconcerting. The surgical procedures performed in the 179 patients operated on ranged from exploration and biopsy to extended total gastrectomy, and in 50, the operating surgeon indicated by intent that he had performed a curative resection. Operative staging in these patients revealed involvement of the stomach alone in 12.3%, contiguous structure involvement in 48% and distant organ spread in 25% of patients. The overall incidence of histologically positive nodes was 40%. In view of these findings it is apparent that disseminated cancer frequently found after recent, supposedly curative surgery is best explained by tumor cell spillage due to surgical manipulation of the tumor or by the presence of preexisting micrometastases in nodal tissue, distant visceral sites and peritoneal membranes. Although it is not possible in most cases to document spillage or microscopic metastatic disease, in view of the high incidence of carcinomatosis found after supposedly curative resections, treatment should be directed at a wider base than resection of the primary tumor alone. Some form of adjuvant therapy is indicated at a time when the host tumor burden is low to eradicate remaining subclinical disease. HISTORICAL EVOLUTION OF GASTRIC CANCER TREATMENT 34. 79

Although Hippocrates and Galen made reference to an entity that in retrospect may have been a gastric cancer, the first description of symptoms and findings associated with gastric cancer was recorded by Avicenna in the 1 lth century. Other references and descriptions of the disease process were made during the next 600 years, but not until the early 19th century was significant experimental investigation done which resulted in attempts at surgical extirpation of gastric cancers. The first experimental work directed toward the alleviation of this disease was reported in 1810 by Merrem, who described successful pylorectomy in 3 dogs. Boyle, in his book dealing with gastric carcinoma in 1839 noted the importance of early diagnosis. His thoughts on this disease were far ahead of his contemporaries. 25

The first gastrectomy on a h u m a n was performed by the Paris i a n s u r g e o n Jules Pean in 1879, but resulted in failure since the patient died on the 5th postoperative day. The second gastrectom y in a human, by Rydygier in 1880, was also unsuccessful, and the patient died 12 hours postoperatively. One year later, Theodore Billroth performed the first successful gastrectomy by resecting an advanced colloid carcinoma of the distal stomach. Reconstruction of the GI tract was accomplished by a gastroduodenostomy using 33 sutures. There was no peritoneal drainage or lavage, the operation lasted approximately 11/2 hours and by the 22d postoperative day the patient was discharged from the hospital. Fourteen months later, the patient, Theresa Heller, died from advanced carcinoma, as documented by postmortem examination. Billroth's subsequent attempts at duplicating his initial result were discouraging. The 2nd and 3rd patients who underwent gastrectomy died on the 8th postoperative day and the evening of operation, respectively, and the 4th survived only 4 months. Although Billroth himself had aspirations of achieving the first surgical "cure" of a gastric carcinoma, he soon became dismayed at the high mortality associated with gastric resection and strongly cautioned against injudicious selection of cases for operation and casual attempts by inexperienced surgeons at gastric resection. He stated that not more than 1 patient in 200 with gastric cancer met criteria suitable to attempt a resection, b u t later raised this estimate to 1 patient in 50 or 60. The first analysis of any series of patients with gastric cancer treated by surgical resection was made by William Welch in the late 19th century. ~9 Operative mortality ranged from 37% in Billroth's series of 13 patients to 88% in the remaining 24 patients. Welch noted that the mortality from operation was prohibitively high and that no patient undergoing surgical resection had survived longer than 11/2 years. He cited 6 reasons why gastric resection was not applicable to the average case of gastric carcinoma, several of which remain insurmountable obstacles to today's modern surgical techniques and procedures: (1) distant metastases frequently are present when the patient is first seen; (2) tumor location m a y prohibit removal (cardia); (3) extent m a y prohibit removal (linitis plastica); (4) widespread involvement of the colon and pancreas; (5) extreme debilitation of the patient; and (6) the need for a specially trained surgical team. Conner, in this country, first attempted total g a s t r e c t o m y i n 1883, but was unsuccessfulY t In 1897, Schlatter ~ performed the first successful total gastrectomy in the human and achieved a survival for almost 14 months. Gastrointestinal reconstruction was by end-to-side esophagojejunostomy. After that, sporadic cases of total gastric.resection were r e p o r t e d a n d Finney and Reinhoffin 1929 were the first to appraise the procedure from an 26

analysis of 122 collected cases. A mortality of 53.7% was found for patients with complete gastric resections. During the period 1890-1920, more favorable figures were reported, i.e., 5-year survivals reached 8-12% of all patients who underwent resection, operability rates increased significantly~ resectability rates approached 20%, there were longer periods of survival and operative mortality was reduced to as low as 20%. This period witnessed a number of modifications of Billroth's original procedure, some of which are still practiced today. Shoemaker modified the Billroth I gastroduodenostomy by partially closing the lesser curvature of the gastric remnant to allow better approximation of the stomach and duodenum. In 1888, Eiselberg first performed the Hofmeister modification of the Billroth II type of reconstruction. This consisted of closing the upper portion of the cut end of the stomach using the lower end near the greater curvature to establish the end-to-side gastrojejunostomy. In 1911, Polya reported using a retrocolic loop of jejunum to form an endto-side anastomosis with the entire length of the cut end of the stomach. Other modifications of the original Billroth II procedure have been suggested, but in most instances the basic principle of the Billroth II reconstruction remains the same. As for total gastrectomy, the first 4 decades of the 20th century witnessed many studies reviewing total gastrectomy for gastric cancer, but few contributions were made. Pack and McNeer,8~in 1943, reviewed 303 total gastric resections from 1897 to 1942. Postoperative mortality remained quite high (37%) and there was a discouraging 5-year survival of less than 1%. Despite some improvement in technique and in the management of patients pre- and postoperatively, basic aspects of the problem remained unsolved. In 1944, total gastrectomy was proposed as the routine surgical procedure for all patients with malignant gastric tumors. Longmire's proposal did not withstand the test of time despite the low operative mortality rate of 9.5% reported at the Johns Hopkins Hospi~tal.8~ In 1960, a comprehensive review and comparison of total gastrectomy and subtotal gastrectomy done for similar types of malignant lesions was reported by Rush et al. 8~ This series clearly demonstrated a higher operative mortality rate and lower 5-year survival resulting from total gastrectomy compared to partial resection. From then through the 1960s and 70s no other serious suggestions were made for the routine use of total gastrectomy for gastric malignancy. Patient selection, the clarification of indications for the operation and improvements in surgical technique have given the procedure a definite and valuable place in the surgical armamentarium in dealing with gastric cancer. In the excellent review of Paulino and Roselli3~ of 200 cases of gastric cancer, the authors suggest that total gastrectomy should 27

have been used more frequently, especially for lesions of the body of the stomach judged curable by the operating surgeon. These pathologic findings revealed a high incidence of involved pancreatic and splenic lymph nodes for m a l i g n a n t lesions of the body of the stomach in which en bloc resection of the distal pancreas and spleen was done. On the other hand, Paulino and Roselli do reiterate t h a t total gastrectomy should never be used as a palliative procedure in patients with distant metastases or extensive peritoneal dissemination of tumor. At the present time, the preferred t r e a t m e n t for gastric adenocarcinoma in which the lesion is located in the distal h a l f of the stomach consists of a radical subtotal resection of the stomach including en bloc removal of the lesion, omentum, 80-85% of the stomach, the first portion of the duodenum, the node-bearing tissue of the hepaticoduodenal pedicle, the gastrohepatic omentum, the gastrocolic omentum with or without the spleen and its hilar nodes, as described by ReMine et al. 34 Total gastric resection including splenectomy with or without distal pancreatectomy is reserved only for the patient with a potentially curable lesion where partial gastric resection would not remove all areas of malignant involvement. TWENTY-FIVE-YEAR EXPERIENCE WITH GASTRIC CANCER- 1497 CASES46 ALL PATIENTS

The Charity Hospital experience with gastric cancer during the 25-year-period 1948-1973 consists of 1,926 histologically proved m a l i g n a n t neoplasms of the stomach. Four hundred and twentynine of these were omitted because the neoplasm was a sarcoma, lymphoma, lymphosarcoma, carcinoid or epidermoid lesion. The records of the remaining 1,497 cases of microscopically proved adenocarcinoma were analyzed in this report. Patients were followed on a yearly basis and follow-up was available on 99% of all TABLE 10.-SEX AND RACE DISTRIBUTION (1497 PATIENTS, CHARITY tIOSPITAL, 1948-1973) PERIOD

1948-1962

Male

1963- 1973

Female Male

WIIITE

BLACK

206

543

749

69 47

217 244

286 291

Female 26 145 TOTAL 348 1,149 (From Dupont,J. B., et a12~Used by permission.) 28

TOTAL

171 1,497

1,0406 457~ 1,497

AGE 5001

4501 4001

[] 1948-62

1963-73

~300~ 250 t ~' 2001

Fig 2 . - A g e distribution of 1,497 patients. The shaded area is the distribution of patients in the first study period, 1948-1962; the unshaded area is the distribution of patients in the recent study period, 1963-1973.

50] ~

' 2b '4b '6b "sb 'ldo Decode(years)

patients in this series. Where appropriate, interesting comparative observations were made between two t r e a t m e n t periods, 1948-1962 and 1963-1973 (Table 10). Age distribution in this series was similar to that reported by other investigators and ranged from the youngest of 20 years to the oldest of 99. The median age was 65 (Fig 2). RESULTS AND DISCUSSION

Five-year survival analysis for the entire series of 1,497 patients revealed 111 patients survived five years or more, 74 patients from the first period 1948-1962 and 37 from the second period 1963-1973. Sex and race distribution for the five-year survivors were comparable to that of the entire series (Table 11). An abdominal operation ranging from exploratory laparotomy and biopsy to extended total gastrectomy was done in 1,222 patients (Table 12). The operability rate decreased from 82% in the first study period (1948-1962) to 76% in the second (1963 - 1973). Microscopic diagnosis was made at autopsy in 250 patients who did not have an operation. The resectability rate for the 1,497 patients was 48% and compares favorably with other series (Table 13). The percent of operations performed with curative intent almost doubled in the later study period (Table 14). There were 134 distinctly palliative bypass procedures in the earlier study period, plus an unstated number done for palliation among the 366 subtotal gastrectomies. In the second period, 32% of the procedures were considered 29

TABLE ll.-FIVE-YEAR SURVIVAL (111 PATIENTS, CttARITY HOSPITAL, 1948-1973) GROUP

NO.

FIVE-YEAR SURVIVAL (%)

All patients 1,497 Patients observed 5 years 1,333 Blacks 1,149 Whites 348 Males 1,040 Females 457 Patients with localized disease 149 Patients with regional disease 665 Patients with distant spread 540 Subtotal gastrectomy 485 Radical subtotal gastrectomy 144 Total gastrectomy 84 Esophagogastrcctomy 25 Normal age-adjusted population (From Dupont, J. B., et al. 46Used by permission.)

7.35 7.84 5.95 6.67 9.02 30.28 10.14 0.2 14.41 22.05 7.6 1.97 83.5

p a l l i a t i v e , 49 b y p a s s p r o c e d u r e s a n d 97 s u b t o t a l g a s t r e c t o m i e s . E x p l o r a t o r y l a p a r o t o m y a n d b i o p s y w e r e p e r f o r m e d in 301 of t h e 1,497 p a t i e n t s . In addition, 291 p a t i e n t s (19.4%) w e r e n o t o p e r a t ed on b e c a u s e t h e y w e r e in t e r m i n a l condition or r e f u s e d operation. L o c a l i z a t i o n of c a n c e r s t e n d e d t o w a r d distal g a s t r i c involvem e n t ; m o r e t h a n 80% of all 5 y e a r s u r v i v o r s h a d lesions in t h e d i s t a l h a l f of t h e s t o m a c h . No 5 - y e a r s u r v i v o r in the r e c e n t g r o u p h a d a lesion in the c a r d i a , f u n d u s or e s o p h a g o g a s t r i c j u n c t i o n . T h e p o o r e r p r o g n o s i s of lesions in t h e p r o x i m a l portion of t h e s t o m a c h is p r o b a b l y r e l a t e d to t h e l a t e r o n s e t of o b s t r u c t i v e s y m p t o m s for lesions in t h e p r o x i m a l p o r t i o n w h e r e t h e g a s t r i c l u m e n is l a r g e r a n d also to t h e g r e a t e r difficulty in r e m o v i n g all t h e l y m p h a t i c d r a i n a g e of lesions a r i s i n g in t h i s area. All of t h e 5 - y e a r s u r v i v o r s u n d e r w e n t a resection of t h e priTABLE 12.-TYPE OF OPERATION (1,222 PATIENTS, CttARITY HOSPITAL, 1948-1973) PROCEDURE

NO.

Exploratory laparotomy and biopsy 301 Gastrojejunostomy 183 Subtotal gastrectomy 485 Radical subtotal gastrectomy 144 Total gastrectomy 84 Esophagogastrectomy 25 TOTAL 1,222 (From Dupont, J. B., et al26 Used by permission.) 30

%

24.63 14.98 39.69 11.78 6.87 2.05 100

TABLE 13.-RESECTABILITY RATES P E R C E N T RESECTED

SOURCE

NO. OF PATIENTS

(ALL PATIENTS)

10,115 11,817 574 227 901

42 50 39 60 53

385 2,590 238 854 209 226 1,497

50 31 54 45 45 66 48

Cancer Prognosis Manual ReMine, 1964 Keller, 1965 Gilbertsen, 1969 Lundh, 1974 Nielsen, 1974 Inberg, 1975 Kenter, 1975 Cassell, 1976 Svennevig, 1976 Costel]o, 1977 CHNO

CItNO = Charity Hospital at New Orleans. (From Dupont, J. B., et a12GUsed by permission.)

m a r y lesion. S u b t o t a l g a s t r e c t o m y , the p r o c e d u r e p e r f o r m e d m o s t f r e q u e n t l y , h a d t h e l a r g e s t n u m b e r of s u r v i v o r s (58) a n d a n overall 5 - y e a r s u r v i v a l of 14.2%. Six of t h e 84 p a t i e n t s w h o h a d total g a s t r e c t o m y s u r v i v e d 5 y e a r s , r e s u l t i n g in a d i s c o u r a g i n g l y low s u r v i v a l r a t e of 7.6%. One of t h e 6 died of r e c u r r e n t d i s e a s e 7 y e a r s a f t e r operation; t h e r e m a i n i n g 5 w e r e a l i v e a n d well a t t h e e n d of t h e study. O f t h e 25 p a t i e n t s who u n d e r w e n t e s o p h a g o g a s t r e c t o m y , 2 survived 5 y e a r s or m o r e a n d o n e s u r v i v e d l o n g e r t h a n 10 years. T h e a v e r a g e s u r v i v a l a f t e r this p r o c e d u r e w a s s h o r t e r t h a n a f t e r a n y a b l a t i v e p r o c e d u r e a n d , in o u r e x p e r i e n c e , t h i s p r o c e d u r e offers little hope o f c u r e . Radical s u b t o t a l g a s t r e c t o m y r e s u l t e d in t h e b e s t s u r v i v a l , 22.1% o v e r a l l a n d t h e lowest m o r t a l i t y (Table 15). O f the 144 pat i e n t s w h o h a d radical s u b t o t a l g a s t r e c t o m i e s , 43 s u r v i v e d 5 y e a r s or m o r e . R a d i c a l s u b t o t a l g a s t r e c t o m y w a s defined as a t l e a s t a 75% distal g a s t r e c t o m y , p l u s r e s e c t i o n of o m e n t u m a n d TABLE 14.-CURATIVE VERSUS PALLIATIVE PROCEDURES (CtIARITY HOSPITAL, 1948-1973) PROCEDURE

Curative resection Palliative

1948--

1962

147 (17.2)

1963- 1973

TOTAL

127 (36.0)

274 (22.5)

Bypass 134 49 Resection Unknown 97 Diagnostic procedure 242 59 Numbers in parentheses represent percentages. (From Dupont. J. B., et al. 4~Used by permission.)

183 (15.0) 97 Plus 301 (20.2)

31

TABLE 1 5 . - O P E R A T I V E MORTALITY (353 PATIENTS, CHARITY HOSPITAL, 1963-1973) 9P R O C E D U R E

Overall Palliative Curative Diagnostic Esophagogastrectomy Total gastrcctomy Subtotal gastrectomy Radical subtotal gastrectomy Gastrojejunostomy Exploratory laparotomy and biopsy Other

NO. O F C A S E S

OPERATIVE MORTALITY (%)

353 169 108 65 11 27 118 66 49 58 24

26.5 30.7 20.3 28.9 27.3 37.2 23.7 16.4 36.7 28.8 5.2

(From Dupont, J. B., et al. 4~Used by permission.)

lymph nodes along the right and left gastric arteries. In some patients, the procedure was extended to remove one or more of the following: spleen, transverse colon, tail of the pancreas, celiac axis nodes or nodes along the porta hepatis. In conjunction with total, subtotal or radical subtotal gastrectomy, 5 patients had contiguous involvement of the transverse colon and underwent a transverse colectomy. The most frequently involved contiguous organs were omentum, pancreas and colon. The omentum and transverse colon can be removed and, as some would also agree, at least a portion of the pancreas. The potential involvement of the colon makes it imperative to have the colon prepared in any patient who is to undergo operation for gastric carcinoma. Since contiguous structure involvement was histologically demonstrated by presence of a tumor in so many cases and by inflammatory response in another large group, it is no wonder the surgeon often thought he was doing a palliative procedure. It is important to remove the involved area, since it has been demonstrated that long-term survival can occur in the presence of other organ involvement. The 5-year or longer survival of 5 patients who had simultaneous removal of the stomach and transverse colon demonstrates this point quite clearly. The surgeon described the procedure as palliative in 54 patients who became 5-year survivors. Similarly unreliable prognostications have been a part of every busy surgeon's practice and serve to emphasize the importance of persisting in attempts to eliminate tumor bulk during the original operative procedure, since this m a y not only aid in palliation but also may be associated with long-term survival. The superiority of radical subtotal gastrectomy over subtotal gastrectomy has been confirmed in each of our 2 study periods, most convincingly in the recent period 1963-1973, where the 532

year survival was 27.3% as compared to 11.5% for subtotal gastrectomy. According to the Hoerr classification, 63 patients had a stage A lesion. The tumors were confined to the mucosa or muscularis in 40. Subtotal gastrectomy was performed in 30 and radical subtotal gastrectomy in 25 of the 63 patients with stage A lesions. Since similarly staged lesions treated by subtotal gastrectomy appeared to result in similar long-term survival, some might question the need for nodal dissection. In an attempt to resolve this dilemma, survival was analyzed further by eliminating from the entire series (1,497 patients) those patients who underwent subtotal gastrectomy for Hoerr stage C lesions. The resulting figures show that subtotal gastrectomy was performed on 73 patients with Hoerr stage A lesions and 277 patients with stage B lesions, a total of 350 subtotal resections. Radical subtotal gastrectomy was performed on 25 patients with stage A lesions and 93 with stage B lesions, a total of 118 radical subtotal resections. Subtotal gastrectomy resulted in 45% 5-year survival for patients with stage A lesions and a 7.2% survival for those with stage B l e s i o n s - a n overall 5-year survival of 15.7%. Radical subtotal gastrectomy resulted in 100% survival of patients with stage A lesions, and a 17.3% 5-year survival for patients with stage B lesions, an overall 5-year survival of 36.4%. The difference in survival between subtotal gastrectomy and radical subtotal gastrectomy is statistically significant and further confirms the value of the radical procedure. The absolute necessity of completely ruling out cancer is therefore quite evident. In the absence of a preoperative biopsy or if a biopsy is inadequate, the operating surgeon should perform a gastrotomy with open biopsy, and minimize spillage. The efficacy of any method of treating carcinoma can be judged in part by comparisons of the median survival time and of the survival curves following various methods of treatment. The median survival (Table 16) of 3 months for all patients in the series is a quick way to determine how serious is the diagnosis of carcinoma of the stomach. The further reduction of this time for those patients who had a gastrojejunostomy indicates what poor palliation this procedure achieved. When the disease is far advanced, most patients should have only simple exploration and biopsy, which actually has the same average survival as a bypass procedure but a lower mortality. Since a good portion of the 2 - 3 months may be spent in the hospital, a bypass is not likely to offer any real palliation, and probably should not be done. Further, it may function poorly. The survival curves (Fig 3) confirmed the results noted above, and elsewhere in this report. The 5-year survival rates for the total Charity Hospital series are very close to those reported by others (Table 17). Radical subtotal gastrectomy has the best re33

TABLE 16.-MEAN AND MEDIAN SURVIVAL TIME (CHARITY HOSPITAL, 1948- 1973) OPERATION

MEAN S U R V I V A L (MONTIIS)

MEDIAN SURVIVAL (MONTIIS)

All cases 12.3 Exploratory laparotomy/biopsy 4.0 Gastrojejunostomy 4.1 Esophagogastrectomy 7.6 Total gastrectomy 17.5 Subtotal gastrcctomy 23.8 Radical subtotal gastrectomy 24.7 (From Dupont, J. B., et al? ~Used by permission.)

3 2 2 5 5 10 13

s u i t s t h r o u g h o u t t h e 10-year s u r v i v a l period studied and d e m o n s t r a t e s its s u p e r i o r i t y o v e r t h e s u b t o t a l g a s t r e c t o m y from a b o u t t h e 2d or 3d y e a r on and t h e difference b e t w e e n t h e two b e c o m e s m o r e n o t i c e a b l e as t i m e progresses. O n t h e basis of m e d i a n s u r vival, as well as on j u s t a b o u t e v e r y o t h e r p a r a m e t e r considered, r a d i c a l s u b t o t a l g a s t r e c t o m y h a s the b e s t record a n d , therefore, is t h e p r o c e d u r e to be r e c o m m e n d e d . T o t a l g a s t r e c t o m y is not q u i t e as good as t h e subtotal, b u t t h e differences b e t w e e n the two m a y be r e l a t e d to t h e s m a l l size of t h e total g a s t r e c t o m y series r a t h e r t h a n to r e a l differences b e t w e e n the results. Since n e i t h e r h a s as good a s u r v i v a l c u r v e as radical s u b t o t a l g a s t r e c t o m y a n d the t o t a l g a s t r e c t o m y h a s a g r e a t e r o p e r a t i v e r i s k , it h a s less to reco m m e n d it. T h e e x t r e m e l y poor r e s u l t s w i t h e s o p h a g o g a s t r e c t o m y , e x p l o r a t i o n and biopsy, a n d g a s t r o j e j u n o s t o m y all i n d i c a t e

SURVIVALAFTEROPERATION Fig 3.-Survival, computed by the life-table method, after various procedures for adenocarcinoma of the stomach.

I00" 80"

~oi~ 4o

.~ 20 i ~

RcdicolSutfotcl G~ttectomy

!5,oo, Co(lS~Ieclomy

h 2 345

34

6 78910 Ye0rs

It I m

TABLE 17.-FIVE-YEAR SURVIVAL FOR GASTRIC ADENOCARCINOMA SOURCE

NO. O F P A T I E N T S

Cancer Prognosis Manual 10,115 Keller, 1965 574 Gilbertsen, 1969 1,983 Crumb, 1970 123 Nielsen, 1974 385 Inberg, 1975 2,590 Kenter, 1975 238 Cassell, 1976 827 Svcnnevig, 1976 209 Costello, 1977 226 CHNO 1,497 CIINO = Charity Hospital at New Orleans. (From Dupont,J. B., et a126Used by permission.)

FIVE~YEAR SURVIVAL PERCENT

9.0 4.7 10.2 5.1 12.0 5.8 16.9 8.8 i0.0 8.5 7.4

that these procedures have little to offer. The very short average survival with gastrojejunostomy is further emphasized by the observation t h a t almost all patients who undergo this procedure are dead by the end of the 1st postoperative y e a r and that none are alive by the 2d year. Similar results are obtained in those who have simple exploration and biopsy. The gentle s l o p e - o r straight l i n e - a f t e r the 5th year suggests t h a t most patients who survive 5 years after some procedure for carcinoma of the stomach have a very good chance for longer survival and may even have had the lesion completely removed.

ADJUVANT TREATMENT As noted from the Charity Hospital necropsy series of 348 cases, the unexpected high incidence of carcinornatosis documented in patients recently operated on for cure suggests the need for primary t r e a t m e n t aimed at a wider base t h a n j u s t resection of the primary tumor alone. The concept of adjuvant cancer therapy provides a logical but untested approach in f u r t h e r treating these patients at high risk of developing widespread disease. Simply stated, this concept consists of eradication of as much disease as possible by surgical resection to reduce the m a l i g n a n t cell burden on the host for a more effective cell kill by chemotherapeutic agents. Schabel sz has postulated t h a t as the tumor mass is significantly reduced, the growth fraction of the remaining viable tumor cells increases, rendering malignant cells more sensitive to antimetabolite drugs. The increase in growth fraction is proportional to the percentage reduction of tumor cells by partially effective therapy and the temporal aspects of t u m o r mass reduction by lysis and reabsorption. Theoretically, if this principle is 35

valid, adjuvant therapy can effectively control subclinical circulating or metastatic disease. No patient in the Charity Hospital experience during the 25 years analyzed received chemotherapy or radiotherapy as a component of their primary treatment. Many forms of adjuvant chemotherapy are presently being analyzed worldwide. Criticism of reports on the use of adjuvant forms of treatment has centered on patient selection and on actual dosage protocols for administering the drugs. Patient selection in previously reviewed studies frequently neglected important progtmstic variables, such as type of surgery, depth of gastric wall invasion and degree of nodal involvement or microscopic grading of the primary tumor. All these factors, if improperly distributed, may alter and skew results of any analysis. Drug dosages in previous adjuvant studies have also been criticized. Short-term chemotherapy of moderate intensity, as reflected by a low incidence of drug toxicity, frequently characterized adjuvant therapy protocols in the past. As pointed out by Carter and Comis,83 "It is more likely that the 80% failure rate for curative surgery is related to the presence of established microscopic foci outside the operative field rather than to dislodged tumor cells:" Thus, an intensive and protracted regimen of adjuvant chemotherapy aimed at eliminating metastatic disease would be in order. The choice of chemotherapeutic agents used in adjuvant treatment has for the most part stemmed from the early work of Lawrence et al. s4 with adjuvant chemotherapy for colon carcinoma. A recent review of chemotherapy for gastric carcinoma by Carter and Comis s3 concluded that 5-FU, Mitomycin C and BCNU are the only known drugs that exhibit clinical activity in patients with disseminated disease. Reports from the Mayo Clinic Group have documented consistent response rates of 20- 25% for periods averaging 4-5 months using 5-FU in the treatment of metastatic disease. In Japan, Mitomycin C is used most commonly for metastatic gastric cancer. An overall objective response rate with Mitomycin C ranges from 20-30% for periods averaging 1-3 months. The nitrosoureas 1,3-bis(2-chlor-methyl)-l-nitrosourea (BCNU), 1,3-cis(2-choloethyl)-l-nitrosourea (CCNU), and methyl CCNU (MeCCNU) also have shown evidence of activity against gastric cancer. BCNU yielded an objective response rate of 18% and an average duration of response of 4.5 months in gastric cancer treatment reported by the Mayo Clinic. 8~,s6 Combined approaches using several drugs for gastric cancer treatment have resulted in more encouraging response rates than those observed for other GI neoplasms. The higher response rates obtained by the Japanese with 5-FU, Mitomycin C and cytosine arabinoside have been confirmed at the Memorial Sloan-Kettering Cancer Center. In addition, a 41% response rate with 5-FU 36

and MeCCNU combined was observed at the Mayo Clinic and survival was superior to concomitant controls of both single agents. F u r t h e r investigation should be focused on specific areas of adjuvant chemotherapy using combinations of these various drugs. The scant single-drug adjuvant treatment studies for gastric carcinoma have for the most part been unsuccessful in increasing 5-year survival rates. The pilot study of Lerner, s7 who analyzed a series of 109 patients with and without curative surgical resection of the primary gastric tumor and a series of 33 patients operated on for cure documented an increase in median survival among those patients receiving combined adjuvant 5-FU and hydroxyurea. Median survival in the group treated with adjuvant chemotherapy was 25 months, an increase of 10 months as compared to that of the patients treated with curative surgical resections alone (15.5 months). Similar findings were documented by Franz and Cruz ~s in their analysis of 156 gastric cancer patients receiving 5-FU adjuvant chemotherapy. A significant increase in survival rates for the adjuvant chemotherapy group was documented as opposed to the surgery-only group at 1 year, 46.7% vs. 85.7% at 2 years, 40% vs. 64.3% and at 3 years, 26.7% vs 35.7%. As the authors pointed out, patient survival increased for 1 - 3 years among those treated with adjuvant chemotherapy; thereafter, t r e a t m e n t was no longer effective, probably as a rcsult of loss of control and regrowth of the larger tumor cell mass. The Veterans Administration Surgical Adjuvant Group (VASAG), initiated in 1957 to investigate adjuvant chemotherapy in the treatment of a number of malignancies, reported in their preliminary findings that no increase in survival was found among patients treated with adjuvant Thio-TEPA or 5-FUDR (5-Fluorodeoxyuridine) after gastric resection29,9~ This finding was documented again by Serlin et al. 9' at 14 years postoperatively for the Thio-TEPA group and at 6 years postoperatively for the 5-FUDR group. In addition, nodal involvement, resection of esophagus and serosal penetration were predictive factors of recurrence up to 36 months. A cure rate of 26% was identified and, among these patients, absence of blood vessel invasion, serosal penetration, lymphatic invasion and nodal involvement was the rule. No predictive factors for recurrence from 36 to 60 months were identified. In summary, the efficacy of adjuvant chemotherapy given after curative gastric resections for carcinoma remains to be documented adequately. Combined drug protocols administered in adequate dosages appear to offer the best chance for increasing survival after curative surgical therapy. Most important, proper patient selection for different protocols is essential since prospec37

rive randomized analysis of those cases with serosal involvement, lymph node metastases, contiguous spread and type of surgical procedure will help identify the stages of disease where adjuvant therapy can be shown to be of benefit. MISCELLANEOUS FORMS OF ADJUVANT THERAPY

Fujimoto et al22 reported on 62 patients with gastric cancer who were treated preoperatively with intra-arterial chemotherapy for 1 5 - 2 0 hours. Survival rates analyzed with particular emphasis on degree of serosal invasion of the stomach yielded several encouraging findings. The overall survival at the end of 5 years was 33.3% among treated patients as compared to 29.7% in the control patients. Also at 5 years, the 39 treated patients with serosal invasion had a survival rate of 32% as opposed to 23.7% for controls. Although this series consists of a small number of patients, the combination preoperative arterial infusion of chemotherapeutic agents followed by operation warrants further investigation.

PALLIATION FOR UNRESECTABLE GASTRIC CANCER BYPASS PROCEDURES VS. RESECTION

One controversial aspect in the surgical treatment of gastric c~ircinoma centers around the efficacy of palliative gastrojejunostomy for an unresectable malignant gastric tumor. The superiority of palliative resection over bypass has been well documented in the literature in terms of survival and quality of life in patients with incurable disease. However, there have been few re~ ported studies of gastroenterostomy as a palliative procedure, and those few have not shown promising results. Analysis of the 1,497 cases of adenocarcinoma of the stomach during the 25 years 1 9 4 8 - 1 9 7 3 revealed that 183 palliative gastroenterostomies were performed for unresectable disease. A preoperative diagnosis was made if intractable vomiting with or without nausea was present or if there was radiologic or gastroscopic evidence of gastric outlet obstruction. Eighty-four of the 183 patients had obstruction preoperatively and an additional 93 patients underwent prophylactic gastrojejunostomy for imminent obstruction as judged by the operating surgeon (Table 18). The reasons for not resecting the tumor were: infiltration of vital surrounding structures in 82 patients (44.8%), distant metastases in 72 (39.3%) and cachexia in 10 (5.5%). No reason was given in 13 cases. As expected, the operative findings revealed that the most common location of the primary lesion was in the antrum, pylorus or body (94% of patients). Distant organ metastases were doc38

TABLE 18.-PALLIATIVE GASTROENTEROSTOMY (183 PATIENTS, CHARITY HOSPITAL, 1948-1973) No. (%) Patients with preoperative obstruction Patients with "imminent"obstruction Unknown status

84 (45.9) 93 (50.8) 6 (3.3)

umented in 95 (51.9%) patients and contiguous structure involvement in 76 (41.5%) patients, a total of 93.4%. Only 11 patients who underwent palliative gastrojejunostomy had cancer limited to the stomach alone or stomach and its surrounding nodes. Of the 84 patients who had preoperative obstruction, in 24 it was impossible to determine a n y beneficial effect from their gastrojejunostomy because of postoperative mortality or morbidity. Of the remaining 60 patients, 5 had no relief of symptoms, 10 were relieved for one month and 33 were relieved for less than 3 months. Fourteen patients had relief of symptoms for a 4 - 6 month period and only 12 had relief for longer t h a n 6 months. In all, 57 patients had poor relief of symptoms after palliative gastrojejunostomy (Table 19). Ironically, obstruction developed postoperatively in 6 patients who underwent prophylactic gastrojejunostomy. The average hospital stay for the 183 patients was 9.6 days and the overall operative mortality rate determined for the first 30 days postoperatively was 21.3%. Gastrojejunostomy for relief of obstruction resulted in a postoperative mortality of 29.7% as opposed to 14% for those patients who underwent prophylactic gastrojejunostomy. Seven patients who received a palliative gastrojejunostomy for an unresectable gastric carcinoma developed obstructive symptoms postoperatively. All 7 had the procedure performed prophylactically because the operating surgeon beTABLE 19.-RELIEF OF OBSTRUCTION AFTER GASTROJEJUNOSTOMY IN 84 PATIENTS WITII OBSTRUCTION (CHARITY HOSPITAL, 1948-1973) DEGREE OF PALLIATION

Poor

Fair Good TOTAL

RELIEF OF SYMP'fOMS

None Relief 1 month Relief 2 months Relief 3 months Relief 4-6 months Relief 6 months Indeterminable because of mortality/morbidity

NO. OF PATIENTS

5 l0 14 4 14 12 24 84 39

lieved t h a t gastric outlet obstruction was imminent. In 6 patients, the primary lesion extensively infiltrated contiguous structures, whereas the remaining p a t i e n t was only noted to have distant hepatic metastasis. Four patients had the primary lesion arising in the a n t r u m from either the greater or lesser curvatures. Three patients had extensive p r i m a r y lesions involving both curvatures of the stomach as well as the anterior and posterior walls. All 7 patients survived the operation and were discharged from the hospital. One patient died within the first month postoperatively; the average survival for the remaining 6 patients was 6.5 months. None of these 7 patients was autopsied, thus no information is available on the status of involvement of the gastrojejunostomy. The average survival for the entire group of patients undergoing palliative gastrojejunostomy was 2.9 months, which was essentially unchanged whether the procedure was done for relief of obstruction or prophylactically. When these survival figures are compared with palliative resection, a definite trend for increased survival can be seen with the latter procedure (Table 20). Survival after operation was classified into 3 groups; i.e., poor (less t h a n 3 months); fair ( 3 - 6 months); and good (longer t h a n 6 months) (Table 21). Approximately one third of the patients died within the first month. One hundred twenty-four had poor palliative survival, living less t h a n 3 months. An additional 39 had fair results, and 17 had good palliation. Only 3 of the 183 patients lived more than 1 year. All patients were dead by December 31, 1973, the longest survival lasting for 20 months. Autopsies were performed on 27 of the 183 patients. Twenty patients had patent anastomoses, 18 without tumor involvement, whereas 4 had m a l i g n a n t disease at the anastomotic site. Of the 4 patients with tumor involvement of the anastomosis, one had an obstructing lesion at autopsy. This p a t i e n t survived 3 months after operation and was relieved of obstructive symptoms for 2 months. Two patients succumbed to their disease in less t h a n 1 month postoperatively and had no relief of nausea and vomiting. The 4th survived for 4 months and was relieved of obstructive symptoms until his death. TABLE 20.-SURVIVAL AFTER PALLIATIVEOPERATIVE PROCEDURES (CttARITY HOSPITAL, 1948-1973) MEAN SURVIVAL (MONTIIS)

Gastrojejunostomyfor relief of obstruction Gastrojejunostomyfor prophylaxis Subtotal gastrectomy (palliative)~6 40

MEDIAN SURVIVAL (MONTHS)

RANGE (MONTIIS)

NO. OF PATIENTS

2.0

2

0-15

84

2.8

2

0-20

93

10.7

6

0-93

87

TABLE 21.-DEGREE OF PALLIATION BASED ON SURVIVAL (183 PALLIATIVE GASTROJEJUNOSTOMIES, CttARITY ttOSPITAL, 1948-1973) DEGREE OF

N O . OF

PALLIATION

SURVIVAL

PATIENTS (%)

Poor Fair Good

Less than 3 months 4-6 months 6-12 months 1 year or more

124 (67.8) 39 (21.3) 16 (9.0) 3 (1.5)

A major problem in treating gastric carcinoma is providing true palliation when cure is not possible. Due to the nature of gastric carcinoma, m a n y patients present with advanced disease not amenable to curative resection. Palliative surgery for gastric carcinoma has been studied by Zwaveling9'~ who found increased survival with resection versus bypass for similarly staged lesions (17 vs. 5 months). Stern et al. g~ had reported an average survival of 19.4 months and 15.5 months after palliative resection for Tumor Node Metastsis (TNM) stage III and IV gastric carcinoma as compared to 7.0 and 5.6 months for nonresected lesions. Lawrence and McNeer 95 relieved obstructive symptoms in more than 50% of patients who had a palliative subtotal resection. In our series, the superiority in survival following resection is again evident (10.7 vs. 2.9 months). In addition, we found t h a t gastroenterostomy done as a prophylactic procedure provided no increase in patient survival. Also, 6 patients operated on, previously without obstruction, developed signs and symptoms of obstruction. As seen in other series, this procedure carries a mortality equal to t h a t associated with exploratory laparotomy and biopsy. In this series, a high operative mortality and poor relief of symptoms were similar to those recorded in other reports. Lawrence and McNeer reported an average survival of 3.9 months following gastroenterostomy. Similar results were documented by ReMine et al. 3' from the Mayo Clinic, where 33% of patients undergoing palliative gastroenterostomy died within 3 months and 65% died within 6 months. Poor relief of obstructive symptoms was recorded for 65% of their patients. In our study, 68% had poor results. From this study it can be concluded t h a t gastroenterostomy done as a therapeutic or prophylactic procedure for gastric carcinoma does little to prolong life or relieve obstruction. Undoubtedly, some patients have had palliation of obstructive symptoms but one must question whether this benefit is not negated by high postoperative mortality and morbidity and failure in the remainder. 41

B a s e d on this e x p e r i e n c e a t C h a r i t y H o s p i t a l a t New O r l e a n s , a p a l l i a t i v e g a s t r o e n t e r o s t o m y for n o n r e s e c t a b l e gastric c a r c i n o m a c a n n o t be r e c o m m e n d e d .

SUMMARY In spite of t h e declining incidence of gastric a d e n o c a r c i n o m a observed d u r i n g the last 30 y e a r s in the U.S., this disease continues to c a r r y a v e r y b l e a k prognosis. E v e n with the best f o r m s of t r e a t m e n t , the overall s u r v i v a l r e m a i n s a p p r o x i m a t e l y 7%. Epidemiologic d a t a w i t h i n the p a s t d e c a d e h a v e given considerable n e w i n s i g h t into t h e carcinogenesis o f gastric c a n c e r in highrisk a r e a s worldwide as it r e l a t e s to in vivo n i t r a t e c o n v e r s i o n to p r e c a r c i n o g e n s or carcinogenic substances. It is hoped t h a t furt h e r epidemiologic i n f o r m a t i o n will help to identify specific prev e n t i v e m e a s u r e s to e l i m i n a t e those e n v i r o n m e n t a l d i e t a r y fac: tors t h a t c o n t r i b u t e to the incidence of g a s t r i c cancer in c e r t a i n e n d e m i c areas. T h e only hope for c u r e a f t e r a diagnosis of gastric c a n c e r is est a b l i s h e d lies w i t h a n e x t i r p a t i v e surgical procedure possibly combined w i t h a n a d j u v a n t c h e m o t h e r a p e u t i c regimen. In t h e p r e s e n c e of incurable disease, t h e best form of p a l l i a t i o n is a c h i e v e d w i t h resection of t h e p r i m a r y t u m o r , s h o r t of total gast r e c t o m y . P a l l i a t i v e bypass p r o c e d u r e s do not increase s u r v i v a l and a n y hope of i m p r o v i n g t h e q u a l i t y of life is h i g h l y questionable. A d j u v a n t forms of t h e r a p y using t h e k n o w n c h e m o t h e r a p e u t i c a g e n t s active a g a i n s t g a s t r i c a d e n o c a r c i n o m a provide the m o s t likely m e a n s of i m p r o v i n g s u r v i v a l associated with gastric cancer. REFERENCES 1. Pack, G. T.: Cancer ofthe stomach, Am. J. Gastroenterol. 44:18, 1965. 2. Goldsmith, It. S., and Ghosh, B. C.: Carcinoma ofthe stomach, Am. J. Surg. 120:317, 1970. 3. Kaneko, E., Nakamura, T., Umeda, N., Fujino, M., and Niwa, H.: Outcome of gastric carcinoma detected by gastric mass survey in Japan, Gut 18:626, 1977. 4. Segi, M., Kurihara, M., and Matsuyama, T.: Cancer Mortality for Selected Sites in 24 Countries-No. 5 (1964-1965), Dept. of Public Health, Tohoku U. Sch. Med., Sendal, Japan, 1969. 5. Bjelke, E.: Epidemiologic studies of cancer of the stomach, colon, and rectum, with special emphasis on the role of diet, Scand. J. Gastroenterol. 9(suppl. 31):1, 1974. 6. Wynder, E. L., Kmet, J., Dungal, N., and Segi, M.: An epidemiological investigation of gastric cancer, Cancer 16:1461, 1963. 7. Boyd, J., Langman, M., and Doll, R.: The epidemiology of gastrointestinal cancer with special reference to causation, Gut 5:196, 1964. 8. Haenszel, W.: Variation in incidence of and mortality from stomach cancer, with particular reference to the United States, J. Natl. Cancer Inst. 21:213, 1958. 42

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