Choong-kun Lee and Minkyu Jung contributed equally to this work.
We conducted a randomized, multicenter, phase III trial to compare S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP) as adjuvant chemotherapy for stage III gastric cancer patients.
Stage III gastric cancer patients who had received curative gastrectomy with D2 lymphadenectomy were randomized into equal groups to receive adjuvant chemotherapy of eight cycles of DS (S-1 70 mg/m2/day on days 1-14 plus docetaxel 35 mg/m2on days 1 and 8) every 3 weeks or SP (S-1 70 mg/m2/day on days 1-14 plus cisplatin 60 mg/m2on day 1) every 3 weeks. The primary endpoint was 3-year disease-free survival (DFS) rate.
Between November 2010 and July 2013, 153 patients (75 patients to DS and 78 patients to SP) were enrolled from 8 institutions in Korea. After the capecitabine plus oxaliplatin was approved based on the CLASSIC study, itwas decided to close the study early. With a median follow-up duration of 56.9 months, the 3-year DFS rate between two groups was not significantly different (49.14% in DS group vs. 52.5% in SP group). The most common grade 3-4 adverse event was neutropenia (42.7% in DS and 38.5% in SP, p=0.351). SP group had more grade 3-4 anemia (1.3% vs. 11.5%, p=0.037), whereas grade 3-4 hand-foot syndrome (4.1% vs. 0%, p=0.025) and mucositis (10.7% vs. 2.6%, p=0.001) were more common in DS group. Fifty-one patients (68%) in DS group and 52 (66.7%) in SP group finished planned treatment.
Our findings suggest that SP or DS is an effective and tolerable option for patients with curatively resected stage III gastric cancer.
Gastric cancer is the second leading cause of the cancer death worldwide, and is particularly prevalent in Eastern Asia, Eastern Europe, and South America [
In order to identify an efficient doublet antineoplastic regimen that could improve treatment outcome, among late stage advanced gastric cancer patients after D2 gastrectomy, the Post Operation chemotherapy with S-1 and Taxotere in curatively resected gastric cancer of stage III (POST) study was designed. This study compared the effect of two adjuvant S-1 based doublet regimens, S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP), on the disease-free survival (DFS) of D2 resected stage III gastric cancer patients. There have been several previous randomized control trials of DS or SP as palliative treatments in metastatic gastric cancer [
The POST trial was an open-label, phase III, randomized controlled study, performed in eight centers in South Korea. The primary aim of the study was to compare the DFS following S-1 doublets between DS and SP. Gastrectomy with D2 lymphadenectomy has been performed as a standard procedure by all of the surgeons who participated in this trial and the pathology reports were standardized based on D2 dissection in each institute. The patients were randomly assigned to 6 months of treatment with eight cycles of either DS (intravenous docetaxel [35 mg/m2 on days 1 and 8 of each cycle] plus oral S-1 [35 mg/m2 twice daily on days 1 to 14 of each cycle]) every 3 weeks, or SP (intravenous cisplatin [60 mg/m2 on day 1] plus S-1 [same dosage utilized in DS]) every 3 weeks. Oral S-1 was ministered after meal within one hour. Pre-hydration before intravenous cisplatin following the institutional protocol was mandatory to prevent nephrotoxicity. The randomization was stratified by institution and disease stage (IIIA vs. IIIB vs. IIIC). Each stratum was randomized using the randomly permuted block method.
Inclusion criteria for patients were that they should have histopathologically confirmed AJCC seventh stage III gastric adenocarcinoma; undergone R0 resection (with no residual microscopic tumor cells including margin) with D2 lymph node dissection; age of 20 years or older; adequate renal function (creatinine clearance > 50 mL/min), hepatic function (total bilirubin ≤ 1.5 times the upper limit of normal [ULN], aspartate or alanine aminotransferase ≤ 2.5 times the ULN, alkaline phosphatase ≤ 2.5 times the ULN), and hematological function (absolute neutrophil count ≥ 1.5×109/L or platelet count ≥ 100×109/L); and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion criteria were as follows: a tumor other than adenocarcinoma; pregnancy or breast feeding; evidence of metastasis including peritoneal or distant metastasis; any previous treatment of cytotoxic chemotherapy, radiotherapy, or immunotherapy for gastric cancer; previous major surgery within 4 weeks before the start of the trial, or a failure to recover from the surgery; previous history of other malignancies within 5 years except for cured skin basal cell carcinoma or cured
Three-year DFS rate was chosen as the primary endpoint because a recent meta-analysis showed that DFS is an acceptable surrogate end point for overall survival (OS) in trials of cytotoxic agents for gastric cancer in the adjuvant setting [
Toxicity was closely monitored during each treatment cycle, and adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events ver. 4.0. The dose of each chemotherapeutic agent could be reduced if any of the following toxicities occurred in the preceding cycle: grade 4 leukopenia, neutropenia or thrombocytopenia, febrile neutropenia grade 3 or higher, non-hematologic toxicity grade 3 or higher except for hand foot syndrome, cardiac toxicity, and elevated bilirubin of grade 2 or higher. The study drugs were discontinued if recovery did not occur within 3 weeks from the planned day 1.
The intent-to-treat (ITT) patient population, the population for all primary analyses, included all randomly assigned patients who had received at least one cycle of their allocated treatment. Three-year DFS rate, the primary end point, was predicted to be 40.0% and 55.0% in SP group and DS group, respectively (hazard ratio [HR], 0.65), based on two docetaxel and cisplatin combined studies [
In January 2012, the phase III capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study showed a survival benefit of adjuvant capecitabine and oxaliplatin chemotherapy compared to surgery alone, among stage II-III gastric cancer patients who had undergone curative D2 gastrectomy [
The protocol was approved by the institutional review and ethics board of each participating center. The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines defined by the International Conference on Harmonization. All patients provided written, informed consent before enrollment. The trial is registered at ClinicalTrials.gov (NCT01283217).
Between November 2010 and July 2013, a total of 153 patients from eight centers in South Korea were randomly assigned to DS (n=75) or SP (n=78) treatment groups (
The median number of treatment cycles in each group was 8 (range, 1 to 8 cycles). The median relative dose intensity (RDI) was 0.86 for both docetaxel and S-1 in DS group and 0.83 for cisplatin and 0.86 for S-1 in SP group. The RDI of S-1 in both groups was reduced from the second cycle, and the RDI of docetaxel in DS group and cisplatin in SP group was reduced from the third cycle (
Most patients (98.7%) reported at least one adverse event. The total incidence of grade 3 or 4 adverse events was 46 (61.3%) in DS group and 44 (56.4%) in SP group (p=0.536). The most common grade 3 or 4 adverse event was neutropenia (42.7% in DS group and 38.5% in SP group, p=0.351) (
Among total 495 treatment cycles for DS group and 512 cycles for SP group, 130 cycles (26.3%) in DS group and 172 cycles (33.6%) in SP group (p=0.011) were delayed. The chemotherapy dose was reduced in 71 cycles (14.3%) in DS group and 56 cycles (10.9%) in SP group (p=0.104). Overall, the most common reason for delay in the initiation of treatment in each cycle and for the dose reduction was neutropenia (76.8% for of delayed cycles and 52.0% of dose reduced cycles) (
The treatment discontinuations were permanently developed from 24 patients in DS group and from 26 patients in SP groups. The main reason for discontinued treatment was toxicity (12 [50.0%] in DS group and 13 [50.0%] in SP group) (S1 Fig.). The reasons for discontinuation due to toxicity in DS group were allergic reaction (n=3), neutropenia, afferent loop syndrome, skin rash, thromboembolic event, ileus, hand-foot syndrome, general weakness, dyspnea, and nausea/vomiting (n=1 for each). In SP group, toxicities that resulted in treatment discontinuation were neutropenia (n=3), general weakness (n=2), thrombocytopenia, myocardiac infarction, neuropathy, skin rash, anorexia, acute cerebral infarction and pneumonitis (n=1 for each). Three patients in DS group and four patients in SP group were off the study because of gastric cancer recurrence during the course of the trial treatment.
The median duration of follow-up was 53.6 months (range, 1.1 to 74.0 months) for DS group and 57.3 months (range, 1.7 to 73.1 months) for SP group. At the cut-off date for data collection on April 30, 2017, 43 patients (57.3%) in DS group and 40 patients (53.3%) in SP group developed DFS events. The most common site of recurrence was the peritoneum (20 and 11 cases in DS and SP groups, respectively) (Table comparing pattern of recurrences in
This POST trial is the first randomized phase III trial comparing efficacy and tolerability of two S-1 based doublet regimens, DS and SP, in curatively resected stage III gastric cancer patients based on the AJCC seventh edition. Unfortunately, because of the early termination, we could not show any statistically significant advantage in terms of OS or DFS for either regimen. However, both treatments seem to be an effective and tolerable option for these patients.
S-1 was regarded to have advantages over capecitabine among Asians in terms of reducing incidence of toxicities such as stomatitis and hand-foot syndrome [
The addition of docetaxel or cisplatin to S-1 was well-tolerated. We compared compliances and toxicities of our study (POST) with three published phase III studies of adjuvant chemotherapy for gastric cancer; ACTS-GC, CLASSIC, and SAMIT (
The relative small number of accrued patients reduced the statistical power of our study. It is hard to compare survival outcomes of our study to that of previous studies, because this study only included stage III gastric cancer patients diagnosed on the basis of the AJCC seventh edition, and the previous adjuvant phase III studies included patients with stage II or III gastric cancer based on the AJCC sixth edition [
In conclusion, postoperative DS and SP regimens were well tolerated, and the safety data presented here are comparable with that of previous studies. Since the trial was closed early, it didn’t have sufficient statistical power to show a survival advantage for either regimen. We believe that our preliminary findings warrant further clinical investigation.
Supplementary materials are available at Cancer Research and Treatment website (
The drugs were supplied by Sanofi-Aventis Korea and Jeil Pharmaceutical.
We thank the patients, their families, all the investigators, subinvestigators, nurses and study teams. This research was supported by the Public Welfare & Safety Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (2010-0020841).
Median relative dose intensities per regimen and cycle. Median relative dose intensities (RDIs) of S-1 in both groups (A) and RDIs of docetaxel in docetaxel plus S-1 (DS) group or cisplatin in S-1 plus cisplatin (SP) group (B).
Kaplan-Meier curves of disease-free survival (A) and overall survival (B) in the intention-to-treat population.
Baseline patients’ characteristics
Characteristic | DS (n=75) | SP (n=78) |
---|---|---|
Male | 46 (61.3) | 56 (71.8) |
Female | 29 (38.7) | 22 (28.2) |
54 (33-74) | 58 (25-72) | |
0 | 45 (60.0) | 53 (67.9) |
1 | 30 (40.0) | 25 (32.1) |
Tubular adenocarcinoma well differentiated | 0 | 2 (0.3) |
Tubular adenocarcinoma moderately differentiated | 20 (26.7) | 26 (33.3) |
Tubular adenocarcinoma poorly differentiated | 34 (45.2) | 35 (44.9) |
Signet ring cell | 17 (22.7) | 13 (16.7) |
Hepatoid adenocarcinoma | 1 (2.4) | 0 |
Mucinous adenocarcinoma | 2 (2.7) | 1 (2.4) |
Undifferentiated adenocarcinoma | 1 (2.4) | 1 (2.4) |
Intestinal type | 11 (14.7) | 16 (20.5) |
Diffuse type | 29 (38.7) | 18 (23.1) |
Mixed | 2 (2.7) | 8 (10.3) |
Unknown | 33 (44.0) | 36 (45.2) |
43 (34-55) | 40 (29-53) | |
T2 | 2 (2.7) | 3 (3.8) |
T3 | 15 (20.0) | 24 (30.8) |
T4 | 58 (77.3) | 51 (65.4) |
0 | 1 (1.3) | 0 |
1 | 5 (6.7) | 1 (1.3) |
2 | 23 (30.7) | 24 (30.8) |
3 | 46 (61.3) | 53 (56.7) |
9 (12.0) | 10 (12.8) | |
IIIA | ||
IIIB | 33 (44.0) | 36 (46.2) |
IIIC | 33 (44.0) | 32 (41.0) |
4 (5.3) | 6 (7.7) | |
II | ||
IIIA | 26 (34.7) | 31 (39.7) |
IIIB | 18 (24.0) | 20 (25.6) |
IV | 25 (33.3) | 20 (25.6) |
6.13 (2.7-8.7) | 5.66 (2.5-7.8) |
Values are presented as number (%) unless otherwise indicated. DS, docetaxel plus S-1; SP, S-1 plus cisplatin; ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; AJCC, American Joint Committee on Cancer.
Adverse events (n=153)
Treatment-related adverse event | DS (n=75) |
SP (n=78) |
p-value | ||
---|---|---|---|---|---|
All | G3/4 | All | G3/4 | ||
74 (98.7) | 46 (61.3) | 77 (98.7) | 44 (56.4) | 0.536 | |
Febrile neutropenia | 3 (4.0) | 2 (2.7) | 3 (3.8) | 3 (3.8) | 0.548 |
Neutropenia | 51 (68.0) | 32 (42.7) | 28 (35.9) | 30 (38.5) | 0.351 |
Anemia | 41 (54.0) | 1 (1.3) | 45 (57.6) | 9 (11.5) | 0.037 |
Thrombocytopenia | 2 (2.6) | 1 (1.3) | 19 (24.3) | 1 (1.3) | < 0.001 |
Abdominal pain | 24 (32.0) | 3 (4.1) | 15 (19.2) | 2 (2.6) | 0.193 |
Anorexia | 48 (64.0) | 5 (6.7) | 47 (60.2) | 5 (6.4) | 0.892 |
Nausea | 49 (65.3) | 2 (2.7) | 51 (65.4) | 2 (2.6) | 0.999 |
Vomiting | 16 (21.3) | 1 (1.3) | 17 (21.8) | 1 (1.3) | 0.997 |
Hand foot syndrome | 18 (24.0) | 3 (4.1) | 7 (9.0) | 0 | 0.025 |
Mucositis | 39 (52.0) | 8 (10.7) | 18 (23.1) | 2 (2.6) | 0.001 |
Diarrhea | 40 (53.3) | 2 (2.7) | 35 (44.9) | 3 (3.8) | 0.478 |
Paronychia | 8 (10.7) | 0 | 0 | 0 | 0.003 |
Alopecia | 34 (45.3) | 0 | 4 (5.1) | 0 | < 0.001 |
Fatigue | 12 (16.0) | 1 (1.3) | 14 (18.0) | 1 (1.3) | 0.944 |
General weakness | 16 (21.3) | 1 (1.3) | 23 (29.5) | 2 (2.6) | 0.493 |
Neuropathy | 17 (22.7) | 0 | 15 (19.2) | 1 (1.3) | 0.487 |
Values are presented as number (%). One treatment related death in DS group: thromboembolism event. DS, docetaxel plus S-1; SP, S-1 plus cisplatin.
The reasons for chemotherapy cycle delays and reductions
Delayed cycles |
Dose reduced cycles |
|||
---|---|---|---|---|
DS (n=495) | SP (n=512) | DS (n=495) | SP (n=512) | |
84 | 152 | 35 | 33 | |
Neutropenia | 83 | 149 | 35 | 31 |
Febrile neutropenia | 1 | 1 | 0 | 1 |
Anemia | 0 | 1 | 0 | 0 |
Thrombocytopenia | 0 | 1 | 0 | 1 |
46 | 20 | 36 | 23 | |
General weakness | 8 | 2 | 4 | 4 |
Nausea/Vomiting | 5 | 1 | 5 | 4 |
Patients' refusal | 4 | 6 | 2 | 0 |
Mucositis | 4 | 2 | 9 | 2 |
Urticaria/Skin rash | 4 | 0 | 1 | 0 |
Anorexia | 3 | 4 | 3 | 3 |
Hand-foot syndrome | 3 | 0 | 4 | 0 |
Weight loss | 3 | 0 | 1 | 3 |
Fatigue | 0 | 3 | 3 | 1 |
Diarrhea | 0 | 2 | 1 | 3 |
Hemorrhoid | 2 | 0 | 0 | 0 |
Nail Infection | 2 | 0 | 1 | 0 |
Abdominal pain | 1 | 0 | 0 | 2 |
Generalized edema | 2 | 0 | 0 | 0 |
Common cold | 2 | 0 | 0 | 0 |
Herpes zoster | 1 | 0 | 1 | 0 |
Intestinal obstruction | 1 | 0 | 0 | 0 |
Bilirubin elevation | 1 | 0 | 1 | 0 |
Dizziness | 0 | 0 | 0 | 1 |
130 (26.3) | 172 (33.6) | 71 (14.3) | 56 (10.9) |
DS, docetaxel plus S-1; SP, S-1 plus cisplatin.
Comparison of phase III gastric cancer adjuvant chemotherapy studies
Reference | Study design | No. | Stage | Regimen | Completion of total cycles (%) | RDI | Median follow up duration (mo) | 3-Year DFS rate (%) | G3/4 hematologic toxicity, n (%) | G3/4 nonhematologic toxicities, n (%) |
---|---|---|---|---|---|---|---|---|---|---|
ACTS-GC [ |
S-1 vs. observation | 529 | AJCC 6th II-IIIB | S-1 80 mg/m2/D D1-28, q6wks, for 1 yr | 65.8 | N/A | 34.8 | 72.2 | Leukopenia 6 (1.2), anemia 6 (1.2) | Anorexia 31 (6.0), nausea 19 (3.7), deiarrhea 16 (3.1) |
CLASSIC [ |
XELOX vs. observation | 520 | AJCC 6th II-IIIB | Capecitabine 1,000 mg/m2 BID D1-14, oxaliplatin 130 mg/m2 D1, q3wks, 8 cycles | 67.0 | 85% (capecitabine) | 34.2 | 74 | Neutropenia 107 (22), thrombocytopenia 40 (8) | Nausea 39 (8.0), vomiting 37 (7.0), decreased appetite, fatigue 23 (5.0) |
98% (oxaliplatin) | ||||||||||
SAMIT (S-1 only) [ |
UFT±paclitaxel vs. S-1±paclitaxel | 364 | AJCC 6th I-IV (M0) | S-1 80 mg/m2 BID D1-14, q3wks, 16 cycles | 61.5 | N/A | 62.8 | N/A (54.0 for monotherapy group) | Neutropenia 48 (13), anemia 11 (3) | Anorexia 24 (7), fatigue 12 (3), abnormal total bilirubin 10 (3) |
SAMIT (paclitaxel then S-1) [ |
UFT±paclitaxel vs. S-1±paclitaxel | 355 | AJCC 6th I-IV (M0) | Palitaxel 80 mg/m2 D1, 8, 1 wk rest then D1, 15 q4wks, 2 cycles (total 3 cycles) → S-1 80 mg/m2 BID D1-14, q3wks, 12 cycles | 70.4 | N/A | 61.3 | N/A (57.2 for sequential group) | Neutropenia 83 (23), leukopenia 16 (4) | Anorexia 18 (5), fatigue 16 (4), diarrhea 11 (3) |
Current study (DS) | DS vs. SP | 75 | AJCC 6th IIIB-IV (AJCC 7th III) | S-1 70 mg/m2/D D1-14, docetaxel 35 mg/m2, D1, 8, q3wks, 8 cycles | 68.0 | 86% (S-1 and docetaxel) | 53.6 | 49.1 | Neutropenia 32 (42.7) | Mucositis 8 (10.8), anorexia 5 (6.8), abd pain 3 (4.1), HFS 3 (4.1) |
Current study (SP) | DS vs. SP | 78 | AJCC 6th IIIB-IV (AJCC 7th III) | S-1 70 mg/m2/D D1-14, docetaxel 60 mg/m2, D1, 8, q3wks, 8 cycles | 66.7 | 86% (S-1) | 57.3 | 52.5 | Neutropenia 30 (38.5), anemia 9 (11.7) | Anorexia 5 (6.5), nausea 3 (3.9) |
83% (cisplatin) |
RDI, relative dose intensity; DFS, disease-free survival; ACTS-GC, Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer; AJCC, American Joint Committee on Cancer; q6wks, ever 6 weeks; N/A, not available; XELOX, Xeloda (capecitabine) plus oxaliplatin; BID, twice a day; q3wks, ever 3 weeks; UFT, uracil-tegafur; q4wks, every 4 weeks; DS, docetaxel plus S-1; SP, S-1 plus cisplatin; HFS, hand-foot syndrome.