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Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer
The American Journal of Surgery 187 (2004) 440 – 445
Scientific paper
Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer Jacques Chipponi, M.D.*, Michel Huguier, M.D., Denis Pezet, M.D., Nicolas Basso, M.D., Jean-Marie Hay, M.D., Pierre Quandalle, M.D., Daniel Jaeck, M.D., Pierre-Louis Fagniez, M.D., Alain Gainant, M.D., and the French Association for Research in Surgery (AURC) Hoˆtel-Dieu Boulevard Leon Malfreyt 63058, Clermont-Ferrand, Cedex 1, France Manuscript received November 2, 2002; revised manuscript May 29, 2003
Abstract Background: The aim of the study was to evaluate the efficacy of adjuvant chemotherapy on survival after resection for gastric cancer. Methods: Patients were enrolled if they underwent resection of gastric cancer but had lymph node or serosal involvement or both. Surgical resection was either total or partial gastrectomy according to the site of the tumor, and surgeons were allowed to perform either D1 or D2 gastrectomy. The subjects were random assigned in two treatment groups as follows: surgery alone as the control group, or surgery and adjuvant chemotherapy. Nine cycles of 5 days protocol every 4 weeks was proposed to the patients of the chemotherapy group. The protocol included a daily administration of 200 mg/m2 of folinic acid, 5-fluorouracil (375 mg/m2 during the first session increasing 25 mg by session until reaching 500 mg/m2) and CDDP 15 mg/m2. Two hundred patients were required. Kaplan-Meier survival curves were compared according to the log-rank and the Mantel-Haenszel methods. Results: In all, 205 patients were enrolled in the study; 104 had surgery alone and 101 had surgery and adjuvant chemotherapy. The patients’ characteristics were similar except for the mean age, which was 4 years less in the control group. Because of toxicity, 54% of the patients stopped the protocol before the end of the nine courses, and 46% of the patients received the nine courses including 32% with a decreased dose and 14% with a full dose. The 5-year survival rate was 39% in the control group and 39% in the chemotherapy group. Conclusions: This protocol of adjuvant chemotherapy failed to improve the 5-year survival after resection for gastric cancer. © 2004 Excerpta Medica, Inc. All rights reserved. Keywords: Gastric cancer; Chemotherapy; Adjuvant treatment
In Western countries, the reported 5-year survival rates after gastric resection varies from 35% to 45% [1– 4]. Unfortunately, results of randomized studies failed to demonstrate any advantage of extended lymph-node dissection [1,2]. Adjuvant chemotherapy or radiotherapy, or both, at the time of minimal residual disease would provide the best chances of improving outcome [5]. From 1960 to 1987 a number of adjuvant trials have been carried out. Two controlled trials studied thio-thepa as adjuvant chemotherapy for gastric cancer. The survival rate at 5 years was not different in the two groups [6,7]. A controlled trial evaluated the combination of 5-fluorouracil (5* Corresponding author. Tel.: ⫹33-4-7375-0494; fax: ⫹33-4-73930211. E-mail address: [email protected]
FU) and methyl-CCNU. A significant difference in the 5-year survival rate was detected over the control group [8]. However, two similar studies did not find any difference between the two groups [9,10]. Several trials evaluated mitomycin C alone or associated with other drugs such as 5-FU. In one study the 8-year survival rate in the group of patients treated with mitomycin C was significantly better than in the controlled group [11]. But in most other trials no difference was observed except for stage III gastric cancer [12–14]. According these results phase II trials that combined 5-FU and cisplatinum (CDDP) were initiated and found a response rate between 43% and 50% [15,16]. Thus, the French Association for Surgical Research initiated a multicentric, prospective, randomized trial comparing survival after adjuvant 5-FU, leucovorin, and CDDP with a control group undergoing sur-
0002-9610/04/$ – see front matter © 2004 Excerpta Medica, Inc. All rights reserved. doi:10.1016/j.amjsurg.2003.12.014
J. Chipponi et al. / The American Journal of Surgery 187 (2004) 440 – 445
gery alone. The aim of this paper was to present the results of this trial with a minimum follow-up of 4 years.
Methods Patients were included in the trial between October 1989 and September 1997. Participating investigators are listed at the end of this paper. All patients gave their informed consent to be enrolled in the trial, approved by the Saint Antoine University Ethics Committee.
441
neuropathy or serum creatinine more than 1.5 of normal value, CDDP was definitively withdrawn from the therapeutic regimen. When there was no adverse events, chemotherapy was continued until nine courses had been given. For evaluating hematological tolerance of chemotherapy, patients were evaluated before each cycle of chemotherapy and for digestive, cardiovascular, and neurological tolerance after each cycle. If necessary, appropriate supportive care was given to patients of both groups without other chemotherapy than the protocol regimen. Statistical analysis
Inclusion criteria Patients aged less than 75 years who had undergone a resection for cure (resection with neither macroscopic residual tumor nor resection line involvement) for histologically proven gastric adenocarcinoma, including cancer of the cardia but excluding other malignant diseases, were eligible for the study. Only patients with lymph node involvement or serosal involvement at pathological examination were included in the study. The patients with adjacent tissues invasion, which was amenable to an en-bloc resection, were also eligible. Exclusion criteria were prior other malignancy, chemotherapy or radiotherapy, and contraindication to chemotherapy. Patients were entered into the study within 1 month of surgery. Treatments Surgeons were free to perform either D1 or D2 resection, and any type of gastrectomy according to the site of the tumor. Chemotherapy consisted of a 5-day course of leucovorin (200mg/m2/day) through an intravenous bolus injection followed by infusion of 5-FU (375 mg/m2 daily in 1 L saline over 2 hours) followed by infusion of CDDP (15 mg/m2 daily in 250 mL saline over 1 hour). After CDDP administration, saline,1 L, was infused over 1 hour. Cycles were repeated every 21 days. In the absence of gastrointestinal, renal, or hematological toxicity, the daily dose of 5-FU was increased by 25mg/m2/day at each subsequent cycle (the maximum daily dose was 500 mg/m2/day). Antiemetics were routinely given and consisted of intravenous metoclopramide, granisetron, or ondansetron. Careful dental hygiene, including the prophylactic use of antiseptic and antimycotic solutions, was recommended to prevent oral mucositis. Most of the patients had a permanent venous access device. If at the time of the ongoing course, the neutrophil count had not reached 1.5 ⫻ 109/L or the platelet count 100 ⫻ 109/L, the treatment was delayed until the values reached normal level, and the doses of 5-FU were decreased by 25 mg/m2 daily and 5 mg/m2 daily, respectively. In instances of WHO grade III to IV gastrointestinal toxicity, the 5-FU dose has to be reduced from 25 to 50 mg/m2 daily. In instances of greater than WHO grade I peripheral
The primary end point was survival as the time from operation to death. The other end point was side effects of the chemotherapy. Sample size calculations were based on a baseline 5-year survival rate of 35% and an improvement of survival to 50%. Thus, using a two-sided significance level of 0.05 and a power of 0.90, 200 patients had to be enrolled in the study. Treatment was randomly assigned after the eligibility of the patient to participate in the study. Assignment of patients to the chemotherapy or control group used a centralized random permuted block technique. Comparisons between the two groups were tested with the corrected chi-square test for nominal variables, and with the unpaired two-sided Mann-Whitney test for continuous variables. Survival time distribution was evaluated using the Kaplan-Meier method, and differences between the control group and the chemotherapy group were tested with the log rank test. The analysis of survival was done on an intent-to-treat basis. Survival was censored at January 31, 2001, when all the patients had been in the study for at least 3 years. The median follow-up period was 101 months (range 43 to 140).
Results Two hundred and five patients were included in the study. One hundred and four patients were allocated for surgery and 1 was lost during the follow-up. Of 101 patients allocated to surgery and chemotherapy, 6 were excluded after randomization (3 for pathological ineligibility, 1 for renal failure, 1 for cirrhosis, and 1 for associated bladder carcinoma). Two patients refused chemotherapy but were included in the analysis, and 2 patients were lost to followup. Table 1 shows patients’ characteristics and pathological staging of cancer. The only difference was a lower mean age (4 years) in patients undergoing chemotherapy. The 625 reported drug courses represented 75% of the potential. The percentages of potential courses that were reported were 98% for the first course and declined with succeeding courses (Fig. 1). Only 382 courses were performed with full doses (61%), and 243 (39%) with decreased doses for 5-FU alone (n ⫽ 158), 5-FU and CCPD (n ⫽ 30), for 5-FU without CCDP (n ⫽ 21), for CCPD alone
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J. Chipponi et al. / The American Journal of Surgery 187 (2004) 440 – 445
Table 1 Patients’ characteristics, types of resection, and clinicopathological staging Total Surgery Surgery and P value (n ⫽ 196) (n ⫽ 103) chemotherapy (n ⫽ 93) Mean age (year) 61 Sex (male/female) 129/67 Location of tumor Upper third 45 (23) Middle third 58 (29) Distal third 90 (46) More than two-thirds 3 (2) Type of gastrectomy Partial 99 (51) Total 97 (49) Lymph node involvement No 33 (17) Yes 163 (83) Penetration ⬍Serosa 53 (27) Serosa 121 (62) ⬎Serosa 32 (16)
63 71/32
59 58/35
0.01 NS
23 (22) 24 (23) 55 (54) 1 (1)
22 (24) 34 (36) 35 (38) 2 (2)
NS NS NS NS
51 (50) 52 (50)
48 (52) 45 (48)
NS NS
14 (14) 89 (86)
19 (20) 74 (80)
NS NS
20 (19) 67 (65) 16 (16)
23 (25) 54 (58) 16 (17)
NS NS NS
Numbers in parentheses are percentages. NS ⫽ not significant.
(n ⫽ 10), or normal doses of 5-FU without CCPD (n ⫽ 20). Forty-six percent of the patients received the nine courses of chemotherapy, 14% the full dose and 32% a decreased dose. The other patients (54%) were obliged to stop the chemotherapy without completing the nine courses. Table 2 shows toxic side effects according the WHO classification (Table 3). The most frequent grade III or IV adverse reactions were nausea, or vomiting (31%), and diarrhea (27%). Ten patients experienced grade III or IV granulocytopenia (26%), 10 experienced anemia (12%), and 12 thrombocytopenia (14%) without purpura or hemorrhage. No grades III or IV cardiac, neurological, or renal toxicity were observed. There were 4 deaths as the result of chemotherapy toxicity, 1 from hemotological aplasia, 1 from both hematological and di-
Table 2 Toxic side effects WHO toxicity grade
Granulocytes Hemoglobin Platelets Vomiting Stomatitis esophagitis Diarrhea Cardiac Neurosensory, neuromotor Renal Alopecia
II
III
IV
12 (13) 6 (6) 4 (4) 38 (41) 16 (17)
14 (15) 8 (10) 8 (9) 26 (28) 9 (10)
10 (11) 2 (2) 5 (5) 3 (3) 6 (6)
32 (34) 5 (5) 18 (19)
18 (19) 0 (0) 0 (0)
7 (8) 0 (0) 0 (0)
7 (7) 2 (2)
0 (0) 2 (2)
0 (0) 0 (0)
Number in parentheses are percentages. WHO ⫽ World Health Organization.
gestive toxicity, 1 from cardiovascular collapse, and 1 at home from unknown cause. The actuarial survival curves of the two groups of patients are shown in Fig. 2. According to a proportionalhazards analysis, the hazard ratio comparing the risk of death within 5 years after surgery for the eligible patients was 39% (95% CI 28.4% to 56%) for the control group and 38.7% (95% CI 27.2% to 51.5%) for the chemotherapy group. Only 46% of the patients received the nine courses of chemotherapy. We compared the survival curves of this group of patients with the group of patients treated by surgery alone and did not observe any significant difference between the two groups (Fig. 3). We analyzed the survival of the 163 patients with lymph node involvment and compared the survival of the 89 patients treated by surgery alone with that of the 74 patients treated by surgery and chemotherapy. In this subgroup of patients, N⫹, we did not find any significant difference in their actuarial survival curves (Fig. 4).
Comments
Fig. 1. Black column: percentages of potential courses (total). Lined column: percentages of potential courses with full doses. White column: percentage of potential courses with decreased doses.
The results of this randomized trial showed that the adjuvant combination of 5-FU, leucovorin, and CDDP failed to influence survival of patients with gastric cancer resected for cure. Patients without lymph node and serosal involvement have been excluded from the study because they have a good prognosis after surgery alone with 5-year survival rates of 70% [2,17]. The present trial focused on higher risk patients who may be the group who could benefit most from adjuvant therapies, as has been recommended in 1999 by Earle and Maroun [18]. The chemotherapy regimen was elected on the results of three phase II studies with a response rate of 35% to 50% [15,16]. Surgeons were free to perform any type of surgical resection, the only criteria for
J. Chipponi et al. / The American Journal of Surgery 187 (2004) 440 – 445
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Table 3 Toxic side effects, WHO classification
Granulocytes (1,000/mm3) Hemoglobin (g/100 mL) Platelets (1,000/mm3) Vomiting Stomatitis, esophagitis Diarrhea Cardiac dysrhythmias Neurosensory, neuromotor Renal (serum creatinine ⫻ N) Alopecia
Grade II
Grade III
Grade IV
1.0–1.4 8.0–9.4 50–74 1 episode in 24 hours Painful erythema, can eat 4–6 stools/day Recurrent, no therapy required Moderate paresthesias 2.6–5 Pronounced hair loss
0.5–0.9 6.5–7.9 25–49 2–5 episodes in 24 hours Painful erythema, cannot eat 7–9 stools/day Requires treatment Severe paresthesias 5.1–20 Total hair loss
⬍0.5 ⬍6.5 ⬍25 ⬎10 episodes in 24 hours Requires parenteral or enteral support ⬎10 stools/day Requires monitoring Paralysis ⬎20
WHO ⫽ World Health Organization.
inclusion being a complete macroscopic clearance and a free section line at microscopic examination. As later results of randomized studies comparing D1 and D2 resections [1,2] and for antrum gastric cancer subtotal and total gastrectomy [19,20] failed to detect a survival difference between these different procedures, type of resection may be considered as having no influence on results. As the delay in time to recurrence is an endpoint that is difficult to measure reliably in gastric cancer, the present trial was restricted to assessing the effects of combined chemotherapy on survival, and its toxicity. The trial started in 1989 when health-related quality of life (HRQL) was not considered. For gastric cancer, first evaluations about HRQL were published in 1996 and 1997 [21]. As new procedures are developed, an estimation of their effect on HRQL should be added to evaluation of adjuvant treatments. The present trial was not designed specifically to look at subgroups. However, we performed an analysis for lymph node involvement, which has shown no benefit in each subgroup. The difficulty in obtaining good compliance with treatment is a major problem of this study. Digestive toxicity is common with this chemotherapeutic regimen and was the most frequent side effect in our study. On the other hand, gastrectomized patients present frequently with postprandial diarrhea and nutritional difficulties. The association of sur-
gery and chemotherapy side effects is probably the main reason for this very low compliance with treatment. Even if we observed a slight advantage on the actuarial survival curve of patients receiving the nine courses of chemotherapy (Fig. 3), it is not possible to assess that this difference could have been significant in case of better compliance with treatment. Unfortunately, we did not have in this study sufficient data to evaluate correctly the time to disease progression of these patients. A meta-analysis of 11 randomized trials reported between 1980 and 1991 and comparing adjuvant chemotherapy with surgery alone found a nonsignificant trend toward improved survival with an odds ratio of 0.88 (95% CI: 0.78 to 1.08) [22]. However, this meta-analysis was subject to criticism for lacking sufficient power to detect a difference, and for selection of trials [23]. A review of 13 randomized controlled trials of adjuvant chemotherapy versus observation, in non-Asian countries, has also been published [18]. Statistical testing found no significant heterogeneity in the effect of adjuvant chemotherapy between the trials. Metaanalysis involving a total of 1,990 patients showed an odds ratio of 0.80 (95% CI: 0.66 to 0.97) in favor of adjuvant chemotherapy. Another meta-analysis of 20 trials has been recently published; the statistical analysis found a benefit of
Fig. 2. Survival by treatments. Solid line 1: chemotherapy group. Broken line 2: control group.
Fig. 3. Survival by treatment. Solid line 1: patients receiving nine courses of chemotherapy. Broken line 2: patients treated by surgery alone.
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J. Chipponi et al. / The American Journal of Surgery 187 (2004) 440 – 445
Hennet (Romorantin), P. Letreut (Marseille), G. Lorimier (Angers), J. C. Sarles, B. Sastre (Marseille).
References
Fig. 4. Survival by treatments for patients N⫹. Solid line 1: chemotherapy group. Broken line 2: control group.
adjuvant chemotherapy with an odds ratio of 0.82 (CI: 0.75 to 0.82). Monotherapy give significantly better results than polychemotherapy. This result is based on two large randomized trials with mitomycin as monotherapy [24]. However, journals, and more commonly investigators themselves, are more likely to publish positive results, and publication bias alone can influence such a meta-analysis [25]. The results of the US cooperative groups suggested that postoperative chemoradiation (5-FU, leucovorin, and 45 Gy) for high-risk R0 resected locally advanced adenocarcinoma of the stomach and gastroesophageal junction may be considered a standard of care [26]. However, significant improvement was observed at 3 years and not on actuarial curves using a log rank test. There was 1% toxic death, and grade III and grade IV toxicity occurred in 41% and 32% of cases, respectively. Another study suggested that neoadjuvant 5-FU, leucovorin, adriamycin, and CDDP, radical resection with intraoperative radiotherapy, and postoperative radiotherapy may result in long-term survival [27]. However, these results may be the consequence of the selection of patients. This randomized trial was unable to demonstrate any statistically significant difference in survival of patients after resection for gastric cancer.
Acknowledgments The following surgeons took part in the study: J. Chipponi, D. Pezet (Clermont-Ferrand), N. Basso (Italy), J. M. Hay (Colombes), M. Huguier, S. Houry (Paris), D. Jaeck (Strasbourg), P. L. Fagniez (Cre´ teil), J. F. Charles (Brest), P. Cubertafond, A. Gainant (Limoges), J. P. Lenriot (Longjumeau), J. Testard (Rouen), B. Millat (Montpellier), J. F. Warlin (Argenteuil), G. Kohlman (Corbeil), P. Quandalle (Lille), P. Bloch (Neuilly), F. Dazza (Paris), P. Letoublon (Grenoble), E. Pe´ lissier (Besanc¸ on), X. Pouliquen (Argenteuil), P. Vicq (Paris), B. Descottes (Limoges), H.
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J. Chipponi et al. / The American Journal of Surgery 187 (2004) 440 – 445 [19] Gouzi JL, Huguier M, Fagniez PL, et al. Total versus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A French prospective controlled study. Ann Surg 1989;209:162– 6. [20] Bozzetti F, Marubini E, Bonfanti G, et al, the Italian Gastrointestinal Tumor Study Group. Subtotal versus total gastrectomy for gastric cancer. Five-year survival rates in a multicenter randomized Italian trial. Ann Surg 1999;230:170 – 8. [21] Schmier J, Elixhauser A, Halpern MT. Health-related quality of life evaluations of gastric and pancreatic cancer. Hepato-gastroenterol 1999;46:1998 –2004. [22] Hermans J, Bonenkamp JJ, Boon MC, et al. Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol 1993;11:1441–7. [23] Pignon JP, Ducreux M, Rougier P. Meta-analysis of adjuvant che-
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Scientific paper
Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer Jacques Chipponi, M.D.*, Michel Huguier, M.D., Denis Pezet, M.D., Nicolas Basso, M.D., Jean-Marie Hay, M.D., Pierre Quandalle, M.D., Daniel Jaeck, M.D., Pierre-Louis Fagniez, M.D., Alain Gainant, M.D., and the French Association for Research in Surgery (AURC) Hoˆtel-Dieu Boulevard Leon Malfreyt 63058, Clermont-Ferrand, Cedex 1, France Manuscript received November 2, 2002; revised manuscript May 29, 2003
Abstract Background: The aim of the study was to evaluate the efficacy of adjuvant chemotherapy on survival after resection for gastric cancer. Methods: Patients were enrolled if they underwent resection of gastric cancer but had lymph node or serosal involvement or both. Surgical resection was either total or partial gastrectomy according to the site of the tumor, and surgeons were allowed to perform either D1 or D2 gastrectomy. The subjects were random assigned in two treatment groups as follows: surgery alone as the control group, or surgery and adjuvant chemotherapy. Nine cycles of 5 days protocol every 4 weeks was proposed to the patients of the chemotherapy group. The protocol included a daily administration of 200 mg/m2 of folinic acid, 5-fluorouracil (375 mg/m2 during the first session increasing 25 mg by session until reaching 500 mg/m2) and CDDP 15 mg/m2. Two hundred patients were required. Kaplan-Meier survival curves were compared according to the log-rank and the Mantel-Haenszel methods. Results: In all, 205 patients were enrolled in the study; 104 had surgery alone and 101 had surgery and adjuvant chemotherapy. The patients’ characteristics were similar except for the mean age, which was 4 years less in the control group. Because of toxicity, 54% of the patients stopped the protocol before the end of the nine courses, and 46% of the patients received the nine courses including 32% with a decreased dose and 14% with a full dose. The 5-year survival rate was 39% in the control group and 39% in the chemotherapy group. Conclusions: This protocol of adjuvant chemotherapy failed to improve the 5-year survival after resection for gastric cancer. © 2004 Excerpta Medica, Inc. All rights reserved. Keywords: Gastric cancer; Chemotherapy; Adjuvant treatment
In Western countries, the reported 5-year survival rates after gastric resection varies from 35% to 45% [1– 4]. Unfortunately, results of randomized studies failed to demonstrate any advantage of extended lymph-node dissection [1,2]. Adjuvant chemotherapy or radiotherapy, or both, at the time of minimal residual disease would provide the best chances of improving outcome [5]. From 1960 to 1987 a number of adjuvant trials have been carried out. Two controlled trials studied thio-thepa as adjuvant chemotherapy for gastric cancer. The survival rate at 5 years was not different in the two groups [6,7]. A controlled trial evaluated the combination of 5-fluorouracil (5* Corresponding author. Tel.: ⫹33-4-7375-0494; fax: ⫹33-4-73930211. E-mail address: [email protected]
FU) and methyl-CCNU. A significant difference in the 5-year survival rate was detected over the control group [8]. However, two similar studies did not find any difference between the two groups [9,10]. Several trials evaluated mitomycin C alone or associated with other drugs such as 5-FU. In one study the 8-year survival rate in the group of patients treated with mitomycin C was significantly better than in the controlled group [11]. But in most other trials no difference was observed except for stage III gastric cancer [12–14]. According these results phase II trials that combined 5-FU and cisplatinum (CDDP) were initiated and found a response rate between 43% and 50% [15,16]. Thus, the French Association for Surgical Research initiated a multicentric, prospective, randomized trial comparing survival after adjuvant 5-FU, leucovorin, and CDDP with a control group undergoing sur-
0002-9610/04/$ – see front matter © 2004 Excerpta Medica, Inc. All rights reserved. doi:10.1016/j.amjsurg.2003.12.014
J. Chipponi et al. / The American Journal of Surgery 187 (2004) 440 – 445
gery alone. The aim of this paper was to present the results of this trial with a minimum follow-up of 4 years.
Methods Patients were included in the trial between October 1989 and September 1997. Participating investigators are listed at the end of this paper. All patients gave their informed consent to be enrolled in the trial, approved by the Saint Antoine University Ethics Committee.
441
neuropathy or serum creatinine more than 1.5 of normal value, CDDP was definitively withdrawn from the therapeutic regimen. When there was no adverse events, chemotherapy was continued until nine courses had been given. For evaluating hematological tolerance of chemotherapy, patients were evaluated before each cycle of chemotherapy and for digestive, cardiovascular, and neurological tolerance after each cycle. If necessary, appropriate supportive care was given to patients of both groups without other chemotherapy than the protocol regimen. Statistical analysis
Inclusion criteria Patients aged less than 75 years who had undergone a resection for cure (resection with neither macroscopic residual tumor nor resection line involvement) for histologically proven gastric adenocarcinoma, including cancer of the cardia but excluding other malignant diseases, were eligible for the study. Only patients with lymph node involvement or serosal involvement at pathological examination were included in the study. The patients with adjacent tissues invasion, which was amenable to an en-bloc resection, were also eligible. Exclusion criteria were prior other malignancy, chemotherapy or radiotherapy, and contraindication to chemotherapy. Patients were entered into the study within 1 month of surgery. Treatments Surgeons were free to perform either D1 or D2 resection, and any type of gastrectomy according to the site of the tumor. Chemotherapy consisted of a 5-day course of leucovorin (200mg/m2/day) through an intravenous bolus injection followed by infusion of 5-FU (375 mg/m2 daily in 1 L saline over 2 hours) followed by infusion of CDDP (15 mg/m2 daily in 250 mL saline over 1 hour). After CDDP administration, saline,1 L, was infused over 1 hour. Cycles were repeated every 21 days. In the absence of gastrointestinal, renal, or hematological toxicity, the daily dose of 5-FU was increased by 25mg/m2/day at each subsequent cycle (the maximum daily dose was 500 mg/m2/day). Antiemetics were routinely given and consisted of intravenous metoclopramide, granisetron, or ondansetron. Careful dental hygiene, including the prophylactic use of antiseptic and antimycotic solutions, was recommended to prevent oral mucositis. Most of the patients had a permanent venous access device. If at the time of the ongoing course, the neutrophil count had not reached 1.5 ⫻ 109/L or the platelet count 100 ⫻ 109/L, the treatment was delayed until the values reached normal level, and the doses of 5-FU were decreased by 25 mg/m2 daily and 5 mg/m2 daily, respectively. In instances of WHO grade III to IV gastrointestinal toxicity, the 5-FU dose has to be reduced from 25 to 50 mg/m2 daily. In instances of greater than WHO grade I peripheral
The primary end point was survival as the time from operation to death. The other end point was side effects of the chemotherapy. Sample size calculations were based on a baseline 5-year survival rate of 35% and an improvement of survival to 50%. Thus, using a two-sided significance level of 0.05 and a power of 0.90, 200 patients had to be enrolled in the study. Treatment was randomly assigned after the eligibility of the patient to participate in the study. Assignment of patients to the chemotherapy or control group used a centralized random permuted block technique. Comparisons between the two groups were tested with the corrected chi-square test for nominal variables, and with the unpaired two-sided Mann-Whitney test for continuous variables. Survival time distribution was evaluated using the Kaplan-Meier method, and differences between the control group and the chemotherapy group were tested with the log rank test. The analysis of survival was done on an intent-to-treat basis. Survival was censored at January 31, 2001, when all the patients had been in the study for at least 3 years. The median follow-up period was 101 months (range 43 to 140).
Results Two hundred and five patients were included in the study. One hundred and four patients were allocated for surgery and 1 was lost during the follow-up. Of 101 patients allocated to surgery and chemotherapy, 6 were excluded after randomization (3 for pathological ineligibility, 1 for renal failure, 1 for cirrhosis, and 1 for associated bladder carcinoma). Two patients refused chemotherapy but were included in the analysis, and 2 patients were lost to followup. Table 1 shows patients’ characteristics and pathological staging of cancer. The only difference was a lower mean age (4 years) in patients undergoing chemotherapy. The 625 reported drug courses represented 75% of the potential. The percentages of potential courses that were reported were 98% for the first course and declined with succeeding courses (Fig. 1). Only 382 courses were performed with full doses (61%), and 243 (39%) with decreased doses for 5-FU alone (n ⫽ 158), 5-FU and CCPD (n ⫽ 30), for 5-FU without CCDP (n ⫽ 21), for CCPD alone
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Table 1 Patients’ characteristics, types of resection, and clinicopathological staging Total Surgery Surgery and P value (n ⫽ 196) (n ⫽ 103) chemotherapy (n ⫽ 93) Mean age (year) 61 Sex (male/female) 129/67 Location of tumor Upper third 45 (23) Middle third 58 (29) Distal third 90 (46) More than two-thirds 3 (2) Type of gastrectomy Partial 99 (51) Total 97 (49) Lymph node involvement No 33 (17) Yes 163 (83) Penetration ⬍Serosa 53 (27) Serosa 121 (62) ⬎Serosa 32 (16)
63 71/32
59 58/35
0.01 NS
23 (22) 24 (23) 55 (54) 1 (1)
22 (24) 34 (36) 35 (38) 2 (2)
NS NS NS NS
51 (50) 52 (50)
48 (52) 45 (48)
NS NS
14 (14) 89 (86)
19 (20) 74 (80)
NS NS
20 (19) 67 (65) 16 (16)
23 (25) 54 (58) 16 (17)
NS NS NS
Numbers in parentheses are percentages. NS ⫽ not significant.
(n ⫽ 10), or normal doses of 5-FU without CCPD (n ⫽ 20). Forty-six percent of the patients received the nine courses of chemotherapy, 14% the full dose and 32% a decreased dose. The other patients (54%) were obliged to stop the chemotherapy without completing the nine courses. Table 2 shows toxic side effects according the WHO classification (Table 3). The most frequent grade III or IV adverse reactions were nausea, or vomiting (31%), and diarrhea (27%). Ten patients experienced grade III or IV granulocytopenia (26%), 10 experienced anemia (12%), and 12 thrombocytopenia (14%) without purpura or hemorrhage. No grades III or IV cardiac, neurological, or renal toxicity were observed. There were 4 deaths as the result of chemotherapy toxicity, 1 from hemotological aplasia, 1 from both hematological and di-
Table 2 Toxic side effects WHO toxicity grade
Granulocytes Hemoglobin Platelets Vomiting Stomatitis esophagitis Diarrhea Cardiac Neurosensory, neuromotor Renal Alopecia
II
III
IV
12 (13) 6 (6) 4 (4) 38 (41) 16 (17)
14 (15) 8 (10) 8 (9) 26 (28) 9 (10)
10 (11) 2 (2) 5 (5) 3 (3) 6 (6)
32 (34) 5 (5) 18 (19)
18 (19) 0 (0) 0 (0)
7 (8) 0 (0) 0 (0)
7 (7) 2 (2)
0 (0) 2 (2)
0 (0) 0 (0)
Number in parentheses are percentages. WHO ⫽ World Health Organization.
gestive toxicity, 1 from cardiovascular collapse, and 1 at home from unknown cause. The actuarial survival curves of the two groups of patients are shown in Fig. 2. According to a proportionalhazards analysis, the hazard ratio comparing the risk of death within 5 years after surgery for the eligible patients was 39% (95% CI 28.4% to 56%) for the control group and 38.7% (95% CI 27.2% to 51.5%) for the chemotherapy group. Only 46% of the patients received the nine courses of chemotherapy. We compared the survival curves of this group of patients with the group of patients treated by surgery alone and did not observe any significant difference between the two groups (Fig. 3). We analyzed the survival of the 163 patients with lymph node involvment and compared the survival of the 89 patients treated by surgery alone with that of the 74 patients treated by surgery and chemotherapy. In this subgroup of patients, N⫹, we did not find any significant difference in their actuarial survival curves (Fig. 4).
Comments
Fig. 1. Black column: percentages of potential courses (total). Lined column: percentages of potential courses with full doses. White column: percentage of potential courses with decreased doses.
The results of this randomized trial showed that the adjuvant combination of 5-FU, leucovorin, and CDDP failed to influence survival of patients with gastric cancer resected for cure. Patients without lymph node and serosal involvement have been excluded from the study because they have a good prognosis after surgery alone with 5-year survival rates of 70% [2,17]. The present trial focused on higher risk patients who may be the group who could benefit most from adjuvant therapies, as has been recommended in 1999 by Earle and Maroun [18]. The chemotherapy regimen was elected on the results of three phase II studies with a response rate of 35% to 50% [15,16]. Surgeons were free to perform any type of surgical resection, the only criteria for
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Table 3 Toxic side effects, WHO classification
Granulocytes (1,000/mm3) Hemoglobin (g/100 mL) Platelets (1,000/mm3) Vomiting Stomatitis, esophagitis Diarrhea Cardiac dysrhythmias Neurosensory, neuromotor Renal (serum creatinine ⫻ N) Alopecia
Grade II
Grade III
Grade IV
1.0–1.4 8.0–9.4 50–74 1 episode in 24 hours Painful erythema, can eat 4–6 stools/day Recurrent, no therapy required Moderate paresthesias 2.6–5 Pronounced hair loss
0.5–0.9 6.5–7.9 25–49 2–5 episodes in 24 hours Painful erythema, cannot eat 7–9 stools/day Requires treatment Severe paresthesias 5.1–20 Total hair loss
⬍0.5 ⬍6.5 ⬍25 ⬎10 episodes in 24 hours Requires parenteral or enteral support ⬎10 stools/day Requires monitoring Paralysis ⬎20
WHO ⫽ World Health Organization.
inclusion being a complete macroscopic clearance and a free section line at microscopic examination. As later results of randomized studies comparing D1 and D2 resections [1,2] and for antrum gastric cancer subtotal and total gastrectomy [19,20] failed to detect a survival difference between these different procedures, type of resection may be considered as having no influence on results. As the delay in time to recurrence is an endpoint that is difficult to measure reliably in gastric cancer, the present trial was restricted to assessing the effects of combined chemotherapy on survival, and its toxicity. The trial started in 1989 when health-related quality of life (HRQL) was not considered. For gastric cancer, first evaluations about HRQL were published in 1996 and 1997 [21]. As new procedures are developed, an estimation of their effect on HRQL should be added to evaluation of adjuvant treatments. The present trial was not designed specifically to look at subgroups. However, we performed an analysis for lymph node involvement, which has shown no benefit in each subgroup. The difficulty in obtaining good compliance with treatment is a major problem of this study. Digestive toxicity is common with this chemotherapeutic regimen and was the most frequent side effect in our study. On the other hand, gastrectomized patients present frequently with postprandial diarrhea and nutritional difficulties. The association of sur-
gery and chemotherapy side effects is probably the main reason for this very low compliance with treatment. Even if we observed a slight advantage on the actuarial survival curve of patients receiving the nine courses of chemotherapy (Fig. 3), it is not possible to assess that this difference could have been significant in case of better compliance with treatment. Unfortunately, we did not have in this study sufficient data to evaluate correctly the time to disease progression of these patients. A meta-analysis of 11 randomized trials reported between 1980 and 1991 and comparing adjuvant chemotherapy with surgery alone found a nonsignificant trend toward improved survival with an odds ratio of 0.88 (95% CI: 0.78 to 1.08) [22]. However, this meta-analysis was subject to criticism for lacking sufficient power to detect a difference, and for selection of trials [23]. A review of 13 randomized controlled trials of adjuvant chemotherapy versus observation, in non-Asian countries, has also been published [18]. Statistical testing found no significant heterogeneity in the effect of adjuvant chemotherapy between the trials. Metaanalysis involving a total of 1,990 patients showed an odds ratio of 0.80 (95% CI: 0.66 to 0.97) in favor of adjuvant chemotherapy. Another meta-analysis of 20 trials has been recently published; the statistical analysis found a benefit of
Fig. 2. Survival by treatments. Solid line 1: chemotherapy group. Broken line 2: control group.
Fig. 3. Survival by treatment. Solid line 1: patients receiving nine courses of chemotherapy. Broken line 2: patients treated by surgery alone.
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Hennet (Romorantin), P. Letreut (Marseille), G. Lorimier (Angers), J. C. Sarles, B. Sastre (Marseille).
References
Fig. 4. Survival by treatments for patients N⫹. Solid line 1: chemotherapy group. Broken line 2: control group.
adjuvant chemotherapy with an odds ratio of 0.82 (CI: 0.75 to 0.82). Monotherapy give significantly better results than polychemotherapy. This result is based on two large randomized trials with mitomycin as monotherapy [24]. However, journals, and more commonly investigators themselves, are more likely to publish positive results, and publication bias alone can influence such a meta-analysis [25]. The results of the US cooperative groups suggested that postoperative chemoradiation (5-FU, leucovorin, and 45 Gy) for high-risk R0 resected locally advanced adenocarcinoma of the stomach and gastroesophageal junction may be considered a standard of care [26]. However, significant improvement was observed at 3 years and not on actuarial curves using a log rank test. There was 1% toxic death, and grade III and grade IV toxicity occurred in 41% and 32% of cases, respectively. Another study suggested that neoadjuvant 5-FU, leucovorin, adriamycin, and CDDP, radical resection with intraoperative radiotherapy, and postoperative radiotherapy may result in long-term survival [27]. However, these results may be the consequence of the selection of patients. This randomized trial was unable to demonstrate any statistically significant difference in survival of patients after resection for gastric cancer.
Acknowledgments The following surgeons took part in the study: J. Chipponi, D. Pezet (Clermont-Ferrand), N. Basso (Italy), J. M. Hay (Colombes), M. Huguier, S. Houry (Paris), D. Jaeck (Strasbourg), P. L. Fagniez (Cre´ teil), J. F. Charles (Brest), P. Cubertafond, A. Gainant (Limoges), J. P. Lenriot (Longjumeau), J. Testard (Rouen), B. Millat (Montpellier), J. F. Warlin (Argenteuil), G. Kohlman (Corbeil), P. Quandalle (Lille), P. Bloch (Neuilly), F. Dazza (Paris), P. Letoublon (Grenoble), E. Pe´ lissier (Besanc¸ on), X. Pouliquen (Argenteuil), P. Vicq (Paris), B. Descottes (Limoges), H.
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