Annals of Oncology Advance Access originally published online on February 13, 2007
Annals of Oncology 2007 18(5):886-891; doi:10.1093/annonc/mdl501
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© 2007 European Society for Medical Oncology
gastrointestinal tumors |
Prognostic model to predict survival following first-line chemotherapy in patients with metastatic gastric adenocarcinoma
1 Division of Hematology/Oncology
2 Department of Surgery
3 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
4 Division of Hematology/Oncology, Department of Medicine, Dankook University Hospital, Cheonan
5 Division of Hematology and Oncology, Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, South Korea
* Correspondence to: Dr W. K. Kang, Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong Kangnam-gu, Seoul 135-710, South Korea. Tel: +82-2-3410-3451, Fax: +82-2-3410-0041; E-mail: wkkang{at}smc.samsung.co.kr
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Abstract |
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Background: This study was to devise a prognostic model for metastatic gastric cancer patients undergoing first-line chemotherapy.
Patients and methods: A retrospective analysis was carried out on 1455 gastric cancer patients, who received first-line chemotherapy from September 1994 to February 2005.
Results: At multivariate level, poor prognostic factors were no previous gastrectomy [P = 0.003; relative risk (RR), 1.191; 95% confidence interval (CI) 1.061–1.338], albumin <3.6 g/dl (P = <0.001; RR, 1.245; 95% CI 1.106–1.402), alkaline phosphatase >85 U/l (P = <0.001; RR, 1.224; 95% CI 1.092–1.371), Eastern Cooperative Oncology Group performance status of two or more (P = <0.001; RR, 1.690; 95% CI 1.458–1.959), the presence of bone metastases (P = 0.001; RR, 1.460; 95% CI 1.616–1.836), and the presence of ascites (P = <0.001; RR, 1.452; 95% CI 1.295–1.628). Of 1434 patients, 489 patients (34.1%) were categorized as low-risk group (zero to one factors), 889 patients (62.0%) as intermediate-risk group (two to four factors), and 56 patients (3.9%) as high-risk group (five to six factors). Median survival durations for low, intermediate, and high-risk groups were 12.5 months, 7.0 months, and 2.7 months, respectively.
Conclusions: This model should facilitate the individual patient risk stratification and thus, more appropriate therapies for each metastatic gastric cancer patient.
Key words: advanced gastric cancer, chemotherapy, prognosic factor
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Gastric cancer is the leading cause of cancer death worldwide with the incidence of 18.9/100 000 per year [1]. Gastric cancer is the most commonly diagnosed malignancy in Korea, Japan, China, South America, and Eastern European nations with the lowest frequency observed in the United States and Canada [2, 3]. Although the surgery is the best curative treatment option for gastric cancer, only 30% to 60% of patients undergo curative surgical resections [4, 5]. Moreover, we and few other groups have reported recurrence rate of 40% to 60% following curative surgery, most of whom died of the disease [3, 6–8]. Therefore, the role of palliative chemotherapy in treatment of gastric cancer is of paramount importance. An accurate acquisition of prognostic parameters for each patient may contribute in implementation of risk-based stratification of therapy in metastatic, recurrent gastric cancer patients, and thus, identifying patient groups likely and unlikely to benefit from the available chemotherapies. Most of the previous studies have investigated prognostic factors in gastroesophageal junction tumors or esophageal tumors, whereas very few have focused on patients with stomach cancer. As the palliative chemotherapy is a pertinent therapeutic approach for gastric cancer patients, identification of variables that are predictive of treatment outcome and/or survival should allow better differentiation among patient populations and better assessment of different chemotherapeutic agents. Prognostic scoring systems have been delineated in several cancer types and are being increasingly used in clinics to segregate different risk groups for patients with aggressive lymphoma [9], breast cancer [10, 11], prostate cancer [12], multiple myeloma [13], esophageal/gastroesophageal junction tumors/gastric cancer [14], and renal cell carcinoma [15]. The objective of this study was to delineate a prognostic model, which can effectively identify different risk groups on the basis of initial clinical parameters that are easily accessible to clinicians for metastatic gastric cancer patients undergoing first-line palliative chemotherapy. We used the Samsung Medical Center experience with gastric cancer patients receiving first-line chemotherapy in a palliative setting to explore the independent variables associated with survival by using a multivariate analysis.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients
From September 1994 to February 2005, 1598 patients received palliative chemotherapy for metastatic, unresectable, or recurrent gastric cancer at Samsung Medical Center. The criteria for case inclusion were as follows: (i) histologically confirmed diagnosis of gastric cancer; (ii) availability of clinical data at the first administration of palliative chemotherapeutic agents; and (iii) age
18. Patients with the following clinical data were considered eligible: patient demographics, complete blood count, surgical record, pathologic report, tumor–node–metastasis stage, and computer tomography (CT) scan of abdomen. Patients with esophageal cancer, small cell carcinoma, lymphoma, and squamous cell carcinoma were excluded from the analysis. Of the 1598 patients screened, 1455 patients fulfilled the inclusion criteria and were retrospectively included in the analysis.
treatment
The taxane-based chemotherapy consisted of the following: (i) docetaxel (Taxotere, Aventis) or paclitaxel (Taxol, Bristol Myers Squibb), cisplatin (n = 476); (ii) epirubicin, cisplatin, docetaxel (n = 27). The 5-fluorouracil (5-FU)-based chemotherapy included as follows: (i) 5-FU, leucovorin, cisplatin (n = 783); (ii) epirubicin, cisplatin, 5-FU (n = 44); (iii) irinotecan or oxaliplatin, leucovorin, 5-FU (modified FOLFIRI or FOLFOX) (n = 46); (iv) irinotecan, oxaliplatin, leucovorin, 5-FU (modified FOLFOXIRI) (n = 29); and (v) capecitabine, cisplatin, (n = 25). Others included (i) alimta, cisplatin (n = 4) and (ii) etoposide, doxorubicin, cisplatin (n = 21).
treatment outcome
The clinical tumor response was assessed according to World Health Organization (WHO) criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria. According to the WHO criteria, a complete response (CR) was defined as disappearance of all clinically detectable disease for at least 4 weeks. Partial response (PR) was defined as a 50% decrease in tumor size without the appearance of new disease or increase in any single lesion of >25%. Stable disease (SD) was defined as no significant change in measurable or assessable malignant disease without the appearance of new lesions. This included a <50% decrease in tumor size and a <25% increase in any tumor site. SD required no worsening in Karnofsky performance status (KPS). Progressive disease (PD) was defined as the appearance of new malignant lesions, a 25% increase in measurable disease (25% increase in estimated size for assessable disease) at any site of >2 cm2, or a 50% increase in size for any site of <2 cm2 in size at the initiation of treatment. The RECIST criteria were as follows: PR was defined as a 30% decrease in tumor size without the appearance of new disease and PD was defined as 20% increase in tumor size or the appearance of a new lesion.
statistical analysis
The primary end point of the study was overall survival (OS). OS was estimated using the Kaplan–Meier product-limit method. OS was measured from the date of diagnosis to the date of death or the last follow-up visit. Survival rates were compared for statistical differences by using log-rank analysis. A prognostic model was established by searching all variables that significantly influenced OS at a level of P values 
0.05 in the univariate analysis. Multivariate analysis, stratifying for chemotherapy regimens (taxane-based versus nontaxane-based), was carried out using stepwise Cox proportional hazards regression modeling. P values <0.05 were considered statistically significant and all P values correspond to two-sided significance tests.
Factors included in the univariate analyses were as follows: age, performance status (PS), previous gastrectomy, tumor grade, Lauren classification, tumor location, hemoglobin, white blood cell (WBC), platelet count, serum albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (ALP,) serum calcium, year of treatment, metastasis to liver, bone, bone marrow, ovary, intestine, the presence of ascites at the start of chemotherapy, and the presence of measurable lesion according to the WHO or RECIST criteria. Laboratory variables were initially recorded as continuous variables and later dichotomized according to the median value of each variable.
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results |
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patient characteristics
From September 1994 to February 2005, 1455 advanced gastric cancer patients were included in this analysis. The median age was 54 with a range of 21–86 (Table 1). Eighty-two percent (n = 1189) of the patients had Eastern Cooperative Oncology Group (ECOG) zero to one at the time of the first-line chemotherapy. Ninety-seven percent (1412 of 1455) of the patients had metastatic disease. Approximately half of the patients previously underwent gastrectomies, either in curative or palliative setting. About 10% of the patients had gastroesophageal or cardial tumors. The median survival time (MST) of all patients was 8.6 months [95% confidence interval (CI) 8.1, 9.1] (Figure 1). Of the 1227 assessable patients for treatment response, there were 17 CRs (1.4%) and 283 PRs (23.1%), giving an overall response rate of 24.5%. A total of 594 (40.8%) patients received second-line chemotherapy.
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univariate analyses
At univariate analyses, PS (ECOG 2–4), no previous gastrectomy, WBC count >6370/µl, albumin
3.6 g/dl, bilirubin >0.5 mg/dl, ALP >85 U/l, calcium 8.9 mg/dl, the presence of bone, bone marrow, and ascites, and the presence of measurable lesion at the time of the first-line chemotherapy all adversely influenced the survival (Table 2) with statistical significances.
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prognostic model
Clinical parameters that were included in the multivariate analysis were ECOG PS, previous gastrectomy, WBC count, albumin, bilirubin, ALP, calcium, bone, bone marrow, ascites, and measurable lesion. The forward conditional Cox regression model was used to delineate significant prognostic factors for survival. Prognostic factors for poor survival were no previous gastrectomy [P = 0.003; relative risk (RR), 1.191; 95% CI 1.061–1.338], albumin <3.6 g/dl (P = <0.001; RR, 1.245; 95% CI 1.106–1.402), ALP >85 U/l (P = <0.001; RR, 1.224; 95% CI 1.092–1.371), ECOG PS of two or more (P = <0.001; RR, 1.690; 95% CI 1.458–1.959), the presence of bone metastases (P = 0.001; RR, 1.460; 95% CI 1.616–1.836), and the presence of ascites (P = <0.001; RR, 1.452; 95% CI 1.295–1.628) (Table 3). Of the 1455 patients, 1434 patients had complete data on six parameters and therefore included in the final prognostication. The prognostic grouping of the 1434 patients was carried out according to the following criteria: low-risk group, zero to one factor; intermediate-risk group, two to four factors; high-risk group, five to six factors. The survival curves according to the prognostic model are provided in Figure 2. The prognostic model separated the patients into three risk groups with markedly different survival outcomes. Of 1434 patients, 489 patients (34.1%) were categorized as low-risk group, 889 patients (62.0%) as intermediate-risk group, and 56 patients (3.9%) as high-risk group. Median survival for low- and intermediate-risk groups was 12.5 months (95% CI 11.3–13.7) and 7.0 months (95% CI 6.6–7.5), respectively. One-year survival rates for low, intermediate, and, high-risk groups were 52.4%, 27.3%, and 8.9%, respectively. Patients categorized as high-risk group pursued a rapidly deteriorating clinical course and showed a MST of only 2.7 months (95% CI 1.6–3.8). The high-risk group demonstrated an approximately four-fold (RR, 3.9; 95% CI 2.9–5.1) increased risk of death.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In an attempt to enhance risk-based stratification for chemotherapy, we analyzed prognostic factors for survival in metastatic gastric cancer patients who were undergoing first-line palliative chemotherapy. Despite the high incidence of gastric cancer, especially in the Asian region, there is no single chemotherapy regimen as a standard treatment with definite superiority over others. Moreover, systemic analyses of prognostic factors reflecting poor survival have not been conducted in gastric cancer patients who are candidates for palliative chemotherapy. A convenient prognostic model incorporating readily available clinical parameters may assist clinicians for risk stratification and thus, individualization of therapeutic approach. In this study, no previous gastrectomy, low albumin, high ALP, ECOG PS of two or more, presence of bone metastases, and presence of ascites were significant prognostic factors for poor survival in metastatic gastric cancer patients receiving first-line chemotherapy. To the best of our knowledge, this is the first report to systematically identify prognostic factors in a large series of this specific subset of patients.
A recently reported study analyzed 1080 patients with locally advanced and metastatic esophageal (n = 295), esophagogastric junctional (n = 248), and gastric cancer (n = 512), treated within three randomized controlled trials [14]. Four independent poor prognostic factors were identified: PS of two or more, liver metastases, peritoneal metastases, and ALP 100 U/l. The Japan Clinical Oncology Group (JCOG) analyzed prognostic factors in 643 patients in four phase II and one phase III trials, and reported that PS, number of metastatic sites, and macroscopically scirrhous type tumors were significantly associated with poor survival in metastatic gastric cancer patients [16]. A majority of studies on prognostication of gastric cancer patients were focused on postoperative survival rather than postchemotherapy survival [17–20].
The patient population in this analysis was different from other studies; 97% of the included patients had metastatic disease and only 0.5% of the patients had gastroesophageal junction tumors. A potential advantage of our study is the homogeneity of the clinical, radiologic, and pathologic assessment. All patients were treated by one of four medical oncologists, CT scans were reviewed by one of three reference radiologists, gastric resections with extended lymph node dissection were carried out by one of seven gastrointestinal tumor surgeons, and pathology specimens were reviewed by two reference pathologists. On the other hand, a potential weakness would lie in the retrospective nature of the study with various chemotherapeutic regimens. Due to this reason, predictive factor analyses for treatment response were not carried out, although a recent study suggests a correlation between tumor response to first-line chemotherapy and survival in gastric cancer patients [21]. Our data on a prognostic model may be used as a reference when designing future prospective studies.
The role of cytoreductive surgery in patients with metastatic gastric cancer is still disputed. The rationale for offering palliative gastrectomy to patients with unresectable or metastatic gastric cancer patients is to avoid tumor bleeding, perforation, obstruction, or complicated ascites and to improve the outcome by reducing tumor burden. Although limited by a small number of patients, Saidi et al. [22] has demonstrated a significantly better survival in those with resection and adjuvant chemotherapy as compared with a chemotherapy group (P = 0.01; mean survival 16.3 months versus 5.9 months) in accordance with other studies [23–25]. Furthermore, the JCOG study also revealed that eight of 11 5-year survivors received surgical resections for primary sites [16]. In the current study, patients with previous gastrectomy, either palliative or curative, pursued favorable clinical course when compared with those without previous gastrectomy (MST 9.7 versus 7.6 months, P <0.001) and its prognostic significance was retained in multivariate level (Table 3).
The presence of bone metastases was an independent prognostic factor in our analysis [MST, 4.0 versus 8.7 months, bone metastasis (+) versus (–), P = 0.001] This is in accordance with a recent study which analyzed 304 metastatic gastric cancer patients treated with cisplatin-containing chemotherapy [26]. In their multivariate analysis, poor performance, presence of malignant ascites, bone metastasis, number of metastatic sites, and elevation of serum total bilirubin were significant adverse factors for survival. The prognosis of bone metastases from gastric cancer is very poor according to previous studies [27, 28]. Because a great proportion of bone metastases are asymptomatic and bone scintigraphy is not a routine clinical practice, the incidence of bone metastases may be underestimated in gastric cancer patients. This is supported by a 10-fold higher incidence of bone metastasis in autopsy series compared with the clinical detection rate [28]. The elevated serum ALP may reflect the presence of bone metastasis; nevertheless, an elevated ALP level was an independent prognostic factor to bone metastasis. Elevated ALP has been found to be a meaningful prognostic factor in patients with metastatic esophageal/gastric cancer [14], and those with metastatic colorectal cancer receiving 5-FU-based chemotherapy [29].
In agreement with previous studies [14], the presence of ascites at the time of first-line chemotherapy was an independent poor prognostic factor. The presence of ascites was defined as if there was an evidence of paracentesis in the medical record or there was suspicious malignant fluid collection at the initial abdominal CT. It is often postulated that the effect of intravenous chemotherapy is limited by the peritoneal blood barrier and the paucity of subperitoneal blood vessels [30]. Notably, patients categorized as high-risk group did very poorly with MST of 2.7 months. Therefore, gastric cancer patients with five or six clinical parameters at the start of chemotherapy should be carefully offered with different therapeutic strategies. One of the therapeutic options in this subset of patients would be to provide best supportive care.
In conclusion, six poor prognostic factors have been delineated in patients receiving first-line chemotherapy for metastatic gastric cancer. The prognostic model on the basis of these six parameters separated patients into three groups with distinct prognosis. This model should facilitate the individual patient risk stratification and thus, more appropriate therapies for each patient.
Received for publication October 31, 2006. Revision received December 17, 2006. Accepted for publication December 18, 2006.
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