Original Article
Prognostic Factors and Predictive Model in Patients With Advanced Biliary Tract Adenocarcinoma Receiving First-Line Palliative Chemotherapy Inkeun Park, MD1; Jae-Lyun Lee, MD, PhD1; Min-Hee Ryu, MD, PhD1; Tae-Won Kim, MD, PhD1; Sung Sook Lee, MD, MSc1; Do Hyun Park, MD, PhD2; Sang Soo Lee, MD, PhD2; Dong Wan Seo, MD, PhD2; Sung Koo Lee, MD, PhD2; and Myung-Hwan Kim, MD, PhD2
BACKGROUND: Advanced biliary tract adenocarcinoma (BTA) has been a rare but fatal cancer. If unresectable, palliative chemotherapy improved the quality and length of life, but to the authors’ knowledge, prognostic factors in such patients have not been well established to date. In the current study, prognostic factors were investigated in patients with advanced BTA receiving first-line palliative chemotherapy. METHODS: Data from 213 patients with advanced BTA who were in prospective phase 2 or retrospective studies from September 2000 through October 2007 were used. RESULTS: With a median follow-up duration of 29.7 months, the median overall survival (OS) was 7.3 months (95% confidence interval [95% CI], 6.3 months-8.3 months). A Cox proportional hazards model indicated that metastatic disease (hazards ratio [HR], 1.521; P ¼ .011), intrahepatic cholangiocellular carcinoma (HR, 1.368; P ¼ .045), liver metastasis (HR, 1.845; P < .001), Eastern Cooperative Oncology Group performance status (HR, 1.707; P < .001), and alkaline phosphatase level (IU/L) (HR, 1.001; P < .001) were statistically significant independent predictors of poor prognosis. Patients were classified into 3 risk groups based on the prognostic index (PI), which was constructed using the regression coefficients of each variable. The median OS was 11.5 months (95% CI, 9.6 months-13.5 months) for the low-risk group (PI 1.5; n ¼ 67), 7.3 months (95% CI, 5.7 months-8.9 months) for the intermediate-risk group (PI > 1.5 but 2.2; n ¼ 75), and 3.6 months (95% CI, 2.9 months-4.1 months) for the high-risk group (PI > 2.2; n ¼ 70 [P < .001]). CONCLUSIONS: Five prognostic factors in patients with advanced BTA were identified. The predictive model based on PI appears to be promising and may be used for the management of individual patients and to guide the C 2009 design of future clinical trials, although external validation is needed. Cancer 2009;115:4148–55. V American Cancer Society. KEY WORDS: biliary tract cancer, chemotherapy, palliation, prognosis, multivariate analysis.
Advanced biliary tract adenocarcinoma (BTA) is a rare but fatal cancer. BTA includes a heterogeneous group of cancers: intrahepatic cholangiocellular carcinoma (IHCCC), gallbladder cancer (GBC), extrahepatic bile duct carcinoma (EHBDC), and ampulla of Vater cancer (AoVC). In the United States, BTAs affect Corresponding author: Jae-Lyun Lee, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-dong, Songpa-gu, Seoul, South Korea; Fax: (011) 82-2-3010-6961;
[email protected] 1 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 2Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Received: August 13, 2008; Revised: January 14, 2009; Accepted: February 6, 2009 Published online June 17, 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/cncr.24472, www.interscience.wiley.com
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Prognostic Factors in Advanced BTA/Park et al
approximately 12,000 people annually and the incidence of IHCCC has increased in recent years.1 In Korea, BTA accounts for approximately 4.8% of all malignant neoplasms and is estimated to be the seventh most common cancer.2 Complete resection is the only cure for BTA, but only 10% of patients present with early stage disease and are candidates for surgical resection.3 In addition, among patients who undergo curative surgery, recurrence rates are extremely high. For patients with unresectable advanced or recurrent BTA, 5-fluorouracil-based palliative chemotherapy, which can improve the quality and length of life,4,5 is the mainstay of treatment.3 To our knowledge, because of the rarity of BTA and the heterogeneity of the patient population, there are no well-designed, large-scale randomized controlled trials. Most trials published to date have been small phase 2 studies. Furthermore, only a minority of BTA patients treated with chemotherapy experience favorable responses, and few achieve long-term survival. Therefore, the confirmation of a standard therapeutic regimen and the identification of new chemotherapeutic agents is a high priority. In designing and interpreting phase 2 or 3 clinical trials for the treatment of BTA, it is important to identify factors associated with patient survival. In particular, phase 3 trials that include survival as a primary endpoint must account for prognostic factors so that treatment groups are comparable and trial outcomes are properly interpreted. In addition, adequate assessment of patient survival will also aid patients and physicians in their clinical judgment. Several studies have investigated prognostic factors associated with survival from BTA, but the majority addressed only the risk of disease recurrence after curative resection.6-12 To our knowledge, only 1 small study to date has investigated prognostic factors for patients with advanced GBC and EHBDC who received palliative chemotherapy.13 The objective of the current study was to evaluate the prognostic factors that affect the overall survival (OS) of patients with BTA and to establish a prognostic prediction model for patients with advanced BTA who receive palliative chemotherapy.
were included in a retrospective cohort study from September 2000 through October 2007. The first prospective study was a phase 2 trial (capecitabine plus cisplatin protocol) in which 42 patients were treated with oral capecitabine (at a dose of 1250 mg/m2 twice per day from Day 1 to Day 14) and cisplatin (at a dose of 60 mg/m2 intravenously at Day 1 every 3 weeks).14 The second phase 2 study (gemcitabine plus capecitabine protocol) was a prospective study in which 38 patients received gemcitabine (at a dose of 1000 mg/m2 intravenously for 30 minutes on Days 1, 8, and 15) and oral capecitabine (at a dose of 830 mg/m2 twice per day from Day 1 to Day 21 every 4 weeks).15 The cohort study was a retrospective review of 133 patients who were treated with oral S-1 monotherapy (at a dose of 40 mg/m2 twice per day from Day 1 to Day 14 every 3 weeks) and who fulfilled the preset eligibility criteria.16 The inclusion criteria for both prospective studies were as follows: 1) histologically or cytologically confirmed adenocarcinoma of the biliary tract; 2) distant metastases or locally advanced disease that was not eligible for curative surgery; 3) ages 18 to 75 years; 4) Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better; 5) presence of measurable lesions; 6) no serious or uncontrolled concomitant medical illness; and 7) adequate bone marrow and organ function (absolute neutrophil count 2000/lL, platelet count 100,000/ lL, and serum creatinine 1.5 mg/dL). The eligibility criteria for the retrospective study were not significantly different. However, in the retrospective study, patients with elevated transaminase and hyperbilirubinemia (total bilirubin 2 mg/dL) associated with biliary obstruction caused by the disease were included so that the efficacy and safety of S-1 monotherapy for patients with impaired liver function could be assessed. In addition, patients with evaluable disease, but not measurable disease based on Response Evaluation Criteria in Solid Tumor criteria, were included because the primary endpoint of the retrospective study was OS.
Data Analysis and Statistical Consideration
MATERIALS AND METHODS Patients We evaluated data from 213 patients with advanced BTA who were enrolled in 2 prospective phase 2 studies or who Cancer
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The data analyzed included sex; age; ECOG performance status; macroscopic and microscopic characteristics of the tumors, including primary site (IHCCC, GBC, EHBDC, and AoVC); disease status (initially locally advanced, locoregionally recurrent, initially metastatic, 4149
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and recurrence with distant metastasis); histologic differentiation; sites of metastases; number of metastases; baseline biochemical parameters, including white blood cell (WBC) count (/lL), hemoglobin concentration (Hb) (g/dL), platelet count (/lL), bilirubin (mg/dL), alkaline phosphatase (ALP) (reference value, 40-120 IU/ L), calcium (mg/dL), alanine aminotransferase (ALT) (IU/L), aspartate aminotransferase (AST) (IU/L), albumin (g/dL), and carbohydrate antigen 19-9 (CA 19-9) (reference value, 0-37 U/mL); experience of biliary decompression procedures; chemotherapy regimens; date of treatment; and date and cause of death or date of the last follow-up. The primary endpoint was OS, defined as the date from the first chemotherapeutic cycle to the date of death. The Kaplan-Meier algorithm was used to estimate OS. We compared survival using the Cox proportional hazards model according to clinicopathologic characteristics including age, sex, ECOG performance status, disease status at palliative chemotherapy, primary tumor site, metastasis site, laboratory values, chemotherapeutic regimen, and whether biliary obstruction was present. All potential prognostic factors with a probability value .20 on univariate analyses were entered into the multivariable Cox models. The final models were determined by backward elimination. Schoenfeld residuals and the log (-log [survival rate]) were used to verify that the proportional hazards assumptions were not violated. The Statistical Package for the Social Sciences (SPSS) for Windows (SPSS Inc, Chicago, Ill) and S-plus 2000 (Mathsoft Inc, Seattle, Wash) were used for statistical analyses.
RESULTS Patient Characteristics Baseline clinical and laboratory characteristics are summarized in Table 1. The median age of the patients was 59 years (range, 21 years-83 years) and 120 patients (56.3%) were men. Primary sites of disease were IHCCC (85 patients; 39.9%), GBC (72 patients; 33.8%), EHBDC (39 patients; 18.3%), and AoVC (17 patients; 8.0%). Forty-nine patients (23.0%) had biliary obstruction and underwent drainage procedures, such as percutaneous 4150
transhepatic biliary drainage or endoscopic retrograde biliary stent. Fifty-nine patients (27.7%) received secondline chemotherapy.
Survival Distribution At the time of analysis (June 2008), 192 patients had died (90.1%) and the median OS time was 7.3 months (95% CI, 6.3 months-8.3 months) (Fig. 1), with a median follow-up duration of 29.7 months (95% CI, 16.9 months42.5 months). The 6-month survival rate was 57.5%, and the 1-year survival rate was 28.5%.
Univariate Survival Analysis A univariate analysis indicated that disease status (metastatic [initially metastatic or disease recurrence with distant metastasis] vs locally advanced [initially locally advanced or locoregionally recurrent]), primary site (IHCCC vs GBC or EHBDC or AoVC), peritoneal metastasis, liver metastasis, bone metastasis, lung metastasis, ECOG performance status, WBC counts, Hb levels, total bilirubin levels, ALP values, AST values, albumin levels, and corrected calcium levels17 were statistically associated with OS (Table 2). Age, gender, chemotherapy regimen, and CA 19-9 values were found to have no influence on patient survival.
Multivariable Analysis, Prognostic Index, and Risk Groups Among the parameters considered, initial disease status, primary tumor site (IHCCC vs GBC or EHBDC or AoVC), ECOG performance status, liver metastasis, and ALP values were found to be significant prognostic factors (Table 3). Of the 213 patients, we had complete data for 212 patients (99.5%) with regard to 5 parameters and therefore these patients were included in the prognosis prediction model. For the clinical application of these findings, a prognostic index (PI) was calculated based on the regression coefficients derived from the 5 variables identified by multivariable analysis. The index equation was as follows: 0.42 X (0, locally advanced disease; 1, metastatic disease) þ 0.31 (0, extrahepatic biliary tract adenocarcinoma; 1, IHCCC) þ 0.61 X (0, no Cancer
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Prognostic Factors in Advanced BTA/Park et al
Table 1. (Continued) Table 1. Characteristics of Patients With Advanced Biliary Tract Cancer (n ¼ 213)
Characteristic
No.
%
Age, median (range), y
59 (21-83)
Sex Male Female
120 93
56.3 43.7
10 51 25 127
4.7 23.9 11.7 59.6
85 72 39 17
39.9 33.8 18.3 8.0
108 104 51 16 33 8
50.7 48.8 23.9 7.5 15.5 3.8
35 82 54 31 11
16.4 38.5 25.4 14.6 5.2
133 42 38
62.4 19.7 17.8
12 89 56 56 191 49
5.6 41.8 26.3 26.3 90.5 23.0
35 140 38
16.4 65.7 17.8
Initial status Recurrence, locoregional Recurrence, distant metastasis Initially locally advanced Initially metastatic
Characteristic Calcium, mg/dL CA 19-9,U/mL
No.
%
9.0 (7.5-12.4) 72.1 (1.5-310000)
IHCCC indicates intrahepatic cholangiocellular carcinoma; GBC, gallbladder cancer; EHBDC, extrahepatic bile duct cancer; AoVC, ampulla of Vater cancer; XP, capecitabine plus cisplatin; GX, gemcitabine plus capecitabine; ECOG, Eastern Cooperative Oncology Group; ALP, alkaline phosphatase, ALT, alanine aminotransferase; AST, aspartate aminotransferase; CA 19-9, carbohydrate antigen 19-9.
Primary site IHCCC GBC EHBDC AoVC
Metastasis site Abdominal lymph node (M1) Liver Peritoneum Cervical lymph node Lung Bone
No. of metastatic organ 0 1 2 3 ‡4
Chemotherapeutic regimen S-1 XP GX
Histologic grade Well differentiated Moderately differentiated Poorly differentiated Unknown Measurable disease Bile duct obstruction
ECOG performance status 0 1 2
Laboratory tests, median (range) White blood cells, /lL Hemoglobin, g/dL Total bilirubin, mg/dL ALP, IU/L ALT, IU/L AST, IU/L Albumin, g/dL
7200 12.3 0.9 146 27 32 3.6
(2200-24400) (8.5-16.1) (0.3-12.0) (41-1543) (5-322) (11-317) (1.9-4.8)
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FIGURE 1. Overall survival of patients with advanced biliary tract adenocarcinoma (n ¼ 213) undergoing first-line palliative chemotherapy is shown.
liver metastasis; 1, liver metastasis) þ 0.54 X (ECOG performance status) þ 0.001 X (ALP [IU/L]). The individual PI values for the patients ranged from 0.47 to 3.63, with a median of 1.82. The patients were then reclassified into 3 risk groups according to the PI values (33%ile and 66%ile): the low-risk group had a PI 1.5 (n ¼ 67), the intermediate-risk group had a PI of > 1.5 but 2.2 (n ¼ 75), and the high-risk group had a PI > 2.2 (n ¼ 70). The resulting Kaplan-Meier curves for the 3 groups (P < .001) (Fig. 2) indicated marked differences in survival. The median OS was 11.5 months (95% CI, 9.6 months-13.5 months) for the low-risk group (PI 1.5; n ¼ 67), 7.3 months (95% CI, 5.7 months-8.9 months) for the intermediate-risk group (PI > 1.5 but 2.2; n ¼ 75), and 3.6 months (95% CI, 2.9 months-4.1 months) for the high-risk group (PI > 2.2; n ¼ 70). The 4151
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1-year survival rates for each group were 48.2%, 26.3%, and 4.2%, respectively. Compared with the low-risk group, the intermediate-risk group had a 2.1-fold increased risk of death (hazards ratio [HR], 2.08; 95% CI, 1.43-3.01), and the high-risk group had a 4.3-fold increased risk of death (HR, 4.27; 95% CI, 2.89-6.31).
Table 2. Univariate Analysis of Prognostic Factors Affecting Overall Survival in Patients With Advanced Biliary Tract Adenocarcinoma
Variable
P*
HR (95% CI)
Age, y Sex, male vs female
.329 .527
0.992 (0.977-1.008) 1.097 (0.824-1.459)
Treatment
.119
GX vs XP S-1 vs XP Initial status, metastatic vs locally advanced Primary site, IHCCC vs others Peritoneal metastasis, yes vs no Liver metastasis, yes vs no Abdominal LN metastasis, yes vs no Bone metastasis, yes vs no Lung metastasis, yes vs no ECOG performance status Leukocyte counts, /lLy Hemoglobin, g/dL Bilirubin, mg/dL ALP, IU/L AST, IU/L ALT, IU/L Albumin, g/dL Corrected calcium, mg/dL CA 19-9, U/mL
.040 .257
