Chemotherapy and antiangiogenics in biliary tract cancer
Authors: Lipika Goyal, Dawn Q Chong, Dan G Duda, Andrew X Zhu
Journal: The Lancet Oncology (2015)

In the landmark phase 3 ABC-02 trial, Valle and colleagues1Valle J Wasan H Palmer DH et al.Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N Engl J Med. 2010; 362: 1273-1281Crossref PubMed Scopus (2668) Google Scholar established the combination of gemcitabine and cisplatin as the standard of care for first-line treatment of patients with advanced biliary tract cancer. This regimen showed a median overall survival of nearly 1 year, and based on this encouraging result, the combination of gemcitabine and platinum has emerged as the chemotherapy backbone for testing the addition of targeted treatments. Unfortunately, trials combining an anti-VEGF agent or an anti-EGFR agent with gemcitabine and platinum have yielded disappointing results,2Malka D Cervera P Foulon S et al.Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial.Lancet Oncol. 2014; 15: 819-828Summary Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 3Hezel AF Noel MS Allen JN et al.Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer.Br J Cancer. 2014; 111: 430-436Crossref PubMed Scopus (57) Google Scholar, 4Lee J Park SH Chang HM et al.Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study.Lancet Oncol. 2012; 13: 181-188Summary Full Text Full Text PDF PubMed Scopus (355) Google Scholar, 5Zhu AX Meyerhardt JA Blaszkowsky LS et al.Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study.Lancet Oncol. 2010; 11: 48-54Summary Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 6Lee JK Capanu M O'Reilly EM et al.A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas.Br J Cancer. 2013; 109: 915-919Crossref PubMed Scopus (93) Google Scholar but similar efforts with agents targeting alternative pathways are underway. With insufficient effective second-line systemic regimens in advanced biliary tract cancer, enhancing the efficacy of first-line treatment is a rational strategy to improve patient outcomes in this aggressive disease. In The Lancet Oncology, Valle and colleagues7Valle JW Wasan H Lopes A et al.Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.Lancet Oncol. 2015; (published online July 13.)http://dx.doi.org/10.1016/S1470-2045(15)00139-4PubMed Google Scholar report the results of the ABC-03 trial, a randomised phase 2 trial of gemcitabine and cisplatin with or without cediranib in the first-line treatment of patients with advanced biliary tract cancer. Cediranib is an oral potent inhibitor of the VEGF receptor tyrosine kinases. The strategy of simultaneously targeting the tumour microenvironment with antiangiogenic treatment and tumour cells with chemotherapy has improved patient survival in advanced colon, lung, gastric, and ovarian cancers. However, similar to other trials of anti-VEGF treatment in advanced biliary tract cancer, the ABC-03 trial was negative and findings showed no difference in the primary endpoint, progression free survival, between the two groups (HR 0·93, 95% CI 0·65–1·35; p=0·72). Why did the addition of cediranib fail in this context? First, the combination of chemotherapy with kinase inhibitors of VEGF pathway have largely been ineffective across disease types and have not matched the efficacy of anti-VEGF and anti-VEGFR antibodies in a similar setting. These findings might be due to differential mechanisms of action and increased off-target effects with kinase inhibitors. Second, the lack of validated predictive biomarkers for the identification of patients likely to benefit from cediranib led to an unselected study population. Most previous clinical trials including anti-VEGF agents in advanced biliary tract cancer were also done in unselected populations and have not reported analysis of VEGF-related biomarkers. A randomised phase 2 trial8Moehler M Maderer A Schimanski C et al.Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme.Eur J Cancer. 2014; 50: 3125-3135Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar of gemcitabine with or without sorafenib showed that PDGFR-β expression in tumour stroma was associated with improved progression-free survival, but this result has not been further validated. Similarly, studies of cediranib in other cancers have not shown consistent predictive biomarkers that could be used for future trials. Valle and colleagues should be commended for reporting circulating biomarker analysis in the largest cohort of patients with advanced biliary tract cancer in a trial of antiangiogenic treatment so far. Additional data for outcomes by anatomic location might also yield hypotheses regarding subpopulations likely to benefit from cediranib. Third, the toxic effects of cediranib could have limited drug exposure. Frequencies of grade 3 and 4 adverse events related to VEGFR inhibition were significantly higher in the cediranib group than the placebo group including hypertension and diarrhoea. Patients who received cediranib more frequently required at least one dose reduction compared with placebo from the already attenuated dose of 20 mg once a day. Fourth, VEGF inhibition could have paradoxically fuelled tumour growth and led to chemoresistance. Although objective responses were more common in the cediranib group than in the placebo group, the duration of response was longer in the placebo group. Several explanations could account for this, including random statistical error, but one explanation could be that cediranib-induced vascular pruning initially led to tumour regression but the ensuing hypoxia ultimately promoted tumour progression. Increasing evidence has shown that hypoxia can create a hostile environment that promotes tumour growth by inducing angiogenesis, genetic instability, cancer cell invasion, stem-like phenotype, epithelial-to-mesenchymal transition, and resistance to apoptosis.9Jain RK Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia.Cancer Cell. 2014; 26: 605-622Summary Full Text Full Text PDF PubMed Scopus (941) Google Scholar The success of antiangiogenic drugs could rest on achieving balance between therapeutic and pathological angiogenesis in which tumour vascular normalisation rather than vascular pruning is the goal. In view of the negative results of several anti-VEGF agents in advanced biliary tract cancer, future efforts with randomised trials should aim to use alternative strategies (eg, anti-VEGFR antibodies), inhibit alternative targets in angiogenesis, or use a biomarker-driven trial design to select patients likely to benefit from this strategy. Two merits of the ABC-03 trial deserve comment. First, the researchers are to be commended for requiring a high threshold of activity to declare the trial positive. With less than 5% of positive phase 2 combination therapy trials eventually improving the standard of care in oncology,10Maitland ML Hudoba C Snider KL Ratain MJ Analysis of the yield of phase II combination therapy trials in medical oncology.Clin Cancer Res. 2010; 16: 5296-5302Crossref PubMed Scopus (39) Google Scholar aiming for a large effect size can ultimately save resources and protect patients from receiving ineffective, toxic regimens in futile phase 3 trials. However, the design of a robust randomised phase 2 trial can necessitate a large sample size, a challenge in a rare cancer like advanced biliary tract cancer. The ABC investigators addressed this issue with their second merit: collaboration. The consortium they have developed in the UK allowed them to accrue 124 patients across 14 centres in 18 months and collect blood for biomarker analysis from many of these patients. This structure can serve as a model for other countries to execute efficient trials with generalisable results in advanced biliary tract cancer. In conclusion, gemcitabine and platinum will remain the standard first-line treatment for patients with advanced biliary tract cancer. Further efforts to characterise the biology of both the tumour and its microenvironment in advanced biliary tract cancer, coupled with well-designed clinical trials, will hopefully bring us closer to finding the next effective treatment in this disease. We declare no competing interests. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trialCediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational. Full-Text PDF Open Access