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Page 8 of 19 Hewitt et al. Hepatoma Res 2021;7:75 https://dx.doi.org/10.20517/2394-5079.2021.83

Periampullary carcinomas arise within 2 cm of the major duodenal papilla and include 4 possible sites of
origin: biliary tract (periampullary CCA), pancreas, ampulla of Vater, and duodenum. Survival rates for
ampullary and duodenal cancers are highest, followed by periampullary CCAs and pancreatic cancer. The
majority of these cancers (80%) are resectable at the time of diagnosis. Like DCCA, the preferred surgical
approach for periampullary CCA is pancreaticoduodenectomy. Transduodenal ampullectomy has been
performed in highly selected patients with T1 disease. However, due to early lymph node metastases, over
10% in some series, even for these early-stage tumors, such local approaches carry higher risks of local
recurrence and worst survival [117,118] .

ADJUVANT THERAPY
Surgical resection for CCA offers the best chance for long-term survival, yet recurrence rates remain high,
suggesting the need for more effective systemic therapy . The low prevalence of biliary tract malignancies
[119]
makes it rather difficult to study and find effective therapies. Clinical trials of adjuvant chemotherapy and
radiation are limited. Additionally, in order to achieve sufficient statistical power, these studies often include
[120]
a heterogenous cohort with ICCA, extrahepatic cholangiocarcinoma (ECCA), and gallbladder cancers . In
addition to studies having mixed pathologies, historically, studies of adjuvant therapy for biliary tract
cancers have been small, nonrandomized, and retrospective .
[121]

While population-based cohort studies support the use of adjuvant chemotherapy, the results of recent
randomized controlled trials demonstrate conflicting results . Horgan et al. performed a meta-analysis
[122]
[123]
on studies published between 1960 and November 2010 on adjuvant chemotherapy, radiotherapy, or both
compared with curative-intent surgery alone for resected biliary tract cancer. These authors reported a
nonsignificant improvement in OS with any adjuvant therapy compared with surgery alone (P = 0.06).
Patients who received chemotherapy or chemoradiotherapy had a greater benefit than individuals who
received radiation alone. The greatest benefit with adjuvant therapy was noted in patients with lymph node
[124]
metastasis or R1 resection . Ghidini et al. performed a meta-analysis of 50 studies including 22,499
[123]
patients, 3967 of which underwent surgical resection, to compare any adjuvant therapy, including
chemotherapy and chemoradiation, and found any use of adjuvant therapy increased survival by 4.3 months
compared to surgery alone.

The main deterrent to widespread acceptance of adjuvant therapy for biliary tract cancers has been the lack
of sufficient data from randomized clinical trials. Clinical trials such as ABC-02, PRODIGE-12/ACCORD-
18, and BILCAP have attempted to answer the need for effective adjuvant therapy [Table 1]. As there was no
established adjuvant chemotherapy for patients with resected pancreaticobiliary malignancies, in 2002,
Takada et al. investigated the use of mitomycin C at the time of surgery and 5-FU in 2 courses for 5
[125]
consecutive days during postoperative weeks 1 and 3, followed by 5-FU daily from postoperative week 5
until disease recurrence. In total, 436 patients were randomized: 158 patients with pancreatic
adenocarcinoma, 118 with bile duct cancer, 112 with gallbladder cancer, and 48 with cancer of the ampulla
of Vater. The 5-year OS was significantly better in patients with gallbladder cancer who received adjuvant
mitomycin C and 5-FU compared with control, but there was no difference in OS or DFS in patients with
pancreatic, bile duct, or ampullary cancer .
[125]

ABC-02
This phase III randomized clinical trial by Valle et al. was performed comparing cisplatin plus
[126]
gemcitabine vs. gemcitabine alone in patients with locally advanced or metastatic cholangiocarcinoma,
gallbladder cancer, or ampullary cancer. Four hundred and ten patients were randomized to receive
cisplatin plus gemcitabine for eight cycles or gemcitabine alone for six cycles for up to 24 weeks. The