Abstract
Evaluation of: Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273–1281 (2010).
Biliary tract cancer is a rare disease and it is associated with a poor clinical outcome and survival. A standard therapy has not been established yet. The evaluated article reports on the first Phase III randomized controlled multicenter trial (ABC-02 trial) on palliative chemotherapy for biliary tract cancer. A total of 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary cancer were included to receive either cisplatin followed by gemcitabine or gemcitabine alone for up to 24 weeks. The primary end point was overall survival and the secondary end point was progression-free survival. The median overall survival was 11.7 months in the cisplatin plus gemcitabine group and 8.1 months in the gemcitabine only group. The median progression-free survival was 8.0 months in the cisplatin plus gemcitabine group and 5.0 months in the gemcitabine-only group (p < 0.001). Adverse events were comparable in the two groups. Cisplatin plus gemcitabine, compared with gemcitabine alone, was associated with a significant survival advantage without an increase in substantial toxicity.
Methods & results
This multicenter trial (ABC-02 trial) Citation[1] was conducted as an extension of the Phase II trial (ABC-01 trial Citation[2]) that had already shown the benefit of cisplatin plus gemcitabine. Patients with different types of biliary malignancies, including intra- or extra-hepatic cholangiocarcinoma, gallbladder cancer and ampullary cancer, were included.
Patients were randomized to receive either cisplatin (25 mg/m2 body surface area) followed by gemcitabine (1000 mg/m2 body surface area) or gemcitabine (1000 mg/m2 body surface area) alone. Cisplatin and gemcitabine were administered on days 1 and 8 every 3 weeks. Gemcitabine alone was given on days 1, 8 and 15 every 4 weeks. Initial therapy was planned for 12 weeks on an outpatient basis. If patients did not have disease progression, according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 criteria after 12 weeks, therapy was extended up to 24 weeks. Treatment ended after 24 weeks or earlier owing to disease progression, patients or physicians choice or significant side effects. After documented disease progression, patients were only followed-up for survival. Analysis was performed on an intention-to-treat basis. In total, 410 patients from 37 centers in the UK were recruited; 204 patients received cisplatin plus gemcitabine and 206 patients received gemcitabine monotherapy. There was no statistical difference between both treatment groups. At the final analysis, 327 deaths had occurred and 362 patients had progressive disease, of whom 278 died. The median survival was 11.7 months (9.5–14.3 months) in the cisplatin plus gemcitabine group and 8.1 months (7.1–8.7 months; p < 0.0001) in the gemcitabine alone group. Progression-free survival was 8 months (6.6–8.6 months) in the cisplatin plus gemcitabine group, compared with 5 months (4–5.9 months) in the gemcitabine alone group. The duration of treatment was significantly higher in the cisplatin plus gemcitabine group, compared with the gemcitabine alone group (21 vs 14 weeks, respectively; p = 0.03), reflecting a lower rate of abortion of treatment owing to progressive disease (26 vs 49 patients, respectively). Significantly more patients in the cisplatin plus gemcitabine group than in the gemcitabine alone group continued treatment after the initial 12 weeks (63 vs 52%; p = 0.02). Tumor control, defined as stable disease, complete or partial response, was achieved in 81.4% of patients in the cisplatin plus gemcitabine group and in 71.8% of patients who received gemcitabine alone (p = 0.049). There were no differences in response rates between the subgroups of different tumor types. Adverse side effects of treatment were comparable in both treatment groups. In total, only one chemotherapy-associated death occurred because of renal failure in the cisplatin plus gemcitabine group.
Discussion
Biliary tract cancer is a relatively uncommon disease and if not resectable it is associated with a poor clinical outcome and survival. Standard therapy is not yet available. The most common therapy regimens are based on gemcitabine, 5-fluorouracil, oxaliplatine or photodynamic therapy in combination with endoscopic therapies, such as stenting, to resolve biliary obstruction. Liver function is critical for the survival of patients with biliary tract cancer. A significant impairment of liver function and infectious complications, such as cholangitis, preclude the use of chemotherapy. Therefore, adequate endoscopic biliary drainage is necessitated and should always be carried out in parallel with medical treatment Citation[3].
The result of the study, that the combination of cisplatin plus gemcitabine is superior to the treatment with gemcitabine alone in patients with advanced or unresectable biliary tract cancer, represents new important and clinically relevant information. A synergistic effect of cisplatin and gemcitabine has been proposed in vitro and in vivoCitation[4,5] and now this Phase III randomized controlled trial study proves the concept in the clinical setting. Recent Phase II trials did not include enough patients to draw significant therapeutic conclusions, although they showed similar results.
A potential limitation of the study is the heterogeneity of biliary tract malignancies that were included. The clinical courses of Klatskin tumors, intrahepatic cholangiocarcinoma and ampullary tumors are different and the range of clinical symptoms varies considerably. Ampullary tumors and extrahepatic bile duct cancers usually appear at an earlier stage with lower tumor mass because of symptoms, such as jaundice, appearing early. This is usually not the case for intrahepatic cholangiocarcinoma, which is usually diagnosed at a more advanced stage. However, subgroup analysis of the different tumor entities that were all diagnosed at an advanced stage, confirms the overall results. This finding is encouraging and represents important progress in the management of patients with cholangiocarcinoma.
The setup of the ABC-02 trial contains an interesting detail. Patients from the previous Phase II trial ABC-01 were included in the ABC-02 trial. Since the protocols are very similar and the inclusion and exclusion criteria exactly match, this is not disturbing. On the contrary, this design helped a rapid transition from the results of a Phase II trial into a Phase III trial Citation[6], by helping to include a larger number of patients.
In summary, the results of this trial indicate that the combination of cisplatin and gemcitabine should be considered as the current standard medical treatment for advanced biliary tract cancer, in addition to endoscopic biliary drainage.
Five-year view
The ABC-02 trial is a relevant step forward in the palliative therapy of biliary tract cancer. More studies of this size and quality in malignant biliary disease should be encouraged to help advance the management of patients affected by this malignant disease. In this trial, the maximum duration of treatment was 24 weeks and there are few previous data regarding the duration of chemotherapies in biliary malignancy. There is a need for second-line therapies for this condition. In addition to progress with chemotherapies, advances in endoscopic techniques, such as recent developments in cholangioscopy, will hopefully allow earlier detection of biliary tract cancers and permit biliary drainage, even in difficult cases Citation[7,8].
Key issues
• The ABC-02 Trial is the first available Phase III randomized controlled trial for chemotherapy in biliary tract cancer.
• Smaller previous trials provided similar information regarding chemotherapy options in biliary tract cancer, but were underpowered and were not sufficient to allow clinical conclusions to be drawn.
• Cisplatin plus gemcitabine, compared with gemcitabine alone, is associated with a significant survival advantage without significant aggravation of toxicity.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript
References
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