Abstract #656P
Treatment Strategy for Conversion Therapy Using Docetaxel/CDDP/S-1 (DCS) or DCS-Trastuzumab (DCS-T)
According to HER2 Status in Metastatic Gastric Cancer Patients
Yasushi Sato1, Hiroyuki Ohnuma1, Tetsuji Takayama2, Tamotsu Sagawa3, Masahiro Hirakawa1, Yasuhiro Sato3, Yasuo Takahashi3, Minoru Takahashi4, Masahiro Maeda5, Shinich Katsuki6, Michiaki Hirayama7, Kohichi Takada1, Tsuyoshi Hayashi1, Tsutomu Sato1, Koji Miyanishi1, Masayoshi Kobune1, Rishu Takimoto1, Takayuki Nobuoka8, Koichi Hirata8 and Junji Kato1
1) Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan; 2) Department of Gastroenterology and Oncology, Tokushima University, Tokushima, Japan; 3) Division of Gastroenterology, Hokkaido Cancer Center, Sapporo, Japan;4) Division of Gastroenterology, Sapporo Kyoritu Gorinbashi Hospital, Sapporo, Japan;
5) Division of Gastroenterology, Steel Memorial Muroran Hospital, Muroran, Japan; 6) Division of Gastroenterology, Otaru Ekisaikai Hospital, Otaru, Japan; 7) Division of Gastroenterology, Tonan Hospital, Sapporo, Japan; 8) Department of Surgical Oncology & Gastroenterological Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan Abstract
Methods
Results
We examined patients with UMGC were enrolled in clinical trials of DCS A flow diagram from chemotherapy to surgery
Patients Background of conversion cases
000005984) between December 2002 and December 2013. RR:100%
(RECIST)
22 / 11
6/3
NS
23 / 7 / 3
8/1/0
NS
Intestinal/Diffuse
13 / 20
6/3
NS
IHC 3+ /2+ /1+,0 /Not tested
T stage (JGCA v.14)
-/-/5/28
8/1/0/0
NA
NS
T3
4
5
T4a
22
4
T4b
7
0
N0
1
0
N1
5
0
N2
9
2
N3
18
7
L/N
16
7
Liver
6
2
Peritoneum
9
2
Bone
2
0
Lung
Ovary
1
2
2
1
0/1/2
Histology
n= 7
Conversion 62.5 % (10/16)
Conversion 35.0 % (35/100) Refused surgery
N=2
Pending surgery
N=1
N stage (JGCA v.14)
Distant metastases
NS
Conversion surgery 56.3 % (9/16)
cutoff date：2014/03/01
DCS (n=100)
Age, years
P
Median (range)
63 (26-78)
60 (34-76)
NS
71/29
11/5
NS
Sex
Male/Female
24 / 9
1/ ≥2
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Histologic confirmation of adenocarcinoma of the stomach
HER2 positive (IHC3+ or IHC2+/FISH+) (for DCS-‐‑‒T)
Unresectable distant metastatic disease
Presence of evaluable disease
Age 20 – 80
Performance status (PS); 0,1,2 (ECOG scale)
No prior chemotherapy regimen Adequate bone marrow function (ANC >1,500/mm3 and platelet >100,000/mm3)
Adequate liver, kidney, lung and heart function
Normal left ventricular ejection fraction (LVEF>50%) (for DCS-‐‑‒T)
0/1/2
47/27/26
10/4/2
NS
39/61
11/5
0.0257
Histology
Intestinal/Diffuse
5/4
No. of cycle
• 
• 
• 
• 
Treatment was discontinued if the tumor progressed, severe toxicity
occurred, or if requested by the patient.
Conversion surgery were considered when metastatic lesions were judged
to be curatively resectable as determined by conventional examinations or
a staging laparoscopy.
Objective tumor response was defined according to the RECIST ver. 1.1
Overall survival was measured from the time of starting treatment to death
or last contact with the patient.
1b
10
1
2
10
4
3
4
3
NS
NS
Fisher's exact test
DCS-T (n=9)
n (%)
DSC-T
100
Entire population
P
N=100
Median (M)
1-‐‑‒yr OS (%)
21.7
75.4
60
40
20
0
(Months)
80
CR
2 (6)
2 (22)
PR
30 (91)
7 (78)
NC
1 (3)
0 (0)
0 (0)
0 (0)
97%
100%
NS
2 (1-6)
1 (1-3)
NS
Response
2
N1
N2
18
18
0
3
N3
61
11
Median treatment cycle to response
(range)
Adverse events (grade 3/4)
Neutropenia
24 (73)
7 (78)
NS
Leucopenia
24 (73)
5 (56)
NS
Anemia
4 (12)
0 (0)
NS
Febrile neutropenia
2 (6)
2 (22)
NS
Anorexia
7 (21)
2 (22)
NS
Nausea
4 (12)
1 (11)
NS
Diarrhea
4 (12)
3 (33)
NS
Stomatitis
1 (3)
1 (11)
NS
NS
NS
9/7
Toxicity (NCI–CTC)
Fisher's exact test
Entire population
80
NS
NA
NS
Fisher's exact test
1
4 (9%)
3
JGCA, Japanese Gastric Cancer Association.
9
10 (30%)
N0
1/ ≥2
JGCA, Japanese Gastric Cancer Association
[14th 47/53
Edition]
1a
Cycle delays > 7 days
Response rate
Non-curative factors
0 (0)
100
1
1
2
1
5 (15)
NS
14
6
6
5
R1
10 (22%)
T4b
Bone
Lung
Ovary
9 (100)
10 (30%)
5
7
4
28 (85)
Dose reductions
67
29
33
R0
NS
T4a
Liver
Peritoneum
1 (11)
6 (3-6)
PD
11
1 (3)
4 (2-12)
10
61
Total gastrectomy ≥ D2 + PHx
Median No. of cycle (range)
19
L/N
2 (22)
45
13/3/0/0
NS
4 (12)
142
-/-/14/86
N stage (JGCA v.14)
Distal gastrectomy + D2
DCS
Administration
HER2
IHC 3+ /2+ /1+,0 /Not tested
T stage (JGCA v.14)
T3
NS
No major complication/ No perioperative mortality
Fisher's exact test
DCS (n=33)
n (%)
Characteristics
Performance status
Inclusion criteria (DCS / DCS-T)
6 (67)
NS
Non-curative factors
Response and adverse events in preoperative-chemotherapy
DCS-T (n=16)
28 (85)
Overall survival
JGCA, Japanese Gastric Cancer Association.
Patients characteristics at baseline
Total gastrectomy ≥ D2
Pathological
response
(primary site)
NS
Patients characteristics at baseline
Conversion surgery 33.0 % (33/100)
p
Resection
margin
HER2
n= 28
DCS-T (n=9)
n (%)
Operative
procedure
Performance status
Distant metastases
The aim of this retrospective study was to determine the conversion rate and
prognosis in patients with initially unresectable gastric cancer treated with DCS or
DCS-T, which were used according to their Her2 status.
NS
Male/Female
2nd line CPT-‐‑‒11
Characteristics
Objective
60 (34-76)
DCS (n=33)
n (%)
Sex
Background
it has been elucidated recently that conversion from unresectable to resectable
metastatic colorectal cancer by progress in systemic chemotherapy, termed
“conversion surgery,” can improve disease prognosis. However, the feasibility
and efficacy of "conversion therapy" with curative surgery remains unclear in
patients with UMGC. Since, there has been a paucity of information on the value
of conversion surgery after chemotherapy in gastric cancer patients mainly
because of insufficient response of chemotherapy regimens.
We have developed a triplet-drug combination regimen consisting of docetaxel,
CDDP and S-1 (DCS regimen) and reported that the regimen provides a high
response rate (BJC 2007; CCP 2009 and 2013). We carried out a feasibility study
of the DCS-Tmab (DCS-T) regimen for patients with HER2-positive UMGC
(ASCO-GI 2014).
62 (34-79)
Age, years
Median (range)
n= 54 RR:81.4%
(RECIST)
P
Percent survival
1st line DCS-‐‑‒T (n=16)
DCS-T
(n=9)
Characteristics
0
200
400
N=16
Conversion (+)
Conversion (-‐‑‒)
(Months)
Median (M)
1-yr OS (%)
Conversion (-); n=67
15.7
64.9
Conversion (+); n=33
80.3
93.7
Median follow-up of 16.1 months (3.2–100.5 months) Cut off date; Jan 23, 2014
Percent survival
1st line DCS (n=100)
DCS
(n=33)
Surgical outcomes and pathological findings
Percent survival
or DCS-‐‑‒T chemotherapy (UMIN-‐‑‒CTR: C000000080, 000002361, Percent survival
Aim: The feasibility of "conversion chemotherapy,” which is an attempt to convert
an initially unresectable cancer to resectable status, has not been fully examined
in patients with unresectable metastatic gastric cancer (UMGC). We have
developed a triplet-drug combination regimen consisting of docetaxel, CDDP, and
S-1 (DCS), and recently we carried out a feasibility study of DCS-trastuzumab
(DCS-T) for patients with HER2-positive UMGC. We reported that both regimens
are associated with a high response rate and downstaging in patients with initially
UMGC. The aim of this study was to clarify the conversion rate and prognosis in
patients with initially UMGC treated with DCS or DCS-T according to their HER2
status.
Methods: Patients with UMGC were enrolled in clinical trials of DCS or DCS-T
chemotherapy. Patients received oral S-1 (40 mg/m2 BID) on days 1-14,
intravenous cisplatin (60 mg/m2), and docetaxel (50-80 mg/m2) on day 8 every 3
weeks. In the DCS-T group, trastuzumab was added on day 8 at a dose of 8 mg/
kg in the first cycle and 6 mg/kg in the second cycle and thereafter. Conversion
surgery was considered when patients underwent downstaging as determined by
conventional examinations or staging laparoscopy and were deemed able to
tolerate a curative surgical operation.
Results: The study included 100 patients in the DCS group: median age, 63
years; PS, 0/1/2: 47/27/26 patients; and well-differentiated/undifferentiated
adenocarcinoma, 39/61 patients. The objective response rate was 81.4%.
Conversion was achieved in 35/100 (35%) patients and 28/33 (84.8%) underwent
curative surgery. A total of 24 (72.7%) of the 33 resected cases were histological
chemotherapeutic responders. The median OS of the resected patients was 47.8
months. The DCS-T study included 16 patients: median age, 60 years; PS 0/1/2,
10/4/2 patients; HER2 3+, 13 patients; HER2 2+/FISH+, 3 patients. The objective
response rate was 100%. Non-curative factors disappeared in 10 of 16 cases and
R0 resection was carried out in 9 (56.3%). A pathological response was seen in 8
(88.9%) of the resected cases. At a median follow-up of 14.1 months (range, 4.7 –
29.3 months), median OS was not yet reached.
Conclusions: DCS and DCS-T provided a high conversion rate and better
prognosis. Our data warrant further prospective investigations to establish a
conversion therapeutic strategy for UMGC patients according to their HER2
expression status.
Treatment
600
800
1000 (days)
Median (M)
1-‐‑‒yr OS (%)
NR
91.7
Conversion (+)
60
40
20
0
Conversion (-‐‑‒)
0
200
400
600
800
1000 (days)
Median (M)
1-yr OS (%)
Conversion (-); n=7
18.6
80
Conversion (+); n=9
NR
100
Median follow-up of 14.1 months (4.7–29.3 months) Cut off date; Mar 1, 2014
Conclusions
DCS and DCS-‐‑‒T provided a high conversion rate and better prognosis and our data warrant further prospective investigations to establish a “conversion” therapeutic strategy for initially unresectable gastric cancer patients, according to their HER2 expression status.