Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_775_Библиотеки_им_академика_М_И_Перельмана.pdf
19 Recent Update inChemotherapy ofCholangiocarcinoma
167
p=0.031) in 162 CCA patients following progression after
rst-line gemcitabine/cisplatin therapy. Median OS
(months), 6m and 12m OS-rate (%) were 6.2 m, 50.6%,
and 25.9% for the mFOLFOX and 5.3m, 35.5%, and 11.4%
for the active supportive care, respectively. Other novel regimens, such as FOLFIRINOX (5-FU, irinotecan, and oxaliplatin) [15], and nal-irinotecan based regimens (the
NALIRICC trial; NCT03043547, the NAPOLI-2 trial;
NCT04005339) are currently under investigation as secondline chemotherapy for CCA.
19.3 Targeted Therapy
Recently the advent of next-generation sequencing has substantially improved the ability of scientists to understand the
complex molecular events occurring in CCA, including
interactions between gene mutations and disease risk factors.
Among the discoveries regarding the important mutations
associated with the pathogenesis of CCA are mutations in
isocitrate dehydrogenase (IDH) 1/2, as well as mutations in
the genes involved in chromatin remodeling, such as
ARID1A, PBRM1, and BAP1. The deregulation of several
growth factor tyrosine kinases, noted in various malignancies including CCA, also plays a critical role in tumor initiation and progression. These include the FGFR pathway and
EGFR and HGFR pathways. The most promising target for
CCA identied in recent years is within the FGF signaling
pathway.
Molecular proles of CCA have been recently investigated. In addition to the combination of cytotoxic
chemotherapeutic agents, combination regimen with target
agents was studied in several trials. A couple of studies evaluated possibility of growth factor inhibitors as combination
agent with conventional chemotherapeutic agents, such as
EGFR [16–18] and VEGF receptor inhibiting agents [19,
20]. However, there was not enough evidence yet to use these
target agents in advanced CCA.
Recent updates about fusion genes as therapeutic target of
CCA are notable. Research has shown that broblast growth
factor receptor (FGFR) or neurotropic tyrosine kinase receptor (NTRK) fusions and IDH-1/2 or BRAF mutations may be
potential therapeutic targets in CCA [21–23]. A phase II
study of BGJ398 [24], an pan-FGFR kinase inhibitor, has
shown clinical activity against CCA with FGFR alterations.
Sixty-one patients with FGFR2 fusion, mutation, or amplication were enrolled and the overall response rate was 14.8%,
disease control rate was 75.4%, and median PFS was
5.8months (95% CI, 4.3 to 7.6 months). Another phase II
trial with Derazantinib (ARQ 087) [25], a pan-FGFR kinase
inhibitor, presented encouraging anti-tumor activity with 29
iCCA patients with FGFR2 fusion. Overall response rate
was 20.7%, disease control rate was 82.8%, median PFS was
5.7months (95% CI: 4.04–9.2months). Currently, there are
several ongoing trials of FGFR inhibitors; Ingratinib, pemigatinib, and futibatinib have been studied in the Phase III
trials as rst-line therapy (NCT03773302, NCT03656536,
and NCT04093362). In the Phase III ClarIDHy trial [26],
ivosidenib (AG-120), a targeted inhibitor of mutated IDH1,
was evaluated in 230 patients with IDH1-mutant,
chemotherapy- refractory CCA. Median PFS was signicantly improved with ivosidenib compared with placebo (2.7
vs. 1.4 months; hazard ratio 0.37; one-sided p < 0.0001).
Other ongoing clinical trials targeting the IDH1 mutation in
CCA are also being investigated (NCT03212274 and
NCT03878095) and results are expected. However, FGFR
and IHD inhibitors have only proven to be effective in about
20% of iCCA patients with FGFR fusion and IHD mutations. Other druggable targets need to be developed to oppose
CCA for the future.
19.4 Immunotherapy
Advances in the eld of cancer immunology has made it possible to apply immunotherapy as a new therapeutic option for
CCA. Immunotherapy strengthens the immune system of
patients to struggle against cancer through personalized vaccination, adoptive immunotherapy, or immune checkpoint
inhibitor therapy. Pembrolizumab, an immune checkpoint
inhibitor that blocks programmed cell death 1 (PD-1) pathway
and its ligands (PD-L1 and PD-L2), has been reported as a
possible promising anti-tumor agent in patients with advanced
CCA in the interim results of the clinical trial, KEYNOTE-028.
In the study, objective response rate was 17% (four partial
response and four had stable disease) [27]. Recently, nal
result from the KEYNOTE-158 (NCT02628067; phase II)
and KEYNOTE-028 (NCT02054806; phase Ib) studies [28]
reported the efcacy and safety of pembrolizumab for the
treatment of advanced CCA. Total 104 patients from
KEYNOTE-158 and 24 patients from KENOTE-028 presented ORR; 5.8%, median OS/PFS; 7.5/2.0 months and
ORR; 13%, median OS/PFS; 5.7/1.8 months, respectively.
The response of pembrolizumab was not related to PD-L1
expression of the tumor.
The therapeutic efcacy of immunotherapy as monotherapy is a disappointment so far. Consequently, combinations
of immunotherapy and other therapies are under evaluation.
Nivolumab alone or in combination with cisplatin plus gemcitabine was tested in phase I trial with 30 advanced CCA
patients [29]. The median OS and PFS were much longer in
combined therapy cohort than nivolumab monotherapy (OS;
15.4 vs. 5.2months, PFS; 4.2 vs. 1.4months). In the phase I
JVDF study [30], ramucirumab, a VEFG inhibitor, in combination with pembrolizumab was used to treat advanced
CCA.Of the total 26 patients, objective response rate was
168
J. H. Jo et al.
4%. Median PFS and OS were 1.6months and 6.4months,
respectively. Immunotherapy and chemotherapy combinations are currently ongoing in phase III studies, TOPAZ-1
(Durvalumab with Gemcitabine/Cisplatin, NCT03875235)
and KEYNOTE-966 (Pembrolizumab with Gemcitabine/
Cisplatin, NCT04003636). In addition to the immune
checkpoint inhibitor, NK cell, T-cell, and dendritic cell based
therapies have been tested to treat CCA.Depending on the
ndings of ongoing research, immunotherapy may be a new
treatment option for CCA.
19.5 Precision Medicine
Personalized therapy has come into focus with the recent
advances in targeted therapy and immunotherapy, in conjunction to systemic chemotherapy or chemoradiation for the
treatment of CCA. Understanding the molecular pathways
associated with the development and progression of CCA
may help identify novel biomarkers and develop potential
therapeutic targets. With further development of gene
sequencing technic, it is expected that precision therapy will
be possible by judging the presence or absence of a specic
gene and selecting an optimized therapeutic drug accordingly. So far, most previous studies have viewed cholangiocarcinoma and gallbladder cancer as a group of biliary tract
cancers. However, recent studies revealed that molecular
proling of CCA is different from gallbladder cancer.
Furthermore, several studies reported that iCCA and eCCA
have different molecular features. Jusakul et al. reported
their research combining whole-genome sequencing and
epigenomic analysis of CCA with 489 patients from 10
countries [31]. In the study, CCA was subgrouped into four
clusters according to their molecular features. Cluster 1 comprised mostly uke positive tumors with enrichment of
ARID1A and BRCA1/2 mutations. Cluster 2 was characterized by a mix of uke positive and negative tumors with
upregulated CTNNB1, WNT5B, and NKT1. Clusters 1 and
2 were enriched in TP53 mutation and ERBB2 gene expression. Clusters 3 and 4 were mostly uke negative tumors,
and cluster 3 exhibited specic upregulation of immune
checkpoint genes; PD-1, PD-L2, and BTLA.Cluster 4 had
BAP1, IDH1/2 mutations, and FGFR alterations. Anatomical
classication of CCA was associated with clusters. Clusters
1 and 2 were enriched in eCCA, whereas clusters 3 and 4
consisted almost of iCCA.Moreover, iCCA was more frequently mutated in BAP1 and KRAS.Clinically, each clusters had different OS; clusters 3 and 4 had signicantly better
OS than clusters 1 and 2. These ndings suggest heterogenic
clinical features of CCA were also based on genetic and epi-
genetic variance of tumors, and further studies have to
focus on classifying subgroups according to treatment strategy and identifying novel therapeutic targets for personalized therapy.
19.6 Summary andConclusion
Adjuvant chemotherapy is effective in patients with CCA after
curative surgery, especially with lymph node-positive and
resection margin-positive disease. Although there are limited
clinical trial data to establish a standard chemotherapy regimen for CCA after surgery, current recommended regimens
are 5-FU-based or gemcitabine-based chemotherapies.
Palliative chemotherapy has an important role in the treatment of advanced and recurrent CCA. According to the
results of randomized controlled phase III trial, gemcitabine
plus cisplatin combination became the standard treatment
option for rst-line chemotherapy of advanced and metastatic CCA.The efcacy of second-line chemotherapy was
not denite until now. Novel targeted therapies reported
promising results especially with fusion gene targets in
iCCA but immunotherapies demonstrated disappointing
results so far.
Precision medicine is recently on the rise in addition to
cytotoxic systemic chemotherapy or chemoradiation. The
identication of novel therapeutic targets based on nextgeneration sequencing technology and immunologic assessment is actively being researched. In the future, anti-cancer
therapy for CCA will develop to identify specic genes
expressed in individual patients and provide personalized
therapies accordingly.
However, the therapeutic landscape for CCA has expanded
considerably in recent years after being nearly forgotten for
a few decades. Combined therapy with chemotherapy,
locoregional treatment, and immunotherapy are promising
strategies. The knowledge of the biology of CCA is still limited compared to that of other solid cancers, but the available
data on target therapies have added hopes for the future management of CCA and will likely continue to improve patient
outcomes. Results from ongoing clinical trials are eagerly
awaited to further elucidate the optimal management of this
aggressive malignancy.
References
1. Jo JH, Song SY. Chemotherapy of cholangiocarcinoma: current
management and future directions. Topics in the surgery of the biliary tree. IntechOpen. 2018;2:35–52.
2. Siegel RL, Miller KD, Jemal A.Cancer statistics, 2017. CA Cancer
J Clin. 2017;67:7–30.
19 Recent Update inChemotherapy ofCholangiocarcinoma
169
3. Korea Central Cancer Registry NCC.Annual report of cancer statistics in Korea in 2014. Ministry of Health and Welfare; 2016.
4. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC,
Bodniewicz BJ, etal. Staging, resectability, and outcome in 225
patients with hilar cholangiocarcinoma. Ann Surg. 2001;234:507–
17. discussion 517–509
5. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the
treatment of biliary tract cancer: a systematic review and metaanalysis. J Clin Oncol. 2012;30:1934–40.
6. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH,
McDonald AC, etal. Effect of adjuvant chemotherapy with uorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma:
the espac-3 periampullary cancer randomized trial. JAMA.
2012;308:147–56.
7. Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M,
et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg.
2018;105:192–202.
8. Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P,
Joly JP, et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD
18-UNICANCER GI): a randomized phase III study. J Clin Oncol.
2019;37:658–67.
9. Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D,
etal. Capecitabine compared with observation in resected biliary
tract cancer (BILCAP): a randomised, controlled, multicentre,
phase 3 study. Lancet Oncol. 2019;20:663–73.
10. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A,
Maraveyas A, etal. Cisplatin plus gemcitabine versus gemcitabine
for biliary tract cancer. N Engl J Med. 2010;362:1273–81.
11. Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda
M, etal. Combination gemcitabine plus s-1 versus gemcitabine plus
cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT
(JCOG1113) randomized phase III clinical trial. Ann Oncol.
2019;30:1950–8.
12. Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff
RA, etal. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial.
JAMA Oncol. 2019;5:824–30.
13. Lamarca A, Hubner RA, David Ryder W, Valle JW.Second-line
chemotherapy in advanced biliary cancer: a systematic review. Ann
Oncol. 2014;25:2328–38.
14. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, etal.
ABC-06 | a randomised phase III, multi-centre, open-label study of
active symptom control (ASC) alone or asc with oxaliplatin / 5-FU
chemotherapy (ASC+mFOLFOX) for patients (pts) with locally
advanced / metastatic biliary tract cancers (ABC) previouslytreated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin
Oncol. 2019;37:4003.
15. Belkouz A, Vos-Geelen J, Eskens F, Mathot RAA, van Gulik T,
van Oijen MGH, et al. Efcacy and safety of FOLFIRINOX in
advanced biliary tract cancer after failure of gemcitabine plus cisplatin: a phase II trial. J Clin Oncol. 2019;37:4086.
16. Sohal DP, Mykulowycz K, Uehara T, Teitelbaum UR, Damjanov
N, Giantonio BJ, etal. A phase II trial of gemcitabine, irinotecan
and panitumumab in advanced cholangiocarcinoma. Ann Oncol.
2013;24:3061–5.
17. Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl
D, Kaczirek K, etal. Cetuximab, gemcitabine, and oxaliplatin in
patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol. 2010;11:1142–8.
18. Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardiere
C, Boucher E, 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;15:819–28.
19. Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, Morris
K, 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;16:967–78.
20. Moehler M, Maderer A, Schimanski C, Kanzler S, Denzer U,
Kolligs FT, et al. Gemcitabine plus sorafenib versus gemcitabine
alone in advanced biliary tract cancer: a double-blind placebocontrolled multicentre phase II AIO study with biomarker and
serum programme. Eur J Cancer. 2014;50:3125–35.
21. Lamarca A, Barriuso J, McNamara MG, Valle JW.Molecular targeted therapies: ready for “prime time” in biliary tract cancer. J
Hepatol. 2020;73:170–85.
22. Sia D, Losic B, Moeini A, Cabellos L, Hao K, Revill K, et al.
Massive parallel sequencing uncovers actionable FGFR2-PPHLN1
fusion and ARAF mutations in intrahepatic cholangiocarcinoma.
Nat Commun. 2015;6:6087.
23. Wang Y, Ding X, Wang S, Moser CD, Shaleh HM, Mohamed
EA, et al. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. Cancer Lett.
2016;380:163–73.
24. Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad
MJ, et al. Phase II study of BGJ398 in patients with fgfr-altered
advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276–82.
25. Mazzaferro V, El-Rayes BF, Droz Dit Busset M, Cotsoglou C,
Harris WP, Damjanov N, etal. Derazantinib (ARQ 087) in advanced
or inoperable fgfr2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120:165–71.
26. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ,
Adeva J, etal. Ivosidenib in idh1-mutant, chemotherapy- refractory
cholangiocarcinoma (ClarIDHy): a multicentre, randomised, doubleblind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:
796–807.
27. Bang YJ, Doi T, De Braud F, Piha-Paul S, Hollebecque A, Razak
ARA, et al. Safety and efcacy of pembrolizumab (mk-3475) in
patients (pts) with advanced biliary tract cancer: interim results of
keynote-028. Eur J Cancer. 2015;51:S112.
28. Piha-Paul SA, Oh DY, Ueno M, Malka D, Chung HC, Nagrial A,
et al. Efcacy and safety of pembrolizumab for the treatment of
advanced biliary cancer: results from the keynote-158 and keynote 028 studies. Int J Cancer. 2020;147:2190–8.
29. Ueno M, Ikeda M, Morizane C, Kobayashi S, Ohno I, Kondo S,
etal. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary
tract cancer: a non-randomised, multicentre, open-label, phase 1
study. Lancet Gastroenterol Hepatol. 2019;4:611–21.
30. Arkenau HT, Martin-Liberal J, Calvo E, Penel N, Krebs MG,
Herbst RS, et al. Ramucirumab plus pembrolizumab in patients
with previously treated advanced or metastatic biliary tract cancer: nonrandomized, open-label, phase I trial (JVDF). Oncologist.
2018;23:1407–e1136.
31. Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN,
Padmanabhan N, etal. Whole-genome and epigenomic landscapes
of etiologically distinct subtypes of cholangiocarcinoma. Cancer
Discov. 2017;7:1116–35.
Chemotherapy inPancreatic Ductal
Adenocarcinoma
HeeSeungLee, SeungWooPark, andSiYoungSong
20
Abstract
Pancreatic ductal adenocarcinoma (PDAC) can be divided
into four groups: (1) resectable, (2) borderline, (3) locally
advanced, and (4) disseminated. Resection followed by
adjuvant chemotherapy remains the standard of care for
resectable PDAC.All patients with resected PDAC should
be offered six months of adjuvant chemotherapy in the
absence of contraindications. The modied FOLFIRINOX
(mFOLFIRINOX) is preferred in the absence of concerns
for toxicity or tolerance. Alternatively, combination therapy with gemcitabine and capecitabine, monotherapy
with gemcitabine alone or (Fluorouracil) plus folinic acid
can be offered as adjuvant chemotherapy. Recently, there
has been increasing interest in neoadjuvant treatment due
to the inability of some patients from adjuvant chemotherapy and the possibility of early micrometastasis even
in resectable and borderline resectable PDAC. Patients at
high risk for positive surgical margins are not considered
to be good candidates for an upfront resection but may be
potentially downstaged and safely resected following
neoadjuvant therapy. Recent clinical trials suggested that
neoadjuvant chemotherapy with FOLFIRINOX, gemcitabine plus nanoparticle albumin- bound paclitaxel (nabpaclitaxel), and S-1 might be useful. However, future
conrmative prospective studies are required.
Unfortunately, most PDAC patients are metastatic at their
diagnosis. FOLFIRINOX and gemcitabine plus nabpaclitaxel are the rst recommended chemotherapeutic
drugs. FOLFIRINOX and gemcitabine plus nab-paclitaxel combination therapy has shown remarkable effects
in patients with advanced PDAC with relatively good systemic conditions, bringing new hope in the treatment of
advanced PDAC.In addition, new targeted treatments and
H. S. Lee · S. W. Park · S. Y. Song (*)
Division of Gastroenterology, Department of Internal Medicine,
Yonsei University College of Medicine, Seoul, South Korea
e-mail: sysong@yuhs.ac
immune treatments using cancer cell-specic targets, and
new treatments for desmoplastic characteristics of PDAC
tissues are being attempted.
20.1 Introduction
PDAC is a highly lethal malignancy originating from the
exocrine pancreas [1]. Radical resection is the only hope to
expect long-term survival; however, at the time of diagnosis,
resectable PDAC accounts for only about 20% of all patients,
and most patients were diagnosed as advanced stages [2–4].
Even, cancer recurrence occurs in 70–80% of patients with
PDAC discovered in the early stages after radical surgery [5].
Including surgery, chemotherapy, radiation therapy, chemocombined radiotherapy, and palliative care are treatment
options depending on the stage of PDAC [6, 7]. For decades,
various types of anti-cancer treatment have been tried.
However, PDAC shows a remarkable resistance to established therapeutic options due to various innate mechanisms
of resistance like genetic and epigenetic alterations and a
complex and dense tumor microenvironment. Here, we
aimed to discuss briey the present and future of anticancer
therapy in PDAC.
20.2 Chemotherapy inPDAC
20.2.1 Neoadjuvant Chemotherapy
The benets of neoadjuvant therapy include the potential to
downsize tumors in order to increase the possibility of a
margin- free resection, select PDAC patients with more stable disease, and to treat micrometastases at an earlier stage
[8]. Preoperative chemotherapy in borderline resectable
PDAC can be effective and well-tolerated [8, 9]. Patients
with borderline resectable PDAC demonstrated a higher possibility for an R0 resection after neoadjuvant therapies, and
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_20
171
172
H. S. Lee et al.
survival of patients who underwent surgical resection was
better than that of those who did not [10]. However, further
research is necessary to discover the best regimens to use in
a neoadjuvant setting.
Recently, neoadjuvant chemotherapy was also used in
patients with resectable cases, especially in those with
high- risk features. The phase III study (Prep-02/JSAP-05)
of neoadjuvant gemcitabine plus S-1 conducted in Japan
[11] demonstrated a signicant survival benet of neoadjuvant chemotherapy, with a median overall survival (OS) of
36.7months vs. 26.6months for upfront surgery (Hazard
ratio (HR) 0.72, p=0.015). Approximately 80% of patients
enrolled in this study had resectable PDAC at diagnosis. On
the other hand, perioperative mFOLFIRINOX and gemcitabine/nab-paclitaxel showed similar efcacy, with
acceptable safety and resectability rates. The 2-year OS
was 41.6% with mFOLFIRINOX (p = 0.42) and 48.8%
with gemcitabine/nab-paclitaxel (p = 0.12) [12]. Median
OS was 22.4months and 23.6months, respectively. Median
disease- free survival (DFS) after resection was 10.9months
with mFOLFIRINOX and 14.2months with gemcitabine/
nab- paclitaxel. Neither arm’s two-year OS estimate was
statistically signicantly higher than the prior historical
threshold of 40%. The National Comprehensive Cancer
Network (NCCN) guideline of the USA recommends neoadjuvant therapy for selected patients who appear technically resectable but have poor prognostic features (i.e.,
markedly elevated CA 19–9, large primary tumors, large
regional lymph nodes, excessive weight loss, and extreme
pain) [13].
20.2.2 Adjuvant Chemotherapy
pared to gemcitabine monotherapy (25.5 vs. 28.0 months,
HR 0.82, p=0.032) [17, 18].
In the phase III PRODIGE 24/Canadian Cancer Trials
Group (CCTG) PA.6 trial, patients aged 18−79 years with
resected (R0 or R1) PDAC, who had not received prior chemotherapy or radiation therapy were randomly assigned to
receive six months of adjuvant therapy with either gemcitabine or mFOLFIRINOX [19]. Median DFS, the primary
end point of the study, was signicantly prolonged for patients
receiving mFOLFIRINOX compared with gemcitabine
monotherapy (21.6 vs. 12.8 months, HR 0.58, p < 0.001).
Furthermore, median OS, a secondary end point of the study,
was 54.4months and 35.0months for those receiving mFOLFIRINOX and gemcitabine, respectively (HR 0.64, p=0.003).
However, grade 3/4 adverse events were more frequent in the
mFOLFIRINOX compared with the gemcitabine (75.9% vs.
52.9%), including fatigue, diarrhea, nausea, vomiting,
abdominal pain, sensory peripheral neuropathy, paresthesia,
mucositis, and increased γ-glutamyl transferase level.
The global phase III APACT trial evaluated adjuvant chemotherapy with gemcitabine plus nab-paclitaxel versus gemcitabine alone in patients with resectable PDAC [20]. The
primary endpoint, DFS by independent assessment, was not
met. The median DFS was 19.4months with gemcitabine
plus nab-paclitaxel compared to 18.8 months with gemcitabine monotherapy (HR=0.88, p=0.1824). However, in
the prespecied sensitivity analysis of investigator-assessed
DFS, a benet was shown for the combination, with a median
DFS of 16.6months vs. 13.7months for gemcitabine monotherapy (HR=0.82, p=0.0168). OS data are immature, yet.
The interim median OS was 40.5 vs. 36.2months, respectively (HR=0.82, p=0.045).
Postoperative adjuvant chemotherapy is routinely performed
in all resectable PDAC.It was proven effective by improving
recurrence free survival and OS after curative resection. The
ESPAC-1 trial demonstrated a benet of adjuvant chemotherapy with 5-FU and folinic acid (leucovorin) in patients
following resection. The CONKO-001 trial showed increased
DFS and OS with the use of adjuvant gemcitabine for six
cycles compared with no adjuvant treatment [14].
The Japan Adjuvant Study Group of Pancreatic Center
(JASPAC) conducted a phase III comparative study of
postoperative adjuvant chemotherapy with gemcitabine
alone versus S-1 alone in patients who had undergone resection for PDAC [15, 16]. A total of 385 patients were enrolled,
and the ve-year survival rate and median survival time were
44.1% vs. 24.4% and 46.5 vs. 25.5months in both groups. It
has been reported that S-1 is superior to gemcitabine (HR
0.56, p<0.0001). The ESPAC-4 trial demonstrated that the
combined gemcitabine plus capecitabine regimen yielded a
signicantly prolonged OS after PDAC resection as com-
20.2.3 Palliative Chemotherapy
In the majority of patients with PDAC, the cancer is already
at an advanced unresectable stage at the time of diagnosis.
Therefore, chemotherapy is the mainstay of treatment for
metastatic PDAC [21, 22]. After a landmark clinical trial to
compare gemcitabine and 5-FU in 1997, gemcitabine has
been a standard of chemotherapy, and numerous clinical trials have compared novel regimens against gemcitabine
monotherapy [23]. In a phase III trial, the addition of erlotinib to gemcitabine improved progression-free survival
(PFS) and OS compared with gemcitabine alone, although
this benet was marginal.
In the phase III ACCORD-11 trial, the FOLFIRINOX
regimen (oxaliplatin 85mg/m
notecan 180mg/m2, bolus uorouracil 400mg/m2, infusional
5-FU 2400mg/m2 over 46hr., every 14days) had a median
OS of 11.1months when compared to the existing standard
therapy, gemcitabine alone, which was signicantly
2
, folinic acid 400mg/m2, iri-
20 Chemotherapy inPancreatic Ductal Adenocarcinoma
173
improved compared to 6.8months in the gemcitabine alone
group (HR 0.57, p<0.001) [24]. Median PFS was 6.4months,
showing a prolonged effect compared to 3.3months of the
gemcitabine alone group (HR 0.47, p < 0.001). However,
treatment-related toxicity was also signicantly worse with
FOLFIRINOX, including grade 3/4 neutropenia (45.7%),
thrombocytopenia (9.1%), and diarrhea (12.7%). Therefore,
this regimen is recommended for relatively younger patients
with good performance status. Another phase III trial, the
MPACT trial, showed that gemcitabine plus nab-paclitaxel
was superior to gemcitabine alone in terms of response, PFS,
and OS in patients with metastatic PDAC [25, 26]. The
median OS was signicantly improved at 8.5 vs. 6.7months
(HR 0.72, p<0.001), and the median PFS was also at 5.5 vs.
3.7months (HR 0.69, p<0.001). Some studies investigated
the biological effects of gemcitabine plus nab-paclitaxel and
suggested that this regimen decreases cancer associated
broblast (CAF) content inducing a marked alteration in
cancer stroma that results in tumor softening. Since the two
drugs showed an improvement in survival time compared to
the gemcitabine alone group, FOLFIRINOX and gemcitabine plus nab-paclitaxel could be considered as rst-line
chemotherapeutic agents.
Recently, efcacy of maintenance Olaparib (PARP inhibitor) in patients with a germline BRCA mutation and metastatic PDAC that had not progressed after at least 16weeks
of rst-line platinum-based chemotherapy was reported
(POLO trial) [27]. This was an international, double-blind,
placebo-controlled, phase III trial that randomized a total of
154 patients to either Olaparib (n=92) or placebo (n=62).
If there is a germline BRCA1 or BRCA2 mutation, Olaparib
(300mg twice a day) was used as maintenance therapy. The
median PFS was 7.4months, which was signicantly longer
than the placebo group, 3.8months (HR 0.53, p = 0.004).
POLO is the rst randomized trial to study the efcacy of
PARP inhibitors in germline BRCA-mutated patients. The
study is the rst proof of concept of the feasibility of an individualized strategy in the choice of therapy based on a
genomic marker in PDAC.
For patients who are refractory to rst-line chemotherapeutic regimen, it is reasonable to consider further secondline chemotherapy in patients who maintain a good performance status. For patients with advanced disease who have
received prior gemcitabine-based therapy, 5-FU-based chemotherapy regimens are acceptable second-line options.
Alternatively, gemcitabine-based therapy can be given to those
previously treated with 5-FU-based therapy. However, there
are no widely accepted optimal regimens for second-line
therapy yet. In the recent NAPOLI-1 phase III randomized
trial, the effects of nanoliposomal irinotecan were examined
in patients with metastatic PDAC who previously received
gemcitabine-based therapy [28]. Median PFS (3.1 vs.
1.5months, HR 0.56, p<0.001) and OS (6.2 vs. 4.2months,
HR 0.75, p=0.042) were signicantly greater for patients
who received nanoliposomal irinotecan with 5-FU/leucovorin, compared to patients who did not receive irinotecan.
When the above treatments are not suitable, gemcitabine
alone therapy, TS-1 therapy, gemcitabine combined with
other drugs (erlotinib, cisplatin, or capecitabine) are also
possible [29–32].
Second-line treatment options for patients with good performance status and previously treated with gemcitabinebased therapy include: 5-FU/leucovorin/liposomal
irinotecan, FOLFIRI, FOLFIRINOX, 5-FU/leucovorin/
oxaliplatin (OFF), FOLFOX, CapeOx, capecitabine, and
continuous infusion 5-FU [7, 33, 34]. Options for patients
with good performance status and previously treated with
5-FU-based therapy include: gemcitabine/albumin-bound
paclitaxel, gemcitabine/cisplatin, gemcitabine/erlotinib, and
gemcitabine monotherapy [13].
20.3 Immunotherapy
Immunotherapy is one of the emerging therapeutic options.
However, previous clinical trials of immunotherapy did not
show benet in OS in PDAC.Immunotherapy stimulates a
host immune response that results in long-term tumor
destruction [35, 36]. The stroma of PDAC is particularly rich
in inammatory cells that are proposed to mediate drug
resistance and tumor progression. Therefore, immune cells—
such as T-cells and macrophages—inltrating the peritumoral stroma represent a promising target for
immunotherapeutic approaches. T-cell mediated immunity
includes multiple sequential steps that are regulated by counterbalancing stimulatory and inhibitory signals that ne-tune
the response [37, 38]. These inhibitory pathways are referred
to as immune checkpoints and these are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses.
A new treatment option uses human immune-check
point-inhibitor antibodies that inhibit the interactions
between immune cells and antigen-presenting cells, including tumor cells. There is evidence that PD-1 blockade with
pembrolizumab may be effective in tumors with mismatch
repair deciency (dMMR) [39, 40]. Pembrolizumab is an
anti-PD-1 receptor antibody which blocks its interaction
with PD-L1 and PD-L2, releasing the PD-1-mediated inhibition of the immune response, which improves antitumor
immunity. The results of a phase II study in patients with 12
different dMMR advanced cancers, including pancreas,
found that treatment with pembrolizumab resulted in durable responses (ORR in 53% of patients, with 21% complete
response). There were six patients with PDAC with an ORR
in 62% of patients (two had complete response and three
had progressive disease).
174
H. S. Lee et al.
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
is an immune checkpoint that plays a critical role in regulating and limiting immune responses, and it can be blocked by
specic antibodies such as ipilimumab, a fully human
antibody [41, 42]. The binding of ipilimumab to CTLA-4
blocks the immune limiting activity of CTLA-4, thereby sustaining an active immune response against the cancer cells.
Early phase trials are currently underway in PDAC for ipilimumab (NCT01473940). Another promising immune-modulatory target is CD40, which is a co-stimulatory molecule
for antigen presenting cells [43, 44]. Gemcitabine treatment
combined with CD40 agonist-activated T-cells reduced the
tumor burden in advanced PDAC patients in a phase I study
by decreasing tumor stroma and increasing the tumor inltration of activated macrophages [45]. In addition to enhancing the systemic immune response, attracting selected
antitumor cytokines is also a promising concept that is currently under intense preclinical and clinical investigation.
One of the most tumor selective antigens that can be used to
guide cytokines to the site of a tumor is the extradomain B
(ED-B) of bronectin. The fusion product consisting of the
ED-B antibody fragment L19 and interleukin-2 is currently
being tested in a phase I/II trial in PDAC (NCT01198522).
20.4 Tumor Microenvironment
Other promising novel approaches to PDAC treatment
include therapies targeting the desmoplastic stroma [46].
PDAC is characterized by the presence of a dense brous
stromal tissue that represents up to 90% of the tumor volume
[38]. This pancreatic extracellular matrix, produced by CAF,
is predominantly made of collagen, hyaluronic acid, and
bronectin [47]. The full implications of this extracellular
matrix and associated cells are still under investigation, but
this dense stroma has been shown to limit efcacy of standard cytotoxic, immune, and targeted agents [48, 49].
Inefcient drug deliveries due to the intense stromal reaction
may be an important contributor to chemo-resistance in
PDAC [50]. The inhibition of stroma-related signaling path-
ways is considered to be a promising tool to decrease stromal
density and to facilitate the access of cytotoxic drugs to the
tumor cells. A cellular matrix component is currently being
evaluated as targets for therapeutic intervention. Human
recombinant PH20 hyaluronidase (PEGPH20) enzymatically depletes hyaluronan (highly abundant in the extracellular matrix of both human and murine PDAC tissues),
thereby inducing the re-expansion of tumor blood vessels
and increasing the concentration of gemcitabine within the
tumor [51]. PEGPH20 resulted in signicantly diminished
tumor growth and prolonged survival in mice. Increased
hyaluronic acid is associated with decreased survival in
patients with PDAC, probably through increased interstitial
pressure that impedes diffusion of therapeutic agents and
nutrients into the tumor microenvironment. Hyaluronidase
was investigated to break down hyaluronic acid. A phase 1b
study of PEGPH20in combination with gemcitabine showed
an OS of 6.6months in all-comers, but an OS of 13months
in the six patients with elevated hyaluronic acid concentrations [52]. This study was followed by a randomized phase II
trial of gemcitabine and nab-paclitaxel with or without
PEGPH20 [53]. The PEGPH20 group of this trial had an
improvement in PFS (6.0 vs. 5.3m), which was amplied in
patients with tumors with high hyaluronic acid expression
(9.2 vs. 5.2m). But phase III trial evaluating PEGPH20in
combination with gemcitabine and nab-paclitaxel in patients
who have tumors with high hyaluronic acid concentrations
reported no improvement in OS compared with gemcitabine
alone, leading to a suspension of further exploration of
PEGPH20.
20.5 Summary
As the landscape of cancer treatment continues to evolve,
understanding and targeting driver mutations will become
the cornerstone of anticancer chemotherapy. In cancers such
as PDAC that have an extremely poor prognosis and limited
treatment options, molecular targeted therapy is even more
important. Multiple clinical trials are currently under way,
and more promising data will soon be available.
References
1. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N
Engl J Med. 2014;371:1039–49.
2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM,
Matrisian LM.Projecting cancer incidence and deaths to 2030: the
unexpected burden of thyroid, liver, and pancreas cancers in the
United States. Cancer Res. 2014;74:2913–21.
3. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer.
Lancet. 2016;388:73–85.
4. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence
and mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.
5. Siegel RL, Miller KD, Jemal A.Cancer statistics, 2020. CA Cancer
J Clin. 2020;70:7–30.
6. Hartwig W, Werner J, Jager D, Debus J, Buchler MW.Improvement
of surgical results for pancreatic cancer. Lancet Oncol.
2013;14:e476–85.
7. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined
radiation and chemotherapy following curative resection. Arch
Surg. 1985;120:899–903.
8. Muller PC, Frey MC, Ruzza CM, etal. Neoadjuvant chemotherapy
in pancreatic cancer: an appraisal of the current high-level evidence. Pharmacology. 2020;106(3–4):143–53.
20 Chemotherapy inPancreatic Ductal Adenocarcinoma
175
9. Christians KK, Tsai S, Mahmoud A, et al. Neoadjuvant
FOLFIRINOX for borderline resectable pancreas cancer: a new
treatment paradigm? Oncologist. 2014;19:266–74.
10. Tinchon C, Hubmann E, Pichler A, etal. Safety and efcacy of neoadjuvant FOLFIRINOX treatment in a series of patients with borderline resectable pancreatic ductal adenocarcinoma. Acta Oncol.
2013;52:1231–3.
11. Motoi F, Kosuge T, Ueno H, etal. Randomized phase II/III trial
of neoadjuvant chemotherapy with gemcitabine and S-1 versus
upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05).
Jpn J Clin Oncol. 2019;49:190–4.
12. Ahmad SA, Duong M, Sohal DPS, etal. Surgical outcome results
from SWOG S1505: a randomized clinical trial of mFOLFIRINOX versus gemcitabine/nab-paclitaxel for perioperative treatment of resectable pancreatic ductal adenocarcinoma. Ann Surg.
2020;272(3):481–6.
13. Tempero MA, Malafa MP, Chiorean EG, et al. Pancreatic adenocarcinoma, version 1.2019. J Natl Compr Cancer Netw.
2019;17:202–10.
14. Neoptolemos JP, Stocken DD, Friess H, etal. A randomized trial of
chemoradiotherapy and chemotherapy after resection of pancreatic
cancer. N Engl J Med. 2004;350:1200–10.
15. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with
gemcitabine vs observation in patients undergoing curative-intent
resection of pancreatic cancer: a randomized controlled trial.
JAMA. 2007;297:267–77.
16. Uesaka K, Boku N, Fukutomi A, etal. Adjuvant chemotherapy of
S-1 versus gemcitabine for resected pancreatic cancer: a phase 3,
open-label, randomised, non-inferiority trial (JASPAC 01). Lancet.
2016;388:248–57.
17. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of
adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4):
a multicentre, open-label, randomised, phase 3 trial. Lancet.
2017;389:1011–24.
18. Valle JW, Palmer D, Jackson R, etal. Optimal duration and timing
of adjuvant chemotherapy after denitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3
study. J Clin Oncol. 2014;32:504–12.
19. Vivaldi C, Fornaro L, Vasile E.FOLFIRINOX adjuvant therapy for
pancreatic cancer. N Engl J Med. 2019;380:1187–8.
20. Tempero MA, Reni M, Riess H, etal. APACT: phase III, multicenter, international, open-label, randomized trial of adjuvant
nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G)
for surgically resected pancreatic adenocarcinoma. J Clin Oncol.
2019;37:4000.
21. Sohal DP, Mangu PB, Khorana AA, et al. Metastatic pancreatic
cancer: American Society of Clinical Oncology Clinical Practice
Guideline. J Clin Oncol. 2016;34(23):2784–96.
22. Ko AH.Progress in the treatment of metastatic pancreatic cancer and
the search for next opportunities. J Clin Oncol. 2015;33:1779–86.
23. Burris HA 3rd, Moore MJ, Andersen J, etal. Improvements in survival and clinical benet with gemcitabine as rst-line therapy for
patients with advanced pancreas cancer: a randomized trial. J Clin
Oncol. 1997;15:2403–13.
24. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med.
2011;364:1817–25.
25. Von Hoff DD, Ervin T, Arena FP, etal. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med.
2013;369:1691–703.
26. Von Hoff DD, Ramanathan RK, Borad MJ, etal. Gemcitabine plus
nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548–54.
27. Golan T, Hammel P, Reni M, etal. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med.
2019;381:317–27.
28. Wang-Gillam A, Hubner RA, Siveke JT, etal. NAPOLI-1 phase 3
study of liposomal irinotecan in metastatic pancreatic cancer: nal
overall survival analysis and characteristics of long-term survivors.
Eur J Cancer. 2019;108:78–87.
29. Cunningham D, Chau I, Stocken DD, etal. Phase III randomized
comparison of gemcitabine versus gemcitabine plus capecitabine
in patients with advanced pancreatic cancer. J Clin Oncol.
2009;27:5513–8.
30. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus
capecitabine compared with gemcitabine alone in advanced
pancreatic cancer: a randomized, multicenter, phase III trial
of the Swiss Group for Clinical Cancer Research and the
Central European Cooperative Oncology Group. J Clin Oncol.
2007;25:2212–7.
31. Moore MJ, Goldstein D, Hamm J, etal. Erlotinib plus gemcitabine
compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of
Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.
32. Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of
gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients
with locally advanced and metastatic pancreatic cancer in Japan
and Taiwan: GEST study. J Clin Oncol. 2013;31:1640–8.
33. Louvet C, Labianca R, Hammel P, etal. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone inlocally
advanced or metastatic pancreatic cancer: results of a GERCOR
and GISCAD phase III trial. J Clin Oncol. 2005;23:3509–16.
34. Oettle H, Riess H, Stieler JM, etal. Second-line oxaliplatin, folinic
acid, and uorouracil versus folinic acid and uorouracil alone
for gemcitabine-refractory pancreatic cancer: outcomes from the
CONKO-003 trial. J Clin Oncol. 2014;32:2423–9.
35. Ribas A.Releasing the brakes on cancer immunotherapy. N Engl J
Med. 2015;373:1490–2.
36. Wu J, Cai J.Dilemma and challenge of immunotherapy for pancreatic cancer. Dig Dis Sci. 2021;66(2):359–68.
37. Balachandran VP, Beatty GL, Dougan SK.Broadening the impact
of immunotherapy to pancreatic cancer: challenges and opportunities. Gastroenterology. 2019;156:2056–72.
38. Immunotherapy shows promise in pancreatic cancer. Cancer
Discov. 2019;9:1330.
39. Le DT, Durham JN, Smith KN, et al. Mismatch repair deciency
predicts response of solid tumors to PD-1 blockade. Science.
2017;357:409–13.
40. Asaoka Y, Ijichi H, Koike K. PD-1 blockade in tumors with
mismatch- repair deciency. N Engl J Med. 2015;373:1979.
41. Bengsch F, Knoblock DM, Liu A, McAllister F, Beatty GL.CTLA-4/
CD80 pathway regulates T cell inltration into pancreatic cancer.
Cancer Immunol Immunother. 2017;66:1609–17.
42. Bajor DL, Vonderheide RH.Cracking the stone: combination vaccination and CTLA-4 blockade in pancreatic cancer. J Immunother.
2013;36:362–4.
43. Beatty GL, Chiorean EG, Fishman MP, etal. CD40 agonists alter
tumor stroma and show efcacy against pancreatic carcinoma in
mice and humans. Science. 2011;331:1612–6.
44. Van Audenaerde JR, Marcq E, von Scheidt B, et al. Novel combination immunotherapy for pancreatic cancer: potent anti-tumor
effects with CD40 agonist and interleukin-15 treatment. Clin Transl
Immunology. 2020;9:e1165.
45. Vonderheide RH, Bajor DL, Winograd R, Evans RA, Bayne LJ,
Beatty GL. CD40 immunotherapy for pancreatic cancer. Cancer
Immunol Immunother. 2013;62:949–54.
46. Karamitopoulou E. The tumor microenvironment of pancreatic
cancer. Cancers (Basel). 2020;12:3076.
176
H. S. Lee et al.
47. Karamitopoulou E. Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features. Br J Cancer. 2019;121:5–14.
48. Christenson ES, Jaffee E, Azad NS.Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma:
a bright future. Lancet Oncol. 2020;21:e135–45.
49. DuFort CC, DelGiorno KE, Hingorani SR. Mounting pressure in
the microenvironment: uids, solids, and cells in pancreatic ductal
adenocarcinoma. Gastroenterology. 2016;150:1545–57.e2.
50. Ligorio M, Sil S, Malagon-Lopez J, etal. Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer.
Cell. 2019;178:160–75.e27.
51. PEGPH20 may improve standard-of-care therapy in pancreatic cancer. Cancer Discov. 2018;8:136.
52. Hingorani SR, Harris WP, Beck JT, et al. Phase Ib study of
PEGylated recombinant human hyaluronidase and gemcitabine
in patients with advanced pancreatic cancer. Clin Cancer Res.
2016;22:2848–54.
53. Hingorani SR, Zheng L, Bullock AJ, etal. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine
versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018;36:
359–66.
Immune-Checkpoint Inhibitors
inHepatocellular Carcinoma
RubensCopiaSperandio, RobertoCarmagnaniPestana,
andAhmedO.Kaseb
21
Abstract
Hepatocellular carcinoma (HCC) is a major cause of
cancer- related death worldwide. Prognosis is grim, with
5-year overall survival <10% for patients with advanced
disease, and the management is complex, demanding a
multidisciplinary approach. Recently, a better understanding of the pathophysiology and immune microenvironment of HCC has led to advances in systemic treatment
with the incorporation of immunotherapeutic strategies.
The rationale behind immunotherapy as a treatment
modality for HCC include the immunosuppressive effects
of chronic inammatory conditions associated with cirrhosis and hepatitis. Initially, anti-PD-1 immunecheckpoint inhibitors (ICIs)—nivolumab and
pembrolizumab—were evaluated in single-arm earlyphase trials, with promising efcacy. However, larger
conrmatory studies of anti-PD1 ICI alone have yielded
disappointing results. This insufcient activity of singleagent ICI led to interest in combination strategies, and the
association of atezolizumab (an anti-PD-L1 ICI) and bevacizumab (an anti-VEGF antibody) has been established
as the new standard of care for rst-line systemic therapy
in advanced HCC.Furthermore, there is increasing interest in assessing the usefulness of ICIs as an option to earlier stages—either in the neoadjuvant or adjuvant settings
or combined with locoregional approaches. In this chapter, we aim to review the rationale, efcacy data and
future perspectives regarding the use of ICI for HCC.
R. C. Sperandio · R. C. Pestana
Centro de Oncologia e Hematologia Einstein Familia DayanDaycoval, Hospital Israelita Albert Einstein, São Paulo, Brazil
A. O. Kaseb (
Department of Gastrointestinal Medical Oncology, The University
of Texas MD Anderson Cancer Center, Houston, TX, USA
e-mail: akaseb@mdanderson.org
*)
21.1 Background
Hepatocellular carcinoma (HCC) is the fourth leading cause
of cancer-related mortality worldwide, accountable for over
780,000 deaths in 2018 [1]. The major risk factor is cirrhosis
from any etiology, most notably viral hepatitis, environmental toxins, alcohol abuse, and metabolic factors leading to
non-alcoholic fatty liver disease (NAFLD) [2]. As a heterogeneous disease that most commonly arises in this background of chronic inammatory liver conditions, the
management of HCC is complex and demands a multidisciplinary approach. Regrettably, less than 20% of patients are
diagnosed at early stages, when a curative treatment with
surgical resection, ablation or liver transplantation is feasible
[3]; the majority get the diagnosis when disease is already
locally advanced or metastatic and prognosis is grim, with
5-year overall survival of less than 10% [4]. Additionally,
over 70% of patients will experience recurrence following
curative-intent therapy [5].
Historically, effective systemic therapies for advanced
HCC have been scarce. HCC is a chemotherapy-refractory
tumor and no cytotoxic agent has been shown to meaningfully improve survival [6, 7]. A more rened understanding
of the pathophysiology of HCC lead to the discovery that
hypervascularity and vascular abnormalities such as arterialization and sinusoidal capillarization, mediated by the
action of proangiogenic factors such as vascular endothelial
growth factor (VEGF), are common ndings in HCC and
shed light on angiogenesis as a potential therapeutic target
[8]. In fact, the treatment landscape of advanced, unresectable HCC substantially evolved with clinical development of
tyrosine-kinase inhibitors (TKI) that target the VEGF pathway. Initially, in 2008, sorafenib, an orally-available TKI,
was approved based on data from the phase III SHARP trial,
demonstrating a modest but signicant overall survival benet versus best supportive care alone (10.7 versus 7.9months,
HR 0.69; p<0.001) [9]. This targeted-therapy became the
standard of care and was the only rst-line approved sys-
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_21
177