1Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
2Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea
3Department of Oncology, Asan Medical Center, Seoul, Korea
4Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
5Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Korea
6Division of Oncology and Hematology, Department of Internal Medicine, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
7Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
8Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea
9Department of Hematology-Oncology, Inje University Haeundae Paik Hospital, Busan, Korea
10Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
11Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
12Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, Korea
13Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
14HERINGS, The Institution of Advanced Clinical & Biomedical Research, Seoul, Korea
Copyright © 2023 by the Korean Cancer Association
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ethical Statement
The study protocol was reviewed and approved by the institutional review board at each institution. All patients enrolled in this study provided informed consent to participate in this trial. This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Choi IS.
Collected the data: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Choi IS.
Contributed data or analysis tools: Nam BH.
Performed the analysis: Lee KW, Nam BH, Choi IS.
Wrote the paper: Lee KW, Choi IS.
Writing-review and editing: Lee KW, Zang DY, Ryu MH, Han HS, Kim KH, Kim MJ, Koh SA, Lee SS, Koo DH, Ko YH, Sohn BS, Kim JW, Park JH, Nam BH, Choi IS.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Group | Regimen | Starting dose (cycle 1)a) | Full dose (cycle 2 or later)b) |
---|---|---|---|
A | 5-FU, leucovorin and oxaliplatin (FOLFOX) | Oxaliplatin (80 mg/m2) IV on day 1, leucovorin (80 mg/m2) IV on day 1, and 5-FU (1,900 mg/m2; over 46 hr) IV on day 1 every 2 wk | Oxaliplatin (100 mg/m2) IV on day 1, leucovorin (100 mg/m2) IV on day 1, and 5-FU (2,400 mg/m2; over 46 hr) IV on day 1 every 2 wk |
Capecitabine and oxaliplatin (CAPOX) | Oxaliplatin (100 mg/m2) IV on day 1, and capecitabine (800 mg/m2) orally twice a day (days 1–14) every 3 wk | Oxaliplatin (130 mg/m2) IV on day 1, and capecitabine (1,000 mg/m2) orally twice a day (days 1–14) every 3 wk | |
S-1 and cisplatin | Cisplatin (50 mg/m2) IV on day 1, and S-1 (30 mg/m2) orally twice a day (days 1–14) every 3 wk | Cisplatin (60 mg/m2) IV on day 1, and S-1 (40 mg/m2) orally twice a day (days 1–14) every 3 wk | |
Capecitabine and cisplatin | Cisplatin (50 mg/m2) IV on day 1, and capecitabine (1,000 mg/m2) orally twice a day (days 1–14) every 3 wk | Cisplatin (60 mg/m2) IV on day 1, and capecitabine (1,250 mg/m2) orally twice a day (days 1–14) every 3 wk | |
B | 5-FU and leucovorin (FL) | Leucovorin (100 mg/m2) IV on day 1, and 5-FU (2,400 mg/m2; over 46 hr) IV on day 1 every 2 wk | Same as cycle 1 |
Capecitabine | Capecitabine (1,250 mg/m2) orally twice a day (days 1–14) every 3 wk when CCr ≥ 60 mL/min; capecitabine (1,000 mg/m2) twice a day (days 1–14) every 3 wk when CCr < 60 mL/min | Same as cycle 1 | |
S-1 | S-1 (40 mg/m2) orally twice a day (days 1–14) every 3 wk when CCr ≥ 60 mL/min; S-1 (30 mg/m2) twice a day (days 1–14) every 3 wk when CCr < 60 mL/min | Same as cycle 1 |
5-FU, 5-fluorouracil; CCr, creatinine clearance; IV, intravenously.
a) In group A, starting dose was about 80% of standard dose in each regimen. In contrast, in group B, study treatment was started with standard dose (100%),
b) In group A, after the completion of first cycle of chemotherapy, the dose of chemotherapeutic agents could be escalated to 100%. This was at the discretion of the investigator based on the observed toxicities during the first cycle.
Variable | Total (n=104) | Combination therapy (group A, n=53) | Monotherapy (group B, n=51) | p-value |
---|---|---|---|---|
Age (yr) | ||||
< 75 | 44 (42.3) | 22 (41.5) | 22 (43.1) | 0.867a) |
≥75 | 60 (57.7) | 31 (58.5) | 29 (56.9) | |
Sex | ||||
Male | 76 (73.1) | 38 (71.7) | 38 (74.5) | 0.747a) |
Female | 28 (26.9) | 15 (28.3) | 13 (25.5) | |
ECOG performance status | ||||
0–1 | 82 (78.8) | 43 (81.1) | 39 (76.5) | 0.561a) |
2 | 22 (21.2) | 10 (18.9) | 12 (23.5) | |
Fluoropyrimidine backbone | ||||
5-FU | 40 (38.5) | 21 (39.6) | 19 (37.3) | 0.940a) |
Capecitabine | 35 (33.7) | 17 (32.1) | 18 (35.3) | |
S-1 | 29 (27.9) | 15 (28.3) | 14 (27.5) | |
Lauren classification | ||||
Intestinal | 31 (29.8) | 20 (37.7) | 11 (21.6) | 0.106b) |
Diffuse | 25 (24.0) | 9 (17.0) | 16 (31.4) | |
Mixed | 1 (1.0) | 1 (1.9) | 0 | |
Unknown | 47 (45.2) | 23 (43.4) | 24 (47.1) | |
Gastrectomy | ||||
Primary metastatic without gastrectomy | 73 (70.2) | 35 (66.0) | 38 (74.5) | 0.591a) |
Primary metastatic with gastrectomy | 13 (12.5) | 7 (13.2) | 6 (11.8) | |
Recurrent | 18 (17.3) | 11 (20.8) | 7 (13.7) | |
Previous adjuvant chemotherapy | ||||
No | 97 (93.3) | 49 (92.5) | 48 (94.1) | > 0.99b) |
Yes | 7 (6.7) | 4 (7.5) | 3 (5.9) | |
No. of metastatic organs | ||||
0–1 | 62 (59.6) | 34 (64.2) | 28 (54.9) | 0.337a) |
2 | 26 (25.0) | 10 (18.9) | 16 (31.4) | |
3 or more | 16 (15.4) | 9 (17.0) | 7 (13.7) | |
Metastatic organs | ||||
Distant abdominal lymph nodes | 43 (41.3) | 22 (41.5) | 21 (41.2) | 0.973a) |
Peritoneum | 39 (37.5) | 16 (30.2) | 23 (45.1) | 0.116a) |
Liver | 32 (30.8) | 19 (35.8) | 13 (25.5) | 0.253a) |
Lung | 13 (12.5) | 8 (15.1) | 5 (9.8) | 0.415a) |
Bone | 6 (5.8) | 3 (5.7) | 3 (5.9) | > 0.99b) |
Neck and mediastinal lymph nodes | 5 (4.8) | 1 (1.9) | 4 (7.8) | 0.201b) |
Others | 22 (21.2) | 10 (18.9) | 12 (23.5) | 0.561a) |
Comorbidities | ||||
Hypertension | 43 (41.3) | 25 (47.2) | 18 (35.3) | 0.219a) |
Diabetes mellitus | 20 (19.2) | 11 (20.8) | 9 (17.6) | 0.688a) |
Cerebrovascular disease | 7 (6.7) | 3 (5.7) | 4 (7.8) | 0.713b) |
Chronic obstructive pulmonary disease or asthma | 6 (5.8) | 4 (7.5) | 2 (3.9) | 0.678b) |
Coronary heart disease | 5 (4.8) | 1 (1.9) | 4 (7.8) | 0.201b) |
Arrhythmia | 5 (4.8) | 3 (5.7) | 2 (3.9) | > 0.99b) |
Combination therapy (group A, n=35) | Monotherapy (group B, n=36) | p-value | |
---|---|---|---|
Complete response | 0 | 0 | |
Partial response | 12 (34.3) | 9 (25.0) | |
Stable disease | 15 (42.9) | 12 (33.3) | |
Progressive disease | 3 (8.6) | 8 (22.2) | |
Not evaluable | 5 (14.3) | 7 (19.4) | |
Objective response rate (ORR) | 12 (34.3) | 9 (25.0) | 0.391a) |
95% Confidence interval (ORR, %) | 19.1–52.2 | 12.1–42.2 | |
Disease control rate (DCR) | 27 (77.1) | 21 (58.3) | 0.090a) |
95% Confidence interval (DCR, %) | 59.9–89.6 | 40.8–74.5 |
Dosage and administration of study treatment regimens
Group | Regimen | Starting dose (cycle 1) |
Full dose (cycle 2 or later) |
---|---|---|---|
A | 5-FU, leucovorin and oxaliplatin (FOLFOX) | Oxaliplatin (80 mg/m2) IV on day 1, leucovorin (80 mg/m2) IV on day 1, and 5-FU (1,900 mg/m2; over 46 hr) IV on day 1 every 2 wk | Oxaliplatin (100 mg/m2) IV on day 1, leucovorin (100 mg/m2) IV on day 1, and 5-FU (2,400 mg/m2; over 46 hr) IV on day 1 every 2 wk |
Capecitabine and oxaliplatin (CAPOX) | Oxaliplatin (100 mg/m2) IV on day 1, and capecitabine (800 mg/m2) orally twice a day (days 1–14) every 3 wk | Oxaliplatin (130 mg/m2) IV on day 1, and capecitabine (1,000 mg/m2) orally twice a day (days 1–14) every 3 wk | |
S-1 and cisplatin | Cisplatin (50 mg/m2) IV on day 1, and S-1 (30 mg/m2) orally twice a day (days 1–14) every 3 wk | Cisplatin (60 mg/m2) IV on day 1, and S-1 (40 mg/m2) orally twice a day (days 1–14) every 3 wk | |
Capecitabine and cisplatin | Cisplatin (50 mg/m2) IV on day 1, and capecitabine (1,000 mg/m2) orally twice a day (days 1–14) every 3 wk | Cisplatin (60 mg/m2) IV on day 1, and capecitabine (1,250 mg/m2) orally twice a day (days 1–14) every 3 wk | |
B | 5-FU and leucovorin (FL) | Leucovorin (100 mg/m2) IV on day 1, and 5-FU (2,400 mg/m2; over 46 hr) IV on day 1 every 2 wk | Same as cycle 1 |
Capecitabine | Capecitabine (1,250 mg/m2) orally twice a day (days 1–14) every 3 wk when CCr ≥ 60 mL/min; capecitabine (1,000 mg/m2) twice a day (days 1–14) every 3 wk when CCr < 60 mL/min | Same as cycle 1 | |
S-1 | S-1 (40 mg/m2) orally twice a day (days 1–14) every 3 wk when CCr ≥ 60 mL/min; S-1 (30 mg/m2) twice a day (days 1–14) every 3 wk when CCr < 60 mL/min | Same as cycle 1 |
5-FU, 5-fluorouracil; CCr, creatinine clearance; IV, intravenously.
a)In group A, starting dose was about 80% of standard dose in each regimen. In contrast, in group B, study treatment was started with standard dose (100%),
b)In group A, after the completion of first cycle of chemotherapy, the dose of chemotherapeutic agents could be escalated to 100%. This was at the discretion of the investigator based on the observed toxicities during the first cycle.
Patient characteristics (full-analysis set)
Variable | Total (n=104) | Combination therapy (group A, n=53) | Monotherapy (group B, n=51) | p-value |
---|---|---|---|---|
Age (yr) | ||||
< 75 | 44 (42.3) | 22 (41.5) | 22 (43.1) | 0.867 |
≥75 | 60 (57.7) | 31 (58.5) | 29 (56.9) | |
Sex | ||||
Male | 76 (73.1) | 38 (71.7) | 38 (74.5) | 0.747 |
Female | 28 (26.9) | 15 (28.3) | 13 (25.5) | |
ECOG performance status | ||||
0–1 | 82 (78.8) | 43 (81.1) | 39 (76.5) | 0.561 |
2 | 22 (21.2) | 10 (18.9) | 12 (23.5) | |
Fluoropyrimidine backbone | ||||
5-FU | 40 (38.5) | 21 (39.6) | 19 (37.3) | 0.940 |
Capecitabine | 35 (33.7) | 17 (32.1) | 18 (35.3) | |
S-1 | 29 (27.9) | 15 (28.3) | 14 (27.5) | |
Lauren classification | ||||
Intestinal | 31 (29.8) | 20 (37.7) | 11 (21.6) | 0.106 |
Diffuse | 25 (24.0) | 9 (17.0) | 16 (31.4) | |
Mixed | 1 (1.0) | 1 (1.9) | 0 | |
Unknown | 47 (45.2) | 23 (43.4) | 24 (47.1) | |
Gastrectomy | ||||
Primary metastatic without gastrectomy | 73 (70.2) | 35 (66.0) | 38 (74.5) | 0.591 |
Primary metastatic with gastrectomy | 13 (12.5) | 7 (13.2) | 6 (11.8) | |
Recurrent | 18 (17.3) | 11 (20.8) | 7 (13.7) | |
Previous adjuvant chemotherapy | ||||
No | 97 (93.3) | 49 (92.5) | 48 (94.1) | > 0.99 |
Yes | 7 (6.7) | 4 (7.5) | 3 (5.9) | |
No. of metastatic organs | ||||
0–1 | 62 (59.6) | 34 (64.2) | 28 (54.9) | 0.337 |
2 | 26 (25.0) | 10 (18.9) | 16 (31.4) | |
3 or more | 16 (15.4) | 9 (17.0) | 7 (13.7) | |
Metastatic organs | ||||
Distant abdominal lymph nodes | 43 (41.3) | 22 (41.5) | 21 (41.2) | 0.973 |
Peritoneum | 39 (37.5) | 16 (30.2) | 23 (45.1) | 0.116 |
Liver | 32 (30.8) | 19 (35.8) | 13 (25.5) | 0.253 |
Lung | 13 (12.5) | 8 (15.1) | 5 (9.8) | 0.415 |
Bone | 6 (5.8) | 3 (5.7) | 3 (5.9) | > 0.99 |
Neck and mediastinal lymph nodes | 5 (4.8) | 1 (1.9) | 4 (7.8) | 0.201 |
Others | 22 (21.2) | 10 (18.9) | 12 (23.5) | 0.561 |
Comorbidities | ||||
Hypertension | 43 (41.3) | 25 (47.2) | 18 (35.3) | 0.219 |
Diabetes mellitus | 20 (19.2) | 11 (20.8) | 9 (17.6) | 0.688 |
Cerebrovascular disease | 7 (6.7) | 3 (5.7) | 4 (7.8) | 0.713 |
Chronic obstructive pulmonary disease or asthma | 6 (5.8) | 4 (7.5) | 2 (3.9) | 0.678 |
Coronary heart disease | 5 (4.8) | 1 (1.9) | 4 (7.8) | 0.201 |
Arrhythmia | 5 (4.8) | 3 (5.7) | 2 (3.9) | > 0.99 |
Values are presented as number (%). 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group.
a)Chi-square test,
b)Fisher’s exact test.
Tumor response (full-analysis set)
Combination therapy (group A, n=35) | Monotherapy (group B, n=36) | p-value | |
---|---|---|---|
Complete response | 0 | 0 | |
Partial response | 12 (34.3) | 9 (25.0) | |
Stable disease | 15 (42.9) | 12 (33.3) | |
Progressive disease | 3 (8.6) | 8 (22.2) | |
Not evaluable | 5 (14.3) | 7 (19.4) | |
Objective response rate (ORR) | 12 (34.3) | 9 (25.0) | 0.391 |
95% Confidence interval (ORR, %) | 19.1–52.2 | 12.1–42.2 | |
Disease control rate (DCR) | 27 (77.1) | 21 (58.3) | 0.090 |
95% Confidence interval (DCR, %) | 59.9–89.6 | 40.8–74.5 |
Values are presented as number (%) unless otherwise indicated.
a)Chi-square test.
Treatment-related adverse events
Combination therapy (group A, n=53) |
Monotherapy (group B, n=51) | |||
---|---|---|---|---|
Any grade | ≥Grade 3 | Any grade | ≥Grade 3 | |
Neutropenia | 23 (43.4) | 2 (3.8) | 11 (21.6) | 1 (2.0) |
Anemia | 49 (92.5) | 6 (11.3) | 46 (90.2) | 4 (7.8) |
Thrombocytopenia | 22 (41.5) | 0 | 10 (19.6) | 0 |
Fatigue | 25 (47.2) | 2 (3.8) | 14 (27.5) | 1 (2.0) |
Anorexia | 34 (64.2) | 1 (1.9) | 18 (35.3) | 1 (2.0) |
Nausea | 20 (37.7) | 3 (5.7) | 18 (35.3) | 1 (2.0) |
Vomiting | 8 (15.1) | 2 (3.8) | 5 (9.8) | 1 (2.0) |
Diarrhea | 12 (22.6) | 1 (1.9) | 6 (11.8) | 0 |
Stomatitis | 7 (13.2) | 0 | 5 (9.8) | 1 (2.0) |
Abdominal pain | 6 (11.3) | 0 | 8 (15.7) | 1 (2.0) |
Constipation | 5 (9.4) | 0 | 4 (7.8) | 0 |
Dyspepsia | 5 (9.4) | 0 | 2 (3.9) | 0 |
Hand-foot syndrome | 7 (13.2) | 0 | 4 (7.8) | 1 (2.0) |
Peripheral neuropathy | 26 (49.1) | 2 (3.8) | 0 | 0 |
Pruritis | 3 (5.7) | 0 | 1 (2.0) | 0 |
Weight loss | 3 (5.7) | 0 | 1 (2.0) | 0 |
Dizziness | 3 (5.7) | 0 | 1 (2.0) | 0 |
Flu-like symptoms | 3 (5.7) | 0 | 0 | 0 |
Hiccups | 3 (5.7) | 0 | 0 | 0 |
Hyponatremia | 18 (34.0) | 1 (1.9) | 20 (39.2) | 2 (3.9) |
Increased bilirubin | 12 (22.6) | 0 | 11 (21.6) | 0 |
Increased creatinine | 4 (7.6) | 0 | 4 (7.8) | 0 |
Values are presented as number (%).
5-FU, 5-fluorouracil; CCr, creatinine clearance; IV, intravenously. In group A, starting dose was about 80% of standard dose in each regimen. In contrast, in group B, study treatment was started with standard dose (100%), In group A, after the completion of first cycle of chemotherapy, the dose of chemotherapeutic agents could be escalated to 100%. This was at the discretion of the investigator based on the observed toxicities during the first cycle.
Values are presented as number (%). 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group. Chi-square test, Fisher’s exact test.
Values are presented as number (%) unless otherwise indicated. Chi-square test.
Values are presented as number (%).