Prognostic factors in metastatic gastric carcinoma

DOI 10.32471/exp-oncology.2312-8852.vol-41-no-2.13283

Although its incidence is decreasing in recent decades, gastric cancer is the second leading cause of cancer-related death. It is marked by a large disparity of its impact in terms of geographical distribution: the highest incidences are observed in East Asia (62 new cases/100,000 for men and 26 for women) with lowest rate in North America. In Africa, the estimated incidence is 4.7 new cases/100,000 for men and 3.3 for women) [1]. In Tunisia, gastric cancer represents 4.5% of cancers in men (7^th men cancer) and 3.7% of cancers in women (9^th women cancer). It represents 24% of digestive cancers [2]. In ⅔ of the patients, gastric cancer is diagnosed at stage IV (unresectable or metastatic tumor). Despite advances in palliative chemotherapy mainly based on cisplatin, the median survival of these patients is around one year. The 5-year survival rate does not exceed 5%. Recently the introduction of trastuzumab in the treatment of tumors expressing Her-2/neu has improved survival rates [3]. Some particularly Asian studies have focused on identifying prognostic factors influencing the survival of metastatic patients in order to improve the different therapeutic approaches. The aim of our study is to identify the parameters correlated with survival in our Tunisian population and to compare them to those described in the literature.

MATERIALS AND METHODS

This is a retrospective study including 49 patients with histological proven gastric cancer treated in the Department of Medical Oncology in the Habib Bourguiba Hospital in southern Tunisia, between January 2000 and December 2010. Our study included patients who had metastases at initial diagnosis of the disease (synchronous metastases) and patients who developed metastatic relapse after initial treatment (metachronous metastases). All patients underwent staging with a physical examination, chest X ray, abdominal ultrasound, thoracoabdominal computed tomography. The treatment consisted in palliative chemotherapy based on cisplatin. Overall survival was calculated from the date of diagnosis to the date of the latest news in synchronous metastatic patients and from the date of relapse in metachronous metastatic patients, according to Kaplan — Meier. We conducted a study of survival with prognostic factors in univariate analysis according to the test of log-rank and multivariate Cox model with significant value for p ≤ 0.05. The factors studied were: sex, age (less than 45 years), the sequence of metastases (synchronous vs metachronous), treatment of the primary tumor (gastrectomy), performance status according to the World Health Organization (WHO 0–1 vs greater than 1), the number of metastatic sites (unique vs multiple), the site of metastases (liver, peritoneum, other), the response to chemotherapy and the hemoglobin level less or greater than 10 g/dl.

RESULTS

Patient characteristics

The mean age was 48.9 years, ranging from 27 to 74 years. There were 30 men and 19 women. Details are presented in Table 1. Thirty-three patients had more than 1^st line chemotherapy based on 5-fluorouracil and cisplatin with an objective response rate of 37% and an average time to progression of 7 months. Gastrectomy was performed in 7 patients among 28 patients with synchronous metastases.

Survival and prognostic factors

The median overall survival was 8.6 months. The 1-year, 2-year, 3-year and 5-year survival rate were 26%, 10%, 6% and 2%, respectively (Figure). Prognostic factors for better survival in univariate analysis were: character synchronous metastases, good condition, good response to chemotherapy and single metastatic site. The other studied factors had no impact on survival (Table 2). The synchronous nature of metastases and the single site of metastasis were independent prognostic factors in multivariate analysis (Table 3).

DISCUSSION

Several authors were interested in studying the prognostic factors and survival in patients with metastatic gastric cancer.

Sex was not identified as a prognostic factor in almost all series. Nevertheless, age less than 50 years or 60 years in the series Kanagavel et al. [3] and Yoshida et al. [4] was a factor correlated with better survival in univariate analysis. These two factors were not statistically significant in our series.

As in our series, the nature of the site of metastases (liver, peritoneum etc) had no impact on survival in the literature. However, the number of metastatic sites (single or multiple) was a significant factor in both uni- or multivariate analysis varied in the series of Yoshida et al. [4] with survival rates at 2 years of 9.5%, 5.4% and 2.9% in case of one site, two or more than three metastatic sites respectively. By cons, this factor has not been found by the other authors [3, 5]. In our patients, the number of metastatic sites showed a significant difference in survival among patients with a single site of metastasis compared with those with multiple metastatic sites (p = 0.04).

In most trials, patients initially and secondarily metastatic are pooled together. From some studies survival data, it appears that among all patients in the metastatic setting, survival is better in case of synchronous metastatic disease versus metachronous metastatic disease with median survival about 12 month [6, 7] and 6 months, respectively [8]. This has been well demonstrated in our series with better survival in synchronous metastatic patients (p = 0.01) compared to secondary metastatic patients.

Performance status with a WHO ≥ 2 is a poor prognosis factor in almost series as well as in multivariate analysis and univariate ones.It represents an independent factor influencing negatively the overall survival [3, 4, 9]. In the series of Chau et al. [9] including 1080 patients with metastatic gastric cancer cases treated with different chemotherapy regimens (as part of three randomized Phase III studies), performance status according to WHO at diagnosis was an independent factor of overall survival with a survival significantly deteriorated if WHO ≥ 2.

In the Japanese series of Yoshida et al. [4], the study of survival according to the general state at dia­gnosis was conducted in 643 patients with metasta­tic gastric adenocarcinoma. Survival was significantly influenced with a 2-year survival of 11%, 8.5% and 0% for a WHO 0, 1 and 2, respectively. In our series, a performance status greater than 1 was significantly associated with shorter survival with p = 0.05.

In advanced disease, gastrectomy is usually done if the patient is symptomatic: tumor stenosis or in case of bleeding. Apart from these situations, palliative gastrectomy is debated.

In a Japanese series including 164 cases of metastatic [10] gastric cancer, palliative gastrectomy was beneficial in case of well-differentiated histology, in the absence of peritoneal metastasis and when surgery is followed or preceded by chemotherapy.

In a Polish retrospective study [11], from 2258 gastr­ectomy patients, 415 were metastatic. In this series, survival was significantly better in patients undergoing optimal curative gastrectomy to those undergoing non-curative gastrectomy with median survival of 10.6 months and 4.4 months respectively. In the series of Blank et al. [5], patients who underwent curative gastrectomy with good histologic response after preoperative chemotherapy, have a good median survival which joins that of non-metastatic patients with a median survival of 35.3 months and a 3-year survival of 47.6%. In the series of Chau et al. [9], palliative gastrectomy improved survival and especially the quality of life of patients with gastric adenocarcinoma. In our work, palliative gastrectomy was not associated with a survival benefit.

In a Chinese retrospective series, 39 patients with metastatic gastric tumor were treated with palliative chemotherapy based on 5-fluorouracil and folinic acid. In this study, an objective response to chemotherapy was associated with better survival with median survival of 10.5 months against 5 months in the absence of response [12]. In another study evaluating the FAM protocol for gastric adenocarcinoma in metastatic patients, median survival was 12.5 months in responding patients to treatment vs 3.5 months in non respon­ders [13]. In the series of Yoshida et al. [4], the good response to chemotherapy was an independent factor for better survival. In our study, an objective response to palliative chemotherapy (complete or partial response) was significantly associated with better survival (p = 0.01).

Anemia with a hemoglobin level less than 10 g/dl was an independent factor, in a multivariate analysis, for a low survival in the series of Yoshida et al. [4]. This factor was not observed in our series.

CONCLUSION

The factors that have a negative impact on survival reported in the literature are: bad performance status (WHO ≥ 2), advanced age, multiple metastatic sites, metachronous metastasis, anemia, lack of gastrectomy and poor response to chemotherapy. Independent factors are: bad performance statue, multiple metastatic sites, anemia and poor response to chemotherapy.The majority of these factors were confirmed in our series, particularly metachronous and multiple sites that were found in multivariate analysis.

CONFLICTS OF INTEREST

None.

AUTHOR CONTRIBUTIONS

All authors contributed to this article.

REFERENCES

1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 200. Int J Cancer 2010; 127: 2893–917.
2. Hsairi M, Fakfakh R, Ben Abdallah M, et al. Assessment of cancer incidence in Tunisia. La Tunis Med 2002; 80: 57–64.
3. Kanagavel D, Pokataev IA, Fedyanin MY, et al. A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy. Ann Oncol 2010; 21: 1779–85.
4. Yoshida M, Ohtsu A, Boku N, et al. Long-term survival and prognostic factors in patients with metastatic gastric cancers treated with chemotherapy in the Japan clinical oncology group (JCOG) Study. Jpn J Clin Oncol 2004; 34: 654–9.
5. Blank S, Lordick F, Dobritz M, et al. A reliable risk score for stage IV sophagogastric cancer. EJSO 2013; 39: 823–30.
6. Rivera F, Vega-Villegas ME, Lopez-Brea MF. Chemotherapy of advanced gastric cancer. Cancer Treat Rev 2007; 33: 315–24.
7. Power D, Kelsen DP, Shah MA. Advanced gastric cancer — Slow but steady progress. Cancer Treat Rev 2010; 36: 384–92.
8. D’Angelica M, Gonen M, Brennan MF, et al. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 2004; 240: 808–16.
9. Chau I, Norman AR, Cunningham D, et al. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer — pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004; 22: 2395–403.
10. Kunisaki C, Makino H, Takagawai R, et al. Impact of palliative gastrectomy in patients with incurable advanced gastric cancer. Anticancer Res 2008; 28: 1309–16.
11. Kulig P, Sierzega M, Kowalczyk T, et al. Non-curative gastrectomy for metastatic gastric cancer: Rationale and long-term outcome in multicenter settings. EJSO 2012; 38: 490–6.
12. Lin YC, Liu HE, Wang CH, et al. Clinical benefit and response in patients with gastric cancer to weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV). Anticancer Res 1999; 19: 5615–20.
13. MacDonald JS, Schein PS, Woolley PV, et al. 5-Fluorouracil, Doxorubicin, and Mitomycine (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 1980; 93: 533–6.

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