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Randomized open-label phase II study of adjuvant chemotherapy of S-1 plus metformin vs. S-1 alone in patients with resected pancreatic cancer (Randomized open-label phase II study of adjuvant chemotherapy of S-1 plus metformin vs. S-1 alone in patients with resected pancreatic cancer(ASMET))

ASMET (ASMET)

76

The median age was 69.5 years (range 49-81 years) in group A(S-1 and metformin combination therapy ) and 70 years (range 52-83 years) in group B(S-1 monotherapy). There were 23 males and 15 females in group A and 20 males and 17 females in group B. 29 patients in group A and 32 patients in group B had a PS of 0, and 9 patients in group A and 5 patients in group B had a PS of 1. The median BMI was 20.3 in group A and 20.2 in group B. The number of patients who underwent pancreaticoduodenectomy was 26 in group A and 23 in group B, and the number of patients who underwent distal pancreatectomy was 12 in group A and 14 in group B. The stage of disease was stage<= II in 37 patients in group A and 37 in group B, and stage III in 1 patient in group A and 0 patients in group B. Regarding residual cancer status, 37 patients in group A and 35 patients in group B had R0, and 1 patient in group A and 2 patients in group B had R1. Regarding lymph node metastasis, 17 patients in group A and 17 patients in group B were N0, and 21 patients in group A and 20 patients in group B were N1. The median CEA/CA19-9/HbA1c values were 2.6/32.8/6.2 in group A and 2.4/39.3/6.2 in group B, respectively. The duration of diabetes was 5 to 10 years in 0 patients in group A and 1 patient in group B, 2 to 5 years in 2 patients in group A and 0 patients in group B, and less than 2 years in 18 patients in group A and 13 patients in group B. It was the first time that diabetes was detected in 18 patients in group A and 23 patients in group B.

The registration period was set to three years at the start of the study, and registration proceeded smoothly as planned at the beginning. However, due to the rapid spread of DPP-4 inhibitors and SGLT2 inhibitors, which are prohibited for concomitant use according to the protocol, the number of non-compliant cases increased and registration slowed. Furthermore, neoadjuvant chemotherapy for resectable pancreatic cancer became recognized as one of the new standard therapies, and the registration pace slowed down. Therefore, on October 8, 2020, the protocol was revised and the registration period was extended to four years. However, with the emergence of the COVID19 pandemic, several academic societies announced that "postoperative adjuvant chemotherapy is not recommended for certain types of cancer," and the registration pace further slowed. It was determined that no further case registrations could be expected, so the registration period was not extended again. The original planned number of cases was 160, but on January 26, 2022, 91 cases had agreed to participate in the study, of which 76 cases had been assigned, and case enrollment was closed.

The incidence of adverse events during the S-1 administration and observation periods was 76.3% in group A and 75.7% in group B. Major grade 3 non-hematological toxicities were cholangitis (7.9% in group A, 5.4% in group B), anorexia (0% in group A, 2.7% in group B), nausea (2.6% in group A, 0% in group B), diarrhea (0% in group A, 2.7% in group B), and fatigue/general malaise (0% in group A, 2.7% in group B). Grade 3 hematological toxicities were neutropenia (2.6% in group A, 0% in group B), and anemia (5.3% in group A, 2.7% in group B). No adverse events of grade 4 or higher were observed.

In this study, the primary endpoint was overall survival (2-year survival rate), and the efficacy and safety of S-1 and metformin combination therapy as adjuvant chemotherapy for patients with resected pancreatic cancer were exploratory studies. The primary outcome was that the 2-year survival rate for all eligible patients was 66.7% for S-1 and metformin combination therapy and 66.1% for S-1 monotherapy. Secondary endpoints were recurrence-free survival and adverse event rate, the former of which was a median of 17.9 months(95%:7.3-46.8)for S-1 and metformin combination therapy and 12.6 months(95%: 9.1-57.6) for S-1 monotherapy. The adverse event rate was as described above.

A prospective randomized comparative study was conducted on the combination of S-1 and metformin with S-1 monotherapy as postoperative adjuvant chemotherapy for patients with diabetes after radical resection of pancreatic cancer. No significant additional benefit of metformin to S-1 therapy was confirmed. In this study, both groups were administered S-1 on a new schedule of two weeks on and one week off, and both groups showed efficacy comparable to previously reported results, with safety superior.

Dec. 22, 2025

No

no

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180270

Hisano Terumasa

National Hospital Organization Kyushu Cancer Center

3-1-1 Notame Minami-ku Fukuoka,Japan

idling3000@yahoo.co.jp

Furukawa Masayuki

National Hospital Organization Kyushu Cancer Center

3-1-1 Notame Minami-ku Fukuoka,Japan

+81-92-541-3231

nhoebm@gmail.com

Complete

Jan. 26, 2018

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1)Histologically confirmed invasive ductal carcinoma of pancreas and after radical pancreatic resection
2)The primary tumor has been macroscopically complete resected and meet all of the following the histopathological staging in UICC seventh edition
StageIIor less
StageIII underwent celiac artery resection for complete tumor removal
Local residual tumor status is
R0 or R1
Intraoperative peritoneal lavage cytology is negative
3)Neither distant metastasis nor malignant ascites
4)Oral nutrition is sufficiently maintained
5)No previous cancer treatment history other than pancreatic resection for pancreatic cancer
6)The patient is >= 20 years old at the time of obtaining informed consent
7)The patient has an Eastern Cooperative Oncology Group(ECOG)Performance Status (PS) of 0 or 1
8)The patient discontinued any chemotherapy and any radiotherapy>= 3years prior to randomization
9)The patient received radical pancreatic resection within 12 weeks prior to randomization
10)Impaired glucose tolerance was observed to meet one of the following diagnostic criteria for diabetes even once throughout the entire period prior to randomization
Fasting plasma glucose level>= 126mg/dl
Plasma glucose level at any time>=200mg/dl
Diabetes type in 75gOGTT
HbA1c(NGSP) >= 6.5%
HbA1c(JDS) >= 6.1%
11)The patient has adequate major organ function and meet all of the following requirements within 7 days prior to randomization:(HBs antigen test is only allowed within 28 days prior to randomization.)
White blood cell count(WBC) >=3,000/mm3 and<= 12,000/mm3
Absolute neutrophil count(ANC) >=1,500/mm3
Platelets>=100,000/mm3
Hemoglobin>=8.0g/dL
Total bilirubin<=2.0mg/dL
Aspartate transaminase(AST) and alanine transaminase(ALT) <=150IU/L
Serum creatinine<=1.5mg/dL
Ccr>=50mL/min
HBs antigen is negative
12)The patient has provided signed informed consent prior to randomization

1)Any previous therapy with S-1 or any DPP-4 inhibitor or any GLP-1
2)Any anticancer therapy,(including hormone therapy, immunotherapy, and natural-origin and plant supplement etc.)within 1-year prior to randomization and any neoadjuvant therapy
3)A history of serious complications associated with resection
4)Reccurence in the examination prior to randomization
*But it is not concluded that only incomplete decrease of tumor marker or only tiny ascites with CT means recurrence
5)Moderate or more pleural effusion or ascites with chest X-ray or abdominal CT
6)Apparent pulmonary fibrosis or interstitial pneumonia with chest X-ray or with clinical symptom
7)A history of gastrointestinal disorder concerning for dehydration status
8)Symptomatic congestive heart failure: New York Heart Association III-IV
9)Severe ketosis, diabetic coma or pre-coma, or type 1 diabetes
10)Malnutrition, starvation, general prostration condition, pituitary dysfunction or adrenal insufficiency.
11)A history of onset of myocardial infarction within 6 months
12)Active infection
13)Positive for HBs antigen
14)A history blood transfusion within 2 weeks prior to randomization
15)A history of lactic acidosis
16)Moderate or severe renal dysfunction or has received dialysis
17)Severe liver dysfunction
18)The patient tends to run into hypoxia status
19)The patient intakes excessive alcohol
20)Other severe complication
21)Any psychosis or psychiatric symptoms
22)Active multiple primary cancer(simultaneous one or heterochronous one accompanied by disease-free time within 3 years)
23)A female with pregnancy , breast-feeding,possibility of pregnancy,intention of pregnancy, or desire od delivery
24)A male with intention of having children.
25)The patient receives flucytosine, phenytoin, or warfarin potassium
26)The patient is determined to be unsuitable to safely carry out the study

Both

pancreatic cancer

A:S-1+Metformin
S-1 day1-14 of each 21-day cycle, until progression disease or completion of the planned 6 months
Treatment for diabetes: Metformin 500mg/day day1-21, subsequently 750mg/day for 2 years
B:S-1
S-1 day1-14 of each 21-day cycle, until progression disease or completion of the planned 6 months
Treatment for diabetes: Any diabetic treatment without Metformin for 2 years

2-years survival rate (overall survaival)

Recurrence free survival time
Adverse event rate

+81-52-951-1111

Feb. 18, 2019

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