INTERVENTION

Adjuvant chemotherapy associated with improved survival in resected gastric cancer Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, Jolis L, Saigi E, Guasch I, Badia A, Boleda M. Randomized clinical trial o f adjuvant mitomycin plus tegafur in patients with resected stage 111 gastric cancer. J Clin Oncol 1999;7: 3810-3815

QUESTION Does combination mitomycin/tegafur as adjuvant chemotherapy prolong dsease-free and overall survival in patients with resected stage I11 gastric cancer? DESIGN

MAIN RESULTS

Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The treatment and control groups included 76 and 72 patients, respectively. The median follow-up period was 37 months. The tolerability of the treatment was excellent. Side-effects were generally mild or moderate, and no modfication of the treatment regmen was required in any patient. Frequency of grade 1-2 toxicity was 15, and a single case of grade 3 toxicity (neurocerebellar) occurred. The overall survival and disease-free survival were hgher in the group of patients treated with chemotherapy (P = 0.04 for survival and P = 0.01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56 and 51% in the treatment group and 36 and 31% in the control group.

Phase 111, randomized, multicenter clinical trial.

SETTING Ten hospitals in the Barcelona area of Spain. PATIENTS Patients were eligble for t h s study if they had undergone curative resection of a pathologcally confirmed gastric adenocarcinoma in stage 111; were < 7 5 years of age; had a IGrnofsky performance status 3 70; had normal renal, liver, and bone marrow function; had no associated diseases contraindicating chemotherapy; and had provided informed consent. INTERVENTIONS Patients with resected stage I11 gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started withn 28 days after surgery according to the following schedule: mitomycin 20 mg/m2 intravenously (bolus) at day 1 of chemotheraphy; 30 days later, oral tegafur 400 mg bid daily for 3 months.

CONCLUSION These results are consistent with the results of recent studm, w h c h conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer. Sources offunding: Not spe@ed

MAIN OUTCOME MEASURES Disease-free survival and

Correspondence to: U u i s Cirera, MD) Medical Oncolog Unit, Hospital Mutua de Terrassa-Universitat de Barcelona, Placa Dr Robert 5, 08221 Terrassa) Barcelona, Spain.

overall survival were estimated using the IGplan-Meier analysis and the Cox proportional hazards model Fable 1).

Table I Treatments

Effect measures

Outcomes

Benefits

NNT

ARR

RRR

(95% CI)

(95% CI)

(95% CI)

7 (4.55)

( I .8,26.2)

33.33 (8.72.57.95)

64

6 (3.16)

18 (6.36,29.64)

33.33 (14.66.52)

36

56

5

20

3 I .25

51

(3,I I) 5

(9.32,30.68) 20

( I 6.37.46.13)

31

(3.10)

( 10.0 I, 29.99)

( I 5.84.42.13)

Control (n = 72)

Treatment (n = 76)

Survival (%) 2 years

58

72

Disease-free survival (%)

46

2 years Survival (%) 5 years Disease-free survival (%)

5 years

14

28.99

Harms

Adverse effects grade I12

0

15

Adverse effects grade 314

0

I

NNH

ARI

(95% CI) 7 (4,14)

(95% CI) 15 (6.95,23.03)

I00

(31,-81) Abbrev: NNT = number needed to treat; ARR ARI = absolute risk increase.

= absolute

(

-

I I .24,3.24)

risk reduction; RRR = relative risk reduction; NNH = number needed to harm;

Evidence-based Oncology (2000) I, 6&6 I doi:I0.I054/ebon.2000.0029, available online at http://www.idealibrary.com on

ImEbl'

0 2000 Harcoun Publishers Ltd

Commentary Despite a large body o f clinical trials in gastric cancer, many questions remain unsolved. For those patients having undergone potentially curative resection, there are n o confirmed Western trials in which systematic adjuvant therapy has been of benefit. Most information about effective drugs such as mitomycin, doxorubicin or 5-fluoracil stem from Japanese trials. Methodological differences between Japanese and Western trials involve the staging procedure, the delay in starting therapy and the use o f appropriate control groups. In addition, almost all clinical trials reported hitherto involve relatively small number o f patients. The later finding also applies t o the study reported by Cirera e t al. They randomized a total o f 148 patients treated at I 0 different hospitals in Spain for stage 111 gastric cancer between surgery followed by oral 5-fluoracil for 3 months. The tolerability mitomycin C (20 mg/m*) o f the treatment was excellent. Overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (n = 76) compared with the operation only group (n = 72). Though the data are thoroughly presented showing statistical significance f o r both end-points, they can just be taken as another hint towards a potential benefit from adjuvant chemotherapy in resected gastric cancer clearly warranting larger randomized trials. Before doing so, however, critical questions such as the exact staging procedure, choice o f drugs, use of intraperitoneal chemotherapy, neoadjuvant or adjuvant setting, beginning o f treatment, etc., have to be worked o u t very carefully. Currently, important larger trials are o n the way to investigate potentially more effective combinations or scheduled. Most of these trials

are encouraged by the trend towards improved survival seen in several of reported clinical trials such as the one by Cirera e t al. A more recent analysis, however, failed to convincingly demonstrate that routine use of postoperative intravenous therapy is appropriate. A more recent meta-analysis of adjuvant chemotherapy vs observation following curative resection of stomach cancer that took place in non-Asian countries showed an odds ratio f o r death in the treated group o f 0.80. Subgroup analysis revealed a trend towards a larger magnitude o f the effect when analysis was restricted to the trials in which at least 2/3 o f patients had noted ‘positive disease’. These data suggest that adjuvant chemotherapy may produce a small survival benefit o f borderline statistical significance asking f o r large clinical trials t o confirm this strategies. Andreas Engert, MD Senior Consultant, University of Koln, Koln, Germany

+

0 2000 Harcourt Publishers Ltd

Literature cited

I. Earle CC. Adjuvant chemotherapy after curative resection f o r gastric cancer in non-Asian patients: revisiting a meta-analysis of randomized trials. Eur J Cancer 1999; 3 7 1059%1064. 2. Shimada K, Ajani JA.Adjuvanttherapyfor gastric carcinoma patients in the past I 5 years: a review of western and oriental trials. Cancer 1999; 86: 1657-1 668.

Level and quality of evidence (See Table A, p. 64): I c

Evidence-based Oncology (2000) I, 60-6 I