REVIEW

How I treat biliary tract cancer

A. Lamarca1,2*, J. Edeline3 & L. Goyal4
1
Department of Medical Oncology, The Christie NHS Foundation, Manchester; 2Division of Cancer Sciences, University of Manchester, Manchester, UK; 3Department of
Medical Oncology, Centre Eugène Marquis, Rennes, France; 4Department of Medical Oncology, Mass General Cancer Center, Harvard Medical School, Boston, USA

Available online xxx

Management of biliary tract cancers (BTCs) is rapidly evolving. Curative management relies on surgical resection
followed by adjuvant capecitabine for cholangiocarcinoma and gallbladder cancers. Unfortunately relapse rate
remains high, and better adjuvant strategies are urgently required. A majority of patients are diagnosed with
advanced disease, when chemotherapy with cisplatin and gemcitabine followed by second-line 5-FU and oxaliplatin /
irinotecan is the cornerstone of treatment for most patients in the absence of targetable alterations. Targeted
therapies, including therapies for tumours with fibroblast growth factor receptor-2 (FGFR-2) fusions, isocitrate
dehydrogenase-1 (IDH-1) mutations, B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutations,
neurotrophic tyrosine receptor kinase (NTRK) fusions, Human epidermal growth factor-2 (HER-2) amplifications, and/
or microsatellite instability are rapidly changing the treatment paradigm for many patients with advanced BTC,
especially for patients with intrahepatic cholangiocarcinoma. Because of this, molecular profiling should be
considered early on patients pathway to allow adequate planning of therapy. Ongoing research is likely to clarify
the role of immunotherapy, liver-directed therapy, and liver transplant for BTCs in the future.
Key words: biliary tract cancer, cholangiocarcinoma, gallbladder cancer, ampullary cancer, treatment, chemotherapy,
surgery, targeted

INTRODUCTION addition, for those patients diagnosed in early stages,

Biliary tract cancers (BTCs) include cholangiocarcinoma relapse rate remains high at >50%. Thus the majority of
(CCA), gallbladder cancer (GBC), and ampullary tumours.1 patients will be ultimately managed with systemic therapy
CCAs can be subdivided depending on their location be- over the course of their disease, regardless of whether they
tween intrahepatic CCA (iCCA) and extrahepatic CCA present with advanced disease or develop recurrence after
(eCCA). eCCA can be also subdivided between hilar and surgery.
distal CCA depending on their location.2 It is important to
highlight that patients’ demographics, mode of presenta- DIAGNOSIS AND WORK-UP
tion, and tumour mutational profiles have both overlap and Diagnosis of CCA has traditionally been difficult due to the
distinctions within these subgroups (Figure 1). paucity of tissue obtained from fine-needle aspirates and
BTCs are rare cancers, with estimated incidence of <6 bile duct brushings, the lack of viable tumour cells in these
cases per 100 000 habitants.2 However, incidence is often desmoplastic tumours with significant necrosis, and
increasing, mainly due to an increased incidence of iCCA. the lack of a pathognomonic immunohistochemical stain or
BTCs are known to have a poor prognosis, with an esti- staining pattern.3 Core biopsies are therefore recommended
mated 5-year overall survival (OS) rate of <20% when all where feasible and safe, for both histologic confirmation and
stages are analysed together. This is attributable to the high obtaining sufficient tissue for molecular profiling in cases of
rate of diagnosis in the advanced stages, when the disease advanced disease. Cross-sectional imaging with compu-
is mainly managed by palliative therapeutic approaches. In terised tomography of the chest, abdomen, and pelvis and/
or magnetic resonance as needed are recommended for
complete staging. 18F-fluorodeoxyglucose positron emission
*Correspondence to: Dr Angela Lamarca, The Christie NHS Foundation Trust, tomography can be used for assessment of lymph node and
Wilmslow Road, M20 4BX Manchester, UK. Tel: þ44-(0)-161-446-3000; Fax: distant metastases and also to confirm disease recurrence if
þ44-(0)-161-446-3468
E-mail: [email protected] (A. Lamarca). the identification of occult sites of disease would change
management (i.e. surgery/local therapies) or if diagnosis
2059-7029/© 2021 The Author(s). Published by Elsevier Ltd on behalf of
European Society for Medical Oncology. This is an open access article under the of relapse remains unclear following standard of care
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). imaging.4

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ESMO Open A. Lamarca et al.

GALLBLADDER CANCER (GBC)

• Females > males

• Adenocarcinoma
• Risk factors: gallstones, gallbladder polyps, chronic

• Typically presented as incidental finding following

cholecystomectomy (localised stage) for abdominal
pain (advanced stage)
• Adjuvant chemotherapy (capecitabine-based)

• FOLFOX/FOLFIRI (nal-IRI)
chemotherapy

(47.1%–59%); (9.8%–19%);
CDKN2A/B loss (5.9%–19%); ARID1A

(1%–5.9%)

AMPULLARY CANCER
iCCA
• Adenocarcinoma
eCCA (HILAR/DISTAL) • Risk factors: polyposis syndromes (Lynch syndrome, • Adenocarcinoma
familial adenomatous polyposis), inflammatory • Risk factors: bile duct morphological anomalies,
• Adenocarcinoma bowel disease , cirrhosis, Lynch
• Risk factors: bile duct morphological anomalies, • Typically presented with syndrome, Opisthorchis viverrini, obesity, diabetes
, gallstones, Lynch (+/− PEI) • Typically presented as incidental finding or with
syndrome, Opisthorchis viverrini, obesity, diabetes • Adjuvant chemotherapy (5FU-based or abdominal discomfort, nausea, and weight loss
• Typically presented with gemcitabine-based) • Adjuvant chemotherapy (capecitabine-based)
• Adjuvant chemotherapy (capecitabine-based) .
5FU-based first-line treatment has also been • FOLFOX/FOLFIRI (nal-IRI)
• FOLFOX/FOLFIRI (nal-IRI) chemotherapy
chemotherapy adenocarcinoma • (liver-predominant disease)
• FOLFOX/FOLFIRI (nal-IRI) FGFR2 fusions (13%–14%);
chemotherapy
(21%); CDKN2A/B loss (17%), (4.9%–36%); (6.9%–36%);
(11%–17%); (12%); IDH1/2

CDKN2A/B loss (19%);

(13%–17%)

Figure 1. Biliary tract cancers (BTCs) are a heterogeneous group of malignancies.

5-FU, 5-fluorouracil; eCCA, extrahepatic cholangiocarcinoma; FOLFOX, 5-fluorouracil and oxaliplatin; FOLFIRI, 5-fluorouracil and irinotecan; iCCA, intrahepatic chol-
angiocarcinoma; nal-IRI, nanoliposomal irinotecan; PEI, pancreatic exocrine insufficiency. Adapted from Lamarca A, Frizziero M, McNamara MG, Valle JW. Clinical and
translational research challenges in biliary tract cancers. Curr Med Chem. 2020;27(29):4756-4777.

MANAGEMENT OF RESECTABLE DISEASE single-agent gemcitabine in the BCAT studydand showed no

A summary of the management algorithm for patients with benefit over observation alone.7 A recent meta-analysis of
BTCs, based on current scientific evidence and latest guide- these two studies confirmed such findings.8 However, and
lines recommendations, is provided in Figure 2. Surgery with based on the phase III randomised BILCAP clinical trial,5 which
curative intent is the current gold standard for patients who randomised patients to capecitabine or observation, current
are diagnosed with resectable disease.1 As mentioned guidelines do recommend the use of a 6-month period of
earlier, relapse rate remains high and ranges between 42% adjuvant capecitabine for resected CCA and GBC.9 This
and 70% based on latest data.5-7 recommendation stands despite the fact that the BILCAP
Following curative resection, including resections study did not meet its primary endpoint, OS in the intention-
achieving complete margin clearance (R0) or microscopic to-treat population. The study showed a median OS of 51.1
(R1) margin infiltration, current evidence supports the role months [95% confidence interval (CI) 34.6-59.1] in the
of adjuvant treatment for BTCs.7 capecitabine arm and 36.4 months (95% CI 29.7-44.5 months)
Since 2017, data from three phase III randomised studies in the control arm [hazard ratio (HR) 0.81, 95% CI 0.63-1.04;
evaluating adjuvant therapy after surgical resection of CCA P ¼ 0.097] and did show benefit for OS in the prespecified
and GBC have been reported. Two of these studies explored sensitivity analysis [53 months (95% CI 40 months-not
the role of gemcitabine-based adjuvant treatmentd reached) versus 36 months (95% CI 30-44 months), HR 0.75
gemcitabine and oxaliplatin in the PRODIGE-12 study and (95% CI 0.58-0.98); P ¼ 0.033]. The latter adjusted the

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A. Lamarca et al. ESMO Open

IS TUMOUR RESECTABLE?

YES NO

Proceed with surgery (curative intent) Proceed with palliative treatment

1. ECOG performance status

≥ 3)
2. Molecular profiling (FGFR-2, IDH-1, MMR, NTRK,
BRAF V600E, dMMR/MSI/TMB, HER-2)
3. (i.e. liver-predominant iCCA)

ADJUVANT THERAPY SYSTEMIC CHEMOTHERAPY IN DEVELOPMENT

• Adjuvant chemotherapy with 6 months 1st line: CisGem • Novel chemotherapy agents/
of capecitabine recommended for Gemcitabine alone if ECOG PS = 2
GBC and CCA • Liver directed therapies
• Consider chemoradiotherapy for eCCA
2nd line: FOLFOX/FOLFIRI (nal-IRI)

IMMUNOTHERAPY

• Adjuvant 5-fluorouracil-based or TARGETED THERAPIES (iCCA > others) PD-1 inhibitors:

gemcitabine-based chemotherapy for dMMR/MSI-high/TMB ≥ 10 mut/Mb
ampullary tumours FGFR inhibitors BRAF/MEK inhibitors
IDH-1 inhibitors HER-2 inhibitors
TRK inhibitors

Figure 2. Biliary tract cancers (BTCs): Diagnosis and management algorithm.

BRAF, B-Raf proto-oncogene serine/threonine kinase; CCA, cholangiocarcinoma; dMMR, deficient DNA mismatch repair; eCCA, extrahepatic cholangiocarcinoma; ECOG
PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; HER-2, human epidermal growth factor-
2; iCCA, intrahepatic cholangiocarcinoma; IDH-1, isocitrate dehydrogenase-1; MEK, mitogen-activated extracellular signal-regulated kinase; MSI, microsatellite insta-
bility; nal-IRI, nanoliposomal irinotecan; NTRK, neurotrophic tyrosine receptor kinase; TMB, tumour mutational burden; TRK, tyrosine receptor kinase. Adapted from2.

survival analysis for other prognostic factors such as nodal ampullary malignancies. In some centres, choice of chemo-
status, grade of disease, and gender. A current ongoing trial therapy may be driven by histological subtype (‘intestinal
is exploring the role of combination chemotherapy with type’ versus ‘pancreato-biliary type’ versus ‘indeterminate’).
cisplatin and gemcitabine (CisGem) in this setting compared
with capecitabine alone (ACTICCA-1; NCT02170090). In addi- MANAGEMENT OF ADVANCED DISEASE
tion, there is nonrandomised evidence to consider the use of
chemoradiotherapy for eCCA and GBC with R1 resection and/ Chemotherapy
or node positive disease.9,10 In the setting of advanced disease and adequate perfor-
For adjuvant therapy for ampullary tumours, the rando- mance status, CisGem is the current first-line standard of
mised phase III ESPAC-3 clinical trial recruited patients with care based on the survival benefit shown with this regimen
periampullary malignancies, including tumours from the over gemcitabine alone in the ABC-02 clinical trial.11 Esti-
ampulla of Vater.6 The study had three arms: adjuvant mated median progression-free survival (PFS) and OS with
gemcitabine, adjuvant 5-fluorouracil (5-FU), and a third arm CisGem in this trial were 8.0 months (versus 5.0 months
with observation alone. The use of 5-FU (compared with with gemcitabine alone; HR 0.63, 95% CI 0.51-0.77; P <
observation) did not reach statistical significance [HR 0.79, 0.001) and 11.7 months (versus 8.1 months with gemcita-
95% CI 0.58-18; P ¼ 0.13]. By contrast, the gemcitabine arm bine alone; HR 0.64, 95% CI 0.52-0.80; P < 0.001),
showed a reduction in risk of death compared with obser- respectively. In the event of performance status of 2, sig-
vation alone (HR 0.70, 95% CI 0.51-0.97; P ¼ 0.03). There are nificant comorbidities, or contraindication for cisplatin,
some challenges at the time to interpreting the ESPAC-3 single-agent gemcitabine is a reasonable option. Alternative
study. First, a variety of tumours besides ampullary malig- chemotherapy combinations are currently being explored,
nancies were included in the study. Second, the study was mainly in the form of triple chemotherapy schedules and
powered to identify an OS benefit when comparing the combinations of chemotherapy with immunotherapy. The
joined arms with adjuvant chemotherapy versus observation TOPAZ-1 trial comparing CisGem combined with durvalu-
alone; therefore the study was not powered to select the mab/placebo has been recently reported as positive, with
most effective adjuvant chemotherapy. Based on these full data awaited at the time of this publication.12 The
findings, use of 5-FU-based or gemcitabine-based adjuvant recently presented PRODIGE 38 AMEBICA study compared
chemotherapy can be considered following surgery for modified 5-FU, oxaliplatin, and irinotecan (mFOLFIRINOX)

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ESMO Open A. Lamarca et al.

with CisGem and did not meet its primary endpoint of on the results, performing such analyses at time of diag-
improving the 6-month PFS rate (44.6% with mFOLFIRINOX nosis or during first-line treatment of advanced disease is
versus 47.3% with CisGem).13 A third triplet regimen, Cis- recommended.19
Gem with nab-paclitaxel, achieved an objective response Selective FGFR inhibitors have shown significant activity
rate (ORR) of 45% in the evaluable population of a single- in patients with refractory advanced CCA harbouring
arm phase II study,14 and the results of the randomised an FGFR-2 fusion or other rearrangement, with multiple
phase III study (SWOG0809) of this regimen against CisGem ATP-competitive and covalently binding inhibitors in
in advanced BTC are awaited. development. Phase II single-arm registrational trials of
Following progression to first-line CisGem, second-line FGFR inhibitors in this population show an ORR of 23%-42%
treatment with 5-FU and oxaliplatin (FOLFOX) is consid- and a median PFS of 7-9 months.20-22 Currently, two of
ered current standard of care in patients with advanced BTC these compounds have been approved by regulatory
in the absence of targetable alterations or biomarkers that agencies: pemigatinib [Food and Drug Administration (FDA)
could predict response to immunotherapy (see “Targeted and European Medicines Agency (EMA) approved in 2020
treatments” and “Immunotherapy” sections below). The and 2021, respectively] and infigratinib (FDA approved in
ABC-06 trial showed that FOLFOX improved OS compared 2021).18
with active symptom control alone in patients with pro- For patients with advanced IDH-1-mutant CCA refractory
gression after CisGem (median OS: 6.2 versus 5.3 months, to one or two lines of systemic therapy, the IDH-1 inhibitor
respectively, adjusted HR 0.69, 95% CI 0.50-0.97; P ¼ ivosidenib has shown activity in the ClarIDHy phase III
0.031), with benefit also in the 6- (50.6% versus 35.5%) and clinical trial when compared with placebo.23 This study met
12-month (25.9% versus 11.4%) OS rate.15 Promising results its primary endpoint, showing an improvement in median
were recently presented for the phase II NIFTY study which PFS from 1.4 months with placebo to 2.7 months with
randomised patients to nanoliposomal irinotecan (nal-IRI) ivosidenib (HR 0.37, 95% CI 0.25-0.54; P ¼ 0.001), gaining it
and 5-FU versus 5-FU alone following progression after FDA approval in this setting. Median OS in the ivosidenib
CisGem treatment. The study met its primary endpoint arm was 10.3 months (95% CI 7.8-12.4 months) versus 7.5
showing a median PFS of 7.1 months in the combination months (95% CI 4.8-11.1 months) with placebo (HR 0.79,
arm versus 1.4 months with 5-FU alone (HR 0.56, 95% CI 95% CI 0.56-1.12; one-sided P ¼ 0.09). When adjusted for
0.39-0.81; P ¼ 0.0019)16; this study was conducted in a crossover, median OS with placebo was 5.1 months (95% CI
Korean population, and confirmatory studies in Western 3.8-7.6 months); HR 0.49 (95% CI 0.34-0.70; one-sided P <
population are likely to be required prior to considering this 0.001).24 Other targetable alterations include BRAF V600E
option as standard of care in view of discrepant results with mutations25 and NTRK fusions,26 and also HER-2 amplifica-
previous randomised phase II studies comparing FOLFOX tions27 and mutations.28 A recent phase II study exploring
and 5-FU and irinotecan (FOLFIRI) in advanced chemo- the combination of the BRAF inhibitor dabrafenib and the
refractory BTC, which showed similar outcomes with both MEK inhibitor trametinib in patients with BRAF V600E-
schedules.17 While these results are awaited, FOLFIRI (with mutated BTC reported an independent reviewer-assessed
irinotecan or nal-IRI if accesible), may be considered as a ORR of 51% (95% CI 36%-67%).25 Following a tumour-
treatment option if oxaliplatin contraindicated or in the agnostic approach, targeting NTRK fusions with tropomy-
presence of progression to oxaliplatin. osin receptor kinase (TRK) inhibitors such as larotrectinib
and entrectinib (both FDA and EMA approved) have re-
Targeted treatments ported an ORR of 57%-79% with a complete response rate
Targeted treatments following a precision medicine of 7%-16%.26,29 Finally, recent studies have explored the
approach have revolutionised the management of BTCs, HER2 pathway in patients with advanced BTC.27,28 The
especially iCCA.18 As mentioned previously, BTCs include a MyPathway study explored the activity of pertuzumab
heterogeneous group of malignancies that also differ in combined with trastuzumab in chemorefractory advanced
their mutational profiles (Figure 1). In iCCA, isocitrate BTC with HER-2 amplification, HER-2 overexpression, or
dehydrogenase-1 (IDH-1) mutations (15%-20% frequency) both, and the ORR was 23% (95% CI 11%-39%).27 For pa-
and fibroblast growth factor receptor-2 (FGFR-2) fusions tients with advanced BTCs harbouring an HER-2 mutation,
(10%-15%) are the most common actionable alterations. the ORR achieved with the pan-Her inhibitor neratinib was
Human epidermal growth factor-2 (HER-2) amplification 12% (95% CI 3%-31%), with tumour shrinkage enriched in
is more prevalent in eCCA and GBC but also seen in iCCA gallbladder and extrahepatic subtypes of BTC.28
(5%-15%). Finally, B-Raf proto-oncogene serine/threonine
kinase (BRAF) V600E mutations are seen across BTCs
(4%-5%). In addition, some tumour-agnostic approaches Immunotherapy
such as neurotrophic tyrosine receptor kinase (NTRK) may Pembrolizumab is indicated for patients with BTC deficient
play a role for a small proportion of patients with BTCs in mismatch repair proteins or with microsatellite
(<1%). To identify these potentially targetable alterations, instability-high tumours30; it is also FDA approved for tu-
performing molecular profiling for patients diagnosed with mours with high tumour mutational burden (10 mut/
CCA (especially iCCA) is now considered standard of care; to Mb).31 In addition, the TOPAZ-1 trial, as mentioned earlier,
allow adequate time to plan therapeutic strategies based explored the combinations of CisGem with durvalumab/

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A. Lamarca et al. ESMO Open

placebo in the frontline setting for advanced BTC in a of cure. In the advanced setting, chemotherapy with Cis-
biomarker-unselected population. The study was recently Gem followed by second-line FOLFOX is the cornerstone of
reported as positive, with full data awaited at the time of treatment for the majority of patients in the absence
this publication.12 Outside of this, the use of immuno- of targetable alterations. Targeted therapies are rapidly
therapy remains limited to clinical trials.2 changing the treatment paradigm for many patients with
advanced BTC, especially for patients with iCCA. Molecular
Other medical scenarios and treatment approaches to take profiling is therefore now the standard of care and should
into account be obtained early in patients’ care to allow adequate
planning of therapy. Ongoing research is likely to clarify the
Liver transplant. Liver transplant after neoadjuvant che-
role of immunotherapy, liver-directed therapy, and liver
moradiation in cases of unresectable, locally advanced transplant for BTCs. With the expanding treatment options
perihilar CCA has shown promising results in retrospective
for advanced BTC, identifying biomarkers to match patients
series and stands as an option for patients in some coun-
with the highest yield therapies will be critical for max-
tries.32-34 The role of liver transplant for iCCA has had
imising survival for patients with this disease.
limited study and remains controversial. A case series
demonstrated encouraging survival rates in a series of
FUNDING
carefully selected patients with advanced iCCA,35 but
definitive evidence to support the role of transplant for this This work was supported by The Christie Charity and the
indication remains unclear. European Union’s Horizon 2020 Research and Innovation
Programme [grant number 825510, ESCALON] to AL; this
Liver-directed therapies. It is expected that a significant article/publication is based on work from COST Action Eu-
proportion of patients with iCCA may present with multi- ropean Cholangiocarcinoma Network, supported by COST
focal liver disease in the absence of extrahepatic metasta- (European Cooperation in Science and Technology (no grant
ses.36 In this scenario, liver radioembolisation (selective number); www.cost.eu), a funding agency for research and
internal radiation therapy) has been explored in phase II innovation networks; the American Cancer Society Clinical
studies,37 including in combination with CisGem, and shown Scientist Development Grant [grant number 134013-CSDG-
benefit including conversion to resectable disease in some 19-163-01-TBG], the National Institutes of Health/National
patients. As it stands, the role of selective internal radiation Cancer Institute Gastrointestinal Cancer SPORE [grant
therapy remains investigational and to be used upon number P50 CA127003], V Foundation for Cancer Research
availability and adequate patient selection. Translational Grant (no grant number), and the Chol-
angiocarcinoma Foundation Andrea Marie Fuquay Research
Management of cancer-related complications: biliary
Fellowship (no grant number) to LG.
obstruction. Especially for patients with eCCA and ampul-
lary malignancies, obstructive jaundice at the time of
diagnosis is a common scenario. In addition, recurrence of DISCLOSURE
stent-related events such as stent obstruction or cholangitis AL has received travel and educational support from Ipsen,
during treatment may occur within a median time of 4.4 Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan, and Delcath;
months from first stent insertion in up to 43% of patients speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA,
with a metal stent in situ.38 Prompt identification and QED, Servier, and EISAI; advisory honoraria from EISAI,
management of such complications to avoid clinical dete- Nutricia Ipsen, QED, Roche, Servier, and Boston Scientific; is
rioration and life-threatening complications are critical. a member of the Knowledge Network and NETConnect
Initiatives funded by Ipsen. JE has received honoraria from
Pancreatic exocrine insufficiency for patients undergoing Servier, Incyte, Basilea, Boston Scientific, MSD, AstraZeneca,
Whipple resection. A proportion of patients with BTC, Roche, Eisai, Ipsen, and Bayer. LG reports research funding
mainly patients with distal CCA and ampullary tumours, (to the institution) from Adaptimmune, Bayer, Merck,
may undergo a Whipple resection with curative intent. In MacroGenics, Genentech, Novartis, Incyte, Loxo Oncology,
these scenarios, proactive management of pancreatic Relay Therapeutics, QED, Taiho Oncology, Leap Therapeu-
exocrine insufficiency and adequate dosing of pancreatic tics, Bristol Myers Squibb, NuCana, and Servier; honoraria
exocrine replacement therapy should be secured to enable (to self) for serving on scientific advisory committees or as a
a good quality of life and good treatment tolerance and to consultant from Alentis Therapeutics AG, Black Diamond,
minimise weight loss.39 Basilea, Genentech, Exelixis, H3Biomedicine, Incyte Corpo-
ration, QED Therapeutics, Sirtex Medical Ltd, The Servier
CONCLUSIONS AND FUTURE STEPS Group, Sirtex, and Taiho Oncology and participation on data
Management of BTCs is rapidly changing, with multiple safety monitoring boards for AstraZeneca.
clinical trials informing best practice. Curative management
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