Improving the standard of care for biliary tract cancers around the world
Biliary Tract Cancer (BTC) is a type of Hepato-pancreatico-biliary (HPB) cancer and is associated with high mortality. With around 2,500 in the UK affected by the disease each year, BTCs are relatively low-incidence malignancies in most high-income countries. However, incidence and causes vary between BTC subgroups and represent a major health problem in endemic areas such as Thailand and China where incidence is up to 40 times higher. With a rising global occurrence of BTCs, there has been a drive for our researchers in the field to improve patient outcomes.
BTCs in the past have just been considered too rare to do any research so we have gone for decades with no evidence or poor evidence-based studies on which to base our practice. This meant that it was difficult to establish standards of care for treatments in patients.
Consultant in Medical Oncology at The Christie
Professor Juan Valle
Juan Valle, Professor and Honorary Consultant in Medical Oncology, who has affiliations with both The Christie and the University of Manchester, has been leading a series of BTC clinical trials alongside other Medical Oncology clinicians including Dr Richard Hubner, Dr Mairéad McNamara and Dr Angela Lamarca.
Along with other oncologists, Juan realised that a main problem was a lack of collaboration in the field. As a result, he and others pushed for a UK collaboration which has now spread to an international level. This collaboration saw the start of using clinical trials to effect change of clinical practice around BTCs.
“The lack of collaboration was what really hampered us having standards of care for treatments for these patients,” he said.
Over the past two decades, Manchester researchers have developed a strong international reputation in HPB cancers such as cholangiocarcinoma (bile duct cancer) and continue to improve patient outcomes in this area.
The ABC-02 (Advanced Biliary Tract Cancer-02) trial, published in the New England Journal of Medicine, was the first practice-changing clinical trial in an ongoing series that demonstrated BTC trials could be carried out in countries of low incidence of the disease. The UK-wide study was the largest randomised clinical trial of its type and was funded by Cancer Research UK whereby Manchester clinicians and scientists collaborated to develop and enable the study of novel treatment options.
Historically there were only a few options to treat BTC due to its rarity, but the ABC-02 trial defined the global standard of care by providing level one trial evidence to show how BTC patients should be managed. This 410-patient trial set cisplatin and gemcitabine as the comparator drug for all treatments, on the basis of an improved overall survival. Since 2010 nothing has been shown to be superior to this for first-line therapy for advanced disease, and it is still the benchmark for future studies.
The ABC studies have continued as a series of clinical trials. The ABC-06 study which has recently been published in The Lancet Oncology has now set the standard of care for second-line chemotherapy with the drug combination FOLFOX (oxaliplatin and 5-fluorouracil) by demonstrating improved overall survival. Industry partners are now benchmarking findings of their own studies in the second line setting, using the robust results from the phase III ABC-06 study.
In addition, the BILCAP study acted to show that a six-month course of chemotherapy post-surgery improves patient survival. There was previously no evidence to show the best strategy after patients had received a potentially-curative operation for BTC. BILCAP randomised patients into two categories, these being: surgical follow-up only (no chemotherapy) and a six-month course of chemotherapy (capecitabine). Capecitabine was shown to be associated with an improved survival post-surgery when adjusted for prognostic factors. This study is now another international benchmark for treatment of care with the ACTICCA-1 study now comparing two chemotherapy drugs, cisplatin and gemcitabine, to capecitabine.
The importance of international collaboration
With the ABC-02, ABC-06 and BILCAP studies proving to be game changers in the management of BTC, the importance we place on international collaborations was signposted through these research exemplars.
The relatively low incidence of BTC in the UK makes progress in the understanding of the biology, natural history and treatment of BTC slow and laborious. Through international collaboration, this progress has been accelerated and streamlined (for example, by sharing data, peer reviewing proposed research and avoiding duplication of efforts).
Sharing these standards of practice and learnings was proven to be an important process in improving patient outcomes for everyone affected by cancer. These standards of care have been adopted into a number of guidelines on an international level, such as those in the US, France and Japan.
We’re in an era where we are looking at patients from a precision medicine point of view. The main challenge at the moment is to undertake molecular profiling and push to have that incorporated within standard NHS testing.
The team are now looking at how precision treatments can be improved through identifying BTC patients whose cancer falls within particular molecular subgroups.
The latest study in the ABC series, ABC-10, is in its early stages of development and is a joint collaboration with other countries which currently include France and Belgium. Our researchers are currently opening up discussions with Spain and Germany. This study will see patients undergo molecular profiling during their first induction chemotherapy. Subsequently patients will be offered maintenance therapy through a targeted therapy dependent on their molecular profile.
After recently receiving funding from Cancer Research UK and French and Belgium equivalents, this study should act as a collaborative basis upon which precision medicine in BTCs can be informed.
Manchester is already seen as a leader in the field of BTC with a focus on systemic therapies for both advanced disease and in the adjuvant setting (following curative surgery). Juan and the team aspire to extend this global leadership to radiation-based studies; strengthening basic and translational science as well as understanding how to harness the immune response in BTC.