Gastric Cancer: Preoperative chemotherapy of locally advanced gastric cancer

Annals of Oncology 5 (Suppl. 3): S59-S68, 1994. O 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Symposium article Preoperative chemotherapy of locally advanced gastric cancer Ph. Rougier, Ph. Lasser, M. Ducreux, M. Mahjoubi, C. Bognel & D. Elias Institut Gustave-Roussy,

Villejuif Cedex, France

able: a major response (R) observed in 24% and 31%, the resectability rates were 72% and 77% and the median survivGastric adenocarcinomas, even in the absence of distant al 15 and 16 months, respectively. Our experience is based on 30 patients treated with a metastases, have a poor prognosis which is particularly dismal when tumors are located in the cardia, in the event of combination of continuous i.v. 5-FU and CDDP. Fifteen had a tumor of the cardia, 15/30 had enlarged lymph nodes and locoregional lymph node involvement and/or bulky tumors. Postoperative adjuvant chemotherapy has never clearly 7/30 a linitis plastica (diffuse type). After a mean number of demonstrated its efficacy on survival. Besides ongoing trials 3 cycles, 27/30 patients were evaluable for response. One using new and more active regimens, preoperative chemo- patient achieved a CR and 14 a PR (OR rate 56%, 95% CI: therapy has been used for unresectable cancer due to loco- 38% to 74%) but only one of those with linitis plastica reregional extension and when locally advanced cancer is po- sponded. Twenty-eight patients underwent surgery and 23 tentially resectable but with poor prognosis such as bulki- had a macroscopically complete resection (82%). Resectness, when tumors are located in the cardia and when there is ability rate was higher after OR (13/15) than in nonrespondtumor in the coeliac area at CAT-scan with suspected meta- ing patients (4/12). Toxicity was acceptable, however grade 4 leucopenia in 5 patients and one toxicity-related death were static lymph nodes. In case of unresectable tumor at initial surgery five publi- observed. There was no increase in postoperative complicacations have reported the ability of chemotherapy to reduce tions. Nine patients received postoperative chemotherapy the tumor volume and to allow subsequent resection of the and 3 patients with positive margins received postoperative gastric tumor in 40% to 60% of the cases. In these cases there external radiotherapy. Eighteen patients were free of disease is a clear survival advantage as the median survival reported after completion of the protocol. The median survival was 16 in 2 of these studies was 12 and 18 months compared to the months and 3 year-survival 38%. Two factors influenced the 4 to 6 months median survival reported in historical studies survival: performance status (p — 0.0001) and histology as patients with linitis plastica had a shorter survival (p < in case of unresectable cancer [17,18]. In case of locally advanced gastric tumors some Japanese 0.002). These experiences demonstrated that preoperative case reports have demonstrated the ability of preoperative chemotherapy to concentrate in the tumor tissue and to chemotherapy is feasible in patients with locally advanced downstage the tumors. Four North American and European gastric carcinoma and prompts the initiation of randomized studies have demonstrated that preoperative chemotherapy trials in this category of patients. is feasible, and will probably increase the resection rate. J. Ajani has reported 2 studies in which tolerance was accept- Key words: gastric cancer, preoperative chemotherapy Summary

Although surgery is the main treatment for gastric cancer less than 20% of patients will be cured by surgery alone [1-3] and less than 50% of the resected patients will have a RO resection and be cured [2, 4-7]. This poor prognosis has not been greatly ameliorated by the administration of adjuvant post-operative chemotherapy [5,8], or by the administration of combined radiation and chemotherapy (GITSG 2). Resectability is one of the main prognostic factors in patients with locally advanced gastric carcinomas and the survival is longer when tumors are resected [6, 9-11]. Unfortunately in more than two-thirds of the cases local extension prevents curative resection [3]. In these cases chemotherapy can be given to facilitate sub-

sequent resection if tumor regression is achieved. This has been done in some trials and we will analyse their main results. When patients undergo resection for gastric carcinoma the failure rate is particularly high when tumors are located in the cardia [12], when there is locoregional lymph node involvement [3], when tumors are larger than 7 cm {13}, and for infiltrative types such as linitis plastica [1, 9, 14]. These cases correspond to clinical stage IHB and IV for which the long term survival rate is less than 10% [3, 7]. Based on these data and the results of chemotherapy in gastric cancer [15], it seemed reasonable to investigate the feasibility and efficacy of preoperative chemotherapy in locally advanced gastric cancers with a view to decrease the tumor mass, to improve the resectability rate and, to evaluate the toxicity

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Introduction

60 of such an approach and its impact on time to disease progression and on overall survival. This has been done in many recently reported trials and will be analysed there. Chemotherapy in unresectable gastric cancers

Table 1. Preoperative chemotherapy in unresectable gastric cancer at prior laparotomy. NB

Chemotherapy

NB cycles

Response

Surgery

Tolerance

Outcome

Bonats 1985 [16]

5

FAM

2

OR: 4 CR: 1

- reoperation: 4 - RO: 3 (?)

hospitalisation: mucositis + thrombopenia: 1/5

- 1 NED at 2 yrs - 2 death at 1 and 2 yrs

Plukker 1991 [17]

20 (st IIIB or IV) upper third

Fu: 1.5 gr/m2 MTX: 1.5 gr/m2 / 3 weeks

4

8/17 at laparotomy (47%)

- reoperation : 14 - complete (RO) resections :40%

- 1 death by gastric bleeding before surgery

- 2 pts alive at 41 and 54 mths - M S : 12mth

Wilke 1989

34 71%cardia

Etoposide: Adriblastine: Cisplatin: / 3 - 4 weeks

2 to 5 and 2 postop if OR

OR: 23/33 (70%) CR; 7/33 (21%)

- reoperation :20 (59%) - R 0 : 16 (47%)

- 1 death by perforation -WBCgr IV: 18%

-5pCR - M S : 18mth - Relapse R; 60% at 20 mth

Wilke 1990

10

Etoposide: 5-FU: Folonic ac: / 3 weeks

2 to 5

OR: 7/10 (70%)

- not reported

- Fair

- not reported

Kato 1990 [201

8

Etoposide: MMC: Cisplatin: Ftorafur: 400 mg/m2

1 to 5 and postop if active

7/8 (88%)

- operation: 5 -RO:2 - R1-R2: 3

- non reported

- non reported

Chung 1990 [21]

1

Etoposide: Adriblastine: Cisplatine: 5-FU:

3

cCR: 1

- RO resection done

- mild (vomiting)

-pathological major response

Study [ref.[

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In case of unresectable tumor at initial surgery, five publications have reported the ability of chemotherapy to reduce the tumor volume and to allow a subsequent resection of the gastric tumor in about 40% of the cases (Table 1). Plukker [17] was one of the first authors to report the positive effect of preoperative chemotherapy in patients with surgically proven unresectable gastric cancer. He used a combination of 5-FU and methotrexate which rendered the tumor resectable in 8 out of 17 patients after chemotherapy. However the largest trial with such a design was reported by Wilke et al. [18] who treated 33 patients with surgically proven unresectable tumors by aggressive chemotherapy combining etoposide, adriamycin and cisplatin (EAP). Their results were impressive, with 21% cCR and 70% OR. Nineteen of the 23 patients who achieved an OR

underwent second look laparotomy for removal of their primary tumor. Fifteen of these 19 patients were able to have a complete resection (5 of whom patients had a pathological CR). The resectability rate for surgery with a curative intent, in this very poor group of patients with initially inoperable gastric tumor, was 45%. Thus, this trial provided very strong evidence on the ability of preoperative chemotherapy to improve the resectability of initially unresectable tumors. These results have been partially confirmed by Lerner et al. [22] who applied the same protocol in 28 patients with advanced gastric carcinoma. He reported 43% OR (12/28) with 3 cCR and a small benefit in terms of resectability, as 4 out of 11 patients with unresectable tumor were disease free after chemotherapy and surgery. However the EAP regimen cannot be recommended as neoadjuvant chemotherapy because its superiority over other protocols has not been demonstrated and due to its high hematological toxicity [22]. Moreover a randomized trial comparing FAMTX to EAP reported by Kelsen et al. [23] has demonstrated that FAMTX was slightly more active than EAP and much less toxic. More recently Wilke et al. [19] have reported a high response rate (70%) with a better tolerated combina-

61

Preoperative chemotherapy in locally advanced gastric cancers When patients have gastric tumors with poor prognostic features such as location at the cardia or the upper third of the stomach, or as enlarged lymph nodes on CAT-scan, chemotherapy can be advocated to decrease the tumor mass, to increase the resectability rate, to test preoperatively the tumor sensitivity at chemotherapy and finally to increase the disease-free and the overall survival. However one has to demonstrate that such a strategy is not too toxic and does not increase the surgical complications. Eight studies, including ours, have tested the efficacy of preoperative systemic chemotherapy and have been summarized in Tables 2 and 3; three studies have tested the efficacy and feasibility of intra-arterial chemotherapy (Table 4). Systemic chemotherapy Three Japanese publications have been reported. Two studies have reported isolated cases of short-term preoperative chemotherapy with fluoridinated pyrimidine which resulted, in one case, in a pathological CR [31] and in the other case in downstaging, allowing a curative resection [30]. The third study [32] reported 13 patients treated with FAM regimen who achieved a

high RR (69.2%) and pathological down staging was obtained in 54% of the cases; the survival was longer in case of down staging (34 mos vs. 10.5 mos). North American and European studies have been conducted more systematically, particularly at the MD Anderson where J. Ajani conducted two phase II trials. In the first trial [24], 25 patient received the EFP regimen (see Table 2) for 2 cycles. WHO criteria for tumor response was not applicable and only patients with substantial tumor shrinkage were considered as responders. Major responses were only observed in 24%, but 80% were subjectively improved and only one patient has progressive disease during chemotherapy. The resectability rate was high and the post-operative mortality rate was 4%. Compliance was good as 72% of patients completed all planned therapy. The second trial [26], which included 48 patients, was reported at the 1992 ASCO meeting. The EAP regimen was used and resolved in 31% major or complete responses but with a high toxicity. Resectability rate was 77%, median follow-up was 16 months and 2-year survival rate 37%. In these 2 trials the chemotherapy was restarted after surgery in responders. L. Leichman has tested a more sophisticated regimen combining 2 cycles of preoperative intravenous chemotherapy and 2 cycles of intraperitoneal postoperative chemotherapy [27,28]. The systemic regimen combined continuous low dose i.v. perfusion 5-FU for 21 days with a monthly administration of CDDP and a weekly administration of folinic acid. The OR was 56% with 25% CR and histological evidence of tumor necrosis in 12/16 patients [27, 28]. At the Gustave Roussy Institute, we have tested the combination of 5-Fluorouracil (FU) and cisplatdn (P) in patients with LAGC. This regimen has demonstrated its efficacy and is well tolerated in patients with metastatic gastric carcinoma [36, 37]. Thirty patients were entered, four had proven adenocarcinoma of the stomach that was unresectable according to prior laparotomy, and 26 had LAGC characterized by enlarged (>2 cm) abdominal lymph nodes in the coeliac area at CT scan, by tumor size exceeding 7 cm [13] or by tumor localization in the cardia [12]. All patients had measurable disease on CAT scan and at upper GI tract endoscopy. Tumor size, thickness and the percentage of the circumference involved were carefully checked at endoscopy. Pretreatment evaluation included a complete physical examination, an oesogastric endoscopy and an abdominal CT scan. A thoracic CT scan was also performed for tumors of the cardia. The chemotherapy regimen was: 5-FU: 1 g/sqm/day (d) continuous i.v. infusion for 5 days every 4 weeks and CDDP: 100 mg/sqm/d on day 2. Toxicity and response were assessed using WHO criteria. The duration of treatment was dependent on response and toxicity. One additional cycle was planed prior to surgery for patients who achieved disease stabilization or an objective response (OR) after 2 cycles. Patients who had signs of progression were referred to the surgeon after the first

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tion (etoposide + 5-FU + folinic acid) but gave no information resectability rate and survival with this regimen. Japanese and Corean studies have reported some cases of unresectable tumor which have been treated with various chemotherapy regimens and have been subsequently resected. In one of these studies [21] a clinical CR has been reported which corresponded to a major pathological PR and allowed a curative resection. The largest series from Asia has been reported by Kato [20] who treated 8 patients with a combination containing CDDP; he observed 88% OR and 5 patients subsequently underwent surgery (2 curative, and 3 palliative). These studies have demonstrated that chemotherapy may allow the resection of initially unresectable tumors. They also gave clear evidence that survival is increased as the median survival reported in 2 of these studies [17, 18] was 12 and 18 months which is superior to the 4 to 6 months median survival reported in historical studies in case of unresectable cancer. But these median survival rates are not better than the 12 months median survival reported by GITSG for patients with unresected tumors treated by postoperative chemotherapy alone [9]. However, in this study the long-term survival rate was very poor (approximately 5% at 3 year) and the benefit of secondary resections after neoadjuvant chemotherapy has to be judged with a longer follow-up.

62 Table 2. Preoperative chemotherapy in potentially resectable gastric cancer. NB

Chemotherapy (mg/m2)

Ajani 1991 [24, 25]

25

Etoposide: 90 (dl; 3; 5) 5-Fu ci: 900 + CDDP: 20 day 1-5 every 4w

Ajani 1992 [26]

48

Leichman 19901991 [27, 28]

16

Kang 1992 (randomized study) [29]

(1>24 chemot. vs (2>27 control

Etoposide: 100 dl;3;5 5-Fu ci: 800 dl-5 CDDP: 20 d l - 5 every 3 w

Rougier 1992 [this study]

30

5-Fu ci: 1000 dl-5 CDDP: 100 dl every 4 w

upper third: 71%

upper third: 50%

NB cycles

2

Etoposide: 120 d4-6 Adriblastine: 20 dl;7 CDDP: 40 d2; 8 every 4 w 5-Fu ci: 200 dl-21 CDDP: 100 dl folinic ac: 1/w every 4 w

2

2-3

Response

Surgery

Tolerance

Outcome

- 16 major R 24% (2cCR) - 16 minor R -20 subjective - pCR: 0

- curative: 18/25 (72%)

- 47% gr4 neutropeni a or gr3 non hem. tox. - 1 post-op death

- complete program: 72% -MS: 15 m - 2 year S: 50%

- 6 CR (13%) - 9 major R - RR: 31% -pCR:0

- operated: 41/48 - curative: 37 (77%)

- 1 post-op death

- MS: 16 m - 2 year S: 37% - MS resected: 25 m -MS unresect: 5 m

-4cCR - 9 OR (56%) -pCR:0

- no information

- fair

- median followup: l l m ; 1/16 death - post-operative intraperitoneal ct: 8/16

- RRnot reported -pCR3

- curative: (1): 75% vs

- fair no postop complication

- preliminary report - downstaging: (l)vs(2): TOT1: 20% vs 0% T4: 16% vs 44% (p - 0.03)

{!)-. 56% (p - 0.14)

2-3

- evaluable: 27 - 1 cCR - 1 4 PR - RR: 56% -pCR: 0

- operated: 28/30 - curative: 23 (77%)

-grlV neutropeni a 4/30 - 1 toxic death

- MS: 16 m - 2 year S: 42% - 3 year S: 38% - 5 NED at 4 years — downstaging

Hiromoto 1990 [30]

1

5'DFUR: 100 'short term'

1

- 1 minor R

- curative

- fair

Uesugi 1989 [31]

1

Futraful: 600 dl-21

1

- 1 major R -pCR: 1

- curative

- fair

Sugiyama 1992 [32]

13 locally ad vane.

FAM + angiotensine

- RR: 69.2%

- resected: 13/13

or the second cycle of chemotherapy. After surgery additional chemotherapy was given for responders when lymph node or serosal involvement existed. In case of incomplete excision external radiation therapy was indicated. Among patient characteristics it is of interest to note that 15 had a tumor in the cardia, 15 enlarged lymph node at CAT-scan, 15 of the 30 patients had poorlydifferentiated adenocarcinoma with more than 50% of independent cells (signet-ring cells) [38] and 7 had linitis plastica [39]. Response to chemotherapy was evaluable in 27 pa-

- MS: 28 mths - pathological downstaging: 54%

tients: 1 complete response (CR) at upper endoscopy (negative biopsy) and CAT-scan and 14 partial responses (PR) were observed. The overall response rate was 56% (95% confidence interval: 38% to 74%). Four patients ad a minor response (MR), 8 patients were stabilized (SD), and there was no case of tumor progression or deterioration in PS. Patients who had a tumor in the cardia and patients with no or less than 50% of independent cells had a better response to chemotherapy than the others. In contrast only one response was observed among the 6 evaluable patients with linitis plastica.

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Study [ref.]

63 Table 3. Treatment results according to response to chemotherapy in Gustave Roussy experience of preoperative chemotherapy in locally advanced gastric cancers (30 patients; 28 operated). Type of response

Oper- Unreated sectab. patients tumors

Type of resection macroscopically uncom- complete plete

OR (n-15) NR (n - 12) NE (n-3) Total (n - 30)

— micr. complete

months survival

15

0

0

15

13

93%

12

4

1

7

4

42%

1

0

0

1

1

33%

28

4

1

23

18

no OR (33.3%; CI 17%-50%) (chi square = 8.34, p < 0.01). Of the 4 patients whose tumor was not resectable at a prior laparotomy, 2 achieved an objective response to chemotherapy followed by a curative resection of tumor. The other 2 patients who had linitis plastica with local peritoneal extension, were unresponsive to chemotherapy and their tumor was not resectable at second laparotomy. No CR were confirmed by pathological analysis. In the patient who had a clinical CR, no macroscopic evidence of tumor was found at operation. However, small foci of active tumor located into the mucosa with major areas of necrosis and fibrosis were present.

Table 4. Preoperative intra arterial chemotherapy in potentially resectable gastric cancer. Study [ref.]

NB

Chemotherapy (mg/m2)

Fujimoto 1976 [33]

62

MTX: 2/kg (n - 9) VLB: 0.21/kg (n-11) MMC + MTX MMC + 5Fu + VLB

Stephens 1986 [34]

39 33 eval.: 16 palliat.

BCNU: 150 dl 5Fu: 500 dl ADRIA: 15 d2 MMC: 4 d3, 4, 5

17 curable Mai 1990 [35]

24 Bonn an gr4

FAM + OK 432 or MTX-5-Fu of Futraful-MMC

NB cycles

Response

Surgery

Tolerance

Outcome

- 49/62 had curative resection

- not reported

3 to 5

- not evaluated - histological modification after CT

- increase survival compared to 99 control (3 yr S: 54.2% vs 37.1% - 5 yr S: NS)

1 cycle every 6 d for 1 mth cont. inf.

-palliat g: 45% 'detectable R' - curable g:79% 'detectable R'

33/39 resected

- not reported

- palliat g: 2 alive at 36 and 81 mths - curable g: 14 alive at mean t: 47 mths

- 1 CR - 3 PR-4 MR -pCR; 1

- curative: 17/24

- not reported

- better survival in case of response

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Tolerance. Hematologic toxicity was present in grade 3 neutropenia in 13/87 cycles (8 patients) and grade 4 in Abbreviations: OR; objective response, NR: non responders, NE: 8 cycles (5 patients). There were 5 episodes of febrile non evaluable, mien microscopically. aplasia with one case of documented sepsis and death. Other toxiciti.es were mild and manageable. PostSurgery was performed in 28/30 patients (Table 3). operative complications were not increased. One paTwo patients were not operated (1 early toxicity-related tient died one month after a total gastrectomy due to death and 1 lost to follow-up). Among the 28 patients intravascular disseminated coagulation (IDC) with who were operated, 23/28 (82%) had a macroscopical- anastomotic leakage. Two patients experienced severe ly complete resection. One patient had a cephalic duo- post-operative pneumonia and 2 patients developed a denopancreatectomy associated with a colectomy but subphrenic abcess. the resection was not complete due to peritoneal carSurvival has been achieved with a median follow-up cinomatosis; 3 patients only had an explorative laparo- of 48 months (range: 1 to 63 months). Thirteen (72%) tomy because of peritoneal carcinomatosis. Thus 77% of the 18 disease-free patients after the initial treatment of the 30 patients entered in the study had a complete have relapsed. surgical resection, 60% had NED after surgery (RO reThe patient who achieved the clinical CR did not resection). 17% had microscopically positive margins (Rl ceive any post-operative treatment and is still alive and resection), 3% had an incomplete resection (R2 resec- disease free at 63 months. Three of the 12 patients with tion), 13% of tumors were totally unresectable and 7% a PR are still alive and disease free 49, 50 and 54 were not operated. Interestingly, the curative resection months after the beginning of preoperative chemorate was higher for patients who had an OR to chemo- therapy. The 2 PR with positive margins (palliative surtherapy (86%; CI 60%-100%) than for patients with gery) received both radiation therapy and chemothera-

64

Intra-Arterial Chemotherapy This approach has seldom been used due to its technical complexity, and only two Japanese studies have been reported (Table 4). Fujimotot [33] reported more than 15 years ago that intra-arterial chemotherapy (IAC), delivered directly into the aorta at the level of the celiac trunk using various types of chemotherapy, allowed a curative resection in 49/62 (79%) patients with LAGC, and increased the 3 year survival when compared to historical controls. However, there was no significant increase at 5 years and it is well known that historical controls do not allow valid comparisons but only provide indications for the conduct of prospective randomized trials. Unfortunately this has not been done and the only other Japanese study reported was done by Mai [35] who treated 24 patients with IAC using the FAM protocol or other schedules and observed 4 OR. The rate of curative resection with R2 or R3 type lymph node dissection was 71%, and a better survival was observed in the event of tumor response. This was not a controlled study and these conclusions are only indicative of the feasibility of such an approach. One study has been reported by Stephens [34] from Australia (Table 4). In his experience on 39 patients, 33 patients were evaluable as they underwent successful resection after IAC. Sixteen patients were considered to have LAGC and probably non accessible to a curable resection (palliative group), and 17 patients, with, potentially resectable tumors (curative group). In the palliative group all patients underwent resection but only 2 patients were alive at 3 and 7 years. In the curative group all the patients underwent surgery with a curative intent and with a 4 year mean duration of follow-up there were 14/16 patients alive. These results are interesting as they potentially demonstrate that this strategy is feasible and leads to a high rate of survival for patients with curable tumors.

Thus IAC seems to be feasible, and has a low toxicity. However no prospective study using a standardized technique has been reported and only randomized trials could demonstrate its interest for patient's survival. Discussion Preoperative or neoadjuvant chemotherapy has two main aims in gastric cancer, namely to decrease the tumor mass or its extension and thereby facilitate surgical resection in locally advanced disease, and to prolong the survival of patients. These two aims will be discussed separately. Resectability. In a recent retrospective study, Hideobaba et al. [40] reported that among 275 patients with gastric carcinoma, only 142 (51%) underwent extensive curative surgery. More recently Rohde et al. [7] reported that complete resection was only possible in 740 (54%) of 1360 patients with gastric cancer. Furthermore they reported that in 186 out of 845 patients (22%) classified as RO by the surgeons, histopathological examination of specimens revealed tumor at the resection margins. Compared to these data, the results of the studies discussed here support the ability of CT to increase resectability of locally advanced gastric carcinoma as the resection rates were between 72% and 77%, but have yet to be clearly demonstrated since only one randomized trial has been reported to date [29]. This trial is very preliminary and has included only 51 patients but seems to have a higher resection rate (75% vs. 56%; p - 0.14) for patients receiving preoperative chemotherapy. Among the factors predictive of resectability, the ability to obtain an objective response to CT seems to be high on the list. Twelve out of the 14 responders in our study were rendered disease free after chemotherapy and surgery, whereas only 4 of the 12 non responders were able to achieve the same results. Similar data were reported by Plukker et al. and Wilke et al. [17,18]. These results pave the way for the development of new chemotherapy regimens able to increase the objective response rate and perhaps the surgical resectability consistently. Wills and the EORTC-GI group [41] recently reported the results of a randomized phase HI trial testing the FAMTX regimen (5-fluorouracil, adriamycin and methotrexate) versus the FAM regimen (5fluorouracil, adriamycin and mitomycin C). Although they demonstrated a significant advantage in survival and response for the FAMTX arm, little information was provided on the ability of this regimen to improve the resectability rate in locally advanced gastric carcinomas but this regimen would be tested in a randomized trial on preoperative chemotherapy. In our opinion the highest priority should be given to investigational new combinations in this field as the combination of continuous i.v. 5FU, epiadriamycin,

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py; their disease progressed 3 and 12 months after the completion of therapy and these patients survived 17 and 48+ months. The 4 patients stabilized after chemotherapy and who had NED after surgery did not receive any adjuvant treatment. Three of them relapsed after surgery, and 1 patient is disease free at 51 months. Finally, of the initial 30 patients only 6 had NED at 4 years (20%). The median survival is 16 months and the survival rate at 12, 24 and 36 months is 67%, 42%, and 38% respectively. Factors influencingsurvival were the performance status (p = 0.0001) and the histological type. The survival of patients without linitis plastica was significantly longer (p - 0.002) than that of those with linitis. These studies have demonstrated that preoperative systemic chemotherapy was indeed a reasonable approach for patients with LAGC and allows a high resection rate with acceptable toxicity.

65 and CDDP and eventually intensive chemotherapy with hematopoietic growth factor rescue. The relation between response and resectability is also an argument for a better selection of patients in future trials to avoid inclusion of patients with a poor performance status and/or with diffuse type linitis plastica, as in our experience, as these patients have a very low response rate and the likelihood of tumor resectability is low.

Thus, complementary trials are needed, however, many problems of methodology have to be solved before large randomized trials could be initiated. In particular we have to define precisely what is a LAGC? What are the main criteria of tumor response in LAGC? What are the indications for preoperative chemotherapy? And what are the best trials that need to be conducted?

There are a lot of discrepancies in the definition of what gastric tumor should be considered as LAGC. The definition is different for surgeons who operate the patients and medical oncologists who explore the patients with endoscopic and radiological techniques. For patients submitted to surgery, LAGC could be defined as tumors which cannot be totally removed by the surgeon due to local extension (to pancreas, aorta, coeliac or hepatic lymph nodes) in the absence of distant metastases and in particular, peritoneal dissemination. For patients who do not undergo surgery only clinical, endoscopic and radiological explorations can be used and none of these techniques provide conclusive information on the local and distant extension of gastric tumors. However, some characteristics are known to be of poor prognosis and could be used as clinical criteria of LAGC: a bulky tumor (>7 cm) [13], a tumor located at the cardia (12), or a tumor with enlarged lymph nodes in the coeliac or hepatic area at CATscan. Unfortunately the ability of the CAT scan to evaluate the locoregional tumor extension is not well established. For instance, in a small series of 22 patients Moss et al. [47] reported that CAT scan was able to predict tumor unresectability due to regional or distant metastatic extension in 5 cases. This was not confirmed by Cook et al. [48] who underlined that in 51% of the cases (19/37) the CAT scan underestimated the stage of the tumors, even if 17/31 (60%) stage m or IV tumors were correctly detected. Finally Sussman et al. [49] have shown that the CAT scan has an accuracy of 80% to 90% for the estimation of locoregional (pancreas, aorta, omentum, esophagus) or hepatic extension, but of only 64% for the detection of pathological lymph nodes. In a series out of 75 patients they reported 14 false negatives, 13 false positives and only 28 genuinely positive lymph nodes. However, lymph nodes were considered as pathological when they were more than 8 mm in diameter, which might explain a low specificity rate, and 8/13 of the false positive corresponded to unique adenopathy to be compared to 7/28 true positive. These considerations underline the limits of the CAT scan which is more appropriate for the evaluation of local extension at the level of adjacent organs than metastatic lymph nodes. Fortunately the recent development of echo-endoscopy (EE) is very encouraging as this exploratory technique is able to detect parietal extension with a sensitivity of 81% and a specificity close to 90% {50}. Moreover the accuracy in detecting lymph node involvement according to the TNM-classification was 87% in Grimm's study conducted on 111 cases [51]. Results can be enhanced if 20% sesam emulsion is administered orally 2-3 hours prior to the EE. In these conditions the sensitivity for the detection of metastatic lymph nodes over 5 mm diameter is 90%, specificity 91% and the accuracy 91% [52]. Thus EE seems to be

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Survival. Since experiences with adjuvant chemotherapy have failed to demonstrate a significant survival advantage, it is worthwhile evaluating the impact of neoadjuvant chemotherapy on survival. Theoretical considerations and experimental data [42, 43] have shown a possible benefit with preoperative chemotherapy. In most of the reported series, the median survival of patients with locally advanced unresectable gastric cancer was dramatically low, ranging between 4 and 8 months, depending on whether they were palliatively treated or not [44, 45]. In contrast the survival of patients undergoing curative resection is far better. However, the cumulative 5 year survival rate does not exceed 20% (range 5% to 40%) when they are treated by surgery alone [1,46]. In the studies that we have discussed [9, 17, 18, 24, 26] and in ours, the median survival reported (16 to 18 months) seems significantly higher than that of historical controls, but no firm conclusion can be drawn on the effect of neoadjuvant chemotherapy on survival. In effect, since unresectability was not surgically proven in all of these studies, except the German study [18], and as the relapse rate remained unsatisfactorily high (range between 40% to 60%, despite pre and postoperative chemotherapy) it is impossible to assess whether surgery alone would have achieved the same results or not. Obviously, only randomized trials comparing preoperative chemotherapy with initial surgical treatment, in a population of patients with locally advanced disease, is likely to establish the exact benefit of neoadjuvant chemotherapy. The only randomized trial, published as an abstract, has been conducted in Korea and the preliminary results have only demonstrated significant downstaging by chemotherapy and no differences in postoperative complications [29]. Other randomized trials are urgently needed, as the toxicity of preoperative chemotherapy is far from negligible and some toxicity-related deaths have been reported (Plukker, Rougier) and should be taken into account in the design of future trials.

Definition of locally advanced gastric cancers (LAGC)

66 the best exploratory technique for the detection of lymph node invasion with good accuracy and should be used to select poor risk patients eligible for studies on preoperative chemotherapy. Criteria of tumor response in LAGC

In parallel it seems useful to consider the evolution of tumor markers, especially CA19-9 and/or CA72.4, which in most of the cases is indicative of the tumor development. Indications ofpreoperative chemotherapy in LAGC From the studies reported here it is possible to isolate two main indications for preoperative chemotherapy in LAGC: surgically proven unresectable gastric cancers and locally extended tumors at endoscopic and radiological preoperative work-up. In the case of surgically proven unresectable tumor, previous reports [17, 18] seem to demonstrate that chemotherapy is able to induce substantial tumor regressions and to allow secondary resections when efficient schedules are used. Even in the absence of a controlled study, this indication of preoperative chemotherapy is well accepted by most of the surgeons working in multi'disciplinary teams and seems valid. In the case of locally extended tumors, in the absence

What controlled trials have to be conducted in LAGC? The design of future controlled trials on preoperative chemotherapy should be: - In case of surgically proven unresectable tumor it is important to determine what locoregional treatment should be offered after 'effective' chemotherapy. It is not well established that surgery is superior to radiation therapy and the GITSG has reported long-term survival in non resected patients treated with combined chemoradiotherapy. It is also important to determine the role of post operative chemotherapy and the eventual interest of combined intraperitoneal chemotherapy. Finally, as in our experience it appeared that linitis plastica was poorly responsive to chemotherapy, it is important to isolate these very particular tumors and to conduct specific trials with better adapted chemotherapy to try to ameliorate their very poor prognosis. - In case of locally extended tumors, in the absence of surgical staging, in patients with poor prognostic factors, randomized trials have to be conducted. These trials have to use the most efficient and least toxic schedules and must ask two main questions: does preoperative chemotherapy increase the resectability rate and does it translate into increased survival? As there are many prognostic factors (Wilke, Rougier) it is important to enter a great number of patients in these studies and to stratify at least on performance status, tumor site, histology, and suspicion of lymph node extension or not. Control group in any case should be surgery alone.

Conclusion Many studies on preoperative chemotherapy in gastric cancers have shown that it is possible to increase the re-

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In general it is very difficult to measure the tumor mass precisely in LAGC. For this reason some investigators [24] only report major responses without estimating the percentage of the decrease in tumor volume. However, it seems essential to try to better define and standardize what should be considered an objective response. As many techniques are able to estimate tumor volume abdominal echography, CATscan, endoscopy and echo-endoscopy), it is important to use a minimum of two different techniques and have concordant results on the evolution of the tumor mass before reaching a definitive conclusion regarding an OR. As the maximal diameter of the tumor is often the height, it must be estimated as precisely as possible by measuring the level of the upper and the lower edge of the tumor by endoscopy or on CAT scan. If this measurement seems reliable the second 'diameter5 to be chosen is the thickness determined at endoscopy compared to the size of thewith forceps or at CAT scan at the level of maximal thickness. Then WHO criteria can be used: a partial response is defined as a decrease of more than 50% in the product of the two maximal diameters without the appearance of extra gastric metastases, a complete response, a normalisation of all endoscopic and radiological abnormalities and negative multiple biopsies obtained at the tumor site. In the absence of two measurable diameters frequently only the thickness of the tumor can be evaluated, in which case the CR definition remains the same. However, in case of uncomplete response, a 33% decrease in the maximal thickness seems sufficient to characterize a PR.

of surgical staging, it is possible to select patients with poor prognostic factors and to try to improve their prognosis by administering preoperative chemotherapy. In these cases it is important to choose efficient and non toxic chemotherapy regimens in order to avoid preoperative lethality in this group of potentially resectable patients, and to conduct prospective randomized trials to demonstrate its usefulness for the resectability rate and survival. This has been done by Kang et al. [29] who have shown that preoperative chemotherapy increases the resectability rate, but this finding has to be confirmed by other studies and the impact on survival has to be clearly demonstrated with more and better characterized patients. In our opinion all patients less than 70 years of age with a tumor exceeding 7 cm, or located at the cardia, or with enlarged coeliac lymph nodes at CAT-scan or echo-endoscopy, or invading the adjacent structures (T4), could be entered in these studies. These patients should be considered as LAGC and could be included in trials testing preoperative chemotherapy if their general condition is good enough.

67

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Acknowledgements

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We are very grateful to Mrs Lorna Saint Ange for the revision and preparation of the manuscript and Mrs Katia Garbolen and Josseline Lorillon for their secretarial assistance.

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17.

18.

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23.

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