Clinicopathological characteristics
A total of 27 PACC patients were identified from 4508 patients diagnosed as pancreatic neoplasms in Sun Yat-sen University cancer center. We excluded 5 patients without treatment and enrolled 22 patients in our study. There were 17 non-metastatic patients and 5 metastatic patients at initial diagnosis. Table 1 shows the patients’ baseline characteristics. Most patients had bulky primary disease with median size of 9.2cm (range from 3 cm to 17 cm). Primary lesions were evenly distributed throughout the pancreas (9 cases in the head, 13 cases in the body or tail). Main metastatic sites were liver (n = 10), distant lymph node (n = 6) and peritoneum (n = 5). Evaluated CA199 level (43.46-123.32 U/ml) was found in 7 patients. Elevated alpha fetoprotein (AFP) level (50.43-23778.56 ng/ml) was detected in 3 patients who developed liver metastasis. Three patients with elevated serum lipase level suffered from subcutaneous fat necrosis and developed distant metastasis. Four patients had family history of cancer including rectal cancer, breast cancer, nasopharyngeal carcinoma or pancreatic cancer.
Table 1
Patient demographics and clinicopathological characteristics (n = 22)
Characteristics
|
No. of Patients
|
Sex
|
|
Male
|
15 (68.2%)
|
Female
|
7 (31.8%)
|
Age, years
|
|
Median, (range)
|
51 (7–79)
|
ECOG performance status
|
|
0
|
4 (18.2%)
|
1
|
18 (81.8%)
|
Size of primary disease, cm
|
|
Median, (range)
|
9.2 (3.0–17.0)
|
Location of primary lesions
|
|
Head
|
9 (40.9%)
|
Body/Tail
|
13 (59.1%)
|
Histology
|
|
PACC
|
19 (86.4%)
|
Mixed PACC
|
3 (13.6%)
|
Common symptom
|
|
Abdominal pain
|
11 (50.0%)
|
Weight loss
|
5 (28.6%)
|
Abdominal mass
|
5 (28.6%)
|
Subcutaneous fat necrosis
|
3 ( 13.6%)
|
Metastases at initial diagnosis
|
|
Yes
|
5 (22.7%)
|
No
|
17 (77.3%)
|
Main metastatic site
|
|
Liver
|
10 (45.5%)
|
Distant lymph node
|
6 (27.3%)
|
Peritoneum
|
5 (22.7%)
|
Serum CA-199
|
|
Elevated
|
7 (31.8%)
|
Normal
|
15 (68.2%)
|
Serum AFP
|
|
Elevated
|
3 (13.6%)
|
Normal
|
14 (63.6%)
|
Not available
|
5 (22.7%)
|
Tumor family history
|
4 (18.2%)
|
Non-metastases cases
|
n = 17
|
Radical surgery
|
17 (100%)
|
Adjuvant chemotherapy
|
8 (47.1%)
|
Regional lymph node metastasis
|
3 (17.6%)
|
High Ki 67 index (≥ 30%)
|
4 (23.5%)
|
Lymph-vascular invasion
|
6 (35.3%)
|
Treatment for metastases cases
|
n = 14
|
1st palliative chemotherapy
|
8 (57.1%)
|
2nd palliative chemotherapy
|
4 (28.6%)
|
Abbreviations: ECOG, Eastern Cooperative Oncology Group; PACC, acinar cell carcinoma; CA-199, Carbohydrate antigen 199; AFP, alpha fetoprotein.
|
Gene alteration
Next generation sequences (NGS) on tumor sample was performed in 4 PACC patients. All of them showed microsatellite stability (MSS) and wild-type RAS /BRAF and low tumor mutational burden (TMB) (range from 6.72–8.16 mutations/mb). Two patients with BRCA2 germline mutation were identified, including one male patient with somatic mutation of IGF1R, FAT3, SMAD4, APC, SPENA and MLH1 whose mother and sister were diagnosed as breast cancer and one female patient with somatic mutation of TP53, CRTC1, SMAD4, ROS1, NTRK1, ATM and KIF5B, whose grandmother was suspected with pancreatic tumor. One male patient showed mutation of TP53, PML, ATM, ENDRA, ZNF703, whose father and grandfather were diagnosed as rectal cancer. No gene mutation was showed in the last patient.
Treatment for non-metastatic PACC
17 non-metastatic patients performed radical surgery with mDFS of 57 months. 8/17 (47.1%) patients received adjuvant chemotherapy. 9 /17 (52.9%) patients after radical surgery developed metastasis. 6 /6 patients with pathological lymph-vascular invasion developed metastasis and 3/11 patients without lymph-vascular invasion developed metastasis. Ki 67 expression on tumor was positive in 9 patients. By a cut-off of 30%, 4 patients with high index of Ki 67 (≥ 30%) developed metastasis while 5 patients with low index of Ki 67 (< 30%) remained disease free. 5/8 (62.5%) patients in adjuvant therapy group had lymph-vascular invasion or Ki 67 high index, while 2/9 (22.2%) patients in non-adjuvant therapy group had these risk factors.
The chemotherapy regimens include gemcitabine (n = 4), S-1 (n = 2), Gemcitabine + Oxaliplatin (GEMOX) (n = 1) and S-1 + Oxalipaltin (SOX) (n = 1). Most of patients received adjuvant therapy of 2–4 cycles and only 2 patients received more than 6 cycles with DFS over 4 years. Table 2 listed the specific information of adjuvant chemotherapy. There were 5/8 patients with adjuvant therapy and 4 / 9 patients without adjuvant therapy who developed metastasis. mDFS of 9 patients without adjuvant chemotherapy seemed numerically better than that of 8 patients with adjuvant chemotherapy (69 months vs. 42 months). mDFS of 5 patients receiving gemcitabine-based adjuvant chemotherapy was 27 months, while mDFS of 3 patients receiving fluoropyrimidine-based adjuvant chemotherapy has not reached.
Table 2
Adjuvant chemotherapy for non-metastatic patients and outcome
Patient sex, age
|
Regimes
|
Cycles
|
DFS (mos)
|
LV invasion
|
Ki 67 index
|
Metastasis
|
Male 68 yrs
|
GEM
|
4
|
5
|
Yes
|
70%
|
Yes
|
Male 54 yrs
|
GEM
|
4
|
5
|
Yes
|
Unknown
|
Yes
|
Male 50 yrs
|
S1
|
2
|
26
|
Yes
|
Unknown
|
Yes
|
Female 53 yrs
|
GEMOX
|
2
|
27
|
Yes
|
30%
|
Yes
|
Male 54 yrs
|
GEM
|
10
|
57
|
No
|
30%
|
Yes
|
Female 48 yrs
|
S1
|
12
|
51
|
No
|
15%
|
No
|
Male 53 yrs
|
SOX
|
5
|
62
|
No
|
20%
|
No
|
Male 15 yrs
|
GEM
|
4
|
141
|
No
|
10%
|
No
|
Abbreviation: LV invasion, lymph-vascular invasion; GEM, Gemcitabine; GEMOX, Gemcitabine + Oxaliplatin; S1, Tegafur/Gemeracil/ Potassium; SOX, S1 + Oxaliplatin.
|
Treatment for metastatic PACC patients
There were 8 metastatic PACC patients received 1st -line chemotherapy, including 5 patients at initial diagnosis and 3 patients after radical surgery. The chemotherapy regimens include Oxaliplatin + Irinotecan + 5-Fluoropyrimidine (FOLFIRINOX) (n = 3), GEMOX (n = 1), Gemicitabine + Cisplatin (GP) (n = 1), Capecitabine + Oxaliplatin (CAPOX) (n = 1), Albumin-bound paclitaxel + Gemcitabine (AG) (n = 1) and S-1 (n = 1). The chemotherapy regimens and results were shown in Table 3. The ORR of fluoropyrimidine-based regimen was 80% (4/5), which was much better than gemcitabine-based regimen (0/3, all 3 patients got progressive disease).
Table 3
The systemic chemotherapy and response for metastasis patients in our center
1st line
|
Response
|
PFS1
(mos)
|
2nd line
|
Response
|
PFS2
(mos)
|
3rd line
|
Response
|
PFS3
(mos)
|
PFS4
(mos)
|
OS
(mos)
|
CAPOX
|
PR
|
16
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
24
|
GEMOX
|
PD
|
2
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
57
|
FOLFIRINOX
|
PD
|
2
|
GP/Nimotuzumab
|
SD
|
2
|
---
|
---
|
---
|
---
|
61
|
S1
|
PR
|
23
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
66
|
AG
|
PD
|
3
|
FOLFIRINOX
|
PR
|
6
|
S1/PD-1
|
PD
|
2
|
2
|
16
|
#GP
|
PD
|
2
|
FOLFIRINOX
|
PR
|
9
|
Lenvatinib/PD-1
|
SD
|
4
|
---
|
17
|
FOLFIRINOX
|
PR
|
9
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
32
|
#FOLFIRINOX
|
PR
|
18
|
GP
|
PD
|
1.5
|
Olaparib
|
PD
|
2
|
1
|
39
|
Abbreviation: PR, partial response; SD, stable disease; PD, progressive disease; GEMOX, Gemcitabine + Oxaliplatin; AG, Albumin-bound paclitaxel + Gemcitabine; S1, Tegafur/Gemeracil/Potassium; CAPOX, Oxaliplatin + Capecitabine; GP: Gemcitabine + Cisplatin; FOLFIRINOX, 5-FU + Oxaliplatin + Leucovorin + Irinotecan. F, female; M, male; PFS1 means the PFS for first-line chemotherapy; PFS2 means the PFS for second-line chemotherapy. Note: #Patients was detected with BRCA2 mutation. |
Four patients received 2nd -line chemotherapy after failing to 1st -line chemotherapy. 2 patients who received 2nd -line FOLFIRINOX regimen achieved partial response (PR) after failing to 1st -line AG regimen. One patient got PD with 2nd -line AG regimen, and one patient with RAS wide-type achieved stable disease (SD) to 2nd -line AG plus nimotuzumab with disease controlled for 2 months.
Two patients with BRCA2 germline mutation had good response to FOLFIRINOX regimen and received Olaparib treatment. One patient achieved PR to 2nd -line FOLFIRINOX regimen and then received the maintenance Olaparib treatment for 5 months with good tolerance. Another patient achieved PR to 1st -line FOLFIRINOX regimen with PFS of 18 months and appeared PD to 2nd -line AG regimen and 3rd -line Olaparib.
Review of published literatures on chemotherapy of metastatic PACC
31 literatures and a total of 86 cases were included. The selection procedure was shown in Fig. 1 and treatment details were shown in Table 4. 86 cases received 1st -line treatment and 33/86 cases failing to 1st -line treatment received 2nd line. All enrolled cases were divided into two groups: fluoropyrimidine-based regimen group and gemcitabine-based regimen group. We classified the cases receiving gemcitabine plus fluorouracil into fluoropyrimidine-based regimen group.
Table 4
Palliative chemotherapy for metastatic patients: Data from literature
Regimen
|
Response
|
Author
|
Publication(year)
|
1st Line regimen
|
|
|
|
Gemcitabine-based
|
|
|
|
AG
|
1SD/2PD
|
Brunetti O [23]
|
2018
|
GEM
|
1PR/10SD/11PD
|
Fujii M [24]/ Yokode M [25]/ Seki Y [26]/ Brunetti O [23] / Lowery MA[27]/ Simon M [28]/ Yoo C [15]/ Kuji M[29]/ Kruger S [30]/ Toda, H [31]
|
2009–2012
2016–2018
|
GEMOX/GEM + CDDP
|
4PR/2SD/2PD
|
Brunetti O [23]/ Kruger S [30]
Lowery MA[27]
|
2011/2016/2018
|
GEM + Irinotecan
|
2SD
|
Lowery MA[27]
|
2011
|
GEM + Erlotinib
|
1PR/3PD
|
Lowery MA[27]/ Kruger S [30]
|
2016
|
Fluoropyrimidine-based
|
|
|
|
5-FU/S1/CAP
|
7 PR
|
Yamamoto T[32]/ Morishima K[33]/
Kanemasa Y [34]/ Sumiyoshi T [35]
Yoo C [15]/ Kruger S [30]/
|
2010/2012
2013/2015
|
GEM + 5FU/GEM + S1
|
2CR/4PR/1SD
|
Nishimizu T [36]/ Fukui H[37]/ Hatata T [38]
Miyagawa K[39]/Toda H[31]/ Brunetti O [23]
|
2010/2011
2016/2018
|
FOLFOX/CAPEOX
|
4PR/3SD/1PD
|
Yoo C [15]/ Fontenot J[40]/ Morales M[41]
Brunetti O [23]/Kruger S [30]/Jordan E [42]
|
2013/2016–2018
2020
|
5FU + CDDP
|
3PR/2SD
|
Brunetti O [23]/ Butturini, G [5]
|
1999/2011
|
|
|
Ukei, T [43]/ Jauch S [44]
|
2016/2018
|
GEM + CAP
|
1PR/2SD/1PD
|
Yoo C [15]/ Lowery MA[27]
Sorscher SM[45]
|
2011/2017
|
PEXG
|
5SD
|
Brunetti O [23]
|
2011
|
GTX
|
1PR/1SD
|
Lowery MA[27]
|
2011
|
CAPE/ Temozolomide
|
1PD
|
Callata-Carhuapoma, H. R [46]
|
2015
|
FOLFIRINOX
|
6PR/2SD
|
Li M [47]/ Yoshihiro T [48]
Kryklyva V[49]/Schempf U[50]
Kruger S [30]/Pfrommer S [51]
|
2013/2014
2016–2019
|
2nd Line regimen
|
|
|
|
Gemcitabine-based
|
|
|
|
AG/GEMOX
|
1PR/1SD/2PD
|
Brunetti O [23]/ Lowery MA[27]
Kruger S [30]
|
2011/2016
2018
|
GEM
|
2SD/4PD
|
Brunetti O [23]/ Yoo C [15]/ Kanemasa Y [34]
|
2013/2017/2018
|
Fluoropyrimidine-based
|
S1
|
2PR/3PD
|
Fujii M [24]/ Yokode M [25]/ Seki Y [26]
|
2009/2010/2017
|
GEM + CAP/GEM + S1
|
1PR/1SD/1PD
|
Brunetti O [23]/ Lowery MA[27]/ Kuji M[29]
|
2011/2018
|
FOLFIRI
|
1PR/2PD
|
Lowery MA[27]/ Morales M[41]
|
2011/2013
|
FOLFOX
|
4PR/1SD
|
Yoo C [15]/ Brunetti O [23]
Kruger S [30]/ Simon M [28]
|
2016–2018
|
FOLFIRINOX
|
2PR/1SD
|
Brunetti O [23]/ Kruger S [30]
Callata-Carhuapoma HR[46]
|
2015/2016/2018
|
Abbreviations: GEM, Gemcitabine; 5-FU, 5- Fluorouracil ; S1, Tegafur/Gemeracil/Potassium; CDDP, Cisplatin; AG, Albumin paclitaxel + Gemcitabine; GEMOX, Gemcitabine Oxaliplatin; GEM + S1, Gemcitabine + Tegafur/Gemeracil/Potassium; FOLFOX, 5-FU + Oxaliplatin + Leucovorin; CAPOX, Oxaliplatin + Capecitabine; GEM + CAP, Gemcitabine + Capecitabine; PEXG, Cisplatinum + Epribicin + Gemcitabine + Gemcitabine; FOLFIRINOX, 5-Fluorouracil + Oxaliplatin + Leucovorin + Irinotecan. |
For first-line chemotherapy, ORR of 86 patients was 39.5%. There were 39 cases in gemcitabine-based regimen group and 47 cases in fluoropyrimidine-based regimen group. ORR of fluoropyrimidine-based group (59.6%, 28/47) was higher than gemcitabine-based group (15.4%, 6/39) ( P < 0.001). 8 patients received FOLFIRINOX as 1st -line chemotherapy and 6 of them achieved PR. The survival data was available for 74 cases including 42 patients in fluoropyrimidine-based group and 32 patients in gemcitabine-based group. The mPFS and mOS of 74 cases was 8 months and 25.4 months, respectively. mPFS in fluoropyrimidine-based group were significantly better than gemcitabine-based group (mPFS: 12 months vs. 6 months, P < 0.001, Fig. 2) .
For second-line chemotherapy, ORR of 29 patients were 37.9%. There were 10 cases in gemcitabine-based regimen group and 19 cases in fluoropyrimidine-based regimen group. ORR of fluoropyrimidine-based group (52.6%, 10/19) was much higher than gemcitabine-based group (10%, 1/10) (P < 0.05). The comparison of response between fluoropyrimidine-based regimen and gemcitabine-based regimen for metastatic PACC were shown in Table 5.
Table 5
Comparison of response between fluoropyrimidine-based regimen and gemcitabine-based regimen for metastatic PACC
|
Gemcitabine-based
|
|
Fluoropyrimidine-based
|
P
|
Cases
|
ORR(%)
|
|
Cases
|
ORR(%)
|
value
|
Our study
|
1st -line (n = 8)
|
3
|
0 (0)
|
5
|
4 (80)
|
> 0.05
|
2nd -line (n = 4)
|
2
|
0 (0)
|
2
|
2 (100)
|
> 0.05
|
Literatures
|
1st -line (n = 86)
|
39
|
6 (15.3)
|
47
|
28 (59.6)
|
< 0.001
|
|
2nd -line (n = 29)
|
10
|
1 (10.0)
|
19
|
10 (52.6)
|
< 0.05
|
Abbreviations: ORR, objective response rate
|