- Email: [email protected]
Open European multicentre gastric cancer trials
Clhtical trials
590
oncologist. Peri-operative care deserves more a t t e n t i o n as well. because in Japan, where gastric cancer surgery is performed by gastric cancer surgeons only, extended lymp h a d e n e c t o m y is associated with morbidity rates as high as in the West, but without the increased mortality. These facts c a n n o t be fully explained by patient- or tumour-related factors, such as age, weight, height/weight index and conc o m i t a n t disease. `'.-'° In order to minimize complications associated with pancreatic tail resection and splenectomy, the Japanese have developed pancreas- and spleen-preserving techniques. The results achieved with these methods justify a more refined surgical approach: pancreatectomy and splenectomy "de necessitC should be applied instead of "de principe'. -'w-' While awaiting the results of the D G C G and the M R C trials, to continue to a p p r o a c h this disease in randomized trials is recommended. in a meta-analysis of randomized trials studying the effect of adjuvant c h e m o t h e r a p y after a curative resection, only a marginal survival advantage was found. However, preoperative c h e m o t h e r a p y seems promising; both the M R C and the D G C G have initiated such trials.
References • 1. Whelan SL, Parkin DM. Masuyer E. Trends ht Cancer hwidence and Mortality. Lyon. France: IARC Scientific publications, 1993. (IARC scientific publications no. 102). 2. Noguchi Y. lmada T, Matsumoto A, Coit DG, Brennan MF. Radical surgery for gastric cancer. A review of the Japanese experience. Cancer 1989: 64: 2053-62. 3. Maruyama K. Okabayashi K, Kinoshita T. Progress in gastric cancer surgery and its limits of radicality. Worm J Sur9 1987: I1: 418-26. 4. Kaibara N, Sumi K, Yonekawa M. Ohta M, Makino M, Kimura O, Nishidoi H. Koga S. Does extensive dissection of lymph nodes improve the results of surgical treatment of gastric cancer. Am J Sur9 1990; 159:218-21. 5. Soga J, Kobayashi K. Saito J, Fujimaki M, Muto T. The role • of lymphadenectomy in curative surgery for gastric cancer. WorM J Sur9 1979: 3: 701-8. 6. Cady B. Lymph node metastases, indicators but not governors of survival. Arch Surg 1984: i 19: 1067-72. 7. Siewert JR. Maruyama K. What's new in gastric cancer? Worhl J Surq 1995; 19: 483. 8. Kajitani T. The general rules for gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg 1981; 11: 127-39.
9. Bonenkamp JJ, van de Velde CJH, Kampscfi6er GHM, et al. Comparison of factors influencing the prognosis of Japanese, German and Dutch gastric cancer patients. IVorMJ Surg 1993; 17: 410-5. 10. Dent DM, Madden MV. Price SK. Randomized comparison of RI and R2 gastrectomy for gastric carcinoma. Br J Surg 1988: 75:110-2. I I. Robertson CS, Chung SCS, Woods SDS. Griffin SM, Raimes SA, Lau JTF, Li AKC. A Prospective randomized trial comparing R I subtotal gastrectomy with R3 total gastrectomy for antral cancer. ,,hm Surq 1994: 220: 176-82. 12. Gouzi JL, Huguier M, Fagniez PL, Launois B, Flamant Y, Lacaine F, Paquet JC, Hay JM. Total versus subtotal gastrectomy for adenocarcinoma of tile gastric antrum, .4ms Sur.q 1989: 209:162-6. 13. Bozzetti F, Gennari L, Bonfanti G and the Italian Gastrointestinal Tumor Study Group. Italian Gastric Cancer Study Group: Italian Gastric Cancer Study--Preliminary results. First International Gastric Cancer Congress (Kyoto, Japan. 29 March to I April 1995): abstr P-3-5. 14. Bonenkamp JJ, Songun I. Hermans J. et al. Randomized comparison of morbidity after DI and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 1995: 345: 745-8. 15. Songun I, Bonenkamp J J, Sasako M. Bunt AMG, Hermans J, van de Velde CJH, on behalf of the Dutch Gastric Cancer Group. Current results of randomized studies about the extent of lymph node dissection. Quality control in ly.nphadenectomy for gastric cancer in a prospective randomized multicenter trial in the Netherlands. Dig Sur9 1994: ll: 86-92. 16. Fayers PM, Cushieri A, Joypaul V. on behalf of the MRC Gastric Cancer Working Party. British Gastric Cancer Study Group: DI versus D2 Surgery for gastric cancer: morbidity and postoperative mortality in the UK MRC R~,ndomized Trial. First International Gastric Cancer Congress (Kyoto, Japan, 29 March to I April 1995): abstr P-3-1. 17. Siewert JR, B6ttcher K, Roder JD, Busch R, Hermanek P, Meyer HJ and tile German Gastric Carcinoma Study Group. Prognostic relevance of systematic lymph node dissection in gastric carcinoma. Br J Sttr q 1993; 80: I 015-8. 18. Hermans J, Bonenkamp JJ, Boon MC, Bunt AMG, Ohyama S, Sasako M, van de Velde CJH. Meta-analysis of adjuvant chemotherapy for gastric cancer. J Clin Oncol 1993; I 1:1 '4417. 19. McCulloch P. Should general surgeons treat gastric carcinoma? An audit of practice and results. 1980-1985. Br J Surg 1994: 81: 417-20. 20. Kampsch6er GHM. Nakajima T. van de Velde CJH. Changing patterns in gastric adenocarcinoma. Br J Sur,q 1989: 76:914-6. 21. Maruyama K. Sasako M. Kinoshita T, Sano T, Katai H, Okajima K. Pancreas-preserving total gastrectomy for proximal gastric cancer. WorldJ Surg 1995: 19: 532-6. 22. Okajima K. Isozaki H. Spelenectomy for treatment of gastric cancer: Japanese experience. WorMJ Surg 1995; 19: 537-540.
Open European multicentre gastric cancer trials Philip T. Nicholl and J. W. L. Fielding D e p a r t m e n t o f Surgical Oncology, Queen Elizabeth Hospital, Queen Elizabeth M e d i c a l Centre, Edgbaston, BirmhTgham, U K
Introduction Gastric cancer remains one of the most c o m m o n malignant diseases in the world. The extensive international experience
of the changing incidence and possible aetiological factors has opened up avenues that can be utilized to c o m b a t this disease. The Japanese experience in screening offers opportunities for the identification of high-risk patients and early
Clinical trials diagnosis. Surgery has remained the mainstay of treatment and offers absolute cure to patients with early lesions and a good chance of cure for patients with locally resectable disease. Our understanding of the aetiology, particularly in relation to diet and the possible significance of H. pylori opens up opportunities of primary prevention programmes. Secondary prevention can possibly be achieved through screening and appropriate surgery for those with localized disease. However, many patients present with advanced disease and it is in tiffs area that there is a significant failure in our treatment. Various drug treatments have been proposed for this condition but there is nothing to date to suggest that chemotherapy or radiotherapy can offer significant improvements in outcome. It is in these areas that trials have become of increasing importance. Many studies have been unable to show significant benefits because of small numbers of patients. The concept of multicentre controlled trials in this disease is central to our future development. It is imperative that Europe. which still has a high incidence of gastric cancer, should combine its efforts and support open trials by providing sufficient numbers of patients to produce statistically justified results. This paper outlines the major trials going on in a number ofdifferent areas and would encourage support from all the specialized units across Europe. When considering gastric" cancer trials it is convenient to look at them in the following way: (I) primary prevention; (2) secondary prevention: (3) trials of treatment. The majority of current European studies are in the trials of treatment group.
( I ) Prhnm3" prerention trials Epidemiological studies have provided clues, but not conclusive evidence, to the causation and, therefore, the prevention of gastric cancer. Apart from environmental factors, i.e. diet (poor nutrition and food high in N-nitroso compounds), ~cigarette smoking, and alcohol consumption, and genetic/familial associations (pernicious anaemia and hypogammaglobulinaemia), the main postulated aetiological factor is infection with the Helicobacter pylori organism. The only open trial in this category.is a European Cancer Prevention Organisation Study looking at the effect of Helicobacter pylori eradication and of ascorbic acid supplementation on the rate of change of pre-cancerous gastric mucosal lesions. The objective is to study the effect of H. pylori eradication and the administration of ascorbic acid supplementation on the change in pattern of intestinal metaplasia. There is an established histological sequence in gastric carcinogenesis of the intestinal type. ~ One stage is chronic atrophic gastritis, progressing in a proportion of cases to intestinal metaplasia. If intestinal metaplasia develops there is an increased risk of the development of severe epithelial dysplasia and eventually carcinoma. There is a growing body of evidence suggesting that progression from high gastric acidity and chroqic atrophic gastritis through intestinal metaplasia and epithelial dysplasia is associated with an increased formulation of N-nitroso compounds in the gastric milieu. Potentially this stage of the histopathological sequence can be negated by either decreasing the nitrate intake or increasing the intake ofantioxidants,
591
such as ascorbic acid. Results from the ECP-EURONUT Intestinal Metaplasia Study show that intestinal metaplasia was associated with a low plasma level of ascorbic acid..The other variable strongly associated with intestinal metaplasia was the carriage of H. pylori on the gastric mucosal biopsies. It has already been shown that ascorbic acid has an inhibiting effect on the formation of nitrite and N-nitroso compounds in the stomach. It has also been reported that H. pylori carriage is associated with decreased intragastric ascorbic acid levels and that eradication of this organism restores the luminal levels of ascorbic acid to normality.-' All this evidence provides strong reasons for establishing the present study. The study tests three hypotheses: (I) H. pylori eradication causes a statistically signifcant change in the pattern of intestinal metaplasia; (2) Ascorbic acid supplements of 2 g per day for 3 years causes a statistically significant change in the pattern of intestinal metaplasia; (3) There is an interaction between H. pylori eradication and ascorbic acid supplementation. The study is a prospective, randomized, double-blind, placebo-controlled study with parallel groups. The study is divided into two sub-groups according to H. pylori status at entry. A total of 1500 patients with biopsy-proven gastric intestinal metaplasia aged 18-70 will be recruited in approximately 30 centres throughout Europe. Patients positive for H. pylori will be given eradication treatment prior to the vitamin supplementation phase. Eradication ofH. pyloriwill be tested by the C I3-urea breath test. Randomization of the H. pylori-positive patients will be to a factorial design with twice as many patients receiving active eradication therapy as placebo. Patients negative for the organism will proceed directly to the supplementation phase. All patients will receive vitamin C supplementation or placebo for a period of 3 years. (2) Secondat 3" prevention trials The concept of secondary prevention is to identify treatable pre-malignant conditions or cancers at a stage when they are curable. There has been no major study of screening in Europe. The data come from the Japanese who have undertaken mass screening since the 1950s. ~ Today over 6 million people are screened annually. The 5-year survival rate is 15 to 30% better in screen-detected cancers than in symptom-diagnosed cancers but this is subject to lead-time bias and length bias. There have been no randomized controlled studies which have reported the efficacy of screening. The Japanese have reported some observational studies which showed a decreased risk of mortality from gastric cancer in the screened subject. The Japanese feel that their programme is effective in reducing cancer mortality. In the United Kingdom the British Stomach Cancer Group has conducted a study of early diagnosis and surveillance of high-risk groups. In this programme dyspeptic patients over the age of 40 were offered early endoscopy and those with chronic atrophic gastritis, intestinal metaplasia or dysplasia were entered into a surveillance screening programme. The early results of this study suggest that the proportion of patients with early lesions and locally resectable lesions have increased. 4 Many European eentres now run open access for patients with dyspepsia and benefits
592
Cl&ical trials
have been reported from this approach. However, there are no randomized open studies within Europe.
(3) Trials of treatment The current trials category can be further divided into three groups: (A) those comparing surgical techniques; (B) those looking at surgery plus adjuvant treatments; (C) those comparing chemotherapeutic regimes in advanced gastric cancer. (A) There are two phase three studies both comparing the effect of extended lymph node dissection vs conventional surgery on recurrence and survival in patients with gastric cancer. The organizing bodies are The University Hospital of Leiden, Netherlands, and The United Kingdom Medical Research Council. These trials were set up to compare the results of the standard European DI resection with the more radical D2 resection practised by members of the Japanese Research Society for Gastric Cancer during the past decade. The rationale for.these trials is that effective loco-regional control of gastric cancer is likely to impart substantial benefit to patients. This is because widespread dissemination of tumour not within the confines of the abdomen is not a common feature of gastric cancer and in the 53% of patients who relapse after resection, the stomach remnant and the adjacent bed is the only site of recurrent disease. -~ The overall 5-year survival of patients with gastric cancer worldwide remains at 10-15°/o. 6 However, the Japanese Research Society for Gastric Cancer has consistently reported markedly improved survival during the past decade. 7-9 This has been attributed to two main factors. Firstly~ they have an agreed system of macroscopic and histological staging of gastric cancer cases allowing the aims of the procedure to be categorized. Secondly, they have standardized and performed more radical gastric resections (D2 & D3). Better results from more radical surgical resections remain an important aim because the results of adjuvant chemotherapy trials to date have not been encouraging. Few studies have shown any real clinical benefit post-operatively.4'*°'*~ The trials require staging of patients with histologically or cytologically proven gastric cancer at laparotomy and entering only those patients with Stage 1 and II gastric cancer who are then randomized to either a DI or D2 resection. Both the Dutch and British studies are now closed. Fortunately their selection criteria was the same and because of close co-operation between the two groups it should be possible to analyse them together. The numbers should be able to demonstrate a statistically important result. (B) A number of current trials are comparing adjuvant therapy plus surgery with surgery alone. In most of these the adjuvant treatment is chemotherapy and in one the adjuvant treatment is radiotherapy. Population-based studies have demonstrated that < 1% of all gastric cancer patients have disease limited to the mucosa or submucosa, although surgical series have documented incidence rates of early gastric cancer of approximately 10%. These rates have increased to approximately 25% in studies of early investigation of symptomatic patients. .2 Because many patients are likely to have residual
disease following radical surgery, improvemerits in survival may be achieved with appropriate adjuvant regimens. The British Stomach Cancer Group has already undertaken two large prospective controlled trials of adjuvant chemotherapy and adjuvant radiotherapy. Neither of these trials demonstrated any advantage to the regimens ofchemotherapy or radiotherapy when compared with surgery alone. ~3'~4 Further evidence for the failure of adjuvant chemotherapy to influence outcome has been reported by the Dutch Stomach Cancer Group in a meta-analysis of all published randomized trialsJ ~ However, several groups have demonstrated reproducible response rates which included significant numbers of complete responses using cisplatinum-based regimens for patients with locally advanced disease and with metastatic disease. ~6There are results suggesting that the ECF regimen can achieve a response rate of over 70%. This includes 13% having complete responses on clinical and radiological grounds. More specifically, in those patients with locally advanced disease response rates have been similar, with a significant number becoming operable (i.e. down grading of tumour stage). ~7 The effect on locally advanced disease suggests an interesting role in the neo-adjuvant setting, using the combination pre-operatively. Although pre-operative assessment may suggest that turnout spread is limited to tissues included within a radical resection intraoperative staging demonstrates that only 50% of cases are suitable, the remainder havirtg more advanced disease. A reduction in primary tumour volume induced by pre-operative chemotherapy may therefore irf6rease resectability rates and the associated systemic may improve overall survival. This is the rationale for the trials involving pre-operative adjuvant chemotherapy. The M A G I C (MRC Adjuant Gastric Infusional Chemotherapy) Trial compares pre-operative epirubicin, cisplatin, and 5FU plus surgery to surgery alone. The primary endpoint is survival time with quality of life as a secondary endpoint. A parallel trial has been started in the Netherlands but using a different chemotherapy regimen. In this POCOM trial four courses of FEMTX (5-FU-doxorubicin-methotrexate) are given pre-operatively. An EORTC Trial compares post-operative 5-FU, doxorubicin, and methotrexate following potentially curative resection to surgery alone. The other open trial in this group compares post-operative high dose methotrexate, 5FU, and epirubicin plus surgery to surgery alone. The objective is to ascertain if six cycles of FEMTX result in a longer disease-free and overall survival than observation alone after potentially curative surgery for carcinoma of the stomach. Two further studies should be mentioned in this context. Firstly, an EORTC Trial comparing intraoperative radiotherapy plus surgery to surgery alone and including patients with stage IB, II, IliA, and IIIB disease. Secondly, the British Stomach Cancer Group Trial I V - - A Trial of Cimetidine Treatment in Gastric Cancer, where the objective is to assess the possible survival benefit of adjuvant cimetidine in all stages of gastric cancer (this trial is now closed). (C) There are a number of phase I and phase 2 studies being undertaken. This is important for development of future strategies. These are usually in patients with advanced
CIh~ical trials
disease. Surgeons should be encouraged to ask their medical oncology colleagues to support these studies.
Conclusion This paper has attempted to identify the major European studies that are being conducted in gastric cancer, it is hoped that they will be supported by most centres in Europe to allow them to come to a fast conclusion. It is only by European co-operation that we will be able to answer important questions about this disease.
References I. Correa P. A human model of gastric carcinogenesis. Cam'er Research 1988: 48: 3554-60. 2. Sobala GM, Crabtree J. Dixon MF. et al. Acute Helicobacter pylori infection: clinical features, local, and systemic immune responses, gastric mucosal histology and gastric juice ascorbic acid concentration. Gttt 1991: 32: 1415-8. 3. Hisimichi S, Tsupono Y, Fukao A. Screening for gastric cancer: a critical appraisal of the Japanese experience. GI Cam'er 1995: l: 87-93. 4. Gunderson L. Radiation therapy: results and future possibilities. Clinics hi Gastroenterology'1976: 5: 743-76. 5. Hallissey MT, Allure WH, Jewkes A. Ellis DJ. Fielding JWL. Early detection of gastric cancer. Br Med J 1990; 301:513-5. 6. Hirayama T, Waterhouse ,IAH, Fraumeni ,IF, Jr (eds). Cancer risk h.v Site. UICC Technical Report Series. Vol 41, Geneva 1980.
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7. Kajitani T, Miwak. Treatment results of stomach carcinoma in Japan 1963-1966. WHO-CC Mom~graph 2, WHO Tokyo 1979. 8. lmanaga H, Nakazoto H. Results of surgery for gastric cancer and the effect of adjuvant Mitomycin C on cancer recurrence. WorMJ Surg 1977; I: 213-27. 9. Miwa K. Cancer of the stomach in Japan. Gain1 Mom)graph on Cancer Research 1979: 22: 61-75. 10. Kovach J. Moertel C, Schutt A. et al. A controlled study of 1,3Bis-(2 chloroethyl)-l-nitrosourea and 5-fluorouracil therapy for advanced gastric cancer and pancreatic cancers. Cancer 1974; 33: 865-7. II. Kingston RD, Ellis DJ. Powell ,i. et al. The West Midlands Gastric Carcinoma Chemotherapy Trial: planning and results. CIh~ Oncol 1978: 4: 55-69. 12. The Gastrointestinal Tumour Study Group. Controlled trial of adjuvant chemotherapy tbllowing curative resection for gastric cancer. Cancer 1982: 49: 1115-22. 13. Allum WH, Hallissey MT, Kelly KA for the British Stomach Cancer Group. Adjuvant chemotherapy in operable gastric cancer (5-year follow-up of the Ist British Stomach Cancer Group Trial). Lam'et 1989: 1571-4. 14. Allure WH, Hallissey MT, Hockey MS, Ward LC. A controlled prospective randomised trial of adjuvant chemotherapy or radiotherapy in resectable gastric cancer: an interim report. Br J Cam'er 1989: 60: 739~1.4. 15. Hermans J, Bonenkamp J,i. Boon MC, Bunt AMG, Ohyama S, Sasako M. Van de Velde C,IH. Adjuvant therapy after curative resection for gastric cancer: metanalysis of randomised trials. J Clin Onco11993; ll: 1441-7. 16. Wilke H, Preusser P, Fink U. et al. New developments in the treatment of gastric carcinoma. Semha Oncol 1990; 17(Suppl. 2): 61-70. 17. Findlay M. Cunningham D, Norman A, et al. A pllase 11 study in advanced gastro-oesophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ares Oncol 1994; 5: 609-16.
Possible items to be studied in future randomized studies for gastric cancer J. R. Siewert, J. D. Roder and U. Fink Department of Surgert', Teclmische Unieersitdt Mfbwhen, Germant'
There is no doubt that prospective randomized controlled therapeutic studies are the safest way to establish the medical truth. At the same time this way is costly and expensive and full of obstacles and dangers. The situation is relatively easy when drugs are studied. The randomized classification of different medications to selected groups of patients is unproblematic--the therapeutic principle is clearly defined, unchangeable because of the pre-defined medication and cannot be influenced by the therapist. The patient's compliance is easily controllable. For this reason prospective randomized controlled studies are the 'gold standard' in evaluating medications. The situation becomes even more difficult when two therapeutic protocols are compared, e.g. chemotherapy protocols for gastric car~cer. The influence of the therapist and the way and correctness of performing the protocol can influence the
results tremendously. The factor 'therapist' has to be added as difficult to control. Nevertheless controlled therapeutic studies are hard to replace if they are sufficiently supervised and documented. Most problems occur with studies that evaluate surgical therapy. As a rule surgical therapeutic principles cannot be defined, more they are decisively formed by the surgeon. Furthermore randomization forces the surgeon to use a certain therapeutic principle--maybe against his inner conviction. Quality control is difficult to perform and the question remains of whether or not the therapeutic principle has been carried out according to the protocol in every single case. The only way is for quality control to be conducted by the pathologist via the specimen. The problem escalates when large numbers are needed in order to establish significant differences. Multicentre studies with numerous surgeons
590
oncologist. Peri-operative care deserves more a t t e n t i o n as well. because in Japan, where gastric cancer surgery is performed by gastric cancer surgeons only, extended lymp h a d e n e c t o m y is associated with morbidity rates as high as in the West, but without the increased mortality. These facts c a n n o t be fully explained by patient- or tumour-related factors, such as age, weight, height/weight index and conc o m i t a n t disease. `'.-'° In order to minimize complications associated with pancreatic tail resection and splenectomy, the Japanese have developed pancreas- and spleen-preserving techniques. The results achieved with these methods justify a more refined surgical approach: pancreatectomy and splenectomy "de necessitC should be applied instead of "de principe'. -'w-' While awaiting the results of the D G C G and the M R C trials, to continue to a p p r o a c h this disease in randomized trials is recommended. in a meta-analysis of randomized trials studying the effect of adjuvant c h e m o t h e r a p y after a curative resection, only a marginal survival advantage was found. However, preoperative c h e m o t h e r a p y seems promising; both the M R C and the D G C G have initiated such trials.
References • 1. Whelan SL, Parkin DM. Masuyer E. Trends ht Cancer hwidence and Mortality. Lyon. France: IARC Scientific publications, 1993. (IARC scientific publications no. 102). 2. Noguchi Y. lmada T, Matsumoto A, Coit DG, Brennan MF. Radical surgery for gastric cancer. A review of the Japanese experience. Cancer 1989: 64: 2053-62. 3. Maruyama K. Okabayashi K, Kinoshita T. Progress in gastric cancer surgery and its limits of radicality. Worm J Sur9 1987: I1: 418-26. 4. Kaibara N, Sumi K, Yonekawa M. Ohta M, Makino M, Kimura O, Nishidoi H. Koga S. Does extensive dissection of lymph nodes improve the results of surgical treatment of gastric cancer. Am J Sur9 1990; 159:218-21. 5. Soga J, Kobayashi K. Saito J, Fujimaki M, Muto T. The role • of lymphadenectomy in curative surgery for gastric cancer. WorM J Sur9 1979: 3: 701-8. 6. Cady B. Lymph node metastases, indicators but not governors of survival. Arch Surg 1984: i 19: 1067-72. 7. Siewert JR. Maruyama K. What's new in gastric cancer? Worhl J Surq 1995; 19: 483. 8. Kajitani T. The general rules for gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg 1981; 11: 127-39.
9. Bonenkamp JJ, van de Velde CJH, Kampscfi6er GHM, et al. Comparison of factors influencing the prognosis of Japanese, German and Dutch gastric cancer patients. IVorMJ Surg 1993; 17: 410-5. 10. Dent DM, Madden MV. Price SK. Randomized comparison of RI and R2 gastrectomy for gastric carcinoma. Br J Surg 1988: 75:110-2. I I. Robertson CS, Chung SCS, Woods SDS. Griffin SM, Raimes SA, Lau JTF, Li AKC. A Prospective randomized trial comparing R I subtotal gastrectomy with R3 total gastrectomy for antral cancer. ,,hm Surq 1994: 220: 176-82. 12. Gouzi JL, Huguier M, Fagniez PL, Launois B, Flamant Y, Lacaine F, Paquet JC, Hay JM. Total versus subtotal gastrectomy for adenocarcinoma of tile gastric antrum, .4ms Sur.q 1989: 209:162-6. 13. Bozzetti F, Gennari L, Bonfanti G and the Italian Gastrointestinal Tumor Study Group. Italian Gastric Cancer Study Group: Italian Gastric Cancer Study--Preliminary results. First International Gastric Cancer Congress (Kyoto, Japan. 29 March to I April 1995): abstr P-3-5. 14. Bonenkamp JJ, Songun I. Hermans J. et al. Randomized comparison of morbidity after DI and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 1995: 345: 745-8. 15. Songun I, Bonenkamp J J, Sasako M. Bunt AMG, Hermans J, van de Velde CJH, on behalf of the Dutch Gastric Cancer Group. Current results of randomized studies about the extent of lymph node dissection. Quality control in ly.nphadenectomy for gastric cancer in a prospective randomized multicenter trial in the Netherlands. Dig Sur9 1994: ll: 86-92. 16. Fayers PM, Cushieri A, Joypaul V. on behalf of the MRC Gastric Cancer Working Party. British Gastric Cancer Study Group: DI versus D2 Surgery for gastric cancer: morbidity and postoperative mortality in the UK MRC R~,ndomized Trial. First International Gastric Cancer Congress (Kyoto, Japan, 29 March to I April 1995): abstr P-3-1. 17. Siewert JR, B6ttcher K, Roder JD, Busch R, Hermanek P, Meyer HJ and tile German Gastric Carcinoma Study Group. Prognostic relevance of systematic lymph node dissection in gastric carcinoma. Br J Sttr q 1993; 80: I 015-8. 18. Hermans J, Bonenkamp JJ, Boon MC, Bunt AMG, Ohyama S, Sasako M, van de Velde CJH. Meta-analysis of adjuvant chemotherapy for gastric cancer. J Clin Oncol 1993; I 1:1 '4417. 19. McCulloch P. Should general surgeons treat gastric carcinoma? An audit of practice and results. 1980-1985. Br J Surg 1994: 81: 417-20. 20. Kampsch6er GHM. Nakajima T. van de Velde CJH. Changing patterns in gastric adenocarcinoma. Br J Sur,q 1989: 76:914-6. 21. Maruyama K. Sasako M. Kinoshita T, Sano T, Katai H, Okajima K. Pancreas-preserving total gastrectomy for proximal gastric cancer. WorldJ Surg 1995: 19: 532-6. 22. Okajima K. Isozaki H. Spelenectomy for treatment of gastric cancer: Japanese experience. WorMJ Surg 1995; 19: 537-540.
Open European multicentre gastric cancer trials Philip T. Nicholl and J. W. L. Fielding D e p a r t m e n t o f Surgical Oncology, Queen Elizabeth Hospital, Queen Elizabeth M e d i c a l Centre, Edgbaston, BirmhTgham, U K
Introduction Gastric cancer remains one of the most c o m m o n malignant diseases in the world. The extensive international experience
of the changing incidence and possible aetiological factors has opened up avenues that can be utilized to c o m b a t this disease. The Japanese experience in screening offers opportunities for the identification of high-risk patients and early
Clinical trials diagnosis. Surgery has remained the mainstay of treatment and offers absolute cure to patients with early lesions and a good chance of cure for patients with locally resectable disease. Our understanding of the aetiology, particularly in relation to diet and the possible significance of H. pylori opens up opportunities of primary prevention programmes. Secondary prevention can possibly be achieved through screening and appropriate surgery for those with localized disease. However, many patients present with advanced disease and it is in tiffs area that there is a significant failure in our treatment. Various drug treatments have been proposed for this condition but there is nothing to date to suggest that chemotherapy or radiotherapy can offer significant improvements in outcome. It is in these areas that trials have become of increasing importance. Many studies have been unable to show significant benefits because of small numbers of patients. The concept of multicentre controlled trials in this disease is central to our future development. It is imperative that Europe. which still has a high incidence of gastric cancer, should combine its efforts and support open trials by providing sufficient numbers of patients to produce statistically justified results. This paper outlines the major trials going on in a number ofdifferent areas and would encourage support from all the specialized units across Europe. When considering gastric" cancer trials it is convenient to look at them in the following way: (I) primary prevention; (2) secondary prevention: (3) trials of treatment. The majority of current European studies are in the trials of treatment group.
( I ) Prhnm3" prerention trials Epidemiological studies have provided clues, but not conclusive evidence, to the causation and, therefore, the prevention of gastric cancer. Apart from environmental factors, i.e. diet (poor nutrition and food high in N-nitroso compounds), ~cigarette smoking, and alcohol consumption, and genetic/familial associations (pernicious anaemia and hypogammaglobulinaemia), the main postulated aetiological factor is infection with the Helicobacter pylori organism. The only open trial in this category.is a European Cancer Prevention Organisation Study looking at the effect of Helicobacter pylori eradication and of ascorbic acid supplementation on the rate of change of pre-cancerous gastric mucosal lesions. The objective is to study the effect of H. pylori eradication and the administration of ascorbic acid supplementation on the change in pattern of intestinal metaplasia. There is an established histological sequence in gastric carcinogenesis of the intestinal type. ~ One stage is chronic atrophic gastritis, progressing in a proportion of cases to intestinal metaplasia. If intestinal metaplasia develops there is an increased risk of the development of severe epithelial dysplasia and eventually carcinoma. There is a growing body of evidence suggesting that progression from high gastric acidity and chroqic atrophic gastritis through intestinal metaplasia and epithelial dysplasia is associated with an increased formulation of N-nitroso compounds in the gastric milieu. Potentially this stage of the histopathological sequence can be negated by either decreasing the nitrate intake or increasing the intake ofantioxidants,
591
such as ascorbic acid. Results from the ECP-EURONUT Intestinal Metaplasia Study show that intestinal metaplasia was associated with a low plasma level of ascorbic acid..The other variable strongly associated with intestinal metaplasia was the carriage of H. pylori on the gastric mucosal biopsies. It has already been shown that ascorbic acid has an inhibiting effect on the formation of nitrite and N-nitroso compounds in the stomach. It has also been reported that H. pylori carriage is associated with decreased intragastric ascorbic acid levels and that eradication of this organism restores the luminal levels of ascorbic acid to normality.-' All this evidence provides strong reasons for establishing the present study. The study tests three hypotheses: (I) H. pylori eradication causes a statistically signifcant change in the pattern of intestinal metaplasia; (2) Ascorbic acid supplements of 2 g per day for 3 years causes a statistically significant change in the pattern of intestinal metaplasia; (3) There is an interaction between H. pylori eradication and ascorbic acid supplementation. The study is a prospective, randomized, double-blind, placebo-controlled study with parallel groups. The study is divided into two sub-groups according to H. pylori status at entry. A total of 1500 patients with biopsy-proven gastric intestinal metaplasia aged 18-70 will be recruited in approximately 30 centres throughout Europe. Patients positive for H. pylori will be given eradication treatment prior to the vitamin supplementation phase. Eradication ofH. pyloriwill be tested by the C I3-urea breath test. Randomization of the H. pylori-positive patients will be to a factorial design with twice as many patients receiving active eradication therapy as placebo. Patients negative for the organism will proceed directly to the supplementation phase. All patients will receive vitamin C supplementation or placebo for a period of 3 years. (2) Secondat 3" prevention trials The concept of secondary prevention is to identify treatable pre-malignant conditions or cancers at a stage when they are curable. There has been no major study of screening in Europe. The data come from the Japanese who have undertaken mass screening since the 1950s. ~ Today over 6 million people are screened annually. The 5-year survival rate is 15 to 30% better in screen-detected cancers than in symptom-diagnosed cancers but this is subject to lead-time bias and length bias. There have been no randomized controlled studies which have reported the efficacy of screening. The Japanese have reported some observational studies which showed a decreased risk of mortality from gastric cancer in the screened subject. The Japanese feel that their programme is effective in reducing cancer mortality. In the United Kingdom the British Stomach Cancer Group has conducted a study of early diagnosis and surveillance of high-risk groups. In this programme dyspeptic patients over the age of 40 were offered early endoscopy and those with chronic atrophic gastritis, intestinal metaplasia or dysplasia were entered into a surveillance screening programme. The early results of this study suggest that the proportion of patients with early lesions and locally resectable lesions have increased. 4 Many European eentres now run open access for patients with dyspepsia and benefits
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Cl&ical trials
have been reported from this approach. However, there are no randomized open studies within Europe.
(3) Trials of treatment The current trials category can be further divided into three groups: (A) those comparing surgical techniques; (B) those looking at surgery plus adjuvant treatments; (C) those comparing chemotherapeutic regimes in advanced gastric cancer. (A) There are two phase three studies both comparing the effect of extended lymph node dissection vs conventional surgery on recurrence and survival in patients with gastric cancer. The organizing bodies are The University Hospital of Leiden, Netherlands, and The United Kingdom Medical Research Council. These trials were set up to compare the results of the standard European DI resection with the more radical D2 resection practised by members of the Japanese Research Society for Gastric Cancer during the past decade. The rationale for.these trials is that effective loco-regional control of gastric cancer is likely to impart substantial benefit to patients. This is because widespread dissemination of tumour not within the confines of the abdomen is not a common feature of gastric cancer and in the 53% of patients who relapse after resection, the stomach remnant and the adjacent bed is the only site of recurrent disease. -~ The overall 5-year survival of patients with gastric cancer worldwide remains at 10-15°/o. 6 However, the Japanese Research Society for Gastric Cancer has consistently reported markedly improved survival during the past decade. 7-9 This has been attributed to two main factors. Firstly~ they have an agreed system of macroscopic and histological staging of gastric cancer cases allowing the aims of the procedure to be categorized. Secondly, they have standardized and performed more radical gastric resections (D2 & D3). Better results from more radical surgical resections remain an important aim because the results of adjuvant chemotherapy trials to date have not been encouraging. Few studies have shown any real clinical benefit post-operatively.4'*°'*~ The trials require staging of patients with histologically or cytologically proven gastric cancer at laparotomy and entering only those patients with Stage 1 and II gastric cancer who are then randomized to either a DI or D2 resection. Both the Dutch and British studies are now closed. Fortunately their selection criteria was the same and because of close co-operation between the two groups it should be possible to analyse them together. The numbers should be able to demonstrate a statistically important result. (B) A number of current trials are comparing adjuvant therapy plus surgery with surgery alone. In most of these the adjuvant treatment is chemotherapy and in one the adjuvant treatment is radiotherapy. Population-based studies have demonstrated that < 1% of all gastric cancer patients have disease limited to the mucosa or submucosa, although surgical series have documented incidence rates of early gastric cancer of approximately 10%. These rates have increased to approximately 25% in studies of early investigation of symptomatic patients. .2 Because many patients are likely to have residual
disease following radical surgery, improvemerits in survival may be achieved with appropriate adjuvant regimens. The British Stomach Cancer Group has already undertaken two large prospective controlled trials of adjuvant chemotherapy and adjuvant radiotherapy. Neither of these trials demonstrated any advantage to the regimens ofchemotherapy or radiotherapy when compared with surgery alone. ~3'~4 Further evidence for the failure of adjuvant chemotherapy to influence outcome has been reported by the Dutch Stomach Cancer Group in a meta-analysis of all published randomized trialsJ ~ However, several groups have demonstrated reproducible response rates which included significant numbers of complete responses using cisplatinum-based regimens for patients with locally advanced disease and with metastatic disease. ~6There are results suggesting that the ECF regimen can achieve a response rate of over 70%. This includes 13% having complete responses on clinical and radiological grounds. More specifically, in those patients with locally advanced disease response rates have been similar, with a significant number becoming operable (i.e. down grading of tumour stage). ~7 The effect on locally advanced disease suggests an interesting role in the neo-adjuvant setting, using the combination pre-operatively. Although pre-operative assessment may suggest that turnout spread is limited to tissues included within a radical resection intraoperative staging demonstrates that only 50% of cases are suitable, the remainder havirtg more advanced disease. A reduction in primary tumour volume induced by pre-operative chemotherapy may therefore irf6rease resectability rates and the associated systemic may improve overall survival. This is the rationale for the trials involving pre-operative adjuvant chemotherapy. The M A G I C (MRC Adjuant Gastric Infusional Chemotherapy) Trial compares pre-operative epirubicin, cisplatin, and 5FU plus surgery to surgery alone. The primary endpoint is survival time with quality of life as a secondary endpoint. A parallel trial has been started in the Netherlands but using a different chemotherapy regimen. In this POCOM trial four courses of FEMTX (5-FU-doxorubicin-methotrexate) are given pre-operatively. An EORTC Trial compares post-operative 5-FU, doxorubicin, and methotrexate following potentially curative resection to surgery alone. The other open trial in this group compares post-operative high dose methotrexate, 5FU, and epirubicin plus surgery to surgery alone. The objective is to ascertain if six cycles of FEMTX result in a longer disease-free and overall survival than observation alone after potentially curative surgery for carcinoma of the stomach. Two further studies should be mentioned in this context. Firstly, an EORTC Trial comparing intraoperative radiotherapy plus surgery to surgery alone and including patients with stage IB, II, IliA, and IIIB disease. Secondly, the British Stomach Cancer Group Trial I V - - A Trial of Cimetidine Treatment in Gastric Cancer, where the objective is to assess the possible survival benefit of adjuvant cimetidine in all stages of gastric cancer (this trial is now closed). (C) There are a number of phase I and phase 2 studies being undertaken. This is important for development of future strategies. These are usually in patients with advanced
CIh~ical trials
disease. Surgeons should be encouraged to ask their medical oncology colleagues to support these studies.
Conclusion This paper has attempted to identify the major European studies that are being conducted in gastric cancer, it is hoped that they will be supported by most centres in Europe to allow them to come to a fast conclusion. It is only by European co-operation that we will be able to answer important questions about this disease.
References I. Correa P. A human model of gastric carcinogenesis. Cam'er Research 1988: 48: 3554-60. 2. Sobala GM, Crabtree J. Dixon MF. et al. Acute Helicobacter pylori infection: clinical features, local, and systemic immune responses, gastric mucosal histology and gastric juice ascorbic acid concentration. Gttt 1991: 32: 1415-8. 3. Hisimichi S, Tsupono Y, Fukao A. Screening for gastric cancer: a critical appraisal of the Japanese experience. GI Cam'er 1995: l: 87-93. 4. Gunderson L. Radiation therapy: results and future possibilities. Clinics hi Gastroenterology'1976: 5: 743-76. 5. Hallissey MT, Allure WH, Jewkes A. Ellis DJ. Fielding JWL. Early detection of gastric cancer. Br Med J 1990; 301:513-5. 6. Hirayama T, Waterhouse ,IAH, Fraumeni ,IF, Jr (eds). Cancer risk h.v Site. UICC Technical Report Series. Vol 41, Geneva 1980.
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7. Kajitani T, Miwak. Treatment results of stomach carcinoma in Japan 1963-1966. WHO-CC Mom~graph 2, WHO Tokyo 1979. 8. lmanaga H, Nakazoto H. Results of surgery for gastric cancer and the effect of adjuvant Mitomycin C on cancer recurrence. WorMJ Surg 1977; I: 213-27. 9. Miwa K. Cancer of the stomach in Japan. Gain1 Mom)graph on Cancer Research 1979: 22: 61-75. 10. Kovach J. Moertel C, Schutt A. et al. A controlled study of 1,3Bis-(2 chloroethyl)-l-nitrosourea and 5-fluorouracil therapy for advanced gastric cancer and pancreatic cancers. Cancer 1974; 33: 865-7. II. Kingston RD, Ellis DJ. Powell ,i. et al. The West Midlands Gastric Carcinoma Chemotherapy Trial: planning and results. CIh~ Oncol 1978: 4: 55-69. 12. The Gastrointestinal Tumour Study Group. Controlled trial of adjuvant chemotherapy tbllowing curative resection for gastric cancer. Cancer 1982: 49: 1115-22. 13. Allum WH, Hallissey MT, Kelly KA for the British Stomach Cancer Group. Adjuvant chemotherapy in operable gastric cancer (5-year follow-up of the Ist British Stomach Cancer Group Trial). Lam'et 1989: 1571-4. 14. Allure WH, Hallissey MT, Hockey MS, Ward LC. A controlled prospective randomised trial of adjuvant chemotherapy or radiotherapy in resectable gastric cancer: an interim report. Br J Cam'er 1989: 60: 739~1.4. 15. Hermans J, Bonenkamp J,i. Boon MC, Bunt AMG, Ohyama S, Sasako M. Van de Velde C,IH. Adjuvant therapy after curative resection for gastric cancer: metanalysis of randomised trials. J Clin Onco11993; ll: 1441-7. 16. Wilke H, Preusser P, Fink U. et al. New developments in the treatment of gastric carcinoma. Semha Oncol 1990; 17(Suppl. 2): 61-70. 17. Findlay M. Cunningham D, Norman A, et al. A pllase 11 study in advanced gastro-oesophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ares Oncol 1994; 5: 609-16.
Possible items to be studied in future randomized studies for gastric cancer J. R. Siewert, J. D. Roder and U. Fink Department of Surgert', Teclmische Unieersitdt Mfbwhen, Germant'
There is no doubt that prospective randomized controlled therapeutic studies are the safest way to establish the medical truth. At the same time this way is costly and expensive and full of obstacles and dangers. The situation is relatively easy when drugs are studied. The randomized classification of different medications to selected groups of patients is unproblematic--the therapeutic principle is clearly defined, unchangeable because of the pre-defined medication and cannot be influenced by the therapist. The patient's compliance is easily controllable. For this reason prospective randomized controlled studies are the 'gold standard' in evaluating medications. The situation becomes even more difficult when two therapeutic protocols are compared, e.g. chemotherapy protocols for gastric car~cer. The influence of the therapist and the way and correctness of performing the protocol can influence the
results tremendously. The factor 'therapist' has to be added as difficult to control. Nevertheless controlled therapeutic studies are hard to replace if they are sufficiently supervised and documented. Most problems occur with studies that evaluate surgical therapy. As a rule surgical therapeutic principles cannot be defined, more they are decisively formed by the surgeon. Furthermore randomization forces the surgeon to use a certain therapeutic principle--maybe against his inner conviction. Quality control is difficult to perform and the question remains of whether or not the therapeutic principle has been carried out according to the protocol in every single case. The only way is for quality control to be conducted by the pathologist via the specimen. The problem escalates when large numbers are needed in order to establish significant differences. Multicentre studies with numerous surgeons