Abstract
Background/purpose
Complications from biliary drainage in biliary tract cancer (BTC) may influence the relative dose intensity of chemotherapy or increase adverse events during chemotherapy. BT22 was a randomized phase II trial, the results of which were consistent with those of a phase III trial in non-Japanese that demonstrated the effectiveness of gemcitabine plus cisplatin combination therapy (GC) in BTC. The purpose of this exploratory analysis of the BT22 study was to identify the possible effects of biliary drainage on the efficacy and safety of GC or gemcitabine monotherapy (G).
Patients and Methods
The 83 BTC patients who received GC or G in BT22 were retrospectively analysed in two subgroups dependent upon whether biliary drainage was performed before study entry. Efficacy and safety of treatment (GC vs. G) were compared in these two groups.
Results
The GC arm had a higher 1-year survival rate and longer median survival time (MST) than the G arm independent of prior biliary drainage. Patients in the drainage subgroup developed cholangitis more frequently, however, the frequency of grade 3/4 adverse events did not differ between the treatment regimens with/without drainage.
Conclusions
Biliary drainage before chemotherapy did not affect the therapeutic efficacy or tolerability of chemotherapy using G or GC.
Keywords: biliary drainage, chemotherapy, gemcitabine, cholangitis, cisplatin, biliary tract cancer
Introduction
Biliary tract cancer (BTC), while relatively rare in Western countries, is more common in Japan where it is the sixth leading cause of cancer death with approximately 17 000 deaths every year.1 The mortality caused by BTC in Japan is higher than any other country, and far exceeds all Western countries.2
Developing an effective BTC treatment has become a high priority for Japan. At present the only curative treatment is surgical resection, and although an increasing number of patients undergo surgery each year, outcomes have met with only a varying degree of success. Patients with unresectable disease can only be managed with chemotherapy and supportive care for palliation of disease including biliary decompression. However, prognosis remains extremely poor in these patients.
No standard chemotherapy for BTC has been established. Many clinical trials of systemic chemotherapy have been conducted in BTC patients, but most of these were phase II trials that had small sample sizes and lacked a control group because of the rarity and heterogeneity of BTC. In 2009, the results of a phase III study of gemcitabine plus cisplatin (GC) vs. gemcitabine monotherapy (G) conducted in the United Kingdom (ABC-02 Study) were reported.3 This previous study included 410 patients and is the largest clinical trial to be conducted in this field. The GC arm had a significantly better median survival time (MST) [11.7 months (95% confidence interval (CI) 9.5 to 14.3) vs. 8.1 months (95% CI 7.1 to 8.7); P < 0.001] and progression-free survival (PFS) [8.0 months (95% CI 6.6 to 8.6) vs. 5.0 months (95% CI 4.0 to 5.9); P < 0.001] than the G arm. A comparison of grade 3 and 4 toxicities showed that the GC combination added little toxicity. From the results of the ABC-02 study, GC was recognized as the standard of care for the treatment of advanced BTC. A randomized phase II study comparing GC and G was also conducted in Japan (BT22 study; Clinical Trial.gov Identifier NCT00380588). Median survival time [11.2 vs. 7.7 months; hazard ratio (HR) 0.69 (95% CI 0.42 to 1.13)] and PFS [5.8 vs. 3.7 months; HR 0.66 (95% CI 0.41 to 1.05)] were similar to the results seen in the ABC-02 study confirming the status of GC as the worldwide standard.4
For patients with unresectable disease, biliary decompression is often required if chemotherapy is contemplated.5 Usually, biliary obstruction will be managed by percutaneous or endoscopic drainage rather than a surgical approach because of the presence of incurable disease and high operative risk. However, complications resulting from insufficient biliary drainage, morbidities such as obstructive jaundice, cholangitis, and sepsis, often require that chemotherapy be interrupted or discontinued.6 Obstructive jaundice may impact on prognosis by necessitating dose modification of chemotherapy or by complications as a consequence of biliary obstruction.
In the present study, we analysed the data from the BT22 study conducted in Japan to determine the impact of biliary drainage on the efficacy and adverse events associated with gemcitabine-based chemotherapy.
Patients and methods
Patients
This analysis included all patients who received at least one dose of study treatment in the BT22 study, a multicentre study conducted at nine medical institutions in Japan. From September 2006 to October 2008, 84 BTC patients were enrolled. The patients were randomized to either the GC arm [a weekly intravenous (i.v.) infusion of cisplatin 25 mg/m2 followed by gemcitabine 1000 mg/m2 for 2 weeks, followed by dose suspension at the third week, repeated as one course] or the G arm (weekly i.v. infusion of gemcitabine 1000 mg/m2 for 3 weeks followed by dose suspension at the fourth week, repeated as one course). Randomization was stratified by primary tumour site (gallbladder cancer or other BTC) and the presence or absence of a primary tumour. One patient in the GC arm was discontinued before the start of the study treatment for deterioration of a general condition caused by another complication, so the analysis was conducted with 41 GC arm patients and 42 G arm patients (Fig. 1).
Figure 1.
Patient disposition of the BT22 Study. BTC, biliary tract cancer; G arm, gemcitabine monotherapy; GC arm, combination therapy with gemcitabine and cisplatin
The specific criteria for study eligibility have been reported previously4 and are only summarized here:
patients with unresectable locally advanced or metastatic intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary carcinoma that is histologically or cytologically confirmed adenocarcinoma (including adenosquamous carcinoma);
patients with at least one measurable lesion;
patients with no prior chemotherapy;
patients with a performance status of 0 or 1;
patients with an estimated life expectancy of more than 3 months; and
patients with adequate organ function (e.g. bone marrow, liver and kidney).
Methods
The BT22 study was a randomized study that compared patients from two arms: GC vs. G.
Patients with obstructive jaundice had to achieve a certain degree of jaundice reduction with biliary drainage before study entry (i.e. total bilirubin was three times the upper limit of normal or less). The protocol contained no specific provisions about biliary drainage. The approach (endoscopic or percutaneous transhepatic), drainage type (internal biliary drainage or external biliary drainage) and stent material (plastic stent or metallic stent) could be decided by the investigator. The primary endpoint was 1-year survival rate. Sample size was calculated by the method proposed by Simon et al.7 The 83 treated patients were retrospectively analysed and classified into subgroups of patients who had undergone biliary drainage before the start of the study (BD subgroup) and patients who had not (non-BD subgroup) to compare the efficacy and safety of the treatment regimens (GC vs. G arms). Progression-free survival and overall survival (OS) curves were constructed using the Kaplan–Meier method, and estimates of median OS and the respective 95% CIs were calculated from the Kaplan–Meier estimates. Cox's proportional hazard model was used to estimate the HR. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v. 3.0). A multivariate Cox proportional hazard model was used to identify prognostic factors.
Results
Of the 83 patients treated in the BT22 study, 34 were in the BD sugroup (16 in the GC arm and 18 in the G arm) and 49 were in the non-BD subgroup (25 in the GC arm and 24 in the G arm). Table 1 shows patient baseline characteristics. More of the patients in the BD subgroup (n = 34) had a primary tumour [GC: (14/16) 87.5%, G: (18/18) 100%], whereas the percentages of patients in the non-BD subgroup (n = 49) without a primary tumour were relatively higher [GC: (9/25) 36.0%, G: (11/24) 45.8%]. However, no substantial imbalances were noted between the two subgroups in gender, age or primary tumour site.
Table 1.
Patient characteristics at baseline
| Characteristics | BD (n = 34) | Non-BD (n = 49) | ||
|---|---|---|---|---|
| n (%) | n (%) | |||
| GC arm (n = 16) | G arm (n = 18) | GC arm (n = 25) | G arm (n = 24) | |
| Gender | ||||
| Male | 7 (43.8) | 9 (50.0) | 11 (44.0) | 12 (50.0) |
| Female | 9 (56.3) | 9 (50.0) | 14 (56.0) | 12 (50.0) |
| Age | ||||
| Median (years) | 64.5 | 65.5 | 65.0 | 68.5 |
| PS | ||||
| 0 | 13 (81.3) | 12 (66.7) | 21 (84.0) | 16 (66.7) |
| 1 | 3 (18.8) | 6 (33.3) | 4 (16.0) | 8 (33.3) |
| Primary tumour site | ||||
| Gallbladder | 6 (37.5) | 9 (50.0) | 9 (36.0) | 8 (33.3) |
| Non-gallbladder | 10 (62.5) | 9 (50.0) | 16 (64.0) | 16 (66.7) |
| Presence of a primary tumour | ||||
| Present | 14 (87.5) | 18 (100.0) | 16 (64.0) | 13 (54.2) |
| Absent | 2 (12.5) | 0 (0.0) | 9 (36.0) | 11 (45.8) |
| Extent of disease | ||||
| Locally advanced | 5 (31.3) | 7 (38.9) | 0 (0.0) | 1 (4.2) |
| Metastatic | 11 (68.8) | 11 (61.1) | 25 (100.0) | 23 (95.8) |
BD, biliary drainage; G arm, gemcitabine monotherapy; GC arm, combination therapy with gemcitabine and cisplatin; PS, performance status.
Efficacy
Efficacy data for the subgroups are shown in Table 2 and Fig. 2. In the BD subgroup, a comparison of OS in the GC and G arms showed 1-year survival of 40.9% vs. 27.8% and MST of 11.3 vs. 8.1 months [HR of 0.59 (95% CI 0.27 to 1.30)], respectively. In the non-BD subgroup, a comparison between the GC and C arms showed 1-year survival rate of 37.8% vs. 33.3% and MST of 9.6 vs. 7.5 months [HR of 0.76 (95% CI 0.40 to 1.45)], respectively.
Table 2.
Overall survival and progression-free survival with or without biliary drainage by treatment arm
| BD (n = 34) | Non-BD (n = 49) | |||
|---|---|---|---|---|
| GC arm (n = 16) | G arm (n = 18) | GC arm (n = 25) | G arm (n = 24) | |
| Overall survival | ||||
| 1-year survival rate | 40.9% | 27.8% | 37.8% | 33.3% |
| Median survival time (months) | 11.3 | 8.1 | 9.6 | 7.5 |
| Hazard ratio (95% confidence interval) | 0.588 (0.266–1.301) | 0.758 (0.397–1.447) | ||
| Progression-free survival | ||||
| 6-month progression-free survival | 53.3% | 27.8% | 43.7% | 27.5% |
| Median progression-free survival (months) | 7.1 | 3.9 | 4.5 | 3.3 |
| Hazard ratio (95% confidence interval) | 0.479 (0.222–1.032) | 0.748 (0.407–1.374) | ||
BD, biliary drainage; G arm, gemcitabine monotherapy; GC arm, combination therapy with gemcitabine and cisplatin.
Figure 2.
Survival curves in the BD subgroup (a) and non-BD subgroup (b) by the treatment arm. Solid line (—) indicates the GC arm and the broken line (---) the G arm. BD, biliary drainage; G arm, gemcitabine monotherapy; GC arm, combination therapy with gemcitabine and cisplatin
Subgroup analysis results based on HRs for OS by biliary drainage, performance status (PS), primary tumour site, presence of primary tumour and extent of disease are shown in Fig. 3. Hazard ratios (GC vs. G) for OS were less than one in every subgroup.
Figure 3.
Hazard ratios for overall survival by patient baseline characteristics. HR*, hazard ratio of the combination therapy with gemcitabine and cisplatin (GC) arm to the gemcitabine monotherapy (G) arm
Safety
Adverse events observed in the GC and G arms with a frequency of at least 30% in the BT22 study have been reported.4 In this analysis, the frequency of grade 3 and 4 events for the most common adverse events (frequency ≥30%) in the BD subgroup was compared with that in the non-BD subgroup (Table 3). Events in the BD subgroup that were more common in the GC arm were haemoglobin decrease (43.8% vs. 5.6%), thrombocytopenia (37.5% vs. 5.6%) and red blood cell decrease (37.5% vs. 5.6%). Events in the non-BD subgroup that were more common in the GC arm were leukopaenia (32.0% vs. 12.5%), neutoropenia (64.0% vs. 33.3%), and thrombocytopaenia (40.0% vs. 8.3%). There were no significant differences in the incidence of non-haematological events between the GC and G arms in either the BD or non-BD subgroup.
Table 3.
Incidence of grade 3 or 4 events among most common adverse eventsa
| Most common adverse events | BD (n = 34) | Non-BD (n = 49) | ||
|---|---|---|---|---|
| n (%) | n (%) | |||
| GC arm (n = 16) | G arm (n = 18) | GC arm (n = 25) | G arm (n = 24) | |
| Hematologic | ||||
| WBC count decreased | 4 (25.0) | 5 (27.8) | 8 (32.0) | 3 (12.5) |
| Neutrophil count decreased | 7 (43.8) | 8 (44.4) | 16 (64.0) | 8 (33.3) |
| RBC decreased | 6 (37.5) | 1 (5.6) | 8 (32.0) | 5 (20.8) |
| Haemoglobin decreased | 7 (43.8) | 1 (5.6) | 8 (32.0) | 6 (25.0) |
| Haematocrit decreased | 1 (6.3) | 0 (0.0) | 1 (4.0) | 0 (0.0) |
| Platelet count decreased | 6 (37.5) | 1 (5.6) | 10 (40.0) | 2 (8.3) |
| Non-haematological | ||||
| Anorexia | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (8.3) |
| Nausea | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Vomiting | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Constipation | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Diarrhoea | 1 (6.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Fatigue | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.2) |
| Pyrexia | 0 (0.0) | 2 (11.1) | 0 (0.0) | 0 (0.0) |
| Weight decreased | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| AST increased | 3 (18.8) | 5 (27.8) | 4 (16.0) | 2 (8.3) |
| ALT increased | 4 (25.0) | 5 (27.8) | 6 (24.0) | 2 (8.3) |
| GGT increased | 6 (37.5) | 7 (38.9) | 6 (24.0) | 8 (33.3) |
| LDH increased | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| ALP increased | 1 (6.3) | 3 (16.7) | 2 (8.0) | 4 (16.7) |
| Blood sodium decreased | 4 (25.0) | 2 (11.1) | 3 (12.0) | 2 (8.3) |
| C-reactive protein increased | 0 (0.0) | 2 (11.1) | 0 (0.0) | 1 (4.2) |
Most common, incidence ≥30% of all grades; events were graded according to CTCAE v3.0.
AST, aspartate aminotransferase; ALP, alkaline phosphatase; ALT, alanine aminotransferase; GGT, gamma-glutamyltransferase; BD, biliary drainage; G arm, gemcitabine monotherapy; GC arm, combination therapy with gemcitabine and cisplatin.
Although the incidence of cholangitis was higher in the BD subgroup than in the non-BD subgroup, the ratio of cholangitis in the GC arm to that in the G arm was not appreciably different in each of the BD and non-BD subgroups. For the BD subgroup, the incidence of Grade 3 and 4 cholangitis in the G arm was relatively higher than that in the GC arm (Table 4).
Table 4.
Incidence of cholangitis with or without biliary drainage by treatment arm
| BD (n = 34) | Non-BD (n = 49) | |||
|---|---|---|---|---|
| n (%) | n (%) | |||
| GC arm (n = 16) | G arm (n = 18) | GC arm (n = 25) | G arm (n = 24) | |
| Cholangitis (all grades) | 5 (31.3) | 7 (38.9) | 2 (8.0) | 3 (12.5) |
| Cholangitis (≥ grade 3) | 2 (12.5) | 5 (27.8) | 0 (0.0) | 1 (4.2) |
BD, biliary drainage; G arm, gemcitabine monotherapy; GC arm, combination therapy with gemcitabine and cisplatin.
Prognostic factors
A multivariate Cox's proportional hazard model was used with the following six factors: biliary drainage, PS (0 vs. 1), primary tumour site (gallbladder vs. non-gallbladder), the presence of a primary tumour (present vs. absent), extent of disease (locally advanced vs. metastatic) and chemotherapy regimen (GC arm vs. G arm) (Table 5). The HR of the GC arm to the G arm was 0.72 [95% CI 0.44 to 1.20] after multivariate adjustment for several variables. The primary tumour site of non-gallbladder [HR of gallbladder vs. non-gallbladder 1.72 (95% CI 1.01 to 2.93)] and the absence of a primary tumour [HR of presence vs. absence 2.79 (95% CI 1.40 to 5.56)] were significantly related to a longer OS. Biliary drainage was suggested to have favourable clinical relevance [HR 0.72 (95% CI 0.39 to 1.32)], as well as PS 0 and locally advanced disease.
Table 5.
Multivariate analysis of prognostic factors using Cox's proportional hazard model
| Covariate | P-value* | Hazard ratio (95% CI) |
|---|---|---|
| Biliary drainage (BD vs. non-BD) | 0.2875 | 0.717 (0.389–1.323) |
| PS (1 vs. 0) | 0.1620 | 1.532 (0.843–2.785) |
| Primary tumour site (gallbladder vs. non-gallbladder) | 0.0454 | 1.722 (1.011–2.934) |
| Presence of primary tumour (present vs. absent) | 0.0036 | 2.789 (1.398–5.564) |
| Extent of disease (metastatic vs. locally advanced) | 0.4333 | 1.391 (0.609–3.176) |
| Treatment arm (GC arm vs. G arm) | 0.2093 | 0.724 (0.437–1.199) |
Chi-square test.
BD, biliary drainage; CI, confidence interval; G arm, emcitabine monotherapy; GC arm, combination therapy with gemcitabine and cisplatin; PS, performance status.
Discussion
Many studies on unresectable BTC retrospectively investigated whether biliary drainage should be performed endoscopically or with a percutaneous transhepatic approach,8,9 and whether a plastic or metallic stent should be used.10–15 Several of the few prospective studies conducted have stent patency or complication-free survival as a primary endpoint. However, only a few of those have considered the impact of drainage on chemotherapy efficacy or adverse events. This analysis represents an important exploratory investigation of the impact of biliary drainage on chemotherapy efficacy in the BT22 study which was a prospectively controlled study.
Insufficient biliary drainage leads to problems during chemotherapy, such as recurrent obstructive jaundice with or without cholangitis, which in turn often results in suspension or discontinuation of chemotherapy. In the BT22 study, the incidence of cholangitis during initial chemotherapy in the GC and G arms in the BD subgroup was higher than that in the respective arms of the non-BD subgroup. Although the profiles of grade 3 and 4 non-haematological adverse events in the GC and G arms did not differ, haematological toxicities were slightly more severe in the GC arm. GC therapy is expected to lead to an increased incidence of cholangitis or progression to severe cholangitis in patients undergoing biliary drainage who are at high risk of cholangitis mainly because the regimen has a more severe haematological toxicity profile than G. These events could undermine the efficacy of GC therapy.
In the BD subgroup, however, MST in the GC and G arms were 11.3 vs. 8.1 months, respectively, with an HR of 0.59 (95% CI 0.27 to 1.30). Median survival time in the GC arm was longer than MST in the G arm. As with adverse events overall, grade 3 and 4 adverse events in the BD subgroup were slightly more severe in the GC arm than in the G arm, but no particularly frequent events were encountered. In addition, patients with biliary drainage in the G arm had a relatively increased incidence of grade 3 and 4 cholangitis, possibly as a result of a lack of efficacy and inferior biliary drainage. Although careful monitoring of cholangitis is still needed, the above findings indicate GC to be an appropriate standard chemotherapy for unresectable BTC in both patients with and without biliary drainage.
Because this analysis was a retrospective investigation of the BT22 study, several biases could arise after this retrospective approach. Although the biases cannot be completely circumvented using a multivariate Cox's proportional hazard model, the results adjusted with other prognostic factors suggested that biliary drainage would not have a negative impact on the anti-cancer effect of chemotherapy. The results suggested that baseline biliary drainage did not adversely impact patient prognosis. The presence of a primary tumour (present vs. absent) and primary tumour site (gallbladder vs. non-gallbladder) had the greatest impact on the prognosis, which suggests that the stratification factors of the present study were appropriately selected.
As the BT22 study was conducted to compare chemotherapy regimens, the data available for investigating biliary drainage, e.g. the site of bile duct obstruction, the approach (endoscopic or percutaneous transhepatic) and the stent material (plastic stent or metallic stent), were limited. Thus, patient baseline characteristics varied substantially. A detailed subgroup analysis on biliary drainage was unfortunately infeasible with the limited sample size of the study. Moreover, this analysis was conducted to investigate the impact of whether or not biliary drainage was performed before starting chemotherapy, and patients requiring biliary drainage during chemotherapy were consequently included in the non-BD subgroup. Data on adverse events occurring during the primary treatment period are available, but adverse events occurring with more advanced cancer in secondary and subsequent treatments were not investigated. No definite conclusions about the relationship of biliary drainage to chemotherapy may therefore be drawn based on the findings of this analysis alone.
Conclusion
In this analysis, GC combination therapy was safely administered and the therapeutic efficacy of the GC arm was maintained in patients with or without biliary drainage. The presence or absence of biliary drainage was not found to impact the efficacy or adverse events in each treatment arm for unresectable BTC. Based on these results, it appears that adequate efficacy with gemcitabine-based chemotherapy can be expected in patients with BTC even with biliary drainage.
Acknowledgments
We acknowledge and thank the following members of Eli Lilly Japan KK: Natsuko Kitagawa for clarifying research questions, Yuko Shibasaki for data collection, Soshi Nagaoka for conducting the statistical analysis and Masumi Tatsumi for her assistance in writing the manuscript.
Conflicts of interest
Masanori Taketsuna and Minori Koshiji are employees of Eli Lilly Japan K.K. Takuji Okusaka has received funding to research and attend/present at conference from Eli Lilly Japan K.K. Junji Furuse has received funding to attend/present at conference from Eli Lilly Japan K.K. The authors report no other conflicts of interest.
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