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Multimodality Treatment Including Triplet Regimen as First-Line Chemotherapy May Improve Prognosis of Serum AFP-Elevated Gastric Cancer with Liver Metastasis.

1. Introduction

Serum [alpha]-fetoprotein (AFP) has been proposed as a tumor marker for screening liver tumor and germ cell tumors in the clinic [1-3]. 70-95% of hepatocellular cancers are associated with increased AFP level. Serum AFP-elevated gastric cancer was first reported by Alpert et al. in 1970 [4]. Many other reports followed. The incidence of AFP-producing gastric cancer was merely 1.3-15.0% worldwide [5]. In most literatures, the gastric cancer patients with serum AFP elevation were found to have doughty invasiveness and poor prognosis [6-9]. Also, Liu et al. reported that the dismal prognosis of serum AFP-elevated gastric cancer was mainly due to high incidence of synchronous and metachronous liver metastasis, even when radical operation was done [5]. Therefore, systemic chemotherapy became the predominant treatment method for serum AFP-elevated gastric cancer with liver metastasis (GCLM).

Due to the rarity of this special cancer, there is limited data in the literature about optimal treatment modality. Although previous studies reported that conventional chemotherapy was predominantly ineffective for these patients [10,11], it remains controversial whether to perform systemic chemotherapy for this subtype of GCLM, and there had been so far no suggestion for choosing the optimal regimen.

The potential underlying molecular mechanism of AFP-producing gastric cancer maybe the common embryonic origin of the stomach and liver from the foregut [12]. Koide et al. found that AFP-related gastric cancers had higher proliferative activity, weaker apoptosis, and richer neovascularization, compared with that of AFP-negative gastric cancers [13]. As the precise underlying mechanism of serum AFP-elevated GC remains to be elucidated, the optimal treatment approach requires further consideration. We aim to discover the optimal treatment modality for this special subtype GCLM.

2. Patients and Methods

2.1. Patient Selection. Between 2005 and 2016, 2047 patients were diagnosed with advanced gastric adenocarcinoma in our institute. 516 of them were diagnosed with liver metastasis (LM), including postoperative LM and LM at the initial diagnosis. We included subjects who had serum AFP test result before treatment, leaving 319 patients for analysis. Pretreatment serum AFP was assessed by radioimmunoassay (normal value: <7.0 ng/ml).

2.2. Data Collection. We collected age, gender, ECOG, primary lesion site, histological type, Lauren classification, human epidermal growth factor receptor-2 (HER2) status, serum AFP level before treatment, first-line chemotherapy regimens, response, local treatment for LM, and survival information.

2.3. Follow-Up Care. All patients were regularly followed up from the date of the first hospitalization at our center. Objective response rate (ORR) were evaluated by RECIST version 1.0 (before 2009) and RECIST version 1.1, and severe adverse events ([greater than or equal to] grade 3) were recorded. Overall survival (OS) was defined as the time from inspection of liver metastasis to death from any cause or last follow-up.

2.4. Statistics. The Pearson chi-square test was used to measure the differences between variables. The Fisher exact test was used when the numbers were less than five. To identify prognostic factors of overall GCLM patients and the AFP [greater than or equal to] 20 ng/ml subgroup, survival durations were calculated using the Kaplan-Meier method and Cox regression. For all tests, a P value < 0.05 was defined as significant. The SPSS software program (version 21.0; SPSS, Chicago, Illinois) was used for the analyses. The GraphPad Prism 6 (GraphPad Software Inc., La Jolla, CA) was used for chart making.

3. Results

3.1. Characteristics of GCLM of the AFP [greater than or equal to] 20ng/ml Group and AFP < 20ng/ml Group. Of the 319 eligible patients, 74 (23.2%) were found to have serum AFP [greater than or equal to] 20 ng/ml. Table 1 compared the clinicopathologic features of patients between the AFP [greater than or equal to] 20 ng/ml group (n = 74) and AFP < 20 ng/ml group (n = 245). Results of age, gender, ECOG, disease status, primary lesion site, Lauren classification, HER2 status, peritoneal metastasis, and number of LM were similar between two groups.

Notably, compared with the serum AFP < 20 ng/ml group, 10 (13.5%) patients were diagnosed with hepatoid adenocarcinoma in the AFP [greater than or equal to] 20 ng/ml group. Gastric hepatoid adenocarcinoma (GHA) was defined as a special subtype of primary gastric adenocarcinoma characterized by the histologic structures of "hepatocellular carcinoma- (HCC-) like differentiation" with or without excessive production of AFP [14, 15].

In addition, portal vein tumor thrombus (PVTT) occurred frequently in the AFP [greater than or equal to] 20 ng/ml group, while it is rarely observed in the AFP < 20 ng/ml group (14.9% versus 2.0%, P <0.001). The clinicopathologic features of the two groups were detailed in Table 1.

3.2. Treatment Modality and Response to First-Line Chemotherapy between GCLM of the AFP [greater than or equal to] 20 ng/ml Group and AFP < 20 ng/ml Group. In the analysis of first-line chemotherapy regimens, for the AFP [greater than or equal to] 20 ng/ml group, 46 (62.2%) received platinum-based doublet regimen, including oxaliplatin + capecitabine in 23 patients, oxaliplatin + S-1 in 8 patients, cisplatin + capecitabine in 9 patients, cisplatin + S-1 in 2 patients, oxaliplatin + 5-FU in 3 patients, and cisplatin + 5-FU in 1 patient. 13 (17.6%) received taxane-based doublet regimen, including paclitaxel + capecitabine in 10 patients, paclitaxel +S-1 in 1 patient, paclitaxel + 5-FU in 1 patient, and docetaxel + capecitabine in 1 patient. 9 (12.2%) received triplet regimen (specific regimens were shown in Table 5), and 6 (8.1%) received single-drug regimen (including paclitaxel, S-1, and capecitabine).

For the AFP < 20 ng/ml group, 156 (63.7%) received platinum-based doublet regimen, including oxaliplatin + capecitabine in 68 patients, oxaliplatin + S-1 in 30 patients, cisplatin+capecitabine in 41 patients, cisplatin + S-1 in 5 patients, oxaliplatin+ 5-FU in 8 patients, and cisplatin+ 5FU in 4 patients. 44 (18.0%) received taxane-based doublet regimen, including paclitaxel + capecitabine in 28 patients, paclitaxel + S-1 in 10 patients, paclitaxel+oxaliplatin in 2 patients, docetaxel + 5-FU in 1 patient, and docetaxel + oxaplitatin in 3 patients. Also, there were 17 (6.9%) patients who received triplet regimen (combination of platinum, taxanes, and fluorouracil drugs), and 19 (7.8%) received singledrug regimen (including paclitaxel, S-1, and capecitabine). Analysis showed no significant differences between two groups.

Among the original 319 patients, there were 68 (93.2%) and 189 (77.1%) patients evaluable for their response to first-line chemotherapy in the two groups, respectively. Compared with the AFP < 20 ng/ml group, overall objective response rate (ORR) to first-line chemotherapy was significantly lower in the AFP [greater than or equal to] 20 ng/ml group (41.2% versus 56.1%, P = 0.024).

With regard to second-line chemotherapy, there were fewer patients of the AFP [greater than or equal to] 20 ng/ml group who received second-line chemotherapy than the AFP < 20 ng/ml group (40.0% versus 53.0%, P = 0.055). Regimens mainly involved taxanes and fluorouracil. Moreover, there were 1 (1.4%) and 8 (3.3%) patients who received surgery treatment after first-line chemotherapy in the two groups. In addition, 23 (31.1%) and 60 (24.5%) patients received local treatment for LM in the two groups, respectively, and there were no significant differences between them, either. Comparison of treatments and response between two groups were shown in Table 2.

3.3. Objective Response Rate (ORR) of Doublet and Triplet Regimens between the AFP [greater than or equal to] 20 ng/ml Group and AFP < 20ng/ ml Group. Table 3 summarized the response to doublet and triplet regimen between two groups. Result showed that compared with the AFP < 20 ng/ml group, the AFP [greater than or equal to] 20 ng/ml group had a significantly poor response to platinum/taxane-based doublet regimen (38.2% versus 56.9%, P = 0.013). However, with chemotherapy of triplet regimen, ORR was similar between two groups (66.7% versus 66.7%, P = 0.676).

We further compared ORR and occurrence of severe adverse events of different regimens in the AFP [greater than or equal to] 20 ng/ml group in Table 4. Result showed that ORR of triplet regimen was higher than doublet regimen (66.7% versus 25.0-43.9%), but analysis showed no significance (P = 0.162). Notably, ORR of taxane-based doublet regimen was especially low (25.0%).

In the analysis of adverse events, triplet regimen showed a significantly higher rate of >grade3 adverse events (66.7% versus 22.0-25.0%, P = 0.014).

3.4. Case by Case Analysis of Nine GCLM Patients with AFP [greater than or equal to] 20 ng/ml Who Received Triplet Regimen as First-Line Chemotherapy. In the AFP [greater than or equal to] 20 ng/ml group, nine patients received triplet regimen as first-line chemotherapy. Among them, six were male, and only one patient was more than 60 years old. Serum AFP levels ranged from 22 ng/ml to 208,072 ng/ml. One patient's primary tumor was located at GEJ, others' primary tumor was located at gastric body or antrum. Three patients were diagnosed with hepatoid adenocarcinoma, the six left were common adenocarcinoma. Of five cases that Lauren's classification and HER2 status were known, one case was with intestinal type, two with diffuse type, and two with mixed type, only one case was examined as HER2 positive.

Two-thirds of patients (6/9) achieved PR after triplet regimen as first-line chemotherapy, and two achieved SD with tumor shrinkage of 18%. Only one patient's disease progressed quickly after only one cycle of chemotherapy. Two-thirds of patients (6/9) suffered from [greater than or equal to] grade 3 adverse events, and four of them had to change treatment regimens because of intolerable toxicity. Disease-free survival (DFS) and overall survival (OS) data were also included in Table 5.

3.5. Prognostic Factors of Overall GCLM and GCLM with Serum AFP [greater than or equal to] 20 ng/ml. Median serum AFP level was 480.9 ng/ml and 3.1 ng/ml in the AFP [greater than or equal to] 20 ng/ml group and AFP < 20 ng/ml group, respectively. Median overall survival period was 10.9 m and 15.7 m in the two groups (P = 0.004, Figure 1). Furthermore, multivariate analysis revealed that besides typical prognostic factors of histologic type, extrahepatic unresectable advanced/metastatic sites, response to chemotherapy, and so on, elevation of serum AFP was also an independent prognostic factor for overall GCLM (details were shown in Table 6).

We further investigated the prognostic factors of GCLM patients with serum AFP [greater than or equal to] 20 ng/ml. While the ORR of triplet regimen was excellent in AFP-elevated GCLM, analysis showed no significant difference in survival between doublet and triplet regimens (37.6 m versus 9.9 m, P = 0.157) due to the rather small number (9/74, 12.2%) of patients receiving triplet regimens. In addition, for GCLM patients with serum AFP [greater than or equal to] 20 ng/ml, univariate and multivariate analysis revealed that response to first-line chemotherapy was an independent prognostic factor. Patients reached PR had a better prognosis, similar to overall population, while patients evaluated as SD/PD had the worst survival prognosis (P < 0.001, Figure2). Also, survival analysis showed that combined with local treatment for LM may result in better prognosis and significant difference exist (19.2 m versus 8.4 m, P = 0.003) (Figure 3).

4. Discussion

The main findings of this study are as follows: (1) serum AFP [greater than or equal to] 20 ng/ml GCLM showed a poorer prognosis than the AFP < 20 ng/ml group. (2) Doublet regimen was significantly less effective for the AFP [greater than or equal to] 20 ng/ml group than in the AFP < 20 ng/ml group. (3) Triplet regimen increased ORR compared to doublet regimen when treating serum AFP [greater than or equal to] 20 ng/ml GCLM, but result showed no significance on survival.

AFP is a fetal serum protein by fetal and yolk sac cells and by some fetal gastrointestinal cells [16]. After birth, the level of AFP rapidly decreased. The elevation of AFP in serum of people older than one year is indicative of either HCC or yolk sac tumor. In addition, some reports showed that AFP could also be produced by other tumors, including gastric cancer, rectal cancer, pancreas cancer, gallbladder cancer, lung cancer, and bladder cancer [17].

In 1970, Alpert et al. first reported a case of AFP-producing GC, which refers to a type of gastric cancer that AFP is positive in the immunohistochemical staining of pathological specimen [4]. In 1985, Ishikura et al. proposed a new entity, hepatoid adenocarcinoma of the stomach, which showed a histologic appearance typical of HCC, including solid, trabecular, and pseudogranular structure, tumor cells were round or polygonal in shape [18]. In addition, Nagai et al. clarified that hepatoid adenocarcinoma of the stomach had characteristic histologic features and a poor prognosis irrespective of AFP production and should be distinguished from AFP-positive GC without hepatoid features [14]. However, due to focal distribution and high heterogeneity of gastric hapatoid adenocarcinoma (GHA) [9, 19], almost all GHA cases reported in previous literatures were diagnosed from postoperative specimens. On the other hand, due to aggressive behavior and high frequency of liver metastasis [8], most patients had lost operation opportunity at diagnosis. Thus, most of our patients' feature was just with serum AFP elevation, with only ten patients diagnosed as GHA. The definition of AFP-producing GC varies between studies owing to difficulty in setting the cut-off value; considering liver metastasis can be a factor for mild increase in AFP level, we chose AFP [greater than or equal to] 20 ng/ml as a cut-off value in this study.

Serum AFP-elevated gastric cancer is rare, only accounts for 2.3-7.1% of all gastric cancers [6, 20], but in GCLM population, our result showed that 23.2% (73/319) patients' serum AFP exceeded 20 ng/ml. To clarify the variables associated with the poor prognosis of the AFP [greater than or equal to] 20 ng/ml group, we next reviewed the data of patients and analyzed the differences between two groups. Result showed the serum AFP [greater than or equal to] 20 ng/ml group had a significantly poorer response to first-line chemotherapy in comparison to the AFP < 20 ng/ml group. Also, survival analysis revealed that response to firstline chemotherapy was significantly associated with survival prognosis, and for the AFP [greater than or equal to] 20 ng/ml group, those who reached PR after first-line chemotherapy had a similar survival period as those AFP < 20 ng/ml. These results indicate that choosing effective chemotherapy regimen may improve prognosis of serum AFP-elevated GCLM.

In general treatment of inoperable locally advanced and/or metastatic (stage IV) GC, doublet combinations of platinum and fluropyrimidines are generally used, with an overall ORR of 52.2-58.7% [21, 22]. There remains controversy regarding the utility of triplet regimes, especially in China and Japan [23]. Although there is considerable improvement in medicine science, serum AFP-elevated GC is found to have a poor response to chemotherapy and thus associated with a poor prognosis [24]; basic research indicated that AFP-producing cell lines were not sensitive to many drugs [25]. This clinical study further suggest that this special subtype of gastric cancer may be less sensitive to doublet regimen including platinum and fluoropyrimidines, which was in accordance with a previous study reported that for GHA, ORR and disease control rate (DCR) to palliative chemotherapy was only 7.7% (1/13) and 45.1% (6/13), respectively [24]. However, by comparing ORR and AEs of different regimens used in the AFP [greater than or equal to] 20 ng/ml group, we found that triplet regimens combining platinum, taxanes, and fluoropyrimidines achieved a satisfactory ORR in this special subtype of GCLM. Although [greater than or equal to] grade 3 adverse events were reported in 66.7% patients, they were all reversible and there was no treatment-related death occurred.

Despite the excellent ORR of triplet regimen, median OS was similar in patients who received triplet regimen and doublet regimen. This phenomenon that could mainly attribute to the rate of patients who received triplet regimen was relatively low in our study (9/73), and four of nine patients were still alive until the last follow-up. On the other hand, in clinic practice, triplet regimen was always used in patients with heavy tumor burden, which may be associated with poor prognosis as well. Case by case analysis revealed there were two patients who lived longer than two years. Both of them reached PR after triplet regimen chemotherapy. One of them was examined as HER2 positive and received Herceptin treatment at second-line chemotherapy. In addition, the patient also received TACE for LM, which may also improve survival prognosis of gastric cancer with liver metastasis [11, 26]. The other case was diagnosed as GHA, who also received multiline systemic treatment, including apatinib. We noted that there were two patients complicated with PVTT, which is a special characteristic of AFP-related gastric cancer [27]; a high rate of PVTT in AFP-producing gastric cancer (14.9% in our study) may indicate high intendancy of vascular invasion and angiogenesis [28, 29]. It was reported that silencing AFP inhibits VEGF production in human HCC cells [30]. The function of apatinib, as a small molecular tyrosine kinase targeting VEGF-R2 (vascular endothelial growth factor receptor-2), is antiangiogenesis. There is another case report of targeted therapy with apatinib in a patient with advanced gastric cancer and high serum level of AFP and PFS achieved five months [31]. Thus, the inhibitors of VEGF or VEGFR might become potential drugs to treat this special subtype of gastric cancer. This long-time survivor in our study also received TACE for LM during treatment process.

We also showed that the only patient resistant to triplet regimen was a young female, with diffuse type Lauren classification and peritoneal metastasis and ascites, which were associated with poor prognosis and bad response to conventional systemic chemotherapy [32]. Furthermore, in our study, almost half of patients (cases 1, 4, 7, and 8) had to stop triplet regimen during treatment process because of intolerable adverse events; thus, severe toxicity of triplet regimen may also attribute to poor survival prognosis, and optimizing triplet regimens deserves further study.

In a word, survival analysis and the two successfully treated cases indicate that although AFP-producing gastric cancer is often advanced and complicated with liver metastasis, long-term survival can be achieved by multimodality treatment including triplet regimen chemotherapy; those had a PR response of first-line chemotherapy could get more chance to be treated.

5. Conclusions

Serum AFP-elevated gastric cancer is a small subgroup of gastric carcinoma with high metastatic potential to the liver and poor prognosis. Multimodality treatment including aggressive chemotherapy of triplet regimen may be worthwhile to improve prognosis of serum AFP-elevated GCLM; better tolerated regimens should be investigated further in the future.

6. Shortcomings and Perspectives

Although the retrospective nature of this study and the number of cases treated with triplet regimen were relatively small, the results could still provide some clinical value. With such rare tumors, for which large clinical trials are not feasible, it became very important to summarize clinical experience retrospectively. Not limited within GCLM, maybe triplet regimen can be tried to be used in all AFP-elevated gastric cancer in future clinical practice. Although this type of gastric cancer is rare, it deserves further studies.

Ethical Approval

This study was approved by the Ethics Committee of Beijing University Cancer Hospital.

Consent

Patients were not required to give informed consent for this study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Authors' Contributions

Yakun Wang helped in collecting and analyzing the data and wrote the manuscript. Ming Lu and Zhi Ji helped in collecting the data. Xiaotian Zhang and Lin Shen were in charge of the project and revised the manuscript.

Acknowledgments

This work was supported by the National Key Research and Development Program of China (no. 2017YFC1308900) and the Capital Health Research and Development of Special (no. 2016-1-1021).

https://doi.org/10.1155/2017/5080361

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Yakun Wang, Lin Shen, Ming Lu, Zhi Ji, and Xiaotian Zhang

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China

Correspondence should be addressed to Xiaotian Zhang; zhangxiaotianmed@163.com

Received 31 August 2017; Accepted 27 November 2017; Published 24 December 2017

Academic Editor: Haruhiko Sugimura

Caption: Figure 1: The median OS of group 1 (AFP > 20 ng/ml GCLM) and group 2 (AFP < 20 ng/ml GCLM) was 10.9 m and 15.7 m, respectively (P = 0.002).

Caption: Figure 2: The median OS of group 1 (AFP [greater than or equal to] 20 ng/ml and reached PR after first-line chemotherapy), group 2 (AFP [greater than or equal to] 20 ng/ml and achieved SD/PD after first-line chemotherapy), group 3 (AFP < 20 ng/ml) was 17.6 m, 9.4 m, 17.3 m, respectively (P < 0.001).

Caption: Figure 3: In serum AFP [greater than or equal to] 20 ng/ml GCLM, the median OS of group 1 (with local treatment for LM) and group 2 (without local treatment for LM) was 19.2 m and 18.3 m, respectively (P = 0.003).
Table 1: Comparison of characteristics of GCLM between the
AFP [greater than or equal to] 20 ng/ml group and AFP < 20 ng/ml group.

Variable                         AFP [greater than or   AFP < 20 ng/ml
                                  equal to] 20 ng/ml       (n = 245)
                                       (n = 74)
Gender
Male                                  57 (77.0%)          198 (80.8%)
Female                                17 (23.0%)          47 (19.2%)

Age (years)

[greater than or equal to] 65         56 (75.7%)          165 (67.3%)
<65                                   18 (24.3%)          80 (32.7%)

ECOG

0-1                                   66 (89.2%)          220 (89.8%)
2-3                                   8 (10.8%)           25 (10.2%)

Disease status

LM after radical resection            10 (13.5%)          45 (18.4%)
LM at first diagnosis                 64 (86.5%)          200 (81.6%)

Primary lesion site

GEJ                                   24 (33.3%)          101 (42.4%)
Non-GEJ                               48 (66.7%)          137 (57.6%)
Unknown                                   2                    7

Histological type

Well                                  23 (31.5%)          94 (39.3%)

differentiated (a)

Poorly                                40 (54.8%)          145 (60.7%)

differentiated (b)

GHA                                   10 (13.7%)            0 (0%)
Unknown                                   1                    6

Lauren classification

Intestinal type                       34 (70.8%)          103 (65.6%)
Diffused type                         5 (10.4%)           25 (15.9%)
Mixed type                            9 (18.8%)           29 (18.5%)
Unknown                                   26                  88

HER2 status

Positive                              13 (24.5%)          54 (30.9%)
Negative                              40 (75.5%)          121 (69.1%)
Unknown                                   21                  70

Peritoneal metastasis

Yes                                   9 (12.2%)           38 (15.5%)
No                                    65 (87.8%)          207 (84.5%)

Number of LM

1-3                                   12 (16.2%)          48 (20.3%)
>3                                    62 (83.8%)          188 (80.7%)

PVTT

Yes                                   11 (14.9%)           5 (2.0%)
No                                    63 (85.1%)          240 (98.0%)

Variable                           P

Gender
Male                             0.288
Female

Age (years)

[greater than or equal to] 65    0.111
<65

ECOG

0-1                              0.514
2-3

Disease status

LM after radical resection]      0.216
LM at first diagnosis

Primary lesion site

GEJ
Non-GEJ                          0.385
Unknown

Histological type

Well

differentiated (a)

Poorly                           <0.001

differentiated (b)

GHA
Unknown

Lauren classification

Intestinal type
Diffused type                    0.633
Mixed type
Unknown

HER2 status

Positive
Negative                         0.240
Unknown

Peritoneal metastasis

Yes                              0.321
No

Number of LM

1-3                              0.367
>3

PVTT

Yes                              <0.001
No

(a)Including welldifferentiated and moderately differentiated
adenocarcinoma. (b) Including poorly differentiated and signet
ring cell adenocarcinoma. GHA = gastric hepatoid adenocarcinoma;
ECOG = Eastern Cooperative Oncology Group; GEJ = gastroesophageal
junction; HER2 = human epidermal growth factor receptor-2; AFP =
[alpha]-fetoprotein; LM = liver metastasis; PVTT = portal vein tumor
thrombus.

Table 2: Comparison of treatments and response in GCLM between the
AFP [greater than or equal to] 20 ng/ml group and AFP < 20 ng/ml group.

Variables                    AFP [greater     AFP < 20 ng/ml        P
                            than or equal
                             to] 20 ng/ml

First-line chemotherapy
regimens

Platinum-based doublet        46 (62.2%)        156 (63.7%)
regimen

Taxane-based doublet          13 (17.6%)        44 (18.0%)
regimen

Triplet regimen                9 (12.2%)         17 (6.9%)        0.325

Single-drug regimen            6 (8.1%)          19 (7.8%)

Others                         0 (0.0%)          9 (3.7%)

Response of first-line
chemotherapy

PR                            28 (41.2%)        106 (56.1%)       0.024

SD + PD                       40 (58.8%)        83 (43.9%)

Subsequent therapies
after the first-line
chemo

Second-line chemotherapy

Yes                           24 (40.0%)        97 (53.0%)        0.055

No                            36 (60.0%)        86 (47.0%)

Surgery treatment

Yes                            1 (1.4%)          8 (3.3%)         0.344

No                            73 (98.6%)        237 (96.7%)

Local treatment of LM (a)

Yes                           23 (31.1%)        60 (24.5%)        0.163

No                            51 (68.9%)        185 (75.5%)

(a) Including TACE, ablation, radiotherapy, and liver resection.
PR = partial response; SD = stable disease; PD = progressive disease;
TACE = transcatheter arterial chemoembolization.

Table 3: Comparison of ORR of different chemotherapy regimens
between two groups.

Regimens                     AFP [greater     AFP < 20 ng/ml        P
                            than or equal
                             to] 20 ng/ml
Platinum/taxane-based
doublet regimen

PR                            21 (38.2%)        91 (56.9%)        0.013
SD + PD                       34 (61.8%)        69 (43.1%)

Triplet regimen

PR                             6 (66.7%)         8 (66.7%)        0.676
SD + PD                        3 (33.3%)         4 (33.3%)

Table 4: ORR and severe AEs of different regimens in the
AFP [greater than or equal to] 20 ng/ml group.

                            Platinum-based    Taxane-based
ORR and AEs                 doublet regimen   doublet regimen
                            (n = 41)          (n = 12)

PR                          18 (43.9%)        3 (25.0%)

SD + PD                     23 (56.1%)        9 (75.0%)

[greater than or equal      9 (22.0%)         3 (25.0%)
to]grade 3 AEs

                            Triplet
ORR and AEs                 regimen      P
                            (n = 9)

PR                          6 (66.7%)    0.162

SD + PD                     3 (33.3%)

[greater than or equal      6 (66.7%)    0.014
to]grade 3 AEs

AE = adverse event; OS = overall survival.

Table 5: Case by case analysis of nine AFP [greater than or equal to]
20 ng/ml GCLM received triplet regimen as first-line chemotherapy.

(a)

Age/sex     Primary        Histological type      Serum AFP
             lesion                                 level
              site                                 (ng/ml)

34/M          Body                GHA                455

59/M         Antrum               GHA              208,072

43/M          Body       Poorly differentiated       7307
                             adenocarcinoma

58/M         Antrum      Poorly differentiated       113
                             adenocarcinoma

39/F          Body       Poorly differentiated       3042
                             adenocarcinoma

56/F         Antrum      Middle-differentiated        22
                             adenocarcinoma

75/F         Antrum      Middle-differentiated       131
                             adenocarcinoma

59/M          Body       Middle-differentiated       2108
                             adenocarcinoma

42/M           GEJ                GHA                868

Age/sex        Lauren          HER2       PVTT     Peritoneal
           classification      status              metastasis

34/M         Intestinal       Negative     No          No

59/M             NK              NK        No          No

43/M             NK              NK        Yes         No

58/M            Mixed         Negative     No          No

39/F           Diffuse        Negative     No         Yes

56/F         Intestinal       Positive     No          No

75/F             NK              NK        No          No

59/M             NK              NK        No          No

42/M            Mixed         Negative     Yes         No

(b)

Regimen    Cycles    Evaluation   PFS    [greater than or equal
                                  (m)    to] grade 3 toxicity

PCF           4          PR       9.5             BWL

PCF           6          PR       4.2           Vomiting

POS           5          SD       6.0              No

POS           5          PR       6.2    Hematological; sensory
                                               neuropathy

DCF           1          PD       0.8              No

ECF           6          PR       6.1              No

DCF           4          PR       3.4       Hematological;
                                           vomiting; mucosal
                                                reaction

PCF           3          PR       2.6       Cardiac toxicity

POS           5          SD       5.83       Hematological

Regimen    Other treatments         OS     Follow-up
                                    (m)    status

PCF        FOLFIRINOX; olaparib;    22.8     Alive
              apatinib; PD-1
               antibody; TACE

PCF                  No             7.1       Dead

POS                  No             11.0     Alive

POS             Radiotherapy        8.0      Alive

DCF                  No             1.7       Dead

ECF           Herceptin; TACE       37.6      Dead

DCF                  No             10.9      Dead

PCF             Gastrectomy         10.9      Dead

POS         Gastrectomy; liver      13.6     Alive
            resection; apatinib;
               PD-1 antibody

F = female; M = male; NK = not known; BWL = body weight loss;
PVTT = portal vein tumor thrombus; PCF = paclitaxel +
cisplatin+ 5-fluorouracil; POS = paclitaxel + oxaplatin + S-1;
DCF = docetaxel + cisplatin+ 5-fluorouracil; ECF = epirubicin +
cisplatin+ 5-fluorouracil.

Table 6: Univariate and multivariate analysis of survival
outcomes in overall GCLM and of the subgroup of serum AFP
[greater than or equal to] 20 ng/ml.

                                      GCLM with serum AFP
                                      [greater than or equal to]
                                       20 ng/ml (n = 74)
                                      Univariate analysis
                                             (KM)
Variable                              mOS (m)    P value     HR

Gender
Male                                    9.9       0.608
Female                                  15.1
Age
[greater than or equal to] 65           9.2       0.773
>65                                     11.3
ECOG
0-1                                     9.2       0.095
2-3                                     11.3
Disease status
LM after radical resection              10.4      0.411
LM at first diagnosis                   10.9
Primary lesion site
GEJ                                     14.9      0.103
Non-GEJ                                 9.4
Histologic classification
Intestinal                              12.7      0.757
Nonintestinal                           12.0
HER2 status
Positive                                12.7      0.888
Negative Extrahepatic M                 15.1
Present                                 10.4      0.116
Absent                                  12.2
Peritoneal M
Present                                 4.6      <0.001     4.411
Absent                                  11.3
LM numbers
1-3                                     17.6      0.115
>3                                      9.9
First-line chemo regimen
Doublet regimen                         9.9       0.157
Triplet regimen                         37.6
Response to first-line chemo
PR                                      15.4      0.017     0.328
SD + PD                                 9.4
Local treatment for LM
Yes                                     19.2      0.003     0.356
No                                      8.4
Serum AFP level (ng/ml)
[greater than or equal to] 20 ng/ml
<20 ng/ml

                                      Multivariate analysis
                                               (Cox)
Variable                                 95% CI      P value

Gender
Male
Female
Age
[greater than or equal to] 65
>65
ECOG
0-1
2-3
Disease status
LM after radical resection
LM at first diagnosis
Primary lesion site
GEJ
Non-GEJ
Histologic classification
Intestinal
Nonintestinal
HER2 status
Positive
Negative Extrahepatic M
Present
Absent
Peritoneal M
Present                               1.817-10.712    0.001
Absent
LM numbers
1-3
>3
First-line chemo regimen
Doublet regimen
Triplet regimen
Response to first-line chemo
PR                                    0.173-0.624     0.001
SD + PD
Local treatment for LM
Yes                                   0.179-0.710     0.003
No
Serum AFP level (ng/ml)
[greater than or equal to] 20 ng/ml
<20 ng/ml

                                      Overall GCLM (n = 319)
                                      Univariate analysis
                                               (KM)
Variable                              mOS (m)    P value     HR

Gender
Male                                    14.1      0.609
Female                                  14.8
Age
[greater than or equal to] 65           14.8      0.379
>65                                     14.9
ECOG
0-1                                     16.5      0.227
2-3                                     14.5
Disease status
LM after radical resection              19.3      0.046     0.700
LM at first diagnosis                   14.5
Primary lesion site
GEJ                                     15.2      0.600
Non-GEJ                                 14.5
Histologic classification
Intestinal                              16.1      0.021     0.558
Nonintestinal                           11.2
HER2 status
Positive                                17.3      0.293
Negative Extrahepatic M                 15.2
Present                                 14.6      0.952
Absent                                  15.5
Peritoneal M
Present                                 10.8      0.001     1.953
Absent                                  15.4
LM numbers
1-3                                     19.5      0.002     0.416
>3                                      12.7
First-line chemo regimen
Doublet regimen                         14.9      0.816
Triplet regimen                         17.3
Response to first-line chemo
PR                                      19.2      <0.001    0.506
SD + PD                                 11.4
Local treatment for LM
Yes                                     20.8      <0.001    0.623
No                                      12.4
Serum AFP level (ng/ml)
[greater than or equal to] 20 ng/ml     10.9      0.004     1.553
<20 ng/ml                               15.7

                                      Multivariate analysis
                                               (Cox)
Variable                                 95%CI       P value

Gender
Male
Female
Age
[greater than or equal to] 65
>65
ECOG
0-1
2-3
Disease status
LM after radical resection            0.359-1.364     0.295
LM at first diagnosis
Primary lesion site
GEJ
Non-GEJ
Histologic classification
Intestinal                            0.370-0.840     0.005
Nonintestinal
HER2 status
Positive
Negative Extrahepatic M
Present
Absent
Peritoneal M
Present                               1.105-3.451     0.021
Absent
LM numbers
1-3                                   0.236-0.733     0.002
>3
First-line chemo regimen
Doublet regimen
Triplet regimen
Response to first-line chemo
PR                                    0.334-0.768     0.001
SD + PD
Local treatment for LM
Yes                                   0.394-0.986     0.043
No
Serum AFP level (ng/ml)
[greater than or equal to] 20 ng/ml   1.006-2.397     0.047
<20 ng/ml
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Title Annotation:Research Article
Author:Wang, Yakun; Shen, Lin; Lu, Ming; Ji, Zhi; Zhang, Xiaotian
Publication:Gastroenterology Research and Practice
Date:Jan 1, 2018
Words:6375
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