American Journal of Therapeutics 0, 000–000 (2014)
A Prognostic Index to Identify Patients With Intrahepatic Cholangiocarcinoma Who Could Benefit From Gemcitabine Plus Cisplatin Suk-young Lee, MD, PhD,1 Hye sook Kim, MD,1 Yoon Ji Choi, MD,1 Kyong Hwa Park, MD, PhD,1 Sang Won Shin, MD, PhD,1 Yeul Hong Kim, MD, PhD,1 and Seung Tae Kim, MD, PhD1,2*
Biliary tract cancer is a heterogenous group. Gemcitabine plus cisplatin has been the standard chemotherapy for advanced biliary tract cancer, but there is lack of evidence on treatment in patients with intrahepatic cholangiocarcinoma (IHC). We analyzed 29 patients with only IHC who received gemcitabine plus cisplatin between June 2010 and February 2013. The median age was 63 years (range, 40–78 years), and Eastern Cooperative Oncology Group performance status of all patients was ,2. The median progression-free survival and median overall survival (OS) were 4.3 and 7.3 months, respectively. Multivariate analysis showed that platelet count (#180 3 109 per liter), metastatic site of more than 2, and albumin level (#3.5 g/dL) were independent prognostic factors for decreased OS. OS was estimated based on the number of adverse prognostic factors: zero or 1 (good prognostic group), 2 (intermediate group), or 3 (poor prognostic group). The median OS for good (n 5 15), intermediate (n 5 10), and poor (n 5 4) prognostic group was 10.5, 6.1, and 1.6 months, respectively (P , 0.005). Relatively better prognosis of the good prognosis group comparing to other prognosis groups can be expected from the prognostic model established in this study by analyzing patients with IHC treated with gemcitabine. Keywords: cholangiocarcinoma, prognostic model, overall survival
INTRODUCTION Biliary tract cancer is composed of heterogenous groups of disease that include cholangiocarcinoma, gallbladder, and ampullary cancers. Cholangiocarcinoma is a malignant tumor that arises from epithelium of biliary tract
1 Division of Hematology and Oncology, Department of Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea; and 2Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Hematology and Oncology, Department of Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, South Korea. E-mail: [email protected]
1075–2765 2014 Lippincott Williams & Wilkins
and is further classified into intrahepatic cholangiocarcinoma (IHC) and extrahepatic cholangiocarcinoma, which is again consisted with hilar cholangiocarcinoma and distal cholangiocarcinoma.1 It is known that those each tumor type may show different behavior, biologic feature, and epidemiology.1–3 A number of studies concerning cancer stem cells in cholangiocarcinoma have demonstrated heterogenous origin of biliary tract cancer. These studies have suggested 2 different stem cell niches in liver and biliary tract with implication of different source of cancer cells in carcinogenesis of cholangiocarcinoma.4–7 Stem cell niches that have been found within liver are known as canals of Hering. Progenitor cells residing the canals of Hering can differentiate into hepatocytes and cholangiocytes, and these are potential source of cancer cells of hepatocellular carcinoma or cholangiocellular carcinoma.3 Peribiliary glands, additionally identified stem www.americantherapeutics.com
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Lee et al
2
cell niches located in the wall of the extrahepatic and large intrahepatic bile duct, are mucin-producing glandular elements.6,7 Peribiliary glands are known to start from the level of the segmental ducts intrahepatically and have particularly high distribution to the sites such as cystic duct, hilum of hepatic duct, and periampular region extrahepatically where cholangiocarcinoma usually emerge.6,7 Furthermore, recent studies on the epidemiology of cholangiocarcinoma have reported different tendency in incidence and mortality between intrahepatic and extrahepatic cholangiocarcinoma. It has been reported that incidence and mortality for the former are increasing, whereas those for the latter are stable or decreasing, implicating different classification between those 2 cancers.8–11 These results suggest that intrahepatic and extrahepatic cholangiocarcinoma are heterogenous category of biliary tract cancer. Most patients with biliary tract cancer have advanced stage at the time of diagnosis12 and carry very poor prognosis with survival reported to be ,1 year for the difficulty of detection of the cancer at early stage.13,14 Although lots of conditions, such as obstructive jaundice, poor performance status, and sepsis due to recurrent cholangitis, in patients with unresectable biliary tract cancer make it difficult to receive chemotherapy, palliative chemotherapy for relief of symptoms and improvement of survival has been performed. There had been no consensus on the standard chemotherapy for the biliary tract cancer until the large randomized controlled trial (RCT) comparing gemcitabine plus cisplatin (GC) combination chemotherapy to gemcitabine alone. The RCT proved superior survival advantage of the combination chemotherapy to the therapy with the single agent,15 and the combination chemotherapy has been the standard chemotherapy for advanced biliary tract cancer. One of the limitations of studies that have reported on treatments for the biliary cancer including the RCT is the heterogenous group of patients consisted with gallbladder cancer, ampullary cancer, and biliary duct cancer despite different characteristics of each biliary tract cancer.15–19 Here, we intended to analyze outcomes of IHC patients treated with the GC combination chemotherapy and to develop prognostic model to identify patients who could potentially benefit from GC regimen.
METHODS
histopathologic confirmation and classification of site of disease was made with imaging modalities such as computed tomography and magnetic resonance imaging accompanied by radiologist review. Clinical parameters analyzed as prognostic factors for survival were as follows: age (#60 vs. .60 years), gender (male vs. female), histology (adenocarcinoma vs. carcinoma, type not specified), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), disease status (recurrence vs. metastasis), number of metastatic site (1 vs. .1), chronic hepatitis (yes vs. no), CA 19-9 level (#85 vs. ,85 U/mL), hemoglobin level (#12 vs. ,12 g/dL), platelet count (#180 vs. ,180 3 109 per liter), bilirubin level (#0.5 vs. ,0.5), and albumin level (#3.5 vs. ,3.5 mg/dL). Treatment Each cycle of GC chemotherapy consists of the administration with 25 mg/m2 cisplatin followed by 1000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks.15 Patients received the same regimen until disease progression or the development of unacceptable toxicity. Response of tumor to the chemotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with measuring by computed tomography or magnetic resonance imaging. Response evaluation was performed every 6 weeks of chemotherapy. Statistics Treatment outcomes were estimated as response rate, disease control rate, progression-free survival (PFS), and overall survival (OS). The efficacy analysis was based on the intent to treat population. Laboratory variables were initially recorded as continuous variables and later dichotomized for the ease of statistical analysis and clinical application. A Cox proportional hazards regression model was used in univariate and multivariate analyses to identify the significant independent prognostic factors of various clinical parameters for survival. Significant prognostic variables in univariate analysis for OS were included in multivariate analysis. A value of P , 0.05 was considered statistically significant. Survival curves were constructed using the Kaplan–Meier method, and the differences between curves were evaluated by the log-rank test.
RESULTS
Patients A total of 29 patients diagnosed as advanced IHC who received GC combination chemotherapy between June 2010 and February 2013 in Korea University Anam hospital were analyzed. Diagnosis was made by American Journal of Therapeutics (2014) 0(0)
Clinical characteristics of patients The characteristics of 29 patients analyzed in this study are summarized in Table 1. The median age at the start of the palliative chemotherapy is 63 years www.americantherapeutics.com
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Intrahepatic Cholangiocarcinoma
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Table 1. Clinical characteristics of patients with advanced IHC (N 5 29).
Table 2. The efficacy of GC as first line therapy. N 5 29 (%)
Characteristics Characteristics Age at treatment, yrs Median (range) .60 #60 Gender Male Female Histology Adenocarcinoma Carcinoma, type not specified ECOG performance status 0 1 Disease status Recurrence Metastatic No. metastatic site 1 .1 Prior treatment Surgery No surgery Chronic hepatitis Yes No CA 19-9 .85 #85 Hemoglobin Median (range) .12 #12 Platelet number Median (range) .180 #180 Bilirubin Median (range) .0.5 #0.5 Albumin Median (range) .3.5 #3.5
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N 5 29 (%) 63 (40–78) 15 (51.7) 14 (48.3) 16 (55.2) 13 (44.8) 22 (75.9) 7 (24.1) 10 (34.5) 19 (65.5) 7 (24.1) 22 (75.9) 13 (44.8) 16 (55.2) 7 (24.1) 22 (75.9) 8 (27.6) 21 (72.4) 16 (57.1) 13 (42.9) 12.2 (8.2–15.4) 17 (58.6) 12 (41.4) 202 (98–518) 18 (62.1) 11 (37.9) 0.49 (0.14–3.45) 14 (48.3) 15 (51.7) 3.7 (2.3–4.4) 16 (55.2) 13 (44.8)
Response CR PR SD PD Overall response rate Disease control rates
6 15 8 6 21
0 (20.7) (51.7) (27.6) (20.7) (72.4)
CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease.
(range, 40–78 years) with 51.7% of the patients older than 60 years. The male to female ratio is 1.23 with the sex distribution of almost equality. All of them showed ECOG performance status ,2. Seven of all patients (24.1%) received treatment before the chemotherapy with surgery. Regarding histologic type, 22 patients (75.9%) were diagnosed as adenocarcinoma with various degrees of differentiation, and carcinoma whose type was not specified in the other patients. Thirteen of all patients (44.8%) had metastasis in 1 organ, and others (55.2%) had metastasis in more than 2 organs. Eight (27.6%) of the 29 patients had a history of chronic hepatitis. Response rate All 29 patients were analyzed for treatment response. No complete response and 6 partial response were observed (overall response rate: 20.7%). Stable disease was observed in 15 patients (51.7%) and progressive disease in 8 patients (27.6%). The disease control rate was 72.4%. All patients had experienced disease progression before death (Table 2). Univariate and multivariate analysis for OS and PFS With a median follow-up of 16.8 months, the median OS was 7.3 months [95% confidence interval (CI), 5.56– 9.04] (Figure 1A) and median PFS was 4.3 months (95% CI, 3.72–4.87) (Figure 1B). Univariate analysis revealed that a decreased OS was significantly associated with the following variables: metastatic site of 2 or more, albumin level #3.5 g/dL, bilirubin level .0.5 mg/dL, and platelet number #180 3 109 per liter. In multivariate analysis, metastatic site of 2 or more [hazard ratio (HR), 3.051; 95% CI, 1.040–8.953; P , 0.050], albumin level #3.5 g/dL (HR, 6.806; 95% CI, 2.077–22.300; P , 0.005), and platelet number #180 3 109 per liter (HR, 5.884; 95% CI, 1.804–19.191; P , 0.005) were independent prognostic factors for OS in all 29 patients (Table 3). By univariate analysis, metastatic site of 2 or more and American Journal of Therapeutics (2014) 0(0)
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FIGURE 1. (A) OS and (B) progression-free survival in patients with IHC treated with GC.
albumin level #3.5 g/dL were associated with decreased PFS. Multivariate analysis demonstrated that decreased PFS was associated with the metastatic site of 2 or more (HR, 2.884; 95% CI, 0.955–8.708; P 5 0.060) without statistical significance (Table 4). Prognostic index and risk groups OS decreased significantly as the number of adverse prognostic factors increased. Risk scoring in the prognostic model was in accordance with the number of risk factors that were found to be significant in the multivariate analysis for OS. Therefore, patients were
categorized into 3 prognosis groups: zero or 1 (good), 2 (intermediate), and 3 (poor), based on the number of measured prognostic factors for OS. The median OS for the good, intermediate, and poor prognostic groups was 10.5, 6.1, and 1.6 months, respectively (P , 0.05) (Figure 2).
DISCUSSION Chemotherapy with GC in advanced biliary tract cancer has been the standard palliative chemotherapy
Table 3. Univariate and multivariate analysis for OS. OS Univariate Variables Age .60 Sex (male vs. female) Prior treatment (surgery vs. No surgery) Second-line chemotherapy (only first line vs. $Second line) No. metastasis (#1 vs. .1) History of hepatitis (yes vs. no) CA 19-9 (.85 vs. #85 U/mL) Bilirubin (.0.5 vs. #0.5 mg/dL) Hemoglobin (.12 vs. #12 g/dL) Platelet number (.180 vs. #180 3 109 per liter) Albumin (.3.5 vs. #3.5 g/dL) American Journal of Therapeutics (2014) 0(0)
P
Multivariate HR (95% CI)
P
3.051 (1.040–8.953)
0.042
2.397 (0.941–6.060)
0.067
5.884 (1.804–19.191) 6.806 (2.077–22.300)
0.003 0.002
0.413 0.772 0.903 0.618 0.001 0.344 0.087 0.023 0.554 0.037 0.000
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Intrahepatic Cholangiocarcinoma
5
Table 4. Univariate and multivariate analysis for PFS. Progression-free survival Univariate Variables Age .60 Sex (male vs. female) Prior treatment (surgery vs. No surgery) Second-line chemotherapy (only first line vs. $second line) No. metastasis (#1 vs. .1) History of hepatitis (yes vs. no) CA 19-9 (.85 vs. #85 U/mL) Bilirubin (.0.5 vs. #0.5 mg/dL) Hemoglobin (.12 vs. #12 g/dL) Platelet number (.180 vs. #180 3 109 per liter) Albumin (.3.5 vs. #3.5 g/dL)
since the RCT (ABC-02). Median OS and PFS in patients with biliary cancer who received GC chemotherapy in the ABC-02 trial were reported to be 11.7 and 8 months, respectively, with the superiority as compared with gemcitabine monotherapy.15 However, few outcomes have been reported in regard to the results of the treatment on patients with each
P
Multivariate HR (95% CI)
P
0.011 0.489 0.254 0.113 0.357 0.15
2.884 (0.955–8.708)
0.060
0.026
1.915 (0.750–4.889)
0.174
0.771 0.648 0.298 0.724
classification of cholangiocarcinoma for its rarity and heterogeneity.20 In this study, we reported clinical outcomes in patients with IHC treated with GC. Tumor response, OS, and PFS were analyzed in this study and were revealed to be 20.7%, 7.3, and 4.3 months, respectively. Our results seem to be inferior to those of previous data from ABC-02 trial.15 Clinical
FIGURE 2. A novel prognostic model for patients with IHC. Patients treated with GC were classified into 3 risk groups: good-, intermediate-, and poor-risk group (P , 0.005). www.americantherapeutics.com
American Journal of Therapeutics (2014) 0(0)
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Lee et al
6 Table 5. Studies of prognosis factors in patients with biliary tract cancer.
Study Nakagawa et al25
No. patients
Classification
Treatment
53
IHC
Hepatic resection (44 patients)
Paik et al23 Jiang et al24
97 102
IHC IHC
Hepatic resection Laparotomy
Suzuki et al22
100
Biliary tract cancer
Gemcitabine
Jiang et al21
344
IHC
Hepatic resection
Hilar and IHC
Chemotherapy*
Eckmann et al20
85
Prognosis factors Multiple lesion Noncurative Multiple lesion Intrahepatic metastasis Noncurative TNM stage IVa Performance status .1 CRP $3 mg/dL CEA $10 U/mL Albumin ,3.5 g/dL ALP .147 U/L CA 19-9 .37 mg/L Multiple lesion Diameter of IHC Obscure tumor boundary Elevated CA 19-9 Prior chemoradiotherapy Initial diagnosis of CUP
Relative risk 2.242 2.2 NE 1.73 1.78 3.71 5.42 2.79 2.14 2.01 1.64 1.81 1.66 1.53 2.23 1.007 5.831 3.42
*Chemotherapy consisted of gemcitabine/cisplatine, capecitabine/oxaliplatin, capecitabine, other gemcitabine-based regimen. NE, nonevaluated; CUP, cancer of unknown primary; CEA, carcinoembryonic antigen; CRP, C-reactive protein; TNM, tumor node metastasis.
characteristics of patients analyzed in this study, including age, gender, and ECOG performance status, were almost similar to those in the previous studies.15,20 We thought that the relatively inferior outcomes observed in this study might be attributed to several other reasons. First, there was reduced dose-intensity of chemotherapeutic agents. Six (20.7%) patients had chemotherapy with reduced dose in various reasons, such as old age or high level of baseline creatinine. Second, extent of disease could have contributed to the different outcomes. All patients in this study had at least one distant metastasis to other organs, although about 70% of patients analyzed had metastasis in the ABC-02 trial. Third, racial difference may affect outcomes of patients.15,20 Previous studies using GC had been conducted in Western patients, but our study was performed in Asian patients. There might be the difference of response to the chemotherapeutic agent according to races. In addition, we thought the biological difference of cancer cells according to the difference of disease distribution could be another possible reason. To examine the possibility, we analyzed the OS of 39 patients with extrahepatic cholangiocarcinoma and gallbladder cancer to compare with that of patients with IHC. Median OS American Journal of Therapeutics (2014) 0(0)
was revealed to be 7.3 months (95% CI, 4.69–9.91), and there was no significant difference in OS (P 5 0.322) between those 2 groups. Although same result was observed in OS between 2 groups, direct comparison might not be appropriate because the data used in this study are not from prospectively designed registry data, and there might be confounding factors. Despite the limitation on the direct comparison of 2 groups, we cannot really state that the difference in results observed in this study is attributed to site of disease until welldesigned prospective study is performed. Number of metastasis to other organs, albumin level, and platelet count at the start of treatment were identified as prognostic factors in our study. Although most reports on prognosis factors in biliary tract cancer were studied with patients who received hepatic resection, albumin level and extent of disease were revealed to be consistent prognosis factors (Table 5). Prognosis factors studied in the past are summarized in Table 5.20–25 Common factors for poor prognosis in patients who received surgical therapy were multiple lesions and noncurative lesions. Elevated serum level of a tumor marker such as CA 19-9 was significant in both patients groups that received hepatic resection or gemcitabine. www.americantherapeutics.com
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Intrahepatic Cholangiocarcinoma
Our prognostic model is simple and easy to apply to patients in clinical field. It is consisted with only 3 factors, and the factors can also be measured without difficulty practically. Despite these merits of the prognostic model, it has several limitations. First, the prognosis model could not have a definitive influence on routine clinical practice because only small numbers of patients were analyzed. Also, it is further required to be clarified whether the same results can be acquired on applying to the independent cohort. Second, heterogeneity of stem cells according to niches might further classify IHC, but anatomical classification was used in this study. Third, use of the prognosis model might be helpful to predict prognosis and spare patients from the potentially toxic chemotherapy during the terminal period of their lives, but it cannot be the absolute standard in selecting patients for GC chemotherapy because of the lack of evidence as a predictive model. Further prospective study through multicenter collaboration will verify the utility of this prognosis scoring model.
REFERENCES 1. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med. 1999;341:1368–1378. 2. Cardinale V, Semeraro R, Torrice A, et al. Intra-hepatic and extra-hepatic cholangiocarcinoma: new insight into epidemiology and risk factors. World J Gastrointest Oncol. 2010;2:407–416. 3. Roskams T. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene. 2006; 25:3818–3822. 4. Theise ND, Saxena R, Portmann BC, et al. The canals of Hering and hepatic stem cells in humans. Hepatology. 1999;30:1425–1433. 5. Kuwahara R, Kofman AV, Landis CS, et al. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology. 2008;47:1994–2002. 6. Cardinale V, Wang Y, Carpino G, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology. 2011;54:2159–2172. 7. Carpino G, Cardinale V, Onori P, et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat. 2012;220:186–199. 8. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006;98:873–875. 9. Alvaro D, Crocetti E, Ferretti S, et al; committee AC. Descriptive epidemiology of cholangiocarcinoma in Italy. Dig Liver Dis. 2010;42:490–495. www.americantherapeutics.com
7 10. McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev. 2006;15:1198–1203. 11. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353–1357. 12. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234:507–517; discussion 517–519. 13. Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist. 2008;13:415–423. 14. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1–VI9. 15. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–1281. 16. Rao S, Cunningham D, Hawkins RE, et al. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005;92:1650–1654. 17. Ducreux M, Van Cutsem E, Van Laethem JL, et al. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial. Eur J Cancer. 2005;41:398–403. 18. Gebbia V, Giuliani F, Maiello E, et al. Treatment of inoperable and/or metastatic biliary tree carcinomas with singleagent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001;19:4089–4091. 19. Kornek GV, Schuell B, Laengle F, et al. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol. 2004;15:478–483. 20. Eckmann KR, Patel DK, Landgraf A, et al. Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: a retrospective analysis. Gastrointest Cancer Res. 2011;4:155–160. 21. Jiang W, Zeng ZC, Tang ZY, et al. A prognostic scoring system based on clinical features of intrahepatic cholangiocarcinoma: the Fudan score. Ann Oncol. 2011;22:1644–1652. 22. Suzuki E, Furuse J, Ikeda M, et al. Treatment efficacy/ safety and prognostic factors in patients with advanced biliary tract cancer receiving gemcitabine monotherapy: an analysis of 100 cases. Oncology. 2010;79:39–45. 23. Paik KY, Jung JC, Heo JS, et al. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol. 2008;23:766–770. 24. Jiang BG, Sun LL, Yu WL, et al. Retrospective analysis of histopathologic prognostic factors after hepatectomy for intrahepatic cholangiocarcinoma. Cancer J. 2009;15:257–261. 25. Nakagawa T, Kamiyama T, Kurauchi N, et al. Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma. World J Surg. 2005; 29:728–733. American Journal of Therapeutics (2014) 0(0)
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A Prognostic Index to Identify Patients With Intrahepatic Cholangiocarcinoma Who Could Benefit From Gemcitabine Plus Cisplatin Suk-young Lee, MD, PhD,1 Hye sook Kim, MD,1 Yoon Ji Choi, MD,1 Kyong Hwa Park, MD, PhD,1 Sang Won Shin, MD, PhD,1 Yeul Hong Kim, MD, PhD,1 and Seung Tae Kim, MD, PhD1,2*
Biliary tract cancer is a heterogenous group. Gemcitabine plus cisplatin has been the standard chemotherapy for advanced biliary tract cancer, but there is lack of evidence on treatment in patients with intrahepatic cholangiocarcinoma (IHC). We analyzed 29 patients with only IHC who received gemcitabine plus cisplatin between June 2010 and February 2013. The median age was 63 years (range, 40–78 years), and Eastern Cooperative Oncology Group performance status of all patients was ,2. The median progression-free survival and median overall survival (OS) were 4.3 and 7.3 months, respectively. Multivariate analysis showed that platelet count (#180 3 109 per liter), metastatic site of more than 2, and albumin level (#3.5 g/dL) were independent prognostic factors for decreased OS. OS was estimated based on the number of adverse prognostic factors: zero or 1 (good prognostic group), 2 (intermediate group), or 3 (poor prognostic group). The median OS for good (n 5 15), intermediate (n 5 10), and poor (n 5 4) prognostic group was 10.5, 6.1, and 1.6 months, respectively (P , 0.005). Relatively better prognosis of the good prognosis group comparing to other prognosis groups can be expected from the prognostic model established in this study by analyzing patients with IHC treated with gemcitabine. Keywords: cholangiocarcinoma, prognostic model, overall survival
INTRODUCTION Biliary tract cancer is composed of heterogenous groups of disease that include cholangiocarcinoma, gallbladder, and ampullary cancers. Cholangiocarcinoma is a malignant tumor that arises from epithelium of biliary tract
1 Division of Hematology and Oncology, Department of Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea; and 2Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Hematology and Oncology, Department of Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, South Korea. E-mail: [email protected]
1075–2765 2014 Lippincott Williams & Wilkins
and is further classified into intrahepatic cholangiocarcinoma (IHC) and extrahepatic cholangiocarcinoma, which is again consisted with hilar cholangiocarcinoma and distal cholangiocarcinoma.1 It is known that those each tumor type may show different behavior, biologic feature, and epidemiology.1–3 A number of studies concerning cancer stem cells in cholangiocarcinoma have demonstrated heterogenous origin of biliary tract cancer. These studies have suggested 2 different stem cell niches in liver and biliary tract with implication of different source of cancer cells in carcinogenesis of cholangiocarcinoma.4–7 Stem cell niches that have been found within liver are known as canals of Hering. Progenitor cells residing the canals of Hering can differentiate into hepatocytes and cholangiocytes, and these are potential source of cancer cells of hepatocellular carcinoma or cholangiocellular carcinoma.3 Peribiliary glands, additionally identified stem www.americantherapeutics.com
Copyright ª Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lee et al
2
cell niches located in the wall of the extrahepatic and large intrahepatic bile duct, are mucin-producing glandular elements.6,7 Peribiliary glands are known to start from the level of the segmental ducts intrahepatically and have particularly high distribution to the sites such as cystic duct, hilum of hepatic duct, and periampular region extrahepatically where cholangiocarcinoma usually emerge.6,7 Furthermore, recent studies on the epidemiology of cholangiocarcinoma have reported different tendency in incidence and mortality between intrahepatic and extrahepatic cholangiocarcinoma. It has been reported that incidence and mortality for the former are increasing, whereas those for the latter are stable or decreasing, implicating different classification between those 2 cancers.8–11 These results suggest that intrahepatic and extrahepatic cholangiocarcinoma are heterogenous category of biliary tract cancer. Most patients with biliary tract cancer have advanced stage at the time of diagnosis12 and carry very poor prognosis with survival reported to be ,1 year for the difficulty of detection of the cancer at early stage.13,14 Although lots of conditions, such as obstructive jaundice, poor performance status, and sepsis due to recurrent cholangitis, in patients with unresectable biliary tract cancer make it difficult to receive chemotherapy, palliative chemotherapy for relief of symptoms and improvement of survival has been performed. There had been no consensus on the standard chemotherapy for the biliary tract cancer until the large randomized controlled trial (RCT) comparing gemcitabine plus cisplatin (GC) combination chemotherapy to gemcitabine alone. The RCT proved superior survival advantage of the combination chemotherapy to the therapy with the single agent,15 and the combination chemotherapy has been the standard chemotherapy for advanced biliary tract cancer. One of the limitations of studies that have reported on treatments for the biliary cancer including the RCT is the heterogenous group of patients consisted with gallbladder cancer, ampullary cancer, and biliary duct cancer despite different characteristics of each biliary tract cancer.15–19 Here, we intended to analyze outcomes of IHC patients treated with the GC combination chemotherapy and to develop prognostic model to identify patients who could potentially benefit from GC regimen.
METHODS
histopathologic confirmation and classification of site of disease was made with imaging modalities such as computed tomography and magnetic resonance imaging accompanied by radiologist review. Clinical parameters analyzed as prognostic factors for survival were as follows: age (#60 vs. .60 years), gender (male vs. female), histology (adenocarcinoma vs. carcinoma, type not specified), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), disease status (recurrence vs. metastasis), number of metastatic site (1 vs. .1), chronic hepatitis (yes vs. no), CA 19-9 level (#85 vs. ,85 U/mL), hemoglobin level (#12 vs. ,12 g/dL), platelet count (#180 vs. ,180 3 109 per liter), bilirubin level (#0.5 vs. ,0.5), and albumin level (#3.5 vs. ,3.5 mg/dL). Treatment Each cycle of GC chemotherapy consists of the administration with 25 mg/m2 cisplatin followed by 1000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks.15 Patients received the same regimen until disease progression or the development of unacceptable toxicity. Response of tumor to the chemotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with measuring by computed tomography or magnetic resonance imaging. Response evaluation was performed every 6 weeks of chemotherapy. Statistics Treatment outcomes were estimated as response rate, disease control rate, progression-free survival (PFS), and overall survival (OS). The efficacy analysis was based on the intent to treat population. Laboratory variables were initially recorded as continuous variables and later dichotomized for the ease of statistical analysis and clinical application. A Cox proportional hazards regression model was used in univariate and multivariate analyses to identify the significant independent prognostic factors of various clinical parameters for survival. Significant prognostic variables in univariate analysis for OS were included in multivariate analysis. A value of P , 0.05 was considered statistically significant. Survival curves were constructed using the Kaplan–Meier method, and the differences between curves were evaluated by the log-rank test.
RESULTS
Patients A total of 29 patients diagnosed as advanced IHC who received GC combination chemotherapy between June 2010 and February 2013 in Korea University Anam hospital were analyzed. Diagnosis was made by American Journal of Therapeutics (2014) 0(0)
Clinical characteristics of patients The characteristics of 29 patients analyzed in this study are summarized in Table 1. The median age at the start of the palliative chemotherapy is 63 years www.americantherapeutics.com
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Intrahepatic Cholangiocarcinoma
3
Table 1. Clinical characteristics of patients with advanced IHC (N 5 29).
Table 2. The efficacy of GC as first line therapy. N 5 29 (%)
Characteristics Characteristics Age at treatment, yrs Median (range) .60 #60 Gender Male Female Histology Adenocarcinoma Carcinoma, type not specified ECOG performance status 0 1 Disease status Recurrence Metastatic No. metastatic site 1 .1 Prior treatment Surgery No surgery Chronic hepatitis Yes No CA 19-9 .85 #85 Hemoglobin Median (range) .12 #12 Platelet number Median (range) .180 #180 Bilirubin Median (range) .0.5 #0.5 Albumin Median (range) .3.5 #3.5
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N 5 29 (%) 63 (40–78) 15 (51.7) 14 (48.3) 16 (55.2) 13 (44.8) 22 (75.9) 7 (24.1) 10 (34.5) 19 (65.5) 7 (24.1) 22 (75.9) 13 (44.8) 16 (55.2) 7 (24.1) 22 (75.9) 8 (27.6) 21 (72.4) 16 (57.1) 13 (42.9) 12.2 (8.2–15.4) 17 (58.6) 12 (41.4) 202 (98–518) 18 (62.1) 11 (37.9) 0.49 (0.14–3.45) 14 (48.3) 15 (51.7) 3.7 (2.3–4.4) 16 (55.2) 13 (44.8)
Response CR PR SD PD Overall response rate Disease control rates
6 15 8 6 21
0 (20.7) (51.7) (27.6) (20.7) (72.4)
CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease.
(range, 40–78 years) with 51.7% of the patients older than 60 years. The male to female ratio is 1.23 with the sex distribution of almost equality. All of them showed ECOG performance status ,2. Seven of all patients (24.1%) received treatment before the chemotherapy with surgery. Regarding histologic type, 22 patients (75.9%) were diagnosed as adenocarcinoma with various degrees of differentiation, and carcinoma whose type was not specified in the other patients. Thirteen of all patients (44.8%) had metastasis in 1 organ, and others (55.2%) had metastasis in more than 2 organs. Eight (27.6%) of the 29 patients had a history of chronic hepatitis. Response rate All 29 patients were analyzed for treatment response. No complete response and 6 partial response were observed (overall response rate: 20.7%). Stable disease was observed in 15 patients (51.7%) and progressive disease in 8 patients (27.6%). The disease control rate was 72.4%. All patients had experienced disease progression before death (Table 2). Univariate and multivariate analysis for OS and PFS With a median follow-up of 16.8 months, the median OS was 7.3 months [95% confidence interval (CI), 5.56– 9.04] (Figure 1A) and median PFS was 4.3 months (95% CI, 3.72–4.87) (Figure 1B). Univariate analysis revealed that a decreased OS was significantly associated with the following variables: metastatic site of 2 or more, albumin level #3.5 g/dL, bilirubin level .0.5 mg/dL, and platelet number #180 3 109 per liter. In multivariate analysis, metastatic site of 2 or more [hazard ratio (HR), 3.051; 95% CI, 1.040–8.953; P , 0.050], albumin level #3.5 g/dL (HR, 6.806; 95% CI, 2.077–22.300; P , 0.005), and platelet number #180 3 109 per liter (HR, 5.884; 95% CI, 1.804–19.191; P , 0.005) were independent prognostic factors for OS in all 29 patients (Table 3). By univariate analysis, metastatic site of 2 or more and American Journal of Therapeutics (2014) 0(0)
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4
FIGURE 1. (A) OS and (B) progression-free survival in patients with IHC treated with GC.
albumin level #3.5 g/dL were associated with decreased PFS. Multivariate analysis demonstrated that decreased PFS was associated with the metastatic site of 2 or more (HR, 2.884; 95% CI, 0.955–8.708; P 5 0.060) without statistical significance (Table 4). Prognostic index and risk groups OS decreased significantly as the number of adverse prognostic factors increased. Risk scoring in the prognostic model was in accordance with the number of risk factors that were found to be significant in the multivariate analysis for OS. Therefore, patients were
categorized into 3 prognosis groups: zero or 1 (good), 2 (intermediate), and 3 (poor), based on the number of measured prognostic factors for OS. The median OS for the good, intermediate, and poor prognostic groups was 10.5, 6.1, and 1.6 months, respectively (P , 0.05) (Figure 2).
DISCUSSION Chemotherapy with GC in advanced biliary tract cancer has been the standard palliative chemotherapy
Table 3. Univariate and multivariate analysis for OS. OS Univariate Variables Age .60 Sex (male vs. female) Prior treatment (surgery vs. No surgery) Second-line chemotherapy (only first line vs. $Second line) No. metastasis (#1 vs. .1) History of hepatitis (yes vs. no) CA 19-9 (.85 vs. #85 U/mL) Bilirubin (.0.5 vs. #0.5 mg/dL) Hemoglobin (.12 vs. #12 g/dL) Platelet number (.180 vs. #180 3 109 per liter) Albumin (.3.5 vs. #3.5 g/dL) American Journal of Therapeutics (2014) 0(0)
P
Multivariate HR (95% CI)
P
3.051 (1.040–8.953)
0.042
2.397 (0.941–6.060)
0.067
5.884 (1.804–19.191) 6.806 (2.077–22.300)
0.003 0.002
0.413 0.772 0.903 0.618 0.001 0.344 0.087 0.023 0.554 0.037 0.000
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Intrahepatic Cholangiocarcinoma
5
Table 4. Univariate and multivariate analysis for PFS. Progression-free survival Univariate Variables Age .60 Sex (male vs. female) Prior treatment (surgery vs. No surgery) Second-line chemotherapy (only first line vs. $second line) No. metastasis (#1 vs. .1) History of hepatitis (yes vs. no) CA 19-9 (.85 vs. #85 U/mL) Bilirubin (.0.5 vs. #0.5 mg/dL) Hemoglobin (.12 vs. #12 g/dL) Platelet number (.180 vs. #180 3 109 per liter) Albumin (.3.5 vs. #3.5 g/dL)
since the RCT (ABC-02). Median OS and PFS in patients with biliary cancer who received GC chemotherapy in the ABC-02 trial were reported to be 11.7 and 8 months, respectively, with the superiority as compared with gemcitabine monotherapy.15 However, few outcomes have been reported in regard to the results of the treatment on patients with each
P
Multivariate HR (95% CI)
P
0.011 0.489 0.254 0.113 0.357 0.15
2.884 (0.955–8.708)
0.060
0.026
1.915 (0.750–4.889)
0.174
0.771 0.648 0.298 0.724
classification of cholangiocarcinoma for its rarity and heterogeneity.20 In this study, we reported clinical outcomes in patients with IHC treated with GC. Tumor response, OS, and PFS were analyzed in this study and were revealed to be 20.7%, 7.3, and 4.3 months, respectively. Our results seem to be inferior to those of previous data from ABC-02 trial.15 Clinical
FIGURE 2. A novel prognostic model for patients with IHC. Patients treated with GC were classified into 3 risk groups: good-, intermediate-, and poor-risk group (P , 0.005). www.americantherapeutics.com
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Lee et al
6 Table 5. Studies of prognosis factors in patients with biliary tract cancer.
Study Nakagawa et al25
No. patients
Classification
Treatment
53
IHC
Hepatic resection (44 patients)
Paik et al23 Jiang et al24
97 102
IHC IHC
Hepatic resection Laparotomy
Suzuki et al22
100
Biliary tract cancer
Gemcitabine
Jiang et al21
344
IHC
Hepatic resection
Hilar and IHC
Chemotherapy*
Eckmann et al20
85
Prognosis factors Multiple lesion Noncurative Multiple lesion Intrahepatic metastasis Noncurative TNM stage IVa Performance status .1 CRP $3 mg/dL CEA $10 U/mL Albumin ,3.5 g/dL ALP .147 U/L CA 19-9 .37 mg/L Multiple lesion Diameter of IHC Obscure tumor boundary Elevated CA 19-9 Prior chemoradiotherapy Initial diagnosis of CUP
Relative risk 2.242 2.2 NE 1.73 1.78 3.71 5.42 2.79 2.14 2.01 1.64 1.81 1.66 1.53 2.23 1.007 5.831 3.42
*Chemotherapy consisted of gemcitabine/cisplatine, capecitabine/oxaliplatin, capecitabine, other gemcitabine-based regimen. NE, nonevaluated; CUP, cancer of unknown primary; CEA, carcinoembryonic antigen; CRP, C-reactive protein; TNM, tumor node metastasis.
characteristics of patients analyzed in this study, including age, gender, and ECOG performance status, were almost similar to those in the previous studies.15,20 We thought that the relatively inferior outcomes observed in this study might be attributed to several other reasons. First, there was reduced dose-intensity of chemotherapeutic agents. Six (20.7%) patients had chemotherapy with reduced dose in various reasons, such as old age or high level of baseline creatinine. Second, extent of disease could have contributed to the different outcomes. All patients in this study had at least one distant metastasis to other organs, although about 70% of patients analyzed had metastasis in the ABC-02 trial. Third, racial difference may affect outcomes of patients.15,20 Previous studies using GC had been conducted in Western patients, but our study was performed in Asian patients. There might be the difference of response to the chemotherapeutic agent according to races. In addition, we thought the biological difference of cancer cells according to the difference of disease distribution could be another possible reason. To examine the possibility, we analyzed the OS of 39 patients with extrahepatic cholangiocarcinoma and gallbladder cancer to compare with that of patients with IHC. Median OS American Journal of Therapeutics (2014) 0(0)
was revealed to be 7.3 months (95% CI, 4.69–9.91), and there was no significant difference in OS (P 5 0.322) between those 2 groups. Although same result was observed in OS between 2 groups, direct comparison might not be appropriate because the data used in this study are not from prospectively designed registry data, and there might be confounding factors. Despite the limitation on the direct comparison of 2 groups, we cannot really state that the difference in results observed in this study is attributed to site of disease until welldesigned prospective study is performed. Number of metastasis to other organs, albumin level, and platelet count at the start of treatment were identified as prognostic factors in our study. Although most reports on prognosis factors in biliary tract cancer were studied with patients who received hepatic resection, albumin level and extent of disease were revealed to be consistent prognosis factors (Table 5). Prognosis factors studied in the past are summarized in Table 5.20–25 Common factors for poor prognosis in patients who received surgical therapy were multiple lesions and noncurative lesions. Elevated serum level of a tumor marker such as CA 19-9 was significant in both patients groups that received hepatic resection or gemcitabine. www.americantherapeutics.com
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Intrahepatic Cholangiocarcinoma
Our prognostic model is simple and easy to apply to patients in clinical field. It is consisted with only 3 factors, and the factors can also be measured without difficulty practically. Despite these merits of the prognostic model, it has several limitations. First, the prognosis model could not have a definitive influence on routine clinical practice because only small numbers of patients were analyzed. Also, it is further required to be clarified whether the same results can be acquired on applying to the independent cohort. Second, heterogeneity of stem cells according to niches might further classify IHC, but anatomical classification was used in this study. Third, use of the prognosis model might be helpful to predict prognosis and spare patients from the potentially toxic chemotherapy during the terminal period of their lives, but it cannot be the absolute standard in selecting patients for GC chemotherapy because of the lack of evidence as a predictive model. Further prospective study through multicenter collaboration will verify the utility of this prognosis scoring model.
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