Biliary tract cancer (BTC) refers to a group of cancers of the biliary tract, including gallbladder cancer, cholangiocarcinoma of intrahepatic and extrahepatic bile ducts, and cancers of the ampulla and papilla of Vater [1,2]. Despite its relatively rarity, the incidence of BTC varies widely in different geographic regions, with the lowest incidence rates in Western countries, including the United States and western Europe, and the highest rates in Asia and Latin America [3]. Gallbladder cancer is the most common type of BTC; however, the proportion of BTC tumors that originate in the gallbladder varies geographically [3,4]. Most patients with BTC are diagnosed at a late stage, in part because there are few, if any, specific symptoms [5]. Surgery is the only curative treatment; however, most patients are ineligible for surgery, either because their tumors are unresectable or because they have other comorbidities that preclude surgical intervention [2,5]. The prognosis for patients with advanced (unresectable and/or metastatic) BTC is very poor, and most survive for less than a year after diagnosis [5,6].

Although surgery remains the only curative treatment, chemotherapy can extend survival of patients with BTC [2]. For example, in an early randomized controlled trial (RCT) of chemotherapy in BTC and pancreatic cancer, treatment with 5-fluorouracil and leucovorin, with or without etoposide, increased median survival of patients with BTC to 6.5 months, compared with 2.5 months achieved with best supportive care [7]. Historically, due to the relative rarity of BTC, conduct of clinical studies of potential therapies has been difficult, and physicians have often used chemotherapy regimens that benefit patients with other gastrointestinal cancers, particularly pancreatic cancer. One such chemotherapeutic agent is gemcitabine, which is a standard of care for patients with advanced, unresectable pancreatic cancer [8], and has been approved by the Food and Drug Administration (FDA) as monotherapy for these patients [9]. In pancreatic cancer, additional survival benefit can be achieved by combining gemcitabine and a platinum agent, such as cisplatin; however, combination therapy may be associated with greater toxicity than gemcitabine monotherapy [10].

Evidence of the efficacy of several gemcitabine-based combination therapies, such as gemcitabine-oxaliplatin and combinations involving targeted therapies, in patients with BTC has been reported [2,11-14], with the most substantial evidence reported for gemcitabine combined with cisplatin.

Evidence of the efficacy of gemcitabine-cisplatin combination therapy was initially provided by small observational and retrospective studies [15]. The first major RCT to assess the efficacy and safety of gemcitabine-cisplatin in BTC was the phase 2 ABC-01 trial [16], which was extended into the phase 3 ABC-02 trial, the largest (n=410) RCT in patients with BTC [17]. In the ABC-02 trial, gemcitabine-cisplatin significantly improved overall survival (OS), progression-free survival (PFS), and tumor control rates compared with gemcitabine monotherapy [17]. Based on the ABC-02 trial, gemcitabine-cisplatin combination therapy has rapidly been accepted as the standard first-line treatment for advanced BTC. Currently, gemcitabine-cisplatin is approved as a firstline treatment for BTC in Korea and Chile, and gemcitabine monotherapy is approved in Thailand, Mexico, Ukraine, and Japan.

The ABC-02 trial is the largest RCT conducted to date, although many smaller clinical studies have been conducted in patients with BTC. However, due to the relative rarity of BTC, enrolling an adequate sample size has often limited these prospective studies. In addition, patients with biliary tract obstruction or infection, which are common concurrent conditions, are excluded from most clinical studies. To maximize enrollment, many studies have used broad inclusion criteria, resulting in heterogeneity of patient characteristics, including primary tumor site and cancer stage (i.e., locally advanced vs. metastatic). However, some evidence suggests that the efficacy of chemotherapy may differ for different tumor types and cancer stages. For example, higher response rate has been reported for patients with gallbladder cancer, but OS was lower after chemotherapy compared to patients with other forms of BTC [18]. Similarly, both intrahepatic cholangiocarcinoma (compared with gallbladder and other BTC sites) and metastatic disease (compared with locally advanced disease) have been identified as independent predictors of poor prognosis in patients receiving chemotherapy [19]. However, the possible effect of primary tumor site on prognosis and response to chemotherapy has yet to be confirmed. Another complicating factor in the assessment of gemcitabine-cisplatin efficacy is the range of regimens used. Most recent studies have followed the ABC-02 trial regimen (1,000 mg/m² gemcitabine and 25 mg/m² cisplatin administered on days 1 and 8 of a 21-day cycle [17]); however, other regimens have also been used. Thus, questions remain regarding the optimal regimen for maximizing efficacy while minimizing toxicity. Finally, given the higher incidence of BTC in Asia compared with most Western countries, it is important to assess whether the efficacy and safety of gemcitabine-cisplatin in Asian patients is similar to that in patients from other countries.

The primary objective of this systematic review is to present collated evidence from randomized and nonrandomized prospective studies for the efficacy of gemcitabine-cisplatin in patients with advanced or metastatic BTC. We chose to focus on the gemcitabine-cisplatin combination, rather than other chemotherapeutic regimens, because of its current status as the treatment of choice for BTC and because the relatively large number of studies provide an opportunity to explore potential subgroup differences in efficacy and safety. As such, the secondary objectives of the review are to assess whether the efficacy of gemcitabine-cisplatin is influenced by primary tumor site, disease stage, or geographic region, and to present collated evidence from prospective and retrospective studies of toxicities, including whether these toxicities are influenced by the dose or regimen used.

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This systematic review presents collated evidence for the efficacy and acceptable safety profile of gemcitabine-cisplatin combination therapy for treatment of advanced BTC. Seventeen publications of prospective studies and three publications of retrospective studies, involving a total of almost 1,000 participants, were summarized. Despite heterogeneity in study design, disease characteristics, and treatment regimen, the results from these studies provide a large evidence base supporting the efficacy and safety profile of gemcitabine-cisplatin in patients with advanced BTC. Although the ABC-02 trial was pivotal in establishing the efficacy of gemcitabine-cisplatin [17], the collective results of the observational studies included in this review confirm that gemcitabine-cisplatin is effective in patients from diverse countries and with heterogeneous disease characteristics.

Our review provides collective evidence for the beneficial effects of gemcitabine-cisplatin on survival and tumor response in patients with BTC. Although not directly compared in a RCT, the results from prospective studies suggest that gemcitabine-cisplatin extends OS (approximately 5 to 12 months) compared with best supportive care (historically 2.5 to 4.5 months [7,13,18]). In addition, a sizeable proportion of participants in these studies responded to treatment, with tumor response rates ranging from 17.1% to 36.6% and disease control rates ranging from 45.7% to 81.4%. However, because only the four RCTs prospectively compared gemcitabine-cisplatin with other treatments [16,17,27,32], direct comparison with other chemotherapy options is limited. Compared with gemcitabine monotherapy, gemcitabine-cisplatin was associated with longer survival (OS and/or PFS) and greater response and disease control rates [16,17,32,37,38]. One retrospective study (n=85) reported no significant difference in OS or disease control rate between gemcitabine-cisplatin and all other chemotherapy regimens (gemcitabine- or capecitabine-based) [24]. However, this finding should be interpreted with caution, given the retrospective nature of the study and the inclusion of triple therapies involving gemcitabine-cisplatin within the other chemotherapy group. As the range of potential combination therapies expands, including gemcitabine paired with other platinum agents such as oxaliplatin [12,39] and carboplatin [40,41] or with targeted agents such as erlotinib [12], high-quality, prospective, comparative trials similar to the ABC-02 trial are needed for assessment of the relative efficacy of different treatments.

The prognosis for patients with advanced gallbladder cancer is worse than for patients with BTC originating at other sites, with a median survival of 2.8 months if untreated, compared with 5.5 to 10.1 months for untreated cholangiocarcinoma [42]. A pooled analysis of 104 trials (3 of which were included in this review), published in 2007, suggested that patients with gallbladder cancer respond differently to chemotherapy than those with cholangiocarcinoma [15]. Patients with gallbladder cancer (n=500) showed a higher response rate to any chemotherapy (median, 35.5% vs. 17.7%; p=0.008), but a shorter OS (median, 7.2 months vs. 9.3 months; p=0.048), than patients with cholangiocarcinoma (n=471); disease control rate did not differ between the tumor site groups. In contrast, an analysis of participants enrolled in two phase 2 studies or a retrospective cohort study conducted in South Korea identified intrahepatic cholangiocarcinoma as an independent negative prognostic factor for survival [19]. Based on these observations, we explored whether the efficacy of gemcitabine-cisplatin differed depending on the primary tumor site. In the three included studies in which subgroup analyses were performed, response rates tended to be higher [17,30], and OS shorter [32], in participants with gallbladder cancer than in those with other primary tumor sites, which is in agreement with the 2007 pooled analysis for all chemotherapies [15]. However, statistical analysis of the differences between tumor site groups was not performed (presumably because studies were underpowered for subgroup analysis). Consistent with these findings, of all the studies included in this review, the only study that exclusively enrolled participants with gallbladder cancer reported the lowest median OS (20 weeks; 4.6 months) and the highest response rate (36.6%) [23]. A formal, pooled analysis of the relationship between tumor site and efficacy from the studies included in this review was not possible because of study heterogeneity and lack of subgroup data. Based on informal assessment, there was no apparent relationship between the percentage of participants with gallbladder cancer and survival, response rate, or disease control rate. Elucidation of any dependence of efficacy on primary tumor site would require either a prespecified analysis of a large prospective study or a pooled analysis of subgroup-level data from completed studies. Such an analysis, however, would be complicated by the histological heterogeneity even within anatomical tumor sites, as described in recent guidelines on intrahepatic cholangiocarcinoma [43].

We also explored whether the presence or absence of metastatic disease was related to the efficacy of gemcitabinecisplatin. In a phase 3 trial comparing gemcitabine-cisplatin with gemcitabine monotherapy in patients with advanced pancreatic cancer, metastatic disease was identified as a predictor of poor survival [44]. Metastatic disease has also been identified as a predictor of poor outcomes in patients with BTC [19]. Among the studies included in this review, only the ABC-02 trial analyzed the efficacy of gemcitabinecisplatin in participants with or without metastatic disease. Although the advantageous response to gemcitabinecisplatin compared with gemcitabine monotherapy did not differ between groups, a lower hazard ratio was observed in participants with locally advanced disease, suggesting a greater benefit of combination therapy in these participants than in those with metastatic disease [17]. The proportion of participants with metastatic or locally advanced disease was reported in approximately two-thirds of the prospective studies included in this review. However, the available data were insufficient for performance of any formal analysis of the relationship between metastatic disease and efficacy. Once again, we did not identify any clear relationship between the percentage of participants with metastatic disease and survival or response outcomes.

Given the geographic variations in the incidence and type of BTC, it is important to examine any differences in the efficacy of gemcitabine-cisplatin among patients from different geographic regions. We were particularly interested in whether the response of patients from Asia, where both the overall incidence of BTC and the proportion of extrahepatic cholangiocarcinoma are high compared with most Western countries [3], to gemcitabine-cisplatin was similar to that of other patients. In general, similar OS and response rate were reported in studies conducted in Asia [23,27-30,32-34,36] and in Western and other non-Asian countries [17,20,25,26,31]. This observation is supported by comparison of the British ABC-02 [17] and Japanese BT 22 [25] RCTs, which reported similar median OS (11.7 and 11.2 months) and treatment effects of gemcitabine-cisplatin compared with gemcitabine monotherapy (OS hazard ratios of 0.64 [95% CI, 0.52 to 0.80] and 0.69 [0.42 to 1.13]). Collectively, this evidence suggests that gemcitabine-cisplatin is equally effective in both Asian and non-Asian patients with BTC.

In general, the reported toxicities associated with gemcitabine-cisplatin therapy were acceptable and manageable, although the incidence rates varied widely. Of particular importance, few deaths related to treatment were reported, and the overall rate of discontinuation due to toxicity was low (12.9%). In addition, no relationship was found between gemcitabine dose or cisplatin frequency and the incidence of the most common hematologic (anemia, neutropenia, thrombocytopenia) and nonhematologic (nausea, vomiting) toxicities. Although cisplatin administered at lower doses twice per cycle is intended to reduce potential toxicity, use of this approach did not result in any apparent decrease in the incidence rates of toxicities, at least among the studies examined. However, the relatively low number of studies and the differences in study design, participant characteristics, and other aspects of treatment restricts our ability to draw any conclusions. Given the lack of any clear relationship between treatment regimen and toxicity, clinicians may choose to simplify dosing by administering cisplatin at a higher dose once per cycle or to follow the ABC-02 regimen and adjust dosing as needed if high-grade toxicities occur.

As with all systematic reviews, our review is limited by the quality of the studies available for inclusion. Only four RCTs on the use of gemcitabine-cisplatin in advanced BTC have been published, and only one of these was a large, phase 3 trial. All RCTs were open-label by necessity, given the different treatment regimens involved. Most of the other included studies were nonrandomized and uncontrolled, with small sample sizes, reflecting the relative rarity of BTC. To increase recruitment, most studies included participants with different tumor origins and disease stages, resulting in heterogeneous study populations. Unfortunately, the data as presented did not allow performance of any pooled subgroup analyses of the effects of primary tumor site or disease stage. Separate analysis of specific subgroups would require larger sample sizes (e.g., through multinational, collaborative trials) or pooled subgroup-level data, but may reveal differences in the efficacy of gemcitabine-cisplatin in patients with specific disease characteristics. In addition, some studies excluded from this review reported combined data for different chemotherapeutic treatments (e.g., gemcitabine in combination with any platinum agent) or disease (e.g., pancreatic cancer), which, if reported separately, might have been useful in the assessment of gemcitabine-cisplatin in BTC. Reporting of outcomes also varied; for example, not all studies reported deaths or discontinuations. A wide range of treatment regimens were used in the included studies and none of the studies specifically examined the effect of treatment regimen on efficacy or safety/tolerability. Ideally, chemotherapy regimens should be tailored for optimal efficacy balanced with manageable levels of toxicity, and a more systematic assessment of different treatment regimens may indicate which factors (e.g., dose, frequency, cycle length) are most critical to efficacy or tolerability. Finally, there are many other clinically important issues requiring further exploration, but were not the focus of the current review. These issues include optimizing gemcitabine-cisplatin therapy in individual patients (such as those with inadequate biliary drainage), the role of new, targeted agents as adjuncts to standard chemotherapy, and strategies to facilitate conduct of future clinical trials of this rare, but aggressive, family of cancers.

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In conclusion, this systematic review presents collective evidence from a range of study designs that supports the use of gemcitabine-cisplatin combination therapy as standard treatment for advanced or metastatic BTC. However, detailed information regarding the effectiveness of gemcitabine-cisplatin in different types of BTC, or toxicities associated with different regimens, is lacking, in part because of the difficulty of conducting studies of sufficient sample size. Of particular importance, despite heterogeneity in the study designs, no substantial difference in toxicity was observed among the different dosing schedules of gemcitabine and cisplatin. In lieu of a large, multinational, collaborative RCT powered to enable subgroup analyses, a meta-analysis of patient-level data could help to address these questions. Alternatively, individual research teams conducting smaller studies should report subgroup-level data, which could facilitate future pooled analyses.

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