Clinical Study Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
Received: April 22, 2014 Accepted after revision: July 8, 2014 Published online: October 21, 2014
Chemotherapy and Targeted Therapy in Advanced Biliary Tract Carcinoma: A Pooled Analysis of Clinical Trials Florian Eckel a, b Roland M. Schmid a
b
Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, and Department of Internal Medicine, RoMed Klinik Bad Aibling, Bad Aibling, Germany
Key Words Bile duct carcinoma · Biliary tract carcinoma · Cholangiocarcinoma · Gallbladder carcinoma · Gemcitabine · Platinum compounds · Molecular targeted therapy · Systematic review
Abstract Background: In biliary tract cancer, gemcitabine platinum (GP) doublet palliative chemotherapy is the current standard treatment. The aim of this study was to analyze recent trials, even those small and nonrandomized, and identify superior new regimens. Methods: Trials published in English between January 2000 and January 2014 were analyzed, as well as ASCO abstracts from 2010 to 2013. Results: In total, 161 trials comprising 6,337 patients were analyzed. The pooled results of standard therapy GP (no fluoropyrimidine, F, or other drug) were as follows: the median response rate (RR), tumor control rate (TCR), time to tumor progression (TTP) and overall survival (OS) were 25.9 and 63.5%, and 5.3 and 9.5 months, respectively. GFP triplets as well as G-based chemotherapy plus targeted therapy were significantly superior to GP concerning tumor control (TCR, TTP) and OS, with no
© 2014 S. Karger AG, Basel 0009–3157/14/0601–0013$39.50/0 E-Mail [email protected] www.karger.com/che
difference in RR. Conclusion: Triplet combinations of GFP as well as G-based chemotherapy with (predominantly EGFR) targeted therapy are most effective concerning tumor control and survival. © 2014 S. Karger AG, Basel
Introduction
Biliary tract cancers (BTC) are uncommon but highly fatal malignancies in the USA and Europe. BTC comprise gallbladder carcinoma (GBC) and cholangiocarcinoma (CC; bile duct cancer), which arise from the epithelial cells of the intrahepatic and extrahepatic bile ducts. The anatomical location of CC can be described as intrahepatic, distal extrahepatic or hilar [1]. Approximately 5,000 cases of GBC and 2,500 cases of CC are diagnosed annually in the USA [2]. The incidence of CC (particularly intrahepatic CC) has been rising over the past 2 decades in the USA, the UK and Australia [3]. A large proportion of nearly 40% of CC cases are associated with cirrhosis, of which up to 83% are intrahepatic CC [4]. Worldwide, the highest prevalence of GBC is seen Dr. Florian Eckel Department of Internal Medicine RoMed Klinik Bad Aibling Harthauser Strasse 16, DE–83043 Bad Aibling (Germany) E-Mail florian.eckel @ lrz.tum.de
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
a
14
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
Methods Data for this analysis were identified by searches of PubMed and references from relevant articles using the search terms ‘biliary tract neoplasms’, ‘bile duct neoplasms’, ‘cholangiocarcinoma’ and ‘gallbladder neoplasms’. Only papers reporting the results of chemotherapy trials published in English between January 2000 and January 2014 were included. Abstracts from ASCO annual meetings presented between 2010 and 2013 as well as from ASCO gastrointestinal cancers symposia presented between 2010 and 2014 were also included. Trials of intra-arterial hepatic chemotherapy or of chemoradiotherapy were excluded. For the inclusion of a trial in the analysis, the number of patients (included, treated or evaluable) and the RR (complete response + partial response), TCR (complete response + partial response + stable disease), time to tumor progression (TTP) or progression-free survival (PFS) if TTP was not available, or overall survival (OS) were at least required. Definitions of tumor control and stable disease may be insignificantly different in the trials analyzed depending on the frequency of tumor reevaluation, which depends on the chemotherapy regimen and duration of cycles. We assumed that TCR and stable disease required no signs of disease progression for at least 8 weeks [13]. Rates were calculated as intent-to-treat. In trials with more than one treatment arm, the arms were analyzed separately as single-arm trials. All the trials included were analyzed independently of the tumor classification for BTC. Patients with progression after first-line therapy were enrolled in some trials, and these trials were included in this analysis. For subgroup analysis, results of the trials were compared and tested by nonparametric tests (Mann-Whitney, Kruskal-Wallis). Furthermore, RR and TCR data were pooled by summarizing the number of patients in the trials. For example, a pooled RR was computed as the sum of the responders of a subgroup divided by the sum of the patients of this subgroup. The Clopper-Pearson method was used to calculate 95% confidence intervals (CI). Nonparametric correlation was tested according to Spearman’s method.
Results
A total of 161 published trials were included in this analysis (for references see Appendix). They comprise of 181 trial arms reporting RR. Only 13 trials were randomized, including three phase III trials [10, 14, 15]. The number of patients per trial arm ranged from 5 to 206. The 161 trials analyzed comprised a total of 6,337 enrolled patients, including 1,306 responders (mean 7.2 of 35.0 patients per trial), and a total of 5,825 enrolled patients, including 3,529 patients with tumor control (mean 21.7 of 35.7 patients per trial), respectively (table 1). The pooled RR was 20.6% (95% CI 19.6–21.6) and the pooled TCR was 60.6% (95% CI 59.3–61.8). The median TTP and OS were 4.1 and 8.8 months, respectively. The RR and TCR of all the trials analyzed sorted by the number of patients are shown in figure 1. Figure 2 shows waterfall plots Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
in India, Pakistan, Ecuador, Israel, Mexico, Chile and Japan, and among Native American women, particularly those living in New Mexico. Mortality rates in these areas can reach 5–10 times that in the USA [5, 6]. Worldwide, CC accounts for 3% of all gastrointestinal cancers and is the second most common primary hepatic tumor [7]. The incidence of CC is highest in Israel, Japan, among Native Americans and in Southeast Asia, where it can reach 87 per 100,000 [3]. This indicates the global significance of both GBC and CC. Even in patients undergoing aggressive surgery, the general outcome of patients with BTC has been disappointing. Five-year survival rates are 5–10% for GBC and 10–40% for CC [2]. Unfortunately, most BTC are diagnosed at advanced stages when the tumor is unresectable. The median survival of patients with advanced disease is in the range of only a few months. However, analysis of mortality rates for GBC across the world for the period 1992–2002 demonstrated a decline in age-standardized mortality rates in most countries [8]. Better diagnostic modalities and changes in the ICD classification, as well as better treatment options, may have contributed to this trend. Seven years ago we published our first pooled analysis of clinical trials in this disease. We demonstrated that regimens based on gemcitabine (G) combined with platinum (P) compounds, i.e. cisplatin and oxaliplatin, were most effective concerning response rate (RR) and tumor control rate (TCR) [9]. The randomized phase III ABC-02 trial published in 2010 confirmed our results and demonstrated significant prolongation of survival by G plus cisplatin compared to G alone [10]. Based on this trial, GP is the standard chemotherapy in BTC. Progress has been made in the last decade to identify effective targeted therapies in many cancers. Some years ago we published a review of emerging drugs for biliary cancer [11]. New derivatives, such as the oral fluoropyrimidine (F) S1, have been developed from 5-fluorouracil, and new classes of drugs have been introduced, such as antibodies (mabs) and kinase inhibitors (nibs) – so-called biologicals (bio). Mabs and nibs act against defined molecular targets, such as EGFR, VEGF or the RAS-MAPK pathway [12]. However, for separate analysis of a new agent subgroup, the number of trials and patients was too low in our first pooled analysis of clinical trials. The aim of this study was to analyze recently published clinical trials, even those small and nonrandomized, with a focus on GP as well as on new agents. If possible, we also aimed to identify new regimens superior to GP, which is the current standard of care as palliative chemotherapy in advanced BTC.
100
Single trial arm
90
95% CI
80
95% CI
Pooled RR
70
RR (%)
60 50 40 30 20 10 0 0
20
40
60
a
80
100
120
140
160
180
Patients (n) 100 90 80 70
TCR (%)
60 50 40 30
Single trial arm
20
Fig. 1. RR (a) and TCR (b) of all trials ana-
lyzed, sorted by the number of patients. The horizontal gray line represents the pooled RR of all patients (20.6%) and the pooled TCR (60.6%), respectively. The limits of the 95% CI calculated with the corresponding number of patients are shown by gray curved lines.
95% CI Pooled TCR
10
95% CI
0 0
20
40
60
b
80
100
120
140
160
180
Patients (n)
Table 1. Outcome parameters of all trials and patients analyzed
All trials
RR
TCR
TTP
OS
Trial arms, n Patients, n Median Mean
181 6,337 20.0% 20.6% (19.6–21.6)
163 5,825 60.0% 60.6% (59.3–61.8)
140 5,282 4.1 months
154 5,744 8.8 months
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
15
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Mean values are given with 95% CI in parentheses.
100
RR Pooled RR
90 80 70
RR (%)
60 50 40 30 20 10
a
0
Single trial arms
100
TCR Pooled TCR
90 80 70
TCR (%)
60 50 40 30 20 10
b
0
of the RR and TCR, with corresponding 95% CI, of all the trials analyzed. The RR of 12 trials was higher than the calculated 95% CI of the pooled RR with the same number of patients (above the gray line indicating the upper 95% CI in fig. 1a). All 12 trials evaluated a combination of at least two drugs: 11 regimens containing P, 8 regimens containing G, 4 containing F, and 3 containing targeted therapy (cetuximab, panitumumab, erlotinib) combined with G-based chemotherapy. Twenty-one trials had a high TCR above the 95% CI of the corresponding pooled TCR. Among these 21 trials were 18 regimens containing 16
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
Single trial arms
G, 13 containing P, 11 containing F, and 8 containing targeted therapy (cetuximab, panitumumab, bevacizumab, erlotinib, sorafenib) combined with G-based chemotherapy. Among trials with inferior RR or TCR lower than the calculated 95% CI of the pooled RR or TCR, were trials evaluating monotherapy of G or F, new agents (rebeccamycin, exatecan, dolastatin, ixabepilone, bendamustine) and targeted therapy without a chemotherapy backbone (lapatinib, sorafenib, erlotinib, sunitinib, sirolimus), as well as trials evaluating second-line therapy. The outcome parameters RR, TCR, TTP and OS were all significantly correlated (p = 0.000). Correlation coefEckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Fig. 2. Waterfall plots of RR (a) and TCR (b) with 95% CI of all trials analyzed. The horizontal black line represents the pooled RR of all patients (20.6%) and the pooled TCR (60.6), respectively.
15
r = 0.72, p = 0.000
TTP (months)
12
9
6
3
0 0
a
20
40
60
80
100
60
80
100
TCR (%) 24
r = 0.59, p = 0.000
21
18
OS (months)
15 12 9 6 3 0
b
0
20
40 TCR (%)
ficients ranged from r = 0.48 (RR – OS) to r = 0.78 (TTP – OS). Figure 3 shows TCR and its correlation with TTP and OS, respectively. Initial subgroup analysis focused on the current standard therapy, GP. The pooled RR was 24.1% (95% CI
22.1–26.3) and the pooled TCR was 62.8% (95% CI 60.4– 65.2). The median TTP and OS were 5.3 and 9.5 months, respectively (table 2). There was no trial evaluating targeted therapy by means of mabs and nibs (bio) in combination with F without G, and the results of trials of
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
17
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Fig. 3. Chart showing the correlation between TCR and TTP (a) and OS (b).
Table 2. Outcome parameters of all trials and patients evaluating G plus P
GP
RR
TCR
TTP
OS
Trial arms, n Patients, n Median Mean
36 1,599 25.9% 24.1% (22.1–26.3)
36 1,641 63.5% 62.8% (60.4–65.2)
33 1,484 5.3 months
35 1,566 9.5 months
Mean values are given with 95% CI in parentheses.
Table 3. Outcome parameters of all trials and patients evaluating G, an F and P triplets (GFP), as well as targeted
therapy combined with G-based chemotherapy (bioG) RR
TCR
TTP
OS
GFP Trial arms, n Patients, n Median Mean
9 373 30.4% 25.7% (21.4–30.5)
8 317 78.6% 73.2% (67.9–78.0)
5 215 9.0 months
5 215 12.5 months
bioG Trial arms, n Patients, n Median Mean
14 546 30.0% 28.8% (25.0–32.8)
12 481 79.2% 75.7% (71.6–79.4)
11 535 7.1 months
11 526 12.7 months
Mean values are given with 95% CI in parentheses.
18
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
pared to GF there was a (nonsignificant) trend toward better results for the GFP and bioG subgroups. Concerning RR, all differences were small and not statistically significant.
Discussion
This pooled analysis of all published clinical trials since 2000 showed that triplet chemotherapy with G, an F and P compared to standard palliative chemotherapy (GP) increases tumor control (TCR, TTP) and OS in advanced BTC. Furthermore, we could demonstrate that Gbased chemotherapy in combination with targeted therapy is significantly superior compared to GP concerning tumor control and OS. The present analysis is our second systematic review of clinical trials of palliative therapy in BTC. A total of 161 trials comprising 181 trial arms and 6,337 patients were included and analyzed. The pooled RR of all patients was 20.6%, which is lower than the RR of our first Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
targeted therapy without an effective chemotherapy backbone were dismal (data not shown). Therefore, we continued to analyze subgroups defined by G, F and P without new agents, as well as defined by targeted therapy combined with G-based chemotherapy (bioG: cetuximab, n = 6; panitumumab, n = 3; erlotinib, n = 3; bevacizumab, n = 2; sorafenib, n = 1). The chemotherapy backbone of the bioG subgroup was G alone in one trial only. In the other trials, G was combined with other drugs (oxaliplatin, n = 11; cisplatin, n = 1; capecitabine, n = 2; irinotecan, n = 1) or combinations of these drugs. The results (RR, TCR, TTP, OS) of the doublet GF were slightly better than those of the doublet GP, but differences were small and not statistically significant (p values ≥0.1; data not shown). Therefore, a combined subgroup comprising GP and GF doublets was defined (GP+GF). Next, the subgroups of triplet GFP as well as bioG were compared to GP, GF and GP+GF, respectively (table 3; fig. 4); all p values are listed in table 4. TCR, TTP and OS in the subgroups GFP and bioG were significantly better compared to GP and GP+GF. Com-
100
a
60
90
50
80
40
70
TCR (%)
RR (%)
70
30
60
20
50
10
40
b
0
Trials (n) (patients)
GP 36 (1,599)
GF 18 (639)
GFP 9 (373)
bioG 14 (546)
30
Trials (n) (patients)
15
GP 36 (1,641)
GF 15 (544)
GFP 8 (317)
bioG 12 (481)
GP 35 (1,566)
GF 17 (630)
GFP 5 (215)
bioG 11 (526)
27 24 21
9
OS (months)
TTP (months)
12
6
18 15 12 9
3
6
c
d
0
Trials (n) (patients)
GP 33 (1,484)
GF 15 (553)
GFP 5 (215)
bioG 11 (535)
3
Trials (n) (patients)
Fig. 4. Boxplots of the outcome parameters RR (a), TCR (b) TTP (c) and OS (d). The width of the boxes correlates with the number of
analysis (22.6%). In contrast, TCR increased to 60.6% compared to our first analysis, which found a lower TCR of 57.3%. Median TTP was unchanged (4.1 months for both) and median OS increased from 8.2 to 8.8 months. The results of the present analysis confirm the results of our first study, suggesting an improvement in therapies over the last 7 years concerning TCR and OS, but not RR. Our pooled analysis published in 2007 provided the first evidence that a chemotherapy consisting of G combined with P improves survival in advanced BTC [9]. Our
results were confirmed in 2010 when the results of the large phase III ABC-02 trial evaluating G with or without cisplatin were fully published. This trial demonstrated an increased RR (26 vs. 16%), TCR (81 vs. 72%), PFS (8.0 vs. 5.0 months) and OS (11.7 vs. 8.1 months) by the addition of cisplatin to G, despite rather good results in the Galone arm, defining a new standard in palliative chemotherapy in BTC [10]. The pooled results of GP chemotherapy in the present analysis were inferior, with RR 24%, TCR 63%, TTP 5.3 months and OS 9.5 months. The remarkably high TCR and long OS of the ABC-02 trial
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
19
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
trials. p values are listed in table 4.
GP
GF
GP+GF
0.348 0.370
0.743 0.621
0.421 0.408
0.001 0.001
0.076 0.064
0.004 0.002
0.000 0.002
0.002 0.069
0.001 0.003
0.003 0.017
0.164 0.278
0.016 0.036
RR GFP bioG TCR GFP bioG TTP GFP bioG OS GFP bioG
could not be reproduced in other trials evaluating GP chemotherapy. Chemotherapy of many solid cancers is traditionally based on 5-fluorouracil. Regimens have evolved from simple bolus to sophisticated combination regimens, such as FOLFOX, FOLFIRI or FOLFIRINOX [16]. Furthermore, the oral F S1 [17], capecitabine and UFT [18] have been developed. Therefore, we analyzed the subgroup of trials evaluating doublets of G and F. Interestingly, the results of GF were largely similar to or even better by trend than those of GP. Thus, to identify new superior regimens, we compared the triplet combination GFP with GP as the current standard, as well as GF and a combined subgroup of GP and GF doublets for a larger number of trials and patients in order to enhance statistical power. Only a few trials evaluated GFP, but results were promising with significantly superior tumor control (TCR, TTP) and OS compared to GP and GP+GF. There was no randomized trial evaluating GFP. The toxicity of GFP varied from ‘well tolerated’ to ‘tolerable but substantial’, which was nevertheless increased compared to doublets. The hematologic toxicity grade 3/4 was 24–37% (neutropenia) and 12–36% (platelets). Targeted therapy by means of mabs or nibs acting against molecular defined targets has evolved in the last 2 decades [12]. Targeted therapy is now the standard of care in some solid cancers. Targeted therapy alone is sufficient in some cancers, e.g. sorafenib in HCC, or under some circumstances, e.g. panitumumab last line for KRAS wild-type metastatic colorectal cancer after other drugs have failed. However, targeted therapy in combination with an effective chemotherapy backbone is generally 20
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
more active [19]. Therefore, we identified targeted therapy in combination with G-based chemotherapy (bioG) as a subgroup for further analysis. It is noteworthy that the majority of trials in this subgroup evaluated G combined with oxaliplatin plus targeted therapy. Genetics of BTC have been reviewed recently [20]. According to the mutational spectrum of oncogenes in BTC and available drugs, the molecular target of trials evaluating bioG was mostly EGFR. Activating mutations in KRAS, which result in constitutive activation of the RAS-RAF-ERK pathway, result in resistance to anti-EGFR therapy [21]. KRAS mutations were found in 10–64% of the trials in the present analysis. KRAS wild-type was an inclusion criterion in two trials. The present analysis demonstrated significantly superior tumor control (TCR, TTP) and OS of trials evaluating bioG treatment compared to GP and GP+GF. Three of the bioG trials were randomized trials. One of these was recently fully published by Lee et al. [15], who reported the results of a phase III trial evaluating G and oxaliplatin with or without erlotinib in BTC. Erlotinib significantly increased the RR (30 vs. 16%, p = 0.005) and prolonged PFS (5.8 vs. 4.2 months, HR 0.80, p = 0.087). No difference concerning TCR and OS was noted among the 268 patients enrolled. The other two randomized trials were phase II trials presented at ASCO meetings. The TCOG trial evaluated GemOx with or without cetuximab. TCR (82 vs. 60%, p = 0.009) and PFS (7.1 vs. 4.0 months, p = 0.007) were significantly superior in the cetuximab arm [22]. KRAS mutated tumors benefited more from cetuximab therapy (TCR 78 vs. 38%, p = 0.013, PFS 7.0 vs. 1.9 months, p = 0.035). However, results of the GemOx arm without cetuximab were remarkably poor and the number of patients accrued was adequate only for a phase II trial (n = 122; subgroup analysis with KRAS mutated tumors, n = 43). Another phase II trial evaluating GemOx with or without cetuximab found no differences in PFS and OS among the 150 patients enrolled [23]. However, results of the GemOx-only arm were remarkable, with a high TCR (77%) and a long OS (12.4 months). The classic endpoint of phase II trials was tumor response with complete and partial response evaluated after a defined number of treatment cycles. OS is the gold standard for the demonstration of a clinical benefit in phase III cancer trials. Despite a growing number of publications in this field there is no accepted surrogate endpoint in advanced BTC and other solid cancers [24]. Based on the results presented and the fact that most new targeted agents are more cytostatic as opposed to cytotoxic, tumor Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Table 4. p values of figure 4
control seems to be the more adequate endpoint compared to tumor response in phase II trials. The primary objective of phase II trials is to determine whether a new drug or regimen has sufficient activity. Statistical designs have been developed based on testing a null hypothesis (true response probability is less than some uninteresting level = response probability of a poor drug) and a specified alternative hypothesis (true response probability is at least some desirable target level = response probability of a good drug) [25]. Concerning TCR, we suggest a design with a response probability of at least 60% for ‘poor drug’. Alternatively, PFS at 4 or 6 months reflects tumor control too and may be an adequate surrogate endpoint. Based on our data, a 5-month PFS of at least 50% for ‘poor drug’ may be reasonable. Considering the wide range of the results presented, the 6-month PFS of 59% in the G plus cisplatin arm of the ABC-02 trial was rather high. This level seems to be too high for the probability of a poor drug and may lead to negative trials, as others have recognized. A phase II trial evaluating G cisplatin plus sorafenib resulted in a high TCR (88%) and long TTP (8.2 months) and OS (14.4 months), but failed improvement of the primary endpoint 6-month PFS from 57 to 77% [26]. The development of cytotoxic chemotherapy in BTC was traditionally influenced by regimens in pancreatic cancer. Recently, the triplet FOLFIRINOX has been proven to be superior compared to G in pancreatic cancer at the cost of increased toxicity [27]. In the present analysis, the triplet GFP was superior compared to GP, also at the cost of increased toxicity, and may be an option for patients with a good performance status. However, phase III trials evaluating GFP are lacking. Considering toxicity, GF may be an option compared to GP, especially for patients with neuropathy or renal insufficiency. Most recently, G plus nab-paclitaxel was superior compared to G alone in a phase III trial, but the rates of peripheral neuropathy and myelosuppression were increased [28]. It remains questionable whether or not regimens that are effective in pancreatic cancer are worthy of evaluation in BTC. Transfer of successful regimens from one cancer to another was reasonable for the development of cytotoxic drugs in the past, but current development of molecular targeted therapy follows other principles [29]. The evidence level of the present pooled analysis of predominately rather small phase II trials remains limited. However, the results of our first pooled analysis have been confirmed by a phase III trial. It remains unclear which P, which F and which targeted therapy is optimal, and which schedule of administration should be used.
In conclusion, we suggest a chemotherapy triplet of G, an F and P, as well as EGFR targeted therapy combined with G-based chemotherapy, as the most active in advanced BTC, and therefore a standard option for patients with a good performance status. The doublet G plus an F seems to be at least as active as the doublet G plus P, and may be an option with more favorable toxicity for some patients.
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
Abou-Alfa, G.K., Am J Clin Oncol, 2005. Alberts, S.R., Cancer, 2005. Alberts, S.R., Int J Gastrointest Cancer, 2002. Alberts, S.R., J Gastrointest Cancer, 2007. Andre, T., Br J Cancer, 2008. Andre, T., Ann Oncol, 2004. Androulakis, N., Oncology, 2006. Bekaii-Saab, T., J Clin Oncol, 2011. Bengala, C., Br J Cancer, 2010. Berglund, A., Med Oncol, 2010. Bhargava, P., Oncology, 2003. Borbath, I., Ann Oncol, 2013. Buzzoni, R., ASCO Meeting Abstracts, 2010. Charoentum, C., ASCO Meeting Abstracts, 2013. Chatni, S.S., J Cancer Res Ther, 2008. Chen, J.S., Cancer Chemother Pharmacol, 2009. Chen, J.S., Anticancer Drugs, 2001. Chen, J.S., Jpn J Clin Oncol, 2003. Chen, L.-T., ASCO Meeting Abstracts, 2013. Chiorean, E.G., Oncologist, 2012. Cho, J.Y., Yonsei Med J, 2005. Cho, J.Y., Cancer, 2005. Choi, C.W., Am J Clin Oncol, 2000. Chung, M.J., Chemotherapy, 2011. Ciombor, K.K., ASCO Meeting Abstracts, 2012. Ciuleanu, T., Invest New Drugs, 2007. Doval, D.C., Br J Cancer, 2004. Dowlati, A., Cancer Chemother Pharmacol, 2009. Ducreux, M., Eur J Cancer, 2005. Eckel, F., Ann Oncol, 2000. El-Khoueiry, A.B., Br J Cancer, 2014. El-Khoueiry, A.B., Invest New Drugs, 2012. Eng, C., Am J Clin Oncol, 2004. Feisthammel, J., Am J Clin Oncol, 2007. Ferrari, V.D., Am J Clin Oncol, 2004. Fiebiger, W.C., Scand J Gastroenterol, 2002. Furuse, J., Cancer Chemother Pharmacol, 2008. Furuse, J., Jpn J Clin Oncol, 2006. Furuse, J., Cancer Chemother Pharmacol, 2009. Gallardo, J.O., Ann Oncol, 2001. Gebbia, V., J Clin Oncol, 2001. Gelibter, A., Cancer, 2005. Giuliani, F., Ann Oncol, 2006. Goldstein, D., Cancer Chemother Pharmacol, 2011. Gruenberger, B., Lancet Oncol, 2010. Halim, A., Jpn J Clin Oncol, 2011. Harder, J., Br J Cancer, 2006. Hong, Y.S., Cancer Chemother Pharmacol, 2007. Hsu, C., Br J Cancer, 2004. Ikeda, M., Jpn J Clin Oncol, 2005. Iqbal, S., Cancer Chemother Pharmacol, 2011. Iyer, R.V., Ann Surg Oncol, 2007. Jang, J.S., Cancer Chemother Pharmacol, 2010. Jensen, L.H., Ann Oncol, 2012. Jensen, L.H., ASCO Meeting Abstracts, 2014. Julka, P.K., Hepatobiliary Pancreat Dis Int, 2006. Kameda, R., Jpn J Clin Oncol, 2013. Kanai, M., Cancer Chemother Pharmacol, 2012. Kanai, M., Cancer Chemother Pharmacol, 2011. Kang, M.J., Acta Oncol, 2012. Karachaliou, N., Oncology, 2010. Kim, H.J., Cancer Chemother Pharmacol, 2009. Kim, K.P., Br J Cancer, 2011. Kim, S.T., Cancer, 2006. Kim, T.W., Ann Oncol, 2003. Kim, Y.J., Ann Oncol, 2008. Kindler, H.L., Invest New Drugs, 2005. Knox, J.J., J Clin Oncol, 2005. Knox, J.J., Ann Oncol, 2004. Kobayashi, K., BMC Cancer, 2006. Koeberle, D., J Clin Oncol, 2008. Kornek, G.V., Ann Oncol, 2004. Kruth, J., J Cancer Res Clin Oncol, 2010. Kubicka, S., Hepatogastroenterology, 2001. Kuhn, R., Invest New Drugs, 2002. Lamarca, A., ASCO Meeting Abstracts, 2014. Lassen, U., Acta Oncol, 2011. Leal, J.L., ASCO Meeting Abstracts, 2014. Lee, G.W., Am J Clin Oncol, 2006. Lee, J., Cancer Chemother Pharmacol, 2008. Lee, J., Lancet Oncol, 2012. Lee, J.E., ASCO Meeting Abstracts, 2012. Lee, J.K., Br J Can-
21
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Appendix
cer, 2013. Lee, M.A., J Cancer Res Clin Oncol, 2004. Lee, S., ASCO Meeting Abstracts, 2011. Lee, S., Am J Clin Oncol, 2009. Lim, J.Y., Anticancer Drugs, 2008. Lim, K.H., Oncology, 2012. Lin, M.H., Chemotherapy, 2003. Lubner, S.J., J Clin Oncol, 2010. Mahipal, A., ASCO Meeting Abstracts, 2011. Malik, I.A., Am J Clin Oncol, 2003. Malik, I.A., Am J Clin Oncol, 2003. Malka, D., ASCO Meeting Abstracts, 2012. Manzione, L., Oncology, 2007. Meyerhardt, J.A., Dig Dis Sci, 2008. Morizane, C., Oncology, 2003. Morizane, C., Cancer Sci, 2013. Murad, A.M., Am J Clin Oncol, 2003. Nehls, O., Br J Cancer, 2002. Nehls, O., Br J Cancer, 2008. Nimeiri, H.S., Invest New Drugs, 2010. Noel, M.S., ASCO Meeting Abstracts, 2014. Novarino, A.M., Am J Clin Oncol, 2013. Ocean, A.J., Cancer Chemother Pharmacol, 2011. Oh, S.Y., Invest New Drugs, 2011. Oh, S.Y., Chemotherapy, 2008. Okusaka, T., Cancer Chemother Pharmacol, 2006. Okusaka, T., Br J Cancer, 2010. Papakostas, P., Eur J Cancer, 2001. Park, B.K., J Gastroenterol Hepatol, 2006. Park, J.S., Jpn J Clin Oncol, 2005. Park, K.H., Cancer, 2005. Park, S.H., Cancer, 2006. Patt, Y.Z., ASCO Meeting Abstracts, 2010. Patt, Y.Z., Cancer, 2004. Patt, Y.Z., Clin Cancer Res, 2001. Paule, B., Oncology, 2007. Peck, J., Oncology, 2012. Penz, M., Ann Oncol, 2001. Philip, P.A., J Clin Oncol, 2006. Ramanathan, R.K., Cancer Chemother Pharmacol, 2009. Rao, S., Br J Cancer, 2005. Riechelmann,
R.P., Cancer, 2007. Rizell, M., Int J Clin Oncol, 2008. Roth, A., Onkologie, 2011. Rubovszky, G., Eur J Cancer, 2013. Ryoo, H., ASCO Meeting Abstracts, 2011. Santini, D., Oncology, 2012. SanzAltamira, P.M., Ann Oncol, 2001. Sasaki, T., Cancer Chemother Pharmacol, 2010. Sasaki, T., Cancer Chemother Pharmacol, 2013. Sasaki, T., Invest New Drugs, 2012. Sasaki, T., Invest New Drugs, 2011. Schoppmeyer, K., Anticancer Drugs, 2007. Sebbagh, S., ASCO Meeting Abstracts, 2014. Sharma, A., J Clin Oncol, 2010. Sharma, A., Cancer Chemother Pharmacol, 2010. Sirohi, B., ASCO Meeting Abstracts, 2014. Sohal, D., ASCO Meeting Abstracts, 2012. Sohn, B.S., Tumori, 2013. Suzuki, E., Cancer Chemother Pharmacol, 2013. Taieb, J., Ann Oncol, 2002. Takezako, Y., Hepatogastroenterology, 2008. Thongprasert, S., Ann Oncol, 2005. Tsavaris, N., Invest New Drugs, 2004. Ueno, H., Br J Cancer, 2004. Valle, J., N Engl J Med, 2010. Verderame, F., Ann Oncol, 2006. von Delius, S., BMC Cancer, 2005. Wagner, A.D., Br J Cancer, 2009. Weatherly, J., ASCO Meeting Abstracts, 2011. Williams, K.J., HPB (Oxford), 2010. Woo, S.M., Gut Liver, 2013. Yamashita, Y., Anticancer Res, 2006. Yamashita, Y., Jpn J Clin Oncol, 2010. Yi, J.H., Eur J Cancer, 2012. Yokoyama, T., J Nippon Med Sch, 2012. Yonemoto, N., Jpn J Clin Oncol, 2007. Yoon, D.H., Invest New Drugs, 2011. Zhu, A.X., Lancet Oncol, 2010.
1 Patel T: Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33–42. 2 de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM: Biliary tract cancers. N Engl J Med 1999;341:1368–1378. 3 Rajagopalan V, Daines WP, Grossbard ML, Kozuch P: Gallbladder and biliary tract carcinoma: a comprehensive update, part 1. Oncology (Huntingt) 2004;18:889–896. 4 Pracht M, Le Roux G, Sulpice L, Mesbah H, Manfredi S, Audrain O, Boudjema K, Raoul JL, Boucher E: Chemotherapy for inoperable advanced or metastatic cholangiocarcinoma: retrospective analysis of 78 cases in a single center over four years. Chemotherapy 2012; 58:134–141. 5 Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba, II, Alonso de Ruiz P, Aristi Urista G, Nervi F: Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001; 51: 349–364. 6 Randi G, Franceschi S, La Vecchia C: Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006; 118:1591–1602. 7 Khan SA, Thomas HC, Davidson BR, TaylorRobinson SD: Cholangiocarcinoma. Lancet 2005;366:1303–1314. 8 Hariharan D, Saied A, Kocher HM: Analysis of mortality rates for gallbladder cancer across the world. HPB (Oxford) 2008;10:327–331. 9 Eckel F, Schmid RM: Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007;96:896– 902. 10 Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan
22
11 12
13
14
15
16
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273–1281. Eckel F, Schmid RM: Emerging drugs for biliary cancer. Expert Opin Emerg Drugs 2007; 12:571–589. Marino D, Leone F, Cavalloni G, Cagnazzo C, Aglietta M: Biliary tract carcinomas: from chemotherapy to targeted therapy. Crit Rev Oncol Hematol 2013;85:136–148. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216. Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR: 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. Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, Jang JS, Jeung HC, Kang JH, Lee HW, Shin DB, Kang HJ, Sun JM, Park JO, Park YS, Kang WK, Lim HY: Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012;13:181–188. Ychou M, Conroy T, Seitz JF, Gourgou S, Hua A, Mery-Mignard D, Kramar A: An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every
17
18
19
20 21
22
2 weeks in patients with advanced solid tumors. Ann Oncol 2003;14:481–489. Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M: Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7:548–557. Nakayama T, Noguchi S: Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan. Oncologist 2010;15:26–36. Bonetti A, Giuliani J, Muggia F: Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer. Anticancer Res 2014;34:423–434. Hezel AF, Deshpande V, Zhu AX: Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol 2010;28:3531–3540. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765. Chen L-T, Chen J-S, Chao Y, Tsai C-S, Shan Y-S, Hsu C, Huang S-F, Tsou H-H, Lee K-D, Chiu C-F, Rau K-M, Ho C-L, Yu M-S, Taiwan Cooperative Oncology Group: KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): the TCOG t1210 trial. J Clin Oncol 2013; 31(suppl):abstr 4018.
Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
References
Pooled Analysis of Chemotherapy in BTC
25 Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10. 26 Lee JK, Capanu M, O’Reilly EM, Ma J, Chou JF, Shia J, Katz SS, Gansukh B, Reidy-Lagunes D, Segal NH, Yu KH, Chung KY, Saltz LB, Abou-Alfa GK: A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas. Br J Cancer 2013;109:915–919. 27 Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M: Folfirinox versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817–1825.
28 von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, van Cutsem E, Wei X, Iglesias J, Renschler MF: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691– 1703. 29 Izar B, Rotow J, Gainor J, Clark J, Chabner B: Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer. Pharmacol Rev 2013; 65: 1351–1395.
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
23
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
23 Malka D, Fartoux L, Rousseau V, Trarbach T, Boucher E, de la Fouchardiere C, Faivre SJ, Viret F, Blanc J-F, Assenat E, Hammel P, Louvet C, von Wichert G, Ducreux M, Rosmorduc O, Pignon J-P, Greten TF: Gemcitabine and oxaliplatin (GEMOX) alone or in combination with cetuximab as first-line treatment for advanced biliary cancer: final analysis of a randomized phase II trial (BINGO). J Clin Oncol 2012;30(suppl):abstr 4032. 24 Piedbois P, Miller Croswell J: Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician’s perspective. Stat Methods Med Res 2008;17:519–527.
Received: April 22, 2014 Accepted after revision: July 8, 2014 Published online: October 21, 2014
Chemotherapy and Targeted Therapy in Advanced Biliary Tract Carcinoma: A Pooled Analysis of Clinical Trials Florian Eckel a, b Roland M. Schmid a
b
Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, and Department of Internal Medicine, RoMed Klinik Bad Aibling, Bad Aibling, Germany
Key Words Bile duct carcinoma · Biliary tract carcinoma · Cholangiocarcinoma · Gallbladder carcinoma · Gemcitabine · Platinum compounds · Molecular targeted therapy · Systematic review
Abstract Background: In biliary tract cancer, gemcitabine platinum (GP) doublet palliative chemotherapy is the current standard treatment. The aim of this study was to analyze recent trials, even those small and nonrandomized, and identify superior new regimens. Methods: Trials published in English between January 2000 and January 2014 were analyzed, as well as ASCO abstracts from 2010 to 2013. Results: In total, 161 trials comprising 6,337 patients were analyzed. The pooled results of standard therapy GP (no fluoropyrimidine, F, or other drug) were as follows: the median response rate (RR), tumor control rate (TCR), time to tumor progression (TTP) and overall survival (OS) were 25.9 and 63.5%, and 5.3 and 9.5 months, respectively. GFP triplets as well as G-based chemotherapy plus targeted therapy were significantly superior to GP concerning tumor control (TCR, TTP) and OS, with no
© 2014 S. Karger AG, Basel 0009–3157/14/0601–0013$39.50/0 E-Mail [email protected] www.karger.com/che
difference in RR. Conclusion: Triplet combinations of GFP as well as G-based chemotherapy with (predominantly EGFR) targeted therapy are most effective concerning tumor control and survival. © 2014 S. Karger AG, Basel
Introduction
Biliary tract cancers (BTC) are uncommon but highly fatal malignancies in the USA and Europe. BTC comprise gallbladder carcinoma (GBC) and cholangiocarcinoma (CC; bile duct cancer), which arise from the epithelial cells of the intrahepatic and extrahepatic bile ducts. The anatomical location of CC can be described as intrahepatic, distal extrahepatic or hilar [1]. Approximately 5,000 cases of GBC and 2,500 cases of CC are diagnosed annually in the USA [2]. The incidence of CC (particularly intrahepatic CC) has been rising over the past 2 decades in the USA, the UK and Australia [3]. A large proportion of nearly 40% of CC cases are associated with cirrhosis, of which up to 83% are intrahepatic CC [4]. Worldwide, the highest prevalence of GBC is seen Dr. Florian Eckel Department of Internal Medicine RoMed Klinik Bad Aibling Harthauser Strasse 16, DE–83043 Bad Aibling (Germany) E-Mail florian.eckel @ lrz.tum.de
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
a
14
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
Methods Data for this analysis were identified by searches of PubMed and references from relevant articles using the search terms ‘biliary tract neoplasms’, ‘bile duct neoplasms’, ‘cholangiocarcinoma’ and ‘gallbladder neoplasms’. Only papers reporting the results of chemotherapy trials published in English between January 2000 and January 2014 were included. Abstracts from ASCO annual meetings presented between 2010 and 2013 as well as from ASCO gastrointestinal cancers symposia presented between 2010 and 2014 were also included. Trials of intra-arterial hepatic chemotherapy or of chemoradiotherapy were excluded. For the inclusion of a trial in the analysis, the number of patients (included, treated or evaluable) and the RR (complete response + partial response), TCR (complete response + partial response + stable disease), time to tumor progression (TTP) or progression-free survival (PFS) if TTP was not available, or overall survival (OS) were at least required. Definitions of tumor control and stable disease may be insignificantly different in the trials analyzed depending on the frequency of tumor reevaluation, which depends on the chemotherapy regimen and duration of cycles. We assumed that TCR and stable disease required no signs of disease progression for at least 8 weeks [13]. Rates were calculated as intent-to-treat. In trials with more than one treatment arm, the arms were analyzed separately as single-arm trials. All the trials included were analyzed independently of the tumor classification for BTC. Patients with progression after first-line therapy were enrolled in some trials, and these trials were included in this analysis. For subgroup analysis, results of the trials were compared and tested by nonparametric tests (Mann-Whitney, Kruskal-Wallis). Furthermore, RR and TCR data were pooled by summarizing the number of patients in the trials. For example, a pooled RR was computed as the sum of the responders of a subgroup divided by the sum of the patients of this subgroup. The Clopper-Pearson method was used to calculate 95% confidence intervals (CI). Nonparametric correlation was tested according to Spearman’s method.
Results
A total of 161 published trials were included in this analysis (for references see Appendix). They comprise of 181 trial arms reporting RR. Only 13 trials were randomized, including three phase III trials [10, 14, 15]. The number of patients per trial arm ranged from 5 to 206. The 161 trials analyzed comprised a total of 6,337 enrolled patients, including 1,306 responders (mean 7.2 of 35.0 patients per trial), and a total of 5,825 enrolled patients, including 3,529 patients with tumor control (mean 21.7 of 35.7 patients per trial), respectively (table 1). The pooled RR was 20.6% (95% CI 19.6–21.6) and the pooled TCR was 60.6% (95% CI 59.3–61.8). The median TTP and OS were 4.1 and 8.8 months, respectively. The RR and TCR of all the trials analyzed sorted by the number of patients are shown in figure 1. Figure 2 shows waterfall plots Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
in India, Pakistan, Ecuador, Israel, Mexico, Chile and Japan, and among Native American women, particularly those living in New Mexico. Mortality rates in these areas can reach 5–10 times that in the USA [5, 6]. Worldwide, CC accounts for 3% of all gastrointestinal cancers and is the second most common primary hepatic tumor [7]. The incidence of CC is highest in Israel, Japan, among Native Americans and in Southeast Asia, where it can reach 87 per 100,000 [3]. This indicates the global significance of both GBC and CC. Even in patients undergoing aggressive surgery, the general outcome of patients with BTC has been disappointing. Five-year survival rates are 5–10% for GBC and 10–40% for CC [2]. Unfortunately, most BTC are diagnosed at advanced stages when the tumor is unresectable. The median survival of patients with advanced disease is in the range of only a few months. However, analysis of mortality rates for GBC across the world for the period 1992–2002 demonstrated a decline in age-standardized mortality rates in most countries [8]. Better diagnostic modalities and changes in the ICD classification, as well as better treatment options, may have contributed to this trend. Seven years ago we published our first pooled analysis of clinical trials in this disease. We demonstrated that regimens based on gemcitabine (G) combined with platinum (P) compounds, i.e. cisplatin and oxaliplatin, were most effective concerning response rate (RR) and tumor control rate (TCR) [9]. The randomized phase III ABC-02 trial published in 2010 confirmed our results and demonstrated significant prolongation of survival by G plus cisplatin compared to G alone [10]. Based on this trial, GP is the standard chemotherapy in BTC. Progress has been made in the last decade to identify effective targeted therapies in many cancers. Some years ago we published a review of emerging drugs for biliary cancer [11]. New derivatives, such as the oral fluoropyrimidine (F) S1, have been developed from 5-fluorouracil, and new classes of drugs have been introduced, such as antibodies (mabs) and kinase inhibitors (nibs) – so-called biologicals (bio). Mabs and nibs act against defined molecular targets, such as EGFR, VEGF or the RAS-MAPK pathway [12]. However, for separate analysis of a new agent subgroup, the number of trials and patients was too low in our first pooled analysis of clinical trials. The aim of this study was to analyze recently published clinical trials, even those small and nonrandomized, with a focus on GP as well as on new agents. If possible, we also aimed to identify new regimens superior to GP, which is the current standard of care as palliative chemotherapy in advanced BTC.
100
Single trial arm
90
95% CI
80
95% CI
Pooled RR
70
RR (%)
60 50 40 30 20 10 0 0
20
40
60
a
80
100
120
140
160
180
Patients (n) 100 90 80 70
TCR (%)
60 50 40 30
Single trial arm
20
Fig. 1. RR (a) and TCR (b) of all trials ana-
lyzed, sorted by the number of patients. The horizontal gray line represents the pooled RR of all patients (20.6%) and the pooled TCR (60.6%), respectively. The limits of the 95% CI calculated with the corresponding number of patients are shown by gray curved lines.
95% CI Pooled TCR
10
95% CI
0 0
20
40
60
b
80
100
120
140
160
180
Patients (n)
Table 1. Outcome parameters of all trials and patients analyzed
All trials
RR
TCR
TTP
OS
Trial arms, n Patients, n Median Mean
181 6,337 20.0% 20.6% (19.6–21.6)
163 5,825 60.0% 60.6% (59.3–61.8)
140 5,282 4.1 months
154 5,744 8.8 months
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
15
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Mean values are given with 95% CI in parentheses.
100
RR Pooled RR
90 80 70
RR (%)
60 50 40 30 20 10
a
0
Single trial arms
100
TCR Pooled TCR
90 80 70
TCR (%)
60 50 40 30 20 10
b
0
of the RR and TCR, with corresponding 95% CI, of all the trials analyzed. The RR of 12 trials was higher than the calculated 95% CI of the pooled RR with the same number of patients (above the gray line indicating the upper 95% CI in fig. 1a). All 12 trials evaluated a combination of at least two drugs: 11 regimens containing P, 8 regimens containing G, 4 containing F, and 3 containing targeted therapy (cetuximab, panitumumab, erlotinib) combined with G-based chemotherapy. Twenty-one trials had a high TCR above the 95% CI of the corresponding pooled TCR. Among these 21 trials were 18 regimens containing 16
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
Single trial arms
G, 13 containing P, 11 containing F, and 8 containing targeted therapy (cetuximab, panitumumab, bevacizumab, erlotinib, sorafenib) combined with G-based chemotherapy. Among trials with inferior RR or TCR lower than the calculated 95% CI of the pooled RR or TCR, were trials evaluating monotherapy of G or F, new agents (rebeccamycin, exatecan, dolastatin, ixabepilone, bendamustine) and targeted therapy without a chemotherapy backbone (lapatinib, sorafenib, erlotinib, sunitinib, sirolimus), as well as trials evaluating second-line therapy. The outcome parameters RR, TCR, TTP and OS were all significantly correlated (p = 0.000). Correlation coefEckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Fig. 2. Waterfall plots of RR (a) and TCR (b) with 95% CI of all trials analyzed. The horizontal black line represents the pooled RR of all patients (20.6%) and the pooled TCR (60.6), respectively.
15
r = 0.72, p = 0.000
TTP (months)
12
9
6
3
0 0
a
20
40
60
80
100
60
80
100
TCR (%) 24
r = 0.59, p = 0.000
21
18
OS (months)
15 12 9 6 3 0
b
0
20
40 TCR (%)
ficients ranged from r = 0.48 (RR – OS) to r = 0.78 (TTP – OS). Figure 3 shows TCR and its correlation with TTP and OS, respectively. Initial subgroup analysis focused on the current standard therapy, GP. The pooled RR was 24.1% (95% CI
22.1–26.3) and the pooled TCR was 62.8% (95% CI 60.4– 65.2). The median TTP and OS were 5.3 and 9.5 months, respectively (table 2). There was no trial evaluating targeted therapy by means of mabs and nibs (bio) in combination with F without G, and the results of trials of
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
17
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Fig. 3. Chart showing the correlation between TCR and TTP (a) and OS (b).
Table 2. Outcome parameters of all trials and patients evaluating G plus P
GP
RR
TCR
TTP
OS
Trial arms, n Patients, n Median Mean
36 1,599 25.9% 24.1% (22.1–26.3)
36 1,641 63.5% 62.8% (60.4–65.2)
33 1,484 5.3 months
35 1,566 9.5 months
Mean values are given with 95% CI in parentheses.
Table 3. Outcome parameters of all trials and patients evaluating G, an F and P triplets (GFP), as well as targeted
therapy combined with G-based chemotherapy (bioG) RR
TCR
TTP
OS
GFP Trial arms, n Patients, n Median Mean
9 373 30.4% 25.7% (21.4–30.5)
8 317 78.6% 73.2% (67.9–78.0)
5 215 9.0 months
5 215 12.5 months
bioG Trial arms, n Patients, n Median Mean
14 546 30.0% 28.8% (25.0–32.8)
12 481 79.2% 75.7% (71.6–79.4)
11 535 7.1 months
11 526 12.7 months
Mean values are given with 95% CI in parentheses.
18
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
pared to GF there was a (nonsignificant) trend toward better results for the GFP and bioG subgroups. Concerning RR, all differences were small and not statistically significant.
Discussion
This pooled analysis of all published clinical trials since 2000 showed that triplet chemotherapy with G, an F and P compared to standard palliative chemotherapy (GP) increases tumor control (TCR, TTP) and OS in advanced BTC. Furthermore, we could demonstrate that Gbased chemotherapy in combination with targeted therapy is significantly superior compared to GP concerning tumor control and OS. The present analysis is our second systematic review of clinical trials of palliative therapy in BTC. A total of 161 trials comprising 181 trial arms and 6,337 patients were included and analyzed. The pooled RR of all patients was 20.6%, which is lower than the RR of our first Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
targeted therapy without an effective chemotherapy backbone were dismal (data not shown). Therefore, we continued to analyze subgroups defined by G, F and P without new agents, as well as defined by targeted therapy combined with G-based chemotherapy (bioG: cetuximab, n = 6; panitumumab, n = 3; erlotinib, n = 3; bevacizumab, n = 2; sorafenib, n = 1). The chemotherapy backbone of the bioG subgroup was G alone in one trial only. In the other trials, G was combined with other drugs (oxaliplatin, n = 11; cisplatin, n = 1; capecitabine, n = 2; irinotecan, n = 1) or combinations of these drugs. The results (RR, TCR, TTP, OS) of the doublet GF were slightly better than those of the doublet GP, but differences were small and not statistically significant (p values ≥0.1; data not shown). Therefore, a combined subgroup comprising GP and GF doublets was defined (GP+GF). Next, the subgroups of triplet GFP as well as bioG were compared to GP, GF and GP+GF, respectively (table 3; fig. 4); all p values are listed in table 4. TCR, TTP and OS in the subgroups GFP and bioG were significantly better compared to GP and GP+GF. Com-
100
a
60
90
50
80
40
70
TCR (%)
RR (%)
70
30
60
20
50
10
40
b
0
Trials (n) (patients)
GP 36 (1,599)
GF 18 (639)
GFP 9 (373)
bioG 14 (546)
30
Trials (n) (patients)
15
GP 36 (1,641)
GF 15 (544)
GFP 8 (317)
bioG 12 (481)
GP 35 (1,566)
GF 17 (630)
GFP 5 (215)
bioG 11 (526)
27 24 21
9
OS (months)
TTP (months)
12
6
18 15 12 9
3
6
c
d
0
Trials (n) (patients)
GP 33 (1,484)
GF 15 (553)
GFP 5 (215)
bioG 11 (535)
3
Trials (n) (patients)
Fig. 4. Boxplots of the outcome parameters RR (a), TCR (b) TTP (c) and OS (d). The width of the boxes correlates with the number of
analysis (22.6%). In contrast, TCR increased to 60.6% compared to our first analysis, which found a lower TCR of 57.3%. Median TTP was unchanged (4.1 months for both) and median OS increased from 8.2 to 8.8 months. The results of the present analysis confirm the results of our first study, suggesting an improvement in therapies over the last 7 years concerning TCR and OS, but not RR. Our pooled analysis published in 2007 provided the first evidence that a chemotherapy consisting of G combined with P improves survival in advanced BTC [9]. Our
results were confirmed in 2010 when the results of the large phase III ABC-02 trial evaluating G with or without cisplatin were fully published. This trial demonstrated an increased RR (26 vs. 16%), TCR (81 vs. 72%), PFS (8.0 vs. 5.0 months) and OS (11.7 vs. 8.1 months) by the addition of cisplatin to G, despite rather good results in the Galone arm, defining a new standard in palliative chemotherapy in BTC [10]. The pooled results of GP chemotherapy in the present analysis were inferior, with RR 24%, TCR 63%, TTP 5.3 months and OS 9.5 months. The remarkably high TCR and long OS of the ABC-02 trial
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
19
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
trials. p values are listed in table 4.
GP
GF
GP+GF
0.348 0.370
0.743 0.621
0.421 0.408
0.001 0.001
0.076 0.064
0.004 0.002
0.000 0.002
0.002 0.069
0.001 0.003
0.003 0.017
0.164 0.278
0.016 0.036
RR GFP bioG TCR GFP bioG TTP GFP bioG OS GFP bioG
could not be reproduced in other trials evaluating GP chemotherapy. Chemotherapy of many solid cancers is traditionally based on 5-fluorouracil. Regimens have evolved from simple bolus to sophisticated combination regimens, such as FOLFOX, FOLFIRI or FOLFIRINOX [16]. Furthermore, the oral F S1 [17], capecitabine and UFT [18] have been developed. Therefore, we analyzed the subgroup of trials evaluating doublets of G and F. Interestingly, the results of GF were largely similar to or even better by trend than those of GP. Thus, to identify new superior regimens, we compared the triplet combination GFP with GP as the current standard, as well as GF and a combined subgroup of GP and GF doublets for a larger number of trials and patients in order to enhance statistical power. Only a few trials evaluated GFP, but results were promising with significantly superior tumor control (TCR, TTP) and OS compared to GP and GP+GF. There was no randomized trial evaluating GFP. The toxicity of GFP varied from ‘well tolerated’ to ‘tolerable but substantial’, which was nevertheless increased compared to doublets. The hematologic toxicity grade 3/4 was 24–37% (neutropenia) and 12–36% (platelets). Targeted therapy by means of mabs or nibs acting against molecular defined targets has evolved in the last 2 decades [12]. Targeted therapy is now the standard of care in some solid cancers. Targeted therapy alone is sufficient in some cancers, e.g. sorafenib in HCC, or under some circumstances, e.g. panitumumab last line for KRAS wild-type metastatic colorectal cancer after other drugs have failed. However, targeted therapy in combination with an effective chemotherapy backbone is generally 20
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
more active [19]. Therefore, we identified targeted therapy in combination with G-based chemotherapy (bioG) as a subgroup for further analysis. It is noteworthy that the majority of trials in this subgroup evaluated G combined with oxaliplatin plus targeted therapy. Genetics of BTC have been reviewed recently [20]. According to the mutational spectrum of oncogenes in BTC and available drugs, the molecular target of trials evaluating bioG was mostly EGFR. Activating mutations in KRAS, which result in constitutive activation of the RAS-RAF-ERK pathway, result in resistance to anti-EGFR therapy [21]. KRAS mutations were found in 10–64% of the trials in the present analysis. KRAS wild-type was an inclusion criterion in two trials. The present analysis demonstrated significantly superior tumor control (TCR, TTP) and OS of trials evaluating bioG treatment compared to GP and GP+GF. Three of the bioG trials were randomized trials. One of these was recently fully published by Lee et al. [15], who reported the results of a phase III trial evaluating G and oxaliplatin with or without erlotinib in BTC. Erlotinib significantly increased the RR (30 vs. 16%, p = 0.005) and prolonged PFS (5.8 vs. 4.2 months, HR 0.80, p = 0.087). No difference concerning TCR and OS was noted among the 268 patients enrolled. The other two randomized trials were phase II trials presented at ASCO meetings. The TCOG trial evaluated GemOx with or without cetuximab. TCR (82 vs. 60%, p = 0.009) and PFS (7.1 vs. 4.0 months, p = 0.007) were significantly superior in the cetuximab arm [22]. KRAS mutated tumors benefited more from cetuximab therapy (TCR 78 vs. 38%, p = 0.013, PFS 7.0 vs. 1.9 months, p = 0.035). However, results of the GemOx arm without cetuximab were remarkably poor and the number of patients accrued was adequate only for a phase II trial (n = 122; subgroup analysis with KRAS mutated tumors, n = 43). Another phase II trial evaluating GemOx with or without cetuximab found no differences in PFS and OS among the 150 patients enrolled [23]. However, results of the GemOx-only arm were remarkable, with a high TCR (77%) and a long OS (12.4 months). The classic endpoint of phase II trials was tumor response with complete and partial response evaluated after a defined number of treatment cycles. OS is the gold standard for the demonstration of a clinical benefit in phase III cancer trials. Despite a growing number of publications in this field there is no accepted surrogate endpoint in advanced BTC and other solid cancers [24]. Based on the results presented and the fact that most new targeted agents are more cytostatic as opposed to cytotoxic, tumor Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Table 4. p values of figure 4
control seems to be the more adequate endpoint compared to tumor response in phase II trials. The primary objective of phase II trials is to determine whether a new drug or regimen has sufficient activity. Statistical designs have been developed based on testing a null hypothesis (true response probability is less than some uninteresting level = response probability of a poor drug) and a specified alternative hypothesis (true response probability is at least some desirable target level = response probability of a good drug) [25]. Concerning TCR, we suggest a design with a response probability of at least 60% for ‘poor drug’. Alternatively, PFS at 4 or 6 months reflects tumor control too and may be an adequate surrogate endpoint. Based on our data, a 5-month PFS of at least 50% for ‘poor drug’ may be reasonable. Considering the wide range of the results presented, the 6-month PFS of 59% in the G plus cisplatin arm of the ABC-02 trial was rather high. This level seems to be too high for the probability of a poor drug and may lead to negative trials, as others have recognized. A phase II trial evaluating G cisplatin plus sorafenib resulted in a high TCR (88%) and long TTP (8.2 months) and OS (14.4 months), but failed improvement of the primary endpoint 6-month PFS from 57 to 77% [26]. The development of cytotoxic chemotherapy in BTC was traditionally influenced by regimens in pancreatic cancer. Recently, the triplet FOLFIRINOX has been proven to be superior compared to G in pancreatic cancer at the cost of increased toxicity [27]. In the present analysis, the triplet GFP was superior compared to GP, also at the cost of increased toxicity, and may be an option for patients with a good performance status. However, phase III trials evaluating GFP are lacking. Considering toxicity, GF may be an option compared to GP, especially for patients with neuropathy or renal insufficiency. Most recently, G plus nab-paclitaxel was superior compared to G alone in a phase III trial, but the rates of peripheral neuropathy and myelosuppression were increased [28]. It remains questionable whether or not regimens that are effective in pancreatic cancer are worthy of evaluation in BTC. Transfer of successful regimens from one cancer to another was reasonable for the development of cytotoxic drugs in the past, but current development of molecular targeted therapy follows other principles [29]. The evidence level of the present pooled analysis of predominately rather small phase II trials remains limited. However, the results of our first pooled analysis have been confirmed by a phase III trial. It remains unclear which P, which F and which targeted therapy is optimal, and which schedule of administration should be used.
In conclusion, we suggest a chemotherapy triplet of G, an F and P, as well as EGFR targeted therapy combined with G-based chemotherapy, as the most active in advanced BTC, and therefore a standard option for patients with a good performance status. The doublet G plus an F seems to be at least as active as the doublet G plus P, and may be an option with more favorable toxicity for some patients.
Pooled Analysis of Chemotherapy in BTC
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
Abou-Alfa, G.K., Am J Clin Oncol, 2005. Alberts, S.R., Cancer, 2005. Alberts, S.R., Int J Gastrointest Cancer, 2002. Alberts, S.R., J Gastrointest Cancer, 2007. Andre, T., Br J Cancer, 2008. Andre, T., Ann Oncol, 2004. Androulakis, N., Oncology, 2006. Bekaii-Saab, T., J Clin Oncol, 2011. Bengala, C., Br J Cancer, 2010. Berglund, A., Med Oncol, 2010. Bhargava, P., Oncology, 2003. Borbath, I., Ann Oncol, 2013. Buzzoni, R., ASCO Meeting Abstracts, 2010. Charoentum, C., ASCO Meeting Abstracts, 2013. Chatni, S.S., J Cancer Res Ther, 2008. Chen, J.S., Cancer Chemother Pharmacol, 2009. Chen, J.S., Anticancer Drugs, 2001. Chen, J.S., Jpn J Clin Oncol, 2003. Chen, L.-T., ASCO Meeting Abstracts, 2013. Chiorean, E.G., Oncologist, 2012. Cho, J.Y., Yonsei Med J, 2005. Cho, J.Y., Cancer, 2005. Choi, C.W., Am J Clin Oncol, 2000. Chung, M.J., Chemotherapy, 2011. Ciombor, K.K., ASCO Meeting Abstracts, 2012. Ciuleanu, T., Invest New Drugs, 2007. Doval, D.C., Br J Cancer, 2004. Dowlati, A., Cancer Chemother Pharmacol, 2009. Ducreux, M., Eur J Cancer, 2005. Eckel, F., Ann Oncol, 2000. El-Khoueiry, A.B., Br J Cancer, 2014. El-Khoueiry, A.B., Invest New Drugs, 2012. Eng, C., Am J Clin Oncol, 2004. Feisthammel, J., Am J Clin Oncol, 2007. Ferrari, V.D., Am J Clin Oncol, 2004. Fiebiger, W.C., Scand J Gastroenterol, 2002. Furuse, J., Cancer Chemother Pharmacol, 2008. Furuse, J., Jpn J Clin Oncol, 2006. Furuse, J., Cancer Chemother Pharmacol, 2009. Gallardo, J.O., Ann Oncol, 2001. Gebbia, V., J Clin Oncol, 2001. Gelibter, A., Cancer, 2005. Giuliani, F., Ann Oncol, 2006. Goldstein, D., Cancer Chemother Pharmacol, 2011. Gruenberger, B., Lancet Oncol, 2010. Halim, A., Jpn J Clin Oncol, 2011. Harder, J., Br J Cancer, 2006. Hong, Y.S., Cancer Chemother Pharmacol, 2007. Hsu, C., Br J Cancer, 2004. Ikeda, M., Jpn J Clin Oncol, 2005. Iqbal, S., Cancer Chemother Pharmacol, 2011. Iyer, R.V., Ann Surg Oncol, 2007. Jang, J.S., Cancer Chemother Pharmacol, 2010. Jensen, L.H., Ann Oncol, 2012. Jensen, L.H., ASCO Meeting Abstracts, 2014. Julka, P.K., Hepatobiliary Pancreat Dis Int, 2006. Kameda, R., Jpn J Clin Oncol, 2013. Kanai, M., Cancer Chemother Pharmacol, 2012. Kanai, M., Cancer Chemother Pharmacol, 2011. Kang, M.J., Acta Oncol, 2012. Karachaliou, N., Oncology, 2010. Kim, H.J., Cancer Chemother Pharmacol, 2009. Kim, K.P., Br J Cancer, 2011. Kim, S.T., Cancer, 2006. Kim, T.W., Ann Oncol, 2003. Kim, Y.J., Ann Oncol, 2008. Kindler, H.L., Invest New Drugs, 2005. Knox, J.J., J Clin Oncol, 2005. Knox, J.J., Ann Oncol, 2004. Kobayashi, K., BMC Cancer, 2006. Koeberle, D., J Clin Oncol, 2008. Kornek, G.V., Ann Oncol, 2004. Kruth, J., J Cancer Res Clin Oncol, 2010. Kubicka, S., Hepatogastroenterology, 2001. Kuhn, R., Invest New Drugs, 2002. Lamarca, A., ASCO Meeting Abstracts, 2014. Lassen, U., Acta Oncol, 2011. Leal, J.L., ASCO Meeting Abstracts, 2014. Lee, G.W., Am J Clin Oncol, 2006. Lee, J., Cancer Chemother Pharmacol, 2008. Lee, J., Lancet Oncol, 2012. Lee, J.E., ASCO Meeting Abstracts, 2012. Lee, J.K., Br J Can-
21
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
Appendix
cer, 2013. Lee, M.A., J Cancer Res Clin Oncol, 2004. Lee, S., ASCO Meeting Abstracts, 2011. Lee, S., Am J Clin Oncol, 2009. Lim, J.Y., Anticancer Drugs, 2008. Lim, K.H., Oncology, 2012. Lin, M.H., Chemotherapy, 2003. Lubner, S.J., J Clin Oncol, 2010. Mahipal, A., ASCO Meeting Abstracts, 2011. Malik, I.A., Am J Clin Oncol, 2003. Malik, I.A., Am J Clin Oncol, 2003. Malka, D., ASCO Meeting Abstracts, 2012. Manzione, L., Oncology, 2007. Meyerhardt, J.A., Dig Dis Sci, 2008. Morizane, C., Oncology, 2003. Morizane, C., Cancer Sci, 2013. Murad, A.M., Am J Clin Oncol, 2003. Nehls, O., Br J Cancer, 2002. Nehls, O., Br J Cancer, 2008. Nimeiri, H.S., Invest New Drugs, 2010. Noel, M.S., ASCO Meeting Abstracts, 2014. Novarino, A.M., Am J Clin Oncol, 2013. Ocean, A.J., Cancer Chemother Pharmacol, 2011. Oh, S.Y., Invest New Drugs, 2011. Oh, S.Y., Chemotherapy, 2008. Okusaka, T., Cancer Chemother Pharmacol, 2006. Okusaka, T., Br J Cancer, 2010. Papakostas, P., Eur J Cancer, 2001. Park, B.K., J Gastroenterol Hepatol, 2006. Park, J.S., Jpn J Clin Oncol, 2005. Park, K.H., Cancer, 2005. Park, S.H., Cancer, 2006. Patt, Y.Z., ASCO Meeting Abstracts, 2010. Patt, Y.Z., Cancer, 2004. Patt, Y.Z., Clin Cancer Res, 2001. Paule, B., Oncology, 2007. Peck, J., Oncology, 2012. Penz, M., Ann Oncol, 2001. Philip, P.A., J Clin Oncol, 2006. Ramanathan, R.K., Cancer Chemother Pharmacol, 2009. Rao, S., Br J Cancer, 2005. Riechelmann,
R.P., Cancer, 2007. Rizell, M., Int J Clin Oncol, 2008. Roth, A., Onkologie, 2011. Rubovszky, G., Eur J Cancer, 2013. Ryoo, H., ASCO Meeting Abstracts, 2011. Santini, D., Oncology, 2012. SanzAltamira, P.M., Ann Oncol, 2001. Sasaki, T., Cancer Chemother Pharmacol, 2010. Sasaki, T., Cancer Chemother Pharmacol, 2013. Sasaki, T., Invest New Drugs, 2012. Sasaki, T., Invest New Drugs, 2011. Schoppmeyer, K., Anticancer Drugs, 2007. Sebbagh, S., ASCO Meeting Abstracts, 2014. Sharma, A., J Clin Oncol, 2010. Sharma, A., Cancer Chemother Pharmacol, 2010. Sirohi, B., ASCO Meeting Abstracts, 2014. Sohal, D., ASCO Meeting Abstracts, 2012. Sohn, B.S., Tumori, 2013. Suzuki, E., Cancer Chemother Pharmacol, 2013. Taieb, J., Ann Oncol, 2002. Takezako, Y., Hepatogastroenterology, 2008. Thongprasert, S., Ann Oncol, 2005. Tsavaris, N., Invest New Drugs, 2004. Ueno, H., Br J Cancer, 2004. Valle, J., N Engl J Med, 2010. Verderame, F., Ann Oncol, 2006. von Delius, S., BMC Cancer, 2005. Wagner, A.D., Br J Cancer, 2009. Weatherly, J., ASCO Meeting Abstracts, 2011. Williams, K.J., HPB (Oxford), 2010. Woo, S.M., Gut Liver, 2013. Yamashita, Y., Anticancer Res, 2006. Yamashita, Y., Jpn J Clin Oncol, 2010. Yi, J.H., Eur J Cancer, 2012. Yokoyama, T., J Nippon Med Sch, 2012. Yonemoto, N., Jpn J Clin Oncol, 2007. Yoon, D.H., Invest New Drugs, 2011. Zhu, A.X., Lancet Oncol, 2010.
1 Patel T: Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33–42. 2 de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM: Biliary tract cancers. N Engl J Med 1999;341:1368–1378. 3 Rajagopalan V, Daines WP, Grossbard ML, Kozuch P: Gallbladder and biliary tract carcinoma: a comprehensive update, part 1. Oncology (Huntingt) 2004;18:889–896. 4 Pracht M, Le Roux G, Sulpice L, Mesbah H, Manfredi S, Audrain O, Boudjema K, Raoul JL, Boucher E: Chemotherapy for inoperable advanced or metastatic cholangiocarcinoma: retrospective analysis of 78 cases in a single center over four years. Chemotherapy 2012; 58:134–141. 5 Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba, II, Alonso de Ruiz P, Aristi Urista G, Nervi F: Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001; 51: 349–364. 6 Randi G, Franceschi S, La Vecchia C: Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006; 118:1591–1602. 7 Khan SA, Thomas HC, Davidson BR, TaylorRobinson SD: Cholangiocarcinoma. Lancet 2005;366:1303–1314. 8 Hariharan D, Saied A, Kocher HM: Analysis of mortality rates for gallbladder cancer across the world. HPB (Oxford) 2008;10:327–331. 9 Eckel F, Schmid RM: Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007;96:896– 902. 10 Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan
22
11 12
13
14
15
16
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273–1281. Eckel F, Schmid RM: Emerging drugs for biliary cancer. Expert Opin Emerg Drugs 2007; 12:571–589. Marino D, Leone F, Cavalloni G, Cagnazzo C, Aglietta M: Biliary tract carcinomas: from chemotherapy to targeted therapy. Crit Rev Oncol Hematol 2013;85:136–148. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216. Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR: 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. Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, Jang JS, Jeung HC, Kang JH, Lee HW, Shin DB, Kang HJ, Sun JM, Park JO, Park YS, Kang WK, Lim HY: Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012;13:181–188. Ychou M, Conroy T, Seitz JF, Gourgou S, Hua A, Mery-Mignard D, Kramar A: An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every
17
18
19
20 21
22
2 weeks in patients with advanced solid tumors. Ann Oncol 2003;14:481–489. Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M: Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7:548–557. Nakayama T, Noguchi S: Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan. Oncologist 2010;15:26–36. Bonetti A, Giuliani J, Muggia F: Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer. Anticancer Res 2014;34:423–434. Hezel AF, Deshpande V, Zhu AX: Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol 2010;28:3531–3540. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765. Chen L-T, Chen J-S, Chao Y, Tsai C-S, Shan Y-S, Hsu C, Huang S-F, Tsou H-H, Lee K-D, Chiu C-F, Rau K-M, Ho C-L, Yu M-S, Taiwan Cooperative Oncology Group: KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): the TCOG t1210 trial. J Clin Oncol 2013; 31(suppl):abstr 4018.
Eckel/Schmid
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
References
Pooled Analysis of Chemotherapy in BTC
25 Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10. 26 Lee JK, Capanu M, O’Reilly EM, Ma J, Chou JF, Shia J, Katz SS, Gansukh B, Reidy-Lagunes D, Segal NH, Yu KH, Chung KY, Saltz LB, Abou-Alfa GK: A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas. Br J Cancer 2013;109:915–919. 27 Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M: Folfirinox versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817–1825.
28 von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, van Cutsem E, Wei X, Iglesias J, Renschler MF: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691– 1703. 29 Izar B, Rotow J, Gainor J, Clark J, Chabner B: Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer. Pharmacol Rev 2013; 65: 1351–1395.
Chemotherapy 2014;60:13–23 DOI: 10.1159/000365781
23
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/4/2015 11:47:17 PM
23 Malka D, Fartoux L, Rousseau V, Trarbach T, Boucher E, de la Fouchardiere C, Faivre SJ, Viret F, Blanc J-F, Assenat E, Hammel P, Louvet C, von Wichert G, Ducreux M, Rosmorduc O, Pignon J-P, Greten TF: Gemcitabine and oxaliplatin (GEMOX) alone or in combination with cetuximab as first-line treatment for advanced biliary cancer: final analysis of a randomized phase II trial (BINGO). J Clin Oncol 2012;30(suppl):abstr 4032. 24 Piedbois P, Miller Croswell J: Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician’s perspective. Stat Methods Med Res 2008;17:519–527.
