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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 742-747

Advanced signet-ring cell carcinoma of the stomach: Clinicopathological characteristics of patients and efficacy of the modified docetaxel, cisplatin, and fluorouracil regimen


Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey

Date of Web Publication24-Sep-2018

Correspondence Address:
Yakup Bozkaya
Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara 06100
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.184514

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 > Abstract 


Background: The aim of this retrospective study was to investigate the clinicopathological characteristics of patients with signet-ring cell carcinoma (SRCC) of the stomach, and the efficacy of the modified docetaxel, cisplatin, and fluorouracil (mDCF) chemotherapy regimen.
Patients and Methods: Sixty-five patients diagnosed with metastatic or recurrent SRCC and treated with at least one course of mDCF regimen as the first-line treatment at our hospital July 2007 and January 2015, were included in this study. The mDCF protocol comprised docetaxel at 60 mg/m2/day (day 1), cisplatin at 60 mg/m2/day (day 1), and 5-fluorouracil at 600 mg/m2/day (days 1–5) for every 3 weeks.
Results: The median age was 53 years (range, 25–69 years). The most frequent sites of metastasis were the peritoneum (50.8%) and liver (21.5%). The median number of chemotherapy courses was six. In assessing 61 patients for response evaluation, one patient (1.6%) achieved a complete response, and 36 (59.0%) achieved a partial response. Fifteen patients (24.6%) had stable disease and nine (14.8%) had progressive disease. Grades 3–4 hematological toxicity revealed anemia in three (4.6%) patients, thrombocytopenia in two (3.1%), and neutropenia in five (7.7%). Grades 3–4 nonhematological side effects revealed nausea and vomiting in four (6.1%) patients and mucositis in one (1.5%). The overall survival (OS) and progression-free survival (PFS) were 10.4 months (95% confidence interval [95% CI], 8.9–12.0) and 6.1 months (95% CI, 5.1–7.0), respectively. Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) performance score of 2 and a high pretreatment carcinoembryonic antigen level were statistically significant.
Conclusions: mDCF is an effective regimen in patients with SRCC of the stomach who have ECOG performance score of 0–1 when the PFS, OS, and tumor response rate are considered. Further prospective studies including more patients should be conducted on this subject.

Keywords: Gastric cancer, modified docetaxel, cisplatin, and fluorouracil, prognosis, signet-ring cell carcinoma


How to cite this article:
Bozkaya Y, Erdem GU, Özdemir NY, Hocazade C, Yazici O, Demirci NS, Zengin N. Advanced signet-ring cell carcinoma of the stomach: Clinicopathological characteristics of patients and efficacy of the modified docetaxel, cisplatin, and fluorouracil regimen. J Can Res Ther 2018;14, Suppl S3:742-7

How to cite this URL:
Bozkaya Y, Erdem GU, Özdemir NY, Hocazade C, Yazici O, Demirci NS, Zengin N. Advanced signet-ring cell carcinoma of the stomach: Clinicopathological characteristics of patients and efficacy of the modified docetaxel, cisplatin, and fluorouracil regimen. J Can Res Ther [serial online] 2018 [cited 2019 Sep 21];14:742-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/742/184514




 > Introduction Top


Although the general incidence of stomach cancer has been decreasing in recent years, the incidence of signet-ring cell carcinoma (SRCC) has been increasing. This tumor is present in 8–30% of all patients with gastric cancer.[1],[2],[3] The World Health Organization classifies SRCC as an adenocarcinoma characterized by a prominent intracellular mucin content in more than 50% of the tumor cells.[4] SRCC has also been classified as the diffuse type, infiltrative type, and undifferentiated type.[5],[6],[7]

Most patients with SRCC of the stomach are admitted to the hospital at an advanced stage because of the presence of nonspecific symptoms.[8] Patients with advanced-stage SRCC are treated similarly to patients with other subtypes of gastric carcinoma, and they are basically administered combination chemotherapy. After the efficacy of cisplatin-fluorouracil (CF) combination chemotherapy was shown in Phase 3 randomized studies, this regimen was first clinically used in patients with advanced gastric cancers including patients with SRCC. After the addition of docetaxel to the CF (DCF) regimen in the Phase 3 V325 study, a better time to progression and overall survival (OS) were provided with the DCF regimen (time to progression, 5.6 vs. 9.2 months, respectively; P = 0.02).[9] The modified DCF (mDCF) chemotherapy regimen was initiated because the standard DCF chemotherapy was more toxic and more frequently associated with febrile neutropenia. Studies showed that the mDCF regimen was an effective treatment modality in patients with advanced-stage gastric cancers and had fewer side effects.[10],[11],[12] However, the studies analyzed treatment efficacy in general, and the efficacy was not determined in relation to the histological subtypes.

Although it has been thought that the biological behavior of SRCC is different from that of other cell types, the clinical characteristics and prognosis have been inconsistently reported. Some studies reported similar OS rates in relation to other histological subtypes of gastric carcinoma in advanced stage.[13] However, many others reported a poorer prognosis.[2],[14],[15],[16] Therefore, further studies are needed on this subject.

Due to the inconsistency in the clinicopathological characteristics and prognosis of this histological subtype and a small number of randomized studies specific to the treatment of this subtype,[17],[18] we retrospectively investigated the clinicopathological characteristics of patients with SRCC and the efficacy of the mDCF chemotherapy regimen.


 > Patients and Methods Top


Sixty-five patients diagnosed with metastatic or recurrent SRCC and treated with at least one course of mDCF regimen as the first-line treatment at our hospital between July 2007 and January 2015, were included in this study. The criterion for the histopathological diagnosis of SRCC was the presence of prominent intracellular mucin in more than 50% of the tumor cells. Patients with tumors containing mucin in <50% of the tumor cells, as well as those with a second primary malignant tumor, were excluded from the study.

The clinicopathological characteristics, laboratory findings, treatments, treatment efficacies, and adverse effects were obtained from retrospective examination of the files and histopathological reports of the patients. The mDCF protocol comprised docetaxel at 60 mg/m2/day (day 1), cisplatin at 60 mg/m2/day (day 1), and 5-fluorouracil (5-FU) at 600 mg/m2/day (days 1–5) for every 3 weeks.

Tumor response was classified using the standard Response Evaluation Criteria in Solid Tumors, version 1.1. A complete response (CR) was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. A partial response (PR) was defined as a ≥30% decrease in the sum of the longest diameters of the target lesions for more than 4 weeks with no new area of malignant disease. Progressive disease (PD) indicated a ≥20% increase in the sum of the longest diameter of the target lesions or the appearance of a new malignant lesion. Stable disease (SD) was defined as an insufficient shrinkage to qualify for PR and an insufficient increase to qualify for PD. Toxicity evaluations were performed based on the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0.

The survival statuses of the patients were determined from the hospital files and the records of Central Civil Registration System using the Turkish Republic Registration Number of the patients.

Statistical analysis

The Statistical Package for the Social Sciences, version 18.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. A P < 0.05 was deemed to indicate statistical significance. Categorical variables were analyzed using the Chi-squared or Fisher's exact test. Survival analysis was performed according to the Kaplan–Meier method. Progression-free survival (PFS) was defined as the time from the start of chemotherapy to disease recurrence or the last follow-up. OS was defined as the time from the start of chemotherapy to death of any cause or the last follow-up. The possible factors identified with univariate analyses were further entered into Cox regression analysis with backward selection to determine independent predictors of survival.


 > Results Top


In total, 65 patients were diagnosed with metastatic SRCC (36 [55.4%] males and 29 [44.6%] females). The median age was 53 years (range, 25–69 years). Twelve of 13 patients who had early disease at the time of diagnosis and developed metastasis later had previously received adjuvant chemotherapy plus chemoradiotherapy (all of these 12 patients had stage 3 disease at the time of diagnosis). The most frequent sites of metastasis were the peritoneum (50.8%, n = 33) and liver (21.5%, n = 14). Peritoneal metastasis was diagnosed during laparotomy in seven patients. The Eastern Cooperative Oncology Group (ECOG) score was 0–1 in 76.9% (n = 50) of the patients before the administration of mDCF. The demographic and clinicopathological characteristics of the patients are presented in [Table 1].
Table 1: The demographic and clinicopathological characteristics of the patients

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Treatment

Three hundred twenty-nine courses of chemotherapy were administered. The median number of chemotherapy courses was six (range, 1–8). The rate of patients who underwent at least three courses of chemotherapy was 89.2% (n = 58) and 67.7% (n = 44) of the patients completed the scheduled six courses. Second-line treatment was administered to 44.6% (n = 29) of the patients; 72.4% (n = 21) received epirubicin, oxaliplatin, and capecitabine, and 27.6% (n = 8) received folinic acid, 5-FU, and irinotecan.

Analysis of the treatment response

Four (6.1%) patients could not be evaluated with respect to their treatment response because they underwent only one course of treatment; therefore, the treatment response was analyzed in 61 patients. One patient (1.6%) achieved CR and 36 (59.0%) achieved PR. Fifteen patients (24.6%) had SD and nine (14.8%) had PD. The total disease control rate was 85.2% (n = 52).

Analysis of toxicity

Analysis of Grades 3–4 hematological toxicity revealed anemia in three (4.6%) patients, thrombocytopenia in two (3.1%), and neutropenia in five (7.7%). Two patients (3.1%) were hospitalized due to febrile neutropenia. Only two patients were administered secondary granulocyte colony-stimulating factor prophylaxis because of Grades 3–4 neutropenia.

Analysis of Grades 3–4 nonhematological side effects revealed nausea and vomiting in four (6.1%) patients and mucositis in one (1.5%). One patient developed the prerenal type of acute renal failure due to Grades 3–4 nausea and vomiting and was hospitalized.

Course delay was performed in three (4.6%) patients, and dose reduction was performed in four (6.1%) because of Grades 3–4 hematological and nonhematological adverse effects. There were no chemotherapy toxicity-related deaths [Table 2].
Table 2: Toxicity in patients that were administered modified docetaxel, cisplatin, and fluorouracil regimen

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Survival

The median follow-up period was 8.9 months (range, 1.0–25.8 months). The median PFS was 6.1 months (95% confidence interval [95% CI], 5.1–7.0), and the median OS was 10.4 months (95% CI, 8.9–12.0). The 1-year OS was 42% and the 1-year PFS was 18%. The survival curves are presented in [Figure 1] and [Figure 2].
Figure 1: Kaplan–Meier curves for overall survival of the patients with signet-ring cell carcinoma

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Figure 2: Kaplan–Meier curves for progression-free survival of patients with signet-ring cell carcinoma

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The subgroup univariate analysis of factors affecting OS indicated that an ECOG performance score of 2, a high pretreatment carcinoembryonic antigen (CEA) level, and two or more metastatic sites were statistically significant. Multivariate analysis showed that an ECOG performance score of 2 and a high pretreatment CEA level were statistically significant [Table 3].
Table 3: Univariate and multivariate statistical analysis in relation with signet-ring cell carcinoma subgroups in the patients that were administered modified docetaxel, cisplatin, and fluorouracil regimen

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 > Discussion Top


SRCC is an increasingly appearing significant histological subtype of gastric adenocarcinoma.[19] This increase may be related to changes in the pathological classifications used for the characterization of gastric carcinomas.

Gastric adenocarcinomas occur twice more frequently in males than females. Similarly, SRCC occurs more frequently in males; however, it is more frequently seen in females compared with other histopathological subtypes of gastric adenocarcinomas.[1] We found the male/female ratio to be 1.2 in accordance with the literature, with male predominance. SRCC is seen between the mean ages of 55 and 61 years, and it is seen at younger ages compared with non-SRCC.[1],[14] The median age was 53 years in our study, and we detected SRCC at an earlier age, similar to aforementioned studies. It is not clear why SRCC is more frequently seen in young females compared with non-SRCC. One hypothesis may be the association of this subtype with sex hormones.[20] Therefore, new studies may be conducted to investigate the correlation between sex hormones and SRCC.

Gastric adenocarcinomas have demonstrated localization in the more distal parts of the stomach; however, their occurrence in the proximal parts of the stomach has increased recently due to gastroesophageal reflux, obesity, and dietary habits.[21] However, previous studies have reported that SRCC is localized in the middle third of the stomach, in contrast to non-SRCC.[22] We found that our patients had SRCC in the middle third of the stomach. This finding provides additional evidence for the tendency of SRCC to occur at this location.

Organ metastasis through a hematological route, such as liver metastasis, is more frequent in differentiated gastric adenocarcinomas; however, undifferentiated adenocarcinomas such as SRCC are characterized by peritoneal involvement.[23] The most frequently employed imaging modality for gastric carcinomas is computed tomography, and it has a limited value in demonstrating peritoneal involvement.[24] In our study, peritoneal involvement was found to be the most frequent metastasis pattern, and peritoneal metastasis was found during laparotomy in seven patients who showed no distant metastasis on standard radiological imaging. Therefore, investigation of the additional benefit of laparoscopic staging in SRCC subtypes, in which peritoneal involvement is frequent, may be performed.

The prognosis of SRCC depends on the stage at the time of diagnosis. Because the patients with early SRCC were younger, had fewer lymph node metastases, and more frequently had a tumor confined to the mucosa, their prognosis was better than that of the patients with non-SRCC gastric cancer.[25] However, studies have indicated a poor prognosis in patients with advanced-stage SRCC.[15],[16] Although a poor prognosis has been reported, patients with advanced-stage SRCC are treated similarly to other histopathological subtypes of gastric adenocarcinomas. Only a few studies have analyzed the treatment of SRCC as a distinct histopathological subtype. Those studies reported that docetaxel was effective in SRCC.[17],[18]

In the Tax 325 study, docetaxel was combined with cisplatin and 5-FU (DCF), and the DCF regimen was shown to be effective in patients with metastatic gastric cancer. In that study, the overall disease control rate was 67% (2% CR, 35% PR, and 30% SD). However, at least one treatment-related side effect was seen in all of the patients who were administered the DCF regimen, and Grades 3–4 side effects were reported in 69% of the patients. In addition, secondary granulocyte colony-stimulating factor was administered to patients with complicated neutropenia.[9] Although this regimen was effective, it had a low tolerability because of its toxicity. Therefore, studies were performed using the mDCF regimen, which had a reduced dose.[10],[11],[12] Ozdemir et al. reported an overall disease control rate of 64.9% (5.4% CR, 21.6% PR, and 37.9% SD) in patients who were administered the mDCF regimen. Regarding the hematological toxicity, Grades 3–4 neutropenia and anemia were seen in 8.1% and 5.4% of the patients, respectively, and nausea and diarrhea were seen in 5.4% of the patients as nonhematological toxicities.[11] The authors showed that the mDCF regimen had an efficacy similar to that of the standard DCF regimen but had a lower toxicity rate. In another study, Keskin et al. determined the overall disease control rate to be 90% (2% CR, 54% PR, and 34% SD). The authors reported Grades 3–4 anemia in 11% of patients, neutropenia in 4%, and Grades 3–4 nausea and vomiting in 15%. Only 2% of the patients developed febrile neutropenia.[10] Wang et al. performed a randomized prospective study to compare the mDCF and CF regimens, and a better response was obtained in patients who were administered the mDCF regimen, with an overall response rate (ORR) of 48.7% (CR and PR). However, Grades 3–4 side effects were higher in this study with a rate of 77.3%.[26] The high toxicity rate reported in this prospective study may be due to the differences in mDCF tolerability among different geographical regions, and previous studies could not determine the toxicity reliably due to their retrospective design. Two retrospective studies performed in our country by Kos et al. and Inal et al. evaluated the efficacy of mDCF.[27],[28] Kos et al. compared the efficacy and toxicity of mDCF and cisplatin, 5-FU, folinic acid (CFF) in the first-line treatment of patients with advanced-stage gastric cancer. The objective response rate (CR and PR) was higher in the mDCF arm than in the CFF arm (30.0% vs. 13.3%, respectively), and both groups had acceptable toxicity rates. In the mDCF arm, the most frequently encountered Grades 3–4 toxicities were anemia in 5.0% of patients, neutropenia in 7.5%, febrile neutropenia in 5.0%, and diarrhea in 5.0%.[27] Inal et al. compared the standard DCF and mDCF regimens in terms of efficacy and tolerability. The response rates were similar in both arms (standard DCF, 46%; mDCF, 47%). However, Grades 3–4 neutropenia (48.2% vs. 13.6%; P = 0.003), anemia (21.2% vs. 4.5%; P = 0.06), nausea (44.7% vs. 13.6%; P = 0.008), and vomiting (31.8% vs. 4.5%; P = 0.01) were significantly higher in the standard DCF arm.[28] In our study, the overall disease control rate was 85.2% (1.6% CR, 59.0% PR, and 24.6% SD) and the ORR was 60.6%. Compared with other studies, we obtained similar toxicity and overall disease control rates and a higher ORR. These results may indicate that the mDCF chemotherapy regimen is as effective in SRCC as it is in non-SRCC histological subtypes.

The studies on patients who were administered the mDCF regimen showed a median OS of 8.7–10.7 months and a median PFS of 6.2–7.4 months.[10],[12],[27],[28] In our study, the median OS and PFS were 10.4 and 6.1 months, respectively, with a mean follow-up period of 8.9 months, similar to other studies.

The ECOG performance status is the most important parameter that predicts the survival and chemotherapy response, and it is associated with several factors including nutritional status, comorbidity, and age.[29] An ECOG performance score of 2 was shown to have a significant negative effect on survival compared with an ECOG score of 0 to 1.[30] Therefore, instead of combination chemotherapy, the use of a single chemotherapeutic agent would be more appropriate in patients with an ECOG score higher than 1. A high CEA level before treatment is closely associated with a poor prognosis and tumor load in patients with colon cancer.[31] Although there is no consensus on this subject in patients with gastric cancer, a high pretreatment CEA level is usually considered a poor prognostic factor.[32] In our study, we determined that the patients with high CEA levels at the time of diagnosis had poor prognoses. Therefore, an intensive treatment would be more appropriate in patients who have high CEA levels at the time of diagnosis.

Our study has some limitations such as its retrospective design, the small number of included patients, and the inability to perform a comprehensive toxicity analysis due to the retrospective design.


 > Conclusions Top


mDCF is an effective regimen in patients with SRCC of the stomach who have ECOG performance score of 0–1 when the PFS, OS, and tumor response rate are considered. Further prospective studies including more patients should be conducted on this subject because our study was retrospective.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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