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 / @xirurgi_2025 / @xirurgi_2025 - 436 - файл
.pdf
396 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
The deliverability of chemotherapy may be more feasible in
the neoadjuvant setting, as shown in the phase 2 AGITG GAP
study with 93% of patients completing two cycles of neoadjuvant chemotherapy with gemcitabine/nab-paclitaxel, compared to 63% of patients who completed all four cycles of
postoperative chemotherapy (Barbour et al. 2020). Achieving
an R0 resection translated to an increase in mOS of a further 10
months compared to an R1 resection.
To date, there is no Phase III RCT data supporting the use of
neoadjuvant therapy in patients with resectable pancreatic cancer. It should only be considered in the setting of a clinical trial.
Summary of Indications for Neoadjuvant
therapy
Resectable
• Neoadjuvant therapy remains unproven and should be explored
within clinical trials.
Borderline resectable
• Neoadjuvant therapy should be recommended.
• The recommended chemotherapy regimens are (m)FOLFIRINOX, or
gemcitabine + nab-paclitaxel.
• Neoadjuvant CRT has the most compelling mature randomized data
with an improved OS and R0 resection rate.
Locally advanced
• Consider enrolling the patient in a clinical trial
• 20–30% of patients who undergo neoadjuvant therapy may convert
to surgical resection
• Chemotherapy, chemoradiation, or a combination can be considered
status or comorbidities which would limit multi-agent chemotherapy, gemcitabine monotherapy is preferred. If a patient is
unsuitable for platinum-based chemotherapy, such as the
presence of peripheral neuropathy, then the combination of
gemcitabine and capecitabine is used.
Summary of adjuvant systemic therapy for resected pancreatic
cancer
Study ESPAC-4
(Neoptolemos et al.
2017,
Neoptolemos et al.
2020)
Population Complete macroscopic resection R0 or R1
a
Regimen
Comparator
arm
Duration of
treatment
Median
follow-up
Median OS 27.7 mo v 26 mo
Gemcitabine +
capecitabine
Gemcitabine Gemcitabine Observation
6 mo 6 mo 6 mo
60 mo 33.6 mo 136 mo
(5-yr survival 28% v
20%; HR=0.84
[95% CI, 0.70 –
0.99]; P=0.049)
PRODIGE-24
(Conroy
et al. 2018)
mFOLFIRINOX Gemcitabine
54.5 mo v 35
mo
HR 0.64 [95%
CI, 0.48 to
0.86; P=0.003]
CONKO-
001(Oettle
Oettle
et al. 2007)
22.8 mo v 20.2
mo
HR 0.76 [95%
CI, 0.61–0.95;
P =0.01]
Adjuvant Therapy
For all patients who did not receive neoadjuvant therapy, the
current guidelines, including ASCO (Khorana et al. 2019),
ESMO (Ducreux et al. 2015), and NCCN (Tempero et al. 2021)
recommend six months of adjuvant therapy. These are summarized in the Table below. A new baseline CT of the chest,
abdomen and pelvis post-surgery, and CA19.9 measurement
should be performed. If metastatic disease is not identified,
then adjuvant therapy is recommended, and should commence
within 12 weeks of surgical resection. The preferred options are
for adjuvant chemotherapy, or a combination of chemotherapy
± chemoradiation. As completion of six months of adjuvant
chemotherapy is an independent prognostic factor for overall
survival, so adequate time should be given for the patient to
recover from surgery but still commence within the 12-week
window (Valle et al. 2014). The options for chemotherapy
include modified FOLFIRNOX (Conroy et al. 2018), gemcitabine/capecitabine (Neoptolemos et al. 2017), or gemcitabine monotherapy (Oettle et al. 2013) [see Table below].
FOLFIRINOX is suitable for patients with an excellent
performance status. If a patient has a borderline performance
In Australia, modified FOLFIRINOX tends to be used over
standard FOLFIRINOX (Conroy et al. 2018). Of note, the trial
included patients up to age 79 in the mFOLFIRINOX arm, with
19% of patients aged 70 or over. There was no difference in
adverse events from treatment between the treatment arms in
older patients (age ≥70 years).
The evidence for combination gemcitabine and capecitabine
comes from the ESPAC-4 trial (Neoptolemos et al. 2017).
Five-year OS data showed 28% overall survival with gemcitabine/capecitabine compared with 20% in the gemcitabine
only arm [HR 0.84; 95% CI, 0.70 – 0.99; p=0.049]. Adjuvant
gemcitabine doubles OS with gemcitabine (20.7%) compared
to observation (10.4%) (Oettle et al. 2013) at 5 years, and the
benefit is maintained at 10 years (OS 12.2% GEM v 7.7%
OBS).
The use of nab-paclitaxel/gemcitabine in the adjuvant setting
was evaluated in APACT. This study did not meet its primary
end point of DFS as assessed by independent review (Reni et al.
2019). The authors commented that the DFS in the gemcitabine
arm was higher than historical controls, and the use of independently assessed as opposed to investigator assessed endpoints may have had an impact.
20 MANAGEMENT OF PRIMARY PANCREATIC CANCER 397
https://t.me/medicina_free
There is no conclusive evidence for adjuvant therapy in
patients who received neoadjuvant therapy, with no RCT showing that further chemotherapy beyond six months of neoadjuvant or perioperative chemotherapy has any benefit.
Chemoradiation for those patients with a positive R1 resection
margin and/or positive lymph node after preoperative therapy
can be considered (Khorana et al. 2019) but there is no
randomized evidence supporting this approach.
Other Considerations for Systemic Therapy
The most common mutations in familial pancreatic cancer are
BRCA1 and BRCA2, detected in 2–3% (Petersen 2016; Young et
al. 2018) of patients with pancreas cancer, with higher rates
seen in patients of Ashkenazi Jewish heritage (Pilarski 2019).
Recent data suggests platinum sensitivity of BRCA-mutated
PDAC (Kowalewski et al. 2018).
The use of a PARPi as maintenance treatment has been evaluated in a phase 3 trial for patients with PDAC associated with
a germline BRCA mutation (POLO – (Golan et al. 2019)). In
this trial, after an initial response of at least stable disease to
upfront platinum-based chemotherapy of at least 16 weeks’
duration; patients were randomized to receive either Olaparib
or placebo. Patients in the Olaparib arm had a higher PFS of 7.4
months compared with 3.8 months in patients who received
placebo (HR 0.53, 95% CI 0.35, 0.82; p = 0.004), however there
was no significant difference in median OS at median 31-month
follow-up – 19.0 months in the olaparib arm compared to 19.2
months with placebo (HR 0.83, 95% CI 0.56, 1.22; p = 0.3487).
A combination approach of a PARPi with chemotherapy in
the upfront setting for advanced PDAC (Stage III/IV) was
evaluated with veliparib in the phase II trial with gemcitabine
and capecitabine. There was no statistically significant benefit
to the addition of veliparib to chemotherapy (O’Reilly et al.
2020).
An emerging option is the combination of PARPi with ICI
which has shown promising results in a proof-of-concept study
(Lampert et al. 2020). The combination of Olaparib with the
PD-1 inhibitor pembrolizumab as maintenance therapy after
platinum based chemotherapy is being evaluated in a
randomized phase II trial SWOG S2001 [NCT04548752].
Metastatic Disease
It is important to discuss the goals of care at the outset of a
patient diagnosed with metastatic PDAC and early referral
to palliative care service is recommended. Enrolment in a
clinical trial should be considered for all patients deemed
suitable by the treating clinician. Other considerations
include performance status, patient preference for systemic
therapy, cancer-related symptoms, comorbidities, impact of
disease on quality of life and psychological status, and
support systems (Sohal et al. 2016). A suggested treatment
algorithm is shown in Figure 2. Best supportive care is recommended for patients with a poor performance status
(ECOG PS 3) and comorbidities which impact treatment,
but systemic therapy can be considered for individual
patients. Biliary obstruction should be relieved with stenting
as required, and adequate liver function is required for
administration of systemic therapy. Many published studies
allow bilirubin levels up to 1.5 times the upper limit of
normal (Conroy et al. 2011). The use of immune checkpoint
Figure 2 Systemic therapy for metastatic pancreatic cancer.
398 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
inhibitors and NTRK inhibitors are discussed in the previous
section (Other considerations for systemic therapy).
For patients with comorbidities impacting treatment or ECOG
PS 2, either gemcitabine monotherapy (Burris et al. 1997),
capecitabine or infusional 5-fluourouacil can be used as per the
NCCN (Tempero et al. 2021) and ESMO Guidelines (Ducreux et
al. 2015). In certain cases, such as young patients with ECOG PS
2 and no comorbidities, a more intensive regimen may be considered as per the clinician’s discretion. FOLFIRINOX (or modified FOLFIRINOX) should be offered to patients with a good
performance status (ECOG PS 0 or 1) and well-controlled
comorbidities (Conroy et al. 2011). Median OS was greater in
patients who received FOLFIRINOX (11.1 months v 6.8 months)
compared to gemcitabine [HR 0.57; 95% CI, 0.45 – 0.73;
p=0.001]. Of note, only patients up to age 75 were enrolled in this
study so the use of FOLFIRINOX/mFOLFIRINOX in older
patients should be carefully considered. Gemcitabine/cisplatin
can be considered for patients with a BRCA1/2 or PALB2 mutation as an alternate platinum containing regimen.
An alternative first-line therapy is gemcitabine/nab-paclitaxel
(Von Hoff et al. 2013). In this study, median overall survival was
greater for patients who received gemcitabine/nab-paclitaxel
compared with patients who received gemcitabine alone (8.5
months vs 6.7 months) [HR, 0.72; 95% CI, 0.62 to 0.83; p=0.001].
Common Grade 3/4 toxicities include neutropenia, fatigue,
peripheral neuropathy, febrile neutropenia, and diarrhea.
Based on expert consensus recommendations, patients who
received FOLFIRINOX as first-line treatment can be offered
gemcitabine/nab-paclitaxel as second-line therapy, and vice
versa, as long as their performance status and comorbidities
allow further systemic therapy (Sohal et al. 2016). Other second line therapies can be offered to patients with an adequate
performance status allowing further systemic therapy (ECOG
PS 2). Selected patients who have progression at single sites
may benefit from chemoradiation (Tempero et al. 2021).
Immune checkpoint inhibitor therapy may be considered for
patients with MSI-H/dMMR pancreatic cancer (Marabelle et al.
2020). On the basis of the results of basket trials, larotrectinib
(Drilon et al. 2018), and entrectinib (Doebele et al. 2020) have
been approved for patients with NTRK gene fusions. As there is
currently no evidence guiding duration of therapy, this should be
guided by patient preference for continued systemic therapy,
response to treatment, and toxicity of therapy (Sohal et al. 2016).
Radiation Therapy
Stephen R. Thompson
The only curative treatment for pancreatic cancer is surgery,
but as discussed above, only 20–30% of patients will have
resectable disease (Butturini et al. 2008). The role of radiation
therapy (RT) is controversial, and can be classified as definitive
for locally advanced disease, neoadjuvant or adjuvant in
addition to surgery, or palliative for medically unfit patients or
in the presence of metastatic disease (Tempero et al. 2021).
Each of these will be outlined below, including a summary of
the highest quality data available, RT approaches, and results.
Locally Advanced Pancreatic Cancer
For those patients with LAPC, the mainstay of management is
with palliative chemotherapy (Tempero et al. 2021). Data
regarding the potential additional benefit of adding RT has
been confounded by a lack of high quality randomized evidence, with those few randomized studies that have been performed being antiquated and/or underpowered (Hazel et al.
1981; Klaassen et al. 1985; Loehrer et al. 2011) or detrimental
with irradiation that was too toxic (60Gy with concurrent
cisplatin/5FU) (Chauffert et al. 2008). One large, modern trial
has been conducted: LAP07 (Hammel et al. 2016), showing
that after 16 weeks of induction gemcitabine (allowing time for
the potential early development of metastatic disease), chemoradiotherapy with capecitabine (830mg/m2 BD on RT days) to
54Gy in 30 fractions targeting the gross tumor only, compared
to continuing gemcitabine, resulted in a small benefit: reduced
local progression (32% versus 46%, p=0.03), borderline
significant improvement in progression-free survival (9.9
months versus 8.4 months, p=0.06) with similar toxicity except
increased G3-4 nausea (5.9% vs 0%, p=0.008). Thus, for LAPC,
options include systemic treatment alone or the addition of
chemoradiotherapy after chemotherapy. It may be that with
better hematogenous disease control with more effective
systemic treatment (Suker et al. 2016), the addition of RT may
be more important in achieving local control.
Borderline Resectable Pancreatic Cancer
Neoadjuvant treatment potentially reduces the significant risks
of positive margins and local and distant recurrence, and avoids
futile surgery by identification of early development of metastatic disease (Toesca et al. 2018). Two small randomized phase
II studies (Golcher et al. 2015; Jang et al. 2018) and a Phase III
study (Versteijne et al. 2020) have shown that for BRPC, neoadjuvant chemoradiotherapy reduces the rate of positive margins
and improves local control, disease-free survival, and overall
survival (17.6 versus 13.2 months, p=0.029). The data does not
however prove that RT is an essential component of the neoadjuvant treatment. Our approach for fit patients is to treat with
neoadjuvant modified FOLFIRINOX 4–8 cycles, and if insufficient response then RT 45 Gy in 25 fractions (often with simultaneous integrated boost to 50 Gy to sites of threatened margins
along vessels) with concurrent capecitabine 830 mg/m2 BD on
RT days (Tempero et al. 2021) aiming to achieve resectability
with negative margins.
20 MANAGEMENT OF PRIMARY PANCREATIC CANCER 399
https://t.me/medicina_free
Resected Pancreatic Cancer
Randomized trials regarding potential benefits of adjuvant RT
are confounded by underpowering (Van Laethem et al. 2010)
or antiquated toxic RT negatively impacting on adjuvant chemotherapy delivery and thus survival (Neoptolemos et al.
2004). Adjuvant chemotherapy improves survival and should
be prioritized (Conroy et al. 2018). However, between ¼ and ½
of patients will develop loco-regional recurrence (Conroy et al.
2018, Jones et al. 2019), with associated morbidity such as pain,
bleeding, or obstruction and with resulting survival being as
poor as for patients that develop metastatic disease (Jones et al.
2019). This provides a rationale for adding adjuvant RT which
reduces local recurrence (Van Laethem et al. 2010) and by
extrapolation from neoadjuvant trials (Versteijne et al. 2020)
may thereby improve overall survival. We recommend adjuvant chemotherapy for 4–6 months, re-stage, and if no distant
disease offer selected patients adjuvant chemoradiotherapy to
45 Gy in 25 fractions (with simultaneous integrated boost to 50
Gy to sites of close margins along vessels) with concurrent
capecitabine 830 mg/m2 BD on RT days (Tempero et al. 2021).
Stereotactic Body Radiation Therapy (SBRT)
SBRT is an RT technique that precisely applies high doses of
hypofractionated RT to small volumes and has shown promising results for LAPC (Petrelli et al. 2017) and for BRPC
(Mellon et al. 2015). The addition of SABR to chemotherapy
did not improve outcomes in BRPC in the Alliance randomized
phase II trial (Katz et al. 2021). For both BRPC and LAPC this
approach is being tested in the MASTERPLAN randomized
phase II trial (Oar et al. 2021).
Palliative Radiotherapy
Locally uncontrolled disease commonly causes symptoms
including pain, bleeding, or obstruction (Tempero et al. 2021).
Short courses of palliative radiotherapy utilizing schedules such as
8 Gy times 1–3 fractions (Ebrahimi et al. 2018) or 25 Gy in 5 fractions (Wang et al. 2018) usually achieve improvement in pain
(66% and 79% respectively) and are relatively well tolerated with
commonest toxicities being mild acute nausea (51% and 30%) and
pain flare (33% and 21%). Palliative radiotherapy may also be used
for symptomatic sites of metastatic disease (Tempero et al. 2021).
Palliative Medicine
Jessica AL Borbasi & Rebecca Strutt
Quality of life and timely referral to specialized Palliative
Medicine is of paramount importance for patients with
pancreatic cancer (Sohal et al. 2016). Nearly all patients with
pancreatic cancer report pain, and of these the majority have
moderate to severe pain (Lohse and Brothers 2020; Westermann
et al. 2019). Pain is caused by perineural invasion of the coeliac
plexus, tumor obstruction of the main pancreatic duct, bowel
or gastric outlet obstruction, infiltrative or metastatic pain
(liver and peritoneum), surgical pain, and ascites (Drewes et al.
2018; Lohse and Brothers 2020). The pain is nociceptive,
somatic, neuropathic, and visceral in nature (Lohse and
Brothers 2020), and inadequate pain management can interfere
with quality of life impairing activity and emotions (Damm
etal. 2020).
The initial management of pain should follow the guidelines
of the World Health Organization (WHO) analgesic pain ladder
with the use of regular paracetamol or non-steroidal
anti-inflammatory agents – unless pre-existing conditions preclude their use (Drewes et al. 2018). Given the severity of pain
many patients require opioids (Zylberberg et al. 2022). Clinician
expertise can overcome common fears regarding the use of opioids, and neuropathic agents should also be considered such as
gabapentinoids or duloxetine (Lee et al. 2021; Reid et al. 2008).
Non-opioid options include radiotherapy and nerve blocks
(Buwenge et al. 2018; Wang et al. 2018). The pancreas is innervated by the coeliac plexus; the pancreatic tail also has innervation from the splenic plexus (Bapat et al. 2011). Direct perineural
invasion occurs in the majority of patients causing typical epigastric and back pain (Bapat et al. 2011). Neurolytic blocks are
recommended for patients with uncontrolled pancreatic pain
despite opioids or those experiencing unacceptable opioid side
effects (Amr and Makharita, 2013; Drewes et al. 2018).
Coeliac Plexus Block (CPB) and Coeliac Plexus Neurolysis
(CPN) are often used interchangeably but a block is a transient
interruption of pain transmission, usually with a local anesthetic without causing permanent nerve damage, whereas
neurolysis is generally considered to be permanent procedure
(Sachdev and Gress 2018). Neurolysis can be achieved via
chemical (alcohol or phenol) or thermal (radiofrequency
ablation-RFA) techniques. CPN can be performed via surgical splanchnectomy, percutaneously (PQ)-CPN, or via an
endoscopic ultrasound guide (EUS)-CPN. A meta-analysis
showed that CPN improved analgesia and decreased opioid–
induced adverse effects in comparison with conventional
analgesic treatment (Mercadante et al. 2015). Regarding the
method of neurolysis, a small randomized single blinded study
showed that EUS-RFA provided more pain relief over EUSCPN (chemical) and improved the quality of life for patients
with pancreatic cancer (Bang et al. 2019). However, there is
not enough evidence currently to recommend EUS-RFA over
EUS-CPN. It is important not to indicate to patients that they
will be able to stop opioids completely after CPN. The most
common side effects are orthostatic hypotension and diarrhea, but complications are rare (Nagels et al. 2013). Patients
with disease at the head of the pancreas are more likely to
respond positively to CPN compared to patients with disease
400 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
in the body or tail of the pancreas (Rykowski and Hilgier
2000). In addition patients with more locally advanced disease or metastatic disease are less likely to respond, possibly
due to more pain mechanisms being involved (Rykowski and
Hilgier 2000).
As such, there is good quality evidence demonstrating the
analgesic efficacy of CPN but limited data regarding the technique of choice (Mercadante et al. 2015). However, CPN has
not been shown to consistently improve quality of life, improve
survival, or reduce opioid consumption (Nagels et al. 2013;
Wong et al. 2004) . Nonetheless, interventional techniques such
as CPN have been described as a fourth step in the WHO analgesic pain ladder; these procedures may be necessary for
patients with severe pain (Pergolizzi and Raffa 2014). Most
patients receive partial or complete symptomatic relief up until
their death (Kawamata et al. 1996). Clinicians should refer to
interventional radiologists or pain specialists to ascertain what
procedures are available locally.
Pain is not the only burdensome symptom in this group who
also suffer nausea, anorexia, depression, fatigue, dry mouth,
cachexia, maldigestion, and other symptoms from pancreatic
exocrine insufficiency (Labori et al. 2006). Palliative Medicine
is well placed to address these physical burdens as well as
patient’s psychosocial and spiritual needs (WHO). Care extends
to families including partners of patients with pancreatic cancer. Caregivers are known to carry a high psychological burden
and have an increased risk of depression requiring medications
(Dengsø et al. 2021).
Early palliative care results in fewer inappropriate admissions
to the Intensive Care Unit (ICU) at the end of life and fewer presentations to the Emergency Department (ED). These patients
tended to be female and older (Bevins et al. 2021). A Canadian
study showed that provision of inpatient or outpatient Palliative
Care was associated with a reduction in all four measures of
aggressive care near death (chemotherapy, ICU admissions,
multiple ED visits, and hospitalizations), compared to patients
who did not receive Palliative Care. Also, as the frequency of
Palliative Care consultations rose, the likelihood of inappropriate interventions fell (Jang et al. 2015). This supports referral
at the time of diagnosis (Sohal et al. 2016).
Summary
Omali Pitiyarachchi & David Goldstein
Patients with pancreatic cancer have a poor prognosis and are
often diagnosed late with advanced disease due to vague presenting symptoms. When a pancreatic tumor is suspected,
prompt investigation is recommended to make a tissue diagnosis. Patients should be referred to a recognized sub-specialty
MDT with the capability of managing patients with pancreatic
tumors. Network MDTs can be used to include clinicians from
more regional centers or centers without the subspecialty expertise, to provide multimodality therapy options for all patients.
Some patients may proceed straight to resection, but confirmation of malignancy is required for patients with metastatic
disease, and for patients where neoadjuvant therapy is being
considered. A dual phase contrast enhanced computed tomography is the preferred imaging modality to evaluate resectability, and should be performed within four weeks of diagnosis
(Imaging section). Patients are categorized as having resectable, borderline resectable, locally advanced and metastatic disease depending on the extent of tumor spread, and the
anatomic, biological, and conditional factors as outlined in the
Surgical section of this chapter. The only chance of a cure is
with surgical resection, so it is important to consider neoadjuvant therapy for patients with borderline resectable and locally
advanced disease. As outlined in the Systemic therapy and
Radiation sections, neoadjuvant therapy can convert patients
with unresectable disease at diagnosis to potentially resectable.
Consider enrolling patients into a clinical trial if possible.
The mainstay of systemic therapy is with chemotherapy, but
in special cases such as patients with MSI-H/dMMR or NTRK
gene fusions, more targeted treatment could be considered. All
patients diagnosed with pancreatic cancer, but especially those
with unresectable and metastatic disease, should be referred to
Palliative Care early in the diagnosis. It is important to consider the burden on caregivers.
There have been some small gains in outcomes over the past
few years and the impact of best practice adjuvant and neoadjuvant therapy is likely to lead to additional gains. However, it
is still a very poor outcome cancer with an unacceptably high
mortality to incidence ratio.
Key Take Home Messages
• Reliable, cost-effective early diagnosis, and screening proto-
cols for high-risk individuals
• The role of novel circulating biomarkers such as circulating
tumor DNA and tumor cells
• The identification of more active anti-tumor therapeutics
• Active stromal reprogramming techniques
• Reversing immune suppression
Areas for Further Research
1 Diagnostic, predictive, and prognostic biomarkers
Combined targeted and immunotherapy regimens
2
3 Improved very early detection surveillance programs
Trusted Websites for Further Reading
https://www.pancreaticcancer.org.uk
https://www.cancer.org/cancer/pancreatic-cancer.html
20 MANAGEMENT OF PRIMARY PANCREATIC CANCER 401
https://t.me/medicina_free
Key Action Points
• Staging using appropriate imaging techniques
• Incorporate staging laparoscopy where appropriate
• Obtain adequate tissue for diagnosis, especially if embarking on
neoadjuvant therapy
• Discussion at MDT and review of operability using appropriate
guidelines (Isaji et al. 2018)
• Consideration of neoadjuvant therapy
• Inclusion of suitable patients in clinical trials
• Consistent use of adjuvant therapy
• Early referral for supportive care
• Careful integration of translational and clinical research (which is the
key to future success and improved outcomes)
Further Resources
• Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical
Practice Guidelines in Oncology, (https://jnccn.org/view/journals/
jnccn/19/4/article-p439.xml)
• Cancer of the pancreas: ESMO Clinical Practice Guidelines for
diagnosis, treatment, and follow-up (https://www.esmo.org/
guidelines/guidelines-by-topic/gastrointestinal-cancers/pancreaticcancer/eupdate-cancer-of-the-pancreas-treatment-recommendations)
• Isaji S, Mizuno S, Windsor JA, Bassi C, Fernández-Del Castillo C,
Hackert T, Hayasaki A, Katz MHG, Kim SW, Kishiwada M, Kitagawa H,
Michalski CW, Wolfgang CL. International consensus on definition
and criteria of borderline resectable pancreatic ductal
adenocarcinoma 2017. Pancreatology. 2018 Jan;18(1):2–11. doi:
10.1016/j.pan.2017.11.011. Epub 2017 Nov 22. PMID: 29191513.
Acknowledgments
We also acknowledge funding from the University Postgraduate
Award (UNSW Sydney, O.P.), Pancare Foundation (O.P.),
Australian Government Research Training Program Scholarship
and UNSW Sydney Scientia PhD Scholarships (J.K.), NHMRC
(Ideas Grant, APP2002707, P.A.P, G.S.), Cancer-Institute NSW
CDF (CDF181166, G.S.), Maridulu Budyari Gumal Sydney
Partnership for Health, Education, Research, and Enterprise
[SPHERE] Cancer Clinical Academic Group Senior Research
Fellowship (Funded by Cancer Institute NSW Translational
Cancer Research Capacity Building Grant, 2021/CBG0003, G.S.)
and PhD Scholarship Top-Up Award (O.P.), and Cancer Institute
NSW Translational Program Grant (2020/TPG2100, P.A.P, D.G.).
References
AIHW. (2021). Australian Institute of Health and Welfare [Online]. Available:
https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/
contents/cancer-data-commentaries/how-are-pancreatic-cancer-rateschanging (Accessed on 25th July 2023).
Amr, Y.M. and Makharita, M.Y. (2013). Comparative study between 2
protocols for management of severe pain in patients with unresectable
pancreatic cancer: one-year follow-up. Clin J Pain 29: 807–813.
Azari, F.S., Vollmer, C.M., Jr., Roses, R.E. et al. (2020). A contemporary
analysis of palliative procedures in aborted pancreatoduodenectomy:
morbidity, mortality, and impact on future therapy. Surgery 168:
1026–1031.
Bailey, P., Chang, D.K., Nones, K. et al. (2016). Genomic analyses identify
molecular subtypes of pancreatic cancer. Nature 531: 47–52.
Bang, J.Y., Sutton, B., Hawes, R.H., and Varadarajulu, S. (2019). EUS-
guided celiac ganglion radiofrequency ablation versus celiac plexus
neurolysis for palliation of pain in pancreatic cancer: a randomized
controlled trial (with videos). Gastrointest Endosc 89: 58–66.e3.
Bapat, A.A., Hostetter, G., Von Hoff, D.D., and Han, H. (2011). Perineural
invasion and associated pain in pancreatic cancer. Nat Rev Cancer 11:
695–707.
Barbour, A.P., Samra, J.S., Haghighi, K.S. et al. (2020). The AGITG GAP
study: a phase II study of perioperative gemcitabine and nab-paclitaxel
for resectable pancreas cancer. Ann Surg Oncol 27: 2506–2515.
Baugh, K.A., Tran Cao, H.S., Van Buren, G., 2nd et al. (2019). Understaging
of clinical stage I pancreatic cancer and the impact of multimodality
therapy. Surgery 165: 307–314.
Beleù, A., Calabrese, A., Rizzo, G. et al. (2019). Preoperative imaging
evaluation after downstaging of pancreatic ductal adenocarcinoma: a
multi-center study. Cancers 11: 267.
Bevins, J., Bhulani, N., Goksu, S.Y. et al. (2021). Early palliative care is
associated with reduced emergency department utilization in pancreatic
cancer. Am J Clin Oncol 44: 181–186.
Bockhorn, M., Uzunoglu, F.G., Adham, M. et al. (2014). Borderline
resectable pancreatic cancer: a consensus statement by the
International Study Group of Pancreatic Surgery (ISGPS). Surgery
155: 977–988.
Bonin, E.A. and Baron, T.H. (2011). Preoperative biliary stents in pancreatic
cancer. J Hepatobiliary Pancreat Sci 18: 621–629.
Boone, B.A., Steve, J., Zenati, M.S. et al. (2014). Serum CA 19-9 response to
neoadjuvant therapy is associated with outcome in pancreatic
adenocarcinoma. Ann Surg Oncol, 21, 4351–4358.
Bray, F., Ferlay, J., Soerjomataram, I. et al. (2018). Global cancer statistics
2018: GLOBOCAN estimates of incidence and mortality worldwide for
36 cancers in 185 countries. CA: A Cancer J Clin 68: 394–424.
Bundred, J.R., Kamarajah, S.K., Hammond, J.S. et al. (2020). Prehabilitation
prior to surgery for pancreatic cancer: a systematic review. Pancreatology
20: 1243–1250.
Burge, M.E., O’rourke, N., Cavallucci, D. et al. (2015). A prospective study
of the impact of fluorodeoxyglucose positron emission tomography with
concurrent non-contrast CT scanning on the management of operable
pancreatic and peri-ampullary cancers. HPB (Oxford) 17: 624–631.
Burmeister, E.A., Oʼconnell, D.L., Beesley, V.L. et al. (2015). Describing
patterns of care in pancreatic cancer: a population-based study. Pancreas
44: 1259–1265.
Burris, H.A., 3rd, Moore, M.J., Andersen, J. et al. (1997). Improvements in
survival and clinical benefit with gemcitabine as first-line therapy for
patients with advanced pancreas cancer: a randomized trial. J Clin Oncol
15: 2403–2413.
Butturini, G., Stocken, D.D., Wente, M.N. et al. (2008). Influence of
resection margins and treatment on survival in patients with pancreatic
cancer: meta-analysis of randomized controlled trials. Arch Surg 143:
75–83; discussion 83.
Buwenge, M., Macchia, G., Arcelli, A. et al. (2018). Stereotactic radiotherapy
of pancreatic cancer: a systematic review on pain relief. J Pain Res 11:
2169–2178.
402 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
Casciani, F., Bassi, C., and Vollmer, C.M., Jr. (2021). Decision points in
pancreatoduodenectomy: insights from the contemporary experts on
prevention, mitigation, and management of postoperative pancreatic
fistula. Surgery 170: 889–909.
Catenacci, D.V., Junttila, M.R., Karrison, T. et al. (2015). Randomized
phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog
pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin
Oncol 33: 4284–4292.
Chaika, N.V., Gebregiworgis, T., Lewallen, M.E. et al. (2012). MUC1 mucin
stabilizes and activates hypoxia-inducible factor 1 alpha to regulate
metabolism in pancreatic cancer. Proc Natl Acad Sci U S A 109:
13787–13792.
Chauffert, B., Mornex, F., Bonnetain, F. et al. (2008). Phase III trial
comparing intensive induction chemoradiotherapy (60 Gy, infusional
5-FU and intermittent cisplatin) followed by maintenance gemcitabine
with gemcitabine alone for locally advanced unresectable pancreatic
cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol
19: 1592–1599.
Chen, J., Yang, R., Lu, Y. et al. (2012). Diagnostic accuracy of endoscopic
ultrasound-guided fine-needle aspiration for solid pancreatic lesion: a
systematic review. J Cancer Res Clin Oncol 138: 1433–1441.
Cheng, X.B., Sato, N., Kohi, S., and Yamaguchi, K. (2013). Prognostic
impact of hyaluronan and its regulators in pancreatic ductal
adenocarcinoma. PLoS One 8: e80765.
Cheng, Z.-X., Wang, D.-W., Liu, T. et al. (2014). Effects of the HIF-1α and
NF-κB loop on epithelial
induced by hypoxia in pancreatic cancer cells. Oncol Rep 31: 1891–1898.
Chun, Y.S., Pawlik, T.M., and Vauthey, J.N. (2018). 8th edition of the AJCC
cancer staging manual: pancreas and hepatobiliary cancers. Ann Surg
Oncol 25: 845–847.
Collisson, E.A., Sadanandam, A., Olson, P. et al. (2011). Subtypes of
pancreatic ductal adenocarcinoma and their differing responses to
therapy. Nat Med 17: 500–503.
Conroy, T., Desseigne, F., Ychou, M. et al. (2011). FOLFIRINOX versus
gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:
1817–1825.
Conroy, T., Hammel, P., Hebbar, M. et al. (2018). FOLFIRINOX or
gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 379:
2395–2406.
Croke, J.M. and El-Sayed, S. (2012). Multidisciplinary management of
cancer patients: chasing a shadow or real value? An overview of the
literature. Curr Oncol (Toronto, Ont) 19: e232–e238.
Da Costa, W.L., Jr, Tran Cao, H.S., and Massarweh, N.N. (2020).
Neoadjuvant treatment for patients with localized pancreatic
adenocarcinoma: are we there yet? JAMA Oncol 6: 1163–1164.
Damm, M., Weniger, M., Kölsch, A.K. et al. (2020). The quality of pain
management in pancreatic cancer: a prospective multi-center study.
Pancreatology 20: 1511–1518.
Dengsø, K.E., Thomsen, T., Andersen, E.W. et al. (2021). The psychological
symptom burden in partners of pancreatic cancer patients: a populationbased cohort study. Support Care Cancer 29: 6689–6699.
Ding, D., Javed, A.A., Cunningham, D. et al. (2021). Challenges of the
current precision medicine approach for pancreatic cancer: a single
institution experience between 2013 and 2017. Cancer Lett 497:
221–228.
Diop-Frimpong, B., Chauhan, V.P., Krane, S. et al. (2011). Losartan inhibits
collagen I synthesis and improves the distribution and efficacy of
nanotherapeutics in tumors. Proc Natl Acad Sci U S A 108: 2909–2914.
-mesenchymal transition and chemoresistance
Doebele, R.C., Drilon, A., Paz-Ares, L. et al. (2020). Entrectinib in patients
with advanced or metastatic NTRK fusion-positive solid tumours:
integrated analysis of three phase 1-2 trials. Lancet Oncol 21: 271–282.
Drewes, A.M., Campbell, C.M., Ceyhan, G.O. et al. (2018). Pain in
pancreatic ductal adenocarcinoma: a multidisciplinary, international
guideline for optimized management. Pancreatology 18: 446–457.
Drilon, A., Laetsch, T.W., Kummar, S. et al. (2018). Efficacy of larotrectinib
in TRK fusion–positive cancers in adults and children. N Engl J Med 378:
731–739.
Ducreux, M., Cuhna, A.S., Caramella, C. et al. (2015). Cancer of the
pancreas: ESMO clinical practice guidelines for diagnosis, treatment
and follow-up. Ann Oncol 26: v56–v68.
Ebrahimi, G., Rasch, C.R.N., and Van Tienhoven, G. (2018). Pain relief
after a short course of palliative radiotherapy in pancreatic cancer, the
Academic Medical Center (AMC) experience. Acta Oncol 57: 697–700.
Elyada, E., Bolisetty, M., Laise, P. et al. (2019). Cross-species single-cell
analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting
cancer-associated fibroblasts. Cancer Discov 9: 1102–1123.
Erkan, M., Hausmann, S., Michalski, C.W. et al. (2012). The role of stroma
in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev
Gastroenterol Hepatol 9: 454–467.
Erkan, M., Michalski, C.W., Rieder, S. et al. (2008). The activated stroma
index is a novel and independent prognostic marker in pancreatic ductal
adenocarcinoma. Clin Gastroenterol Hepatol 6: 1155–1161.
Farma, J.M., Santillan, A.A., Melis, M. et al. (2008). PET/CT fusion scan
enhances CT staging in patients with pancreatic neoplasms. Ann Surg
Oncol 15: 2465–2471.
Ferrone, C.R., Marchegiani, G., Hong, T.S. et al. (2015). Radiological and
surgical implications of neoadjuvant treatment with FOLFIRINOX for
locally advanced and borderline resectable pancreatic cancer. Ann Surg
261: 12–17.
Gandy, R.C., Barbour, A.P., Samra, J. et al. (2016). Refining the care of
patients with pancreatic cancer: the AGITG Pancreatic Cancer
Workshop consensus. Med J Aust 204: 419–422.
Gemenetzis, G., Groot, V.P., Blair, A.B. et al. (2019). Survival in locally
advanced pancreatic cancer after neoadjuvant therapy and surgical
resection. Ann Surg 270: 340–347.
Ghaneh, P., Palmer, D.H., Cicconi, S. et al. (2020). ESPAC-5F: four-arm,
prospective, multicenter, international randomized phase II trial of
immediate surgery compared with neoadjuvant gemcitabine plus
capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy
(CRT) in patients with borderline resectable pancreatic cancer. J Clin
Oncol 38: 4505-4505.
Glimelius, B., Hoffman, K., Sjödén, P.O. et al. (1996). Chemotherapy
improves survival and quality of life in advanced pancreatic and biliary
cancer. Ann Oncol 7: 593–600.
Golan, T., Hammel, P., Reni, M. et al. (2019). Maintenance olaparib for
germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med
381: 317–327.
Golcher, H., Brunner, T.B., Witzigmann, H. et al. (2015). Neoadjuvant
chemoradiation therapy with gemcitabine/cisplatin and surgery versus
immediate surgery in resectable pancreatic cancer: results of the first
prospective randomized phase II trial. Strahlenther Onkol 191: 7–16.
Hackert, T., Sachsenmaier, M., Hinz, U. et al. (2016). Locally advanced
pancreatic cancer: neoadjuvant therapy with folfirinox results in
resectability in 60% of the patients. Ann Surg 264: 457–463.
Hammel, P., Huguet, F., Van Laethem, J.L. et al. (2016). Effect of
chemoradiotherapy vs chemotherapy on survival in patients with locally
20 MANAGEMENT OF PRIMARY PANCREATIC CANCER 403
https://t.me/medicina_free
advanced pancreatic cancer controlled after 4 months of gemcitabine
with or without erlotinib: the LAP07 randomized clinical trial. Jama
315: 1844–1853.
Hartwig, W., Vollmer, C.M., Fingerhut, A. et al. (2014). Extended
pancreatectomy in pancreatic ductal adenocarcinoma: definition and
consensus of the International Study Group for Pancreatic Surgery
(ISGPS). Surgery 156: 1–14.
Hazel, J.J., Thirlwell, M.P., Huggins, M. et al. (1981). Multi-drug chemotherapy
with and without radiation for carcinoma of the stomach and pancreas: a
prospective randomized trial. J Can Assoc Radiol 32: 164–165.
Hidalgo, M. (2010). Pancreatic cancer. N Engl J Med 362: 1605–1617.
Hong, S.B., Lee, S.S., Kim, J.H. et al. (2018). Pancreatic cancer CT: prediction
of resectability according to NCCN criteria. Radiol. 289 (3): 710–718. doi:
10.1148/radiol.2018180628.
Huber, M., Brehm, C.U., Gress, T.M. et al. (2020). The immune
microenvironment in pancreatic cancer. Int J Mol Sci 21 (19): 7307.
Published 2020 Oct 3. doi: 10.3390/ijms21197307.
Hwang, R.F., Moore, T.T., Hattersley, M.M. et al. (2012). Inhibition of the
hedgehog pathway targets the tumor-associated stroma in pancreatic
cancer. Mol Cancer Res 10: 1147–1157.
Iglesias-Garcia, J., Dominguez-Munoz, J.E., Abdulkader, I. et al. (2011).
Influence of on-site cytopathology evaluation on the diagnostic accuracy
of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of
solid pancreatic masses. Am J Gastroenterol 106 (9): 1705–1710. doi:
10.1038/ajg.2011.119.
Isaji, S., Mizuno, S., Windsor, J.A. et al. (2018). International consensus on
definition and criteria of borderline resectable pancreatic ductal
adenocarcinoma 2017. Pancreatology 18: 2–11.
Jalil, R., Ahmed, M., Green, J.S., and Sevdalis, N. (2013). Factors that can
make an impact on decision-making and decision implementation in
cancer multidisciplinary teams: an interview study of the provider
perspective. Int J Surg 11: 389–394.
Jang, J.Y., Han, Y., Lee, H. et al. (2018). Oncological benefits of neoadjuvant
chemoradiation with gemcitabine versus upfront surgery in patients
with borderline resectable pancreatic cancer: a prospective, randomized,
open-label, multicenter phase 2/3 trial. Ann Surg 268: 215–222.
Jang, R.W., Krzyzanowska, M.K., Zimmermann, C. et al. (2015). Palliative
care and the aggressiveness of end-of-life care in patients with advanced
pancreatic cancer. J Natl Cancer Inst 107 (3): dju424. Published 2015 Jan
20. doi: 10.1093/jnci/dju424.
Janssen, Q.P., Buettner, S., Suker, M. et al. (2019). Neoadjuvant FOLFIRINOX
in patients with borderline resectable pancreatic cancer: a systematic
review and patient-level meta-analysis. J Natl Cancer Inst 111: 782–794.
Jones, R.P., Psarelli, E.E., Jackson, R. et al. (2019). Patterns of recurrence
after resection of pancreatic ductal adenocarcinoma: a secondary
analysis of the ESPAC-4 randomized adjuvant chemotherapy trial.
JAMA Surg 154 (11): 1038–1048. doi: 10.1001/jamasurg.2019.3337.
Jones, W.E., Suh, W.W., Abdel-Wahab, M. et al., Expert Panel on Radiation,
O. (2017). ACR appropriateness criteria® resectable pancreatic cancer.
Am J Clin Oncol 40: 109–117.
Kamphorst, J.J., Nofal, M., Commisso, C. et al. (2015). Human pancreatic
cancer tumors are nutrient poor and tumor cells actively scavenge
extracellular protein. Cancer Res 75: 544–553.
Karamitopoulou, E. (2019). Tumour microenvironment of pancreatic
cancer: immune landscape is dictated by molecular and histopathological
features. Br J Cancer 121: 5–14.
Katz, M.H., Fleming, J.B., Bhosale, P. et al. (2012). Response of borderline
resectable pancreatic cancer to neoadjuvant therapy is not reflected by
radiographic indicators. Cancer 118: 5749–5756.
Katz, M.H., Pisters, P.W., Evans, D.B. et al. (2008). Borderline resectable
pancreatic cancer: the importance of this emerging stage of disease. J
Am Coll Surg 206: 833–846; discussion 846-8.
Katz, M.H.G., Shi, Q., Meyers, J.P. et al. (2021). Alliance A021501:
preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated
radiation therapy (RT) for borderline resectable (BR) adenocarcinoma
of the pancreas. J Clin Oncol 39: 377-377.
Kawamata, M., Ishitani, K., Ishikawa, K. et al. (1996). Comparison between
celiac plexus block and morphine treatment on quality of life in patients
with pancreatic cancer pain. Pain 64: 597–602.
Khan, M.A., Grimm, I.S., Ali, B. et al. (2017). A meta-analysis of endoscopic
ultrasound-fine-needle aspiration compared to endoscopic ultrasoundfine-needle biopsy: diagnostic yield and the value of onsite
cytopathological assessment. Endosc Int Open 5: E363–e375.
Khorana, A.A., Mckernin, S.E., Berlin, J. et al. (2019). Potentially curable
pancreatic adenocarcinoma: ASCO clinical practice guideline update. J
Clin Oncol 37: 2082–2088.
Kim, E.J., Sahai, V., Abel, E.V. et al. (2014). Pilot clinical trial of hedgehog
pathway inhibitor GDC-0449 (vismodegib) in combination with
gemcitabine in patients with metastatic pancreatic adenocarcinoma.
Clin Cancer Res 20: 5937–5945.
Klaassen, D.J., Macintyre, J.M., Catton, G.E. et al. (1985). Treatment of
locally unresectable cancer of the stomach and pancreas: a randomized
comparison of 5-fluorouracil alone with radiation plus concurrent and
maintenance 5-fluorouracil–an Eastern Cooperative Oncology Group
study. J Clin Oncol 3: 373–378.
Kokkinos, J., Jensen, A., Sharbeen, G. et al. (2021a). Does the
microenvironment hold the hidden key for functional precision
medicine in pancreatic cancer? Cancers (Basel) 13.
Kokkinos, J., Sharbeen, G., Haghighi, K.S. et al. (2021b). Ex vivo culture of
intact human patient derived pancreatic tumour tissue. Sci Rep 11: 1944.
Kowalewski, A., Szylberg, Ł., Saganek, M. et al. (2018). Emerging strategies
in BRCA-positive pancreatic cancer. J Cancer Res Clin Oncol 144:
1503–1507.
Kunzmann, V., Algül, H., Goekkurt, E. et al. (2019). Conversion rate in
locally advanced pancreatic cancer (LAPC) after nab-paclitaxel/
gemcitabine- or FOLFIRINOX-based induction chemotherapy
(NEOLAP): final results of a multicenter randomised phase II AIO trial.
Ann Oncol 30: v253.
Labori, K.J., Hjermstad, M.J., Wester, T. et al. (2006). Symptom profiles and
palliative care in advanced pancreatic cancer: a prospective study.
Support Care Cancer 14: 1126–1133.
Lakatos, G., Petranyi, A., Szűcs, A. et al. (2017). Efficacy and safety of
FOLFIRINOX in locally advanced pancreatic cancer. a single center
experience. Pathol Oncol Res 23: 753–759.
Lamb, B.W., Green, J.S., Benn, J. et al. (2013). Improving decision making
in multidisciplinary tumor boards: prospective longitudinal evaluation
of a multicomponent intervention for 1,421 patients. J Am Coll Surg 217:
412–420.
Lampert, E.J., Zimmer, A., Padget, M. et al. (2020). Combination of PARP
inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian
cancer: a proof-of-concept phase II study. Clin Cancer Res 26: 4268–4279.
Lee, K.G., Roy, V., Laszlo, M. et al. (2021). Symptom management in
pancreatic cancer. Curr Treat Options Oncol 22: 8.
Li, J., Wientjes, M.G., and Au, J.L. (2010). Pancreatic cancer: pathobiology,
treatment options, and drug delivery. Aaps j 12: 223–232.
Ligorio, M., Sil, S., Malagon-Lopez, J. et al. (2019). Stromal microenvironment
shapes the intratumoral architecture of pancreatic cancer. Cell 178: 160–
175.e27.
404 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
Loehrer, P.J., Sr., Feng, Y., Cardenes, H. et al. (2011). Gemcitabine alone
versus gemcitabine plus radiotherapy in patients with locally advanced
pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin
Oncol 29: 4105–4112.
Lohse, I. and Brothers, S.P. (2020). Pathogenesis and treatment of pancreatic
cancer related pain. Anticancer Res 40: 1789–1796.
Luz, L.P., Al-Haddad, M.A., Sey, M.S.L., and Dewitt, J.M. (2014).
Applications of endoscopic ultrasound in pancreatic cancer. World J
Gastroenterol 20: 7808–7818.
Maharaj, A.D., Evans, S.M., Zalcberg, J.R. et al. (2021). Barriers and enablers to
the implementation of multidisciplinary team meetings: a qualitative study
using the theoretical domains framework. BMJ Qual Saf 30: 792–803.
Marabelle, A., Le, D.T., Ascierto, P.A. et al. (2020). Efficacy of pembrolizumab
in patients with noncolorectal high microsatellite instability/mismatch
repair-deficient cancer: results from the phase II KEYNOTE-158 study. J
Clin Oncol 38 (1): 1–10. doi: 10.1200/JCO.19.02105.
Martinez-Useros, J., Li, W., Cabeza-Morales, M., and Garcia-Foncillas, J.
(2017). Oxidative stress: a new target for pancreatic cancer prognosis
and treatment. J Clin Med 6 (3): 29. Published 2017 Mar 9. doi: 10.3390/
jcm6030029.
Mayo, S.C., Gilson, M.M., Herman, J.M. et al. (2012). Management of
patients with pancreatic adenocarcinoma: national trends in patient
selection, operative management, and use of adjuvant therapy. J Am Coll
Surg 214: 33–45.
Mcisaac, D.I., Taljaard, M., Bryson, G.L. et al. (2020). Frailty as a predictor
of death or new disability after surgery: a prospective cohort study. Ann
Surg 271: 283–289.
Mellon, E.A., Hoffe, S.E., Springett, G.M. et al. (2015). Long-term outcomes
of induction chemotherapy and neoadjuvant stereotactic body
radiotherapy for borderline resectable and locally advanced pancreatic
adenocarcinoma. Acta Oncol 54: 979–985.
Mercadante, S., Klepstad, P., Kurita, G.P. et al. (2015). Sympathetic
blocks for visceral cancer pain management: a systematic review and
EAPC recommendations. Crit Rev Oncol Hematol 96: 577–583.
Miller, B.W., Morton, J.P., Pinese, M. et al. (2015). Targeting the LOX/
hypoxia axis reverses many of the features that make pancreatic cancer
deadly: inhibition of LOX abrogates metastasis and enhances drug
efficacy. EMBO Mol Med 7: 1063–1076.
Moffitt, R.A., Marayati, R., Flate, E.L. et al. (2015). Virtual microdissection
identifies distinct tumor- and stroma-specific subtypes of pancreatic
ductal adenocarcinoma. Nat Genet 47: 1168–1178.
Motoi, F., Kosuge, T., Ueno, H. et al. (2019). 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 49: 190–194.
Motosugi, U., Ichikawa, T., Morisaka, H. et al. (2011). Detection of pancreatic
carcinoma and liver metastases with gadoxetic acid–enhanced MR
imaging: comparison with contrast-enhanced multi–detector row CT.
Radiol. 260 (2): 446–453. doi: 10.1148/radiol.11103548.
Murakami, Y., Satoi, S., Motoi, F. et al. (2015). Portal or superior mesenteric
vein resection in pancreatoduodenectomy for pancreatic head carci
noma. Br J Surg 102: 837–846.
Nagels, W., Pease, N., Bekkering, G. et al. (2013). Celiac plexus neurolysis for
abdominal cancer pain: a systematic review. Pain Med 14: 1140–1163.
(2004). N Engl J Med 350: 1200–1210. doi: 10.1056/NEJMoa032295.
Neoptolemos, J.P., Stocken, D.D., Friess, H., Bassi, C. et al. (2004). A
randomized trial of chemoradiotherapy and chemotherapy after
resection of pancreatic cancer. N Engl J Med 350 (12): 1200–1210. doi:
10.1056/NEJMoa032295.
Neoptolemos, J.P., Palmer, D.H., Ghaneh, P. et al. (2017). 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 389: 1011–1024.
Neoptolemos, J.P., Palmer, D.H., Ghaneh, P. et al. (2020). ESPAC-4: a
multicenter, international, open-label randomized controlled phase III
trial of adjuvant combination chemotherapy of gemcitabine (GEM) and
capecitabine (CAP) versus monotherapy gemcitabine in patients with
resected pancreatic ductal adenocarcinoma: five year follow-up. J Clin
Oncol 38: 4516–4516.
Norris, C.M. and Close, J.C.T. (2020). Prehabilitation for the frailty
syndrome: improving outcomes for our most vulnerable patients. Anesth
Analg 130: 1524–1533.
O’Reilly, E.M., Lee, J.W., Zalupski, M. et al. (2020). Randomized,
multicenter, phase II trial of gemcitabine and cisplatin with or without
veliparib in patients with pancreas adenocarcinoma and a germline
BRCA/PALB2 mutation. J Clin Oncol 38: 1378–1388.
Oar, A., Lee, M., Le, H. et al. (2021). AGITG MASTERPLAN: a randomised
phase II study of modified FOLFIRINOX alone or in combination with
stereotactic body radiotherapy for patients with high-risk and locally
advanced pancreatic cancer. BMC Cancer 21: 936.
Oettle, H., Neuhaus, P., Hochhaus, A. et al. (2013). Adjuvant chemotherapy
with gemcitabine and long-term outcomes among patients with resected
pancreatic cancer: the CONKO-001 randomized trial. Jama 310:
1473–1481.
Oettle, H., Post, S., Neuhaus, P. et al. (2007). Adjuvant chemotherapy with
gemcitabine vs observation in patients undergoing curative-intent resection
of pancreatic cancera randomized controlled trial. JAMA 297: 267–277.
Öhlund, D., Handly-Santana, A., Biffi, G. et al. (2017). Distinct populations
of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J
Exp Med 214: 579–596.
Olive, K.P., Jacobetz, M.A., Davidson, C.J. et al. (2009a). Inhibition of
Hedgehog signaling enhances delivery of chemotherapy in a mouse
model of pancreatic cancer. Science 324: 1457–1461.
Olive, K.P., Jacobetz, M.A., Davidson, C.J. et al. (2009b). Inhibition of
Hedgehog signaling enhances delivery of chemotherapy in a mouse
model of pancreatic cancer. Science 324: 1457–1461.
Ouaïssi, M., Turrini, O., Hubert, C. et al. (2014). Vascular resection during
radical resection of pancreatic adenocarcinomas: evolution over the past
15 years. J Hepatobiliary Pancreat Sci 21: 623–638.
Ozaki, H., Hiraoka, T., Mizumoto, R. et al. (1999). The prognostic significance
of lymph node metastasis and intrapancreatic perineural invasion in
pancreatic cancer after curative resection. Surg Today 29: 16–22.
Pan, M., Reid, M.A., Lowman, X.H. et al. (2016). Regional glutamine
deficiency in tumours promotes dedifferentiation through inhibition of
histone demethylation. Nat Cell Biol 18: 1090–1101.
Pan, X., Zhou, J., Xiao, Q. et al. (2021). Cancer-associated fibroblast
heterogeneity is associated with organ-specific metastasis in pancreatic
-
ductal adenocarcinoma. J Hematol Oncol 14: 184.
Pawlik, T.M., Laheru, D., Hruban, R.H. et al. (2008). Evaluating the impact
of a single-day multidisciplinary clinic on the management of pancreatic
cancer. Ann Surg Oncol 15: 2081–2088.
Peng, J.S., Mino, J., Monteiro, R. et al. (2017). Diagnostic laparoscopy prior
to neoadjuvant therapy in pancreatic cancer is high yield: an analysis of
outcomes and costs. J Gastrointest Surg 21: 1420–1427.
20 MANAGEMENT OF PRIMARY PANCREATIC CANCER 405
https://t.me/medicina_free
Pergolizzi, J. and Raffa, R. (2014). The WHO pain ladder: do we need
another step? Pract Pain Manag 14 (1).
Petersen, G.M. (2016). Familial pancreatic cancer. Semin Oncol 43:
548–553.
Petrelli, F., Comito, T., Ghidini, A. et al. (2017). Stereotactic body radiation
therapy for locally advanced pancreatic cancer: a systematic review and
pooled analysis of 19 trials. Int J Radiat Oncol Biol Phys 97: 313–322.
Phillips, P. (2012). Pancreatic stellate cells and fibrosis. In: Pancreatic
Cancer and Tumor Microenvironment (ed. P.J. Grippo and H.G. Munshi).
Trivandrum (India): Transworld Research Network Copyright © 2012,
Transworld Research Network.
Pilarski, R. (2019). The role of BRCA testing in hereditary pancreatic and
prostate cancer families. Am Soc Clin Oncol EducBook 39: 79–86.
Pishvaian, M.J., Blais, E.M., Brody, J.R. et al. (2020). Overall survival in
patients with pancreatic cancer receiving matched therapies following
molecular profiling: a retrospective analysis of the Know Your Tumor
registry trial. Lancet Oncol 21: 508–518.
Provenzano, P.P., Cuevas, C., Chang, A.E. et al. (2012). Enzymatic targeting
of the stroma ablates physical barriers to treatment of pancreatic ductal
adenocarcinoma. Cancer Cell 21: 418–429.
Qayyum, A., Tamm, E.P., Kamel, I.R. et al. (2017). ACR appropriateness
criteria(®) staging of pancreatic ductal adenocarcinoma. J Am Coll
Radiol 14: S560–s569.
Qin, C., Yang, G., Yang, J. et al. (2020). Metabolism of pancreatic cancer:
paving the way to better anticancer strategies. Mol Cancer 19: 50.
Rahib, L., Smith, B.D., Aizenberg, R. et al. (2014). Projecting cancer
incidence and deaths to 2030: the unexpected burden of thyroid, liver,
and pancreas cancers in the United States. Cancer Res 74: 2913–2921.
Ravikumar, R., Sabin, C., Abu Hilal, M. et al. (2014). Portal vein resection
in borderline resectable pancreatic cancer: a United Kingdom
multicenter study. J Am Coll Surg 218: 401–411.
Reid, C.M., Gooberman-Hill, R., and Hanks, G.W. (2008). Opioid analgesics
for cancer pain: symptom control for the living or comfort for the dying?
A qualitative study to investigate the factors influencing the decision to
accept morphine for pain caused by cancer. Ann Oncol 19: 44–48.
Reni, M., Riess, H., O’Reilly, E. et al. (2019). An international, randomized,
open-label, phase III trial of adjuvant nab-paclitaxel plus gemcitabine vs
gemcitabine alone for surgically resected pancreatic adenocarcinoma
(APACT): primary analysis and quality of life outcomes. Ann Oncol 30:
iv126.
Rombouts, S.J., Walma, M.S., Vogel, J.A. et al. (2016). Systematic review of
resection rates and clinical outcomes after FOLFIRINOX-based
treatment in patients with locally advanced pancreatic cancer. Ann Surg
Oncol 23: 4352–4360.
Rykowski, J.J. and Hilgier, M. (2000). Efficacy of neurolytic celiac plexus
block in varying locations of pancreatic cancer: influence on pain relief.
Anesthesiology 92: 347–354.
Sachdev, A.H. and Gress, F.G. (2018). Celiac plexus block and neurolysis: a
review. Gastrointest Endosc Clin N Am 28: 579–586.
Seo, D.W., Sherman, S., Dua, K.S. et al. (2019). Covered and uncovered
biliary metal stents provide similar relief of biliary obstruction during
neoadjuvant therapy in pancreatic cancer: a randomized trial.
Gastrointest Endosc 90: 602-612.e4.
Sharbeen, G., Mccarroll, J.A., Akerman, A. et al. (2021). Cancer-associated
fibroblasts in pancreatic ductal adenocarcinoma determine response to
SLC7A11 inhibition. Cancer Res 81: 3461–3479.
Sharpe, S.M., Talamonti, M.S., Wang, C.E. et al. (2015). Early national
experience with laparoscopic pancreaticoduodenectomy for ductal
adenocarcinoma: a comparison of laparoscopic pancreaticoduodenectomy
and open pancreaticoduodenectomy from the national cancer data base.
J Am Coll Surg 221: 175–184.
Shrikhande, S.V., Barreto, S.G., Goel, M., and Arya, S. (2012). Multimodality
imaging of pancreatic ductal adenocarcinoma: a review of the literature.
HPB: Official J Int Hepato Pancreato Biliary Assoc 14: 658–668.
Shukla, S.K., Purohit, V., Mehla, K. et al. (2017). MUC1 and HIF-1alpha
signaling crosstalk induces anabolic glucose metabolism to impart
gemcitabine resistance to pancreatic cancer. Cancer Cell 32: 71-87.e7.
Siegel, R.L., Miller, K.D., Fuchs, H.E., and Jemal, A. (2022). Cancer
statistics, 2022. CA: A Cancer J Clin 72: 7–33.
Sohal, D.P., Mangu, P.B., Khorana, A.A. et al. (2016). Metastatic pancreatic
cancer: American society of clinical oncology clinical practice guideline.
J Clin Oncol 34: 2784–2796.
Sohal, D.P.S., Duong, M., Ahmad, S.A. et al. (2021). Efficacy of perioperative
chemotherapy for resectable pancreatic adenocarcinoma: a phase 2
randomized clinical trial. JAMA Oncol 7: 421–427.
Stairmand, J., Signal, L., Sarfati, D. et al. 2015. Consideration of comorbidity
in treatment decision making in multidisciplinary cancer team meetings:
a systematic review. Ann Oncol, 26, 1325–1332.
Stauffer, J.A., Coppola, A., Villacreses, D. et al. (2017). Laparoscopic versus
open pancreaticoduodenectomy for pancreatic adenocarcinoma: longterm results at a single institution. Surg Endosc 31: 2233–2241.
Suker, M., Beumer, B.R., Sadot, E. et al. (2016). FOLFIRINOX for locally
advanced pancreatic cancer: a systematic review and patient-level metaanalysis. Lancet Oncol 17: 801–810.
Ta, R., O’Connor, D.B., Sulistijo, A. et al. (2019). The role of staging
laparoscopy in resectable and borderline resectable pancreatic cancer: a
systematic review and meta-analysis. Dig Surg 36: 251–260.
Tao, J., Yang, G., Zhou, W. et al. (2021). Targeting hypoxic tumor
microenvironment in pancreatic cancer. J Hematol Oncol 14: 14.
Tas, F., Sen, F., Odabas, H. et al. (2013). Performance status of patients is the
major prognostic factor at all stages of pancreatic cancer. Int J Clin Oncol
18: 839–846.
Taylor, C., Finnegan-John, J., and Green, J.S. (2014). “No decision about me
without me” in the context of cancer multidisciplinary team meetings: a
qualitative interview study. BMC Health Serv Res 14: 488.
Tempero, M.A., Malafa, M.P., Al-Hawary, M. et al. (2021). Pancreatic
adenocarcinoma, version 2.2021, NCCN clinical practice guidelines in
oncology. J Natl Compr Canc Netw 19: 439–457.
Tempero, M.A., Malafa, M.P., Chiorean, E.G. et al. (2019). Pancreatic
adenocarcinoma, version 1.2019. J Natl Compr Canc Netw 17: 202–210.
Toesca, D.A.S., Koong, A.J., Poultsides, G.A. et al. (2018). Management of
borderline resectable pancreatic cancer. Int J Radiat Oncol Biol Phys 100:
1155–1174.
Tran Cao, H.S., Balachandran, A., Wang, H. et al. (2014). Radiographic
tumor-vein interface as a predictor of intraoperative, pathologic, and
oncologic outcomes in resectable and borderline resectable pancreatic
cancer. J Gastrointest Surg 18: 269–278; discussion 278.
Tran Cao, H.S., Zhang, Q., Sada, Y.H. et al. (2017). Value of lymph node
positivity in treatment planning for early stage pancreatic cancer.
Surgery 162: 557–567.
Tréhoux, S., Duchêne, B., Jonckheere, N., and Van Seuningen, I. (2015). The
MUC1 oncomucin regulates pancreatic cancer cell biological properties
Соседние файлы в папке @xirurgi_2025